US20160340354A1 - Methods for treating cancer and non-neoplastic conditions - Google Patents

Methods for treating cancer and non-neoplastic conditions Download PDF

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US20160340354A1
US20160340354A1 US15/133,359 US201615133359A US2016340354A1 US 20160340354 A1 US20160340354 A1 US 20160340354A1 US 201615133359 A US201615133359 A US 201615133359A US 2016340354 A1 US2016340354 A1 US 2016340354A1
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compound
viral
compounds
leukemia
tumor
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Thomas W. Davis
Marla L. Weetall
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PTC Therapeutics Inc
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PTC Therapeutics Inc
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Assigned to PTC THERAPEUTICS, INC. reassignment PTC THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DAVIS, THOMAS W., WEETALL, MARLA L.
Publication of US20160340354A1 publication Critical patent/US20160340354A1/en
Priority to US16/121,956 priority patent/US20190194188A1/en
Priority to US16/909,394 priority patent/US11613538B2/en
Priority to US18/126,198 priority patent/US20240043422A1/en
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Definitions

  • vascular endothelial growth factor vascular endothelial growth factor
  • Compounds that selectively inhibit pathological production of human vascular endothelial growth factor (VEGF) and compositions comprising such Compounds are described.
  • Compounds that inhibit viral replication or the production of viral RNA or DNA or viral protein and compositions comprising such Compounds are described.
  • methods of reducing VEGF using such Compounds and methods for treating cancer and non-neoplastic conditions involving the administration of such Compounds are further described. methods of inhibiting viral replication or the production of viral RNA or DNA or viral protein using such Compounds and methods for treating viral infections involving the administration of such Compounds.
  • the Compounds may be administered as a single agent therapy or in combination with one or more additional therapies to a human in need of such treatments.
  • Cancer is one of the most significant health conditions. In the United States, cancer is second only to heart disease in mortality accounting for one of four deaths. The incidence of cancer is widely expected to increase as the US population ages, further augmenting the impact of this condition.
  • Standard oncology regimens have often been largely designed to administer the highest dose of irradiation or a chemotherapeutic agent without undue toxicity, i.e., often referred to as the “maximum tolerated dose” (MTD) or “no observed adverse effect level” (NOAEL).
  • MTD maximum tolerated dose
  • NOAEL no observed adverse effect level
  • Many conventional cancer chemotherapies and conventional irradiation therapies exert their toxic effects on cancer cells largely by interfering with cellular mechanisms involved in cell growth and DNA replication.
  • Chemotherapy protocols also often involve administration of a combination of chemotherapeutic agents in an attempt to increase the efficacy of treatment. Despite the availability of a large variety of chemotherapeutic agents, these therapies have many drawbacks.
  • chemotherapeutic agents are notoriously toxic due to non-specific side effects on fast-growing cells whether normal or malignant; e.g. chemotherapeutic agents cause significant, and often dangerous, side effects, including bone marrow depression, immunosuppression, and gastrointestinal distress, etc.
  • Angiogenesis is implicated in the pathogenesis of a variety of non-neoplastic conditions, e.g., intraocular neovascular syndromes such as proliferative retinopathies or age-related macular degeneration (AMD), rheumatoid arthritis, and psoriasis.
  • intraocular neovascular syndromes such as proliferative retinopathies or age-related macular degeneration (AMD), rheumatoid arthritis, and psoriasis.
  • VEGF vascular endothelial growth factor
  • Inhibitory anti-VEGF receptor antibodies, soluble receptor constructs, antisense strategies, RNA aptamers against VEGF and low molecular weight VEGF receptor tyrosine kinase (RTK) inhibitors have all been proposed for use in interfering with VEGF signaling (Sieffle et al. (1998) Cancer Metastasis Rev., 17(2):241-248).
  • RTK low molecular weight VEGF receptor tyrosine kinase
  • these agents all have drawbacks in that they can cause toxic side effects in the patient and often are not curative of the non-neoplastic condition. Accordingly, new therapies for treating patients with non-neoplastic conditions that are associated with angiogenesis, particularly VEGF production, are needed.
  • viruses are intimately dependent upon the biological functions of their hosts.
  • Small molecules that affect the host cell biological processes involved in viral replication or the production of viral RNA or DNA or viral protein may therefore inhibit a wide variety of viruses requiring these functions for essential events in the viral life cycle and therefore can be used for treatment of virus infection.
  • molecules directly affecting host functions that are essential for viral replication or the production of viral RNA or DNA or viral protein should provide a high barrier to the emergence of resistant strains relative to classical antivirals that directly target viral enzymes.
  • hepatitis C virus An estimated 170 million people worldwide are reported to be infected with hepatitis C virus, of which at least 6 known genotypes are the causative agent of hepatitis C infection. Up to 80 percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (see Saito I, et al., Hepatitis C virus infection is associated with the development of hepatocellular carcinoma, Proc Natl Acad Sci USA, 1990, 87:6547-6549).
  • HPV human papillomavirus
  • PV poliovirus
  • ASN Formagio et al European Journal of Medicinal Chemistry, 2009, 44(11):4695-4701).
  • International Patent publications WO2006/015035 and WO2007/002051 describe ⁇ -carboline compounds with antiviral activity against human papillomavirus infection (HPV) and a flavivirus infections, including dengue virus, yellow fever virus, West Nile virus and hepatitis C virus (HCV) infection. Accordingly, new small molecule therapies for treating patients with viral conditions
  • Compound Encompassed herein are compounds having the formula set forth in Section 5.1 (“Compound”) and compositions comprising such Compounds.
  • the Compounds can demonstrate one or more of the following activities: (a) selective inhibition of the pathological production of human VEGF; (b) inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema and/or tumor growth; (c) prolongation of the G1/S phase of the cell cycle; (d) inhibition of angiogenesis and/or inflammation associated with a non-neoplastic condition; and/or (e) inhibition of a viral infection.
  • the Compound used in the therapeutic method demonstrates one or more of the following activities as determined in cell culture and/or animal model systems, such as those described herein: (a) selective inhibition of the pathological production of human VEGF; (b) inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema and/or tumor growth; (c) prolongation of the G1/S phase of the cell cycle; (d) inhibition of angiogenesis and/or inflammation associated with a non-neoplastic condition; and/or (e) inhibition of viral infection.
  • activities as determined in cell culture and/or animal model systems, such as those described herein: (a) selective inhibition of the pathological production of human VEGF; (b) inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema and/or tumor growth; (c) prolongation of the G1/S phase of the cell cycle; (d) inhibition of angiogenesis and/or inflammation associated with a non-neoplastic condition; and/or (e) inhibition of viral infection.
  • the Compound can be administered as a single agent therapy to a human in need of such treatment.
  • the Compound can be administered in combination with one or more additional therapies to a human in need of such treatment.
  • Such therapies may include the use of anti-cancer agents (e.g., cytotoxic agents, anti-angiogenesis agents, tyrosine kinase inhibitors or other enzyme inhibitors).
  • the therapies described herein should be effective because they are aimed at interfering with basic mechanisms required for manifestation of each disease (i.e., the pathological production of human VEGF, uncontrolled growth of tumors or inflammation or edema associated with tumors, the pathological angiogenesis or inflammation associated with a non-neoplastic condition, the pathological angiogenesis associated with cancer, or the biological processes involved in viral replication or the production of viral RNA or DNA or viral protein).
  • the therapies described are based, in part, on the pharmacodynamic activities of the Compounds as measured in cell culture and in animal models; in particular, these include: (a) selective inhibition of the pathological production of human VEGF; (b) inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema, and/or tumor growth; (c) prolongation of the G1/S phase of the cell cycle of aberrantly proliferating cells and/or (d) inhibition of viral replication or the production of viral RNA or DNA or viral protein.
  • pharmacologic activities contribute to limiting solid tumor growth or tumor-related inflammation, tumor-related edema and/or pathological angiogenesis, in several ways.
  • inhibition of pathological production of human VEGF by the tumor will inhibit tumor angiogenesis, thereby limiting vascularization and further growth of solid tumors.
  • An additional benefit is achieved for tumors that respond to VEGF as a growth factor—in such cases, the Compound can limit proliferation of such tumor cells independent of their angiogenic status, that is angiogenesis and vascularization need not be present for the Compound to limit proliferation of the tumor cells. Because the process of tumorigenesis can result in inflammation and edema, a Compound may limit such inflammation or edema.
  • prolongation of the cell cycle may contribute to the induction of apoptotic death of the tumor cells, and/or allow for increased efficacy when the Compound is used in combination with a therapy or therapies (e.g., chemotherapeutic agents or radiation) that interfere with nucleic acid synthesis during the cell cycle (e.g., the G1/S phase).
  • a therapy or therapies e.g., chemotherapeutic agents or radiation
  • nucleic acid synthesis during the cell cycle e.g., the G1/S phase
  • a Compound that interferes with cellular molecular processes that participate in viral replication may inhibit one or more events of the viral life cycle and thus be used for treatment of a viral infection.
  • a Compound that interferes with viral replication or the production of viral RNA or DNA or viral protein may inhibit relapse of one or more symptoms associated with recurrence of a viral infection.
  • the methods for treating cancer can result in inhibition or reduction of the pathological production of human VEGF (including intratumoral VEGF production), thus reducing VEGF concentrations in biological specimens of an afflicted subject; inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema, and/or tumor growth in the subject; stabilization or reduction of tumor volume or tumor burden in the subject; stabilization or reduction of peritumoral inflammation or edema in the subject; reduction of the concentrations of angiogenic or inflammatory mediators in biological specimens (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids); and/or a delayed or prolonged late G1/S phase of the cell cycle (i.e., the period between the late resting or pre-DNA synthesis phase, and the early DNA synthesis phase) in tumor cells of the subject.
  • VEGF including intratumoral VEGF production
  • the methods of treating non-neoplastic conditions can result in the inhibition or reduction of pathological angiogenesis; the inhibition or reduction of plasma human VEGF concentrations in an afflicted subject; the inhibition or reduction in inflammation; and/or stabilization or reduction of the one or more symptoms of the non-neoplastic condition in the subject.
  • the methods of treating a viral infection can result in interference with viral replication in infected cells in an afflicted subject and prevent or reduce the ability of the virus to appropriate the host apparatus and molecular processes in the subject.
  • Existing antiangiogenic therapies that have been developed for other diseases (e.g., certain cancers and retinopathies including macular degeneration and the like) are directed at globally neutralizing VEGF activity (e.g., using anti-VEGF antibodies), or inhibiting downstream effects of VEGF signaling (e.g., using tyrosine kinase inhibitors to block the signaling activity of the VEGF receptor).
  • VEGF activity e.g., using anti-VEGF antibodies
  • VEGF signaling e.g., using tyrosine kinase inhibitors to block the signaling activity of the VEGF receptor.
  • these existing antiangiogenic therapies neutralize or inhibit physiological or homeostatic VEGF, as well as pathologically produced human VEGF, activity resulting in side effects that, while tolerated for the treatment of life-threatening cancers or to prevent or slow the development of hearing loss or blindness, may not be acceptable for the treatment of certain cancers and non-neoplastic conditions. Since the Compounds used in the therapeutic methods described herein selectively inhibit pathologic production of human VEGF, and do not disturb the production of human VEGF under physiological conditions, side effects that are unacceptable for the treatment of cancer or non-neoplastic conditions may be reduced.
  • Existing antiviral therapies are a combination of interferon and ribavirin, leading to variable outcomes among the six major HCV genotypes.
  • an “effective amount” in the context of administering a Compound to a subject with cancer refers to the amount of a Compound that results in a beneficial or therapeutic effect.
  • an “effective amount” of a Compound refers to an amount of a Compound which is sufficient to achieve at least one, two, three, four or more of the following effects: (i) the reduction or amelioration of the severity of one or more symptoms associated with cancer; (ii) the reduction in the duration of one or more symptoms associated with cancer; (iii) the prevention in the recurrence of a tumor or one or more symptoms associated with cancer; (iv) the regression of cancer and/or one or more symptoms associated therewith; (v) the reduction in hospitalization of a subject; (vi) the reduction in hospitalization length; (vii) an increase in the survival of a subject; (viii) the inhibition of the progression of cancer and/or one or more symptoms associated therewith; (ix) the enhancement of or improvement of the therapeutic effect of another therapy; (x)
  • an “effective amount” of a Compound refers to an amount of a Compound which is sufficient to achieve at least one, two, three, four or more of the following effects: (i) the reduction or amelioration of the severity of a non-neoplastic condition and/or one or more symptoms associated therewith; (ii) the reduction in the duration of one or more symptoms associated with a non-neoplastic condition; (iii) the prevention in the recurrence of a one or more symptoms associated with a non-neoplastic condition; (iv) the regression of the non-neoplastic condition and/or one or more symptoms associated therewith; (v) the inhibition of the progression of a non-neoplastic condition and/or one or more symptoms associated therewith; (vi) the enhancement or improvement the
  • an “effective amount” in the context of administering a Compound to a subject with a viral infection refers to the amount of a Compound that results in a beneficial or therapeutic effect.
  • an “effective amount” of a Compound refers to an amount of a Compound which is sufficient to achieve at least one, two, three, four or more of the following effects: (i) the reduction or amelioration of the severity of one or more symptoms associated with viral infection; (ii) the reduction in the duration of one or more symptoms associated with viral infection; (iii) the prevention in the recurrence of a viral infection or one or more symptoms associated with viral infection; (iv) the regression of viral infection and/or one or more symptoms associated therewith; (v) the inhibition of the progression of viral infection and/or one or more symptoms associated therewith; (vi) the enhancement of and/or improvement of the therapeutic effect of another antiviral therapy; (vii) a reduction in a viral titer; (viii) a reduction in the progression of viral
  • yielderly human refers to a human 65 years or older.
  • human adult refers to a human that is 18 years or older.
  • mis-aged human refers to a human between the ages of 30 and 64.
  • human child refers to a human that is 1 year to 18 years old.
  • human toddler refers to a human that is 1 year to 3 years old.
  • human infant refers to a newborn to 1 year old year human.
  • the terms “subject” and “patient” are used interchangeably to refer to an individual being treated for cancer, a non-neoplastic condition or a viral infection.
  • the individual is a human. See Section 5.4 and 5.5 for more information concerning patients treated for cancer or a non-neoplastic condition in accordance with the methods provided herein.
  • the terms “therapies” and “therapy” can refer to any protocol(s), method(s), compositions, formulations, and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a condition or disorder or one or more symptoms thereof (e.g., cancer or one or more symptoms or one or more conditions associated therewith; a non-neoplastic condition or one or more symptoms or one or more conditions associated therewith; or, a viral infection or one or more symptoms or one or more conditions associated therewith).
  • a condition or disorder or one or more symptoms thereof e.g., cancer or one or more symptoms or one or more conditions associated therewith; a non-neoplastic condition or one or more symptoms or one or more conditions associated therewith; or, a viral infection or one or more symptoms or one or more conditions associated therewith.
  • the terms “therapies” and “therapy” refer to drug therapy such as chemotherapy, adjuvant therapy, radiation, surgery, biological therapy, supportive therapy, antiviral therapy and/or other therapies useful in treatment, management, prevention, or amelioration of a condition or disorder or one or more symptoms thereof (e.g., cancer or one or more symptoms or one or more conditions associated therewith; a non-neoplastic condition or one or more symptoms or one or more conditions associated therewith; or, a viral infection or one or more symptoms or one or more conditions associated therewith).
  • the term “therapy” refers to a therapy other than a Compound or pharmaceutical composition thereof.
  • an “additional therapy” and “additional therapies” refer to a therapy other than a treatment using a Compound or pharmaceutical composition thereof.
  • a therapy includes the use of a Compound as an adjuvant therapy.
  • a drug therapy such as chemotherapy, biological therapy, surgery, supportive therapy, antiviral therapy and/or other therapies useful in treatment, management, prevention, or amelioration of a condition or disorder or one or more symptoms thereof (e.g., cancer or one or more symptoms or one or more conditions associated therewith; a non-neoplastic condition or one or more symptoms or one or more conditions associated therewith; or, a viral infection or one or more symptoms or one or more conditions associated therewith).
  • the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base.
  • Suitable pharmaceutically acceptable base addition salts of the Compounds provided herein include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic
  • Non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids.
  • Examples of specific salts thus include hydrochloride and mesylate salts.
  • Others are well-known in the art, see for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton Pa. (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton Pa. (1995).
  • the terms “Compound” or “Compound provided herein” generally refer to a compound described in Section 5.1, Section 6.24, and Table 1, and pharmaceutically acceptable salts, racemates and stereoisomers thereof.
  • the terms refer to a compound of Formula I, II, III or IV.
  • the terms refer to a compound of Formula Ia, IIa, IIIa or IVa.
  • the terms refer to a compound depicted in Table 1.
  • the terms refer to a Compound disclosed in WO2005/089764, e.g., Compounds in the table on pages 26-98; WO2006/113703, e.g., Compounds in the table on pages 29-102; WO2008/127715, e.g., Compounds in the table on pages 52-126; WO2008/127714, e.g., Compounds in the table on pages 48-123; and United States Provisional Patent Application 61/181,653, entitled: METHODS FOR TREATING CANCER AND NON-NEOPLASTIC CONDITIONS, filed May 27, 2009, all of which are herewith incorporated by reference in their entirety.
  • the terms “Compound” or “Compound provided herein” refer to a stereoisomer of a compound described in Section 5.1.
  • the “Compound” or “Compound provided herein” may comprise one or more asymmetric carbon atoms, i.e. n asymmetric carbon atoms, having either R or S configuration as determined by a person skilled in the art.
  • the terms refer to a particular enantiomer, such as an R or S enantiomer of a “Compound” or “Compound provided herein”.
  • the terms refer to an R or S enantiomer of a compound of Formula I, II, III or IV.
  • the “Compound” or “Compound provided herein” may be a substantially pure (e.g., about 90%, about 95%, about 98%, about 99%, or about 99.9% pure) single stereoisomer or a mixture of two or more stereoisomers.
  • pathologic refers to the stress-induced expression of VEGF protein.
  • oncongenic transformation-induced expression of VEGF protein by tumor cells or other cells in the tumor environment is encompassed by the terms.
  • hypoxia-induced expression of VEGF protein in a chronic or traumatic inflammatory condition is encompassed by the terms.
  • cells that disregulate or overproduce VEGF protein is also encompassed by the terms.
  • expression of VEGF protein supports inflammation, angiogenesis and tumor growth. The inhibition or reduction in pathological production of VEGF protein by a Compound can be assessed in cell culture and/or animal models as described herein.
  • the term “about” means a range around a given value wherein the resulting value is substantially the same as the expressly recited value. In one embodiment, “about” means within 25% of a given value or range. For example, the phrase “about 70% by weight” comprises at least all values from 52% to 88% by weight. In another embodiment, the term “about” means within 10% of a given value or range. For example, the phrase “about 70% by weight” comprises at least all values from 63% to 77% by weight. In another embodiment, the term “about” means within 7% of a given value or range. For example, the phrase “about 70% by weight” comprises at least all values from 65% to 75% by weight.
  • viral infection refers to one or more RNA viruses belonging to families Bunyaviridae, Coronaviridae, Filoviridae, Flaviviridae, Paramyxoviridae, Picornaviridae, Orthomyxoviridae or Rhabdoviridae.
  • Other embodiments include one or more viruses belonging to families Hepadnaviridae, Reoviridae or Retroviridae.
  • Another embodiment includes one or more DNA viruses belonging to families Adenoviridae, Herpesviridae, Papillomaviridae or Papovaviridae.
  • the term “viral replication,” in the context of viral infection, refers to production of viral RNA or DNA or production of one or more viral proteins from viruses using double-stranded (ds) DNA or RNA and/or single-stranded (ss) RNA and/or partial-double-stranded (ps) DNA or RNA and/or positive (+) strand RNA and/or negative ( ⁇ ) strand RNA.
  • the term includes viral DNA replication or viral RNA replication or viral RNA transcription and translation, resulting in the expression of one or more viral proteins by infected cells in tissues of a subject.
  • the term includes viral expression and/or sequestration and/or latency of viral proteins in chronic viral infection.
  • the term includes the effect of viruses on cellular biological processes to produce viral RNA or DNA or one or more viral proteins.
  • expression of one or more viral proteins may result in viral sequestration and/or latency, inflammation, organ failure and/or tumor growth.
  • the inhibition or reduction in production of viral RNA or DNA or one or more viral proteins by a Compound can be assessed in cell culture and/or animal models as described herein.
  • viral replication complex in the context of viral infection, refers to a membrane-associated complex composed of viral proteins, replicating RNA and altered cellular membranes where viral RNA is replicated.
  • FIG. 1 Dose Response of Compound 1205 and Compound #10: Inhibition of the Production of Hypoxia-Induced VEGF in HeLa Cells.
  • FIG. 2A-B Effect of Compound 1205 on Intra-Tumor Human VEGF Levels.
  • FIG. 2A Effect of treatment with vehicle and Compound 1205 on intra-tumor VEGF levels for Study #21 (target tumor size: 1200 mm 3 ) and Study #23 (target tumor size: 1500 mm 3 ).
  • FIG. 2B Intra-tumor VEGF levels normalized to tumor size.
  • FIG. 3 Effect of Compound 1205 on Levels of Homeostatic Plasma Human VEGF for Study #21 and Study #23.
  • FIG. 4 Inhibition of HT1080 Tumor Growth by Compound #10, 1205 and 1330.
  • the symbol “**” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in Compound 1205 (S,S diastereoisomer) treated mice were significantly different from tumor size in vehicle-treated mice and that the differences in tumor size in Compound 1205 (S,S diastereoisomer) treated mice were significantly different from tumor size in Compound 1330 (R,S diastereoisomer)-treated mice (ANOVA, multiple comparisons).
  • FIG. 5A-B Cell Cycle Delay After Overnight Exposure to Compound 1205. Histograms depicting relative DNA content in HT1080 cells under normoxic conditions after treatment with Compound 1205 compared to vehicle. FIG. 5A . Histogram showing the effect of treatment with Compound 1205 at 10 nm. FIG. 5B . Histogram showing the effect of treatment with vehicle.
  • FIG. 7A-B Effect of Compound #10 as monotherapy and in combination with a PI3-K inhibitor in a 786-0 Renal Cancer Cell Line.
  • FIG. 7A The effect of Compound #10 as monotherapy (test concentrations of 1 ⁇ M and 10 ⁇ M) and in combination with a PI3-K inhibitor (test concentrations of 1 ⁇ M and 10 ⁇ M) on protein expression in a series of Western blot analyses of lysates of various cell lines.
  • FIG. 7B The effect of Compound #10 as monotherapy and in combination with a PI3-K inhibitor on VEGF expression in a 786-0 Renal Cancer Cell.
  • FIG. 8A-B -C Effect of Compound #10 as monotherapy on Protein Expression in Various Renal Cancer Cell Lines.
  • FIG. 8A The effect of Compound #10 as monotherapy on protein expression in a series of Western blot analyses of lysates of various cell lines from a 786-0 Renal Cancer Cell line.
  • FIG. 8B The effect of Compound #10 as monotherapy on protein expression in a series of Western blot analyses of lysates of various cell lines from a 769-P Renal Cancer Cell line.
  • FIG. 8C The effect of Compound #10 as monotherapy on protein expression in a series of Western blot analyses of lysates of various cell lines from a A498 Renal Cancer Cell line.
  • FIG. 9 Effect of Compound #10 monotherapy and combination therapy with Sunitinib on Tumor Volume in a VHL-Negative Tumor.
  • Symbols for each agent represent the mean ⁇ SD for each treatment group (10 mice per group); where the symbol “*” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in vehicle-treated mice (ANOVA, multiple comparisons vs vehicle) from Day 7 through Day 57, at which time vehicle-treated mice were taken off study; where the symbol “ a ” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in Compound #10-treated mice (ANOVA, multiple comparisons vs Compound #10) from Day 33 through Day 88, at which time Compound #10-treated mice were taken off study; and, where the symbol “ ⁇ ” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in sunitinib-treated or rapamycin
  • FIG. 10 Effect of Compound #10 monotherapy and combination therapy with Sunitinib on Body Weight in a VHL-Negative Tumor.
  • Symbols for each agent represent the mean ⁇ SD for each treatment group (10 mice per group); where the symbol “*” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in vehicle-treated mice (ANOVA, multiple comparisons vs vehicle) from Day 7 through Day 57, at which time vehicle-treated mice were taken off study; where the symbol “ # ” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in Compound #10-treated mice (ANOVA, multiple comparisons vs Compound #10) from Day 33 through Day 88, at which time Compound #10-treated mice were taken off study; and, where the symbol “ ⁇ ” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in sunitinib-treated or rapamycin-treated
  • FIG. 12 Effect of Compound #10 monotherapy and combination therapy with Rapamycin on Body Weight in a VHL-Negative Tumor.
  • Symbols for each agent represent the mean ⁇ SD for each treatment group (10 mice per group); where the symbol “*” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in vehicle-treated mice (ANOVA, multiple comparisons vs vehicle) from Day 7 through Day 57, at which time vehicle-treated mice were taken off study; where the symbol “#” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in Compound #10-treated mice (ANOVA, multiple comparisons vs Compound #10) from Day 33 through Day 88, at which time Compound #10-treated mice were taken off study; and, where the symbol “ ⁇ ” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in sunitinib-treated or rapamycin-treated mice were significantly
  • FIG. 16 Effect of Compound #10 monotherapy and combination therapy with Rapamycin on Body Weight in a VHL-Positive Tumor.
  • Symbols for each agent represent the mean ⁇ SD for each treatment group (10 mice per group); where the symbol “*” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in vehicle-treated mice (ANOVA, multiple comparisons vs vehicle) from Day 11 through Day 25, at which time vehicle-treated mice were taken off study; where the symbol “ # ” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in Compound #10-treated mice (ANOVA, multiple comparisons vs Compound #10); and, where the symbol “ ⁇ ” represents a p value of p ⁇ 0.05, signifying that the differences in tumor size in sunitinib-treated or rapamycin-treated mice were significantly different from tumor size in their respective combination-treated mice (ANOVA, multiple comparisons).
  • FIG. 17 Effect of Compound #10 monotherapy on target plasma concentrations.
  • Target plasma trough levels between 550 and 1010 ng/mL have been achieved in patients having a variety of cancers.
  • FIG. 18 Effect of Compound #10 monotherapy and combination therapy with docetaxel on target plasma concentrations.
  • Target plasma trough levels between 550 and 1010 ng/mL have been achieved in patients having a variety of cancers.
  • the “*” symbol represents that the docetaxel PK profile is consistent with historical data (see, Bruno, et al., 1994, JCO, 16:187)
  • FIG. 19 Effect of Compound #10 monotherapy in a patient having thyroid cancer.
  • the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 20 Effect of Compound #10 monotherapy in a patient having melanoma.
  • the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 21 Effect of Compound #10 monotherapy in a patient having chondrosarcoma.
  • the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 22 Effect of Compound #10 monotherapy in a patient having cholangiocarcinoma.
  • a patient having cholangiocarcinoma after four previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization for a tumor marker.
  • FIG. 23 Effect of Compound #10 monotherapy and combination therapy with docetaxel in a patient having head and neck cancer.
  • a patient having head and neck cancer with metastasis to the lung after previous radiotherapy and no prior chemotherapy, the result of treatment with a combination of Compound #10 and docetaxel led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • the arrow symbol represents the timepoint at which docetaxel was reduced to 60 mg/m 2 .
  • FIG. 24 Effect of Compound #10 monotherapy in a patient jejunal adenocarcinoma.
  • a patient having cholangiocarcinoma with metastasis to the lung after five previous therapeutic modalities for the metastasis, the result of monotherapy treatment with Compound #10 is presented.
  • FIG. 25 Use of Compound #10 monotherapy at various concentrations for treatment of various cancers.
  • Compounds capable of inhibiting the pathological production of human VEGF are Compounds capable of inhibiting the pathological production of human VEGF. Also encompassed herein are methods of treating cancer and non-neoplastic conditions using the Compounds as well as methods of using the Compounds to reduce pathological human VEGF production. Further encompassed herein are methods of treating viral infections using the Compounds as well as methods of using the Compounds to inhibit or reduce viral replication and/or production of viral RNA or DNA or viral protein.
  • Compounds provided herein comprise at least one stereocenter, and may exist as a racemic mixture or as an enantiomerically pure composition.
  • a Compound provided herein is the (S) isomer, in an enantiomerically pure composition.
  • the enantiomeric excess e.e. is about 90%, about 95%, about 99% or about 99.9% or greater.
  • X is chloro or bromo.
  • R d is chloro or bromo.
  • R o is OR a .
  • R a is methyl, ethyl, propyl, isopropyl, butyl, or pentyl, each optionally substituted with one or more hydroxyl substituents.
  • Compounds described herein inhibit the translation of pathologically expressed human VEGF mRNA and, thus, inhibit the pathologic production of human VEGF protein.
  • the Compounds act specifically through a mechanism dependent on the 5′ untranslated region (UTR) of the human VEGF mRNA to inhibit the pathologic production of human VEGF protein.
  • UTR 5′ untranslated region
  • the activity of the Compounds tested is post-transcriptional since quantitative real-time polymerase chain reaction (PCR) assessments of mRNA have shown that the Compounds do not alter the levels of human VEGF mRNA.
  • VEGF also known as VEGF-A and vascular permeability factor (VPF)
  • VEGF-A vascular permeability factor
  • VPF vascular permeability factor
  • the human VEGF-A gene encodes a number of different products (isoforms) due to alternative splicing.
  • the VEGF-A isoforms include VEGF 121 , VEGF 165 , VEGF 189 and VEGF 206 having 121, 165, 189 and 206 amino acids, respectively.
  • VEGF 165 and VEGF 121 isoforms are soluble, whereas VEGF 189 and VEGF 206 isoforms are sequestered within the extracellular matrix.
  • the activity of the Compounds tested was assessed by measuring the concentrations of soluble VEGF in cell culture systems. In preclinical tumor models, the activity of the Compounds tested was assessed by measuring the concentrations of soluble VEGF. The data indicate that the Compounds tested inhibit the production of soluble forms of tumor derived VEGF.
  • a Compound provided herein has been shown to selectively inhibit stress (e.g., hypoxia) induced production of soluble human VEGF isoforms in cell culture without affecting soluble human VEGF production under normoxic conditions (see Section 8.1 et seq.).
  • stress e.g., hypoxia
  • the Compound was shown to preferentially inhibit pathological production of soluble human VEGF isoforms resulting from hypoxia while sparing homeostatic production of soluble isoforms in unperturbed cells.
  • a Compound selectively inhibits or reduces the pathological production of a soluble human VEGF isoform over inhibiting or reducing physiological or homeostatic production of a soluble human VEGF isoform.
  • a Compound selectively inhibits or reduces the pathological production of a matrix-bound human VEGF isoform over inhibiting or reducing physiological production of a matrix-bound human VEGF isoform.
  • a Compound selectively inhibits or reduces the pathological production of one or more soluble human VEGF isoforms and one or more matrix-bound VEGF isoforms.
  • a Compound provided herein has been shown to have a profound effect on the architecture of the tumor vasculature in animal models with pre-established human tumors. The Compound reduced the total volume and diameter of blood vessels formed compared to vehicle treated subjects. See Section 8.2. A Compound showed inhibition of tumor growth in the model. A dose-response effect of the Compound that correlated with decreases in tumor and plasma VEGF concentrations was observed when tumor size was assessed. See Section 8.1.3.
  • the concentration of soluble human VEGF in human plasma is used to assess and monitor the pharmacodynamic effect of a Compound provided herein.
  • the concentration of either VEGF 121 , VEGF 165 , or both in human plasma are used to assess and monitor the pharmacodynamic effect of a Compound provided herein.
  • a Compound provided herein provokes a late G 1 /early S-Phase cell cycle delay, i.e., between the late resting or pre-DNA synthesis phase, and the early DNA synthesis phase in those tumor cell lines in which VEGF generation is decreased by the Compound. See Section 8.3. Further characterization indicates that this effect is concentration dependent, occurring at low nanomolar EC 50 values similar to those associated with reducing pathological VEGF production.
  • the cell cycle delay and inhibition of pathological VEGF protein production occur in concert, linking these phenotypes in inflammation, pathological angiogenesis and tumor growth.
  • RNA or DNA or viral protein production is decreased by a Compound
  • further characterization indicates that inhibition of viral replication and production of viral RNA or DNA or viral protein is concentration dependent.
  • the Compound appears to inhibit viral replication and production of viral RNA or DNA or viral protein by interefering with the biological processes of the host cell to inhibit or prevent the formation of a viral replication complex in a cell or in the endoplasmic reticulum.
  • the interference of the Compound with the biological processes of the host cell is supported by data that includes: (1) broad spectrum activity against viruses from diverse and not closely related taxa; (2) the failure to select a resistant viral replicon despite long-term exposure at inhibitory concentrations of a Compound in cell culture; and (3) the lack of antiviral activity in a cell line which is resistant to the cell cycle delay induced by the Compound.
  • these experiments indicate that the effects of the Compound on the host cell processes occur in parallel with the effects on viral replication and production of viral RNA or DNA or viral protein.
  • the Compounds provided herein can be administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups.
  • suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient selected from fillers or diluents, binders, disintegrants, lubricants, flavoring agents, preservatives, stabilizers, suspending agents, dispersing agents, surfactants, antioxidants or solubilizers.
  • Excipients that may be selected are known to those skilled in the art and include, but are not limited to fillers or diluents (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate and the like), a binder (e.g., cellulose, carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol or starch and the like), a disintegrants (e.g., sodium starch glycolate, croscarmellose sodium and the like), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate and the like), a flavoring agent (e.g., citric acid, or menthol and the like), a
  • the amount of the Compound provided herein administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • the Compound provided herein can be formulated for any route of administration.
  • the Compound provided herein is formulated for intradermal, intramuscular, intraperitoneal, percutaneous, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, or mucosal administration, for inhalation, or topical administration to to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.
  • the Compound provided herein is administered orally using a capsule dosage form composition, wherein the capsule contains the Compound provided herein without an additional carrier, excipient or vehicle.
  • compositions comprising an effective amount of a Compound provided herein and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • the composition is a pharmaceutical composition.
  • compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit.
  • the composition is prepared according to known methods in pharmaceutical chemistry.
  • Capsules can be prepared by mixing a Compound provided herein with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
  • a method for inhibiting or reducing pathological production of human VEGF comprises contacting a Compound or a composition thereof with a cell or cell line that pathologically produces human VEGF or are induced to pathologically produce human VEGF.
  • the cell or cell line may be a cancer cell that pathologically produces human VEGF.
  • the cell or cell line may be induced to pathologically produce human VEGF by, e.g., exposure to stress such as hypoxia.
  • Non-limiting examples of cell lines include HeLa, HT1080, HCT116, HEK293, NCI H460, U-87MG, ASPC-1, PL-45, HPAF-2, PC-3, MDA-MB-231, MDA-MB-468, A431, SNU-1, AGS, Kato III, A549, Calu-6, A375, SY5Y, SKOV3, Capan-1, sNF96.2, TIVE-L1, TIVE-L2, and LNCaP cells.
  • a method for inhibiting or reducing pathological production of human VEGF in a subject comprises administering to a subject a Compound or a composition thereof.
  • the subject has a condition associated with the pathological production of human VEGF.
  • the subject is diagnosed with cancer or a non-neoplastic condition associated with pathological production of human VEGF.
  • the methods for inhibiting or reducing the pathological production of human VEGF provided herein inhibit or decrease pathological production of human VEGF by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to pathological production of human VEGF prior to administration of a Compound, as assessed by methods well known in the art.
  • the methods for inhibiting or reducing the pathological production of human VEGF provided herein inhibit or decrease pathological production of human VEGF in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 40% to 100%, relative to pathological production of human VEGF prior to administration of a Compound or any range in between, as assessed by methods well known in the art.
  • a method for inhibiting or reducing pathological angiogenesis or vascularization in a subject comprises administering to a subject a Compound or a composition thereof.
  • the subject has a condition associated with the pathological angiogenesis or vascularization.
  • the subject is diagnosed with cancer or a non-neoplastic condition associated with pathological production of human VEGF.
  • the methods inhibiting or reducing pathological angiogenesis or vascularization provided herein inhibit or reduce angiogenesis or vascularization, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to angiogenesis or vascularization prior to administration of a Compound, as assessed by methods well known in the art, e.g., MRI scan, CT scan, PET scan.
  • the methods for inhibiting or reducing pathological angiogenesis or vascularization provided herein inhibit or reduce angiogenesis or vascularization in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 40% to 100%, relative to angiogenesis or vascularization prior to administration of a Compound or any range in between, as assessed by methods well known in the art, e.g., MRI scan, CT scan, PET scan.
  • a method for inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein comprises contacting a Compound or a composition thereof with a cell or cell line that produces a virus or viral RNA or DNA or viral protein or may be induced to produce the virus or viral RNA or DNA or viral protein.
  • the cell or cell line may be a virus-infected cell that constitutively produces a virus or viral RNA or DNA or viral protein.
  • the cell or cell line may be induced to produce a virus or viral RNA or DNA or viral protein by, e.g., exposure to an active virus.
  • Non-limiting examples of viral cell lines include HeLa, Vero, Vero E6, MDCK, MT-2 and the like.
  • a method for treating a viral infection by inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein in a subject comprises administering to a subject a Compound or a composition thereof.
  • the subject has a viral infection or a condition associated with viral replication or the production of viral RNA or DNA or viral protein.
  • the subject is diagnosed with a viral infection associated with viral replication or the production of viral RNA or DNA or viral protein.
  • the methods for treating a viral infection by inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein inhibit or decrease viral replication or the production of viral RNA or DNA or viral protein by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to viral replication or the production of viral RNA or DNA or viral protein prior to administration of a Compound, as assessed by methods well known in the art.
  • the methods for inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein inhibit or decrease viral replication or the production of viral RNA or DNA or viral protein in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 40% to 100%, relative to viral replication or the production of viral RNA or DNA or viral protein prior to administration of a Compound or any range in between, as assessed by methods well known in the art.
  • Methods for treating cancer, non-neoplastic conditions and viral infections are also presented herein.
  • the methods for treating cancer or a non-neoplastic condition or a viral infection involve the administration of a Compound, as a single agent therapy, to a patient in need thereof.
  • presented herein is a method for treating cancer or a non-neoplastic condition or a viral infection, comprising administering to a patient in need thereof an effective amount of a Compound, as a single agent.
  • a method for treating cancer or a non-neoplastic condition or a viral infection comprising administering to a patient in need thereof a pharmaceutical composition comprising a Compound, as the single active ingredient, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • the methods for treating cancer or a non-neoplastic condition or a viral infection involve the administration of a Compound in combination with another therapy (e.g., one or more additional therapies that do not comprise a Compound, or that comprise a different Compound) to a patient in need thereof.
  • another therapy e.g., one or more additional therapies that do not comprise a Compound, or that comprise a different Compound
  • Such methods may involve administering a Compound prior to, concurrent with, or subsequent to administration of the additional therapy.
  • such methods have an additive or synergistic effect.
  • presented herein is a method for treating cancer or a non-neoplastic condition, comprising administering to a patient in need thereof an effective amount of a Compound and an effective amount of another therapy.
  • any cancer or non-neoplastic condition that is associated with pathological production of VEGF or a viral infection associated with viral replication or the production of viral RNA or DNA or viral protein can be treated in accordance with the methods provided herein.
  • the cancer treated in accordance with the methods provided herein is a solid tumor cancer.
  • Solid tumor cancers include, but are not limited to, sarcomas, carcinomas, and lymphomas.
  • cancers that can be treated in accordance with the methods described include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, esophagus, chest, bone, lung, kidney, colon, rectum or other gastrointestinal tract organs, stomach, spleen, skeletal muscle, subcutaneous tissue, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system.
  • cancers that can be treated in accordance with the methods provided herein include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplastic syndrome, chronic leukemias such as but not limited to, chronic myclocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease
  • cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.
  • cancers that can be treated in accordance with the methods provided herein include, the following: pediatric solid tumor, Ewing's sarcoma, Wilms tumor, neuroblastoma, neurofibroma, carcinoma of the epidermis, malignant melanoma, cervical carcinoma, colon carcinoma, lung carcinoma, renal carcinoma, breast carcinoma, breast sarcoma, metastatic breast cancer, HIV-related Kaposi's sarcoma, prostate cancer, androgen-independent prostate cancer, androgen-dependent prostate cancer, neurofibromatosis, lung cancer, non-small cell lung cancer, KRAS-mutated non-small cell lung cancer, malignant melanoma, melanoma, colon cancer, KRAS-mutated colorectal cancer, glioblastoma multiforme, renal cancer, kidney cancer, bladder cancer, ovarian cancer, hepatocellular carcinoma, thyroid carcinoma, rhabdomyosarcoma, acute myeloid leukemia, and multiple myeloma.
  • cancers and conditions associated therewith that are treated in accordance with the methods provided herein are breast carcinomas, lung carcinomas, gastric carcinomas, esophageal carcinomas, colorectal carcinomas, liver carcinomas, ovarian carcinomas, thecomas, arrhenoblastomas, cervical carcinomas, endometrial carcinoma, endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma, head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinomas, hepatoblastoma, Kaposi's sarcoma, melanoma, skin carcinomas, hemangioma, cavernous hemangioma, hemangioblastoma, pancreas carcinomas, retinoblastoma, astrocytoma, glioblastoma, Schwannoma, oligodendroglioma, medulloblastoma, neurode carcinomas,
  • the cancer an astrocytoma, an oligodendroglioma, a mixture of oligodendroglioma and an astrocytoma elements, an ependymoma, a meningioma, a pituitary adenoma, a primitive neuroectodermal tumor, a medullblastoma, a primary central nervous system (CNS) lymphoma, or a CNS germ cell tumor.
  • the cancer treated in accordance with the methods provided herein is an acoustic neuroma, an anaplastic astrocytoma, a glioblastoma multiforme, or a meningioma.
  • the cancer treated in accordance with the methods provided herein is a brain stem glioma, a craniopharyngioma, an ependyoma, a juvenile pilocytic astrocytoma, a medulloblastoma, an optic nerve glioma, primitive neuroectodermal tumor, or a rhabdoid tumor.
  • non-neoplastic conditions that can be treated in accordance with the methods described herein include cystic fibrosis, muscular dystrophy, polycystic autosomal-dominant kidney disease, cancer-induced cachexia, benign prostatic hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, retinopathies (including diabetic retinopathy and retinopathy of prematurity), retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, exudative macular degeneration, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, and pterygium keratitis sicca, viral infections, inflammation associated with viral infections, chronic inflammation, lung inflammation, nephrotic syndrome, preeclam
  • viral infections that can be treated in accordance with the methods described herein include those associated with (+) strand RNA or ( ⁇ ) strand RNA viruses belonging to the families Bunyaviridae, Coronaviridae, Filoviridae, Flaviviridae, Paramyxoviridae, Picornaviridae, Orthomyxoviridae or Rhabdoviridae.
  • Other embodiments include viral infections associated with double-stranded RNA viruses belonging to the family Reoviridae or viruses belonging to the families Retroviridae or Hepadnaviridae.
  • Another embodiment includes viral infections by DNA viruses belonging to the families Adenoviridae, Herpesviridae, Papillomaviridae or Papovaviridae.
  • viral infections include viral infections, including but not limited to, those associated with viruses belonging to Flaviviridae (such as West Nile virus (WNV), hepatitis C virus (HCV), yellow fever virus (YFV) and dengue virus (DENV)), Paramyxoviridae (such as parainfluenza virus and respiratory syncytial virus (RSV)), Picornaviridae (such as poliovirus (PV), hepatitis A virus (HAV), coxsackievirus and rhinovirus), Coronaviridae (such as severe acute respiratory syndrome coronavirus (SARS-CoV)), Orthomyxoviridae (such as influenza virus), or Filoviridae (such as Ebola and Marburg viruses).
  • Flaviviridae such as West Nile virus (WNV), hepatitis C virus (HCV), yellow fever virus (YFV) and dengue virus (DENV)
  • Paramyxoviridae such as parainfluenza virus and respiratory syncytial virus
  • the term refers to viral infections by members of the family Retroviridae (such as human immunodeficiency virus (HIV) and human T cell leukemia viruses (HTLV)), Hepadnaviridae (such as hepatitis B virus (HBV)).
  • Retroviridae such as human immunodeficiency virus (HIV) and human T cell leukemia viruses (HTLV)
  • Hepadnaviridae such as hepatitis B virus (HBV)
  • the term refers to viral infections by DNA viruses (such as herpes simplex virus (HSV), Kaposi's sarcoma-associated herpesvirus, adenovirus, vaccinia virus or human papilloma virus (HPV)).
  • HSV herpes simplex virus
  • HPV human papilloma virus
  • the viral infection is by West Nile virus, hepatitis C virus, yellow fever virus, dengue virus, respiratory syncytial virus, poliovirus, severe acute respiratory syndrome coronavirus, influenza virus, parainfluenza virus, human immunodeficiency virus, human T cell leukemia viruses, herpes simplex virus or vaccinia virus.
  • the viral infection is by West Nile virus, hepatitis C virus, dengue virus, respiratory syncytial virus, poliovirus, influenza virus, parainfluenza virus or human immunodeficiency virus.
  • the viral infection is by a known or unknown genotype of the hepatitis C virus.
  • the genotype of the hepatitis C virus is the hepatitis C virus genotype 1a, the hepatitis C virus genotype 1b or the hepatitis C virus genotype 2a.
  • non-neoplastic conditions associated with pathological production of VEGF that can be treated with the methods described herein include diabetic retiopathy, exudative macular degeneration, rheumatoid arthritis, psoriasis, artheriosclerosis, chronic inflammation, obesity, and polycystic autosomal-dominant kidney disease.
  • VEGF or other angiogenic or inflammatory mediators e.g., P1GF, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, IL-6 and/or IL-8) in a biological specimen (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids)
  • a biological specimen e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids
  • a biological specimen e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids
  • a biological specimen e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids
  • a biological specimen e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids
  • a compound that inhibits or reduces the pathological production of human VEGF such as a Compound described herein or a compound described in U.S. Publication No. 2005-0272759
  • the dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient may also be modified as a result of the concentration of VEGF or other angiogenic or inflammatory mediators.
  • the changes in these monitoring the concentration of VEGF or other angiogenic or inflammatory mediators might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the cancer or a non-neoplastic condition.
  • the concentration of VEGF or other angiogenic or inflammatory mediators in biological specimens (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids) of a patient is monitored before, during and/or after a course of treatment for cancer involving the administration of a Compound or a pharmaceutical composition thereof to the patient.
  • the tumoral blood flow or metabolism, or peritumoral inflammation or edema in a patient is monitored before, during and/or after a course of treatment for cancer involving the administration of a Compound or a pharmaceutical composition.
  • the dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient might be modified as a result of the concentration of VEGF or other angiogenic or inflammatory mediators, or of tumoral blood flow or metabolism, or peritumoral inflammation or edema as assessed by imaging techniques.
  • the changes in these monitoring parameters e.g., concentration of VEGF or other angiogenic or inflammatory mediators, or of tumoral blood flow or metabolism, or peritumoral inflammation or edema
  • concentration of VEGF or other angiogenic or inflammatory mediators, or of tumoral blood flow or metabolism, or peritumoral inflammation or edema might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the cancer.
  • a method for treating cancer comprising: (a) administering to a patient in need thereof one or more doses of a Compound or a pharmaceutical composition thereof; and (b) monitoring the concentration of VEGF or other angiogenic, or inflammatory mediators (e.g., detected in biological specimens such as plasma, serum, cerebral spinal fluid, urine, or any other biofluids), or monitoring tumoral blood flow or metabolism, or peritumoral inflammation or edema, before and/or after step (a).
  • step (b) comprises monitoring the concentration of one or more inflammatory mediators including, but not limited to, cytokines and interleukins such as IL-6 and IL-8.
  • step (b) comprises monitoring the concentration of VEGF-A, VEGF-R, P1GF, VEGF-C, and/or VEGF-D.
  • the monitoring step (b) is carried out before and/or after a certain number of doses (e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, or 29 doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 doses) or a certain time period (e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks) of administering the Compound.
  • doses e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, or 29 doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 doses
  • a certain time period e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks
  • one or more of these monitoring parameters are detected prior to administration of
  • a decrease in the concentration of VEGF or other angiogenic or inflammatory mediators or a change in tumoral blood flow or metabolism, or peritumor edema following administration of the Compound or pharmaceutical composition thereof indicates that the course of treatment is effective for treating the cancer.
  • a change in the concentration of VEGF or other angiogenic or inflammatory mediators or a change in tumoral blood flow or metabolism, or peritumoral inflammation or edema following administration of the Compound or pharmaceutical composition thereof may indicate that the dosage, frequency and/or length of administration of the Compound or a pharmaceutical composition thereof may be adjusted (e.g., increased, reduced or maintained).
  • the cancer is a solid tumor.
  • the concentration of VEGF or other angiogenic or inflammatory mediators in biological specimens (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids) of a patient is monitored before, during and/or after a course of treatment for a non-neoplastic condition involving the administration of a Compound or a pharmaceutical composition thereof to the patient.
  • the dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient might be modified as a result of the concentration of VEGF or other angiogenic or inflammatory mediators.
  • the changes in these monitoring parameters might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the non-neoplastic condition.
  • a method for treating a non-neoplastic condition comprising: (a) administering to a patient in need thereof one or more doses of a Compound or a pharmaceutical composition thereof; and (b) monitoring the concentration of VEGF or other angiogenic, or inflammatory mediators (e.g., detected in biological specimens such as plasma, serum, cerebral spinal fluid, urine, or any other biofluids) before and/or after step (a).
  • step (b) comprises monitoring the concentration of one or more inflammatory mediators including, but not limited to, cytokines and interleukins such as IL-6 and IL-8.
  • step (b) comprises monitoring the concentration of VEGF-A, VEGF-R, P1GF, VEGF-C, and/or VEGF-D.
  • the monitoring step (b) is carried out before and/or after a certain number of doses (e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, or 20 doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 doses) or a certain time period (e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks) of administering the Compound.
  • doses e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, or 20 doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 doses
  • a certain time period e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks
  • one or more of these monitoring parameters are detected prior to administration of
  • a decrease in the concentration of VEGF or other angiogenic or inflammatory mediators following administration of the Compound or pharmaceutical composition thereof indicates that the course of treatment is effective for treating the non-neoplastic condition.
  • a change in the concentration of VEGF or other angiogenic or inflammatory mediators following administration of the Compound or pharmaceutical composition thereof may indicate that the dosage, frequency and/or length of administration of the Compound or a pharmaceutical composition thereof may be adjusted (e.g., increased, reduced or maintained).
  • the concentration of VEGF or other angiogenic or inflammatory mediators or a change in tumor blood flow or metabolism, or peritumoral inflammation or edema of a patient may be detected by any technique known to one of skill in the art.
  • the method for detecting the concentration of VEGF or other angiogenic or inflammatory mediators of a patient involves obtaining a biological sample (e.g., tissue or fluid sample) from the patient and detecting the concentration of VEGF or other angiogenic or inflammatory mediators in the biological sample (e.g., from plasma, serum, cerebral spinal fluid, urine, or any other biofluids), that has been subjected to certain types of treatment (e.g., centrifugation), and detection by use of immunological techniques, such as ELISA.
  • a biological sample e.g., tissue or fluid sample
  • the concentration of VEGF or other angiogenic or inflammatory mediators in the biological sample e.g., from plasma, serum, cerebral spinal fluid, urine, or any other bio
  • an ELISA described herein may be used to detect the concentration of VEGF or other angiogenic or inflammatory mediators, in a biological sample (e.g., from plasma, serum, cerebral spinal fluid, urine, or any other biofluids) that has been subjected to certain types of treatment (e.g., centrifugation).
  • a biological sample e.g., from plasma, serum, cerebral spinal fluid, urine, or any other biofluids
  • Other techniques known in the art that may be used to detect the concentration of VEGF or other angiogenic or inflammatory mediators, in a biological sample, include multiplex or proteomic assays.
  • a CT scan, an MRI scan, or a PET scan may be used to detect the tumor blood flow or metabolism, or peritumoral inflammation or edema.
  • the methods for treating cancer or a non-neoplastic condition provided herein alleviate or manage one, two or more symptoms associated with the cancer or the non-neoplastic condition. Alleviating or managing one, two or more symptoms of cancer or a non-neoplastic condition may be used as a clinical endpoint for efficacy of a Compound for treating the cancer or non-neoplastic condition. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein reduce the duration and/or severity of one or more symptoms associated with the cancer or the non-neoplastic condition.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit the onset, progression and/or recurrence of one or more symptoms associated with the cancer or the non-neoplastic condition. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein reduce the number of symptoms associated with the cancer or the non-neoplastic condition.
  • the cancer is a solid tumor cancer.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce pathological production of human VEGF.
  • the methods for treating cancer or a non-neoplastic condition provided herein selectively inhibit pathologic production of human VEGF (e.g., by the tumor), but do not disturb the physiological activity of human VEGF protein.
  • the methods for treating cancer or a non-neoplastic condition provided herein do not significantly inhibit or reduce physiological or homeostatic production of human VEGF. For example, blood pressure, protein levels in urine, and bleeding are maintained within normal ranges in treated subjects.
  • the treatment does not result in adverse events as defined in Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS Mar. 31, 2003 (http://cstep.cancer.gov), publish date Aug. 9, 2006, which is incorporated by reference herein in its entirety.
  • the methods for treating brain tumors provided herein do not result in adverse events of grade 2 or greater as defined in the Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, supra.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or decrease pathological production of VEGF by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to the pathological production of VEGF observed prior to the administration of a Compound as assessed by methods well known in the art.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or decrease pathological production of VEGF in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to the pathological production of VEGF observed prior to administration of a compound, as assessed by methods well known in the art.
  • the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins, such as IL-6) of a subject as assessed by methods well known in the art, e.g., ELISA.
  • VEGF vascular endothelial growth factor
  • other angiogenic or inflammatory mediators e.g., cytokines or interleukins, such as IL-6
  • the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins, such as IL-6) in a subject in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 99%, 30% to 100%, or any range in between, relative to the respective concentration prior to administration of a Compound, as assessed by methods well known in the art, e.g., ELISA.
  • VEGF angiogenic or inflammatory mediators
  • the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentrations of P1GF, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, IL-6 and/or IL-8 in the blood of a subject as assessed by methods well known in the art, e.g., ELISA.
  • the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentrations of P1GF, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, IL-6 and/or IL-8 in the blood of a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to the respective concentration observed prior to administration of a Compound as assessed by methods well known in the art, e.g., ELISA.
  • the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentrations of P1GF, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, IL-6 and/or IL-8 in the blood of a subject in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to the respective concentration observed prior to administration of a Compound, as assessed by methods well known in the art, e.g., ELISA.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce pathological angiogenesis or vascularization.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce pathological angiogenesis or vascularization, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to angiogenesis or vascularization observed prior to administration of a Compound as assessed by methods well known in the art, e.g., MRI scan, CT scan, PET scan.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce pathological angiogenesis or vascularization, in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to angiogenesis or vascularization observed prior to administration of a Compound, as assessed by methods well known in the art, e.g., MRI scan, CT scan, PET scan.
  • the methods for treating cancer or a neoplastic condition provided herein inhibit or reduce inflammation, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to inflammation observed prior to administration of a Compound, or any percentage in between, as assessed by methods well known in the art, e.g., CT scan, MM scan, or PET scan.
  • the methods for treating cancer or a neoplastic condition provided herein inhibit or reduce inflammation, in the range of about 5% to 15%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 99%, 30% to 100%, or any range in between, relative to inflammation observed prior to administration of a Compound, or any percentage in between, as assessed by methods well known in the art, e.g., CT scan, MRI scan, or PET scan.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce edema such as tumor-related edema, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to the edema observed prior to administration of a Compound, or any percentage in between, as assessed by methods well known in the art, e.g., CT scan, MRI scan, or PET scan.
  • the methods for treating NF provided herein inhibit or reduce edema such as tumor-related, in the range of about 5% to 15%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 99%, 30% to 100%, or any range in between, relative to the edema observed prior to administration of a Compound, or any percentage in between, as assessed by methods well known in the art, e.g., CT scan, Mill scan, or PET scan.
  • the methods for treating cancer or a non-neoplastic condition provided herein prolong or delay the G1/S or late G1/S phase of the cell cycle (i.e., the period between the late resting or pre-DNA synthesis phase, and the early DNA synthesis phase).
  • the methods for treating cancer or a non-neoplastic condition provided herein reduce, ameliorate, or alleviate the severity of the cancer or the non-neoplastic condition and/or one or more symptoms thereof.
  • the methods for treating cancer or a non-neoplastic condition provided herein reduce hospitalization (e.g., the frequency or duration of hospitalization) of a subject diagnosed with the cancer or the non-neoplastic condition.
  • the methods for treating cancer or a non-neoplastic condition provided herein reduce hospitalization length of a subject diagnosed with the cancer or the non-neoplastic condition.
  • the methods provided herein increase the survival of a subject diagnosed with cancer or a non-neoplastic condition.
  • the methods provided herein increase the survival of a subject diagnosed with cancer or a non-neoplastic condition by about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, or about 12 months or more.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce the progression of the cancer or the non-neoplastic condition, or one or more symptoms associated therewith.
  • the methods for treating cancer or a non-neoplastic condition provided herein enhance or improve the therapeutic effect of another therapy (e.g., an anti-cancer agent, radiation, drug therapy, such as chemotherapy, anti-androgen therapy, or surgery).
  • the methods for treating cancer or a non-neoplastic condition provided herein involve the use of a Compound as an adjuvant therapy.
  • the methods for treating cancer provided herein improve the ease in removal of tumors (e.g., enhance resectability of the tumors) by reducing vascularization prior to surgery.
  • the methods for treating cancer provided herein reduce vascularization after surgery, for example, reduce vascularization of the remaining tumor mass not removed by surgery.
  • the methods for treating cancer provided herein prevent recurrence of a tumor or one or more symptoms associated with cancer, e.g., recurrence of vascularization and/or tumor growth.
  • the methods for treating a non-neoplastic condition provided herein prevent the recurrence of the non-neoplastic condition or one or more symptoms thereof.
  • the methods for treating cancer or a non-neoplastic condition provided herein reduce the mortality of subjects diagnosed with the cancer or the non-neoplastic condition.
  • the methods for treating cancer or a non-neoplastic condition provided herein increase the number of patients in remission or decrease the hospitalization rate.
  • the methods for treating cancer or a non-neoplastic condition provided herein prevent the development, onset or progression of one or more symptoms associated with the cancer or a non-neoplastic condition.
  • the methods for treating cancer or a non-neoplastic condition provided herein increase symptom-free survival of cancer patients or the non-neoplastic condition patients.
  • the methods for treating cancer or a non-neoplastic condition provided herein do not cure the cancer or non-neoplastic condition in patients, but prevent the progression or worsening of the disease. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein improve the patient's quality of life.
  • the methods for treating cancer provided herein inhibit, reduce, diminish, arrest, or stabilize a tumor associated with the cancer. In other embodiments, the methods for treating cancer provided herein inhibit, reduce, diminish, arrest, or stabilize the blood flow, metabolism, or edema in a tumor associated with the cancer or one or more symptoms thereof. In specific embodiments, the methods for treating cancer provided herein cause the regression of a tumor, tumor blood flow, tumor metabolism, or peritumor edema, and/or one or more symptoms associated with the cancer.
  • the methods for treating cancer provided herein maintain the size of the tumor so that it does not increase, or so that it increases by less than the increase of a tumor after administration of a standard therapy as measured by conventional methods available to one of skill in the art, such as digital rectal exam, ultrasound (e.g., transrectal ultrasound), CT Scan, MRI, dynamic contrast-enhanced MM, or PET Scan.
  • the methods for treating cancer provided herein decrease tumor size.
  • the methods for treating cancer provided herein reduce the formation of a tumor.
  • the methods for treating cancer provided herein eradicate, remove, or control primary, regional and/or metastatic tumors associated with the cancer.
  • the methods for treating cancer provided herein decrease the number or size of metastases associated with the cancer.
  • the methods for treating cancer provided herein reduce the tumor size (e.g., volume or diameter) in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to tumor size (e.g., volume or diameter) prior to administration of a Compound as assessed by methods well known in the art, e.g., CT Scan, MRI, DCE-MRI, or PET Scan.
  • the methods for treating cancer provided herein reduce the tumor volume or tumor size (e.g., diameter) in a subject by an amount in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to tumor size (e.g., diameter) in a subject prior to administration of a Compound as assessed by methods well known in the art, e.g., CT Scan, MM, DCE-MM, or PET Scan.
  • a Compound as assessed by methods well known in the art, e.g., CT Scan, MM, DCE-MM, or PET Scan.
  • the methods for treating cancer provided herein reduce the tumor perfusion in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to tumor perfusion prior to administration of a Compound as assessed by methods well known in the art, e.g., MRI, DCE-MRI, or PET Scan.
  • the methods for treating cancer provided herein reduce the tumor perfusion in a subject by an amount in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to tumor perfusion prior to administration of a Compound, as assessed by methods well known in the art, e.g., MRI, DCE-MRI, or PET Scan.
  • the methods for treating cancer provided herein inhibit or decrease tumor metabolism in a subject as assessed by methods well known in the art, e.g., PET scanning.
  • the methods for treating cancer provided herein inhibit or decrease tumor metabolism in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to tumor metabolism prior to administration of a Compound, as assessed by methods well known in the art, e.g., PET scanning.
  • the methods for treating cancer provided herein inhibit or decrease tumor metabolism in a subject in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to tumor metabolism prior to administration of a Compound, as assessed by methods well known in the art, e.g., PET scan.
  • the methods for treating cancer provided herein decrease the number of circulating tumor cells (CTCs) in the blood of the subject as assessed by methods known in the art, such as CellSearch immunomagnetic-capture (see, e.g., Danila D C, Heller G, Gignac G A, Gonzalez-Espinoza R, Anand A, Tanaka E, Lilja H, Schwartz L, Larson S, Fleisher M, Scher H I. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007 Dec.
  • the methods for treating cancer provided herein decrease the number of CTCs in the blood of a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to the number of CTCs observed prior to administration of a Compound, as assessed by methods well known in the art.
  • the methods for treating cancer provided herein decrease the number of CTCs in the blood of a subject in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to the number of CTCs in the blood observed prior to the administration of a Compound, as assessed by methods well known in the art, such as CellSearch immunomagnetic-capture.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce inflammation, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, or any percentage in between, relative to inflammation observed prior to administration of a Compound as assessed by methods well known in the art.
  • the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce inflammation, in the range of about 5% to 15%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 99%, 30% to 100%, or any range in between, relative to inflammation observed prior to administration of a Compound, as assessed by methods well known in the art.
  • the methods for treating cancer provided herein increase the cancer-free survival rate of patients diagnosed with the cancer. In some embodiments, the methods for treating cancer provided herein increase relapse-free survival. In certain embodiments, the methods for treating cancer provided herein increase the number of patients in remission. In other embodiments, the methods for treating cancer provided herein increase the length of remission in patients.
  • the methods for treating cancer or a non-neoplastic condition provided herein minimize the severity and/or frequency of one or more side effects observed with current anti-angiogenesis therapies. In certain embodiments, the methods for treating cancer or a non-neoplastic condition provided herein do not cause one or more side effects observed with current anti-angiogenesis therapies.
  • Such side effects include, but are not limited to, bleeding, arterial and venous thrombosis, hypertension, delayed wound healing, proteinuria, nasal septal perforation, reversible posterior leukoencephalopathy syndrome in association with hypertension, light-headedness, ataxia, headache, hoarseness, nausea, vomiting, diarrhea, rash, subungual hemorrhage, myelosuppression, fatigue, hypothyroidism, QT interval prolongation, and heart failure.
  • the treatment of cancer comprises the administration of a Compound described herein or a compound described in U.S. Publication Nos. 2005-0272759 (having corresponding International Application Publication No. WO2005/089764), U.S. Publication No. 2005-0282849 (having corresponding International Application Publication No. WO2006/113703), or U.S. Publication No. 2007-0254878 (having corresponding International Application Publication No. WO2008/127715), or U.S. Provisional Application Ser. No. 60/181,649, filed May 27, 2009 entitled “Methods for Treating Prostate Cancer;” or U.S. Provisional Application Ser. No.
  • the concentration of viral RNA or DNA or viral protein in a biological specimen may be used to monitor the efficacy of a course of treatment for viral infection involving the administration of a compound that inhibits or reduces viral replication or the production of viral RNA or DNA or viral protein, such as a Compound described herein or a compound described in U.S. Publication No. 2005-0272759 (having corresponding International Application Publication No. WO2005/089764), U.S. Publication No. 2005-0282849 (having corresponding International Application Publication No. WO2006/113703), U.S. Publication No. 2007-0254878 (having corresponding International Application Publication No.
  • WO2008/127715 or International Application Publication No. WO2008/127714, each of which is incorporated herein by reference in its entirety.
  • the dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient may also be modified as a result of the concentration of viral RNA or DNA or viral protein.
  • the changes in the concentration of viral RNA or DNA or viral protein might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the viral infection.
  • the concentration of viral RNA or DNA or viral protein in biological specimens (e.g., plasma, serum, urine, or any other biofluids or tissues) of a patient is monitored before, during and/or after a course of treatment for viral infection involving the administration of a Compound or a pharmaceutical composition thereof to the patient.
  • the viral titer in a patient is monitored before, during and/or after a course of treatment for viral infection involving the administration of a Compound or a pharmaceutical composition thereof.
  • the dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient might be modified as a result of the concentration of viral RNA or DNA or viral protein as assessed by standard techniques.
  • the changes in the concentration of viral RNA or DNA or viral protein might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the viral infection.
  • a method for treating a viral infection comprising: (a) administering to a patient in need thereof one or more doses of a Compound or a pharmaceutical composition thereof; and (b) monitoring the concentration of viral RNA or DNA or viral protein (e.g., detected in biological specimens such as plasma, serum, urine, or any other biofluids or tissues) before and/or after step (a).
  • step (b) comprises monitoring the patient's viral titer.
  • the monitoring step (b) is carried out before and/or after a certain number of doses (e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, 30 or more doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 or more doses) or a certain time period (e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks) of administering the Compound.
  • a certain number of doses e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, 30 or more doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 or more doses
  • a certain time period e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks
  • one or more of these monitoring parameters are detected prior to administration of the Compound or pharmaceutical composition thereof.
  • a change in the concentration of viral RNA or DNA or viral protein following administration of the Compound or pharmaceutical composition thereof may indicate that the dosage, frequency and/or length of administration of the Compound or a pharmaceutical composition thereof may be adjusted (e.g., increased, reduced or maintained).
  • the concentration of viral RNA or DNA or viral protein in a patient may be detected by any technique known to one of skill in the art.
  • the method for detecting the concentration of viral RNA or DNA or viral protein in a patient involves obtaining a biological sample (e.g., tissue or fluid sample) from the patient and detecting the concentration of viral RNA or DNA or viral protein in the biological sample (e.g., from plasma, serum, urine, or any other biofluids or tissues), that has been subjected to certain types of treatment (e.g., centrifugation), and detection by use of standard molecular techniques known to a person of ordinary skill in the art, such as by polymerase chain reaction (PCR) or ELISA.
  • PCR polymerase chain reaction
  • an ELISA described herein e.g., in the working examples in Section 8.1.1. et seq. may be used to detect the concentration of viral protein.
  • PCR may be used to detect the concentration of viral RNA or DNA in a biological sample (e.g., from plasma, serum, urine, or any other biofluids or tissues) that has been subjected to certain types of treatment (e.g., centrifugation).
  • a biological sample e.g., from plasma, serum, urine, or any other biofluids or tissues
  • Other techniques known in the art that may be used to detect the concentration of viral RNA or DNA in a biological sample, including nucleic acid hybridization or a combination of PCR and nucleic acid hybridization assays.
  • the methods for treating a viral infection provided herein alleviate or manage one, two or more symptoms associated with the viral infection. Alleviating or managing one, two or more symptoms of viral infection may be used as a clinical endpoint for efficacy of a Compound for treating the viral infection.
  • the methods for treating a viral infection provided herein reduce the duration and/or severity of one or more symptoms associated with the viral infection. In some embodiments, the methods for treating viral infection provided herein inhibit the onset, progression and/or recurrence of one or more symptoms associated with the viral infection. In some embodiments, the methods for treating the viral infection provided herein reduce the number of symptoms associated with the viral infection.
  • the methods for treating a viral infection provided herein inhibit or reduce viral replication or the production of viral RNA or DNA or viral protein.
  • the methods for treating the viral infection provided herein selectively inhibit the production of viral RNA or DNA or viral protein.
  • the treatment does not result in an adverse event as defined in according to government safety standards or regulations.
  • the methods for treating a viral infection inhibit or decrease viral replication or the production of viral RNA or DNA or viral protein by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to viral replication or the production of viral RNA or DNA or viral protein observed prior to the administration of a Compound as assessed by methods well known in the art, e.g., PCR or ELISA.
  • the methods for treating the viral infection provided herein inhibit or decrease viral replication or the production of viral RNA or DNA or viral protein in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to viral replication or the production of viral RNA or DNA or viral protein observed prior to administration of a compound, as assessed by methods well known in the art, e.g., PCR or ELISA.
  • the methods for treating a viral infection provided herein reduce, ameliorate, or alleviate the severity of the viral infection and/or one or more symptoms thereof.
  • the methods for treating viral infection provided herein reduce hospitalization (e.g., the frequency or duration of hospitalization) of a subject diagnosed with the viral infection.
  • the methods for treating a viral infection provided herein reduce hospitalization length of a subject diagnosed with the viral infection.
  • the methods provided herein increase the survival of a subject diagnosed with the viral infection.
  • the methods provided herein increase the survival of a subject diagnosed with a viral infection by about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, or about 12 months or more.
  • the methods for treating a viral infection provided herein inhibit or reduce the progression of the viral infection, or one or more symptoms associated therewith.
  • the methods for treating viral infection provided herein enhance or improve the therapeutic effect of another therapy (e.g., an antiviral agent, drug therapy, such as interferon, or transplant surgery).
  • the methods for treating viral infection provided herein involve the use of a Compound as an adjuvant therapy.
  • the methods for treating viral infection provided herein prevent recurrence of the viral infection or one or more symptoms associated with the viral infection.
  • the methods for treating viral infection provided herein reduce the mortality of subjects diagnosed with the viral infection.
  • the methods for treating a viral infection provided herein increase the number of patients in remission or decrease the hospitalization rate.
  • the methods for treating viral infection provided herein prevent the development, onset or progression of one or more symptoms associated with the viral infection.
  • the methods for treating the viral infection provided herein increase symptom-free survival of the infected patients.
  • the methods for treating the viral infection provided herein do not cure the viral infection in patients, but prevent the progression or worsening of the disease.
  • the methods for treating viral infection provided herein improve the patient's quality of life.
  • the methods for treating viral infection provided herein inhibit, reduce, diminish, arrest, or stabilize the production of viral RNA or DNA or viral protein associated with the virus.
  • the methods for treating viral infection provided herein reduce viral RNA or DNA or viral protein production in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to viral RNA or DNA or viral protein production prior to administration of a Compound as assessed by methods well known in the art, e.g., PCR or ELISA.
  • the methods for treating viral infection reduce the viral titer in a subject by an amount in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to the viral titer in a subject prior to administration of a Compound as assessed by methods well known in the art, e.g., PCR or ELISA.
  • the methods for treating viral infection provided herein decrease the number of circulating viral proteins (CVPs) in the blood of the subject as assessed by methods known in the art.
  • the methods for treating viral infection provided herein decrease the number of CVPs in the blood of a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to the number of CVPs observed prior to administration of a Compound, as assessed by methods well known in the art.
  • the methods for treating viral infection provided herein increase the viral-free survival rate of patients diagnosed with the viral infection. In some embodiments, the methods for treating viral infection provided herein increase relapse-free survival. In certain embodiments, the methods for treating viral infection provided herein increase the number of patients in remission. In other embodiments, the methods for treating viral infection provided herein increase the length of remission in patients.
  • the methods for treating viral infection provided herein minimize the severity and/or frequency of one or more side effects observed with current antiviral therapies. In certain embodiments, the methods for treating viral infection provided herein do not cause one or more side effects observed with current antiviral therapies.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human who has or is diagnosed with cancer or a non-neoplastic condition or a viral infection.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human predisposed or susceptible to cancer or a non-neoplastic condition or a viral infection.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human at risk of developing cancer or a non-neoplastic condition or a viral infection.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human infant.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human toddler.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human child.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human adult.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a middle-aged human.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is an elderly human.
  • a subject treated for cancer in accordance with the methods provided herein has a cancer that metastasized to other areas of the body, such as the bones, lung and liver. In certain embodiments, a subject treated for cancer in accordance with the methods provided herein is in remission from the cancer. In some embodiments, a subject treated for cancer in accordance with the methods provided herein that has a recurrence of the cancer. In certain embodiments, a subject treated in accordance with the methods provided herein is experiencing recurrence of one or more tumors associated with cancer.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that is about 1 to about 5 years old, about 5 to 10 years old, about 10 to about 18 years old, about 18 to about 30 years old, about 25 to about 35 years old, about 35 to about 45 years old, about 40 to about 55 years old, about 50 to about 65 years old, about 60 to about 75 years old, about 70 to about 85 years old, about 80 to about 90 years old, about 90 to about 95 years old or about 95 to about 100 years old, or any age in between.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that is 18 years old or older.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human child that is between the age of 1 year old to 18 years old.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that is between the age of 12 years old and 18 years old.
  • the subject is a male human.
  • the subject is a female human.
  • the subject is a female human that is not pregnant or is not breastfeeding.
  • the subject is a female that is pregnant or will/might become pregnant, or is breast feeding.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that is in an immunocompromised state or immunosuppressed state.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human receiving or recovering from immunosuppressive therapy.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has or is at risk of getting cancer (e.g., metastatic cancer), AIDS, or a bacterial infection.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human who is, will or has undergone surgery, drug therapy, such as chemotherapy, hormonal therapy and/or radiation therapy.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is suffering from a condition, e.g., stroke or cardiovascular conditions that may require VEGF therapy, wherein the administration of anti-angiogenic therapies other than a Compound may be contraindicated.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has suffered from a stroke or is suffering from a cardiovascular condition.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is a human experiencing circulatory problems.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is a human with diabetic polyneuropathy or diabetic neuropathy.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is a human receiving VEGF protein therapy.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is not a human receiving VEGF protein therapy.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is administered a Compound or a pharmaceutical composition thereof, or a combination therapy before any adverse effects or intolerance to therapies other than the Compound develops.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a refractory patient.
  • a refractory patient is a patient refractory to a standard therapy (e.g., surgery, radiation, anti-androgen therapy and/or drug therapy such as chemotherapy or antiviral therapy).
  • a patient with cancer or a non-neoplastic condition or a viral infection is refractory to a therapy when the cancer or the non-neoplastic condition or the viral infection has not significantly been eradicated and/or the one or more symptoms have not been significantly alleviated.
  • the determination of whether a patient is refractory can be made either in vivo or in vitro by any method known in the art for assaying the effectiveness of a treatment of cancer or a non-neoplastic condition or a viral infection, using art-accepted meanings of “refractory” in such a context.
  • a patient with cancer is refractory when one or more tumors associated with cancer, have not decreased or have increased.
  • a patient with cancer is refractory when one or more tumors metastasize and/or spread to another organ.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has proven refractory to therapies other than treatment with a Compound, but is no longer on these therapies.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human already receiving one or more conventional anti-cancer therapies, such as surgery, drug therapy such as chemotherapy, antiviral therapy, anti-androgen therapy or radiation.
  • conventional anti-cancer therapies such as surgery, drug therapy such as chemotherapy, antiviral therapy, anti-androgen therapy or radiation.
  • these patients are refractory patients, patients who are too young for conventional therapies, and patients with recurring tumors or viral infection despite treatment with existing therapies.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human susceptible to adverse reactions to conventional therapies.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has not received a therapy, e.g., drug therapy such as chemotherapy, surgery, antiviral therapy, anti-androgen therapy or radiation therapy, prior to the administration of a Compound or a pharmaceutical composition thereof.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has received a therapy prior to administration of a Compound.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has experienced adverse side effects to the prior therapy or the prior therapy was discontinued due to unacceptable levels of toxicity to the human.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has had no prior exposure to another anti-angiogenic therapy (e.g., an anti-VEGF monoclonal antibody, an anti-VEGFR monoclonal antibody, a tyrosine kinase inhibitor, or other angiogenesis pathway modulator).
  • another anti-angiogenic therapy e.g., an anti-VEGF monoclonal antibody, an anti-VEGFR monoclonal antibody, a tyrosine kinase inhibitor, or other angiogenesis pathway modulator.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein does not have uncontrolled hypertension, major bleeding, HIV infection or recent acute cardiovascular event.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident, transient ischemic attack, an arterial thromboembolic event, or pulmonary embolism.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is not, has not and/or will not receive a drug that is primarily metabolized by CYP2D6.
  • a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein has not and will not received a drug that is primarily metabolized by CYP2D6 1, 2, 3 or 4 weeks before receiving a Compound or a pharmaceutical composition thereof and 1, 2, 3 or 4 weeks after receiving the Compound or pharmaceutical composition.
  • drugs include, without limitation, some antidepressants (e.g., tricyclic antidepressants and selective serotonin uptake inhibitors), some antipsychotics, some beta-adrenergic receptor blockers, certain antiviral agents and certain anti-arrhythmics.
  • some antidepressants e.g., tricyclic antidepressants and selective serotonin uptake inhibitors
  • some antipsychotics e.g., tricyclic antidepressants and selective serotonin uptake inhibitors
  • beta-adrenergic receptor blockers e.g., beta-adrenergic receptor blockers
  • certain antiviral agents e.g., certain anti-arrhythmics.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is not, has not and/or will not receive tamoxifen.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has not and will not received tamoxifen 1, 2, 3 or 4 weeks before receiving a Compound or a pharmaceutical composition thereof and 1, 2, 3 or 4 weeks after receiving the Compound or pharmaceutical composition.
  • a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has received tamoxifen, e.g., for 1, 2, 3 or 4 weeks before receiving a Compound or a pharmaceutical composition thereof.
  • a Compound or a pharmaceutical composition thereof can be administered to a subject in need thereof by a variety of routes in amounts which result in a beneficial or therapeutic effect.
  • a Compound or pharmaceutical composition thereof may be orally administered to a subject in need thereof in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein.
  • the oral administration of a Compound or a pharmaceutical composition thereof may facilitate subjects in need of such treatment complying with a regimen for taking the Compound or pharmaceutical composition.
  • a Compound or pharmaceutical composition thereof is administered orally to a subj ect in need thereof.
  • a Compound provided herein can be administered orally, with or without food or water.
  • routes of administration include, but are not limited to, intravenous, intradermal, intrathecal, intramuscular, subcutaneous, intranasal, inhalation, transdermal, topical, transmucosal, intracranial, intratumoral, epidural and intra-synovial.
  • a Compound or a pharmaceutical composition thereof is administered systemically (e.g., parenterally) to a subject in need thereof.
  • a Compound or a pharmaceutical composition thereof is administered locally (e.g., intratumorally) to a subject in need thereof.
  • a Compound or a pharmaceutical composition thereof is administered via a route that permits the Compound to cross the blood-brain barrier (e.g., orally).
  • Table 6 provides brain tissue plasma concentration ratios determined by whole-body autoradiography at specified times after a single oral administration of 14 C-Compound #10 to rats (50 mg/kg).
  • the Compound and one or more additional therapies may be administered by the same route or a different route of administration.
  • the dosage and frequency of administration of a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein will be efficacious while minimizing any side effects.
  • the exact dosage and frequency of administration of a Compound or a pharmaceutical composition thereof can be determined by a practitioner, in light of factors related to the subject that requires treatment. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
  • the dosage and frequency of administration of a Compound or a pharmaceutical composition thereof may be adjusted over time to provide sufficient levels of the Compound or to maintain the desired effect.
  • a Compound or pharmaceutical composition thereof is administered to a subject in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein once a day, twice a day, three times a day, or four times a day.
  • a Compound or pharmaceutical composition thereof is administered to a subject in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein once, twice, three times, or four times every other day (i.e., on alternate days), once, twice, three times, or four times every two days, once every three days, once, twice, three times, or four times every four days, once, twice, three times, or four times every 5 days, once, twice, three times, or four times a week, once, twice, three times, or four times every two weeks, once, twice, three times, or four times every three weeks, once, twice, three times, or four times every four weeks, once, twice, three times, or four times every 5 weeks, once, twice, three times, or four times every 6 weeks, once, twice, three times, or four times every 7 weeks, or once, twice, three times, or four times every 8 weeks.
  • a Compound or pharmaceutical composition thereof is administered to a subject in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein in cycles, wherein the Compound or pharmaceutical composition is administered for a period of time, followed by a period of rest (i.e., the Compound or pharmaceutical composition is not administered for a period of time).
  • a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating cancer provided herein at a dosage and a frequency of administration that achieves one or more of the following: (i) decreases the production and/or concentration of VEGF or other angiogenic or inflammatory mediators or a change in tumor blood flow or metabolism, or peritumoral inflammation or edema of a subject with cancer or a non-neoplastic condition or an animal model with a pre-established human tumor; (ii) decreases the concentration of one, two, three or more, or all of the following of a subject with cancer or an animal model with a pre-established human tumor: VEGF-C, VEGF-D, P1GF, VEGFR-1, VEGFR-2, IL-6 and/or IL-8; (iii) reduces or ameliorates the severity of the cancer and/or one or more symptoms associated therewith in a subject with the cancer; (iv) reduces the number symptoms and/or
  • a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating cancer provided herein at a dosage and a frequency of administration that results in one or more of the following: (i) a decrease in the number of circulating tumor cells (CTCs) in the blood of a subject with cancer or an animal model with a pre-established human tumor; (iii) survival of patients with cancer for about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, or about 12 months or more; (iv) regression of a tumor associated with cancer and/or inhibition of the progression of a tumor associated with the cancer in a subject with cancer or an animal model with a pre-established human tumor; (v) reduction in the growth of a tumor or neoplasm associated with the cancer and/or decrease in the tumor size (e.g., volume or diameter) of tumors associated with the cancer in a subject with cancer or an animal model with a pre-established human tumor; (vi) the size
  • a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating a non-neoplastic condition provided herein at a dosage and a frequency of administration that achieves one or more of the following: (i) decreases the production or concentration of VEGF or other angiogenic or inflammatory mediators; (ii) decreases the concentration of one, two, three or more, or all of the following of a subject with a non-neoplastic condition or an animal model: VEGF-C, VEGF-D, P1GF, VEGFR-1, VEGFR-2, IL-6 and/or IL-8; (iii) reduces or ameliorates the severity of the non-neoplastic condition and/or one or more symptoms associated therewith in a subject with the non-neoplastic condition; (iv) reduces the number symptoms and/or the duration of one or more symptoms associated with the non-neoplastic condition in a subject with the non-neoplastic condition; (i) decreases
  • a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating a viral infection provided herein at a dosage and a frequency of administration that achieves one or more of the following: (i) decreases the production or concentration of viral RNA or DNA or viral protein; (ii) decreases the viral titer of a subject or an animal model with a viral infection; (iii) reduces or ameliorates the severity of the viral infection and/or one or more symptoms associated therewith in a subject with the viral infection; (iv) reduces the number symptoms and/or the duration of one or more symptoms associated with the viral infection in a subject with the viral infection; (v) prevents the onset, progression or recurrence of one or more symptoms associated with the viral infection in a subject with the viral infection; (vi) inhibits or reduces viral replication or the production or concentration of viral RNA or DNA or viral protein associated with the viral infection in a subject or an animal model; and/or (vii) enhances or improve
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a unit dosage of a Compound or a pharmaceutical composition thereof.
  • the dosage may be administered as often as determined effective (e.g., once, twice or three times per day, every other day, once or twice per week, biweekly or monthly).
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof that ranges from about 0.001 milligram (mg) to about 1500 mg, from about 0.001 mg per kg to about 1400 mg per kg, from about 0.001 mg per kg to about 1300 mg per kg, from about 0.001 mg per kg to about 1200 mg per kg, from about 0.001 mg per kg to about 1100 mg per kg, from about 0.001 mg per kg to about 1000 mg per kg, from about 0.01 mg to about 1500 mg, from about 0.01 mg per kg to about 1000 mg per kg, from about 0.1 mg per kg to about 1500 mg per kg, from about 0.1 mg per kg to about 1000 mg per kg, from about 0.1 mg per kg to about 500 mg per kg, from about 0.05 mg to about 1000 mg, from about 0.1 mg per kg to about 100 mg per kg, from about 1 mg per kg to about 100 mg per kg, from about
  • oral doses for use in the methods provided herein are from about 0.01 mg to about 300 mg per kg body weight, from about 0.1 mg to about 75 mg per kg body weight, or from about 0.5 mg to 5 mg per kg body weight.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of about 15 mg, 16, mg, 17 mg, 18 mg, 19 mg, 20 mg, 21, mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg or 40 mg.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of at least about 0.1 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg or more.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of less than about 35 mg, less than about 40 mg, less than about 45 mg, less than about 50 mg, less than about 60 mg, less than about 70 mg, or less than about 80 mg.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of from about 20 mg to about 500 mg, from about 40 mg to about 500 mg, from about 40 mg to about 200 mg, from about 40 mg to about 150 mg, from about 75 mg to about 500 mg, from about 75 mg to about 450 mg, from about 75 mg to about 400 mg, from about 75 mg to about 350 mg, from about 75 mg to about 300 mg, from about 75 mg to about 250 mg, from about 75 mg to about 200 mg, from about 100 mg to about 200 mg, or any range in between.
  • a Compound or a pharmaceutical composition thereof of from about 20 mg to about 500 mg, from about 40 mg to about 500 mg, from about 40 mg to about 200 mg, from about 40 mg to about 150 mg, from about 75 mg to about 500 mg, from about 75 mg to about 450 mg, from about 75 mg to about 400 mg, from about 75 mg to about 350 mg, from about
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of about 20 mg, 35 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg or 300 mg.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of about 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg.
