US20190015377A1 - Compositions for Use in Treating Pulmonary Arterial Hypertension - Google Patents

Compositions for Use in Treating Pulmonary Arterial Hypertension Download PDF

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US20190015377A1
US20190015377A1 US16/036,291 US201816036291A US2019015377A1 US 20190015377 A1 US20190015377 A1 US 20190015377A1 US 201816036291 A US201816036291 A US 201816036291A US 2019015377 A1 US2019015377 A1 US 2019015377A1
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alkyl
cyano
compound
halo
further embodiment
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Darryl David DIXON
Jonas Grina
John A. Josey
James P. Rizzi
Stephen T. Schlachter
Eli M. Wallace
Bin Wang
Paul WEHN
Rui Xu
Hanbiao Yang
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Peloton Therapeutics Inc
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Peloton Therapeutics Inc
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Assigned to PELOTON THERAPEUTICS, INC. reassignment PELOTON THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WALLACE, ELI M., GRINA, JONAS, JOSEY, JOHN A., RIZZI, JAMES P., WANG, BIN, WEHN, PAUL, XU, RUI, YANG, HANBIAO, SCHLACHTER, STEPHEN T., DIXON, DARRYL DAVID
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • An adequate supply of oxygen to tissues is essential in maintaining mammalian cell function and physiology.
  • a deficiency in oxygen supply to tissues is a characteristic of a number of pathophysiologic conditions in which there is insufficient blood flow to provide adequate oxygenation, for example, ischemic disorders, cancer, and atherosclerosis.
  • the hypoxic (low oxygen) environment of tissues activates a signaling cascade that drives the induction or repression of the transcription of a multitude of genes implicated in events such as angiogenesis (neo-vascularization), glucose metabolism, and cell survival/death.
  • a key to this hypoxic transcriptional response lies in the transcription factor, the hypoxia-inducible factor (HIF).
  • HIF hypoxia-inducible factor
  • HIFs consist of an oxygen-sensitive HIF ⁇ subunit and constitutively expressed HIF ⁇ subunit. When HIFs are activated, the HIF ⁇ and HIF ⁇ subunits assemble a functional heterodimer (the a subunit heterodimerizes with the ⁇ subunit). Both HIF ⁇ and HIF ⁇ have two identical structural characteristics, a basic helix-loop-helix (bHLH) and PAS domains (PAS is an acronym referring to the first proteins, PER, ARNT, SIM, in which this motif was identified). There are three human HIF ⁇ subunits (HIF-1 ⁇ , HIF-2 ⁇ , and HIF-3 ⁇ ) that are oxygen sensitive.
  • bHLH basic helix-loop-helix
  • PAS PAS domains
  • HIF-1 ⁇ is the most ubiquitously expressed and induced by low oxygen concentrations in many cell types.
  • HIF-2 ⁇ is highly similar to HIF-1 ⁇ in both structure and function, but exhibits more restricted tissue-specific expression, and might also be differentially regulated by nuclear translocation.
  • HIF-3 ⁇ also exhibits conservation with HIF-1 ⁇ and HIF-2 ⁇ in the HLH and PAS domains.
  • HIF ⁇ also referred to as ARNT—Aryl Hydrocarbon Receptor Nuclear Translocator
  • the dimerization partner of the HIF ⁇ subunits is constitutively expressed in all cell types and is not regulated by oxygen concentration.
  • Pulmonary arterial hypertension is a serious, progressive and life-threatening disease of the pulmonary vasculature, characterized by profound vasoconstriction and an abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries. Severe constriction of the blood vessels in the lungs leads to very high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from extreme shortness of breath as the heart struggles to pump against these high pressures. Patients with PAH typically develop significant increases in pulmonary vascular resistance (PVR) and sustained elevations in pulmonary artery pressure (PAP), which ultimately lead to right ventricular failure and death.
  • PVR pulmonary vascular resistance
  • PAP pulmonary artery pressure
  • the present disclosure provides a method of treating pulmonary arterial hypertension (PAH) in a subject in need thereof.
  • the method comprises administering a composition comprising an effective amount of a HIF-2 ⁇ inhibitor to said subject.
  • the amount of HIF-2 ⁇ inhibitor is effective in delaying the onset of or reducing the incidence of one or more symptoms of PAH.
  • the amount of HIF-2 ⁇ inhibitor is effective in (a) stabilizing pulmonary arterial pressure (PAP) as compared to a PAP trend in the subject prior to treatment, (b) reducing PAP relative to a starting level of PAP in the subject, or (c) reducing right ventricular hypertrophy as measured by Fulton's Index relative to an untreated population of subjects having PAH; wherein the PAP is systolic pulmonary arterial pressure (SPAP) or diastolic pulmonary arterial pressure (DPAP).
  • PAP systolic pulmonary arterial pressure
  • DPAP diastolic pulmonary arterial pressure
  • the amount of HIF-2 ⁇ inhibitor is effective in (a) reducing one or more of: pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and brain natriuretic peptide level; and/or (b) increasing one or more of: mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, six-minute walk distance, and lung diffusion capacity.
  • the amount of HIF-2 ⁇ inhibitor is effective in reducing vascular smooth muscle hypertrophy.
  • the HIF-2 ⁇ inhibitor inhibits one or more biological effects selected from the group consisting of heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ , HIF-2 ⁇ target gene expression, VEGF gene expression, and VEGF protein secretion. In some embodiments, the HIF-2 ⁇ inhibitor inhibits heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ but not heterodimerization of HIF-1 ⁇ to HIF-1 ⁇ . In some embodiments, the HIF-2 ⁇ inhibitor binds the PAS-B domain cavity of HIF-2 ⁇ . In some embodiments, the HIF-2 ⁇ inhibitor is a compound of any of the formulas provided herein.
  • the present invention provides a compound of Formula I:
  • R 1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. In some embodiments, R 1 is phenyl or pyridyl. In yet other embodiments, R 1 is cycloalkyl or heterocycloalkyl. Compounds of Formula I are also provided wherein R 1 is substituted with at least one substituent selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 2 and R 3 are independently selected from halo, cyano and alkyl.
  • R 3 is —(CH 2 ) n OH and n is 1, 2 or 3.
  • n is 1.
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In other embodiments, R 4 is fluoroalkyl or fluoroalkylsulfonyl.
  • Z is O. In some embodiments, Z is S. In still other embodiments, Z is NR 8 . In another embodiment, Z is CHR 7 . In some embodiments, Z is absent. In some embodiments, X is N and Y is CR 6 . In another embodiment, X is CR 5 and Y is N. In yet another embodiment, X is N and Y is N. In still another embodiment, X is CR 5 and Y is CR 6 .
  • the invention provides a compound of Formula I-A:
  • R 3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R 2 and R 3 taken together form a cyclic moiety;
  • R 4 is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl;
  • the invention provides a compound of Formula I-B:
  • the invention provides a compound of Formula I-C:
  • R 1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. In some embodiments, R 1 is phenyl or pyridyl. In yet other embodiments, R 1 is cycloalkyl or heterocycloalkyl. Compounds of Formula I-C are also provided wherein R 1 is substituted with at least one substituent selected from the group consisting of halo, alkyl, C 1 -C 4 alkoxy and cyano.
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In other embodiments, R 4 is fluoroalkyl or fluoroalkylsulfonyl. In some other embodiments, R 11 is hydroxy or amino. In further embodiments, R 11 is hydroxy. In yet other embodiments, R 12 is hydrogen. In yet another embodiment, R 13 is fluoro and n is 1, 2 or 3.
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R 11 is hydroxy or amino; and R 12 is hydrogen.
  • R 13 is fluoro.
  • Z is O.
  • Z is S.
  • Z is NR 8 .
  • Z is CHR 7 .
  • Z is absent.
  • R 4 is fluoroalkyl; n is 0, 1, 2 or 3; Z is O; R 11 is hydroxy; and R 12 is hydrogen. In still other embodiments, R 4 is sulfonyl; n is 0, 1, 2 or 3; Z is O; R 11 is hydroxy; and R 12 is hydrogen. In yet other embodiments, R 1 is phenyl, pyridyl, cycloalkyl or heterocycloalkyl. In some embodiments, X is N and Y is CR 6 . In another embodiment, X is CR 5 and Y is N. In yet another embodiment, X is N and Y is N.
  • the invention provides a compound of Formula I-D, I-E, I-F or I-G:
  • the invention provides a compound of Formula I-H, I-I, I-J or I-K:
  • the invention provides a compound of Formula II:
  • the invention provides a compound of Formula II-A:
  • the invention provides a compound of Formula II-B:
  • the composition administered to the subject is provided in a unit dose.
  • the composition is administered orally, intravenously, subcutaneously, intranasally, transdermally, intraperitoneally, intramuscularly, or intrapulmonarily.
  • a second agent is administered simultaneously or sequentially with the HIF-2 ⁇ inhibitor. The second agent may form part of the composition.
  • the second agent is selected from the group consisting of mitotic kinesis inhibitors, JAK2 inhibitors, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, prostacyclin receptor agonists, anticoagulants, diuretics, calcium channel blockers, digoxin, oxygen therapy, nitric oxide therapy, tyrosine kinases, statins, 5-hydroxytryptamine (5-HT) receptor antagonists, phosphatidylinositol 3-kinase inhibitors, soluble guanylate cyclase activators, adrenomedullin, platelet-derived growth factor (PDGF) inhibitors, Rho-kinase inhibitors, and mTOR inhibitors.
  • mitotic kinesis inhibitors JAK2 inhibitors, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, prostacyclin receptor agonists, anticoagulants, diuretics, calcium channel blockers, digoxin, oxygen therapy, nitric oxide
  • the method further comprises (a) measuring a physiological indicator of PAH before and after the administering, and (b) adjusting dosage or discontinuing use of the HIF-2 ⁇ inhibitor based on results of step (a).
  • the physiological indicator of PAH is selected from the group consisting of: pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six-minute walk distance, brain natriuretic peptide level, and lung diffusion capacity.
  • FIG. 1 is a bar graph illustrating effects of HIF-2 ⁇ inhibitors on reducing systolic pulmonary artery pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 2 is a bar graph illustrating effects of HIF-2 ⁇ inhibitors on mean pulmonary artery pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 3 is a bar graph illustrating effects of HIF-2 ⁇ inhibitors on reducing diastolic pulmonary artery pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 4 illustrates effects of HIF-2 ⁇ inhibitors treatment on heart rate. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 5 illustrates effects of HIF-2 ⁇ inhibitors treatment on systolic arterial pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 6 illustrates effects of HIF-2 ⁇ inhibitors treatment on mean arterial pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 7 illustrates effects of HIF-2 ⁇ inhibitors treatment on diastolic arterial pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 8 illustrates effects of HIF-2 ⁇ inhibitors treatment on Fulton's index (RV/LV+S). Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 9 shows the histopathology of lung tissues in a normal animal. Short arrow points to a completely muscularized arteriole. Long, thin arrow points to a partially muscularized arteriole. The long arrow points to the non-muscularized portion of the partially muscularized arteriole.
  • FIG. 10 shows the histopathology of lung tissues in a hypoxia-induced animal treated with a vehicle. Arrows point to completely muscularized arteriole. The letter “P” indicates a partially muscularized arteriole. The arteriolar lumens have thick muscular walls.
  • FIG. 11 shows the histopathology of lung tissues in a hypoxia-induced animal treated with 100 mg/kg Compound 231.
  • Arrows point to partially muscularized arterioles.
  • the letter “C” indicates a completely muscularized arteriole.
  • the completely muscularized arteriole has a diameter greater than 50 ⁇ m and would not have been included in the categorization of small arterioles.
  • the arrows point to the non-muscularized portion of the partially muscularized arterioles.
  • the arteriolar walls are thinner than those of similarly sized arterioles in FIG. 10 .
  • FIG. 12 shows the histopathology of lung tissues in a hypoxia-induced animal treated with 300 mg/kg Compound 231. Arrows point to partially muscularized arterioles. The arrows point to the non-muscularized portion of the partially muscularized arterioles. The arteriolar walls are thinner than those of similar sized arterioles in FIGS. 10 and 11 .
  • FIG. 13 shows the histopathology of lung tissues in a hypoxia-induced animal treated with 30 mg/kg bid sildenafil. Short arrows point to completely muscularized arterioles. Long arrows point to partially muscularized arterioles. The long arrows point to the non-muscularized portion of the partially muscularized arterioles. The amount of muscular hypertrophy is slightly less than that in FIG. 11 .
  • FIG. 14 illustrates effects of HIF-2 ⁇ inhibitors on preventing pulmonary vascular muscularization.
  • FIG. 15 is a bar graph illustrating effects of HIF-2 ⁇ inhibitors on treating PAH.
  • HIF-2 ⁇ inhibitors reduce systolic pulmonary artery pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 16 is a bar graph illustrating effects of HIF-2 ⁇ inhibitors on treating PAH.
  • HIF-2 ⁇ inhibitors reduce mean pulmonary artery pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 17 is a bar graph illustrating effects of HIF-2 ⁇ inhibitors on treating PAH.
  • HIF-2 ⁇ inhibitors reduce diastolic pulmonary artery pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 18 illustrates effects of HIF-2 ⁇ inhibitors on heart rate in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 19 illustrates effects of HIF-2 ⁇ inhibitors on systolic arterial pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 20 illustrates effects of HIF-2 ⁇ inhibitors on mean arterial pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 21 illustrates effects of HIF-2 ⁇ inhibitors on diastolic arterial pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 22 shows the histopathology of lung tissues in a model of active PAH treated with a vehicle for 14 days. Short arrow points to a completely muscularized small pulmonary arteriole. Long, thin arrows point to a partially muscularized small pulmonary arterioles.
  • FIG. 23 shows the histopathology of lung tissues in a model of active PAH treated with a vehicle for 28 days. Arrows point to completely muscularized small pulmonary arterioles. The arteriolar walls are thick relative to the size of the lumens. There are minimal inflammatory infiltrates surrounding the arterioles.
  • FIG. 24 shows the histopathology of lung tissues in a model of active PAH treated with 300 mg/kg Compound 231. Arrows point to completely muscularized small pulmonary arterioles.
  • FIG. 25 shows the histopathology of lung tissues in a model of active PAH treated with 30 mg/kg bid sildenafil. Arrows point to partially muscularized small pulmonary arterioles. There are minimal inflammatory infiltrates around one partially muscularized arteriole and the completely muscularized arteriole in the lower left corner of the image.
  • FIG. 26 depicts effects of HIF-2 ⁇ inhibitors on treating pulmonary vascular muscularization in a model of active PAH.
  • FIG. 27 depicts results of a co-immunoprecipitation assay for measuring inhibition of HIF-2 ⁇ and ARNT dimerization.
  • the term “effective amount” or “therapeutically effective amount” refers herein to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g. delaying the onset of or reducing the incidence of one or more symptoms of PAH.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • treatment or “treating,” or “palliating” and “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the composition may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • co-administration encompasses administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time.
  • Co-administration includes simultaneous administration in separate composition, administration at different times in separate composition, or administration in a composition in which both agents are present.
  • Combination therapy and “co-therapy” means the administration of a first active agent and at least a second, different active agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of the at least two active agents.
  • the beneficial effect of the combination may include, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • Combination therapy is not intended to encompass the administration of two or more different therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily results in a combination therapy of the invention.
  • Combination therapy includes administration of at least two different therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of at least two different therapeutic agents in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in separate capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the two different therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the second therapeutic agent of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not critical, unless otherwise stated.
  • Combination therapy also includes the administration of the different therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or physical therapy).
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • pharmaceutically acceptable salt refers herein to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • agent or “biologically active agent” refers herein to a biological, pharmaceutical, or chemical compound or other moiety.
  • Non-limiting examples include simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound.
  • Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures.
  • various natural sources can provide compounds for screening, such as plant or animal extracts, and the like.
  • subject refers to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both human therapeutics and veterinary applications.
  • the patient is a mammal, and in some embodiments, the patient is human.
  • in vivo refers to an event that takes places in a subject's body.
  • in vitro refers to an event that takes place outside of a subject's body.
  • an in vitro assay encompasses any assay run outside of a subject's body.
  • in vitro assays encompass cell-based assays in which cells alive or dead are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • heterodimerization refers to the complex formed by the non-covalent binding of HIF-2 ⁇ to HIF-1 ⁇ (ARNT).
  • HIF-2 ⁇ to HIF-1 ⁇ (ARNT) is required for HIF-2 ⁇ DNA binding and transcriptional activity and is mediated by the HLH and PAS-B domains.
  • Transcriptional activity following heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ can affect four groups of target genes including angiogenic factors, glucose transporters and glycolytic enzymes, survival factors, and invasion factors.
  • HIF-2 ⁇ refers to a monomeric protein that contains three conserved structured domains: basic helix-loop-helix (bHLH), and two Per-ARNT-Sim (PAS) domains designated PAS-A and PAS-B, in addition to C-terminal regulatory regions.
  • bHLH basic helix-loop-helix
  • PAS Per-ARNT-Sim
  • PAS-A and PAS-B Per-ARNT-Sim domains
  • HIF-2 ⁇ is also alternatively known by several other names in the scientific literature, most commonly EPAS 1 and MOP2.
  • ARNT also known as HIF-1 ⁇
  • PAS-B domain cavity refers to an internal cavity within the PAS-B domain of HIF-2 ⁇ .
  • the crystal structure of the PAS-B domain can contain a large (approximately 290 A) cavity in its core.
  • the amino acid side chains in the solution structure are dynamic. For example, those side chains can tend to intrude more deeply in the core, and can shrink the cavity to 1 or 2 smaller cavities or can even expand the cavity.
  • the cavity is lined by amino acid residues comprising PHE-244, SER-246, HIS-248, MET-252, PHE-254, ALA-277, PHE-280, TYR-281, MET-289, SER-292, HIS-293, LEU-296, VAL-302, VAL-303, SER-304, TYR-307, MET-309, LEU-319, THR-321, GLN-322, GLY-323, ILE-337, CYS-339, and ASN-341 of HIF-2 ⁇ PAS-B domain.
  • the numbering system is from the known structures reported in the RCSB Protein Data Bank with PDB code 3H7W. Other numbering systems in the PDB could define the same amino acids, expressed above, that line the cavity.
  • a biological marker generally refers to a measurable indicator of some biological state or condition. Biological markers are often measured and evaluated to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.
  • a biomarker may be any molecular structure produced by a cell, expressed inside the cell, accessible on the cell surface, or secreted by the cell.
  • a marker may be any protein, carbohydrate, fat, nucleic acid, catalytic site, or any combination of these such as an enzyme, glycoprotein, cell membrane, virus, cell, organ, organelle, or any uni- or multimolecular structure or any other such structure now known or yet to be disclosed whether alone or in combination.
  • polynucleotide refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof.
  • Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown.
  • polynucleotides coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • loci locus defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched poly
  • a polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
  • Controlled release refers to a drug-containing formulation or unit dose form thereof from which release of the drug is not immediate, i.e., with a controlled release formulation, administration does not result in immediate release of all of the drug administered into an absorption pool.
  • controlled release formulations include sustained release and delayed release formulations.
  • sustained release and extended release refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and typically, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • Delayed release refers to a drug formulation that, following administration to a patient, provides a measurable time delay before drug is released from the formulation into the patient's body.
  • Dosage form means any form of a pharmaceutical composition for administration to a subject (typically a human or animal of veterinary interest suffering from a disease or condition to be treated). “Dose” refers to an amount of active agent. “Unit dosage form” refers to a dosage form that contains a fixed amount of active agent. A single tablet or capsule is a unit dosage form. Multiple unit dosage forms can be administered to provide a therapeutically effective dose. A dosage form can include a combination of dosage forms.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs are also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • alkyl refers to a straight or branched hydrocarbon chain radical comprising carbon and hydrogen atoms, containing no unsaturation, and having from one to ten carbon atoms (e.g., C 1 -C 10 alkyl).
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, it is a C 1 -C 4 alkyl group.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like.
  • the alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl, (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
  • an alkyl group is optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R)) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a , —C( ⁇ O)N(R a ) 2 , —N(R a )C( ⁇ O)OR a , —C( ⁇ O
  • fluoroalkyl refers to an alkyl group substituted with one or more fluorine atoms. In some embodiments, it is a C 1 -C 4 alkyl group substituted with one or more fluorine atoms.
  • Typical fluoroalkyl groups include, but are in no way limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • alkenyl refers to a straight or branched hydrocarbon chain radical group comprising carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C 2 -C 10 alkenyl).
  • a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • an alkenyl comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenyl).
  • an alkenyl comprises two to five carbon atoms (i.e., C 2 -C 5 alkenyl).
  • the alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a , —C( ⁇ O)N(R a ) 2 , —N(R a )C( ⁇ O)OR a , —C(
  • alkynyl refers to a straight or branched hydrocarbon chain radical group comprising carbon and hydrogen atoms, containing at least one triple bond, and having from two to ten carbon atoms (i.e., C 2 -C 10 alkynyl). In some embodiments, an alkynyl group may contain one or more double bonds. Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkynyl group may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • an alkynyl comprises two to eight carbon atoms (i.e., C 2 -C 8 alkynyl). In other embodiments, an alkynyl has two to five carbon atoms (i.e., C 2 -C 5 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a , —C( ⁇ O)N(R a ) 2 , —N(R a )C( ⁇ O)OR a , —C
  • aromatic refers to an aromatic radical with six to ten ring atoms (i.e., C 6 -C 10 aromatic or C 6 -C 10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
  • a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.
  • an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a
  • Alkyl or “arylalkyl” refers to an (aryl)alkyl-radical wherein the arylalkyl moiety is attached via the alkyl portion of the moiety.
  • Aryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl, respectively.
  • heteroaryl or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (i.e., C 5 -C 18 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system.
  • a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms.
  • heteroaryl refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • the polycyclic heteroaryl group may be fused or non-fused.
  • the heteroatom(s) in the heteroaryl radical e.g., nitrogen or sulfur, is optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyr
  • a heteroaryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a , —C( ⁇ O)N(R a ) 2 , —N(R a )
  • monocylic heteroaryls include, but are not limited to, imidazolyl, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl and thienyl.
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide substituents, such as pyridinyl N-oxides.
  • Heteroarylalkyl refers to a moiety having a heteroaryl moiety, as described herein, connected to an alkyl moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkyl group. Heteroaryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroaryl and alkyl, respectively.
  • acyl refers to a —C( ⁇ O)R radical, wherein R is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, which are as described herein.
  • R group is attached to the parent structure through the carbonyl functionality.
  • it is a C 1 -C 10 acyl radical which refers to the total number of chain or ring atoms of the alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl portion of the acyl group plus the carbonyl carbon of acyl, i.e. ring or chain atoms plus carbonyl.
  • R radical is heteroaryl or heterocycloalkyl
  • the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • the “R” of an acyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a ,
  • halo means fluoro, chloro, bromo or iodo.
  • haloalkyl means fluoro, chloro, bromo or iodo.
  • haloalkenyl means fluoro, chloro, bromo or iodo.
  • haloalkynyl means alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and fluoroalkoxy refer to haloalkyl and haloalkoxy groups, respectively, in which the halo is fluoro.
  • fluoroalkyl examples include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CF 2 CH 3 , —CH 2 CF 3 , and —CF 2 CF 3 .
  • the alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
  • cyano refers to a —CN radical.
  • alkoxy refers to an —O-alkyl radical, including from wherein alkyl is as described herein and contains 1 to 10 carbon atoms (i.e., C 1 -C 10 alkoxy) of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C 1 -C 4 alkoxy group.
  • Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
  • an alkoxy moiety may be substituted by one or more of the substituents described as suitable substituents for an alkyl radical.
  • sp 3 hybridized carbon refers to a carbon atom that is bonded to four other atoms. sp 3 hybridization results from the combination of the s orbital and all three p orbitals in the second energy level of carbon. It results in four equivalent orbitals and the geometric arrangement of those four orbitals is tetrahedral.
  • sulfonyl refers to a —S( ⁇ O) 2 R a radical, wherein R a is selected from the group consisting of alkyl, amino, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). Unless stated otherwise specifically in the specification, the R a group may be substituted by one or more of the substituents described as suitable substituents for an alkyl, an aryl or a heteroaryl radical.
  • sulfoximinyl refers to a —S( ⁇ O)( ⁇ NR a )R b radical, wherein R a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cyano, carbamoyl, acyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon) and R b is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon).
  • the R a and R b groups may be substituted by one or more of the substituents described as suitable substituents for an alkyl, an aryl or a heteroaryl radical.
  • “Sulfonamide,” “sulfonamidyl” or “sulfonamido” refers to a —S( ⁇ O) 2 N(R a ) 2 radical, wherein each R a is selected independently from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl.
  • the R a groups in —N(R a ) 2 of the ⁇ S( ⁇ O) 2 —N(R a ) 2 radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring.
  • each R a in sulfonamido contains 1 carbon, 2 carbons, 3 carbons or 4 carbons total.
  • a sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl and heteroaryl, respectively.
  • fluoroalkylsulfonyl refers to a —S( ⁇ O) 2 R a radical, wherein R a is fluoroalkyl.
  • R a is C 1 -C 4 alkyl, substituted with one or more fluorines.
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical that contains carbon and hydrogen, and may be saturated, or partially unsaturated.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms (e.g., C 3 -C 10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon ring atoms, 4 carbon ring atoms, 5 carbon ring atoms, etc., up to and including 10 carbon ring atoms.
  • cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
  • a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a , —C( ⁇ O)N(R a ) 2 , —N(R a )C( ⁇ O)OR a ,
  • heterocyclyl or “heterocycloalkyl” refers to a stable 3- to 18-membered nonaromatic ring (e.g., C 3 -C 18 heterocycloalkyl) radical that comprises two to twelve ring carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • the heteroatoms in the heterocycloalkyl radical may be optionally oxidized.
  • One or more nitrogen atoms, if present, may optionally be quaternized.
  • the heterocycloalkyl radical may be partially or fully saturated.
  • heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).
  • heterocycloalkyl radicals include, but are not limited to, 6,7-dihydro-5H-cyclopenta[b]pyridine, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidin
  • a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a , —C( ⁇ O)N(R a ) 2 , —N(R a )C( ⁇ O)OR a , —N(R a )
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected form oxygen, sulfur and nitrogen and is not aromatic.
  • heteroalkyl examples include optionally substituted alkyl, alkenyl and alkynyl radicals, which respectively have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range, which refers to the chain length in total, may be given.
  • C 3 -C 4 heteroalkyl has a chain length of 3-4 atoms.
  • a —CH 2 OCH 2 CH 3 radical is referred to as a “C 4 heteroalkyl”, which includes the heteroatom in the atom chain length description.
  • a heteroalkyl may be a substituted alkyl.
  • the same definition applies to heteroalkenyl or heteroalkynyl.
  • a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a )
  • amino refers to a —N(R a ) 2 radical group, where each R a is independently hydrogen, alkyl, heteroalkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, heteroalkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, heteroalkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the
  • —N(R a ) 2 is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a , —C( ⁇ O
  • substituted amino also refers to N-oxides of N(R a ) 2 as described above.
  • N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
  • the person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
  • acyloxy refers to a RC( ⁇ O)O— radical wherein R is alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl, which are as described herein. In some embodiments, it is a C 1 -C 4 acyloxy radical, which refers to the total number of chain or ring atoms of the alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e., the other ring or chain atoms plus carbonyl.
  • R radical is heteroaryl or heterocycloalkyl
  • the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • the “R” of an acyloxy group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a ,
  • amide refers to a chemical moiety with formula —C( ⁇ O)N(R a ) 2 or —NR a C( ⁇ O)R a , wherein each of R a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl.
  • R a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl.
  • Two R a s may optionally be taken together with the nitrogen to which it is attached to form a 4-10 membered ring.
  • it is a C 1 -C 4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical.
  • an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • An amide may be an amino acid or a peptide molecule attached to a compound having an amine or a carboxylic acid moiety, thereby forming a prodrug. Any amine, hydroxy or carboxyl side chain on the compounds described herein can be amidified.
  • Carboxaldehyde refers to a —C( ⁇ O)H radical.
  • Carboxyl refers to a —C( ⁇ O)OH radical.
  • Ester refers to a chemical radical of formula —C( ⁇ O)OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those skilled in the art and can readily be found in reference sources such as Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Ed., Wiley, New York, N.Y., 2014, which is incorporated herein by reference in its entirety.
  • an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)N(R a ) 2 , —N(R a ) 2 , —C( ⁇ O)OR a , —C( ⁇ O)R a , —C( ⁇ O)N(R a ) 2 , —N(R a )C( ⁇ O)OR a , —C( ⁇ O
  • Imino refers to a ⁇ N—R a radical, wherein IV is hydrogen, alkyl, heteroalkyl, cycloalkyl, cyano, aryl, heterocycloalkyl or heteroaryl.
  • Mercaptyl refers to an ⁇ S(alkyl) or —SH radical.
  • Haldroxy refers to a —OH radical.
  • Oxa refers to a —O— radical.
  • Oxo refers to a ⁇ O radical
  • Niro refers to a —NO 2 radical.
  • Oxime refers to a ⁇ N(—OR) radical, where R is hydrogen or alkyl.
  • “Sulfinyl” refers to a —S( ⁇ O)R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). In some embodiments, R is fluoroalkyl.
  • “Sulfoxyl” refers to a —S( ⁇ O) 2 OH radical.
  • “Sulfonate” refers to a —S( ⁇ O) 2 OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heteroalkyl (bonded through a ring carbon).
  • R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heteroalkyl (bonded through a ring carbon).
  • the R group is optionally substituted by one or more of the substituents described for alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, respectively.
  • Thiocyanato refers to a —CNS radical.
  • Thioxo refers to a ⁇ S radical.
  • “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • “Substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, heteroalkyl, cycloalkyl, aralkl, heterocycloalkyl, aryl, carbohydrate, carbonate, heteroaryl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups and the protected derivatives thereof.
  • substituents themselves may be substituted, for example, a cycloalkyl substituent may have a halide substituted at one or more ring carbons, and the like.
  • the protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Ed., Wiley, New York, N.Y., 2014.
  • alkyl optionally substituted with encompasses both “alkyl” and “alkyl” substituted with groups as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns which would be deemed unacceptable by one of ordinary skill in the art.
  • Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof “Crystalline form,” “polymorph,” and “novel form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • the compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. See Pleiss and Voger, Synthesis and Applications of Isotopically Labeled Compounds , Vol. 7, Wiley, ISBN-10: 0471495018, published on Mar. 14, 2001.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or ( ⁇ ) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E-form (or cis- or trans-form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.
  • “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
  • Protecting group has the meaning conventionally associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete.
  • a variety of protecting groups are disclosed, for example, in Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Ed., Wiley, New York, N.Y., 2014. For example, a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected.
  • Solid refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent. It will be understood that the present chemical entities encompass the present chemical entities and solvates of the compound, as well as mixtures thereof.
  • solvent each means a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like.
  • the solvents used in the reactions described herein are inert organic solvents. Unless specified to the contrary, for each gram of the limiting reagent, one cc (or mL) of solvent constitutes a volume equivalent.
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
  • the (R)- and (S)-isomers of the compounds of the present invention may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diasteroisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one en
  • the compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts.
  • Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • the compounds described herein are in the form of pharmaceutically acceptable salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate
  • NBS N-Bromosuccinimide
  • PPTS Pyridinium p-toluenesulfonate
  • certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • the single enantiomers or diastereomers i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers.
  • Racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column.
  • HPLC high-pressure liquid chromatography
  • a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
  • certain small molecules include Z- and E-forms (or cis- and trans-forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds.
  • the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule.
  • R a is attached to the para position of a fluorophenyl ring through a single bond.
  • R a is phenyl, it can also be drawn a:
  • the waved line “ ” means a bond with undefined stereochemistry.
  • R b may be attached to any one of the —CH 2 — in the five-membered ring.
  • the disclosure provides a method of treating pulmonary arterial hypertension (PAH).
  • the method comprises administering a composition comprising an effective amount of a HIF-2 ⁇ inhibitor to said subject.
  • PAH is a life-threatening and progressive disease of various origins characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. The most common symptom at presentation is breathlessness, with impaired exercise capacity as a hallmark of the disease.
  • PAH includes idopathic PAH, heritable PAH (e.g. BMPR2, ALK1, endoglin), drug-induced PAH, toxin-induced PAH, and PAH associated with another condition (e.g.
  • Idiopathic PAH occurs in the absence of known risk factors and is the most common form of the disease.
  • the PAH condition treated in accordance with the present disclosure can include any of these PAH conditions.
  • the median period of survival of PAH after diagnosis is less than 3 years for 194 untreated patients with idiopathic or heritable PAH (formerly called primary pulmonary hypertension) with a mean age of 36 years.
  • average survival after diagnosis in adults is estimated at 5 to 7 years, with a similarly poor overall prognosis in children.
  • the HIF-2 ⁇ inhibitor is administered in an amount effective to increase average survival among a treated population of subjects, such as by about or more than about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or more years.
  • the pathology of PAH can include pathologic changes in the intima, media, and adventitial layers of the vascular wall.
  • Both vascular endothelial and smooth muscle cells have characteristics of abnormal growth, with excess cellular proliferation and apoptosis resistance.
  • These abnormalities in resident vascular cells, in combination with inflammation, excess vasoconstriction, and in situ thrombosis, can contribute to physical narrowing of the distal pulmonary arterioles. Without being bound by any theory, this narrowing can cause increase in pulmonary vascular resistance, which leads to the chronic and progressive elevation of pulmonary arterial pressure.
  • PAH can be induced by hypoxia.
  • the HIF-2 ⁇ inhibitor is administered in an amount effective to delay, reduce the incidence of, or reduce the severity of one or more such symptoms associated with PAH.
  • Treating PAH includes treating a subject diagnosed with existing PAH, as well as preventing PAH.
  • the amount of HIF-2 ⁇ inhibitor administered to the subject is effective in delaying the onset of or reducing the incidence of one or more symptoms of PAH.
  • the delay or reduction in incidence may be with respect to a reference population, such as an untreated population of subjects having PAH or subjects having PAH but treated with another agent.
  • Delay or reduction in incidence of one or more symptoms of PAH may be a reduction of about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • delay or reduction in incidence is measured by an increased time in disease progression, such as between the appearance of one or more first symptoms, and the appearance of one or more second symptoms.
  • Delay may be about or more than about days, weeks, months, or years (e.g. 1, 2, 3, 4, 5, 6, 7, or more days; 1, 2, 3, 4, 5, 6, 7, 8, or more weeks; 1, 2, 3, 4, 5, 6, or more months; or 1, 2, 3, 4, 5, or more years).
  • the subject may be an individual at risk of developing PAH.
  • the amount of HIF-2 ⁇ inhibitor administered to the subject is effective in (a) stabilizing pulmonary arterial pressure (PAP) as compared to a PAP trend in the subject prior to treatment, or (b) reducing PAP relative to a starting level of PAP in the subject; wherein the PAP is systolic pulmonary arterial pressure (SPAP) or diastolic pulmonary arterial pressure (DPAP).
  • PAP systolic pulmonary arterial pressure
  • DPAP diastolic pulmonary arterial pressure
  • a variety of methods for measuring PAP are available.
  • the PAP can be measured by inserting a catheter into the pulmonary artery.
  • the mean pressure is 9-18 mmHg
  • the wedge pressure measured in the left atrium can be 6-12 mmHg.
  • the wedge pressure may be elevated in left heart failure, mitral valve stenosis, and other conditions, such as sickle cell disease.
  • PAP in a subject may be stabilized at a level existing at the start of treatment, such as for days, weeks, months or years.
  • a starting level of PAP in the subject may be reduced by about or more than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more.
  • a rate of PAP increase may be reduced by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • the amount of HIF-2 ⁇ inhibitor administered to the subject can be effective in reducing right ventricular hypertrophy as measured by Fulton's Index relative to an untreated population of subjects having PAH.
  • Fulton's Index is a measure of the ratio between the mass of the right ventricle to the combined mass of the left ventricle and septum (RV/(LV+S)). Mass can be measured directly (e.g. in the context of an animal study) or extrapolated from volume measurements of a live subject (e.g. as determined by echocardiogram). Reduction may be with respect to an untreated population of subjects with PAH.
  • the average reduction in the Fulton Index among a population of PAH subjects treated with a HIF-2 ⁇ inhibitor as compared to an untreated population of PAH subjects can be about or more than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the reduction in Fulton's Index is at least about 20%.
  • the amount of HIF-2 ⁇ inhibitor administered to the subject is effective in reducing a physiological indicator of PAH.
  • the reduction may be measured over a specified period, such as a level of reduction days (e.g. about or more than about 1, 2, 3, 4, 5, 6, 7 or more days), weeks (e.g. 1, 2, 3, 4, 5, 6, or more weeks), months (e.g. 1, 2, 3, 4, 5, 6, 8, 10, or more months), or longer (e.g. 1, 2, 3, 4, 5, or more years) after treatment is initiated (which treatment may be ongoing through the period).
  • the HIF-2 ⁇ inhibitor may be present in an amount effective in (a) reducing one or more of: pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and brain natriuretic peptide level; and/or (b) increasing one or more of: mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, six-minute walk distance, and lung diffusion capacity.
  • the amount of HIF-2 ⁇ inhibitor may be effective in increasing time to death, increasing time to clinical worsening, reducing incidence of right heart failure, or promoting a favorable change in WHO functional class (see Table 1).
  • the baseline or reference PVR level can be 200 dyn ⁇ sec/cm 5 or greater, 240 dyn ⁇ sec/cm 5 or greater, 300 dyn ⁇ sec/cm 5 or greater, 400 dyn ⁇ sec/cm 5 or greater, 500 dyn ⁇ sec/cm 5 or greater, 600 dyn ⁇ sec/cm 5 or greater, 700 dyn ⁇ sec/cm 5 or greater, or 800 dyn ⁇ sec/cm 5 or greater.
  • a treatment provided herein is efficacious if after treatment has started, the endpoint PVR level of the subject decreases from the baseline or reference PVR level by 70 dyn ⁇ sec/cm 5 or more, 100 dyn ⁇ sec/cm 5 or more, 130 dyn ⁇ sec/cm 5 or more, or 160 dyn ⁇ sec/cm 5 or more.
  • PAP pulmonary arterial pressure
  • the baseline or reference PAP level can be 20 mmHg or greater, 25 mmHg or greater, 30 mmHg or greater, 35 mmHg or greater, 40 mmHg or greater, 45 mmHg or greater, 50 mmHg or greater, 60 mmHg or greater, or 70 mmHg or greater.
  • a treatment provided herein is efficacious if, after treatment has started, the endpoint PAP level of the subject decreases from the baseline or reference PAP level by 0.5 mmHg or more, 1 mmHg or more, 1.5 mmHg or more, 5 mmHg or more, 10 mmHg or more, 20 mmHg or more, 30 mmHg or more, 40 mmHg or more, or 50 mmHg.
  • a baseline or reference CI level can be 5 L/min/m 2 or lower, 2.5 L/min/m 2 or lower, 2 L/min/m 2 or lower, 1.5 L/min/m 2 or lower, or 1 L/min/m 2 or lower.
  • a treatment provided herein is efficacious if, after treatment has started, the endpoint CI level increases from the baseline or reference CI level by 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.5 or more, 1 or more, or 2 or more.
  • a baseline or reference PCWP level can be 36 mmHg or less, 24 mmHg or less, 18 mmHg or less, 10 mmHg, or 5 mmHg or less.
  • a treatment provided herein is efficacious if, after treatment has started, the endpoint PCWP level increases from the baseline or reference PCWP level by 0.2 mmHg or more, 0.3 mmHg or more, 0.4 mmHg or more, 0.5 mmHg or more, 0.6 mmHg or more, 1 mmHg or more, or 5 mmHg or more.
  • a baseline or reference RAP level can be 4 mmHg or more, 6 mmHg or more, 8 mmHg or more, 10 mmHg or more, 12 mmHg or more, 16 mmHg or more, 20 mmHg or more, or 25 mmHg or more.
  • a treatment provided herein is efficacious if after treatment has started, the endpoint RAP level of the subject decreases from the baseline or reference RAP level by 5 mmHg or more, 2.5 mmHg or more, 1 mmHg or more, 0.5 mmHg or more, or 0.2 mmHg or more.
  • a baseline or reference 6 MWD can be 50 m or less, 100 m or less, 200 m or less, 300 m or less, 400 m or less, or 500 m or less.
  • a treatment provided herein is efficacious if, after treatment has started, the endpoint 6 MWD of the subject increases from the baseline or reference 6 MWD by 10 m or more, 15 m or more, 20 m or more, 25 m or more, 30 m or more, or 50 m or more; or if the endpoint 6 MWD of the subject increases by 3% or more, 4% or more, 5% or more, 10% or more, or 20% or more of the baseline level.
  • a baseline or reference BNP level can be 60 pg/mL or higher, 80 pg/mL or higher, 100 pg/mL or higher, 120 pg/mL or higher, 140 pg/mL or higher, 200 pg/mL or higher, 500 pg/mL or higher, or 1000 pg/mL or higher.
  • a treatment provided herein is efficacious if, after treatment has started, the endpoint BNP level of the subject decreases from the baseline or reference BNP level.
  • the endpoint BNP level of the subject can decrease by 1 pg/mL or more, 2 pg/mL or more, 5 pg/mL or more, 10 pg/mL or more, 20 pg/mL or more, 100 pg/mL or more, 500 pg/mL or more, or 1000 pg/mL or more.
  • Diffusion of lung capacity (DLCO), or diffusion capacity of CO can also be used as a physiological indicator of PAH.
  • a baseline or reference DLCO can be 90% or less, 80% or less, 70% or less, 50% or less, 45% or less, or 40% or less.
  • a treatment provided herein is efficacious if, after treatment has started, the endpoint DLCO is increased from the baseline level.
  • the endpoint DLCO can be increased from the baseline or reference DLCO by 1% or more, 5% or more, 10% or more, 15% or more, 20% or more, or 50% or more.
  • Average survival rate can be used as a parameter to determine efficacy in a population of one or more subjects.
  • a reference average survival rate can be 95% or lower, 93% or lower, 90% or lower, 86% or lower, 82% or lower, or 78% or lower.
  • the average survival rate can be an average 1-year survival rate.
  • a treatment provided herein is efficacious in a population of one or more subjects if, after treatment has started, the average survival rate increases.
  • the average survival rate can increase from the reference average survival rate by 1% or more, 2% or more, 5% or more, 10% or more, or 20% or more.
  • a reference time to death can be 1 year or less, 2 years or less, 5 years or less, or 7 years or less.
  • a treatment provided herein is efficacious if, after treatment has started, the time to death of the subject is higher than the reference time to death.
  • the time to death of the subject can increase from the reference time to death by 0.5 years or more, 1 year or more, 2 years or more, 3 years or more, 4 years or more, 5 years or more, or 6 years or more.
  • compositions and methods of the invention can increase the survival rate of PAH patients.
  • an increase in the average 1-year survival rate of PAH patients indicates efficacious treatment.
  • compositions and methods disclosed herein can be effective in increasing the 1-year average survival rate of PAH patients to 82% or greater, 86% or greater, or 93% or greater.
  • an increase in the time to death after diagnosis of a PAH patient indicates efficacious treatment.
  • a HIF-2 ⁇ inhibitor of the invention extends the time to death of a PAH patient by at least 1, 2, 3, 4, 5, or 6 years beyond the current average lifespan of PAH patients.
  • the amount of HIF-2 ⁇ inhibitor administered to the subject can be effective in reducing vascular smooth muscle hypertrophy, such as with respect to a starting level of hypertrophy in the subject or a reference level of hypertrophy in an untreated population of subjects.