  • a unit dose of a Compound or a pharmaceutical composition thereof is administered to a subject once per day, twice per day, three times per day; once, twice or three times every other day (i.e., on alternate days); once, twice or three times every two days; once, twice or three times every three days; once, twice or three times every four days; once, twice or three times every five days; once, twice, or three times once a week, biweekly or monthly, and the dosage may be administered orally.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof ranges from about 0.001 mg per kg to about 1500 mg per kg per day, from about 0.001 mg per kg to about 1400 mg per kg per day, from about 0.001 mg per kg to about 1300 mg per kg per day, from about 0.001 mg per kg to about 1200 mg per kg per day, from about 0.001 mg per kg to about 1100 mg per kg per day, from about 0.001 mg per kg to about 1000 mg per kg per day, 0.001 mg/kg to about 500 mg/kg, from about 0.01 mg per kg to about 1500 mg per kg per day, from about 0.01 mg per kg to about 1000 mg per kg per day, from about 0.1 mg per kg to about 1500 mg per kg per day, from about 0.1 mg per kg to about 1000 mg per kg per day, from about 0.1 mg per kg to about 500 mg per kg per
  • a unit dose of a Compound or a pharmaceutical composition thereof ranges from about 0.01 mg to about 300 mg per kg body weight per day, from about 0.1 mg to about 75 mg per kg body weight per day, or from about 0.5 mg to 5 mg per kg body weight per day. In another specific embodiment, a unit dose of a Compound or a pharmaceutical composition thereof ranges from about 20 mg to about 1000 mg per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof that ranges from about 80 mg to about 800 mg per day, from about 100 mg to about 800 mg per day, from about 80 mg to about 600 mg per day, from about 80 mg to about 400 mg per day, from about 80 mg to about 200 mg per day, from about 200 mg to about 300 mg per day, from about 200 mg to about 400 mg per day, from about 200 mg to about 800 mg per day, or any range in between.
  • a unit dose of a Compound that may be used in the methods provided herein include doses of about 0.1 mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.6 mg/kg/day, 0.7 mg/kg/day, 0.8 mg/kg/day, 0.9 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day, 2 mg/kg/day, 2.5 mg/kg/day, 2.75 mg/kg/day, 3 mg/kg/day, 4 mg/kg/day, 5 mg/kg/day, 6 mg/kg/day, 6.5 mg/kg/day, 6.75 mg/kg/day, 7 mg/kg/day, 7.5 mg/kg/day, 8 mg/kg/day, 8.5 mg/kg/day, 9 mg/kg/day, 10 mg/kg/day, 11 mg/kg/day, 12 mg/kg/day, 13 mg/kg/day, 14 mg/kg/day or 15 mg
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration of a unit dose of about 20 mg of a Compound or a pharmaceutical composition thereof once, twice or three times per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of about 40 mg of a Compound or a pharmaceutical composition thereof once, twice or three times per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration of a unit dose of about 60 mg of a compound or a pharmaceutical composition thereof once, twice or three times per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of about 80 mg of a Compound or a pharmaceutical composition thereof once, twice or three times per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of from about 100 mg to about 250 mg, from about 150 mg to about 250 mg, from about 175 mg to about 250 mg, from about 200 mg to about 250 mg, or from about 200 mg to about 225 mg of a Compound or a pharmaceutical composition thereof once, twice or three times per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a dosage of a Compound or a pharmaceutical composition thereof that is expressed as mg per meter squared (mg/m 2 ).
  • the mg/m 2 for a Compound may be determined, for example, by multiplying a conversion factor for an animal by an animal dose in mg per kilogram (mg/kg) to obtain the dose in mg/m 2 for human dose equivalent.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of an amount of a Compound or a pharmaceutical composition thereof in the range of from about 0.1 mg/m 2 to about 1000 mg/m 2 , or any range in between.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof that ranges from about from about 0.001 mg/kg to about 1500 mg/kg per day, from about 0.001 mg/kg to about 1400 mg/kg per day, from about 0.001 mg/kg to about 1300 mg/kg per day, from about 0.001 mg/kg to about 1200 mg/kg per day, from about 0.001 mg/kg to about 1100 mg/kg per day, from about 0.001 mg/kg to about 1000 mg/kg per day, 0.001 mg/kg to about 500 mg/kg, from about 0.01 mg/kg to about 1500 mg/kg per day, from about 0.01
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof that ranges from about 0.001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 50 mg/kg, from about 0.001 mg/kg to about 25 mg/kg, from about 0.001 mg/kg to about 10 mg/kg, from about 0.001 mg/kg to about 5 mg/kg; from about 0.001 mg/kg to about 1 mg/kg; or from about 0.001 mg/kg to about 0.01 mg/kg.
  • a dosage of a Compound or a pharmaceutical composition thereof that may be used in the methods provided herein include doses of about 0.1 mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.6 mg/kg/day, 0.7 mg/kg/day, 0.8 mg/kg/day, 0.9 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day, 2 mg/kg/day, 2.5 mg/kg/day, 2.75 mg/kg/day, 3 mg/kg/day, 4 mg/kg/day, 5 mg/kg/day, 6 mg/kg/day, 6.5 mg/kg/day, 6.75 mg/kg/day, 7 mg/kg/day, 7.5 mg/kg/day, 8 mg/kg/day, 8.5 mg/kg/day, 9 mg/kg/day, 10 mg/kg/day, 11 mg/kg/day, 12 mg/kg/day, 13 mg/kg/day, 14 mg/kg/day,
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof that ranges from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.01 mg/kg to about 5 mg/kg, from about 0.01 mg to about 1 mg/kg, or from about 0.01 mg/kg to about 0.1 mg/kg.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof that ranges from about 0.1 mg/kg to about 100 mg/kg, from about 0.1 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 25 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 5 mg/kg, from about 0.1 mg/kg to about 4 mg/kg; from about 0.1 mg/kg to about 3 mg/kg; from about 0.1 mg/kg to about 2 mg/kg; from about 0.1 mg to about 1.5 mg/kg, from about 0.1 mg to about 1.2 mg/kg, from about 0.1 mg to about 1 mg/kg, or from about 0.5 mg/kg to about 1.5 mg/kg.
  • the dosage may be administered once, twice or three times per day, every other day, or once or twice per week and the
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof of from about 0.1 mg/kg to about 5 mg/kg, from about 0.1 mg/kg to about 4 mg/kg, from about 0.1 mg/kg to about 3 mg/kg, from about 0.1 mg/kg to about 2 mg/kg, from about 0.5 mg/kg to about 2 mg/kg, or from about 1 mg/kg to about 1.5 mg/kg is administered once, twice or three times per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof of about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg or about 1 mg/kg once, twice or three times per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof of about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, 1.9 mg/kg or about 2 mg/kg once, twice or three times per day.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a target plasma concentration of the Compound in a subject with the cancer or the non-neoplastic condition or a viral infection or an animal model (e.g., an animal model with a pre-established human tumor or a viral infection).
  • an animal model e.g., an animal model with a pre-established human tumor or a viral infection.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a plasma concentration of the Compound ranging from approximately 0.001 ⁇ g/mL to approximately 100 mg/mL, approximately 0.01 ⁇ g/mL to approximately 100 mg/mL, approximately 0.01 ⁇ g/mL to approximately 10 mg/mL, approximately 0.1 ⁇ g/mL to approximately 10 mg/mL, approximately 0.1 ⁇ g/mL to approximately 500 ⁇ g/mL, approximately 0.1 ⁇ g/mL to approximately 200 ⁇ g/mL, approximately 0.1 ⁇ g/mL to approximately 100 ⁇ g/mL, or approximately 0.1 ⁇ g/mL to approximately 75 ⁇ g/mL in a subject with the cancer or the non-neoplastic condition or the viral infection or an animal model (e.g., an animal model with a pre-established human tumor
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a plasma concentration of the Compound ranging from approximately 0.1 to approximately 50 ⁇ g/mL, approximately 0.1 ⁇ g/mL to approximately 25 ⁇ g/mL, approximately 0.1 ⁇ g/mL to approximately 20 ⁇ g/mL or approximately 5 ⁇ g/mL to approximately 10 ⁇ g/mL in a subject with the cancer or the non-neoplastic condition or the viral infection or an animal model (e.g., an animal model with a pre-established human tumor or viral infection).
  • an animal model e.g., an animal model with a pre-established human tumor or viral infection.
  • a Compound or a pharmaceutical composition thereof may be administered at doses that vary from 0.001 ⁇ g to 100,000 mg, depending upon the route of administration.
  • subsequent doses of a Compound may be adjusted accordingly based on the plasma concentrations of the Compound achieved with initial doses of the Compound or pharmaceutical composition thereof administered to the subject.
  • a method for treating cancer or a non-neoplastic condition presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a target plasma concentration of VEGF-A, P1GF, VEGF-C, VEGF-D, IL-6, IL-8, VEGFR1 and/or VEGFR2 in a subject with the cancer or the non-neoplastic condition or an animal model (e.g., an animal model with a pre-established human tumor).
  • an animal model e.g., an animal model with a pre-established human tumor.
  • a method for treating cancer or a non-neoplastic condition presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a plasma concentration of VEGF-A, P1GF, VEGF-C, VEGF-D, IL-6, IL-8, VEGFR1 and/or VEGFR2 ranging from approximately 0.1 pg/mL to approximately 100 mg/mL, approximately 0.1 pg/mL to approximately 1 mg/mL, approximately 0.1 pg/mL to approximately 500 ⁇ g/mL, approximately 0.1 pg/mL to approximately 500 ⁇ g/mL, approximately 0.1 pg/mL to approximately 100 ⁇ g/mL, or approximately 4 pg/mL to approximately 10 ⁇ g/mL in a subject with cancer or a non-neoplastic condition or an animal model (e.g., an animal model with a pre-established human tumor).
  • an animal model e.g.,
  • a Compound or a pharmaceutical composition thereof may be administered at doses that vary from 0.1 pg to 100,000 mg, depending upon the route of administration.
  • subsequent doses of a Compound or a pharmaceutical composition thereof may be adjusted accordingly based on the plasma concentrations of VEGF-A, P1GF, VEGF-C, VEGF-D, IL-6, IL-8, VEGFR1 or VEGFR2 achieved with initial doses of the Compound or pharmaceutical composition thereof administered to the subject.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves the desired tissue to plasma concentration ratios of the Compound as determined, e.g., by any imaging techniques known in the art such as whole-body autoradiography, in a subject with the cancer or the non-neoplastic condition or the viral infection or an animal model (such as an animal model with a pre-established human tumor or a viral infection).
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of one or more doses of an effective amount of a Compound or a pharmaceutical composition, wherein the effective amount may or may not be the same for each dose.
  • a first dose of a Compound or pharmaceutical composition thereof is administered to a subject in need thereof for a first period of time, and subsequently, a second dose of a Compound is administered to the subject for a second period of time.
  • the first dose may be more than the second dose, or the first dose may be less than the second dose.
  • a third dose of a Compound also may be administered to a subject in need thereof for a third period of time.
  • the dosage amounts described herein refer to total amounts administered; that is, if more than one Compound is administered, then, in some embodiments, the dosages correspond to the total amount administered.
  • oral compositions contain about 5% to about 95% of a Compound by weight.
  • the length of time that a subject in need thereof is administered a Compound or a pharmaceutical composition in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein will be the time period that is determined to be efficacious.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for a period of time until the severity and/or number of one or more symptoms associated with the cancer or the non-neoplastic condition or the viral infection decrease.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for up to 48 weeks.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for up to 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 26 weeks (0.5 year), 52 weeks (1 year), 78 weeks (1.5 years), 104 weeks (2 years), or 130 weeks (2.5 years) or more.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for an indefinite period of time.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for a period of time followed by a period of rest (i.e., a period wherein the Compound is not administered) before the administration of the Compound or pharmaceutical composition thereof is resumed.
  • a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or pharmaceutical composition thereof in cycles, e.g., 1 week cycles, 2 week cycles, 3 week cycles, 4 week cycles, 5 week cycles, 6 week cycles, 8 week cycles, 9 week cycles, 10 week cycles, 11 week cycles, or 12 week cycles.
  • the Compound or a pharmaceutical composition thereof may be administered once, twice, three times, or four times daily.
  • a method for treating a prostate condition presented herein involves the administration of a Compound or a pharmaceutical composition thereof twice daily in 4 week cycles.
  • the period of time of administration of a Compound or pharmaceutical composition thereof may be dictated by one or more monitoring parameters, e.g., concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins such as IL-6 or IL-8); tumor size, blood flow, or metabolism; peritumoral inflammation or edema.
  • monitoring parameters e.g., concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins such as IL-6 or IL-8); tumor size, blood flow, or metabolism; peritumoral inflammation or edema.
  • the period of time of administration of a Compound or pharmaceutical composition thereof may be adjusted based on one or more monitoring parameters, e.g., concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins such as IL-6 or IL-8); tumor size, blood flow, or metabolism; and/or peritumoral inflammation or edema.
  • concentration of VEGF or other angiogenic or inflammatory mediators e.g., cytokines or interleukins such as IL-6 or IL-8
  • tumor size e.g., blood flow, or metabolism
  • peritumoral inflammation or edema e.g., peritumoral inflammation or edema.
  • a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof prior to, concurrently with, or after a meal (e.g., breakfast, lunch, or dinner).
  • a meal e.g., breakfast, lunch, or dinner.
  • a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in the morning (e.g., between 5 am and 12 pm).
  • a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof at noon (i.e., 12 pm).
  • a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in the afternoon (e.g., between 12 pm and 5 pm), evening (e.g., between 5 pm and bedtime), and/or before bedtime.
  • a dose of a Compound or a pharmaceutical composition thereof is administered to a subject once per day, twice per day, three times per day; once, twice or three times every other day (i.e., on alternate days); once, twice or three times every two days; once, twice or three times every three days; once, twice or three times every four days; once, twice or three times every five days; once, twice, or three times once a week, biweekly or monthly.
  • combination therapies for the treatment of cancer or a non-neoplastic condition or a viral infection which involve the administration of a Compound in combination with one or more additional therapies to a subject in need thereof.
  • combination therapies for the treatment of cancer or a non-neoplastic condition or a viral infection which involve the administration of an effective amount of a Compound in combination with an effective amount of another therapy to a subject in need thereof.
  • the term “in combination,” refers, in the context of the administration of a Compound, to the administration of a Compound prior to, concurrently with, or subsequent to the administration of one or more additional therapies (e.g., agents, surgery, or radiation) for use in treating cancer or a non-neoplastic condition or a viral infection.
  • additional therapies e.g., agents, surgery, or radiation
  • the use of the term “in combination” does not restrict the order in which one or more Compounds and one or more additional therapies are administered to a subject.
  • the interval of time between the administration of a Compound and the administration of one or more additional therapies may be about 1-5 minutes, 1-30 minutes, 30 minutes to 60 minutes, 1 hour, 1-2 hours, 2-6 hours, 2-12 hours, 12-24 hours, 1-2 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 26 weeks, 52 weeks, 11-15 weeks, 15-20 weeks, 20-30 weeks, 30-40 weeks, 40-50 weeks, 1 month, 2 months, 3 months, 4 months 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, or any period of time in between.
  • a Compound and one or more additional therapies are administered less than 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years apart.
  • the combination therapies provided herein involve administering a Compound daily, and administering one or more additional therapies once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every month, once every 2 months (e.g., approximately 8 weeks), once every 3 months (e.g., approximately 12 weeks), or once every 4 months (e.g., approximately 16 weeks).
  • a Compound and one or more additional therapies are cyclically administered to a subject. Cycling therapy involves the administration of the Compound for a period of time, followed by the administration of one or more additional therapies for a period of time, and repeating this sequential administration.
  • cycling therapy may also include a period of rest where the Compound or the additional therapy is not administered for a period of time (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 20 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, or 3 years).
  • the number of cycles administered is from 1 to 12 cycles, from 2 to 10 cycles, or from 2 to 8 cycles.
  • the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein comprise administering a Compound as a single agent for a period of time prior to administering the Compound in combination with an additional therapy. In certain embodiments, the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein comprise administering an additional therapy alone for a period of time prior to administering a Compound in combination with the additional therapy.
  • the administration of a Compound and one or more additional therapies in accordance with the methods presented herein have an additive effect relative the administration of the Compound or said one or more additional therapies alone. In some embodiments, the administration of a Compound and one or more additional therapies in accordance with the methods presented herein have a synergistic effect relative to the administration of the Compound or said one or more additional therapies alone.
  • the term “synergistic,” refers to the effect of the administration of a Compound in combination with one or more additional therapies (e.g., agents), which combination is more effective than the additive effects of any two or more single therapies (e.g., agents).
  • a synergistic effect of a combination therapy permits the use of lower dosages (e.g., sub-optimal doses) of a Compound or an additional therapy and/or less frequent administration of a Compound or an additional therapy to a subject.
  • the ability to utilize lower dosages of a Compound or of an additional therapy and/or to administer a Compound or said additional therapy less frequently reduces the toxicity associated with the administration of a Compound or of said additional therapy, respectively, to a subject without reducing the efficacy of a Compound or of said additional therapy, respectively, in the treatment of cancer or a non-neoplastic condition or a viral infection.
  • a synergistic effect results in improved efficacy of a Compound and each of said additional therapies in treating cancer or a non-neoplastic condition or a viral infection.
  • a synergistic effect of a combination of a Compound and one or more additional therapies avoids or reduces adverse or unwanted side effects associated with the use of any single therapy.
  • a Compound and one or more additional therapies can be administered to a subject in the same pharmaceutical composition.
  • a Compound and one or more additional therapies can be administered concurrently to a subject in separate pharmaceutical compositions.
  • a Compound and one or more additional therapies can be administered sequentially to a subject in separate pharmaceutical compositions.
  • a Compound and one or more additional therapies may also be administered to a subject by the same or different routes of administration.
  • the combination therapies provided herein involve administering to a subject to in need thereof a Compound in combination with conventional, or known, therapies for treating cancer or a non-neoplastic condition or a viral infection.
  • Other therapies for cancer or a non-neoplastic condition or a viral infection or a condition associated therewith are aimed at controlling or relieving one or more symptoms.
  • the combination therapies provided herein involve administering to a subject to in need thereof a pain reliever, or other therapies aimed at alleviating or controlling one or more symptoms associated with cancer or a non-neoplastic condition or a viral infection or a condition associated therewith.
  • a hormonal agent e.g., aromatase inhibitor, selective estrogen receptor modulator (SERM), and estrogen receptor antagonist
  • chemotherapeutic agent e.g., microtubule dissembly blocker, antimetabolite, topisomerase inhibitor, and DNA crosslinker or damaging agent
  • anti-angiogenic agent e.g., VEGF antagonist, receptor antagonist,
  • Non-limiting examples of hormonal agents that may be used in combination with a Compound for treating cancer or a non-neoplastic condition include aromatase inhibitors, SERMs, and estrogen receptor antagonists.
  • Hormonal agents that are aromatase inhibitors may be steroidal or nonsteroidal.
  • Non-limiting examples of nonsteroidal hormonal agents include letrozole, anastrozole, aminoglutethimide, fadrozole, and vorozole.
  • Non-limiting examples of steroidal hormonal agents include aromasin (exemestane), formestane, and testolactone.
  • Non-limiting examples of hormonal agents that are SERMs include tamoxifen (branded/marketed as Nolvadex®), afimoxifene, arzoxifene, avalycoxifene, clomifene, femarelle, lasofoxifene, ormeloxifene, raloxifene, and toremifene.
  • Non-limiting examples of hormonal agents that are estrogen receptor antagonists include fulvestrant.
  • Other hormonal agents include but are not limited to abiraterone and lonaprisan.
  • Non-limiting examples of chemotherapeutic agents that may be used in combination with a Compound for treating cancer include microtubule disasssembly blocker, antimetabolite, topisomerase inhibitor, and DNA crosslinker or damaging agent.
  • Chemotherapeutic agents that are microtubule dissemby blockers include, but are not limited to, taxenes (e.g., paclitaxel (branded/marketed as TAXOL®), docetaxel, abraxane, larotaxel, ortataxel, and tesetaxel); epothilones (e.g., ixabepilone); and vinca alkaloids (e.g., vinorelbine, vinblastine, vindesine, and vincristine (branded/marketed as ONCOVIN®)).
  • taxenes e.g., paclitaxel (branded/marketed as TAXOL®), docetaxel, abraxane, larotaxel, ortat
  • Chemotherapeutic agents that are antimetabolites include, but are not limited to, folate anitmetabolites (e.g., methotrexate, aminopterin, pemetrexed, raltitrexed); purine antimetabolites (e.g., cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine); pyrimidine antimetabolites (e.g., 5-fluorouracil, capcitabine, gemcitabine (GEMZAR®), cytarabine, decitabine, floxuridine, tegafur); and deoxyribonucleotide antimetabolites (e.g., hydroxyurea).
  • folate anitmetabolites e.g., methotrexate, aminopterin, pemetrexed, raltitrexed
  • purine antimetabolites e.g., cladribine, clofarabine, fludarabine, mercapto
  • Chemotherapeutic agents that are topoisomerase inhibitors include, but are not limited to, class I (camptotheca) topoisomerase inhibitors (e.g., topotecan (branded/marketed as HYCAMTIN®) irinotecan, rubitecan, and belotecan); class II (podophyllum) topoisomerase inhibitors (e.g., etoposide or VP-16, and teniposide); anthracyclines (e.g., doxorubicin, epirubicin, Doxil, aclarubicin, amrubicin, daunorubicin, idarubicin, pirarubicin, valrubicin, and zorubicin); and anthracenediones (e.g., mitoxantrone, and pixantrone).
  • class I camptotheca
  • topotecan branded/marketed as HYCAMTIN®
  • irinotecan ir
  • Chemotherapeutic agents that are DNA crosslinkers include, but are not limited to, alkylating agents (e.g., cyclophosphamide, mechlorethamine, ifosfamide (branded/marketed as IFEX®), trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine (branded/marketed as BiCNU®), lomustine, semustine, fotemustine, nimustine, ranimustine, streptozocin, busulfan, mannosulfan, treosulfan, carboquone, N,N′N′-triethylenethiophosphoramide, triaziquone, triethylenemelamine); alkylating-like agents (e.g., carboplatin (branded/marketed as PARAPLATIN), cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate
  • Non-limiting examples of anti-angiogenic agents that may be used in combination with a Compound for treating cancer or a non-neoplastic condition include VEGF antagonists, receptor antagonists, integrin antagonists (e.g., vitaxin, cilengitide, and S247), and VTAs/VDAs (e.g., fosbretabulin).
  • VEGF antagonists include, but are not to, anti-VEGF antibodies (e.g., bevacizumab (branded/marketed as AVASTIN®) and ranibizumab (branded/marketed as LUCENTIS)), VEGF traps (e.g., aflibercept), VEGF antisense or siRNA or miRNA, and aptamers (e.g., pegaptanib (branded/marketed as MACUGEN®)).
  • anti-VEGF antibodies e.g., bevacizumab (branded/marketed as AVASTIN®) and ranibizumab (branded/marketed as LUCENTIS)
  • VEGF traps e.g., aflibercept
  • VEGF antisense or siRNA or miRNA e.g., aflibercept
  • aptamers e.g., pegaptanib (branded/marketed as MACUGEN®)
  • Anti-angiogenic agents that are receptor antagonists include, but are not limited to, antibodies (e.g., ramucirumab) and kinase inhibitors (e.g., sunitinib, sorafenib, cediranib, panzopanib, vandetanib, axitinib, and AG-013958) such as tyrosine kinase inhibitors.
  • kinase inhibitors e.g., sunitinib, sorafenib, cediranib, panzopanib, vandetanib, axitinib, and AG-013958
  • anti-angiogenic agents include ATN-224, anecortave acetate (branded/marketed as RETAANE), microtubule depolymerization inhibitor such as combretastatin A4 prodrug, and protein or protein fragment such as collagen 18 (endostatin).
  • Non-limiting examples of other therapies that may be administered to a subject in combination with a Compound for treating cancer or a non-neoplastic condition include:
  • Non-limiting examples of other therapies that may be administered to a subject in combination with a Compound for treating cancer or a non-neoplastic condition include: a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone such as leuprolide acetate (branded/marketed as LUPRON®); a nonsteroidal, anti-androgen such as flutamide (branded/marketed as EULEXIN®) or nilutamide (branded/marketed as) NILANDRON®; a non-steroidal androgen receptor inhibitor such as bicalutamide (branded/marketed as CASODEX®); steroid hormone such as progesterone; anti-fungal agent such as Ketoconazole (branded/marketed as NIZORAL®); glucocorticoid such as prednisone; estramustine phosphate sodium (branded/marketed as EMCYT®); and bisphosphonate such as pamidronate, alendronate, and risedronate.
  • agents alleviating side-effects associated with cancer or a non-neoplastic condition include, but are not limited to: antiemetics, e.g., Ondansetron hydrochloride (branded/marketed as ZOFRAN®), Granisetron hydrochloride (branded/marketed as KYTRIL®), Lorazepam (branded/marketed as ATIVAN®) and Dexamethasone (branded/marketed as DECADRON®).
  • antiemetics e.g., Ondansetron hydrochloride (branded/marketed as ZOFRAN®), Granisetron hydrochloride (branded/marketed as KYTRIL®), Lorazepam (branded/marketed as ATIVAN®) and Dexamethasone (branded/marketed as DECADRON®).
  • combination therapies provided herein for treating cancer or a non-neoplastic condition comprise administering a Compound in combination with one or more agents used to treat and/or manage a side effect, such as, bleeding (usually transient, low-grade epistaxis), arterial and venous thrombosis, hypertension, delayed wound healing, asymptomatic proteinuria, nasal septal perforation, reversible posterior leukoencephalopathy syndrome in association with hypertension, light-headedness, ataxia, headache, hoarseness, nausea, vomiting, diarrhea, rash, subungual hemorrhage, myelosuppression, fatigue, hypothyroidism, QT interval prolongation, or heart failure.
  • a side effect such as, bleeding (usually transient, low-grade epistaxis), arterial and venous thrombosis, hypertension, delayed wound healing, asymptomatic proteinuria, nasal septal perforation, reversible posterior leukoencephalopathy syndrome in association with hypertension, light-headedness, ataxia,
  • a Compound is not used in combination with a drug that is primarily metabolized by CYP2D6 (such as an antidepressant (e.g, a atricyclic antidepressant, a selective serotonin reuptake inhibitor, and the like), an antipsychotic, a beta-adrenergic receptor blocker, or certain types of anti-arrhythmics) to treat cancer or a non-neoplastic condition.
  • an antidepressant e.g, a atricyclic antidepressant, a selective serotonin reuptake inhibitor, and the like
  • an antipsychotic e.g, a beta-adrenergic receptor blocker, or certain types of anti-arrhythmics
  • Non-limiting examples of other therapies that may be used in combination with a Compound for treating a viral infection include a HCV protease inhibitor such as a NS2 protease inhibitor, a NS3 protease inhibitor, a peptide or dipeptide NS3 protease inhibitor or a NS4a protease cofactor inhibitor; a nucleoside or non-nucleoside HCV NS5b polymerase inhibitor; one or more agents such as a NS4b inhibitor, NS5a inhibitor, IRES inhibitor (such as a steroid, a ribozyme, miRNA, siRNA or an antisense RNA), p7 inhibitor, entry inhibitor, fusion inhibitor, helicase inhibitor, ribavirin, a ribavirin analogue, ribavirin and at least one or more of a nonpegylated interferon or a pegylated interferon, a TLR agonist, cyclophilin inhibitor, caspase or
  • a specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the NS3 HCV protease inhibitor BI 201335 (Boehringer Ingelheim Pharma), boceprevir (also referred to as SCH-503034, Schering-Plough Corporation), ciluprevir (also referred to as BILN-2061, Boehringer Ingelheim Pharma), IDX136 (Idenix Pharmaceuticals, Inc.), IDX316 (Idenix Pharmaceuticals, Inc.), ITMN-191 (also referred to as R-7227, InterMune/Roche Pharmaceuticals), MK-7009 (Merck), PHX1766 (Phenomix), SCH-6 (Schering-Plough Corporation), SCH-900518 (also referred to as SCH-518, Schering-Plough Corporation), telaprevir (also referred to as VX 950, Vertex Pharmaceuticals, Inc.), TMC435350 (also referred to as TMC435, Medivir/T
  • HCV NS4a protease cofactor inhibitor or HCV NS4a protease cofactor inhibitor ACH-806 (also referred to as GS-9132, Achillion/Gilead) or ACH-1095 (also known as GS-9525, Gilead/Achillion.
  • nucleoside or non-nucleoside NS5b polymerase inhibitor A-837093 (Abbott Laboratories), A-848837 (Abbott Laboratories), ABT-333 (Abbott Laboratories), AG-021541 (Pfizer Pharmaceuticals), ANA598 (Anadys Pharmaceuticals, Inc.), BILN-1941 (Boehringer Ingelheim Pharma), GL-59728 (Genelabs), GL-60667 (Genelabs), GS-9190 (Gilead), GSK-625433 (GlaxoSmithKline), HCV-796 (Wyeth/Viropharma, Inc.), HCV-896 (ViroPharma, Inc.), IDX102 (Idenix Pharmaceuticals, Inc.), IDX184 (Idenix Pharmaceuticals, Inc.), IDX375 (Idenix Pharmaceuticals, Inc.), JDK-003 (Akro
  • NS4b inhibitor anguizole Genelabs/GSK/Viropharma, Inc.
  • clemizole Stanford University
  • BMS Compound A
  • NS5a inhibitor A-689 also referred to as AZD7295, Arrow Therapeutics, Ltd./AstraZeneca
  • A-831 also referred to as AZD2836, Arrow Therapeutics, Ltd./AstraZeneca
  • BMS-790052 Bristol-Myers Squibb
  • IRES inhibitor steroid mifepristone also referred to as VGX-410C, VGX Pharmaceuticals
  • an antisense oligonucleotide ISIS-14803 Isis Pharmaceuticals
  • a ribozyme such as HEPTAZYME®, (a synthetic ribozyme, Ribozyme Pharmaceuticals, Inc.
  • a RNAi such as TT033 (Benitec/Tacere Bio/Pfizer) or SIRNA-034 (Sirna Therapeutics)
  • a miRNA such as SPC3649 (LNA-antimiRTM-122 brand, Santaris Pharma) or an anti-miR-122 miRNA (Regulus Therapeutics) or siRNA.
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the p7 inhibitor BIT225 (Biotron Limited), the viral entry inhibitor ITX5061 (iTherX Pharmaceuticals, Inc.), PRO 206 (Progenics), an SP-30 entry inhibitor (Samaritan Pharmaceuticals) or a broad spectrum entry inhibitor such as REP 9AC (an amphipathic DNA polymer, REPLICor, Inc.).
  • ribavirin VIRAZOLE® and VILONA® brands, ICN Pharmaceuticals
  • ribavirin for oral administration REBETOL® brand, Schering-Plough Corporation
  • ribavirin tablets COPEGUS® brand, Roche Pharmaceuticals
  • ribavirin capsules RIBASPHERE® brand, Three Rivers Pharmaceuticals, LLC
  • ribavirin analogue levovirin Lisomer of ribavirin, Valeant Pharmaceuticals
  • R1518 a prodrug of levovirin, also referred to as levovirin valinate, Roche Pharmaceuticals
  • taribavirin an oral prodrug of ribavirin, also referred to as viramidine, Valeant Pharmaceuticals.
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the non-pegylated interferon (optionally administered with ribavirin) interferon alfa-2a (ROFERON®-A brand, Roche Pharmaceuticals), interferon alfa-2b (INTRON® A brand, Schering-Plough Corporation), interferon alfa-2c (BEROFOR® brand, Boehringer Ingelheim), interferon-alpha variant GEA007.1 (GenOdyssee SA), interferon-alpha for low dose oral administration (Amarillo Biosciences, Inc./CytoPharm, Inc.), interferon-alpha for oral administration (BELEROFON® brand, Nautilus Biotech), long-acting interferon-alpha (LOCTERON® brand, also referred to as BLX-883, Biolex Therapeutics/OctoPlus), long-acting albuminfusion interferon alfa-2b (ALBUFERON®
  • Pegylated interferon (optionally administered with ribavirin) Peginterferon alfa-2a (PEGASYS® brand, Roche Pharmaceuticals), Peginterferon alfa-2b (PEGINTRON® brand, Schering-Plough Corporation), Peginterferon alfacon-1 (pegylated form of interferon alfacon-1, also referred to as PEG-Alfacon, InterMune), Peg-Interferon Lambda IL-29 (Zymogenetics/Bristol-Myers Squibb).
  • TLR agonist ANA773 Anadys Pharmaceuticals, Inc.
  • TLR-7 agonist selected from isatoribine also referred to as ANA245, Anadys Pharmaceuticals, Inc.
  • ANA-971 a prodrug of TLR-7 agonist isatoribine, Anadys Pharmaceuticals, Inc.
  • ANA975 a prodrug of TLR-7 agonist isatoribine, Anadys Pharmaceuticals, Inc.
  • a TLR9 agonist selected from IMO-2125 (Idera Pharmaceuticals)
  • TLR9 agonist Actilon brand, Coley
  • a cyclophilin B inhibitor selected from Debio 025 (Debiopharm Group) or SCY-635 (Scynexis) or a cyclosporin A analog selected from NIM811 (Novartis), a pancaspase inhibitor selected from PF-03491390 (also referred to as IDN
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the non-specific pharmaceutical histamine dihydrochloride (CEPLENE® and MAXAMINE® brands, Maxim Pharmaceuticals), an immunosuppressive agent selected from mycophenolate mofetil (Roche Pharmaceuticals), mycophenolic acid (Roche Pharmaceuticals), or al-antichymotrypsin.
  • CEPLENE® and MAXAMINE® brands Maxim Pharmaceuticals
  • an immunosuppressive agent selected from mycophenolate mofetil (Roche Pharmaceuticals), mycophenolic acid (Roche Pharmaceuticals), or al-antichymotrypsin.
  • a pharmaceutical pack or kit comprising one or more containers filled with a Compound or pharmaceutical composition thereof. Additionally, one or more other therapies useful for the treatment of cancer or a non-neoplastic condition, or other relevant agents can also be included in the pharmaceutical pack or kit. Also provided herein is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein. Optionally associated with such kits can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999.
  • the protecting groups may be removed at a convenient subsequent stage using methods known in the art.
  • the processes for the preparation of the Compounds provided herein give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography.
  • the Compounds provided herein may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the Compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as ( ⁇ )-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the Compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the Compounds may be resolved using a chiral HPLC column.
  • Compound 1205 may be prepared by reacting allyl bromide (79.2 g, 656 mmol) and 4-hydroxybenzaldehyde A (40.0 g, 328 mmol) in the presence of potassium carbonate (90.6 g, 656 mmol) in acetonitrile (400 mL). The reaction is stirred at ambient temperature under an atmosphere of nitrogen for 4 hours. The reaction is filtered, washed with acetonitrile (200 mL), and concentrated in-vacuo. The residue is chromatographed on silica gel using a gradient of ethyl acetate from 10% to 30% in hexanes to give 50.0 g of aldehyde B as a colorless oil.
  • the Pictet-Spengler intermediate C (50.0 g, 133 mmol) is suspended in ethyl acetate (2 L) and 15% aqueous ammonium hydroxide (1 L) and stirred vigorously for 1 hour. The organic layer is separated, washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the free base D as a pale yellow oil. The pale yellow oil is used for the next stage without further purification.
  • Phenol A (1.85 g, 5.00 mmol), potassium carbonate (1.52 g, 11.0 mol), and nosyl glycidol B (1.56 g, 6.00 mmol) were combined in acetonitrile (50 mL) at room temperature and stirred at 40° C. for 48 hours.
  • the reaction was cooled to ambient temperature and filtered.
  • the solids were washed with acetonitrile (50 mL).
  • the washings were combined with the original mother liquor and concentrated in-vacuo.
  • the residue was chromatographed on silica gel using a gradient (0-30%) of ethyl acetate in methylene chloride to give 1.72 g of C (1730) as a white foam.
  • Epoxide A (280 mg, 0.600 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to 0° C. After adding the chiral (S,S) oligomeric Salen cobalt (III) catalyst (12.0 mg, 0.015 mmol—provided by Prof. Eric Jacobson, Harvard U.) and water (12 ⁇ l, 0.66 mmol), the reaction was stirred while warming to ambient temperature until all epoxide was consumed. The solvent was removed under a stream of nitrogen and the brown residue was purified by preparative HPLC without any buffer to give chiral diol 1382.
  • Triol A (22.3 g, 166 mmol), acetal B (26.0 g, 250 mmol), and p-toluene sulfonic acid (1.58 g, 8.32 mol) were combined in THF (1 L) and stirred at ambient temperature until all starting material was consumed (6.5 hr).
  • the reaction was monitored by TLC (1:1 hexanes:EtOAc, stained with KMnO 4 .
  • Triethyl amine (15 mL) was added to raise the pH the reaction and the solvent was removed in-vacuo. The residue was passed through a plug of silica gel, eluting with 1:1 hexanes in EtOAc to produce C as a colorless oil (24.4 g).
  • Diastereomeric salt A (3.0 g, 5.5 mmol), dissolved in EtOAc (100 mL), was washed with about 15% aqueous ammonium hydroxide solution (2 ⁇ 100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in-vacuo.
  • the free base B was dissolved in DCM (10 mL) and pyridine (1 mL) and added to the chilled chloroformate solution. The reaction was warmed slowly to ambient temperature over 5 hours. The reaction was poured into saturated sodium bicarbonate solution (100 mL) and the layers were separated.
  • Amine salt A (140 mg, 0.40 mol) was added to a solution containing DIEA (155 mg, 1.2 mmol), EDC, 115 mg, 0.60 mol), DMAP (4.9 mg, 0.040 mmol), and HOBt (92 mg, 0.60 mmol) in DMF (6 mL). The reaction was stirred at ambient temperature for 15 hours, filtered, and concentrated in-vacuo. The residue was purified by preparative HPLC to give 1505.
  • DIEA 155 mg, 1.2 mmol
  • EDC 115 mg, 0.60 mol
  • DMAP 4.9 mg, 0.040 mmol
  • HOBt 92 mg, 0.60 mmol
  • reaction material A (4.0 g, 20.40 mmol) and 1-(dimethylamino)-2-nitroethylene (2.04 g, 17.57 mmol) in 20 mL of TFA was stirred for 45 min.
  • the reaction mixture was poured into saturated aqueous NaHCO3 solution (250 mL) and extracted repeatedly with EtOAc (4 ⁇ 75 mL). The combined organic layers are dried and evaporated under vacuum.
  • the red-orange solid is triturated with CH2Cl2/THF (3 ⁇ 100 mL), and filtered to give 3.10 g (66%) indole product B.
  • 4-Difluoromethoxybenzaldehyde (1.16 g, 6.66 mmol) is dissolved in 22 mL of acetic acid at room temperature. The reaction mixture is then heated to 90° C.; six 52 mg portions (309 mg total, 1.11 mmol) of indole C is added in equal time intervals over 1 h, and the mixture heated to reflux overnite. The mixture was cooled to room temperature and put in the refrigerator for 1 day.
  • step-1 product O-propargyl benzaldehyde, Compound B
  • step-1 product O-propargyl benzaldehyde, Compound B
  • Step-1 product 0-propargyl benzaldehyde (10.75 g, 0.073 mol of compound B).
  • the reaction mixture was heated to 100° C. for 8 hours.
  • the reaction mixture was allowed to come to rt and stirred overnite.
  • the precipitated white solid was filtered under suction.
  • the residue was washed with glacial AcOH (200 mL), DCM (200 mL) and dried to get step-2 product, compound C, as a white solid (17 g, 77%): MS [MH + ] 337 (M, 336 Calcd.
  • Step-3 product (3.9 g, 0.011 mol of compound D) in abs. EtOH (80 mL) was added N-acetyl-L-phenylalanine (1.44 g, 0.0069 mol) and refluxed for 2 hours. The reaction mixture was allowed to cool to RT and stand for 20 hours. The separated solid was filtered and dried (2.8 g). It was further crystallized in 1:1 mixture of IPA and MeOH (100 mL) to get final compound E as a white solid (1.71 g, 26%). For the purpose of chiral HPLC and 1 H-NMR a small amount of salt was suspended in EtOAc and treated with 5% NH 4 OH solution.
  • step-5 product (320 mg, 94% of compound F) as a pale yellow solid.
  • step-1
  • Step-1 product 14 g, 0.08 mol of compound B.
  • the reaction mixture was heated to 100° C. for 8 hours.
  • the reaction mixture was allowed to come to rt and stirred overnite.
  • the precipitated white solid was filtered under suction.
  • the residue was washed with glacial AcOH (200 mL), DCM (200 mL) and dried to get step-2 product, compound C, as a white solid (16 g, 63%): MS 351 [MH + ] (M, 350.84 Calcd.
  • Step-2 HCl salt 2.0 g of compound C
  • EtOAc 40 mL
  • 10% aqueous NaHCO 3 solution 20 mL
  • the reaction mixture was vigorously stirred at rt for 30 minutes.
  • the clear biphasic mixture was separated.
  • the organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under vacuum to get a gummy product. This was washed with hexane to get step-3 product, compound D, as a white powder (1.71 g, 95%). This was found to be pure enough for the next step.
  • step-3 product 26 g, 0.074 mol of compound D
  • EtOH 1000 mL
  • N-acetyl-L-phenylalanine 9.24 g, 0.044 mol
  • the mixture was refluxed for 2 hours, cooled to rt and left to stand for 20 hours.
  • the separated solid was filtered and dried to get a white powder (19.5 g, 46% of compound E).
  • small amount of salt was suspended in EtOAc and treated with 5% NH 4 OH solution.
  • Step-1 product (9.36 g, 0.048 mol of compound B).
  • the reaction mixture was heated to 100° C. for 8 hours.
  • the reaction mixture was allowed to come to rt and stirred overnite.
  • the precipitated white solid was filtered under suction.
  • the residue was washed with glacial AcOH (100 mL), MDC (150 mL) and dried to get step-2 product, compound C, as a white solid (10 g, 58%): MS 365 [MH + ] (M, 401.344, Calcd.
  • Step-2 HCl salt 7.5 g of compound C
  • EtOAc 150 mL
  • 10% aqueous NaHCO 3 solution 75 mL
  • the reaction mixture was vigorously stirred at RT for 30 minutes.
  • the clear biphasic mixture was separated.
  • the organic layer was washed with water (75 mL), brine (75 mL), dried over anhydrous Na 2 SO 4 and concentrated under vacuum to get gummy product. This was washed with hexane to get step-3 product, compound D, as a white powder (6.7 g, 98%).
  • step-3 product (6.6 g, 0.018 mol of compound D) in abs. EtOH (150 mL) was added N-acetyl-L-isoleucine (1.87 g, 0.01 mol) and refluxed for 2 hours. The reaction mixture was allowed to cool to rt and stand for 20 hours. The solid separated was filtered and dried to get white powder. This was further crystallized in ethanol (125 mL) to get step-4 salt, compound E, as off-white solid (2.4 g, 24%). For the purpose of chiral HPLC and 1 H NMR, small amount of salt was suspended in EtOAc and treated with 5% NH 4 OH solution.
  • Step-1 product (4.57 g, 0.0284 mol of compound B).
  • the reaction mixture was heated to 115° C. overnite.
  • the reaction mixture was allowed to come to rt and the precipitated white solid was filtered under suction.
  • the residue was washed with 50% glacial AcOH/Et 2 O (50 mL), DCM (50 mL) and dried to get a mixture of step-2 products, compound C and compound D (about 85:15 ratio), as a beige solid (6.88 g, 75%):
  • Mixture LCMS [MH + ] 338, 356, Rt 1.77.
  • step-3 products 60 mg, 54% of compound F and 8 mg (7%) of compound E
  • step-1 product 4-(tetrahydropyran-4-yloxy)benzonitrile), as a white solid.
  • Step-2 product (6.80 g, 0.033 mol of compound B) in glacial AcOH (380 mL) heated to 90° C. was added 5-Chlorotryptamine.HCl salt (6.80 g, 0.0294 mol) in four portions added 30 min apart.
  • the reaction mixture was heated to reflux overnite.
  • the reaction mixture was allowed to come to rt and put in the refrigerator overnite.
  • the precipitated white solid was filtered under suction.
  • the solid residue residue was washed with 40% glacial AcOH/Et 2 O (100 mL), Et 2 O (100 mL) and dried under vacuum to get step-3 product, compound C, as a white solid (10.37 g, 84%).
  • Step-3 HCl salt (10.56 g, 0.0252 mol of compound C) in EtOAc (300 mL) was added saturated aqueous NaHCO 3 solution (150 mL). The reaction mixture was vigorously stirred at rt for 30 minutes. The clear biphasic mixture was separated. The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous MgSO 4 and concentrated under vacuum to get a foam. This was washed with hexane to afford the step-4 product, compound D, (9.64 g, 100%): This material was taken directly into the next reaction without further purification.
  • Step-4 product (9.64 g, 25.18 mmol of compound D) in abs. EtOH (930 mL) was added N-acetyl-L-phenylalanine (3.39 g, 0.0164 mol) and refluxed until dissolution occurred. The reaction mixture was allowed to cool to RT and stand for 48 hours. The separated solid was filtered and dried (6.80 g, 46% recovery, 95% ee by chiral LC of free base form). It was further crystallized in abs. EtOH (500 mL) to get the step-5 product, compound E as a white solid (6.60 g, 44% recovery, >98.5% ee by chiral LC of free base form). This salt was taken directly into the next reaction without further purification. Data for E: Chiral HPLC ODH-280-40 column (rt 47.29 min).
  • step-1 product 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester, (12.60 g, 0.0417 mol) and the mixture stirred 2 h, and 150 mL of 67% Et 2 O/hexanes added.
  • the resulting slurry was filtered and dried under vacuum (1 torr, 60° C.) to afford the step-2 product, 4-(piperidin-4-yloxy)benzonitrile hydrochloride, as a white solid (9.10 g, 91%): LCMS [MH + ] 203, Rt 1.23.
  • step-3 product 4-[1-(2-trimethylsilanylethanesulfonyl)piperidin-4-yloxy]benzonitrile (12.30 g, 0.0336 mol of compound B) in dry DCM (83 mL) was added 1M DIBALH in DCM (44 mL, 0.044 mol) and the mixture stirred 30 min at 0° C. The reaction mixture was cooled to ⁇ 20° C., and EtOAc (7 mL) was added slowly dropwise. The mixture was stirred 15 min, a solution of saturated aqueous Rochelle's salt added (85 mL), the mixture warmed to 0° C. and stirred 1 h.
  • Step-4 product (12.40 g, 0.034 mol of compound C) in glacial AcOH (380 mL) heated to 90° C. was added 5-Chlorotryptamine.HCl salt (6.75 g, 0.029 mol) in four portions added 30 min apart.
  • the reaction mixture was heated to reflux overnite.
  • the reaction mixture was allowed to come to rt and put in the refrigerator overnite.
  • the precipitated white solid was filtered under suction.
  • the solid residue was washed with 40% glacial AcOH/Et 2 O (100 mL), Et 2 O (100 mL) and dried under vacuum to get step-5 product, compound D, as a white solid (7.76 g, 45%).
  • Step-5 HCl salt (10.3 g, 17.67 mmol of compound D) in EtOAc (300 mL) was added saturated aqueous NaHCO 3 solution (150 mL). The reaction mixture was vigorously stirred at rt for 30 minutes. The clear biphasic mixture was separated. The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous MgSO 4 and concentrated under vacuum to get a foam. This was washed with hexane to afford the step-6 product, compound E, (9.65 g, 100%): This material was taken directly into the next reaction without further purification.
  • Step-6 product 9.65 g, 0.0177 mol of compound E) in abs. EtOH (200 mL) was added N-acetyl-L-leucine (1.99 g, 0.0115 mol) and refluxed until dissolution occurred. The reaction mixture was allowed to cool to rt and stand for 48 hours. The separated solid was filtered and dried (5.30 g, 40% recovery, 72% ee by chiral LC of free base form). It was further crystallized in abs. EtOH (150 mL) to get the step-7 product, compound F, as a white solid (3.86 g, 29% recovery, 99% ee by chiral LC of free base form). This salt was taken directly into the next reaction without further purification. Data for F: Chiral HPLC ODH-280-40 column (rt 19.01 min).
  • Methylsulfide A (718 mg, 1.25 mmol) was dissolved in 20 mL of dichloromethane and cooled to 0° C. with stirring.
  • MCPBA 453.3 mg, 2.62 mmol
  • the reaction was allowed to warm to room temperature over a 2-hour period and to stir at room temperature for an additional 4 hours at which time the reaction was complete.
  • the reaction was concentrated in situ. The residue was dissolved in 40% EtOAc/60% hexanes and purified on a SiO 2 column.
  • the EC 50 for a series of Compounds is provided in Table 2.
  • the EC 50 data was obtained using the protocol set forth below in Section 8.1.1.
  • LC/MS for certain Compounds was performed on either a Waters 2795 or 2690 model separations module coupled with a Waters Micromass ZQ mass spectrometer using a Waters Xterra MS C 18 4.6 ⁇ 50 mm reverse phase column (detection at 254 nM).
  • the methods employed a gradient of acetonitrile (ACN) in water at 2 mL/min at ambient temperature as shown in Table 2a.
  • the mobile phase was buffered with a 0.1 N formic acid.
  • the standard 6 minute method maintains a constant 85/5/10 ratio of water/ACN/1% aqueous formic acid from 0 minutes to 0.5 minutes.
  • the method runs a linear gradient from 85/5/10 at 0.5 minutes to 0/90/10 at 3.5 minutes.
  • the methods holds at 0/90/10 until 4.5 minutes then immediately drops back down to 85/5/10 and holds there until 6 minutes.
  • the non-polar 6 minute method maintains a constant 60/30/10 ratio of water/ACN/1% aqueous formic acid from 0 minutes to 0.5 minutes.
  • the method runs a linear gradient from 60/30/10 at 0.5 minutes to 0/90/10 at 3.5 minutes.
  • the methods holds at 0/90/10 until 4.5 minutes then immediately drops back down to 60/30/10 and holds there until 6 minutes.
  • the polar 6 minute method maintains a constant 90/0/10 ratio of water/ACN/1% aqueous formic acid from 0 minutes to 0.5 minutes.
  • the method runs a linear gradient from 90/0/10 at 0.5 minutes to 20/70/10 at 3.5 minutes.
  • the methods holds at 20/70/10 until 4.5 minutes then immediately drops back down to 90/0/10 and holds there until 6 minutes.
  • LC/MS for Compounds 1611 and 1669 was performed using a C18-BDS 5 (250 ⁇ 4.6 mm) column with a 0.7 mL/min flow rate.
  • the following solvent gradient was employed using 0.1% TFA/water as solvent A and acetonitrile as solvent B: 20% B for 0-20 minutes, 70% B for 20-30 minutes, 100% B for 30-40 minutes, 20% B for 40-50 minutes.
  • Compound 1205 is bioavailable in vivo when administered in an aqueous suspension. It is anticipated that Compound 1205 can be clinically administered via a solid-dosage form. For all the studies outlined herein, Compound 1205 was lyophilized prior to formulation to minimize batch-to-batch variations in particle-size.
  • the compound was dissolved in acetonitrile at a concentration of 15 mg/mL. An equal amount of water was added to bring the final concentration to 7.5 mg/mL in a 1:1 acetonitrile/water solution (v/v). The solution was frozen on the shelf of the freeze dryer for a minimum of 3 hours and then lyophilized. The resulting solid was determined to be amorphous by differential scanning calorimetry and polarized light microscopy. Suspensions were prepared by the addition of 0.5% HPMC with 1% Tween-80, followed by stirring and homogenization for 2 minutes.
  • VEGF protein levels may be monitored by an ELISA assay (R&D Systems). Briefly, HeLa cells may be cultured for 24-48 hours under hypoxic conditions (1% O 2 , 5% CO 2 , balanced with nitrogen) in the presence or absence of a Compound. The conditioned media may then be assayed by ELISA, and the concentration of VEGF calculated from the standard ELISA curve of each assay.
  • a dose-response analysis may be performed using the ELISA assay and conditions described above.
  • the conditions for the dose-response ELISA are analogous to those described above.
  • a series of, e.g., seven different concentrations may be analyzed.
  • a dose-response cytotoxicity assay may be performed using Cell Titer Glo (Promega) under the same conditions as the ELISA to ensure that the inhibition of VEGF expression was not due to the cytotoxicity.
  • Dose-response curves may be plotted using percentage inhibition versus concentration of the Compound, and EC 50 and CC 50 values may be generated for each Compound with the maximal inhibition set as 100% and the minimal inhibition as 0%.
  • Compounds will have an EC 50 of less than 50, less than 10, less than 2, less than 0.5, or less than 0.01.
  • This example demonstrates the selective inhibition of Compound 1205 on pathological human VEGF production in transformed HeLa cells grown under stressed conditions while sparing human VEGF production in HeLa cells grown under non-stressed conditions.
  • HeLa (human cervical carcinoma) cell cultures were established under normoxic conditions (21% oxygen). HeLa cells increase VEGF production 4- to 5-fold in response to hypoxia.
  • vehicle (0.5% DMSO) alone, or a range of concentrations of Compound #10, Compound 1205, or Compound 1330 was added to the culture medium and the cells were incubated for 48 hours.
  • the conditioned media were collected and the VEGF protein levels were assayed in an enzyme-linked immunosorbent assay (ELISA) with primary antibodies that recognize the soluble VEGF 121 and VEGF 165 isoforms (R & D Systems, Minneapolis, Minn., USA).
  • ELISA enzyme-linked immunosorbent assay
  • FIG. 1 shows the concentrations of VEGF in conditioned media across the dose range tested for Compound #10, Compound 1205 and Compound 1330. The data indicate that Compound #10 and Compound 1205 inhibit stress-induced VEGF production.
  • Human HT1080 cells (5 ⁇ 10 6 cells/mice) were implanted subcutaneously into male athymic nude mice. Human HT1080 cells constitutively produce human VEGF. Treatment with vehicle alone or Compound 1205 was initiated when the median tumor volume was approximately 311 ⁇ 88 mm 3 . Table 3 and Table 4 provide the study design for assessing tumor and pathological plasma VEGF concentrations—each group in each study included eight (8) mice. When the tumors in vehicle-treated mice had reached the target size of about 1200 mm 3 for study #21 and about 1500 mm 3 for study #23, all mice in the study were sacrificed, and excised tumors were homogenized in buffer containing protease inhibitors.
  • Intra-tumor VEGF levels were normalized to the total tumor protein concentration and plasma VEGF levels were expressed in pg/mL. Because smaller tumors produce less VEGF per mg of tumor protein, intra-tumor VEGF levels were normalized to tumor size. Table 4 provides the study design for assessing tumor and plasma VEGF.
  • Compound 1205 inhibits both tumor and plasma VEGF levels by more than 95%. Even with the reduction in tumor size in the treated groups, the volume normalized intra-tumor VEGF levels were significantly reduced ( FIG. 2 ; Table 3).
  • HT1080 cells (5 ⁇ 10 6 cells/mouse) were implanted subcutaneously in male athymic nude mice. When tumors had become established (i.e., the mean tumor size had reached 311 ⁇ 88 mm 3 ), mice were divided into 5 groups and treatment was administered as shown in Tables 4 and 5.
  • Compound 1330 is a relatively inactive (R,S) diastereomer of Compound 1205, which has (S,S) configuration.
  • Compound #10 was included in this study.

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Abstract

Compounds that selectively inhibit pathological production of human vascular endothelial growth factor (VEGF) and compositions comprising such Compounds are described. Compounds that inhibit viral replication or the production of viral RNA or DNA or viral protein and compositions comprising such Compounds are described. Also described are methods of reducing VEGF using such Compounds and methods for treating cancer and non-neoplastic conditions involving the administration of such Compounds. Further described are methods of inhibiting viral replication or the production of viral RNA or DNA or viral protein using such Compounds and methods for treating viral infections involving the administration of such Compounds. The Compounds may be administered as a single agent therapy or in combination with one or more additional therapies to a human in need of such treatments.

Description

    REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. application Ser. No. 13/321,257, filed Nov. 18, 2011, currently allowed, which is a U.S. national stage application of International Application No. PCT/US2010/036467, filed May 27, 2010, which claims the benefit of priority to U.S. Provisional Patent application 61/181,653, filed May 27, 2009, each of which is incorporated by reference herein in its entirety.
    • STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
  • Certain aspects of this invention may have been made with government support under Federal Award ID 1R43CA108330-01 awarded by the National Institutes of Health. The government may have certain rights in the invention.
    • 1. INTRODUCTION
  • Compounds that selectively inhibit pathological production of human vascular endothelial growth factor (VEGF) and compositions comprising such Compounds are described. Compounds that inhibit viral replication or the production of viral RNA or DNA or viral protein and compositions comprising such Compounds are described. Also described are methods of reducing VEGF using such Compounds and methods for treating cancer and non-neoplastic conditions involving the administration of such Compounds. Further described are methods of inhibiting viral replication or the production of viral RNA or DNA or viral protein using such Compounds and methods for treating viral infections involving the administration of such Compounds. The Compounds may be administered as a single agent therapy or in combination with one or more additional therapies to a human in need of such treatments.
    • 2. BACKGROUND 2.1 Cancer
  • Cancer is one of the most significant health conditions. In the United States, cancer is second only to heart disease in mortality accounting for one of four deaths. The incidence of cancer is widely expected to increase as the US population ages, further augmenting the impact of this condition.
  • The current treatment regimens for cancer established in the 1970s and 1980s, have not changed dramatically. These treatments, which include chemotherapy, radiation and other modalities including newer targeted therapies, have shown limited overall survival benefit when utilized in most advanced stage common cancers since, among other things, these therapies primarily target tumor bulk.
  • Standard oncology regimens have often been largely designed to administer the highest dose of irradiation or a chemotherapeutic agent without undue toxicity, i.e., often referred to as the “maximum tolerated dose” (MTD) or “no observed adverse effect level” (NOAEL). Many conventional cancer chemotherapies and conventional irradiation therapies exert their toxic effects on cancer cells largely by interfering with cellular mechanisms involved in cell growth and DNA replication. Chemotherapy protocols also often involve administration of a combination of chemotherapeutic agents in an attempt to increase the efficacy of treatment. Despite the availability of a large variety of chemotherapeutic agents, these therapies have many drawbacks. For example, chemotherapeutic agents are notoriously toxic due to non-specific side effects on fast-growing cells whether normal or malignant; e.g. chemotherapeutic agents cause significant, and often dangerous, side effects, including bone marrow depression, immunosuppression, and gastrointestinal distress, etc.
  • Other types of traditional cancer therapies include surgery, hormonal therapy, immunotherapy, anti-angiogenesis therapy, targeted therapy, and radiation treatment to eradicate neoplastic cells in a patient. All of these approaches can pose significant drawbacks for the patient including a lack of efficacy and toxicity. Accordingly, new therapies for improving the long-term prospect of cancer patients are needed.
    • 2.2 Non-Neoplastic Conditions
  • Angiogenesis is implicated in the pathogenesis of a variety of non-neoplastic conditions, e.g., intraocular neovascular syndromes such as proliferative retinopathies or age-related macular degeneration (AMD), rheumatoid arthritis, and psoriasis.
  • The recognition of VEGF as a primary stimulus of angiogenesis in pathological conditions has led to various attempts to block VEGF activity. Inhibitory anti-VEGF receptor antibodies, soluble receptor constructs, antisense strategies, RNA aptamers against VEGF and low molecular weight VEGF receptor tyrosine kinase (RTK) inhibitors have all been proposed for use in interfering with VEGF signaling (Siemeister et al. (1998) Cancer Metastasis Rev., 17(2):241-248). However, these agents all have drawbacks in that they can cause toxic side effects in the patient and often are not curative of the non-neoplastic condition. Accordingly, new therapies for treating patients with non-neoplastic conditions that are associated with angiogenesis, particularly VEGF production, are needed.
    • 2.3 Viral Conditions
  • As obligate intracellular parasites, viruses are intimately dependent upon the biological functions of their hosts. Small molecules that affect the host cell biological processes involved in viral replication or the production of viral RNA or DNA or viral protein may therefore inhibit a wide variety of viruses requiring these functions for essential events in the viral life cycle and therefore can be used for treatment of virus infection. Notably, molecules directly affecting host functions that are essential for viral replication or the production of viral RNA or DNA or viral protein should provide a high barrier to the emergence of resistant strains relative to classical antivirals that directly target viral enzymes.
  • An estimated 170 million people worldwide are reported to be infected with hepatitis C virus, of which at least 6 known genotypes are the causative agent of hepatitis C infection. Up to 80 percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (see Saito I, et al., Hepatitis C virus infection is associated with the development of hepatocellular carcinoma, Proc Natl Acad Sci USA, 1990, 87:6547-6549). References have described small molecule β-carboline compounds with antiviral activity against viruses such as human papillomavirus (HPV)(J F Miller et al, Bioorganic & Medicinal Chemistry Letters, 2010, 20(1):256-259), poliovirus (PV) and herpes simplex virus (ASN Formagio et al, European Journal of Medicinal Chemistry, 2009, 44(11):4695-4701). International Patent publications WO2006/015035 and WO2007/002051 describe β-carboline compounds with antiviral activity against human papillomavirus infection (HPV) and a flavivirus infections, including dengue virus, yellow fever virus, West Nile virus and hepatitis C virus (HCV) infection. Accordingly, new small molecule therapies for treating patients with viral conditions, particularly dengue virus and HCV, are needed.
    • 3. SUMMARY
  • Encompassed herein are compounds having the formula set forth in Section 5.1 (“Compound”) and compositions comprising such Compounds. The Compounds can demonstrate one or more of the following activities: (a) selective inhibition of the pathological production of human VEGF; (b) inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema and/or tumor growth; (c) prolongation of the G1/S phase of the cell cycle; (d) inhibition of angiogenesis and/or inflammation associated with a non-neoplastic condition; and/or (e) inhibition of a viral infection.
  • Methods for treating cancer as well as non-neoplastic conditions and viral infections are described, involving the administration of a Compound to a human subject in need of such treatment. Preferably, the Compound used in the therapeutic method demonstrates one or more of the following activities as determined in cell culture and/or animal model systems, such as those described herein: (a) selective inhibition of the pathological production of human VEGF; (b) inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema and/or tumor growth; (c) prolongation of the G1/S phase of the cell cycle; (d) inhibition of angiogenesis and/or inflammation associated with a non-neoplastic condition; and/or (e) inhibition of viral infection. The Compound can be administered as a single agent therapy to a human in need of such treatment. Alternatively, the Compound can be administered in combination with one or more additional therapies to a human in need of such treatment. Such therapies may include the use of anti-cancer agents (e.g., cytotoxic agents, anti-angiogenesis agents, tyrosine kinase inhibitors or other enzyme inhibitors).
  • Despite differences in the bases for cancer, non-neoplastic conditions and viral infection, the therapies described herein should be effective because they are aimed at interfering with basic mechanisms required for manifestation of each disease (i.e., the pathological production of human VEGF, uncontrolled growth of tumors or inflammation or edema associated with tumors, the pathological angiogenesis or inflammation associated with a non-neoplastic condition, the pathological angiogenesis associated with cancer, or the biological processes involved in viral replication or the production of viral RNA or DNA or viral protein). While not bound by any theory, the therapies described are based, in part, on the pharmacodynamic activities of the Compounds as measured in cell culture and in animal models; in particular, these include: (a) selective inhibition of the pathological production of human VEGF; (b) inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema, and/or tumor growth; (c) prolongation of the G1/S phase of the cell cycle of aberrantly proliferating cells and/or (d) inhibition of viral replication or the production of viral RNA or DNA or viral protein.
  • These pharmacologic activities contribute to limiting solid tumor growth or tumor-related inflammation, tumor-related edema and/or pathological angiogenesis, in several ways. For example, inhibition of pathological production of human VEGF by the tumor will inhibit tumor angiogenesis, thereby limiting vascularization and further growth of solid tumors. An additional benefit is achieved for tumors that respond to VEGF as a growth factor—in such cases, the Compound can limit proliferation of such tumor cells independent of their angiogenic status, that is angiogenesis and vascularization need not be present for the Compound to limit proliferation of the tumor cells. Because the process of tumorigenesis can result in inflammation and edema, a Compound may limit such inflammation or edema. Additionally, prolongation of the cell cycle may contribute to the induction of apoptotic death of the tumor cells, and/or allow for increased efficacy when the Compound is used in combination with a therapy or therapies (e.g., chemotherapeutic agents or radiation) that interfere with nucleic acid synthesis during the cell cycle (e.g., the G1/S phase). Because viral replication is directly dependent on host cells, a Compound that interferes with cellular molecular processes that participate in viral replication may inhibit one or more events of the viral life cycle and thus be used for treatment of a viral infection. Finally, a Compound that interferes with viral replication or the production of viral RNA or DNA or viral protein may inhibit relapse of one or more symptoms associated with recurrence of a viral infection.
  • Thus, in specific embodiments, the methods for treating cancer can result in inhibition or reduction of the pathological production of human VEGF (including intratumoral VEGF production), thus reducing VEGF concentrations in biological specimens of an afflicted subject; inhibition of tumor angiogenesis, tumor-related inflammation, tumor-related edema, and/or tumor growth in the subject; stabilization or reduction of tumor volume or tumor burden in the subject; stabilization or reduction of peritumoral inflammation or edema in the subject; reduction of the concentrations of angiogenic or inflammatory mediators in biological specimens (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids); and/or a delayed or prolonged late G1/S phase of the cell cycle (i.e., the period between the late resting or pre-DNA synthesis phase, and the early DNA synthesis phase) in tumor cells of the subject. In other specific embodiments, the methods of treating non-neoplastic conditions can result in the inhibition or reduction of pathological angiogenesis; the inhibition or reduction of plasma human VEGF concentrations in an afflicted subject; the inhibition or reduction in inflammation; and/or stabilization or reduction of the one or more symptoms of the non-neoplastic condition in the subject. In another specific embodiment, without being bound by any particular theory, the methods of treating a viral infection can result in interference with viral replication in infected cells in an afflicted subject and prevent or reduce the ability of the virus to appropriate the host apparatus and molecular processes in the subject.
  • Existing antiangiogenic therapies that have been developed for other diseases (e.g., certain cancers and retinopathies including macular degeneration and the like) are directed at globally neutralizing VEGF activity (e.g., using anti-VEGF antibodies), or inhibiting downstream effects of VEGF signaling (e.g., using tyrosine kinase inhibitors to block the signaling activity of the VEGF receptor). As a result, these existing antiangiogenic therapies neutralize or inhibit physiological or homeostatic VEGF, as well as pathologically produced human VEGF, activity resulting in side effects that, while tolerated for the treatment of life-threatening cancers or to prevent or slow the development of hearing loss or blindness, may not be acceptable for the treatment of certain cancers and non-neoplastic conditions. Since the Compounds used in the therapeutic methods described herein selectively inhibit pathologic production of human VEGF, and do not disturb the production of human VEGF under physiological conditions, side effects that are unacceptable for the treatment of cancer or non-neoplastic conditions may be reduced. Existing antiviral therapies are a combination of interferon and ribavirin, leading to variable outcomes among the six major HCV genotypes. However, only about one-half of all treated patients respond to this combination therapy. Since the Compounds used in the therapeutic methods described herein are small molecules that selectively inhibit viral replication or the production of viral RNA or DNA or viral protein, side effects that are unacceptable for standard antiviral treatment may be reduced.
  • The efficacy of the therapeutic intervention is supported by the data presented herein, demonstrating that the Compounds inhibit the pathological production of human VEGF (see Section 8.1 et. seq., infra); the Compounds inhibit tumor growth (see Section 8.2 et. seq., infra); the Compounds delay the cell cycle by prolonging the G1/S phase (see Section 8.3 et. seq., infra); and the Compounds inhibit viral replication or the production of viral RNA or DNA or viral protein by interfering with biological processes involved in viral replication or the production of viral RNA or DNA or viral protein (see Section 8.4 et. seq., infra).
    • 3.1 Definitions
  • As used herein, the term “effective amount” in the context of administering a Compound to a subject with cancer refers to the amount of a Compound that results in a beneficial or therapeutic effect. In specific embodiments, an “effective amount” of a Compound refers to an amount of a Compound which is sufficient to achieve at least one, two, three, four or more of the following effects: (i) the reduction or amelioration of the severity of one or more symptoms associated with cancer; (ii) the reduction in the duration of one or more symptoms associated with cancer; (iii) the prevention in the recurrence of a tumor or one or more symptoms associated with cancer; (iv) the regression of cancer and/or one or more symptoms associated therewith; (v) the reduction in hospitalization of a subject; (vi) the reduction in hospitalization length; (vii) an increase in the survival of a subject; (viii) the inhibition of the progression of cancer and/or one or more symptoms associated therewith; (ix) the enhancement of or improvement of the therapeutic effect of another therapy; (x) a reduction in tumor vascularization before surgery; (xi) a reduction in the growth of a tumor or neoplasm; (xii) a decrease in tumor size (e.g., in volume or diameter); (xiii) a reduction in the formation of a newly formed tumor; (xiv) eradication, removal, or control of primary, regional and/or metastatic cancer; (xv) a decrease in the number or size of metastases; (xvi) a reduction in mortality; (xvii) an increase in tumor-free survival rate of patients; (xviii) an increase in relapse free survival; (xix) an increase in the number of patients in remission; (xx) a decrease in hospitalization rate; (xxi) the size of the tumor is maintained and does not increase or increases by less of the tumor after administration of a standard therapy as measured by conventional methods available to one of skill in the art, such as magnetic resonance imaging (MM), dynamic contrast-enhanced MRI (DCE-MRI), X-ray, computed tomography (CT) scan, or a positron emission tomography scan; (xxii) the prevention of the development or onset of one or more symptoms associated with cancer; (xxiii) an increase in the length of remission in patients; (xxiv) the reduction in the number of one or more symptoms associated with cancer; (xxv) an increase in symptom-free survival of cancer patients; (xxvi) a decrease in the concentration of circulating VEGF in the plasma of a subject with cancer; (xxvii) a decrease in circulating tumor cells (CTCs) in the blood of a subject with cancer; (xxviii) a decrease in the concentration of VEGF-C, VEGF-D, P1GF, VEGFR-1, VEGFR-2, IL-6 and/or IL-8 in a biological specimen (e.g., the plasma, serum, urine or cerebrospinal fluid (CSF)) of a subject with cancer; (xxix) the inhibition or reduction in tumor vascularization following surgery; (xxx) improvement in neural function, e.g., hearing, balance, tinnitus, or vision; (xxxi) the inhibition or reduction in pathological production of human VEGF; (xxxii) the stabilization or reduction of peritumoral inflammation or edema in a subject; (xxxiii) the reduction of the concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins) in biological specimens (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids); (xxxiv) the inhibition or decrease in tumor metabolism or perfusion; (xxxv) the inhibition or reduction in pathological angiogenesis or vascularization; (xxxvi) the improvement in quality of life as assessed by methods well known in the art, e.g., questionnaires; (xxxvii) ease in removal of tumors by reducing vascularization prior to surgery; and/or (xxxviii) an alteration (e.g, a decrease) in a marker for cancer (e.g., a decrease of prostate-specific antigen (PSA) in prostate cancer subjects). In specific embodiments, an “effective amount” of a Compound refers to an amount of a Compound specified in Section 5.6 below.
  • As used herein, the term “effective amount” in the context of administering a Compound to a subject with a non-neoplastic condition refers to the amount of a Compound that results in a beneficial or therapeutic effect. In specific embodiments, an “effective amount” of a Compound refers to an amount of a Compound which is sufficient to achieve at least one, two, three, four or more of the following effects: (i) the reduction or amelioration of the severity of a non-neoplastic condition and/or one or more symptoms associated therewith; (ii) the reduction in the duration of one or more symptoms associated with a non-neoplastic condition; (iii) the prevention in the recurrence of a one or more symptoms associated with a non-neoplastic condition; (iv) the regression of the non-neoplastic condition and/or one or more symptoms associated therewith; (v) the inhibition of the progression of a non-neoplastic condition and/or one or more symptoms associated therewith; (vi) the enhancement or improvement the therapeutic effect of another therapy; (vii) the prevention of the development or onset of one or more symptoms associated with a non-neoplastic condition; (viii) the reduction in the number of one or more symptoms associated with a non-neoplastic condition; (ix) a decrease in the concentration of circulating VEGF in the plasma of a subject with the non-neoplastic condition; (x) a decrease in the concentration of VEGF-C, VEGF-D, P1GF, VEGFR-1, VEGFR-2, IL-6 and/or IL-8 in a biological specimen (e.g., the plasma, serum, urine or CSF) of a subject with a non-neoplastic condition; (xi) the reduction in hospitalization of a subject; (xii) the reduction in hospitalization length; (xiii) an increase in the survival of a subject; (xiv) the enhancement or improvement of the therapeutic effect of another therapy; (xv) a decrease in hospitalization rate; (xvi) a decrease in pathological production of human VEGF; (xvii) the inhibition or reduction in pathological angiogenesis or vascularization; (xviii) the improvement in the quality of life as assessed, e.g., by questionnaires; (xix) a decrease in mortality; (xx) an increase in duration of survival; and/or (xv) an increase in survival rate. In specific embodiments, an “effective amount” of a Compound refers to an amount of a Compound specified in Section 5.6 below.
  • As used herein, the term “effective amount” in the context of administering a Compound to a subject with a viral infection refers to the amount of a Compound that results in a beneficial or therapeutic effect. In specific embodiments, an “effective amount” of a Compound refers to an amount of a Compound which is sufficient to achieve at least one, two, three, four or more of the following effects: (i) the reduction or amelioration of the severity of one or more symptoms associated with viral infection; (ii) the reduction in the duration of one or more symptoms associated with viral infection; (iii) the prevention in the recurrence of a viral infection or one or more symptoms associated with viral infection; (iv) the regression of viral infection and/or one or more symptoms associated therewith; (v) the inhibition of the progression of viral infection and/or one or more symptoms associated therewith; (vi) the enhancement of and/or improvement of the therapeutic effect of another antiviral therapy; (vii) a reduction in a viral titer; (viii) a reduction in the progression of viral infection; (ix) a reduction in viral sequestration and/or latency; (x) a decrease in viral proteins in the cells of a subject having a viral infection; (xi) an increase in relapse free infection; (xii) an increase in the number of patients in remission of viral infection; (xiii) a decrease in hospitalization rate associated with viral infection; (xiv) a decrease in organ transplant rate associated with viral infection; (xv) the prevention of the development or onset of one or more symptoms associated with viral infection; (xvi) an increase in the length of remission of viral infection in patients; (xvii) the reduction in the number of one or more symptoms associated with viral infection; (xviii) an increase in symptom-free survival of patients having a viral infection; (xix) a decrease in the concentration of circulating viral RNA or DNA or viral protein in the plasma of a subject having a viral infection; (xx) a decrease in viral replication in the cells of a subject having a viral infection; (xxi) a decrease in the concentration of viral RNA or DNA or viral protein in a biological specimen (e.g., the plasma, serum, urine or tissue of a subject having a viral infection; (xxii) the inhibition or reduction in viral re-infection following organ transplant; (xxiii) the inhibition or reduction in the occurrence of viral infection following a period of latency; (xxiv) improvement in organ function, e.g., liver cirrhosis; (xxv) a decrease in organ function pathology, e.g., liver failure; (xxvi) the inhibition or reduction in production of viral RNA or DNA or viral protein; (xxvii) the stabilization or reduction of viral replication in the cells of a subject; (xxviii) the reduction of the concentration of viral RNA or DNA or viral protein or other viral mediators (e.g., chemokines, cytokines or interleukins) in biological specimens (e.g., plasma, serum, urine, or any other biofluids or tissue specimens); (xxix) the decrease in production of viral proteins; (xxx) the inhibition or reduction in viral protein translation; (xxxi) the inhibition or reduction in viral RNA or DNA or viral protein synthesis; (xxxii) inhibition or prevention of the formation of a viral replication complex in a cell; (xxxiii) inhibition or prevention of the assembly of a viral replication complex in the endoplasmic reticulum (ER); (xxxiv) inhibition or prevention of the assembly and/or release of viral particles from cells; (xxxv) the improvement in quality of life after a viral infection as assessed by methods well known in the art, e.g., questionnaires; (xxxvi) ease in treating, preventing or ameliorationg viral infection by oral delivery of a Compound; and/or (xxxvii) an alteration (e.g, a decrease) in a viral marker (e.g., a decrease of viral RNA or DNA or viral protein in a subject having a viral infection). In specific embodiments, an “effective amount” of a Compound refers to an amount of a Compound specified in Section 5.6 below.
  • As used herein, the term “elderly human” refers to a human 65 years or older.
  • As used herein, the term “human adult” refers to a human that is 18 years or older.
  • As used herein, the term “middle-aged human” refers to a human between the ages of 30 and 64.
  • As used herein, the term “human child” refers to a human that is 1 year to 18 years old.
  • As used herein, the term “human toddler” refers to a human that is 1 year to 3 years old.
  • As used herein, the term “human infant” refers to a newborn to 1 year old year human.
  • As used herein, the terms “subject” and “patient” are used interchangeably to refer to an individual being treated for cancer, a non-neoplastic condition or a viral infection. In a specific embodiment, the individual is a human. See Section 5.4 and 5.5 for more information concerning patients treated for cancer or a non-neoplastic condition in accordance with the methods provided herein.
  • As used herein, the terms “therapies” and “therapy” can refer to any protocol(s), method(s), compositions, formulations, and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a condition or disorder or one or more symptoms thereof (e.g., cancer or one or more symptoms or one or more conditions associated therewith; a non-neoplastic condition or one or more symptoms or one or more conditions associated therewith; or, a viral infection or one or more symptoms or one or more conditions associated therewith). In certain embodiments, the terms “therapies” and “therapy” refer to drug therapy such as chemotherapy, adjuvant therapy, radiation, surgery, biological therapy, supportive therapy, antiviral therapy and/or other therapies useful in treatment, management, prevention, or amelioration of a condition or disorder or one or more symptoms thereof (e.g., cancer or one or more symptoms or one or more conditions associated therewith; a non-neoplastic condition or one or more symptoms or one or more conditions associated therewith; or, a viral infection or one or more symptoms or one or more conditions associated therewith). In certain embodiments, the term “therapy” refers to a therapy other than a Compound or pharmaceutical composition thereof. In specific embodiments, an “additional therapy” and “additional therapies” refer to a therapy other than a treatment using a Compound or pharmaceutical composition thereof. In a specific embodiment, a therapy includes the use of a Compound as an adjuvant therapy. For example, using a Compound in conjunction with a drug therapy such as chemotherapy, biological therapy, surgery, supportive therapy, antiviral therapy and/or other therapies useful in treatment, management, prevention, or amelioration of a condition or disorder or one or more symptoms thereof (e.g., cancer or one or more symptoms or one or more conditions associated therewith; a non-neoplastic condition or one or more symptoms or one or more conditions associated therewith; or, a viral infection or one or more symptoms or one or more conditions associated therewith).
  • As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the Compounds provided herein include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art, see for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton Pa. (1995).
  • As used herein, the terms “Compound” or “Compound provided herein” generally refer to a compound described in Section 5.1, Section 6.24, and Table 1, and pharmaceutically acceptable salts, racemates and stereoisomers thereof. In one embodiment, the terms refer to a compound of Formula I, II, III or IV. In another embodiment, the terms refer to a compound of Formula Ia, IIa, IIIa or IVa. In a specific embodiment, the terms refer to a compound depicted in Table 1. In one embodiment, the terms refer to a Compound disclosed in WO2005/089764, e.g., Compounds in the table on pages 26-98; WO2006/113703, e.g., Compounds in the table on pages 29-102; WO2008/127715, e.g., Compounds in the table on pages 52-126; WO2008/127714, e.g., Compounds in the table on pages 48-123; and United States Provisional Patent Application 61/181,653, entitled: METHODS FOR TREATING CANCER AND NON-NEOPLASTIC CONDITIONS, filed May 27, 2009, all of which are herewith incorporated by reference in their entirety. In certain embodiments, the terms “Compound” or “Compound provided herein” refer to a stereoisomer of a compound described in Section 5.1. The “Compound” or “Compound provided herein” may comprise one or more asymmetric carbon atoms, i.e. n asymmetric carbon atoms, having either R or S configuration as determined by a person skilled in the art. In one embodiment, the terms refer to a particular enantiomer, such as an R or S enantiomer of a “Compound” or “Compound provided herein”. In one embodiment, the terms refer to an R or S enantiomer of a compound of Formula I, II, III or IV. In another embodiment, the terms refer to an R or S enantiomer of a compound of Formula Ia, IIa, Ma or IVa. In a specific embodiment, the terms refer to an R or S enantiomer of a compound depicted in Table 1. It is understood that the terms “Compound” or “Compound provided herein” encompass all possible stereoisomers that may be generated based on all asymmetric carbon atoms. For example, if a Compound has two (n=2) assymetric carbon atoms, the terms “Compound” or “Compound provided herein” encompass all four, i.e. 2n=22=4, stereoisomers (R,S; R,R; S,S; S;R). The “Compound” or “Compound provided herein” may be a substantially pure (e.g., about 90%, about 95%, about 98%, about 99%, or about 99.9% pure) single stereoisomer or a mixture of two or more stereoisomers.
  • As used herein, the terms “pathologic,” “pathological” or “pathologically-induced,” in the context of the production of VEGF described herein, refer to the stress-induced expression of VEGF protein. In one embodiment, oncongenic transformation-induced expression of VEGF protein by tumor cells or other cells in the tumor environment is encompassed by the terms. In another embodiment, hypoxia-induced expression of VEGF protein in a chronic or traumatic inflammatory condition is encompassed by the terms. In another embodiment, in response to environmental stimuli, cells that disregulate or overproduce VEGF protein is also encompassed by the terms. As applicable, expression of VEGF protein supports inflammation, angiogenesis and tumor growth. The inhibition or reduction in pathological production of VEGF protein by a Compound can be assessed in cell culture and/or animal models as described herein.
  • As used herein, the term “about” means a range around a given value wherein the resulting value is substantially the same as the expressly recited value. In one embodiment, “about” means within 25% of a given value or range. For example, the phrase “about 70% by weight” comprises at least all values from 52% to 88% by weight. In another embodiment, the term “about” means within 10% of a given value or range. For example, the phrase “about 70% by weight” comprises at least all values from 63% to 77% by weight. In another embodiment, the term “about” means within 7% of a given value or range. For example, the phrase “about 70% by weight” comprises at least all values from 65% to 75% by weight.
  • Concentrations, amounts, cell counts, percentages and other numerical values may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • As used herein, the term “viral infection” refers to one or more RNA viruses belonging to families Bunyaviridae, Coronaviridae, Filoviridae, Flaviviridae, Paramyxoviridae, Picornaviridae, Orthomyxoviridae or Rhabdoviridae. Other embodiments include one or more viruses belonging to families Hepadnaviridae, Reoviridae or Retroviridae. Another embodiment includes one or more DNA viruses belonging to families Adenoviridae, Herpesviridae, Papillomaviridae or Papovaviridae.
  • As used herein, the term “viral replication,” in the context of viral infection, refers to production of viral RNA or DNA or production of one or more viral proteins from viruses using double-stranded (ds) DNA or RNA and/or single-stranded (ss) RNA and/or partial-double-stranded (ps) DNA or RNA and/or positive (+) strand RNA and/or negative (−) strand RNA. In one embodiment, the term includes viral DNA replication or viral RNA replication or viral RNA transcription and translation, resulting in the expression of one or more viral proteins by infected cells in tissues of a subject. In another embodiment, the term includes viral expression and/or sequestration and/or latency of viral proteins in chronic viral infection. In another embodiment, the term includes the effect of viruses on cellular biological processes to produce viral RNA or DNA or one or more viral proteins. As applicable, expression of one or more viral proteins may result in viral sequestration and/or latency, inflammation, organ failure and/or tumor growth. The inhibition or reduction in production of viral RNA or DNA or one or more viral proteins by a Compound can be assessed in cell culture and/or animal models as described herein.
  • As used herein, the term “viral replication complex,” in the context of viral infection, refers to a membrane-associated complex composed of viral proteins, replicating RNA and altered cellular membranes where viral RNA is replicated.
    • 4. DESCRIPTION OF THE DRAWINGS
  • FIG. 1. Dose Response of Compound 1205 and Compound #10: Inhibition of the Production of Hypoxia-Induced VEGF in HeLa Cells.
  • FIG. 2A-B. Effect of Compound 1205 on Intra-Tumor Human VEGF Levels. FIG. 2A. Effect of treatment with vehicle and Compound 1205 on intra-tumor VEGF levels for Study #21 (target tumor size: 1200 mm3) and Study #23 (target tumor size: 1500 mm3). FIG. 2B. Intra-tumor VEGF levels normalized to tumor size.
  • FIG. 3. Effect of Compound 1205 on Levels of Homeostatic Plasma Human VEGF for Study #21 and Study #23.
  • FIG. 4. Inhibition of HT1080 Tumor Growth by Compound # 10, 1205 and 1330. The symbol “++” represents a p value of p=0.051, signifying the difference in tumor size in Compound #10 treated mice from tumor size in vehicle-treated mice (Student's t-test) on Day 11. The symbol “**” represents a p value of p<0.05, signifying that the differences in tumor size in Compound 1205 (S,S diastereoisomer) treated mice were significantly different from tumor size in vehicle-treated mice and that the differences in tumor size in Compound 1205 (S,S diastereoisomer) treated mice were significantly different from tumor size in Compound 1330 (R,S diastereoisomer)-treated mice (ANOVA, multiple comparisons).