  • the development of ventricular muscle cell hypertrophy can be measured in a variety of ways, including by increase in cell size, induction of a genetic marker of ventricular muscle cell hypertrophy, increase in the assembly of an individual contractile protein such as myosin light chain-2v (MLC-2v) into organized contractile units, accumulating of contractile units, activation of a program of immediate early gene expression, and the induction of genes encoding contractile and embryonic proteins.
  • MLC-2v myosin light chain-2v
  • ventricular muscle cell hypertrophy can be measured by determining the expression of an atrial marker, for example, atrial natriuretic factor (ANH).
  • ANH atrial natriuretic factor
  • a measure of vascular smooth muscle hypertrophy is reduced by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • Measuring inhibition of biological effects of HIF-2 ⁇ can comprise performing an assay on a biological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to blood samples (e.g. blood plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.
  • blood samples e.g. blood plasma or serum
  • exhaled breath condensate samples e.g. blood plasma or serum
  • bronchoalveolar lavage fluid e.g. bronchoalveolar lavage fluid
  • sputum samples e.g., urine samples, and tissue samples.
  • a subject being treated with a HIF-2 ⁇ inhibitor may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject's physiological response to treatment. For example, if inhibition of a biological effect of HIF-2 ⁇ inhibition is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively. Alternatively, the treatment regimen may be adjusted to include, remove, or adjust an amount of a second agent.
  • the methods can further comprise continuing the therapy if the therapy is determined to be efficacious.
  • the methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound or compounds in the therapy if the therapy is determined to be efficacious.
  • the methods can comprise increasing the administered amount of a compound or compounds in the therapy if it is determined not to be efficacious.
  • the methods can comprise stopping therapy if it is determined not to be efficacious.
  • treatment with the HIF-2 ⁇ is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction.
  • the biological effect may be a change in any of a variety of physiological indicators of PAH, examples of which are provided herein.
  • HIF-2 ⁇ inhibitor can be indicated by a variety of methods. For example, it can be evaluated by adjustment of one or more hemodynamic parameters towards a more normal level, for example lowering mean PAP or PVR, PCWP or LVEDP, or raising cardiac index or output versus baseline. It can also be evaluated by improvement of cardiopulmonary efficiency versus baseline, for example increasing exercise capacity, illustratively as measured in a test of 6-minute walking distance (6MWD), or lowering Borg dyspnea index (BDI).
  • an indicator can be improvement of one or more quality of life parameters versus baseline, for example an increase in score on at least one of the SF-36® health survey functional scales.
  • Another example is general improvement versus baseline in the severity of the condition, for example by movement to a lower WHO functional class.
  • Another example is improvement of clinical outcome following a period of treatment, versus expectation in absence of treatment (e.g., in a clinical trial setting, as measured by comparison with placebo), including improved prognosis, extending time to or lowering probability of clinical worsening, extending quality of life (e.g., delaying progression to a higher WHO functional class or slowing decline in one or more quality of life parameters such as SF-36® health survey parameters), and/or increasing longevity.
  • a biomarker can be used for the evaluation.
  • a more normal level of one or more molecular markers that can be predictive of clinical outcome e.g., plasma concentrations of endothelin-1 (ET-1), cardiac troponin T (cTnT) or B-type natriuretic peptide (BNP)).
  • ETP endothelin-1
  • cTnT cardiac troponin T
  • BNP B-type natriuretic peptide
  • a HIF-2 ⁇ inhibitor is a compound that inhibits one or more biological effects of HIF-2 ⁇ .
  • biological effects of HIF-2 ⁇ include, but are not limited to, heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ , HIF-2 ⁇ target gene expression, VEGF gene expression, and VEGF protein secretion.
  • the HIF-2 ⁇ inhibitor is selective for HIF-2 ⁇ , such that the inhibitor inhibits heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ but not heterodimerization of HIF-1 ⁇ to HIF-1 ⁇ .
  • Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • Hypoxia-inducible factors like HIF-2 ⁇ , are transcription factors that respond to changes in available oxygen in the cellular environment (e.g. a decrease in oxygen, or hypoxia).
  • the HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos, and cancer tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium.
  • a HIF-2a inhibitor of the present disclosure may be administered in an amount effective in reducing any one or more of such effects of HIF-2 ⁇ activity.
  • HIF-2 ⁇ activity can be inhibited by inhibiting heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ (ARNT), such as with inhibitor compounds disclosed herein.
  • a variety of methods for measuring HIF-2 ⁇ dimerization are available.
  • inhibition of heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ (ARNT) may be determined in an Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen).
  • AlphaScreen an in vitro assay, employs “PAS-B*” variants (R247E HIF-2a and E362R ARNT; Scheuermann et al, PNAS 2009) to assess functional disruption of PAS-PAS interactions in a high throughput screening (HTS) format.
  • Inhibition of heterodimerization may also be determined by a reduction in HIF-2 ⁇ target gene mRNA expression, and/or co-immunoprecipitation.
  • a HIF-2 ⁇ inhibitor inhibits heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ (ARNT) with an IC 50 value not exceeding 30 ⁇ M, for example, ranging from 10 to 30 ⁇ M, and further, for example, ranging from 1 to 30 ⁇ M, as determined by AlphaScreen.
  • the HIF-2 ⁇ inhibitor has an IC 50 value not exceeding 1 ⁇ M as determined by AlphaScreen.
  • the HIF-2 ⁇ inhibitor binds the PAS-B domain cavity of HIF-2a. Binding may be covalent or non-covalent, including but not limited to Van der Waals, hydrogen bond, and electrostatic interaction. In some embodiments, the binding is determined by co-crystallography.
  • Inhibition of heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ may also be determined by a reduction in HIF-2 ⁇ target gene mRNA expression.
  • mRNA quantitation can be performed using real-time PCR technology. (Wong, et al., “Real-time PCR for mRNA quantitation”, 2005. BioTechniques 39, 1: 1-1.).
  • Yet another method for determining inhibition of heterodimerization of HIF-2 ⁇ to HIF-1 ⁇ (ARNT) is by co-immunoprecipitation.
  • HIF-2 ⁇ is a transcription factor that plays important roles in regulating expression of target genes.
  • HIF-2 ⁇ target gene include HMOX1, SFTPA1, CXCR4, PAIL BDNF, hTERT, ATP7A, and VEGF.
  • HIF-2a is an activator of VEGFA.
  • HIF-2 ⁇ target genes include HMOX1, EPO, CXCR4, PAII, CCND1, CLUT1, IL6, and VEGF.
  • a HIF-2 ⁇ inhibitor of the present disclosure may be administered in an amount effective in reducing expression of any one or more of genes induced by HIF-2 ⁇ activity.
  • a variety of methods are available for the detection of gene expression level, and include the detection of gene transcription products (polynucleotides) and translation products (polypeptides). For example, gene expression can be detected and quantified at the DNA, RNA or mRNA level.
  • Various methods that have been used to quantify mRNA include in situ hybridization techniques, fluorescent in situ hybridization techniques, reporter genes, RNase protection assays, Northern blotting, reverse transcription (RT)-PCR, SAGE, DNA microarray, tiling array, and RNA-seq.
  • Examples of methods for the detection of polynucleotides include, but are not limited to selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles, and solution phase detection of polynucleotides using interacting fluorescent labels and competitive hybridization.
  • Examples for the detection of proteins include, but are not limited to microscopy and protein immunostaining, protein immunoprecipitation, immunoelectrophoresis, western blot, BCA assay, spectrophotometry, mass spectrophotometry and enzyme assay.
  • inhibition of HIF-2 ⁇ is characterized by a decrease in VEGF gene expression.
  • the decrease may be measure by any of a variety of methods, such as those described herein.
  • the mRNA expression level of VEGF can be measured by quantitative PCR (QT-PCR), microarray, RNA-seq and nanostring.
  • QT-PCR quantitative PCR
  • microarray microarray
  • RNA-seq RNA-seq
  • nanostring RNA-seq
  • an ELISA assay can be used to measure the level VEGF protein secretion.
  • the HIF-2 ⁇ inhibitor administered to the subject is a compound of Formula I:
  • R 1 is phenyl or monocyclic heteroaryl. In some further embodiments, R 1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is bicyclic heteroaryl.
  • the bicyclic heteroaryl is substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is pyridyl N-oxide.
  • the pyridyl N-oxide is substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • aryl ring may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
  • substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • W 1 is N or CR 10
  • R 9 is cyano, halo, alkyl or alkoxy
  • R 10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • R 9 is cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy
  • R 10 is hydrogen, cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted with one or more substituents described for aryl and heteroaryl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted with one or more substituents described for cycloalkyl.
  • the substituent(s) is selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano and oxo.
  • R 1 is cycloalkyl. In other embodiments, R 1 is heterocycloalkyl. In a further embodiment, R 1 is C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In yet a further embodiment, R 1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • R 1 is acyl or cyano. In a further embodiment, R 1 is acetyl.
  • R 1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1 is heteroalkyl.
  • R 1 is selected from the group consisting of:
  • each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
  • the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 2 is cyano, halo or alkyl. In some embodiments, R 2 is halo or alkyl. In some embodiments, R 2 is fluoro, chloro, bromo or iodo. In some embodiments, R 2 is fluoroalkyl. In some further embodiments, R 2 is —CH 2 F, —CHF 2 or —CF 3 . In another embodiment, R 2 is hydrogen. In some other embodiments, R 2 is heteroalkyl, alkenyl or alkynyl.
  • R 3 is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R 2 and R 3 taken together form a cyclic moiety.
  • R 3 is halo, cyano or alkyl.
  • R 3 is —(CH 2 )—OH, wherein n is 1, 2 or 3.
  • R 3 is —CH 2 OH.
  • R 2 and R 3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp a hybridized carbon.
  • Representative compounds with the carbocycle include, but are not limited to, the following:
  • the carbocycle formed by linking R 2 and R 3 may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R 2 and R 3 .
  • the substituent(s) is C 3 -C 5 cycloalkyl or C 3 -C 5 heterocycloalkyl.
  • the substituent is oxo.
  • R 2 and R 3 taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 4 is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R 4 is fluoroalkyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a further embodiment, R 4 is fluoroalkyl. In yet another embodiment, R 4 is sulfonyl. In still another embodiment, R 4 is fluoroalkylsulfonyl.
  • R 4 is —S( ⁇ O) 2 R a , wherein R a is alkyl or cycloalkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R a is methyl, optionally substituted with one or more fluorines.
  • R 4 is —S( ⁇ O)( ⁇ NR b )R a , wherein R a is alkyl or cycloalkyl and R b is hydrogen, cyano or alkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R 4 is —S( ⁇ O) 2 N(R a ) 2 , wherein each R a is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a is hydrogen. In a further embodiment, both R a s are hydrogen. In another further embodiment, one R a is hydrogen and the other R a is C 1 -C 4 alkyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , ⁇ S( ⁇ ) 2 CH 3 , ⁇ S( ⁇ ) 2 CH 2 F, ⁇ S( ⁇ ) 2 CHF 2 , ⁇ S( ⁇ ) 2 CF 3 , ⁇ S( ⁇ ) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 5 is hydrogen. In some other embodiments, R 5 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 5 is methyl.
  • R 6 is hydrogen. In some other embodiments, R 6 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 6 is methyl.
  • R 7 is hydrogen. In some other embodiments, R 7 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 7 is methyl.
  • R 8 is hydrogen. In some other embodiments, R 8 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 8 is methyl.
  • R 3 is hydrogen
  • R 4 is —S( ⁇ O) 2 R a or —S( ⁇ O)( ⁇ NR b )R c , wherein R a is fluoroalkyl, R b is hydrogen, cyano or alkyl and R c is alkyl.
  • R 1 is selected from the group consisting of
  • W 1 is N or CR 10
  • R 9 is cyano, halo, alkyl or alkoxy
  • R 10 is hydrogen, cyano, halo, alkyl or alkoxy
  • the alkyl is C 1 -C 4 alkyl.
  • the alkoxy is C 1 -C 4 alkoxy.
  • each of R 2 and R 3 is independently alkyl and R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl.
  • R 3 is —CH 2 OH.
  • R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl and R 5 is hydrogen.
  • R 2 is cyano, halo or alkyl.
  • R 1 is phenyl or monocyclic heteroaryl
  • R 2 is nitro, halo, cyano or alkyl
  • R 3 is halo, cyano or alkyl
  • R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 5 is hydrogen.
  • R 1 is bicyclic heteroaryl
  • R 2 is nitro, halo, cyano or alkyl
  • R 3 is halo, cyano or alkyl
  • R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl
  • R 5 is hydrogen
  • R 1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl;
  • R 2 is halo, cyano or alkyl;
  • R 3 is halo, cyano or alkyl;
  • R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and
  • R 5 is hydrogen.
  • R 2 and R 3 together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp a hybridized carbon;
  • R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and
  • R 5 is hydrogen.
  • R 1 is phenyl or monocyclic heteroaryl. In another further embodiment, R 1 is bicyclic heteroaryl.
  • X is N and Y is CR 6 . In other embodiments, X is CR 5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5 and Y is CR 6 .
  • Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR 7 . In yet other embodiments, Z is NR 8 . In some embodiments, Z is absent.
  • the invention provides a compound of Formula I-A:
  • R 2 is cyano, halo or alkyl. In some embodiments, R 2 is halo or alkyl. In some embodiments, R 2 is fluoro, chloro, bromo or iodo. In some embodiments, R 2 is fluoroalkyl. In some further embodiments, R 2 is —CH 2 F, —CHF 2 or —CF 3 .
  • R 3 is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R 2 and R 3 taken together form a cyclic moiety.
  • R 3 is halo, cyano or alkyl.
  • R 3 is —(CH 2 )—OH, wherein n is 1, 2 or 3.
  • R 3 is —CH 2 OH.
  • R 2 and R 3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp a hybridized carbon.
  • Representative compounds with the carbocycle include, but are not limited to, the following:
  • the carbocycle formed by linking R 2 and R 3 may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R 2 and R 3 .
  • the substituent(s) is C 3 -C 5 cycloalkyl or C 3 -C 5 heterocycloalkyl.
  • the substituent is oxo.
  • R 2 and R 3 taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 4 is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R 4 is fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4 is fluoroalkyl. In yet another embodiment, R 4 is sulfonyl. In still another embodiment, R 4 is fluoroalkylsulfonyl.
  • R 4 is —S( ⁇ O) 2 R a , wherein R a is alkyl or cycloalkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R a is methyl, optionally substituted with one or more fluorines.
  • R 4 is —S( ⁇ O)( ⁇ NR b )R a , wherein R a is alkyl or cycloalkyl and R b is hydrogen, cyano or alkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R 4 is —S( ⁇ O) 2 N(R a ) 2 , wherein each R a is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a is hydrogen. In a further embodiment, both R a s are hydrogen. In another further embodiment, one R a is hydrogen and the other R a is C 1 -C 4 alkyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , S( ⁇ O)CH 3 , ⁇ S( ⁇ O) 2 CH 3 , ⁇ S( ⁇ O) 2 CH 2 F, ⁇ S( ⁇ O) 2 CHF 2 , ⁇ S( ⁇ O) 2 CF 3 , ⁇ S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 5 is hydrogen. In some other embodiments, R 5 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 5 is methyl.
  • R 6 is hydrogen. In some other embodiments, R 6 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 6 is methyl.
  • R 7 is hydrogen. In some other embodiments, R 7 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 7 is methyl.
  • R 8 is hydrogen. In some other embodiments, R 8 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 8 is methyl.
  • R 9 is cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • R 10 is hydrogen, cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • R 2 and R 3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp a hybridized carbon and R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl.
  • R 3 is —CH 2 OH and R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl.
  • R 5 is hydrogen.
  • R 2 is cyano, halo or alkyl.
  • R 2 is halo, cyano or alkyl
  • R 3 is CH 2 OH
  • R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • X is N and Y is CR 6 . In other embodiments, X is CR 5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5 and Y is CR 6 .
  • Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR 7 . In yet other embodiments, Z is NR 8 . In some embodiments, Z is absent.
  • the invention provides a compound of Formula I-B:
  • R c is hydrogen, cyano, halo, alkyl or alkoxy
  • R 2 is cyano, halo or alkyl. In some embodiments, R 2 is halo or alkyl. In some embodiments, R 2 is fluoro, chloro, bromo or iodo. In some embodiments, R 2 is fluoroalkyl. In some further embodiments, R 2 is —CH 2 F, —CHF 2 or —CF 3 .
  • R 3 is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R 2 and R 3 taken together form a cyclic moiety.
  • R 3 is halo, cyano or alkyl.
  • R 3 is —(CH 2 )—OH, wherein n is 1, 2 or 3.
  • R 2 and R 3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp a hybridized carbon.
  • Representative compounds with the carbocycle include, but are not limited to, the following:
  • the carbocycle formed by linking R 2 and R 3 may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R 2 and R 3 .
  • the substituent(s) is C 3 -C 5 cycloalkyl or C 3 -C 5 heterocycloalkyl.
  • the substituent is oxo.
  • R 2 and R 3 taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 3 is hydrogen
  • R 4 is is —S( ⁇ O) 2 R a or —S( ⁇ O)( ⁇ NR b )R d , wherein R a is fluoroalkyl, R b is hydrogen, cyano or alkyl and R d is alkyl.
  • R 4 is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R 4 is fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4 is fluoroalkyl. In yet another embodiment, R 4 is sulfonyl. In still another embodiment, R 4 is fluoroalkylsulfonyl.
  • R 4 is —S( ⁇ O) 2 R a , wherein R a is alkyl or cycloalkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R a is methyl, optionally substituted with one or more fluorines.
  • R 4 is —S( ⁇ O)( ⁇ NR b )R a , wherein R a is alkyl or cycloalkyl and R b is hydrogen, cyano or alkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R 4 is —S( ⁇ O) 2 —N(R a ) 2 , wherein each R a is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a is hydrogen. In a further embodiment, both R a s are hydrogen. In another further embodiment, one R a is hydrogen and the other R a is C 1 -C 4 alkyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , ⁇ S( ⁇ O) 2 CH 3 , ⁇ S( ⁇ O) 2 CH 2 F, ⁇ S( ⁇ O) 2 CHF 2 , ⁇ S( ⁇ O) 2 CF 3 , ⁇ S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 5 is hydrogen. In some other embodiments, R 5 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 5 is methyl.
  • R 6 is hydrogen. In some other embodiments, R 6 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 6 is methyl.
  • R 7 is hydrogen. In some other embodiments, R 7 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 7 is methyl.
  • R 8 is hydrogen. In some other embodiments, R 8 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 8 is methyl.
  • R 2 and R 3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp a hybridized carbon and R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , ⁇ S( ⁇ O) 2 CH 2 F, ⁇ S( ⁇ O) 2 CHF 2 , ⁇ S( ⁇ O) 2 CF 3 , ⁇ S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 3 is —CH 2 OH and R 4 is fluoroalkyl, sulfonamidyl, sulfonyl, sulfinyl or sulfoximinyl.
  • R 5 is hydrogen.
  • R 2 is cyano, halo or alkyl.
  • R 2 is halo, cyano or alkyl
  • R 3 is CH 2 OH
  • R 4 is fluoroalkyl, sulfonamidyl, sulfonyl, sulfinyl or sulfoximinyl.
  • R 4 is selected from the group consisting of —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • X is N and Y is CR 6 . In other embodiments, X is CR 5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5 and Y is CR 6 .
  • Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR 7 . In yet other embodiments, Z is NR 8 . In some embodiments, Z is absent.
  • R c is cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • the invention provides a compound of Formula I-C:
  • R 1 is phenyl or monocyclic heteroaryl. In some further embodiments, R 1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R 1 is
  • R 1 is
  • W 1 is N or CR 10
  • R 9 is cyano, halo, alkyl or alkoxy
  • R 10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • R 1 is bicyclic heteroaryl.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted with one or more substituents described for aryl and heteroaryl.
  • the substituent(s) is selected from the group consisting of halo, alkyl, alkoxy and cyano.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted with one or more substituents described for cycloalkyl.
  • the substituent(s) is selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano and oxo.
  • R 1 is cycloalkyl. In other embodiments, R 1 is heterocycloalkyl. In a further embodiment, R 1 is C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In yet a further embodiment, R 1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • R 1 is acyl or cyano. In a further embodiment, R 1 is acetyl.
  • R 1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1 is heteroalkyl.
  • R 1 is selected from the group consisting of:
  • each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
  • the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In some embodiments, R 4 is fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4 is fluoroalkyl. In yet another embodiment, R 4 is sulfonyl. In still another embodiment, R 4 is fluoroalkylsulfonyl.
  • R 4 is —S( ⁇ O) 2 R a , wherein R a is alkyl or cycloalkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R a is methyl, optionally substituted with one or more fluorines.
  • R 4 is —S( ⁇ O)( ⁇ NR b )R a , wherein R a is alkyl or cycloalkyl and R b is hydrogen, cyano or alkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R 4 is —S( ⁇ O) 2 N(R a ) 2 , wherein each R a is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a is hydrogen. In another further embodiment, one R a is hydrogen and the other R a is C 1 -C 4 alkyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , ⁇ S( ⁇ O) 2 CH 3 , ⁇ S( ⁇ O) 2 CH 2 F, ⁇ S( ⁇ O) 2 CHF 2 , ⁇ S( ⁇ O) 2 CF 3 , ⁇ S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 5 is hydrogen or alkyl. In some other embodiments, R 5 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 5 is methyl.
  • R 6 is hydrogen or alkyl. In some other embodiments, R 6 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 6 is methyl.
  • R 7 is hydrogen or alkyl. In some other embodiments, R 7 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 7 is methyl.
  • R 8 is hydrogen or alkyl. In some other embodiments, R 8 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 8 is methyl.
  • R 11 is hydroxy or amino. In a further embodiment, R 11 is hydroxy. In another further embodiment, R 11 is amino.
  • R 12 is hydrogen. In some other embodiments, R 12 is alkyl or alkenyl.
  • R 13 is fluoro. In a further embodiment, n is 1, 2 or 3. In a further embodiment, two R 13 s in combination form oxo, oxime or methylene. In still further embodiments, two R 13 s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety.
  • R 1 is monocyclic aryl or monocyclic heteroaryl and is hydroxy or amino.
  • R 13 is fluoro.
  • n is 1, 2 or 3.
  • R 1 is phenyl or monocyclic heteroaryl
  • R 11 is hydroxy or amino
  • R 13 is fluoro
  • n is 1, 2 or 3
  • R 5 is hydrogen
  • R 1 is bicyclic heteroaryl and R 11 is hydroxy or amino.
  • R 13 is fluoro.
  • n is 1, 2 or 3.
  • R 1 is bicyclic heteroaryl
  • R 11 is hydroxy or amino
  • le is fluoro
  • n is 1, 2 or 3
  • R 5 is hydrogen
  • R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl, and is hydroxy or amino.
  • R 12 is hydrogen.
  • R 13 is fluoro.
  • n is 1, 2 or 3.
  • R 4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R 11 is hydroxy or amino; R 13 is fluoro; n is 1, 2 or 3; and R 5 is hydrogen. In a further embodiment, R 12 is hydrogen.
  • R 11 is hydroxy or amino and R 12 is hydrogen.
  • R 13 is fluoro.
  • n is 1, 2 or 3.
  • R 11 is hydroxy or amino
  • R 12 is hydrogen
  • R 13 is fluoro
  • n is 1, 2 or 3
  • R 5 is hydrogen.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN
  • R 4 is fluoroalkyl; n is 0, 1, 2 or 3; Z is O; R 11 is hydroxy; and R 12 is hydrogen.
  • R 4 is sulfonyl or fluoroalkylsulfonyl; n is 0, 1, 2 or 3; Z is O; R 11 is hydroxy; and R 12 is hydrogen.
  • X is N and Y is CR 6 . In other embodiments, X is CR 5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5 and Y is CR 6 .
  • Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR′. In yet other embodiments, Z is NR B . In some embodiments, Z is absent.
  • the invention provides a compound of Formula I-D, I-E, I—F or I-G:
  • R 1 is monocyclic aryl or monocyclic heteroaryl. In some further embodiments, R 1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R 1 is
  • R 1 is
  • W 1 is N or CR 19
  • R 9 is cyano, halo, alkyl or alkoxy
  • R 10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • R 1 is bicyclic heteroaryl having at least one N atom.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted with one or more substituents described for aryl and heteroaryl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted with one or more substituents described for cycloalkyl.
  • the substituent(s) is selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano and oxo.
  • R 1 is cycloalkyl. In other embodiments, R 1 is heterocycloalkyl. In a further embodiment, R 1 is C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In yet a further embodiment, R 1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • R 1 is acyl or cyano. In a further embodiment, R 1 is acetyl.
  • R 1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1 is heteroalkyl.
  • R 1 is selected from the group consisting of:
  • each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
  • the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In some embodiments, R 4 is fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4 is fluoroalkyl. In yet another embodiment, R 4 is sulfonyl. In still another embodiment, R 4 is fluoroalkylsulfonyl.
  • R 4 is —S( ⁇ O) 2 R a , wherein R a is alkyl or cycloalkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines.
  • fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R 4 is —S( ⁇ O)( ⁇ NR b )R a , wherein R a is alkyl or cycloalkyl and R b is hydrogen, cyano or alkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R 4 is —S( ⁇ O) 2 N(R a ) 2 , wherein each R a is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a is hydrogen. In another further embodiment, both R a s are hydrogen. In a further embodiment, one R a is hydrogen and the other R a is C 1 -C 4 alkyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , ⁇ S( ⁇ O) 2 CH 3 , ⁇ S( ⁇ O) 2 CH 2 F, ⁇ S( ⁇ O) 2 CHF 2 , ⁇ S( ⁇ O) 2 CF 3 , ⁇ S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 5 is hydrogen or alkyl. In some other embodiments, R 5 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 5 is methyl.
  • R 6 is hydrogen or alkyl. In some other embodiments, R 6 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 6 is methyl.
  • R 7 is hydrogen or alkyl. In some other embodiments, R 7 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 7 is methyl.
  • R 8 is hydrogen or alkyl. In some other embodiments, R 8 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 8 is methyl.
  • R 11 is hydroxy. In another further embodiment, is amino.
  • R 1 is phenyl or monocyclic heteroaryl and R 11 is hydroxy or amino.
  • R 1 is bicyclic heteroaryl and R 11 is hydroxy or amino.
  • X is CR 5 and R 5 is hydrogen.
  • R 5 is alkyl.
  • R 5 is C 1 -C 4 alkyl.
  • R 1 is bicyclic heteroaryl and R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl.
  • X is CR 5 and R 5 is hydrogen.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 1 is bicyclic heteroaryl
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl
  • R 11 is hydroxy or amino
  • X is CR 5 or N
  • R 5 is hydrogen.
  • R 11 is hydroxy.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 1 is phenyl or monocyclic heteroaryl and R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl.
  • X is CR 5 and R 5 is hydrogen.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 1 is phenyl or monocyclic heteroaryl
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl
  • R 11 is hydroxy or amino
  • X is CR 5 or N
  • R 5 is hydrogen.
  • R 11 is hydroxy.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , ⁇ S( ⁇ O) 2 CH 2 F, ⁇ S( ⁇ O) 2 CHF 2 , ⁇ S( ⁇ O) 2 CF 3 , ⁇ S( ⁇ O) 2 NH 2 , ⁇ S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • X is N and Y is CR 6 . In other embodiments, X is CR 5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5 and Y is CR 6 .
  • Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR 7 . In yet other embodiments, Z is NR 8 . In some embodiments, Z is absent.
  • the invention provides a compound of Formula I-H, I-I, I-J or I-K:
  • R 1 is monocyclic aryl or monocyclic heteroaryl. In some further embodiments, R 1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R 1 is
  • R 1 is
  • W 1 is N or CR 10
  • R 9 is cyano, halo, alkyl or alkoxy
  • R 10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • R 1 is bicyclic heteroaryl.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted with one or more substituents described for aryl and heteroaryl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted with one or more substituents described for cycloalkyl.
  • the substituent(s) is selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano and oxo.
  • R 1 is cycloalkyl. In other embodiments, R 1 is heterocycloalkyl. In a further embodiment, R 1 is C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In yet a further embodiment, R 1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • R 1 is acyl or cyano. In a further embodiment, R 1 is acetyl.
  • R 1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1 is heteroalkyl.
  • R 1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1 is heteroalkyl.
  • R 1 is selected from the group consisting of:
  • each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
  • the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4 is fluoroalkyl. In yet another embodiment, R 4 is sulfonyl. In still another embodiment, R 4 is fluoroalkylsulfonyl.
  • R 4 is —S( ⁇ O) 2 R a , wherein R a is alkyl or cycloalkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R a is methyl, optionally substituted with one or more fluorines.
  • R 4 is —S( ⁇ O)( ⁇ NR b )R a , wherein R a is alkyl or cycloalkyl and R b is hydrogen, cyano or alkyl.
  • R a is C 1 -C 4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4 alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3 and —CF 2 CH 3 .
  • R 4 is —S( ⁇ O) 2 N(R a ) 2 , wherein each R a is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a is hydrogen. In another further embodiment, both R a s are hydrogen. In a further embodiment, one R a is hydrogen and the other R a is C 1 -C 4 alkyl.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , ⁇ S( ⁇ O) 2 CH 3 , ⁇ S( ⁇ O) 2 CH 2 F, ⁇ S( ⁇ O) 2 CHF 2 , ⁇ S( ⁇ O) 2 CF 3 , ⁇ S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 5 is hydrogen or alkyl. In some other embodiments, R 5 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 5 is methyl.
  • R 6 is hydrogen or alkyl. In some other embodiments, R 6 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 6 is methyl.
  • R 7 is hydrogen or alkyl. In some other embodiments, R 7 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 7 is methyl.
  • R 8 is hydrogen or alkyl. In some other embodiments, R 8 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy. In a further embodiment, R 8 is methyl.
  • R 11 is hydroxy. In another further embodiment, is amino.
  • R 1 is phenyl or monocyclic heteroaryl and R 11 is hydroxy or amino.
  • R 1 is bicyclic heteroaryl and R 11 is hydroxy or amino.
  • X is CR 5 and R 5 is hydrogen.
  • R 5 is alkyl.
  • R 5 is C 1 -C 4 alkyl.
  • R 1 is bicyclic heteroaryl and R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl.
  • X is CR 5 and R 5 is hydrogen.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 1 is bicyclic heteroaryl
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl
  • R 11 is hydroxy or amino
  • X is CR 5 or N
  • R 5 is hydrogen.
  • R 11 is hydroxy.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 1 is phenyl or monocyclic heteroaryl and R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl.
  • X is CR 5 and R 5 is hydrogen.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • R 1 is phenyl or monocyclic heteroaryl
  • R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl
  • R 11 is hydroxy or amino
  • X is CR 5 or N
  • R 5 is hydrogen.
  • R 11 is hydroxy.
  • R 4 is selected from the group consisting of —CN, —CF 3 , —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , —S( ⁇ O) 2 CH 2 F, —S( ⁇ O) 2 CHF 2 , —S( ⁇ O) 2 CF 3 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NHCH 3 , —S( ⁇ O)( ⁇ NH)CH 3 , —S( ⁇ O)( ⁇ NH)CH 2 F, —S( ⁇ O)( ⁇ NH)CHF 2 , —S( ⁇ O)( ⁇ NH)CF 3 , —S( ⁇ O)( ⁇ N—CN)CH 3 , —S( ⁇ O)( ⁇ N—CN)CH 2 F, —S( ⁇ O)( ⁇ N—CN)CHF 2 and —S( ⁇ O)( ⁇ N—CN)CF 3 .
  • X is N and Y is CR 6 . In other embodiments, X is CR 5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5 and Y is CR 6 .
  • Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR 7 . In yet other embodiments, Z is NR 8 . In some embodiments, Z is absent.
  • a compound of any one of Formulae I-H-I-K may have an enantiomeric excess of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or even higher.
  • a compound of any one of Formulae I-H-I-K may have an enantiomeric excess of about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%.
  • the invention provides a compound of Formula II:
  • R 7 and R 8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • R 1 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is cycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is aryl or heteroaryl. In a further embodiment, R 1 is phenyl. In another further embodiment, R 1 is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl.
  • R 1 is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each of R e is independently hydrogen or alkyl, or two R e s and the carbon atom to which they are attached form a 4- to 8-membered cyclic moiety; each of R f is independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n′′ is 0, 1, 2, 3 or 4.
  • the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted by one or more substituents described for aryl and heteroaryl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is cycloalkyl. In other embodiments, R 1 is heterocycloalkyl. In a further embodiment, R 1 is C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In yet a further embodiment, R 1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • R 1 is acyl or cyano. In a further embodiment, R 1 is acetyl.
  • R 1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1 is heteroalkyl.
  • R 1 is selected from the group consisting of:
  • each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
  • the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 2 is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R 2 is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R 2 is cyano, halo or alkyl. In some embodiments, R 2 is halo or alkyl. In a further embodiment, R 2 is fluoroalkyl. In a still further embodiment, R 2 is C 1 -C 4 fluoroalkyl. Exemplary C 1 -C 4 fluoroalkyl includes, but is not limited to, —CH 2 F, —CHF 2 , —CF 2 CH 3 and the like.
  • R 11 is hydrogen or deuterium. In some embodiments, R 11 is alkyl. In a further embodiment, R 11 is C 1 -C 4 alkyl.
  • R 15 is hydroxy or amino. In some embodiments, R 15 is hydroxy. In some embodiments, R 15 is amino. In a further embodiment, R 15 is NH 2 .
  • each of R 16 and R 17 is independently hydrogen or fluoro. In some embodiments, each of R 16 and R 17 is hydrogen. In some embodiments, each of R 16 and R 17 is fluoro. In some embodiments, at least one of R 16 and R 17 is fluoro.
  • R 18 is O, N—CN, or NH. In some embodiments, R 18 is O. In some embodiments, R 18 is NH. In some embodiments, R 18 is N—CN.
  • R 11 is hydrogen and R 15 is hydroxy or amino.
  • R 1 is aryl or heteroaryl.
  • R 2 is cyano, halo or alkyl.
  • R 16 and R 17 are fluoro.
  • R 15 is hydroxy or amino and R 2 is cyano, halo or alkyl. In a further embodiment, R 2 is fluoroalkyl. In a still further embodiment, at least one R 16 and R 17 is fluoro. In a yet still further embodiment, n′′ is 1.
  • R 18 is O or NH and R 14 is hydrogen.
  • R 1 is aryl or heteroaryl.
  • R 2 is cyano, halo or alkyl.
  • at least one of R 16 and R 17 is fluoro.
  • n′′ is 1.
  • R 15 is hydroxy or amino and R 16 and R 17 are fluoro.
  • R 1 is aryl or heteroaryl.
  • R 1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkoxy, cyano and alkyl.
  • the invention provides a compound of Formula II-A:
  • R 1 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is cycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is aryl or heteroaryl. In a further embodiment, R 1 is phenyl. In another further embodiment, R 1 is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl.
  • R 1 is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted by one or more substituents described for aryl and heteroaryl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is cycloalkyl. In other embodiments, R 1 is heterocycloalkyl. In a further embodiment, R 1 is C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In yet a further embodiment, R 1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • R 1 is acyl or cyano. In a further embodiment, R 1 is acetyl.
  • R 1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1 is heteroalkyl.
  • R 1 is selected from the group consisting of:
  • each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
  • the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 2 is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R 2 is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R 2 is cyano, halo or alkyl. In some embodiments, R 2 is halo or alkyl. In a further embodiment, R 2 is fluoroalkyl. In a still further embodiment, R 2 is C 1 -C 4 fluoroalkyl. Exemplary C 1 -C 4 fluoroalkyl includes, but is not limited to, —CH 2 F, —CHF 2 , —CF 2 CH 3 and the like.
  • R 14 is hydrogen or deuterium. In some embodiments, R 14 is alkyl. In a further embodiment, R 14 is C 1 -C 4 alkyl.
  • R 15 is hydroxy or amino. In some embodiments, R 15 is hydroxy. In some embodiments, R 15 is amino. In a further embodiment, R 15 is NH 2 .
  • R 18 is O, N—CN, or NH. In some embodiments, R 18 is O. In some embodiments, R 18 is NH. In some embodiments, R 18 is N—CN.
  • R 18 is O or NH and R 14 is hydrogen.
  • R 1 is aryl or heteroaryl.
  • R 2 is cyano, halo or alkyl.
  • at least one of R 16 and R 17 is fluoro.
  • the invention provides a compound of Formula II-B:
  • R 1 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is cycloalkyl, aryl or heteroaryl. In some embodiments, R 1 is aryl or heteroaryl. In a further embodiment, R 1 is phenyl. In another further embodiment, R 1 is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl.
  • R 1 is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each of R e is independently hydrogen or alkyl, or two R e s and the carbon atom to which they are attached form a 4- to 8-membered cyclic moiety; each of R f is independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n′′ is 0, 1, 2, 3 or 4.
  • the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.
  • R 1 is selected from the group consisting of:
  • R 1 may optionally be substituted by one or more substituents described for aryl and heteroaryl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 1 is cycloalkyl. In other embodiments, R 1 is heterocycloalkyl. In a further embodiment, R 1 is C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In yet a further embodiment, R 1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • R 1 is acyl or cyano. In a further embodiment, R 1 is acetyl.
  • R 1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1 is heteroalkyl.
  • R 1 is selected from the group consisting of:
  • each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
  • the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
  • R 2 is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R 2 is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R 2 is cyano, halo or alkyl. In some embodiments, R 2 is halo or alkyl. In a further embodiment, R 2 is fluoroalkyl. In a still further embodiment, R 2 is C 1 -C 4 fluoroalkyl. Exemplary C 1 -C 4 fluoroalkyl includes, but is not limited to, —CH 2 F, —CHF 2 , —CF 2 CH 3 and the like.
  • R 15 is hydroxy. In some embodiments, R 15 is amino. In a further embodiment, R 15 is NH 2 .
  • R 18 is O, N—CN, or NH. In some embodiments, R 18 is O. In some embodiments, R 18 is NH. In some embodiments, R 18 is N—CN.
  • a compound of Formula II-B may have an enantiomeric excess of at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99%.
  • the compound has an enantiomeric excess of at least about 90%.
  • the present disclosure provides a compound or pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of the compounds given in Table 2.
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about ⁇ 10° C. to about 110° C. over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • a compound of Formula 1-9 can be prepared according to steps outlined in Scheme 1.
  • the synthesis starts with phenol 1-1.
  • Reaction of 1-1 with chloride 1-2 (wherein R g and R h are independently alkyl) provides intermediate 1-3.
  • the reaction may be carried out in a suitable organic solvent in the presence of a base.
  • Suitable bases for the reaction include, but are not limited to, organic bases, for example, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, and inorganic bases, for example, sodium hydroxide, cesium carbonate, cesium bicarbonate, sodium carbonate, and potassium carbonate.
  • a compound of Formula 1-3 is then subjected to a rearrangement reaction to give a compound of Formula 1-4.
  • Elevated temperature may be needed for the rearrangement to occur.
  • the temperature may be in a range of 100° C. to 300° C. In some embodiments, the temperature is in a range of 180° C. to 240° C.
  • Hydrolysis of a compound of Formula 1-4 provides thiophenol 1-5, which is alkylated to provide a compound if Formula 1-6.
  • a variety of alkyl groups may be introduced in Step D.
  • IV is a C 1 -C 4 alkyl.
  • R a is a C 1 -C 4 fluoroalkyl.
  • Oxidation of a compound of Formula 1-6 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl 3 catalyzed oxidation in the presence of NaIO 4 , oxidation with m-chloroperoxybenzoic acid (mCPBA) and oxidation with Oxone®. Ketone 1-7 is then reduced to give alcohol 1-8, which then undergoes a nucleophilic aromatic substitution (SNAr) reaction with a suitable substrate R 1 OH to give a compound of Formula 1-9. Temperatures for carrying out the SNAr reaction may depend on the reactivity of both R 1 OH and/or compound 1-8. The reaction may be carried out in a temperature range from about room temperature to 200° C. In some embodiments, the temperature range is from room temperature to 60° C. In some other embodiments, the temperature range is from 60° C. to 100° C. In some other embodiments, the temperature range is from 100° C. to 200° C.
  • a compound of Formula 1-9 can be prepared asymmetrically to give a compound of Formula 2-2 (Scheme 2).
  • direct asymmetric reduction of ketone 1-7 may be accomplished chemically or enzymatically.
  • Examples of chemical asymmetric reduction of ketones include, but are not limited to, Corey-Bakshi-Shibata (CBS) reduction, asymmetric hydrogenation and asymmetric transfer hydrogenation.
  • the asymmetric transfer hydrogenation is catalyzed by ruthenium.
  • exemplary catalysts for asymmetric transfer hydrogenation include, but are not limited to, the following (shown as the R, R configuration):
  • the asymmetric transfer hydrogenation may be carried out at or below room temperature. In some embodiments, the asymmetric transfer hydrogenation is carried out at about 4° C.
  • the alcohol product may have an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, or even higher. It is well understood by one skilled in the art that changing the catalyst configuration will lead to a product with the opposite configuration.
  • Chiral alcohol 2-1 can be coupled with a suitable substrate, for example, a phenol, to give a compound of Formula 2-2 without significant loss of enantiomeric excess.
  • the loss of enantiomeric excess (ee) in the coupling step for 2-2 may be less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6% or less than about 8%.
  • a compound of Formula 3-6 may be prepared according to Scheme 3.
  • the ketone in 1-7 is protected as a ketal to give a compound of Formula 3-1, wherein each of R i and R j is independently an alkyl group.
  • R i and R j may optionally be connected to form a cyclic ketal.
  • Exemplary structures of ketal 3-1 include, but are not limited to, the following:
  • a compound of Formula 3-1 and a suitable R 1 OH may undergo a nucleophilic aromatic substitution reaction (SNAr) to give biaryl ether 3-2.
  • SNAr nucleophilic aromatic substitution reaction
  • the reaction temperature of the SNAr reaction may depend on the reactivity of the aryl halide (i.e. compound 3-1) and/or R 1 OH.
  • Ketone 3-3, resulting from the deprotection of ketal 3-2, is condensed with an amine to form imine 3-4, wherein R k is alkyl.
  • the imine functional group in a compound of Formula 3-4 may exist as a mixture of E and Z isomers.
  • Fluorination of 3-4 can be accomplished with a fluorinating reagent, for example, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate, to give difluoroketone 3-5 after acid hydrolysis. Finally, reduction of ketone 3-5 with a hydride donor gives a compound of Formula 3-6.
  • a fluorinating reagent for example, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate
  • a compound of Formula 4-1 (Scheme 4) can be prepared asymmetrically following the general procedure described above in Scheme 2.
  • the asymmetric reduction gives a compound of Formula 4-1 with an enantiomeric excess of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or even higher.
  • the enantiomeric excess of a compound of Formula 2-2 or 4-1 may be determined by chiral HPLC or Mosher ester analysis. For determination of ee with Mosher ester, see Hoye, et al. Natural Protocol, 2: 2451, 2007.
  • a compound of Formula 4-1 may be prepared according to Scheme 5.
  • Ketone 5-1 is fluorinated to give monofluoroketone 5-2, which is then converted to a silylenol ether, e.g., TBS enol ether 5-3.
  • silylenol ether e.g., TBS enol ether 5-3.
  • Other silyl protecting groups may also be used, for example, triisopropylsilyl or diphenyl-t-butylsilyl.
  • the resulting enol ether is further fluorinated to give difluoroketone 5-4, which undergoes an asymmetric reduction, such as asymmetric transfer hydrogenation as described herein, to give chiral alcohol 5-5. Protection of the hydroxy moiety, followed by SNAr reaction and deprotection of the alcohol, provides a compound of Formula 4-1.
  • a compound of Formula 3-6 can be prepared according to Scheme 6.
  • Treatment of aryl halide 3-1 with a hydroxide source gives phenol 6-1.
  • Suitable hydroxide sources include, but are not limited to, sodium hydroxide and potassium hydroxide.
  • Suitable solvents for the reaction include, but are not limited to, DMSO, DMA, DMF and EtOH.
  • Phenol 6-1 can react with a suitable halide via an SNAr reaction to give ether 3-2, which can be converted to a compound of Formula 3-6 as described in Scheme 3.
  • Compounds of Formulae 7-3 and 7-4 may be prepared according to Scheme 7. For example, condensation of NH 2 R k with difluoroketone 7-1, wherein R a is aryl, heteroaryl, alkyl, heteroalkyl, heterocycle, or cycloalkyl, gives intermediate 7-2.
  • R k is a chiral auxiliary.
  • Exemplary chiral auxiliaries include, but are not limited to:
  • a compound of Formula 8-2 can be prepared according to Scheme 8.
  • ketone 3-3 is monofluorinated to give a monofluoroketone of Formula 8-1.
  • the monofluorination can be achieved with a variety of fluorinating reagents, e.g., N-Fluoro-O-benzenedisulfonimide, acetyl hypofluorite, Accufluor®, Selectfluor®, Selectfluor® II, or N-fluorobenzenesulfonimide, in the presence or absence of a base.
  • a compound of Formula 8-1 is reduced to give a compound of Formula 8-2.
  • the reduction is highly diastereoselective to give a compound of Formula 8-2 with greater than 80%, greater than 82%, greater than 84%, greater than 86%, greater than 88%, greater than 90%, greater than 92%, greater than 94%, greater than 96% or even greater than 96% diastereoselectivity.
  • the reduction is highly enantioselective to give a compound of Formula 8-2 with greater than 80%, greater than 82%, greater than 84%, greater than 86%, greater than 88%, greater than 90%, greater than 92%, greater than 94%, greater than 96% or even greater than 96% enantioselectivity.
  • Reduction conditions to achieve high enantioselectivity include, but are not limited to, asymmetric transfer hydrogenation and enzymatic reduction as described herein.
  • the bromide of compound 9-3 can be replaced with a hydroxy group in a solvent comprising water in the presence of a silver salt, e.g., Ag 2 CO 3 or AgClO 4 or AgBF 4 .
  • a silver salt e.g., Ag 2 CO 3 or AgClO 4 or AgBF 4 .
  • fluorination of a compound of Formula 9-4 followed by deprotection gives a compound of Formula 9-6.
  • direct benzylic oxidation may be used for converting a compound of Formula 9-2 to a compound of Formula 9-4, thus bypassing an intermediate bromination step.
  • a compound of Formula 10-7 can be prepared according to Scheme 10.
  • a compound of Formula 10-3 may be prepared from a compound of Formula 3-2 following a similar sequence as outlined in Scheme 9. Further functional group manipulations lead to a compound of Formula 10-7.
  • a compound of Formula 10-3 can be deprotected to give diketone 11-1, which is fluorinated to give difluorodiketone 11-2. Asymmetric reduction of 11-2 provides diol 11-3.
  • a fluorination step is performed to give a compound of Formula 10-7.
  • a compound of Formula 10-7 may be prepared according to Scheme 12.
  • difluoroketone 12-2 is reduced to give hydroxyketone 12-3.
  • the reduction may be enantioselective under transfer hydrogenation conditions with a Ru-catalysis as described herein.
  • One of the aryl fluorines may be selectively displaced with an alkyl thiol to give a compound of Formula 12-4.
  • Oxidation, fluorination, nucleophilic aromatic substitution (SNAr) and asymmetric reduction give a compound of Formula 10-7.
  • a compound of Formula 13-4 can be prepared according to Scheme 13.
  • An aryl sulfide of Formula 13-1 is treated with H 2 N—R b and an oxidant, e.g., diacetoxyiodobenzene or dipivaloyloxyiodobenzene, in a suitable solvent, such as acetonitrile, to obtain aryl sulfinimide 13-2.
  • R a is fluoroalkyl
  • the addition of rhodium(II) acetate or Rh 2 (esp) 2 catalyst along with magnesium oxide is helpful in Step A.
  • Oxidation of aryl sulfinimide 13-2 to substituted sulfoximine 13-3 may be accomplished with catalytic ruthenium(III) chloride and sodium periodate in a suitable solvent, such as a mixture of water, acetonitrile, and carbon tetrachloride.
  • a suitable solvent such as a mixture of water, acetonitrile, and carbon tetrachloride.
  • Substituted sulfoximine 13-3 is then manipulated similarly as described in Schemes 3 and 4 to afford sulfoximines of Formula 13-4 as a diastereomeric mixture.
  • the diastereomers may be separated by column chromatography.
  • a compound of Formula 14-10 can be prepared according to steps outlined in Scheme 14, wherein R 1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R 2 is halo, cyano, alkyl, alkenyl or alkynyl; and R 16 and R 17 are fluoro or alkyl, or R 16 and R 17 and the carbon to which they are attached form C 3 -C 8 cycloalkyl or C 5 -C 8 heterocycloalkyl.
  • the synthesis commences with compounds of Formula 14-1. Orthoiodination of 14-1 provides compound 14-2.
  • the hydrolysis and alkylation may be carried out in a one-pot procedure without purification. In some embodiments, this is carried out by treating a compound of Formula 14-4 with a carbonate base in a suitable solvent at or near room temperature for a period ranging from 0.1 to 24 hours, followed by addition of an alkyl halide.
  • Carbonate bases include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate and cesium bicarbonate.
  • Oxidation of a compound of Formula 14-5 to give a compound of Formula 14-6 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl 3 catalyzed oxidation in the presence of NaIO 4 , oxidation with m-chloroperoxybenzoic acid (mCPBA), and oxidation with Oxone®.
  • a compound of Formula 14-6 is then subjected to a nucleophilic aromatic substitution (SNAr) reaction with R 1 OH (wherein R 1 is alkyl, aryl or heteroaryl) to give a compound of Formula 14-7.
  • SNAr nucleophilic aromatic substitution
  • Temperature for carrying out the SNAr reaction may depend on the reactivity of both R 1 OH and/or a compound of Formula 14-6.
  • the reaction may be carried out at a temperature ranging from ⁇ 10° C. to 200° C. In some embodiments, the temperature range is from 30° C. to 120° C. In some other embodiments, the temperature range is from 0° C. to room temperature.
  • Cyclization of a compound of Formula 14-7 may be effected with a base, e.g., sodium hydride, in a suitable solvent to yield a compound of Formula 14-8. After the cyclization, a variety of R 16 and R 17 groups may be introduced.
  • a compound of Formula 14-8 is difluorinated to give a compound of Formula 14-9, formed by treatment with a fluorinating agent, e.g., 1-(chloromethyl)-4-fluoro-1,4-diazo niabicyclo[2.2.2]octane ditetrafluoroborate (Selectfluor®), in the presence of suitable base, e.g., sodium carbonate.
  • a fluorinating agent e.g., 1-(chloromethyl)-4-fluoro-1,4-diazo niabicyclo[2.2.2]octane ditetrafluoroborate (Selectfluor®)
  • suitable base e.g., sodium carbonate
  • Reduction of a compound of Formula 14-9 yields a compound of Formula 14-10.
  • the reduction is carried out with a hydride, e.g., sodium borohydride and sodium triacetoxyborohydride, to give a racemic mixture.
  • a compound of Formula 14-8 may be prepared according to Scheme 15.
  • lithiation of a compound of Formula 15-1 followed by trapping of the resulting lithio intermediate with a suitable electrophile gives a compound of Formula 15-2.
  • the electrophile is N,N-dimethylformamide and R 2 is —CHO.
  • —CHO is converted to —CHF 2 through addition of a fluorinating reagent, e.g., diethylaminosulfur trifluoride.
  • a fluorinating reagent e.g., diethylaminosulfur trifluoride.
  • One of the fluorines in a compound of Formula 15-2 may be selectively displaced with a thiomethoxide, e.g., sodium thiomethoxide, to give compounds of Formula 15-3.
  • the reaction temperature may be in a range of ⁇ 50 to 40° C. In some embodiments, the temperature is at or about 0° C.
  • Oxidation of a compound of Formula 15-3, followed by SNAr reaction with R 1 OH and base-mediated cyclization provides a compound of Formula 14-8.
  • a compound of Formula 16-6 may be prepared according to Scheme 16.
  • Oxidation of a compound of Formula 15-3 gives a compound of Formula 16-1.
  • the oxidation may be accomplished with Oxone® or mCPBA.
  • the amount of oxidant used for the oxidation may be about 1.5 equivalent, about 1.4 equivalent, about 1.3 equivalent, about 1.2 equivalent, about 1.1 equivalent or about 1.0 equivalent.
  • SNAr reaction of a compound of Formula 16-1 with R 1 OH (wherein R 1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl) in the presence of a base gives a compound of Formula 16-2.
  • a sulfoximine moiety may be installed to give a compound of Formula 16-3 through a transition-metal catalyzed insertion of a suitable nitrogen donor.
  • suitable transition-metal catalysts include, but are not limited to, copper and rhodium catalysts, e.g., bis(rhodium( ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethyl-1,3-benezenedipropionic acid)) and dirhodium tetraacetate.
  • Suitable nitrogen donors include, but are not limited to, PhI ⁇ NNs, cyanamide, and fluoroalkylamides, e.g., trifluoromethyl acetamide.
  • Cyclization of a compound of Formula 16-3 to give a compound of Formula 16-4 may be achieved with a base, e.g., sodium hydride, at about room temperature.
  • a base e.g., sodium hydride
  • reduction of a compound of Formula 16-5 as outlined in Scheme 14 provides a compound of Formula 16-6.
  • a compound of Formula 16-6 may exist as a mixture of diastereomers and/or enantiomers. Diastereomers may be separated by conventional column chromatography, while enantiomers may be separated by chiral column chromatography.
  • a compound of Formula 17-5 can be prepared according to Scheme 17. Reaction of a compound of Formula 15-3 with cyanamide in the presence of an oxidant, e.g., (diacetoxyiodo)benzene, affords a compound of Formula 15-1. Further oxidation of a compound of Formula 15-1 provides a compound of Formula 15-2, which undergoes SNAr reaction, cyclization and reduction to give a compound of Formula 17-5.
  • an oxidant e.g., (diacetoxyiodo)benzene
  • compounds of Formula 18-8a and 18-8b may be prepared according to Scheme 18.
  • pyridine 18-1 may be converted to alkylaryl derivative 18-2 in Step A, wherein R 4 is, for example, trifluoromethyl.
  • the ketone may be converted to protected enol ether 18-3, then fluorinated to give fluoroketal 18-4.
  • Treatment of a compound of Formula 18-4 with a suitable hydroxide source as described in Scheme 6 gives a mixture of phenols 18-5a and 18-5b.
  • the phenols can undergo an SNAr reaction with a suitable halide to give aryl ethers of Formulae 18-6a and 18-6b, which may be deprotected to give the resultant ketones.
  • a compound of Formula 18-7 is reduced with a hydride source to give a racemic mixture.
  • an asymmetric reduction is carried out as described in Scheme 2, affording alcohols 18-8a and 18-8b, separable by methods known to one skilled in the art, such as, for example, conventional column chromatography.
  • a compound of Formula 18-8a can be prepared according to Scheme 19.
  • conversion of a compound of Formula 19-1 to a phenol is followed by coupling to form an aryl ether and deprotection to give a ketone of Formula 18-7b as described above.
  • Ketone 18-7b is converted to silyl enol ether 19-5 using a suitable silyl protecting group, including, for example, tert-butyldimethylsilyl, triisopropylsilyl or diphenyl-t-butylsilyl.
  • the resulting silyl enol ether is fluorinated to give fluoroketone 18-7a, which undergoes an asymmetric reduction, such as asymmetric transfer hydrogenation as described herein, to give chiral alcohol 18-8a.
  • a compound of Formula 20-9 can be prepared following the general procedure outlined in Scheme 20, wherein the aryl fluoride of a compound of Formula 20-1 is displaced with an alkyl thiol to give 20-2. Formation of benzaldehyde 20-3 may be followed by, for example, a Wittig reaction, to give alkene 20-4, which is reduced to an alkane of Formula 20-5 under suitable conditions. In some embodiments, a Dieckmann condensation reaction is followed by a decarboxylation to give ketone 20-6.
  • Oxidation of a compound of Formula 20-6 to give a compound of Formula 20-7 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl 3 catalyzed oxidation in the presence of NaIO 4 , oxidation with m-chloroperoxybenzoic acid (mCPBA) and oxidation with Oxone®. Protection of the ketone, for example, as the cyclic ketal (20-8) is followed by the general procedure outlined in Scheme 19 to give a compound of Formula 20-9.
  • a compound of Formula 21-7 may be prepared according to Scheme 21. Formation of a chloropyridine of Formula 21-2 may be followed by an SNAr reaction with a suitable alcohol of formula R 1 OH as described above to give a compound of Formula 21-3. Aryl bromide 21-3 may undergo a transition-metal catalyzed coupling reaction with a thioate to give a compound of Formula 21-4, analogously to the procedure detailed in Scheme 14. Hydrolysis, alkylation with a suitable alkyl halide and oxidation affords a compound of Formula 21-7.
  • a ketone of Formula 22-1 may be reduced to give 22-2, optionally with high enantioselectivity using asymmetric transfer hydrogenation or enzymatic reduction conditions as described herein.
  • a compound of Formula 22-2 and a suitable coupling partner including, but not limited to, a boronic acid of formula R 1 B(OH) 2 , may undergo a coupling reaction to give a compound of Formula 22-3.
  • R 1 can be coupled to a compound of Formula 23-1 or 23-4 via a reaction scheme represented generally in Scheme 23.
  • an aryl halide of Formula 23-1 is coupled to a suitably substituted amine, i.e. NHR 1 R 8 , via a Buchwald-Hartwig amination to give a compound of Formula 23-2.
  • Step A is a cross coupling reaction, including, but not limited to, a Stille, Negishi or Suzuki reaction, wherein an aryl halide of Formula 23-1 is combined with an appropriate reactant containing R 1 and a suitable catalyst to afford a compound of Formula 23-3.
  • a compound of Formula 23-4 undergoes an SNAr reaction and a subsequent deprotection to give a compound of Formula 23-3.
  • R 1 in a compound of Formula 23-5 may be, for example, morpholine, wherein a C—N bond connects said morpholine to the aryl ring.
  • Z is S, and R 1 S— is attached to a compound of Formula 23-1 via an SNAr reaction to give a compound of Formula 23-6.
  • a compound of Formula 24-2 can be prepared according to steps outlined in Scheme 24.
  • a compound of Formula 12-6 is prepared via an asymmetric variation of the sequence presented in Scheme 12, then reacted with an amine, i.e. (3S)-3-piperidinol hydrochloride, to give a compound of Formula 24-1.
  • Asymmetric reduction as described above gives a compound of Formula 24-2.
  • a compound of Formula 25-3 or 25-4 may be prepared according to steps outlined in Scheme 25.
  • 25-2 may be prepared via a cross coupling reaction, i.e., a Suzuki reaction with a boronic acid of formula R 1 B(OH) 2 . Hydride reduction of 25-2 gives a mixture of alcohols 25-3 and unsaturated alcohol 25-4.
  • a compound of Formula 26-5 can be synthesized according to Scheme 26.
  • treatment of compound 26-1 with base can provides difluoroalkene 26-2.
  • the amount of base may be about 1 equivalent to avoid byproduct formation.
  • the olefin in 26-2 may be hydrogenated to give a compound of Formula 26-3 with cis difluoro configuration.
  • an alkoxy group can be introduced by displacement of the aryl fluoride in 26-3 by an alcohol in the presence of a base.
  • deprotection followed by reduction of the resulting ketone provides a compound of Formula 26-5.
  • Intermediate 26-3 may be separated, for example, by chiral column chromatography, to give both enantiomers, each of which can be functionalized as outlined in Scheme 26 to provide either enantiomer of a compound of Formula 26-5.
  • a compound of Formula 27-6 may be synthesized according to Scheme 27.
  • alkylation of compound 27-1 provides a compound of Formula 27-2, wherein R 1 is alkyl, cycloalkyl, or heterocycloalkyl.
  • a compound of Formula 27-2 can be selectively iodinated to give aryl iodide 27-3.
  • a compound of Formula 27-3 can be difluorinated as previously described. Installation of a CF 3 group followed by asymmetric reduction provides a compound of Formula 27-6.
  • a compound of a formula given in Table 2 is synthesized according to one of the general routes outlined in Schemes 1-27, Examples 1-32 or by methods generally known in the art.
  • 602 371 (M ⁇ H) 603 (300 MHz, CDCl 3 ): ⁇ 7.85 (d, 1H), 6.95 (d, 1H), 5.56 (m, 1H), 4.91 (m, 1H), 3.18 (m, 1H), 3.10 (m, 1H), 2.87 (m, 1H), 2.32 (m, 1H), 2.25 (m, 1H), 1.56-1.99 (m, 8H).
  • 604 387 (M ⁇ H) 605 385 (M ⁇ H) 606 (300 MHz, CDCl 3 ): ⁇ 7.92 (d, 1H), 7.04 (d, 1H), 5.36 (d, 1H), 4.60 (m, 1H), 3.46 (m, 1H), 3.39 (m, 1H), 3.14 (m, 2H), 2.80 (m, 2H), 2.05 (m, 2H), 1.76 (m, 2H), 1.55 (m, 4H) 607 402 (M + H) 608 389 (M ⁇ H) 609 (300 MHz, CDCl 3 ): ⁇ 7.90 (d, 1H), 6.94 (d, 1H), 5.60 (m, 1H), 4.04 (m, 2H), 3.20 (m, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.40 (m, 1H), 2.31 (m, 1H), 1.54 (s, 3H), 1.53 (s, 3H) 610 398 (M
  • a composition of the present disclosure may be formulated in any suitable pharmaceutical formulation.
  • a pharmaceutical composition of the present disclosure typically contains an active ingredient (e.g., a compound of the present disclosure or a pharmaceutically acceptable salt and/or coordination complex thereof), and one or more pharmaceutically acceptable excipients, carriers, including but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • a composition of the present disclosure may be formulated in any suitable pharmaceutical formulation.
  • the pharmaceutical acceptable carriers, excipients are selected from the group consisting of water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, and dimethyl sulfoxide (DMSO).
  • compositions may be provided in any suitable form, which may depend on the route of administration.
  • the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject.
  • the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and/or intraperitoneal administration.
  • the dosage form is formulated for oral intervention administration.
  • the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder.
  • the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi-solid, or solid form.
  • the disclosure provides a pharmaceutical composition comprising an amount of a HIF-2 ⁇ inhibitor, e.g. Compound 231, formulated for administration to a subject in need thereof.
  • the pharmaceutical composition comprises between about 0.0001-500 g, 0.001-250 g, 0.01-100 g, 0.1-50 g, or 1-10 g of HIF-2 ⁇ inhibitor.
  • the pharmaceutical composition comprises about or more than about 0.0001 g, 0.001 g, 0.01 g, 0.1, 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g, 50 g, 100 g, 200 g, 250 g, 300 g, 350 g, 400 g, 450 g, 500 g, or more of a HIF-2 ⁇ inhibitor.
  • the pharmaceutical composition comprises between 0.001-2 g of a HIF-2 ⁇ inhibitor in a single dose.
  • the pharmaceutical composition comprises an amount between about 50-150 g of a HIF-2 ⁇ inhibitor.
  • a therapeutically effective amount of HIF-2 ⁇ inhibitor which can be a daily amount administered over the course of a period of treatment, can sufficiently provide any one or more of the therapeutic effects described herein.
  • the therapeutic effective amount can be in the range of about 0.001-1000 mg/kg body weight, 0.01-500 mg/kg body weight, 0.01-100 mg/kg body weight, 0.01-30 mg/kg body weight, 0.1-200 mg/kg body weight, 3-200 mg/kg body weight, 5-500 mg/kg body weight, 10-100 mg/kg body weight, 10-1000 mg/kg body weight, 50-200 mg/kg body weight, 100-1000 mg/kg body weight, 200-500 mg/kg body weight, 250-350 mg/kg body weight, or 300-600 mg/kg body weight of a HIF-2 ⁇ inhibitor.
  • the therapeutic amount can be about or more than about 0.001 mg/kg body weight, 0.01 mg/kg body weight, 0.1 mg/kg body weight, 0.5 mg/kg body weight, 1 mg/kg body weight, 2 mg/kg body weight, 3 mg/kg body weight, 4 mg/kg body weight, 5 mg/kg body weight, 6 mg/kg body weight, 7 mg/kg body weight, 8 mg/kg body weight, 9 mg/kg body weight, 10 mg/kg body weight, 15 mg/kg body weight, 20 mg/kg body weight, 25 mg/kg body weight, 50 mg/kg body weight, 100 mg/kg body weight, 200 mg/kg body weight, 250 mg/kg body weight, 300 mg/kg body weight, 350 mg/kg body weight, 400 mg/kg body weight, 450 mg/kg body weight, 500 mg/kg body weight, 600 mg/kg body weight, 800 mg/kg body weight, 1000 mg/kg body weight, or more of a HIF-2a inhibitor.
  • the effective amount is at least about 0.01 mg/kg body weight of a HIF-2 ⁇ inhibitor. In some embodiments, the effective amount is an amount between about 0.01-30 mg/kg body weight of a HIF-2 ⁇ inhibitor. In some embodiments, the therapeutic amount can be an amount between about 50-150 mg/kg body weight of a HIF-2 ⁇ inhibitor.
  • the composition is provided in one or more unit doses.
  • the composition can be administered in 1, 2, 3, 4, 5, 6, 7, 14, 30, 60, or more doses.
  • Such amount can be administered each day, for example in individual doses administered once, twice, or three or more times a day.
  • dosages stated herein on a per day basis should not be construed to require administration of the daily dose each and every day.
  • the HIF-2 ⁇ inhibitor is provided in a suitably slow-release form, two or more daily dosage amounts can be administered at a lower frequency, e.g., as a depot every second day to once a month or even longer.
  • HIF-2 ⁇ inhibitor can be administered once a day, for example in the morning, in the evening or during the day.
  • the unit doses can be administered simultaneously or sequentially.
  • the composition can be administered for an extended treatment period.
  • the treatment period can be at least about one month, for example at least about 3 months, at least about 6 months or at least about 1 year. In some cases, administration can continue for substantially the remainder of the life of the subject.
  • the HIF-2 ⁇ inhibitor is administered as part of a therapeutic regimen that comprises administering one or more second agents (e.g. 1, 2, 3, 4, 5, or more second agents), either simultaneously or sequentially with the HIF-2 ⁇ inhibitor.
  • the HIF-2 ⁇ inhibitor may be administered before or after the one or more second agents.
  • the HIF-2 ⁇ inhibitor and the one or more second agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising the HIF-2 ⁇ inhibitor and the one or more second agents).
  • second agents and therapies suitable for combination therapy for the treatment of PAH are available, and may be combined with one or more HIF-2 ⁇ inhibitors.
  • second agents include, but are not limited to, mitotic kinesis inhibitors, JAK2 inhibitors, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, prostacyclin receptor agonists (e.g., selexipag), anticoagulants, diuretics, calcium channel blockers, digoxin, oxygen therapy, nitric oxide therapy, tyrosine kinases, statins, 5-hydroxytryptamine (5-HT) receptor antagonists, phosphatidylinositol 3-kinase inhibitors, soluble guanylate cyclase activators, adrenomedullin, platelet-derived growth factor (PDGF) inhibitors, Rho-kinase inhibitors, and mTOR inhibitors, treprostinil, bosentan, iloprost, ambrisentan, si
  • mitotic kinesin inhibitors are compounds that act to inhibit the activity of one or more mitotic kinesins.
  • inhibition refers to a decrease in mitotic kinesin activity as a direct or indirect response to the presence of a chemical entity (e.g., a mitotic kinesin inhibitor), relative to the activity of the mitotic kinesin in the absence of the chemical entity.
  • the decrease in activity is due to the direct interaction of the chemical entity with mitotic kinesin.
  • the decrease in activity is due to the interaction of the chemical entity with one or more other factors that affect mitotic kinesin activity.
  • the presence of the chemical entity may decrease mitotic kinesin activity by directly binding to the mitotic kinesin, by causing (directly or indirectly) another factor to decrease mitotic kinesin activity, or by (directly or indirectly) decreasing the amount of mitotic kinesin present in the cell or organism.
  • mitotic kinesin inhibitors may act by increasing or decreasing spindle pole separation, causing malformation (e.g., splaying) of mitotic spindle poles, or otherwise causing morphological perturbation of the mitotic spindle or by interfering with the normal function of the mitotic spindle (e.g. misalignment and inappropriate segregation of chromosomes). Meiotic spindles may also be disrupted.
  • Mitotic kinesin inhibitors may be reversible or irreversible, may bind to the kinesin's active site or an allosteric site, and may act as competitive, uncompetitive or non-competitive inhibitors. In all instances, mitotic kinesin inhibitors halt or slow the normal process of cell division and proliferation.
  • JAK2 inhibitors include Pacritinib, CEP-33779, SB1578, TG101348, TG101209, AZD1480, AZ960, LY2784544, BMS911543, SGI-1252, MK0457, XL019, NVP-BSK805, Ruxolitinib, Baricitinib and CYT387. Further examples are described in WO2014161046A1 and U.S. Pat. No. 8,410,173.
  • a second agent can be a prostanoid.
  • prostanoids include, but are not limited to, prostacyclin (epoprostenol, epoprostenol sodium) and prostacyclin analogs such as treprostinil sodium, iloprost, cisaprost, beraprost, and ciprostene sodium.
  • a second agent is an endothelin receptor antagonist.
  • the endothelin receptor antagonist can be an agent that selectively or preferentially inhibits type A endothelin receptor (ET A ).
  • the endothelin receptor antagonist is an agent that selectively or preferentially inhibits type B endothelin receptor (ET B ).
  • the endothelin receptor antagonist is an agent that inhibits both ET A and ET B .
  • pulmonary arterial hypertension is treated in a subject by administering to the subject a therapeutically effective amount of a mitotic kinesin inhibitor, an agent that selectively or preferentially inhibits ET A , and an agent that selectively or preferentially inhibits ET B .
  • Examples of endothelin receptor antagonists include bosentan, tazosentan, BQ123, ambrisentan, atrasentan, sitaxsentan, BQ788 and macitentan.
  • PDE inhibitors include selective and non-selective inhibitors of any of the PDE isoforms, including, for example, PDE1 and PDE5 inhibitors.
  • PDE inhibitors include sildenafil, tadalafil, vardenafil, udenafil avanafil, dipyridamole, and vinpocetine.
  • Anticoagulants can include, for example, coumarins (e.g., warfarin, acenocoumarol, phenprocoumon, phenindione), heparin, low molecular weight heparin, and direct thrombin inhibitors (e.g., argatroban, lepirudin, bivalirudin, dabigatran).
  • coumarins e.g., warfarin, acenocoumarol, phenprocoumon, phenindione
  • heparin e.g., heparin, low molecular weight heparin
  • direct thrombin inhibitors e.g., argatroban, lepirudin, bivalirudin, dabigatran.
  • diuretics include thiazide-like diuretics (e.g., chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone), loop diuretics (e.g., bumetanide, furosemide, torsemide) and potassium-sparing diuretics (e.g., amiloride hydrochloride, spironolactone, triamterene).
  • thiazide-like diuretics e.g., chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone
  • loop diuretics e.g., bumetanide, furosemide, torsemide
  • potassium-sparing diuretics e.g., amiloride hydrochloride, spironolactone, triamterene
  • calcium channel blocker Another example of a second agent is calcium channel blocker.
  • calcium channel blockers include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil.
  • Tyrosine kinases include, for example, axitinib, bosutinib, cediranib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, neratinib, nilotinib, semaxanib, sorafenib, sunitinib, toceranib, vandetanib, and vatalanib.
  • the second agent is a statin.
  • statins include atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, simvastatin/ezetimibe, lovastatin/niacin, atorvastatin/amlodipine and simvastatin/niacin.
  • a second agent is a 5-HT receptor antagonist.
  • 5-HT receptor antagonists include selective and non-selective antagonists of any of the 5-HT receptor isoforms, including, for example, 5-HT 1B , 5-HT 2A and/or 5-HT 2C receptor antagonists. Examples of 5-HT receptor antagonists include citalopram, clozapine, fluoxetine, ketanserin and paroxetine.
  • PDGF inhibitors can include imatinib, sorafenib, sunitinib, lefluonamide, midostaurin, semaxanib and vatalanib.
  • the second agent can be a phosphatidylinositol 3-kinase inhibitor.
  • potential PI3 kinase inhibitor can include the class I PI 3-kinase, p110 ⁇ isoform specific inhibitors, IC486068 and IC87114, ICOS Corporation and GDC-0941.
  • a second agent can be a soluble guanylate cyclase inhibitor.
  • a soluble guanylate cyclase activator is riociguat.
  • a second agent can be a Rho-kinase inhibitor.
  • a Rho-kinase inhibitor is fasudil (fasudil hydrochloride).
  • a second agent can be an mTOR inhibitor.
  • mTOR inhibitors include rapamycin, temsirolimus and resveratrol.
  • the agents may be administered separately, at the same, or at different times of the day, or they may be administered in a single composition.
  • each agent can be administered in an “immediate release” manner or in a “controlled release manner.”
  • the additional active agent is a vasodilator
  • any dosage form containing both active agents, such as both the HIF-2 ⁇ inhibitor and the vasodilator can provide for immediate release or controlled release of the vasodilator, and either immediate release or controlled release of the HIF-2 ⁇ inhibitor.
  • a combination dosage form for once-daily administration might contain in the range of about 0.001 mg/kg body weight to about 350 mg/kg body weight of a HIF-2 ⁇ inhibitor, such as about 0.01 mg/kg body weight to about 50 mg/kg body weight of a HIF-2 ⁇ inhibitor, or about 0.05 mg/kg body weight to about 15 mg/kg body weight of a HIF-2 ⁇ inhibitor, or about 0.01 mg/kg body weight to about 30 mg/kg body weight in a controlled release (e.g., sustained release) or immediate release form, and either sildenafil in immediate release form, or in controlled release form, with the additional active agent present in an amount that provides a weight ratio of the HIF-2 ⁇ inhibitor to sildenafil, or a weight ratio of the HIF-2 ⁇ inhibitor to sildenafil, specified as above.
  • a controlled release e.g., sustained release
  • sildenafil in immediate release form, or in controlled release form
  • two or more additional active agents which may or may not be in the same class of drug (e.g., vasodilators) can be present in combination, along with the leukotriene inhibitor.
  • the effective amount of either or each individual additional active agent present will generally be reduced relative to the amount that would be required if only a single added agent were used.
  • the disclosure provides a pharmaceutical composition for oral administration containing a compound of the present disclosure, and a pharmaceutical excipient suitable for oral administration.
  • the composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid.
  • the composition further comprises a second agent.
  • composition of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs.
  • dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient into association with the carrier.
  • the composition are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • anhydrous pharmaceutical composition and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds.
  • water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
  • Anhydrous pharmaceutical composition and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical composition and dosage forms of the disclosure which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous composition may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Binders suitable for use in pharmaceutical composition and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrroli
  • suitable fillers for use in the pharmaceutical composition and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the composition of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may alter the rate and extent of release of the active ingredient(s) from the dosage form. A sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof.
  • calcium stearate e.g., magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc
  • hydrogenated vegetable oil e.g., peanut oil, cottonseed oil,
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactant which can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value).
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures
  • ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate,
  • Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivative
  • hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl oleate
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for composition for non-oral use, e.g., composition for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ⁇ -caprolactam
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation.
  • the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic
  • compositions for Topical e.g., Transdermal Delivery.
  • the disclosure provides a pharmaceutical composition for transdermal delivery containing a compound of the present disclosure and a pharmaceutical excipient suitable for transdermal delivery.
  • the composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid.
  • the composition further comprises a second agent.
  • Composition of the present disclosure can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • the pharmaceutical composition also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation.
  • humectants e.g., urea
  • glycols e.g., propylene glycol
  • alcohols e.g., ethanol
  • fatty acids e.g., oleic acid
  • surfactants e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
  • amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Formulations for topical administration may include ointments, lotions, creams, gels (e.g., poloxamer gel), drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • the disclosed compositions can be administered, for example, in a microfiber, polymer (e.g., collagen), nanosphere, aerosol, lotion, cream, fabric, plastic, tissue engineered scaffold, matrix material, tablet, implanted container, powder, oil, resin, wound dressing, bead, microbead, slow release bead, capsule, injectables, intravenous drips, pump device, silicone implants, or any bio-engineered materials.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present disclosure in controlled amounts, either with or without another agent.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the disclosure provides a pharmaceutical composition for injection containing a compound of the present disclosure and a pharmaceutical excipient suitable for injection.
  • Components and amounts of agents in the composition are as described herein.
  • Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described vide supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder composition may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • compositions may also be prepared from a composition described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art.
  • compositions and methods further comprises administering, separately or simultaneously one or more additional agents (e.g. 1, 2, 3, 4, 5, or more).
  • additional agents can included those useful in wound healing.
  • additional agents include antibiotics (e.g. Aminoglycosides, Cephalosporins, Chloramphenicol, Clindamycin, Erythromycins, Fluoroquinolones, Macrolides, Azolides, Metronidazole, Penicillin's, Tetracycline's, Trimethoprim-sulfamethoxazole, Vancomycin), steroids (e.g. Andranes (e.g. Testosterone), Cholestanes (e.g.
  • Cholesterol Cholic acids (e.g. Cholic acid), Corticosteroids (e.g. Dexamethasone), Estraenes (e.g. Estradiol), Pregnanes (e.g. Progesterone), narcotic and non-narcotic analgesics (e.g. Morphine, Codeine, Heroin, Hydromorphone, Levorphanol, Meperidine, Methadone, Oxydone, Propoxyphene, Fentanyl, Methadone, Naloxone, Buprenorphine, Butorphanol, Nalbuphine, Pentazocine), chemotherapy (e.g.
  • Cholic acids e.g. Cholic acid
  • Corticosteroids e.g. Dexamethasone
  • Estraenes e.g. Estradiol
  • Pregnanes e.g. Progesterone
  • narcotic and non-narcotic analgesics e.g. Morphine, Codeine, Heroin
  • anti-cancer drugs such as but not limited to Altretamine, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Cyclophosphamide, Cytarabine, dacarbazine, Diethylstilbesterol, Ethinyl estradiol, Etoposide, Floxuridine, Fludarabine, Fluorouracil, Flutamide, Goserelin, Hydroxyurea, Idarubicin, Ifosfamide, Leuprolide, Levamisole, Lomustine, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Paclitaxel, pentastatin, Pipobroman, Plicamycin, Prednisone, Procarbazine, Streptozocin, Tamoxifen,
  • Alclofenac Alclometasone Dipropionate; Algestone Acetonide; alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Decanoate; Deflazacort; Delatestryl; Depo-Testosterone; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; D
  • Ethanolamines like diphenhydrmine carbinoxamine
  • Ethylenediamine like tripelennamine pyrilamine
  • Alkylamine like chlorpheniramine, dexchlorpheniramine, brompheniramine, triprolidine
  • other anti-histamines like astemizole, loratadine, fexofenadine, Bropheniramine, Clemastine, Acetaminophen, Pseudoephedrine, Triprolidine).
  • Step A Preparation of 3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile
  • Step B Preparation of 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
  • Step C Preparation of (E,Z)-3-((1-(butylimino)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
  • Step D Preparation of 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
  • Step E Preparation of (S)-3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (Compound 15)
  • Step A Preparation of 4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]
  • Step B Preparation of 3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile
  • dichloro[1;1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (784 mg, 0.97 mmol) was quickly added to a degassed mixture of 4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (4.3 g, 9.7 mmol), zinc cyanide (1.14 g, 9.7 mmol) and zinc powder (761 mg, 11.6 mmol) in DMF (60 mL) under nitrogen. The reaction mixture was then warmed to 110° C. for 2 hours.
  • Step D Preparation of 3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile
  • Butan-1-amine (5.15 mL, 52 mmol) was added to 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (450 mg, 1.3 mmol) and trifluoroacetic acid (19.96 ⁇ L, 0.26 mmol) in benzene (10 mL) at room temperature then warmed to reflux with the azeotropic removal of water by a Dean-Stark apparatus. Progress of the reaction was monitored by 1 H-NMR. When complete, the reaction was cooled to room temperature then concentrated in vacuo.
  • Step E Preparation of 3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile
  • Step F Preparation of (S)-3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (Compound 163)
  • Step B Synthesis of Compound 183: A stirred mixture of 5-chloro-4-nitro-2,1,3-benzoxadiazole (20 mg, 0.1 mmol), 3-chlorobenzen-4,6-t 2 -amine (600 mCi) and Cs 2 CO 3 (65 mg, 0.20 mmol) in DMF (1 mL) was heated at 60° C. for 1 h. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by preparative HPLC on an ACE-5 C18 Semi-prep column, 250 ⁇ 10 mm, 100 ⁇ . Elution was carried out isocratically using 0.1% TFA in water/Acetonitrile (35:65) to give Compound 183 (478 mCi, 80%).
  • Step A N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo) ⁇ 6 -sulfanylidene)cyanamide
  • Step B N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo) ⁇ 6 -sulfanylidene)cyanamide
  • Dess-Martin periodinane (192 mg, 0.45 mmol) was added to a solution of N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo) ⁇ 6 -sulfanylidene)cyanamide (200 mg, 0.54 mmol) in dichloromethane (50 mL). After 10 minutes, the reaction mixture was evaporated and the residue was partitioned between EtOAc and aqueous sodium thiosulfate and saturated aqueous NaHCO 3 .
  • Step C (E/Z)-N-((7-(3-cyano-5-fluorophenoxy)-3-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo) ⁇ 6 -sulfanylidene)cyanamide
  • Step D N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo) ⁇ 6 -sulfanylidene)cyanamide
  • Step E N-q(S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo) ⁇ 6 -sulfanylidene)cyanamide (Compound 240)
  • RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.5 mg, 0.020 mmol) was added to a nitrogen-sparged, ice-cold solution of N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo) ⁇ 6 -sulfanylidene)cyanamide (49 mg, 0.120 mmol), triethylamine (0.022 mL, 0.16 mmol), and formic acid (0.01 mL, 0.24 mmol) in dichloromethane (5 mL).
  • Step A [(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate
  • Step B [(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate and [(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate
  • Step C [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate
  • Step D [(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate
  • Step E 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile (Compound 289)
  • Step A [(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate and [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate
  • the crude product was dissolved in 1,2-dimethoxyethane (11 mL) and water (0.11 mL). Silver perchlorate hydrate (0.35 g, 1.55 mmol) was added. The reaction mixture was heated at 70° C. overnight. After cooling, the reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried and concentrated.
  • Step B [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-yl]acetate
  • Step C 3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (Compound 292)
  • Step E Preparation of 3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile
  • Step F Preparation of 3-((4-(difluoromethyl)-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile
  • Step G Preparation of 3-((4-(difluoromethyl)-2,2-difluoro-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile
  • Step H Preparation of 3-((4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile
  • Step I Preparation of (R)-3-((4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile
  • Example 8 Synthesis of (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465) and (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466)
  • Step A Preparation of 4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one
  • Step B Preparation of 4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] and 4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine
  • Trimethylsilyl trifluoromethanesulfonate (75.9 ⁇ L, 0.42 mmol) was added to a solution of 4-bromo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (389 mg, 1.39 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.37 mL, 5.56 mmol) in dichloromethane (13.6 mL) cooled in an ice bath. The mixture was allowed to slowly warm to ambient temperature.
  • Step C Preparation of 4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]
  • Step D Preparation of 6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol and 1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol
  • reaction mixture was then treated sequentially with potassium hydroxide (47.3 mg, 0.84 mmol), water (101 ⁇ L, 5.62 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-t-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (6.0 mg, 0.007 mmol) under continuous nitrogen stream.
  • the vessel was sealed and heated to 80 C for 1 h and 30 min.
  • the reaction mixture was quenched by the addition of acetic acid (64.3 ⁇ L, 1.13 mmol).
  • Step E Preparation of 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] and 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]
  • Step F Preparation of 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one and 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one
  • Step G Preparation of (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465) and (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466)
  • Step A Preparation of 1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol
  • reaction mixture was then treated sequentially with potassium hydroxide (117.6 mg, 2.10 mmol), water (252 ⁇ L, 13.97 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (14.9 mg, 0.017 mmol) under continuous nitrogen stream.
  • the vessel was sealed and heated to 80 C for 1 h and 30 min.
  • the reaction mixture was quenched by the addition of acetic acid (160 ⁇ L, 2.79 mmol).
  • Step B Preparation of 3-fluoro-5-((1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile
  • a suspension of potassium tert-butoxide (28.4 mg, 0.25 mmol) in tetrahydrofuran (1.5 mL) at 0 C was treated with 1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (60.0 mg, 0.23 mmol) and stirred at 0 C for 15 min.
  • the resulting mixture was treated with (3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium; 4-methylbenzenesulfonate (144.8 mg, 0.28 mmol) and heated to 40 C.
  • Step C Preparation of 3-fluoro-5-((7-oxo-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile
  • Step D Preparation of 3-((7-((tert-butyldimethylsilyl)oxy)-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile
  • Step E Preparation of 3-fluoro-5-((6-fluoro-7-oxo-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile
  • Step F Preparation of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 467)
  • reaction mixture was quenched by the addition of N,N-dimethylformamide (0.94 mL, 12.09 mmol). 15 minutes following addition of the DMF, the reaction mixture was quenched by the addition of 40 mL of 10% citric acid solution (aqueous) and the reaction warmed to room temperature. After stirring for 30 min, excess THF removed by concentration under reduced pressure. The leftover mixture was poured into 120 mL of 3% citric acid (aqueous) and extracted with 3 ⁇ 50 mL EtOAc. The combined organics were dried with MgSO 4 , filtered, and concentrated to dryness. 2.41 g of an orange solid was isolated and used without further purification. The material was contaminated with about 22% citric acid based on proton integration of the unpurified NMR spectra. LCMS ESI (+) (M+H) m/z 276/278.
  • Step C Preparation of methyl (E)-5-bromo-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-(methylthio)nicotinate
  • Step D Preparation of methyl 5-bromo-4-(3-ethoxy-3-oxopropyl)-2-(methylthio)nicotinate
  • Step E Preparation of ethyl 4-bromo-1-(methylthio)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one
  • the reaction mixture was quenched by the addition of 30 mL of saturated aqueous NH 4 Cl. THF was removed by concentration under reduced pressure. The reaction mixture diluted with 60 mL of EtOAc and an additional 30 mL of water. A thick precipitate formed that could be eliminated by the addition of 10% citric acid solution. The reaction mixture was extracted with 3 ⁇ 30 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The intermediate product was transferred into a microwave tube using 9.1 mL of DMSO. The resulting mixture was diluted with 900 ⁇ L of water. The vessel was sealed and heated to 150 C by microwave irradiation for 40 min.
  • Step F Preparation of 4-bromo-1-(methylsulfonyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one
  • Step G Preparation of 4-bromo-1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]
  • Trimethylsilyl trifluoromethanesulfonate (331 ⁇ L, 1.83 mmol) was added to a solution of 4-bromo-1-methylsulfonyl-5,6-dihydrocyclopenta[c]pyridin-7-one (354 mg, 1.22 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.20 mL, 4.88 mmol) in dichloromethane (14 mL) cooled in an ice bath. The ice bath was removed. After 3 h, an additional portion of trimethyl(2-trimethylsilyloxyethoxy)silane (1.20 mL, 4.88 mmol) was added. The reaction was left to stir overnight.