  • FIG. 5A-B. Cell Cycle Delay After Overnight Exposure to Compound 1205. Histograms depicting relative DNA content in HT1080 cells under normoxic conditions after treatment with Compound 1205 compared to vehicle. FIG. 5A. Histogram showing the effect of treatment with Compound 1205 at 10 nm. FIG. 5B. Histogram showing the effect of treatment with vehicle.
  • FIG. 6. Effect of Compound 1205 on Mouse Kidney VEGF Levels. Differences in VEGF levels are not statistically significant (p=0.38, ANOVA).
  • FIG. 7A-B. Effect of Compound #10 as monotherapy and in combination with a PI3-K inhibitor in a 786-0 Renal Cancer Cell Line. FIG. 7A. The effect of Compound #10 as monotherapy (test concentrations of 1 μM and 10 μM) and in combination with a PI3-K inhibitor (test concentrations of 1 μM and 10 μM) on protein expression in a series of Western blot analyses of lysates of various cell lines. FIG. 7B. The effect of Compound #10 as monotherapy and in combination with a PI3-K inhibitor on VEGF expression in a 786-0 Renal Cancer Cell.
  • FIG. 8A-B-C. Effect of Compound #10 as monotherapy on Protein Expression in Various Renal Cancer Cell Lines. FIG. 8A. The effect of Compound #10 as monotherapy on protein expression in a series of Western blot analyses of lysates of various cell lines from a 786-0 Renal Cancer Cell line. FIG. 8B. The effect of Compound #10 as monotherapy on protein expression in a series of Western blot analyses of lysates of various cell lines from a 769-P Renal Cancer Cell line. FIG. 8C. The effect of Compound #10 as monotherapy on protein expression in a series of Western blot analyses of lysates of various cell lines from a A498 Renal Cancer Cell line.
  • FIG. 9. Effect of Compound #10 monotherapy and combination therapy with Sunitinib on Tumor Volume in a VHL-Negative Tumor. Symbols for each agent represent the mean±SD for each treatment group (10 mice per group); where the symbol “*” represents a p value of p<0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in vehicle-treated mice (ANOVA, multiple comparisons vs vehicle) from Day 7 through Day 57, at which time vehicle-treated mice were taken off study; where the symbol “a” represents a p value of p<0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in Compound #10-treated mice (ANOVA, multiple comparisons vs Compound #10) from Day 33 through Day 88, at which time Compound #10-treated mice were taken off study; and, where the symbol “α” represents a p value of p<0.05, signifying that the differences in tumor size in sunitinib-treated or rapamycin-treated mice were significantly different from tumor size in their respective combination-treated mice (ANOVA, multiple comparisons) from Day 63 through Day 119, at which time combination-treated mice were taken off study. The Abbreviations are defined as follows: PO=oral dosing, QD=once per day, SE=standard error.
  • FIG. 10. Effect of Compound #10 monotherapy and combination therapy with Sunitinib on Body Weight in a VHL-Negative Tumor. Symbols for each agent represent the mean±SD for each treatment group (10 mice per group); where the symbol “*” represents a p value of p<0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in vehicle-treated mice (ANOVA, multiple comparisons vs vehicle) from Day 7 through Day 57, at which time vehicle-treated mice were taken off study; where the symbol “#” represents a p value of p<0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in Compound #10-treated mice (ANOVA, multiple comparisons vs Compound #10) from Day 33 through Day 88, at which time Compound #10-treated mice were taken off study; and, where the symbol “α” represents a p value of p<0.05, signifying that the differences in tumor size in sunitinib-treated or rapamycin-treated mice were significantly different from tumor size in their respective combination-treated mice (ANOVA, multiple comparisons) from Day 63 through Day 119, at which time combination-treated mice were taken off study. The Abbreviations are defined as follows: PO=oral dosing, QD=once per day, SE=standard error.
  • FIG. 11. Effect of Compound #10 monotherapy and combination therapy with Rapamycin on Tumor Volume in a VHL-Negative Tumor. Symbols for each agent represent the mean±SD for each treatment group (10 mice per group). The Abbreviations are defined as follows: PO=oral dosing, QD=once per day, SE=standard error.
  • FIG. 12. Effect of Compound #10 monotherapy and combination therapy with Rapamycin on Body Weight in a VHL-Negative Tumor. Symbols for each agent represent the mean±SD for each treatment group (10 mice per group); where the symbol “*” represents a p value of p<0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in vehicle-treated mice (ANOVA, multiple comparisons vs vehicle) from Day 7 through Day 57, at which time vehicle-treated mice were taken off study; where the symbol “#” represents a p value of p<0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in Compound #10-treated mice (ANOVA, multiple comparisons vs Compound #10) from Day 33 through Day 88, at which time Compound #10-treated mice were taken off study; and, where the symbol “α” represents a p value of p<0.05, signifying that the differences in tumor size in sunitinib-treated or rapamycin-treated mice were significantly different from tumor size in their respective combination-treated mice (ANOVA, multiple comparisons) from Day 63 through Day 119, at which time combination-treated mice were taken off study. The Abbreviations are defined as follows: PO=oral dosing, QD=once per day, SE=standard error.
  • FIG. 13. Effect of Compound #10 monotherapy and combination therapy with Sunitinib on Tumor Volume in a VHL-Positive Tumor. Symbols for each agent represent the mean±SD for each treatment group (10 mice per group). The Abbreviations are defined as follows: PO=oral dosing, QD=once per day, SE=standard error.
  • FIG. 14. Effect of Compound #10 monotherapy and combination therapy with Sunitinib on Body Weight in a VHL-Positive Tumor. Symbols for each agent represent the mean±SD for each treatment group (10 mice per group). The Abbreviations are defined as follows: PO=oral dosing, QD=once per day, SE=standard error.
  • FIG. 15. Effect of Compound #10 monotherapy and combination therapy with Rapamycin on Tumor Volume in a VHL-Positive Tumor. Symbols for each agent represent the mean±SD for each treatment group (10 mice per group). The Abbreviations are defined as follows: PO=oral dosing, QD=once per day, SE=standard error.
  • FIG. 16. Effect of Compound #10 monotherapy and combination therapy with Rapamycin on Body Weight in a VHL-Positive Tumor. Symbols for each agent represent the mean±SD for each treatment group (10 mice per group); where the symbol “*” represents a p value of p<0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in vehicle-treated mice (ANOVA, multiple comparisons vs vehicle) from Day 11 through Day 25, at which time vehicle-treated mice were taken off study; where the symbol “#” represents a p value of p<0.05, signifying that the differences in tumor size in treated mice were significantly different from tumor size in Compound #10-treated mice (ANOVA, multiple comparisons vs Compound #10); and, where the symbol “α” represents a p value of p<0.05, signifying that the differences in tumor size in sunitinib-treated or rapamycin-treated mice were significantly different from tumor size in their respective combination-treated mice (ANOVA, multiple comparisons). The Abbreviations are defined as follows: PO=oral dosing, QD=once per day, SE=standard error.
  • FIG. 17. Effect of Compound #10 monotherapy on target plasma concentrations. Target plasma trough levels between 550 and 1010 ng/mL have been achieved in patients having a variety of cancers.
  • FIG. 18. Effect of Compound #10 monotherapy and combination therapy with docetaxel on target plasma concentrations. Target plasma trough levels between 550 and 1010 ng/mL have been achieved in patients having a variety of cancers. The “*” symbol represents that the docetaxel PK profile is consistent with historical data (see, Bruno, et al., 1994, JCO, 16:187)
  • FIG. 19. Effect of Compound #10 monotherapy in a patient having thyroid cancer. In a patient having thyroid cancer, after three previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 20. Effect of Compound #10 monotherapy in a patient having melanoma. In a patient having melanoma, after two previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 21. Effect of Compound #10 monotherapy in a patient having chondrosarcoma. In a patient having chondrosarcoma, after one previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 22. Effect of Compound #10 monotherapy in a patient having cholangiocarcinoma. In a patient having cholangiocarcinoma, after four previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization for a tumor marker.
  • FIG. 23. Effect of Compound #10 monotherapy and combination therapy with docetaxel in a patient having head and neck cancer. In a patient having head and neck cancer with metastasis to the lung, after previous radiotherapy and no prior chemotherapy, the result of treatment with a combination of Compound #10 and docetaxel led to stabilization and reduction in a number of clinical parameters and tumor markers. The arrow symbol represents the timepoint at which docetaxel was reduced to 60 mg/m2.
  • FIG. 24. Effect of Compound #10 monotherapy in a patient jejunal adenocarcinoma. In a patient having cholangiocarcinoma with metastasis to the lung, after five previous therapeutic modalities for the metastasis, the result of monotherapy treatment with Compound #10 is presented.
  • FIG. 25. Use of Compound #10 monotherapy at various concentrations for treatment of various cancers. The scope of cancers being treated using Compound #10 monotherapy, where the data represented by the arrow symbol indicate individual patients continuing in therapy.
    •  5. DETAILED DESCRIPTION
  • Encompassed herein are Compounds capable of inhibiting the pathological production of human VEGF. Also encompassed herein are methods of treating cancer and non-neoplastic conditions using the Compounds as well as methods of using the Compounds to reduce pathological human VEGF production. Further encompassed herein are methods of treating viral infections using the Compounds as well as methods of using the Compounds to inhibit or reduce viral replication and/or production of viral RNA or DNA or viral protein.
    • 5.1 Compounds
  • In one embodiment, provided herein are Compounds having Formula (I):
  • Figure US20160340354A1-20161124-C00001
  • or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
    • X is hydrogen; C1 to C6 alkyl optionally substituted with one or more halogen substituents; hydroxyl; halogen; or C1 to C5 alkoxy optionally substituted with aryl;
    • A is CH or N;
    • B is CH or N, with the proviso that at least one of A or B is N, and that when A is N, B is CH;
    • R1 is hydroxyl; C1 to C8 alkyl optionally substituted with alkylthio, 5 to 10 membered heteroaryl, or aryl optionally substituted with one or more independently selected Ro substituents; C2 to C8 alkyenyl; C2 to C8 alkynyl; 3 to 12 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, oxo, amino, alkylamino, acetamino, thio, or alkylthio; 5 to 12 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, amino, alkylamino, acetamino, thio, or alkylthio; or aryl, optionally substituted with one or more independently selected Ro substituents;
    • Ro is a halogen; cyano; nitro; sulfonyl optionally substituted with C1 to C6 alkyl or 3 to 10 membered heterocycle; amino optionally substituted with C1 to C6 alkyl, —C(O)—Rb, —C(O)O—Rb, sulfonyl, alkylsulfonyl, 3 to 10 membered heterocycle optionally substituted with —C(O)O—Rn; —C(O)—NH—Rb; 5 to 6 membered heterocycle; 5 to 6 membered heteroaryl; C1 to C6 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, amino, or 3 to 12 membered heterocycle wherein amino and 3 to 12 membered heterocycle are optionally substituted with one or more C1 to C4 alkyl substituents optionally substituted with one or more substituents independently selected from C1 to C4 alkoxy, amino, alkylamino, or 5 to 10 membered heterocycle; —C(O)—Rn; or —ORa;
    • Ra is hydrogen; C2 to C8 alkylene; —C(O)—Rn; —C(O)O—Rb; —C(O)—NH—Rb; C3-C14cycloalkyl; aryl; heteroaryl; heterocyclyl; C1 to C8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C1 to C4 alkoxy, amino, alkylamino, acetamide, —C(O)—Rb, —C(O)O—Rb, aryl, 3 to 12 membered heterocycle, or 5 to 12 membered heteroaryl, further wherein the alkylamino is optionally substituted with hydroxyl, C1 to C4 alkoxy, or 5 to 12 membered heteroaryl optionally substituted with C1 to C4 alkyl, further wherein the acetamide is optionally substituted with C1 to C4 alkoxy, sulfonyl, or alkylsulfonyl, further wherein the 3 to 12 membered heterocycle is optionally substituted with C1 to C4 alkyl optionally substituted with hydroxyl, —C(O)—Rn, —C(O)O—Rn, or oxo, further wherein the amino is optionally substituted with C1 to C4 alkoxycarbonyl, imidazole, isothiazole, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, thiazole or sulfonyl substituted with C1 to C6 alkyl, wherein pyridine and thiazole are each optionally substituted with C1 to C4 alkyl;
    • Rb is hydroxyl; amino; alkylamino optionally substituted with hydroxyl, amino, alkylamino, C1 to C4 alkoxy, 3 to 12 membered heterocycle optionally substituted with one or more independently selected C1 to C6 alkyl, oxo, —C(O)O—Rn, or 5 to 12 membered heteroaryl optionally substituted with C1 to C4 alkyl; C1 to C4 alkoxy; C2 to C8 alkenyl; C2 to C8 alkynyl; aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from halogen or C1 to C4 alkoxy; 5 to 12 membered heteroaryl; 3 to 12 membered heterocycle optionally substituted with one or more substituents independently selected from acetamide, —C(O)O—Rn, 5 to 6 membered heterocycle, or C1 to C6 alkyl optionally substituted with hydroxyl, C1 to C4 alkoxy, amino, or alkylamino; or C1 to C8 alkyl optionally substituted with one or more substituents independently selected from C1 to C4 alkoxy, aryl, amino, or 3 to 12 membered heterocycle, wherein the amino and 3 to 12 membered heterocycle are optionally substituted with one or more substituents independently selected from C1 to C6 alkyl, oxo, or —C(O)O—Rn;
    • R2 is hydrogen; hydroxyl; 5 to 10 membered heteroaryl; C1 to C8 alkyl optionally substituted with hydroxyl, C1 to C4 alkoxy, 3 to 10 membered heterocycle, 5 to 10 membered heteroaryl, or aryl; —C(O)—Rc; —C(O)O—Rd; —C(O)—N(RdRd); —C(S)—N(RdRd); —C(S)—O—Re; —S(O2)—Re; —C(NRe)—S—Re; or —C(S)—S—Rf;
    • Rc is hydrogen; amino optionally substituted with one or more substituents independently selected from C1 to C6 alkyl or aryl; aryl optionally substituted with one or more substituents independently selected from halogen, haloalkyl, hydroxyl, C1 to C4 alkoxy, or C1 to C6 alkyl; —C(O)—Rn; 5 to 6 membered heterocycle optionally substituted with —C(O)—Rn; 5 to 6 membered heteroaryl; thiazoleamino; C1 to C8 alkyl optionally substituted with one or more substituents independently selected from halogen, C1 to C4 alkoxy, phenyloxy, aryl, —C(O)—Rn, —O—C(O)—Rn, hydroxyl, or amino optionally substituted with —C(O)O—Rn;
    • Rd is independently hydrogen; C2 to C8 alkenyl; C2 to C8 alkynyl; aryl optionally substituted with one or more substituents independently selected from halogen, nitro, C1 to C6 alkyl, —C(O)O—Re, or —ORe; or C1 to C8 alkyl optionally substituted with one or more substituents independently selected from halogen, C1 to C4 alkyl, C1 to C4 alkoxy, phenyloxy, aryl, 5 to 6 membered heteroaryl, —C(O)—Rn, —C(O)O—Rn, or hydroxyl, wherein the aryl is optionally substituted with one or more substituents independently selected from halogen or haloalkyl;
    • Re is hydrogen; C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halogen or alkoxy; or aryl optionally substituted with one or more substituents independently selected from halogen or alkoxy;
    • Rf is C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C1 to C4 alkoxy, cyano, aryl, or —C(O)—Rn, wherein the alkoxy is optionally substituted with one or more C1 to C4 alkoxy substituents and the aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C1 to C4 alkoxy, cyano, or C1 to C6 alkyl;
    • Rn is hydroxyl, C1 to C4 alkoxy, amino, or C1 to C6 alkyl;
    • R3 is hydrogen or —C(O)—Rg; and
    • Rg is hydroxyl; amino optionally substituted with cycloalkyl or 5 to 10 membered heteroaryl; or 5 to 10 membered heterocycle, wherein the 5 to 10 membered heterocycle is optionally substituted with —C(O)—Rn,
      with the proviso that the compound of Formula (I) is other than:
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole,
    • 1-(benzo[d][1,3]dioxol-5-yl)-N-benzyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-benzyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-benzyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • N-benzyl-1-phenyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • N,1-diphenyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • N-(naphthalen-1-yl)-1-phenyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • 1-(benzo[d][1,3]dioxol-5-yl)-N-cyclohexyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • 1-(benzo[d][1,3]dioxol-5-yl)-N-phenyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • 1-(3-chloro-4-methoxyphenyl)-N-phenyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N—((R)-1-phenylethyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N—((S)-1-phenylethyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-benzoyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxamide,
    • (R)—N-(1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonothioyl)benzamide,
    • benzyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate,
    • (R)-benzyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate,
    • methyl 1-phenyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate,
    • methyl 5-oxo-5-(1-phenyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)pentanoate,
    • 5-(1-(3-chloro-4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-5-oxopentanoic acid,
    • 5-(1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-5-oxopentanoic acid,
    • 3-(2-aminophenyl)-1-(1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)propan-1-one,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-chlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2,4-dichlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-fluorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N—((S)-1-phenylethyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-4-((1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbothioamido)methyl)benzoic acid,
    • (R)-methyl 4-((1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbothioamido)methyl)benzoate,
    • (R)-3-((1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbothioamido)methyl)benzoic acid,
    • (R)-methyl 3-((1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbothioamido)methyl)benzoate,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(trifluoromethyl)phenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(3-fluorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(4-chlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(3,4-dichlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(4-fluorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(3,4-dimethylbenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(3-chlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(naphthalen-1-ylmethyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbothioamide,
    • (3,4-difluorophenyl)-(1-phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-methanone,
    • 6-methoxy-1,2,3,4-tetrahydronorharmane,
    • 1,2,3,4-tetrahydronorharman-3-carboxylic acid,
    • 6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid,
    • 1-(4-methoxyphenyl)-1,2,3,4-tetrahydronorharman-3-carboxylic acid,
    • 1-methyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid,
    • 1-methyl-1,2,3,4-tetrahydronorharman-1,3-dicarboxylic acid,
    • 1-(diethylmethyl)-1,2,3,4-tetrahydronorharman-3-carboxylic acid,
    • (6-bromo-1,2,3,4-tetrahydronorharman-1-yl)-3-propionic acid,
    • 1-isobutyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid,
    • 1-phenyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid,
    • 1-propyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid,
    • 1-methyl-1-methoxycarbonyl-6-benzyloxy-1,2,3,4-tetrahydronorharmane,
    • 1-methyl-1-methoxycarbonyl-6-methoxy-1,2,3,4-tetrahydronorharmane,
    • 1-methyl-1-methoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydronorharmane,
    • 1-methyl-1-methoxycarbonyl-6-chloro-1,2,3,4-tetrahydronorharmane,
    • 1-methyl-1-methoxycarbonyl-6-bromo-1,2,3,4-tetrahydronorharmane,
    • 1-methyl-2-N-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline,
    • 2-N-acetyl-1,2,3,4-tetrahydro-β-carboline,
    • 1-methyl-2-N-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline,
    • 4-chlorobenzyl (1S,3R)-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxamide,
    • (3R)-1-(1-benzylindol-3-yl)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,
    • (3R)-1-(1-butylindol-3-yl)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,
    • (1S,3R)-1-(indol-3-yl)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,
    • (1S,3R)-1-(1-methylindol-3-yl)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,
    • benzothiazol-2-yl (1S,3R)-1-cyclohexyl-2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,
    • benzothiazol-2-yl (1S,3R)-1-cyclohexyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid,
    • 1-(4-chlorophenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(4-bromophenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(4-nitrophenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(4-dimethylaminophenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(4-diethylaminophenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(2,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(2,5-dimethoxyphenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(3,5-dimethoxyphenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(4-nitrobenzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(2-fluorenyl)-1,2,3,4-tetrahydro-β-carboline,
    • 1-(9-ethyl-9H-carbazol-3-yl)-1,2,3,4-tetrahydro-β-carb oline,
    • 6-chloro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • methyl 6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate,
    • 6-chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • phenylmethyl 6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate,
    • 6-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • methyl 6-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate,
    • 6-fluoro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • phenylmethyl 6-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate,
    • 6-bromo-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • methyl 6-bromo-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate,
    • 6-bromo-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • phenylmethyl 6-bromo-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate,
    • (1R)-6-chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • (1 S)-6-chloro-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • 1-(4-methylphenyl)-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • 2-acetyl-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • 1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • 6-(methyloxy)-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • 6-methyl-1-(4-methylphenyl)-2-(3-phenylpropanoyl)-2,3,4,9-tetrahydro-1H-β-carboline,
    • (1R/1S)-1-(2,3-dihydro-1-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline, or
    • 1-(1,3-benzodioxol-5-yl)-2-(2-pyrimidinyl)-2,3,4,9-tetrahydro-1H-β-carboline.
  • As will be evident to one of skill in the art, Compounds provided herein comprise at least one stereocenter, and may exist as a racemic mixture or as an enantiomerically pure composition. In one embodiment, a Compound provided herein is the (S) isomer, in an enantiomerically pure composition. In certain embodiments, the enantiomeric excess (e.e.) is about 90%, about 95%, about 99% or about 99.9% or greater.
  • In another embodiment, provided herein are Compounds having Formula (II):
  • Figure US20160340354A1-20161124-C00002
      • or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
      • X is hydrogen; C1 to C6 alkyl optionally substituted with one or more halogen substituents; hydroxyl; halogen; or C1 to C5 alkoxy optionally substituted with phenyl;
      • Ro is halogen; cyano; nitro; sulfonyl substituted with C1 to C6 alkyl or morpholinyl; amino optionally substituted with C1 to C6 alkyl, C(O)Rb, —C(O)O—Rb, alkylsulfonyl, morpholinyl or tetrahydropyranyl; C1 to C6 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen or amino; C(O)—Rn; or —ORa;
      • Ra is hydrogen; C2 to C8 alkenyl; —C(O)—Rn; —C(O)O—Rb; —C(O)—NH—Rb; C1 to C8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C1 to C4 alkoxy, C1 to C4 alkoxy C1 to C4 alkoxy, amino, alkylamino, dialkylamino, acetamide, —C(O)—Rb, —C(O)O—Rb, aryl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxolan-2-one, oxiranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3-triazole, 1,2,4-triazole, furan, imidazole, isoxazole, isothiazole, oxazole, pyrazole, thiazole, thiophene or tetrazole;
      • wherein amino is optionally substituted with C1 to C4 alkoxycarbonyl, imidazole, isothiazole, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, thiazole or sulfonyl substituted with C1 to C6 alkyl, wherein pyridine and thiazole are each optionally substituted with C1 to C4 alkyl;
      • wherein alkylamino and dialkylamino are each optionally substituted on alkyl with hydroxyl, C1 to C4 alkoxy, imidazole, pyrazole, pyrrole or tetrazole; and,
      • wherein morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl and oxiranyl are each optionally substituted with —C(O)—Rn, —C(O)O—Rn or C1 to C4 alkyl, wherein C1 to C4 alkyl is optionally substituted with hydroxyl;
      • Rb is hydroxyl; amino; alkylamino, optionally substituted on alkyl with hydroxyl, amino, alkylamino or C1 to C4 alkoxy; C1 to C4 alkoxy; C2 to C8 alkenyl; C2 to C8 alkynyl; aryl optionally substituted with one or more substituents independently selected from halogen and C1 to C4 alkoxy; furan; or C1 to C8 alkyl optionally substituted with one or more substituents independently selected from C1 to C4 alkoxy, aryl, amino, morpholinyl, piperidinyl or piperazinyl;
      • Rd is aryl optionally substituted with one or more substituents independently selected from halogen, nitro, C1 to C6 alkyl, —C(O)O—Re, and —ORe;
      • Re is hydrogen; C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halogen and alkoxy; or phenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from halogen and alkoxy; and
      • Rn is hydroxyl, C1 to C4 alkoxy, amino or C1 to C6 alkyl.
  • In another embodiment, provided herein are Compounds having Formula (II):
  • Figure US20160340354A1-20161124-C00003
  • or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
    • X is halogen;
    • Ro is halogen, substituted or unsubstituted C1 to C8 alkyl or ORa;
    • Ra is H, C1 to C8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and
    • Rd is phenyl optionally substituted with one or more alkoxy or halogen substituents.
  • In one embodiment, X is chloro or bromo.
  • In one embodiment, Rd is chloro or bromo.
  • In one embodiment, Ro is ORa.
  • In one embodiment, Ra is methyl, ethyl, propyl, isopropyl, butyl, or pentyl, each optionally substituted with one or more hydroxyl substituents.
  • In another embodiment, provided herein are Compounds having Formula (II):
  • Figure US20160340354A1-20161124-C00004
  • or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
    • X is halogen;
    • Ro is halogen, substituted or unsubstituted C1 to C8 alkyl or ORa;
    • Ra is H, or C1 to C8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and
    • Rd is phenyl optionally substituted with one or more halogen substituents.
  • In another embodiment, provided herein are Compounds having Formula (III):
  • Figure US20160340354A1-20161124-C00005
  • or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
    • X is halogen;
    • Ra is H, C1 to C8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and
    • Rd is phenyl substituted with one or more halogen substituents.
  • In another embodiment, provided herein are Compounds having Formula (IV):
  • Figure US20160340354A1-20161124-C00006
  • or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
    • X is halogen;
    • Ra is H, C1 to C8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and
    • Rd is phenyl substituted with one or more halogen substituents.
  • In another embodiment, provided herein are Compounds having Formula (IV):
  • Figure US20160340354A1-20161124-C00007
  • or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
    • X is halogen;
    • Ra is H, C1 to C8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and
    • Rd is phenyl substituted on a para position with a halogen substituent.
  • In another embodiment, the Compounds set forth above having a formula selected from Formula (Ia), Formula (IIa), Formula (IIIa) and Formula (IVa):
  • Figure US20160340354A1-20161124-C00008
  • Illustrative examples of Compounds or a pharmaceutically acceptable salt, racemate or stereoisomer thereof provided herein include:
  • TABLE 1
    Figure US20160340354A1-20161124-C00009
         		999
    Figure US20160340354A1-20161124-C00010
         		1000
    Figure US20160340354A1-20161124-C00011
         		1001
    Figure US20160340354A1-20161124-C00012
         		1002
    Figure US20160340354A1-20161124-C00013
         		1003
    Figure US20160340354A1-20161124-C00014
         		1004
    Figure US20160340354A1-20161124-C00015
         		1005
    Figure US20160340354A1-20161124-C00016
         		1006
    Figure US20160340354A1-20161124-C00017
         		1007
    Figure US20160340354A1-20161124-C00018
         		1008
    Figure US20160340354A1-20161124-C00019
         		1009
    Figure US20160340354A1-20161124-C00020
         		1010
    Figure US20160340354A1-20161124-C00021
         		1011
    Figure US20160340354A1-20161124-C00022
         		1012
    Figure US20160340354A1-20161124-C00023
         		1013
    Figure US20160340354A1-20161124-C00024
         		1014
    Figure US20160340354A1-20161124-C00025
         		1015
    Figure US20160340354A1-20161124-C00026
         		1016
    Figure US20160340354A1-20161124-C00027
         		1017
    Figure US20160340354A1-20161124-C00028
         		1018
    Figure US20160340354A1-20161124-C00029
         		1019
    Figure US20160340354A1-20161124-C00030
         		1020
    Figure US20160340354A1-20161124-C00031
         		1021
    Figure US20160340354A1-20161124-C00032
         		1022
    Figure US20160340354A1-20161124-C00033
         		1023
    Figure US20160340354A1-20161124-C00034
         		1024
    Figure US20160340354A1-20161124-C00035
         		1025
    Figure US20160340354A1-20161124-C00036
         		1026
    Figure US20160340354A1-20161124-C00037
         		1027
    Figure US20160340354A1-20161124-C00038
         		1028
    Figure US20160340354A1-20161124-C00039
         		1029
    Figure US20160340354A1-20161124-C00040
         		1030
    Figure US20160340354A1-20161124-C00041
         		1031
    Figure US20160340354A1-20161124-C00042
         		1032
    Figure US20160340354A1-20161124-C00043
         		1033
    Figure US20160340354A1-20161124-C00044
         		1034
    Figure US20160340354A1-20161124-C00045
         		1035
    Figure US20160340354A1-20161124-C00046
         		1036
    Figure US20160340354A1-20161124-C00047
         		1037
    Figure US20160340354A1-20161124-C00048
         		1038
    Figure US20160340354A1-20161124-C00049
         		1039
    Figure US20160340354A1-20161124-C00050
         		1040
    Figure US20160340354A1-20161124-C00051
         		1041
    Figure US20160340354A1-20161124-C00052
         		1042
    Figure US20160340354A1-20161124-C00053
         		1043
    Figure US20160340354A1-20161124-C00054
         		1044
    Figure US20160340354A1-20161124-C00055
         		1045
    Figure US20160340354A1-20161124-C00056
         		1046
    Figure US20160340354A1-20161124-C00057
         		1047
    Figure US20160340354A1-20161124-C00058
         		1048
    Figure US20160340354A1-20161124-C00059
         		1049
    Figure US20160340354A1-20161124-C00060
         		1050
    Figure US20160340354A1-20161124-C00061
         		1051
    Figure US20160340354A1-20161124-C00062
         		1052
    Figure US20160340354A1-20161124-C00063
         		1053
    Figure US20160340354A1-20161124-C00064
         		1054
    Figure US20160340354A1-20161124-C00065
         		1055
    Figure US20160340354A1-20161124-C00066
         		1056
    Figure US20160340354A1-20161124-C00067
         		1057
    Figure US20160340354A1-20161124-C00068
         		1058
    Figure US20160340354A1-20161124-C00069
         		1059
    Figure US20160340354A1-20161124-C00070
         		1060
    Figure US20160340354A1-20161124-C00071
         		1061
    Figure US20160340354A1-20161124-C00072
         		1062
    Figure US20160340354A1-20161124-C00073
         		1063
    Figure US20160340354A1-20161124-C00074
         		1064
    Figure US20160340354A1-20161124-C00075
         		1066
    Figure US20160340354A1-20161124-C00076
         		1067
    Figure US20160340354A1-20161124-C00077
         		1068
    Figure US20160340354A1-20161124-C00078
         		1069
    Figure US20160340354A1-20161124-C00079
         		1070
    Figure US20160340354A1-20161124-C00080
         		1071
    Figure US20160340354A1-20161124-C00081
         		1072
    Figure US20160340354A1-20161124-C00082
         		1073
    Figure US20160340354A1-20161124-C00083
         		1074
    Figure US20160340354A1-20161124-C00084
         		1075
    Figure US20160340354A1-20161124-C00085
         		1076
    Figure US20160340354A1-20161124-C00086
         		1077
    Figure US20160340354A1-20161124-C00087
         		1078
    Figure US20160340354A1-20161124-C00088
         		1079
    Figure US20160340354A1-20161124-C00089
         		1080
    Figure US20160340354A1-20161124-C00090
         		1081
    Figure US20160340354A1-20161124-C00091
         		1082
    Figure US20160340354A1-20161124-C00092
         		1083
    Figure US20160340354A1-20161124-C00093
         		1084
    Figure US20160340354A1-20161124-C00094
         		1085
    Figure US20160340354A1-20161124-C00095
         		1086
    Figure US20160340354A1-20161124-C00096
         		1087
    Figure US20160340354A1-20161124-C00097
         		1088
    Figure US20160340354A1-20161124-C00098
         		1089
    Figure US20160340354A1-20161124-C00099
         		1090
    Figure US20160340354A1-20161124-C00100
         		1091
    Figure US20160340354A1-20161124-C00101
         		1092
    Figure US20160340354A1-20161124-C00102
         		1093
    Figure US20160340354A1-20161124-C00103
         		1094
    Figure US20160340354A1-20161124-C00104
         		1095
    Figure US20160340354A1-20161124-C00105
         		1096
    Figure US20160340354A1-20161124-C00106
         		1097
    Figure US20160340354A1-20161124-C00107
         		1098
    Figure US20160340354A1-20161124-C00108
         		1099
    Figure US20160340354A1-20161124-C00109
         		1100
    Figure US20160340354A1-20161124-C00110
         		1101
    Figure US20160340354A1-20161124-C00111
         		1102
    Figure US20160340354A1-20161124-C00112
         		1103
    Figure US20160340354A1-20161124-C00113
         		1104
    Figure US20160340354A1-20161124-C00114
         		1105
    Figure US20160340354A1-20161124-C00115
         		1106
    Figure US20160340354A1-20161124-C00116
         		1107
    Figure US20160340354A1-20161124-C00117
         		1108
    Figure US20160340354A1-20161124-C00118
         		1109
    Figure US20160340354A1-20161124-C00119
         		1110
    Figure US20160340354A1-20161124-C00120
         		1111
    Figure US20160340354A1-20161124-C00121
         		1112
    Figure US20160340354A1-20161124-C00122
         		1113
    Figure US20160340354A1-20161124-C00123
         		1114
    Figure US20160340354A1-20161124-C00124
         		1115
    Figure US20160340354A1-20161124-C00125
         		1116
    Figure US20160340354A1-20161124-C00126
         		1117
    Figure US20160340354A1-20161124-C00127
         		1118
    Figure US20160340354A1-20161124-C00128
         		1119
    Figure US20160340354A1-20161124-C00129
         		1120
    Figure US20160340354A1-20161124-C00130
         		1121
    Figure US20160340354A1-20161124-C00131
         		1122
    Figure US20160340354A1-20161124-C00132
         		1123
    Figure US20160340354A1-20161124-C00133
         		1124
    Figure US20160340354A1-20161124-C00134
         		1125
    Figure US20160340354A1-20161124-C00135
         		1126
    Figure US20160340354A1-20161124-C00136
         		1127
    Figure US20160340354A1-20161124-C00137
         		1128
    Figure US20160340354A1-20161124-C00138
         		1129
    Figure US20160340354A1-20161124-C00139
         		1130
    Figure US20160340354A1-20161124-C00140
         		1131
    Figure US20160340354A1-20161124-C00141
         		1132
    Figure US20160340354A1-20161124-C00142
         		1133
    Figure US20160340354A1-20161124-C00143
         		1134
    Figure US20160340354A1-20161124-C00144
         		1135
    Figure US20160340354A1-20161124-C00145
         		1136
    Figure US20160340354A1-20161124-C00146
         		1137
    Figure US20160340354A1-20161124-C00147
         		1138
    Figure US20160340354A1-20161124-C00148
         		1139
    Figure US20160340354A1-20161124-C00149
         		1140
    Figure US20160340354A1-20161124-C00150
         		1141
    Figure US20160340354A1-20161124-C00151
         		1142
    Figure US20160340354A1-20161124-C00152
         		1143
    Figure US20160340354A1-20161124-C00153
         		1144
    Figure US20160340354A1-20161124-C00154
         		1145
    Figure US20160340354A1-20161124-C00155
         		1146
    Figure US20160340354A1-20161124-C00156
         		1147
    Figure US20160340354A1-20161124-C00157
         		1148
    Figure US20160340354A1-20161124-C00158
         		1149
    Figure US20160340354A1-20161124-C00159
         		1150
    Figure US20160340354A1-20161124-C00160
         		1151
    Figure US20160340354A1-20161124-C00161
         		1152
    Figure US20160340354A1-20161124-C00162
         		1153
    Figure US20160340354A1-20161124-C00163
         		1154
    Figure US20160340354A1-20161124-C00164
         		1155
    Figure US20160340354A1-20161124-C00165
         		1156
    Figure US20160340354A1-20161124-C00166
         		1157
    Figure US20160340354A1-20161124-C00167
         		1158
    Figure US20160340354A1-20161124-C00168
         		1159
    Figure US20160340354A1-20161124-C00169
         		1160
    Figure US20160340354A1-20161124-C00170
         		1161
    Figure US20160340354A1-20161124-C00171
         		1162
    Figure US20160340354A1-20161124-C00172
         		1163
    Figure US20160340354A1-20161124-C00173
         		1164
    Figure US20160340354A1-20161124-C00174
         		1165
    Figure US20160340354A1-20161124-C00175
         		1166
    Figure US20160340354A1-20161124-C00176
         		1167
    Figure US20160340354A1-20161124-C00177
         		1168
    Figure US20160340354A1-20161124-C00178
         		1169
    Figure US20160340354A1-20161124-C00179
         		1170
    Figure US20160340354A1-20161124-C00180
         		1171
    Figure US20160340354A1-20161124-C00181
         		1172
    Figure US20160340354A1-20161124-C00182
         		1173
    Figure US20160340354A1-20161124-C00183
         		1174
    Figure US20160340354A1-20161124-C00184
         		1175
    Figure US20160340354A1-20161124-C00185
         		1176
    Figure US20160340354A1-20161124-C00186
         		1177
    Figure US20160340354A1-20161124-C00187
         		1178
    Figure US20160340354A1-20161124-C00188
         		1179
    Figure US20160340354A1-20161124-C00189
         		1180
    Figure US20160340354A1-20161124-C00190
         		1181
    Figure US20160340354A1-20161124-C00191
         		1182
    Figure US20160340354A1-20161124-C00192
         		1183
    Figure US20160340354A1-20161124-C00193
         		1184
    Figure US20160340354A1-20161124-C00194
         		1185
    Figure US20160340354A1-20161124-C00195
         		1186
    Figure US20160340354A1-20161124-C00196
         		1187
    Figure US20160340354A1-20161124-C00197
         		1188
    Figure US20160340354A1-20161124-C00198
         		1189
    Figure US20160340354A1-20161124-C00199
         		1190
    Figure US20160340354A1-20161124-C00200
         		1191
    Figure US20160340354A1-20161124-C00201
         		1192
    Figure US20160340354A1-20161124-C00202
         		1193
    Figure US20160340354A1-20161124-C00203
         		1194
    Figure US20160340354A1-20161124-C00204
         		1195
    Figure US20160340354A1-20161124-C00205
         		1196
    Figure US20160340354A1-20161124-C00206
         		1197
    Figure US20160340354A1-20161124-C00207
         		1198
    Figure US20160340354A1-20161124-C00208
         		1199
    Figure US20160340354A1-20161124-C00209
         		1200
    Figure US20160340354A1-20161124-C00210
         		1201
    Figure US20160340354A1-20161124-C00211
         		1202
    Figure US20160340354A1-20161124-C00212
         		1203
    Figure US20160340354A1-20161124-C00213
         		1204
    Figure US20160340354A1-20161124-C00214
         		1205
    Figure US20160340354A1-20161124-C00215
         		1206
    Figure US20160340354A1-20161124-C00216
         		1207
    Figure US20160340354A1-20161124-C00217
         		1208
    Figure US20160340354A1-20161124-C00218
         		1209
    Figure US20160340354A1-20161124-C00219
         		1210
    Figure US20160340354A1-20161124-C00220
         		1211
    Figure US20160340354A1-20161124-C00221
         		1212
    Figure US20160340354A1-20161124-C00222
         		1213
    Figure US20160340354A1-20161124-C00223
         		1214
    Figure US20160340354A1-20161124-C00224
         		1215
    Figure US20160340354A1-20161124-C00225
         		1216
    Figure US20160340354A1-20161124-C00226
         		1217
    Figure US20160340354A1-20161124-C00227
         		1218
    Figure US20160340354A1-20161124-C00228
         		1219
    Figure US20160340354A1-20161124-C00229
         		1220
    Figure US20160340354A1-20161124-C00230
         		1221
    Figure US20160340354A1-20161124-C00231
         		1222
    Figure US20160340354A1-20161124-C00232
         		1223
    Figure US20160340354A1-20161124-C00233
         		1224
    Figure US20160340354A1-20161124-C00234
         		1225
    Figure US20160340354A1-20161124-C00235
         		1226
    Figure US20160340354A1-20161124-C00236
         		1227
    Figure US20160340354A1-20161124-C00237
         		1228
    Figure US20160340354A1-20161124-C00238
         		1229
    Figure US20160340354A1-20161124-C00239
         		1230
    Figure US20160340354A1-20161124-C00240
         		1231
    Figure US20160340354A1-20161124-C00241
         		1232
    Figure US20160340354A1-20161124-C00242
         		1233
    Figure US20160340354A1-20161124-C00243
         		1234
    Figure US20160340354A1-20161124-C00244
         		1235
    Figure US20160340354A1-20161124-C00245
         		1236
    Figure US20160340354A1-20161124-C00246
         		1237
    Figure US20160340354A1-20161124-C00247
         		1238
    Figure US20160340354A1-20161124-C00248
         		1239
    Figure US20160340354A1-20161124-C00249
         		1240
    Figure US20160340354A1-20161124-C00250
         		1241
    Figure US20160340354A1-20161124-C00251
         		1242
    Figure US20160340354A1-20161124-C00252
         		1243
    Figure US20160340354A1-20161124-C00253
         		1244
    Figure US20160340354A1-20161124-C00254
         		1245
    Figure US20160340354A1-20161124-C00255
         		1246
    Figure US20160340354A1-20161124-C00256
         		1247
    Figure US20160340354A1-20161124-C00257
         		1248
    Figure US20160340354A1-20161124-C00258
         		1249
    Figure US20160340354A1-20161124-C00259
         		1250
    Figure US20160340354A1-20161124-C00260
         		1251
    Figure US20160340354A1-20161124-C00261
         		1252
    Figure US20160340354A1-20161124-C00262
         		1253
    Figure US20160340354A1-20161124-C00263
         		1254
    Figure US20160340354A1-20161124-C00264
         		1255
    Figure US20160340354A1-20161124-C00265
         		1256
    Figure US20160340354A1-20161124-C00266
         		1257
    Figure US20160340354A1-20161124-C00267
         		1258
    Figure US20160340354A1-20161124-C00268
         		1259
    Figure US20160340354A1-20161124-C00269
         		1260
    Figure US20160340354A1-20161124-C00270
         		1261
    Figure US20160340354A1-20161124-C00271
         		1262
    Figure US20160340354A1-20161124-C00272
         		1263
    Figure US20160340354A1-20161124-C00273
         		1264
    Figure US20160340354A1-20161124-C00274
         		1265
    Figure US20160340354A1-20161124-C00275
         		1266
    Figure US20160340354A1-20161124-C00276
         		1267
    Figure US20160340354A1-20161124-C00277
         		1268
    Figure US20160340354A1-20161124-C00278
         		1269
    Figure US20160340354A1-20161124-C00279
         		1270
    Figure US20160340354A1-20161124-C00280
         		1271
    Figure US20160340354A1-20161124-C00281
         		1272
    Figure US20160340354A1-20161124-C00282
         		1273
    Figure US20160340354A1-20161124-C00283
         		1274
    Figure US20160340354A1-20161124-C00284
         		1275
    Figure US20160340354A1-20161124-C00285
         		1276
    Figure US20160340354A1-20161124-C00286
         		1277
    Figure US20160340354A1-20161124-C00287
         		1278
    Figure US20160340354A1-20161124-C00288
         		1279
    Figure US20160340354A1-20161124-C00289
         		1280
    Figure US20160340354A1-20161124-C00290
         		1281
    Figure US20160340354A1-20161124-C00291
         		1282
    Figure US20160340354A1-20161124-C00292
         		1283
    Figure US20160340354A1-20161124-C00293
         		1284
    Figure US20160340354A1-20161124-C00294
         		1285
    Figure US20160340354A1-20161124-C00295
         		1286
    Figure US20160340354A1-20161124-C00296
         		1287
    Figure US20160340354A1-20161124-C00297
         		1288
    Figure US20160340354A1-20161124-C00298
         		1289
    Figure US20160340354A1-20161124-C00299
         		1290
    Figure US20160340354A1-20161124-C00300
         		1291
    Figure US20160340354A1-20161124-C00301
         		1292
    Figure US20160340354A1-20161124-C00302
         		1293
    Figure US20160340354A1-20161124-C00303
         		1294
    Figure US20160340354A1-20161124-C00304
         		1295
    Figure US20160340354A1-20161124-C00305
         		1296
    Figure US20160340354A1-20161124-C00306
         		1297
    Figure US20160340354A1-20161124-C00307
         		1298
    Figure US20160340354A1-20161124-C00308
         		1299
    Figure US20160340354A1-20161124-C00309
         		1300
    Figure US20160340354A1-20161124-C00310
         		1301
    Figure US20160340354A1-20161124-C00311
         		1302
    Figure US20160340354A1-20161124-C00312
         		1303
    Figure US20160340354A1-20161124-C00313
         		1304
    Figure US20160340354A1-20161124-C00314
         		1305
    Figure US20160340354A1-20161124-C00315
         		1306
    Figure US20160340354A1-20161124-C00316
         		1307
    Figure US20160340354A1-20161124-C00317
         		1308
    Figure US20160340354A1-20161124-C00318
         		1309
    Figure US20160340354A1-20161124-C00319
         		1310
    Figure US20160340354A1-20161124-C00320
         		1311
    Figure US20160340354A1-20161124-C00321
         		1312
    Figure US20160340354A1-20161124-C00322
         		1313
    Figure US20160340354A1-20161124-C00323
         		1314
    Figure US20160340354A1-20161124-C00324
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    Figure US20160340354A1-20161124-C00325
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    Figure US20160340354A1-20161124-C00326
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    Figure US20160340354A1-20161124-C00327
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    Figure US20160340354A1-20161124-C00328
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    Figure US20160340354A1-20161124-C00329
         		1320
    Figure US20160340354A1-20161124-C00330
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    Figure US20160340354A1-20161124-C00331
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    Figure US20160340354A1-20161124-C00332
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    Figure US20160340354A1-20161124-C00333
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    Figure US20160340354A1-20161124-C00334
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    Figure US20160340354A1-20161124-C00335
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    Figure US20160340354A1-20161124-C00336
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    Figure US20160340354A1-20161124-C00337
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    Figure US20160340354A1-20161124-C00338
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    Figure US20160340354A1-20161124-C00339
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    Figure US20160340354A1-20161124-C00340
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    Figure US20160340354A1-20161124-C00341
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    Figure US20160340354A1-20161124-C00342
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    Figure US20160340354A1-20161124-C00343
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    Figure US20160340354A1-20161124-C00344
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    Figure US20160340354A1-20161124-C00345
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    Figure US20160340354A1-20161124-C00346
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    Figure US20160340354A1-20161124-C00347
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    Figure US20160340354A1-20161124-C00348
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    Figure US20160340354A1-20161124-C00349
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    Figure US20160340354A1-20161124-C00350
         		1341
    Figure US20160340354A1-20161124-C00351
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    Figure US20160340354A1-20161124-C00352
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    Figure US20160340354A1-20161124-C00353
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    Figure US20160340354A1-20161124-C00354
         		1345
    Figure US20160340354A1-20161124-C00355
         		1346
    Figure US20160340354A1-20161124-C00356
         		1347
    Figure US20160340354A1-20161124-C00357
         		1348
    Figure US20160340354A1-20161124-C00358
         		1349
    Figure US20160340354A1-20161124-C00359
         		1350
    Figure US20160340354A1-20161124-C00360
         		1351
    Figure US20160340354A1-20161124-C00361
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    Figure US20160340354A1-20161124-C00362
         		1353
    Figure US20160340354A1-20161124-C00363
         		1354
    Figure US20160340354A1-20161124-C00364
         		1355
    Figure US20160340354A1-20161124-C00365
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    Figure US20160340354A1-20161124-C00366
         		1357
    Figure US20160340354A1-20161124-C00367
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    Figure US20160340354A1-20161124-C00368
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    Figure US20160340354A1-20161124-C00369
         		1360
    Figure US20160340354A1-20161124-C00370
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    Figure US20160340354A1-20161124-C00371
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    Figure US20160340354A1-20161124-C00372
         		1363
    Figure US20160340354A1-20161124-C00373
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    Figure US20160340354A1-20161124-C00374
         		1365
    Figure US20160340354A1-20161124-C00375
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    Figure US20160340354A1-20161124-C00376
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    Figure US20160340354A1-20161124-C00377
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    Figure US20160340354A1-20161124-C00378
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    Figure US20160340354A1-20161124-C00379
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    Figure US20160340354A1-20161124-C00380
         		1371
    Figure US20160340354A1-20161124-C00381
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    Figure US20160340354A1-20161124-C00382
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    Figure US20160340354A1-20161124-C00383
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    Figure US20160340354A1-20161124-C00384
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    Figure US20160340354A1-20161124-C00385
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    Figure US20160340354A1-20161124-C00386
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    Figure US20160340354A1-20161124-C00387
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    Figure US20160340354A1-20161124-C00388
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    Figure US20160340354A1-20161124-C00389
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    Figure US20160340354A1-20161124-C00390
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    Figure US20160340354A1-20161124-C00391
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    Figure US20160340354A1-20161124-C00392
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    Figure US20160340354A1-20161124-C00393
         		1384
    Figure US20160340354A1-20161124-C00394
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    Figure US20160340354A1-20161124-C00395
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    Figure US20160340354A1-20161124-C00396
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    Figure US20160340354A1-20161124-C00397
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    Figure US20160340354A1-20161124-C00398
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    Figure US20160340354A1-20161124-C00399
         		1390
    Figure US20160340354A1-20161124-C00400
         		1391
    Figure US20160340354A1-20161124-C00401
         		1392
    Figure US20160340354A1-20161124-C00402
         		1393
    Figure US20160340354A1-20161124-C00403
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    Figure US20160340354A1-20161124-C00404
         		1395
    Figure US20160340354A1-20161124-C00405
         		1396
    Figure US20160340354A1-20161124-C00406
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    Figure US20160340354A1-20161124-C00407
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    Figure US20160340354A1-20161124-C00408
         		1399
    Figure US20160340354A1-20161124-C00409
         		1400
    Figure US20160340354A1-20161124-C00410
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    Figure US20160340354A1-20161124-C00411
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    Figure US20160340354A1-20161124-C00412
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    Figure US20160340354A1-20161124-C00413
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    Figure US20160340354A1-20161124-C00414
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    Figure US20160340354A1-20161124-C00415
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    Figure US20160340354A1-20161124-C00416
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    Figure US20160340354A1-20161124-C00417
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    Figure US20160340354A1-20161124-C00418
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    Figure US20160340354A1-20161124-C00419
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    Figure US20160340354A1-20161124-C00420
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    Figure US20160340354A1-20161124-C00421
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    Figure US20160340354A1-20161124-C00422
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    Figure US20160340354A1-20161124-C00423
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    Figure US20160340354A1-20161124-C00424
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    Figure US20160340354A1-20161124-C00425
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    Figure US20160340354A1-20161124-C00426
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    Figure US20160340354A1-20161124-C00427
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    Figure US20160340354A1-20161124-C00428
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    Figure US20160340354A1-20161124-C00429
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    Figure US20160340354A1-20161124-C00430
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    Figure US20160340354A1-20161124-C00431
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    Figure US20160340354A1-20161124-C00432
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    Figure US20160340354A1-20161124-C00433
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    Figure US20160340354A1-20161124-C00434
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    Figure US20160340354A1-20161124-C00435
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    Figure US20160340354A1-20161124-C00436
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    Figure US20160340354A1-20161124-C00437
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    Figure US20160340354A1-20161124-C00438
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    Figure US20160340354A1-20161124-C00439
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    Figure US20160340354A1-20161124-C00440
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    Figure US20160340354A1-20161124-C00441
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    Figure US20160340354A1-20161124-C00442
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    Figure US20160340354A1-20161124-C00443
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    Figure US20160340354A1-20161124-C00444
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    Figure US20160340354A1-20161124-C00445
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    Figure US20160340354A1-20161124-C00446
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    Figure US20160340354A1-20161124-C00447
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    Figure US20160340354A1-20161124-C00448
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    Figure US20160340354A1-20161124-C00449
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    Figure US20160340354A1-20161124-C00450
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    Figure US20160340354A1-20161124-C00451
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    Figure US20160340354A1-20161124-C00452
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    Figure US20160340354A1-20161124-C00453
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    Figure US20160340354A1-20161124-C00454
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    Figure US20160340354A1-20161124-C00455
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    Figure US20160340354A1-20161124-C00456
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    Figure US20160340354A1-20161124-C00457
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    Figure US20160340354A1-20161124-C00458
         		1449
    Figure US20160340354A1-20161124-C00459
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    Figure US20160340354A1-20161124-C00460
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    Figure US20160340354A1-20161124-C00461
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    Figure US20160340354A1-20161124-C00462
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    Figure US20160340354A1-20161124-C00463
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    Figure US20160340354A1-20161124-C00464
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    Figure US20160340354A1-20161124-C00465
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    Figure US20160340354A1-20161124-C00466
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    Figure US20160340354A1-20161124-C00467
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    Figure US20160340354A1-20161124-C00468
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    Figure US20160340354A1-20161124-C00469
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    Figure US20160340354A1-20161124-C00470
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    Figure US20160340354A1-20161124-C00471
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    Figure US20160340354A1-20161124-C00472
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    Figure US20160340354A1-20161124-C00473
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    Figure US20160340354A1-20161124-C00474
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    Figure US20160340354A1-20161124-C00475
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    Figure US20160340354A1-20161124-C00476
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    Figure US20160340354A1-20161124-C00477
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    Figure US20160340354A1-20161124-C00478
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    Figure US20160340354A1-20161124-C00479
         		1470
    Figure US20160340354A1-20161124-C00480
         		1471
    Figure US20160340354A1-20161124-C00481
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    Figure US20160340354A1-20161124-C00482
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    Figure US20160340354A1-20161124-C00483
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    Figure US20160340354A1-20161124-C00484
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    Figure US20160340354A1-20161124-C00485
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    Figure US20160340354A1-20161124-C00486
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    Figure US20160340354A1-20161124-C00487
         		1478
    Figure US20160340354A1-20161124-C00488
         		1479
    Figure US20160340354A1-20161124-C00489
         		1480
    Figure US20160340354A1-20161124-C00490
         		1481
    Figure US20160340354A1-20161124-C00491
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    Figure US20160340354A1-20161124-C00492
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    Figure US20160340354A1-20161124-C00493
         		1484
    Figure US20160340354A1-20161124-C00494
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    Figure US20160340354A1-20161124-C00495
         		1486
    Figure US20160340354A1-20161124-C00496
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    Figure US20160340354A1-20161124-C00497
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    Figure US20160340354A1-20161124-C00498
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    Figure US20160340354A1-20161124-C00499
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    Figure US20160340354A1-20161124-C00500
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    Figure US20160340354A1-20161124-C00501
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    Figure US20160340354A1-20161124-C00502
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    Figure US20160340354A1-20161124-C00503
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    Figure US20160340354A1-20161124-C00504
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    Figure US20160340354A1-20161124-C00505
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    Figure US20160340354A1-20161124-C00506
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    Figure US20160340354A1-20161124-C00507
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    Figure US20160340354A1-20161124-C00508
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    Figure US20160340354A1-20161124-C00509
         		1500
    Figure US20160340354A1-20161124-C00510
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    Figure US20160340354A1-20161124-C00511
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    Figure US20160340354A1-20161124-C00513
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    Figure US20160340354A1-20161124-C00514
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    Figure US20160340354A1-20161124-C00515
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    Figure US20160340354A1-20161124-C00516
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    Figure US20160340354A1-20161124-C00517
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    Figure US20160340354A1-20161124-C00518
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    Figure US20160340354A1-20161124-C00519
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    Figure US20160340354A1-20161124-C00520
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    Figure US20160340354A1-20161124-C00521
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    Figure US20160340354A1-20161124-C00522
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    Figure US20160340354A1-20161124-C00523
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    Figure US20160340354A1-20161124-C00524
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    Figure US20160340354A1-20161124-C00525
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    Figure US20160340354A1-20161124-C00526
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    Figure US20160340354A1-20161124-C00527
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    Figure US20160340354A1-20161124-C00528
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    Figure US20160340354A1-20161124-C00529
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    Figure US20160340354A1-20161124-C00530
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    Figure US20160340354A1-20161124-C00531
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    Figure US20160340354A1-20161124-C00532
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    Figure US20160340354A1-20161124-C00533
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    Figure US20160340354A1-20161124-C00534
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    Figure US20160340354A1-20161124-C00535
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    Figure US20160340354A1-20161124-C00536
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    Figure US20160340354A1-20161124-C00537
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    Figure US20160340354A1-20161124-C00538
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    Figure US20160340354A1-20161124-C00539
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    Figure US20160340354A1-20161124-C00540
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    Figure US20160340354A1-20161124-C00544
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    Figure US20160340354A1-20161124-C00545
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    Figure US20160340354A1-20161124-C00546
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    Figure US20160340354A1-20161124-C00549
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    Figure US20160340354A1-20161124-C00550
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    Figure US20160340354A1-20161124-C00551
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    Figure US20160340354A1-20161124-C00552
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    Figure US20160340354A1-20161124-C00553
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    Figure US20160340354A1-20161124-C00554
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    Figure US20160340354A1-20161124-C00555
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    Figure US20160340354A1-20161124-C00556
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    Figure US20160340354A1-20161124-C00557
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    Figure US20160340354A1-20161124-C00558
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    Figure US20160340354A1-20161124-C00559
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    Figure US20160340354A1-20161124-C00560
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    Figure US20160340354A1-20161124-C00561
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    Figure US20160340354A1-20161124-C00562
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    Figure US20160340354A1-20161124-C00563
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    Figure US20160340354A1-20161124-C00564
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    Figure US20160340354A1-20161124-C00565
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    Figure US20160340354A1-20161124-C00566
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    Figure US20160340354A1-20161124-C00567
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    Figure US20160340354A1-20161124-C00568
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    Figure US20160340354A1-20161124-C00569
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    Figure US20160340354A1-20161124-C00570
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    Figure US20160340354A1-20161124-C00571
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    Figure US20160340354A1-20161124-C00572
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    Figure US20160340354A1-20161124-C00573
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    Figure US20160340354A1-20161124-C00574
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    Figure US20160340354A1-20161124-C00575
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    Figure US20160340354A1-20161124-C00576
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    Figure US20160340354A1-20161124-C00578
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         		#10
  • Compounds can be prepared by those skilled in the art using known methods, including those set forth in International Publication Nos. WO2005/089764, WO2006/113703, WO2008/127715, WO2008/127714, and as disclosed in copending U.S. Provisional Patent Application Ser. No. 61/181,652, filed May 27, 2009, entitled “Processes for the Preparation of Substituted Tetrahydro Beta-Carbolines,” each of which is incorporated by reference herein in its entirety, as well as the procedures set forth below in Section 6.
    • 5.2 Pharmaceutical Properties and Formulations
  • 5.2.1 Activity
  • Without being bound by any theory, Compounds described herein inhibit the translation of pathologically expressed human VEGF mRNA and, thus, inhibit the pathologic production of human VEGF protein. In particular, the Compounds act specifically through a mechanism dependent on the 5′ untranslated region (UTR) of the human VEGF mRNA to inhibit the pathologic production of human VEGF protein. The activity of the Compounds tested is post-transcriptional since quantitative real-time polymerase chain reaction (PCR) assessments of mRNA have shown that the Compounds do not alter the levels of human VEGF mRNA.
  • For the antiviral activity of the Compounds, without being bound by any particular theory, several lines of evidence appear to indicate that the precise molecular target of the Compounds is a host cell target rather than a direct viral target (see Section 10, et. seq., infra). For example, (1) broad spectrum activity against viruses from diverse and not closely related taxa; (2) the failure to select for a resistant HCV replicon despite long-term exposure at inhibitory concentrations of a Compound in cell culture; and (3) the lack of anti-PV activity in an HT-1080 cell line which is resistant to the cell cycle delay induced by a Compound.
  • 5.2.1.1 Inhibition of Pathological VEGF Production
  • Compounds are described that reduce or inhibit pathological production of human VEGF (also known as VEGF-A and vascular permeability factor (VPF)). Exemplary Compounds have been shown to reduce or inhibit tumor production of VEGF as measured in cell culture and/or preclinical tumor models. Furthermore, the Compounds tested do not affect physiological plasma VEGF levels in healthy humans.
  • By way of background, the human VEGF-A gene encodes a number of different products (isoforms) due to alternative splicing. The VEGF-A isoforms include VEGF121, VEGF165, VEGF189 and VEGF206 having 121, 165, 189 and 206 amino acids, respectively. VEGF165 and VEGF121 isoforms are soluble, whereas VEGF189 and VEGF206 isoforms are sequestered within the extracellular matrix. The activity of the Compounds tested was assessed by measuring the concentrations of soluble VEGF in cell culture systems. In preclinical tumor models, the activity of the Compounds tested was assessed by measuring the concentrations of soluble VEGF. The data indicate that the Compounds tested inhibit the production of soluble forms of tumor derived VEGF.
  • In particular, a Compound provided herein has been shown to selectively inhibit stress (e.g., hypoxia) induced production of soluble human VEGF isoforms in cell culture without affecting soluble human VEGF production under normoxic conditions (see Section 8.1 et seq.). Thus, the Compound was shown to preferentially inhibit pathological production of soluble human VEGF isoforms resulting from hypoxia while sparing homeostatic production of soluble isoforms in unperturbed cells. Accordingly, in specific embodiments, a Compound selectively inhibits or reduces the pathological production of a soluble human VEGF isoform over inhibiting or reducing physiological or homeostatic production of a soluble human VEGF isoform.
  • In a specific embodiment, a Compound selectively inhibits or reduces the pathological production of a matrix-bound human VEGF isoform over inhibiting or reducing physiological production of a matrix-bound human VEGF isoform. In another specific embodiment, a Compound selectively inhibits or reduces the pathological production of one or more soluble human VEGF isoforms and one or more matrix-bound VEGF isoforms.
  • 5.2.1.2 Inhibition of Pathological Angiogenesis and Tumor Growth
  • Compounds are described that reduce or inhibit tumor growth. A Compound provided herein has been shown to have a profound effect on the architecture of the tumor vasculature in animal models with pre-established human tumors. The Compound reduced the total volume and diameter of blood vessels formed compared to vehicle treated subjects. See Section 8.2. A Compound showed inhibition of tumor growth in the model. A dose-response effect of the Compound that correlated with decreases in tumor and plasma VEGF concentrations was observed when tumor size was assessed. See Section 8.1.3. Thus, in one embodiment, the concentration of soluble human VEGF in human plasma is used to assess and monitor the pharmacodynamic effect of a Compound provided herein. In a specific embodiment, the concentration of either VEGF121, VEGF165, or both in human plasma are used to assess and monitor the pharmacodynamic effect of a Compound provided herein.
  • 5.2.1.3 Prolongation of Early G1/Early S-Phase Cell Cycle Delay
  • Provided herein are Compounds that provoke a prolongation of early G1/early S-Phase cell cycle delay.
  • In addition to its effects on pathological VEGF production, a Compound provided herein provokes a late G1/early S-Phase cell cycle delay, i.e., between the late resting or pre-DNA synthesis phase, and the early DNA synthesis phase in those tumor cell lines in which VEGF generation is decreased by the Compound. See Section 8.3. Further characterization indicates that this effect is concentration dependent, occurring at low nanomolar EC50 values similar to those associated with reducing pathological VEGF production. The cell cycle delay and inhibition of pathological VEGF protein production occur in concert, linking these phenotypes in inflammation, pathological angiogenesis and tumor growth. Inhibition of pathological VEGF production in these same tumor cells with small interfering RNA (siRNA) does not induce a cell cycle defect (data not shown). Conversely, mimosine, a DNA synthesis inhibitor that halts cell cycle progression at the G1/S interface, does not reduce VEGF production (data not shown). In vivo, a Compound provided herein demonstrated in a HT1080 xenograft model that the Compound delays cycling through S-phase; this effect is distinct from that with bevacizumab, which has no effect on tumor cell cycling. Thus, these experiments indicate that the effects of the Compound on the tumor cell cycle occur in parallel with its actions on pathological VEGF production in tumors.
  • 5.2.1.4 Inhibition of Viral Replication and the Production of Viral RNA or DNA or Viral Protein
  • Provided herein are Compounds that dose-dependently inhibit viral replication or the production of viral RNA or DNA or viral protein in a diverse panel of viruses. See Section 10.
  • In viral cell lines in which viral RNA or DNA or viral protein production is decreased by a Compound, further characterization indicates that inhibition of viral replication and production of viral RNA or DNA or viral protein is concentration dependent. Without being bound by any particular theory, the Compound appears to inhibit viral replication and production of viral RNA or DNA or viral protein by interefering with the biological processes of the host cell to inhibit or prevent the formation of a viral replication complex in a cell or in the endoplasmic reticulum. The interference of the Compound with the biological processes of the host cell is supported by data that includes: (1) broad spectrum activity against viruses from diverse and not closely related taxa; (2) the failure to select a resistant viral replicon despite long-term exposure at inhibitory concentrations of a Compound in cell culture; and (3) the lack of antiviral activity in a cell line which is resistant to the cell cycle delay induced by the Compound. Thus, these experiments indicate that the effects of the Compound on the host cell processes occur in parallel with the effects on viral replication and production of viral RNA or DNA or viral protein.
    • 5.3 Formulations
  • The Compounds provided herein can be administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups. Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient selected from fillers or diluents, binders, disintegrants, lubricants, flavoring agents, preservatives, stabilizers, suspending agents, dispersing agents, surfactants, antioxidants or solubilizers.
  • Excipients that may be selected are known to those skilled in the art and include, but are not limited to fillers or diluents (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate and the like), a binder (e.g., cellulose, carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol or starch and the like), a disintegrants (e.g., sodium starch glycolate, croscarmellose sodium and the like), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate and the like), a flavoring agent (e.g., citric acid, or menthol and the like), a preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben and the like), a stabilizer (e.g., citric acid, sodium citrate or acetic acid and the like), a suspending agent (e.g., methylcellulose, polyvinyl pyrrolidone or aluminum stearate and the like), a dispersing agent (e.g., hydroxypropylmethylcellulose and the like), surfactants (e.g., sodium lauryl sulfate, polaxamer, polysorbates and the like), antioxidants (e.g., ethylene diamine tetraacetic acid (EDTA), butylated hydroxyl toluene (BHT) and the like) and solubilizers (e.g., polyethylene glycols, SOLUTOL®, GELUCIRE® and the like). The effective amount of the Compound provided herein in the pharmaceutical composition may be at a level that will exercise the desired effect. Effective amounts contemplated are further discussed in Section 5.6 infra.
  • In any given case, the amount of the Compound provided herein administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • The Compound provided herein can be formulated for any route of administration. In a specific embodiment the Compound provided herein is formulated for intradermal, intramuscular, intraperitoneal, percutaneous, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, or mucosal administration, for inhalation, or topical administration to to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.
  • In one embodiment, the Compound provided herein is administered orally using a capsule dosage form composition, wherein the capsule contains the Compound provided herein without an additional carrier, excipient or vehicle.
  • In another embodiment, provided herein are compositions comprising an effective amount of a Compound provided herein and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.
  • Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit. In general, the composition is prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing a Compound provided herein with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
    • 5.4 Methods of Use
  • Presented herein are methods for inhibiting or reducing pathological production of human VEGF. In a specific embodiment, a method for inhibiting or reducing pathological production of human VEGF, comprises contacting a Compound or a composition thereof with a cell or cell line that pathologically produces human VEGF or are induced to pathologically produce human VEGF. The cell or cell line may be a cancer cell that pathologically produces human VEGF. Alternatively, or in addition, the cell or cell line may be induced to pathologically produce human VEGF by, e.g., exposure to stress such as hypoxia. Non-limiting examples of cell lines include HeLa, HT1080, HCT116, HEK293, NCI H460, U-87MG, ASPC-1, PL-45, HPAF-2, PC-3, MDA-MB-231, MDA-MB-468, A431, SNU-1, AGS, Kato III, A549, Calu-6, A375, SY5Y, SKOV3, Capan-1, sNF96.2, TIVE-L1, TIVE-L2, and LNCaP cells. In another embodiment, a method for inhibiting or reducing pathological production of human VEGF in a subject, comprises administering to a subject a Compound or a composition thereof. In certain embodiments, the subject has a condition associated with the pathological production of human VEGF. In specific embodiments, the subject is diagnosed with cancer or a non-neoplastic condition associated with pathological production of human VEGF.
  • In specific embodiments, the methods for inhibiting or reducing the pathological production of human VEGF provided herein inhibit or decrease pathological production of human VEGF by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to pathological production of human VEGF prior to administration of a Compound, as assessed by methods well known in the art. In particular embodiments, the methods for inhibiting or reducing the pathological production of human VEGF provided herein inhibit or decrease pathological production of human VEGF in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 40% to 100%, relative to pathological production of human VEGF prior to administration of a Compound or any range in between, as assessed by methods well known in the art.
  • Methods for inhibiting or reducing pathological angiogenesis or vascularization are also presented herein. In a specific embodiment, a method for inhibiting or reducing pathological angiogenesis or vascularization in a subject, comprises administering to a subject a Compound or a composition thereof. In certain embodiments, the subject has a condition associated with the pathological angiogenesis or vascularization. In specific embodiments, the subject is diagnosed with cancer or a non-neoplastic condition associated with pathological production of human VEGF.
  • In specific embodiments, the methods inhibiting or reducing pathological angiogenesis or vascularization provided herein inhibit or reduce angiogenesis or vascularization, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to angiogenesis or vascularization prior to administration of a Compound, as assessed by methods well known in the art, e.g., MRI scan, CT scan, PET scan. In particular embodiments, the methods for inhibiting or reducing pathological angiogenesis or vascularization provided herein inhibit or reduce angiogenesis or vascularization in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 40% to 100%, relative to angiogenesis or vascularization prior to administration of a Compound or any range in between, as assessed by methods well known in the art, e.g., MRI scan, CT scan, PET scan.
  • Presented herein are methods for treating a viral infection by inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein. In a specific embodiment, a method for inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein comprises contacting a Compound or a composition thereof with a cell or cell line that produces a virus or viral RNA or DNA or viral protein or may be induced to produce the virus or viral RNA or DNA or viral protein. The cell or cell line may be a virus-infected cell that constitutively produces a virus or viral RNA or DNA or viral protein. Alternatively, or in addition, the cell or cell line may be induced to produce a virus or viral RNA or DNA or viral protein by, e.g., exposure to an active virus. Non-limiting examples of viral cell lines include HeLa, Vero, Vero E6, MDCK, MT-2 and the like. In another embodiment, a method for treating a viral infection by inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein in a subject, comprises administering to a subject a Compound or a composition thereof. In certain embodiments, the subject has a viral infection or a condition associated with viral replication or the production of viral RNA or DNA or viral protein. In specific embodiments, the subject is diagnosed with a viral infection associated with viral replication or the production of viral RNA or DNA or viral protein.
  • In specific embodiments, the methods for treating a viral infection by inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein provided herein inhibit or decrease viral replication or the production of viral RNA or DNA or viral protein by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to viral replication or the production of viral RNA or DNA or viral protein prior to administration of a Compound, as assessed by methods well known in the art. In particular embodiments, the methods for inhibiting or reducing viral replication or the production of viral RNA or DNA or viral protein provided herein inhibit or decrease viral replication or the production of viral RNA or DNA or viral protein in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 40% to 100%, relative to viral replication or the production of viral RNA or DNA or viral protein prior to administration of a Compound or any range in between, as assessed by methods well known in the art.
  • Methods for treating cancer, non-neoplastic conditions and viral infections are also presented herein. In one aspect, the methods for treating cancer or a non-neoplastic condition or a viral infection involve the administration of a Compound, as a single agent therapy, to a patient in need thereof. In a specific embodiment, presented herein is a method for treating cancer or a non-neoplastic condition or a viral infection, comprising administering to a patient in need thereof an effective amount of a Compound, as a single agent. In another embodiment, presented herein is a method for treating cancer or a non-neoplastic condition or a viral infection, comprising administering to a patient in need thereof a pharmaceutical composition comprising a Compound, as the single active ingredient, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • In another aspect, the methods for treating cancer or a non-neoplastic condition or a viral infection involve the administration of a Compound in combination with another therapy (e.g., one or more additional therapies that do not comprise a Compound, or that comprise a different Compound) to a patient in need thereof. Such methods may involve administering a Compound prior to, concurrent with, or subsequent to administration of the additional therapy. In certain embodiments, such methods have an additive or synergistic effect. In a specific embodiment, presented herein is a method for treating cancer or a non-neoplastic condition, comprising administering to a patient in need thereof an effective amount of a Compound and an effective amount of another therapy.
  • In specific embodiments, any cancer or non-neoplastic condition that is associated with pathological production of VEGF or a viral infection associated with viral replication or the production of viral RNA or DNA or viral protein can be treated in accordance with the methods provided herein.
  • In another specific embodiment, the cancer treated in accordance with the methods provided herein is a solid tumor cancer. Solid tumor cancers include, but are not limited to, sarcomas, carcinomas, and lymphomas. In specific embodiments, cancers that can be treated in accordance with the methods described include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, esophagus, chest, bone, lung, kidney, colon, rectum or other gastrointestinal tract organs, stomach, spleen, skeletal muscle, subcutaneous tissue, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system.
  • Specific examples of cancers that can be treated in accordance with the methods provided herein include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplastic syndrome, chronic leukemias such as but not limited to, chronic myclocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, non-Hodgkin's disease; multiple myelomas such as but not limited to smoldering multiple mycloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget's disease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease (including juvenile Paget's disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; KRAS-mutated colorectal cancer; colon carcinoma; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, androgen-independent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer); renal carcinoma; Wilms' tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.
  • In certain embodiments cancers that can be treated in accordance with the methods provided herein include, the following: pediatric solid tumor, Ewing's sarcoma, Wilms tumor, neuroblastoma, neurofibroma, carcinoma of the epidermis, malignant melanoma, cervical carcinoma, colon carcinoma, lung carcinoma, renal carcinoma, breast carcinoma, breast sarcoma, metastatic breast cancer, HIV-related Kaposi's sarcoma, prostate cancer, androgen-independent prostate cancer, androgen-dependent prostate cancer, neurofibromatosis, lung cancer, non-small cell lung cancer, KRAS-mutated non-small cell lung cancer, malignant melanoma, melanoma, colon cancer, KRAS-mutated colorectal cancer, glioblastoma multiforme, renal cancer, kidney cancer, bladder cancer, ovarian cancer, hepatocellular carcinoma, thyroid carcinoma, rhabdomyosarcoma, acute myeloid leukemia, and multiple myeloma.
  • In certain embodiments, cancers and conditions associated therewith that are treated in accordance with the methods provided herein are breast carcinomas, lung carcinomas, gastric carcinomas, esophageal carcinomas, colorectal carcinomas, liver carcinomas, ovarian carcinomas, thecomas, arrhenoblastomas, cervical carcinomas, endometrial carcinoma, endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma, head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinomas, hepatoblastoma, Kaposi's sarcoma, melanoma, skin carcinomas, hemangioma, cavernous hemangioma, hemangioblastoma, pancreas carcinomas, retinoblastoma, astrocytoma, glioblastoma, Schwannoma, oligodendroglioma, medulloblastoma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, renal cell carcinoma, prostate carcinoma, abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), or Meigs' syndrome. In specific embodiment, the cancer an astrocytoma, an oligodendroglioma, a mixture of oligodendroglioma and an astrocytoma elements, an ependymoma, a meningioma, a pituitary adenoma, a primitive neuroectodermal tumor, a medullblastoma, a primary central nervous system (CNS) lymphoma, or a CNS germ cell tumor. In specific embodiments, the cancer treated in accordance with the methods provided herein is an acoustic neuroma, an anaplastic astrocytoma, a glioblastoma multiforme, or a meningioma. In other specific embodiments, the cancer treated in accordance with the methods provided herein is a brain stem glioma, a craniopharyngioma, an ependyoma, a juvenile pilocytic astrocytoma, a medulloblastoma, an optic nerve glioma, primitive neuroectodermal tumor, or a rhabdoid tumor.
  • Specific examples of non-neoplastic conditions that can be treated in accordance with the methods described herein include cystic fibrosis, muscular dystrophy, polycystic autosomal-dominant kidney disease, cancer-induced cachexia, benign prostatic hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, retinopathies (including diabetic retinopathy and retinopathy of prematurity), retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, exudative macular degeneration, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, and pterygium keratitis sicca, viral infections, inflammation associated with viral infections, chronic inflammation, lung inflammation, nephrotic syndrome, preeclampsia, ascites, pericardial effusion (such as that associated with pericarditis), pleural effusion, Sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infection, Herpes zoster infections, protozoan infections, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, Paget's disease, scleritis, Stevens-Johnson's disease, pemphigoid, radial keratotomy, Eales' disease, Behcet's disease, sickle cell anemia, pseudoxanthoma elasticum, Stargardt's disease, pars planitis, chronic retinal detachment, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, ocular histoplasmosis, Mycobacteria infections, Lyme's disease, Best's disease, myopia, optic pits, hyperviscosity syndromes, toxoplasmosis, sarcoidosis, trauma, post-laser complications, diseases associated with rubeosis (neovascularization of the iris and of the angle), and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue, including all forms of prolific vitreoretinopathy.
  • In another embodiment, viral infections that can be treated in accordance with the methods described herein include those associated with (+) strand RNA or (−) strand RNA viruses belonging to the families Bunyaviridae, Coronaviridae, Filoviridae, Flaviviridae, Paramyxoviridae, Picornaviridae, Orthomyxoviridae or Rhabdoviridae. Other embodiments include viral infections associated with double-stranded RNA viruses belonging to the family Reoviridae or viruses belonging to the families Retroviridae or Hepadnaviridae. Another embodiment includes viral infections by DNA viruses belonging to the families Adenoviridae, Herpesviridae, Papillomaviridae or Papovaviridae.
  • Certain examples of viral infections that can be treated in accordance with the methods described herein include viral infections, including but not limited to, those associated with viruses belonging to Flaviviridae (such as West Nile virus (WNV), hepatitis C virus (HCV), yellow fever virus (YFV) and dengue virus (DENV)), Paramyxoviridae (such as parainfluenza virus and respiratory syncytial virus (RSV)), Picornaviridae (such as poliovirus (PV), hepatitis A virus (HAV), coxsackievirus and rhinovirus), Coronaviridae (such as severe acute respiratory syndrome coronavirus (SARS-CoV)), Orthomyxoviridae (such as influenza virus), or Filoviridae (such as Ebola and Marburg viruses). In one embodiment, the term refers to viral infections by members of the family Retroviridae (such as human immunodeficiency virus (HIV) and human T cell leukemia viruses (HTLV)), Hepadnaviridae (such as hepatitis B virus (HBV)). In another embodiment, the term refers to viral infections by DNA viruses (such as herpes simplex virus (HSV), Kaposi's sarcoma-associated herpesvirus, adenovirus, vaccinia virus or human papilloma virus (HPV)).
  • In one embodiment, the viral infection is by West Nile virus, hepatitis C virus, yellow fever virus, dengue virus, respiratory syncytial virus, poliovirus, severe acute respiratory syndrome coronavirus, influenza virus, parainfluenza virus, human immunodeficiency virus, human T cell leukemia viruses, herpes simplex virus or vaccinia virus. In another embodiment, the viral infection is by West Nile virus, hepatitis C virus, dengue virus, respiratory syncytial virus, poliovirus, influenza virus, parainfluenza virus or human immunodeficiency virus. In another embodiment, the viral infection is by a known or unknown genotype of the hepatitis C virus. In another embodiment, the genotype of the hepatitis C virus is the hepatitis C virus genotype 1a, the hepatitis C virus genotype 1b or the hepatitis C virus genotype 2a.
  • In certain embodiments examples of non-neoplastic conditions associated with pathological production of VEGF that can be treated with the methods described herein include diabetic retiopathy, exudative macular degeneration, rheumatoid arthritis, psoriasis, artheriosclerosis, chronic inflammation, obesity, and polycystic autosomal-dominant kidney disease.
  • The concentration of VEGF or other angiogenic or inflammatory mediators (e.g., P1GF, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, IL-6 and/or IL-8) in a biological specimen (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids) may be used to monitor the efficacy of a course of treatment for cancer or a non-neoplastic condition involving the administration of a compound that inhibits or reduces the pathological production of human VEGF, such as a Compound described herein or a compound described in U.S. Publication No. 2005-0272759 (having corresponding International Application Publication No. WO2005/089764), U.S. Publication No. 2005-0282849 (having corresponding International Application Publication No. WO2006/113703), U.S. Publication No. 2007-0254878 (having corresponding International Application Publication No. WO2008/127715), International Application Publication No. WO2008/127714, U.S. Provisional Application Ser. No. 60/181,649, filed May 27, 2009, entitled “Methods for Treating Prostate Cancer;” U.S. Provisional Application Ser. No. 60/181,651, filed May 27, 2009, entitled “Methods for Treating Kaposi's Sarcoma;” U.S. Provisional Application Ser. No. 60/181,650, filed May 27, 2009, entitled “Methods for Treating Neurofibromatosis;” U.S. Provisional Application Ser. No. 60/181,654, filed May 27, 2009, entitled “Methods for Treating Brain Cancer;” or U.S. Provisional Application Ser. No. 60/253,086, filed Oct. 20, 2009, entitled “Methods for Treating Breast Cancer,” each of which is incorporated herein by reference in its entirety. The dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient may also be modified as a result of the concentration of VEGF or other angiogenic or inflammatory mediators. Alternatively, the changes in these monitoring the concentration of VEGF or other angiogenic or inflammatory mediators might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the cancer or a non-neoplastic condition.
  • In certain embodiments, the concentration of VEGF or other angiogenic or inflammatory mediators in biological specimens (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids) of a patient is monitored before, during and/or after a course of treatment for cancer involving the administration of a Compound or a pharmaceutical composition thereof to the patient. In certain embodiments, the tumoral blood flow or metabolism, or peritumoral inflammation or edema in a patient is monitored before, during and/or after a course of treatment for cancer involving the administration of a Compound or a pharmaceutical composition. The dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient might be modified as a result of the concentration of VEGF or other angiogenic or inflammatory mediators, or of tumoral blood flow or metabolism, or peritumoral inflammation or edema as assessed by imaging techniques. Alternatively, the changes in these monitoring parameters (e.g., concentration of VEGF or other angiogenic or inflammatory mediators, or of tumoral blood flow or metabolism, or peritumoral inflammation or edema) might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the cancer.
  • In a specific embodiment, presented herein is a method for treating cancer, comprising: (a) administering to a patient in need thereof one or more doses of a Compound or a pharmaceutical composition thereof; and (b) monitoring the concentration of VEGF or other angiogenic, or inflammatory mediators (e.g., detected in biological specimens such as plasma, serum, cerebral spinal fluid, urine, or any other biofluids), or monitoring tumoral blood flow or metabolism, or peritumoral inflammation or edema, before and/or after step (a). In specific embodiments, step (b) comprises monitoring the concentration of one or more inflammatory mediators including, but not limited to, cytokines and interleukins such as IL-6 and IL-8. In particular embodiments, step (b) comprises monitoring the concentration of VEGF-A, VEGF-R, P1GF, VEGF-C, and/or VEGF-D. In certain embodiments, the monitoring step (b) is carried out before and/or after a certain number of doses (e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, or 29 doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 doses) or a certain time period (e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks) of administering the Compound. In certain embodiments, one or more of these monitoring parameters are detected prior to administration of the Compound or pharmaceutical composition thereof. In specific embodiments, a decrease in the concentration of VEGF or other angiogenic or inflammatory mediators or a change in tumoral blood flow or metabolism, or peritumor edema following administration of the Compound or pharmaceutical composition thereof indicates that the course of treatment is effective for treating the cancer. In some embodiments, a change in the concentration of VEGF or other angiogenic or inflammatory mediators or a change in tumoral blood flow or metabolism, or peritumoral inflammation or edema following administration of the Compound or pharmaceutical composition thereof may indicate that the dosage, frequency and/or length of administration of the Compound or a pharmaceutical composition thereof may be adjusted (e.g., increased, reduced or maintained). In specific embodiments, the cancer is a solid tumor.
  • In certain embodiments, the concentration of VEGF or other angiogenic or inflammatory mediators in biological specimens (e.g., plasma, serum, cerebral spinal fluid, urine, or any other biofluids) of a patient is monitored before, during and/or after a course of treatment for a non-neoplastic condition involving the administration of a Compound or a pharmaceutical composition thereof to the patient. The dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient might be modified as a result of the concentration of VEGF or other angiogenic or inflammatory mediators. Alternatively, the changes in these monitoring parameters (e.g., concentration of VEGF or other angiogenic or inflammatory mediators) might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the non-neoplastic condition.
  • In a specific embodiment, presented herein is a method for treating a non-neoplastic condition, comprising: (a) administering to a patient in need thereof one or more doses of a Compound or a pharmaceutical composition thereof; and (b) monitoring the concentration of VEGF or other angiogenic, or inflammatory mediators (e.g., detected in biological specimens such as plasma, serum, cerebral spinal fluid, urine, or any other biofluids) before and/or after step (a). In specific embodiments, step (b) comprises monitoring the concentration of one or more inflammatory mediators including, but not limited to, cytokines and interleukins such as IL-6 and IL-8. In particular embodiments, step (b) comprises monitoring the concentration of VEGF-A, VEGF-R, P1GF, VEGF-C, and/or VEGF-D. In certain embodiments, the monitoring step (b) is carried out before and/or after a certain number of doses (e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, or 20 doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 doses) or a certain time period (e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks) of administering the Compound. In certain embodiments, one or more of these monitoring parameters are detected prior to administration of the Compound or pharmaceutical composition thereof. In specific embodiments, a decrease in the concentration of VEGF or other angiogenic or inflammatory mediators following administration of the Compound or pharmaceutical composition thereof indicates that the course of treatment is effective for treating the non-neoplastic condition. In some embodiments, a change in the concentration of VEGF or other angiogenic or inflammatory mediators following administration of the Compound or pharmaceutical composition thereof may indicate that the dosage, frequency and/or length of administration of the Compound or a pharmaceutical composition thereof may be adjusted (e.g., increased, reduced or maintained).
  • The concentration of VEGF or other angiogenic or inflammatory mediators or a change in tumor blood flow or metabolism, or peritumoral inflammation or edema of a patient may be detected by any technique known to one of skill in the art. In certain embodiments, the method for detecting the concentration of VEGF or other angiogenic or inflammatory mediators of a patient involves obtaining a biological sample (e.g., tissue or fluid sample) from the patient and detecting the concentration of VEGF or other angiogenic or inflammatory mediators in the biological sample (e.g., from plasma, serum, cerebral spinal fluid, urine, or any other biofluids), that has been subjected to certain types of treatment (e.g., centrifugation), and detection by use of immunological techniques, such as ELISA. In a specific embodiment, an ELISA described herein, e.g., in the working examples in Section 8.1.1. et seq. may be used to detect the concentration of VEGF or other angiogenic or inflammatory mediators, in a biological sample (e.g., from plasma, serum, cerebral spinal fluid, urine, or any other biofluids) that has been subjected to certain types of treatment (e.g., centrifugation). Other techniques known in the art that may be used to detect the concentration of VEGF or other angiogenic or inflammatory mediators, in a biological sample, include multiplex or proteomic assays. In a specific embodiment, a CT scan, an MRI scan, or a PET scan may be used to detect the tumor blood flow or metabolism, or peritumoral inflammation or edema.
  • In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein alleviate or manage one, two or more symptoms associated with the cancer or the non-neoplastic condition. Alleviating or managing one, two or more symptoms of cancer or a non-neoplastic condition may be used as a clinical endpoint for efficacy of a Compound for treating the cancer or non-neoplastic condition. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein reduce the duration and/or severity of one or more symptoms associated with the cancer or the non-neoplastic condition. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit the onset, progression and/or recurrence of one or more symptoms associated with the cancer or the non-neoplastic condition. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein reduce the number of symptoms associated with the cancer or the non-neoplastic condition. In a specific embodiment, the cancer is a solid tumor cancer.
  • The methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce pathological production of human VEGF. In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein selectively inhibit pathologic production of human VEGF (e.g., by the tumor), but do not disturb the physiological activity of human VEGF protein. Preferably, the methods for treating cancer or a non-neoplastic condition provided herein do not significantly inhibit or reduce physiological or homeostatic production of human VEGF. For example, blood pressure, protein levels in urine, and bleeding are maintained within normal ranges in treated subjects. In a specific embodiment, the treatment does not result in adverse events as defined in Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS Mar. 31, 2003 (http://cstep.cancer.gov), publish date Aug. 9, 2006, which is incorporated by reference herein in its entirety. In other embodiments, the methods for treating brain tumors provided herein do not result in adverse events of grade 2 or greater as defined in the Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, supra.
  • In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or decrease pathological production of VEGF by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to the pathological production of VEGF observed prior to the administration of a Compound as assessed by methods well known in the art. In particular embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or decrease pathological production of VEGF in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to the pathological production of VEGF observed prior to administration of a compound, as assessed by methods well known in the art.
  • In specific aspects, the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins, such as IL-6) of a subject as assessed by methods well known in the art, e.g., ELISA. In particular embodiments, the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins, such as IL-6) in a subject in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 99%, 30% to 100%, or any range in between, relative to the respective concentration prior to administration of a Compound, as assessed by methods well known in the art, e.g., ELISA.
  • In specific aspects, the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentrations of P1GF, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, IL-6 and/or IL-8 in the blood of a subject as assessed by methods well known in the art, e.g., ELISA. In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentrations of P1GF, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, IL-6 and/or IL-8 in the blood of a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to the respective concentration observed prior to administration of a Compound as assessed by methods well known in the art, e.g., ELISA. In particular embodiments, the methods for treating cancer or a non-neoplastic condition provided herein decrease the concentrations of P1GF, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, IL-6 and/or IL-8 in the blood of a subject in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to the respective concentration observed prior to administration of a Compound, as assessed by methods well known in the art, e.g., ELISA.
  • In certain embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce pathological angiogenesis or vascularization. In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce pathological angiogenesis or vascularization, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to angiogenesis or vascularization observed prior to administration of a Compound as assessed by methods well known in the art, e.g., MRI scan, CT scan, PET scan. In particular embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce pathological angiogenesis or vascularization, in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to angiogenesis or vascularization observed prior to administration of a Compound, as assessed by methods well known in the art, e.g., MRI scan, CT scan, PET scan.
  • In specific embodiments, the methods for treating cancer or a neoplastic condition provided herein inhibit or reduce inflammation, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to inflammation observed prior to administration of a Compound, or any percentage in between, as assessed by methods well known in the art, e.g., CT scan, MM scan, or PET scan. In particular embodiments, the methods for treating cancer or a neoplastic condition provided herein inhibit or reduce inflammation, in the range of about 5% to 15%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 99%, 30% to 100%, or any range in between, relative to inflammation observed prior to administration of a Compound, or any percentage in between, as assessed by methods well known in the art, e.g., CT scan, MRI scan, or PET scan.
  • In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce edema such as tumor-related edema, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to the edema observed prior to administration of a Compound, or any percentage in between, as assessed by methods well known in the art, e.g., CT scan, MRI scan, or PET scan. In particular embodiments, the methods for treating NF provided herein inhibit or reduce edema such as tumor-related, in the range of about 5% to 15%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 99%, 30% to 100%, or any range in between, relative to the edema observed prior to administration of a Compound, or any percentage in between, as assessed by methods well known in the art, e.g., CT scan, Mill scan, or PET scan.
  • In certain embodiments, the methods for treating cancer or a non-neoplastic condition provided herein prolong or delay the G1/S or late G1/S phase of the cell cycle (i.e., the period between the late resting or pre-DNA synthesis phase, and the early DNA synthesis phase).
  • In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein reduce, ameliorate, or alleviate the severity of the cancer or the non-neoplastic condition and/or one or more symptoms thereof. In other embodiments, the methods for treating cancer or a non-neoplastic condition provided herein reduce hospitalization (e.g., the frequency or duration of hospitalization) of a subject diagnosed with the cancer or the non-neoplastic condition. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein reduce hospitalization length of a subject diagnosed with the cancer or the non-neoplastic condition. In certain embodiments, the methods provided herein increase the survival of a subject diagnosed with cancer or a non-neoplastic condition. In specific embodiments, the methods provided herein increase the survival of a subject diagnosed with cancer or a non-neoplastic condition by about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, or about 12 months or more. In particular embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce the progression of the cancer or the non-neoplastic condition, or one or more symptoms associated therewith. In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein enhance or improve the therapeutic effect of another therapy (e.g., an anti-cancer agent, radiation, drug therapy, such as chemotherapy, anti-androgen therapy, or surgery). In certain embodiments, the methods for treating cancer or a non-neoplastic condition provided herein involve the use of a Compound as an adjuvant therapy. In certain embodiments, the methods for treating cancer provided herein improve the ease in removal of tumors (e.g., enhance resectability of the tumors) by reducing vascularization prior to surgery. In particular embodiments, the methods for treating cancer provided herein reduce vascularization after surgery, for example, reduce vascularization of the remaining tumor mass not removed by surgery. In some embodiments, the methods for treating cancer provided herein prevent recurrence of a tumor or one or more symptoms associated with cancer, e.g., recurrence of vascularization and/or tumor growth. In certain embodiments, the methods for treating a non-neoplastic condition provided herein prevent the recurrence of the non-neoplastic condition or one or more symptoms thereof.
  • In particular embodiments, the methods for treating cancer or a non-neoplastic condition provided herein reduce the mortality of subjects diagnosed with the cancer or the non-neoplastic condition. In certain embodiments, the methods for treating cancer or a non-neoplastic condition provided herein increase the number of patients in remission or decrease the hospitalization rate. In other embodiments, the methods for treating cancer or a non-neoplastic condition provided herein prevent the development, onset or progression of one or more symptoms associated with the cancer or a non-neoplastic condition. In particular embodiments, the methods for treating cancer or a non-neoplastic condition provided herein increase symptom-free survival of cancer patients or the non-neoplastic condition patients. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein do not cure the cancer or non-neoplastic condition in patients, but prevent the progression or worsening of the disease. In some embodiments, the methods for treating cancer or a non-neoplastic condition provided herein improve the patient's quality of life.
  • In particular embodiments, the methods for treating cancer provided herein inhibit, reduce, diminish, arrest, or stabilize a tumor associated with the cancer. In other embodiments, the methods for treating cancer provided herein inhibit, reduce, diminish, arrest, or stabilize the blood flow, metabolism, or edema in a tumor associated with the cancer or one or more symptoms thereof. In specific embodiments, the methods for treating cancer provided herein cause the regression of a tumor, tumor blood flow, tumor metabolism, or peritumor edema, and/or one or more symptoms associated with the cancer. In other embodiments, the methods for treating cancer provided herein maintain the size of the tumor so that it does not increase, or so that it increases by less than the increase of a tumor after administration of a standard therapy as measured by conventional methods available to one of skill in the art, such as digital rectal exam, ultrasound (e.g., transrectal ultrasound), CT Scan, MRI, dynamic contrast-enhanced MM, or PET Scan. In specific embodiments, the methods for treating cancer provided herein decrease tumor size. In certain embodiments, the methods for treating cancer provided herein reduce the formation of a tumor. In certain embodiments, the methods for treating cancer provided herein eradicate, remove, or control primary, regional and/or metastatic tumors associated with the cancer. In some embodiments, the methods for treating cancer provided herein decrease the number or size of metastases associated with the cancer.
  • In certain embodiments, the methods for treating cancer provided herein reduce the tumor size (e.g., volume or diameter) in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to tumor size (e.g., volume or diameter) prior to administration of a Compound as assessed by methods well known in the art, e.g., CT Scan, MRI, DCE-MRI, or PET Scan. In particular embodiments, the methods for treating cancer provided herein reduce the tumor volume or tumor size (e.g., diameter) in a subject by an amount in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to tumor size (e.g., diameter) in a subject prior to administration of a Compound as assessed by methods well known in the art, e.g., CT Scan, MM, DCE-MM, or PET Scan.
  • In certain embodiments, the methods for treating cancer provided herein reduce the tumor perfusion in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to tumor perfusion prior to administration of a Compound as assessed by methods well known in the art, e.g., MRI, DCE-MRI, or PET Scan. In particular embodiments, the methods for treating cancer provided herein reduce the tumor perfusion in a subject by an amount in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to tumor perfusion prior to administration of a Compound, as assessed by methods well known in the art, e.g., MRI, DCE-MRI, or PET Scan.
  • In particular aspects, the methods for treating cancer provided herein inhibit or decrease tumor metabolism in a subject as assessed by methods well known in the art, e.g., PET scanning. In specific embodiments, the methods for treating cancer provided herein inhibit or decrease tumor metabolism in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100%, relative to tumor metabolism prior to administration of a Compound, as assessed by methods well known in the art, e.g., PET scanning. In particular embodiments, the methods for treating cancer provided herein inhibit or decrease tumor metabolism in a subject in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to tumor metabolism prior to administration of a Compound, as assessed by methods well known in the art, e.g., PET scan.
  • In specific embodiments, the methods for treating cancer provided herein decrease the number of circulating tumor cells (CTCs) in the blood of the subject as assessed by methods known in the art, such as CellSearch immunomagnetic-capture (see, e.g., Danila D C, Heller G, Gignac G A, Gonzalez-Espinoza R, Anand A, Tanaka E, Lilja H, Schwartz L, Larson S, Fleisher M, Scher H I. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007 Dec. 1; 13(23):7053-8; Shaffer D R, Leversha M A, Danila D C, Lin O, Gonzalez-Espinoza R, Gu B, Anand A, Smith K, Maslak P, Doyle G V, Terstappen L W, Lilja H, Heller G, Fleisher M, Scher H I. Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin Cancer Res. 2007 Apr. 1; 13(7):2023-9). In specific embodiments, the methods for treating cancer provided herein decrease the number of CTCs in the blood of a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to the number of CTCs observed prior to administration of a Compound, as assessed by methods well known in the art. In particular embodiments, the methods for treating cancer provided herein decrease the number of CTCs in the blood of a subject in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to the number of CTCs in the blood observed prior to the administration of a Compound, as assessed by methods well known in the art, such as CellSearch immunomagnetic-capture.
  • In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce inflammation, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, or any percentage in between, relative to inflammation observed prior to administration of a Compound as assessed by methods well known in the art. In particular embodiments, the methods for treating cancer or a non-neoplastic condition provided herein inhibit or reduce inflammation, in the range of about 5% to 15%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 99%, 30% to 100%, or any range in between, relative to inflammation observed prior to administration of a Compound, as assessed by methods well known in the art.
  • In certain embodiments, the methods for treating cancer provided herein increase the cancer-free survival rate of patients diagnosed with the cancer. In some embodiments, the methods for treating cancer provided herein increase relapse-free survival. In certain embodiments, the methods for treating cancer provided herein increase the number of patients in remission. In other embodiments, the methods for treating cancer provided herein increase the length of remission in patients.
  • In specific embodiments, the methods for treating cancer or a non-neoplastic condition provided herein minimize the severity and/or frequency of one or more side effects observed with current anti-angiogenesis therapies. In certain embodiments, the methods for treating cancer or a non-neoplastic condition provided herein do not cause one or more side effects observed with current anti-angiogenesis therapies. Such side effects include, but are not limited to, bleeding, arterial and venous thrombosis, hypertension, delayed wound healing, proteinuria, nasal septal perforation, reversible posterior leukoencephalopathy syndrome in association with hypertension, light-headedness, ataxia, headache, hoarseness, nausea, vomiting, diarrhea, rash, subungual hemorrhage, myelosuppression, fatigue, hypothyroidism, QT interval prolongation, and heart failure.
  • In certain embodiments, treatment of cancer with a Compound described herein or a compound described in U.S. Publication Nos. 2005-0272759 (having corresponding International Application Publication No. WO2005/089764), U.S. Publication No. 2005-0282849 (having corresponding International Application Publication No. WO2006/113703), or U.S. Publication No. 2007-0254878 (having corresponding International Application Publication No. WO2008/127715); or U.S. Provisional Application Ser. No. 60/181,649, filed May 27, 2009 entitled “Methods for Treating Prostate Cancer;” or U.S. Provisional Application Ser. No. 60/181,651, filed May 27, 2009, entitled “Methods for Treating Kaposi's Sarcoma;” or U.S. Provisional Application Ser. No. 60/181,650, filed May 27, 2009, entitled “Methods for Treating Neurofibromatosis;” U.S. Provisional Application Ser. No. 60/181,654, filed May 27, 2009, entitled “Methods for Treating Brain Cancer;” or U.S. Provisional Application Ser. No. 60/253,086, filed Oct. 20, 2009, entitled “Methods for Treating Breast Cancer” (each of which is incorporated herein by reference in its entirety) inhibits or reduces tumor-induced cachexia. In specific embodiments, when the treatment of cancer comprises the administration of a Compound described herein or a compound described in U.S. Publication Nos. 2005-0272759 (having corresponding International Application Publication No. WO2005/089764), U.S. Publication No. 2005-0282849 (having corresponding International Application Publication No. WO2006/113703), or U.S. Publication No. 2007-0254878 (having corresponding International Application Publication No. WO2008/127715), or U.S. Provisional Application Ser. No. 60/181,649, filed May 27, 2009 entitled “Methods for Treating Prostate Cancer;” or U.S. Provisional Application Ser. No. 60/181,651, filed May 27, 2009, entitled “Methods for Treating Kaposi's Sarcoma;” or U.S. Provisional Application Ser. No. 60/181,650, filed May 27, 2009, entitled “Methods for Treating Neurofibromatosis;” U.S. Provisional Application Ser. No. 60/181,654, filed May 27, 2009, entitled “Methods for Treating Brain Cancer;” or U.S. Provisional Application Ser. No. 60/253,086, filed Oct. 20, 2009, entitled “Methods for Treating Breast Cancer,” (each of which is incorporated herein by reference in its entirety) in combination with one or more additional therapies, cachexia induced by the one or more additional therapies is reduced due to administration of a Compound.
  • The concentration of viral RNA or DNA or viral protein in a biological specimen (e.g., plasma, serum, urine, or any other biofluids or tissues) may be used to monitor the efficacy of a course of treatment for viral infection involving the administration of a compound that inhibits or reduces viral replication or the production of viral RNA or DNA or viral protein, such as a Compound described herein or a compound described in U.S. Publication No. 2005-0272759 (having corresponding International Application Publication No. WO2005/089764), U.S. Publication No. 2005-0282849 (having corresponding International Application Publication No. WO2006/113703), U.S. Publication No. 2007-0254878 (having corresponding International Application Publication No. WO2008/127715) or International Application Publication No. WO2008/127714, each of which is incorporated herein by reference in its entirety. The dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient may also be modified as a result of the concentration of viral RNA or DNA or viral protein. Alternatively, the changes in the concentration of viral RNA or DNA or viral protein might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the viral infection.
  • In certain embodiments, the concentration of viral RNA or DNA or viral protein in biological specimens (e.g., plasma, serum, urine, or any other biofluids or tissues) of a patient is monitored before, during and/or after a course of treatment for viral infection involving the administration of a Compound or a pharmaceutical composition thereof to the patient. In certain embodiments, the viral titer in a patient is monitored before, during and/or after a course of treatment for viral infection involving the administration of a Compound or a pharmaceutical composition thereof. The dosage, frequency and/or length of administration of a Compound or a pharmaceutical composition thereof to a patient might be modified as a result of the concentration of viral RNA or DNA or viral protein as assessed by standard techniques. Alternatively, the changes in the concentration of viral RNA or DNA or viral protein might indicate that the course of treatment involving the administration of the Compound or pharmaceutical composition thereof is effective in treating the viral infection.
  • In a specific embodiment, presented herein is a method for treating a viral infection, comprising: (a) administering to a patient in need thereof one or more doses of a Compound or a pharmaceutical composition thereof; and (b) monitoring the concentration of viral RNA or DNA or viral protein (e.g., detected in biological specimens such as plasma, serum, urine, or any other biofluids or tissues) before and/or after step (a). In specific embodiments, step (b) comprises monitoring the patient's viral titer. In certain embodiments, the monitoring step (b) is carried out before and/or after a certain number of doses (e.g., 1, 2, 4, 6, 8, 10, 12, 14, 15, 30 or more doses, or more doses; 2 to 4, 2 to 8, 2 to 20 or 2 to 30 or more doses) or a certain time period (e.g., 1, 2, 3, 4, 5, 6, or 7 days; or 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 45, 48, or 50 weeks) of administering the Compound. In certain embodiments, one or more of these monitoring parameters are detected prior to administration of the Compound or pharmaceutical composition thereof. In specific embodiments, a decrease in the concentration of viral RNA or DNA or viral protein following administration of the Compound or pharmaceutical composition thereof indicates that the course of treatment is effective for treating the viral infection. In some embodiments, a change in the concentration of viral RNA or DNA or viral protein following administration of the Compound or pharmaceutical composition thereof may indicate that the dosage, frequency and/or length of administration of the Compound or a pharmaceutical composition thereof may be adjusted (e.g., increased, reduced or maintained).
  • The concentration of viral RNA or DNA or viral protein in a patient may be detected by any technique known to one of skill in the art. In certain embodiments, the method for detecting the concentration of viral RNA or DNA or viral protein in a patient involves obtaining a biological sample (e.g., tissue or fluid sample) from the patient and detecting the concentration of viral RNA or DNA or viral protein in the biological sample (e.g., from plasma, serum, urine, or any other biofluids or tissues), that has been subjected to certain types of treatment (e.g., centrifugation), and detection by use of standard molecular techniques known to a person of ordinary skill in the art, such as by polymerase chain reaction (PCR) or ELISA. In a specific embodiment, an ELISA described herein, e.g., in the working examples in Section 8.1.1. et seq. may be used to detect the concentration of viral protein. In another specific embodiment, PCR may be used to detect the concentration of viral RNA or DNA in a biological sample (e.g., from plasma, serum, urine, or any other biofluids or tissues) that has been subjected to certain types of treatment (e.g., centrifugation). Other techniques known in the art that may be used to detect the concentration of viral RNA or DNA in a biological sample, including nucleic acid hybridization or a combination of PCR and nucleic acid hybridization assays.
  • In specific embodiments, the methods for treating a viral infection provided herein alleviate or manage one, two or more symptoms associated with the viral infection. Alleviating or managing one, two or more symptoms of viral infection may be used as a clinical endpoint for efficacy of a Compound for treating the viral infection. In some embodiments, the methods for treating a viral infection provided herein reduce the duration and/or severity of one or more symptoms associated with the viral infection. In some embodiments, the methods for treating viral infection provided herein inhibit the onset, progression and/or recurrence of one or more symptoms associated with the viral infection. In some embodiments, the methods for treating the viral infection provided herein reduce the number of symptoms associated with the viral infection.
  • The methods for treating a viral infection provided herein inhibit or reduce viral replication or the production of viral RNA or DNA or viral protein. In specific embodiments, the methods for treating the viral infection provided herein selectively inhibit the production of viral RNA or DNA or viral protein. In a specific embodiment, the treatment does not result in an adverse event as defined in according to government safety standards or regulations.
  • In specific embodiments, the methods for treating a viral infection provided herein inhibit or decrease viral replication or the production of viral RNA or DNA or viral protein by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, or 100% relative to viral replication or the production of viral RNA or DNA or viral protein observed prior to the administration of a Compound as assessed by methods well known in the art, e.g., PCR or ELISA. In particular embodiments, the methods for treating the viral infection provided herein inhibit or decrease viral replication or the production of viral RNA or DNA or viral protein in the range of about 5% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to viral replication or the production of viral RNA or DNA or viral protein observed prior to administration of a compound, as assessed by methods well known in the art, e.g., PCR or ELISA.
  • In some embodiments, the methods for treating a viral infection provided herein reduce, ameliorate, or alleviate the severity of the viral infection and/or one or more symptoms thereof. In other embodiments, the methods for treating viral infection provided herein reduce hospitalization (e.g., the frequency or duration of hospitalization) of a subject diagnosed with the viral infection. In some embodiments, the methods for treating a viral infection provided herein reduce hospitalization length of a subject diagnosed with the viral infection. In certain embodiments, the methods provided herein increase the survival of a subject diagnosed with the viral infection. In specific embodiments, the methods provided herein increase the survival of a subject diagnosed with a viral infection by about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, or about 12 months or more. In particular embodiments, the methods for treating a viral infection provided herein inhibit or reduce the progression of the viral infection, or one or more symptoms associated therewith. In specific embodiments, the methods for treating viral infection provided herein enhance or improve the therapeutic effect of another therapy (e.g., an antiviral agent, drug therapy, such as interferon, or transplant surgery). In certain embodiments, the methods for treating viral infection provided herein involve the use of a Compound as an adjuvant therapy. In some embodiments, the methods for treating viral infection provided herein prevent recurrence of the viral infection or one or more symptoms associated with the viral infection.
  • In particular embodiments, the methods for treating viral infection provided herein reduce the mortality of subjects diagnosed with the viral infection. In certain embodiments, the methods for treating a viral infection provided herein increase the number of patients in remission or decrease the hospitalization rate. In other embodiments, the methods for treating viral infection provided herein prevent the development, onset or progression of one or more symptoms associated with the viral infection. In particular embodiments, the methods for treating the viral infection provided herein increase symptom-free survival of the infected patients. In some embodiments, the methods for treating the viral infection provided herein do not cure the viral infection in patients, but prevent the progression or worsening of the disease. In some embodiments, the methods for treating viral infection provided herein improve the patient's quality of life.
  • In particular embodiments, the methods for treating viral infection provided herein inhibit, reduce, diminish, arrest, or stabilize the production of viral RNA or DNA or viral protein associated with the virus. In certain embodiments, the methods for treating viral infection provided herein reduce viral RNA or DNA or viral protein production in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to viral RNA or DNA or viral protein production prior to administration of a Compound as assessed by methods well known in the art, e.g., PCR or ELISA. In particular embodiments, the methods for treating viral infection provided herein reduce the viral titer in a subject by an amount in the range of about 5% to 20%, 10% to 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, 30% to 100%, or any range in between, relative to the viral titer in a subject prior to administration of a Compound as assessed by methods well known in the art, e.g., PCR or ELISA.
  • In specific embodiments, the methods for treating viral infection provided herein decrease the number of circulating viral proteins (CVPs) in the blood of the subject as assessed by methods known in the art. In specific embodiments, the methods for treating viral infection provided herein decrease the number of CVPs in the blood of a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95%, 99%, or 100%, relative to the number of CVPs observed prior to administration of a Compound, as assessed by methods well known in the art.
  • In certain embodiments, the methods for treating viral infection provided herein increase the viral-free survival rate of patients diagnosed with the viral infection. In some embodiments, the methods for treating viral infection provided herein increase relapse-free survival. In certain embodiments, the methods for treating viral infection provided herein increase the number of patients in remission. In other embodiments, the methods for treating viral infection provided herein increase the length of remission in patients.
  • In specific embodiments, the methods for treating viral infection provided herein minimize the severity and/or frequency of one or more side effects observed with current antiviral therapies. In certain embodiments, the methods for treating viral infection provided herein do not cause one or more side effects observed with current antiviral therapies.
    • 5.5 Patient Population
  • In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human who has or is diagnosed with cancer or a non-neoplastic condition or a viral infection. In other embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human predisposed or susceptible to cancer or a non-neoplastic condition or a viral infection. In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human at risk of developing cancer or a non-neoplastic condition or a viral infection.
  • In one embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human infant. In another embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human toddler. In another embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human child. In another embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human adult. In another embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a middle-aged human. In another embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is an elderly human.
  • In certain embodiments, a subject treated for cancer in accordance with the methods provided herein has a cancer that metastasized to other areas of the body, such as the bones, lung and liver. In certain embodiments, a subject treated for cancer in accordance with the methods provided herein is in remission from the cancer. In some embodiments, a subject treated for cancer in accordance with the methods provided herein that has a recurrence of the cancer. In certain embodiments, a subject treated in accordance with the methods provided herein is experiencing recurrence of one or more tumors associated with cancer.
  • In certain embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that is about 1 to about 5 years old, about 5 to 10 years old, about 10 to about 18 years old, about 18 to about 30 years old, about 25 to about 35 years old, about 35 to about 45 years old, about 40 to about 55 years old, about 50 to about 65 years old, about 60 to about 75 years old, about 70 to about 85 years old, about 80 to about 90 years old, about 90 to about 95 years old or about 95 to about 100 years old, or any age in between. In a specific embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that is 18 years old or older. In a particular embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human child that is between the age of 1 year old to 18 years old. In a certain embodiment, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that is between the age of 12 years old and 18 years old. In a certain embodiment, the subject is a male human. In another embodiment, the subject is a female human. In one embodiment, the subject is a female human that is not pregnant or is not breastfeeding. In one embodiment, the subject is a female that is pregnant or will/might become pregnant, or is breast feeding.
  • In particular embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that is in an immunocompromised state or immunosuppressed state. In certain embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human receiving or recovering from immunosuppressive therapy. In certain embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has or is at risk of getting cancer (e.g., metastatic cancer), AIDS, or a bacterial infection. In certain embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human who is, will or has undergone surgery, drug therapy, such as chemotherapy, hormonal therapy and/or radiation therapy.
  • In specific embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is suffering from a condition, e.g., stroke or cardiovascular conditions that may require VEGF therapy, wherein the administration of anti-angiogenic therapies other than a Compound may be contraindicated. For example, in certain embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has suffered from a stroke or is suffering from a cardiovascular condition. In some embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is a human experiencing circulatory problems. In certain embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is a human with diabetic polyneuropathy or diabetic neuropathy. In some embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is a human receiving VEGF protein therapy. In other embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is not a human receiving VEGF protein therapy.
  • In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is administered a Compound or a pharmaceutical composition thereof, or a combination therapy before any adverse effects or intolerance to therapies other than the Compound develops. In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a refractory patient. In a certain embodiment, a refractory patient is a patient refractory to a standard therapy (e.g., surgery, radiation, anti-androgen therapy and/or drug therapy such as chemotherapy or antiviral therapy). In certain embodiments, a patient with cancer or a non-neoplastic condition or a viral infection is refractory to a therapy when the cancer or the non-neoplastic condition or the viral infection has not significantly been eradicated and/or the one or more symptoms have not been significantly alleviated. The determination of whether a patient is refractory can be made either in vivo or in vitro by any method known in the art for assaying the effectiveness of a treatment of cancer or a non-neoplastic condition or a viral infection, using art-accepted meanings of “refractory” in such a context. In various embodiments, a patient with cancer is refractory when one or more tumors associated with cancer, have not decreased or have increased. In various embodiments, a patient with cancer is refractory when one or more tumors metastasize and/or spread to another organ.
  • In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has proven refractory to therapies other than treatment with a Compound, but is no longer on these therapies. In certain embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human already receiving one or more conventional anti-cancer therapies, such as surgery, drug therapy such as chemotherapy, antiviral therapy, anti-androgen therapy or radiation. Among these patients are refractory patients, patients who are too young for conventional therapies, and patients with recurring tumors or viral infection despite treatment with existing therapies.
  • In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human susceptible to adverse reactions to conventional therapies. In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has not received a therapy, e.g., drug therapy such as chemotherapy, surgery, antiviral therapy, anti-androgen therapy or radiation therapy, prior to the administration of a Compound or a pharmaceutical composition thereof. In other embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has received a therapy prior to administration of a Compound. In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is a human that has experienced adverse side effects to the prior therapy or the prior therapy was discontinued due to unacceptable levels of toxicity to the human.
  • In some embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has had no prior exposure to another anti-angiogenic therapy (e.g., an anti-VEGF monoclonal antibody, an anti-VEGFR monoclonal antibody, a tyrosine kinase inhibitor, or other angiogenesis pathway modulator). In particular embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein does not have uncontrolled hypertension, major bleeding, HIV infection or recent acute cardiovascular event. In some embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident, transient ischemic attack, an arterial thromboembolic event, or pulmonary embolism.
  • In some embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein is not, has not and/or will not receive a drug that is primarily metabolized by CYP2D6. In particular embodiments, a subject treated for cancer or a non-neoplastic condition or a viral infection in accordance with the methods provided herein has not and will not received a drug that is primarily metabolized by CYP2D6 1, 2, 3 or 4 weeks before receiving a Compound or a pharmaceutical composition thereof and 1, 2, 3 or 4 weeks after receiving the Compound or pharmaceutical composition. Examples of such drugs include, without limitation, some antidepressants (e.g., tricyclic antidepressants and selective serotonin uptake inhibitors), some antipsychotics, some beta-adrenergic receptor blockers, certain antiviral agents and certain anti-arrhythmics. In specific embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein is not, has not and/or will not receive tamoxifen. In particular embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has not and will not received tamoxifen 1, 2, 3 or 4 weeks before receiving a Compound or a pharmaceutical composition thereof and 1, 2, 3 or 4 weeks after receiving the Compound or pharmaceutical composition. In specific embodiments, a subject treated for cancer or a non-neoplastic condition in accordance with the methods provided herein has received tamoxifen, e.g., for 1, 2, 3 or 4 weeks before receiving a Compound or a pharmaceutical composition thereof.
    • 5.6 Dosage and Administration
  • In accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein, a Compound or a pharmaceutical composition thereof can be administered to a subject in need thereof by a variety of routes in amounts which result in a beneficial or therapeutic effect. A Compound or pharmaceutical composition thereof may be orally administered to a subject in need thereof in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein. The oral administration of a Compound or a pharmaceutical composition thereof may facilitate subjects in need of such treatment complying with a regimen for taking the Compound or pharmaceutical composition. Thus, in a specific embodiment, a Compound or pharmaceutical composition thereof is administered orally to a subj ect in need thereof.
  • A Compound provided herein can be administered orally, with or without food or water.
  • Other routes of administration include, but are not limited to, intravenous, intradermal, intrathecal, intramuscular, subcutaneous, intranasal, inhalation, transdermal, topical, transmucosal, intracranial, intratumoral, epidural and intra-synovial. In one embodiment, a Compound or a pharmaceutical composition thereof is administered systemically (e.g., parenterally) to a subject in need thereof. In another embodiment, a Compound or a pharmaceutical composition thereof is administered locally (e.g., intratumorally) to a subject in need thereof. In one embodiment, a Compound or a pharmaceutical composition thereof is administered via a route that permits the Compound to cross the blood-brain barrier (e.g., orally).
  • Evaluation has indicated that Compound #10 penetrates the blood-brain barrier. Table 6 provides brain tissue plasma concentration ratios determined by whole-body autoradiography at specified times after a single oral administration of 14C-Compound #10 to rats (50 mg/kg).
  • TABLE 6
    Blood-Brain Barrier Penetration
    6 Hours 12 Hours 24 Hours 48 Hours 72 Hours
    Tissue M F M F M F M F M F
    Cerebellum 1.55 1.23 1.85 2.85 1.74 1.59 1.21 1.17 NA 2.04
    Cerebrum 1.52 1.22 1.75 2.79 1.89 1.57 1.35 1.68 NA 1.56
    Medulla 1.60 1.42 1.98 3.82 1.83 1.69 1.20 2.01 NA 1.88
    Olfactory 1.42 1.38 1.35 2.45 1.23 1.13 0.967 NA NA 3.33
    lobe
    Pituitary 4.06 4.27 3.22 5.48 2.72 2.33 0.890 3.68 NA 1.58
    gland
    Spinal cord 1.14 0.898 1.24 1.92 1.75 1.60 1.43 1.60 1.84 2.75
  • In accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein that involve administration of a Compound in combination with one or more additional therapies, the Compound and one or more additional therapies may be administered by the same route or a different route of administration.
  • The dosage and frequency of administration of a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein will be efficacious while minimizing any side effects. The exact dosage and frequency of administration of a Compound or a pharmaceutical composition thereof can be determined by a practitioner, in light of factors related to the subject that requires treatment. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. The dosage and frequency of administration of a Compound or a pharmaceutical composition thereof may be adjusted over time to provide sufficient levels of the Compound or to maintain the desired effect.
  • In certain embodiments, a Compound or pharmaceutical composition thereof is administered to a subject in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein once a day, twice a day, three times a day, or four times a day. In some embodiments, a Compound or pharmaceutical composition thereof is administered to a subject in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein once, twice, three times, or four times every other day (i.e., on alternate days), once, twice, three times, or four times every two days, once every three days, once, twice, three times, or four times every four days, once, twice, three times, or four times every 5 days, once, twice, three times, or four times a week, once, twice, three times, or four times every two weeks, once, twice, three times, or four times every three weeks, once, twice, three times, or four times every four weeks, once, twice, three times, or four times every 5 weeks, once, twice, three times, or four times every 6 weeks, once, twice, three times, or four times every 7 weeks, or once, twice, three times, or four times every 8 weeks. In particular embodiments, a Compound or pharmaceutical composition thereof is administered to a subject in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein in cycles, wherein the Compound or pharmaceutical composition is administered for a period of time, followed by a period of rest (i.e., the Compound or pharmaceutical composition is not administered for a period of time).
  • In certain embodiments, a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating cancer provided herein at a dosage and a frequency of administration that achieves one or more of the following: (i) decreases the production and/or concentration of VEGF or other angiogenic or inflammatory mediators or a change in tumor blood flow or metabolism, or peritumoral inflammation or edema of a subject with cancer or a non-neoplastic condition or an animal model with a pre-established human tumor; (ii) decreases the concentration of one, two, three or more, or all of the following of a subject with cancer or an animal model with a pre-established human tumor: VEGF-C, VEGF-D, P1GF, VEGFR-1, VEGFR-2, IL-6 and/or IL-8; (iii) reduces or ameliorates the severity of the cancer and/or one or more symptoms associated therewith in a subject with the cancer; (iv) reduces the number symptoms and/or the duration of one or more symptoms associated with the cancer in a subject with the cancer; (v) prevents the onset, progression or recurrence of one or more symptoms associated with the cancer in a subject with the cancer or an animal model with a pre-established human tumor; (vi) reduces the size of the tumor in a subject with the cancer or in an animal model with a pre-established human tumor; (vii) reduces angiogenesis associated with cancer in a subject or an animal model with a pre-established human tumor; and/or (vii) enhances or improves the therapeutic effect of another therapy in a subject with the cancer or an animal model with a pre-established human tumor.
  • In certain embodiments, a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating cancer provided herein at a dosage and a frequency of administration that results in one or more of the following: (i) a decrease in the number of circulating tumor cells (CTCs) in the blood of a subject with cancer or an animal model with a pre-established human tumor; (iii) survival of patients with cancer for about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, or about 12 months or more; (iv) regression of a tumor associated with cancer and/or inhibition of the progression of a tumor associated with the cancer in a subject with cancer or an animal model with a pre-established human tumor; (v) reduction in the growth of a tumor or neoplasm associated with the cancer and/or decrease in the tumor size (e.g., volume or diameter) of tumors associated with the cancer in a subject with cancer or an animal model with a pre-established human tumor; (vi) the size of a tumor associated with cancer is maintained and/or the tumor does not increase or increases by less than the increase of a similar tumor in a subject with cancer or an animal model with a pre-established human tumor after administration of a standard therapy as measured by conventional methods available to one of skill in the art, such as digital rectal exam, ultrasound (e.g., transrectal ultrasound), CT Scan, PET scan, DCE-MRI, and MRI; (vii) reduction in the formation of a tumor associated with the cancer in a subject with the cancer or an animal model with a pre-established human tumor; (viii) the eradication, removal, or control of primary, regional and/or metastatic tumors associated with the cancer in a subject with the cancer or an animal model with a pre-established human tumor; (ix) a decrease in the number or size of metastases associated with the cancer in a subject with the cancer or an animal model with a pre-established human tumor; (x) a reduction or inhibition of the recurrence of a tumor; (xi) a reduction in edema or inflammation associated with a tumor; (xii) an inhibition or reduction in tumor vascularization; (xiii) a reduction of pathologic angiogenesis; and/or (x) reduction in the growth of a pre-established tumor or neoplasm and/or decrease in the tumor size (e.g., volume or diameter) of a pre-established tumor in a subject with the cancer or an animal model with a pre-established human tumor.
  • In certain embodiments, a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating a non-neoplastic condition provided herein at a dosage and a frequency of administration that achieves one or more of the following: (i) decreases the production or concentration of VEGF or other angiogenic or inflammatory mediators; (ii) decreases the concentration of one, two, three or more, or all of the following of a subject with a non-neoplastic condition or an animal model: VEGF-C, VEGF-D, P1GF, VEGFR-1, VEGFR-2, IL-6 and/or IL-8; (iii) reduces or ameliorates the severity of the non-neoplastic condition and/or one or more symptoms associated therewith in a subject with the non-neoplastic condition; (iv) reduces the number symptoms and/or the duration of one or more symptoms associated with the non-neoplastic condition in a subject with the non-neoplastic condition; (v) prevents the onset, progression or recurrence of one or more symptoms associated with the non-neoplastic condition in a subject with the non-neoplastic condition; (vi) reduces inflammation associated with the non-neoplastic condition; (vii) reduces pathologic angiogenesis associated with the non-neoplastic condition in a subject or an animal model; and/or (viii) enhances or improves the therapeutic effect of another therapy in a subject with the non-neoplastic condition or an animal model.
  • In certain embodiments, a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in accordance with the methods for treating a viral infection provided herein at a dosage and a frequency of administration that achieves one or more of the following: (i) decreases the production or concentration of viral RNA or DNA or viral protein; (ii) decreases the viral titer of a subject or an animal model with a viral infection; (iii) reduces or ameliorates the severity of the viral infection and/or one or more symptoms associated therewith in a subject with the viral infection; (iv) reduces the number symptoms and/or the duration of one or more symptoms associated with the viral infection in a subject with the viral infection; (v) prevents the onset, progression or recurrence of one or more symptoms associated with the viral infection in a subject with the viral infection; (vi) inhibits or reduces viral replication or the production or concentration of viral RNA or DNA or viral protein associated with the viral infection in a subject or an animal model; and/or (vii) enhances or improves the therapeutic efficacy of another antiviral therapy in a subject with the viral infection or an animal model.
  • In one aspect, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a unit dosage of a Compound or a pharmaceutical composition thereof. The dosage may be administered as often as determined effective (e.g., once, twice or three times per day, every other day, once or twice per week, biweekly or monthly). In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof that ranges from about 0.001 milligram (mg) to about 1500 mg, from about 0.001 mg per kg to about 1400 mg per kg, from about 0.001 mg per kg to about 1300 mg per kg, from about 0.001 mg per kg to about 1200 mg per kg, from about 0.001 mg per kg to about 1100 mg per kg, from about 0.001 mg per kg to about 1000 mg per kg, from about 0.01 mg to about 1500 mg, from about 0.01 mg per kg to about 1000 mg per kg, from about 0.1 mg per kg to about 1500 mg per kg, from about 0.1 mg per kg to about 1000 mg per kg, from about 0.1 mg per kg to about 500 mg per kg, from about 0.05 mg to about 1000 mg, from about 0.1 mg per kg to about 100 mg per kg, from about 1 mg per kg to about 100 mg per kg, from about 10 mg to about 500 mg, from about 100 mg to about 500 mg, from about 150 mg to about 500 mg, from about 150 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 300 mg to about 1000 mg, or from about 500 mg to about 1000 mg, or any range in between. In specific embodiments, oral doses for use in the methods provided herein are from about 0.01 mg to about 300 mg per kg body weight, from about 0.1 mg to about 75 mg per kg body weight, or from about 0.5 mg to 5 mg per kg body weight. In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of about 15 mg, 16, mg, 17 mg, 18 mg, 19 mg, 20 mg, 21, mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg or 40 mg. In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.
  • In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of at least about 0.1 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg or more. In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of less than about 35 mg, less than about 40 mg, less than about 45 mg, less than about 50 mg, less than about 60 mg, less than about 70 mg, or less than about 80 mg.
  • In specific embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of from about 20 mg to about 500 mg, from about 40 mg to about 500 mg, from about 40 mg to about 200 mg, from about 40 mg to about 150 mg, from about 75 mg to about 500 mg, from about 75 mg to about 450 mg, from about 75 mg to about 400 mg, from about 75 mg to about 350 mg, from about 75 mg to about 300 mg, from about 75 mg to about 250 mg, from about 75 mg to about 200 mg, from about 100 mg to about 200 mg, or any range in between. In other specific embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of about 20 mg, 35 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg or 300 mg. In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof of about 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. In some embodiments, a unit dose of a Compound or a pharmaceutical composition thereof is administered to a subject once per day, twice per day, three times per day; once, twice or three times every other day (i.e., on alternate days); once, twice or three times every two days; once, twice or three times every three days; once, twice or three times every four days; once, twice or three times every five days; once, twice, or three times once a week, biweekly or monthly, and the dosage may be administered orally.
  • In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof ranges from about 0.001 mg per kg to about 1500 mg per kg per day, from about 0.001 mg per kg to about 1400 mg per kg per day, from about 0.001 mg per kg to about 1300 mg per kg per day, from about 0.001 mg per kg to about 1200 mg per kg per day, from about 0.001 mg per kg to about 1100 mg per kg per day, from about 0.001 mg per kg to about 1000 mg per kg per day, 0.001 mg/kg to about 500 mg/kg, from about 0.01 mg per kg to about 1500 mg per kg per day, from about 0.01 mg per kg to about 1000 mg per kg per day, from about 0.1 mg per kg to about 1500 mg per kg per day, from about 0.1 mg per kg to about 1000 mg per kg per day, from about 0.1 mg per kg to about 500 mg per kg per day, from about 0.1 mg per kg to about 100 mg per kg per day, or from about 1 mg per kg to about 100 mg per kg per day. In a specific embodiment, a unit dose of a Compound or a pharmaceutical composition thereof ranges from about 0.01 mg to about 300 mg per kg body weight per day, from about 0.1 mg to about 75 mg per kg body weight per day, or from about 0.5 mg to 5 mg per kg body weight per day. In another specific embodiment, a unit dose of a Compound or a pharmaceutical composition thereof ranges from about 20 mg to about 1000 mg per day. In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of a Compound or a pharmaceutical composition thereof that ranges from about 80 mg to about 800 mg per day, from about 100 mg to about 800 mg per day, from about 80 mg to about 600 mg per day, from about 80 mg to about 400 mg per day, from about 80 mg to about 200 mg per day, from about 200 mg to about 300 mg per day, from about 200 mg to about 400 mg per day, from about 200 mg to about 800 mg per day, or any range in between.
  • In certain embodiments, a unit dose of a Compound that may be used in the methods provided herein include doses of about 0.1 mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.6 mg/kg/day, 0.7 mg/kg/day, 0.8 mg/kg/day, 0.9 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day, 2 mg/kg/day, 2.5 mg/kg/day, 2.75 mg/kg/day, 3 mg/kg/day, 4 mg/kg/day, 5 mg/kg/day, 6 mg/kg/day, 6.5 mg/kg/day, 6.75 mg/kg/day, 7 mg/kg/day, 7.5 mg/kg/day, 8 mg/kg/day, 8.5 mg/kg/day, 9 mg/kg/day, 10 mg/kg/day, 11 mg/kg/day, 12 mg/kg/day, 13 mg/kg/day, 14 mg/kg/day or 15 mg/kg/day. In accordance with these embodiments, the dosage may be administered once, twice or three times per day, every other day, or once or twice per week and the dosage may be administered orally.
  • In a specific embodiment, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration of a unit dose of about 20 mg of a Compound or a pharmaceutical composition thereof once, twice or three times per day. In another specific embodiment, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of about 40 mg of a Compound or a pharmaceutical composition thereof once, twice or three times per day. In another specific embodiment, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration of a unit dose of about 60 mg of a compound or a pharmaceutical composition thereof once, twice or three times per day. In another specific embodiment, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of about 80 mg of a Compound or a pharmaceutical composition thereof once, twice or three times per day. In specific embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a unit dose of from about 100 mg to about 250 mg, from about 150 mg to about 250 mg, from about 175 mg to about 250 mg, from about 200 mg to about 250 mg, or from about 200 mg to about 225 mg of a Compound or a pharmaceutical composition thereof once, twice or three times per day.
  • In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a dosage of a Compound or a pharmaceutical composition thereof that is expressed as mg per meter squared (mg/m2). The mg/m2 for a Compound may be determined, for example, by multiplying a conversion factor for an animal by an animal dose in mg per kilogram (mg/kg) to obtain the dose in mg/m2 for human dose equivalent. For regulatory submissions the FDA may recommend the following conversion factors: Mouse=3, Hamster=4.1, Rat=6, Guinea Pig=7.7. (based on Freireich et al., Cancer Chemother. Rep. 50(4):219-244 (1966)). The height and weight of a human may be used to calculate a human body surface area applying Boyd's Formula of Body Surface Area. In specific embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of an amount of a Compound or a pharmaceutical composition thereof in the range of from about 0.1 mg/m2 to about 1000 mg/m2, or any range in between.
  • Other non-limiting exemplary doses of a Compound or a pharmaceutical composition that may be used in the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein include mg amounts per kg of subject or sample weight. In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof that ranges from about from about 0.001 mg/kg to about 1500 mg/kg per day, from about 0.001 mg/kg to about 1400 mg/kg per day, from about 0.001 mg/kg to about 1300 mg/kg per day, from about 0.001 mg/kg to about 1200 mg/kg per day, from about 0.001 mg/kg to about 1100 mg/kg per day, from about 0.001 mg/kg to about 1000 mg/kg per day, 0.001 mg/kg to about 500 mg/kg, from about 0.01 mg/kg to about 1500 mg/kg per day, from about 0.01 mg/kg to about 1000 mg/kg per day, from about 0.01 mg/kg to about 500 mg/kg, from about 0.1 mg/kg to about 1500 mg/kg per day, from about 0.1 mg/kg to about 1000 mg/kg per day, from about 0.1 mg/kg to about 500 mg/kg, from about 0.1 mg/kg to about 100 mg/kg per day, from about 1 mg/kg to about 500 mg/kg, from about 1 mg/kg to about 100 mg/kg per day, from about 10 mg/kg to about 500 mg/kg, from about 100 mg to about 500 mg/kg, from about 150 mg/kg to about 500 mg/kg, from about 250 mg/kg to about 500 mg/kg, or from about 300 mg/kg to about 500 mg/kg. In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof that ranges from about 0.001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 50 mg/kg, from about 0.001 mg/kg to about 25 mg/kg, from about 0.001 mg/kg to about 10 mg/kg, from about 0.001 mg/kg to about 5 mg/kg; from about 0.001 mg/kg to about 1 mg/kg; or from about 0.001 mg/kg to about 0.01 mg/kg. In certain embodiments, a dosage of a Compound or a pharmaceutical composition thereof that may be used in the methods provided herein include doses of about 0.1 mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.6 mg/kg/day, 0.7 mg/kg/day, 0.8 mg/kg/day, 0.9 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day, 2 mg/kg/day, 2.5 mg/kg/day, 2.75 mg/kg/day, 3 mg/kg/day, 4 mg/kg/day, 5 mg/kg/day, 6 mg/kg/day, 6.5 mg/kg/day, 6.75 mg/kg/day, 7 mg/kg/day, 7.5 mg/kg/day, 8 mg/kg/day, 8.5 mg/kg/day, 9 mg/kg/day, 10 mg/kg/day, 11 mg/kg/day, 12 mg/kg/day, 13 mg/kg/day, 14 mg/kg/day or 15 mg/kg/day. In accordance with these embodiments, the dosage may be administered once, twice or three times per day, every other day, or once or twice per week and the dosage may be administered orally.
  • In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof that ranges from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.01 mg/kg to about 5 mg/kg, from about 0.01 mg to about 1 mg/kg, or from about 0.01 mg/kg to about 0.1 mg/kg. In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof that ranges from about 0.1 mg/kg to about 100 mg/kg, from about 0.1 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 25 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 5 mg/kg, from about 0.1 mg/kg to about 4 mg/kg; from about 0.1 mg/kg to about 3 mg/kg; from about 0.1 mg/kg to about 2 mg/kg; from about 0.1 mg to about 1.5 mg/kg, from about 0.1 mg to about 1.2 mg/kg, from about 0.1 mg to about 1 mg/kg, or from about 0.5 mg/kg to about 1.5 mg/kg. In accordance with these embodiments, the dosage may be administered once, twice or three times per day, every other day, or once or twice per week and the dosage may be administered orally.
  • In specific embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof of from about 0.1 mg/kg to about 5 mg/kg, from about 0.1 mg/kg to about 4 mg/kg, from about 0.1 mg/kg to about 3 mg/kg, from about 0.1 mg/kg to about 2 mg/kg, from about 0.5 mg/kg to about 2 mg/kg, or from about 1 mg/kg to about 1.5 mg/kg is administered once, twice or three times per day. In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof of about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg or about 1 mg/kg once, twice or three times per day. In certain specific embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the oral administration to a subject in need thereof of a dosage of a Compound or a pharmaceutical composition thereof of about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, 1.9 mg/kg or about 2 mg/kg once, twice or three times per day.
  • In specific aspects, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a target plasma concentration of the Compound in a subject with the cancer or the non-neoplastic condition or a viral infection or an animal model (e.g., an animal model with a pre-established human tumor or a viral infection). In a particular embodiment, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a plasma concentration of the Compound ranging from approximately 0.001 μg/mL to approximately 100 mg/mL, approximately 0.01 μg/mL to approximately 100 mg/mL, approximately 0.01 μg/mL to approximately 10 mg/mL, approximately 0.1 μg/mL to approximately 10 mg/mL, approximately 0.1 μg/mL to approximately 500 μg/mL, approximately 0.1 μg/mL to approximately 200 μg/mL, approximately 0.1 μg/mL to approximately 100 μg/mL, or approximately 0.1 μg/mL to approximately 75 μg/mL in a subject with the cancer or the non-neoplastic condition or the viral infection or an animal model (e.g., an animal model with a pre-established human tumor or viral infection). In specific embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a plasma concentration of the Compound ranging from approximately 0.1 to approximately 50 μg/mL, approximately 0.1 μg/mL to approximately 25 μg/mL, approximately 0.1 μg/mL to approximately 20 μg/mL or approximately 5 μg/mL to approximately 10 μg/mL in a subject with the cancer or the non-neoplastic condition or the viral infection or an animal model (e.g., an animal model with a pre-established human tumor or viral infection). To achieve such plasma concentrations, a Compound or a pharmaceutical composition thereof may be administered at doses that vary from 0.001 μg to 100,000 mg, depending upon the route of administration. In certain embodiments, subsequent doses of a Compound may be adjusted accordingly based on the plasma concentrations of the Compound achieved with initial doses of the Compound or pharmaceutical composition thereof administered to the subject.
  • In specific aspects, a method for treating cancer or a non-neoplastic condition presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a target plasma concentration of VEGF-A, P1GF, VEGF-C, VEGF-D, IL-6, IL-8, VEGFR1 and/or VEGFR2 in a subject with the cancer or the non-neoplastic condition or an animal model (e.g., an animal model with a pre-established human tumor). In a particular embodiment, a method for treating cancer or a non-neoplastic condition presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves a plasma concentration of VEGF-A, P1GF, VEGF-C, VEGF-D, IL-6, IL-8, VEGFR1 and/or VEGFR2 ranging from approximately 0.1 pg/mL to approximately 100 mg/mL, approximately 0.1 pg/mL to approximately 1 mg/mL, approximately 0.1 pg/mL to approximately 500 μg/mL, approximately 0.1 pg/mL to approximately 500 μg/mL, approximately 0.1 pg/mL to approximately 100 μg/mL, or approximately 4 pg/mL to approximately 10 μg/mL in a subject with cancer or a non-neoplastic condition or an animal model (e.g., an animal model with a pre-established human tumor). To achieve such plasma concentrations, a Compound or a pharmaceutical composition thereof may be administered at doses that vary from 0.1 pg to 100,000 mg, depending upon the route of administration. In certain embodiments, subsequent doses of a Compound or a pharmaceutical composition thereof may be adjusted accordingly based on the plasma concentrations of VEGF-A, P1GF, VEGF-C, VEGF-D, IL-6, IL-8, VEGFR1 or VEGFR2 achieved with initial doses of the Compound or pharmaceutical composition thereof administered to the subject.
  • In particular embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of a Compound or a pharmaceutical composition thereof at a dosage that achieves the desired tissue to plasma concentration ratios of the Compound as determined, e.g., by any imaging techniques known in the art such as whole-body autoradiography, in a subject with the cancer or the non-neoplastic condition or the viral infection or an animal model (such as an animal model with a pre-established human tumor or a viral infection).
  • In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration to a subject in need thereof of one or more doses of an effective amount of a Compound or a pharmaceutical composition, wherein the effective amount may or may not be the same for each dose. In particular embodiments, a first dose of a Compound or pharmaceutical composition thereof is administered to a subject in need thereof for a first period of time, and subsequently, a second dose of a Compound is administered to the subject for a second period of time. The first dose may be more than the second dose, or the first dose may be less than the second dose. A third dose of a Compound also may be administered to a subject in need thereof for a third period of time.
  • In some embodiments, the dosage amounts described herein refer to total amounts administered; that is, if more than one Compound is administered, then, in some embodiments, the dosages correspond to the total amount administered. In a specific embodiment, oral compositions contain about 5% to about 95% of a Compound by weight.
  • The length of time that a subject in need thereof is administered a Compound or a pharmaceutical composition in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein will be the time period that is determined to be efficacious. In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for a period of time until the severity and/or number of one or more symptoms associated with the cancer or the non-neoplastic condition or the viral infection decrease.
  • In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for up to 48 weeks. In other embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for up to 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 26 weeks (0.5 year), 52 weeks (1 year), 78 weeks (1.5 years), 104 weeks (2 years), or 130 weeks (2.5 years) or more. In certain embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for an indefinite period of time. In some embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or a pharmaceutical composition thereof for a period of time followed by a period of rest (i.e., a period wherein the Compound is not administered) before the administration of the Compound or pharmaceutical composition thereof is resumed. In specific embodiments, a method for treating cancer or a non-neoplastic condition or a viral infection presented herein involves the administration of a Compound or pharmaceutical composition thereof in cycles, e.g., 1 week cycles, 2 week cycles, 3 week cycles, 4 week cycles, 5 week cycles, 6 week cycles, 8 week cycles, 9 week cycles, 10 week cycles, 11 week cycles, or 12 week cycles. In such cycles, the Compound or a pharmaceutical composition thereof may be administered once, twice, three times, or four times daily. In particular embodiments, a method for treating a prostate condition presented herein involves the administration of a Compound or a pharmaceutical composition thereof twice daily in 4 week cycles.
  • In specific embodiments, the period of time of administration of a Compound or pharmaceutical composition thereof may be dictated by one or more monitoring parameters, e.g., concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins such as IL-6 or IL-8); tumor size, blood flow, or metabolism; peritumoral inflammation or edema. In particular embodiments, the period of time of administration of a Compound or pharmaceutical composition thereof may be adjusted based on one or more monitoring parameters, e.g., concentration of VEGF or other angiogenic or inflammatory mediators (e.g., cytokines or interleukins such as IL-6 or IL-8); tumor size, blood flow, or metabolism; and/or peritumoral inflammation or edema.
  • In certain embodiments, in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein, a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof prior to, concurrently with, or after a meal (e.g., breakfast, lunch, or dinner). In specific embodiments, in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein, a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in the morning (e.g., between 5 am and 12 pm). In certain embodiments, in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein, a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof at noon (i.e., 12 pm). In particular embodiments, in accordance with the methods for treating cancer or a non-neoplastic condition or a viral infection presented herein, a Compound or a pharmaceutical composition thereof is administered to a subject in need thereof in the afternoon (e.g., between 12 pm and 5 pm), evening (e.g., between 5 pm and bedtime), and/or before bedtime.
  • In specific embodiments, a dose of a Compound or a pharmaceutical composition thereof is administered to a subject once per day, twice per day, three times per day; once, twice or three times every other day (i.e., on alternate days); once, twice or three times every two days; once, twice or three times every three days; once, twice or three times every four days; once, twice or three times every five days; once, twice, or three times once a week, biweekly or monthly.
    • 5.7 Combination Therapy
  • Presented herein are combination therapies for the treatment of cancer or a non-neoplastic condition or a viral infection which involve the administration of a Compound in combination with one or more additional therapies to a subject in need thereof. In a specific embodiment, presented herein are combination therapies for the treatment of cancer or a non-neoplastic condition or a viral infection which involve the administration of an effective amount of a Compound in combination with an effective amount of another therapy to a subject in need thereof.
  • As used herein, the term “in combination,” refers, in the context of the administration of a Compound, to the administration of a Compound prior to, concurrently with, or subsequent to the administration of one or more additional therapies (e.g., agents, surgery, or radiation) for use in treating cancer or a non-neoplastic condition or a viral infection. The use of the term “in combination” does not restrict the order in which one or more Compounds and one or more additional therapies are administered to a subject. In specific embodiments, the interval of time between the administration of a Compound and the administration of one or more additional therapies may be about 1-5 minutes, 1-30 minutes, 30 minutes to 60 minutes, 1 hour, 1-2 hours, 2-6 hours, 2-12 hours, 12-24 hours, 1-2 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 26 weeks, 52 weeks, 11-15 weeks, 15-20 weeks, 20-30 weeks, 30-40 weeks, 40-50 weeks, 1 month, 2 months, 3 months, 4 months 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, or any period of time in between. In certain embodiments, a Compound and one or more additional therapies are administered less than 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years apart.
  • In some embodiments, the combination therapies provided herein involve administering a Compound daily, and administering one or more additional therapies once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every month, once every 2 months (e.g., approximately 8 weeks), once every 3 months (e.g., approximately 12 weeks), or once every 4 months (e.g., approximately 16 weeks). In certain embodiments, a Compound and one or more additional therapies are cyclically administered to a subject. Cycling therapy involves the administration of the Compound for a period of time, followed by the administration of one or more additional therapies for a period of time, and repeating this sequential administration. In certain embodiments, cycling therapy may also include a period of rest where the Compound or the additional therapy is not administered for a period of time (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 20 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, or 3 years). In an embodiment, the number of cycles administered is from 1 to 12 cycles, from 2 to 10 cycles, or from 2 to 8 cycles.
  • In some embodiments, the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein comprise administering a Compound as a single agent for a period of time prior to administering the Compound in combination with an additional therapy. In certain embodiments, the methods for treating cancer or a non-neoplastic condition or a viral infection provided herein comprise administering an additional therapy alone for a period of time prior to administering a Compound in combination with the additional therapy.
  • In some embodiments, the administration of a Compound and one or more additional therapies in accordance with the methods presented herein have an additive effect relative the administration of the Compound or said one or more additional therapies alone. In some embodiments, the administration of a Compound and one or more additional therapies in accordance with the methods presented herein have a synergistic effect relative to the administration of the Compound or said one or more additional therapies alone.
  • As used herein, the term “synergistic,” refers to the effect of the administration of a Compound in combination with one or more additional therapies (e.g., agents), which combination is more effective than the additive effects of any two or more single therapies (e.g., agents). In a specific embodiment, a synergistic effect of a combination therapy permits the use of lower dosages (e.g., sub-optimal doses) of a Compound or an additional therapy and/or less frequent administration of a Compound or an additional therapy to a subject. In certain embodiments, the ability to utilize lower dosages of a Compound or of an additional therapy and/or to administer a Compound or said additional therapy less frequently reduces the toxicity associated with the administration of a Compound or of said additional therapy, respectively, to a subject without reducing the efficacy of a Compound or of said additional therapy, respectively, in the treatment of cancer or a non-neoplastic condition or a viral infection. In some embodiments, a synergistic effect results in improved efficacy of a Compound and each of said additional therapies in treating cancer or a non-neoplastic condition or a viral infection. In some embodiments, a synergistic effect of a combination of a Compound and one or more additional therapies avoids or reduces adverse or unwanted side effects associated with the use of any single therapy.
  • The combination of a Compound and one or more additional therapies can be administered to a subject in the same pharmaceutical composition. Alternatively, a Compound and one or more additional therapies can be administered concurrently to a subject in separate pharmaceutical compositions. A Compound and one or more additional therapies can be administered sequentially to a subject in separate pharmaceutical compositions. A Compound and one or more additional therapies may also be administered to a subject by the same or different routes of administration.
  • The combination therapies provided herein involve administering to a subject to in need thereof a Compound in combination with conventional, or known, therapies for treating cancer or a non-neoplastic condition or a viral infection. Other therapies for cancer or a non-neoplastic condition or a viral infection or a condition associated therewith are aimed at controlling or relieving one or more symptoms. Accordingly, in some embodiments, the combination therapies provided herein involve administering to a subject to in need thereof a pain reliever, or other therapies aimed at alleviating or controlling one or more symptoms associated with cancer or a non-neoplastic condition or a viral infection or a condition associated therewith.
  • Specific examples of anti-cancer agents that may be used in combination with a Compound for treating cancer or a non-neoplastic condition include: a hormonal agent (e.g., aromatase inhibitor, selective estrogen receptor modulator (SERM), and estrogen receptor antagonist), chemotherapeutic agent (e.g., microtubule dissembly blocker, antimetabolite, topisomerase inhibitor, and DNA crosslinker or damaging agent), anti-angiogenic agent (e.g., VEGF antagonist, receptor antagonist, integrin antagonist, vascular targeting agent (VTA)/vascular disrupting agent (VDA)), radiation therapy, and conventional surgery.
  • Non-limiting examples of hormonal agents that may be used in combination with a Compound for treating cancer or a non-neoplastic condition include aromatase inhibitors, SERMs, and estrogen receptor antagonists. Hormonal agents that are aromatase inhibitors may be steroidal or nonsteroidal. Non-limiting examples of nonsteroidal hormonal agents include letrozole, anastrozole, aminoglutethimide, fadrozole, and vorozole. Non-limiting examples of steroidal hormonal agents include aromasin (exemestane), formestane, and testolactone. Non-limiting examples of hormonal agents that are SERMs include tamoxifen (branded/marketed as Nolvadex®), afimoxifene, arzoxifene, bazedoxifene, clomifene, femarelle, lasofoxifene, ormeloxifene, raloxifene, and toremifene. Non-limiting examples of hormonal agents that are estrogen receptor antagonists include fulvestrant. Other hormonal agents include but are not limited to abiraterone and lonaprisan.
  • Non-limiting examples of chemotherapeutic agents that may be used in combination with a Compound for treating cancer include microtubule disasssembly blocker, antimetabolite, topisomerase inhibitor, and DNA crosslinker or damaging agent. Chemotherapeutic agents that are microtubule dissemby blockers include, but are not limited to, taxenes (e.g., paclitaxel (branded/marketed as TAXOL®), docetaxel, abraxane, larotaxel, ortataxel, and tesetaxel); epothilones (e.g., ixabepilone); and vinca alkaloids (e.g., vinorelbine, vinblastine, vindesine, and vincristine (branded/marketed as ONCOVIN®)).
  • Chemotherapeutic agents that are antimetabolites include, but are not limited to, folate anitmetabolites (e.g., methotrexate, aminopterin, pemetrexed, raltitrexed); purine antimetabolites (e.g., cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine); pyrimidine antimetabolites (e.g., 5-fluorouracil, capcitabine, gemcitabine (GEMZAR®), cytarabine, decitabine, floxuridine, tegafur); and deoxyribonucleotide antimetabolites (e.g., hydroxyurea).
  • Chemotherapeutic agents that are topoisomerase inhibitors include, but are not limited to, class I (camptotheca) topoisomerase inhibitors (e.g., topotecan (branded/marketed as HYCAMTIN®) irinotecan, rubitecan, and belotecan); class II (podophyllum) topoisomerase inhibitors (e.g., etoposide or VP-16, and teniposide); anthracyclines (e.g., doxorubicin, epirubicin, Doxil, aclarubicin, amrubicin, daunorubicin, idarubicin, pirarubicin, valrubicin, and zorubicin); and anthracenediones (e.g., mitoxantrone, and pixantrone).
  • Chemotherapeutic agents that are DNA crosslinkers (or DNA damaging agents) include, but are not limited to, alkylating agents (e.g., cyclophosphamide, mechlorethamine, ifosfamide (branded/marketed as IFEX®), trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine (branded/marketed as BiCNU®), lomustine, semustine, fotemustine, nimustine, ranimustine, streptozocin, busulfan, mannosulfan, treosulfan, carboquone, N,N′N′-triethylenethiophosphoramide, triaziquone, triethylenemelamine); alkylating-like agents (e.g., carboplatin (branded/marketed as PARAPLATIN), cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, satraplatin, picoplatin); nonclassical DNA crosslinkers (e.g., procarbazine, dacarbazine, temozolomide (branded/marketed as TEMODAR®), altretamine, mitobronitol); and intercalating agents (e.g., actinomycin, bleomycin, mitomycin, and plicamycin).
  • Non-limiting examples of anti-angiogenic agents that may be used in combination with a Compound for treating cancer or a non-neoplastic condition include VEGF antagonists, receptor antagonists, integrin antagonists (e.g., vitaxin, cilengitide, and S247), and VTAs/VDAs (e.g., fosbretabulin). VEGF antagonists include, but are not to, anti-VEGF antibodies (e.g., bevacizumab (branded/marketed as AVASTIN®) and ranibizumab (branded/marketed as LUCENTIS)), VEGF traps (e.g., aflibercept), VEGF antisense or siRNA or miRNA, and aptamers (e.g., pegaptanib (branded/marketed as MACUGEN®)). Anti-angiogenic agents that are receptor antagonists include, but are not limited to, antibodies (e.g., ramucirumab) and kinase inhibitors (e.g., sunitinib, sorafenib, cediranib, panzopanib, vandetanib, axitinib, and AG-013958) such as tyrosine kinase inhibitors. Other non-limiting examples of anti-angiogenic agents include ATN-224, anecortave acetate (branded/marketed as RETAANE), microtubule depolymerization inhibitor such as combretastatin A4 prodrug, and protein or protein fragment such as collagen 18 (endostatin).
  • Non-limiting examples of other therapies that may be administered to a subject in combination with a Compound for treating cancer or a non-neoplastic condition include:
      • (1) a statin such as lovostatin (e.g., branded/marketed as MEVACOR®);
      • (2) an mTOR inhibitor such as sirolimus which is also known as Rapamycin (e.g., branded/marketed as RAPAMUNE®), temsirolimus (e.g., branded/marketed as TORISEL®), evorolimus (e.g., branded/marketed as AFINITOR®), and deforolimus;
      • (3) a farnesyltransferase inhibitor agent such as tipifarnib (e.g., branded/marketed as ZARNESTRA®);
      • (4) an antifibrotic agent such as pirfenidone;
      • (5) a pegylated interferon such as PEG-interferon alfa-2b;
      • (6) a CNS stimulant such as methylphenidate (branded/marketed as RITALIN®);
      • (7) a HER-2 antagonist such as anti-HER-2 antibody (e.g., trastuzumab) and kinase inhibitor (e.g., lapatinib);
      • (8) an IGF-1 antagonist such as an anti-IGF-1 antibody (e.g., AVE1642 and IMC-A11) or an IGF-1 kinase inhibitor;
      • (9) EGFR/HER-1 antagonist such as an anti-EGFR antibody (e.g., cetuximab, panitumamab) or EGFR kinase inhibitor (e.g., erlotinib (e.g., branded/marketed as TARCEVA®), gefitinib);
      • (10) SRC antagonist such as bosutinib;
      • (11) cyclin dependent kinase (CDK) inhibitor such as seliciclib;
      • (12) Janus kinase 2 inhibitor such as lestaurtinib;
      • (13) proteasome inhibitor such as bortezomib;
      • (14) phosphodiesterase inhibitor such as anagrelide;
      • (15) inosine monophosphate dehydrogenase inhibitor such as tiazofurine;
      • (16) lipoxygenase inhibitor such as masoprocol;
      • (17) endothelin antagonist;
      • (18) retinoid receptor antagonist such as tretinoin or alitretinoin;
      • (19) immune modulator such as lenalidomide, pomalidomide, or thalidomide (e.g., branded/marketed as THALIDOMID®);
      • (20) kinase (eg, tyrosine kinase) inhibitor such as imatinib (e.g., branded/marketed as GLEEVEC®), dasatinib, erlotinib, nilotinib, gefitinib, sorafenib, sunitinib (e.g., branded/marketed as SUTENT®), lapatinib, AEE788, or TG100801;
      • (21) non-steroidal anti-inflammatory agent such as celecoxib (branded/marketed as CELEBREX®);
      • (22) human granulocyte colony-stimulating factor (G-CSF) such as filgrastim (branded/marketed as NEUPOGEN®);
      • (23) folinic acid or leucovorin calcium;
      • (24) integrin antagonist such as an integrin α5β1-antagonist (e.g., JSM6427);
      • (25) nuclear factor kappa beta (NF-κβ) antagonist such as OT-551, which is also an anti-oxidant;
      • (26) hedgehog inhibitor such as CUR61414, cyclopamine, GDC-0449, or anti-hedgehog antibody;
      • (27) histone deacetylase (HDAC) inhibitor such as SAHA (also known as vorinostat (branded/marketed as ZOLINZA®)), PCI-24781, SB939, CHR-3996, CRA-024781, ITF2357, JNJ-26481585, or PCI-24781;
      • (28) retinoid such as isotretinoin (e.g., branded/marketed as ACCUTANE®);
      • (29) hepatocyte growth factor/scatter factor (HGF/SF) antagonist such as HGF/SF monoclonal antibody (e.g., AMG 102);
      • (30) synthetic chemical such as antineoplaston;
      • (31) anti-diabetic such as rosiglitazone maleate (e.g., branded/marketed as AVANDIA®);
      • (32) antimalarial and amebicidal drug such as chloroquine (e.g., branded/marketed as ARALEN®);
      • (33) synthetic bradykinin such as RMP-7;
      • (34) platelet-derived growth factor receptor inhibitor such as SU-101;
      • (35) receptor tyrosine kinase inhibitorsof Flk-1/KDR/VEGFR2, FGFR1 and PDGFR beta such as SU5416 and SU6668;
      • (36) anti-inflammatory agent such as sulfasalazine (e.g., branded/marketed as AZULFIDINE®); and
      • (37) TGF-beta antisense therapy.
  • Non-limiting examples of other therapies that may be administered to a subject in combination with a Compound for treating cancer or a non-neoplastic condition include: a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone such as leuprolide acetate (branded/marketed as LUPRON®); a nonsteroidal, anti-androgen such as flutamide (branded/marketed as EULEXIN®) or nilutamide (branded/marketed as) NILANDRON®; a non-steroidal androgen receptor inhibitor such as bicalutamide (branded/marketed as CASODEX®); steroid hormone such as progesterone; anti-fungal agent such as Ketoconazole (branded/marketed as NIZORAL®); glucocorticoid such as prednisone; estramustine phosphate sodium (branded/marketed as EMCYT®); and bisphosphonate such as pamidronate, alendronate, and risedronate.
  • Other specific examples of therapies that may be used in combination with a Compound for treating cancer or a non-neoplastic condition include, but are not limited to, antibodies that specifically bind to a tumor specific antigen or tumor associated antigen, e.g., anti-EGFR/HER-1 antibodies.
  • Additional specific examples of therapies that may be used in combination with a Compound for treating cancer or a non-neoplastic condition include, but are not limited to, agents associated with cancer immunotherapy, e.g., cytokines, interleukins, and cancer vaccines.
  • Specific examples of agents alleviating side-effects associated with cancer or a non-neoplastic condition that can be used as therapies in combination with a Compound, include, but are not limited to: antiemetics, e.g., Ondansetron hydrochloride (branded/marketed as ZOFRAN®), Granisetron hydrochloride (branded/marketed as KYTRIL®), Lorazepam (branded/marketed as ATIVAN®) and Dexamethasone (branded/marketed as DECADRON®).
  • In certain embodiments, combination therapies provided herein for treating cancer or a non-neoplastic condition comprise administering a Compound in combination with one or more agents used to treat and/or manage a side effect, such as, bleeding (usually transient, low-grade epistaxis), arterial and venous thrombosis, hypertension, delayed wound healing, asymptomatic proteinuria, nasal septal perforation, reversible posterior leukoencephalopathy syndrome in association with hypertension, light-headedness, ataxia, headache, hoarseness, nausea, vomiting, diarrhea, rash, subungual hemorrhage, myelosuppression, fatigue, hypothyroidism, QT interval prolongation, or heart failure.
  • In certain embodiments, a Compound is not used in combination with a drug that is primarily metabolized by CYP2D6 (such as an antidepressant (e.g, a atricyclic antidepressant, a selective serotonin reuptake inhibitor, and the like), an antipsychotic, a beta-adrenergic receptor blocker, or certain types of anti-arrhythmics) to treat cancer or a non-neoplastic condition.
  • Non-limiting examples of other therapies that may be used in combination with a Compound for treating a viral infection include a HCV protease inhibitor such as a NS2 protease inhibitor, a NS3 protease inhibitor, a peptide or dipeptide NS3 protease inhibitor or a NS4a protease cofactor inhibitor; a nucleoside or non-nucleoside HCV NS5b polymerase inhibitor; one or more agents such as a NS4b inhibitor, NS5a inhibitor, IRES inhibitor (such as a steroid, a ribozyme, miRNA, siRNA or an antisense RNA), p7 inhibitor, entry inhibitor, fusion inhibitor, helicase inhibitor, ribavirin, a ribavirin analogue, ribavirin and at least one or more of a nonpegylated interferon or a pegylated interferon, a TLR agonist, cyclophilin inhibitor, caspase or pancaspase inhibitor, immunomodulator, immunomodulator/antiinflammatory, antiinflammatory, antiinflammatory/antifibrotic, broad spectrum immune stimulator, antifibrotic, antioxidant, hemopurifier, IMPDH inhibitor, glycosidase inhibitor, glucosidase inhibitor, HCV therapeutic vaccine, A3 adenosine receptor (AR) agonist, polypeptide eglin c analog inhibitor, human pancreatic secretory trypsin and minibody repertoire inhibitor or a monoclonal antibody and fragment thereof; or, one or more different agents such as a HIV inhibitor, HBV inhibitor, RNA inhibitor, RNAi, anti-phospholipid therapy, protein therapeutic, interferon replacement agent, botanical or non-specific pharmaceutical.
  • A specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the NS3 HCV protease inhibitor BI 201335 (Boehringer Ingelheim Pharma), boceprevir (also referred to as SCH-503034, Schering-Plough Corporation), ciluprevir (also referred to as BILN-2061, Boehringer Ingelheim Pharma), IDX136 (Idenix Pharmaceuticals, Inc.), IDX316 (Idenix Pharmaceuticals, Inc.), ITMN-191 (also referred to as R-7227, InterMune/Roche Pharmaceuticals), MK-7009 (Merck), PHX1766 (Phenomix), SCH-6 (Schering-Plough Corporation), SCH-900518 (also referred to as SCH-518, Schering-Plough Corporation), telaprevir (also referred to as VX 950, Vertex Pharmaceuticals, Inc.), TMC435350 (also referred to as TMC435, Medivir/Tibotec), VBY-376 and VBY-106 (Virobay), VP50406 (ViroPharma, Inc.), VX-500 (Vertex Pharmaceuticals, Inc.), VX 550 (Vertex Pharmaceuticals, Inc.) or VX-813 (Vertex Pharmaceuticals, Inc.).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the HCV NS4a protease cofactor inhibitor or HCV NS4a protease cofactor inhibitor ACH-806 (also referred to as GS-9132, Achillion/Gilead) or ACH-1095 (also known as GS-9525, Gilead/Achillion.
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the nucleoside or non-nucleoside NS5b polymerase inhibitor A-837093 (Abbott Laboratories), A-848837 (Abbott Laboratories), ABT-333 (Abbott Laboratories), AG-021541 (Pfizer Pharmaceuticals), ANA598 (Anadys Pharmaceuticals, Inc.), BILN-1941 (Boehringer Ingelheim Pharma), GL-59728 (Genelabs), GL-60667 (Genelabs), GS-9190 (Gilead), GSK-625433 (GlaxoSmithKline), HCV-796 (Wyeth/Viropharma, Inc.), HCV-896 (ViroPharma, Inc.), IDX102 (Idenix Pharmaceuticals, Inc.), IDX184 (Idenix Pharmaceuticals, Inc.), IDX375 (Idenix Pharmaceuticals, Inc.), JDK-003 (Akros Pharmaceuticals), MK-0608 (Merck), MK-3281 (Merck), NM107 (active moiety of valopicitabine, Idenix/Novartis), PF-00868554 (also referred to as PF-868554 or PF-868,554, Pfizer Pharmaceuticals), PSI-6130 (Pharmasset), PSI-7851 (Pharmasset), R1626 (a prodrug of R1479, Roche Pharmaceuticals), R7128 (a prodrug of PSI-6130, Pharmasset/Roche Pharmaceuticals), valopicitabine (also referred to as NM-283, Idenix/Novartis), VBY-708 (Virobay), VCH-222 (Virochem), VCH-759 (Virochem), VCH-916 (Virochem) or XTL-2125 (also referred to as BC2125, XTL Biopharmaceuticals, Ltd.).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the NS4b inhibitor anguizole (Genelabs/GSK/Viropharma, Inc.), clemizole (Stanford University) or Compound A (BMS).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the NS5a inhibitor A-689 (also referred to as AZD7295, Arrow Therapeutics, Ltd./AstraZeneca), A-831 (also referred to as AZD2836, Arrow Therapeutics, Ltd./AstraZeneca), BMS-790052 (Bristol-Myers Squibb).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the IRES inhibitor steroid mifepristone (also referred to as VGX-410C, VGX Pharmaceuticals), an antisense oligonucleotide ISIS-14803 (Isis Pharmaceuticals), a ribozyme such as HEPTAZYME®, (a synthetic ribozyme, Ribozyme Pharmaceuticals, Inc.), a RNAi such as TT033 (Benitec/Tacere Bio/Pfizer) or SIRNA-034 (Sirna Therapeutics), a miRNA such as SPC3649 (LNA-antimiR™-122 brand, Santaris Pharma) or an anti-miR-122 miRNA (Regulus Therapeutics) or siRNA.
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the p7 inhibitor BIT225 (Biotron Limited), the viral entry inhibitor ITX5061 (iTherX Pharmaceuticals, Inc.), PRO 206 (Progenics), an SP-30 entry inhibitor (Samaritan Pharmaceuticals) or a broad spectrum entry inhibitor such as REP 9AC (an amphipathic DNA polymer, REPLICor, Inc.).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include ribavirin (VIRAZOLE® and VILONA® brands, ICN Pharmaceuticals), ribavirin for oral administration (REBETOL® brand, Schering-Plough Corporation), ribavirin tablets (COPEGUS® brand, Roche Pharmaceuticals), ribavirin capsules (RIBASPHERE® brand, Three Rivers Pharmaceuticals, LLC),
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the ribavirin analogue levovirin (L-isomer of ribavirin, Valeant Pharmaceuticals), R1518 (a prodrug of levovirin, also referred to as levovirin valinate, Roche Pharmaceuticals) or taribavirin (an oral prodrug of ribavirin, also referred to as viramidine, Valeant Pharmaceuticals).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the non-pegylated interferon (optionally administered with ribavirin) interferon alfa-2a (ROFERON®-A brand, Roche Pharmaceuticals), interferon alfa-2b (INTRON® A brand, Schering-Plough Corporation), interferon alfa-2c (BEROFOR® brand, Boehringer Ingelheim), interferon-alpha variant GEA007.1 (GenOdyssee SA), interferon-alpha for low dose oral administration (Amarillo Biosciences, Inc./CytoPharm, Inc.), interferon-alpha for oral administration (BELEROFON® brand, Nautilus Biotech), long-acting interferon-alpha (LOCTERON® brand, also referred to as BLX-883, Biolex Therapeutics/OctoPlus), long-acting albuminfusion interferon alfa-2b (ALBUFERON® brand, also referred to as albinterferon alfa-2b, Human Genome Sciences), purified multi-subtype human leukocyte interferon-alpha (MULTIFERON® brand, Swedish Orphan International), interferon beta-la (REBIF® brand, Merck Serono), interferon omega (also referred to as leukocycte (II) interferon, Intarcia Therapeutics), interferon omega (VIRBAGEN OMEGA® brand, Virbac), interferon omega (OMEGA INTERFERON® brand, Biomedicines), consensus interferon (INFERGEN® brand, also referred to as interferon alfacon-1, Three Rivers Pharma), medusa interferon (MEDUSA INTERFERON® brand, Flamel Technologies).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the pegylated interferon (optionally administered with ribavirin) Peginterferon alfa-2a (PEGASYS® brand, Roche Pharmaceuticals), Peginterferon alfa-2b (PEGINTRON® brand, Schering-Plough Corporation), Peginterferon alfacon-1 (pegylated form of interferon alfacon-1, also referred to as PEG-Alfacon, InterMune), Peg-Interferon Lambda IL-29 (Zymogenetics/Bristol-Myers Squibb).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the TLR agonist ANA773 (Anadys Pharmaceuticals, Inc.), a TLR-7 agonist selected from isatoribine (also referred to as ANA245, Anadys Pharmaceuticals, Inc.), ANA-971 (a prodrug of TLR-7 agonist isatoribine, Anadys Pharmaceuticals, Inc.), ANA975 (a prodrug of TLR-7 agonist isatoribine, Anadys Pharmaceuticals, Inc.), a TLR9 agonist selected from IMO-2125 (Idera Pharmaceuticals), a TLR9 agonist (Actilon brand, Coley), a cyclophilin B inhibitor selected from Debio 025 (Debiopharm Group) or SCY-635 (Scynexis) or a cyclosporin A analog selected from NIM811 (Novartis), a pancaspase inhibitor selected from PF-03491390 (also referred to as IDN-6556, Pfizer Pharmaceuticals), an interleukin-7 immunomodulator selected from CYT107 (Cytheris SA), NOV-205 (Novelos Therapeutics), oglufanide disodium (Implicit Bioscience) or thymosin alpha 1 (also referred to as thymalfasin, ZADAXIN® brand, SciClone Pharmaceuticals), a immunomodulator/antiinflammatory selected from NOV205 (Novelos Therapeutics, Inc.), an antiinflammatory selected from CTS-1027, a matrix metalloproteinase selected from a (MMP) inhibitor (Conatus) or CF102, an A3AR agonist (Can-Fite BioPharma, Ltd.), an antiinflammatory/antifibrotic selected from mitoquinone (MitoQ® brand, Antipodean Pharmaceuticals) or PYN17 (Phynova), a broad spectrum immune stimulator selected from SCV-07 (SciClone), an immune regulator selected from ECH18 (Enzo BioChem/Therapeutics), an antifibrotic selected from JKB-122 (Jenken Biosciences), a tumor necrosis factor □ inhibitor antifibrotic selected from ENBREL® brand (Wyeth), a phospholipid antifibrotic for oral administration selected from IP-501 (Indevus Pharmaceuticals), a hemopurifier (Aethlon Medical), an IMPDH inhibitor selected from merimepodib (also referred to as VX-497, Vertex Pharmaceuticals, Inc.), a glucosidase inhibitor selected from celgosivir, an alpha-glucosidase I inhibitor selected from MX-3253 (Migenix), a HCV therapeutic vaccine selected from a DNA vaccine (ChronVac-C® brand, Inovio/Tripep AB), a MVA virus vaccine carrying and expressing HCV non-structural proteins (NS3, NS4 and NS5b) selected from TG4040 (Transgene) or (Inovio/Tripep AB), an antiviral vaccine selected from GNI-103 (GENimmune), a virosome-based combination vaccine of synthetic HCV peptide antigens (Pevion Biotect), an E1 vaccine (Innogenetics), a HCV E1/E2/MF59 vaccine (Chiron/Novartis), a vaccine selected from CSL123 (Chiron/CSL), a targeted molecular immunogen vaccine selected from GI-5005 (Globelmmune), a vaccine having a combination of five synthetic peptides selected from IC-41 (Intercell AG/Novartis), an antiviral vaccine (AMANTADINE® brand, Endo Labs), a monoclonal antibody selected from I70® (also referred to as HCV-ABXTL68 or HCV-AB, Biochem Therapeutics/OSI Pharmaceuticals), an immune globulin polyclonal antibody selected from intravenous human immune globulin (CIVACIR® brand, NABI), a humanized Y-90 labeled antibody (Immunomedics, Inc.) an anti-PD1 antibody selected from MDX-1106 (also referred to as ONO-4538, Medarex, Inc./Ono Pharmaceutical), an anti-CD20 monoclonal antibody (RITUXIMAB® brand, Genentech), a monoclonal antibody selected from XTL-6865 or XTL-002 (XTL Biopharmaceuticals, Ltd.), a HIV fusion inhibitor selected from enfuvirtide (FUZEON® brand, Trimeris/Roche Pharmaceuticals), an anti-phospholipid therapy selected from bavituximab (formerly TARVACIN® brand, Peregrine Pharmaceuticals, Inc.), a protein therapeutic or interferon replacement agent selected from oligoadenylate synthetase stimulant CB-183,872 (Cubist Pharmaceuticals, also referred to as IB657 from Illumigen Biosciences), a botanical selected from an antiviral botanical extract PYN18 (Phynova) or a non-specific pharmaceutical selected from the cholesterol-lowering agent fluvastatin (Oklahoma University Health Sciences Center), atorvastatin (Okayama University, Japan), lovastatin (Okayama University, Japan) or simvastatin (Okayama University, Japan), a thiazolide analog selected from nitazoxanide (ALINIA™ brand, Romark Pharmaceuticals), photo-sensitized methylene blue (SUVUS® brand, Bioenvision), a synthetic phytochemical selected from KPE02003002 (Kemin Pharma) or KPE00001133 (Kemin Pharma), an antiviral agent selected from CB5300 (Canopus BioPharma, Inc.) or a tyrosine phosphatase inhibitor selected from sodium stibogluconate (LENOCTA™ brand, VioQuest Pharmaceuticals).