  • Step H Preparation of 1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol
  • reaction mixture was then treated sequentially with potassium hydroxide (37.5 mg, 0.67 mmol), water (80.3 ⁇ l, 4.46 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (9.5 mg, 0.011 mmol) under continuous nitrogen stream.
  • the vessel was sealed and heated to 80 C for 1 h and 30 min.
  • the reaction mixture was quenched by the addition of acetic acid (51.0 ⁇ L, 0.89 mmol).
  • Step I Preparation of 3-fluoro-5-((1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile
  • a suspension of potassium carbonate (30.6 mg, 0.22 mmol) in acetonitrile (1.5 mL) at 25 C was treated with 1′-methylsulfonylspiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (40.0 mg, 0.15 mmol) and stirred at 25 C for 10 min.
  • the resulting mixture was treated with (3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium; 4-methylbenzenesulfonate (116.2 mg, 0.22 mmol) and heated to 50 C for 3 h. Volatiles were removed by concentration under reduced pressure.
  • Step J Preparation of 3-fluoro-5-((1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile
  • Step K Preparation of 3-((7-((tert-butyldimethylsilyl)oxy)-1-(methylsulfonyl)-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile
  • Step L Preparation of 3-fluoro-5-((6-fluoro-1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile
  • Step M Preparation of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 468)
  • Example 11 Synthesis of 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 469) and 4-(difluoromethylsulfonyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 470)
  • Step A 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine
  • Step B 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 469)
  • Step C S-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate
  • Step D 1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-thiol
  • Step E 4-(difluoromethylsulfanyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine
  • Step F 4-(difluoromethylsulfonyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 470)
  • Step A Preparation of racemic (6R,7S)-4-bromo-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol
  • Step B Preparation of racemic 3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile (Compound 471)
  • Step B Preparation of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione
  • Step D Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one
  • Step E Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • Step F Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one

Abstract

The present disclosure provides methods of treating pulmonary arterial hypertension (PAH) in a subject in need thereof. Compositions for use in these methods are also provided.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. application Ser. No. 15/556,607, filed Sep. 7, 2017 under 35 U.S.C. § 371(c) as the U.S. National Phase of International Application No. PCT/US2016/021492, filed Mar. 9, 2016, which claims the benefit of U.S. Provisional Application No. 62/131,783, filed on Mar. 11, 2015. The contents of the aforementioned priority applications are incorporated herein by reference in their entireties.
    • BACKGROUND
  • An adequate supply of oxygen to tissues is essential in maintaining mammalian cell function and physiology. A deficiency in oxygen supply to tissues is a characteristic of a number of pathophysiologic conditions in which there is insufficient blood flow to provide adequate oxygenation, for example, ischemic disorders, cancer, and atherosclerosis. The hypoxic (low oxygen) environment of tissues activates a signaling cascade that drives the induction or repression of the transcription of a multitude of genes implicated in events such as angiogenesis (neo-vascularization), glucose metabolism, and cell survival/death. A key to this hypoxic transcriptional response lies in the transcription factor, the hypoxia-inducible factor (HIF). HIF is overexpressed in a vast array of cancers through hypoxia-dependent and independent mechanisms and expression is associated with poor patient prognosis.
  • HIFs consist of an oxygen-sensitive HIFα subunit and constitutively expressed HIFβ subunit. When HIFs are activated, the HIFα and HIFβ subunits assemble a functional heterodimer (the a subunit heterodimerizes with the β subunit). Both HIFα and HIFβ have two identical structural characteristics, a basic helix-loop-helix (bHLH) and PAS domains (PAS is an acronym referring to the first proteins, PER, ARNT, SIM, in which this motif was identified). There are three human HIFα subunits (HIF-1α, HIF-2α, and HIF-3α) that are oxygen sensitive. Among the three subunits, HIF-1α is the most ubiquitously expressed and induced by low oxygen concentrations in many cell types. HIF-2α is highly similar to HIF-1α in both structure and function, but exhibits more restricted tissue-specific expression, and might also be differentially regulated by nuclear translocation. HIF-3α also exhibits conservation with HIF-1α and HIF-2α in the HLH and PAS domains. HIFβ (also referred to as ARNT—Aryl Hydrocarbon Receptor Nuclear Translocator), the dimerization partner of the HIFα subunits, is constitutively expressed in all cell types and is not regulated by oxygen concentration.
  • Pulmonary arterial hypertension (PAH) is a serious, progressive and life-threatening disease of the pulmonary vasculature, characterized by profound vasoconstriction and an abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries. Severe constriction of the blood vessels in the lungs leads to very high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from extreme shortness of breath as the heart struggles to pump against these high pressures. Patients with PAH typically develop significant increases in pulmonary vascular resistance (PVR) and sustained elevations in pulmonary artery pressure (PAP), which ultimately lead to right ventricular failure and death. Patients diagnosed with PAH have a poor prognosis and equally compromised quality of life, with a mean life expectancy of 2 to 5 years from the time of diagnosis if untreated. There is no known cause of PAH, and current treatments only address the symptoms, not the underlying problem.
    • SUMMARY
  • In view of the foregoing, there exists a need for improved compounds for treating PAH and related diseases. This disclosure provides compounds, compositions, and methods that address this need, and provide other advantages as well.
  • In one aspect, the present disclosure provides a method of treating pulmonary arterial hypertension (PAH) in a subject in need thereof. In one embodiment, the method comprises administering a composition comprising an effective amount of a HIF-2α inhibitor to said subject. In some embodiments, the amount of HIF-2α inhibitor is effective in delaying the onset of or reducing the incidence of one or more symptoms of PAH. In some embodiments, the amount of HIF-2α inhibitor is effective in (a) stabilizing pulmonary arterial pressure (PAP) as compared to a PAP trend in the subject prior to treatment, (b) reducing PAP relative to a starting level of PAP in the subject, or (c) reducing right ventricular hypertrophy as measured by Fulton's Index relative to an untreated population of subjects having PAH; wherein the PAP is systolic pulmonary arterial pressure (SPAP) or diastolic pulmonary arterial pressure (DPAP). In some embodiments, the amount of HIF-2α inhibitor is effective in (a) reducing one or more of: pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and brain natriuretic peptide level; and/or (b) increasing one or more of: mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, six-minute walk distance, and lung diffusion capacity. In some embodiments, the amount of HIF-2α inhibitor is effective in reducing vascular smooth muscle hypertrophy. In some embodiments, the HIF-2α inhibitor inhibits one or more biological effects selected from the group consisting of heterodimerization of HIF-2α to HIF-1β, HIF-2α target gene expression, VEGF gene expression, and VEGF protein secretion. In some embodiments, the HIF-2α inhibitor inhibits heterodimerization of HIF-2α to HIF-1β but not heterodimerization of HIF-1α to HIF-1β. In some embodiments, the HIF-2α inhibitor binds the PAS-B domain cavity of HIF-2α. In some embodiments, the HIF-2α inhibitor is a compound of any of the formulas provided herein.
  • In one aspect, the present invention provides a compound of Formula I:
  • Figure US20190015377A1-20190117-C00001
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R2 is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo, sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl;
      • R3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; or R2 and R3 taken together form a cyclic moiety;
      • R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • In some other embodiments of compounds of Formula I, R1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. In some embodiments, R1 is phenyl or pyridyl. In yet other embodiments, R1 is cycloalkyl or heterocycloalkyl. Compounds of Formula I are also provided wherein R1 is substituted with at least one substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In yet other embodiments of compounds of Formula I, R2 and R3 are independently selected from halo, cyano and alkyl. In some further embodiments, R3 is —(CH2)nOH and n is 1, 2 or 3. In still other embodiments, n is 1.
  • In still other embodiments of compounds of Formula I, R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In other embodiments, R4 is fluoroalkyl or fluoroalkylsulfonyl.
  • In some embodiments of compounds of Formula I, R2 and R3 are independently selected from halo, cyano and alkyl; and R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In another embodiment, R3 is CH2OH.
  • In yet another embodiment, Z is O. In some embodiments, Z is S. In still other embodiments, Z is NR8. In another embodiment, Z is CHR7. In some embodiments, Z is absent. In some embodiments, X is N and Y is CR6. In another embodiment, X is CR5 and Y is N. In yet another embodiment, X is N and Y is N. In still another embodiment, X is CR5 and Y is CR6.
  • In another aspect, the invention provides a compound of Formula I-A:
  • Figure US20190015377A1-20190117-C00002
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R2 is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl;
  • R3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R2 and R3 taken together form a cyclic moiety;
  • R4 is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy;
      • W1 is N or CR10;
      • R9 is cyano, halo, alkyl or alkoxy; and
      • R10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • In another aspect, the invention provides a compound of Formula I-B:
  • Figure US20190015377A1-20190117-C00003
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R2 is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl;
      • R3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R2 and R3 taken together form a cyclic moiety;
      • R4 is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy;
      • Rc is hydrogen, cyano, halo, alkyl or alkoxy; and
      • n′ is 0, 1, 2, 3 or 4.
  • In yet another aspect, the invention provides a compound of Formula I-C:
  • Figure US20190015377A1-20190117-C00004
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy;
      • R11 is hydrogen, hydroxy, alkoxy or amino;
      • R12 is hydrogen, alkyl, alkenyl or alkynyl; or R11 and R12 in combination form oxo or oxime;
      • each of R13 is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl, with the proviso that when R13 is hydroxy, n is 1 or 2; or two R13s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety; and
      • n is 0, 1, 2, 3 or 4.
  • In some other embodiments of compounds of Formula I-C, R1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. In some embodiments, R1 is phenyl or pyridyl. In yet other embodiments, R1 is cycloalkyl or heterocycloalkyl. Compounds of Formula I-C are also provided wherein R1 is substituted with at least one substituent selected from the group consisting of halo, alkyl, C1-C4 alkoxy and cyano.
  • In still other embodiments of compounds of Formula I-C, R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In other embodiments, R4 is fluoroalkyl or fluoroalkylsulfonyl. In some other embodiments, R11 is hydroxy or amino. In further embodiments, R11 is hydroxy. In yet other embodiments, R12 is hydrogen. In yet another embodiment, R13 is fluoro and n is 1, 2 or 3.
  • In some embodiments of compounds of Formula I-C, R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R11 is hydroxy or amino; and R12 is hydrogen. In still another embodiment, R13 is fluoro. In yet another embodiment, Z is O. In some embodiments, Z is S. In still other embodiments, Z is NR8. In another embodiment, Z is CHR7. In some embodiments, Z is absent.
  • In some other embodiments of compounds of Formula I-C, R4 is fluoroalkyl; n is 0, 1, 2 or 3; Z is O; R11 is hydroxy; and R12 is hydrogen. In still other embodiments, R4 is sulfonyl; n is 0, 1, 2 or 3; Z is O; R11 is hydroxy; and R12 is hydrogen. In yet other embodiments, R1 is phenyl, pyridyl, cycloalkyl or heterocycloalkyl. In some embodiments, X is N and Y is CR6. In another embodiment, X is CR5 and Y is N. In yet another embodiment, X is N and Y is N.
  • In still another aspect, the invention provides a compound of Formula I-D, I-E, I-F or I-G:
  • Figure US20190015377A1-20190117-C00005
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
      • R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and
      • R11 is hydrogen, hydroxy, alkoxy or amino.
  • In a further aspect, the invention provides a compound of Formula I-H, I-I, I-J or I-K:
  • Figure US20190015377A1-20190117-C00006
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
      • R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and
      • R11 is hydroxy or amino.
  • In yet another aspect, the invention provides a compound of Formula II:
  • Figure US20190015377A1-20190117-C00007
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R2 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl;
      • R14 is hydrogen, deuterium or alkyl;
      • R15 is hydrogen, hydroxy or amino; or R14 and R15 in combination form oxo or methylene;
      • R16 and R17 are independently selected from the group consisting of hydrogen, halo, alkyl, heteroalkyl and cycloalkyl; or R16 and R17 and the carbon to which they are attached form C3-C8 cycloalkyl or C5-C8 heterocycloalkyl;
      • R18 is O or NR19, wherein R19 is selected from the group consisting of hydrogen, alkyl and cyano;
      • n″ is 1 or 2; and
      • R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • In another aspect, the invention provides a compound of Formula II-A:
  • Figure US20190015377A1-20190117-C00008
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R2 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl;
      • R14 is hydrogen, deuterium or alkyl;
      • R15 is hydrogen, hydroxy or amino; or R14 and R15 in combination form oxo or methylene;
      • R18 is O or NR19, wherein R19 is selected from the group consisting of hydrogen, alkyl and cyano; and
      • R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • In still another aspect, the invention provides a compound of Formula II-B:
  • Figure US20190015377A1-20190117-C00009
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R2 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl;
      • R15 is hydroxy or amino;
      • R18 is O or NR19, wherein R19 is selected from the group consisting of hydrogen, alkyl and cyano; and
      • R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • In some embodiments, the composition administered to the subject is provided in a unit dose. In some embodiments, the composition is administered orally, intravenously, subcutaneously, intranasally, transdermally, intraperitoneally, intramuscularly, or intrapulmonarily. In some embodiments, a second agent is administered simultaneously or sequentially with the HIF-2α inhibitor. The second agent may form part of the composition. In some embodiments, the second agent is selected from the group consisting of mitotic kinesis inhibitors, JAK2 inhibitors, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, prostacyclin receptor agonists, anticoagulants, diuretics, calcium channel blockers, digoxin, oxygen therapy, nitric oxide therapy, tyrosine kinases, statins, 5-hydroxytryptamine (5-HT) receptor antagonists, phosphatidylinositol 3-kinase inhibitors, soluble guanylate cyclase activators, adrenomedullin, platelet-derived growth factor (PDGF) inhibitors, Rho-kinase inhibitors, and mTOR inhibitors. In some embodiments, the method further comprises (a) measuring a physiological indicator of PAH before and after the administering, and (b) adjusting dosage or discontinuing use of the HIF-2α inhibitor based on results of step (a). In some embodiments, the physiological indicator of PAH is selected from the group consisting of: pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six-minute walk distance, brain natriuretic peptide level, and lung diffusion capacity.
    • INCORPORATION BY REFERENCE
  • All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a bar graph illustrating effects of HIF-2α inhibitors on reducing systolic pulmonary artery pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 2 is a bar graph illustrating effects of HIF-2α inhibitors on mean pulmonary artery pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 3 is a bar graph illustrating effects of HIF-2α inhibitors on reducing diastolic pulmonary artery pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 4 illustrates effects of HIF-2α inhibitors treatment on heart rate. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 5 illustrates effects of HIF-2α inhibitors treatment on systolic arterial pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 6 illustrates effects of HIF-2α inhibitors treatment on mean arterial pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 7 illustrates effects of HIF-2α inhibitors treatment on diastolic arterial pressure. Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 8 illustrates effects of HIF-2α inhibitors treatment on Fulton's index (RV/LV+S). Bars from left to right correspond to groups listed in the legend from top to bottom. Doses for Compound 231 were in the indicated amount per day (QD).
  • FIG. 9 shows the histopathology of lung tissues in a normal animal. Short arrow points to a completely muscularized arteriole. Long, thin arrow points to a partially muscularized arteriole. The long arrow points to the non-muscularized portion of the partially muscularized arteriole.
  • FIG. 10 shows the histopathology of lung tissues in a hypoxia-induced animal treated with a vehicle. Arrows point to completely muscularized arteriole. The letter “P” indicates a partially muscularized arteriole. The arteriolar lumens have thick muscular walls.
  • FIG. 11 shows the histopathology of lung tissues in a hypoxia-induced animal treated with 100 mg/kg Compound 231. Arrows point to partially muscularized arterioles. The letter “C” indicates a completely muscularized arteriole. The completely muscularized arteriole has a diameter greater than 50 μm and would not have been included in the categorization of small arterioles. The arrows point to the non-muscularized portion of the partially muscularized arterioles. The arteriolar walls are thinner than those of similarly sized arterioles in FIG. 10.
  • FIG. 12 shows the histopathology of lung tissues in a hypoxia-induced animal treated with 300 mg/kg Compound 231. Arrows point to partially muscularized arterioles. The arrows point to the non-muscularized portion of the partially muscularized arterioles. The arteriolar walls are thinner than those of similar sized arterioles in FIGS. 10 and 11.
  • FIG. 13 shows the histopathology of lung tissues in a hypoxia-induced animal treated with 30 mg/kg bid sildenafil. Short arrows point to completely muscularized arterioles. Long arrows point to partially muscularized arterioles. The long arrows point to the non-muscularized portion of the partially muscularized arterioles. The amount of muscular hypertrophy is slightly less than that in FIG. 11.
  • FIG. 14 illustrates effects of HIF-2α inhibitors on preventing pulmonary vascular muscularization.
  • FIG. 15 is a bar graph illustrating effects of HIF-2α inhibitors on treating PAH. HIF-2α inhibitors reduce systolic pulmonary artery pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 16 is a bar graph illustrating effects of HIF-2α inhibitors on treating PAH. HIF-2α inhibitors reduce mean pulmonary artery pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 17 is a bar graph illustrating effects of HIF-2α inhibitors on treating PAH. HIF-2α inhibitors reduce diastolic pulmonary artery pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 18 illustrates effects of HIF-2α inhibitors on heart rate in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 19 illustrates effects of HIF-2α inhibitors on systolic arterial pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 20 illustrates effects of HIF-2α inhibitors on mean arterial pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 21 illustrates effects of HIF-2α inhibitors on diastolic arterial pressure in a model of active PAH. Bars from left to right correspond to groups listed in the legend from top to bottom. The dose for Compound 231 was in the indicated amount per day (QD).
  • FIG. 22 shows the histopathology of lung tissues in a model of active PAH treated with a vehicle for 14 days. Short arrow points to a completely muscularized small pulmonary arteriole. Long, thin arrows point to a partially muscularized small pulmonary arterioles.
  • FIG. 23 shows the histopathology of lung tissues in a model of active PAH treated with a vehicle for 28 days. Arrows point to completely muscularized small pulmonary arterioles. The arteriolar walls are thick relative to the size of the lumens. There are minimal inflammatory infiltrates surrounding the arterioles.
  • FIG. 24 shows the histopathology of lung tissues in a model of active PAH treated with 300 mg/kg Compound 231. Arrows point to completely muscularized small pulmonary arterioles.
  • FIG. 25 shows the histopathology of lung tissues in a model of active PAH treated with 30 mg/kg bid sildenafil. Arrows point to partially muscularized small pulmonary arterioles. There are minimal inflammatory infiltrates around one partially muscularized arteriole and the completely muscularized arteriole in the lower left corner of the image.
  • FIG. 26 depicts effects of HIF-2α inhibitors on treating pulmonary vascular muscularization in a model of active PAH.
  • FIG. 27 depicts results of a co-immunoprecipitation assay for measuring inhibition of HIF-2α and ARNT dimerization.
    •  DETAILED DESCRIPTION
  • The term “effective amount” or “therapeutically effective amount” refers herein to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g. delaying the onset of or reducing the incidence of one or more symptoms of PAH. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • As used herein, “treatment” or “treating,” or “palliating” and “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the composition may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • The term “co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompasses administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate composition, administration at different times in separate composition, or administration in a composition in which both agents are present.
  • “Combination therapy” and “co-therapy” means the administration of a first active agent and at least a second, different active agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of the at least two active agents. The beneficial effect of the combination may include, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). Combination therapy is not intended to encompass the administration of two or more different therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily results in a combination therapy of the invention. Combination therapy includes administration of at least two different therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of at least two different therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in separate capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The two different therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the second therapeutic agent of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not critical, unless otherwise stated. Combination therapy also includes the administration of the different therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or physical therapy). Where a combination therapy comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • The term “pharmaceutically acceptable salt” refers herein to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • As used herein, “agent” or “biologically active agent” refers herein to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like.
  • As used herein, “subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.
  • The term “in vivo” refers to an event that takes places in a subject's body.
  • The term “in vitro” refers to an event that takes place outside of a subject's body. For example, an in vitro assay encompasses any assay run outside of a subject's body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • The term “heterodimerization” as used herein refers to the complex formed by the non-covalent binding of HIF-2α to HIF-1β (ARNT). Heterodimerization of HIF-2α to HIF-1β (ARNT) is required for HIF-2α DNA binding and transcriptional activity and is mediated by the HLH and PAS-B domains. Transcriptional activity following heterodimerization of HIF-2α to HIF-1β (ARNT) can affect four groups of target genes including angiogenic factors, glucose transporters and glycolytic enzymes, survival factors, and invasion factors.
  • The term “HIF-2α” refers to a monomeric protein that contains three conserved structured domains: basic helix-loop-helix (bHLH), and two Per-ARNT-Sim (PAS) domains designated PAS-A and PAS-B, in addition to C-terminal regulatory regions. “HIF-2α” is also alternatively known by several other names in the scientific literature, most commonly EPAS 1 and MOP2. As a member of the bHLH/PAS family of transcription factors, “HIF-2α” forms an active heterodimeric transcription factor complex by binding to the ARNT (also known as HIF-1β) protein through non-covalent interactions.
  • The term “HIF-2α PAS-B domain cavity” refers to an internal cavity within the PAS-B domain of HIF-2α. The crystal structure of the PAS-B domain can contain a large (approximately 290 A) cavity in its core. However, the amino acid side chains in the solution structure are dynamic. For example, those side chains can tend to intrude more deeply in the core, and can shrink the cavity to 1 or 2 smaller cavities or can even expand the cavity. The cavity is lined by amino acid residues comprising PHE-244, SER-246, HIS-248, MET-252, PHE-254, ALA-277, PHE-280, TYR-281, MET-289, SER-292, HIS-293, LEU-296, VAL-302, VAL-303, SER-304, TYR-307, MET-309, LEU-319, THR-321, GLN-322, GLY-323, ILE-337, CYS-339, and ASN-341 of HIF-2α PAS-B domain. The numbering system is from the known structures reported in the RCSB Protein Data Bank with PDB code 3H7W. Other numbering systems in the PDB could define the same amino acids, expressed above, that line the cavity.
  • As described herein “a biological marker”, or “a biomarker”, generally refers to a measurable indicator of some biological state or condition. Biological markers are often measured and evaluated to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. A biomarker may be any molecular structure produced by a cell, expressed inside the cell, accessible on the cell surface, or secreted by the cell. A marker may be any protein, carbohydrate, fat, nucleic acid, catalytic site, or any combination of these such as an enzyme, glycoprotein, cell membrane, virus, cell, organ, organelle, or any uni- or multimolecular structure or any other such structure now known or yet to be disclosed whether alone or in combination.
  • The terms “polynucleotide”, “nucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
  • “Controlled release” refers to a drug-containing formulation or unit dose form thereof from which release of the drug is not immediate, i.e., with a controlled release formulation, administration does not result in immediate release of all of the drug administered into an absorption pool. The term is used interchangeably with “nonimmediate release” as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). In general, controlled release formulations include sustained release and delayed release formulations.
  • “Sustained release” and “extended release” refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and typically, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • “Delayed release” refers to a drug formulation that, following administration to a patient, provides a measurable time delay before drug is released from the formulation into the patient's body.
  • “Dosage form” means any form of a pharmaceutical composition for administration to a subject (typically a human or animal of veterinary interest suffering from a disease or condition to be treated). “Dose” refers to an amount of active agent. “Unit dosage form” refers to a dosage form that contains a fixed amount of active agent. A single tablet or capsule is a unit dosage form. Multiple unit dosage forms can be administered to provide a therapeutically effective dose. A dosage form can include a combination of dosage forms.
  • “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • The term “alkyl” refers to a straight or branched hydrocarbon chain radical comprising carbon and hydrogen atoms, containing no unsaturation, and having from one to ten carbon atoms (e.g., C1-C10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, it is a C1-C4 alkyl group. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like. The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl, (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(R))2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • The term “fluoroalkyl” refers to an alkyl group substituted with one or more fluorine atoms. In some embodiments, it is a C1-C4 alkyl group substituted with one or more fluorine atoms. Typical fluoroalkyl groups include, but are in no way limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3.
  • The term “alkenyl” refers to a straight or branched hydrocarbon chain radical group comprising carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C2-C10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In other embodiments, an alkenyl comprises two to five carbon atoms (i.e., C2-C5 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • The term “alkynyl” refers to a straight or branched hydrocarbon chain radical group comprising carbon and hydrogen atoms, containing at least one triple bond, and having from two to ten carbon atoms (i.e., C2-C10 alkynyl). In some embodiments, an alkynyl group may contain one or more double bonds. Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkynyl group may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl has two to five carbon atoms (i.e., C2-C5 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • The term “aromatic” or “aryl” refers to an aromatic radical with six to ten ring atoms (i.e., C6-C10 aromatic or C6-C10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • “Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical wherein the arylalkyl moiety is attached via the alkyl portion of the moiety. Aryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl, respectively.
  • The term “heteroaryl” or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (i.e., C5-C18 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical, e.g., nitrogen or sulfur, is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. Examples of monocylic heteroaryls include, but are not limited to, imidazolyl, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl and thienyl.
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide substituents, such as pyridinyl N-oxides.
  • “Heteroarylalkyl” refers to a moiety having a heteroaryl moiety, as described herein, connected to an alkyl moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkyl group. Heteroaryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroaryl and alkyl, respectively.
  • The term “acyl” refers to a —C(═O)R radical, wherein R is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, which are as described herein. The R group is attached to the parent structure through the carbonyl functionality. In some embodiments, it is a C1-C10 acyl radical which refers to the total number of chain or ring atoms of the alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl portion of the acyl group plus the carbonyl carbon of acyl, i.e. ring or chain atoms plus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the “R” of an acyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • The term “halo”, “halide”, or alternatively, “halogen” means fluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” refer to haloalkyl and haloalkoxy groups, respectively, in which the halo is fluoro. Examples of fluoroalkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CF2CH3, —CH2CF3, and —CF2CF3. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
  • The term “cyano” refers to a —CN radical.
  • The term “alkoxy” refers to an —O-alkyl radical, including from wherein alkyl is as described herein and contains 1 to 10 carbon atoms (i.e., C1-C10 alkoxy) of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C1-C4 alkoxy group. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Unless stated otherwise specifically in the specification, an alkoxy moiety may be substituted by one or more of the substituents described as suitable substituents for an alkyl radical.
  • The term “sp3 hybridized carbon” refers to a carbon atom that is bonded to four other atoms. sp3 hybridization results from the combination of the s orbital and all three p orbitals in the second energy level of carbon. It results in four equivalent orbitals and the geometric arrangement of those four orbitals is tetrahedral.
  • The term “sulfonyl” refers to a —S(═O)2Ra radical, wherein Ra is selected from the group consisting of alkyl, amino, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). Unless stated otherwise specifically in the specification, the Ra group may be substituted by one or more of the substituents described as suitable substituents for an alkyl, an aryl or a heteroaryl radical.
  • The term “sulfoximinyl” refers to a —S(═O)(═NRa)Rb radical, wherein Ra is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cyano, carbamoyl, acyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon) and Rb is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). Unless stated otherwise specifically in the specification, the Ra and Rb groups may be substituted by one or more of the substituents described as suitable substituents for an alkyl, an aryl or a heteroaryl radical.
  • “Sulfonamide,” “sulfonamidyl” or “sulfonamido” refers to a —S(═O)2N(Ra)2 radical, wherein each Ra is selected independently from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl. The Ra groups in —N(Ra)2 of the ═S(═O)2—N(Ra)2 radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring. In some embodiments, it is a C1-C10 sulfonamido, wherein each Ra in sulfonamido contains 1 carbon, 2 carbons, 3 carbons or 4 carbons total. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl and heteroaryl, respectively.
  • The term “fluoroalkylsulfonyl” refers to a —S(═O)2Ra radical, wherein Ra is fluoroalkyl. In some embodiments, Ra is C1-C4 alkyl, substituted with one or more fluorines.
  • The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical that contains carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (e.g., C3-C10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon ring atoms, 4 carbon ring atoms, 5 carbon ring atoms, etc., up to and including 10 carbon ring atoms. In some embodiments, it is a C3-C8 cycloalkyl radical. In some embodiments, it is a C3-C5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)N(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each IV is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • The term “heterocyclyl” or “heterocycloalkyl” refers to a stable 3- to 18-membered nonaromatic ring (e.g., C3-C18 heterocycloalkyl) radical that comprises two to twelve ring carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C5-C10 heterocycloalkyl. In some embodiments, it is a C4-C10 heterocycloalkyl. In some embodiments, it is a C3-C10 heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, may optionally be quaternized. The heterocycloalkyl radical may be partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, 6,7-dihydro-5H-cyclopenta[b]pyridine, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)N(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • “Heterocycloalkyl” also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected form oxygen, sulfur and nitrogen and is not aromatic.
  • The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals, which respectively have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range, which refers to the chain length in total, may be given. For example, C3-C4 heteroalkyl has a chain length of 3-4 atoms. For example, a —CH2OCH2CH3 radical is referred to as a “C4 heteroalkyl”, which includes the heteroatom in the atom chain length description. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain. A heteroalkyl may be a substituted alkyl. The same definition applies to heteroalkenyl or heteroalkynyl. Unless otherwise stated in the specification, a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • The term “amino” or “amine” refers to a —N(Ra)2 radical group, where each Ra is independently hydrogen, alkyl, heteroalkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a —N(Ra)2 group has two Ra other than hydrogen, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, 7- or 8-membered ring. For example, —N(Ra)2 is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • The term “substituted amino” also refers to N-oxides of N(Ra)2 as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
  • The term “acyloxy” refers to a RC(═O)O— radical wherein R is alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl, which are as described herein. In some embodiments, it is a C1-C4 acyloxy radical, which refers to the total number of chain or ring atoms of the alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e., the other ring or chain atoms plus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the “R” of an acyloxy group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, — N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • The term “amide” or “amido” refers to a chemical moiety with formula —C(═O)N(Ra)2 or —NRaC(═O)Ra, wherein each of Ra is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl. Two Ras may optionally be taken together with the nitrogen to which it is attached to form a 4-10 membered ring. In some embodiments, it is a C1-C4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound having an amine or a carboxylic acid moiety, thereby forming a prodrug. Any amine, hydroxy or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skilled in the art and can readily be found in reference sources such as Wuts, Greene's Protective Groups in Organic Synthesis, 5th Ed., Wiley, New York, N.Y., 2014, which is incorporated herein by reference in its entirety.
  • “Carboxaldehyde” refers to a —C(═O)H radical.
  • “Carboxyl” refers to a —C(═O)OH radical.
  • “Ester” refers to a chemical radical of formula —C(═O)OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those skilled in the art and can readily be found in reference sources such as Wuts, Greene's Protective Groups in Organic Synthesis, 5th Ed., Wiley, New York, N.Y., 2014, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)N(Ra)2, —N(Ra)2, —C(═O)ORa, —C(═O)Ra, —C(═O)N(Ra)2, —N(Ra)C(═O)ORa, —N(Ra)C(═O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)C(═O)Ra, —N(Ra)S(═O)tRa (where t is 1 or 2), —N(Ra)S(═O)tN(Ra)2 (where t is 1 or 2), —S(═O)tRa (where t is 1 or 2), —S(═O)tN(Ra)2 (where t is 1 or 2), —PO3(Ra)2, —OPO3WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron), wherein each IV is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.
  • “Imino” refers to a ═N—Ra radical, wherein IV is hydrogen, alkyl, heteroalkyl, cycloalkyl, cyano, aryl, heterocycloalkyl or heteroaryl.
  • “Isocyanato” refers to a —NCO radical.
  • “Isothiocyanato” refers to a —NCS radical.
  • “Mercaptyl” refers to an ═S(alkyl) or —SH radical.
  • “Methylene” refers to a ═CH2 radical.
  • “Hydroxy” refers to a —OH radical.
  • “Oxa” refers to a —O— radical.
  • “Oxo” refers to a ═O radical.
  • “Nitro” refers to a —NO2 radical.
  • “Oxime” refers to a ═N(—OR) radical, where R is hydrogen or alkyl.
  • “Sulfinyl” refers to a —S(═O)R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). In some embodiments, R is fluoroalkyl.
  • “Sulfoxyl” refers to a —S(═O)2OH radical.
  • “Sulfonate” refers to a —S(═O)2OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heteroalkyl (bonded through a ring carbon). The R group is optionally substituted by one or more of the substituents described for alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, respectively.
  • “Thiocyanato” refers to a —CNS radical.
  • “Thioxo” refers to a ═S radical.
  • “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • “Substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, heteroalkyl, cycloalkyl, aralkl, heterocycloalkyl, aryl, carbohydrate, carbonate, heteroaryl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups and the protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may have a halide substituted at one or more ring carbons, and the like. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Wuts, Greene's Protective Groups in Organic Synthesis, 5th Ed., Wiley, New York, N.Y., 2014.
  • The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and includes instances where the event or circumstance occurs and instances in which it does not. For example, “alkyl optionally substituted with” encompasses both “alkyl” and “alkyl” substituted with groups as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns which would be deemed unacceptable by one of ordinary skill in the art.
  • Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof “Crystalline form,” “polymorph,” and “novel form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. For example, hydrogen has three naturally occurring isotopes, denoted 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant isotope in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. See Pleiss and Voger, Synthesis and Applications of Isotopically Labeled Compounds, Vol. 7, Wiley, ISBN-10: 0471495018, published on Mar. 14, 2001.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E-form (or cis- or trans-form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.
  • The term “enantiomeric excess,” as used herein, is the percent excess of one enantiomer compared to that of the other enantiomer in a mixture, and can be calculated using the following equation: enantiomeric excess=((R−S)/(R+S))×100=% (R*)−% (S*), wherein R and S are the number of moles of each enantiomer in the mixture, and R* and S* are the respective mole fractions of the enantiomers in the mixture. For example, for a mixture with 87% R enantiomer and 13% S enantiomer, the enantiomeric excess is 74%.
  • “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
  • “Protecting group” has the meaning conventionally associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in Wuts, Greene's Protective Groups in Organic Synthesis, 5th Ed., Wiley, New York, N.Y., 2014. For example, a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected.
  • “Solvate” refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent. It will be understood that the present chemical entities encompass the present chemical entities and solvates of the compound, as well as mixtures thereof.
  • “Solvent,” “organic solvent,” and “inert solvent” each means a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert organic solvents. Unless specified to the contrary, for each gram of the limiting reagent, one cc (or mL) of solvent constitutes a volume equivalent.
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
  • When desired, the (R)- and (S)-isomers of the compounds of the present invention, if present, may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diasteroisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • The compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. In addition, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range.
  • Abbreviations used herein have their conventional meaning within the chemical and biological arts.
  • The following abbreviations and terms have the indicated meanings throughout:
  • DAST=Diethylaminosulfur trifluoride
  • DCM=Dichloromethane
  • MTBE=Methyl t-butyl ether
  • HATU=O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate
  • NBS=N-Bromosuccinimide
  • NMP=N-Methyl-2-pyrrolidone
  • e.e. or ee=Enantiomeric excess
  • PPTS=Pyridinium p-toluenesulfonate
  • TLC=Thin Layer Chromatography
  • DMAP=4-Dimethylaminopyridine
  • DMF=N,N-Dimethylformamide
  • When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration. In addition, such certain small molecules include Z- and E-forms (or cis- and trans-forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds. Where certain small molecules described herein exist in various tautomeric forms, the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule.
  • When “
    Figure US20190015377A1-20190117-P00001
    ” is drawn across a bond, it denotes where a bond disconnection or attachment occurs. For example, in the chemical structure shown below,
  • Figure US20190015377A1-20190117-C00010
  • Ra is attached to the para position of a fluorophenyl ring through a single bond. When Ra is phenyl, it can also be drawn a:
  • Figure US20190015377A1-20190117-C00011
  • The waved line “
    Figure US20190015377A1-20190117-P00002
    ” means a bond with undefined stereochemistry. For example,
  • Figure US20190015377A1-20190117-C00012
  • represents a mixture of
  • Figure US20190015377A1-20190117-C00013
  • When a bond is drawn across a ring, it means substitution at a non-specific ring atom or position. For example, in the structure shown below,
  • Figure US20190015377A1-20190117-C00014
  • Rb may be attached to any one of the —CH2— in the five-membered ring.
  • When a bold bond “
    Figure US20190015377A1-20190117-P00003
    ” appears two or more times in the same chemical structure, a mixture of the two cis isomers of the compound is described. For example,
  • Figure US20190015377A1-20190117-C00015
  • represents a mixture of the two isomers
  • Figure US20190015377A1-20190117-C00016
  • In one aspect, the disclosure provides a method of treating pulmonary arterial hypertension (PAH). In one embodiment, the method comprises administering a composition comprising an effective amount of a HIF-2α inhibitor to said subject. PAH is a life-threatening and progressive disease of various origins characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. The most common symptom at presentation is breathlessness, with impaired exercise capacity as a hallmark of the disease. PAH includes idopathic PAH, heritable PAH (e.g. BMPR2, ALK1, endoglin), drug-induced PAH, toxin-induced PAH, and PAH associated with another condition (e.g. connective tissue diseases, HIV infection, portal hypertension, congenital heart diseases, schistosomiasis, or chronic hemolytic anemia). Idiopathic PAH occurs in the absence of known risk factors and is the most common form of the disease. The PAH condition treated in accordance with the present disclosure can include any of these PAH conditions.
  • In general, the median period of survival of PAH after diagnosis, based on an early U.S. National Institutes of Health Registry with prospective follow-up, is less than 3 years for 194 untreated patients with idiopathic or heritable PAH (formerly called primary pulmonary hypertension) with a mean age of 36 years. At present, average survival after diagnosis in adults is estimated at 5 to 7 years, with a similarly poor overall prognosis in children. In some embodiments, the HIF-2α inhibitor is administered in an amount effective to increase average survival among a treated population of subjects, such as by about or more than about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or more years.
  • The pathology of PAH can include pathologic changes in the intima, media, and adventitial layers of the vascular wall. Both vascular endothelial and smooth muscle cells have characteristics of abnormal growth, with excess cellular proliferation and apoptosis resistance. These abnormalities in resident vascular cells, in combination with inflammation, excess vasoconstriction, and in situ thrombosis, can contribute to physical narrowing of the distal pulmonary arterioles. Without being bound by any theory, this narrowing can cause increase in pulmonary vascular resistance, which leads to the chronic and progressive elevation of pulmonary arterial pressure. In some cases, PAH can be induced by hypoxia. In some embodiments, the HIF-2α inhibitor is administered in an amount effective to delay, reduce the incidence of, or reduce the severity of one or more such symptoms associated with PAH.
  • Treating PAH includes treating a subject diagnosed with existing PAH, as well as preventing PAH. In some embodiments, the amount of HIF-2α inhibitor administered to the subject (either in a single dose or over multiple doses) is effective in delaying the onset of or reducing the incidence of one or more symptoms of PAH. The delay or reduction in incidence may be with respect to a reference population, such as an untreated population of subjects having PAH or subjects having PAH but treated with another agent. Delay or reduction in incidence of one or more symptoms of PAH may be a reduction of about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more. In some embodiments, delay or reduction in incidence is measured by an increased time in disease progression, such as between the appearance of one or more first symptoms, and the appearance of one or more second symptoms. Delay may be about or more than about days, weeks, months, or years (e.g. 1, 2, 3, 4, 5, 6, 7, or more days; 1, 2, 3, 4, 5, 6, 7, 8, or more weeks; 1, 2, 3, 4, 5, 6, or more months; or 1, 2, 3, 4, 5, or more years). In the case of prevention, the subject may be an individual at risk of developing PAH.
  • In one embodiment, the amount of HIF-2α inhibitor administered to the subject (either in a single dose or over multiple doses) is effective in (a) stabilizing pulmonary arterial pressure (PAP) as compared to a PAP trend in the subject prior to treatment, or (b) reducing PAP relative to a starting level of PAP in the subject; wherein the PAP is systolic pulmonary arterial pressure (SPAP) or diastolic pulmonary arterial pressure (DPAP). A variety of methods for measuring PAP are available. For example, the PAP can be measured by inserting a catheter into the pulmonary artery. Typically, the mean pressure is 9-18 mmHg, and the wedge pressure measured in the left atrium can be 6-12 mmHg. The wedge pressure may be elevated in left heart failure, mitral valve stenosis, and other conditions, such as sickle cell disease.
  • PAP in a subject may be stabilized at a level existing at the start of treatment, such as for days, weeks, months or years. In some embodiments, a starting level of PAP in the subject may be reduced by about or more than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, a rate of PAP increase may be reduced by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • The amount of HIF-2α inhibitor administered to the subject (either in a single dose or over multiple doses) can be effective in reducing right ventricular hypertrophy as measured by Fulton's Index relative to an untreated population of subjects having PAH. Fulton's Index is a measure of the ratio between the mass of the right ventricle to the combined mass of the left ventricle and septum (RV/(LV+S)). Mass can be measured directly (e.g. in the context of an animal study) or extrapolated from volume measurements of a live subject (e.g. as determined by echocardiogram). Reduction may be with respect to an untreated population of subjects with PAH. For example, the average reduction in the Fulton Index among a population of PAH subjects treated with a HIF-2α inhibitor as compared to an untreated population of PAH subjects can be about or more than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the reduction in Fulton's Index is at least about 20%.
  • In some embodiments, the amount of HIF-2α inhibitor administered to the subject (either in a single dose or over multiple doses) is effective in reducing a physiological indicator of PAH. The reduction may be measured over a specified period, such as a level of reduction days (e.g. about or more than about 1, 2, 3, 4, 5, 6, 7 or more days), weeks (e.g. 1, 2, 3, 4, 5, 6, or more weeks), months (e.g. 1, 2, 3, 4, 5, 6, 8, 10, or more months), or longer (e.g. 1, 2, 3, 4, 5, or more years) after treatment is initiated (which treatment may be ongoing through the period). Any of a variety of physiological indicators can be measured, such as pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six-minute walk distance, brain natriuretic peptide level, and lung diffusion capacity. For example, the HIF-2α inhibitor may be present in an amount effective in (a) reducing one or more of: pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and brain natriuretic peptide level; and/or (b) increasing one or more of: mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, six-minute walk distance, and lung diffusion capacity. The amount of HIF-2α inhibitor may be effective in increasing time to death, increasing time to clinical worsening, reducing incidence of right heart failure, or promoting a favorable change in WHO functional class (see Table 1).
  • TABLE 1
    WHO functional class
    Functional
    Class Symptomatic profile
    I Patients with pulmonary hypertension but without resulting
    limitation of physical activity. Ordinary physical activity
    does not cause dyspnoea or fatigue, chest pain, or near
    syncope.
    II Patients with pulmonary hypertension resulting in slight
    limitation of physical activity. They are comfortable at rest.
    Ordinary physical activity causes undue dyspnoea or fatigue,
    chest pain, or near syncope.
    III Patients with pulmonary hypertension resulting in marked
    limitation of physical activity. They are comfortable at rest.
    Less than ordinary activity causes undue dyspnoea or fatigue,
    chest pain, or near syncope.
    IV Patients with pulmonary hypertension with inability to carry
    out any physical activity without symptoms. These patients
    manifest signs of right heart failure. Dyspnoea and/or
    fatigue may even be present at rest. Discomfort is increased
    by any physical activity.