  • Another specific non-limiting example of other therapies that may be used in combination with a Compound for treating a viral infection include the non-specific pharmaceutical histamine dihydrochloride (CEPLENE® and MAXAMINE® brands, Maxim Pharmaceuticals), an immunosuppressive agent selected from mycophenolate mofetil (Roche Pharmaceuticals), mycophenolic acid (Roche Pharmaceuticals), or al-antichymotrypsin.
    • 5.8 Kits
  • Provided herein is a pharmaceutical pack or kit comprising one or more containers filled with a Compound or pharmaceutical composition thereof. Additionally, one or more other therapies useful for the treatment of cancer or a non-neoplastic condition, or other relevant agents can also be included in the pharmaceutical pack or kit. Also provided herein is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein. Optionally associated with such kits can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
    • 6. GENERAL SYNTHETIC METHODS
  • Compounds provided herein can be synthesized in accordance with the general synthetic schemes described below and are illustrated more particularly in the specific synthetic examples that follow. The general schemes and specific examples are offered by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions expressed. The methods for preparing the various starting materials used in the schemes and examples are well within the skill of persons versed in the art.
  • During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
  • 6.1
  • Figure US20160340354A1-20161124-C00743
  • 6.2
  • Figure US20160340354A1-20161124-C00744
  • 6.3
  • Figure US20160340354A1-20161124-C00745
  • 6.4
  • Figure US20160340354A1-20161124-C00746
  • 6.5
  • Figure US20160340354A1-20161124-C00747
  • 6.6
  • Figure US20160340354A1-20161124-C00748
  • 6.7
  • Figure US20160340354A1-20161124-C00749
  • 6.8
  • Figure US20160340354A1-20161124-C00750
  • 6.9
  • Figure US20160340354A1-20161124-C00751
  • 6.10
  • Figure US20160340354A1-20161124-C00752
  • 6.11
  • Figure US20160340354A1-20161124-C00753
  • 6.12
  • Figure US20160340354A1-20161124-C00754
  • 6.13
  • Figure US20160340354A1-20161124-C00755
  • 6.14
  • Figure US20160340354A1-20161124-C00756
  • 6.15
  • Figure US20160340354A1-20161124-C00757
  • 6.16
  • Figure US20160340354A1-20161124-C00758
  • 6.17
  • Figure US20160340354A1-20161124-C00759
  • 6.18
  • Figure US20160340354A1-20161124-C00760
  • 6.19
  • Figure US20160340354A1-20161124-C00761
  • 6.20
  • Figure US20160340354A1-20161124-C00762
  • 6.21
  • Figure US20160340354A1-20161124-C00763
  • 6.22
  • Figure US20160340354A1-20161124-C00764
  • 6.23
  • Figure US20160340354A1-20161124-C00765
    • 6.24 Synthetic Routes
  • Where the processes for the preparation of the Compounds provided herein give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The Compounds provided herein may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The Compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The Compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the Compounds may be resolved using a chiral HPLC column.
  • The terms used in describing the invention are commonly used and known to those skilled in the art. Some reagents are referred to as a chemical formula. Other reagents are referred to as abbreviations known to persons skilled in the art.
  • Specific Compounds provided herein may be prepared as per the following examples offered by way of illustration and not by way of limitation. No attempt has been made to optimize the yields obtained in any of the reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents. Additional Compounds may be made according to the synthetic methods of the present invention by one skilled in the art, differing only in possible starting materials, reagents and conditions used in the instant methods.
    • Example I
  • Figure US20160340354A1-20161124-C00766
  • To epoxide Compound 460 (prepared as described in U.S. Publication No. 2005-0272759) (0.76 g, 1.5 mmol) was added to a solution of ammonia in MeOH (7 M, excess) and stirred at rt overnight. The mixture was concentrated in-Vacuo and chromatographed (15% MeOH and 0.5% i-Pr2NH in DCM) to give 0.693 g (88%) of the amino alcohol B (1725) as a white solid.
    • Example II
  • Figure US20160340354A1-20161124-C00767
  • To a solution of compound 1 (100 mg, 0.223 mmol) in 1 mL of DMF was added KOH (26 mg, 0.466 mmol). Then it was heated to reflux and overnight. Then it was cooled to r.t. and the solvent was evaporated under reduced pressure. The residue was dissolved with EA (5 mL), washed with water (3×5 mL), brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC to give 34 mg of compound 1005. Yield: 26%.
    • Example III
  • Figure US20160340354A1-20161124-C00768
  • To a solution of compound 1 (3.7 g, 0.01 mol) in 30 mL of DMF was added K2CO3 (4.14 g, 0.03 mol) and ClCH2COOMe (1.62 g, 0.015 mol). The mixture was heated to 80° C. After 4 h, it was cooled to r.t. The solvent was evaporated under reduced pressure and the residue was dissolved with EA (20 mL). The organic layer was washed with water (3×20 mL), brine, dried over Na2SO4 and evaporated under reduced pressure. The crude solid was dissolved with 20 mL of THF. Then LiOH (4N, 20 mL) was added to it. The mixture was stirred overnight. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography to yield 2.2 g compound 2. Yield: 51%
  • To a solution of compound 2 (100 mg, 0.233 mmol) in 1 mL of DMF was added compound 3 (67 mg, 0.466 mmol), HOBT (71 mg, 0.466 mmol), EDCI (89 mg, 0.466 mmol), NMM (116 mg, 1.16 mmol). The mixture was stirred at r.t. for 16 h. Then the solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to yield 42 mg of compound 1003. Yield: 32%
    • Example IV
  • Figure US20160340354A1-20161124-C00769
  • To a solution of compound 1 (1 g, 2.8 mmol) in 10 mL of DMF was added K2CO3 (1.16 g, 8.4 mmol) and BrCH2CH2CH2Cl (0.66 g, 4.2 mmol). Then it was stirred at r.t. overnight. Then it was evaporated under reduced pressure and the residue was dissolved with EA (15 mL). The organic layer was washed with water (3×15 mL), brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC.
  • To a solution of compound 2 (100 mg, 0.23 mmol) in 1 mL of MEK was added DIEA (59 mg, 0.46 mmol), NaI (34 mg, 0.23 mmol), morpholine (40 mg, 0.46 mmol). Then it was heated to 90° C. overnight. The mixture was cooled to r.t. and evaporated under reduced pressure and the residue was dissolved with EA (5 mL). The organic layer was washed with water (3×5 mL), brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC.
    • Example V
  • Figure US20160340354A1-20161124-C00770
  • To a solution of compound 1 (3 g, 8 mmol) in 15 mL of DMF was added K2CO3 (2.3 g, 16 mmol) and epobromohydrin (1.3 g, 9.6 mmol). After the addition, it was stirred at r.t. for 3 days. Then it was quenched with water, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography to give 1.7 g compound 2. Yield: 49%
  • To a solution of compound 2 (100 mg, 0.23 mmol) in 1 mL of methylethylketone was added diisopropylethylamine (59 mg, 0.46 mmol) and morpholine (40 mg, 0.46 mmol). After the addition, it was heated to 90° C. overnight. Then it was cooled to r.t., quenched with water, washed with water, brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by flash column chromatography to give 53 mg of compound 1727. Yield: 45%.
    • Example VI
  • Figure US20160340354A1-20161124-C00771
  • To a solution of 1 (81 mg, 0.21 mmol) in 1 mL of DMF was added K2CO3 (89 mg, 0.63 mmol) and 2 (35 mg, 0.25 mmol). Then it was stirred at r.t. overnight. The solvent was evaporated under reduced pressure and the residue was dissolved with ethyl acetate (5 mL) and washed with water (5 mL×3). The organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Then the crude solid was purified by preparative HPLC to give 41 mg of compound 1728. Yield: 44%
    • Example VII
  • Figure US20160340354A1-20161124-C00772
  • To a solution of compound 1 (100 mg, 0.22 mmol) in 1 mL of MEK was added DIEA (57 mg, 0.44 mmol), NaI (10 mg) and compound 2 (44 mg, 0.44 mmol). Then it was heated to 90° C. and stirred overnight. After cooled to r.t., the solvent was removed under reduced pressure. The residue was treated with EA and water. The organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by flash column chromatography to give 45 mg compound 1112. Yield: 40%
    • Example VIII
  • Figure US20160340354A1-20161124-C00773
  • To a solution of compound 1 (150 mg, 0.29 mmol) in 2 mL of acetonitrile was added NaHCO3 (73 mg, 0.87 mmol) and 2-amino-thiazole (29 mg, 0.29 mmol). The mixture was heated to reflux for 2 days. Then it was evaporated under reduced pressure and dissolved in EA. The organic layer was washed with water and brine, dried, evaporated under reduced pressure and purified by preparative HPLC to give 21 mg of compound 1729. Yield: 12%
    • Example IX
  • Figure US20160340354A1-20161124-C00774
    Figure US20160340354A1-20161124-C00775
  • Compound 1205 may be prepared by reacting allyl bromide (79.2 g, 656 mmol) and 4-hydroxybenzaldehyde A (40.0 g, 328 mmol) in the presence of potassium carbonate (90.6 g, 656 mmol) in acetonitrile (400 mL). The reaction is stirred at ambient temperature under an atmosphere of nitrogen for 4 hours. The reaction is filtered, washed with acetonitrile (200 mL), and concentrated in-vacuo. The residue is chromatographed on silica gel using a gradient of ethyl acetate from 10% to 30% in hexanes to give 50.0 g of aldehyde B as a colorless oil. LC/MS [M+H+] 163.2 (100), 2.85 min; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.67 (d, J=5.03 Hz, 2H) 5.33 (dd, J=23.98, 1.51 Hz, 2H) 6.03 (dt, J=22.39, 5.07 Hz, 1H) 7.12 (d, J=8.72 Hz, 2H) 7.85 (d, J=8.38 Hz, 2H) 9.86 (s, 1H).
  • Aldehyde B (50.0 g, 308 mmol) is dissolved in 1.5 L of glacial acetic acid and heated to 100° C. To this solution is added 5-chlorotryptamine HCl (59.4 g, 257 mmol) in small portions. The reaction is stirred for 48 hours under nitrogen then cooled to ambient temperature. The solids are filtered, washed with glacial acetic acid (2×200 mL), and dried in a stream of nitrogen for 48 hours to produce the Pictet-Spengler intermediate C (73.3 g, 76%). LC/MS: 2.02 min, M−H=337 (100); 1H-NMR (300 MHz, d6-DMSO): δ 11.10 (S, 1H), 10.36 (br-s, 2H), 7.60 (d, J=2.0 Hz, 1H), 7.32 (m, 3H), 7.11 (dd, J=8.6 & 2.0 Hz, 1H), 7.04 (d, J=8.7 Hz, 2H), 6.04 (m, 1H), 5.87 (s, 1H), 5.40 (dd, J=17.3 & 1.7 Hz, 1H), 5.27 (dd, J=10.5 & 1.4 Hz, 1H), 4.61 (br-d, J=5.2 Hz, 2H), 3.38 (m, 2H), 3.06 (m, 2H).
  • The Pictet-Spengler intermediate C (50.0 g, 133 mmol) is suspended in ethyl acetate (2 L) and 15% aqueous ammonium hydroxide (1 L) and stirred vigorously for 1 hour. The organic layer is separated, washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the free base D as a pale yellow oil. The pale yellow oil is used for the next stage without further purification.
  • To the above-described preparation of D, is added absolute ethanol (2 L) and L-N-acetyl-phenylalanine (16.6 g, 79.9 mmol). The mixture is stirred at ambient temperature overnight. The white precipitate (93% ee) is filtered and recrystallized from refluxing absolute ethanol. Upon cooling to ambient temperature, the solid is filtered, washed with ethanol (100 mL), and dried in a stream of nitrogen to give the chiral salt E (28.8 g, 32.7%). Chiral High-Performance Liquid Chromatography (HPLC) indicates the presence of the desired (S) enantiomer at 16.2 minutes, and the absence of the undesired (R) at 19.4 minutes; LC/MS indicates a peak of compound at 2.02 minutes with a parent ion of M−H=337 (100).
  • To a suspension of E (20.0 g, 36.6 mmol) in EtOAc (150 mL) and water (50 mL) at room temperature is added K2CO3 (12.63 g, 91.5 mmol). After all the solid is dissolved, 4-chlorophenyl chloroformate is introduced by dropwise addition over 5 min at 0° C. The mixture is stirred at room temperature for 5.5 h. The two layers are separated. The organic layer is washed with 10% K2CO3 and brine, dried over Na2SO4, and concentrated under reduced pressure to give 18.50 g of crude compound F as a yellowish foam. The crude product is used without further purification in the subsequent reaction.
  • To a N2 degassed solution of crude compound F (about 36.6 mmol) in 360 mL of Acros HPLC grade tetrahydrofuran (THF), 0.98 g (1.396 mmol, 3.8%) of 99.9% pure Aldrich grade PdCl2(PPh3)2 is added. The resulting yellow suspension is stirred for 3-5 minutes, followed by the addition of 12.02 g (56.7 mmol, 1.55 eq) of solid 95% pure Aldrich grade NaBH(OAc)3 in one portion. The mixture, which turns black after about an hour, is stirred at room temperature overnight. The black mixture is concentrated under reduced pressure at room temperature. The residue is taken into EtOAc and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl and brine (saturated aqueous NaCl). The organics are dried over MgSO4, concentrated to about 30 mL, and filtered through a short silica plug, which is eluted with 30% of EtOAc in hexanes. The combined filtrate is concentrated to a thick oil, treated with a minimal amount of dichloromethane (about 15 mL), and stirred at room temperature overnight. An off-white colored solid precipitates out. That solid is filtered, washed with dichloromethane:hexanes:1:2, and dried under vacuum to give compound G as an off-white solid (14.64 g, 88.5%). The filtrate is concentrated and purified by chromatography on silica gel using 30% of EtOAc in hexanes to give 1.33 g of G. Overall yield of G from E: 15.97 g, 96.5%.
  • A suspension of compound G (36.26 g, 80.0 mmol) and K2CO3 (11.04 g, 160.0 mmol) in MeCN (300 mL) at 80° C. is dropped into a solution of (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl 4-methylbenzenesulfonate (26.4 g, 88.0 mmol) in MeCN (60 mL) over 4-5 h. The mixture is heated at 80° C. for 15 h with stirring. The mixture is then concentrated under vacuum, taken into EtOAc, and washed with three portions of water. The organics are dried over Na2SO4, concentrated under vacuum, and purified by chromatography on approximately 400 g of silica gel using 30% EtOAc in hexanes as the eluent. The process provides compound H as a white solid (46.0 g, 98.6%). Chemical purity: >99.5%, LC/MS (Electrospray) indicates a parent ion of 579.61; Chiral LC: 20.07 min, >99% ee. 1H-NMR (300 MHz, CDCl3); □ 7.98 (s, 1H), 7.53 (s, 1H), 7.33 (d, J=8.7 Hz, 2H), 7.25 (d, J=9.3 Hz, 2H), 7.15 (s, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.83 (d, J=7.2, 2H).6.46 (s 1H), 4.45 (dd, J=13.5, 4.2 Hz, 1H), 4.28 (m, J=6.3 Hz, 1H), 4.06 (m, 3H), 3.63 (dd, J=9.0, 7.2 Hz, 1H), 3.32 (m, 1H), 3.00 (m, 1H), 2.85 (dd, J=15.3, 3.3 Hz, 1H), 2.03 (q, J=5.1 Hz, 2H), 1.41 (s, 3H), 1.35 (s, 3H).
  • To a solution of compound H (21.0 g, 36.1 mmol) in MeCN (150 mL) is added 0.1 M H2SO4 (18.0 mL, 1.80 mmol) over 5 minutes. The solution is stirred at room temperature for 15 hours, at which time LC/MS shows no starting material. Solid K2CO3 (2.48 g, 18 mmol) is added and the mixture is concentrated under vacuum. The residue is taken into EtOAc and washed with three portions of water. The organics are concentrated and purified by chromatography on 200 g of silica gel employing 30% EtOAc in hexanes as a first eluent, and 100% EtOAc as a second eluent. Chromatography gives 17.97 g (92%) of Compound 1205 as a white solid. m.p.: 110-130° C.; Solubility in water: about 1 μg/mL; ClogP 5.4; MW: 541.42; Chemical purity: >99.5%; LC/MS (electrospray) 539.29; Chiral LC: 19.96 min, >99% e.e.; 1H-NMR (300 MHz, CDCl3): 8.20 (s, 1H), 7.52 (s, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 1.72 (S, 2H), 7.05 (d, J=8.7, 2H), 6.82 (d, J=7.2 Hz, 2H), 6.43 (s, 1H), 4.44 (dd, J=14.1, 3.9 Hz, 1H), 4.10 (m, 2H), 3.97 (m, 1H), 3.69 (d, J=9.6, 1H), 3.51 (dd, J=11.1, 7.2 Hz, 1H), 3.30 (m, 1H), 2.99 (m, 1H), 2.84 (dd, J=15.6, 3.6 Hz, 1H), 2.16 (s, 1H), 1.90 (q, J=5.7 Hz, 2H).
    • Example X
  • Figure US20160340354A1-20161124-C00776
  • Phenol A (1.85 g, 5.00 mmol), potassium carbonate (1.52 g, 11.0 mol), and nosyl glycidol B (1.56 g, 6.00 mmol) were combined in acetonitrile (50 mL) at room temperature and stirred at 40° C. for 48 hours. The reaction was cooled to ambient temperature and filtered. The solids were washed with acetonitrile (50 mL). The washings were combined with the original mother liquor and concentrated in-vacuo. The residue was chromatographed on silica gel using a gradient (0-30%) of ethyl acetate in methylene chloride to give 1.72 g of C (1730) as a white foam. LCMS [M+H+] 427.2 (100), 3.86 min; Chiral HPLC (OD-H) 40.52 min; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (br. s., 3H) 2.67 (dd, J=5.03, 2.68 Hz, 1H) 2.75 (d, J=4.02 Hz, 2H) 2.81 (dd, J=5.03, 4.36 Hz, 1H) 2.92-3.09 (m, 1H) 3.24-3.31 (m, 1H) 3.78 (dd, J=11.40, 6.71 Hz, 1H) 4.05-4.18 (m, 3H) 4.28 (dd, J=11.40, 2.68 Hz, 1H) 6.31 (br. s., 1H) 6.93 (d, J=8.72 Hz, 2H) 7.05 (dd, J=8.72, 2.01 Hz, 1H) 7.11 (d, J=8.38 Hz, 2H) 7.28 (d, J=8.72 Hz, 1H) 7.49 (d, J=2.01 Hz, 1H) 11.11 (br. s., 1H).
    • Example XI
  • Figure US20160340354A1-20161124-C00777
  • To epoxide A (2.10 g, 4.92 mmol) dissolved in acetone (50 mL) was added ferric perchlorate hydrate (350 mg, 0.982 mmol) dissolved in water (10 mL). Additional acetone was added until the solution was no longer cloudy. The reaction was stirred at ambient temperature for 20 hours then at 30° C. for an additional 18 hours. Water (50 mL) was added to the cooled reaction mixture. The reaction was subsequently washed with methylene chloride (3×100 mL) and the organics were concentrated in-vacuo. The residue was chromatographed on silica gel using ethyl acetate (100%) to give 1.47 g of 1000 as a white foam. LCMS [M+H+] 445.0 (100), 3.12 min; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.22 (br. s., 3H) 2.60-2.86 (m, 2H) 2.91-3.13 (m, 1H) 3.41 (t, J=5.56 Hz, 2H) 3.67-3.86 (m, 2H) 3.95 (dd, J=9.54, 4.13 Hz, 1H) 4.05-4.24 (m, 3H) 4.56-4.72 (m, 1H) 4.92 (d, J=5.09 Hz, 1H) 6.31 (br. s., 1H) 6.90 (d, J=8.58 Hz, 2H) 7.05 (dd, J=8.58, 1.91 Hz, 1H) 7.10 (d, J=8.58 Hz, 2H) 7.28 (d, J=8.58 Hz, 1H) 7.50 (d, J=1.91 Hz, 1H) 11.11 (br. s., 1H).
    • Example XII
  • Figure US20160340354A1-20161124-C00778
  • Epoxide A (280 mg, 0.600 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to 0° C. After adding the chiral (S,S) oligomeric Salen cobalt (III) catalyst (12.0 mg, 0.015 mmol—provided by Prof. Eric Jacobson, Harvard U.) and water (12 μl, 0.66 mmol), the reaction was stirred while warming to ambient temperature until all epoxide was consumed. The solvent was removed under a stream of nitrogen and the brown residue was purified by preparative HPLC without any buffer to give chiral diol 1382. LCMS [M+H+] 485.4 (100), 3.45 min; Chiral HPLC (OD-H) 28.56 min; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.64-1.91 (m, 4H) 1.99 (br. s., 2H) 2.59 (br. s., 1H) 2.67-2.86 (m, 2H) 2.92-3.15 (m, 1H) 3.40 (br. s., 2H) 3.74 (br. s., 1H) 3.77-3.87 (m, 1H) 3.90-4.04 (m, 2H) 4.10 (br. s., 2H) 4.65 (br. s., 1H) 4.93 (br. s., 1H) 6.27 (br. s., 1H) 6.90 (d, J=8.58 Hz, 2H) 7.05 (dd, J=8.58, 1.98 Hz, 1H) 7.09 (d, J=8.58 Hz, 2H) 7.28 (d, J=8.58 Hz, 1H) 7.49 (d, J=1.98 Hz, 1H) 11.11 (br. s., 1H).
    • Example XIII
  • Figure US20160340354A1-20161124-C00779
  • To a solution of A (16.3 g, 28.0 mmol) in MeOH (100 mL) was added PPTS (3.53 g, 14 mmol, 20%). The mixture was stirred at room temperature for 15 h. LC-MS showed about 24% starting material. Another 50% of PPTS was added and the solution was stirred at room temperature for 8 h. LC-MS showed no change. The mixture was concentrated under vacuum at room temperature. The residue was taken into EtOAc, washed by water and brine. The organics were concentrated and purified by chromatography to give 11.45 g (75.6%) of G as a white solid and 3.37 g of SM A. The recovered A and 1.46 g of PPTS were dissolved in MeOH (20 mL). The solution was stirred at room temperature for 15 h. LC-MS showed about 23% SM 9. The same work-up gave 2.4 g of B (1205) and 0.58 g of SM A. Total yield of B (1205): 13.85 g, 91.4%. Chemical purity: >99.5%, LC-MS (ES) 539.29; Chiral LC: 19.96 min, >99% ee. 1H-NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.52 (s, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 1.72 (S, 2H), 7.05 (d, J=8.7, 2H), 6.82 (d, J=7.2 Hz, 2H), 6.43 (s, 1H), 4.44 (dd, J=14.1, 3.9 Hz, 1H), 4.10 (m, 2H), 3.97 (m, 1H), 3.69 (d, J=9.6, 1H), 3.51 (dd, J=11.1, 7.2 Hz, 1H), 3.30 (m, 1H), 2.99 (m, 1H), 2.84 (dd, J=15.6, 3.6 Hz, 1H), 2.16 (s, 1H), 1.90 (q, J=5.7 Hz, 2H).
    • Example XIV
  • Figure US20160340354A1-20161124-C00780
  • To a solution of compound 1 (350 mg, 1.12 mmol) in 3 mL of DMF was added compound 2 (254 mg, 1.34 mmol) and EDC (215 mg, 1.12 mmol), HOBT (151 mg, 1.12 mmol), NMM (226 mg, 2.24 mmol). This reaction mixture was stirred at r.t. for 5 h. Then it was treated with water and EA. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography to give 340 mg of compound 3. Yield 63%
  • To a solution of compound 3 (240 mg, 0.5 mmol) in 2 mL of ether was added 1 M HCl. The mixture was stirred at r.t. for 6 h. Then the solvent was removed under reduced pressure. The residue was dissolved with EA (5 mL), washed with water (5 mL×2), brine, dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by flash column chromatography to give 80 mg of compound 1731. Yield 42%
    • Example XV
  • Figure US20160340354A1-20161124-C00781
  • Triol A (22.3 g, 166 mmol), acetal B (26.0 g, 250 mmol), and p-toluene sulfonic acid (1.58 g, 8.32 mol) were combined in THF (1 L) and stirred at ambient temperature until all starting material was consumed (6.5 hr). The reaction was monitored by TLC (1:1 hexanes:EtOAc, stained with KMnO4. Triethyl amine (15 mL) was added to raise the pH the reaction and the solvent was removed in-vacuo. The residue was passed through a plug of silica gel, eluting with 1:1 hexanes in EtOAc to produce C as a colorless oil (24.4 g). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.74 (t, J=7.71 Hz, 3H) 1.19-1.29 (m, 2H) 1.24-1.32 (m, 6H) 3.25-3.62 (m, 6H) 4.48 (t, J=5.20 Hz, 1H).
  • Protected triol C (24.4 g, 138 mmol), triethyl amine (28 g, 275 mmol), and dimethylaminopyridine (DMAP, 1.7 g, 13.8 mmol) were combined in DCM (1 L) and cooled to 0° C. under nitrogen. 3-Nitrophenyl sulfonyl chloride (NsCl, 37 g, 165 mmol) was dissolved in DCM (500 mL) and added dropwise to the cooled reaction. The reaction was stirred while warming to ambient temperature for 20 hours. The reaction was washed with water (500 mL), concentrated ammonium chloride (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, and concentrated in-vacuo. The residue was passed through a plug of silica gel eluting with 1:1 hexanes:EtOAc to give D (50 g). LCMS [M+H+] 360.2 (100), 3.23 min.
    • Example XVI
  • Figure US20160340354A1-20161124-C00782
  • In a sealed vessel, phosgene (20% in toluene, 5.5 mL, 11.0 mmol) was added to cyclopropanemethanol (793 mg, 11.0 mmol) dissolved in DCM (5 mL) at −40° C. Pyridine (937 mg, 11.0 mmol) was added dropwise and the reaction was stirred at −40° C. for 1 hour. (Caution: this reaction generates a dramatic increase in pressure if the temperature starts to rise because the chloroformate appears to be volatile. It is very important to keep the temperature under control. Venting results in very little carbamate formation). Diastereomeric salt A (3.0 g, 5.5 mmol), dissolved in EtOAc (100 mL), was washed with about 15% aqueous ammonium hydroxide solution (2×100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in-vacuo. The free base B was dissolved in DCM (10 mL) and pyridine (1 mL) and added to the chilled chloroformate solution. The reaction was warmed slowly to ambient temperature over 5 hours. The reaction was poured into saturated sodium bicarbonate solution (100 mL) and the layers were separated. The aqueous layer was washed with DCM (2×20 mL) and the combined organics were dried over anhydrous sodium sulfate. The residue was purified on silica gel with a gradient of EtOAc in hexanes (10-50%) to produce carbamate C as a white foam (4.11 g). LCMS [M+H+] 437.0 (100), 4.15 min; Chiral HPLC (OD-H) 12.70 min; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.28 (br. s., 2H) 0.51 (br. s., 2H) 1.13 (br. s., 1H) 2.67-2.84 (m, 2H) 2.93-3.10 (m, 1H) 3.82-4.02 (m, 2H) 4.17 (br. s., 1H) 4.47-4.56 (m, 2H) 5.16-5.27 (m, 1H) 5.29-5.42 (m, 1H) 5.90-6.09 (m, 1H) 6.31 (br. s., 1H) 6.91 (d, J=8.72 Hz, 2H) 7.05 (dd, J=8.55, 2.18 Hz, 2H) 7.12 (d, J=7.38 Hz, 2H) 7.28 (d, J=8.38 Hz, 1H) 7.50 (d, J=2.01 Hz, 1H) 11.11 (br. s., 1H).
    • Example XVII
  • Figure US20160340354A1-20161124-C00783
  • Compound A (0.91 g, 1.3 mmol) was stirred in a solution of ammonia in methanol (7N, 30 mL) for 72 hours at ambient temperature. The solvent was removed and the residue was dissolved in ether (100 mL) and washed with water (3×25 mL) and brine (20 mL) and dried over anhydrous sodium sulfate to provide 1568 (707 mg). LCMS [M+H+] 593.2 (100), 2.43 min; Chiral HPLC (OD-H) 31.63 min; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.94 (d, J=1.32 Hz, 3H) 2.86 (br. s., 2H) 3.10-3.27 (m, 1H) 3.89 (t, J=5.61 Hz, 2H) 4.12 (t, J=5.44 Hz, 2H) 4.31 (d, J=14.52 Hz, 1H) 6.38 (br. s., 1H) 6.47 (d, J=1.32 Hz, 1H) 6.96 (d, J=8.25 Hz, 2H) 7.07 (dd, J=8.58, 1.98 Hz, 1H) 7.11-7.25 (m, 4H) 7.30 (d, J=8.91 Hz, 1H) 7.44 (d, J=8.58 Hz, 2H) 7.54 (d, J=2.31 Hz, 1H) 8.63 (d, J=83.14 Hz, 1H) 11.06-11.21 (m, 1H).
    • Example XVIII
  • Figure US20160340354A1-20161124-C00784
  • Amine salt A (140 mg, 0.40 mol) was added to a solution containing DIEA (155 mg, 1.2 mmol), EDC, 115 mg, 0.60 mol), DMAP (4.9 mg, 0.040 mmol), and HOBt (92 mg, 0.60 mmol) in DMF (6 mL). The reaction was stirred at ambient temperature for 15 hours, filtered, and concentrated in-vacuo. The residue was purified by preparative HPLC to give 1505. LCMS [M+H+] 502.5 (100), 3.42 min; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74 (s, 3H) 2.28-2.46 (m, 1H) 2.61-3.05 (m, 3H) 3.05-3.25 (m, 1H) 3.66-3.76 (m, 3H) 4.17 (dd, J=14.15, 4.61 Hz, 1H) 4.88-5.19 (m, 1H) 6.71 (s, 1H) 6.82-6.91 (m, 2H) 6.99-7.23 (m, 8H) 7.23-7.33 (m, 1H) 7.39-7.53 (m, 1H) 8.36-8.60 (m, 1H) 11.07-11.19 (m, 1H).
    • Example XIX
  • Figure US20160340354A1-20161124-C00785
  • Step 1:
  • A suspension of reaction material A (4.0 g, 20.40 mmol) and 1-(dimethylamino)-2-nitroethylene (2.04 g, 17.57 mmol) in 20 mL of TFA was stirred for 45 min. The reaction mixture was poured into saturated aqueous NaHCO3 solution (250 mL) and extracted repeatedly with EtOAc (4×75 mL). The combined organic layers are dried and evaporated under vacuum. The red-orange solid is triturated with CH2Cl2/THF (3×100 mL), and filtered to give 3.10 g (66%) indole product B. The crude mother liquor was chromatographed over an Isco 120 g column (eluted with DCM to 50% EtOAc/DCM to afford 1.7 g of solid which after trituration with Et20 afforded 1.0 g (21%) of additional indole product B: LCMS [MH+] 265, 267, Rt=3.13; 1H NMR (300 MHz, DMSO-d6) □ 7.32 (dd, J=8.7, 1.2 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 8.01 (d, J=13.5 Hz, 1H), 8.24 (s, 1H), 8.37 (d, J=13.8 Hz, 1H), 12.28 (s, 1H).
  • Figure US20160340354A1-20161124-C00786
  • Step-2:
  • A solution of sodium borohydride (2.03 g, 60 mmol) in THF (150 mL) cooled to 0° C. was treated with a solution of BF3.(OEt)2 (8.5 mL, 66 mmol) for about 15 minutes and then warmed to rt and stirred 15 min more. To this mixture was added dropwise a solution of 3 g (11.25 mmol) of indole product B in THF (30 mL), and the mixture heated to reflux for 2 h. The reaction was cooled to room temperature for about 1 hour, cooled to 0° C. and the solution adjusted to pH 3 using 1N aqueous HCl. The mixture was extracted with Et2O (3×75 mL) and the aqueous solution made basic using 6N aqueous NaOH to liberate the amine. The aqueous layer was saturated with solid NaCl was extracted with Et2O (10×100 mL). The combined organic layers are dried evaporated under vacuum and used in the next step without further purification.
  • Step-3:
  • The crude was dissolved 4.80 g (22 mmol) of (BOC)2O and 3.1 mL (22 mmol) of Et3N in 30 mL of MeOH. The mixture was stirred 1 h, concentrated and the residue purified over a 120 g Isco column (eluted with hexanes to 80% EtOAc/hexanes) to afford 1.95 g of pure N—BOC precursor to C (51%-2 steps) which was taken directly into the next reaction: LCMS [MH+-1] 293, 295, Rt=3.30; 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.40 (s, 9H), 2.88-2.94 (m, 1H), 3.32-3.39 (m, 1H), 6.01 (s, 1H), 7.15 (dd, J=8.4, 1.8 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 10.17 (s, 1H).
  • Step-4:
  • To 1.86 g (5.50 mmol) of the N—BOC precursor of C dissolved in 12 mL of DCM was added 8 mL (32 mmol) of 4N HCl in dioxanes, The mixture was stirred 2 h, concentrated to around 1 mL of solvent remaining, added dropwise to 65 mL of 30% hexanes/Et2O added to form a precipitate which was filtered and dried overnite (50° C., 5 torr) to afford 1.36 g (90%) of 6-bromotryptamine hydrochloride C as a white solid: LCMS [MH+] 239, 241, Rt=1.60; 1H NMR (300 MHz, DMSO-d6) δ 2.99 (m, 4H), 7.12 (dd, J=8.4, 2.1 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.95 (s, 3H), 11.14 (s, 1H).
  • Figure US20160340354A1-20161124-C00787
  • Step-5:
  • 4-Difluoromethoxybenzaldehyde (1.16 g, 6.66 mmol) is dissolved in 22 mL of acetic acid at room temperature. The reaction mixture is then heated to 90° C.; six 52 mg portions (309 mg total, 1.11 mmol) of indole C is added in equal time intervals over 1 h, and the mixture heated to reflux overnite. The mixture was cooled to room temperature and put in the refrigerator for 1 day. The resulting solid was filtered, washed with AcOH (2×5 mL) followed by hexanes (2×5 mL) and dried under vacuum (1 torr, 70° C.) to afford 190 mg (40%) of the intermediate Pictet-Spengler product, 7-Bromo-1-(4-difluoromethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline hydrochloride. The resultant mother liquor was concentrated under vacuum. The residue is triturated with 20% DCM/hexanes (removes excess aldehyde) to yield a powdery brown solid. This solid was taken up in 8 mL of CH3CN, filtered, washed with 20% DCM/hexanes (2×5 mL) and dried as before to afford an additional 130 mg (27%) of the intermediate Pictet-Spengler product, 7-Bromo-1-(4-difluoromethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline hydrochloride: LCMS [MH+] 393, 395, Rt=2.05.
  • Step-6:
  • To 45 mg (0.105 mmol) of the intermediate Pictet-Spengler product in 6 mL of 50% saturated aqueous NaHCO3/DCM, was added 16 mg (0.126 mmol) of 2-fluoroethyl chloroformate. The mixture was stirred 20 min, the DCM layer separated, concentrated and the crude product purified by preparative HPLC to afford 32.2 mg (64%) of carbamate D(1448): LCMS [MH+] 483, 485, Rt=3.72; 1H NMR (300 MHz, (CD3)2CO-d6) δ 2.86-2.88 (m, 3H), 3.14-3.23 (m, 1H), 4.34-4.36 (m, 1H), 4.43-4.46 (m, 1H), 4.62 (bm, 1H), 4.77 (bm, 1H), 6.50 (bm, 1H), 6.87 (t, J=74.7 Hz, 1H), 7.14-7.21 (m, 3H), 7.37 (bd, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 10.21 (s, 1H).
    • Example XX Preparation of Compounds 1612 and 1674
  • Figure US20160340354A1-20161124-C00788
  • Step-1:
  • To the stirred solution of 4-hydroxy benzaldehyde (compound A, 15 g, 0.122 mol) in dry DMF (120 mL) was added K2CO3 (25.4 g, 0.18 mol), KI (0.04 g, 0.002 mol) and propargyl bromide (21.91 g, 0.18 mol) at rt under inert atmosphere. After stirring at rt for 3 days, it was diluted with water (600 mL). It was then extracted with EtOAc (3×200 mL). The combined organic layer was washed with water (3×150 mL), brine (150 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by passing through silica gel column using 5-20% EtOAc in Pet. Ether as an eluent to get step-1 product (O-propargyl benzaldehyde, Compound B) as a light brown solid. (19.3 g, 98%): Rf=0.7 (PE:EA, 7:3); MS [MH+] 161 (M, 160 Calcd. for C10H8O2); 1H NMR (300 MHz, CDCl3,) δ 2.57 (t, J=3 Hz, 1H), 4.77 (d, J=3 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 9.9 (s, 1H).
  • Step-2:
  • To a stirred suspension of 5-Chlorotryptamine.HCl salt (15 g, 0.064 mol) in glacial AcOH (500 mL) was added Step-1 product, 0-propargyl benzaldehyde (10.75 g, 0.073 mol of compound B). The reaction mixture was heated to 100° C. for 8 hours. The reaction mixture was allowed to come to rt and stirred overnite. The precipitated white solid was filtered under suction. The residue was washed with glacial AcOH (200 mL), DCM (200 mL) and dried to get step-2 product, compound C, as a white solid (17 g, 77%): MS [MH+] 337 (M, 336 Calcd. for C20H17ClN2O.HCl); 1H NMR (400 MHz, DMSO-d6,) δ 2.96-3.00 (m, 1H), 3.06-3.13 (m, 1H), 3.39-3.44 (m, 2H), 3.58 (s, 1H), 4.83 (s, 2H), 5.8 (s, 1H), 7.06-7.11 (m, 3H), 7.27-7.58 (m, 3H), 7.59 (s, 1H), 9.42 (bs, 1H), 10.2 (bs, 1H,), 11.09 (s, 1H).
  • Step-3:
  • To a stirred solution of Step-2 HCl salt (4.5 g of compound C) in EtOAc (90 mL) was added aq. 10% aqueous NaHCO3 solution (45 mL). The reaction mixture was vigorously stirred at rt for 30 minutes. The clear biphasic mixture was separated. The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to get gummy product. This was washed with hexane to afford the step-3 product, compound D, (4.0 g, 98%): Rf=0.3 (PE:EA, 6:4); MS [MH+] 337 (M, 336 Calcd. for C20H17ClN2O); 1H NMR (400 MHz, DMSO-d6,) δ 2.51-2.70 (m, 2H), 2.91 (m, 1H), 3.04-3.07 (m, 1H), 3.30 (s, 1H), 3.56 (t, J=2 Hz, 1H), 4.77 (d, J=2 Hz, 2H), 5.03 (s, 1H, CH), 6.94-7.00 (m, 3H), 7.18-7.22 (m, 3H), 7.43 (s, 1H), 10.61 (s, 1H).
  • Step-4:
  • To a stirred solution of Step-3 product (3.9 g, 0.011 mol of compound D) in abs. EtOH (80 mL) was added N-acetyl-L-phenylalanine (1.44 g, 0.0069 mol) and refluxed for 2 hours. The reaction mixture was allowed to cool to RT and stand for 20 hours. The separated solid was filtered and dried (2.8 g). It was further crystallized in 1:1 mixture of IPA and MeOH (100 mL) to get final compound E as a white solid (1.71 g, 26%). For the purpose of chiral HPLC and 1H-NMR a small amount of salt was suspended in EtOAc and treated with 5% NH4OH solution. The layers were separated and organic layer was concentrated and checked for chiral purity (99% ee): MS [MH+] 337 (M, 336 Calcd. for C20H17ClN2O): 1H NMR (400 MHz, DMSO-d6) δ 2.63 (mc, 2H), 2.90 (mc, 1H), 3.01 (mc, 1H), 3.54 (s, 1H), 4.76 (s, 2H), 5.01 (s, 1H), 6.92-6.98 (m, 3H), 7.16-7.20 (m, 3H), 7.41 (s, 1H), 10.59 (s, 1H).
  • Step-5 Compound F (1612):
  • To a stirred suspension of chiral salt from Step-4 (375 mg, 0.69 mmol of compound E) in EtOAc (8 mL) and water (8 mL) was cooled to 0-5° C. was added K2CO3 (285 mg, 2.06 mmol). The mixture was stirred for 10 min and 4-chlorophenyl chloroformate (197 mg, 1.03 mmol) was added while maintaining the reaction mixture at 0-5° C. The mixture was then warmed to rt, stirred for 3 hours, and the organic layer and aqueous layers partitioned. The aqueous layer was extracted with additional EtOAc (20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and evaporated in vacuum. The crude product was purified by silica gel column using 5-20% EtOAc in hexane as an eluent to afford step-5 product (320 mg, 94% of compound F) as a pale yellow solid. The % ee was checked by chiral HPLC (99% ee): Rf=0.4 (PE:EA, 5:5); MS [M+] 491 (M, 491.365 Calcd. for C27H20Cl2N2O3); 1H NMR (400 MHz, DMSO-d6) δ 3.21 (mc, 2H, CH2), 3.28 (mc, 2H), 3.60 (s, 1H), 4.30 (bs, 1H), 4.78 (s, 2H), 6.40 (bs, 1H), 6.98 (m, 2H), 7.31-7.08 (m, 6H), 7.45 (d, 2H), 8.3 (s, 1H), 11.17 (bs, 1H).
  • Step-6 Compound G (1674):
  • To a stirred suspension of β-carboline carbamate from Step-5 (100 mg, 0.20 mmol of compound F) in 50% tBuOH/H2O (1.2 mL) and 54 mg (0.26 mmol) of 1-azido-1-deoxy-β-D-galactopyranoside (R═H), was added a solution of sodium ascorbate in water (40 μL, 0.03 mmol of a solution of 594 mg sodium ascorbate in 3 mL of water), followed by a solution of CuSO4.5H2O in water (15 μL, 0.003 mmol of a solution of 75 mg of CuSO4.5H2O in 1 mL of water. The mixture was heated to 46° C. for 10 min, THF added to aid solubility (400 μL), an additional portion of CuSO4.5H2O in water (15 μL, 0.003 mmol of a solution of 75 mg of CuSO4.5H2O in 1 mL of water) added, and the mixture was then heated to 75° C. and stirred 2 days. The mixture was evaporated under vacuum and purified by HPLC to afford the step-6 product (R═H, 59 mg, 42% of compound G): LCMS [MH+] 696, Rt=3.33; 1H NMR (300 MHz, (CD3OD) δ 2.80-3.04 (m, 2H), 3.30-3.40 (m, 2H), 3.66-3.76 (m, 3H), 3.81 (q, J=6.3 Hz, 1H), 3.97 (d, J=3.0 Hz, 1H), 4.13 (t, J=9.3 Hz, 1H), 4.30-4.50 (m, 1H), 5.19 (s, 2H), 5.57 (d, J=9.3 Hz, 1H), 6.44-6.56 (bm, 1H), 6.96-7.04 (bm, 2H), 7.06 (dd, J=8.7, 1.9 Hz, 1H), 7.13 (d, J=8.7 Hj, 1H), 7.24 (bd, J=8.4 Hz, 2H), 7.38 (bd, J=8.7 Hz, 1H), 7.49 (d, J=2.1 Hz, 1H), 8.30 (s, 1H).
  • Step-6 Compound H (1675):
  • Following an identical procedure to that used in preparing compound G, but using 99 mg (0.26 mmol) of 1-azido-1-deoxy-β-D-galactopyranoside tetraacetate (R═OAc) instead of 54 mg (0.26 mmol) of 1-azido-1-deoxy-β-D-galactopyranoside (R═H), afforded 54 mg (31%) of the step 6 (R═OAc) product, compound H: LCMS [MH+] 864, Rt=3.88; 1H NMR (300 MHz, (CD3)2CO) δ 1.80 (s, 3H), 1.95 (s, 3H), 1.97 (s, 3H), 2.19 (s, 3H), 2.90-3.05 (m, 1H), 3.30-3.42 (m, 2H), 4.12 (dd, J=11.4, 7.2 Hz, 1H), 4.23 (dd, J=11.4, 5.8 Hz, 1H), 4.36-4.52 (bm, 1H), 4.62 (t, J=6.3 Hz, 1H), 5.22 (s, 2H), 5.45 (dd, J=10.2, 3.3 Hz, 1H), 5.56 (dm, J=2.4 Hz, 1H), 5.72 (t, J=9.7 Hz, 1H), 6.23 (d, J=9.0 Hz, 1H), 6.50-6.60 (bm, 1H), 7.05 (bd, J=8.1 Hz, 2H), 7.12 (dd, J=8.7, 2.1 Hz, 1H), 7.23 (d, J=8.9 Hz, 2H), 7.24-7.28 (m, 1H), 7.37 (bd, J=8.4 Hz, 2H), 7.42 (d, J=8.9 Hz, 2H), 7.56 (d, J=1.5 Hz, 1H), 8.30 (s, 1H). 10.22 (s, 1H).
    • Example XXI
  • Figure US20160340354A1-20161124-C00789
  • step-1:
  • To a stirred solution of DIAD (24.2 g, 0.12 mol) in dry DCM (70 ml) was added triphenylphosphine (22.45 g, 0.0859 mol) and 3-butyn-1-ol (6.36 g, 0.0859 mol) in a dropwise manner at 0-5° C. in a dark. The reaction flask was covered with aluminium foil to avoid the exposure to the light. After stirring for 30 minutes, 4-hydroxy benzaldehyde (7 g, 0.057 mol, compound A) dissolved in dry DCM (30 mL) was added in dropwise manner. The stirring was continued for 4 hours at 0-5° C. The temperature was slowly raised to rt and stirring was continued for 24 hours. After completion of the reaction, it was evaporated under vacuum. The crude product was purified by silica gel column using gradient from 5% to 20% EtOAc in Pet. Ether as an eluent to afford pale yellow solid of step-1 product, compound B (5.6 g, 56%): Rf=0.6 (Pe:EA, 6:4); MS [M+] 174 (M, 174 Calcd. for C11H10O2); 1H NMR (400 MHz, CDCl3) δ 2.08 (s, 1H), 2.74 (m, 2H), 4.20 (t, J=7.2 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 9.91 (s, 1H, CHO).
  • Step-2:
  • To a stirred suspension of 5-Chlorotryptamine.HCl salt (15 g, 0.064 mol) in glacial AcOH (500 mL) was added Step-1 product (14 g, 0.08 mol of compound B). The reaction mixture was heated to 100° C. for 8 hours. The reaction mixture was allowed to come to rt and stirred overnite. The precipitated white solid was filtered under suction. The residue was washed with glacial AcOH (200 mL), DCM (200 mL) and dried to get step-2 product, compound C, as a white solid (16 g, 63%): MS 351 [MH+] (M, 350.84 Calcd. for C21H19ClN2O.HCl); 1H NMR (400 MHz, DMSO-d6) δ 2.63 (m, 2H), 2.88 (s, 1H), 3.1 (m, 2H), 3.38 (m, 2H), 4.08 (t, J=8.0 Hz, 2H), 5.87 (s, 1H), 7.03-7.11 (m, 3H), 7.29 (mc, 3H), 7.59 (s, 1H), 9.38 (bs, 1H), 10.15 (bs, 1H), 11.06 (s, 1H).
  • Step-3:
  • To a stirred solution of Step-2 HCl salt (2.0 g of compound C) in EtOAc (40 mL) was added 10% aqueous NaHCO3 solution (20 mL). The reaction mixture was vigorously stirred at rt for 30 minutes. The clear biphasic mixture was separated. The organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to get a gummy product. This was washed with hexane to get step-3 product, compound D, as a white powder (1.71 g, 95%). This was found to be pure enough for the next step. Rf=0.3 (PE/EA, 6:4); MS 351 [MH+] (M, 350.84 calcd. for C21H19ClN2O); 1H NMR (400 MHz, DMSO-d6) δ 2.48-2.70 (m, 4H), 2.68 (m, 2H), 2.87 (m, 1H), 4.02 (t, J=6.4 Hz, 2H), 5.00 (s, 1H), 6.88-6.98 (m, 3H), 7.14-7.40 (m, 3H), 7.41 (s, 1H), 10.56 (s, 1H).
  • Step-4:
  • To a stirred solution of step-3 product (26 g, 0.074 mol of compound D) in abs. EtOH (1000 mL) was added N-acetyl-L-phenylalanine (9.24 g, 0.044 mol). The mixture was refluxed for 2 hours, cooled to rt and left to stand for 20 hours. The separated solid was filtered and dried to get a white powder (19.5 g, 46% of compound E). For the purpose of chiral HPLC and 1H NMR, small amount of salt was suspended in EtOAc and treated with 5% NH4OH solution. The layers were separated and organic layer was concentrated and checked for chiral purity using chiral LC (% ee=98): MS 351 [MH+] (M, 350.84 Calcd. for C21H19ClN2O); 1H NMR (400 MHz, DMSO-d6) δ 2.50-2.63 (m, 4H), 3.00 (mc, 2H), 3.04 (mc, 1H), 4.04 (t, J=6.4 Hz, 2H), 5.02 (s, 1H), 6.90-7.00 (m, 3H), 7.20 (m, 3H), 7.43 (s, 1H), 10.58 (s, 1H).
  • Step-5 Compound F (1614):
  • To a stirred suspension of chiral salt (1 g, 0.0017 mol of compound E) in EtOAc (15 mL) and water (15 mL) cooled to 0-5° C., was added K2CO3 (0.742 g, 0.00537 mol). The mixture was stirred for 10 minutes, 4-chlorophenylchloroformate (0.573 g, 0.00268 mol) added, and the mixture stirred at rt for 3 hours. The organic and aqueous layers were partitioned and the aqueous layer back extracted with more EtOAc (25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over anhydrous Na2SO4 and evaporated in vacuum. The crude product was purified by silica gel column using 5-20% EtOAc in hexane to get compound F as a pale yellow solid (860 mg, 95%): Rf=0.4 (PE/EA, 5:5); MS 505 [MH+] (M, 505.391 Calcd. for C28H22Cl2N2O3); 1H NMR (400 MHz, DMSO-d6) δ 2.61 (m, 2H), 2.87 (m, 3H), 3.20 (m, 1H), 4.03 (t, J=6.4 Hz, 2H), 4.3 (m, 1H), 6.4 (bs, 1H), 6.95 (m, 2H), 7.31-6.98 (m, 6H), 7.45 (m, 2H), 7.54 (s, 1H), 11.17 (bs, 1H).
  • Step-6 Compound G (1676):
  • Following an identical procedure to that used in preparing compound K, but using compound F (105 mg, 0.207 mmol) as the alkyne and 54 mg (0.26 mmol) of 1-azido-1-deoxy-β-D-galactopyranoside (R═H) as the azide, afforded 96 mg (65%) of the step 6 (R═OAc) product, compound G: LCMS [MH+] 710, Rt=3.33
  • Step-6 Compound H (1677):
  • Following an identical procedure to that used in preparing compound K, but using compound F (105 mg, 0.207 mmol) as the alkyne and 99 mg (0.26 mmol) of 1-azido-1-deoxy-β-D-galactopyranoside tetraacetate (R═OAc) as the azide, afforded 103 mg (58%) of the step 6 (R═OAc) product, compound H: LCMS [MH+] 878, Rt=3.88.
    • Example XXII
  • Figure US20160340354A1-20161124-C00790
  • Step-1:
  • To a stirred solution of 4-hydroxybenzaldehyde (12 g, 0.098 mol, compound A) in dry DMF (93 mL) was added K2CO3 (20.28 g, 0.14 mol), KI (0.32 g, 0.0019 mol), and 5-Chloro-1-pentyne (12.1 g, 0.11 mol) at rt. The mixture was stirred for 3 days, diluted with water (550 mL), and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water (3×100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified through silica gel column using a gradient from 5 to 25% EtOAc in Pet. Ether as an eluent to obtain step-1 product, compound B, as a pale yellow solid (18 g, 97%): LCMS 189 [MH+] (M, 188.22 Calcd. for C12H12O2); 1H NMR (400 MHz, CDCl3) δ 1.60 (s, 1H), 2.00-2.09 (m, 2H), 2.43-2.47 (m, 2H), 4.18 (t, J=6.4 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 9.9 (s, 1H, CHO).
  • Step-2:
  • To a stirred suspension of 5-Chlorotryptamine.HCl salt (10 g, 0.043 mol) in glacial AcOH (430 mL) was added Step-1 product (9.36 g, 0.048 mol of compound B). The reaction mixture was heated to 100° C. for 8 hours. The reaction mixture was allowed to come to rt and stirred overnite. The precipitated white solid was filtered under suction. The residue was washed with glacial AcOH (100 mL), MDC (150 mL) and dried to get step-2 product, compound C, as a white solid (10 g, 58%): MS 365 [MH+] (M, 401.344, Calcd. for C22H21ClN2O.HCl); 1H NMR (400 MHz, DMSO-d6) δ 1.9 (t, J=5.6 Hz, 2H), 2.33 (m, 2H), 2.84 (s, 1H), 3.1 (m, 2H), 3.39 (m, 2H), 4.08 (t, J=6 Hz, 2H,), 5.89 (s, 1H), 7.04-7.13 (m, 3H), 7.29-7.32 (m, 3H), 7.61 (s, 1H), 9.4 (brs, 1H), 10.1 (bs, 1H), 11.08 (s, 1H).
  • Step-3:
  • To a stirred solution of Step-2 HCl salt (7.5 g of compound C) in EtOAc (150 mL) was added 10% aqueous NaHCO3 solution (75 mL). The reaction mixture was vigorously stirred at RT for 30 minutes. The clear biphasic mixture was separated. The organic layer was washed with water (75 mL), brine (75 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to get gummy product. This was washed with hexane to get step-3 product, compound D, as a white powder (6.7 g, 98%). This was found pure enough for the next step: Rf=0.3 (PE:EA, 6:4); MS 365 (M+) (M, 365 Calcd. for C22H21ClN2O); 1H NMR (400 MHz, DMSO-d6) δ 1.88 (m, 2H), 2.32 (m, 2H), 2.65 (m, 2H), 2.86 (s, 1H), 2.82 (m, 1H), 3.04 (m, 1H), 4.02 (t, J=6 Hz, 2H), 5.02 (s, 1H), 6.90 (d, J=8.8 Hz, 2H), 6.98 (s, 1H), 7.16-7.42 (m, 3H), 7.43 (s, 1H), 10.57 (s, 1H).
  • Step-4:
  • To a stirred solution of step-3 product (6.6 g, 0.018 mol of compound D) in abs. EtOH (150 mL) was added N-acetyl-L-isoleucine (1.87 g, 0.01 mol) and refluxed for 2 hours. The reaction mixture was allowed to cool to rt and stand for 20 hours. The solid separated was filtered and dried to get white powder. This was further crystallized in ethanol (125 mL) to get step-4 salt, compound E, as off-white solid (2.4 g, 24%). For the purpose of chiral HPLC and 1H NMR, small amount of salt was suspended in EtOAc and treated with 5% NH4OH solution. The layers were separated and organic layer was concentrated and checked for chiral purity by chiral LC (100% ee): MS 365 (M+) (M, 538 Calcd. for C30H36ClN3O4); 1H NMR (400 MHz, DMSO-d6) δ 1.86 (m, 2H), 2.30 (m, 2H), 2.62 (m, 2H), 2.8 (s, 1H), 2.88 (m, 1H), 3.02 (m, 1H), 4.00 (t, J=6.0 Hz, 2H), 5.00 (s, 1H), 6.88 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.0 Hz, 1H), 7.14-7.20 (m, 3H), 7.41 (s, 1H), 10.55 (s, 1H).
  • Step-5:
  • To a stirred suspension of chiral salt (0.15 g, 000278 mol of compound E) in EtOAc (4 mL) and water (4 mL) cooled to 0-5° C., was added K2CO3 (0.0115 g, 0.000836 mol). The mixture was stirred for 10 minutes and 4-chlorophenyl chloroformate (0.0796 g, 0.0004176 mol) was added. The mixture was stirred at rt for 3 hour, the organic and aqueous layers partitioned and the aqueous layer back extracted with EtOAc (10 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and evaporated in vacuum. The crude product was purified by silica gel column using 5-20% EtOAc in Pet. Ether to get pale yellow colored step-5 product (110 mg, 76% of compound F (1613)). Rf=0.4 (PE:EA, 5:5): MS 519 (M+) (M, 519.418 Calcd. for C29H24Cl2N2O3), 1H NMR (400 MHz, DMSO-d6) δ 1.86 (m, 2H), 2.29 (m, 2H), 2.8 (s, 1H), 2.9 (m, 2H), 3.2 (m, 1H), 4.01 (t, J=6.0 Hz, 2H), 4.30 (m, 1H), 6.4 (s, 1H), 6.94 (m, 2H), 7.07 (m, 1H), 7.22-7.2 (m, 4H), 7.3 (d, J=8.8 Hz, 1H), 7.45 (mc, 2H), 7.54 (s, 1H), 11.16 (bs, 1H).
    • Example XXIII
  • Figure US20160340354A1-20161124-C00791
    Figure US20160340354A1-20161124-C00792
  • Step-1:
  • To the stirred solution of 4-hydroxybenzaldehyde (compound A, 3 g, 0.0246 mol) in dry DMF (24 mL) was added K2CO3 (6.80 g, 0.49 mol), and chloroacetonitrile (1.9 mL, 0.030 mol) at rt under inert atmosphere. After stirring at rt for 3 days, it was diluted with water (50 mL). It was then extracted with 75% Et2O in hexanes (4×75 mL). The combined organic layer was washed with water (2×40 mL), brine (50 mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude product was purified by passing through silica gel column using 0-20% EtOAc in hexanes as an eluent to get step-1 product, Compound B. (2.60 g, 66%): LC Rt=2.38.
  • Step-2:
  • To a stirred suspension of 5-Chlorotryptamine.HCl salt (5.7 g, 0.0245 mol) in glacial AcOH (245 mL) was added Step-1 product, (4.57 g, 0.0284 mol of compound B). The reaction mixture was heated to 115° C. overnite. The reaction mixture was allowed to come to rt and the precipitated white solid was filtered under suction. The residue was washed with 50% glacial AcOH/Et2O (50 mL), DCM (50 mL) and dried to get a mixture of step-2 products, compound C and compound D (about 85:15 ratio), as a beige solid (6.88 g, 75%): Mixture LCMS [MH+] 338, 356, Rt=1.77.
  • Alternative Step-2: Following the above procedure exactly, except that 90% CH3CN/AcOH was used in place of AcOH, gave a >98:2 mixture of C: D.
  • Step-3 Compounds F and E (1543 and 1210):
  • To a stirred suspension of the products from Step-4 (100 mg, 0.27 mmol of compound C/D, 85:15 mixture) in 50% DCM/saturated aqueous NaHCO3 was added ethyl chloroformate (31 μL, 0.32 mmol) and the mixture stirred for 30 min. The organic layer and aqueous layers were partitioned. The aqueous layer was extracted with additional DCM (20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous MgSO4 and evaporated in vacuum. The crude product was purified by preparative HPLC to afford step-3 products (60 mg, 54% of compound F and 8 mg (7%) of compound E): Data for F (1543): LCMS [MH+] 410, Rt=3.53; 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.28 (t, J=6.5 Hz, 3H), 2.84-2.86 (m, 2H), 3.11-3.18 (m, 1H), 4.17 (q, J=6.9 Hz, 1H), 4.30 (bs, 1H), 5.10 (s, 2H), 6.47 (bs, 1H), 7.04-7.12 (m, 3H), 7.29-7.37 (m, 3H), 7.53 (d, J=1.8 Hz, 1H), 10.19 (bs, 1H). Data for E (1210): LCMS [MH+] 428, Rt=3.12; 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.27 (t, J=6.4 Hz, 3H), 2.78-2.86 (m, 2H), 3.11-3.17 (m, 1H), 4.17 (q, J=6.9 Hz, 1H), 4.30 (bs, 1H), 4.44 (s, 2H), 6.45 (bs, 1H), 6.71 (bs, 1H), 6.96 (dm, J=8.7 Hz, 2H), 7.09 (dd, J=2.4 Hz, 1H), 7.18 (m, 1H), 7.24 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 10.19 (bs, 1H).
    • Example XXIV
  • Figure US20160340354A1-20161124-C00793
  • Step-1:
  • To a stirred solution of 4-hydroxytetrahydropyran (3.80 g, 0.0373 mol) in dry DMF (50 mL) was added 95% NaH solid (1.12 g, 0.0466 mol) in small portions over 5-10 min. After the evolution of gas had subsided, 4-chlorobenzonitrile (5.18 g, 0.038 mol) was added in one portion, and the mixture heated to 60° C. overnite. The mixture was diluted with tBuOH (about 5 mL) and neutralized to pH 7 using glacial AcOH. The DMF was concentrated in vacuo, and the crude product chromatographed over a 120 g Isco column using 30% DCM/hexanes to DCM as an eluent to get step-1 product, 4-(tetrahydropyran-4-yloxy)benzonitrile), as a white solid. (5.7 g, 76%): LC Rt=2.72; 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.63-1.75 (m, 2H), 2.02-2.10 (m, 2H), 3.55 (ddd, J=11.8, 9.1, 3.3 Hz, 2H), 3.90 (dt, J=12.0, 4.5 Hz, 2H), 4.76 (septet, J=4.5 Hz, 1H), 7.16 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 2H).
  • Step-2:
  • To the stirred solution of 4-(tetrahydropyran-4-yloxy)benzonitrile (7.50 g, 0.0369 mol) in dry DCM (90 mL) was added 1M DIBALH in DCM (46.50 mL, 0.0465 mol) and the mixture stirred 30 min at 0° C. The reaction mixture was cooled to −20° C., and EtOAc (7 mL) was added slowly dropwise. The mixture was stirred 15 min, a solution of saturated aqueous Rochelle's salt added (85 mL), the mixture warmed to 0° C. and stirred 1 h. The mixture was extracted with DCM (100 mL). The combined organic layers were washed twice with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed over a 80 g Isco column using 70% DCM/hexanes to DCM to 40% EtOAc/DCM as an eluent to get the step-2 product, compound B, as a white solid. (6.80 g, 90%): LCMS [MH+] 207, Rt 2.58; 1H NMR (300 MHz, CDCl3) δ 1.80 (tt, J=12.9, 3.9 Hz, 2H), 1.99-2.07 (m, 2H), 3.58 (ddd, J=11.6, 6.7, 3.3 Hz, 2H), 3.96 (ddd, J=11.2, 6.5, 4.0 Hz, 2H), 4.61 (septet, J=4.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 9.95 (s, 1H).
  • Step-3 Compound C (1220):
  • To a stirred suspension of the Step-2 product (6.80 g, 0.033 mol of compound B) in glacial AcOH (380 mL) heated to 90° C. was added 5-Chlorotryptamine.HCl salt (6.80 g, 0.0294 mol) in four portions added 30 min apart. The reaction mixture was heated to reflux overnite. The reaction mixture was allowed to come to rt and put in the refrigerator overnite. The precipitated white solid was filtered under suction. The solid residue residue was washed with 40% glacial AcOH/Et2O (100 mL), Et2O (100 mL) and dried under vacuum to get step-3 product, compound C, as a white solid (10.37 g, 84%). The mother liquor was concentrated to one-third volume, put in the fridge overnite and the same wash cycle and drying of the solid residue utilized to provide an additional 450 mg (4%) of compound C: LCMS [MH+] 383, Rt 1.85, 193 (salt/nonsalt form); 1H NMR (300 MHz, DMSO-d6,) δ 1.50-1.62 (m, 2H), 1.92-1.98 (m, 2H), 2.93-3.12 (m, 2H), 3.32-3.51 (m, 4H), 3.83 (dt, J=11.7, 4.2 Hz, 2H), 4.61 (septet, 1H), 5.86 (s, 1H), 7.04-7.11 (m, 3H), 7.26-7.30 (m, 3H), 7.59 (d, J=1.8 Hz, 1H), 9.50 (bs, 1H), 10.17 (bs, 1H,), 11.07 (s, 1H).
  • Step-4:
  • To a stirred solution of Step-3 HCl salt (10.56 g, 0.0252 mol of compound C) in EtOAc (300 mL) was added saturated aqueous NaHCO3 solution (150 mL). The reaction mixture was vigorously stirred at rt for 30 minutes. The clear biphasic mixture was separated. The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous MgSO4 and concentrated under vacuum to get a foam. This was washed with hexane to afford the step-4 product, compound D, (9.64 g, 100%): This material was taken directly into the next reaction without further purification.
  • Step-5:
  • To a stirred solution of Step-4 product (9.64 g, 25.18 mmol of compound D) in abs. EtOH (930 mL) was added N-acetyl-L-phenylalanine (3.39 g, 0.0164 mol) and refluxed until dissolution occurred. The reaction mixture was allowed to cool to RT and stand for 48 hours. The separated solid was filtered and dried (6.80 g, 46% recovery, 95% ee by chiral LC of free base form). It was further crystallized in abs. EtOH (500 mL) to get the step-5 product, compound E as a white solid (6.60 g, 44% recovery, >98.5% ee by chiral LC of free base form). This salt was taken directly into the next reaction without further purification. Data for E: Chiral HPLC ODH-280-40 column (rt 47.29 min).
  • Step-6 Compound F (1576):
  • To a stirred suspension of chiral salt from Step-5 (84 mg, 0.14 mmol of compound E) in EtOAc (4 mL) and saturated aqueous K2CO3 (2 mL) was added 2-butynylchloroformate (24 μL, 0.21 mmol) and the mixture stirred for 2.5 hours. The organic layer and aqueous layers were partitioned. The aqueous layer was extracted with additional EtOAc (20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and evaporated in vacuum. The crude product was purified by preparative LC to afford the step-6 product (52.5 mg, 94% of compound F) as a white solid. LCMS [MH+] 479, Rt 3.78; 1H NMR (300 MHz, (CD3)2CO) δ 1.58-1.69 (m, 2H), 1.82 (s, 3H), 1.96-2.05 (m, 2H), 2.80-2.94 (m, 3H), 3.10-3.25 (m, 1H), 3.50 (ddd, J=11.8, 9.0, 2.9 Hz, 2H), 3.96 (dt, J=11.7, 4.5 Hz, 2H), 4.28 (mc, 1H), 4.56 (septet, J=4.0 Hz, 1H), 4.74 (s, 2H), 6.45 (mc, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.11 (dd, J=8.7, 1.8 Hz, 1H), 7.20 (dm, J=8.4 Hz, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.52 (d, J=1.8 Hz, 2H), 10.19 (s, 1H).
    • Example XXV
  • Figure US20160340354A1-20161124-C00794
    Figure US20160340354A1-20161124-C00795
  • Step-1:
  • To a stirred solution of N—BOC 4-hydroxypiperidine (7.50 g, 0.0373 mol) in dry DMF (50 mL) was added 95% NaH solid (1.12 g, 0.047 mol) in small portions over 5-10 min. After the evolution of gas had subsided, 4-chlorobenzonitrile (5.18 g, 0.0376 mol) was added in one portion, and the mixture heated to 60° C. overnite. The mixture was diluted with tBuOH (about 5 mL) and neutralized to pH 7 using glacial AcOH. The DMF was concentrated in vacuo, and the crude product chromatographed over a 120 g Isco column using 20% DCM/hexanes to DCM as an eluent to get step-1 product, 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester, as a white solid (10.33 g, 92%): LC Rt=3.40; 1H NMR (300 MHz, CDCl3,) δ 1.46 (s, 9H), 1.74-1.80 (m, 2H), 1.89-1.97 (m, 2H), 3.40 (ddd, J=10.3, 7.6, 4.0 Hz, 2H), 3.68 (ddd, J=10.3, 8.7, 4.0 Hz, 2H), 4.55 (septet, J=3.6 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H).
  • Step-2:
  • To a stirred solution of 100 mL (400 mmol) of 4N HCl in dioxanes was added the step-1 product, 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester, (12.60 g, 0.0417 mol) and the mixture stirred 2 h, and 150 mL of 67% Et2O/hexanes added. The resulting slurry was filtered and dried under vacuum (1 torr, 60° C.) to afford the step-2 product, 4-(piperidin-4-yloxy)benzonitrile hydrochloride, as a white solid (9.10 g, 91%): LCMS [MH+] 203, Rt 1.23.
  • Step-3:
  • To a stirred solution of 9.84 g (0.049 mol) of 2-trimethylsilanyl-ethanesulfonyl chloride (SESCl) in DCM (100 mL) cooled to −78° C., was added the step-2 product, 4-(piperidin-4-yloxy)benzonitrile hydrochloride, (9.00 g, 0.038 mol). The mixture was stirred 30 min, warmed to −30° C., and stirred 3 h. To this mixture was added 20 mL of 1N NaOH solution added, and the DCM and aqueous layers partitioned. The aqueous layer was back extracted with DCM (50 mL) and the combined organic layers washed with brine (50 mL), saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4) and concentrated in vacuo. The crude product was repeatedly crystallized from the minimum amount of DCM in hexanes to get the step-3 product, 4-[1-(2-trimethylsilanylethanesulfonyl)piperidin-4-yloxy]benzonitrile, compound B, as a white solid. (12.95 g, 94%): LCMS [MH+] 367, Rt 3.53; 1H NMR (300 MHz, (CD3)2CO-d6) δ 0.80 (s, 9H), 0.97-1.02 (m, 2H), 1.79-1.88 (m, 2H), 2.04-2.15 (m, 2H), 3.28-3.36 (m, 2H), 3.52-3.60 (m, 2H), 4.79 (septet, J=3.9 Hz, 1H), 7.16 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H).
  • Step-4:
  • To the stirred solution of the step-3 product, 4-[1-(2-trimethylsilanylethanesulfonyl)piperidin-4-yloxy]benzonitrile (12.30 g, 0.0336 mol of compound B) in dry DCM (83 mL) was added 1M DIBALH in DCM (44 mL, 0.044 mol) and the mixture stirred 30 min at 0° C. The reaction mixture was cooled to −20° C., and EtOAc (7 mL) was added slowly dropwise. The mixture was stirred 15 min, a solution of saturated aqueous Rochelle's salt added (85 mL), the mixture warmed to 0° C. and stirred 1 h. The mixture was extracted with DCM (100 mL). The combined organic layers were washed twice with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed over a 80 g Isco column using 70% DCM/hexanes to DCM to 40% EtOAc/DCM as an eluent to get the step-4 product, compound C, as a white solid. (12.4 g, 99%): LCMS [MH+] 370, Rt 3.45; 1H NMR (300 MHz, (CD3)2CO-d6) δ 0.80 (s, 9H), 0.97-1.04 (m, 2H), 1.80-1.96 (m, 2H), 2.06-2.164 (m, 2H), 2.96-3.02 (m, 2H), 3.29-3.37 (m, 2H), 3.53-3.61 (m, 2H), 4.80 (septet, J=3.9 Hz, 1H), 7.17 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 9.90 (s, 1H).
  • Step-5 Compound D (1556):
  • To a stirred suspension of the Step-4 product (12.40 g, 0.034 mol of compound C) in glacial AcOH (380 mL) heated to 90° C. was added 5-Chlorotryptamine.HCl salt (6.75 g, 0.029 mol) in four portions added 30 min apart. The reaction mixture was heated to reflux overnite. The reaction mixture was allowed to come to rt and put in the refrigerator overnite. The precipitated white solid was filtered under suction. The solid residue was washed with 40% glacial AcOH/Et2O (100 mL), Et2O (100 mL) and dried under vacuum to get step-5 product, compound D, as a white solid (7.76 g, 45%). The mother liquor was concentrated to one-third volume, put in the fridge overnite and the same wash cycle and drying of the solid residue utilized to provide additional compound D (2.28 g, 13.3%). Repetition of this cycle one more time gave additional compound D (0.67 g, 2.5%, only 90% pure by LC/MS): LCMS [MH+] 546, Rt 2.33.
  • Step-6:
  • To a stirred solution of Step-5 HCl salt (10.3 g, 17.67 mmol of compound D) in EtOAc (300 mL) was added saturated aqueous NaHCO3 solution (150 mL). The reaction mixture was vigorously stirred at rt for 30 minutes. The clear biphasic mixture was separated. The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous MgSO4 and concentrated under vacuum to get a foam. This was washed with hexane to afford the step-6 product, compound E, (9.65 g, 100%): This material was taken directly into the next reaction without further purification.
  • Step-7:
  • To a stirred solution of Step-6 product (9.65 g, 0.0177 mol of compound E) in abs. EtOH (200 mL) was added N-acetyl-L-leucine (1.99 g, 0.0115 mol) and refluxed until dissolution occurred. The reaction mixture was allowed to cool to rt and stand for 48 hours. The separated solid was filtered and dried (5.30 g, 40% recovery, 72% ee by chiral LC of free base form). It was further crystallized in abs. EtOH (150 mL) to get the step-7 product, compound F, as a white solid (3.86 g, 29% recovery, 99% ee by chiral LC of free base form). This salt was taken directly into the next reaction without further purification. Data for F: Chiral HPLC ODH-280-40 column (rt 19.01 min).
  • Step-8 Compound G (1606):
  • To a stirred suspension of chiral salt from Step-7 (1200 mg, 1.69 mmol of compound F) in EtOAc (40 mL) and H2O (20 mL) containing K2CO3 (820 mg, 5.93 mmol), was added 2-butynyl chloroformate (231 μL, 2.033 mmol). The mixture was stirred for 2.5 hours, and the organic layer and aqueous layers were partitioned. The aqueous layer was extracted with additional EtOAc (2×70 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous MgSO4 and evaporated under vacuum. The crude residue was chromatographed over a 120 g Isco column using 10% to 40% EtOAc/hexanes as an eluent, to get the step-8 product, compound G, as a white solid (1.08 g, 99%): LCMS [MH+] 642, Rt 4.17; 1H NMR (300 MHz, (CD3)2CO) δ 0.069 (s, 9H), 0.96-1.02 (m, 2H), 1.70-1.85 (m, 2H), 1.82 (s, 3H), 1.98-2.08 (m, 2H), 2.85 (dd, J=7.8, 3.0 Hz, 2H), 2.94-3.00 (m, 2H), 3.12-3.23 (m, 1H), 3.24-3.32 (m, 2H), 3.45 (s, 1H), 3.48-3.56 (m, 2H), 4.18-4.40 (mc, 1H), 4.59 (septet, J=3.9 Hz, 1H), 4.74 (s, 2H), 6.46 (mc, 1H), 6.94 (d, J=8.8 Hz, 2H), 7.10 (dd, J=8.7, 2.1 Hz, 1H), 7.21 (dm, J=8.1 Hz, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.53 (d, J=1.8 Hz, 2H), 10.17 (s, 1H).
  • Step-9, 10 Compounds H and I (1683 and 1678):
  • A stirred suspension of the product from Step-8 (80 mg, 0.12 mmol of compound G) and anhydrous CsF (85 mg, 0.56 mmol), in DMA (0.6 mL) was heated to 73° C. for 20 h. The mixture was cooled to rt, the anion neutralized with glacial AcOH (1 equiv.), and the slurry filtered through a 5μ, frit washing with 1 mL of DMA to afford crude compound H. Data for H: LCMS [MH+] 6478, Rt 2.23.
  • To this solution was added 2-bromopyrimidine (40 mg, 0.248 mmol) and the mixture was heated to 45° C. overnite. The mixture was cooled to rt, filtered through a 5μ. frit and the crude product was purified by preparative HPLC to afford the step-10 product (55 mg, 80% over 2-steps) of compound I: LCMS [MH+] 556, Rt 4.00; 1H NMR (300 MHz, (CD3)2CO) δ 1.63-1.75 (m, 2H), 1.82 (s, 3H), 1.97-2.06 (m, 2H), 2.86 (dd, J=8.1, 3.0 Hz, 2H), 3.20 (mc, 2H), 3.60-3.69 (m, 2H), 4.12-4.34 (m, 2H), 4.70 (septet, J=4.2 Hz, 1H), 4.74 (s, 2H), 6.46 (mc, 1H), 6.59 (t, J=4.8 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 7.10 (dd, J=8.4, 2.1 Hz, 1H), 7.22 (dm, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.53 (d, J=2.1 Hz, 2H), 8.36 (d, J=4.8 Hz, 2H), 10.19 (s, 1H).
    • Example XXVI
  • Figure US20160340354A1-20161124-C00796
  • To a suspension of 2.0 g (4.40 mmol) of phenol A and 1.4 g (9.90 mmol) of K2CO3 in 20 mL of DMF was added 505 mg (4.40 mmol) of 2-chloropyrazine, and the mixture heated 24 h at 80° C. showing incomplete conversion of A by LC/MS. An additional portion of 253 mg (2.20 mmol) of 2-chloropyrazine was added and the reaction heated for an additional 1.5 days then cooled to room temperature. The slurry was diluted with an equal volume of ether, filtered to remove the carbonate salts, and then concentrated in vacuo to afford a brownish crude residue. This residue was absorbed onto 25 g of silica gel and carefully chromatographed over an Isco 80 g column (eluted with 10% to 40% EtOAc/Hexanes) to afford 1100 mg (48%, 90% ee) of the product of step-3, compound B (1732) as a colorless foam: LCMS [MH+] 531, Rt 4.02; Chiral HPLC ODH-280-40 column (rt 21.077 min); 1H NMR (300 MHz, (CD3)2CO) δ 2.91-3.10 (m, 2H), 3.33-3.44 (m, 1H), 4.38-4.58 (m, 1H), 6.58-6.70 (bm, 1H), 7.13 (dd, J=8.4, 1.8 Hz, 1H), 7.40-7.58 (m, 4H), 7.37-7.60 (m, 5H), 7.58 (dm, J=2.4, 1H), 8.15 (dd, J=2.7, 1.2 Hz, 1H), 8.33 (d, J=2.7 Hz, 1H), 8.46 (d, J=1.2 Hz, 1H), 10.32 (s, 1H).
    • Example XXVII
  • Figure US20160340354A1-20161124-C00797
  • To a solution of compound A (1.50 g, 2.83 mmol) in Acetone (20 mL) and DMF (1 mL) at 0° C. was added KI (2.27 g, 13.7 mmol). The mixture was heated to 55° C. overnite to obtain a 60:40 mixture of alkyl iodide/alkyl chloride. The mixture concentrated under vacuum, diluted with 10 mL of DMF and 1.75 g (17.1 mmol) of NaSO2Me. The mixture was heated to 45 overnite for 18 h, then heated to 100° C. for 10 min to complete the reaction. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL) and water (30 mL). The two layers were separated. The organic layer was washed with water (30 mL) brine (30 mL), dried over MgSO4, concentrated and chromatographed over an Isco 80 g column (eluted with 15% to 40% EtOAc/Hexanes) to afford 1.36 g (84%, >99% ee) of the product of step-2, compound B(1551): LCMS [M+-1] 571, Rt 3.80; Chiral HPLC ODH-280-40 column (rt 75.53 min); 1H NMR (300 MHz, CD3)2CO) δ 2.22-2.32 (m, 2H), 2.90-3.10 (m, 5H), 3.26-3.31 (m, 3H), 4.17 (t, J=6.3 Hz, 2H), 4.43 (mc, 1H), 6.52 (bm, 1H), 6.95 (d, J=9.0 Hz, 2H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 7.40-7.58 (m, 4H), 7.37 (d, J=8.4 Hz, 1H), 7.42 (dm, J=9.3 Hz, 2H), 7.56 (d, J=2.2 Hz, 1H), 10.22 (s, 1H).
    • Example XXVIII
  • Figure US20160340354A1-20161124-C00798
  • Step 1:
  • Dissolve A (1.00 g, 3.22 mmol) in 10 mL of dichloromethane with stirring. Add benzoylisothiocyanate (577 mg, 3.54 mmol) in one aliquot. Heat the reaction to 70° C. overnight. The reaction was complete after 16 hours. The reaction mixture was concentrated and washed repeatedly with hexane until a fine yellow powder remained. The acylthiourea product B was pure by LC/MS. LCMS [M+H+] 476.05, Rt=3.27 minutes.
  • Step-2:
  • The acylthiourea B (100 mg, 0.210 mmol) was dissolved in 2 mL of EtOH. 2-Bromo-4-Chloroacetophenone (59 mg, 0.252 mmol) and DIEA (52 uL, 0.315 mmol) were added. The reaction was warmed to 70° C. for 1 hour at which time is was complete by LC/MS. The reactions were concentrated, dissolved in EtOAc and purified on SiO2 with 1:4 EtOAc/Hexanes. The product C (1660) was pure by LC/MS. LC/MS [M+H+] 610.17, Rt=4.02 minutes.
    • Example XXIX
  • Figure US20160340354A1-20161124-C00799
  • Step 1:
  • Dissolve A (5 g, mmol) in 15 mL of dichloromethane. Add Fmoc-NCS in one portion with stirring. The reaction becomes very warm and is complete after 30 minutes. Add 5 mL of piperidine to the reaction. After 15 hours, the reaction mixture has become a white solid and is complete after three hours. The reaction is poured into 10 mL of saturated Na2CO3. The aqueous layer is extracted four times with dichloromethane. The organic layers are combined, dried over MgSO4, filtered, and concentrated. The resulting brown semi-solid is recrystallized from EtOH and hexanes. Product B(1247) is pure by LC/MS. LC/MS [M+H+] 372.1 Rt=3.23 minutes.
  • Step-2:
  • Thiourea B (26.6 mg, 0.071 mmol) was dissolved in 1 mL of isopropyl alcohol. 3-Bromo-trifluoroacetone (17.2 mg, 0.09 mmol) and DIEA (27.9 mg, 0.216 mmol) were added to the reaction with stirring. The reactions were warmed to 70° C. for 2 hours. The reaction was complete at this time. The reaction was concentrated, dissolved in DMF, and purified by reverse-phased HPLC. The trifluoromethyl aminothiazole product C(1589) was pure by LC/MS. LC/MS [M+H+] 464.08, Rt=4.13 minutes.
    • Example XXX
  • Figure US20160340354A1-20161124-C00800
  • Dissolve A (1.00 g, 2.19 mmol) in acetonitrile with stirring. Add Boc2O (1.05 g, 4.81 mmol), DIEA (0.70 mL, 0.55 mmol), and DMAP (26.7 mg, 0.219 mmol). The reaction stirred overnight and was complete after 12 hours. The reaction was concentrated in situ. The residue was dissolved in dichloromethane and purified on a silica gel plug. The pure Di-Boc product B was obtained in 98% yield. LC/MS [M+H+] 515.2, Rt=4.9 minutes.
    • Example XXXI
  • Figure US20160340354A1-20161124-C00801
  • Dissolve Di-Boc A (200 mg, 0.359 mmol) in 10 mL THF under an N2 atmosphere. Cool to −78° C. in a dry ice bath. Add t-butyl lithium drop wise and stir the reaction for 20 minutes at −78° C. Methyl methanethiolsulfonate (136 mg, 1.08 mmol) was dissolved in 4 mL of THF and added to the reaction drop wise through an addition funnel over 5 minutes. Remove the ice bath and allow the reaction to warm to room temperature. Add 10 mL of saturated NH4Cl drop wise to quench the reaction. The organic layer was extracted with EtOAc (4×10 mL). The organic extracts were combined, dried with MgSO4, filtered, and concentrated in situ. The residue was purified on a SiO2 column with 4:1 hexanes/EtOAc. The methylsulfide product B was pure by LC/MS. LC/MS [M+H+] 525.6, Rt=3.22.
    • Example XXXII
  • Figure US20160340354A1-20161124-C00802
  • Methylsulfide A (500 mg, 0.871 mmol) was dissolved in 20 mL of dichloromethane and cooled to 0° C. with stirring. MCPBA (215 mg, 0.871 mmol) was dissolved in dichloromethane and added drop wise the methylsulfide C solution over a 15-minute period. The reaction was allowed to warm to room temperature overnight. The reaction was concentrated in situ. The residue was dissolved in 40% EtOAc/60% hexanes and purified on a SiO2 column. The sulfoxide B was pure by LC/MS. LC/MS [M+H+] 540.0, Rt=3.38 minutes.
    • Example XXXIII
  • Figure US20160340354A1-20161124-C00803
  • Methylsulfide A (718 mg, 1.25 mmol) was dissolved in 20 mL of dichloromethane and cooled to 0° C. with stirring. MCPBA (453.3 mg, 2.62 mmol) was dissolved in 10 mL dichloromethane and added drop wise to the methylsulfide A solution over a 15-minute period. The reaction was allowed to warm to room temperature over a 2-hour period and to stir at room temperature for an additional 4 hours at which time the reaction was complete. The reaction was concentrated in situ. The residue was dissolved in 40% EtOAc/60% hexanes and purified on a SiO2 column. The sulfone B (1482) was pure by LC/MS. LC/MS [M+H+] 557.12, Rt=3.90 minutes.
    • Example XXXIV
  • Figure US20160340354A1-20161124-C00804
  • Step-1:
  • The methylsulfide A (250 mg, 0.477 mmol) was dissolved in 5 mL of TFA. The reaction was stirred overnight under an N2 atmosphere. The deprotection was complete by LC/MS and was then concentrated in situ to give B in quantitative yield. LC/MS [M+H+] 324.94, Rt=2.48 minutes.
  • Step-2:
  • All of the TFA salt of B from the previous step was dissolved in 10 mL EtOAc. 2 mL of this solution (0.095 mmol) was aliquoted into a 20 mL scintillation vial. Saturated NaHCO3 (2 mL) was added to this scintillation vial with stirring. Ethyl chloroformate (13.5 mg, 0.124 mmol) was added with stirring to the reaction. The acylation was complete after 2 hours. The organic layer was removed, dried in situ, and dissolved in 1 mL of DMF. The product was purified with reverse phase chromatography. Pure ethyl carbamate C (1482) was obtained in 30% yield (11 mg, 0.028 mmol). LC/MS [M+H+] 397.28, Rt=3.37 minutes.
    • Example XXXV
  • Figure US20160340354A1-20161124-C00805
  • Di-Boc A (55.6 mg, 0.10 mmol) was dissolved in 2 mL of NMP. CuCN (19 mg, 0.20 mmol) and BHT (22 mg, 0.1 mmol) were added to the reaction vessel with stirring. The heterogeneous suspension was degassed by five cycles of a vacuum purge and back filled with N2. The reaction was microwaved at 150° C. for three hours. The reaction was poured into 4 mL of saturated NaHCO3 and extracted with EtOAc (4×4 mL). The organic extracts were combined, dried with MgSO4, filtered, and concentrated. The residue was dissolved in 2 mL of DMF and purified by reverse phase chromatography. Both Boc groups were removed during the microwave heating process. Pure product B (1519) was obtained. LC/MS [M+H+] 304.19, Rt=2.16 minutes.
    • Example XXXVI
  • Figure US20160340354A1-20161124-C00806
  • POCl3 (3.6 g, 23.3 mmol) was added to anhydrous DMF (3 mL) at 0° C. and stirred for 15 min at r.t. Then the mixture was added dropwise to a solution of compound 1 (3.6 g, 19.5 mmol) in 10 mL of anhydrous DMF at 0° C. and stirred at r.t. for 2 h. The mixture was poured into 50 mL of 40% aq.NaOH at 0° C., followed by 100 mL of water. The precipitate was filtered and washed with water, dried to tgive 3 g of compound 2. Yield: 72%
  • To a solution of compound 2 (3 g, 14.1 mmol) in 10 mL of CH3NO2 was added AcNH4 (1.08 g, 14.1 mmol), CH3NH2HCl (0.95 g, 14.1 mmol). The mixture was stirred at r.t. overnight. After filtration, 3 g of compound 3 was collected. Yield: 83%
  • To a suspension of LAH (1.8 g, 47.4 mmol) in 50 mL of anhydrous THF was added compound 3 (3 g, 11.7 mmol) portionwise at 0° C. After the addition, it was allowed to be warmed to r.t. and stirred overnight. Then it was quenched with 1.8 mL of aq. NaOH (15%). The mixture was filtered through Celite, and washed with THF. The filtrate was removed under reduced pressure. The residue was dissolved with HCl/MeOH to give 1.2 g of compound 4 as precipitate. Yield: 40%
  • To a solution of compound 4 (1.2 g, 4.7 mmol) in 15 mL of AcOH was added 4-methoxybenzaldehyde (0.76 g, 5.6 mmol) and heated to 80° C. stirring overnight. Then it was cooled to r.t., 1.3 g product 5 was collected after filtered and washed with DCM. Yield: 72%
  • To a solution of compound 5 (191 mg, 0.5 mmol) in 10 mL of EA/H2O (1:1) was added NaHCO3 (92 mg, 1.1 mmol) and ethyl chloroformate (60 mg, 0.55 mmol). The mixture was stirred overnight. Then the organic layer was separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography to give 170 mg of compound 1423. Yield: 81%
    • Example XXXVII
  • Figure US20160340354A1-20161124-C00807
  • To a solution of compound 1 (4 g, 7.7 mmol) in 40 mL of EtOH was added 10 mL of NH3.H2O. The mixture was heated to 80° C. overnight. The solvent was evaporated under reduced pressure and the residue was dissolved with EA (40 mL). The organic layer was washed with water (3×40 mL), brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography to yield 2.2 g of compound 2. Yield: 54%
  • To a solution of compound 2 (100 mg, 0.19 mmol) in 1 mL of DCM was added compound 3 (17 mg, 0.22 mmol) and Et3N (57 mg, 0.57 mmol) at 0° C. The mixture was stirred at r.t. for 16 h. Then the solvent was evaporated under reduced pressure and the residue was dissolved with EA (10 mL). The organic layer was washed with water (3×10 mL), brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative TLC to yield 26 mg of compound 1276. Yield: 24%
    • Example XXXVIII
  • Figure US20160340354A1-20161124-C00808
  • To a solution of compound 1 (10 g, 28.6 mmol) in 100 mL of DCM was added Et3N (8.7 g, 85.8 mmol) and DMAP (0.3 g, 2.86 mmol) and ethoxy oxalyl chloride (4.7 g, 34.3 mmol). Then it was stirred at r.t. overnight. The solvent was removed under reduced pressure and the residue was dissolved with EA, washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to give 11 g of compound 2. Yield: 93%
  • To a solution of compound 2 (11 g, 26.6 mmol) in 100 mL of MeOH was added aq. KOH (2 M, 40 mL). It was stirred for 5 h. Then MeOH was removed under reduced pressure and 1M HCl was added to it until it became acidic. EA was added to it and separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give 9.3 g of compound 3. Yield: 93%
  • To a solution of compound 3 (100 mg, 0.26 mmol) in 2 mL of DMF was added ethanamine (23 mg, 0.52 mmol), EDC (50 mg, 0.26 mmol), HOBT (35 mg, 0.26 mmol), NMM (0.168 mL) and it was stirred for 16 h at r.t. Then it was quenched by water (5 mL) and extracted with ethyl acetate (2×5 mL), and the organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using EtOAc/petro ether (1:5) as eluent to give 47 mg of compound 1706. Yield: 44%
    • Example XXXIX
  • Figure US20160340354A1-20161124-C00809
  • To a solution of i-PrOH (108 mg, 1.8 mmol) in 3 mL of DCM was added Et3N (364 mg, 3.6 mmol) and compound 1 (343 mg, 2.7 mmol). After stirred overnight, the solvent was removed under reduced pressure and the residue was dissolved with EA, washed with water and brine, dried over Na2SO4, evaporated under reduced pressure. Then it was purified by flash column chromatography to give 200 mg of compound 2. Yield: 74%
  • To a solution of compound 3 (200 mg, 0.58 mmol) in 4 mL of DCM was added Et3N (232 mg, 2.3 mmol) and compound 2 (130 mg, 0.86 mmol). After stirred overnight, the solvent was removed under reduced pressure and the residue was dissolved with EA, washed with water and brine, dried over Na2SO4, evaporated under reduced pressure. Then it was purified by flash column chromatography to give 151 mg of compound 1338. Yield: 61%
  • Using the procedures shown in the preceding Examples and as described in U.S. Publication No. 2005-0272759 (having corresponding International Application Publication No. WO2005/089764), U.S. Publication No. 2005-0282849 (having corresponding International Application Publication No. WO2006/113703), or U.S. Publication No. 2007-0254878 (having corresponding International Application Publication No. WO2008/127715); and International Application Publication No. WO2008/127714, each of which is incorporated by reference herein in its entirety, additional Compounds presented herein may be prepared including the following, wherein Cpd represents Compound, MS represents mass spec (M+1, unless otherwise indicated) RT represents HPLC retention time (minutes), the RT value of 10-80 and 30-60 represent eluent gradient during the HPLC run and EC50 represents the 50% Effective Concentration value for activity in the Hela cell line tested (μM):
  • The EC50 for a series of Compounds is provided in Table 2.
  • TABLE 2
    Cpd MS NMR RT EC50
    999 493.3 4.43 *****
    1000 445.5 1H NMR (300 MHz, DMSO-d6) δ ppm 1.22 (br. s., 3 H) 2.60- 3.23 ****
    2.86 (m, 2 H) 2.91-3.13 (m, 1 H) 3.41 (t, J = 5.56 Hz, 2 H) 3.67-
    3.86 (m, 2 H) 3.95 (dd, J = 9.54, 4.13 Hz, 1 H) 4.05-4.24 (m, 3
    H) 4.56-4.72 (m, 1 H) 4.92 (d, J = 5.09 Hz, 1 H) 6.31 (br. s., 1
    H) 6.90 (d, J = 8.58 Hz, 2 H) 7.05 (dd, J = 8.58, 1.91 Hz, 1 H)
    7.10 (d, J = 8.58 Hz, 2 H) 7.28 (d, J = 8.58 Hz, 1 H) 7.50 (d,
    J = 1.91 Hz, 1H) 11.11 (br. s., 1 H)
    1001 575.5 2.98 ****
    1002 468.40 2.38 ***
    1003 555.1 1H NMR (DMSO, 300 MHz) δ11.09 (b, 1H), 7.47 (s, 1H), 7.25 10-80 ****
    (cal. 554.2) (d, J = 8.4 Hz, 1H), 7.08-7.01 (m, 3H), 6.84 (d, J = 8.4 Hz, 2H), 3.86
    6.28 (b, 1H), 4.75 (s, 2H), 4.07 (b, 3H), 3.40-3.37 (m, 6H), 3.20
    (b, 4H), 3.18 (s, 3H), 2.99 (b, 1H), 2.73 (b, 1H), 2.32 (b, 3H),
    1.20 (b, 3H)
    1004 541.2 1H NMR (DMSO, 300 MHz) δ11.09 (b, 1H), 7.92 (t, J = 5.1 Hz, 10-80 ****
    (cal. 540.2) 1H), 7.48 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.11-7.01 (m, 3H), 3.82
    6.90 (d, J = 8.4 Hz, 2H), 6.28 (b, 1H), 4.42 (s, 2H), 4.17-4.09 (b,
    3H), 3.48-3.43 (m, 4H), 3.28-3.15 (m, 2H), 2.99-2.94 (m, 1H),
    2.73-2.69 (m, 1H), 2.32-2.20 (m, 7H), 1.20 (b, 3H)
    1005 560.3 1H NMR (CD3OD, 300 MHz) δ7.48 (d, J = 1.8 Hz, 1H), 7.24-7.21 10-80 **
    (cal. 559.2) (m, 3H), 7.07-6.90 (m 7H), 6.53-6.46 (m, 1H), 4.77 (b, 1H), 4.55
    4.42 (b, 1H), 4.15 (b, 1H), 3.77 (s, 3H), 3.52-3.49 (m, 2H),
    3.29-3.19 (m, 1H), 2.95-2.83 (m, 5H), 2.42 (b, 2H), 2.17-2.03
    (m, 5H)
    1006 482.2 1H NMR (CD3OD, 300 MHz) δ7.43 (s, 1H), 7.19-7.18 (m, 3H,), 10-80 ***
    (cal. 481.2) 7.04-7.01 (d, J = 8.7 Hz, 1H), 6.91-6.88 (d, J = 7.8 Hz, 2H), 6.39 (b, 4.11
    1H), 4.73 (b, 1H), 4.19-4.11 (m, 3H), 3.61-3.50 (m, 2H), 3.21-
    3.13 (m, 3H), 2.93-2.89 (m, 3H), 2.81-2.78 (m, 2H), 2.40-1.79
    (m, 6H), 1.28 (b, 3H)
    1007 468.1 1H NMR (CDCl3, 300 MHz) δ7.83-7.78 (m, 1H), 7.50 (s, 1H), 10-80 ***
    (cal. 467.2) 7.24-7.18 (m, 2H), 7.12 (dd, J = 8.7 Hz and 1.8 Hz, 1H), 6.81- 3.90
    6.77 (m, 2H), 6.43-6.40 (m, 1H), 4.72-4.60 (m, 1H), 4.41-4.12
    (m, 2H), 4.00-3.91 (m, 1H), 3.77-3.62 (m, 3H), 2.91-2.72 (m,
    5H), 2.52-2.47 (m, 1H), 2.27-2.65 (m, 2H), 2.07-1.98 (m, 2H)
    1008 548.2 1H NMR (CD3OD, 300 MHz) δ7.49 (s, 1H), 7.24-7.21 (m, 3H), 10-80 ***
    (cal. 547.2) 7.14-6.96 (m 7H), 6.53-6.46 (m, 1H), 4.76 (b, 1H), 4.41 (b, 1H), 4.79
    4.12 (b, 1H), 3.77 (s, 3H), 3.57-3.48 (m, 2H), 2.96-2.84 (m,
    5H), 2.42 (b, 2H), 2.17-1.82 (m, 5H)
    1009 468.1 1H NMR (CDCl3, 300 MHz) δ7.83-7.78 (m, 1H), 7.50 (s, 1H), 10-80 ***
    (cal. 467.2) 7.24-7.18 (m, 2H), 7.12 (dd, J = 8.7 Hz and 1.8 Hz, 1H), 6.81- 3.90
    6.77 (m, 2H), 6.43-6.40 (m, 1H), 4.72-4.60 (m, 1H), 4.41-4.12
    (m, 2H), 4.00-3.91 (m, 1H), 3.77-3.62 (m, 3H), 2.91-2.72 (m,
    5H), 2.52-2.47 (m, 1H), 2.27-2.65 (m, 2H), 2.07-1.98 (m, 2H)
    1010 468.2 1H NMR (CD3OD, 400 MHz) δ7.45 (s, 1H), 7.26-7.20 (m, 3H), 10-80 ***
    (cal. 467.2) 7.06-6.98 (m, 3H), 6.40 (b, 1H), 4.25 (m, 2H), 3.79 (s, 3H), 4.59
    3.61-3.40 (m, 4H), 3.19-3.14 (m, 1H), 2.95-2.65 (m, 5H), 2.00-
    1.93 (m, 6H)
    1011 560.2 1H NMR (CD3OD, 400 MHz) δ7.51 (d, J = 2.0 Hz, 1H), 7.35-7.28 10-80 ***
    (cal. 559.2) (m, 3H), 7.15-7.01-7.18 (m, 5H), 6.93 (d, J = 8.8 Hz, 2H), 4.83- 5.54
    4.76 (m, 1H), 4.52-4.27 (m, 1H), 3.79 (s, 3H), 3.72-3.41 (m,
    4H), 3.05-2.84 (m, 5H), 2.19-1.67 (m, 6H)
    1012 497.8 1H NMR (DMSO, 300 MHz) δ11.09 (b, 1H), 7.48 (s, 1H), 7.24 10-80 ***
    (cal. 497.2) (d, J = 8.4 Hz, 1H), 7.08-7.01 (m, 3H), 6.85 (d, J = 8.4 Hz, 2H), 4.63
    6.28 (b, 1H), 4.77 (s, 2H), 4.17-4.09 (b, 3H), 3.54 (b, 4H), 3.39
    (b, 4H), 3.0 (b, 2H), 2.69-2.68 (m, 1H), 1.20 (b, 3H)
    1013 472.0 1H NMR (CD3OD, 300 MHz) δ7.45 (s, 1H), 7.23-7.20 (m, 3H), 10-80 ****
    (cal. 471.2) 7.04 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.40 5.05
    (b, 1H), 4.49 (s, 2H), 4.25-4.22 (m, 3H), 3.63-3.59 (m, 2H),
    3.40-3.36 (m, 2H), 3.15 (b, 1H), 2.80 (b, 2H), 1.30 (b, 3H)
    1014 541.2 1H NMR (CD3OD, 300 MHz) δ7.45 (s, 1H), 7.23-7.19 (m, 3H), 10-80 ***
    (cal. 540.2) 7.04 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.39 4.41
    (b, 1H), 4.87 (s, 2H), 4.20-4.19 (m, 3H), 3.90-3.85 (m, 2H),
    3.55 (b, 3H), 3.15 (b, 5H), 2.80 (b, 3H), 1.30 (b, 3H)
    1015 486.0 1H NMR (CD3OD, 300 MHz) δ7.45 (s, 1H), 7.23-7.20 (m, 3H), 10-80 ***
    (cal. 485.2) 7.03 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.39 5.48
    (b, 1H), 4.49 (s, 2H), 4.25-4.22 (m, 3H), 3.46-3.41 (m, 4H),
    3.33 (b, 3H), 3.15 (b, 1H), 2.80 (b, 2H), 1.31 (b, 3H)
    1016 560.51 (ES−) 4.23 *
    1017 544.39 (ES−) 4.08 *****
    1018 467.14 3.28 ****
    1019 467.23 3.20 ****
    1020 453.27 (ES−) 3.15 ****
    1021 621.2 1H NMR (DMSO, 400 MHz), δ 7.51 (d, J = 2.4 Hz, 1H), 7.30-7.24 10-80 ***
    (cal. 620.2) (m, 3H), 7.16-7.13 (m, 3H), 7.08 (dd, J = 8.8 Hz and 2.1 Hz, 2H), 4.35
    6.98 (b, 2H), 6.51 (b, 1H), 4.45 (b, 1H), 3.62-3.53 (m, 6H), 3.35
    (s, 3H), 3.11-2.80 (m, 3H), 2.64-2.53 (m, 5H)
    1022 607.2 1H NMR (CD3OD, 300 MHz) δ7.49 (s, 1H), 7.25-7.20 (m, 3H), 10-80 ***
    (cal. 606.2) 7.14-7.05 (m, 5H), 6.99 (b, 2H), 6.50 (b, 1H), 4.52 (s, 2H), 5.05
    4.62-4.58 (m, 4H), 3.42-3.37 (m, 2H), 2.80 (b, 3H), 2.49-2.43
    (m, 6H)
    1023 M + 23: 586.1 1H NMR (CD3OD, 300 MHz) δ7.49 (s, 1H), 7.25-7.22 (m, 3H), 10-80 ****
    (cal. 563.2) 7.14-7.05 (m, 5H), 6.99 (b, 2H), 6.50 (b, 1H), 4.81 (s, 2H), 4.42 5.93
    (m, 2H), 3.67-3.56 (m, 8H), 2.60 (b, 3H))
    1024 591.2 1H NMR (CD3OD, 300 MHz) δ7.49 (s, 1H), 7.25-7.22 (m, 3H), 10-80 ***
    (cal. 590.2) 7.13-7.05 (m, 5H), 6.96 (b, 2H), 6.50 (b, 1H), 4.81 (s, 2H), 4.42 5.01
    (b, 2H), 3.59 (b, 4H), 2.90 (b, 3H), 2.46-2.44 (m, 5H), 1.10 (b, 3H)
    1025 633.2 1H NMR (CD3OD, 300 MHz) δ7.49 (d, J = 1.8 Hz, 1H), 7.26-7.23 10-80 ***
    (cal. 632.2) (m, 3H), 7.09-7.02 (m, 3H), 6.97-6.91 (m, 4H), 6.50 (b, 1H), 4.29
    4.81 (s, 2H), 4.42 (b, 2H), 3.79 (s, 3H), 3.63-3.52 (m, 6H), 3.35
    (s, 3H), 2.90 (b, 3H), 2.61-2.51 (m, 6H)
    1026 619.2 1H NMR (CD3OD, 300 MHz) δ7.49 (d, J = 2.1 Hz, 1H), 7.28-7.22 10-80 ****
    (cal. 618.2) (m, 3H), 7.08-7.02 (m, 5H), 6.93-6.90 (m, 2H), 6.47 (b, 1H), 4.24
    4.52 (s, 2H), 4.41 (b, 2H), 3.78 (s, 3H), 3.60 (t, J = 4.8 Hz, 4H),
    3.40 (t, J = 6.3 Hz, 3H), 2.90 (b, 3H), 2.61-2.51 (m, 6H)
    1027 M − 1: 574.1  1H NMR (DMSO, 300 MHz) δ11.15 (b, 1H), 7.51 (s, 1H), 7.27 10-80 ***
    (cal. 575.2) (d, J = 8.7 Hz, 1H), 7.13 (b, 2H), 7.06-7.02 (m, 3H), 6.90-6.88 5.03
    (m, 4H), 6.40 (b, 1H), 4.79 (s, 2H), 4.27 (b, 2H), 3.71 (s, 3H),
    3.61-3.40 (m, 5H), 3.29 (s, 1H), 3.13 (b, 1H), 2.95-2.69 (m,
    4H),
    1028 603.2 1H NMR (CD3OD, 300 MHz) δ7.48 (d, J = 1.8 Hz, 1H), 7.08-7.01 10-80 ***
    (cal. 602.2) (m, 3H), 6.93-6.90 (m, 4H), 6.47 (b, 1H), 4.81 (s, 2H), 4.40 (b, 4.23
    2H), 3.78 (s, 3H), 3.60-3.56 (m, 4H), 2.89 (b, 2H), 2.50-2.41
    (m, 6H), 1.10 (t, J = 7.2 Hz, 3H)
    1029 660.2 1H NMR (CD3OD, 300 MHz) δ7.48 (s, 1H), 7.24-7.22 (m, 3H), 10-80 *
    (cal. 659.3) 6.93-6.90 (m, 4H), 6.46 (b, 1H), 4.80 (s, 2H), 4.40 (b, 2H), 3.78 3.87
    (s, 3H), 3.58 (b, 4H), 2.89 (b, 2H), 2.49-2.33 (m, 8H), 2.24-2.21
    (m, 6H), 1.70-1.68 (m, 2H)
    1030 576.2 1H NMR (DMSO, 300 MHz) δ11.08 (b, 1H), 7.48 (s, 1H), 7.26- 10-80 ****
    (cal. 575.2) 6.87 (m, 10H), 6.33 (b, 1H), 4.23 (b, 1H), 3.92 (b, 2H), 3.68 (s, 5.29
    3H), 3.29 (b, 4H), 3.11 (b, 1H), 2.66 (b, 2H), 2.32-2.27 (m, 6H),
    1.78 (b, 2H)
    1031 558.0 1H NMR (DMSO, 300 MHz) δ11.30 (b, 1H), 8.13 (s, 1H), 7.71 30-90 *****
    (cal. 557.2) (s, 1H), 7.53 (s, 1H), 7.42-6.81 (m, 10H), 6.42-6.39 (m, 1H), 4.69
    4.53-4.29 (m, 3H), 3.92 (s, 2H), 3.73 (s, 3H), 3.22-3.18 (m,
    1H), 2.92-2.82 (m, 2H), 2.62 (s, 2H)
    1032 443.4 3.55 ****
    1033 456.8 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (t, J = 6.36 Hz, 3 H) 3.75 ****
    2.67-2.82 (m, 2 H) 2.90-3.08 (m, 1 H) 3.78-3.93 (m, 4 H)
    3.93-3.98 (m, 2 H) 4.10 (q, J = 6.78 Hz, 3 H) 5.15 (t, J = 3.97
    Hz, 1 H) 6.30 (br. s., 1 H) 6.92 (d, J = 8.90 Hz, 2 H) 7.05 (dd,
    J = 8.58, 1.91 Hz, 1 H) 7.10 (d, J = 8.58 Hz, 2 H) 7.27 (d, J = 8.58
    Hz, 1 H) 7.49 (d, J = 1.91 Hz, 1 H) 11.10 (br. s., 1 H)
    1034 471.4 3.83 *****
    1035 485.4 3.98 *****
    1036 471.4 3.82 *****
    1037 485.5 3.95 *****
    1038 499.4 4.07 *****
    1039 475.4 3.52 *****
    1040 491.3 3.68 ****
    1041 503.5 (M − H) 3.75 ****
    1042 487.4 3.47 ****
    1043 455.42 3.75 *****
    1044 469.4 3.73 *****
    1045 483.3 3.83 *****
    1046 469.4 3.75 ****
    1047 481.4 3.73 *****
    1048 467.4 3.58 *****
    1049 481.4 3.63 *****
    1050 505.33 3.85 *****
    1051 523.4 3.88 *****
    1052 539.3 3.97 ****
    1053 537.5 1H NMR (300 MHz, DMSO-d6) δ ppm 2.87 (br. s., 2 H) 3.19 4.00 *****
    (br. s., 1 H) 3.79-4.00 (m, 6 H) 4.28 (br. s., 1 H) 5.16 (t,
    J = 3.97 Hz, 1 H) 6.41 (br. s., 1 H) 6.96 (d, J = 7.95 Hz, 2 H) 7.07
    (dd, J = 8.58, 1.91 Hz, 1 H) 7.10-7.24 (m, 4 H) 7.30 (d, J = 8.58
    Hz, 1 H) 7.44 (d, J = 8.58 Hz, 2 H) 7.54 (d, J = 2.23 Hz, 1 H)
    11.14 (br. s., 1 H)
    1054 583.4 4.07 *****
    1055 535.4 3.82 ****
    1056 519.4 3.92 *****
    1057 553.4 4.05 *****
    1058 507.0 1H NMR (CD4O, 300 MHz) δ7.48 (d, J = 1.8 Hz, 1H), 7.25-7.22 10-80 *****
    (cal. 506.2) (m, 3H), 7.07-7.02 (m, 3H), 6.93-6.90 (m, 4H), 6.52-6.46 (m, 5.88
    1H), 4.43-4.39 (m, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.78 (s, 3H),
    3.72 (t, J = 6.3 Hz, 2H), 3.05-2.85 (m, 3H), 2.00-1.94 (m, 2H)
    1059 491.0 1H NMR (DMSO, 300 MHz) δ11.12-11.08 (m, 1H), 7.50 (s, 10-80 *****
    (cal. 490.2) 1H), 7.36-7.26 (m, 6H), 7.06-7.04 (m, 3H), 6.86-6.84 (m, 2H), 5.61
    6.35-6.34 (m, 1H), 5.17-5.10 (m, 2H), 4.20-4.17 (m, 1H), 3.98
    (t, J = 6.3 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H), 3.07-3.02 (m, 1H),
    2.76-2.71 (m, 2H), 1.83-1.79 (m, 2H)
    1060 441.0 1H NMR (DMSO, 300 MHz) δ11.12-11.09 (m, 1H), 7.50 (s, 10-80 *****
    (cal. 440.2) 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.10-7.04 (m, 3H), 6.89 (d, 5.18
    J = 7.5 Hz, 2H), 6.34-6.27 (m, 1H), 5.99-5.91 (m, 1H), 5.31-5.15
    (m, 2H), 4.60-4.58 (m, 1H), 4.19-4.14 (m, 1H), 4.00-3.96 (m,
    2H), 3.51-3.48 (m, 2H), 3.08-3.02 (m, 1H), 2.78-2.71 (m, 2H),
    1.83-1.79 (m, 2H)
    1061 457.1 1H NMR (DMSO, 300 MHz) δ11.09 (s, 1H), 7.48 (d, J = 2.1 Hz, 30-90 *****
    (cal. 456.2) 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.08-7.01 (m, 3H), 6.87 (d, 4.28
    J = 8.7 Hz, 2H), 6.30 (s, 1H), 4.13-4.10 (m, 1H), 3.96 (t,
    J = 6.6 Hz, 2H), 3.87-3.71 (m, 2H), 3.49 (t, J = 6.3 Hz, 2H), 3.08-
    2.97 (m, 1H), 2.74-2.69 (m, 2H), 1.92-1.89 (m, 1H), 1.83-1.77
    (m, 2H), 0.87 (d, J = 6.6 Hz, 6H)
    1062 477.1 1H NMR (CD4O, 300 MHz) δ7.49 (d, J = 1.8 Hz, 1H), 7.39 (t, 10-80 *****
    (cal. 476.2) J = 7.8 Hz, 1H), 7.25-7.22 (m, 4H), 7.13 (d, J = 7.8 Hz, 2H), 7.06 5.53
    (dd, J = 8.7 Hz and 1.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.54-6.48
    (m, 1H), 4.45-4.39 (m, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.72 (t,
    J = 6.0 Hz, 2H), 3.05-2.88 (m, 3H), 2.00-1.94 (m, 2H)
    1063 M + 23: 560.1 1H NMR (CD3OD, 300 MHz) δ7.81 (dd, J = 6.3 Hz and 3.0 Hz, 10-80 ****
    (cal. 537.2) 2H), 7.49 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 6.3 Hz and 3.0 Hz, 1H), 5.47
    7.25-7.23 (m, 1H), 7.14-6.98 (m, 6H), 6.48 (b, 1H), 4.52 (s,
    2H), 4.40 (b, 2H), 3.62 (t, J = 5.7 Hz, 2H), 3.39 (t, J = 5.7 Hz, 2H),
    2.90 (b, 2H)
    1064 607.1 1H NMR (CD3OD, 300 MHz) δ7.49 (d, J = 2.1 Hz, 1H), 7.25-7.22 10-80 ****
    (cal. 606.2) (m, 4H), 7.13-7.05 (m, 4H), 6.96 (b, 2H), 6.50 (b, 1H), 4.80 (s, 4.84
    2H), 4.42 (b, 2H), 3.69-3.53 (m, 5H), 3.34 (s, 2H), 2.90 (b, 3H),
    2.55-2.51 (m, 5H)
    1066 562.55 3.63 *****
    1067 562.1 1H NMR (DMSO, 300 MHz) δ 11.18 (b, 1H), 8.04 (s, 1H), 7.68 10-80 ****
    (cal: 561.2) (s, 1H), 7.52 (s, 1H), 7.30-7.01 (m, 9H), 6.93-6.92 (m, 2H), 5.33
    6.35 (b, 1H), 5.53 (s, 1H), 4.60-4.45 (m, 2H), 4.40-4.20 (m,
    2H), 3.88 (b, 2H), 3.22 (b, 1H), 2.85 (b, 2H)
    1068 562.1 1H NMR (DMSO, 300 MHz) δ 11.18 (b, 1H), 7.81 (s, 3H), 7.74 10-80
    (cal: 561.2) (s, 2H), 7.52 (s, 1H), 7.30-7.01 (m, 6H), 6.93-6.90 (m, 2H), 5.70
    6.35 (b, 1H), 5.43 (s, 1H), 4.54-4.50 (m, 2H), 4.28 (b, 2H), 3.90
    (b, 2H), 2.85 (b, 2H)
    1069 562.27 3.9  *****
    1070 596.24 2.40 *****
    1071 598.21 2.48 *****
    1072 523.3 1H NMR (DMSO, 400 MHz) δ11.12-11.07 (m, 1H), 7.51 (s, 10-80 *****
    (cal. 522.4) 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.13-7.03 (m, 3H), 6.87 (d, 2.67
    J = 8.8 Hz, 2H), 6.31-6.24 (m, 1H), 5.97-5.90 (m, 1H), 5.33-5.16
    (m, 2H), 4.59-4.53 (m, 2H), 4.15-4.14 (m, 1H), 4.01-3.94 (m,
    2H), 3.03-2.97 (m, 1H), 2.75-2.68 (m, 2H), 2.66-2.65 (m, 1H),
    2.42-2.27 (m, 8H), 2.13 (s, 3H), 1.83-1.78 (m, 2H)
    1073 496.1 1H NMR (CDCl3, 300 MHz) δ 7.90 (b, 1H), 7.70 (s, 2H), 7.50 10-80 *****
    (cal: 495.2) (s, 1H), 7.23-7.10 (m, 4H), 6.81 (d, J = 8.4 Hz, 2H), 6.42 (b, 1H), 5.16
    4.69 (d, J = 12.9 Hz, 1H), 3.60-4.54 (m, 1H), 4.48 (b, 1H), 4.38-
    4.12 (m, 3H), 3.99-3.84 (m, 2H), 3.17-3.08 (m, 1H), 2.92-2.74
    (m, 2H), 1.39-1.18 (m, 3H).
    1074 443.1 1H NMR (DMSO, 300 MHz) δ11.09 (s, 1H), 7.47 (d, J = 1.8 Hz, 10-80 *****
    (cal. 442.2) 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.08-7.02 (m, 3H), 6.87 (d, 5.29
    J = 8.7 Hz, 2H), 6.31-6.20 (m, 1H), 4.83-4.79 (m, 1H), 4.17-4.10
    (m, 1H), 3.96 (t, J = 6.3 Hz, 2H), 3.49 (t, J = 6.3 Hz, 2H), 3.05-
    2.96 (m, 1H), 2.70-2.69 (m, 2H), 1.81-1.77 (m, 2H), 1.19 (d,
    J = 6.0 Hz, 6H)
    1075 546.3 1H NMR (DMSO, 300 MHz) δ11.19 (b, 1H), 7.52 (d, J = 1.8 Hz, 10-80 ****
    (cal. 545.2) 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 8.7 Hz, 1H), 7.21 (t, 4.55
    J = 7.5 Hz, 2H), 7.14-7.11 (m, 3H), 7.05 (dd, J = 8.7 Hz and
    2.1 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H), 6.43-6.38 (m, 1H), 4.30-
    4.29 (m, 1H), 3.96 (t, J = 6.3 Hz, 2H), 3.52 (t, J = 4.8 Hz, 4H),
    3.24-3.16 (m, 1H), 2.86-2.85 (m, 2H), 2.47-2.24 (m, 6H),
    1.84-1.79 (m, 2H)
    1076 559.3 1H NMR (DMSO, 400 MHz) δ11.15 (b, 1H), 7.52 (d, J = 1.8 Hz, 10-80 ***
    (cal. 558.2) 1H), 7.37 (t, J = 8.1 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.21 (t, 4.08
    J = 7.5 Hz, 2H), 7.15-7.12 (m, 3H), 7.06 (dd, J = 8.4 Hz and
    2.1 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 6.43-6.37 (m, 1H), 4.32-
    4.21 (m, 1H), 3.95 (t, J = 6.3 Hz, 2H), 3.18-3.11 (m, 1H), 2.89-
    2.81 (m, 2H), 2.41-2.27 (m, 10H), 2.09 (s, 3H), 1.83-1.78 (m, 2H)
    1077 528.1 1H NMR (DMSO, 300 MHz) δ11.15 (b, 1H), 8.12 (s, 1H), 7.69 10-80 ****
    (cal. 527.2) (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.29 (d, 5.51
    J = 8.7 Hz, 1H), 7.21 (t, J = 7.2 Hz, 2H), 7.14-7.11 (m, 3H), 7.06
    (dd, J = 8.4 Hz and 2.1 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 6.43-6.37
    (m, 1H), 4.51 (t, J = 6.9 Hz, 2H), 4.28-4.26 (m, 1H), 3.91 (t,
    J = 6.0 Hz, 2H), 3.22-3.11 (m, 1H), 2.86-2.82 (m, 2H), 2.24-2.22
    (m, 2H)
    1078 528.1 1H NMR (DMSO, 300 MHz) δ11.19 (b, 1H), 7.74 (s, 2H), 7.52 30-90 ****
    (cal. 527.2) (d, J = 1.5 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 4.74
    7.21 (t, J = 7.2 Hz, 2H), 7.14-7.11 (m, 3H), 7.05 (dd, J = 8.4 Hz
    and 1.8 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 6.42-6.37 (m, 1H),
    4.55 (t, J = 6.9 Hz, 2H), 4.32-4.27 (m, 1H), 3.92 (t, J = 6.0 Hz,
    2H), 3.18-3.15 (m, 1H), 2.91-2.83 (m, 2H), 2.27-2.23 (m, 2H)
    1079 510.2 1H NMR (DMSO, 300 MHz) δ11.11 (b, 1H), 7.48 (d, J = 1.8 Hz, 10-80 *****
    (cal. 509.2) 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.08 (J, J = 8.7 Hz, 2H), 7.03 (dd, 4.10
    J = 8.7 Hz and 2.1 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.31 (s, 1H),
    6.01-5.92 (m, 1H), 5.31-5.12 (m, 2H), 4.58 (s, 2H), 4.21-4.12
    (m, 1H), 3.94 (t, J = 6.3 Hz, 2H), 3.52 (t, J = 7.5 Hz, 4H), 3.09-
    3.00 (m, 1H), 2.75-2.69 (m, 2H), 2.37-2.30 (m, 6H), 1.83-1.78
    (m, 2H)
    1080 492.1 1H NMR (DMSO, 300 MHz) δ11.09 (b, 1H), 8.11 (d, J = 0.6 Hz, 10-80 *****
    (cal. 492.2) 1H), 7.68 (d, J = 0.6 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.26 (d, 5.28
    J = 8.4 Hz, 1H), 7.08 (J, J = 8.7 Hz, 2H), 7.03 (dd, J = 8.7 Hz and
    1.8 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.30 (s, 1H), 5.95-5.90 (m,
    1H), 5.30-5.15 (m, 2H), 4.60 (s, 2H), 4.50 (t, J = 6.9 Hz, 2H),
    4.18-4.11 (m, 1H), 3.89 (t, J = 6.0 Hz, 2H), 3.08-3.00 (m, 1H),
    2.79-2.71 (m, 2H), 2.24-2.23 (m, 2H)
    1081 492.1 1H NMR (DMSO, 300 MHz) δ11.10 (b, 1H), 8.74 (s, 2H), 7.48 10-80 *****
    (cal. 491.2) (d, J = 1.8 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.08 (J, J = 8.7 Hz, 4.39
    2H), 7.05 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.86 (d, J = 8.7 Hz,
    2H), 6.30 (s, 1H), 5.98-5.90 (m, 1H), 5.32-5.18 (m, 2H), 4.58
    (s, 2H), 4.54 (t, J = 6.9 Hz, 2H), 4.18-4.11 (m, 1H), 3.89 (t,
    J = 6.0 Hz, 2H), 3.08-2.98 (m, 1H), 2.78-2.72 (m, 2H), 2.26-2.22
    (m, 2H)
    1082 510.2 1H NMR (DMSO, 300 MHz) δ11.10 (b, 1H), 7.48 (d, J = 1.8 Hz, 10-80 ****
    (cal. 509.2) 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.05-7.04 (m, 3H), 6.86 (d, 3.73
    J = 8.7 Hz, 2H), 6.31-6.26 (m, 1H), 4.22-4.15 (m, 3H), 3.93 (t,
    J = 6.6 Hz, 2H), 3.51 (t, J = 4.8 Hz, 6H), 3.28 (s, 3H), 3.04-2.98
    (m, 1H), 2.77-2.74 (m, 2H), 2.41-2.36 (m, 6H), 1.83-1.75 (m, 2H)
    1083 510.2 1H NMR (DMSO, 300 MHz) δ11.11 (b, 1H), 8.12 (s, 1H), 7.68 30-90 ****
    (cal. 509.2) (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.08- 4.21
    7.01 (m, 3H), 6.86 (d, J = 8.7 Hz, 2H), 6.32-6.25 (m, 1H), 4.50
    (t, J = 7.2 Hz, 2H), 4.30-4.06 (m, 3H), 3.89 (t, J = 6.0 Hz, 2H),
    3.68-3.50 (m, 5H), 3.03-3.01 (m, 2H), 2.79-2.73 (m, 1H),
    2.37-2.24 (m, 2H)
    1084 510.2 1H NMR (DMSO, 300 MHz) δ11.11 (b, 1H), 7.74 (s, 2H), 7.52 30-90 ****
    (cal. 509.2) (s, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.09-7.01 (m, 3H), 6.85 (d, 4.67
    J = 8.4 Hz, 2H), 6.28-6.24 (m, 1H), 4.54 (t, J = 6.9 Hz, 2H), 4.29-
    4.09 (m, 4H), 3.90 (t, J = 6.0 Hz, 2H), 3.60-3.53 (m, 2H), 3.24-
    3.16 (m, 2H), 3.13-3.09 (m, 1H), 3.02-2.94 (m, 1H), 2.76-2.69
    (m, 1H), 2.24-2.20 (m, 2H)
    1085 516.1 1H NMR (CDCl3, 300 MHz) δ 7.77 (b, 1H), 7.50 (d, J = 1.5 Hz, 10-80 *****
    (cal: 515.2) 1H), 7.23-7.10 (m, 4H), 6.99 (b, 1H), 6.82 (d, J = 8.4 Hz, 2H), 5.07
    6.40 (b, 1H), 4.45-4.05 (m, 4H), 3.96-3.87 (m, 4H), 3.70-3.60
    (m, 1H), 3.50-3.38 (m, 4H), 3.20-3.08 (m, 1H), 2.96-2.71 (m,
    2H), 1.30 (t, J = 6.6 Hz, 3H).
    1086 577.9 3.73 ****
    1087 591.9 3.78 ****
    1088 605.9 3.87 ****
    1089 577.9 3.75 **
    1090 591.9 3.80 **
    1091 605.9 3.85 **
    1092 595.9 2.45 ****
    1093 610.0 2.47 ****
    1094 624.0 2.48 ****
    1095 596.0 2.47 **
    1096 610.0 2.47 **
    1097 624.0 2.50 ***
    1098 594.57 2.47 ****
    1099 564.52 2.45 ****
    1100 484.3 1H NMR (CD3CN, 300 MHz) δ9.08 (b, 1H), 7.51 (d, J = 1.8 Hz, 10-80 ****
    (cal. 483.2) 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 7.09 (dd, 3.77
    J = 8.4 Hz and 1.8 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 6.41 (s, 1H),
    4.28-4.21 (m, 1H), 4.00 (t, J = 6.9 Hz, 2H), 3.70 (s, 3H), 3.59 (t,
    J = 4.8 Hz, 2H), 3.17-3.12 (m, 1H), 2.81-2.75 (m, 2H), 2.43 (t,
    J = 7.2 Hz, 2H), 2.38-2.32 (m, 4H), 1.90-1.87 (m, 2H)
    1101 497.3 1H NMR (CD3CN, 300 MHz) δ9.07 (b, 1H), 7.51 (d, J = 1.5 Hz, 10-80 ***
    (cal. 496.2) 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 7.08 (dd, 3.52
    J = 8.7 Hz and 2.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.34 (s, 1H),
    4.23-4.20 (m, 1H), 3.98 (t, J = 6.3 Hz, 2H), 3.70 (s, 3H), 3.15-
    3.11 (m, 1H), 2.81-2.76 (m, 2H), 2.44-2.35 (m, 8H), 2.17 (s,
    3H), 1.86-1.81 (m, 2H)
    1102 512.2 1H NMR (CD3CN, 400 MHz) δ9.11 (s, 1H), 7.51 (d, J = 2.1 Hz, 10-80 *****
    (cal. 511.2) 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 7.08 (dd, 4.28
    J = 8.7 Hz and 2.1 Hz, 1H), 6.86 (dd, J = 8.7 Hz and 2.1 Hz, 1H),
    6.36 (s, 1H), 4.95-4.87 (m, 1H), 4.32-4.25 (m, 1H), 4.00 (t,
    J = 6.0 Hz, 2H), 3.59 (t, J = 4.8 Hz, 3H), 3.18-3.06 (m, 1H), 2.83-
    2.73 (m, 2H), 2.45-2.35 (m, 6H), 1.90-1.82 (m, 2H), 1.25 (d,
    J = 6.0 Hz, 6H)
    1103 525.3 1H NMR (DMSO, 300 MHz) δ11.10 (b, 1H), 7.46 (d, J = 1.8 Hz, 30-90 ****
    (cal. 524.3) 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.08-7.00 (m, 3H), 6.86 (d, 2.41
    J = 8.7 Hz, 2H), 6.28-6.22 (m, 1H), 4.84-4.80 (m, 1H), 4.15-4.09
    (m, 1H), 3.92 (t, J = 6.3 Hz, 2H), 3.05-2.96 (m, 1H), 2.72-2.69
    (m, 2H), 2.38-2.20 (m, 10H), 2.11 (s, 3H), 1.81-1.76 (m, 2H),
    1.19 (d, J = 5.4 Hz, 6H)
    1104 539.3 1H NMR (CD3CN, 300 MHz) δ9.13 (b, 1H), 7.51 (d, J = 1.8 Hz, 10-80 ****
    (cal. 538.3) 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.08 (dd, 3.94
    J = 8.4 Hz and 2.1 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.35 (s, 1H),
    4.30-4.25 (m, 1H), 3.97 (t, J = 6.3 Hz, 2H), 3.91-3.86 (m, 4H),
    3.19-3.08 (m, 1H), 2.80-2.77 (m, 2H), 2.43-2.33 (m, 10H),
    2.15 (s, 3H), 1.93-1.82 (m, 2H), 0.93 (d, J = 6.9 Hz, 6H)
    1105 512.2 1H NMR (CD3CN, 300 MHz) δ9.10 (b, 1H), 7.51 (s 1H), 7.28 10-80 *****
    (cal. 511.2) (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.08 (dd, J = 8.7 Hz 4.32
    and 1.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.38 (s, 1H), 4.30-4.24
    (m, 1H), 4.07-3.98 (m, 4H), 3.59 (t, J = 4.8 Hz, 4H), 3.19-3.09
    (m, 1H), 2.80-2.77 (m, 2H), 2.46-2.38 (m, 6H), 1.88-1.65 (m,
    2H), 0.94 (t, J = 4.5 Hz, 3H)
    1106 560.3 1H NMR (DMSO, 300 MHz) δ11.10 (b, 1H), 7.47 (d, J = 2.1 Hz, 10-80 *****
    (cal. 559.2) 1H), 7.35-7.31 (m, 5H), 7.25 (d, J = 8.4 Hz, 1H), 7.06-7.01 (m, 4.62
    3H), 6.84 (d, J = 7.2 Hz, 2H), 6.32 (s, 1H), 5.14-5.07 (m, 2H),
    4.21-4.12 (m, 1H), 3.93 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 4.8 Hz,
    2H), 3.08-3.00 (m, 1H), 2.74-2.68 (m, 2H), 2.49-2.35 (m, 6H),
    2.04-1.82 (m, 2H)
    1107 542.2 1H NMR (DMSO, 300 MHz) δ11.09 (b, 1H), 8.11 (d, J = 0.6 Hz, 10-80 *****
    (cal. 541.2) 1H), 7.68 (d, J = 0.6 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.35-7.29 5.82
    (m, 5H), 7.25 (d, J = 8.7 Hz, 1H), 7.08-7.01 (m, 3H), 6.84 (d,
    J = 8.1 Hz, 2H), 6.31 (s, 1H), 5.19-5.08 (m, 2H), 4.50 (t,
    J = 6.9 Hz, 2H), 4.19-4.16 (m, 1H), 3.89 (t, J = 6.0 Hz, 2H), 3.07-
    3.00 (m, 1H), 2.79-2.71 (m, 2H), 2.26-2.22 (m, 2H)
    1108 589.4 1H NMR (CD3CN, 300 MHz) δ9.14 (b, 1H), 7.55 (d, J = 1.8 Hz, 10-80 ****
    (cal. 588.3) 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.24-7.20 (m, 2H), 7.11 (dd, 3.97
    J = 8.7 Hz and 2.1 Hz, 1H), 7.04-7.00 (m, 2H), 6.93-6.87 (m,
    3H), 6.47 (s, 1H), 4.38 4.36 (m, 1H), 4.00 (t, J = 6.3 Hz, 2H),
    3.78 (s, 3H), 3.27-3.24 (m, 1H), 2.89-2.84 (m, 2H), 2.42 (t,
    J = 7.2 Hz, 2H), 2.37-2.22 (m, 8H), 2.16 (s, 3H), 1.93-1.87 (m,
    2H)
    1109 459.1 1H NMR (DMSO, 300 MHz) δ11.09 (s, 1H), 7.48 (d, J = 2.1 Hz, 10-80 *****
    (cal. 458.2) 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.07-7.01 (m, 3H), 6.86 (d, 4.55
    J = 8.7 Hz, 2H), 6.32-6.28 (m, 1H), 4.25-4.13 (m, 1H), 3.96 (t,
    J = 6.6 Hz, 2H), 3.51-3.47 (m, 4H), 3.30 (s, 3H), 3.05-2.96 (m,
    1H), 2.73-2.68 (m, 2H), 1.81-1.77 (m, 2H)
    1110 M − 1: 493.1  1H NMR (DMSO, 300 MHz) δ11.16 (b, 1H), 7.52 (s, 1H), 7.27 10-80 *****
    (cal. 494.1) (d, J = 8.4 Hz, 1H), 7.23-7.17 (m, 6H), 7.04 (dd, J = 8.4 Hz and 5.48
    2.1 Hz, 1H), 6.90 (d, J = 7.8 Hz, 2H), 6.43-6.35 (m, 1H), 4.30-
    4.28 (m, 1H), 3.98 (t, J = 6.3 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H),
    3.17-3.12 (m, 1H), 2.83-2.69 (m, 2H), 1.84-1.76 (m, 2H)
    1111 509.1 1H NMR (CD4CN 300 MHz) δ 9.12 (s, 1H), 7.56 (d, J = 1.8 Hz, 30-90 *****
    (cal. 510.1) 1H), 7.38 (dd, J = 6.6 Hz and 2.1 Hz 2H), 7.31-7.24 (m, 3H), 7.16- 4.84
    7.09 (m, 3H), 6.91 (d, J = 8.7 Hz, 2H), 6.47 (b, 1H), 4.38 (b, 1H),
    4.05 (t, J = 6.3 Hz, 2H), 3.65 (t, J = 6.3 Hz, 2H), 3.30 (b, 1H), 2.90
    (b, 2H), 1.86 (b, 2H)
    1112 511.3 1H NMR (CD3CN, 300 MHz) δ9.14 (b, 1H), 7.52 (d, J = 2.1 Hz, 10-80 *
    (cal. 510.2) 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.09 (dd, 3.54
    J = 8.7 Hz and 2.1 Hz, 1H), 6.87-6.84 (m, 2H), 6.78 (d, J = 2.1 Hz,
    1H), 6.37 (s, 1H), 4.31-4.25 (m, 1H), 4.19-4.11 (m, 2H), 3.98-
    3.93 (m, 2H), 3.17-3.11 (m, 1H), 2.82-2.78 (m, 2H), 2.49-2.39
    (m, 8H), 2.18-2.15 (m, 5H), 1.89-1.81 (m, 2H), 1.26 (t,
    J = 7.2 Hz, 3H)
    1113 577.4 1H NMR (CDCl3, 300 MHz) δ8.26-8.02 (m, 1H), 7.53 (s, 1H), 10-80 **
    (cal. 576.2) 7.25-7.05 (m, 5H), 6.97-6.86 (m, 4H), 6.47 (s, 1H), 4.56-4.48 34.06 
    (m, 1H), 3.93-3.91 (m, 2H), 3.40-3.30 (m, 1H), 3.07-2.90 (m,
    2H), 2.50-2.47 (m, 8H), 2.30-2.18 (m, 5H), 1.92-1.90 (m, 2H)
    1114 498.3 1H NMR (CD3CN, 300 MHz) δ9.12 (b, 1H), 7.52 (d, J = 2.1 Hz, 10-80 ****
    (cal. 497.2) 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.09 (dd, 4.10
    J = 8.7 Hz and 2.1 Hz, 1H), 6.88-6.83 (m, 2H), 6.79 (d, J = 1.8 Hz,
    1H), 6.39 (s, 1H), 4.32-4.29 (m, 1H), 4.18-4.13 (m, 2H), 3.99-
    3.95 (m, 2H), 3.58 (t, J = 4.8 Hz, 2H), 3.20-3.10 (m, 1H), 2.80-
    2.78 (m, 2H), 2.43-2.33 (m, 6H), 1.90-1.83 (m, 2H), 1.26 (t,
    J = 7.2 Hz, 3H)
    1115 564.3 1H NMR (CD3CN, 300 MHz) δ9.17 (b, 1H), 7.56 (d, J = 1.8 Hz, 10-80 ****
    (cal. 563.2) 1H), 7.33-7.26 (m, 2H), 7.13-7.10 (m, 5H), 6.91-6.84 (m, 3H), 4.61
    6.47 (s, 1H), 4.42-4.39 (m, 1H), 4.00-3.95 (m, 2H), 3.57 (t,
    J = 4.8 Hz, 2H), 3.37-3.27 (m, 1H), 2.90-2.85 (m, 2H), 2.42-2.34
    (m, 6H), 1.88-1.80 (m, 2H)
    1116 514.3 1H NMR (CD3CN, 300 MHz) δ9.14 (b, 1H), 7.52 (d, J = 2.1 Hz, 10-80 ****
    (cal. 513.2) 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.09 (dd, 4.25
    J = 8.7 Hz and 2.1 Hz, 1H), 6.86-6.83 (m, 2H), 6.78 (d, J = 2.1 Hz,
    1H), 6.38 (s, 1H), 4.33-4.28 (m, 1H), 4.20-4.14 (m, 2H), 3.95-
    3.92 (m, 2H), 3.20-3.11 (m, 1H), 2.80-2.78 (m, 2H), 2.63-2.57
    (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.86-1.81 (m, 2H), 1.26 (t,
    J = 7.2 Hz, 3H)
    1117 580.3 1H NMR (CD3CN, 300 MHz) δ9.20 (b, 1H), 7.56 (d, J = 2.4 Hz, 10-80 ****
    (cal. 579.2) 1H), 7.33-7.29 (m, 2H), 7.14-7.11 (m, 5H), 6.90-6.84 (m, 3H), 4.79
    6.47 (s, 1H), 4.43-4.40 (m, 1H), 3.99-3.94 (m, 2H), 3.38-3.27
    (m, 1H), 3.02-2.87 (m, 2H), 2.65-2.60 (m, 8H), 2.47 (t,
    J = 7.2 Hz, 2H), 1.88-1.81 (m, 2H)
    1118 544.3 1H NMR (CD3CN, 300 MHz) δ9.21 (b, 1H), 7.51 (s, 1H), 7.29 10-80 **
    (cal. 543.2) (d, J = 8.7 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.08 (dd, J = 8.7 Hz 4.34
    and 1.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 2H), 6.78 (s, 1H), 6.38 (s,
    1H), 4.32-4.27 (m, 1H), 4.15-4.13 (m, 2H), 4.02-3.99 (m, 2H),
    3.40 (t, J = 6.0 Hz, 4H), 3.21-3.11 (m, 5H), 2.82-2.63 (m, 7H),
    1.83-1.70 (m, 4H), 1.25 (t, J = 6.9 Hz, 3H)
    1119 610.3 1H NMR (CD3CN, 300 MHz) δ9.19 (b, 1H), 7.56 (d, J = 1.8 Hz, 10-80 ***
      (cal. 609.2.2) 1H), 7.33-7.29 (m, 2H), 7.14-7.10 (m, 5H), 6.91-6.85 (m, 3H), 4.85
    6.48 (s, 1H), 4.42-4.39 (m, 1H), 3.96 (t, J = 6.3 Hz, 2H), 3.33 (t,
    J = 6.0 Hz, 4H), 3.30-3.28 (m, 2H), 3.18 (s, 6H), 2.99-2.88 (m,
    2H), 2.60 (t, J = 6.0 Hz, 6H), 1.83-1.79 (m, 2H)
    1120 500.3 1H NMR (CD3CN, 300 MHz) δ9.13 (b, 1H), 7.52 (d, J = 2.1 Hz, 10-80 **
    (cal. 499.2) 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.09 (dd, 4.19
    J = 8.7 Hz and 2.1 Hz, 1H), 6.87-6.84 (m, 2H), 6.78 (s, 1H), 6.39
    (s, 1H), 4.32-4.28 (m, 1H), 4.18-4.12 (m, 2H), 3.97-3.93 (m,
    2H), 3.37 (t, J = 6.0 Hz, 2H), 3.20 (s, 3H), 3.18-3.10 (m, 1H),
    2.82-2.74 (m, 2H), 2.50-2.44 (m, 4H), 2.18 (s, 3H), 1.87-1.78
    (m, 2H), 1.26 (t, J = 6.9 Hz, 3H)
    1121 566.3 1H NMR (CD3CN, 300 MHz) δ9.21 (b, 1H), 7.56 (d, J = 1.5 Hz, 10-80 *
    (cal. 465.2) 1H), 7.33-7.26 (m, 2H), 7.13-7.11 (m, 5H), 6.90-6.85 (m, 3H), 4.74
    6.48 (s, 1H), 4.47-4.45 (m, 1H), 4.00-3.97 (m, 2H), 3.41-3.37
    (m, 2H), 3.20 (s, 3H), 2.91-2.90 (m, 1H), 2.53-2.51 (m, 4H),
    2.22 (s, 3H), 1.85-1.79 (m, 4H)
    1122 479.2 1H NMR (CD3CN, 300 MHz) δ9.29 (b, 1H), 7.52 (s, 1H), 7.38 10-80 *
    (cal. 478.2) (s, 1H), 7.32-7.22 (m, 2H), 7.09 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.18
    7.00 (s, 1H), 6.88-6.85 (m, 3H), 6.77 (s, 1H), 6.34 (s, 1H),
    4.32-4.28 (m, 1H), 4.15-4.09 (m, 4H), 3.89-3.85 (m, 2H),
    3.19-3.12 (m, 1H), 2.81-2.79 (m, 2H), 1.72-1.69 (m, 2H), 1.25
    (t, J = 7.2 Hz, 3H)
    1123 545.2 1H NMR (CD3CN, 300 MHz) δ 9.34 (b, 1H), 7.55 (d, J = 2.1 Hz, 10-80 ***
    (cal. 544.2) 1H), 7.50 (s, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 7.5 Hz, 4.65
    1H), 7.12-7.09 (m, 5H), 7.02 (s, 1H), 6.91-6.84 (m, 4H), 6.45
    (s, 1H), 4.42-4.40 (m, 1H), 4.13 (t, J = 6.6 Hz, 2H), 3.88-3.82
    (m, 2H), 3.36-3.30 (m, 1H), 2.92-2.85 (m, 2H), 1.86-1.84 (m,
    2H)
    1124 480.1 1H NMR (CD3CN, 300 MHz) δ 9.13 (b, 1H), 7.73 (s, 1H), 7.59 10-80 **
    (cal. 479.2) (s, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.24 (d, 5.30
    J = 8.7 Hz, 1H), 7.10 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.88-6.84
    (m, 3H), 6.77 (d, J = 1.8 Hz, 1H), 6.37 (s, 1H), 4.53 (t, J = 6.9 Hz,
    2H), 4.33-4.27 (m, 1H), 4.16-4.13 (m, 2H), 3.92-3.90 (m, 2H),
    3.19-3.11 (m, 1H), 2.81-2.78 (m, 2H), 2.30-2.26 (m, 2H), 1.25
    (t, J = 7.2 Hz, 3H)
    1125 546.1 1H NMR (CD3CN, 300 MHz) δ 9.22 (b, 1H), 7.73 (s, 1H), 7.59 10-80 **
    (cal. 545.2) (s, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.34-7.27 (m, 2H), 7.14-7.10 5.84
    (m, 5H), 6.89-6.83 (m, 3H), 6.48 (s, 1H), 4.53 (t, J = 6.9 Hz,
    2H), 4.43-4.40 (m, 1H), 3.95-3.90 (m, 2H), 3.37-3.29 (m, 1H),
    2.94-2.89 (m, 2H), 2.30-2.24 (m, 2H)
    1126 530.8 1H NMR (CDCl3, 300 MHz), δ 7.89 (d, 1H), 7.54 (s, 1H), 7.33 4.3  **
    (d, 2H), 7.34 (d, 2H), 7.27 (d, 2H), 7.18 (m, 2H), 7.05 (d, 2H),
    6.90 (d, 2H), 6.47 (s, 1H), 4.44 (d, 1H), 4.10 (t, 2H), 3.74 (t,
    2H), 3.00-2.83 (m, 2H), 2.23 (m, 2H)
    1127 562.24 4.20 ***
    1128 530.8 4.32 *****
    1129 562.26 1H NMR (CDCl3, 300 MHz), δ 7.89 (d, 1H), 7.59 (s, 1H), 7.53 4.13 *****
    (s, 1H), 7.34 (d, 2H), 7.26 (d, 2H), 7.20 (m, 1H), 7.06 (d, 2H),
    6.82 (d, 2H), 6.46 (s, 1H), 4.66 (t, 2H), 4.36 (dd, 1H), 3.97 (t,
    2H), 3.32 (m, 1H), 3.00 (m, 1H), 2.85 (m, 2H), 2.43 (m, 2H)
    1130 C32H34ClN3O5, 1H NMR (DMSO-d6, 400 MHz), 11.18(brs, 1H, Ar—NH);  4.668 ****
    (576.3) 7.57(s, 1H, Ar—H); 7.34(d, 1H, Ar—H); 7.25(s, 1H, Ar—H); 7.18(d,
    2H, 2Ar—H); 7.11-7.08(dd, 1H, Ar—H); 6.96(d, 2H, 2Ar—H);
    6.65(brs, 1H, Ar—H); 6.35(brs, 1H, CH); 4.35(s, 1H, CH);
    3.98(t, 2H, CH2); 3.70(s, 3H, —OCH3); 3.56(t, 4H, 2CH2);
    2.90(brs, 2H, CH2); 3.39(t, 6H, 3CH2); 1.86(m, 2H, CH2)
    1131 C33H36ClN3O6,  4.646 ****
    (606.0)
    1132 C33H36ClN3O5, 1H NMR (CD3OD; 400 MHz); 7.51(d, 1H, Ar—H); 7.27(d, 1H,  4.826 ****
    (590.5) Ar—H); 7.22(d, 2H, 2Ar—H); 7.10-7.07(dd, 1H, Ar—H); 7.02-
    6.99(dd, 3H, 3Ar—H); 6.90(brs, 1H, Ar—H); 6.75(brs, 1H, Ar—H);
    6.5(brs, 1H, CH); 4.40(brs, 1H, CH); 4.07(t, 2H, CH2); 3.74(t,
    7H, 2CH2 and —OCH3); 3.4(s, 1H, CH); 3.1(s, 1H, CH); 2.8(s,
    1H, CH); 2.73-2.65(m, 5H, 2CH2 and CH); 2.35(s, 3H, CH3);
    2.27(t, 1H, CH); 2.04(d, 2H, CH2);
    1133 C32H33ClFN3O5,  4.662 *****
    (594.0)
    1134 558.1 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18-2.36 (m, 2 H) 3.68
    2.86 (br. s., 2 H) 3.09-3.26 (m, 1 H) 3.73 (s, 3 H) 3.94 (t,
    J = 6.04 Hz, 2 H) 4.30 (br. s., 1 H) 4.57 (t, J = 6.84 Hz, 2 H) 6.38
    (br. s., 1 H) 6.91 (d, J = 8.90 Hz, 4 H) 7.01-7.10 (m, 3 H) 7.15
    (br. s., 2 H) 7.30 (d, J = 8.58 Hz, 1 H) 7.54 (d, J = 2.23 Hz, 1 H)
    7.84 (br. s., 2 H) 11.15 (br. s., 1 H)
    1135 C30H28ClN5O2,  4.701 ****
    (526.2)
    1136 C31H31Cl2N3O3,  4.747 ***
    (564.0)
    1137 C27H25Cl2N5O2,  4.857 ****
    (546.0)
    1138 C29H25ClFN5O2,  4.471 ****
    (530.0)
    1139 C29H26ClN5O2,  4.433 ****
    (512.0)
    1140 C31H32ClN3O3, 4.29 ***
    (530.0)
    1141 C28H32ClN3O3,  3.900 ***
    (494.0)
    1142 C26H26ClN5O2, 1H NMR (CD3OD, 400 MHz), 8.4(s, 1H, Ar—H); 7.9(s, 1H, Ar—H);  3.888 ****
    (476) 7.4(d, 1H, Ar—H); 7.35(d, 1H, Ar—H); 7.25(d, 1H, Ar—H); 7.07(d,
    1H, Ar—H); 6.87-6.85(1, 3H, 2Ar—H and CH); 4.45(m, 2H, CH2);
    3.9(t, 2H, CH2); 3.32(brs, 1H, CH); 3.3(brs, 2H, CH2); 2.33(t,
    2H, CH2); 2.32(brs, H, CH); 1.1(brs, H, CH); 0.89(d, 3H,
    CH3);
    1143 C26H28ClN5O4,  4.300 ****
    (510)
    1144 C30H28ClN5O4,  4.711 ***
    (558.5)
    1145 C30H28ClN5O4, 5.05 ****
    (558.5)
    1146 C31H30ClN5O5,  5.006 ****
    (588.5)
    1147 C30H27ClFN5O4,  4.734 ****
    (576)
    1148 C30H27ClFN5O4,  5.063 ****
    (576)
    149 C28H28ClN5O4,  4.787 ****
    (510.5)
    1150 C30H28ClN5O4,  4.664 ****
    (558.5)
    1151 C31H30ClN5O5,  4.616 ***
    (588.5)
    1152 C31H30ClN5O4,  4.891 ****
    (572.5)
    1153 C32H34ClN3O4,  4.232 ***
    (560.5)
    1154 C31H31ClFN3O3,  4.397 ***
    (548)
    1155 546.3 1H NMR (CD3CN, 300 MHz) δ9.28 (b, 1H), 8.10 (s, 1H), 7.81 10-80 ***
    (cal. 545.2) (s, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.12-7.10 5.54
    (m, 5H), 6.87-6.84 (m, 3H), 6.46 (s, 1H), 4.42-4.38 (m, 1H),
    4.30 (t, J = 6.9 Hz, 2H), 3.93-3.26 (m, 2H), 3.31-3.26 (m, 1H),
    2.88-2.76 (m, 2H), 2.27-2.23 (m, 2H)
    1156 453.12 3.55 ****
    1157 453.17 3.27 **
    1158 453.14 3.17 *
    1159 493 1H NMR (300 MHz, (CD3)2CO, slight broadening due to 4.22 *****
    rotomers) δ 1.27 (t, J = 6.9 Hz, 3H), 2.90-3.10 (m, 2H), 3.28-
    3.42 (m, 2H), 4.43 (bm, 1H), 4.52-4.60 (m, 2H), 5.20-5.28 (m,
    1H), 5.34-5.45 (m, 1H), 6.00-6.13 (m, 1H), 6.52 (bm, 1H),
    6.90-7.00 (bd, J = 8.8 Hz, 2H), 7.08-7.14 (m,, 1H), 7.20-7.44
    (m, 7H), 7.56 (mc, 1H), 10.22 (s, 1H).
    1160 453 1H NMR (300 MHz, (CD3)2CO, slight broadening due to 3.73 *****
    rotomers) δ 2.90-3.00 (m, 1H), 3.30-3.40 (m, 2H), 3.28-3.42
    (m, 2H), 4.42 (bm, 1H), 6.50 (bm, 1H), 6.90 (d, J = 8.4 Hz,
    2H), 7.09-7.24 (m, 5H), 7.26-7.41 (m, 3H), 7.56 (dc, J = 2.4 Hz,
    1H), 8.48 (s, 1H), 10.20 (s, 1H).
    1161 492 3.65 *****
    1162 579.17 (ES−) 4.28 *****
    1163 497.23 (ES−) 3.93 *****
    1164 513.28 4.12 *****
    1165 527.27 4.28 *****
    1166 523.09 3.88 *****
    1167 541.33 4.43 *****
    1168 547.27 4.18 *****
    1169 565.24 4.17 *****
    1170 561.28 4.37 *****
    1171 577.28 4.13 *****
    1172 539.20 (ES−) 3.58 *****
    1173 459.18 3.10 *****
    1174 473.18 3.28 ****
    1175 487.24 3.45 ****
    1176 500.21 3.20 *****
    1177 501.23 3.58 *****
    1178 507.19 3.37 *****
    1179 525.25 3.38 *****
    1180 521.23 3.52 *****
    1181 537.20 3.35 *****
    1182 542.27 3.70 *****
    1183 556.26 2.45 *****
    1184 600.38 2.43 *****
    1185 508.26 3.77 *****
    1186 508.26 4.03 *****
    1187 508.32 3.42 *****
    1188 508.26 3.42 *****
    1189 475.2 1H NMR (CDCl3, 300 MHz), δ 7.85 (br, 1H), 7.50 (d, 1H), 7.26- 4.23 *****
    7.10 (m, 4H), 6.82(d, 2H), 6.39 (br, 1H), 4.25(br, 1H), 4.09 (t,
    2H), 3.73 (t, 2H), 3.09 (m, 1H), 2.85 (m, 2H), 2.22 (m, 2H),
    1.50 (s, 9H)
    1190 C32H34ClN3O3,  4.562 ***
    (544.1)
    1191 C30H28ClN5O3,  4.385 ***
    (542.5)
    1192 C26H28ClN3O3,  4.248 ****
    (478)
    1193  4.082 ***
    1194  5.237 *****
    1195  5.192 ****
    1196  5.373 ****
    1197  5.156 ****
    1198  4.952 ****
    1199  5.407 ****
    1200 3.63 *****
    1201 3.55 *****
    1202 3.95 *****
    1203 1H NMR δ 7.98 (s, 1 H), 7.53 (s, 1 H), 7.33 (d, J = 8.7 Hz, 2 H), 4.40 *****
    7.25 (d, J = 9.3 Hz, 2 H), 7.15 (s, 2 H), 7.05 (d, J = 9.0 Hz, 2 H),
    6.83 (d, J = 7.2, 2 H). 6.46 (s 1 H), 4.45 (dd, J = 13.5, 4.2 Hz, 1
    H), 4.28 (m, J = 6.3 Hz, 1 H), 4.06 (m, 3 H), 3.63 (dd, J = 9.0,
    7.2 Hz, 1 H), 3.32 (m, 1 H), 3.00 (m, 1 H), 2.85 (dd, J = 15.3,
    3.3 Hz, 1 H), 2.03 (q, J = 5.1 Hz, 2 H), 1.41 (s, 3 H), 1.35 (s, 3
    H)
    1204 3.13
    1205 539.29 (ES−) 1H-NMR (300 MHz, CDCl3): 8.20 (s, 1H), 7.52 (s, 1H), 7.33 3.58 *****
    (d, J = 9.0 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2 H), 1.72 (S, 2 H), 7.05
    (d, J = 8.7, 2 H), 6.82 (d, J = 7.2 Hz, 2 H), 6.43 (s, 1 H), 4.44
    (dd, J = 14.1, 3.9 Hz, 1 H), 4.10 (m, 2 H), 3.97 (m, 1 H), 3.69
    (d, J = 9.6, 1 H), 3.51 (dd, J = 11.1, 7.2 Hz, 1 H), 3.30 (m, 1 H),
    2.99 (m, 1 H), 2.84 (dd, J = 15.6, 3.6 Hz, 1 H), 2.16 (s, 1 H),
    1.90 (q, J = 5.7 Hz, 2 H)
    1206 499.28 3.97 *****
    1207 581.24 4.35 *****
    1208 459.18 3.12 ****
    1209 539.26 (ES−) 3.67 *****
    1210 428 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.27 (t, J = 6.4 Hz, 3H), 3.12 ****
    2.78-2.86 (m, 2H), 3.11-3.17 (m, 1H), 4.17 (q, J = 6.9 Hz, 1H),
    4.30 (bs, 1H), 4.44 (s, 2H), 6.45 (bs, 1H), 6.71 (bs, 1H), 6.96
    (dm, J = 8.7 Hz, 2H), 7.09 (dd, J = 2.4 Hz, 1H), 7.18 (m, 1H),
    7.24 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.52 (d, J =
    2.1 Hz, 1H), 10.19 (bs, 1H).
    1211 446 2.98 ****
    1212 452 3.20 ****
    1213 510 3.45 ***
    1214 554, 556 3.60 ****
    1215 494 3.37 ****
    1216 506 3.37 ****
    1217 411 1H NMR (300 MHz, (CD3)2CO) δ 1.27 (t, J = 6.9 Hz, 3H), 3.93 *****
    2.82-2.85 (m, 2H), 3.15 (dt, J = 14, 7.8 Hz, 2H), 4.16 (q, J = 6.9
    Hz, 2H), 4.23-4.40 (m, 1H), 4.55-4.57 (m, 2H), 5.21-5.26 (m,
    1H), 5.36-5.43 (m, 1H), 5.99-6.12 (m, 1H), 6.44 (bm, 1H), 6.91
    (d, J = 8.8 Hz, 2H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.19 (d, J =
    8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H),
    10.16 (s, 1H).
    1218 371 1H NMR (300 MHz, (CD3)2CO) δ 1.27 (t, J = 6.9 Hz, 3H), 3.32 ****
    2.81-2.87 (m, 2H), 3.11-3.21 (m, 2H), 4.16 (q, J = 6.9 Hz, 2H),
    4.20-4.40 (m, 1H), 6.41 (bm, 1H), 6.78 (dm, J = 8.8 Hz, 2H),
    7.07-7.12 (m, 3H), 7.34 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 1.9 Hz,
    1H), 8.41 (s, 1H), 10.13 (s, 1H).
    1219 399 1H NMR (300 MHz, (CD3)2CO) δ 1.42 (s, 9H), 2.77-2.85 (m, 3.65 ***
    2H), 3.06-3.156 (m, 1H), 4.25 (bm, 1H), 6.38 (bm, 1H), 6.79 (d,
    J = 8.8 Hz, 2H), 7.06-7.10 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H),
    7.51 (d, J = 1.9 Hz, 1H), 8.40 (s, 1H), 10.11 (s, 1H).
    1220 383 1H NMR (300 MHz, DMSO-d6,) δ 1.50-1.62 (m, 2H), 1.92-1.98 1.93 ***
    (m, 2H), 2.93-3.12 (m, 2H), 3.32-3.51 (m, 4H), 3.83 (dt, J =
    11.7, 4.2 Hz, 2H), 4.61 (septet, 1H), 5.86 (s, 1H), 7.04-7.11 (m,
    3H), 7.26-7.30 (m, 3H), 7.59 (d, J = 1.8 Hz, 1H), 9.50 (bs, 1H),
    10.17 (bs, 1H,), 11.07(s, 1H).
    1221 3.13 1H NMR (300 MHz, DMSO-d6) □ ppm 1.22 (br. s., 3 H) 2.65- 445.2   *****
    2.84 (m, 2 H) 2.93-3.10 (m, 1 H) 3.40 (t, J = 5.53 Hz, 2 H) 3.68-
    3.86 (m, 2 H) 3.94 (dd, J = 9.39, 3.69 Hz, 1 H) 4.02-4.26 (m, 3
    H) 4.64 (t, J = 5.53 Hz, 1 H) 4.92 (d, J = 4.70 Hz, 1 H) 6.30 (br. s.,
    1 H) 6.90 (d, J = 8.72 Hz, 2 H) 7.00-7.17 (m, 3 H) 7.28 (d,
    J = 8.72 Hz, 1H) 7.49 (d, J = 1.68 Hz, 1 H) 11.10 (br. S., 1 H)
    1222 3.13 1H NMR (300 MHz, DMSO-d6) □ ppm 1.22 (d, J = 2.68 Hz, 3 445.2   *****
    H) 2.62-2.85 (m, 2 H) 2.89-3.10 (m, 1 H) 3.40 (t, J = 5.53 Hz,
    2 H) 3.67-3.86 (m, 2 H) 3.88-4.00 (m, 1 H) 4.01-4.28 (m, 3
    H) 4.64 (t, J = 5.53 Hz, 1 H) 4.92 (d, J = 5.03 Hz, 1 H) 6.31 (br. s.,
    1 H) 6.90 (d, J = 8.72 Hz, 2 H) 7.01-7.16 (m, 3 H) 7.28 (d,
    J = 8.38 Hz, 1 H) 7.49 (d, J = 1.68 Hz, 1 H) 11.10 (br. s., 1 H)
    1223 527.2 1H NMR (300 MHz, DMSO-d6) □ ppm 2.87 (br. s., 2 H) 3.10- 3.52 *****
    3.26 (m, 1 H) 3.41 (t, J = 5.53 Hz, 2 H) 3.68-3.89 (m, 2 H) 3.91-
    4.03 (m, 1 H) 4.17-4.40 (m, 1 H) 4.65 (t, J = 5.70 Hz, 1 H)
    4.93 (d, J = 5.03 Hz, 1 H) 6.31-6.54 (m, 1 H) 6.93 (d, J = 8.05
    Hz, 2 H) 7.07 (dd, J = 8.55, 1.84 Hz, 1 H) 7.10-7.26 (m, 4 H)
    7.30 (d, J = 8.72 Hz, 1 H) 7.44 (d, J = 8.72 Hz, 2 H) 7.54 (d,
    J = 1.68 Hz, 1 H) 11.02-11.24 (m, 1 H)
    1224 527.0 3.53 *****
    1225 597.9 1H NMR (CD3CN, 300 MHz) δ 9.19 (b, 1H), 7.54 (d, J = 1.8 Hz, 30-90 ****
    (cal: 597.1) 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.30-7.27 (m, 3H), 7.13-7.05 (m, 4.69
    4H), 6.90 (d, J = 8.7 Hz, 2H), 6.46 (b, 1H), 4.39 (b, 1H), 3.98-
    3.86 (m, 3H), 3.81 (s, 2H), 3.46-3.42 (m, 1H), 3.35 (s, 3H),
    3.33-3.26 (m, 2H), 2.88-2.82 (m, 2H).
    1226 485.3 3.83 *****
    1227 565.2 (M − H) 4.18 *****
    1228 567.2 (M − H) 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (t, J = 6.93 Hz, 6 H) 4.37 *****
    2.87 (br. s., 2 H) 3.10-3.27 (m, 1 H) 3.45-3.73 (m, 4 H) 3.92
    (d, J = 5.28 Hz, 2 H) 4.18-4.40 (m, 1 H) 4.78 (t, J = 5.28 Hz, 1
    H) 6.32-6.50 (m, 1 H) 6.96 (d, J = 8.25 Hz, 2 H) 7.07 (dd,
    J = 8.58, 1.98 Hz, 1 H) 7.14 (d, J = 7.92 Hz, 1 H) 7.17-7.25 (m, 3
    H) 7.30 (d, J = 8.58 Hz, 1 H) 7.44 (d, J = 8.91 Hz, 2 H) 7.54 (d,
    J = 1.98 Hz, 1 H) 11.05-11.22 (m, 1 H)
    1229 595.39 4.47 *****
    1230 555.24 3.73 *****
    1231 528 3.48 ****
    1232 C23H20ClFN2O3,  5.221 ***
    (427.5)
    1233 C29H38ClN3O3, 5.107, ****
    (512.5) Chiral
    8.111
    1234 C33H37Cl2N3O3, 5.135, *****
    (594.00) Chiral
    9.655
    1235 C32H33Cl2N3O3,  4.785 ****
    (578.0)
    1236 C28H34ClN3O3, 10.832, ****
    (497.0) Chiral
    10.954
    1237 417.23 (CDCl3, 300 MHz), δ 8.34 (d, 2H), 7.80 (s, 1H), 7.51 (d, 1H), 4.07 *****
    7.32 (d, 2H), 7.20 (d, 1H), 7.10 (d, 1H), 6.84 (dd, 2H), 6.50 (t,
    1H), 6.02 (m, 1H), 5.42-5.24 (m, 2H), 4.96 (dd, 1H), 4.50 (d,
    2H), 3.35-3.25 (m, 1H), 2.98-2.91 (m, 1H), 2.82-2.76 (dd, 1H)
    1238 475.17 4.27 *****
    1239 508.26 3.7  *****
    1240 508.23 3.98 *****
    1241 377.23 3.43 ****
    1242 505.25 4.05 *****
    1243 465.21 3.22 ****
    1244 505.25 4.03 *****
    1245 433.2 3.75 ****
    1246 433.2 3.73 ****
    1247 372.14 3.23 **
    1249 520.3 1H NMR (CDCl3, 300 MHz), δ 8.34 (d, 2H), 7.88 (s, 1H), 7.51 2.15 *****
    (d, 1H), 7.32 (d, 2H), 7.20 (d, 2H), 7.10 (d, 1H), 6.83 (d, 2H),
    6.50 (t, 1H), 4.96 (dd, 1H), 4.07 (m, 1H), 3.94 (d, 2H), 3.72 (m,
    4H), 3.29 (m, 1H), 2.96(m, 2H), 2.80 (dd, 1H), 2.69-2.41 (m, 6H)
    1250 511.07 3.93 *****
    1251 429.06 3.48 *****
    1252 443.31 3.57 *****
    1253 495 4.10 *****
    1254 520.36 1H NMR (CDCl3, 300 MHz), δ 8.34 (d, 2H), 7.88 (s, 1H), 7.51 2.18 *****
    (d, 1H), 7.32 (d, 2H), 7.20 (d, 2H), 7.10 (d, 1H), 6.83 (d, 2H),
    6.50 (t, 1H), 4.96 (dd, 1H), 4.07 (m, 1H), 3.94 (d, 2H), 3.72 (m,
    4H), 3.29 (m, 1H), 2.96(m, 2H), 2.80 (dd, 1H), 2.69-2.41 (m, 6H)
    1255 614.35 2.35 ***
    1256 435.21 3.52 *****
    1257 554.26 2.42 ****
    1258 600.14 2.43 *****
    1259 527.2 3.50 ****
    1260 565.2 (M − H) 4.18 *****
    1261 485.3 3.85 *****
    1262 451.21 1H NMR (CDCl3, 300 MHz), δ 8.10 (br, 1H), 7.50 (d, 1H), 7.19- 4.35 *****
    7.09 (m, 4H), 6.84 (d, 2H), 6.37 (br, 1H), 6.02 (m, 1H), 5.42-
    5.24 (m, 2H), 5.17 (m, 1H), 4.49 (d, 2H), 4.24 (br, 1H), 3.12
    (m, 1H), 2.91-2.72 (m, 2H), 1.76 (m, 8H)
    1263 583.00 3.85 *****
    1264 C26H30ClN3O3, 1HNMR, CD3OD, 400 MHz,  4.584 ****
    (468.0) 7.47(d, 1H, 1Ar—H); 7.25-7.18(dd, 3H, 3Ar—H); 7.07-7.05(dd,
    1H, 1Ar—H); 6.90(d, 2H, 2Ar—H); 6.42(brs, 1H, CH); 4.30(brm,
    3H, 1CH2 and 1CH); 4.00(t, 2H, CH2); 3.30(brm, 1H, CH);
    2.86(t, 5H, CH3 and CH2); 2.20(brm, 1H, CH); 1.98(t, 2H,
    CH2); 1., 33(d, 2H, CH2); 0.50(t, 2H, CH2); 0.38(t, 2H, CH2);
    1265 C25H19ClF2N2O2,  5.478 ****
    (469.0)
    1266 C26H22ClFN2O3, 1HNMR, DMSO-D6 400 MHz,  5.667 *****
    (465.0) 11.09(brs, 1H, Ar—N—H); 7.54(d, 1H, 1Ar—H); 7.30(dd, 1H, 1 Ar—H);
    7.17-7.08(dd, 2H, 2 Ar—H); 7.06(dd, 1H, 1Ar—H); 6.97-
    6.75(brm, 4H, 4Ar—H); 6.73-6.70(brm, 2H, 1Ar—H and 1CH);
    4.29-4.26(brm, 1H, CH); 3.75(s, 3H, O—CH3); 3.22-3.'9(m, 1H,
    CH); 2.85(m, 2H, CH2); 2.27(s, 3H, Ar—CH3);
    1267 C26H22ClFN2O4  5.426 ****
    (481.0)
    1268 C21H20ClFN2O3,  5.224 *****
    (403)
    1269 C25H19Cl2N2FO3,  5.723 *****
    (485.0)
    1270 M + 23: 522.1 1H NMR (DMSO, 300 MHz), δ11.13 (b, 1H), 7.91 (s, 1H), 7.48 30-90 ****
    (cal. 499.2) (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.10-7.03 (m, 3H), 6.88 (d, 3.69
    J = 8.7 Hz, 2H), 6.29 (s, 1H), 4.86 (d, J = 5.4 Hz, 1H), 4.20-4.05
    (m, 3H), 4.00 (t, J = 6.3 Hz, 2H), 3.69-3.62 (m, 1H), 3.10-2.94
    (m, 3H), 2.74-2.69 (m, 2H), 1.84-1.75 (m, 4), 1.64-1.55 (m,
    1H), 1.22-1.20 (m, 3H).
    1271 M + 23: 552.1 1H NMR (DMSO, 300 MHz), δ11.15 (b, 1H), 7.67 (s, 1H), 7.48 10-80 ****
    (cal. 529.2) (s 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.10-7.02 (m, 3H), 6.87 (d, 5.39
    J = 8.4 Hz, 2H), 6.29 (s, 1H), 4.93 (d, J = 5.4 Hz, 1H), 4.10-4.00
    (m, 5H), 3.78-3.76 (m, 2H), 3.64-3.62 (m, 1H), 3.26 (s, 3H),
    3.19-3.11 (m, 1H), 3.09-2.99 (m, 2H), 2.86-2.73 (m, 2H), 1.90-
    1.73 (m, 1H), 1.69-1.59 (m, 1H), 1.22-1.20 (m, 3H).
    1272 528.2 1H NMR (CD3CN, 300 MHz), δ9.21 (b, 1H), 7.50 (d, J = 1.8 Hz, 30-90 *****
    (cal. 527.2) 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.06 (dd, 3.11
    J = 8.7 Hz and 1.8 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 6.34 (s, 1H),
    4.28-4.20 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 4.09-4.02 (m, 2H),
    3.86-3.81 (m, 1H), 3.59 (t, J = 4.8 Hz, 4H), 3.35-3.34 (m, 1H),
    3.13-3.03 (m, 1H), 2.77-2.71 (m, 2H), 2.54-2.48 (m, 2H), 2.30-
    2.27 (m, 4H), 1.90-1.81 (m, 1H), 1.73-1.69 (m, 1H), 1.24 (t,
    J = 7.2 Hz, 3H).
    1273 546.1 1H NMR (DMSO, 300 MHz), δ11.18 (b, 1H), 7.48 (s, 1H), 7.28 30-90 ****
    (cal. 545.2) (d, J = 8.4 Hz, 1H), 7.10-7.02 (m, 3H), 6.89 (d, J = 8.7 Hz, 2H), 2.98
    6.29 (s, 1H), 4.52-4.51 (m, 1H), 4.44-4.42 (m, 2H), 4.11-4.09
    (m, 3H), 4.02 (t, J = 6.6 Hz, 2H), 3.65-3.63 (m, 1H), 3.41-3.39
    (m, 4H), 3.04-2.99 (m, 1H), 2.72-2.71 (m, 2H), 2.54-2.53 (m,
    4H), 2.42-2.36 (m, 2H), 1.90-1.81 (m, 1H), 1.63-1.59 (m, 1H),
    1.22-1.21 (m, 3H).