  • One physiological indicator of PAH is pulmonary vascular resistance (PVR). The baseline or reference PVR level can be 200 dyn·sec/cm5 or greater, 240 dyn·sec/cm5 or greater, 300 dyn·sec/cm5 or greater, 400 dyn·sec/cm5 or greater, 500 dyn·sec/cm5 or greater, 600 dyn·sec/cm5 or greater, 700 dyn·sec/cm5 or greater, or 800 dyn·sec/cm5 or greater. In some embodiments, a treatment provided herein is efficacious if after treatment has started, the endpoint PVR level of the subject decreases from the baseline or reference PVR level by 70 dyn·sec/cm5 or more, 100 dyn·sec/cm5 or more, 130 dyn·sec/cm5 or more, or 160 dyn·sec/cm5 or more.
  • Another physiological indicator of PAH is pulmonary arterial pressure (PAP). The baseline or reference PAP level can be 20 mmHg or greater, 25 mmHg or greater, 30 mmHg or greater, 35 mmHg or greater, 40 mmHg or greater, 45 mmHg or greater, 50 mmHg or greater, 60 mmHg or greater, or 70 mmHg or greater. In some embodiments, a treatment provided herein is efficacious if, after treatment has started, the endpoint PAP level of the subject decreases from the baseline or reference PAP level by 0.5 mmHg or more, 1 mmHg or more, 1.5 mmHg or more, 5 mmHg or more, 10 mmHg or more, 20 mmHg or more, 30 mmHg or more, 40 mmHg or more, or 50 mmHg.
  • Another physiological indicator of PAH is cardiac index (CI). A baseline or reference CI level can be 5 L/min/m2 or lower, 2.5 L/min/m2 or lower, 2 L/min/m2 or lower, 1.5 L/min/m2 or lower, or 1 L/min/m2 or lower. In some embodiments, a treatment provided herein is efficacious if, after treatment has started, the endpoint CI level increases from the baseline or reference CI level by 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.5 or more, 1 or more, or 2 or more.
  • Another physiological indicator of PAH is pulmonary capillary wedge pressure (PCWP). A baseline or reference PCWP level can be 36 mmHg or less, 24 mmHg or less, 18 mmHg or less, 10 mmHg, or 5 mmHg or less. In some embodiments, a treatment provided herein is efficacious if, after treatment has started, the endpoint PCWP level increases from the baseline or reference PCWP level by 0.2 mmHg or more, 0.3 mmHg or more, 0.4 mmHg or more, 0.5 mmHg or more, 0.6 mmHg or more, 1 mmHg or more, or 5 mmHg or more.
  • Another physiological indicator of PAH is right atrial pressure (RAP). A baseline or reference RAP level can be 4 mmHg or more, 6 mmHg or more, 8 mmHg or more, 10 mmHg or more, 12 mmHg or more, 16 mmHg or more, 20 mmHg or more, or 25 mmHg or more. In some embodiments, a treatment provided herein is efficacious if after treatment has started, the endpoint RAP level of the subject decreases from the baseline or reference RAP level by 5 mmHg or more, 2.5 mmHg or more, 1 mmHg or more, 0.5 mmHg or more, or 0.2 mmHg or more.
  • Another physiological indicator of PAH is six-minute walk distance (6 MWD). A baseline or reference 6 MWD can be 50 m or less, 100 m or less, 200 m or less, 300 m or less, 400 m or less, or 500 m or less. In some embodiments, a treatment provided herein is efficacious if, after treatment has started, the endpoint 6 MWD of the subject increases from the baseline or reference 6 MWD by 10 m or more, 15 m or more, 20 m or more, 25 m or more, 30 m or more, or 50 m or more; or if the endpoint 6 MWD of the subject increases by 3% or more, 4% or more, 5% or more, 10% or more, or 20% or more of the baseline level.
  • Another physiological indicator of PAH is brain natriuretic peptide (BNP) level. A baseline or reference BNP level can be 60 pg/mL or higher, 80 pg/mL or higher, 100 pg/mL or higher, 120 pg/mL or higher, 140 pg/mL or higher, 200 pg/mL or higher, 500 pg/mL or higher, or 1000 pg/mL or higher. In some embodiments, a treatment provided herein is efficacious if, after treatment has started, the endpoint BNP level of the subject decreases from the baseline or reference BNP level. For example, the endpoint BNP level of the subject can decrease by 1 pg/mL or more, 2 pg/mL or more, 5 pg/mL or more, 10 pg/mL or more, 20 pg/mL or more, 100 pg/mL or more, 500 pg/mL or more, or 1000 pg/mL or more.
  • Diffusion of lung capacity (DLCO), or diffusion capacity of CO, can also be used as a physiological indicator of PAH. A baseline or reference DLCO can be 90% or less, 80% or less, 70% or less, 50% or less, 45% or less, or 40% or less. In some embodiments, a treatment provided herein is efficacious if, after treatment has started, the endpoint DLCO is increased from the baseline level. For example, the endpoint DLCO can be increased from the baseline or reference DLCO by 1% or more, 5% or more, 10% or more, 15% or more, 20% or more, or 50% or more.
  • Average survival rate can be used as a parameter to determine efficacy in a population of one or more subjects. A reference average survival rate can be 95% or lower, 93% or lower, 90% or lower, 86% or lower, 82% or lower, or 78% or lower. The average survival rate can be an average 1-year survival rate. In some embodiments, a treatment provided herein is efficacious in a population of one or more subjects if, after treatment has started, the average survival rate increases. For example, the average survival rate can increase from the reference average survival rate by 1% or more, 2% or more, 5% or more, 10% or more, or 20% or more.
  • Another physiological indicator of PAH for use in determining efficacy of treatment in a subject is time to death after diagnosis with PAH. A reference time to death can be 1 year or less, 2 years or less, 5 years or less, or 7 years or less. In some embodiments, a treatment provided herein is efficacious if, after treatment has started, the time to death of the subject is higher than the reference time to death. For example, the time to death of the subject can increase from the reference time to death by 0.5 years or more, 1 year or more, 2 years or more, 3 years or more, 4 years or more, 5 years or more, or 6 years or more.
  • Death can also be used as an endpoint for efficacy of treatment of PAH. With the currently available PAH management methods, the average one-year survival rate of CTD-PAH patients is 86%, the average 1-year survival rate of idiopathic PAH patients is 93%, and the average 1-year survival rate of PAH patients with systemic sclerosis is 82%. The compositions and methods of the invention can increase the survival rate of PAH patients. In one embodiment, after treatment with a HIF-2α inhibitor, an increase in the average 1-year survival rate of PAH patients indicates efficacious treatment. For example, compositions and methods disclosed herein can be effective in increasing the 1-year average survival rate of PAH patients to 82% or greater, 86% or greater, or 93% or greater. In another embodiment, an increase in the time to death after diagnosis of a PAH patient indicates efficacious treatment. For example, a HIF-2α inhibitor of the invention extends the time to death of a PAH patient by at least 1, 2, 3, 4, 5, or 6 years beyond the current average lifespan of PAH patients.
  • The amount of HIF-2α inhibitor administered to the subject (either in a single dose or over multiple doses) can be effective in reducing vascular smooth muscle hypertrophy, such as with respect to a starting level of hypertrophy in the subject or a reference level of hypertrophy in an untreated population of subjects. The development of ventricular muscle cell hypertrophy can be measured in a variety of ways, including by increase in cell size, induction of a genetic marker of ventricular muscle cell hypertrophy, increase in the assembly of an individual contractile protein such as myosin light chain-2v (MLC-2v) into organized contractile units, accumulating of contractile units, activation of a program of immediate early gene expression, and the induction of genes encoding contractile and embryonic proteins. In some cases, ventricular muscle cell hypertrophy can be measured by determining the expression of an atrial marker, for example, atrial natriuretic factor (ANH). In some embodiments, a measure of vascular smooth muscle hypertrophy is reduced by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • Measuring inhibition of biological effects of HIF-2α can comprise performing an assay on a biological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to blood samples (e.g. blood plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.
  • A subject being treated with a HIF-2α inhibitor may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject's physiological response to treatment. For example, if inhibition of a biological effect of HIF-2α inhibition is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively. Alternatively, the treatment regimen may be adjusted to include, remove, or adjust an amount of a second agent. The methods can further comprise continuing the therapy if the therapy is determined to be efficacious. The methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound or compounds in the therapy if the therapy is determined to be efficacious. The methods can comprise increasing the administered amount of a compound or compounds in the therapy if it is determined not to be efficacious. Alternatively, the methods can comprise stopping therapy if it is determined not to be efficacious. In some embodiments, treatment with the HIF-2α is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction. The biological effect may be a change in any of a variety of physiological indicators of PAH, examples of which are provided herein.
  • Biological effects for the treatment of HIF-2α inhibitor can be indicated by a variety of methods. For example, it can be evaluated by adjustment of one or more hemodynamic parameters towards a more normal level, for example lowering mean PAP or PVR, PCWP or LVEDP, or raising cardiac index or output versus baseline. It can also be evaluated by improvement of cardiopulmonary efficiency versus baseline, for example increasing exercise capacity, illustratively as measured in a test of 6-minute walking distance (6MWD), or lowering Borg dyspnea index (BDI). In some embodiments, an indicator can be improvement of one or more quality of life parameters versus baseline, for example an increase in score on at least one of the SF-36® health survey functional scales. Another example is general improvement versus baseline in the severity of the condition, for example by movement to a lower WHO functional class. Another example is improvement of clinical outcome following a period of treatment, versus expectation in absence of treatment (e.g., in a clinical trial setting, as measured by comparison with placebo), including improved prognosis, extending time to or lowering probability of clinical worsening, extending quality of life (e.g., delaying progression to a higher WHO functional class or slowing decline in one or more quality of life parameters such as SF-36® health survey parameters), and/or increasing longevity. In some embodiments, a biomarker can be used for the evaluation. For example, adjustment towards a more normal level of one or more molecular markers that can be predictive of clinical outcome (e.g., plasma concentrations of endothelin-1 (ET-1), cardiac troponin T (cTnT) or B-type natriuretic peptide (BNP)).
  • In general, a HIF-2α inhibitor is a compound that inhibits one or more biological effects of HIF-2α. Examples of biological effects of HIF-2α include, but are not limited to, heterodimerization of HIF-2α to HIF-1β, HIF-2α target gene expression, VEGF gene expression, and VEGF protein secretion. In some embodiments, the HIF-2α inhibitor is selective for HIF-2α, such that the inhibitor inhibits heterodimerization of HIF-2α to HIF-1β but not heterodimerization of HIF-1α to HIF-1β. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • Hypoxia-inducible factors (HIFs), like HIF-2α, are transcription factors that respond to changes in available oxygen in the cellular environment (e.g. a decrease in oxygen, or hypoxia). The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos, and cancer tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium. A HIF-2a inhibitor of the present disclosure may be administered in an amount effective in reducing any one or more of such effects of HIF-2α activity.
  • HIF-2α activity can be inhibited by inhibiting heterodimerization of HIF-2α to HIF-1β (ARNT), such as with inhibitor compounds disclosed herein. A variety of methods for measuring HIF-2α dimerization are available. For example, inhibition of heterodimerization of HIF-2α to HIF-1β (ARNT) may be determined in an Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen). AlphaScreen, an in vitro assay, employs “PAS-B*” variants (R247E HIF-2a and E362R ARNT; Scheuermann et al, PNAS 2009) to assess functional disruption of PAS-PAS interactions in a high throughput screening (HTS) format. Inhibition of heterodimerization may also be determined by a reduction in HIF-2α target gene mRNA expression, and/or co-immunoprecipitation. In some embodiments, a HIF-2α inhibitor inhibits heterodimerization of HIF-2α to HIF-1β (ARNT) with an IC50 value not exceeding 30 μM, for example, ranging from 10 to 30 μM, and further, for example, ranging from 1 to 30 μM, as determined by AlphaScreen. In some embodiments, the HIF-2α inhibitor has an IC50 value not exceeding 1 μM as determined by AlphaScreen. A further description of methods for determining inhibition of heterodimerization are described in WO2014078479A2. In some embodiments, the HIF-2α inhibitor binds the PAS-B domain cavity of HIF-2a. Binding may be covalent or non-covalent, including but not limited to Van der Waals, hydrogen bond, and electrostatic interaction. In some embodiments, the binding is determined by co-crystallography.
  • Inhibition of heterodimerization of HIF-2α to HIF-1β (ARNT) may also be determined by a reduction in HIF-2α target gene mRNA expression. mRNA quantitation can be performed using real-time PCR technology. (Wong, et al., “Real-time PCR for mRNA quantitation”, 2005. BioTechniques 39, 1: 1-1.). Yet another method for determining inhibition of heterodimerization of HIF-2α to HIF-1β (ARNT) is by co-immunoprecipitation.
  • As described herein, HIF-2α is a transcription factor that plays important roles in regulating expression of target genes. Non-limiting examples of HIF-2α target gene include HMOX1, SFTPA1, CXCR4, PAIL BDNF, hTERT, ATP7A, and VEGF. For instance, HIF-2a is an activator of VEGFA. Further non-limiting examples of HIF-2α target genes include HMOX1, EPO, CXCR4, PAII, CCND1, CLUT1, IL6, and VEGF. A HIF-2α inhibitor of the present disclosure may be administered in an amount effective in reducing expression of any one or more of genes induced by HIF-2α activity. A variety of methods are available for the detection of gene expression level, and include the detection of gene transcription products (polynucleotides) and translation products (polypeptides). For example, gene expression can be detected and quantified at the DNA, RNA or mRNA level. Various methods that have been used to quantify mRNA include in situ hybridization techniques, fluorescent in situ hybridization techniques, reporter genes, RNase protection assays, Northern blotting, reverse transcription (RT)-PCR, SAGE, DNA microarray, tiling array, and RNA-seq. Examples of methods for the detection of polynucleotides include, but are not limited to selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles, and solution phase detection of polynucleotides using interacting fluorescent labels and competitive hybridization. Examples for the detection of proteins include, but are not limited to microscopy and protein immunostaining, protein immunoprecipitation, immunoelectrophoresis, western blot, BCA assay, spectrophotometry, mass spectrophotometry and enzyme assay.
  • In some embodiments, inhibition of HIF-2α is characterized by a decrease in VEGF gene expression. The decrease may be measure by any of a variety of methods, such as those described herein. As a further example, the mRNA expression level of VEGF can be measured by quantitative PCR (QT-PCR), microarray, RNA-seq and nanostring. As another example, an ELISA assay can be used to measure the level VEGF protein secretion.
  • Pharmaceutical Composition
  • In one aspect, the HIF-2α inhibitor administered to the subject is a compound of Formula I:
  • Figure US20190015377A1-20190117-C00017
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R2 is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo, sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl;
      • R3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; or R2 and R3 taken together form a cyclic moiety;
      • R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • In some embodiments, R1 is phenyl or monocyclic heteroaryl. In some further embodiments, R1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is bicyclic heteroaryl. In a further embodiment, the bicyclic heteroaryl is substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is pyridyl N-oxide. In a further embodiment, the pyridyl N-oxide is substituted with one or more substituents selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is
  • Figure US20190015377A1-20190117-C00018
  • wherein the aryl ring may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is
  • Figure US20190015377A1-20190117-C00019
  • wherein W1 is N or CR10, R9 is cyano, halo, alkyl or alkoxy, and R10 is hydrogen, cyano, halo, alkyl or alkoxy. In a further embodiment, R9 is cyano, halo, C1-C4 alkyl or C1-C4 alkoxy, and R10 is hydrogen, cyano, halo, C1-C4 alkyl or C1-C4 alkoxy.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00020
  • and the rings specified for R1 may optionally be substituted with one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00021
  • and the rings specified for R1 may optionally be substituted with one or more substituents described for cycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, cyano and oxo.
  • In some embodiments, R1 is cycloalkyl. In other embodiments, R1 is heterocycloalkyl. In a further embodiment, R1 is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In yet a further embodiment, R1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • In some embodiments, R1 is acyl or cyano. In a further embodiment, R1 is acetyl.
  • In some embodiments, R1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1 is heteroalkyl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00022
  • wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R2 is cyano, halo or alkyl. In some embodiments, R2 is halo or alkyl. In some embodiments, R2 is fluoro, chloro, bromo or iodo. In some embodiments, R2 is fluoroalkyl. In some further embodiments, R2 is —CH2F, —CHF2 or —CF3. In another embodiment, R2 is hydrogen. In some other embodiments, R2 is heteroalkyl, alkenyl or alkynyl.
  • In some embodiments, R3 is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R2 and R3 taken together form a cyclic moiety. In a further embodiment, R3 is halo, cyano or alkyl. In yet a further embodiment, R3 is —(CH2)—OH, wherein n is 1, 2 or 3. In still a further embodiment, R3 is —CH2OH.
  • In some embodiments, R2 and R3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one spa hybridized carbon. Representative compounds with the carbocycle include, but are not limited to, the following:
  • Figure US20190015377A1-20190117-C00023
  • wherein the carbocycle formed by linking R2 and R3 may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In yet other embodiments, the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R2 and R3. In some embodiments, the substituent(s) is C3-C5 cycloalkyl or C3-C5 heterocycloalkyl. In other embodiments, the substituent is oxo.
  • In some embodiments, R2 and R3 taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R4 is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R4 is fluoroalkyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a further embodiment, R4 is fluoroalkyl. In yet another embodiment, R4 is sulfonyl. In still another embodiment, R4 is fluoroalkylsulfonyl.
  • In some embodiments, R4 is —S(═O)2Ra, wherein Ra is alkyl or cycloalkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3. In still a further embodiment, Ra is methyl, optionally substituted with one or more fluorines.
  • In some embodiments, R4 is —S(═O)(═NRb)Ra, wherein Ra is alkyl or cycloalkyl and Rb is hydrogen, cyano or alkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3.
  • In some embodiments, R4 is —S(═O)2N(Ra)2, wherein each Ra is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one Ra is hydrogen. In a further embodiment, both Ras are hydrogen. In another further embodiment, one Ra is hydrogen and the other Ra is C1-C4 alkyl.
  • In some embodiments, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, ═S(═)2CH3, ═S(═)2CH2F, ═S(═)2CHF2, ═S(═)2CF3, ═S(═)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, R5 is hydrogen. In some other embodiments, R5 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R5 is methyl.
  • In some embodiments, R6 is hydrogen. In some other embodiments, R6 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R6 is methyl.
  • In some embodiments, R7 is hydrogen. In some other embodiments, R7 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R7 is methyl.
  • In some embodiments, R8 is hydrogen. In some other embodiments, R8 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R8 is methyl.
  • In some embodiments, R3 is hydrogen, R4 is —S(═O)2Ra or —S(═O)(═NRb)Rc, wherein Ra is fluoroalkyl, Rb is hydrogen, cyano or alkyl and Rc is alkyl. In a further embodiment, R1 is selected from the group consisting of
  • Figure US20190015377A1-20190117-C00024
  • wherein W1 is N or CR10, R9 is cyano, halo, alkyl or alkoxy, and R10 is hydrogen, cyano, halo, alkyl or alkoxy; and
  • Figure US20190015377A1-20190117-C00025
  • may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the alkyl is C1-C4 alkyl. In another further embodiment, the alkoxy is C1-C4 alkoxy.
  • In some embodiments, each of R2 and R3 is independently alkyl and R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl.
  • In some embodiments, R3 is —CH2OH. In a further embodiment, R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl and R5 is hydrogen. In still a further embodiment, R2 is cyano, halo or alkyl.
  • In some embodiments, R1 is phenyl or monocyclic heteroaryl; R2 is nitro, halo, cyano or alkyl; R3 is halo, cyano or alkyl; R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3. In still a further embodiment, R5 is hydrogen.
  • In some embodiments, R1 is bicyclic heteroaryl; R2 is nitro, halo, cyano or alkyl; R3 is halo, cyano or alkyl; R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R5 is hydrogen.
  • In some embodiments, R1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl; R2 is halo, cyano or alkyl; R3 is halo, cyano or alkyl; R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R5 is hydrogen.
  • In some embodiments, R2 and R3 together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one spa hybridized carbon; R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R5 is hydrogen. In a further embodiment, R1 is phenyl or monocyclic heteroaryl. In another further embodiment, R1 is bicyclic heteroaryl.
  • In some embodiments, X is N and Y is CR6. In other embodiments, X is CR5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR5 and Y is CR6.
  • In some embodiments, Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR7. In yet other embodiments, Z is NR8. In some embodiments, Z is absent.
  • In another aspect, the invention provides a compound of Formula I-A:
  • Figure US20190015377A1-20190117-C00026
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R2 is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl;
      • R3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R2 and R3 taken together form a cyclic moiety;
      • R4 is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy;
      • W1 is N or CR10;
      • R9 is cyano, halo, alkyl or alkoxy; and
      • R10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • In some embodiments, R2 is cyano, halo or alkyl. In some embodiments, R2 is halo or alkyl. In some embodiments, R2 is fluoro, chloro, bromo or iodo. In some embodiments, R2 is fluoroalkyl. In some further embodiments, R2 is —CH2F, —CHF2 or —CF3.
  • In some embodiments, R3 is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R2 and R3 taken together form a cyclic moiety. In a further embodiment, R3 is halo, cyano or alkyl. In yet a further embodiment, R3 is —(CH2)—OH, wherein n is 1, 2 or 3. In still a further embodiment, R3 is —CH2OH.
  • In some embodiments, R2 and R3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one spa hybridized carbon. Representative compounds with the carbocycle include, but are not limited to, the following:
  • Figure US20190015377A1-20190117-C00027
  • wherein the carbocycle formed by linking R2 and R3 may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In yet other embodiments, the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R2 and R3. In some embodiments, the substituent(s) is C3-C5 cycloalkyl or C3-C5 heterocycloalkyl. In other embodiments, the substituent is oxo.
  • In some embodiments, R2 and R3 taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R4 is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R4 is fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R4 is fluoroalkyl. In yet another embodiment, R4 is sulfonyl. In still another embodiment, R4 is fluoroalkylsulfonyl.
  • In some embodiments, R4 is —S(═O)2Ra, wherein Ra is alkyl or cycloalkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3. In still a further embodiment, Ra is methyl, optionally substituted with one or more fluorines.
  • In some embodiments, R4 is —S(═O)(═NRb)Ra, wherein Ra is alkyl or cycloalkyl and Rb is hydrogen, cyano or alkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3.
  • In some embodiments, R4 is —S(═O)2N(Ra)2, wherein each Ra is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one Ra is hydrogen. In a further embodiment, both Ras are hydrogen. In another further embodiment, one Ra is hydrogen and the other Ra is C1-C4 alkyl.
  • In some embodiments, R4 is selected from the group consisting of —CN, —CF3, S(═O)CH3, ═S(═O)2CH3, ═S(═O)2CH2F, ═S(═O)2CHF2, ═S(═O)2CF3, ═S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, R5 is hydrogen. In some other embodiments, R5 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R5 is methyl.
  • In some embodiments, R6 is hydrogen. In some other embodiments, R6 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R6 is methyl.
  • In some embodiments, R7 is hydrogen. In some other embodiments, R7 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R7 is methyl.
  • In some embodiments, R8 is hydrogen. In some other embodiments, R8 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R8 is methyl.
  • In some embodiments, R9 is cyano, halo, C1-C4 alkyl or C1-C4 alkoxy.
  • In some embodiments, R10 is hydrogen, cyano, halo, C1-C4 alkyl or C1-C4 alkoxy.
  • In some embodiments, R2 and R3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one spa hybridized carbon and R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl.
  • In some embodiments, R3 is —CH2OH and R4 is cyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R5 is hydrogen. In still a further embodiment, R2 is cyano, halo or alkyl.
  • In some embodiments, R2 is halo, cyano or alkyl; R3 is CH2OH; R4 is cyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, X is N and Y is CR6. In other embodiments, X is CR5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR5 and Y is CR6.
  • In some embodiments, Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR7. In yet other embodiments, Z is NR8. In some embodiments, Z is absent.
  • In another aspect, the invention provides a compound of Formula I-B:
  • Figure US20190015377A1-20190117-C00028
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R2 is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl;
      • R3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R2 and R3 taken together form a cyclic moiety;
      • R4 is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy;
  • Rc is hydrogen, cyano, halo, alkyl or alkoxy; and
      • n′ is 0, 1, 2, 3 or 4.
  • In some embodiments, R2 is cyano, halo or alkyl. In some embodiments, R2 is halo or alkyl. In some embodiments, R2 is fluoro, chloro, bromo or iodo. In some embodiments, R2 is fluoroalkyl. In some further embodiments, R2 is —CH2F, —CHF2 or —CF3.
  • In some embodiments, R3 is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R2 and R3 taken together form a cyclic moiety. In a further embodiment, R3 is halo, cyano or alkyl. In yet a further embodiment, R3 is —(CH2)—OH, wherein n is 1, 2 or 3.
  • In some embodiments, R2 and R3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one spa hybridized carbon. Representative compounds with the carbocycle include, but are not limited to, the following:
  • Figure US20190015377A1-20190117-C00029
  • wherein the carbocycle formed by linking R2 and R3 may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In yet other embodiments, the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R2 and R3. In some embodiments, the substituent(s) is C3-C5 cycloalkyl or C3-C5 heterocycloalkyl. In other embodiments, the substituent is oxo.
  • In some embodiments, R2 and R3 taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R3 is hydrogen, R4 is is —S(═O)2Ra or —S(═O)(═NRb)Rd, wherein Ra is fluoroalkyl, Rb is hydrogen, cyano or alkyl and Rd is alkyl.
  • In some embodiments, R4 is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R4 is fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R4 is fluoroalkyl. In yet another embodiment, R4 is sulfonyl. In still another embodiment, R4 is fluoroalkylsulfonyl.
  • In some embodiments, R4 is —S(═O)2Ra, wherein Ra is alkyl or cycloalkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3. In still a further embodiment, Ra is methyl, optionally substituted with one or more fluorines.
  • In some embodiments, R4 is —S(═O)(═NRb)Ra, wherein Ra is alkyl or cycloalkyl and Rb is hydrogen, cyano or alkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3.
  • In some embodiments, R4 is —S(═O)2—N(Ra)2, wherein each Ra is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one Ra is hydrogen. In a further embodiment, both Ras are hydrogen. In another further embodiment, one Ra is hydrogen and the other Ra is C1-C4 alkyl.
  • In some embodiments, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, ═S(═O)2CH3, ═S(═O)2CH2F, ═S(═O)2CHF2, ═S(═O)2CF3, ═S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, R5 is hydrogen. In some other embodiments, R5 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R5 is methyl.
  • In some embodiments, R6 is hydrogen. In some other embodiments, R6 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R6 is methyl.
  • In some embodiments, R7 is hydrogen. In some other embodiments, R7 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R7 is methyl.
  • In some embodiments, R8 is hydrogen. In some other embodiments, R8 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R8 is methyl.
  • In some embodiments, R2 and R3 taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one spa hybridized carbon and R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, ═S(═O)2CH2F, ═S(═O)2CHF2, ═S(═O)2CF3, ═S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, R3 is —CH2OH and R4 is fluoroalkyl, sulfonamidyl, sulfonyl, sulfinyl or sulfoximinyl. In a further embodiment, R5 is hydrogen. In still a further embodiment, R2 is cyano, halo or alkyl.
  • In some embodiments, R2 is halo, cyano or alkyl; R3 is CH2OH; R4 is fluoroalkyl, sulfonamidyl, sulfonyl, sulfinyl or sulfoximinyl. In a further embodiment, R4 is selected from the group consisting of —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, X is N and Y is CR6. In other embodiments, X is CR5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR5 and Y is CR6.
  • In some embodiments, Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR7. In yet other embodiments, Z is NR8. In some embodiments, Z is absent.
  • In some embodiments, Rc is cyano, halo, C1-C4 alkyl or C1-C4 alkoxy.
  • In yet another aspect, the invention provides a compound of Formula I-C:
  • Figure US20190015377A1-20190117-C00030
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy;
      • R11 is hydrogen, hydroxy, alkoxy or amino;
      • R12 is hydrogen, alkyl, alkenyl or alkynyl; or R11 and R12 in combination form oxo or oxime;
      • each of R13 is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl, with the proviso that when R13 is hydroxy, n is 1 or 2; or two R13s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety; and
      • n is 0, 1, 2, 3 or 4.
  • In some embodiments, R1 is phenyl or monocyclic heteroaryl. In some further embodiments, R1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R1 is
  • Figure US20190015377A1-20190117-C00031
  • wherein the aryl ring is optionally substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In another further embodiment, R1 is
  • Figure US20190015377A1-20190117-C00032
  • wherein W1 is N or CR10, R9 is cyano, halo, alkyl or alkoxy, and R10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • In some embodiments, R1 is bicyclic heteroaryl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00033
  • and the rings specified for R1 may optionally be substituted with one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, alkyl, alkoxy and cyano.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00034
  • and the rings specified for R1 may optionally be substituted with one or more substituents described for cycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, cyano and oxo.
  • In some embodiments, R1 is cycloalkyl. In other embodiments, R1 is heterocycloalkyl. In a further embodiment, R1 is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In yet a further embodiment, R1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • In some embodiments, R1 is acyl or cyano. In a further embodiment, R1 is acetyl.
  • In some embodiments, R1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1 is heteroalkyl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00035
  • wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In some embodiments, R4 is fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In a further embodiment, R4 is fluoroalkyl. In yet another embodiment, R4 is sulfonyl. In still another embodiment, R4 is fluoroalkylsulfonyl.
  • In some embodiments, R4 is —S(═O)2Ra, wherein Ra is alkyl or cycloalkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3. In still a further embodiment, Ra is methyl, optionally substituted with one or more fluorines.
  • In some embodiments, R4 is —S(═O)(═NRb)Ra, wherein Ra is alkyl or cycloalkyl and Rb is hydrogen, cyano or alkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3.
  • In some embodiments, R4 is —S(═O)2N(Ra)2, wherein each Ra is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one Ra is hydrogen. In another further embodiment, one Ra is hydrogen and the other Ra is C1-C4 alkyl.
  • In some embodiments, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, ═S(═O)2CH3, ═S(═O)2CH2F, ═S(═O)2CHF2, ═S(═O)2CF3, ═S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, R5 is hydrogen or alkyl. In some other embodiments, R5 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R5 is methyl.
  • In some embodiments, R6 is hydrogen or alkyl. In some other embodiments, R6 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R6 is methyl.
  • In some embodiments, R7 is hydrogen or alkyl. In some other embodiments, R7 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R7 is methyl.
  • In some embodiments, R8 is hydrogen or alkyl. In some other embodiments, R8 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R8 is methyl.
  • In some embodiments, R11 is hydroxy or amino. In a further embodiment, R11 is hydroxy. In another further embodiment, R11 is amino.
  • In some embodiments, R12 is hydrogen. In some other embodiments, R12 is alkyl or alkenyl.
  • In some embodiments, R13 is fluoro. In a further embodiment, n is 1, 2 or 3. In a further embodiment, two R13s in combination form oxo, oxime or methylene. In still further embodiments, two R13s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety.
  • In some embodiments, R1 is monocyclic aryl or monocyclic heteroaryl and is hydroxy or amino. In a further embodiment, R13 is fluoro. In still a further embodiment, n is 1, 2 or 3.
  • In some embodiments, R1 is phenyl or monocyclic heteroaryl, R11 is hydroxy or amino, R13 is fluoro, n is 1, 2 or 3, and R5 is hydrogen.
  • In some embodiments, R1 is bicyclic heteroaryl and R11 is hydroxy or amino. In a further embodiment, R13 is fluoro. In still a further embodiment, n is 1, 2 or 3.
  • In some embodiments, R1 is bicyclic heteroaryl, R11 is hydroxy or amino, le is fluoro, n is 1, 2 or 3, and R5 is hydrogen.
  • In some embodiments, R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl, and is hydroxy or amino. In a further embodiment, R12 is hydrogen. In another further embodiment, R13 is fluoro. In still a further embodiment, n is 1, 2 or 3.
  • In some embodiments, R4 is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R11 is hydroxy or amino; R13 is fluoro; n is 1, 2 or 3; and R5 is hydrogen. In a further embodiment, R12 is hydrogen.
  • In some embodiments R11 is hydroxy or amino and R12 is hydrogen. In a further embodiment, R13 is fluoro. In still a further embodiment, n is 1, 2 or 3.
  • In some embodiments R11 is hydroxy or amino, R12 is hydrogen, R13 is fluoro, n is 1, 2 or 3, and R5 is hydrogen. In a further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, R4 is fluoroalkyl; n is 0, 1, 2 or 3; Z is O; R11 is hydroxy; and R12 is hydrogen.
  • In some embodiments, R4 is sulfonyl or fluoroalkylsulfonyl; n is 0, 1, 2 or 3; Z is O; R11 is hydroxy; and R12 is hydrogen.
  • In some embodiments, X is N and Y is CR6. In other embodiments, X is CR5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR5 and Y is CR6.
  • In some embodiments, Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR′. In yet other embodiments, Z is NRB. In some embodiments, Z is absent.
  • In still another aspect, the invention provides a compound of Formula I-D, I-E, I—F or I-G:
  • Figure US20190015377A1-20190117-C00036
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
      • R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and
      • R11 is hydrogen, hydroxy, alkoxy or amino.
  • In some embodiments, R1 is monocyclic aryl or monocyclic heteroaryl. In some further embodiments, R1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R1 is
  • Figure US20190015377A1-20190117-C00037
  • wherein the aryl ring is optionally substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In another further embodiment, R1 is
  • Figure US20190015377A1-20190117-C00038
  • wherein W1 is N or CR19, R9 is cyano, halo, alkyl or alkoxy, and R10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • In some embodiments, R1 is bicyclic heteroaryl having at least one N atom.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00039
  • and the rings specified for R1 may optionally be substituted with one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00040
  • and the rings specified for R1 may optionally be substituted with one or more substituents described for cycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, cyano and oxo.
  • In some embodiments, R1 is cycloalkyl. In other embodiments, R1 is heterocycloalkyl. In a further embodiment, R1 is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In yet a further embodiment, R1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • In some embodiments, R1 is acyl or cyano. In a further embodiment, R1 is acetyl.
  • In some embodiments, R1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1 is heteroalkyl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00041
  • wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In some embodiments, R4 is fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In a further embodiment, R4 is fluoroalkyl. In yet another embodiment, R4 is sulfonyl. In still another embodiment, R4 is fluoroalkylsulfonyl.
  • In some embodiments, R4 is —S(═O)2Ra, wherein Ra is alkyl or cycloalkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3.
  • In some embodiments, R4 is —S(═O)(═NRb)Ra, wherein Ra is alkyl or cycloalkyl and Rb is hydrogen, cyano or alkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3.
  • In some embodiments, R4 is —S(═O)2N(Ra)2, wherein each Ra is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one Ra is hydrogen. In another further embodiment, both Ras are hydrogen. In a further embodiment, one Ra is hydrogen and the other Ra is C1-C4 alkyl.
  • In some embodiments, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, ═S(═O)2CH3, ═S(═O)2CH2F, ═S(═O)2CHF2, ═S(═O)2CF3, ═S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, R5 is hydrogen or alkyl. In some other embodiments, R5 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R5 is methyl.
  • In some embodiments, R6 is hydrogen or alkyl. In some other embodiments, R6 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R6 is methyl.
  • In some embodiments, R7 is hydrogen or alkyl. In some other embodiments, R7 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R7 is methyl.
  • In some embodiments, R8 is hydrogen or alkyl. In some other embodiments, R8 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R8 is methyl.
  • In some embodiments, R11 is hydroxy. In another further embodiment, is amino.
  • In some embodiments, R1 is phenyl or monocyclic heteroaryl and R11 is hydroxy or amino.
  • In some embodiments, R1 is bicyclic heteroaryl and R11 is hydroxy or amino. In a further embodiment, X is CR5 and R5 is hydrogen. In another further embodiment, R5 is alkyl. In still a further embodiment, R5 is C1-C4 alkyl.
  • In some embodiments R1 is bicyclic heteroaryl and R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, X is CR5 and R5 is hydrogen. In another further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments R1 is bicyclic heteroaryl; R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R11 is hydroxy or amino; and X is CR5 or N; and R5 is hydrogen. In a further embodiment, R11 is hydroxy. In another further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments R1 is phenyl or monocyclic heteroaryl and R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, X is CR5 and R5 is hydrogen. In another further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments R1 is phenyl or monocyclic heteroaryl; R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R11 is hydroxy or amino; and X is CR5 or N; and R5 is hydrogen. In a further embodiment, R11 is hydroxy. In another further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, ═S(═O)2CH2F, ═S(═O)2CHF2, ═S(═O)2CF3, ═S(═O)2NH2, ═S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, X is N and Y is CR6. In other embodiments, X is CR5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR5 and Y is CR6.
  • In some embodiments, Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR7. In yet other embodiments, Z is NR8. In some embodiments, Z is absent.
  • In a further aspect, the invention provides a compound of Formula I-H, I-I, I-J or I-K:
  • Figure US20190015377A1-20190117-C00042
  • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X is CR5 or N;
      • Y is CR6 or N;
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
      • R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;
      • R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and
      • R11 is hydroxy or amino.
  • In some embodiments, R1 is monocyclic aryl or monocyclic heteroaryl. In some further embodiments, R1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R1 is
  • Figure US20190015377A1-20190117-C00043
  • wherein the aryl ring is optionally substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In another further embodiment, R1 is
  • Figure US20190015377A1-20190117-C00044
  • wherein W1 is N or CR10, R9 is cyano, halo, alkyl or alkoxy, and R10 is hydrogen, cyano, halo, alkyl or alkoxy.
  • In some embodiments, R1 is bicyclic heteroaryl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00045
  • and the rings specified for R1 may optionally be substituted with one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00046
  • and the rings specified for R1 may optionally be substituted with one or more substituents described for cycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, cyano and oxo.
  • In some embodiments, R1 is cycloalkyl. In other embodiments, R1 is heterocycloalkyl. In a further embodiment, R1 is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In yet a further embodiment, R1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • In some embodiments, R1 is acyl or cyano. In a further embodiment, R1 is acetyl.
  • In some embodiments, R1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1 is heteroalkyl.
  • In some embodiments, R1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1 is heteroalkyl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00047
  • wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R4 is fluoroalkyl. In yet another embodiment, R4 is sulfonyl. In still another embodiment, R4 is fluoroalkylsulfonyl.
  • In some embodiments, R4 is —S(═O)2Ra, wherein Ra is alkyl or cycloalkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3. In still a further embodiment, Ra is methyl, optionally substituted with one or more fluorines.
  • In some embodiments, R4 is —S(═O)(═NRb)Ra, wherein Ra is alkyl or cycloalkyl and Rb is hydrogen, cyano or alkyl. In a further embodiment, Ra is C1-C4 alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C1-C4 alkyl include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCH3 and —CF2CH3.
  • In some embodiments, R4 is —S(═O)2N(Ra)2, wherein each Ra is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one Ra is hydrogen. In another further embodiment, both Ras are hydrogen. In a further embodiment, one Ra is hydrogen and the other Ra is C1-C4 alkyl.
  • In some embodiments, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, ═S(═O)2CH3, ═S(═O)2CH2F, ═S(═O)2CHF2, ═S(═O)2CF3, ═S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, R5 is hydrogen or alkyl. In some other embodiments, R5 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R5 is methyl.
  • In some embodiments, R6 is hydrogen or alkyl. In some other embodiments, R6 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R6 is methyl.
  • In some embodiments, R7 is hydrogen or alkyl. In some other embodiments, R7 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R7 is methyl.
  • In some embodiments, R8 is hydrogen or alkyl. In some other embodiments, R8 is C1-C4 alkyl or C1-C4 alkoxy. In a further embodiment, R8 is methyl.
  • In some embodiments, R11 is hydroxy. In another further embodiment, is amino.
  • In some embodiments, R1 is phenyl or monocyclic heteroaryl and R11 is hydroxy or amino.
  • In some embodiments, R1 is bicyclic heteroaryl and R11 is hydroxy or amino. In a further embodiment, X is CR5 and R5 is hydrogen. In another further embodiment, R5 is alkyl. In still a further embodiment, R5 is C1-C4 alkyl.
  • In some embodiments R1 is bicyclic heteroaryl and R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, X is CR5 and R5 is hydrogen. In another further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments R1 is bicyclic heteroaryl; R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R11 is hydroxy or amino; and X is CR5 or N; and R5 is hydrogen. In a further embodiment, R11 is hydroxy. In another further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments R1 is phenyl or monocyclic heteroaryl and R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, X is CR5 and R5 is hydrogen. In another further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments R1 is phenyl or monocyclic heteroaryl; R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R11 is hydroxy or amino; and X is CR5 or N; and R5 is hydrogen. In a further embodiment, R11 is hydroxy. In another further embodiment, R4 is selected from the group consisting of —CN, —CF3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2CH2F, —S(═O)2CHF2, —S(═O)2CF3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)(═NH)CH3, —S(═O)(═NH)CH2F, —S(═O)(═NH)CHF2, —S(═O)(═NH)CF3, —S(═O)(═N—CN)CH3, —S(═O)(═N—CN)CH2F, —S(═O)(═N—CN)CHF2 and —S(═O)(═N—CN)CF3.
  • In some embodiments, X is N and Y is CR6. In other embodiments, X is CR5 and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR5 and Y is CR6.
  • In some embodiments, Z is O. In other embodiments, Z is S. In further embodiments, Z is CHR7. In yet other embodiments, Z is NR8. In some embodiments, Z is absent.
  • In some embodiments, a compound of any one of Formulae I-H-I-K may have an enantiomeric excess of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or even higher. In some embodiments, a compound of any one of Formulae I-H-I-K may have an enantiomeric excess of about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%.
  • In yet another aspect, the invention provides a compound of Formula II:
  • Figure US20190015377A1-20190117-C00048
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R2 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl;
      • R14 is hydrogen, deuterium or alkyl;
      • R15 is hydrogen, hydroxy or amino; or R14 and R15 in combination form oxo or methylene;
      • R16 and R17 are independently selected from the group consisting of hydrogen, halo, alkyl, heteroalkyl and cycloalkyl; or R16 and R17 and the carbon to which they are attached form C3-C8 cycloalkyl or C5-C8 heterocycloalkyl;
      • R18 is O or NR19, wherein R19 is selected from the group consisting of hydrogen, alkyl and cyano;
      • n″ is 1 or 2; and
  • R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • In some embodiments, R1 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is cycloalkyl, aryl or heteroaryl. In some embodiments, R1 is aryl or heteroaryl. In a further embodiment, R1 is phenyl. In another further embodiment, R1 is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl.
  • In some embodiments, R1 is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • In some embodiments, R1 is
  • Figure US20190015377A1-20190117-C00049
  • wherein each of Re is independently hydrogen or alkyl, or two Res and the carbon atom to which they are attached form a 4- to 8-membered cyclic moiety; each of Rf is independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n″ is 0, 1, 2, 3 or 4. In some further embodiments, the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00050
  • and the rings specified for R1 may optionally be substituted by one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is cycloalkyl. In other embodiments, R1 is heterocycloalkyl. In a further embodiment, R1 is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In yet a further embodiment, R1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • In some embodiments, R1 is acyl or cyano. In a further embodiment, R1 is acetyl.
  • In some embodiments, R1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1 is heteroalkyl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00051
  • wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R2 is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R2 is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R2 is cyano, halo or alkyl. In some embodiments, R2 is halo or alkyl. In a further embodiment, R2 is fluoroalkyl. In a still further embodiment, R2 is C1-C4 fluoroalkyl. Exemplary C1-C4 fluoroalkyl includes, but is not limited to, —CH2F, —CHF2, —CF2CH3 and the like.
  • In some embodiments, R11 is hydrogen or deuterium. In some embodiments, R11 is alkyl. In a further embodiment, R11 is C1-C4 alkyl.