    1274 510.1 1H NMR (DMSO, 300 MHz), δ11.16 (b, 1H), 8.04 (s, 1H), 7.68 30-90 *****
    (cal. 509.2) (s, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.11-7.03 3.97
    (m, 3H), 6.89 (d, J = 8.7 Hz, 2H), 6.30 (s, 1H), 5.26 (d, J = 5.7 Hz,
    1H), 4.50-4.44 (m, 1H), 4.34-4.30 (m, 1H), 4.15-4.00 (m, 6H),
    3.05-2.98 (m, 1H), 2.77-2.74 (m, 2H), 2.65-5.50 (m, 2H), 1.85-
    1.80 (m, 1H), 1.66-1.60 (m, 1H), 1.21-1.15 (m, 3H).
    1275 510.1 1H NMR (CD3CN, 300 MHz), δ9.19 (b, 1H), 7.64 (d, J = 1.8 Hz, 30-90 *****
    (cal. 509.2) 2H), 7.51 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.17 (d, 4.36
    J = 8.4 Hz, 2H), 7.08 (dd, J = 8.4 Hz and 2.1 Hz, 1H), 6.85 (d,
    J = 8.7 Hz, 2H), 6.37 (s, 1H), 4.46-4.42 (m, 2H), 4.32-4.21 (m,
    2H), 4.15-4.03 (m, 4H), 3.15-3.09 (m, 1H), 2.81-2.77 (m, 2H),
    2.65-5.50 (m, 2H), 1.92-1.85 (m, 1H), 1.83-1.71 (m, 1H), 1.25
    (t, J = 7.2 Hz, 3H).
    1276 M + 23: 604.2 1H NMR (CD3CN, 300 MHz), δ9.20 (b, 1H), 7.55 (d, J = 1.8 Hz, 30-90 *****
    (cal. 581.1) 1H), 7.39-7.36 (m, 2H), 7.30-7.22 (m, 3H), 7.15-7.09 (m, 3H), 4.47
    6.89 (d, J = 8.7 Hz, 2H), 6.57 (b, 1H), 6.46 (s, 1H), 4.41-4.33 (m,
    1H), 4.07 (t, J = 6.3 Hz, 2H), 3.81-3.76 (m, 1H), 3.56-3.49 (m,
    1H), 3.30-3.21 (m, 2H), 3.13-3.07 (m, 1H), 2.99-2.81 (m, 2H),
    1.84 (s, 3H), 1.76-1.69 (m, 2H).
    1277 M + 23: 646.2 1H NMR (CD3CN, 300 MHz), δ9.21 (b, 1H), 7.55 (d, J = 1.8 Hz, 30-90 *****
    (cal. 623.2) 1H), 7.40-7.37 (m, 2H), 7.31-7.22 (m, 3H), 7.15-7.09 (m, 3H), 4.83
    6.87 (d, J = 8.7 Hz, 2H), 6.52 (b, 1H), 6.46 (s, 1H), 5.05-5.04 (m,
    1H), 4.41-4.33 (m, 1H), 4.03-3.99 (m, 2H), 3.52-3.51 (m, 1H),
    3.45-3.38 (m, 1H), 3.31-3.21 (m, 2H), 2.99-2.83 (m, 2H), 2.11-
    2.10 (m, 1H), 1.99 (s, 3H), 1.83 (s, 3H).
    1278 M + 23: 634.2 1H NMR (CD3CN, 400 MHz), δ9.20 (b, 1H), 7.55 (d, J = 2.0 Hz, 30-90 *****
    (cal. 611.2) 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.31-7.23 (m, 3H), 7.14-7.10 (m, 4.60
    3H), 7.03 (b, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.45 (s, 1H), 4.41-
    4.33 (m, 1H), 4.08 (t, J = 6.4 Hz, 2H), 3.83-3.80 (m, 3H), 3.51-
    3.49 (m, 1H), 3.37 (s, 3H), 3.32-3.24 (m, 2H), 3.13-3.07 (m,
    1H), 2.99-2.81 (m, 2H), 1.90-1.82 (m, 1H), 1.76-1.69 (m, 1H).
    1279 610.2 1H NMR (CD3CN, 300 MHz), δ9.16 (b, 1H), 7.54 (d, J = 1.8 Hz, 10-80 *****
    (cal. 609.2) 1H), 7.39-7.36 (m, 2H), 7.30-7.21 (m, 3H), 7.14-7.08 (m, 3H), 5.28
    6.89 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 4.41-4.38 (m, 1H), 3.88-
    3.85 (m, 1H), 3.61 (t, J = 4.8 Hz, 4H), 3.30-3.28 (m, 2H), 2.98-
    2.82 (m, 2H), 2.59-2.51 (m, 2H), 2.38-2.29 (m, 4H), 1.90-1.81
    (m, 1H), 1.73-1.69 (m, 1H).
    1280 628.2 1H NMR (CD3CN, 300 MHz), δ9.19 (b, 1H), 7.55 (d, J = 2.1 Hz, 10-80 ****
    (cal. 627.2) 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.31-7.25 (m, 3H), 7.14-7.09 (m, 5.22
    3H), 6.91 (d, J = 8.7 Hz, 2H), 6.47 (s, 1H), 4.41-4.39 (m, 1H),
    4.10 (t, J = 6.0 Hz, 2H), 3.81-3.76 (m, 1H), 3.57-3.48 (m, 7H),
    3.33-3.27 (m, 2H), 2.98-2.82 (m, 3H), 2.77-2.72 (m, 3H), 2.58-
    2.56 (m, 2H), 2.47-2.44 (m, 2H), 1.90-1.81 (m, 1H), 1.73-1.69
    (m, 1H).
    1281 M + 23: 614.1 1H NMR (CD3CN, 300 MHz), δ9.20 (b, 1H), 7.80 (d, J = 0.9 Hz, 30-90 *****
    (cal. 591.1) 1H), 7.63 (d, J = 0.9 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.39-7.36 4.65
    (m, 2H), 7.31-7.23 (m, 3H), 7.13-7.08 (m, 3H), 6.90 (d,
    J = 8.7 Hz, 2H), 6.46 (s, 1H), 4.52-4.46 (m, 1H), 4.38-4.31 (m,
    2H), 4.21-4.15 (m, 1H), 4.12-4.08 (m, 2H), 3.45-3.22 (m, 2H),
    3.02-2.84 (m, 2H), 1.92-1.89 (m, 1H), 1.79-1.71 (m, 1H).
    1282 592.0 1H NMR (CD3CN, 300 MHz), δ9.22 (b, 1H), 8.17 (s, 1H), 7.85 10-80 *****
    (cal. 591.1) (s, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.30-7.24 5.90
    (m, 3H), 7.13-7.09 (m, 3H), 6.90 (d, J = 8.7 Hz, 2H), 6.46 (s, 1H),
    4.42-4.40 (m, 1H), 4.27-4.24 (m, 1H), 4.15-4.08 (m, 4H), 3.45
    (d, J = 4.8 Hz, 1H), 3.32-3.28 (m, 1H), 2.88-2.87 (m, 2H), 1.92-
    1.89 (m, 1H), 1.79-1.71 (m, 1H).
    1283 471.99 (ES−) 3.28 *****
    1284 513.28 4.10 *****
    1285 469.22 3.82 *****
    1286 411.24 3.7  ***
    1287 510.1 1H NMR (DMSO, 300 MHz), δ11.09 (b, 1H), 8.40 (s, 1H), 7.95 30-90 ****
    (cal. 509.2) (s, 1H), 7.49 (d, J = 2.1 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.10 (d, 3.77
    J = 8.7 Hz, 2H), 7.04 (dd, J = 8.4 Hz and 2.1 Hz, 1H), 6.89 (d,
    J = 8.7 Hz, 2H), 6.29 (s, 1H), 5.13 (d, J = 5.4 Hz, 1H), 4.24-4.01
    (m, 8H), 3.05-2.97 (m, 1H), 2.76-2.69 (m, 2H), 1.90-1.81 (m,
    1H), 1.71-1.63 (m, 1H), 1.21-1.18 (m, 3H).
    1288 608.2 1H NMR (CD3CN, 300 MHz), δ9.15 (b, 1H), 7.55 (d, J = 1.8 Hz, 10-80 ****
    (cal. 607.2) 1H), 7.31-7.15 (m, 5H), 7.10 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.99 4.51
    (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.48 (s, 1H), 4.42-4.39
    (m, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.82-3.73 (m, 1H), 3.60-3.45
    (m, 5H), 3.35-2.80 (m, 5H), 2.74-2.42 (m, 7H), 2.33 (s, 3H),
    1.71-1.69 (m, 1H).
    1289 M + 23: 594.2 1H NMR (DMSO, 400 MHz), δ 11.13-11.10 (m, 1H), 8.02 (s, 30-90 *****
    (cal. 571.2) 1H), 7.68 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.80
    7.17-7.15 (m, 4H), 7.06 (dd, J = 8.4 Hz and 2.0 Hz, 1H), 7.00 (d,
    J = 8.4 Hz, 2H), 6.93-6.91 (m, 2H), 6.42-6.37 (m, 1H), 5.20 (d,
    J = 5.6 Hz, 1H), 4.49-4.41 (m, 1H), 4.34-4.28 (m, 2H), 4.06-4.03
    (m, 3H), 3.17-3.12 (m, 1H), 2.89-2.81 (m, 2H), 2.27 (s, 3H),
    1.90-1.80 (m, 1H), 1.70-1.61 (m, 1H).
    1290 M + 23: 594.2 1H NMR (DMSO, 400 MHz), δ 11.17-11.10 (m, 1H), 7.74 (s, 30-90 *****
    (cal. 571.2) 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.17-7.15 5.18
    (m, 4H), 7.06 (dd, J = 8.4 Hz and 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz,
    2H), 6.91 (d, J = 7.6 Hz, 2H), 6.42-6.37 (m, 1H), 5.09 (d,
    J = 6.4 Hz, 1H), 4.39 (d, J = 6.4 Hz, 2H), 4.23-4.19 (m, 1H), 4.14-
    4.10 (m, 1H), 4.04 (t, J = 6.0 Hz, 2H), 3.19-3.11 (m, 1H), 2.89-
    2.81 (m, 2H), 2.27 (s, 3H), 1.90-1.80 (m, 1H), 1.70-1.61 (m, 1H).
    1291 M + 23: 594.2 1H NMR (DMSO, 400 MHz), δ 11.13-11.10 (m, 1H), 8.40 (s, 30-90 ****
    (cal. 571.2) 1H), 7.92 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.88
    7.17-7.15 (m, 4H), 7.06 (dd, J = 8.4 Hz and 2.0 Hz, 1H), 7.00 (d,
    J = 8.0 Hz, 2H), 6.93-6.91 (m, 2H), 6.42-6.37 (m, 1H), 5.14 (d,
    J = 6.0 Hz, 1H), 4.30-4.27 (m, 1H), 4.23-4.19 (m, 1H), 4.14-4.10
    (m, 1H), 4.09-4.06 (m, 2H), 4.03-4.01 (m, 1H), 3.17-3.12 (m,
    1H), 2.89-2.81 (m, 2H), 2.27 (s, 3H), 1.90-1.80 (m, 1H), 1.70-
    1.61 (m, 1H).
    1292 M − 1: 519.2  1H NMR (DMSO, 300 MHz), δ 11.15 (b, 1H), 7.53 (d, J = 2.1 Hz, 10-80 *****
    (cal. 520.2) 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.19-7.16 (m, 4H), 7.07 (dd, 5.53
    J = 8.7 Hz and 2.1 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.93 (d,
    J = 8.1 Hz, 2H), 6.41 (s, 1H), 4.36-4.25 (m, 1H), 4.04 (t, J = 6.3 Hz,
    2H), 3.31-3.26 (m, 2H), 3.20-3.15 (m, 1H), 2.91-2.80 (m, 2H),
    2.27 (s, 3H), 1.94-1.87 (m, 1H), 1.63-1.54 (m, 1H).
    1293 M − 1: 523.2  1H NMR (DMSO, 300 MHz), δ 11.15-11.13 (m, 1H), 7.53 (d, 10-80 *****
    (cal. 524.2) J = 1.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.21-7.19 (m, 6H), 7.07 5.34
    (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.41-6.37
    (m, 1H), 4.35-4.26 (m, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.61-3.57
    (m, 2H), 3.33-3.28 (m, 2H), 3.20-3.15 (m, 1H), 2.91-2.80 (m,
    2H), 1.93-1.84 (m, 1H), 1.63-1.54 (m, 1H).
    1294 471 3.98 *****
    1295 473.30 3.27 *****
    1296 487.17 3.42 ****
    1297 535.31 3.67 ****
    1298 425.1 4.02 *****
    1299 M − 1: 505.2  1H NMR (DMSO, 300 MHz), δ 11.15 (b, 1H), 7.54 (d, J = 2.1 Hz, 10-80 *****
    (cal. 506.2) 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.30 (d, J = 8.7 Hz, 1H), 7.29-7.14 (m, 5.28
    5H), 7.07 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H),
    6.41 (s, 1H), 4.36-4.25 (m, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.62-
    3.58 (m, 1H), 3.36-3.23 (m, 3H), 2.91-2.88 (m, 2H), 1.94-1.87
    (m, 1H), 1.63-1.54 (m, 1H).
    1300 M − 1: 535.2  1H NMR (DMSO, 300 MHz), δ 11.13 (b, 1H), 7.53 (d, J = 1.8 Hz, 10-80 *****
    (cal. 536.2) 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.21-7.18 (m, 2H), 7.09-7.04 (m, 4.55
    3H), 6.94-6.90 (m, 4H), 6.40 (s, 1H), 4.35-4.26 (m, 1H), 4.04 (t,
    J = 6.6 Hz, 2H), 3.73 (s, 3H), 3.62-3.59 (m, 1H), 3.32-3.21 (m,
    2H), 3.19-3.11 (m, 1H), 2.89-2.82 (m, 2H), 1.93-1.84 (m, 1H),
    1.63-1.54 (m, 1H).
    1301 M + 23: 6 14.2 1H NMR (CD3CN, 300 MHz), δ 9.19 (b, 1H), 7.55 (d, J = 1.5 Hz, 10-80 ****
    (cal. 591.2) 1H), 7.31-7.17 (m, 5H), 7.11 (dd, J = 8.4 Hz and 2.1 Hz, 1H), 6.99 5.96
    (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 4.42-4.37
    (m, 1H), 4.08 (s, 2H), 3.86-3.84 (m, 3H), 3.14-3.12 (m, 7H),
    2.96-2.85 (m, 2H), 2.34-2.33 (m, 5H).
    1302 590.2 1H NMR (CD3CN, 300 MHz), δ9.10 (s, 1H), 7.49 (d, J = 1.8 Hz, 10-80 ***
    (cal. 589.2) 1H), 7.22-7.17 (m, 3H), 7.12 (d, J = 8.7 Hz, 2H), 7.04 (dd, 5.37
    J = 8.7 Hz and 1.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.84 (d,
    J = 8.7 Hz, 2H), 6.40 (s, 1H), 4.39-4.15 (m, 2H), 4.08-4.06 (m,
    2H), 3.82-3.74 (m, 4H), 3.29-3.00 (m, 6H), 2.91-2.74 (m, 4H),
    2.24-2.21 (m, 4H).
    1303 C29H32ClN5O3, 9.233, *****
    (534.0) Chiral
    15.390
    1304 C30H34ClN5O2, 4.755, *****
    (532) Chiral
    9.709
    1305 C29H34ClN5O2, 4.703, ****
    (520.5) Chiral,
    8.511
    1306 C30H35ClN6O2, 4.080, ****
    (547) Chiral,
    10.043
    1307 C28H30ClN5O3, 4.230, *****
    (520.0) Chiral,
    33.131
    1308 C29H33ClN6O2, 7.074, *****
    (533.0) Chiral,
    26.147
    1309 C28H32ClN5O2, 4.541, ****
    (506.5) Chiral,
    18.909
    1310 C29H32ClN5O2, 4.595, ****
    (518.0) Chiral,
    19.672
    1311 C28H32ClN5O2, 4.559, ***
    (506.0) Chiral,
    18.552
    1312 C29H33ClN6O2, 7.068, ****
    (533.5) Chiral,
    27.053
    1313 C29H32ClN5O2, 4.573, ****
    (518.05) Chiral,
    27.244
    1314 525.07 4.10 *****
    1315 537.37 (ES−) 4.37 *****
    1316 539.39 4.30 *****
    1317 539.08 4.23 *****
    1318 553.09 4.60 *****
    1319 553.12 4.52 *****
    1320 499.41 3.45 *****
    1321 513.11 3.63 *****
    1322 485.3 3.37 *****
    1323 485.4 3.38 *****
    1324 487.4 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79 (t, J = 7.59 Hz, 3 H) 3.42 *****
    1.21 (br. s., 3 H) 1.33 (q, J = 7.59 Hz, 2 H) 2.62-2.84 (m, 2 H)
    2.92-3.13 (m, 1 H) 3.34 (br. s., 3 H) 3.72 (s, 2 H) 4.02-4.22
    (m, 3 H) 4.38 (t, J = 5.11 Hz, 2 H) 6.31 (br. s., 1 H) 6.88 (d,
    J = 8.58 Hz, 2 H) 6.99-7.17 (m, 3 H) 7.27 (d, J = 8.58 Hz, 1 H)
    7.49 (d, J = 1.98 Hz, 1 H) 11.09 (br. s., 1 H)
    1325 501.4 3.55 WLEN
    NOX
    1326 515.4 3.73 *****
    1327 527.4 3.75 *****
    1328 553.4 3.65 *****
    1329 569.3 3.83 *****
    1330 539.28 (ES−) 3.60 *
    1331 581.25 4.50 *
    1332 451.27 (ES−) 3.75 *
    1333 499.40 3.90 *
    1334 412.9 1H NMR (DMSO, 300 MHz), δ 11.21-11.18 (m, 1H), 7.54 (d, 10-80 ***
    (cal. 412.2) J = 2.1 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.13-7.06 (m, 3H), 6.93 4.59
    (dd, J = 8.7 Hz and 2.1 Hz, 2H), 6.62 (s, 1H), 4.35-4.28 (m, 2H),
    3.72 (s, 3H), 3.62-3.60 (m, 1H), 3.48-3.38 (m, 1H), 2.90-2.80
    (m, 2H), 1.29-1.24 (m, 3H).
    1335 M − 1: 573.0 1H NMR (CD3CN, 300 MHz), δ 9.13 (b, 1H), 7.56 (d, J = 2.1 Hz, 30-90 ****
    (cal. 538.2) 1H), 7.31-7.24 (m, 3H), 7.14-7.09 (m, 5H), 6.92 (d, J = 8.4 Hz, 4.82
    2H), 6.47 (s, 1H), 4.41-4.36 (m, 1H), 3.85 (s, 2H), 3.50 (d,
    J = 8.1 Hz, 4H), 3.33-3.28 (m, 1H), 2.91-2.84 (m, 4H), 0.91 (s, 3H).
    1336 M − 1: 519.1 1H NMR (CDCl3, 400 MHz), δ 8.58-8.26 (m, 1H), 7.51 (s, 1H), 10-80 ****
    (cal. 520.2) 7.37 (t, J = 8.0 Hz, 2H), 7.23-7.20 (m, 3H), 7.11-7.02 (m, 4H), 5.76
    6.82-6.80 (m, 2H), 6.39 (s, 1H), 4.46-4.41 (m, 1H), 3.91-3.84
    (m, 2H), 3.69-3.60 (m, 4H), 3.31-3.25 (m, 1H), 3.02-2.98 (m,
    1H), 2.84-2.54 (m, 3H), 0.94 (s, 3H).
    1337 M − 1: 549.2 1H NMR (CD3CN, 300 MHz), δ 9.13 (b, 1H), 7.55 (d, J = 2.1 Hz, 30-90 ****
    (cal. 550.2) 1H), 7.31-7.23 (m, 3H), 7.11 (dd, J = 8.1 Hz and 2.1 Hz, 1H), 4.33
    7.03-7.00 (m, 2H), 6.93-6.89 (m, 4H), 6.47 (s, 1H), 4.41-4.36
    (m, 1H), 3.85 (s, 2H), 3.78 (s, 3H), 3.50 (d, J = 3.6 Hz, 4H), 3.31-
    3.28 (m, 1H), 2.91-2.84 (m, 4H), 0.91 (s, 3H).
    1338 426.8 1H NMR (DMSO, 400 MHz), δ 11.21-11.18 (m, 1H), 7.55 (s, 10-80 ****
    (cal. 426.1) 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.12-7.07 (m, 3H), 6.93 (d, 5.58
    J = 8.8 Hz, 2H), 6.61-5.90 (m, 1H), 3.72 (s, 3H), 3.62-3.60 (m,
    1H), 3.45-3.38 (m, 1H), 2.90-2.80 (m, 2H), 1.30-1.24 (m, 6H).
    1339 426.8 1H NMR (DMSO, 400 MHz), δ 11.21-11.10 (m, 1H), 7.55 (s, 10-80 ****
    (cal. 426.1) 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.08 (dd, 5.63
    J = 8.4 Hz and 1.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.62-5.92 (m,
    1H), 4.25-4.21 (m, 2H), 3.72 (s, 3H), 3.65-3.63 (m, 1H), 2.92-
    2.76 (m, 2H), 1.69-1.64 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H).
    1340 489.5 3.25 ****
    1341 503.1 3.38 ****
    1342 517.1 3.58 *****
    1343 555.1 3.53 *****
    1344 571.0 3.70 *****
    1345 503.0 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (br. s., 3 H) 1.46- 3.32 *****
    1.67 (m, 1 H) 1.76-1.98 (m, 1 H) 2.60-2.85 (m, 2 H) 2.91-
    3.10 (m, 1 H) 3.18-3.44 (m, 3 H) 3.49-3.66 (m, 1 H) 4.02 (t,
    J = 6.54 Hz, 2 H) 4.05-4.25 (m, 3 H) 4.55 (br. s., 1 H) 6.30 (br.
    s., 1 H) 6.89 (d, J = 8.72 Hz, 2 H) 7.09 (d, J = 8.72 Hz, 2 H) 7.12-
    7.20 (m, 1 H) 7.24 (d, J = 8.72 Hz, 1 H) 7.63 (d, J = 1.68 Hz, 1 H)
    11.11(br. s., 1H)
    1346 517.1 3.45 *****
    1347 531.1 3.65 *****
    1348 569.1 3.60 *****
    1349 585.0 3.77 *****
    1350 531.1 3.62 *****
    1351 545.1 3.80 *****
    1352 583.1 3.72 *****
    1353 599.0 3.88 *****
    1354 531.0 3.62 *****
    1355 545.1 3.77 *****
    1356 559.2 3.87 *****
    1357 597.2 3.77 *****
    1358 613.2 3.93 *****
    1359 M − 1: 499.2  1H NMR (CD3CN, 300 MHz), δ 9.09 (b, 1H), 7.51 (d, J = 1.8 Hz, 10-80 ****
    (cal. 500.2) 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 7.08 (dd, 4.37
    J = 8.4 Hz and 1.8 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.36 (s, 1H),
    4.78 (d, J = 6.0 Hz, 1H), 4.73 (d, J = 6.0 Hz, 1H), 4.29-4.21 (m,
    1H), 4.19-4.11 (m, 2H), 3.98 (s, 2H), 3.84 (d, J = 11.4 Hz, 2H),
    3.75 (d, J = 11.7 Hz, 2H), 3.56 (d, J = 5.4 Hz, 2H), 3.16-3.06 (m,
    1H), 2.85 (t, J = 5.7 Hz, 1H), 2.78-2.76 (m, 2H), 1.26 (t, J = 6.9 Hz, 3H).
    1360 M − 1: 513.2  1H NMR (CD3CN, 300 MHz), δ 9.09 (b, 1H), 7.51 (d, J = 1.8 Hz, 10-80 ****
    (cal. 514.2) 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 7.08 (dd, 5.44
    J = 8.7 Hz and 2.1 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.37 (s, 1H),
    4.92-4.88 (m, 1H), 4.79 (d, J = 5.7 Hz, 1H), 4.73 (d, J = 6.0 Hz,
    1H), 4.19-4.11 (m, 1H), 3.98 (s, 2H), 3.84 (d, J = 11.4 Hz, 2H),
    3.75 (d, J = 10.8 Hz, 2H), 3.56 (d, J = 5.4 Hz, 2H), 3.13-3.06 (m,
    1H), 2.85 (t, J = 5.7 Hz, 1H), 2.78-2.76 (m, 2H), 1.24 (d, J = 6.3 Hz, 6H).
    1361 M − 1: 535.2  1H NMR (CD3CN, 400 MHz), δ 9.19 (b, 1H), 7.54 (d, J = 1.6 Hz, 10-80 ****
    (cal. 536.2) 1H), 7.28-7.22 (m, 3H), 7.10 (dd, J = 8.8 Hz and 2.0 Hz, 1H), 5.42
    7.03-7.00 (m, 2H), 6.91-6.88 (m, 4H), 6.47 (s, 1H), 4.41-4.36
    (m, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.77 (s, 3H), 3.76-3.75 (m, 1H),
    3.51-3.46 (m, 1H), 3.41-3.32 (m, 1H), 3.28-3.22 (m, 1H), 3.11-
    3.02 (m, 1H), 2.91-2.84 (m, 3H), 1.90-1.81 (m, 1H), 1.74-1.69
    (m, 1H).
    1362 622.57 2.53 *****
    1363 539.2 1H NMR (CD3CN, 300 MHz) δ9.13 (b, 1H), 7.52 (d, J = 1.8 Hz, 10-80 ***
    (cal. 538.2) 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.09 (dd, 3.93
    J = 8.7 Hz and 2.1 Hz, 1H), 6.88-6.83 (m, 2H), 6.79 (d, J = 2.1 Hz,
    1H), 6.37 (s, 1H), 4.33-4.28 (m, 1H), 4.18-4.11 (m, 2H), 3.97
    (t, J = 6.3 Hz, 2H), 3.44 (t, J = 5.1 Hz, 2H), 3.37 (t, J = 5.1 Hz, 2H),
    3.19-3.12 (m, 1H), 2.82-2.78 (m, 2H), 2.42 (t, J = 7.2 Hz, 2H),
    2.35 (t, J = 5.4 Hz, 2H), 2.30 (t, J = 5.1 Hz, 2H), 1.97 (s, 3H),
    1.95-1.82 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H)
    1364 605.3 1H NMR (CD3CN, 300 MHz) δ9.17 (b, 1H), 7.56 (d, J = 2.1 Hz, 10-80 ***
    (cal. 604.2) 1H), 7.33-7.26 (m, 2H), 7.14-7.10 (m, 5H), 6.91-6.84 (m, 3H), 4.41
    6.47 (s, 1H), 4.42-4.40 (m, 1H), 3.98 (t, J = 6.3 Hz, 2H), 3.50-
    3.27 (m, 5H), 2.89-2.89 (m, 2H), 2.45-2.30 (m, 6H), 1.97 (s,
    3H), 1.90-1.87 (m, 2H)
    1365 437.22 3.95 *****
    1366 451.21 4.42 *****
    1367 465.23 3.63 *****
    1368 469.23 3.87 *****
    1369 397.24 3.6  ****
    1370 411.18 3.73 ****
    1371 411.27 3.88 ****
    1372 425.28 4.10 *****
    1373 485.36 3.30 *****
    1374 499.36 3.53 *****
    1375 499.06 3.45 *****
    1376 513.10 3.82 *****
    1377 471.3 3.23 *****
    1378 485.3 3.38 *****
    1379 485.4 3.45 *****
    1380 471.3 3.22 *****
    1381 485.3 3.38 *****
    1382 485.3 1H NMR (300 MHz, DMSO-d6) δ ppm 1.64-1.91 (m, 4 H) 3.45 *****
    1.99 (br. s., 2 H) 2.59 (br. s., 1 H) 2.67-2.86 (m, 2 H) 2.92-
    3.15 (m, 1 H) 3.40 (br. s., 2 H) 3.74 (br. s., 1 H) 3.77-3.87 (m,
    1 H) 3.90-4.04 (m, 2 H) 4.10 (br. s., 2 H) 4.65 (br. s., 1 H) 4.93
    (br. s., 1 H) 6.27 (br. s., 1 H) 6.90 (d, J = 8.58 Hz, 2 H) 7.05 (dd,
    J = 8.58, 1.98 Hz, 1 H) 7.09 (d, J = 8.58 Hz, 2 H) 7.28 (d, J = 8.58
    Hz, 1 H) 7.49 (d, J = 1.98 Hz, 1 H) 11.11 (br. s., 1 H)
    1383 513.4 3.58 *****
    1384 527.4 3.73 *****
    1385 527.4 3.82 *****
    1386 M − 1: 539.2  1H NMR (CD3CN, 300 MHz), δ 9.09 (b, 1H), 7.51 (d, J = 2.1 Hz, 10-80 ****
    (cal. 540.2) 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.08 (dd, 4.97
    J = 8.7 Hz and 2.1 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.37 (s, 1H),
    4.79 (d, J = 6.0 Hz, 1H), 4.73 (d, J = 6.0 Hz, 1H), 4.28-4.23 (m,
    1H), 4.16-4.02 (m, 2H), 3.98 (s, 2H), 3.84 (d, J = 11.7 Hz, 2H),
    3.75 (d, J = 11.7 Hz, 2H), 3.56 (d, J = 5.7 Hz, 2H), 3.18-3.09 (m,
    1H), 2.89-2.74 (m, 3H), 2.65-2.60 (m, 1H), 2.10-2.01 (m, 2H),
    1.89-1.75 (m, 4H).
    1387 484.0 1H NMR (CD3OD, 400 MHz), δ 7.83 (d, J = 8.0 Hz, 2H), 7.47 (d, 30-90 ***
    (cal. 483.2) J = 1.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 4.48
    7.06 (dd, J = 8.4 Hz and 1.6 Hz, 1H), 6.49 (b, 1H), 4.25-4.17 (m,
    5H), 4.08 (s, 2H), 3.17-3.09 (m, 1H), 2.90-2.78 (m, 2H), 1.32
    (s, 3H), 1.27 (t, J = 7.2 Hz, 3H)
    1388 456.0 1H NMR (CD3OD, 300 MHz), δ 7.83 (d, J = 8.4 Hz, 2H), 7.46 (d, 10-80 *
    (cal. 455.1) J = 1.8 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 5.49
    7.06 (dd, J = 8.4 Hz and 2.1 Hz, 1H), 6.49 (b, 1H), 4.35-4.19 (m,
    3H), 4.07 (s, 2H), 3.19-3.11 (m, 1H), 2.91-2.76 (m, 2H), 1.31 (t,
    J = 6.9 Hz, 3H)
    1389 470.0 1H NMR (CD3OD, 300 MHz), δ 7.45 (d, J = 6.0 Hz, 2H), 7.40 (s, 10-80 *
    (cal. 469.1) 1H), 7.36 (t, J = 5.1 Hz, 2H), 7.23 (d, J = 8.7 Hz, 1H), 7.05 (dd, 5.57
    J = 8.7 Hz and 1.5 Hz, 1H), 6.42 (b, 1H), 4.35-4.21 (m, 4H), 4.00
    (s, 1H), 3.18-3.1 (m, 1H), 3.02 (s, 3H), 2.85-2.80 (m, 2H), 1.31
    (s, 3H)
    1390 513.9 1H NMR (CD3OD, 300 MHz), δ 7.62 (s, 1H), 7.45 (d, J = 8.4 Hz, 5.66 *
    1H), 7.38 (d, J = 8.4 Hz, 1H), 7.35 (s, 2H), 7.19 (s, 2H), 6.47 (b,
    1H), 4.37-4.20 (m, 5H), 3.21-3.02 (m, 4H), 2.91-2.88 (s, 2H),
    1.30 (s, 3H)
    1391 563.4 1H NMR (300 MHz, Acetone) □ ppm 2.95 (d, J = 5.09 Hz, 2 H) 2.93 *****
    3.24-3.43 (m, 1 H) 3.82 (t, J = 4.77 Hz, 2 H) 4.29 (t, J = 5.25 Hz,
    2 H) 4.44 (br. s., 1 H) 6.53 (br. s., 1 H) 6.86 (d, J = 4.13 Hz, 1 H)
    6.98 (d, J = 8.58 Hz, 2 H) 7.08-7.43 (m, 9 H) 7.56 (d, J = 1.91
    Hz, 1 H) 10.21 (br. s., 1 H)
    1392 577.4 2.82 *****
    1393 579.4 3.08 *****
    1394 593.3 2.95 *****
    1396 486.9 1H NMR (CD3OD, 300 MHz) δ7.48 (s, 1H), 7.32 (d, J = 8.1 Hz, 10-80 *
    (cal. 486.2) 1H), 7.15-7.12 (m, 3H), 691-6.88 (m, 2H), 6.68 (s, 1H), 4.27- 5.13
    4.20 (m, 3H), 4.09-4.01 (m, 3H), 3.77-3.70 (m, 3H), 3.49-3.37
    (m, 2H), 2.85-2.76 (m, 2H), 1.98-1.93 (m, 2H), 1.43-1.29 (m,
    3H)
    1397 456.2 2.33 ***
    1398 493.3 3.47 ***
    1399 494.4 2.63 *****
    1400 498.4 3.40 *****
    1401 505.4 3.52 ****
    1402 480.4 2.38 **
    1403 522.3 3.48 *****
    1404 547.5 3.22 ***
    1405 523.4 4.00 ***
    1406 524.4 3.10 ***
    1407 526.4 3.72 *****
    1408 533.4 3.78 *****
    1409 508.6 2.53 **
    1410 486.4 2.25 *
    1411 525.4 3.52 **
    1412 528.4 3.20 ****
    1413 546.4 3.23 *****
    1414 560.4 2.83 *****
    1415 564.4 3.65 *****
    1416 589.5 3.40 ***
    1417 562.4 3.42 *****
    1418 576.4 2.95 ****
    1419 577.4 4.05 ****
    1420 580.3 3.83 *****
    1421 587.4 3.88 *****
    1422 605.4 3.55 ****
    1423 M − 1: 417.2  1H NMR (DMSO, 400 MHz) δ11.37 (b, 1H), 7.64 (d, J = 8.4 Hz, 10-80 *
    (cal. 418.2) 1H), 7.59 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 4.90
    6.89 (d, J = 8.4 Hz, 2H), 6.38-6.34 (m, 1H), 4.12-4.09 (m, 3H),
    3.70 (s, 3H), 3.06-3.00 (m, 1H), 2.84-2.75 (m, 2H), 1.20-1.13
    (m, 3H)
    1424 M − 1: 483.2  1H NMR (DMSO, 400 MHz) δ11.42-11.35 (m, 1H), 7.69 (d, 30-90 *
    (cal. 484.1) J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.21-7.16 5.39
    (m, 6H), 6.94-6.93 (m, 2H), 6.52-6.41 (m, 1H), 4.34-4.25 (m,
    1H), 3.72 (s, 3H), 3.29-3.19 (m, 1H), 3.00-2.84 (m, 2H)
    1425 M − 1: 495.2  1H NMR (DMSO, 400 MHz) δ11.43-11.36 (m, 1H), 7.69 (d, 30-90 *
    (cal. 496.2) J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.26-7.15 5.33
    (m, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.92-6.90 (m, 2H), 6.52-6.43
    (m, 1H), 4.32-4.30 (m, 1H), 3.72 (s, 3H), 3.22-3.19 (m, 1H),
    3.00-2.91 (m, 2H)
    1426 *
    1427 443.45 3.98 *
    1428 365.42 3.82 *
    1429 445.36 (ES−) 4.18 *
    1430 389.46 3.83 *
    1431 351.41 3.67 *
    1432 531.31 2.48 ****
    1433 492.9 3.37 *****
    1434 528.9 3.53 *****
    1435 483.8 2.40 **
    1436 521.0 3.73 *****
    1437 523.9 2.43 ****
    1438 534.9 3.30 ***
    1439 552.9 2.90 **
    1440 558.9 3.65 *****
    1441 571.5 3.75 ****
    1442 574.9 3.85 *****
    1443 409 3.80 **
    1444   465 (M − H) 4.07 ***
    1445 489 3.88 ***
    1446 547 4.12 ***
    1447 543 3.97 ***
    1448 483-485 1H NMR (300 MHz, (CD3)2CO-d6) δ 2.86-2.88 (m, 3H), 3.14- 3.72 **
    3.23 (m, 1H), 4.34-4.36 (m, 1H), 4.43-4.46 (m, 1H), 4.62 (bm,
    1H), 4.77 (bm, 1H), 6.50 (bm, 1H), 6.87 (t, J = 74.7 Hz, 1H),
    7.14-7.21 (m, 3H), 7.37 (bd, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4
    Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 10.21 (s, 1H).
    1449 549 4.05 **
    1450 531 3.98 ***
    1451 395-397 2.05
    1452 403 3.62
    1453 451 3.97
    1454 513 4.23
    1455 463 3.95 *
    1456 377 3.78 *
    1457 435 4.12 **
    1458 435 3.82 *
    1459 439 3.98 *
    1460 447 3.78 *
    1461 451 3.97 **
    1462 483 3.80 **
    1463 487 3.98 ***
    1464 500.1 1H NMR (CDCl3, 300 MHz) δ 7.87 (b, 1H), 7.50 (d, J = 1.8 Hz, 10-80 ****
    (cal: 499.2) 1H), 7.23-7.10 (m, 4H), 6.82 (d, J = 8.7 Hz, 2H), 6.42 (b, 1H), 5.09
    5.94 (t, J = 3.3 Hz, 1H), 4.40-4.13 (m, 3H), 4.11-4.02 (m, 1H),
    3.90 (d, J = 5.4 Hz, 2H), 3.65-3.55 (m, 1H), 3.42-3.33 (m, 1H),
    3.20-3.07 (m, 1H), 2.92-2.70 (m, 2H), 2.25 (q, J = 7.5 Hz, 2H),
    1.30 (t, J = 6.9 Hz, 3H), 1.16 (t, J = 7.5 Hz, 3H).
    1465 514.1 1H NMR (CDCl3, 300 MHz) δ 7.89 (b, 1H), 7.50 (d, J = 1.5 Hz, 10-80 ****
    (cal: 513.2) 1H), 7.23-7.10 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 6.40 (b, 1H), 5.24
    5.98 (b, 1H), 4.47-4.18 (m, 3H), 4.13-4.02 (m, 1H), 3.90 (d,
    J = 4.8 Hz, 2H), 3.65-3.55 (m, 1H), 3.45-3.33 (m, 1H), 3.19-3.04
    (m, 1H), 2.92-2.70 (m, 2H), 2.45-2.34 (m, 1H), 1.27 (t,
    J = 3.9 Hz, 3H), 1.18 (d, J = 6.3 Hz, 6H).
    1466 512.1 1H NMR (CDCl3, 300 MHz) δ 7.85 (b, 1H), 7.50 (d, J = 1.2 Hz, 10-80 ****
    (cal: 511.2) 1H), 7.23-7.10 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 6.40 (b, 1H), 5.19
    6.12 (b, 1H), 4.45-4.15 (m, 3H), 4.13-4.05 (m, 1H), 3.90 (d,
    J = 5.4 Hz, 2H), 3.67-3.60 (m, 1H), 3.47-3.35 (m, 1H), 3.19-3.06
    (m, 1H), 2.94-2.70 (m, 2H), 1.45-1.28 (m, 4H), 1.00-0.93 (m,
    2H), 0.80-0.76 (m, 2H).
    1467 549.1 1H NMR (DMSO, 300 MHz) δ 11.06 (b, 1H), 8.73-8.63 (m, 3H), 10-80 *****
    (cal: 548.2) 7.68 (b, 2H), 7.44 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.11-6.93 (m, 4.61
    3H), 6.90-6.76 (m, 2H), 6.25 (b, 1H), 5.21 (s, 1H), 4.20-3.78
    (m, 6H), 3.50-3.40 (m, 2H), 2.95 (b, 1H), 2.69 (b, 2H), 1.16 (b, 3H).
    1468 549.1 1H NMR (DMSO, 300 MHz) δ 11.05 (b, 1H), 8.96 (s, 1H), 8.71- 10-80 *****
    (cal: 548.2) 8.62 (m, 2H), 8.13 (d, J = 7.2 Hz, 1H), 7.46-7.42 (m, 2H), 7.24 (d, 4.65
    J = 8.4 Hz, 1H), 7.08-7.01 (m, 3H), 6.87 (d, J = 5.4 Hz, 2H), 6.28
    (b, 1H), 5.21 (d, J = 4.8 Hz, 1H), 4.08-3.83 (m, 6H), 3.50-3.40
    (m, 1H), 3.05-2.90 (m, 1H), 2.78-2.59 (m, 2H), 1.27-1.13 (m, 3H).
    1469 549.1 1H NMR (CDCl3, 300 MHz) δ 8.55 (d, J = 4.2 Hz, 1H), 8.49 (t, 10-80 *****
    (cal: 548.2) J = 3.9 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.87 (t, J = 6.0 Hz, 1H), 5.42
    7.79 (b, 1H), 7.50-7.45 (m, 2H), 7.23-7.11 (m, 4H), 6.85 (d,
    J = 8.1 Hz, 2H), 6.41 (b, 1H), 4.44-4.12 (m, 4H), 3.99 (d,
    J = 5.4 Hz, 2H), 3.98-3.82 (m, 1H), 3.70-3.59 (m, 1H), 3.21-3.09
    (m, 1H), 2.94-2.72 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H).
    1470 516.1 1H NMR (CDCl3, 300 MHz) δ 7.86 (b, 1H), 7.50 (s, 1H), 7.22- 10-80 *****
    (cal: 515.2) 7.10 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 6.41 (b, 1H), 5.09 (b, 1H), 5.39
    4.40-4.05 (m, 6H), 3.95-3.90 (m, 2H), 3.47-3.34 (m, 1H), 3.39-
    3.28 (m, 1H), 3.20-3.05 (m, 1H), 2.96-2.75 (m, 2H), 1.26-1.78
    (m, 6H).
    1471 530.1 1H NMR (CDCl3, 300 MHz) δ 8.15 (b, 1H), 7.49 (s, 1H), 7.20- 10-80 *****
    (cal: 529.2) 7.10 (m, 4H), 6.78 (d, J = 8.1 Hz, 2H), 6.39 (b, 1H), 5.13 (b, 1H), 5.24
    4.43-4.13 (m, 3H), 4.03-3.99 (m, 3H), 3.90 (b, 2H), 3.52-3.43
    (m, 1H), 3.38-3.23 (m, 1H), 3.19-3.04 (m, 1H), 2.95-2.69 (m,
    2H), 1.66-1.59 (m, 2H), 1.27 (t, J = 6.0 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H).
    1472 546.1 1H NMR (CDCl3, 300 MHz) δ 7.85 (b, 1H), 7.50 (d, J = 1.5 Hz, 10-80 *****
    (cal: 545.2) 1H), 7.23-7.10 (m, 4H), 6.82 (d, J = 8.7 Hz, 2H), 6.42 (b, 1H), 5.20
    5.22 (b, 1H), 4.46-4.11 (m, 6H), 3.99-3.87 (m, 2H), 3.60-3.46
    (m, 3H), 3.39 (s, 3H), 3.37-3.31 (m, 1H), 3.20-3.06 (m, 1H),
    2.93-2.72 (m, 2H), 1.30 (t, J = 6.3 Hz, 3H).
    1473 536.1 1H NMR (CDCl3, 300 MHz) δ 7.85 (b, 1H), 7.50 (s, 1H), 7.23- 10-80 *****
    (cal: 535.2) 7.18 (m, 3H), 7.12 (dd, J = 8.4 Hz and 1.8 Hz, 1H), 6.83 (d, 5.23
    J = 8.4 Hz, 2H), 6.42 (b, 1H), 4.70 (t, J = 6 Hz, 1H), 4.21-4.07 (m,
    4H), 3.99 (s, 2H), 3.45-3.37 (m, 1H), 3.31-3.23 (m, 1H), 3.18-
    3.05 (m, 3H), 2.92-2.85 (m, 1H), 2.79-2.74 (m, 1H), 1.38 (t,
    J = 7.5 Hz, 3H), 1.30 (t, J = 6.3 Hz, 3H).
    1474 550.1 1H NMR (CDCl3, 300 MHz) δ 8.89 (b, 1H), 7.46 (s, 1H), 7.19- 10-80 ****
    (cal: 549.2) 7.05 (m, 4H), 6.73 (d, J = 7.8 Hz, 2H), 6.35 (b, 1H), 5.17 (b, 1H), 4.89
    4.20-4.10 (m, 5H), 3.65-3.35 (m, 3H), 3.10-3.02 (m, 2H), 2.84-
    2.68 (m, 3H), 1.37-1.25 (m, 6H), 1.18-1.16 (m, 3H).
    1475 548.1 1H NMR (CDCl3, 300 MHz) δ 7.83 (b, 1H), 7.50 (s, 1H), 7.23- 10-80 *****
    (cal: 547.2) 7.18 (m, 3H), 7.12 (dd, J = 8.4 Hz and 1.5 Hz, 1H), 8.43 (d, 5.31
    J = 8.1 Hz, 2H), 6.41 (b, 1H), 4.73 (s, 1H), 4.25-4.15 (m, 4H),
    4.00-3.99 (m, 2H), 3.45-3.43 (m, 1H), 3.34-3.30 (m, 1H), 3.18-
    3.08 (m, 1H), 2.92-2.74 (m, 2H), 2.45 (b, 1H), 1.32-1.28 (m,
    3H), 1.19-1.18 (m, 2H), 1.02-1.00 (m, 2H).
    1476 580.56 2.43 ***
    1477 464.14 4.25 ****
    1478 464.14 3.88 ***
    1479 468.09 4.10 ****
    1480 387.92 3.70 ****
    1481 414.37 4.05 ****
    1482 397.28 3.37 ***
    1483 478.70 3.90 ****
    1484 474.69 3.62 ***
    1485 464.82 3.55 ***
    1486 478.00 3.73 ****
    1487 324.94 2.48 *
    1488 413.21 2.43 *
    1489 495.15 3.03 *
    1490 491.20 2.73 *
    1491 479.00 2.08 *
    1492 479.00 2.92 ***
    1493 441.04 2.07 *
    1494 441.05 2.00 *
    1495 341.29 1.47 *
    1496 429.05 2.05 *
    1497 511.01 2.78 *
    1498 507.06 2.42 *
    1499 495.01 2.52 *
    1500 511.01 2.80 *
    1502 457.04 2.50 *
    1503 507.26 2.55 *
    1504 357.02 2.42 *
    1505 502.4 3.43 *
    1506 601.6 2.18 *
    1508 C31H28ClN5O2,  4.070 ****
    (538.5)
    1509 C28H32ClN3O3,  3.903 ***
    (494.5)
    1510 C26H26ClN5O2,  4.067 ****
    (476.5)
    1511 C33H34ClN3O4,  4.539 ****
    (556.5)
    1512 376.35 2.27 **
    1513 458.14 2.87 ***
    1514 442.30 2.62 ***
    1515 458.23 2.83 ***
    1516 454.30 2.53 **
    1517 404.36 2.67 **
    1518 404.36 2.73 ***
    1519 304.19 1.73 *
    1520 492 3.87 *****
    1521 429, 431 1H NMR (300 MHz, (CD3)2CO) δ 1.28 (t, J = 6.9 Hz, 3H), 3.87 **
    3.00-3.20 (m, 2H), 3.16-3.23 (m, 2H), 3.25-3.40 (m, 1H), 3.78
    (s, 3H), 4.16 (q, J = 6.9 Hz, 2H), 4.13-4.33 (m, 1H), 6.41 (bm,
    1H), 6.89 (dm, J = 8.7 Hz, 1H), 6.99 (t, J = 8.6 Hz, 2H), 7.17-
    7.25 (m, 3H), 7.35 (dd, J = 8.6, 2.1 Hz, 1H), 7.53 (d, J = 1.8 Hz,
    1H), 8.60 (J = 4.8 Hz, 2H), 10.28 (s, 1H).
    1522 447, 449 3.65 **
    1523 453, 455 3.87 ***
    1524 495, 497 4.02 ***
    1525 511, 513 4.25 ***
    1526 555, 557 4.33 ***
    1527 507, 509 3.98 **
    1528 511, 513 4.18 *
    1529 403 3.60 **
    1530 409 1H NMR (300 MHz, (CD3)2CO)δ 1.82 (s, 3H), 2.96-3.31 (m, 3.82 ***
    3H), 3.78 (s, 3H), 4.25 (mc, 1H), 4.74 (s, 2H), 6.44 (mc, 1H),
    6.90 (dm, J = 9.0 Hz, 2H), 7.00-7.09 (m, , 2H), 7.23 (bm, J = 9.0
    Hz, 1H), 7.31 (dd, J = 7.2, 1.5 Hz, 1.5 Hz, 1H), 10.28 (s, 1H).
    1531 467 4.18 ***
    1532 511, 513 4.25 ***
    1533 451 3.97 ***
    1534 463 3.95 **
    1535 357 1.83 *
    1536 313 1.80 *
    1537 594.23 2.40 *****
    1538 495.2 3.95 *****
    1539 495.08 3.95 ***
    1540 403.21 2.12 ****
    1541 C29H34ClN3O4,  4.127 ****
    (508.5)
    1542 C27H28ClN5O2,  4.282 *****
    (490.5)
    1543 410 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.28 (t, J = 6.5 Hz, 3H), 3.53 *****
    2.84-2.86 (m, 2H), 3.11-3.18 (m, 1H), 4.17 (q, J = 6.9 Hz, 1H),
    4.30 (bs, 1H), 5.10 (s, 2H), 6.47 (bs, 1H), 7.04-7.12 (m, 3H),
    7.29-7.37 (m, 3H), 7.53 (d, J = 1.8 Hz, 1H), 10.19 (bs, 1H).
    1544 428 3.42 ****
    1545 446 2.98 *****
    1546 492 3.85 ***
    1547 534, 536 3.93 *****
    1548 474 3.75 ****
    1549 488 3.77 ****
    1550 338 1.77 **
    1551 (573, 571) 1H NMR (300 MHz, CD3)2CO) δ 2.22-2.32 (m, 2H), 2.90-3.10 3.83 *****
    (M + +1, M + −1) (m, 5H), 3.26-3.31 (m, 3H), 4.17 (t, J = 6.3 Hz, 2H), 4.43 (mc,
    1H), 6.52 (bm, 1H), 6.95 (d, J = 9.0 Hz, 2H), 7.11 (dd, J = 9.0,
    2.4 Hz, 1H), 7.40-7.58 (m, 4H), 7.37 (d, J = 8.4 Hz, 1H), 7.42
    (dm, J = 9.3 Hz, 2H), 7.56 (d, J = 2.2 Hz, 1H), 10.22 (s, 1H).
    1552 555 4.68 *****
    1553 569 4.88 *****
    1554 608 2.40 *
    1555 624 3.80 *****
    1556 546 2.33 ***
    1557 M − 1: 614.2  1H NMR (CD3CN, 300 MHz) δ 9.17 (s, 1H), 7.54 (d, J = 2.1 Hz, 30-90 **
    (cal: 615.2) 1H), 7.32-7.21 (m, 3H), 7.14-7.10 (m, 5H), 6.92 (d, J = 8.4 Hz, 4.52
    2H), 6.45 (b, 1H), 5.28 (b, 1H), 4.39 (b, 1H), 4.00-3.90 (m, 3H),
    3.33-3.10 (m, 4H), 3.02-2.82 (m, 3H), 1.27 (d, J = 6.9 Hz, 6H).
    1558 M + 23: 604.2 1H NMR (CD3CN, 300 MHz) δ 9.25 (s, 1H), 7.53 (d, J = 1.8 Hz, 30-90 ****
    (cal: 581.2) 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.29-7.23 (m, 3H), 7.12-7.07 (m, 4.57
    3H), 6.87 (d, J = 8.1 Hz, 2H), 6.59 (b, 1H), 6.45 (b, 1H), 4.35 (b,
    1H), 3.90-3.85 (m, 3H), 3.42-3.19 (m, 3H), 2.87-2.82 (m, 2H),
    2.14 (q, J = 7.8 Hz, 2H), 1.03 (t, J = 7.5 Hz, 3H).
    1559 596.1 1H NMR (CD3CN, 300 MHz) δ 9.21 (b, 1H), 7.54 (s, 1H), 7.37 30-90 ****
    (cal: 595.2) (d, J = 8.7 Hz, 2H), 7.30-7.23 (m, 3H), 7.12-7.08 (m, 3H), 6.89 4.88
    (d, J = 8.1 Hz, 2H), 6.58 (b, 1H), 6.46 (b, 1H), 4.38 (b, 1H), 3.90-
    3.86 (m, 3H), 3.38-3.34 (m, 1H), 3.29-3.22 (m, 2H), 2.88-2.84
    (m, 3H), 2.38-2.32 (m, 1H), 1.04 (d, J = 6.9 Hz, 6H).
    1560 M + 23: 616.2 1H NMR (CD3CN, 300 MHz) δ 9.29 (b, 1H), 7.53 (s, 1H), 7.35 30-90 ****
    (cal: 593.2) (d, J = 9.0 Hz, 2H), 7.28-7.21 (m, 3H), 7.11-7.07 (m, 3H), 6.88- 4.82
    6.85 (m, 3H), 6.44 (b, 1H), 4.34 (s, 1H) , 3.90-3.85 (m, 3H),
    3.44-3.36 (m, 1H), 3.28-3.19 (m, 2H), 2.87-2.81 (m, 3H), 1.52-
    1.44 (m, 1H), 0.75-0.67 (m, 4H).
    1561 631.1 1H NMR (CD3CN, 300 MHz) δ 9.23 (b, 1H), 8.92 (s, 1H), 8.67 30-90 ****
    (cal: 630.1) (d, J = 3.3 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.43-7.36 4.15
    (m, 3H), 7.30-7.23 (m, 3H), 7.13-7.08 (m, 3H), 7.91 (d,
    J = 8.4 Hz, 2H), 6.46 (s, 1H), 4.38 (b, 1H), 4.10-4.05 (m, 1H),
    4.00-3.96 (m, 2H), 3.65-3.45 (m, 2H), 3.33-3.22 (m, 1H), 2.88-
    2.84 (m, 3H).
    1562 M − 1: 596.0  1H NMR (CDCl3, 300 MHz) δ 8.16-7.95 (m, 1H), 7.52 (s, 1H), 30-90 ****
    (cal: 597.1) 7.32 (d, J = 8.1 Hz, 2H), 7.26-7.22 (m, 2H), 7.14 (s, 2H), 7.04 (d, 4.98
    J = 8.7 Hz, 2H), 6.82 (d, J = 8.1 Hz, 2H), 6.46 (s, 1H), 5.13 (b, 1H),
    4.45-4.42 (m, 1H), 4.15-4.08 (m, 3H), 3.92-3.90 (m, 2H), 3.51-
    3.46 (m, 1H), 3.33-3.19 (m, 3H), 3.03-2.82 (m, 2H), 1.24 (t,
    J = 6.6 Hz, 3H).
    1563 M − 1: 610.0  1H NMR (CD3CN, 300 MHz) δ 9.12 (b, 1H), 7.55 (s, 1H), 7.37 30-90 ****
    (cal: 611.2) (d, J = 8.4 Hz, 2H), 7.30-7.23 (m, 3H), 7.13-7.08 (m, 3H), 6.92- 5.25
    6.89 (d, J = 8.1 Hz, 2H), 6.46 (b, 1H), 5.61 (b, 1H), 4.40-4.32 (m,
    1H), 3.95-3.91 (m, 5H), 3.32-3.14 (m, 3H), 2.97-2.82 (m, 2H),
    1.56 (q, J = 6.9 Hz, 2H), 0.89 (t, J = 7.5 Hz, 3H).
    1564 M + 23: 650.2 1H NMR (CD3CN, 300 MHz) δ 9.16 (b, 1H), 7.54 (s, 1H), 7.37 30-90 *****
    (cal: 627.2) (d, J = 8.7 Hz, 2H), 7.30-7.27 (m, 3H), 7.13-7.08 (m, 3H), 6.90 4.83
    (d, J = 8.4 Hz, 2H), 6.46 (b, 1H), 5.68 (b, 1H), 4.39 (b, 1H), 4.10
    (t, J = 4.5 Hz, 2H), 3.94-3.87 (m, 3H), 3.50-3.47 (m, 3H), 3.22-
    3.15 (m, 6H), 2.88-2.83 (m, 3H).
    1565 M − 1: 616.1  1H NMR (CD3CN, 300 MHz) δ 9.16 (b, 1H), 7.55 (d, J = 1.5 Hz, 30-90 ****
    (cal: 617.1) 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.31-7.28 (m, 3H), 7.13-7.09 (m, 4.83
    3H), 6.92 (d, J = 8.4 Hz, 2H), 6.47 (b, 1H), 5.35 (b, 1H), 4.36 (b,
    1H), 3.98-3.92 (m, 3H), 3.33-3.12 (m, 3H), 3.02 (q, J = 7.5 Hz,
    2H), 2.88-2.84 (m, 3H), 1.11 (t, J = 7.2 Hz, 3H).
    1566 M − 1: 630.1  1H NMR (CD3CN, 300 Hz) δ 9.15 (b, 1H), 7.55 (d, 30-90 ***
    (cal: 631.1) J = 1.8 Hz, 1H), 7.38 (d, J = 9.0 Hz, 2H), 7.31-7.28 (m, 3H), 7.14- 4.85
    7.09 (m, 3H), 6.92 (d, J = 8.7 Hz, 2H), 6.48 (b, 1H), 5.28 (b, 1H),
    4.40 (b, 1H), 3.98-3.91 (m, 3H), 3.28-3.18 (m, 4H), 3.01-2.88
    (m, 3H), 1.27 (d, J = 6.9 Hz, 6H).
    1567 M + 23: 652.1 1H NMR (CD3CN, 300 MHz) δ 9.17 (b, 1H), 7.55 (s, J = 1.8 Hz, 30-90 ***
    (cal: 629.1) 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.30-7.27 (m, 3H), 7.13-7.08 (m, 4.93
    3H), 6.91 (d, J = 8.7 Hz, 2H), 6.46 (b, 1H), 5.38 (b, 1H), 4.35 (b,
    1H), 3.99-3.92 (m, 3H), 3.33-3.15 (m, 3H), 2.88-2.83 (m, 2H),
    2.51-2.43 (m, 1H), 0.98-0.93 (m, 4H).
    1568 593.2 1H NMR (300 MHz, DMSO-d6) δ ppm 1.94 (d, J = 1.32 Hz, 3 2.43 ****
    H) 2.86 (br. s., 2 H) 3.10-3.27 (m, 1 H) 3.89 (t, J = 5.61 Hz, 2
    H) 4.12 (t, J = 5.44 Hz, 2 H) 4.31 (d, J = 14.52 Hz, 1 H) 6.38 (br.
    s., 1 H) 6.47 (d, J = 1.32 Hz, 1 H) 6.96 (d, J = 8.25 Hz, 2 H) 7.07
    (dd, J = 8.58, 1.98 Hz, 1 H) 7.11-7.25 (m, 4 H) 7.30 (d, J = 8.91
    Hz, 1 H) 7.44 (d, J = 8.58 Hz, 2 H) 7.54 (d, J = 2.31 Hz, 1 H) 8.63
    (d, J = 83.14 Hz, 1 H) 11.06-11.21 (m, 1 H)
    1569 615 4.52 *****
    1570 531 3.90 *****
    1571 531 1H NMR (300 MHz, CD3)2CO) δ 2.91-3.10 (m, 2H), 3.33-3.44 4.00 *****
    (m, 1H), 4.38-4.58 (m, 1H), 6.58-6.70 (bm, 1H), 7.13 (dd, J =
    8.4, 1.8 Hz, 1H), 7.40-7.58 (m, 4H), 7.37-7.60 (m, 5H), 7.58
    (dm, J = 2.4, 1H), 8.15 (dd, J = 2.7, 1.2 Hz, 1H), 8.33 (d, J = 2.7
    Hz, 1H), 8.46 (d, J = 1.2 Hz, 1H), 10.32 (s, 1H).
    1572 580 4.53 *****
    1573 449 1H NMR (300 MHz, (CD3)2CO) δ 1.29 (t, J = 6.7 Hz, 3H), 3.53 *****
    2.85-2.89 (m, 1H), 3.16-3.23 (m, 2H), 3.38 (mcc, 1H), 4.17 (q, J =
    6.9 Hz, 2H), 4.20-4.40 (m, 1H), 6.54 (bm, 1H), 7.10 (dd, J =
    8.7, 2.1 Hz, 1H), 7.16 (dm, J = 8.7 Hz, 2H), 7.21 (t, J = 4.8 Hz,
    1H), 7.33-7.39 (m, 3H), 7.53 (d, J = 1.8 Hz, 1H), 8.60 (J = 4.8
    Hz, 2H), 10.28 (s, 1H).
    1574 449 1H NMR (300 MHz, (CD3)2CO) δ 1.28 (t, J = 6.9 Hz, 3H), 3.67 *****
    2.85-2.88 (m, 1H), 3.15-3.25 (m, 2H), 3.60 (mc, 1H), 4.16 (q, J =
    6.9 Hz, 2H), 4.20-4.40 (m, 1H), 6.54 (bm, 1H), 7.10 (dd, J =
    8.8, 1.9 Hz, 1H), 7.18 (dm, J = 8.8 Hz, 2H), 7.36-7.38 (m, 3H),
    7.53 (d, J = 1.9 Hz, 1H), 8.13 (dd, J = 2.6, 1.5 Hz, 1H), 8.31 (d,
    J = 2.6 Hz, 1H), 8.44 (d, J = 1.4 Hz, 1H), 10.13 (s, 1H).
    1575 498 4.15 *****
    1576 479 1H NMR (300 MHz, (CD3)2CO) δ 1.58-1.69 (m, 2H), 1.82 (s, 3.78 *****
    3H), 1.96-2.05 (m, 2H), 2.80-2.94 (m, 3H), 3.10-3.25 (m, 1H),
    3.50 (ddd, J = 11.8, 9.0, 2.9 Hz, 2H), 3.96 (dt, J = 11.7, 4.5 Hz,
    2H), 4.28 (mc, 1H), 4.56 (septet, J = 4.0 Hz, 1H), 4.74 (s, 2H),
    6.45 (mc, 1H), 6.93 (d, J = 8.7 Hz, 2H), 7.11 (dd, J = 8.7, 1.8
    Hz, 1H), 7.20 (dm, J = 8.4 Hz, 2H), 7.36 (d, J = 8.7 Hz, 1H),
    7.52 (d, J = 1.8 Hz, 2H), 10.19 (s, 1H).
    1577 521 3.93 *****
    1578 537 4.12 *****
    1579 642 1H NMR (300 MHz, (CD3)2CO) δ 0.069 (s, 9H), 0.96-1.02 (m, 4.18 *****
    2H), 1.70-1.85 (m, 2H), 1.82 (s, 3H), 1.98-2.08 (m, 2H), 2.85
    (dd, J = 7.8, 3.0 Hz, 2H), 2.94-3.00 (m, 2H), 3.12-3.23 (m, 1H),
    3.24-3.32 (m, 2H), 3.45 (s, 1H), 3.48-3.56 (m, 2H), 4.18-4.40
    (mc, 1H), 4.59 (septet, J = 3.9 Hz, 1H), 4.74 (s, 2H), 6.46 (mc,
    1H), 6.94 (d, J = 8.8 Hz, 2H), 7.10 (dd, J = 8.7, 2.1 Hz, 1H),
    7.21 (dm, J = 8.1 Hz, 2H), 7.36 (d, J = 8.7 Hz, 1H), 7.53 (d, J =
    1.8 Hz, 2H), 10.17 (s, 1H).
    1580 684 4.32 *****
    1581 700 4.60 *****
    1582 461 3.92 *****
    1583 624 438 *****
    1584 410.17 3.57 *****
    1585 468.16 3.93 *****
    1586 412.18 3.07 ***
    1587 452.22 4.80 *****
    1588 481.21 3.40 ***
    1589 464.08 4.13 *****
    1590 473.24 2.62 ****
    1591 502.23 4.13 *****
    1592 473.24 2.55 ***
    1593 454.23 0.88 ***
    1594 473.16 1.62 ***
    1595 478.19 4.08 ****
    1596 452.16 3.37 ****
    1597 506.12 4.47 *****
    1598 472.23 4.22 *****
    1600 610.17 4.02 *****
    1601 606.32 3.62 *****
    1603 479 1H NMR (300 MHz, (CD3)2CO) δ 1.58-1.69 (m, 2H), 1.82 (s, 3.78 *****
    3H), 1.96-2.05 (m, 2H), 2.80-2.94 (m, 3H), 3.10-3.25 (m, 1H),
    3.50 (ddd, J = 11.8, 9.0, 2.9 Hz, 2H), 3.96 (dt, J = 11.7, 4.5 Hz,
    2H), 4.28 (mc, 1H), 4.56 (septet, J = 4.0 Hz, 1H), 4.74 (s, 2H),
    6.45 (mc, 1H), 6.93 (d, J = 8.7 Hz, 2H), 7.11 (dd, J = 8.7, 1.8
    Hz, 1H), 7.20 (dm, J = 8.4 Hz, 2H), 7.36 (d, J = 8.7 Hz, 1H),
    7.52 (d, J = 1.8 Hz, 2H), 10.19 (s, 1H).
    1604 521 3.95 *****
    1605 537 4.13 *****
    1606 642 1H NMR (300 MHz, (CD3)2CO) δ 0.069 (s, 9H), 0.96-1.02 (m, 4.17 *****
    2H), 1.70-1.85 (m, 2H), 1.82 (s, 3H), 1.98-2.08 (m, 2H), 2.85
    (dd, J = 7.8, 3.0 Hz, 2H), 2.94-3.00 (m, 2H), 3.12-3.23 (m, 1H),
    3.24-3.32 (m, 2H), 3.45 (s, 1H), 3.48-3.56 (m, 2H), 4.18-4.40
    (mc, 1H), 4.59 (septet, J = 3.9 Hz, 1H), 4.74 (s, 2H), 6.46 (mc,
    1H), 6.94 (d, J = 8.8 Hz, 2H), 7.10 (dd, J = 8.7, 2.1 Hz, 1H),
    7.21 (dm, J = 8.1 Hz, 2H), 7.36 (d, J = 8.7 Hz, 1H), 7.53 (d, J =
    1.8 Hz, 2H), 10.17 (s, 1H).
    1607 684 4.30 *****
    1608 475.25 3.75 *
    1609 465.25 4.67 *****
    1610 C28H34ClN3O4, 10.208, ***
    (M + 1, 512) Chiral
    13.9 and
    15.057
    1611 C32H30Cl2N4O3, 24.453, *****
    (595.2) Chiral,
    14.878
    1612 C27H20Cl2N2O3, 1H NMR (DMSO-d6, 400 MHz) δ = 11.17 (brs, 1H, NH), 8.3 5.676, *****
    (491.365) (s, 1H, Ar—H), 7.45 (d, 2H, 2Ar—H), 7.31-7.08 (m, 6H, 6Ar—H), Chiral,
    6.98 (m, 2H, 2Ar—H), 6.4 (brs, 1H, CH), 4.78 (s, 2H, CH2), 4.3 17.302
    (brs, 1H, CH), 3.6 (s, 1H, ≡CH), 3.28 (m, 1H, CH), 3.21 (m,
    2H, CH2).
    1613 C29H24Cl2N2O3, 1H NMR (DMSO-d6, 400 MHz) δ = 11.16 (brs, 1H, NH), 7.54 5.932, *****
    (519.5) (s, 1H, Ar—H), 7.45 (d, 2H, 2Ar—H), 7.3 (d, 1H, J = 8.8 Hz, Ar—H), Chiral,
    7.22-7.2 (m, 4H, 4Ar—H), 7.07 (m, 1H, Ar—H), 6.94 (m, 2H, 15.625
    2Ar—H), 6.4 (s, 1H, CH), 4.3 (m, 1H, CH), 4.01 (t, 2H, J = 6 Hz,
    CH2), 3.2 (m, 1H, CH), 2.9 (m, 2H, CH2), 2.8 (s, 1H, ≡CH),
    2.29 (m, 2H, CH2), 1.86 (m, 2H, CH2).
    1614 C28H22Cl2N2O3, 1H NMR (DMSO-d6, 400 MHz) δ = 11.17 (brs, 1H, NH), 7.54 5.775, *****
    (505.5) (s, 1H, Ar—H), 7.45 (d, 2H, 2Ar—H), 7.31-6.98 (m, 6H, 6Ar—H), Chiral,
    6.95 (m, 2H, 2Ar—H), 6.4 (brs, 1H, CH), 4.3 (m, 1H, CH), 4.03 26.04
    (t, 2H, J = 6.4 Hz, CH2), 3.2 (m, 1H, CH), 2.87 (m, 3H, CH and
    ≡CH), 2.61 (m, 2H, CH2).
    1615 M + 23: 536.2 1H NMR (DMSO, 300 MHz), δ11.13 (b, 1H), 7.86 (s, 1H), 7.48 30-90 ****
    (cal. 513.2) (s, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.10-7.03 (m, 3H), 6.88 (d, 3.91
    J = 8.4 Hz, 2H), 6.29 (s, 1H), 4.90 (d, J = 2.1 Hz, 1H), 4.15-4.09
    (m, 3H), 4.00 (t, J = 6.3 Hz, 1H), 3.67-3.61 (m, 1H), 3.11-2.98
    (m, 3H), 2.74-2.69 (m, 2H), 2.06 (q, J = 7.5 Hz, 2H), 1.86-1.78
    (m, 1H), 1.66-1.57 (m, 1H), 1.22-1.20 (m, 3H), 0.95 (t,
    J = 7.5 Hz, 3H).
    1616 M + 23: 550.2 1H NMR (DMSO, 300 MHz), δ11.15 (b, 1H), 7.86 (s, 1H), 7.47 10-80 ****
    (cal. 527.2) (d, J = 8.1 Hz, 1H), 7.30-7.27 (m, 1H), 7.07-7.01 (m, 3H), 6.86- 5.58
    6.83 (m, 2H), 6.28 (s, 1H), 4.93-4.92 (m, 1H), 4.09-4.00 (m,
    5H), 3.69-3.63 (m, 1H), 3.11-2.98 (m, 3H), 2.81-2.69 (m, 3H),
    1.90-1.73 (m, 1H), 1.69-1.59 (m, 1H), 1.22-1.20 (m, 3H), 0.96-
    0.91 (m, 3H).
    1617 563.1 1H NMR (DMSO, 300 MHz), δ11.09 (b, 1H), 8.99 (s, 1H), 8.76- 30-90 ****
    (cal. 562.2) 8.68 (m, 2H), 8.19 (d, J = 8.1 Hz, 1H), 7.50-7.48 (m, 2H), 7.27 (d, 3.27
    J = 8.4 Hz, 1H), 7.09-7.03 (m, 3H), 6.89 (d, J = 8.7 Hz, 2H), 6.29
    (s, 1H), 5.00-4.99 (m, 1H), 4.19-4.01 (m, 5H), 3.85-3.80 (m,
    1H), 3.06-3.00 (m, 1H), 2.77-2.70 (m, 3H), 1.94-1.82 (m, 1H),
    1.71-1.62 (m, 1H), 1.24-1.21 (m, 3H).
    1618 563.1 1H NMR (DMSO, 300 MHz), δ11.13 (s, 1H), 8.66-8.61 (m, 2H), 30-90 *****
    (cal. 562.2) 8.03-7.94 (m, 2H), 7.57 (t, J = 5.4 Hz, 1H), 7.48 (s, 1H), 7.27 (d, 4.30
    J = 8.4 Hz, 1H), 7.09-7.03 (m, 3H), 6.88 (d, J = 8.4 Hz, 2H), 6.29
    (s, 1H), 5.06 (d, J = 5.4 Hz, 1H), 4.16-4.04 (m, 5H), 3.83-3.82 (m,
    1H), 3.01-2.95 (m, 1H), 2.80-2.69 (m, 3H), 1.91-1.79 (m, 1H),
    1.78-1.62 (m, 1H), 1.22-1.20 (m, 3H).
    1619 M + 23: 538.1 1H NMR (DMSO, 300 MHz), δ11.18 (b, 1H), 7.48 (s, 1H), 7.27 30-90 *****
    (cal. 515.2) (d, J = 8.7 Hz, 1H), 7.10-7.02 (m, 4H), 6.87 (d, J = 8.7 Hz, 2H), 4.07
    6.30 (s, 1H), 4.85 (d, J = 5.4 Hz, 1H), 4.11-4.08 (m, 2H), 4.00 (t,
    J = 6.3 Hz, 2H), 3.64-3.60 (m, 1H), 3.48 (s, 3H), 3.09-2.92 (m,
    3H), 2.80-2.62 (m, 2H), 1.79-1.74 (m, 1H), 1.62-1.54 (m, 1H),
    1.22-1.20 (m, 3H).
    1620 544.1 1H NMR (DMSO, 300 MHz), δ11.09 (b, 1H), 7.48 (d, J = 1.5 Hz, 30-90 *****
    (cal. 543.2) 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.10-6.98 (m, 4H), 6.87 (d, 4.56
    J = 8.7 Hz, 2H), 6.29 (s, 1H), 4.75 (d, J = 5.4 Hz, 1H), 4.20-4.06
    (m, 3H), 4.02 (t, J = 6.3 Hz, 2H), 3.87 (t, J = 6.6 Hz, 2H), 3.63-3.61
    (m, 1H), 3.10-2.94 (m, 3H), 2.78-2.67 (m, 2H), 1.89-1.73 (m,
    1H), 1.62-1.45 (m, 3H), 1.23 (t, J = 7.2 Hz, 3H) 0.82 (t, J = 6.6 Hz,
    3H).
    1621 560.1 1H NMR (DMSO, 300 MHz), δ11.18 (b, 1H), 7.48 (s, 1H), 7.28 30-90 *****
    (cal. 559.2) (d, J = 8.4 Hz, 1H), 7.15-7.03 (m, 4H), 6.88 (d, J = 8.4 Hz, 2H), 4.07
    6.29 (s, 1H), 4.82 (d, J = 5.4 Hz, 1H), 4.20-4.00 (m, 7H), 3.62-
    3.61 (m 1H), 3.44 (t, J = 4.8 Hz, 2H), 3.21 (s, 3H), 3.08-2.93 (m,
    3H), 2.82-2.64 (m, 2H), 1.90-1.73 (m, 1H) 1.62-1.49 (m, 1H)
    1.22-1.20 (m, 3H).
    1622 M + 23: 558.0 1H NMR (CD3CN, 300 MHz), δ9.11 (b, 1H), 7.51 (d, J = 1.8 Hz, 10-80 *****
    (cal. 535.2) 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.08 (dd, 3.69
    J = 8.7 Hz and 2.1 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.36 (s, 1H),
    5.32 (b, 1H), 4.28-4.26 (m, 1H), 4.20-4.13 (m, 2H), 4.10-4.05
    (m, 2H), 3.89-3.87 (m, 1H), 3.21 (s, 3H), 3.22-3.00 (m, 4H),
    2.90 (s, 3H), 2.81-2.77 (m, 2H) 1.89-1.71 (m, 2H) 1.26 (t,
    J = 7.2 Hz, 3H).
    1623 M + 23: 572.1 1H NMR (DMSO, 300 MHz), δ11.11 (b, 1H), 7.49 (s, 1H), 7.27 10-80 *****
    (cal. 549.2) (d, J = 8.1 Hz, 1H), 7.11-6.97 (m, 4H), 6.89 (d, J = 8.1 Hz, 2H), 4.80
    6.29 (s, 1H), 4.88 (d, J = 5.4 Hz, 1H), 4.13-4.00 (m, 5H), 3.66-
    3.64 (m, 1H), 3.00 (q, J = 7.2 Hz, 2H), 2.91 (t, J = 6.0 Hz, 2H),
    2.66-2.64 (m, 3H), 1.94-1.88 (m, 1H) 1.68-1.60 (m, 1H) 1.21-
    1.13 (m, 6H).
    1624 M + 23: 584.1 1H NMR (DMSO, 300 MHz), δ11.16 (b, 1H), 7.52 (s, 1H), 7.37- 10-80 *****
    (cal. 561.2) 7.36 (m 1H), 7.11-7.07 (m, 4H), 6.30 (s, 1H), 4.96 (b, 1H), 4.88
    4.20-3.99 (m, 5H), 3.71-3.69 (m, 1H), 3.00-2.99 (m, 3H), 2.73-
    2.70 (m, 3H), 1.94-1.88 (m, 1H) 1.68-1.60 (m, 1H) 1.21-1.13
    (m, 3H), .090-0.88 (m, 3H).
    1625 M + 23: 618.2 1H NMR (CD3CN, 300 MHz), δ9.25 (b, 1H), 7.54 (d, J = 2.1 Hz, 30-90 *****
    (cal. 595.2) 1H), 7.38-7.34 (m, 2H), 7.30-7.21 (m, 3H), 7.14-7.09 (m, 3H), 4.61
    6.87 (d, J = 8.7 Hz, 2H), 6.55 (b, 1H), 6.45 (s, 1H), 4.41-4.33 (m,
    1H), 4.05 (t, J = 6.3 Hz, 2H), 3.81-3.76 (m, 1H), 3.63-3.52 (m,
    1H), 3.32-3.21 (m, 2H), 3.13-3.07 (m, 1H), 2.99-2.81 (m, 2H),
    2.14 (q, J = 7.5 Hz, 2H), 1.90-1.82 (m, 1H), 1.76-1.69 (m, 1H),
    1.04 (t, J = 7.8 Hz, 3H).
    1626 M + 23: 632.2 1H NMR (CD3CN, 400 MHz), δ9.26 (b, 1H), 7.55 (d, J = 2.0 Hz, 30-90 *****
    (cal. 609.2) 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.31-7.23 (m, 3H), 7.13-7.09 (m, 4.76
    3H), 6.89 (d, J = 8.4 Hz, 2H), 6.71 (b, 1H), 6.45 (s, 1H), 4.41-
    4.33 (m, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.81-3.76 (m, 1H), 3.51 (s,
    1H), 3.31-3.24 (m, 2H), 3.13-3.07 (m, 1H), 2.99-2.81 (m, 2H),
    2.41-2.40 (m, 1H), 1.90-1.82 (m, 1H), 1.76-1.69 (m, 1H), 1.05
    (d, J = 7.8 Hz, 6H).
    1627 M + 23: 667.2 1H NMR (CD3CN, 400 MHz), δ9.18 (b, 1H), 8.69 (d, J = 6.0 Hz, 30-90 *****
    (cal. 644.2) 2H), 7.66 (d, J = 6.0 Hz, 2H), 7.56 (s, 1H), 7.39 (d, J = 8.8 Hz, 2H), 3.96
    7.31-7.24 (m, 3H), 7.14-7.10 (m, 3H), 6.91 (d, J = 8.0 Hz, 2H),
    6.49 (s, 1H), 4.41-4.33 (m, 1H), 4.12 (t, J = 6.4 Hz, 2H), 3.94-
    3.92 (m, 1H), 3.54-3.48 (m, 2H), 3.37-3.24 (m, 2H), 3.01-2.81
    (m, 2H), 1.88-1.76 (m, 2H).
    1628 M + 23: 667.1 1H NMR (CD3CN, 400 MHz), δ9.43-9.39 (m, 1H), 8.99-8.86 30-90 *****
    (cal. 644.2) (m, 1H), 8.69-8.68 (m, 1H), 8.13-8.10 (m, 1H), 7.56 (d, 4.03
    J = 2.0 Hz, 1H), 7.44-7.38 (m, 3H), 7.31-7.23 (m, 4H), 7.14-7.10
    (m, 3H), 6.93-6.90 (m, 2H), 6.47 (s, 1H), 4.41-4.33 (m, 1H),
    4.15-4.12 (m, 2H), 3.96-3.92 (m, 1H), 3.54-3.48 (m, 2H), 3.41-
    3.23 (m, 2H), 3.01-2.81 (m, 2H), 1.90-1.76 (m, 2H).
    1629 M + 23: 667.1 1H NMR (CD3CN, 400 MHz), δ9.23 (b, 1H), 8.59 (d, J = 4.8 Hz, 30-90 *****
    (cal. 644.2) 1H), 8.40 (s, 1H), 8.10-8.08 (m, 1H), 7.94-7.92 (m, 1H), 7.55 4.92
    (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.31-7.23 (m, 3H),
    7.14-7.10 (m, 3H), 6.92 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 4.41-
    4.33 (m, 1H), 4.11 (t, J = 6.4 Hz, 2H), 3.96-3.92 (m, 1H), 3.54-
    3.50 (m, 1H), 3.41-3.32 (m, 1H), 3.30-3.27 (m, 1H), 1.90-1.76
    (m, 2H).
    1630 483.22 4.03 *****
    1631 425.18 3.97 ***
    1632 508 3.88 *****
    1633 524 3.62 *****
    1634 524 3.62 *****
    1635 M + 23: 620.1 1H NMR (CD3CN, 300 MHz), δ9.14 (b, 1H), 7.55 (d, J = 2.1 Hz, 30-90 *****
    (cal. 597.1) 1H), 7.40-7.36 (m, 2H), 7.31-7.23 (m, 3H), 7.14-7.09 (m, 3H), 4.73
    6.90 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 5.65 (b, 1H), 4.10-4.05 (m,
    2H), 3.85-3.74 (m, 1H), 3.58 (s, 3H), 3.32-3.16 (m, 3H), 3.07-
    3.00 (m, 1H), 2.96-2.84 (m, 2H), 1.90-1.81 (m, 1H), 1.78-1.71
    (m, 1H).
    1636 M + 23: 634.1 1H NMR (CD3CN, 400 MHz), δ9.17 (b, 1H), 7.55 (d, J = 2.0 Hz, 30-90 *****
    (cal. 611.2) 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.31-7.23 (m, 3H), 7.14-7.10 (m, 4.92
    3H), 6.90 (d, J = 8.0 Hz, 2H), 6.47 (s, 1H), 5.60 (b, 1H), 4.41-
    4.35 (m, 1H), 4.10-4.00 (m, 4H), 3.82-3.76 (m, 1H), 3.32-3.16
    (m, 3H), 3.07-3.00 (m, 1H), 2.96-2.84 (m, 2H), 1.90-1.81 (m,
    1H), 1.76-1.69 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H).
    1637 M + 23: 664.1 1H NMR (DMSO, 400 MHz), δ11.19-11.11 (m, 1H), 7.52 (d, 30-90 *****
    (cal. 641.2) J = 1.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 1H), 5.03
    7.20-7.12 (m, 5H), 7.04 (dd, J = 8.4 Hz and 2.0 Hz, 1H), 6.92-6.90
    (m, 2H), 6.42-6.37 (m, 1H), 4.78 (d, J = 5.6 Hz, 1H), 4.31-4.20
    (m, 1H), 4.01-4.00 (m, 4H), 3.64-3.61 (m, 1H), 3.46-3.43 (m,
    2H), 3.22-3.19 (m, 5H), 2.96 (t, J = 6.0 Hz, 2H), 2.90-2.82 (m,
    2H), 1.91-1.79 (m, 1H), 1.61-1.53 (m, 1H).
    1638 M + 23: 654.1 1H NMR (DMSO, 300 MHz), δ11.19-11.10 (m, 1H), 7.53 (d, 30-90 *****
    (cal. 631.1) J = 2.1 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 5.03
    7.22-7.19 (m, 3H), 7.07 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 6.99 (t,
    J = 6.3 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 6.42-6.37 (m, 1H), 4.88
    (d, J = 5.4 Hz, 1H), 4.33-4.22 (m, 1H), 4.04 (t, J = 6.6 Hz, 2H),
    3.71-3.63 (m, 1H), 3.22-3.12 (m, 1H), 3.02-2.83 (m, 5H), 1.93-
    1.86 (m, 1H), 1.64-1.60 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H).
    1639 M + 23: 666.1 1H NMR (DMSO, 300 MHz), δ11.19-11.12 (m, 1H), 7.53 (d, 30-90 *****
    (cal. 643.1) J = 1.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 5.10
    7.22-7.19 (m, 3H), 7.07 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 7.00-6.96
    (m, 1H), 6.93 (d, J = 9.0 Hz, 2H), 6.45-6.37 (m, 1H), 4.92-4.89
    (m, 1H), 4.35-4.26 (m, 1H), 4.04 (t, J = 6.0 Hz, 2H), 3.71-3.63
    (m, 1H), 3.22-3.12 (m, 1H), 3.00-2.91 (m, 2H), 2.91-2.82 (m,
    2H), 1.97-1.89 (m, 1H), 1.69-1.62 (m, 1H), 0.90-0.88 (m, 4H).
    1640 M + 23: 612.2 1H NMR (DMSO, 400 MHz), δ 11.13-11.10 (m, 1H), 7.73 (s, 30-90 *****
    (cal. 589.2) 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.17-7.15 4.93
    (m, 4H), 7.06 (dd, J = 8.4 Hz and 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz,
    2H), 6.91-6.89 (m, 2H), 6.42-6.37 (m, 1H), 4.84 (d, J = 4.4 Hz,
    1H), 4.30-4.27 (m, 1H), 4.02 (t, J = 6.4 Hz, 2H), 3.64-3.61 (m,
    1H), 3.19-3.13 (m, 1H), 3.09-3.01 (m, 3H), 2.89-2.81 (m, 2H),
    2.27 (s, 3H), 1.82-1.78 (m, 1H), 1.63-1.57 (m, 1H), 0.94 (d,
    J = 6.8 Hz, 6H).