  • In some embodiments, R15 is hydroxy or amino. In some embodiments, R15 is hydroxy. In some embodiments, R15 is amino. In a further embodiment, R15 is NH2.
  • In some embodiments, each of R16 and R17 is independently hydrogen or fluoro. In some embodiments, each of R16 and R17 is hydrogen. In some embodiments, each of R16 and R17 is fluoro. In some embodiments, at least one of R16 and R17 is fluoro.
  • In some embodiments, R18 is O, N—CN, or NH. In some embodiments, R18 is O. In some embodiments, R18 is NH. In some embodiments, R18 is N—CN.
  • In some embodiments, R11 is hydrogen and R15 is hydroxy or amino. In some further embodiments, R1 is aryl or heteroaryl. In a further embodiment, R2 is cyano, halo or alkyl. In a still further embodiment, R16 and R17 are fluoro.
  • In some embodiments, R15 is hydroxy or amino and R2 is cyano, halo or alkyl. In a further embodiment, R2 is fluoroalkyl. In a still further embodiment, at least one R16 and R17 is fluoro. In a yet still further embodiment, n″ is 1.
  • In some embodiments, R18 is O or NH and R14 is hydrogen. In some further embodiments, R1 is aryl or heteroaryl. In a further embodiment, R2 is cyano, halo or alkyl. In a still further embodiment, at least one of R16 and R17 is fluoro.
  • In some embodiments, n″ is 1. In some further embodiments, R15 is hydroxy or amino and R16 and R17 are fluoro. In a further embodiment, R1 is aryl or heteroaryl. In a still further embodiment, R1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkoxy, cyano and alkyl.
  • In another aspect, the invention provides a compound of Formula II-A:
  • Figure US20190015377A1-20190117-C00052
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R2 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl;
      • R14 is hydrogen, deuterium or alkyl;
      • R15 is hydrogen, hydroxy or amino; or R14 and R15 in combination form oxo or methylene;
      • R18 is O or NR19, wherein R19 is selected from the group consisting of hydrogen, alkyl and cyano; and
      • R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • In some embodiments, R1 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is cycloalkyl, aryl or heteroaryl. In some embodiments, R1 is aryl or heteroaryl. In a further embodiment, R1 is phenyl. In another further embodiment, R1 is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl.
  • In some embodiments, R1 is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • In some embodiments, R1 is
  • Figure US20190015377A1-20190117-C00053
      • wherein each of Re is independently hydrogen or alkyl, or two Res and the carbon atom to which they are attached form a 4- to 8-membered cyclic moiety; each of Rf is independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n″ is 0, 1, 2, 3 or 4. In some further embodiments, the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00054
  • and the rings specified for R1 may optionally be substituted by one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is cycloalkyl. In other embodiments, R1 is heterocycloalkyl. In a further embodiment, R1 is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In yet a further embodiment, R1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • In some embodiments, R1 is acyl or cyano. In a further embodiment, R1 is acetyl.
  • In some embodiments, R1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1 is heteroalkyl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00055
  • wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R2 is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R2 is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R2 is cyano, halo or alkyl. In some embodiments, R2 is halo or alkyl. In a further embodiment, R2 is fluoroalkyl. In a still further embodiment, R2 is C1-C4 fluoroalkyl. Exemplary C1-C4 fluoroalkyl includes, but is not limited to, —CH2F, —CHF2, —CF2CH3 and the like.
  • In some embodiments, R14 is hydrogen or deuterium. In some embodiments, R14 is alkyl. In a further embodiment, R14 is C1-C4 alkyl.
  • In some embodiments, R15 is hydroxy or amino. In some embodiments, R15 is hydroxy. In some embodiments, R15 is amino. In a further embodiment, R15 is NH2.
  • In some embodiments, R18 is O, N—CN, or NH. In some embodiments, R18 is O. In some embodiments, R18 is NH. In some embodiments, R18 is N—CN.
  • In some embodiments, R18 is O or NH and R14 is hydrogen. In some further embodiments, R1 is aryl or heteroaryl. In a further embodiment, R2 is cyano, halo or alkyl. In a still further embodiment, at least one of R16 and R17 is fluoro.
  • In still another aspect, the invention provides a compound of Formula II-B:
  • Figure US20190015377A1-20190117-C00056
      • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
      • Z is O, S, CHR7, NR8 or absent;
      • R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;
      • R2 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl;
      • R15 is hydroxy or amino;
      • R18 is O or NR19, wherein R19 is selected from the group consisting of hydrogen, alkyl and cyano; and
      • R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy.
  • In some embodiments, R1 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R1 is cycloalkyl, aryl or heteroaryl. In some embodiments, R1 is aryl or heteroaryl. In a further embodiment, R1 is phenyl. In another further embodiment, R1 is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl.
  • In some embodiments, R1 is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
  • In some embodiments, R1 is
  • Figure US20190015377A1-20190117-C00057
  • wherein each of Re is independently hydrogen or alkyl, or two Res and the carbon atom to which they are attached form a 4- to 8-membered cyclic moiety; each of Rf is independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n″ is 0, 1, 2, 3 or 4. In some further embodiments, the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00058
  • and the rings specified for R1 may optionally be substituted by one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R1 is cycloalkyl. In other embodiments, R1 is heterocycloalkyl. In a further embodiment, R1 is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In yet a further embodiment, R1 is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro.
  • In some embodiments, R1 is acyl or cyano. In a further embodiment, R1 is acetyl.
  • In some embodiments, R1 is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R1 is heteroalkyl.
  • In some embodiments, R1 is selected from the group consisting of:
  • Figure US20190015377A1-20190117-C00059
  • wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and cyano.
  • In some embodiments, R2 is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R2 is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R2 is cyano, halo or alkyl. In some embodiments, R2 is halo or alkyl. In a further embodiment, R2 is fluoroalkyl. In a still further embodiment, R2 is C1-C4 fluoroalkyl. Exemplary C1-C4 fluoroalkyl includes, but is not limited to, —CH2F, —CHF2, —CF2CH3 and the like.
  • In some embodiments, R15 is hydroxy. In some embodiments, R15 is amino. In a further embodiment, R15 is NH2.
  • In some embodiments, R18 is O, N—CN, or NH. In some embodiments, R18 is O. In some embodiments, R18 is NH. In some embodiments, R18 is N—CN.
  • In some embodiments, a compound of Formula II-B may have an enantiomeric excess of at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99%. In a further embodiment, the compound has an enantiomeric excess of at least about 90%.
  • In another aspect, the present disclosure provides a compound or pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of the compounds given in Table 2.
  • The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in Schemes 1-27, the steps in some cases may be performed in a different order than the order shown in Schemes 1-27. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
  • Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from −10° C. to 200° C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about −10° C. to about 110° C. over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • In general, compounds of the invention may be prepared by the following reaction schemes:
  • Figure US20190015377A1-20190117-C00060
    Figure US20190015377A1-20190117-C00061
  • In some embodiments, a compound of Formula 1-9 can be prepared according to steps outlined in Scheme 1. The synthesis starts with phenol 1-1. Reaction of 1-1 with chloride 1-2 (wherein Rg and Rh are independently alkyl) provides intermediate 1-3. The reaction may be carried out in a suitable organic solvent in the presence of a base. Suitable bases for the reaction include, but are not limited to, organic bases, for example, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, and inorganic bases, for example, sodium hydroxide, cesium carbonate, cesium bicarbonate, sodium carbonate, and potassium carbonate. A compound of Formula 1-3 is then subjected to a rearrangement reaction to give a compound of Formula 1-4. Elevated temperature may be needed for the rearrangement to occur. The temperature may be in a range of 100° C. to 300° C. In some embodiments, the temperature is in a range of 180° C. to 240° C. Hydrolysis of a compound of Formula 1-4 provides thiophenol 1-5, which is alkylated to provide a compound if Formula 1-6. A variety of alkyl groups may be introduced in Step D. In some embodiments, IV is a C1-C4 alkyl. In a further embodiment, Ra is a C1-C4 fluoroalkyl. Oxidation of a compound of Formula 1-6 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl3 catalyzed oxidation in the presence of NaIO4, oxidation with m-chloroperoxybenzoic acid (mCPBA) and oxidation with Oxone®. Ketone 1-7 is then reduced to give alcohol 1-8, which then undergoes a nucleophilic aromatic substitution (SNAr) reaction with a suitable substrate R1OH to give a compound of Formula 1-9. Temperatures for carrying out the SNAr reaction may depend on the reactivity of both R1OH and/or compound 1-8. The reaction may be carried out in a temperature range from about room temperature to 200° C. In some embodiments, the temperature range is from room temperature to 60° C. In some other embodiments, the temperature range is from 60° C. to 100° C. In some other embodiments, the temperature range is from 100° C. to 200° C.
  • Figure US20190015377A1-20190117-C00062
  • In some other embodiments, a compound of Formula 1-9 can be prepared asymmetrically to give a compound of Formula 2-2 (Scheme 2). For example, direct asymmetric reduction of ketone 1-7 (Step A) may be accomplished chemically or enzymatically. For a recent review on enzymatic reduction of ketones, see Moore, et al. Acc. Chem. Res. 40: 1412-1419, 2007. Examples of chemical asymmetric reduction of ketones include, but are not limited to, Corey-Bakshi-Shibata (CBS) reduction, asymmetric hydrogenation and asymmetric transfer hydrogenation. In some embodiments, the asymmetric transfer hydrogenation is catalyzed by ruthenium. For examples of methods and catalysts for ruthenium catalyzed transfer hydrogenation, see U.S. Pat. Nos. 6,184,381 and 6,887,820. Exemplary catalysts for asymmetric transfer hydrogenation include, but are not limited to, the following (shown as the R, R configuration):
  • Figure US20190015377A1-20190117-C00063
    Figure US20190015377A1-20190117-C00064
  • The asymmetric transfer hydrogenation may be carried out at or below room temperature. In some embodiments, the asymmetric transfer hydrogenation is carried out at about 4° C. The alcohol product may have an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, or even higher. It is well understood by one skilled in the art that changing the catalyst configuration will lead to a product with the opposite configuration. Chiral alcohol 2-1 can be coupled with a suitable substrate, for example, a phenol, to give a compound of Formula 2-2 without significant loss of enantiomeric excess. The loss of enantiomeric excess (ee) in the coupling step for 2-2 may be less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6% or less than about 8%.
  • Figure US20190015377A1-20190117-C00065
  • In some embodiments, a compound of Formula 3-6 may be prepared according to Scheme 3. The ketone in 1-7 is protected as a ketal to give a compound of Formula 3-1, wherein each of Ri and Rj is independently an alkyl group. In addition, Ri and Rj may optionally be connected to form a cyclic ketal. Exemplary structures of ketal 3-1 include, but are not limited to, the following:
  • Figure US20190015377A1-20190117-C00066
  • A compound of Formula 3-1 and a suitable R1OH may undergo a nucleophilic aromatic substitution reaction (SNAr) to give biaryl ether 3-2. As described in Step G of Scheme 1, the reaction temperature of the SNAr reaction may depend on the reactivity of the aryl halide (i.e. compound 3-1) and/or R1OH. Ketone 3-3, resulting from the deprotection of ketal 3-2, is condensed with an amine to form imine 3-4, wherein Rk is alkyl. The imine functional group in a compound of Formula 3-4 may exist as a mixture of E and Z isomers. Fluorination of 3-4 can be accomplished with a fluorinating reagent, for example, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate, to give difluoroketone 3-5 after acid hydrolysis. Finally, reduction of ketone 3-5 with a hydride donor gives a compound of Formula 3-6.
  • Figure US20190015377A1-20190117-C00067
  • A compound of Formula 4-1 (Scheme 4) can be prepared asymmetrically following the general procedure described above in Scheme 2. In some embodiments, the asymmetric reduction gives a compound of Formula 4-1 with an enantiomeric excess of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or even higher. The enantiomeric excess of a compound of Formula 2-2 or 4-1 may be determined by chiral HPLC or Mosher ester analysis. For determination of ee with Mosher ester, see Hoye, et al. Natural Protocol, 2: 2451, 2007.
  • Figure US20190015377A1-20190117-C00068
  • Alternatively, a compound of Formula 4-1 may be prepared according to Scheme 5. Ketone 5-1 is fluorinated to give monofluoroketone 5-2, which is then converted to a silylenol ether, e.g., TBS enol ether 5-3. Other silyl protecting groups may also be used, for example, triisopropylsilyl or diphenyl-t-butylsilyl. The resulting enol ether is further fluorinated to give difluoroketone 5-4, which undergoes an asymmetric reduction, such as asymmetric transfer hydrogenation as described herein, to give chiral alcohol 5-5. Protection of the hydroxy moiety, followed by SNAr reaction and deprotection of the alcohol, provides a compound of Formula 4-1.
  • Figure US20190015377A1-20190117-C00069
  • Alternatively, a compound of Formula 3-6 can be prepared according to Scheme 6. Treatment of aryl halide 3-1 with a hydroxide source gives phenol 6-1. Suitable hydroxide sources include, but are not limited to, sodium hydroxide and potassium hydroxide. Suitable solvents for the reaction include, but are not limited to, DMSO, DMA, DMF and EtOH. Phenol 6-1 can react with a suitable halide via an SNAr reaction to give ether 3-2, which can be converted to a compound of Formula 3-6 as described in Scheme 3.
  • Figure US20190015377A1-20190117-C00070
  • Compounds of Formulae 7-3 and 7-4 may be prepared according to Scheme 7. For example, condensation of NH2Rk with difluoroketone 7-1, wherein Ra is aryl, heteroaryl, alkyl, heteroalkyl, heterocycle, or cycloalkyl, gives intermediate 7-2. In some embodiments, Rk is a chiral auxiliary. Exemplary chiral auxiliaries include, but are not limited to:
  • Figure US20190015377A1-20190117-C00071
  • and enantiomers thereof. Hydride reduction of intermediate 7-2 yields 7-3. At this stage, the chiral auxiliary may be cleaved under appropriate conditions, e.g., hydrogenation or acid treatment, to give chiral secondary amine 7-4. In some other embodiments, when a compound of Formula 7-3 is desirable and Rk is not hydrogen, asymmetric hydrogenation or asymmetric transfer hydrogenation is applied on intermediate 7-2 to give a compound of Formula 7-3. For a review on asymmetric hydrogenation and asymmetric transfer hydrogenation, see Iwao Ojima ed. Catalytic Asymmetric Synthesis, Wiley-VCH, Inc., 2000, ISBN 0-471-29805-0.
  • Figure US20190015377A1-20190117-C00072
  • In some embodiments, a compound of Formula 8-2 can be prepared according to Scheme 8. For example, ketone 3-3 is monofluorinated to give a monofluoroketone of Formula 8-1. The monofluorination can be achieved with a variety of fluorinating reagents, e.g., N-Fluoro-O-benzenedisulfonimide, acetyl hypofluorite, Accufluor®, Selectfluor®, Selectfluor® II, or N-fluorobenzenesulfonimide, in the presence or absence of a base. A compound of Formula 8-1 is reduced to give a compound of Formula 8-2. In some cases, the reduction is highly diastereoselective to give a compound of Formula 8-2 with greater than 80%, greater than 82%, greater than 84%, greater than 86%, greater than 88%, greater than 90%, greater than 92%, greater than 94%, greater than 96% or even greater than 96% diastereoselectivity. In some cases, the reduction is highly enantioselective to give a compound of Formula 8-2 with greater than 80%, greater than 82%, greater than 84%, greater than 86%, greater than 88%, greater than 90%, greater than 92%, greater than 94%, greater than 96% or even greater than 96% enantioselectivity. Reduction conditions to achieve high enantioselectivity include, but are not limited to, asymmetric transfer hydrogenation and enzymatic reduction as described herein.
  • Figure US20190015377A1-20190117-C00073
  • In some embodiments, a compound of Formula 9-6 may be prepared according to Scheme 9, wherein R13 is hydrogen, alkyl or fluoro. The hydroxy group of compound 9-1 may be protected, for example, with an acyl or methoxymethyl ether (MOM) group, to give a compound of Formula 9-2. Benzylic bromination in Step B may be carried out with a bromide source, e.g., N-bromosuccinimide, in the presence of a radical initiator, e.g., 2,2′-azobis(2-methylpropionitrile) (AIBN) or benzyol peroxide. The bromide of compound 9-3 can be replaced with a hydroxy group in a solvent comprising water in the presence of a silver salt, e.g., Ag2CO3 or AgClO4 or AgBF4. Finally, fluorination of a compound of Formula 9-4 followed by deprotection gives a compound of Formula 9-6. In some cases, direct benzylic oxidation may be used for converting a compound of Formula 9-2 to a compound of Formula 9-4, thus bypassing an intermediate bromination step.
  • Figure US20190015377A1-20190117-C00074
    Figure US20190015377A1-20190117-C00075
  • In some embodiments, a compound of Formula 10-7 can be prepared according to Scheme 10. For example, a compound of Formula 10-3 may be prepared from a compound of Formula 3-2 following a similar sequence as outlined in Scheme 9. Further functional group manipulations lead to a compound of Formula 10-7.
  • Figure US20190015377A1-20190117-C00076
  • Alternatively, a compound of Formula 10-3 can be deprotected to give diketone 11-1, which is fluorinated to give difluorodiketone 11-2. Asymmetric reduction of 11-2 provides diol 11-3. In some embodiments, a fluorination step is performed to give a compound of Formula 10-7.
  • Figure US20190015377A1-20190117-C00077
    Figure US20190015377A1-20190117-C00078
  • Alternatively, a compound of Formula 10-7 may be prepared according to Scheme 12. For example, difluoroketone 12-2 is reduced to give hydroxyketone 12-3. The reduction may be enantioselective under transfer hydrogenation conditions with a Ru-catalysis as described herein. One of the aryl fluorines may be selectively displaced with an alkyl thiol to give a compound of Formula 12-4. Oxidation, fluorination, nucleophilic aromatic substitution (SNAr) and asymmetric reduction give a compound of Formula 10-7.
  • Figure US20190015377A1-20190117-C00079
  • In some embodiments, a compound of Formula 13-4 can be prepared according to Scheme 13. An aryl sulfide of Formula 13-1 is treated with H2N—Rb and an oxidant, e.g., diacetoxyiodobenzene or dipivaloyloxyiodobenzene, in a suitable solvent, such as acetonitrile, to obtain aryl sulfinimide 13-2. In some embodiments, wherein Ra is fluoroalkyl, the addition of rhodium(II) acetate or Rh2(esp)2 catalyst along with magnesium oxide is helpful in Step A. Oxidation of aryl sulfinimide 13-2 to substituted sulfoximine 13-3 may be accomplished with catalytic ruthenium(III) chloride and sodium periodate in a suitable solvent, such as a mixture of water, acetonitrile, and carbon tetrachloride. Substituted sulfoximine 13-3 is then manipulated similarly as described in Schemes 3 and 4 to afford sulfoximines of Formula 13-4 as a diastereomeric mixture. The diastereomers may be separated by column chromatography.
  • Figure US20190015377A1-20190117-C00080
    Figure US20190015377A1-20190117-C00081
  • In some embodiments, a compound of Formula 14-10 can be prepared according to steps outlined in Scheme 14, wherein R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R2 is halo, cyano, alkyl, alkenyl or alkynyl; and R16 and R17 are fluoro or alkyl, or R16 and R17 and the carbon to which they are attached form C3-C8 cycloalkyl or C5-C8 heterocycloalkyl. The synthesis commences with compounds of Formula 14-1. Orthoiodination of 14-1 provides compound 14-2. The reaction may be carried out in a suitable organic solvent in the presence of iodine and a palladium catalyst at an elevated temperature, if needed. After esterification of 14-2, the resulting ester 14-3 may undergo a transition-metal catalyzed coupling reaction with a thioate, e.g., potassium ethanethioate or sodium ethanethioate, to give compounds of Formula 14-4. Suitable transition-metal catalysts include, but are not limited to, Pd(PPh3)4, Pd2(dba)3 chloroform complex or Pd(OAc)2, in the presence or absence of a suitable ligand. Hydrolysis of a compound of Formula 14-4 followed by alkylation of the resulting thiophenol intermediate with an alkyl halide, e.g., methyl iodide, gives a compound of Formula 14-5. The hydrolysis and alkylation may be carried out in a one-pot procedure without purification. In some embodiments, this is carried out by treating a compound of Formula 14-4 with a carbonate base in a suitable solvent at or near room temperature for a period ranging from 0.1 to 24 hours, followed by addition of an alkyl halide. Carbonate bases include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate and cesium bicarbonate. Oxidation of a compound of Formula 14-5 to give a compound of Formula 14-6 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl3 catalyzed oxidation in the presence of NaIO4, oxidation with m-chloroperoxybenzoic acid (mCPBA), and oxidation with Oxone®. A compound of Formula 14-6 is then subjected to a nucleophilic aromatic substitution (SNAr) reaction with R1OH (wherein R1 is alkyl, aryl or heteroaryl) to give a compound of Formula 14-7. Temperature for carrying out the SNAr reaction may depend on the reactivity of both R1OH and/or a compound of Formula 14-6. The reaction may be carried out at a temperature ranging from −10° C. to 200° C. In some embodiments, the temperature range is from 30° C. to 120° C. In some other embodiments, the temperature range is from 0° C. to room temperature. Cyclization of a compound of Formula 14-7 may be effected with a base, e.g., sodium hydride, in a suitable solvent to yield a compound of Formula 14-8. After the cyclization, a variety of R16 and R17 groups may be introduced. In some embodiments, a compound of Formula 14-8 is difluorinated to give a compound of Formula 14-9, formed by treatment with a fluorinating agent, e.g., 1-(chloromethyl)-4-fluoro-1,4-diazo niabicyclo[2.2.2]octane ditetrafluoroborate (Selectfluor®), in the presence of suitable base, e.g., sodium carbonate. Reduction of a compound of Formula 14-9 yields a compound of Formula 14-10. In some embodiments, the reduction is carried out with a hydride, e.g., sodium borohydride and sodium triacetoxyborohydride, to give a racemic mixture. In some embodiments, an asymmetric reduction is carried out as described above (see Scheme 2) to give an enantiomer having an enantiomeric excess as disclosed herein.
  • Figure US20190015377A1-20190117-C00082
  • Alternatively, a compound of Formula 14-8 may be prepared according to Scheme 15. For example, lithiation of a compound of Formula 15-1 followed by trapping of the resulting lithio intermediate with a suitable electrophile gives a compound of Formula 15-2. In some embodiments, the electrophile is N,N-dimethylformamide and R2 is —CHO. In a further embodiment, —CHO is converted to —CHF2 through addition of a fluorinating reagent, e.g., diethylaminosulfur trifluoride. One of the fluorines in a compound of Formula 15-2 may be selectively displaced with a thiomethoxide, e.g., sodium thiomethoxide, to give compounds of Formula 15-3. The reaction temperature may be in a range of −50 to 40° C. In some embodiments, the temperature is at or about 0° C. Oxidation of a compound of Formula 15-3, followed by SNAr reaction with R1OH and base-mediated cyclization provides a compound of Formula 14-8.
  • Figure US20190015377A1-20190117-C00083
  • In some embodiments, a compound of Formula 16-6 may be prepared according to Scheme 16. Oxidation of a compound of Formula 15-3 gives a compound of Formula 16-1. The oxidation may be accomplished with Oxone® or mCPBA. The amount of oxidant used for the oxidation may be about 1.5 equivalent, about 1.4 equivalent, about 1.3 equivalent, about 1.2 equivalent, about 1.1 equivalent or about 1.0 equivalent. SNAr reaction of a compound of Formula 16-1 with R1OH (wherein R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl) in the presence of a base gives a compound of Formula 16-2. At this stage, a sulfoximine moiety may be installed to give a compound of Formula 16-3 through a transition-metal catalyzed insertion of a suitable nitrogen donor. Suitable transition-metal catalysts include, but are not limited to, copper and rhodium catalysts, e.g., bis(rhodium(α,α,α′,α′-tetramethyl-1,3-benezenedipropionic acid)) and dirhodium tetraacetate. Suitable nitrogen donors include, but are not limited to, PhI═NNs, cyanamide, and fluoroalkylamides, e.g., trifluoromethyl acetamide. Cyclization of a compound of Formula 16-3 to give a compound of Formula 16-4 may be achieved with a base, e.g., sodium hydride, at about room temperature. Finally, reduction of a compound of Formula 16-5 as outlined in Scheme 14 provides a compound of Formula 16-6. A compound of Formula 16-6 may exist as a mixture of diastereomers and/or enantiomers. Diastereomers may be separated by conventional column chromatography, while enantiomers may be separated by chiral column chromatography.
  • Figure US20190015377A1-20190117-C00084
  • In some embodiments, a compound of Formula 17-5 can be prepared according to Scheme 17. Reaction of a compound of Formula 15-3 with cyanamide in the presence of an oxidant, e.g., (diacetoxyiodo)benzene, affords a compound of Formula 15-1. Further oxidation of a compound of Formula 15-1 provides a compound of Formula 15-2, which undergoes SNAr reaction, cyclization and reduction to give a compound of Formula 17-5.
  • Figure US20190015377A1-20190117-C00085
    Figure US20190015377A1-20190117-C00086
  • In some embodiments, compounds of Formula 18-8a and 18-8b may be prepared according to Scheme 18. For example, pyridine 18-1 may be converted to alkylaryl derivative 18-2 in Step A, wherein R4 is, for example, trifluoromethyl. The ketone may be converted to protected enol ether 18-3, then fluorinated to give fluoroketal 18-4. Treatment of a compound of Formula 18-4 with a suitable hydroxide source as described in Scheme 6 gives a mixture of phenols 18-5a and 18-5b. The phenols can undergo an SNAr reaction with a suitable halide to give aryl ethers of Formulae 18-6a and 18-6b, which may be deprotected to give the resultant ketones. In some embodiments, a compound of Formula 18-7 is reduced with a hydride source to give a racemic mixture. In other embodiments, an asymmetric reduction is carried out as described in Scheme 2, affording alcohols 18-8a and 18-8b, separable by methods known to one skilled in the art, such as, for example, conventional column chromatography.
  • Figure US20190015377A1-20190117-C00087
  • Alternatively, a compound of Formula 18-8a can be prepared according to Scheme 19. For example, conversion of a compound of Formula 19-1 to a phenol is followed by coupling to form an aryl ether and deprotection to give a ketone of Formula 18-7b as described above. Ketone 18-7b is converted to silyl enol ether 19-5 using a suitable silyl protecting group, including, for example, tert-butyldimethylsilyl, triisopropylsilyl or diphenyl-t-butylsilyl. The resulting silyl enol ether is fluorinated to give fluoroketone 18-7a, which undergoes an asymmetric reduction, such as asymmetric transfer hydrogenation as described herein, to give chiral alcohol 18-8a.
  • Figure US20190015377A1-20190117-C00088
    Figure US20190015377A1-20190117-C00089
  • A compound of Formula 20-9 can be prepared following the general procedure outlined in Scheme 20, wherein the aryl fluoride of a compound of Formula 20-1 is displaced with an alkyl thiol to give 20-2. Formation of benzaldehyde 20-3 may be followed by, for example, a Wittig reaction, to give alkene 20-4, which is reduced to an alkane of Formula 20-5 under suitable conditions. In some embodiments, a Dieckmann condensation reaction is followed by a decarboxylation to give ketone 20-6. Oxidation of a compound of Formula 20-6 to give a compound of Formula 20-7 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl3 catalyzed oxidation in the presence of NaIO4, oxidation with m-chloroperoxybenzoic acid (mCPBA) and oxidation with Oxone®. Protection of the ketone, for example, as the cyclic ketal (20-8) is followed by the general procedure outlined in Scheme 19 to give a compound of Formula 20-9.
  • Figure US20190015377A1-20190117-C00090
  • In some embodiments, a compound of Formula 21-7 may be prepared according to Scheme 21. Formation of a chloropyridine of Formula 21-2 may be followed by an SNAr reaction with a suitable alcohol of formula R1OH as described above to give a compound of Formula 21-3. Aryl bromide 21-3 may undergo a transition-metal catalyzed coupling reaction with a thioate to give a compound of Formula 21-4, analogously to the procedure detailed in Scheme 14. Hydrolysis, alkylation with a suitable alkyl halide and oxidation affords a compound of Formula 21-7.
  • Figure US20190015377A1-20190117-C00091
  • In some embodiments, a ketone of Formula 22-1 may be reduced to give 22-2, optionally with high enantioselectivity using asymmetric transfer hydrogenation or enzymatic reduction conditions as described herein. A compound of Formula 22-2 and a suitable coupling partner, including, but not limited to, a boronic acid of formula R1B(OH)2, may undergo a coupling reaction to give a compound of Formula 22-3.
  • Figure US20190015377A1-20190117-C00092
    Figure US20190015377A1-20190117-C00093
  • In some embodiments, R1 can be coupled to a compound of Formula 23-1 or 23-4 via a reaction scheme represented generally in Scheme 23. In some embodiments, wherein Z is NR8, an aryl halide of Formula 23-1 is coupled to a suitably substituted amine, i.e. NHR1R8, via a Buchwald-Hartwig amination to give a compound of Formula 23-2. In a further embodiment, Step A is a cross coupling reaction, including, but not limited to, a Stille, Negishi or Suzuki reaction, wherein an aryl halide of Formula 23-1 is combined with an appropriate reactant containing R1 and a suitable catalyst to afford a compound of Formula 23-3. In other embodiments, a compound of Formula 23-4 undergoes an SNAr reaction and a subsequent deprotection to give a compound of Formula 23-3. R1 in a compound of Formula 23-5 may be, for example, morpholine, wherein a C—N bond connects said morpholine to the aryl ring. In still other embodiments, Z is S, and R1S— is attached to a compound of Formula 23-1 via an SNAr reaction to give a compound of Formula 23-6.
  • Figure US20190015377A1-20190117-C00094
  • In some additional embodiments, a compound of Formula 24-2 can be prepared according to steps outlined in Scheme 24. A compound of Formula 12-6 is prepared via an asymmetric variation of the sequence presented in Scheme 12, then reacted with an amine, i.e. (3S)-3-piperidinol hydrochloride, to give a compound of Formula 24-1. Asymmetric reduction as described above gives a compound of Formula 24-2.
  • Figure US20190015377A1-20190117-C00095
  • In some embodiments, a compound of Formula 25-3 or 25-4 may be prepared according to steps outlined in Scheme 25. For example, 25-2 may be prepared via a cross coupling reaction, i.e., a Suzuki reaction with a boronic acid of formula R1B(OH)2. Hydride reduction of 25-2 gives a mixture of alcohols 25-3 and unsaturated alcohol 25-4.
  • Figure US20190015377A1-20190117-C00096
  • In some embodiments, a compound of Formula 26-5 can be synthesized according to Scheme 26. For example, treatment of compound 26-1 with base can provides difluoroalkene 26-2. The amount of base may be about 1 equivalent to avoid byproduct formation. The olefin in 26-2 may be hydrogenated to give a compound of Formula 26-3 with cis difluoro configuration. At this stage, an alkoxy group can be introduced by displacement of the aryl fluoride in 26-3 by an alcohol in the presence of a base. Finally, deprotection followed by reduction of the resulting ketone provides a compound of Formula 26-5. Intermediate 26-3 may be separated, for example, by chiral column chromatography, to give both enantiomers, each of which can be functionalized as outlined in Scheme 26 to provide either enantiomer of a compound of Formula 26-5.
  • Figure US20190015377A1-20190117-C00097
  • In some embodiments, a compound of Formula 27-6 may be synthesized according to Scheme 27. For example, alkylation of compound 27-1 provides a compound of Formula 27-2, wherein R1 is alkyl, cycloalkyl, or heterocycloalkyl. A compound of Formula 27-2 can be selectively iodinated to give aryl iodide 27-3. A compound of Formula 27-3 can be difluorinated as previously described. Installation of a CF3 group followed by asymmetric reduction provides a compound of Formula 27-6.
  • In some other embodiments, a compound of a formula given in Table 2 is synthesized according to one of the general routes outlined in Schemes 1-27, Examples 1-32 or by methods generally known in the art.