    1641 M + 23: 647.2 1H NMR (DMSO, 400 MHz), δ 11.14-11.10 (m, 1H), 8.67-8.66 30-90 *****
    (cal. 624.2) (m, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.96 (dd, 5.13
    J = 7.6 Hz and 1.6 Hz, 1H), 7.58-7.56 (m, 1H), 7.52 (d, J = 2.0 Hz,
    1H), 7.29 (d, J = 8.4 Hz, 1H), 7.17-7.10 (m, 3H), 7.06 (dd,
    J = 8.8 Hz and 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.91 (d,
    J = 8.0 Hz, 2H), 6.41-6.32 (m, 1H), 5.02 (d, J = 5.6 Hz, 1H), 4.32-
    4.22 (m, 1H), 4.04 (t, J = 6.4 Hz, 2H), 3.86-3.81 (m, 1H), 3.44-
    3.42 (m, 2H), 3.14-3.12 (m, 1H), 2.87-2.83 (m, 3H), 2.27 (s,
    3H), 1.87-1.82 (m, 1H), 1.71-1.62 (m, 1H).
    1642 M + 23: 600.1 1H NMR (DMSO, 400 MHz), δ 11.17-11.10 (m, 1H), 7.52 (d, 30-90 *****
    (cal. 577.2) J = 2.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.17-7.01 (m, 6H), 7.00 4.92
    (d, J = 8.4 Hz, 2H), 6.92-6.91 (m, 2H), 6.43-6.39 (m, 1H), 4.80
    (d, J = 5.6 Hz, 1H), 4.32-4.22 (m, 1H), 4.01 (t, J = 6.0 Hz, 2H),
    3.63-3.60 (m, 1H), 3.48 (s, 3H), 3.17-3.12 (m, 1H), 2.97 (t,
    J = 6.0 Hz, 2H), 2.87-2.83 (m, 2H), 2.27 (s, 3H), 1.84-1.79 (m,
    1H), 1.61-1.58 (m, 1H).
    1643 M + 23: 614.2 1H NMR (DMSO, 400 MHz), δ 11.17-11.10 (m, 1H), 7.52 (d, 30-90 *****
    (cal. 591.2) J = 1.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.17-7.15 (m, 4H), 7.07- 5.12
    7.01 (m, 4H), 6.92-6.90 (m, 2H), 6.43-6.36 (m, 1H), 4.78 (d,
    J = 5.2 Hz, 1H), 4.35-4.20 (m, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.93 (q,
    J = 7.2 Hz, 2H), 3.63-3.60 (m, 1H), 3.17-3.12 (m, 1H), 2.96 (t,
    J = 6.0 Hz, 2H), 2.87-2.83 (m, 2H), 2.27 (s, 3H), 1.85-1.79 (m,
    1H), 1.61-1.58 (m, 1H).
    1644 M + 23: 628.2 1H NMR (DMSO, 400 MHz), δ 11.17-11.10 (m, 1H), 7.52 (d, 30-90 *****
    (cal. 605.2) J = 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.17-7.15 (m, 4H), 7.07- 5.35
    6.99 (m, 4H), 6.92-6.90 (m, 2H), 6.43-6.36 (m, 1H), 4.79 (d,
    J = 5.2 Hz, 1H), 4.30-4.20 (m, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.84 (q,
    J = 7.2 Hz, 2H), 3.63-3.60 (m, 1H), 3.17-3.12 (m, 1H), 2.96 (t,
    J = 6.0 Hz, 2H), 2.87-2.83 (m, 2H), 2.27 (s, 3H), 1.85-1.79 (m,
    1H), 1.61-1.58 (m, 1H), 1.50 (q, J = 7.2 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H).
    1645 M + 23: 644.2 1H NMR (DMSO, 400 MHz), δ 11.17-11.10 (m, 1H), 7.52 (d, 30-90 *****
    (cal. 621.2) J = 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.17-7.15 (m, 4H), 7.06 4.91
    (dd, J = 8.4 Hz and 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.92-6.90
    (m, 2H), 6.43-6.36 (m, 1H), 4.80 (d, J = 5.2 Hz, 1H), 4.30-4.20
    (m, 1H), 4.00 (s, 3H), 3.64-3.60 (m, 2H), 3.42-3.41 (m, 2H),
    3.21 (s, 3H), 3.16-3.11 (m, 1H), 2.97 (t, J = 6.0 Hz, 2H), 2.87-
    2.83 (m, 2H), 2.27 (s, 3H), 1.85-1.79 (m, 1H), 1.61-1.58 (m, 1H).
    1646 M + 23: 634.2 1H NMR (DMSO, 400 MHz), δ 11.17-11.10 (m, 1H), 7.52 (s, 30-90 *****
    (cal. 611.2) 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.17-7.15 (m, 4H), 7.06 (dd, 4.88
    J = 8.4 Hz and 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.93-6.91 (m,
    2H), 6.43-6.36 (m, 1H), 4.89 (d, J = 5.6 Hz, 1H), 4.30-4.20 (m,
    1H), 4.03 (t, J = 7.2, 2H), 3.67-3.62 (m, 1H), 3.57-3.56 (m, 1H),
    3.16-3.11 (m, 1H), 2.95 (q, J = 7.2 Hz, 2H), 2.91 (t, J = 6.0, 2H),
    2.87-2.81 (m, 1H), 2.27 (s, 3H), 1.90-1.82 (m, 1H), 1.66-1.61
    (m, 1H), 1.15 (t, J = 7.2 Hz, 3H).
    1647 M + 23: 646.2 1H NMR (DMSO, 400 MHz), δ 11.17-11.10 (m, 1H), 7.52 (s, 30-90 *****
    (cal. 623.2) 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.23-7.15 (m, 3H), 7.06 (d, 4.99
    J = 6.8 Hz, 2H), 7.00 (d, J = 8.4H, 2H), 6.92-6.90 (m, 2H), 6.43-
    6.36 (m, 1H), 4.95 (d, J = 5.2 Hz, 1H), 4.03-4.01 (m, 2H), 3.70-
    3.69 (m, 1H), 3.19-3.11 (m, 1H), 2.94-2.91 (m, 2H), 2.84-2.81
    (m, 2H), 2.27 (s, 3H), 1.90-1.86 (m, 1H), 1.66-1.61 (m, 1H),
    0.88-0.85 (m, 4H).
    1648 571 (M + −1) 1H NMR (300 MHz, CD3)2CO) δ 2.22-2.32 (m, 2H), 2.90-3.10 3.80 *****
    (m, 5H), 3.26-3.31 (m, 3H), 4.17 (t, J = 6.3 Hz, 2H), 4.43 (mc,
    1H), 6.52 (bm, 1H), 6.95 (d, J = 9.0 Hz, 2H), 7.11 (dd, J = 9.0,
    2.4 Hz, 1H), 7.40-7.58 (m, 4H), 7.37 (d, J = 8.4 Hz, 1H), 7.42
    (dm, J = 9.3 Hz, 2H), 7.56 (d, J = 2.2 Hz, 1H), 10.22 (s, 1H).
    1649 515 3.50 *****
    1650 516.28 3.38 *****
    1651 516.31 3.38 *****
    1652 700 4.53 *****
    1653 477 3.88 *****
    1654 463 3.77 *****
    1655 464 3.57 ***
    1656 553 1H NMR (300 MHz, (CD3)2CO) δ 1.28 (t, J = 6.9 Hz, 3H), 2.40 *****
    2.85-2.88 (m, 1H), 3.09-3.22 (m, 2H), 3.33 (mcc, 4H), 3.94
    (mc, 4H), 4.17 (q, J = 6.9 Hz, 2H), 4.20-4.40 (m, 1H), 4.58 (s,
    2H), 6.54 (bm, 1H), 7.10 (dd, J = 8.4, 1.9 Hz, 1H), 7.30-7.44
    (m, 6H), 7.54 (d, J = 1.9 Hz, 1H), 10.27 (s, 1H).
    1657 566 2.27 *****
    1658 559 4.25 *****
    1659 545 4.12 *****
    1660 635 2.80 *****
    1661 650 2.47 *****
    1662 439.31 4.3  ****
    1663 M − 1: 580.0 1H NMR (DMSO, 300 MHz), δ 11.14 (b, 1H), 7.54 (s, 1H), 7.30 30-90 *****
    (cal. 581.2) (d, J = 8.4 Hz, 1H), 7.21-7.19 (m, 6H), 7.06 (d, J = 9.0 Hz, 2H), 4.59
    6.92 (d, J = 7.5 Hz, 2H), 6.38 (b, 1H), 5.10 (b, 1H), 4.29 (b, 1H),
    4.05-3.80 (m, 5H), 3.16-2.87 (m, 5H), 1.12-1.04 (m, 3H)
    1664 M − 1: 579.9 1H NMR (DMSO, 300 MHz), δ 11.14 (b, 1H), 7.54 (s, 1H), 7.30 10-80 *****
    (cal. 581.2) (d, J = 8.4 Hz, 1H), 7.21-7.19 (m, 6H), 7.06 (d, J = 9.0 Hz, 2H), 4.84
    6.92 (d, J = 7.5 Hz, 2H), 6.38 (b, 1H), 5.10 (b, 1H), 4.29 (b, 1H),
    4.05-3.80 (m, 5H), 3.16-2.87 (m, 5H), 1.12-1.04 (m, 3H)
    1665 M + 23: 552.2 1H NMR (CD3CN, 300 MHz), δ9.11 (b, 1H), 7.51 (d, J = 1.8 Hz, 10-80 ****
    (cal. 529.2) 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.08 (dd, 5.71
    J = 8.7 Hz and 2.1 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.36 (s, 1H),
    5.59 (b, 1H), 4.28-4.26 (m, 1H), 4.19-4.11 (m, 2H), 4.09-3.99
    (m, 4H), 3.84-3.79 (m, 1H), 3.22-3.02 (m, 4H), 2.79-2.77 (m,
    2H), 1.83-1.81 (m, 1H), 1.73-1.64 (m, 1H), 1.26 (t, J = 6.4 Hz,
    3H), 1.19 (t, J = 7.2 Hz, 3H).
    1666 M + 23: 648.1 1H NMR (CD3CN, 400 MHz), δ9.20-9.18 (m, 1H), 7.56 (d, 10-80 *****
    (cal. 625.2) J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.31-7.24 (m, 3H), 7.15- 5.44
    7.10 (m, 3H), 6.92-6.89 (m, 2H), 6.47 (s, 1H), 5.61 (b, 1H),
    4.41-4.35 (m, 1H), 4.08 (t, J = 6.4 Hz, 2H), 3.95 (t, J = 6.8 Hz, 2H),
    3.82-3.76 (m, 1H), 3.32-3.18 (m, 3H), 3.07-3.00 (m, 1H), 2.96-
    2.84 (m, 2H), 1.90-1.84 (m, 1H), 1.76-1.69 (m, 1H), 1.61-1.56
    (m, 2H), 0.93-0.90 (m, 3H).
    1667 M + 23: 640.1 1H NMR (CD3CN, 300 MHz), δ9.18 (b, 1H), 7.55 (s, 1H), 7.38 30-90 *****
    (cal. 617.1) (d, J = 8.78 Hz, 2H), 7.28-7.23 (m, 3H), 7.14-7.09 (m, 3H), 6.91 4.55
    (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 5.35 (b, 1H), 4.41-4.35 (m, 1H),
    4.09 (t, J = 6.4 Hz, 2H), 3.88-3.82 (m, 1H), 3.35-3.22 (m, 1H),
    3.17-3.11 (m, 1H), 3.07-2.81 (m, 6H), 1.81-1.70 (m, 2H).
    1668 M + 23: 620.1 1H NMR (DMSO, 400 MHz), δ 11.17-11.10 (m, 1H), 7.52 (d, 10-80 ****
    (cal. 597.2) J = 2.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.17-7.15 (m, 3H), 7.06 5.45
    (dd, J = 8.4 Hz and 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.97-6.994
    (m, 3H), 6.43-6.36 (m, 1H), 4.92 (d, J = 5.6 Hz, 1H), 4.30-4.20
    (m, 1H), 4.04-4.00 (m, 2H), 3.67-3.62 (m, 1H), 3.16-3.11 (m,
    2H), 2.93-2.90 (m, 2H), 2.87 (s, 3H), 2.86-2.85 (m, 1H), 2.27
    (s, 3H), 1.90-1.82 (m, 1H), 1.66-1.61 (m, 1H).
    1669 C26H19Cl2N3O3, 13.380, *****
    (M+, 492.1) Chiral,
    22.133
    1670 403.30 2.33 ****
    1671 623.3 3.85 *****
    1672 593.34 3.70 *****
    1673 605.18 3.82 *****
    1674 696 1H NMR (300 MHz, (CD3OD) δ 2.80-3.04 (m, 2H), 3.30-3.40 3.33 **
    (m, 2H), 3.66-3.76 (m, 3H), 3.81 (q, J = 6.3 Hz, 1H), 3.97 (d, J =
    3.0 Hz, 1H), 4.13 (t, J = 9.3 Hz, 1H), 4.30-4.50 (m, 1H), 5.19
    (s, 2H), 5.57 (d, J = 9.3 Hz, 1H), 6.44-6.56 (bm, 1H), 6.96-7.04
    (bm, 2H), 7.06 (dd, J = 8.7, 1.9 Hz, 1H), 7.13 (d, J = 8.7 Hz,
    1H), 7.24 (bd, J = 8.4 Hz, 2H), 7.38 (bd, J = 8.7 Hz, 1H), 7.49
    (d, J = 2.1 Hz, 1H), 8.30 (s, 1H).
    1675 864 1H NMR (300 MHz, (CD3)2CO) δ 1.80 (s, 3H), 1.95 (s, 3H), 3.88 ***
    1.97 (s, 3H), 2.19 (s, 3H), 2.90-3.05 (m, 1H), 3.30-3.42 (m,
    2H), 4.12 (dd, J = 11.4, 7.2 Hz, 1H), 4.23 (dd, J = 11.4, 5.8 Hz,
    1H), 4.36-4.52 (bm, 1H), 4.62 (t, J = 6.3 Hz, 1H), 5.22 (s, 2H),
    5.45 (dd, J = 10.2, 3.3 Hz, 1H), 5.56 (dm, J = 2.4 Hz, 1H), 5.72
    (t, J = 9.7 Hz, 1H), 6.23 (d, J = 9.0 Hz, 1H), 6.50-6.60 (bm, 1H),
    7.05 (bd, J = 8.1 Hz, 2H), 7.12 (dd, J = 8.7, 2.1 Hz, 1H), 7.23
    (d, J = 8.9 Hz, 2H), 7.24-7.28 (m, 1H), 7.37 (bd, J = 8.4 Hz,
    2H), 7.42 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 1.5 Hz, 1H), 8.30 (s,
    1H). 10.22 (s, 1H).
    1676 710 3.33 *
    1677 878 3.90 ***
    1678 556 1H NMR (300 MHz, (CD3)2CO) δ 1.63-1.75 (m, 2H), 1.82 (s, 4.00 *****
    3H), 1.97-2.06 (m, 2H), 2.86 (dd, J = 8.1, 3.0 Hz, 2H), 3.20
    (mc, 2H), 3.60-3.69 (m, 2H), 4.12-4.34 (m, 2H), 4.70 (septet, J =
    4.2 Hz, 1H), 4.74 (s, 2H), 6.46 (mc, 1H), 6.59 (t, J = 4.8 Hz,
    1H), 6.98 (d, J = 8.7 Hz, 2H), 7.10 (dd, J = 8.4, 2.1 Hz, 1H),
    7.22 (dm, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.53 (d, J =
    2.1 Hz, 2H), 8.36 (d, J = 4.8 Hz, 2H), 10.19 (s, 1H).
    1679 591 2.15 ****
    1680 635 2.37 *****
    1681 614 4.42 *****
    1682 649 2.33 *****
    1683 478 2.23 ****
    1684 492 2.18 ****
    1685 499.4 3.63 *****
    1686 499.4 3.62 *****
    1687 541.2 3.97 *****
    1688 315.28 1.7  *
    1689 469.22 1H NMR (DMSO, 300 MHz), δ 11.15 (s, br, 1H), 8.48 (d, 2H), 3.75 ****
    7.56 (d, 1H), 7.43 (dd, 2H), 7.33 (s, 1H), 7.20 (d, 2H), 7.07 (d,
    1H), 6.39 (d, 1H), 4.37 (m, 1H), 3.90 (s, 3H), 3.33 (br, 1H),
    2.89 (m, 2H)
    1690 453.28 3.57 ****
    1691 387.27 1H NMR (DMSO, 300 MHz), δ 11.15 (s, br, 1H), 8.43 (s, 2H), 3.3  ***
    7.52 (d, J = 1.8 Hz, 1H), 7.32 (s, br, 1H), 7.06 (dd, J = 8.7 Hz and
    2.1 Hz, 1H), 6.30 (s, 1H), 4.30-4.05 (m, 3H), 3.88 (s, 3H), 3.16
    (br, 1H), 2.80 (m, 2H), 1.21 (t, 3H)
    1692 411.28 1H NMR (DMSO, 300 MHz), δ 11.15 (s, br, 1H), 8.43 (s, 2H), 3.37 ****
    7.52 (d, J = 2.1 Hz, 1H), 7.35 (s, br, 1H), 7.06 (dd, J = 8.7 Hz and
    1.8 Hz, 1H), 6.31 (s, 1H), 4.72 (s, 2H), 4.2 (br, 1H), 3.88 (s, 3H),
    3.18 (br, 1H), 2.72-2.87 (m, 2H), 1.80 (s, 3H)
    1693 693 2.53 *****
    1694 550 2.40 *****
    1695 615 3.13 **
    1696 533 2.72 *
    1697 552 2.17 *****
    1698 567.19 4.02 *****
    1699 427 3.52 *****
    1700 546 3.45 *****
    1701 509 3.87 *****
    1702 628 3.80 *****
    1703 624 2.35 **
    1704 610 2.40 ****
    1705 566 2.22 ***
    1706 M + 23: 434.0 1H NMR (DMSO, 400 MHz), δ 11.22-11.21 (m, 1H), 8.90-8.79 10-80 ***
    (cal. 411.1) (m, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.15- 4.05
    7.7.11 (m, 2H), 7.07 (dd, J = 8.8 Hz and 2.0 Hz, 1H), 6.92-6.89
    (m, 2H), 6.63-6.60 (m, 1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H),
    3.43-3.39 (m, 1H), 3.22-3.13 (m, 2H), 2.84-2.79 (m, 2H), 1.07-
    1.02 (m, 3H).
    1707 M + 23: 448.0 1H NMR (DMSO, 400 MHz), δ 11.22 (b, 1H), 8.81-8.67 (m, 10-80 ***
    (cal. 425.2) 1H), 7.52 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.15-7.7.11 (m, 2H), 4.25
    7.07 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.62-6.38 (m,
    1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.43-3.39 (m, 1H), 2.90-
    2.79 (m, 2H), 1.14-1.02 (m, 6H).
    1708 M + 23: 448.0 1H NMR (DMSO, 300 MHz), δ 11.22 (b, 1H), 8.74-8.71 (m, 30-90 **
    (cal. 425.2) 1H), 7.52 (s, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.14-7.05 (m, 3H), 2.80
    6.91 (d, J = 9.0 Hz, 2H), 6.62-6.38 (m, 1H), 3.85-3.81 (m, 1H),
    3.71 (s, 3H), 3.43-3.39 (m, 1H), 3.19-3.09 (m, 2H), 2.82-2.79
    (m, 2H), 1.52-1.42 (m, 2H), 0.85 (t, J = 7.5 Hz, 3H).
    1709 M + 23: 438.0 1H NMR (DMSO, 400 MHz), δ 11.32 (b, 1H), 9.01-8.89 (m, 30-90 ***
    (cal. 437.2) 1H), 7.52 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.19-7.05 (m, 3H), 3.81
    6.90 (d, J = 8.4 Hz, 2H), 6.65-6.45 (m, 1H), 3.85-3.82 (m, 1H),
    3.71 (s, 3H), 3.43-3.39 (m, 1H), 3.11-3.07 (m, 2H), 2.82-2.76
    (m, 2H), 1.05-0.95 (m, 1H), 0.42-0.40 (m, 2H), 0.19-0.18 (m, 2H)
    1710 450.2 1H NMR (DMSO, 400 MHz), δ 11.20 (b, 1H), 8.90-8.76 (m, 30-90 ***
    (cal. 451.2) 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.14-7.11 3.91
    (m, 2H), 7.07 (dd, J = 8.8 Hz and 2.0 Hz, 1H), 6.91 (d, J = 8.8 Hz,
    2H), 6.62-6.32 (m, 1H), 4.10-4.02 (m, 1H), 3.72-3.71 (m, 4H),
    3.27-3.20 (m, 1H), 2.90-2.76 (m, 2H), 1.89-1.79 (m, 2H), 1.64-
    1.62 (m, 2H), 1.52-1.48 (m, 4H).
    1711 M − 1: 492.1  1H NMR (DMSO, 400 MHz), δ 11.22-11.11 (m, 1H), 11.10- 30-90 ****
    (cal. 493.1) 11.01 (m, 1H), 7.72-7.67 (m, 2H), 7.54 (d, J = 2.0 Hz, 1H), 7.44- 4.64
    7.40 (m, 2H), 7.32-7.29 (m, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.08
    (dd, J = 8.8 Hz and 2.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.69-6.37
    (m, 1H), 3.90-3.88 (m, 1H), 3.73 (s, 3H), 3.27-3.20 (m, 1H),
    2.96-2.80 (m, 3H).
    1712 M + 23: 496.0 1H NMR (DMSO, 400 MHz), δ 11.32-11.18 (m, 1H), 10.91- 10-80 ****
    (cal. 473.2) 10.82 (m, 1H), 7.60-7.58 (m, 3H), 7.37 (d, J = 8.8 Hz, 1H), 7.25- 5.05
    7.19 (m, 4H), 7.16 (dd, J = 8.0 Hz and 2.0 Hz, 1H), 7.00 (d,
    J = 8.8 Hz, 2H), 6.75-6.42 (m, 1H), 3.94-3.90 (m, 1H), 3.79 (s,
    3H), 3.50-3.45 (m, 1H), 2.96-2.89 (m, 2H), 2.32 (s, 3H).
    1713 M − 1: 476.1  1H NMR (DMSO, 400 MHz), δ 11.28-11.14 (m, 1H), 11.01- 30-90 ***
    (cal. 477.1) 10.92 (m, 1H), 7.68-7.64 (m, 2H), 7.53 (s, 1H), 7.30 (d, 4.42
    J = 8.4 Hz, 1H), 7.20-7.15 (m, 4H), 7.07 (d, J = 8.4 Hz, 1H), 6.93
    (d, J = 8.4 Hz, 2H), 6.69-6.37 (m, 1H), 3.90-3.87 (m, 1H), 3.72 (s,
    3H), 3.43-3.40 (m, 1H), 2.91-2.80 (m, 2H).
    1714 M − 1: 458.1  1H NMR (DMSO, 400 MHz), δ 11.28-11.14 (m, 1H), 10.92- 10-80 ****
    (cal. 459.1) 10.86 (m, 1H), 7.65-7.63 (m, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.36- 4.83
    7.31 (m, 3H), 7.18 (d, J = 8.4 Hz, 2H), 7.14-7.07 (m, 2H), 6.94 (d,
    J = 8.8 Hz, 2H), 6.69-6.37 (m, 1H), 3.90-3.87 (m, 1H), 3.73 (s,
    3H), 3.43-3.40 (m, 1H), 2.91-2.80 (m, 2H).
    1715 412.9 1H NMR (DMSO, 300 MHz), δ 11.20-11.08 (m, 1H), 7.54 (d, 10-80 ***
    (cal. 412.1) J = 1.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 4.59
    7.07 (dd, J = 8.4 Hz and 1.8 Hz, 1H), 6.95-6.91 (m, 2H), 6.62-5.94
    (m, 1H), 4.37-4.30 (m, 2H), 3.72 (s, 3H), 3.69-3.63 (m, 1H),
    3.40-3.32 (m, 1H), 2.94-2.75 (m, 2H), 1.29-1.24 (m, 3H).
    1716 M − 1: 483.1  1H NMR (DMSO, 400 MHz), δ 11.37-11.30 (m, 1H), 11.22- 30-90 **
    (cal. 484.1) 11.08 (m, 1H), 7.89-7.83 (m, 4H), 7.54 (s, 1H), 7.31 (d, 4.41
    J = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.8 Hz, 1H),
    6.94 (d, J = 8.8 Hz, 2H), 6.69-6.37 (m, 1H), 3.91-3.89 (m, 1H),
    3.73 (s, 3H), 3.05-2.90 (m, 3H).
    1717 438.8 1H NMR (DMSO, 300 MHz), δ 11.25-11.16 (m, 1H), 7.55 (s, 10-80 ****
    (cal. 438.1) 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.13-7.07 (m, 3H), 6.93 (d, 5.66
    J = 8.7 Hz, 2H), 6.63-5.95 (m, 1H), 4.20-4.09 (m, 2H), 3.72 (s,
    3H), 3.69-3.62 (m, 1H), 3.45-3.41 (m, 1H), 2.92-2.76 (m, 2H),
    1.22-1.13 (m, 1H), 0.55-0.53 (m, 2H), 0.37-0.34 (m, 2H).
    1718 452.8 1H NMR (CD3CN, 300 MHz), δ 9.19 (b, 1H), 7.53 (d, J = 2.1 Hz, 30-90 ****
    (cal. 452.1) 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.11 (dd, 4.65
    J = 8.7 Hz and 2.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 6.69-5.95 (m,
    1H), 4.32-4.20 (m, 2H), 3.77 (s, 3H), 3.72-3.62 (m, 1H), 3.52-
    3.42 (m, 1H), 2.92-2.86 (m, 2H), 2.76-2.66 (m, 1H), 2.11-2.03
    (m, 2H), 1.90-1.78 (m, 4H).
    1719 452.8 1H NMR (DMSO, 300 MHz), δ 11.22-11.20 (m, 1H), 7.55 (d, 10-80 *
    (cal. 452.1) J = 2.1 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.12-7.06 (m, 3H), 6.96- 5.90
    6.92 (m, 2H), 6.61-5.90 (m, 1H), 5.34-5.30 (m, 1H), 3.72 (s,
    3H), 3.62-3.59 (m, 1H), 3.43-3.40 (m, 1H), 2.92-2.86 (m, 2H),
    1.95-1.86 (m, 2H), 1.72-1.54 (m, 6H).
    1720 494.9 1H NMR (DMSO, 400 MHz), δ 11.22-11.09 (m, 1H), 7.57-7.54 30-90 *
    (cal. 494.1) (m, 3H), 7.39 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.15 (d, 4.82
    J = 8.8 Hz, 2H), 7.09 (dd, J = 8.8 Hz and 2.0 Hz, 1H), 6.95 (d,
    J = 8.4 Hz, 2H), 6.69-6.22 (m, 1H), 3.96-3.91 (m, 1H), 3.76 (s,
    3H), 3.50-3.42 (m, 1H), 3.43-3.40 (m, 2H).
    1721 474.8 1H NMR (DMSO, 400 MHz), δ 11.22-11.09 (m, 1H), 7.55 (s, 30-90 *
    (cal. 474.1) 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.18-7.13 4.74
    (m, 4H), 7.08 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.69-
    6.15 (m, 1H), 3.88-3.85 (m, 1H), 3.72 (s, 3H), 3.50-3.42 (m,
    1H), 2.99-2.89 (m, 2H), 2.30 (s, 3H).
    1722 478.8 1H NMR (DMSO, 300 MHz), δ 11.22-11.12 (m, 1H), 7.55 (d, 10-80 *
    (cal. 478.1) J = 2.1 Hz, 1H), 7.39-7.30 (m, 5H), 7.15 (d, J = 8.7 Hz, 2H), 7.10- 5.87
    7.08 (m, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.69-6.21 (m, 1H), 3.95-
    3.85 (m, 1H), 3.72 (s, 3H), 3.50-3.42 (m, 1H), 2.99-2.89 (m,
    2H).
    1723 M − 1: 489.1  1H NMR (DMSO, 400 MHz), δ 11.28-11.15 (m, 1H), 7.55 (s, 10-80 *
    (cal. 490.1) 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.14 (d, 5.79
    J = 8.4 Hz, 2H), 7.09 (dd, J = 8.4 Hz and 1.6 Hz, 1H), 6.99 (d,
    J = 8.8 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.69-6.17 (m, 1H), 3.90-
    3.85 (m, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 3.50-3.42 (m, 1H),
    2.99-2.89 (m, 2H).
    1724 460.8 1H NMR (DMSO, 400 MHz), δ 11.28-11.15 (m, 1H), 7.56 (s, 10-80 *
    (cal. 460.1) 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.37-7.26 (m, 4H), 7.16 (d, J = 8.4 Hz, 5.80
    2H), 7.09 (dd, J = 8.8 Hz and 1.6 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H),
    6.75-6.20 (m, 1H), 3.90-3.85 (m, 1H), 3.73 (s, 3H), 3.50-3.42
    (m, 1H), 2.99-2.89 (m, 2H).
    #10 467.15 4.51 *****
  • Wherein:
  • 1 star, >1 μM (1000 nM)
  • 2 stars, 0.2 to 1 μM (200 nM to 1000 nM)
  • 3 stars, 0.04 μM to 0.2 μM (40 nM to 200 nM)
  • 4 stars, 0.008 μM to 0.04 μM (8 nM to 40 nM)
  • 5 stars, <0.008 μM (<8 nM)
  • The EC50 data was obtained using the protocol set forth below in Section 8.1.1.
  • LC/MS for certain Compounds was performed on either a Waters 2795 or 2690 model separations module coupled with a Waters Micromass ZQ mass spectrometer using a Waters Xterra MS C18 4.6×50 mm reverse phase column (detection at 254 nM). The methods employed a gradient of acetonitrile (ACN) in water at 2 mL/min at ambient temperature as shown in Table 2a. The mobile phase was buffered with a 0.1 N formic acid.
  • The standard 6 minute method maintains a constant 85/5/10 ratio of water/ACN/1% aqueous formic acid from 0 minutes to 0.5 minutes. The method runs a linear gradient from 85/5/10 at 0.5 minutes to 0/90/10 at 3.5 minutes. The methods holds at 0/90/10 until 4.5 minutes then immediately drops back down to 85/5/10 and holds there until 6 minutes.
  • The non-polar 6 minute method maintains a constant 60/30/10 ratio of water/ACN/1% aqueous formic acid from 0 minutes to 0.5 minutes. The method runs a linear gradient from 60/30/10 at 0.5 minutes to 0/90/10 at 3.5 minutes. The methods holds at 0/90/10 until 4.5 minutes then immediately drops back down to 60/30/10 and holds there until 6 minutes.
  • The polar 6 minute method maintains a constant 90/0/10 ratio of water/ACN/1% aqueous formic acid from 0 minutes to 0.5 minutes. The method runs a linear gradient from 90/0/10 at 0.5 minutes to 20/70/10 at 3.5 minutes. The methods holds at 20/70/10 until 4.5 minutes then immediately drops back down to 90/0/10 and holds there until 6 minutes.
  • TABLE 2A
    %
    1% Aq.
    Time % Acetonitrile % Water Formic Acid Gradient
    Standard
    0.00 5 85 10
    0.50 5 85 10 hold
    3.50 90 0 10 linear
    hold
    4.50 5 85 10 instant
    6.00 5 85 10 hold
    Non-Polar
    0.00 30 60 10
    0.50 30 60 10 hold
    3.50 90 0 10 linear
    hold
    4.50 30 60 10 instant
    6.00 30 60 10 hold
    Polar
    0.00 0 90 10
    0.50 0 90 10 hold
    3.50 70 20 10 linear
    hold
    4.50 0 90 10 instant
    6.00 0 90 10 hold
  • LC/MS for Compounds 1611 and 1669 was performed using a C18-BDS 5 (250×4.6 mm) column with a 0.7 mL/min flow rate. The following solvent gradient was employed using 0.1% TFA/water as solvent A and acetonitrile as solvent B: 20% B for 0-20 minutes, 70% B for 20-30 minutes, 100% B for 30-40 minutes, 20% B for 40-50 minutes.
    • 7. EXAMPLE: FORMULATION OF COMPOUND 1205
  • Compound 1205 is bioavailable in vivo when administered in an aqueous suspension. It is anticipated that Compound 1205 can be clinically administered via a solid-dosage form. For all the studies outlined herein, Compound 1205 was lyophilized prior to formulation to minimize batch-to-batch variations in particle-size.
  • The compound was dissolved in acetonitrile at a concentration of 15 mg/mL. An equal amount of water was added to bring the final concentration to 7.5 mg/mL in a 1:1 acetonitrile/water solution (v/v). The solution was frozen on the shelf of the freeze dryer for a minimum of 3 hours and then lyophilized. The resulting solid was determined to be amorphous by differential scanning calorimetry and polarized light microscopy. Suspensions were prepared by the addition of 0.5% HPMC with 1% Tween-80, followed by stirring and homogenization for 2 minutes.
    • 8. EXAMPLE: PHARMACODYNAMICS OF COMPOUND 1205
  • The examples that follow demonstrate that the Compounds tested can inhibit the production of tumor-generated human VEGF and delay tumor growth. Compounds tested have been shown to inhibit the pathological production of human VEGF by human tumor cells and/or human tumors in an animal model with pre-established human tumors.
    • 8.1 Inhibition of Pathological Production of VEGF
  • 8.1.1 Effect of Compounds on Hypoxia-Inducible Endogenous VEGF Expression
  • The ability of the Compounds to modulate hypoxia-inducible endogenous VEGF expression may be analyzed as follows. VEGF protein levels may be monitored by an ELISA assay (R&D Systems). Briefly, HeLa cells may be cultured for 24-48 hours under hypoxic conditions (1% O2, 5% CO2, balanced with nitrogen) in the presence or absence of a Compound. The conditioned media may then be assayed by ELISA, and the concentration of VEGF calculated from the standard ELISA curve of each assay.
  • A dose-response analysis may be performed using the ELISA assay and conditions described above. The conditions for the dose-response ELISA are analogous to those described above. A series of, e.g., seven different concentrations may be analyzed. In parallel, a dose-response cytotoxicity assay may be performed using Cell Titer Glo (Promega) under the same conditions as the ELISA to ensure that the inhibition of VEGF expression was not due to the cytotoxicity. Dose-response curves may be plotted using percentage inhibition versus concentration of the Compound, and EC50 and CC50 values may be generated for each Compound with the maximal inhibition set as 100% and the minimal inhibition as 0%. In one embodiment, Compounds will have an EC50 of less than 50, less than 10, less than 2, less than 0.5, or less than 0.01.
  • 8.1.2 Compound 1205 Inhibit Pathological VEGF Production in Transformed Cells Grown under hypoxic Conditions
  • This example demonstrates the selective inhibition of Compound 1205 on pathological human VEGF production in transformed HeLa cells grown under stressed conditions while sparing human VEGF production in HeLa cells grown under non-stressed conditions.
  • Experimental Design.
  • HeLa (human cervical carcinoma) cell cultures were established under normoxic conditions (21% oxygen). HeLa cells increase VEGF production 4- to 5-fold in response to hypoxia. In one experimental design, vehicle (0.5% DMSO) alone, or a range of concentrations of Compound #10, Compound 1205, or Compound 1330 was added to the culture medium and the cells were incubated for 48 hours. At the completion of treatment, the conditioned media were collected and the VEGF protein levels were assayed in an enzyme-linked immunosorbent assay (ELISA) with primary antibodies that recognize the soluble VEGF121 and VEGF165 isoforms (R & D Systems, Minneapolis, Minn., USA). To ensure that decreases in VEGF concentration were not due to cytotoxicity, cultures were assayed using a standard assay (CellTiter-Glo® Luminescent Cell Viability Assay; Promega, Madison, Wis., USA) that measures total cellular adenosine triphosphate (ATP) concentrations as an indicator of cell viability.
  • Results.
  • FIG. 1 shows the concentrations of VEGF in conditioned media across the dose range tested for Compound #10, Compound 1205 and Compound 1330. The data indicate that Compound #10 and Compound 1205 inhibit stress-induced VEGF production.
  • 8.1.3 Compound 1205 Reduces Tumor and Pathological Plasma VEGF Concentrations In Vivo
  • This example demonstrates that Compound 1205 reduces intratumoral and pathological plasma human VEGF concentrations in vivo.
  • Experimental Design.
  • Human HT1080 cells (5×106 cells/mice) were implanted subcutaneously into male athymic nude mice. Human HT1080 cells constitutively produce human VEGF. Treatment with vehicle alone or Compound 1205 was initiated when the median tumor volume was approximately 311±88 mm3. Table 3 and Table 4 provide the study design for assessing tumor and pathological plasma VEGF concentrations—each group in each study included eight (8) mice. When the tumors in vehicle-treated mice had reached the target size of about 1200 mm3 for study #21 and about 1500 mm3 for study #23, all mice in the study were sacrificed, and excised tumors were homogenized in buffer containing protease inhibitors. Both intra-tumor and plasma human VEGF levels were measured using an ELISA that recognizes human VEGF121 and VEGF165. Intra-tumor VEGF levels were normalized to the total tumor protein concentration and plasma VEGF levels were expressed in pg/mL. Because smaller tumors produce less VEGF per mg of tumor protein, intra-tumor VEGF levels were normalized to tumor size. Table 4 provides the study design for assessing tumor and plasma VEGF.
  • Results.
  • Treatment with Compound 1205 at 0.5 or 3 mg/kg for 14-days significantly reduced the levels of human VEGF measured in excised tumors (FIG. 2) and in plasma (FIG. 3) compared to levels measured in tumors and plasma from mice treated with vehicle. At the dose of 0.5 or 3 mg/kg QD, Compound 1205 inhibits both tumor and plasma VEGF levels by more than 95%. Even with the reduction in tumor size in the treated groups, the volume normalized intra-tumor VEGF levels were significantly reduced (FIG. 2; Table 3).
  • TABLE 3
    Inhibition of Intra-Tumor and Plasma VEGF by Compound 1205
    Study #21 Study #23
    Vehicle Compound 1205 Vehicle Compound 1205
    1) Dose (mg/kg)  0 0.5  3  0  1
    2) Regimen QD QD QD QD QD
    3) Test-Compound duration (days) 14 14   14 14 14
    4) Mean difference in human NA 95%** 98%** NA  95**
    tumor VEGF (%) at Day 14
    (Compound 1205) or Day 18
    (Compound #10)
    5) Mean difference in human NA 97%** 99%  NA 100%**
    plasma VEGF (%) on Day 14
    (Compound 1205) or on Day
    18 (Compound #10)
    **p < 0.05 (ANOVA vs. vehicle).
    • 8.2 Compound 1205 Inhibits Tumor Growth In Vivo
  • This example demonstrates that Compound 1205 inhibits tumor growth in nude mice bearing HT1080 xenografts.
  • Experimental Design.
  • HT1080 cells (5×106 cells/mouse) were implanted subcutaneously in male athymic nude mice. When tumors had become established (i.e., the mean tumor size had reached 311±88 mm3), mice were divided into 5 groups and treatment was administered as shown in Tables 4 and 5. Compound 1330 is a relatively inactive (R,S) diastereomer of Compound 1205, which has (S,S) configuration. For comparison, Compound #10 was included in this study.
  • TABLE 4
    Study Design for HT1080 Xenograft Studies Assessing In Vivo
    Efficacy of Compound 1205 and Compound #10.
    Dose Dose
    Test # of Animals Dose Volume Conc.
    Compound (Male) (mg/kg) Regimen (mL/kg) (mg/mL) Study # Study Termination
    Vehicle† 8 0 QD 8 0 21 All mice were taken off study
    Compound
    8 0.5 QD 8 0.0625 21 when tumors in vehicle
    1205 reached 1200 mm3
    Compound 8 3 QD 8 0.375 21
    1205
    Vehicle† 8 0 QD 8 0 22 (A) Vehicle-treated mice were
    Compound 8 0.5 QD 8 0.0625 22 taken off study when the
    1205 average tumor size of the
    Compound 8 3 QD 8 0.375 22 group wais 1500 mm3. (B)
    1205 Each treated mouse was taken
    off study when its tumor was
    1500 mm3
    Vehicle† 8 0 QD 8 0 23 All mice were taken off study
    Compound
    8 1 QD 8 0.125 23 when tumors in vehicle
    1205 reached 1500 mm3
    Vehicle† 8 0 QD 8 0 24a A) Vehicle- and Compound
    Compound
    8 10 QD 8 1.25 24a 1330 -treated mice were taken
    1205 off study when the average
    Compound
    8 10 QD 8 1.25 24a tumor size of the group wais
    1330 Φ 1500 mm3. (B) Each treated
    mouse was taken off study
    when its tumor was 1500 mm3
    Vehicle† 8 0 QD 8 0 24b (A) Vehicle-treated mice were
    Compound 8 0.3 QD 8 0.0375 24b taken off study when the
    1205 average tumor size of the
    group wais 1500 mm3. (B)
    Each treated mouse was taken
    off study when its tumor was
    1500 mm3
    †Vehicle was 0.5% HPMC/1% Tween-80
    ‡ Vehicle was L21 (35% Labrasol, 35% Labrafac, and 30% Solutol).
    Φ Inactive (R, S) diastereomer of Compound 1205
    Abbreviations:
    BID = twice per day,
    QD = once per day
  • Results.
  • The results of the studies are described in Table 5 and FIG. 4. The data shown in FIG. 4 is for study #24a. The data indicate that Compound 1205 (S,S) inhibits tumor growth in an animal model with a pre-established human tumor. As shown in FIG. 4, treatment with Compound 1205 (S,S), but not with the (R,S) diastereomer Compound 1330, significantly delayed growth of HT1080 tumor cells in vivo. The growth of the tumors in mice treated with Compound 1330 overlapped with the growth of tumors in mice treated with 0.5% HPMC vehicle. See FIG. 4. This suggests that the relatively inactive (R, S) diastereomer (Compound 1330) does not appreciably isomerize to active Compound 1205 in vivo. Compound 1205 is active at doses as low as 0.3 mg/kg.
  • TABLE 5
    Effect of Compound 1205 and Compound #10 on Growth of HT1080 Tumor Cells in vivo.
    Compound
    Compound 1205 #10
    Study Information
    1) Study #C  24b  22  21  23  22  21  24a  24a
    2) Dose (mg/kg)   0.3   0.5   0.5   1   3   3  10  10
    3) Regimen QD QD QD QD QD QD QD QD
    4) Dose (mg/kg/week)   2.1   3.5   3.5   7  21  21  70  70
    5) Study design Xeno Xeno PD PD Xeno PD Xeno Xeno
    6) Number of days that test  16A  28A  14  14  32A  14  30A  27A
    compound was administered
    7) Initial mean tumor size  204  170  167  157  170  167  311  311
    (mm3)
    8) Day that vehicle-treated  15  11  14  14  11  14  11  11
    mice were taken off study
    9) Mean tumor size in vehicle- 1790 1390 1210 1500 1390 1210 1500 1500
    treated mice when taken off
    study
    10) Final mean terminal tumor 1540 1750  580  710 1840  379 1400 1460
    size in treatment group (mm3)
    Results
    11) Mean difference in tumor  28%  62%**  61%**  59%**  75%**  80%**  76%**  59%**
    growth rate at the Day that the
    vehicle-treated tumors taken
    off study (%)B
    12) Difference vs. vehicle in   0.7  11 NA NA  14** NA  14**   8**
    median number of days to
    reach 1000 mm3 (Days)
    ASee Table 4 for additional study information.
    B% Difference in the rat of growth in compound-treated vs. vehicle-treated
    **P < 0.05 (ANOVA vs. vehicle)
    CAverage time on study.
    NA not applicable. The time to progression could not be calculated for PD (pharmacodynamic) studies
    • 8.3 Compound 1205 Provokes a Late G1/Early S-Phase Cell Cycle Delay
  • This example demonstrates that Compound 1205 provokes a cell cycle delay at the G1/S-phase border.
  • Experimental Design. During the in vitro evaluation of Compound 1205 effects on VEGF expression, an examination of its actions on tumor cell cycling was performed. HT1080 cells were incubated under normoxic conditions (21% oxygen) for 18 hours with vehicle (0.5% DMSO) alone, or with 10 nM of Compound 1205. After treatment, cells were trypsinized, and stained with propidium iodide (PI) dye to measure DNA content of individual cells by flow cytometry. Output comprised histograms showing relative DNA content in 10,000 cells.
  • Results.
  • As shown in FIG. 5, Compound 1205 induced a redistribution of the cycling characteristics of the cell population.
    • 9. EXAMPLE: SELECTIVITY OF COMPOUND 1205 FOR HUMAN VEGF
  • This example demonstrates that Compound 1205 is selective for human VEGF.
  • Experimental Design.
  • After mouse tumors reached 1500 mm3, mice were sacrificed and tissues were collected at the time of necropsy, homogenized, and analyzed. On average, mice treated with Compound 1205 at 0.5 mg/kg were on study for 28 days, and mice treated with Compound 1205 at 3 mg/kg were on study for 32 days.
  • Results.
  • As shown in FIG. 6, Compound 1205 did not significantly decrease murine kidney VEGF levels, indicating that Compound 1205 is likely to act in a species-selective manner.
    • 10. EXAMPLE: INHIBITION OF VIRAL REPLICATION Viral Replication Assays
  • A person of ordinary skill in the art may test a Compound for antiviral activity using a variety of different approaches, with a representative number of selected examples as detailed below.
  • HCV Replicon Assay
  • The lack of validated and readily accessible cell-culture whole virus infection systems and small animal models permissive for HCV replication has limited the development of new anti-HCV agents. Self-replicating genomic and subgenomic HCV systems, termed HCV replicons, have been described and have been widely used to assess the efficacy of anti-HCV inhibitors (see Blight K J, et al., 2000, Efficient initiation of HCV RNA replication in cell culture. Science 290:1972-1974; Blight K J, et al., 2002, Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J Virol 76:13001-13014; Ikeda M, et al., 2002. Selectable subgenomic and genome-length dicistronic RNAs derived from an infectious molecular clone of the HCV-N strain of hepatitis C virus replicate efficiently in cultured Huh? cells. J Virol 76:2997-3006; Lohmann V, et al., 1999, Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110-113; Pietschmann T, et al., 2002, Persistent and transient replication of full-length hepatitis C virus genomes in cell culture. J Virol 76:4008-4021; and, Pietschmann T, et al., 2001, Characterization of cell lines carrying self-replicating hepatitis C virus RNAs. J Virol 75:1252-1264).
  • U.S. Pat. No. 6,630,343 describes a bicistronic HCV 1b replicon and 2a replicon for use in testing a Compound by quantitating replicon RNA (GenBank Accession No. AJ242654) reduction and/or the Fluc reporter signal. The amount of HCV replicon RNA is determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In some cases, a Compound is tested against the HCV replicon in a spheroid culture. Replicon-containing cells may be cultured with a Compound for up to 3 days. Interferon (IFN) a is used as a positive control.
  • Standard cell culture assays employing hepatitis C virus (HCV) subgenomic replicons showed that the Compound had an average IC50 of 0.036 μM against the genotype 1b replicon and an IC50 of <0.003 μM against the genotype 2a replicon. Performing a replicon assay under three-dimensional culture conditions (spheroid culture) resulted in an IC50 of 0.001 μM against the genotype 1b replicon and >310 fold selectivity index. Notably, the R-enantiomer of the Compound failed to exhibit significant antiviral activity in parallel experiments.
  • Attempts to generate resistant HCV replicons using standard virological techniques were unsuccessful despite exposure of replicon cells to the Compound under various conditions for up to four months. Classical antivirals acting directly on viral targets typically generate robustly resistant variants within 3-4 weeks using this technique.
  • Poliovirus (PV) Assay
  • Antiviral activity is tested against PV strain Mahoney (obtained from Dr. Eckard Wimmer, State University of New York at Stony Brook, Stony Brook, N.Y.) in HeLa S3 cells by determining the viral RNA reduction using qRT-PCR. HeLa S3 cells are seeded onto 96 well plates at a density of 5000 cells per well and incubated in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin at 37° C. under 5% CO2 for 24 hours and then treated with a Compound at a series of test concentrations for 18 hours. The cells are then infected with PV at a multiplicity of infection of 0.1 in DMEM without FBS for 30 minutes, followed by treatment with a Compound at a series of concentrations in DMEM with 1% FBS for 20 hours. After removing supernatant and washing the cells with PBS, RNA is prepared by adding 50 μL of Cells-to-cDNA Cell Lysis Buffer (Ambion, Catalog #8723) to each well and then heating at 75° C. for 10 minutes. The cell lysate is then treated with DNase I (DNA-free™ Ambion, Catalog #1906) at 37° C. for 20 minutes and then heated at 75° C. for 5 minutes to inactivate DNase. cDNA is prepared using iScript RT kit (Bio-Rad, Catalog #170-8897). The viral cDNA is determined by qRT-PCR using a pair of primers and a probe complementary to the viral internal ribosome entry site. The IC50 shown in Table 7 is calculated based on percentage of viral RNA reduction under treatment of a Compound using Prism nonlinear fit sigmoidal dose-response variable slope (GraphPad Prism Software).
  • Additionally, in a 24-hour assay of infected HeLa cells when the Compound was added about 16 hours pre-infection, PV was inhibited with an average IC50 of 0.0006 μM. Adding the Compound at the time of infection, though, resulted in a 65-fold decrease in activity. In HT-1080 cells, the Compound inhibited PV with an average IC50 of 0.0004 μM. A variant HT-1080 cell line which displayed resistance to the cell cycle effects of the Compound was generated through serial passage; in these cells the Compound inhibited PV with an average IC50 of 4.7 μM, a 10,000-fold difference in activity from that observed in non-resistant cells.
  • Other Viral Assays
  • Antiviral activity of a Compound against WNV is tested in Vero cells by protection of virus induced cytopathic effects (i.e. cytoprotection measured as cell viability, IC50). The effect of a Compound on inhibition of virus induced cytopathic effects is determined using MTS (CellTiter) assay.
  • Antiviral activity against vaccinia virus is determined in Vero E6 cells by a plaque reduction assay. For a plaque reduction assay, inhibition of viral replication is determined as a reduction in virus-induced plaque formation assessed by microscopic inspection following staining of the culture with crystal violet.
  • Antiviral activity against HIV-1 is determined in a human cell line. The Compound prevented cytopathic effect 3 days post-infection with an EC50 of 0.022 μM when normalized to cell number after treatment in the absence of infection. The activity against HIV may also be tested in human peripheral blood mononuclear cells in cell culture.
  • TABLE 7
    Activity of Compound #10 in Antiviral Assay Panel
    Virus Cell line Assay IC50 (μM) IC90 (μM) CC50 (μM)
    Vaccinia DNA Vero E6 Plaque 0.040 0.080 0.083
    Adenovirus DNA HeLa CPE protection >1 >1 >1
    HSV-1 DNA Vero CPE protection >1 >1 >1
    Influenza A (−) RNA MDCK CPE protection >1 >1 >1
    Parainfluenza (−) RNA Vero CPE protection 0.029 0.044 >1
    RSV (−) RNA Vero CPE protection 0.25 >0.16 >1
    Yellow Fever (+) RNA HeLa CPE protection >1 >1 >1
    Dengue 2 (+) RNA Vero E6 CPE protection >1 >1 0.70
    WNV (+) RNA Vero CPE protection 0.067 0.28 >1
    PV (+) RNA HeLa qRT-PCR 0.00057 0.0028 >1
    HIV-1 Retro MT-2 CPE protection 0.022 NA 0.0041
  • Results.
  • As shown in Table 7, the Compound has inhibitory activity against a diverse panel of DNA viruses, RNA viruses and retroviruses in vitro. At the doses tested in the human or monkey cell lines tested, the Compound did not inhibit the two DNA viruses adenovirus and herpes simplex virus-1 (HSV-1). At the doses tested in the human or monkey cell lines tested, the Compound was inactive against the two RNA viruses dengue and yellow fever. However, the Compound displayed potent activity against the three RNA viruses parainfluenza virus, respiratory syncytial virus (RSV), and West Nile virus (WNV) in the cell lines tested. The Compound did not exhibit any selective inhibition of influenza virus when grown in the canine kidney cell line tested. The broad-spectrum activity of the Compound was demonstrated by its inhibition of both plus-strand (PV, HCV, WNV) and minus-strand (RSV, parainfluenza) RNA viruses. No antiviral activity was detected for the R-enantiomer of the Compound.
    • 11. EXAMPLE: EFFECT OF COMPOUND #10 IN A 786-0 RENAL CANCER CELL LINE (VHL-NEGATIVE)
  • The in vivo activity of Compound #10 was assessed as a monotherapy and in combination with sunitinib (e.g., branded/marketed as SUTENT®) or rapamycin (e.g., branded/marketed as RAPAMUNE®) in a renal cell carcinoma (RCC) model (786-0 cells) in vivo. Both sunitinib and rapamycin are used clinically for treatment of renal cancer.
  • The 786-O cell line does not express the von Hippel-Lindau (VHL) protein (VHL-negative cell), therefore preventing its interaction with HIF-1α (hypoxia-inducible factor 1α), which accumulates and stimulates expression of growth factors, such as vascular endothelial growth factor (VEGF), that are responsible for the high vascularization of RCC (see Turcotte S, Desrosiers RR, Béliveau R. Hypoxia upregulates von Hippel-Lindau tumor-suppressor protein through RhoA-dependent activity in renal cell carcinoma. Am J Physiol Renal Physiol. First published 2003 Oct. 23; doi:10.1152/ajprenal.00254.2003; and, Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL−/− tumors. Mol Cancer Res. 2004 2:89-95). Individuals with mutations in the VHL gene resulting in von Hippel-Lindau disease are at increased risk for developing clear cell carcinoma of the kidney, which is the most common histologic type of renal cancer. Biallelic VHL mutations (frequently involving point mutation of one allele and loss of the other) are common in sporadic renal cell carcinomas of the clear cell type (Kim W Y and Kaelin WG. The role of VHL gene mutation in human cancer. J Clin Oncol. In press 2004). Moreover, VHL inactivation due to DNA hypermethylation has been documented in some renal cell carcinomas that lack VHL mutation (Herman J G, Latif F, Weng Y, et al Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA 1994; 91:9700-4).
  • Sunitinib inhibits the kinase activities of VEGF receptors, platelet derived growth factor (PDGF) receptors, Flt3, and c-kit (CD117; see Mendel D B, Laird A D, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003; 9:327-37). SUTENT® is approved for treatment of RCC, having demonstrating clinical efficacy (Package insert for SUTENT®; http://www.pfizer.com/files/products/uspi_sutent.pdf). Previous studies have demonstrated that Compound #10 demonstrates favorable activities compared with sunitinib and an additive effect with sunitinib in a mouse lung cancer xenograft model. In the previous study, the dose utilized was 50 mg/kg. Here, a dose of 75 mg/kg was used.
  • The mTOR (mammalian target of rapamycin) inhibitors rapamycin and analogs are active in RCC in preclinical models and in the clinic (see Dasanu C A, Clark B A, Alexandrescu DT. mTOR-Blocking Agents in Advanced Renal Cancer: An Emerging Therapeutic Option. Expert opinion on investigational drugs 2009; 18(2):175-87; Package insert for rapamycin: http://www.huntingtonproject.org/Portals/0/rapamycin.pdf). The antitumor activity of agents that block the PI3-K/Akt/mTOR pathway may at least in part be attributable to the suppression of tumor angiogenesis as a result of suppression of VEGF production at the translational level. Although mTOR inhibitors block cap-dependent translation, the VEGF mRNA can be translated by a cap-independent mechanism, possibly involving the use of an internal ribosome entry site (IRES). Stressful conditions (e.g., rapamycin-treatment) may favor the use of this alternative pathway. An additive or synergistic combination between the two approaches (Compound #10 and an mTOR inhibitor) may produce an optimal blockade of VEGF via different pathways.
  • 786-O cells were obtained from the American Type Culture Collection (ATCC) (Manassas, Va.) and cultured using methods provided by the ATCC.
  • Compound #10 was formulated in 30% Solutol HS15®, 35% Labrasol®, and 35% Labrafac® (L21) and stored at room temperature in ambient humidity and protected from light. Rapamycin was formulated in 0.4% ethanol (100%) stock, which was stored at −70° C. in aliquots and aliquot thawed daily for dilution. The stock of rapamycin was then diluted in 5% Tween-80, 5% PEG-400, 90% water. Sunitinib was formulated in 0.5% HPMC and 1% Tween-80.
  • TABLE 8
    Dosing Solutions and Suspensions
    Dose Concentration
    Test Compound Dose (mg/kg) Dosing Volume (mg/mL)a)
    Vehicle (L21) 0 0.1 mL/mouse 0
    Compound #10 10 0.1 mL/mouse 2.8, 2.8, 3.0, 3.1
    Sunitinib 75 0.2 mL/mouse 10.5, 10.5, 11.25,
    11.62, 11.62
    Rapamycin 15 0.1 mL/mouse 4.2
    aMice weighed an average of 28 g at the time dosing was initiated. The concentration of the dosing solution was adjusted as necessary so that a volume of 0.1 mL delivered the target dose. The dosing solutions were prepared five times.
  • Mice were inoculated with 786-0 tumor cells (5×106 cells/mouse) obtained from the ATCC (CRL-1932; Manassas, Va.). Tumor cells were mixed 1:1 with BD MATRIGEL™ (Becton, Dickinson and Company, San Jose, Calif.) prior to inoculation. Mice were inoculated using a 25-gauge needle in the right flank in a volume of 0.2 mL. A total of 100 mice were injected, of which 60 were used in the study.
  • Fourteen days after inoculation, the mice were randomized into six groups as outlined in Table 9. Animals were distributed into groups such that the average tumor size did not differ between groups. Groups were taken off study when the mean tumor volume in a group was 1300 mm3 or more. Vehicle-treatment started on Day 0 and continued through Day 57. Compound #10-treatment started on Day 0 and continued through Day 88.
  • TABLE 9
    Group Designations
    Compound #
    10
    Dose (mg/kg), Chemotherapy No of
    Group Treatment Route, Regimen Treatment Dose (mg/kg), Route, Regimen Mice
    1 Vehicle 0 None None 10
    2 Compound 10, PO, QD None None 10
    #10
    3 Vehicle 0 Sunitinib 75 mg/kg PO, QD 10
    4 Compound 10, PO, QD Sunitinib 75 mg/kg PO, QD 10
    #10
    5 Vehicle 0 Rapamycin 15 mg/kg PO, Days 0-4, 7-11, 10
    65-67, 70-74, 77 and 78
    6 Compound 10, PO, QD Rapamycin 15 mg/kg PO, Days 0-4, 7-11, 10
    #10 65-67, 70-74, 77 and 78
    Abbreviations:
    No = number,
    PO = oral dosing,
    QD = once per day.
  • Body Weight: The mice were weighed once per week.
  • Tumor Size: Tumors were measured twice per week using digital calipers. To calculate tumor volume, the following calculation was used, where L equals the longest dimension measurement and W equals the shortest dimension measurement:
  • Tumor Volume = L × ( W ) 2 2
  • Clinical Observations: Each animal was observed twice daily for mortality and signs of pain or distress. Findings of overt toxicity were recorded as they were observed.
  • Plasma VEGF: Plasma was run in the Human VEGF ELISA, R&D Systems Cat#DY293B. Plasma was diluted at 1:1 with reagent diluent prior to quantification via ELISA.
  • Tumor Growth was calculated as:

  • [1−[(final tumor size minus initial tumor size in test compound treated−mice)/(final tumor size minus initial tumor size in vehicle-treated mice)]×100%
  • Values were calculated for individual mice and then averaged across the group.
  • Body Weight: The mice were weighed once per week. The percent change was calculated as:

  • [(Body weight on Day of study)−(initial body weight)/(initial body weight)]×100%
  • Values were calculated for individual mice and then averaged across the group.
  • The time to progression to reach a tumor volume 1000 mm3 was calculated for each mouse. The median values were reported. For statistical analysis, if the tumor in a given mouse did not reach 1000 mm3, the time on study was utilized (eg, 119 days for mice in the sunitinib-treated group). Differences in tumor size, tumor growth, and body weight change between groups were analyzed by Two-way ANOVA (Bonferroni).
  • Results: Vehicle and Compound #10 Monotherapy:
  • All mice treated with vehicle or with Compound #10 survived until sacrificed (at the time that the mean tumor size of the group reached about 1500 mm3). Mouse 2-10 treated with Compound #10 (10 mg/kg) was cured, as defined by reduction of tumor size (<60 mm3), such that the tumor was not measurable or appeared to be absent.
  • Results: Sunitinib Monotherapy:
  • All mice treated with sunitinib survived until sacrificed (at the time that the mean tumor size of the group reached about 1500 mm3). From Day 7 onward, all mice in Group 3 (sunitinib, 75 mg/kg) had yellow-tinged skin.
  • Results: Combination of Compound #10 and Sunitinib:
  • From Day 7 onward, all mice in Group 4 (Compound #10 and sunitinib) had yellow-tinged skin. Mouse 4-3 and mouse 4-5 in Group 4 (Compound #10 and sunitinib) were sacrificed on Day 87.
  • Results: Rapamycin Monotherapy and Combination of Compound #10 and Rapamycin:
  • All mice treated with rapamycin survived until sacrificed (at the time that the mean tumor size of the group reached about 1500 mm3).
  • Results: Tumor Measurements:
  • A total of 60/100 mice that were inoculated with 786-O cells developed tumors that were within the appropriate range at the start of this study. The tumor volume (mean±SD) for mice used in this study was 297±53 mm3 at the initiation of treatment.
  • FIG. 9 and FIG. 11 show the effect of Compound #10 alone and in combination with sunitinib and rapamycin, respectively, on mean tumor size over the study time period. Tumors in vehicle-treated mice grew from a size (mean±SD) 297±57 mm3 to 1442±322 mm3 on Day 57. The median time to reach 1000 mm3 or more was 50 days.
  • Tumors in Compound #10-treated mice (10 mg/kg QD, PO) grew from a size (mean±SD) of 296±62 mm3 to 1569±671 mm3 on Day 88. Tumors in Compound #10-treated mice were smaller than vehicle-treated mice. On Day 57, tumors in Compound #10-treated mice were 945±408 mm3, or 34% smaller than the mean tumor size in vehicle-treated mice (p<0.05 ANOVA, multiple comparisons vs vehicle). The median time for tumors in Compound #10-treated mice to reach 1000 mm3 was 71 days.
  • Tumors in sunitinib-treated mice (75 mg/kg QD, PO) grew from a size (mean±SD) of 297±24 mm3 on Day 0 to 709±938 mm3 on Day 119. By Day 119, 1 of the 10 mice in the treatment group had died. On Day 57, tumors in sunitinib-treated mice were 83% smaller than those in vehicle-treated mice. The median time for tumors in sunitinib-treated mice to reach 1000 mm3 was 119 days (p<0.05, ANOVA—multiple comparisons vs vehicle control).
  • Tumors in rapamycin-treated mice grew from a size (mean±SD) of 296±64 mm3 on Day 0 to 1715±393 mm3 on Day 93. By Day 93, 1 of the 10 mice in the treatment group had died. On Day 57, tumors in rapamycin-treated mice were 49% smaller than those in vehicle-treated mice. The median time for tumors in rapamycin-treated mice to reach 1000 mm3 was 87 days (p<0.05, ANOVA—multiple comparisons vs vehicle control).
  • The combination of Compound #10 and sunitinib was not more effective than sunitinib only, and unexpectedly, the combination of sunitinib and Compound #10 was less effective than sunitinib only. Tumor volume was significantly smaller in mice treated with sunitinib-only than that in mice treated with the combination of Compound #10 and sunitinib on Days 22 to 84. By Day 119, 2 of the 10 mice in the treatment group were sacrificed due to sickness on Day 87. The median time for tumors in mice treated with the combination of sunitinib and Compound #10-treated mice to reach 1000 mm3 was 119 days.
  • The combination of Compound #10 and rapamycin was more effective than rapamycin only. Differences in tumor volume were significantly different on Day 57 to 88. The median time for tumors in mice treated with the combination of rapamycin and Compound #10 mice to reach 1000 mm3 was 119 days.
  • Effect of Treatment on Body Weight:
  • Mice were not randomized by body weight but by initial tumor size. Nevertheless, the mean initial body weights did not statistically differ between treatment groups. The effect of treatment was determined by normalizing the body weight over time to initial body weight (i.e., by determining the percent change from the initial body weight).
  • FIG. 10 and FIG. 12 show the effect of Compound #10 alone and in combination with sunitinib and rapamycin, respectively, on mean tumor size over the study time period.
  • Vehicle-treated mice did not lose weight from their initial body weight at any point over the course of the study.
  • Compound #10-treated mice did not lose weight from their initial body weight at any point over the course of the study. Body weights did not statistically differ between vehicle-treated and Compound #10-treated mice.
  • Sunitinib-treated mice transiently lost weight as measured at Day 14 (p<0.05, ANOVA—multiple comparisons vs vehicle control, and Compound #10). Mice then gained weight, with the weight gain from Day 0 reaching significance by Day 46 (p<0.05, ANOVA—multiple comparisons vs vehicle control, and Compound #10), and remaining significant through Day 119.
  • Rapamycin-treated mice transiently lost weight as measured at Day 7 and Day 14 (2.4% loss and 2.8% loss on Day 7 and 14, respectively; p<0.05, ANOVA—multiple comparisons vs vehicle control and vs Compound #10).
  • The mean body weight in mice treated with the combination of Compound #10 and sunitinib was greater than that of mice treated with sunitinib-only on Day 14 and Day 57 (p<0.05, ANOVA—multiple comparisons). Therefore, Compound #10 prevented the transient weight loss observed in sunitinib-treated mice.
  • The mean body weight in mice treated with the combination of Compound #10 and rapamycin did not weigh more than those treated with rapamycin-only. Therefore, the addition of Compound #10 did not prevent rapamycin-induced weight loss.
  • Discussion of Results
  • Treatment of mice with Compound #10 delayed the growth of 786-0 renal cells in vivo. The median time to reach 1000 mm3 was 50 days in vehicle-treated mice vs 71 days in Compound #10-treated mice. The median time to reach 1000 mm3 in sunitinib-treated mice was 119 days. Compound #10 was not as effective as sunitinib at the dose of sunitinib used in this study (75 mg/kg). Sunitinib publications describe a typical dose of about 40 mg/kg (see, Bagi C M, Christensen J, Cohen D P, Roberts W G, Wilkie D, Swanson T, Tuthill T, Andresen C J. Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block growth and recovery of human hepatocellular carcinoma in a rat xenograft model. Cancer Biol Ther. 2009 May; 8(9):856-65; Hillman G G, Singh-Gupta V, Zhang H, Al-Bashir A K, Katkuri Y, Li M, Yunker C K, Patel A D, Abrams J, Haacke EM. Dynamic contrast-enhanced magnetic resonance imaging of vascular changes induced by sunitinib in papillary renal cell carcinoma xenograft tumors. Neoplasia. 2009 September; 11(9):910-20; and, Zhang L, Smith K M, Chong A L, Stempak D, Yeger H, Marrano P, Thorner P S, Irwin M S, Kaplan D R, Baruchel S. In vivo antitumor and antimetastatic activity of sunitinib in preclinical neuroblastoma mouse model. Neoplasia. 2009 May; 11(5):426-35). At the dose used in this study, the skin of the mice were yellow-tinged.
  • Rapamycin delayed the growth of 786-0 renal tumor cells in vivo. Dosing of rapamycin was limited by weight loss. In addition, the combination of Compound #10 and rapamycin did not prevent weight loss.
  • The tumor did not induce weight loss, and there were no differences in the body weight gain in the vehicle-treated mice as in the monotherapy Compound #10-treated mice. While sunitinib-treated mice transiently lost weight then regained the weight mice treated with the combination of Compound #10 and sunitinib did not lose weight, indicating that Compound #10 prevented sunitinib-induced transient weight loss. Mice treated with the combination of Compound #10 and rapamycin lost weight, indicating that Compound #10 did not prevent rapamycin-induced weight loss in this cell line.
  • The combination of Compound #10 and sunitinib was not as effective as sunitinib alone, perhaps as a result of either a pharmacodynamic or pharmacokinetic drug-drug interaction.
    • 12. EXAMPLE: EFFECT OF COMPOUND #10 IN A CAM-1 RENAL CANCER ANIMAL MODEL (VHL-POSITIVE)
  • The in vivo activity of Compound #10 was assessed as a monotherapy and in combination with sunitinib (e.g., branded/marketed as SUTENT®) or rapamycin (e.g., branded/marketed as RAPAMUNE®) in a renal cell carcinoma (RCC) model (Caki-1 cells) in vivo. The Caki-1 cell line expresses the von Hippel-Lindau (VHL) protein which acts as a tumor suppressor by promoting the rapid degradation of HIF-1α (hypoxia-inducible factor 1α) under normoxia. Under hypoxic conditions, HIF-1α is stabilized and activated by the inability of VHL to act resulting in increased transcription of VEGF that is responsible for the high vascularization of RCC (see Turcotte et al, 2003, Zimmer et al, 2004).
  • Caki-1 cells were obtained from the American Type Culture Collection (ATCC) (Manassas, Va.) and cultured using methods provided by the ATCC.
  • Compound #10 was formulated in 30% Solutol HS15®, 35% Labrasol®, and 35% Labrafac® (L21) and stored at room temperature in ambient humidity and protected from light.
  • Rapamycin was formulated in 0.4% ethanol (100%) stock, which was stored at −70° C. in aliquots and aliquot thawed daily for dilution. The stock of rapamycin was then diluted in 5% Tween-80, 5% PEG-400, 90% water.
  • Sunitinib was formulated in 0.5% HPMC and 1% Tween-80.
  • TABLE 10
    Dosing Solutions and Suspensions
    Dose Concentration
    Test Compound Dose (mg/kg) Dosing Volume (mg/mL)a)
    Vehicle (L21) 0 0.1 mL/mouse 0
    Compound #10 10 0.1 mL/mouse 3.0, 3.45, 3.23
    Sunitinib 75 0.2 mL/mouse 6.67, 6.90, 6.45
    Rapamycin 15 0.1 mL/mouse 4.35
    aMice weighed an average of 29 g at the time dosing was initiated. The concentration of the dosing solution was adjusted as necessary so that a volume of 0.1 mL delivered the target dose. The dosing solutions were prepared three times.
  • Mice were inoculated with Caki-1 tumor cells (5×106 cells/mouse) obtained from the ATCC (Manassas, Va.). Tumor cells were mixed 1:1 with BD MATRIGEL™ (Becton, Dickinson and Company, San Jose, Calif.) prior to inoculation. Mice were inoculated using a 25-gauge needle in the right flank in a volume of 0.2 mL. A total of 100 mice were injected, of which 60 were used in the study.
  • Thirty days after inoculation, the mice were randomized into six groups as outlined in Table 11. Animals were distributed into groups such that the average tumor size did not differ between groups. Groups were taken off study when the mean tumor volume in a group was 1300 mm3 or more. Vehicle-treatment started on Day 0 and continued through Day 35. Compound #10-treatment started on Day 0 and continued through Day 52.
  • TABLE 11
    Group Designations
    Compound #
    10 Chemotherapy
    Dose (mg/kg), Dose (mg/kg), Route, Number of
    Group Treatment Route, regimen Treatment regimen Mice
    1 Vehicle 0 None None 10
    2 Compound 10, PO, QD None None 10
    #10
    3 Vehicle 0 Sunitinib 75 mg/kg PO, QD 10
    4 Compound 10, PO, QD Sunitinib 75 mg/kg PO, QD 10
    #10
    5 Vehicle 0 Rapamycin 15 mg/kg PO, Days 0-4, 6-10, 10
    51-53, 56-60, 63 and 64
    6 Compound 10, PO, QD Rapamycin 15 mg/kg PO, Days 0-4, 6-10, 10
    #10 51-53, 56-60, 63 and 64
    Abbreviations:
    PO = oral dosing,
    QD = once per day.
  • Tumor Size: Tumors were measured twice per week using digital calipers. To calculate tumor volume, the following calculation was used, where L equals the longest dimension measurement and W equals the shortest dimension measurement:
  • Tumor Volume = L × ( W ) 2 2
  • Clinical Observations: Each animal was observed twice daily for mortality and signs of pain or distress. Findings of overt toxicity were recorded as they were observed.
  • Plasma VEGF: Plasma was run in the Human VEGF Elisa, R&D Systems Cat#DY293B. Plasma was diluted at 1:1 with reagent diluent prior to quantification via ELISA.
  • Tumor Growth was calculated as:

  • [1−[(final tumor size minus initial tumor size in test compound treated-mice)/(final tumor size minus initial tumor size in vehicle-treated mice)]×100%
  • Values were calculated for individual mice and then averaged across the group.
  • Body Weight: The mice were weighed once per week. The percent change was calculated as:

  • [(Body weight on Day of study)−(initial body weight)/(initial body weight)]×100%
  • Values were calculated for individual mice and then averaged across the group.
  • The time to progression to reach a tumor volume 1500 mm3 was calculated for each mouse. The median values were reported. For statistical analysis, if the tumor in a given mouse did not reach 1500 mm3, the time on study was utilized (e.g., 50 days for mice in the Compound #10-treated group). Differences in tumor size, tumor growth, and body weight change between groups were analyzed by Student's t-test).
  • Results: Vehicle and Compound #10 Treatment:
  • All mice treated with vehicle or with Compound #10 survived until sacrificed (at the time that the mean tumor size of the group reached about 1500 mm3).
  • Results: Sunitinib Monotherapy and Combination of Compound #10 and Sunitinib:
  • From Day 8 onward, all mice in Group 3 (sunitinib, 75 mg/kg) and Group 4 (Compound #10 and sunitinib) had yellow-tinged skin. Mouse 3-4 (sunitinib, 75 mg/kg) was sacrificed on Day 4. Mouse 3-7 (sunitinib, 75 mg/kg) was found dead on Day 17. Mouse 3-3 (sunitinib, 75 mg/kg) was found dead on Day 95.
  • Results: Rapamycin Monotherapy:
  • One mouse (5-10) was found dead on Day 14. Two mice (5-1 and 5-2) were found dead on Day 62. Three mice (5-3, 5-4, and 5-5) were found dead on Day 63.
  • Tumor Measurements:
  • A total of 60/100 mice that were inoculated with Caki-1 cells developed tumors that were within the appropriate range at the start of this study. The mean±SD tumor volume for mice used in this study was 286±27 mm3 at the initiation of treatment.
  • FIG. 13 and FIG. 15 show the effect of Compound #10 alone and in combination with sunitinib and rapamycin, respectively, on mean tumor size over the study time period. Tumors in vehicle-treated mice grew from a size (mean±SD) of 285±33 mm3 to 1544±606 mm3 on Day 35. The median time to reach 1000 mm3 was 25 days.
  • Tumors in Compound #10-treated mice (10 mg/kg QD, PO) grew from a size (mean±SD) of 285±26 mm3 to 1538±1070 mm3 on Day 52. Tumors in Compound #10-treated mice were smaller than vehicle-treated mice. On Day 35, tumors in Compound #10-treated mice were 866±450 mm3, or 44% smaller than the mean tumor size in vehicle-treated mice (p<0.05 ANOVA, multiple comparisons vs vehicle). The median time for tumors in Compound #10-treated mice to reach 1000 mm3 was 39 days.
  • Tumors in sunitinib-treated mice (75 mg/kg QD, PO) grew from a size (mean±SD) of 285±25 mm3 on Day 0 to 1494±1150 mm3 on Day 98. On Day 35, tumors in sunitinib-treated mice were 66% smaller than those in vehicle-treated mice. The median time for tumors in sunitinib-treated mice to reach 1000 mm3 was 66 days (p<0.05, ANOVA—multiple comparisons vs. vehicle control).
  • Tumors in rapamycin-treated mice grew from a size (mean±SD) of 286±24 mm3 on Day 0 to 1689±1081 mm3 on Day 63. By Day 65, 6 of the 10 mice in the treatment group had died, and the mice were taken off study. On Day 35, tumors in rapamycin-treated mice were 60% smaller than those in vehicle-treated mice. The median time for tumors in rapamycin-treated mice to reach 1000 mm3 was 43 days.
  • The combination of Compound #10 and sunitinib was not more effective than sunitinib only, and unexpectedly, the combination of sunitinib and Compound #10 was less effective than sunitinib only. Tumor volume was significantly smaller in mice treated with sunitinib-only than that in mice treated with the combination of Compound #10 and sunitinib on Days 49 to 63, at which point the mice treated with the combination of Compound #10 and sunitinib were sacrificed. The median time for tumors in mice treated with the combination of sunitinib and Compound #10 mice to reach 1000 mm3 was 43 days.
  • The combination of Compound #10 and rapamycin was not more effective than rapamycin only. Differences in tumor volume were not significantly different at any time point. The median time for tumors in mice treated with the combination of rapamycin and Compound #10 mice to reach 1000 mm3 was 40 days.
  • Effect of Treatment on Body Weight:
  • Mice were not randomized by body weight but by initial tumor size. Nevertheless, the mean initial body weights did not statistically differ between the two groups. The effect of treatment was determined by normalizing the body weight over time to initial body weight (i.e., by determining the percent change from the initial body weight).
  • FIG. 14 and FIG. 16 show the effect of Compound #10 alone and in combination with sunitinib and rapamycin, respectively, on mean tumor size over the study time period.
  • Vehicle-treated mice did not lose weight from their initial body weight at any point over the course of the study.
  • Compound #10-treated mice transiently lost weight as measured at Day 8 and Day 14 (2.2% loss from Day 0; p<0.05, Paired Student's test comparing Day 0 with Day 8 or Day 0 with Day 14). Mice then gained weight, with the weight gain from Day 0 reaching significance by Day 38 (Paired Student's test comparing Day 0 with Day 38), and remaining significant until these mice were sacrificed.
  • Sunitinib-treated mice transiently lost weight as measured at Day 14, although this difference did not reach statistical significance. Mice then gained weight, with the weight gain from Day 0 reaching significance by Day 38 (Paired Student's test comparing Day 0 with Day 38), and remaining significant through Day 63.
  • Rapamycin-treated mice transiently lost weight as measured at Day 8 and Day 14 (4.3% loss and 5.8% loss on Day 8 and 14, respectively; Paired Student's test comparing Day 0 with Day 8 or Day 0 with Day 14).
  • The body weights in mice treated with the combination of Compound #10 and Sunitinib did not differ from those in mice treated with sunitinib-only (Student's t-test).
  • The body weight in mice treated with the combination of Compound #10 and rapamycin weighed more on Days 8 and 14 than did those treated with rapamycin-only. Therefore, the addition of Compound #10 prevented rapamycin-induced weight loss.
  • Discussion of Results
  • Treatment of mice with Compound #10 delayed the growth of Caki-1 renal cells in vivo. The median time to reach 1500 mm3 was 25 days in vehicle-treated mice vs 39 days in Compound #10-treated mice. The median time to reach 1000 mm3 in sunitinib-treated mice was 66 days. Compound #10 was not as effective as sunitinib as the dose of sunitinib used in this model (75 mg/kg).
  • Rapamycin delayed the growth of Caki-1 renal tumor cells in vivo. Dosing of rapamycin was limited by weight loss. However, the combination of Compound #10 and rapamycin prevented weight loss.
  • The tumor did not induce weight loss, and there were no differences in the body weight gain in the vehicle-treated mice as in the monotherapy Compound #10-treated mice. While monotherapy rapamycin-treatment elicited weight loss, mice treated with the combination of Compound #10 and rapamycin did not lose weight, indicating that Compound #10 prevented rapamycin-induced weight loss in this cell line. Tumors in mice treated with rapamycin and with the combination of Compound #10 and rapamycin were of similar size, indicating that the effect on weight loss was independent of the effect on body weight.
  • The combination of Compound #10 and sunitinib was not as effective as sunitinib alone, perhaps as a result of either a pharmacodynamic or pharmacokinetic drug-drug interaction. The levels of sunitinib were lower in mice treated with the combination of Compound #10 and sunitinib when compared to mice treated with sunitinib alone. However, as the plasma was collected on different days (Day 63 vs. Day 98) and at different times (23 h post-dose vs. 30 h post-dose), the levels could not be directly compared to assess the potential for a drug-drug interaction.
    • 13. EXAMPLE: EFFECT OF COMPOUND #10 AS MONOTHERAPY AND IN COMBINATION WITH A PI3-K INHIBITOR
  • FIG. 7A shows the effect of Compound #10 (“P”) as monotherapy (at μM dose levels) and in combination with a PI3-K inhibitor (“B”) on protein expression in a series of Western blot analyses of lysates of various cell lines treated with various concentrations a PI3-K inhibitor (“B”) and various concentrations of Compound #10 (“P”) in a 786-0 Renal Cancer Cell (RCC) line using techniques known to a person of ordinary skill in the art.
  • The Vinculin, c-Myc, Survivin, ornithine decarboxylase (ODC), Cyclin D and pS6 mRNA are cap-dependent mRNAs that are considered difficult to translate. The blots for each mRNA shown were translated via a cap-independent manner with mTOR inhibition (Akt has been inactivated).
  • FIG. 7A shows that the monotherapy treatment of c-Myc in the 786-0 cell line by the PI3-K inhibitor and Compound #10 at different dose levels was not completely effective in suppressing c-Myc expression. The combination at different dose levels, though, effectively suppressed c-Myc expression. Although the monotherapy treatment of the PI3-K inhibitor was relatively effective at suppressing ODC, survivin, cyclin D and pS6 expression, Compound #10 enhanced the ability of the PI3-K inhibitor “B” to suppress c-myc expression and VEGF production.
  • The ELISA data in FIG. 7B demonstrate the effect of Compound #10 as monotherapy and in combination with a PI3-K inhibitor on VEGF expression in a 786-0 Renal Cancer Cell (RCC) line using techniques familiar to a person of ordinary skill in the art. In general, the tumor cells were exposed to Compound #10, the PI3-K inhibitor and the combination for several hours. The media was then discarded and replaced with fresh agent-containing media. This was done to ensure that the ELISA did not measure VEGF produced before the agent was able to achieve an inhibitory intracellular concentration. This procedure enhances the apparent effectiveness of agents that suppress VEGF synthesis. Although the cells were not rinsed, the ELISA data in FIG. 7B show a significant dose-dependent additive effect of the PI3-K inhibitor and Compound #10 in combination to suppress VEGF production.
  • FIG. 8 shows the effect of various concentrations of Compound #10 as monotherapy (at different μM dose levels) on expression of various proteins in a series of Western blot analyses of lysates of a panel of RCC lines (786-0, 769-P and A498) using techniques known to a person of ordinary skill in the art. The results in FIG. 8 demonstrate that the effect on protein expression was dose-dependent and depended on the RCC line used.
    • 14. EXAMPLE: EFFECT OF COMPOUND #10 AS MONOTHERAPY AND IN COMBINATION WITH CANCER THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER
  • FIG. 17 shows the effect of Compound #10 monotherapy on target plasma concentrations, enabling target plasma trough levels between 550 and 1010 ng/mL to be achieved in patients having a variety of cancers.
  • FIG. 18 shows the effect of Compound #10 monotherapy and combination therapy with docetaxel on target plasma concentrations, enabling target plasma trough levels between 550 and 1010 ng/mL to be achieved in patients having a variety of cancers.
  • FIG. 19 shows the effect of Compound #10 monotherapy in a patient having thyroid cancer where, after three previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 20 shows the effect of Compound #10 monotherapy in a patient having melanoma where, after two previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 21 shows the effect of Compound #10 monotherapy in a patient having chondrosarcoma where, after one previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization and reduction in a number of clinical parameters and tumor markers.
  • FIG. 22 shows the effect of Compound #10 monotherapy in a patient having cholangiocarcinoma where, after four previous therapeutic modalities, the result of monotherapy treatment with Compound #10 has led to stabilization for a tumor marker.
  • FIG. 23 shows the effect of Compound #10 monotherapy and combination therapy with docetaxel in a patient having head and neck cancer with metastasis to the lung where, after previous radiotherapy and no prior chemotherapy, the result of treatment with a combination of Compound #10 and docetaxel led to stabilization and reduction in a number of clinical parameters and tumor markers. The arrow symbol represents the timepoint at which docetaxel was reduced to 60 mg/m2.
  • FIG. 24 shows the effect of Compound #10 monotherapy in a patient jejunal adenocarcinoma with metastasis to the lung where, after five previous therapeutic modalities for the metastasis, the result of monotherapy treatment with Compound #10 is presented.
  • FIG. 25 shows the use Compound #10 monotherapy at various concentrations for treatment of various cancers.
  • The invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.
  • All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims (11)

1-8. (canceled)
9. A compound having the structure:
Figure US20160340354A1-20161124-C00810
or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, for use in treating cancer in a human, wherein the cancer is acute leukemia; acute lymphocytic leukemia; acute myelocytic leukemia; chronic leukemia; polycythemia vera; lymphoma; or multiple myeloma.
10. The use of claim 9, wherein the acute myelocytic leukemia is selected from myeloblastic, promyelocytic, myelomonocytic, monocytic or erythroleukemia leukemia or myelodysplastic syndrome.
11. The use of claim 9, wherein the chronic leukemia is selected from chronic myelocytic leukemia, chronic lymphocytic leukemia or hairy cell leukemia.
12. The use of claim 9, wherein the lymphoma is selected from Hodgkin's disease or non-Hodgkin's disease.
13. The use of claim 9, wherein the multiple myeloma is selected from smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma or plasma cell leukemia.
14. A compound having the structure:
Figure US20160340354A1-20161124-C00811
or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, for use in treating cancer in a human wherein the cancer is acute leukemia; acute lymphocytic leukemia; acute myelocytic leukemia; chronic leukemia; polycythemia vera; lymphoma; or multiple myeloma.
15. The use of claim 14, wherein the acute myelocytic leukemia is selected from myeloblastic, promyelocytic, myelomonocytic, monocytic or erythroleukemia leukemia or myelodysplastic syndrome.
16. The use of claim 14, wherein the chronic leukemia is selected from chronic myelocytic leukemia, chronic lymphocytic leukemia or hairy cell leukemia.
17. The use of claim 14, wherein the lymphoma is selected from Hodgkin's disease or non-Hodgkin's disease.
18. The use of claim 14, wherein the multiple myeloma is selected from smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma or plasma cell leukemia.
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