  • TABLE 2
    Mass
    Character-
    No. Structure ization 1 H NMR Data
    1
    Figure US20190015377A1-20190117-C00098
         		393 (M + H) (400 MHz, CDCl3): δ 7.81 (d, 1H), 7.00-6.89 (m, 3H), 6.73-6.71 (m, 1H), 6.35 (t, 1H), 5.66-5.65 (m, 1H), 3.19- 3.13 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.40 (m, 1H), 2.30-2.24 (m, 1H)
    2
    Figure US20190015377A1-20190117-C00099
         		377 (M + H) (400 MHz, CDCl3): δ 7.81 (d, 1H), 6.96 (d, 1H), 6.73-6.68 (m, 1H), 6.62- 6.61 (m, 2H), 6.36 (t, 1H), 5.66-5.65 (m, 1H), 3.22-3.10 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.40 (m, 1H), 2.29-2.24 (m, 1H)
    3
    Figure US20190015377A1-20190117-C00100
         		376, 378 (M + H) (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.36 (s, 1H), 7.81 (d, 1H), 7.44-7.43 (m, 1H), 6.89 (d, 1H), 6.36 (t, 1H), 5.67-5.66 (m, 1H), 3.23-3.16 (m, 2H), 2.99-2.92 (m, 1H), 2.51-2.42 (m, 1H), 2.32-2.25 (m, 1H)
    4
    Figure US20190015377A1-20190117-C00101
         		367 (M + H) (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.66 (s, 1H), 7.86 (d, 1H), 7.65-7.64 (m, 1H), 6.93 (d, 1H), 6.38 (t, 1H), 5.71-5.65 (m, 1H), 3.20-3.16 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.42 (m, 1H), 2.37-2.24 (m, 1H)
    5
    Figure US20190015377A1-20190117-C00102
         		360 (M + H) (400 MHz, CDCl3): δ 8.41 (s, 1H), 8.32 (s, 1H), 7.82 (d, 1H), 7.22-7.17 (m, 1H), 6.92 (d, 1H), 6.37 (t, 1H), 5.70-5.60 (m, 1H), 3.23-3.18 (m, 2H), 2.99-2.97 (m, 1H), 2.54-2.40 (m, 1H), 2.34-2.22 (m, 1H)
    6
    Figure US20190015377A1-20190117-C00103
         		433 (M − H + 46) (400 MHz, CDCl3): δ 7.77 (d, 1H), 6.91 (d, 1H), 6.54-6.50 (m, 1H), 6.42- 6.38 (m, 2H), 6.39 (t, 1H), 5.67-5.63 (m, 1H), 3.80 (s, 3H), 3.23-3.15 (m, 2H), 2.99-2.92 (m, 1H), 2.50-2.45 (m, 1H), 2.30-2.23 (m, 1H)
    7
    Figure US20190015377A1-20190117-C00104
         		7a, 429, 431 (M + Na) 7b, 429, 431 (M + Na) 7a: (400 MHz, CDCl3): δ 7.81 (d, 1H), 7.01-6.98 (m, 1H), 6.91-6.89 (m, 2H), 6.75-6.71 (m, 1H), 6.34 (t, 1H), 5.58-5.53 (m, 1H), 3.48-3.40 (m, 1H), 3.22 (d, 1H), 2.66-2.59 (m, 1), 1.98- 1.93 (m, 1H), 1.46 (d, 3H) 7b: (400 MHz, CDCl3): δ 7.81 (d, 1H), 7.01-6.97 (m, 1H), 6.92 (d, 1H), 6.89-6.88 (m, 1H), 6.73-6.69 (m, 1H), 6.38 (t, 1H), 5.70-5.67 (m, 1H), 3.71- 3.64 (m, 1H), 3.25 (d, 1H), 2.47-2.41 (m, 1H), 2.14-2.06 (m, 1H), 1.36 (d, 3H)
    8
    Figure US20190015377A1-20190117-C00105
         		429, 431 (M + H) (400 MHz, CDCl3): δ 7.90 (d, 1H), 7.06-7.03 (m, 1H), 6.98 (d, 1H), 6.94- 6.92 (m, 1H), 6.78-6.74 (m, 1H), 6.42 (t, 1H), 5.50 (d, 1H), 3.61-3.43 (m, 2H), 3.24 (s, 1H)
    9
    Figure US20190015377A1-20190117-C00106
         		413 (M + H) (400 MHz, CDCl3): δ 7.90 (d, 1H), 7.01 (d, 1H), 6.80-6.73 (m, 1H), 6.70- 6.63 (m, 2H), 6.43 (t, 1H), 5.50 (m, 1H), 3.60-3.43 (m, 2H), 3.30 (d, 1H)
    10
    Figure US20190015377A1-20190117-C00107
         		375, 377 (M − OH) (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.04-7.00 (m, 1H), 6.97-6.95 (m, 1H), 6.84-6.77 (m, 2H), 6.18 (t, 1H), 5.58- 5.53 (m, 1H), 3.59-3.50 (m, 1H), 3.34-3.26 (m, 1H), 2.60-2.50 (m, 1H), 2.31 (d, 1H), 2.21-2.13 (m, 1H)
    11
    Figure US20190015377A1-20190117-C00108
         		437 (M + NH4) (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.33-7.29 (m, 1H), 7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 7.00 (d, 1H), 6.43 (t, 1H), 5.51 (d, 1H), 3.60-3.43 (m, 2H), 3.30 (br s, 1H)
    12
    Figure US20190015377A1-20190117-C00109
         		451 (M − H) (400 MHz, CDCl3): δ 8.01 (d, 1H), 6.97 (d, 1H), 6.82-6.55 (m, 4H), 5.76- 5.64 (m, 1H), 5.35-5.26 (m, 2H), 3.54-3.44 (m, 2H), 3.31-3.18 (m, 1H), 3.06-2.96 (m, 2H)
    13
    Figure US20190015377A1-20190117-C00110
         		451 (M + NH4) (400 MHz, CDCl3): δ 8.0 (d, 1H), 7.33-7.30 (m, 1H), 7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 6.92 (d, 1H), 6.62 (m, 1H), 3.58-3.49 (m, 2H), 3.34-3.20 (m, 1H), 1.84-1.82 (m, 3H)
    14
    Figure US20190015377A1-20190117-C00111
         		364 (M − H) (400 MHz, CDCl3): δ 7.9 (d, 1H), 6.97 (d, 1H), 6.73-6.67 (m 1H), 6.64- 6.58 (m, 1H), 5.83-5.79 (m, 1H), 6.57-6.53 (m, 1H), 4.22 (d, 1H), 3.20- 3.10 (m, 1H), 2.95-2.85 (m, 2H), 2.60-2.50 (m, 1H), 2.25-2.16 (m, 1H)
    15
    Figure US20190015377A1-20190117-C00112
         		420 (M + H) (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.33-6.98 (m, 4H), 6.44 (t, 1H), 5.51 (d, 1H), 3.61-3.45 (m, 2H)
    16
    Figure US20190015377A1-20190117-C00113
         		437/439 (M − H + 46) (400 MHz, CDCl3): δ 7.81 (d, 1H), 7.00-6.98 (m, 1H), 6.94 (d, 1H), 6.89- 6.88 (m, 1H), 6.74-6.71 (m, 1H), 6.35 (t, 1H), 5.67-5.65 (m, 1H), 3.21-3.13 (m, 2H), 2.96-2.89 (m, 1H), 2.50-2.41 (m, 1H), 2.30-2.23 (m, 1H)
    17
    Figure US20190015377A1-20190117-C00114
         		393 (M + H)
    18
    Figure US20190015377A1-20190117-C00115
         		391, 393 (M + H) (400 MHz, CDCl3): δ 8.15 (d, 1H), 7.14 (d, 1H), 7.12 (t, 1H), 7.07-7.04 (m, 1H), 6.96-6.93 (m, 1H), 6.80-6.76 (m, 1H), 3.23-3.20 (m, 2H), 2.90-2.87 (m, 2H)
    19
    Figure US20190015377A1-20190117-C00116
         		376 (M + H) (400 MHz, CDCl3): δ 7.81 (d, 1H), 6.92 (d, 1H), 6.72-6.67 (m, 1H), 6.62 (t, 1H), 6.63-6.59 (m, 2H), 4.96-4.94 (m, 1H), 3.18-3.10 (m, 1H), 2.99-2.92 (m, 1H), 2.51-2.41 (m, 1H), 2.30-2.00 (m, 3H)
    20
    Figure US20190015377A1-20190117-C00117
         		361 (M + H) (400 MHz, CDCl3): δ 7.76 (d, 1H), 6.87 (d, 1H), 6.69-6.63 (m, 1H), 6.60- 6.55 (m, 2H), 6.18 (t, 1H), 3.37 (t, 2H), 2.93 (t, 2H), 2.20-2.17 (m, 2H)
    21
    Figure US20190015377A1-20190117-C00118
         		359 (M + H) (400 MHz, CDCl3): δ 7.88 (d, 1H), 7.47-7.45 (m, 1H), 6.93-6.90 (m, 2H), 6.71-6.60 (m, 3H), 6.22 (t, 1H), 3.49- 3.48 (m, 1H)
    22
    Figure US20190015377A1-20190117-C00119
         		421 (M − H + 46) (400 MHz, CDCl3): δ 7.79 (d, 1H), 6.90 (d, 1H), 6.72-6.66 (m, 1H), 6.64- 6.57 (m, 2H), 6.19 (t, 1H), 4.85-4.81 (m, 1H), 3.60-3.44 (m, 3H), 3.21-2.99 (m, 2H)
    23
    Figure US20190015377A1-20190117-C00120
         		437 (M − H + 46) (400 MHz, CDCl3): δ 7.83 (d, 1H), 6.98 (d, 1H), 6.74-6.69 (m, 1H), 6.64- 6.62 (m, 2H), 6.36 (t, 1H), 5.37 (brs, 1H), 4.65-4.63 (m, 1H), 3.45-3.39 (m, 2H), 2.92-2.88 (m, 1H)
    24
    Figure US20190015377A1-20190117-C00121
         		391 (M + H) (400 MHz, CDCl3): δ 7.77 (d, 1H), 6.90 (d, 1H), 6.71-6.65 (m, 1H), 6.62- 6.36 (m, 2H), 6.23 (t, 1H), 3.94-3.71 (m, 3H), 2.97-2.89 (m, 2H), 2.84 (s, 1H), 2.40-2.22 (m, 2H)
    25
    Figure US20190015377A1-20190117-C00122
         		410, 412 (M + H) (400 MHz, CDCl3) δ 8.55-8.54 (m, 1H), 8.40-8.39 (m, 1H), 7.91 (d, 1H), 7.52-7.49 (m, 1H), 6.93 (d, 1H), 6.44 (t, 1H), 5.53-5.49 (m, 1H),3.64-3.48 (m, 2H), 3.35 (d, 1H)
    26
    Figure US20190015377A1-20190117-C00123
         		473, 475 (M − H + 46) (400 MHz, CDCl3): δ 7.86 (d, 1H), 7.26-7.22 (m, 2H), 7.05-6.95 (m, 1H), 6.86 (d, 1H), 6.41 (t, 1H), 5.51-5.47 (m, 1H), 3.58-3.51 (m, 2H), 3.26 (brd s, 1H)
    27
    Figure US20190015377A1-20190117-C00124
         		403 (M + H) (400 MHz, CDCl3): δ 8.82 (s, 1H), 8.71 (s, 1H), 7.95 (d, 1H), 7.73-7.71 (m, 1H), 6.95 (d, 1H), 6.44 (t, 1H), 5.55-5.50 (m, 1H), 3.60-3.51 (m, 2H), 3.29 (d, 1H)
    28
    Figure US20190015377A1-20190117-C00125
         		412, 414 (M − H) (400 MHz, CDCl3): δ 8.27 (d, 1H), 7.17-7.14 (m, 1H), 7.03-7.02 (m, 1H), 6.97 (d, 1H), 6.88-6.85 (m, 1H)
    29
    Figure US20190015377A1-20190117-C00126
         		403/405 (M − H) (400 MHz, CDCl3): δ 8.31 (d, 1H), 7.44-7.41 (m, 1H), 7.32-7.31 (m, 1H), 7.24-7.20 (m, 1H), 6.97 (d, 1H)
    30
    Figure US20190015377A1-20190117-C00127
         		385, 387 (M − H) (400 MHz, CDCl3): δ 8.28 (d, 1H), 7.42-7.40 (m, 1H), 7.31-7.26 (m, 1H), 7.22-7.19 (m, 1H), 6.97 (d, 1H), 6.45 (t, 1H)
    31
    Figure US20190015377A1-20190117-C00128
         		[M − H] 374 (400 MHz, CDCl3): δ 8.14 (d, 1H), 7.67-7.61 (m, 2H), 7.48-7.47 (m, 1H), 6.80 (d, 1H), 6.24 (t, 1H), 2.98 (s, 3H)
    32
    Figure US20190015377A1-20190117-C00129
         		[M − 1] 374 (400 MHz, CDCl3): δ 8.15 (d, 1H), 7.12-7.08 (m, 1H), 7.01-6.99 (m, 1H), 6.89 (d, 1H), 6.85-6.81 (m, 1H), 6.24 (t, 1H), 2.97 (s, 3H)
    33
    Figure US20190015377A1-20190117-C00130
         		[M − H] 365 (400 MHz, CDCl3): δ 8.20 (d, 1H), 7.39-7.35 (m, 1H), 7.29-7.27 (m, 1H), 7.20-7.16 (m, 1H), 6.90 (d, 1H), 6.26 (t, 1H), 2.90 (s, 3H)
    34
    Figure US20190015377A1-20190117-C00131
         		[M − H] 358 (400 MHz, CDCl3): δ 8.15 (d, 1H), 6.91 (d, 1H), 6.85-6.79 (m, 1H), 6.77- 6.70 (m, 2H), 6.24 (t, 1H), 2.97 (s, 3H)
    35
    Figure US20190015377A1-20190117-C00132
         		[M + H] 391 (400 MHz, CDCl3): δ 8.07 (d, 1H), 7.13-7.05 (m, 1H), 7.04-6.95 (m, 2H), 6.89-6.85 (m, 1H), 6.26 (t, 1H), 5.60 (s, 2H)
    36
    Figure US20190015377A1-20190117-C00133
         		[M + H] 419 (400 MHz, CDCl3): δ 8.29 (d, 1H), 7.13-7.09 (m, 1H), 7.02 (t, 1H), 7.01- 6.99 (m, 1H), 6.96 (d, 1H), 6.86-6.82 (m, 1H), 4.11 (s, 2H), 2.34 (s, 6H)
    37
    Figure US20190015377A1-20190117-C00134
         		[M − H] 358 (400 MHz, CDCl3): δ 8.07 (d, 1H), 7.07-7.03 (m, 1H), 7.01 (d, 1H), 6.96- 6.94 (m, 1H), 6.81-6.77 (m, 1H), 6.15 (t, 1H), 2.68 (s, 3H)
    38
    Figure US20190015377A1-20190117-C00135
         		[M − H + 18] 413 (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.24 (d, 1H), 7.12-7.08 (m, 1H), 6.96- 6.94 (m, 1H), 6.81-6.77 (m, 1H), 6.41 (t, 1H)
    39
    Figure US20190015377A1-20190117-C00136
         		[M − H + 18] 404 (400 MHz, CDCl3): δ 8.09 (d, 1H), 7.37-7.34 (m, 1H), 7.29 (d, 1H), 7.22- 7.21 (m, 1H), 7.14-7.10 (m, 1H), 6.43 (t, 1H)
    40
    Figure US20190015377A1-20190117-C00137
         		[M − H + 18] 386 (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.68-7.62 (m, 2H), 7.45-7.43 (m, 1H), 7.40-7.36 (m, 1H), 7.17 (d, 1H), 6.41 (t, 1H)
    41
    Figure US20190015377A1-20190117-C00138
         		[M − H + 46] 445 (400 MHz, CDCl3): δ 8.01 (d, 1H), 7.06 (d, 1H), 7.04-7.01 (m, 1H), 6.91- 6.88 (m, 1H), 6.76-6.71 (m, 1H), 6.47 (t, 1H), 5.21 (d, 2H), 2.69 (t, 1H)
    42
    Figure US20190015377A1-20190117-C00139
         		[M − H + 46] 436 (400 MHz, CDCl3): δ 8.06 (d, 1H), 7.28-7.25 (m, 1H), 7.15-7.12 (m, 2H), 7.07-7.03 (m, 1H), 6.50 (t, 1H), 5.21 (d, 2H), 2.70 (t, 1H)
    43
    Figure US20190015377A1-20190117-C00140
         		[M − H + 46] 418 (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.59-7.56 (m, 1H), 7.38-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.00 (d, 1H), 6.48 (t, 1H), 5.22 (d, 2H), 2.71 (t, 1H)
    44
    Figure US20190015377A1-20190117-C00141
         		[M − H + 46] 445 (400 MHz, CDCl3): δ 8.01 (d, 1H), 7.06 (d, 1H), 7.04-7.01 (m, 1H), 6.91- 6.88 (m, 1H), 6.76-6.71 (m, 1H), 6.47 (t, 1H), 5.21 (d, 2H), 2.69 (t, 1H)
    45
    Figure US20190015377A1-20190117-C00142
         		[M + H] 451 (400 MHz, CDCl3): δ 8.06 (d, 1H), 7.67 (s, 1H), 7.12-7.03 (m, 4H), 6.93 (s, 1H), 6.77 (br d, 1H), 5.92 (t, 1H), 5.76 (d, 2H)
    46
    Figure US20190015377A1-20190117-C00143
         		[M − H + 46] 463 (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.07 (d, 1H), 7.06-7.03 (m, 1H), 6.93- 6.91 (m, 1H), 6.78-6.74 (m, 1H), 6.42 (t, 1H), 5.26 (d, 2H)
    47
    Figure US20190015377A1-20190117-C00144
         		[M + H] 482 (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.05-7.01 (m, 2H), 6.90-6.89 (m, 1H), 6.75-6.71 (m, 1H), 6.67 (s, 1H), 6.43 (t, 1H), 4.50 (br s, 2H) 3.40-3.30 (m, 2H)
    48
    Figure US20190015377A1-20190117-C00145
         		[M + H] 484 (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.07 (t, 2H), 7.03-6.99 (m, 2H), 6.89- 6.87 (m, 1H), 6.74-6.70 (m, 1H), 4.40 (s, 2H), 4.05-3.98 (m, 2H) 3.48-3.40 (m, 2H), 2.89-2.81 (m, 1H), 1.97-1.90 (m, 2H), 1.52-1.41 (m, 3H)
    49
    Figure US20190015377A1-20190117-C00146
         		[M + H] 484 (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.09 (t, 2H), 7.03-7.00 (m, 2H), 6.89- 6.88 (m, 1H), 6.74-6.70 (m, 1H), 4.40 (s, 2H), 3.94-3.89 (m, 1H) 3.78-3.71 (m, 1H), 3.56-3.49 (m, 1H), 3.39-3.33 (m, 1H), 2.86-2.79 (m, 1H), 2.06-1.97 (m, 1H), 1.80-1.72 (m, 1H), 1.66-1.46 (m, 3H)
    50
    Figure US20190015377A1-20190117-C00147
         		[M − H] 338 (400 MHz, CDCl3): δ 8.20 (d, 1H), 7.08-7.04 (m, 1H), 6.96-6.94 (m, 1H), 6.87 (d, 1H), 6.81-6.77 (m, 1H), 3.12 (s, 3H), 2.97 (s, 3H)
    51
    Figure US20190015377A1-20190117-C00148
         		[M − H] 329 (400 MHz, CDCl3): δ 8.25 (d, 1H), 7.33-7.30 (m, 1H), 7.22-7.20 (m, 1H), 7.16-7.12 (m, 1H), 6.93-6.89 (m, 1H), 3.13 (s, 3H), 2.98 (s, 3H)
    52
    Figure US20190015377A1-20190117-C00149
         		[M − H] 322 (400 MHz, CDCl3): δ 8.20 (d, 1H), 6.91-6.88 (m, 1H), 6.81-6.75 (m, 1H), 6.72-6.65 (m, 2H), 3.12 (s, 3H), 2.97 (s, 3H)
    53
    Figure US20190015377A1-20190117-C00150
         		[M − H] 363 (400 MHz, CDCl3): δ 8.18 (br d, 1H), 7.26 (t, 1H), 7.01-6.97 (m, 1H), 6.89- 6.84 (m, 2H), 6.71-6.67 (m, 1H), 3.15 (s, 3H), 2.95 (t, 3H)
    54
    Figure US20190015377A1-20190117-C00151
         		[M − H + 46] 425 (400 MHz, CDCl3): δ 8.21 (d, 1H), 7.31 (t, 1H), 7.03-6.98 (m, 2H), 6.89- 6.87 (m, 1H), 6.74-6.70 (m, 1H), 5.27 (d, 2H), 3.30 (s, 3H), 2.96-2.91 (m, 1H)
    55
    Figure US20190015377A1-20190117-C00152
         		[M − H] 393 (400 MHz, CDCl3): δ 7.84 (d, 1H), 6.95 (d, 1H), 6.76-6.70 (m, 1H), 6.66- 6.60 (m, 2H), 5.65-5.60 (m, 1H), 3.25-3.15 (m, 2H), 3.00-2.92 (m, 1H) 2.47-2.28 (m, 2H)
    56
    Figure US20190015377A1-20190117-C00153
         		[M − H + 46] 455 (400 MHz, CDCl3): δ 7.84 (d, 1H), 7.03-6.99 (m, 1H), 6.93 (d, 1H), 6.92- 6.90 (m, 1H), 6.75-6.71 (m, 1H), 5.65-5.61 (m, 1H), 3.24-3.15 (m, 2H), 3.01-2.92 (m, 1H) 2.47-2.28 (m, 2H)
    57
    Figure US20190015377A1-20190117-C00154
         		[M − H + 46] 446 (400 MHz, CDCl3): δ 7.88 (d, 1H), 7.28-7.25 (m, 2H), 7.19-7.17 (m, 1H), 7.09-7.05 (m, 1H), 6.96 (d, 1H), 5.66- 5.62 (m, 1H), 3.23-3.13 (m, 2H), 2.99-2.90 (m, 1H) 2.47-2.29 (m, 2H)
    58
    Figure US20190015377A1-20190117-C00155
         		[M − H] 329 (400 MHz, CDCl3): δ 7.53-7.49 (m, 1H), 6.98-6.95 (m, 1H), 6.62-6.55 (m, 1H), 6.53-6.46 (m, 2H), 5.53 (br s, 1H), 3.11-3.01 (m, 1H), 2.84-2.76 (m, 1H), 2.41-2.31 (m, 1H) 2.25-2.18 (m, 1H), 2.04 (br s, 1H)
    59
    Figure US20190015377A1-20190117-C00156
         		[M − H + 46] 403 (400 MHz, CDCl3): δ 7.81 (d, 1H), 6.97 (d, 1H), 6.70-6.64 (m, 1H), 6.61- 6.55 (m, 2H), 5.70-5.66 (m, 1H), 5.41-5.14 (m, 2H), 3.29 (d, 1H), 3.18- 3.09 (m, 1H), 2.92-2.83 (m, 1H), 2.51-2.42 (m, 1H) 2.27-2.19 (m, 1H)
    60
    Figure US20190015377A1-20190117-C00157
         		[M − H + 46] 403 (400 MHz, CDCl3): δ 7.81 (d, 1H), 6.97 (d, 1H), 6.70-6.64 (m, 1H), 6.61- 6.55 (m, 2H), 5.70-5.66 (m, 1H), 5.42-5.13 (m, 2H), 3.30 (d, 1H), 3.18- 3.09 (m, 1H), 2.92-2.83 (m, 1H), 2.51-2.42 (m, 1H) 2.27-2.19 (m, 1H)
    61
    Figure US20190015377A1-20190117-C00158
         		[M − H + 46] 419 (400 MHz, CDCl3): δ 7.81 (d, 1H), 6.97-6.93 (m, 2H), 6.87-6.85 (m, 1H), 6.71-6.67 (m, 1H), 5.71-5.66 (m, 1H), 5.42-5.13 (m, 2H), 3.30 (d, 1H), 3.18- 3.09 (m, 1H), 2.92-2.84 (m, 1H), 2.51-2.41 (m, 1H) 2.28-2.19 (m, 1H)
    62
    Figure US20190015377A1-20190117-C00159
         		[M − H + 46] 410 (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.23-7.19 (m, 2H), 7.13-7.11 (m, 1H), 7.04-7.00 (m, 1H), 6.98 (d, 1H), 5.72- 5.67 (m, 1H), 5.44-5.12 (m, 2H), 3.29 (d, 1H), 3.16-3.07 (m, 1H), 2.90-2.81 (m, 1H), 2.52-2.42 (m, 1H), 2.29-2.20 (m, 1H)
    63
    Figure US20190015377A1-20190117-C00160
         		[M − H + 46] 446 (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.30-7.26 (m, 1H), 7.20-7.19 (m, 1H), 7.10-7.07 (m, 1H), 7.00 (d, 1H), 5.59- 5.13 (m, 3H), 3.58-3.38 (m, 1H)
    64
    Figure US20190015377A1-20190117-C00161
         		[M − H + 46] 439 (400 MHz, CDCl3): δ 7.90 (d, 1H), 7.01 (d, 1H), 6.77-6.71 (m, 1H), 6.67- 6.60 (m, 2H), 5.58-5.12 (m, 3H), 3.58-3.38 (m, 3H)
    65
    Figure US20190015377A1-20190117-C00162
         		[M − H + 46] 455 (400 MHz, CDCl3): δ 7.90 (d, 1H), 7.03-7.00 (m, 1H), 6.98 (d, 1H), 6.91- 6.90 (m, 1H), 6.76-6.72 (m, 1H), 5.58-5.12 (m, 3H), 3.59-3.39 (m, 3H)
    66
    Figure US20190015377A1-20190117-C00163
         		[M − H] 286 (400 MHz, CDCl3): δ 7.55-7.52 (m, 1H), 6.90 (d, 1H), 6.65-6.60 (m, 1H), 6.55-6.49 (m, 2H), 5.56-5.51 (m, 1H), 3.08-3.00 (m, 1H), 2.80-2.71 (m, 1H), 2.68-2.64 (m, 1H) 2.60-2.50 (m, 1H), 2.17-2.08 (m, 1H)
    67
    Figure US20190015377A1-20190117-C00164
         		[M − H + 46] 368 (400 MHz, CDCl3): δ 7.62 (d, 1H), 6.94 (d, 1H), 6.72-6.67 (m, 1H), 6.61- 6.54 (m, 2H), 5.36-5.30 (m, 1H), 3.54-3.30 (m, 2H), 3.13-3.10 (m, 1H)
    68
    Figure US20190015377A1-20190117-C00165
         		[M + H] 372 (400 MHz, CDCl3): δ 7.87 (d, 1H), 7.25-7.22 (m, 1H), 7.15-7.13 (m, 1H), 7.08-6.97 (m, 2H), 5.86-5.80 (m, 1H), 3.51 (s, 3H), 3.19-3.06 (m, 2H), 2.95- 2.78 (m, 1H), 2.65-2.55 (m, 1H), 2.27-2.14 (m, 1H)
    69
    Figure US20190015377A1-20190117-C00166
         		414, 416, 418 (M + H) (400 MHz, CDCl3): δ 8.34 (d, 1H), 7.96 (m, 1H), 7.08 (d, 1H), 6.99 (m, 1H), 6.86 (m, 1H), 6.70 (m, 1 H), 6.16 (t, 1H), 3.35 (br s, 1H)
    70
    Figure US20190015377A1-20190117-C00167
         		428, 430, 432 (M + H) (400 MHz, CDCl3): δ 8.26 (d, 1H), 7.87 (m, 1H), 7.07 (d, 1H), 6.98 (m, 1H), 6.86 (m, 1H), 6.70 (m, 1H), 6.22 (t, 1H), 2.98 (s, 3H)
    71
    Figure US20190015377A1-20190117-C00168
         		430, 432, 434 (M − H) (400 MHz, CDCl3): δ 8.42 (d, 1H), 8.03 (m, 1H), 7.07 (d, 1H), 7.01 (m, 1H), 6.89 (m, 1H), 6.73 (m, 1 H), 3.65 (br s, 1H)
    72
    Figure US20190015377A1-20190117-C00169
         		377, 379 (M − H) (400 MHz, CDCl3): δ 8.47 (d, 1H), 8.23 (m, 1H), 7.12 (m, 1H), 7.07 (d, 1H), 7.00 (m, 1H), 6.84 (m, 1 H), 3.74 (br s, 1H)
    73
    Figure US20190015377A1-20190117-C00170
         		368 (M − H) (400 MHz, CDCl3): δ 8.50 (d, 1H), 8.28 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.20 (m, 1H), 7.09 (d, 1 H), 3.78 (br s, 1H)
    74
    Figure US20190015377A1-20190117-C00171
         		462, 464, 466 (M + NH4) (400 MHz, CDCl3): δ 8.06 (d, 1H), 7.04-6.99 (m, 2H), 6.90 (m, 1H), 6.73 (m, 1H), 6.48 (t, 1H), 5.25 (d, 2 H), 2.69 (t, 1H)
    75
    Figure US20190015377A1-20190117-C00172
         		464, 466, 468 (M − H) (400 MHz, CDCl3): δ 8.33 (d, 1H), 7.03 (m, 1H), 6.98 (d, 1H), 6.90 (m, 1H), 6.74 (m, 1H), 3.88 (br s, 1H)
    76
    Figure US20190015377A1-20190117-C00173
         		441, 443, 445 (M + H) (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.36 (d, 1H), 7.03 (m, 1H), 6.87 (m, 1H), 6.72 (m, 1H), 6.33 (t, 1H)
    77
    Figure US20190015377A1-20190117-C00174
         		432, 434 (M + H) (400 MHz, CDCl3): δ 8.06 (d, 1H), 7.42 (d, 1H), 7.28 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.36 (t, 1H)
    78
    Figure US20190015377A1-20190117-C00175
         		401 (M + NH4) (400 MHz, CDCl3): δ 7.86 (d, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.97 (d, 1H), 6.37 (t, 1H), 5.69-5.65 (m, 1H), 3.21-3.11 (m, 2H), 2.92 (m, 1H), 2.51-2.41 (m, 1H), 2.32-2.23 (m, 1H)
    79
    Figure US20190015377A1-20190117-C00176
         		(400 MHz, CDCl3): δ 8.16 (d, 1H), 7.43 (m, 1H), 7.34-7.32 (m, 1H), 7.24-7.21 (m, 1H), 7.06 (d, 1H), 2.79 (s, 3H)
    80
    Figure US20190015377A1-20190117-C00177
         		453, 455 (M + NH4) (400 MHz, CDCl3): δ 8.11 (d, 1H), 7.28-7.23 (m, 1H), 7.15-7.13 (m, 1H), 7.09 (d, 1H), 7.05 (m, 1H), 6.50 (t, 1H), 5.25 (d, 2H), 2.69 (t, 1H)
    81
    Figure US20190015377A1-20190117-C00178
         		435, 437 (M + NH4) (400 MHz, CDCl3): δ 8.05 (d, 1H), 7.59-7.56 (m, 2H), 7.39-7.37 (m, 1H), 7.36-7.31 (m, 1H), 6.95 (d, 1H), 6.48 (t, 1H), 5.26 (d, 2H), 2.70 (t, 1H)
    82
    Figure US20190015377A1-20190117-C00179
         		457, 459, 461 (M + H) (400 MHz, CDCl3): δ 8.05 (d, 1H), 7.28 (d, 1H), 6.96 (m, 1H), 6.83-6.81 (m, 1H), 6.66 (m, 1H), 6.58 (m, 1H), 4.04 (t, 3H)
    83
    Figure US20190015377A1-20190117-C00180
         		488, 490, 492 [MH+ − C4H8] (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.02 (m, 1H), 6.99 (d, 1H), 6.90-6.88 (m, 1H), 6.73 (m, 1H), 6.62 (br t, 1H), 5.22 (br s, 1H), 4.95 (d, 2H), 1.45 (s, 9H)
    84
    Figure US20190015377A1-20190117-C00181
         		393, 395 (M + H) (400 MHz, CDCl3): δ 8.07 (d, 1H), 7.11 (m, 1H), 7.04-6.99 (m, 2H), 6.87 (m, 1H), 6.26 (t, 1H), 5.61 (d, 2H)
    85
    Figure US20190015377A1-20190117-C00182
         		444, 446, 448 (M + H) (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.02 (m, 1H), 6.97 (d, 1H), 6.89 (m, 1H), 6.73 (m, 1H), 6.66 (t, 1H), 4.45 (br s, 2H)
    86
    Figure US20190015377A1-20190117-C00183
         		486, 488, 490 (M + H) (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.03 (m, 1H), 6.99 (d, 1H), 6.90 (m, 1H), 6.74 (m, 1H), 6.66 (t, 1H), 6.11 (br s, 1H), 5.05 (d, 2H), 2.00 (s, 3H)
    87
    Figure US20190015377A1-20190117-C00184
         		379, 381 (M + H − 16) (400 MHz, CDCl3): δ 8.07 (d, 1H), 7.02 (d, 1H), 7.00 (m, 1H), 6.90-6.88 (m, 1H), 6.75-6.71 (m, 1H), 6.46 (t, 1H), 5.18 (d, 2H), 5.01 (d, 2H), 3.01 (t, 1H), 2.76 (t, 1H)
    88
    Figure US20190015377A1-20190117-C00185
         		377, 379 (M + H − 16) (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.03 (m, 1H), 6.97-6.94 (m, 2H), 6.80 (m, 1H), 6.67 (m, 1H), 6.20 (t, 1H), 5.57 (m, 1H), 5.39 (d, 1H), 3.33 (d, 1H)
    89
    Figure US20190015377A1-20190117-C00186
         		478, 480 (M + NH4) (400 MHz, CDCl3): δ 8.01 (d, 1H), 7.63-7.55 (m, 2H), 7.41-7.38 (m, 1H), 7.28 (m, 1H), 6.90 (d, 1H), 6.47 (t, 1H), 5.26 (d, 2H), 2.73 (t, 1H)
    90
    Figure US20190015377A1-20190117-C00187
         		339, 341 (M + H − 6) (400 MHz, CDCl3): δ 7.80 (d, 1H), 6.95 (d, 1H), 6.93 (m, 1H), 6.84-6.82 (m, 1H), 6.66 (m, 1H), 5.68 (m, 1H), 3.64 (d, 1H), 3.20 (s, 3H), 3.15-3.06 (m, 1H), 2.83 (m, 1H), 2.53-2.43 (m, 1H), 2.27-2.18 (m, 1H)
    91
    Figure US20190015377A1-20190117-C00188
         		353, 355 (M − OH) (400 MHz, CDCl3): δ 7.74 (d, 1H), 6.95-6.92 (m, 2H), 6.84-6.82 (m, 1H), 6.66 (m, 1H), 5.65-5.60 (m, 1H), 3.70 (d, 1H), 3.35-3.19 (m, 2H), 3.15-3.06 (m, 1H), 2.83 (m, 1H), 2.49-2.39 (m, 1H), 2.27-2.19 (m, 1H), 1.34 (t, 3H)
    92
    Figure US20190015377A1-20190117-C00189
         		393, 395 (M + NH4) (400 MHz, CDCl3): δ 8.29-8.25 (m, 1H), 7.27-7.23 (m, 1H), 7.22 (t, 1H), 7.10-7.06 (m, 1H), 6.93-6.91 (m, 1H), 6.76 (m, 1H), 3.35 (s, 3H)
    93
    Figure US20190015377A1-20190117-C00190
         		377 (M + NH4) (400 MHz, CDCl3): δ 8.29-8.25 (m, 1H), 7.29-7.25 (m, 1H), 7.22 (t, 1H), 6.80 (tt, 1H), 6.69-6.63 (m, 2H), 3.35 (s, 3H)
    94
    Figure US20190015377A1-20190117-C00191
         		384 (M + NH4) (400 MHz, CDCl3): δ 8.34-8.30 (m, 1H), 7.35-7.32 (m, 1H), 7.29-7.25 (m, 1H), 7.21 (t, 1H), 7.21-7.18 (m, 1H), 7.11 (m, 1H), 3.36 (s, 3H)
    95
    Figure US20190015377A1-20190117-C00192
         		379 (M + NH4) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.17 (m, 1H), 7.05-7.03 (m, 1H), 6.97 (m, 1H), 6.95 (d, 1H), 5.44-5.39 (m, 1H), 3.72 (m, 1H), 3.25 (s, 3H), 3.04- 2.95 (m, 1H), 2.58-2.47 (m, 1H), 2.29-2.22 (m, 1H), 2.16-2.03 (m, 1H), 1.91-1.73 (m, 2H)
    96
    Figure US20190015377A1-20190117-C00193
         		(400 MHz, CDCl3): δ 7.85 (d, 1H), 6.94 (d, 1H), 6.93-6.90 (m, 1H), 6.74- 6.73 (m, 1H), 6.61-6.57 (m, 1H)
    97
    Figure US20190015377A1-20190117-C00194
         		(400 MHz, CDCl3): δ 7.68 (d, 1H), 6.99-6.94 (m, 2H), 6.85-6.84 (m, 1H), 6.71-6.67 (m, 1H)
    98
    Figure US20190015377A1-20190117-C00195
         		(M − H) 456, 458 (400 MHz, CDCl3): δ 8.12 (d, 1H), 7.18 (d, 1H), 7.14-7.11 (m, 1H), 6.97- 6.96 (m, 1H), 6.82-6.79 (m, 1H)
    99
    Figure US20190015377A1-20190117-C00196
         		(M + NH4) 448 (400 MHz, CDCl3): δ 8.12 (d, 1H), 7.69-7.63 (m, 2H), 7.46-7.45 (m, 1H), 7.41-7.38 (m, 1H), 7.11 (d, 1H)
    100
    Figure US20190015377A1-20190117-C00197
         		(M + NH4) 466 (400 MHz, CDCl3): δ 8.17 (d, 1H), 7.39-7.36 (m, 1H), 7.24-7.23 (m, 1H), 7.22 (d, 1H), 7.16-7.13 (m, 1H)
    101
    Figure US20190015377A1-20190117-C00198
         		(400 MHz, CDCl3): δ 10.31 (s, 1H), 7.99 (d, 1H), 7.10 (d, 1H), 7.10-7.07 (m, 1H), 6.96-6.94 (m, 1H), 6.81-6.77 (m, 1H)
    102
    Figure US20190015377A1-20190117-C00199
         		(400 MHz, CDCl3): δ 7.77 (d, 1H), 7.16 (d, 1H), 7.00-6.97 (m, 1H), 6.83- 6.82 (m, 1H), 6.70-6.67 (m, 1H), 5.43 (s, 2H)
    103
    Figure US20190015377A1-20190117-C00200
         		(M − H) 475, 477 (400 MHz, CDCl3): δ 8.11 (d, 1H), 7.06-7.03 (m, 1H), 6.95 (d, 1H), 6.92- 6.91 (m, 1H), 6.77-6.74 (m, 1H), 5.88 (m, 1H), 3.38 (d, 1H), 1.81 (d, 3H)
    104
    Figure US20190015377A1-20190117-C00201
         		(M + H) 474.8/ 476.7 (400 MHz, CDCl3): δ 7.97-7.94 (m, 1H), 7.10-7.07 (m, 1H), 7.01 (d, 1H), 6.80-6.77 (m, 1H), 2.71 (s, 3H)
    105
    Figure US20190015377A1-20190117-C00202
         		(M + H) 424, 426 (400 MHz, CDCl3): δ 8.35 (d, 1H), 7.84 (brd s, 1H), 7.26 (d, 1H), 7.15- 7.12 (m, 1H), 7.04-7.03 (m, 1H), 6.89-6.86 (m, 1H)
    106
    Figure US20190015377A1-20190117-C00203
         		(M + H) 492, 494 (400 MHz, CDCl3): δ 7.95-7.94 (m, 1H), 7.09-7.06 (m, 1H), 7.01 (d, 1H), 6.96-6.95 (m, 1H), 6.80-6.77 (m, 1H), 2.70 (s, 3H)
    107
    Figure US20190015377A1-20190117-C00204
         		(M + H) 476, 478 (400 MHz, CDCl3): δ 8.39 (s, 1H), 8.07 (d, 1H), 7.07 (d, 1H), 7.07-7.04 (m, 1H), 6.94-6.93 (m, 1H), 6.79-6.76 (m, 1H)
    108
    Figure US20190015377A1-20190117-C00205
         		(M + H) 506, 508 (400 MHz, CDCl3): δ 8.07 (d, 1H), 7.06-7.03 (m, 1H), 6.98 (d, 1H), 6.93- 6.92 (m, 1H), 6.78-6.74 (m, 1H), 4.32 (s, 2H), 3.72 (t, 2H), 2.97 (t, 2H)
    109
    Figure US20190015377A1-20190117-C00206
         		(M + H) 476, 478 (400 MHz, CDCl3): δ 8.06 (d, 1H), 7.05-7.02 (m, 1H), 6.97 (d, 1H), 6.91- 6.90 (m, 1H), 6.76-6.72 (m, 1H), 4.25 (s, 2H), 2.57 (s, 3H)
    110
    Figure US20190015377A1-20190117-C00207
         		(M + H) 552, 554 (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.39-7.31 (m, 4H), 7.28-7.23 (m, 1H), 7.05-7.02 (m, 1H), 6.94 (d, 1H), 6.91- 6.89 (m, 1H), 6.75-6.72 (m, 1H), 4.30 (s, 2H), 3.96 (s, 2H).
    111
    Figure US20190015377A1-20190117-C00208
         		(M + NH4) 431, 433 (400 MHz, CDCl3): δ 8.08 (d, 1H), 7.23 (d, 1H), 7.14-7.11 (m, 1H), 6.98- 6.96 (m, 1H), 6.83-6.79 (m, 1H)
    112
    Figure US20190015377A1-20190117-C00209
         		(400 MHz, CDCl3): δ 10.43 (s, 1H), 7.96 (d, 1H), 7.15 (d, 1H), 7.09-7.07 (m, 1H), 6.95-6.94 (m, 1H), 6.80-6.77 (m, 1H)
    113
    Figure US20190015377A1-20190117-C00210
         		(M + H) 432, 434 (400 MHz, CDCl3): δ 8.02 (d, 1H), 7.05-7.02 (m, 1H), 7.01 (d, 1H), 6.91- 6.90 (m, 1H), 6.76-6.72 (m, 1H), 4.22 (s, 2H), 2.56 (s, 3H)
    114
    Figure US20190015377A1-20190117-C00211
         		(M + H) 464, 466 (400 MHz, CDCl3): δ 8.02 (d, 1H), 7.06-7.03 (m, 1H), 7.01 (d, 1H), 6.92 (m, 1H), 6.77-6.73 (m, 1H), 4.64 (t, 1H), 4.52 (t, 1H), 4.34 (s, 2H), 3.11- 3.09 (m, 1H), 3.04-3.02 (m, 1H)
    115
    Figure US20190015377A1-20190117-C00212
         		(M + H) 376, 378 (400 MHz, CDCl3): δ 8.50-8.49 (m, 1H), 8.36-8.35 (m, 1H), 7.89 (d, 1H), 7.43 (t, 1H), 6.93 (d, 1H), 5.62-5.58 (m, 1H), 3.62-3.40 (m, 3H), 3.22 (s, 3H)
    116
    Figure US20190015377A1-20190117-C00213
         		431 (M − H) (400 MHz, CDCl3): δ 8.30 (d, 1 H), 7.93 (m, 1 H), 7.08-7.02 (m, 2 H), 6.93-6.91 (m, 1 H), 6.78-6.74 (m, 1 H)
    117
    Figure US20190015377A1-20190117-C00214
         		404 (M − H)
    118
    Figure US20190015377A1-20190117-C00215
         		422 (M − H)
    119
    Figure US20190015377A1-20190117-C00216
         		379 (M − H) (400 MHz, CDCl3): δ 8.35 (d, 1 H), 8.13 (m, 1 H), 7.16-7.13 (m, 1 H), 7.11 (d, 1 H), 7.03-7.01 (m, 1 H), 6.88-6.85 (m, 1 H)
    120
    Figure US20190015377A1-20190117-C00217
         		369 (M − H)
    121
    Figure US20190015377A1-20190117-C00218
         		411 (M − H) (400 MHz, CDCl3): δ 8.58 (d, 1 H), 8.10-8.07 (m, 1 H), 7.14 (d, 1 H), 7.03-7.00 (m, 1 H), 6.91-6.90 (m, 1 H), 6.77-6.73 (m, 1 H), 3.94 (s, 3 H)
    122
    Figure US20190015377A1-20190117-C00219
         		383 (M − H)
    123
    Figure US20190015377A1-20190117-C00220
    124
    Figure US20190015377A1-20190117-C00221
         		(400 MHz, CDCl3): δ 8.35-8.34 (m, 1 H), 8.09-8.05 (m, 1 H), 7.17-6.90 (m, 4 H), 6.82-6.78 (m, 1 H)
    125
    Figure US20190015377A1-20190117-C00222
         		396 (M − H) (400 MHz, CDCl3): δ 8.95 (d, 1 H), 8.07-8.04 (m, 1 H), 7.21 (br s, 1 H), 7.15-7.12 (m, 1 H), 7.05 (d, 1 H), 7.02-7.01 (m, 1 H), 6.86-6.83 (m, 1 H), 6.01 (br s, 1 H)
    126
    Figure US20190015377A1-20190117-C00223
         		457 (M + HCO2 −) (400 MHz, CDCl3): δ 7.96 (d, 1 H), 7.84 (m, 1 H), 7.02-6.98 (m, 2 H), 6.88-6.87 (m, 1 H), 6.73-6.69 (m, 1 H), 3.74-3.60 (m, 2 H), 2.91-2.87 (m, 2 H), 1.97-1.90 (m, 2 H), 1.40-1.37 (m, 1 H)
    127
    Figure US20190015377A1-20190117-C00224
         		397 (M − H) (400 MHz, CDCl3): δ 8.02 (d, 1 H), 7.86 (m, 1 H), 7.02-6.99 (m, 2 H), 6.89-6.87 (m, 1 H), 6.74-6.70 (m, 1 H), 3.98-3.93 (m, 2 H), 3.06 (t, 2 H), 1.50-1.47 (m, 1 H)
    128
    Figure US20190015377A1-20190117-C00225
         		387 (M − H)
    129
    Figure US20190015377A1-20190117-C00226
         		421 (M − H) (400 MHz, CDCl3): δ 8.39-8.38 (m, 1 H), 7.98-7.95 (m, 1 H), 7.15 (d, 1 H), 7.08-7.05 (m, 1 H), 6.95-6.94 (m, 1 H), 6.80-6.77 (m, 1 H)
    130
    Figure US20190015377A1-20190117-C00227
         		389 (M − H) (400 MHz, CDCl3): δ 8.18 (d, 1 H), 7.83-7.80 (m, 1 H), 7.07 (d, 1 H), 6.97-6.94 (m, 1 H), 6.82-6.81 (m, 1 H), 6.70-6.64 (m, 2 H), 6.54-6.50 (m, 1H), 6.13-6.11 (m, 1H)
    131
    Figure US20190015377A1-20190117-C00228
         		413 (M − H) (400 MHz, CDCl3): δ 8.26 (d, 1 H), 7.89-7.87 (m, 1 H), 7.07 (d, 1 H), 7.04-7.00 (m, 1 H), 6.90-6.89 (m, 1 H), 6.75-6.72 (m, 1 H), 6.21 (t, 1 H)
    132
    Figure US20190015377A1-20190117-C00229
         		404 (M − H) (400 MHz, CDCl3): δ 8.30 (d, 1 H), 7.95-7.93 (m, 1 H), 7.27-7.25 (m, 1 H), 7.15-7.13 (m, 2 H), 7.06-7.03 (m, 1 H), 6.24 (t, 1 H)
    133
    Figure US20190015377A1-20190117-C00230
         		360 (M − H) (400 MHz, CDCl3): δ 8.34 (d, 1 H), 8.15-8.12 (m, 1 H), 7.40-7.37 (m, 1 H), 7.31-7.29 (m, 1 H), 7.22-7.19 (m, 1 H), 7.10 (d, 1 H), 6.26 (t, 1 H)
    134
    Figure US20190015377A1-20190117-C00231
         		351 (M − H) (400 MHz, CDCl3): δ 8.34 (d, 1 H), 8.15-8.12 (m, 1 H), 7.40-7.37 (m, 1 H), 7.31-7.29 (m, 1 H), 7.22-7.19 (m, 1 H), 7.10 (d, 1 H), 6.26 (t, 1 H)
    135
    Figure US20190015377A1-20190117-C00232
         		349 (M − H) (400 MHz, CDCl3): δ 7.86 (d, 1 H), 7.80-7.77 (m, 1 H), 7.01 (d, 1 H), 6.98-6.95 (m, 1 H), 6.84-6.83 (m, 1 H), 6.69-6.65 (m, 1 H), 6.19 (t, 1 H), 2.39 (s, 3 H)
    136
    Figure US20190015377A1-20190117-C00233
         		340 (M − H) (400 MHz, CDCl3): δ 7.93 (d, 1 H), 7.85-7.82 (m, 1 H), 7.23-7.20 (m, 1H), 7.11-7.09 (m, 1 H), 7.04 (d, 1 H), 7.03-6.98 (m, 1 H), 6.21 (t, 1 H), 2.39 (s, 3 H)
    137
    Figure US20190015377A1-20190117-C00234
         		395 (M − H) (400 MHz, CDCl3): δ 8.25 (d, 1 H), 7.89-7.86 (m, 1 H), 7.09 (d, 1 H), 7.00-6.97 (m, 1 H), 6.87-6.86 (m, 1 H), 6.72-6.69 (m, 1 H), 5.17 (d, 2 H)
    138
    Figure US20190015377A1-20190117-C00235
         		377 (M − H)
    139
    Figure US20190015377A1-20190117-C00236
         		370 (M + HCO2 −) (400 MHz, CDCl3): δ 8.29-8.28 (m, 1 H), 8.09-8.06 (m, 1 H), 7.10-7.06 (m, 2 H), 6.97-6.96 (m, 1 H), 6.83-6.79 (m, 1 H), 3.10 (s, 3 H)
    140
    Figure US20190015377A1-20190117-C00237
         		445 (M − H) (400 MHz, CDCl3): δ 8.07 (d, 1 H), 7.03-7.00 (m, 1 H), 6.94 (d, 1 H), 6.87-6.86 (m, 1 H), 6.72-6.68 (m, 1 H), 2.52 (s, 3 H)
    141
    Figure US20190015377A1-20190117-C00238
         		438 (M + H)
    142
    Figure US20190015377A1-20190117-C00239
         		412 (M − H) (400 MHz, CDCl3): δ 8.00 (d, 1 H), 7.26-7.23 (m, 1 H), 7.12-7.11 (m, 1 H), 7.03-6.99 (m, 1 H), 6.97 (d, 1 H), 4.62 (d, 2 H), 2.49 (s, 3 H), 1.96-1.91 (m, 1 H)
    143
    Figure US20190015377A1-20190117-C00240
         		401 (M − H) (400 MHz, CDCl3): δ 8.03 (d, 1 H), 7.03-7.00 (m, 1 H), 6.90 (d, 1 H), 6.88-6.86 (m, 1 H), 6.72-6.69 (m, 1 H), 2.47 (s, 3 H)
    144
    Figure US20190015377A1-20190117-C00241
         		392 (M − H) (400 MHz, CDCl3): δ 8.05 (m, 1 H), 7.29-7.26 (m, 1 H), 7.14 (s, 1 H), 7.05-7.02 (m, 1 H), 6.94-6.91 (m, 1 H), 2.46 (s, 3 H)
    145
    Figure US20190015377A1-20190117-C00242
         		386 (M − H) (400 MHz, CDCl3): δ 10.62 (s, 1 H), 7.97 (d, 1 H), 7.30-7.27 (m, 1 H), 7.16-7.15 (m, 1 H), 7.10 (d, 1 H), 7.07-7.03 (m, 1 H), 2.40 (s, 3 H)
    146
    Figure US20190015377A1-20190117-C00243
         		434 (M + HCO2 −) (400 MHz, CDCl3): δ 8.01 (d, 1 H), 7.26-7.23 (m, 1 H), 7.12-7.11 (m, 1 H), 7.03-6.99 (m, 2 H), 4.99 (d, 2 H), 2.50 (s, 3 H)
    147
    Figure US20190015377A1-20190117-C00244
         		442 (M − H) (400 MHz, CDCl3): δ 8.02 (s, 1 H), 7.99 (d, 1 H), 7.28-7.25 (m, 1 H), 7.16-7.15 (m, 1 H), 7.07-7.05 (m, 1 H), 6.98 (d, 1 H), 6.03 (d, 1 H), 3.85 (s, 3 H), 2.34 (s, 3 H)
    148
    Figure US20190015377A1-20190117-C00245
         		458 (M + H) (400 MHz, CDCl3): δ 8.02 (s, 1 H), 7.99 (d, 1 H), 7.28-7.25 (m, 1 H), 7.16-7.15 (m, 1 H), 7.07-7.03 (m, 1 H), 6.98 (d, 1 H), 6.02 (d, 1 H), 4.31 (q, 2 H), 2.34 (s, 3 H), 1.36 (t, 3 H)
    149
    Figure US20190015377A1-20190117-C00246
         		519 (M + H) (400 MHz, CDCl3): δ 8.01 (d, 1 H), 7.79 (d, 1 H), 7.39-7.29 (m, 5 H), 7.27-7.24 (m, 1 H), 7.14-7.13 (m, 1 H), 7.06-7.03 (m, 1 H), 6.97 (d, 1 H), 6.06-6.02 (m, 2 H), 4.60 (d, 2 H), 2.33 (s, 3 H)
    150
    Figure US20190015377A1-20190117-C00247
         		454 (M + H) (400 MHz, CDCl3): δ 8.47 (d, 1 H), 8.05 (d, 1 H), 7.98 (d, 1 H), 7.31-7.27 (m, 1 H), 7.19-7.18 (m, 1 H), 7.10- 7.07 (m, 1 H), 7.01 (d, 1 H), 6.72 (d, 1 H), 2.42 (s, 3 H)
    151
    Figure US20190015377A1-20190117-C00248
         		468 (M + H) (400 MHz, CDCl3): δ 8.03 (d, 1 H), 7.85 (d, 1 H), 7.30-7.27 (m, 1 H), 7.18-7.17 (m, 1 H), 7.09-7.05 (m, 1 H), 6.99 (d, 1 H), 6.62 (d, 1 H), 2.63 (s, 3 H), 2.40 (s, 3 H)
    152
    Figure US20190015377A1-20190117-C00249
         		349 (M − H) (400 MHz, CDCl3): δ 8.32 (d, 1 H), 7.38-7.35 (m, 1 H), 7.26-7.25 (m, 1 H), 7.18-7.15 (m, 1 H), 6.97 (d, 1 H), 3.30 (s, 3 H)
    153
    Figure US20190015377A1-20190117-C00250
         		396 (M − H) (400 MHz, CDCl3): δ 8.01 (d, 1 H), 7.22 (d, 1 H), 7.09-7.05 (m, 1 H), 6.94-6.92 (m, 1 H), 6.80-6.77 (m, 1 H)
    154
    Figure US20190015377A1-20190117-C00251
         		437 (M − H) (400 MHz, CDCl3): δ 7.44-7.40 (m, 1 H), 7.33 (m, 1 H), 7.15 (d, 1 H), 6.91-6.88 (m, 1 H), 6.74-6.73 (m, 1 H), 6.62-6.58 (m, 1 H), 3.95-3.91 (m, 2 H), 3.44-3.40 (m, 2 H), 1.71-1.69 (m, 1 H)
    155
    Figure US20190015377A1-20190117-C00252
         		428 (M + HCO2 −) (400 MHz, CDCl3): δ 7.85 (d, 1 H), 7.26-7.24 (m, 1 H), 7.17-7.15 (m, 1 H), 7.06-7.03 (m, 1 H), 6.97 (d, 1 H), 6.37 (t, 3 H), 5.68-5.65 (m, 1 H), 3.20-3.11 (m, 2H), 2.94-2.87 (m, 1 H), 2.51-2.41 (m, 1 H), 2.31-2.25 (m, 1 H)
    156
    Figure US20190015377A1-20190117-C00253
         		410 (M + HCO2 −) (400 MHz, CDCl3): δ 7.80 (d, 1 H), 7.56-7.54 (m, 2 H), 7.39-7.30 (m, 2 H), 6.88-6.84 (m, 1 H), 6.38 (t, 1 H), 5.68-5.66 (m, 1 H), 3.22-3.13 (m, 2 H), 2.98-2.90 (m, 1 H), 2.50-2.41 (m, 1 H), 2.32-2.22 (m, 1 H)
    157
    Figure US20190015377A1-20190117-C00254
         		437 (M + HCO2 −)
    158
    Figure US20190015377A1-20190117-C00255
         		473 (M + HCO2 −) (400 MHz, CDCl3): δ 7.90 (d, 1 H), 7.06-7.03 (m, 1 H), 6.99 (d, 1 H), 6.94-6.93 (m, 1 H), 6.78-6.75 (m, 1 H), 6.43 (t, 1 H), 5.52-5.48 (m, 1 H), 3.64-3.43 (m, 2 H), 3.29 (s, 1 H)
    159
    Figure US20190015377A1-20190117-C00256
         		421 (M + HCO2 −) (400 MHz, CDCl3): δ 7.89 (d, 1 H), 7.01 (d, 1 H), 6.74-6.68 (m, 1 H), 6.62-6.58 (m, 2 H), 5.61-5.57 (m, 1H), 3.54-3.40 (m, 3 H), 3.22 (s, 3 H)
    160
    Figure US20190015377A1-20190117-C00257
         		393 (M + H) (400 MHz, CDCl3): δ 7.90-7.87 (m, 1 H), 7.01-6.97 (m, 2 H), 6.88-6.87 (m, 1 H), 6.73-6.69 (m, 1 H), 5.61-5.57 (m, 1 H), 3.57-3.37 (m, 3 H), 3.22 (s, 3 H)
    161
    Figure US20190015377A1-20190117-C00258
         		421 (M + HCO2 −) (400 MHz, CDCl3): δ 7.89 (d, 1 H), 7.01 (d, 1 H), 6.74-6.68 (m, 1 H), 6.62-6.58 (m, 2 H), 5.61-5.57 (m, 1H), 3.54-3.40 (m, 3 H), 3.22 (s, 3 H)
    162
    Figure US20190015377A1-20190117-C00259
         		410 (M + HCO2 −)
    163
    Figure US20190015377A1-20190117-C00260
         		428 (M + HCO2 −) (400 MHz, CDCl3): δ 7.93 (d, 1 H), 7.27-7.24 (m, 1 H), 7.15-7.14 (m, 1 H), 7.07-7.03 (m, 1 H), 7.00 (d, 1 H), 5.63-5.58 (m, 1 H), 3.56-3.35 (m, 3 H), 3.24 (s, 3 H)
    164
    Figure US20190015377A1-20190117-C00261
         		383 (M + H) (400 MHz, CDCl3): δ 7.93-7.91 (m, 1 H), 7.25-7.22 (m, 1 H), 7.14-7.13 (m, 1 H), 7.06-7.02 (m, 1 H), 6.96 (d, 1 H), 4.97-4.93 (m, 1 H), 3.55-3.37 (m, 2 H), 3.32 (s, 3 H)
    165
    Figure US20190015377A1-20190117-C00262
         		383 (M + H) (400 MHz, CDCl3): δ 7.93-7.91 (m, 1 H), 7.25-7.22 (m, 1 H), 7.14-7.13 (m, 1 H), 7.06-7.02 (m, 1 H), 6.96 (d, 1 H), 4.97-4.93 (m, 1 H), 3.55-3.37 (m, 2 H), 3.32 (s, 3 H)
    166
    Figure US20190015377A1-20190117-C00263
         		[M − H + 46]: 442 (400 MHz, CDCl3) δ 7.87 (d, 1H), 7.38 (br s, 1H), 7.16 (br d, 1H), 6.88 (d, 1H), 5.58-5.12 (m, 3H), 3.59-3.44 (m, 3H)
    167
    Figure US20190015377A1-20190117-C00264
         		[M − H + 46]: 462 (400 MHz, CDCl3) δ 7.92 (d, 1H), 7.36-7.33 (m, 1H), 7.32-7.27 (m, 1H), 6.97 (d, 1H), 5.58-5.12 (m, 3H), 3.62- 3.38 (m, 3H)
    168
    Figure US20190015377A1-20190117-C00265
         		[M − H + 46]: 429 (400 MHz, CDCl3) δ 8.01 (d, 1H), 7.09 (d, 1H), 6.77-6.67 (m, 1H), 6.64- 6.61 (m, 2H), 6.47 (t, 1H), 5.21 (d, 2H), 2.70 (t, 1H)
    169
    Figure US20190015377A1-20190117-C00266
         		(400 MHz, CDCl3): δ 8.30 (d, 1H), 7.89 (d, 1H), 7.54 (d, 1H), 7.26 (s, 1H), 6.99 (m, 2H)
    170
    Figure US20190015377A1-20190117-C00267
         		(400 MHz, CDCl3): δ 8.30 (s, 1H), 7.88 (d, 1H), 7.21-7.31 (m, 3H), 6.90 (d, 1H)
    171
    Figure US20190015377A1-20190117-C00268
         		(400 MHz, d6-DMSO): δ 8.40 (d, 1H), 8.02 (d, 1H), 7.45 (d, 1H), 7.35 (t, 1H), 7.20 (d, 1H), 6.95 (d, 1H), 2.13 (s, 3H)
    172
    Figure US20190015377A1-20190117-C00269
         		(400 MHz, CDCl3): δ 8.30 (d, 1H), 7.93 (d, 1H), 7.31 (d, 1H), 7.04 (m, 3H)
    173
    Figure US20190015377A1-20190117-C00270
         		(400 MHz, CDCl3): δ 8.26 (d, 1H), 7.81 (d, 1H), 6.95 (s, 1H), 6.91 (d, 1H), 6.74 (s, 2H), 2.35 (s, 6H)
    174
    Figure US20190015377A1-20190117-C00271
         		(400 MHz, CDCl3): δ 8.29 (d, 1H), 7.84 (d, 1H), 7.22-7.27 (m, 2H), 7.06 (s, 1H), 6.78 (d, 1H), 2.16 (s, 3H)
    175
    Figure US20190015377A1-20190117-C00272
         		(400 MHz, d6-DMSO): δ 8.40 (s, 1H), 8.03 (d, 1H), 7.58 (m, 2H), 7.23 (m, 1H), 7.11 (d, 1H)
    176
    Figure US20190015377A1-20190117-C00273
         		(400 MHz, d6-DMSO): δ 8.30 (s, 1H), 7.88 (d, 1H), 7.27-7.32 (m, 1H), 7.08- 7.14 (m, 2H), 6.85 (d, 1H)
    177
    Figure US20190015377A1-20190117-C00274
         		(400 MHz, CDCl3): δ 8.29 (d, 1 H), 7.87 (m, 1 H), 7.06 (d, 1H), 7.02 (d, 1H), 6.94 (d, 1H), 6.77 (m, 1H), 4.75 (d, 2H), 1.83 (t, 1H)
    178
    Figure US20190015377A1-20190117-C00275
         		391 (M − H) (400 MHz, CDCl3): δ 8.18 (d, 1H), 7.38-7.35 (m, 1H), 7.29-7.27 (m, 1H), 7.21-7.18 (m, 1H), 7.07-7.02 (m, 1H), 6.90 (d, 1H), 6.56-6.47 (m, 1H), 6.22 (t, 1H), 2.08-2.06 (m, 1H)
    179
    Figure US20190015377A1-20190117-C00276
         		(400 MHz, CDCl3): δ 8.13 (d, 1H), 7.08-7.05 (m, 1H), 6.95-6.93 (m, 2H), 6.79-6.76 (m, 1H)
    180
    Figure US20190015377A1-20190117-C00277
         		359, 361 (M + H) (400 MHz, CDCl3): δ 8.33 (d, 1H), 7.09 (m, 1H), 6.97-6.95 (m, 1H), 6.94 (d, 1H), 6.81 (m, 1H), 3.32 (s, 3H), 2.94 (br s, 1H)
    181
    Figure US20190015377A1-20190117-C00278
         		359, 361 (M + H) (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.23 (m, 1H), 7.12-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.07 (d, 1H), 5.54- (m, 1H), 3.68 (m, 1H), 3.26 (s, 3H), 3.20 (m, 1H), 2.97-2.86 (m, 1H), 2.63-2.45 (m, 1H), 2.35-2.25 (m, 1H)
    182
    Figure US20190015377A1-20190117-C00279
         		(M + H) 410/ 412
    183
    Figure US20190015377A1-20190117-C00280
         		478 mCi
    184
    Figure US20190015377A1-20190117-C00281
         		[M + H] 394 (400 MHz, CDCl3): δ 8.47 (d, 1H), 8.35 (d, 1H), 7.82 (d, 1H), 7.45 (t, 1H), 6.88 (d, 1H), 5.64-5.59 (m, 1H), 3.30-3.15 (m, 2H), 3.02-2.93 (m, 1H) 2.46-2.26 (m, 2H)
    185
    Figure US20190015377A1-20190117-C00282
         		[M − H] 436 (400 MHz, CDCl3): δ 7.95 (d, 1H), 7.35-7.31 (m, 1H), 7.26-7.23 (m, 1H), 7.15-7.11 (m, 1H), 6.99 (d, 1H), 5.46- 5.39 (m, 1H), 3.63-3.41 (m, 2H), 3.36 (d, 1H)
    186
    Figure US20190015377A1-20190117-C00283
         		[M + H] 430 (400 MHz, CDCl3): δ 8.55 (d, 1H), 8.40 (d, 1H), 7.91 (d, 1H), 7.52 (t, 1H), 6.94 (d, 1H), 5.46-5.40 (m, 1H), 3.85 (d, 1H), 3.66-3.47 (m, 2H)
    187
    Figure US20190015377A1-20190117-C00284
         		[M + H] 394 (400 MHz, CDCl3): δ 8.51 (d, 1H), 8.37 (d, 1H), 7.90 (d, 1H), 7.48 (t, 1H), 6.93 (d, 1H), 5.61-5.11 (m, 3H), 3.94 (d, 1H), 3.62-3.42 (m, 2H)
    188
    Figure US20190015377A1-20190117-C00285
         		[M − H + 46] 457 (400 MHz, CDCl3): δ 7.89 (d, 1H), 6.94 (d, 1H), 6.82-6.71 (m, 2H), 5.59- 5.11 (m, 3H), 3.59-3.38 (m, 3H)
    189
    Figure US20190015377A1-20190117-C00286
         		[M + H] 365 (400 MHz, CDCl3): δ 7.88-7.80 (m, 1H), 6.97 (d, 1H), 6.72-6.65 (m, 1H), 6.63-6.55 (m, 2H), 5.83-5.76 (m, 1H), 3.57 (s, 1H), 3.51 (s, 3H), 3.18-3.07 (m, 1H), 2.93-2.79 (m, 1H), 2.60-2.47 (m, 1H), 2.23-2.11 (m, 1H)
    190
    Figure US20190015377A1-20190117-C00287
         		[M + H] 340 (400 MHz, CDCl3): δ 7.89-7.81 (m, 1H), 6.99-6.94 (m, 1H), 6.66-6.60 (m, 1H), 6.57-6.51 (m, 2H), 5.66-5.59 (m, 1H), 3.28 (s, 3H), 3.24 (s, 1H), 3.15- 3.01 (m, 1H), 2.87-2.71 (m, 1H), 2.55-2.41 (m, 1H), 2.27-2.13 (m, 1H)
    191
    Figure US20190015377A1-20190117-C00288
         		[M + H] 401 (400 MHz, CDCl3): δ 7.98-7.91 (m, 1H), 7.04-7.01 (m, 1H), 6.80-6.73 (m, 1H), 6.69-6.61 (m, 2H), 5.73-5.63 (m, 1H), 3.60 (s, 1H), 3.58-3.40 (m, 5H)
    192
    Figure US20190015377A1-20190117-C00289
         		[M + H] 376 (400 MHz, CDCl3): δ 7.96-7.89 (m, 1H), 7.03-6.98 (m, 1H), 6.73-6.66 (m, 1H), 6.63-6.55 (m, 2H), 5.62-5.56 (m, 1H), 5.47-5.41 (m, 1H), 3.57-3.30 (m, 2H), 3.28 (s, 3H) 3.24-2.88 (m, 1H)
    193
    Figure US20190015377A1-20190117-C00290
         		(400 MHz, CDCl3) δ 8.18 (d, 1H), 7.41-7.39 (m, 1H), 7.30-7.26 (m, 1H), 7.13-7.05 (m, 2H), 6.91 (t, 1H), 3.67 (t, 2H)
    194
    Figure US20190015377A1-20190117-C00291
         		(M + HCOOH − H): 517, 519 (400 MHz, CDCl3) δ 7.86 (d, 1H), 7.37-7.35 (m, 1H), 7.25-7.21 (m, 1H), 7.08-7.04 (m, 1H), 6.86 (d, 1H), 6.41 (t, 1H), 5.51-5.47 (m, 1H), 3.63-3.47 (m, 2H), 3.25 (d, 1H)
    195
    Figure US20190015377A1-20190117-C00292
         		(400 MHz, CDCl3) δ 8.16 (d, 1H), 7.32 (q, 1H), 7.13 (d, 1H), 7.06-7.02 (m, 1H), 6.93-6.91 (m, 1H), 6.90 (t, 1H), 3.67 (t, 2H)
    196
    Figure US20190015377A1-20190117-C00293
         		(M + HCOOH − H) 457 (400 MHz, CDCl3) δ 7.86 (d, 1H), 7.30-7.24 (m, 1H), 7.02-6.97 (m, 1H), 6.89-6.86 (m, 2H), 6.41 (t, 1H), 5.51- 5.47 (m, 1H), 3.63-3.47 (m, 2H), 3.27 (d, 1H)
    197
    Figure US20190015377A1-20190117-C00294
         		(400 MHz, CDCl3) δ 8.14 (d, 1H), 7.15-7.05 (m, 2H), 6.99-6.91 (m, 2H), 6.92 (t, 1H), 3.67 (t, 2H), 2.33 (m, 3H)
    198
    Figure US20190015377A1-20190117-C00295
         		(M + HCOOH − H) 453 (400 MHz, CDCl3) δ 7.82 (d, 1H), 7.09 (t, 1H), 6.93-6.88 (m, 2H), 6.82 (d, 1H), 6.40 (t, 1H), 5.48 (m, 1H), 3.63-3.48 (m, 2H), 3.25 (d, 1H), 2.31 (m, 3H)
    199
    Figure US20190015377A1-20190117-C00296
         		(400 MHz, CDCl3) δ 8.20 (d, 1H), 7.47-7.38 (m, 3H), 7.11 (d, 1H), 6.92 (t, 1H), 3.68 (t, 2H)
    200
    Figure US20190015377A1-20190117-C00297
         		(M + HCOOH − H) 464 (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.41-7.32 (m, 3H), 6.85 (d, 1H), 6.43 (t, 1H), 5.57-5.48 (m, 1H), 3.59-3.49 (m, 2H), 3.29 (d, 1H)
    201
    Figure US20190015377A1-20190117-C00298
         		(M + HCOOH − H) 401 (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.28 (s, 1H), 7.94 (d, 1H), 7.33 (d, 1H), 5.61-5.58 (m, 1H), 3.57 (d, 1H), 3.51-3.28 (m, 2H), 3.24 (s, 3H), 2.44 (s, 3H)
    202
    Figure US20190015377A1-20190117-C00299
         		(M + HCOOH − H) 428 (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.28-7.26 (m, 1H), 7.18 (brd s, 1H), 7.08-7.03 (m, 2H), 6.64-6.47 (m, 1H), 6.34 (t, 1H), 3.23-3.14 (m, 1H), 3.04- 2.95 (m, 1H), 2.57-2.42 (m, 2H)
    203
    Figure US20190015377A1-20190117-C00300
         		(400 MHz, CDCl3) δ 7.78-7.75 (m, 1H), 7.05-7.02 (m, 1H), 7.00-6.98 (m, 1H), 6.93-6.92 (m, 1H), 6.78-6.75 (m, 1H)
    204
    Figure US20190015377A1-20190117-C00301
         		350, 352, 354 (M − H) (400 MHz, CDCl3): δ 7.71 (d, 1H), 7.38 (t, 1H), 7.31-7.26 (m, 1H), 7.14 (t, 1H), 7.03-7.00 (m, 1H), 6.91 (d, 1H)
    205
    Figure US20190015377A1-20190117-C00302
         		(400 MHz, CDCl3): δ 7.79 (d, 1H), 7.18 (d, 1H), 7.09 (s, 1H), 6.98 (m, 2H), 5.65 (m, 1H), 3.69 (d, 1H), 3.29 (m, 2H), 3.08 (m, 1H), 2.83 (m, 1H), 2.45 (m, 1H), 2.24 (m, 1H), 1.36 (t, 3H)
    206
    Figure US20190015377A1-20190117-C00303
         		442 (M + HCO2) (400 MHz, CDCl3): δ 7.86 (m, 1 H), 7.27-7.24 (m, 1 H), 7.16-7.14 (m, 1 H), 7.07-7.04 (m, 1 H), 6.99 (d, 1 H), 5.55-5.51 (m, 1 H), 3.61-3.27 (m, 5 H), 1.35 (t, 3 H)
    207
    Figure US20190015377A1-20190117-C00304
         		419 (M + H) (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.32-7.28 (m, 1H), 7.22-7.19 (m, 1H), 7.12-7.07 (m, 1H), 6.94 (d, 1H), 6.83 (t, 1H), 4.91 (d, 1H), 3.60-3.40 (m, 2H), 1.91 (br s, 2H)
    208
    Figure US20190015377A1-20190117-C00305
         		(400 MHz, CDCl3): δ 7.73 (d, 1H), 7.18 (d, 1H), 7.08 (s, 1H), 6.95 (m, 2H), 5.62 (m, 1H), 4.02 (m, 1H), 3.77 (s, 1H), 3.07 (m, 1H), 2.81 (m, 1H), 2.61 (m, 2H), 2.45 (m 1H), 2.26 (m, 3H), 2.06 (m, 2H)
    209
    Figure US20190015377A1-20190117-C00306
         		468 (M + HCO2) (400 MHz, CDCl3): δ 7.81 (d, 1 H), 7.27-7.24 (m, 1 H), 7.15-7.14 (m, 1 H), 7.06-7.03 (m, 1 H), 6.96 (d, 1 H), 5.50-5.45 (m, 1 H), 3.70 (d, 1 H), 3.55-3.34 (m, 2 H), 2.67-2.50 (m, 2 H), 2.29-2.17 (m, 2 H), 2.08-2.01 (m, 2 H)
    210
    Figure US20190015377A1-20190117-C00307
         		398 (M + H) (400 MHz, CDCl3): δ 7.95 (d, 1H), 7.24 (d, 1H), 7.13 (br s, 1H), 7.05- 7.01 (m, 1H), 6.99 (d, 1H), 5.31 (d, 1H), 3.78 (s, 3H), 3.53-3.32 (m, 2H), 3.19 (s, 3H)
    211
    Figure US20190015377A1-20190117-C00308
         		354 (M − H) (400 MHz, CDCl3): δ 7.75 (d, 1H), 6.94 (d, 1H), 6.65-6.60 (m, 1H), 6.54- 6.52 (m, 2H), 5.77-5.71 (m, 1H), 5.02-4.95 (m, 1H), 3.23-3.18 (m, 1H), 3.12-3.04 (m, 1H), 2.84-2.70 (m, 1H), 2.65 (d, 3H), 2.57-2.47 (m, 1H), 2.19- 2.11 (m, 1H)
    212
    Figure US20190015377A1-20190117-C00309
         		(400 MHz, CDCl3): δ 7.77 (d, 1H), 7.05-7.26 (m, 4H), 6.75 (d, 1H), 5.62 (m, 1H), 3.17-3.30 (m, 2H), 2.98-3.07 (m, 1H), 2.40-2.47 (m, 1H), 2.28-2.37 (m, 1H)
    213
    Figure US20190015377A1-20190117-C00310
         		(400 MHz, CDCl3): δ 7.22-7.25 (m, 1H), 7.08 and 7.12 (m 1H), 6.98-7.04 (m 1H), 6.80 (s, 1H), 5.58 and 5.78 (m 1H), 3.69 (d, 1H), 3.20 and 3.23 (s, 3H), 3.08-3.47 (m, 2H), 2.68 (s, 3H)
    214
    Figure US20190015377A1-20190117-C00311
         		(400 MHz, d6-DMSO): 7.87 (d, 1H), 7.51-7.64 (m, 2H), 7.11-7.16 (m, 1H), 6.96 (d, 1H), 5.51 (m, 1H), 5.30 (d, 1H), 3.04-3.31 (m, 1H), 2.87-2.95 (m, 1H), 2.11-2.30 (m, 1H), 1.99-2.09 (m, 1H)
    215
    Figure US20190015377A1-20190117-C00312
         		(400 MHz, CDCl3): 7.92 (d, 1H), 7.27 (m, 2H), 7.08 (d, 1H), 6.99 (d, 1H), 5.63 (dd, 1H), 4.92 (d, 1H), 4.65 (d, 1H), 3.34-3.49 (m, 2H), 3.21 (s, 1H)
    216
    Figure US20190015377A1-20190117-C00313
         		(400 MHz, CDCl3): 7.83 (d. 1H), 7.26-7.38 (m, 3H), 6.81 (d, 1H), 5.64 (dd, 1H), 3.16-3.25 (m, 2H), 3.00-3.04 (m, 1H), 2.34-2.42 (m, 2H)
    217
    Figure US20190015377A1-20190117-C00314
         		418 (M + HCO2 −) (400 MHz, CDCl3): 7.88 (d, 1H), 7.17 (d, 1H), 7.09 (s, 1H), 7.06 (m, 2H), 5.07 (d, 1H), 3.20 (m, 5H), 2.60 (d, 1H), 1.18-1.32 (m, 2H), 0.68-0.87 (m, 2H)
    218
    Figure US20190015377A1-20190117-C00315
         		(400 MHz, CDCl3): 7.80 (d, 1H), 7.18-7.23 (m, 2H), 6.97-7.01 (m, 1H), 6.80 (d, 1H), 5.63 (m 1H), 3.16-3.29 (m, 2H), 2.96-3.05 (m 1H), 2.29-2.46 (m, 2H)
    219
    Figure US20190015377A1-20190117-C00316
         		(400 MHz, d6-DMSO): δ 7.85 (d, 1H), 7.67 (m, 1H), 7.46 (d, 1H), 6.85 (d, 1H), 5.38 (dd, 1H), 3.40-3.49 (m, 2H), 3.40 (s, 3H)
    220
    Figure US20190015377A1-20190117-C00317
    221
    Figure US20190015377A1-20190117-C00318
         		445, 447 (M − H) (400 MHz, CDCl3): δ 7.97 (d, 1 H), 7.28-7.22 (m, 2 H), 7.02 (d, 1 H), 6.87 (d, 1 H), 5.43-5.39 (m, 1 H), 3.64-3.47 (m, 2 H), 3.26 (d, 1 H)
    222
    Figure US20190015377A1-20190117-C00319
         		392 (M + HCO2 −) (400 MHz, CDCl3): δ 7.84 (d, 1 H), 7.19-7.17 (m, 1 H), 7.08 (s, 1 H), 7.00-6.97 (m, 2 H), 5.71-5.68 (m, 1 H), 3.64 (d, 1 H), 3.21 (s, 3 H), 3.12- 3.04 (m, 1 H), 2.84-2.76 (m, 1 H), 2.52-2.43 (m, 1 H), 2.27-2.19 (m, 1 H)
    223
    Figure US20190015377A1-20190117-C00320
         		428 (M + HCO2 −) (400 MHz, CDCl3): δ 7.93 (d, 1 H), 7.27-7.24 (m, 1 H), 7.15-7.14 (m, 1 H), 7.07-7.03 (m, 1 H), 7.00 (d, 1 H), 5.63-5.58 (m, 1 H), 3.56-3.35 (m, 3 H), 3.24 (s, 3 H)
    224
    Figure US20190015377A1-20190117-C00321
         		399 (M + H) (400 MHz, CDCl3): δ 7.87 (d, 1 H), 7.40 (s, 1 H), 7.36 (s, 1 H), 7.08 (d, 1 H), 5.42-5.38 (m, 1 H), 3.94 (s, 3 H), 3.59-3.52 (m, 2 H), 3.21 (d, 1 H)
    225
    Figure US20190015377A1-20190117-C00322
         		401 (M − H) (400 MHz, CDCl3): δ 8.82 (d, 1 H), 8.70 (d, 1 H), 7.95 (d, 1 H), 7.71-7.69 (m, 1 H), 6.94 (d, 1 H), 5.64-5.59 (m, 1 H), 5.46-5.31 (m, 1 H), 3.36-3.27 (m, 2 H), 3.19 (d, 1 H)
    226
    Figure US20190015377A1-20190117-C00323
         		428 (M + HCO2 −) (400 MHz, CDCl3): δ 7.93 (d, 1 H), 7.27-7.24 (m, 1 H), 7.15-7.14 (m, 1 H), 7.07-7.03 (m, 1 H), 7.00 (d, 1 H), 5.63-5.58 (m, 1 H), 3.56-3.35 (m, 3 H), 3.24 (s, 3 H)
    227
    Figure US20190015377A1-20190117-C00324
         		428 (M + HCO2 −) (400 MHz, CDCl3): δ 7.93 (d, 1 H), 7.27-7.24 (m, 1 H), 7.15-7.14 (m, 1 H), 7.07-7.03 (m, 1 H), 7.00 (d, 1 H), 5.63-5.58 (m, 1 H), 3.56-3.35 (m, 3 H), 3.24 (s, 3 H)
    228
    Figure US20190015377A1-20190117-C00325
         		436 (M − H) (400 MHz, CDCl3): δ 7.90 (d, 1 H), 7.42-7.30 (m, 3 H), 6.86 (d, 1 H), 5.42 (dd, 1H) 3.58-3.47 (m, 2H) 3.32 (d, 1 H)
    229
    Figure US20190015377A1-20190117-C00326
         		432 (M + HCO2 −) (400 MHz, CDCl3): δ 7.92 (d, 1 H), 7.26-7.24 (m, 1 H), 7.15 (s, 1 H), 7.06-7.03 (m, 1 H), 7.01 (d, 1 H), 3.56-3.35 (m, 3 H)
    230
    Figure US20190015377A1-20190117-C00327
         		411 (M − H) (400 MHz, CDCl3): δ 7.85 (d, 1 H), 7.19-7.08 (m, 4 H), 6.83 (d, 1 H), 5.42 (dd, 1 H), 3.65-3.49 (m, 2 H), 3.25 (dd, 1 H)
    231
    Figure US20190015377A1-20190117-C00328
         		383 (M + NH4 +) (400 MHz, CDCl3): δ 7.92 (d, 1 H), 7.21-7.20 (m, 1H) 7.12-7.11 (m, 1 H), 7.03-6.98 (m, 2 H), 5.71-5.65 (m, 1 H), 5.46-5.33 (m, 1 H), 3.66 (dd, 1 H), 3.31 (s, 3 H), 3.27-3.05 (m, 2 H)
    232
    Figure US20190015377A1-20190117-C00329
         		383 (M + NH4 +) (400 MHz, CDCl3): δ 7.92 (d, 1 H), 7.21-7.20 (m, 1 H), 7.12-7.11 (m, 1 H), 7.03-6.98 (m, 2 H), 5.71-5.65 (m, 1 H), 5.46-5.33 (m, 1 H), 3.66 (dd, 1 H), 3.31 (s, 3 H), 3.27-3.05 (m, 2 H)
    233
    Figure US20190015377A1-20190117-C00330
         		429 (M − H) (400 MHz, CDCl3): δ 7.88 (d, 1 H), 7.32-7.25 (m, 1 H), 7.03-6.98 (m, 1 H), 6.91-6.86 (m, 2 H), 5.42 (dd, 1 H), 3.64-3.47 (m, 2 H), 3.22 (d, 1 H)
    234
    Figure US20190015377A1-20190117-C00331
         		444 (M + HCO2 −) (400 MHz, CDCl3): δ 7.92 (d, 1 H), 7.52-7.51 (m, 1 H), 7.32-7.31 (m, 1 H), 7.25-7.24 (m, 1 H), 6.98 (d, 1 H), 5.62-5.58 (m, 1 H), 3.56-3.35 (m, 3 H), 3.24 (s, 3 H)
    235
    Figure US20190015377A1-20190117-C00332
         		419 (M − H) (400 MHz, CDCl3): δ 8.84 (d, 1 H), 8.73 (d, 1 H), 7.96 (d, 1 H), 7.75-7.74 (m, 1 H), 6.95 (d, 1 H), 5.45 (dd, 1 H), 3.64-3.48 (m, 2 H), 3.31 (d, 1 H)
    236 419 (M + NH4) (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.62-7.57 (m, 2H), 7.42 (s, 1H), 7.39- 7.34 (m, 1H), 6.90 (d, 1H), 6.44 (t, 1H), 5.51 (dd, 1H), 5.63-5.45 (m, 2H), 3.37 (d, 1H)
    237
    Figure US20190015377A1-20190117-C00333
    238
    Figure US20190015377A1-20190117-C00334
         		[M + H] 435 (400 MHz, CDCl3): δ 10.35 (br s, 1H), 8.14 (s, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 7.51 (d, 1H), 7.21-7.17 (m, 1H), 6.82 (d, 1H), 5.44 (d, 1H), 3.70- 3.57 (m, 2H), 3.40 (br s, 1H)
    239
    Figure US20190015377A1-20190117-C00335
         		[M + formic acid] 459 (400 MHz, CDCl3): δ 7.78 (d, 1H), 7.68 (d, 1H), 7.44 (d, 1H), 7.37 (t, 1H), 7.23 (d, 1H), 7.00 (d, 1H), 6.71 (d, 1H), 5.73-5.68 (m, 1H), 5.38-5.12 (m, 2H), 3.37-3.33 (m, 1H), 3.32-3.22 (m, 1H) 3.07-2.99 (m, 1H), 2.56-2.46 (m, 1H), 2.35-2.24 (m, 1H)
    240
    Figure US20190015377A1-20190117-C00336
         		[M + H] 408 (400 MHz, CD3OD): δ 8.01 (d, 1H), 7.54-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.40-7.36 (m, 1H), 7.20-7.14 (m, 1H), 5.56 (d, 1H), 3.78-3.61 (m, 1H), 3.62 (s, 3H), 3.55-3.47 (m, 1H)
    241
    Figure US20190015377A1-20190117-C00337
         		[M + 1] 453 (400 MHz, CDCl3): δ 10.55 (br s, 1H), 7.94 (d, 1H), 7.83 (d, 1H), 7.16- 7.10 (m, 1H), 6.86 (d, 1H), 6.83-6.78 (m, 1H), 5.46 (d, 1H), 3.72-3.59 (m, 2H), 3.34 (br s, 1H)
    242
    Figure US20190015377A1-20190117-C00338
         		[M + formic acid] 459 (400 MHz, CDCl3): δ 7.83-7.76 (m, 2H), 7.47 (d, 1H), 7.40 (t, 1H), 7.21- 7.19 (m, 1H), 7.05 (d, 1H), 6.76 (d, 1H), 5.61-5.11 (m, 3H), 3.71-3.57 (m, 2H), 3.30 (br s, 1H)
    243
    Figure US20190015377A1-20190117-C00339
         		[M + H] 435 (400 MHz, CDCl3): δ 10.45 (br s, 1H), 7.93 (s, 1H), 7.84 (d, 1H), 7.48- 7.41 (m, 2H), 6.92 (d, 1H), 6.86 (dd, 1H), 5.46 (d, 1H), 3.72-3.59 (m, 2H), 3.44 (br s, 1H)
    244
    Figure US20190015377A1-20190117-C00340
         		[M + H] 453 (400 MHz, CDCl3): δ 10.35 (br s, 1H), 7.96 (s, 1H), 7.84 (d, 1H), 7.47- 7.43 (m, 1H), 7.39-7.33 (m, 1H), 6.81 (dd, 1H), 5.46 (d, 1H), 3.74-3.59 (m, 2H), 3.36 (br s, 1H)
    245
    Figure US20190015377A1-20190117-C00341
         		[M + H] 408 (400 MHz, CDCl3): δ 8.01 (d, 1H), 7.32-7.28 (m, 1H), 7.22-7.20 (m, 1H), 7.14-7.09 (m, 1H), 7.02 (d, 1H), 5.67 (d, 1H), 4.22 (br s, 1H), 3.65 (s, 3H), 3.60-3.40 (m, 2H)
    246
    Figure US20190015377A1-20190117-C00342
         		[M + H] 435 (400 MHz, CDCl3): δ 8.15 (d, 1H), 7.82 (d, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 6.99 (d, 1H), 6.88-6.81 (m, 2H), 5.43 (d, 1H), 3.76-3.63 (m, 2H), 3.51 (br s, 1H)
    247
    Figure US20190015377A1-20190117-C00343
         		(M + H) 385 (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.27-7.23 (m, 1H), 7.16-7.13 (m, 1H), 7.07-6.98 (m, 2H), 3.56-3.34 (m, 3H), 3.24 (s, 3H)
    248
    Figure US20190015377A1-20190117-C00344
         		(M − H) 402, 404 (400 MHz, CDCl3): δ 7.70 (d, 1H), 7.20-7.15 (m, 1H), 7.10-7.08 (m, 1H), 7.02 (dt, 1H), 6.86 (d, 1H), 3.50 (t, 2H)
    249
    Figure US20190015377A1-20190117-C00345
         		(M + NH4) 397 (400 MHz, CDCl3): δ 7.83 (d, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 6.94 (d, 1H), 6.65 (t, 1H), 5.72- 5.68 (m, 1H), 3.64 (br d, 1H), 3.22 (s, 3H), 3.14-3.04 (m, 1H), 2.81 (ddd, 1H), 2.54-2.43 (m, 1H), 2.28-2.19 (m, 1H)
    250
    Figure US20190015377A1-20190117-C00346
         		414 (M + H) (400 MHz, CDCl3): δ 7.90 (d, 1 H), 7.27-7.24 (m, 1 H), 7.16 (br s, 1 H), 7.06 (d, 1 H), 7.00 (d, 1 H), 5.62 (d, 1 H), 4.00-4.16 (m, 2 H), 3.30-3.74 (m, 4H)
    251
    Figure US20190015377A1-20190117-C00347
         		392 (M + H) (400 MHz, CDCl3): δ 7.82 (d, 1H), 6.97 (d, 1H), 6.69 (t, 1H), 6.64-6.54 (m, 2H), 5.62 (d, 1H), 5.04-4.96 (m, 1H), 3.50-3.30 (m, 2H), 2.64 (d, 3H)
    252
    Figure US20190015377A1-20190117-C00348
         		383 (M − H) (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.26-7.20 (m, 1H), 7.12 (br s, 1H), 7.04-6.96 (m, 2H), 5.74-5.66 (m, 1H), 5.28 (br s, 2H), 3.50-3.32 (m, 2H)
    253
    Figure US20190015377A1-20190117-C00349
         		368 (M + H) (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.58 (s, 1H), 7.85 (d, 1H), 7.58 (s, 1H), 6.89 (d, 1H), 5.54 (d, 2H), 3.50- 3.24 (m, 2H)
    254
    Figure US20190015377A1-20190117-C00350
         		399 (M + H) (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.25-7.18 (m, 1H), 7.13 (brs, 1H), 7.08-6.92 (m, 2H), 5.68-5.56 (m, 1H), 5.05 (br s, 1H), 3.58-3.30 (m, 2H), 2.65 (s, 3H)
    255
    Figure US20190015377A1-20190117-C00351
         		322 (M − H) (400 MHz, CDCl3): δ 8.06 (d, 1H), 6.97-6.93 (m, 1H), 6.85-6.83 (m, 1H), 6.69-6.66 (m, 1H), 3.37 (d, 1H), 3.20- 3.12 (m, 1H), 2.93-2.85 (m, 1H), 2.52-2.43 (m, 1H), 2.32-2.25 (m, 1H)
    256
    Figure US20190015377A1-20190117-C00352
         		378 (M + H) (400 MHz, CDCl3): δ 7.89 (d, 1H), 6.98 (d, 1H), 6.72-6.60 (m, 1H), 6.62- 6.52 (m, 2H), 5.72-5.64 (m, 1H), 5.29 (br s, 2H), 3.56-3.34 (m, 2H)
    257
    Figure US20190015377A1-20190117-C00353
         		340 (M − H) (400 MHz, CDCl3): δ 7.82 (d, 1H), 6.95 (d, 1H), 6.62 (t, 1H), 6.55-6.50 (m, 2H), 5.84-5.80 (m, 1H), 5.34 (br s, 2H), 3.11-3.03 (m, 1H), 2.83-2.75 (m, 1H), 2.61-2.52 (m, 1H), 2.19-2.10 (m, 1H)
    258
    Figure US20190015377A1-20190117-C00354
         		(M − H) 399 (400 MHz, CDCl3): δ 7.96 (d, 1H), 7.27-7.22 (m, 1H), 7.18-7.15 (m, 1H), 7.07-7.03 (m, 1H), 6.97 (d, 1H),5.59 (d, 1H), 4.59 (s, 1H), 3.89 (s, 1H), 3.18 (dt, 1H), 2.96 (ddd, 1H), 2.43- 2.27 (m, 2H)
    259
    Figure US20190015377A1-20190117-C00355
         		(M − H) 399 (400 MHz, CDCl3): δ 8.01 (d, 1H), 7.25-7.21 (m, 1H), 7.17-7.14 (m, 1H), 7.06-7.01 (m, 1H), 6.96 (d, 1H), 5.78- 5.73 (m, 1H), 3.96-3.93 (m, 1H), 3.73 (s, 1H), 3.13 (dt, 1H), 2.87 (ddd, 1H), 2.52-2.41 (m, 1H), 2.31-2.23 (m, 1H)
    260
    Figure US20190015377A1-20190117-C00356
         		(M + H) 446, 448 (400 MHz, CDCl3): δ 8.17 (s, 1H), 8.03 (s, 1H), 7.99 (d, 1H), 7.11 (d, 1H), 7.08 (s, 1H), 5.44 (dd, 1H), 3.64- 3.42 (m, 3H)
    261
    Figure US20190015377A1-20190117-C00357
         		(M + H) 471 (400 MHz, CDCl3): δ 7.95 -7.87 (m, 2H), 6.95 (d, 1H), 6.77 (dd, 1H), 5.46 (d, 1H), 3.66-3.58 (m, 2H), 3.25 (m, 1H)
    262
    Figure US20190015377A1-20190117-C00358
         		(M + H) 453 (400 MHz, CDCl3): δ 7.91-7.88 (m, 2H), 7.12 (d, 1H), 7.03 (d, 1H), 6.66 (d, 1H), 6.46 (d, 1H), 3.66-3.56 (m, 2H), 3.26 (br s, 1H)
    263
    Figure US20190015377A1-20190117-C00359
         		(M + H) 435 (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.84 (d, 1H), 7.48-7.42 (m, 2H), 6.92 (d, 1H), 6.86 (d, 1H), 5.46 (d, 1H), 3.68-3.59 (m, 2H), 3.28 (br s, 1H)
    264
    Figure US20190015377A1-20190117-C00360
         		(M + H) 453 (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.84 (d, 1H), 7.13 (t, 1H), 6.81 (d, 1H), 6.86 (d, 1H), 5.46 (d, 1H), 3.68- 3.69 (m, 2H), 3.29 (br s, 1H)
    265
    Figure US20190015377A1-20190117-C00361
         		419 (M + H) (400 MHz, CDCl3): δ 7.90 (d, 1 H), 7.30-7.28 (m, 1 H), 7.19 (br s, 1 H), 7.10-7.06 (m, 1 H), 6.92 (d, 1 H), 5.44-5.26 (m, 1 H), 4.93 (t, 1 H), 3.40-3.24 (m, 2 H), 1.95 (br s, 2H)
    266
    Figure US20190015377A1-20190117-C00362
         		(M + H) 453 (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.83 (d, 1H), 7.36 (t, 1H), 6.81 (d, 1H), 6.68 (d, 1H), 5.47 (d, 1H), 3.74- 3.65 (m, 2H), 3.28 (br s, 1H)
    267
    Figure US20190015377A1-20190117-C00363
         		(M − H) 435 (400 MHz, CDCl3): δ 8.32 (s, 1H), 8.23 (s, 1H), 8.03 (d, 1H), 7.23 (s, 1H), 7.13 (d, 1H), 5.46 (dd, 1H), 3.64-3.42 (m, 2H), 3.25 (d, 1H)
    268
    Figure US20190015377A1-20190117-C00364
         		419 (M + H) (400 MHz, CDCl3): δ 7.90 (d, 1 H), 7.30-7.28 (m, 1 H), 7.22 (br s, 1 H), 7.12-7.08 (m, 1 H), 6.95 (d, 1 H), 5.25-5.12 (m, 1 H), 4.95 (d, 1 H), 3.52-3.46 (m, 1 H), 3.29-3.18 (m, 1H), 1.73 (br s, 2H)
    269
    Figure US20190015377A1-20190117-C00365
         		398/400 (M + NH4 +) (400 MHz, CDCl3): δ 8.23-8.21 (m, 1 H), 7.35-7.32 (m, 1 H), 7.26-7.24 (m, 1 H), 7.23-7.21 (m, 1 H), 7.14-7.10 (m, 1 H), 3.97-3.78 (m, 2 H), 3.43 (s, 3 H)
    270
    Figure US20190015377A1-20190117-C00366
         		417/419 (M + NH4 +) (400 MHz, CDCl3): δ 7.95-7.91 (m, 1 H), 7.26-7.23 (m, 1 H), 7.14-7.13 (m, 1 H), 7.06-7.00 (m, 2 H), 5.80-5.78 (m, 0.5 H), 5.65-5.61 (m, 0.5 H), 3.81-3.55 (m, 3.5 H), 3.25 (s, 1.5 H), 3.24 (s, 1.5 H)
    271
    Figure US20190015377A1-20190117-C00367
         		383 (M + NH4 +) (400 MHz, CDCl3): δ 7.87 (d, 1 H), 7.23-7.21 (m, 1 H), 7.13-7.12 (m, 1 H), 7.05-7.00 (m, 2 H), 5.62-5.56 (m, 1 H), 5.44-5.29 (m, 1 H), 3.66 (dd, 1 H), 3.49-3.35 (m, 1 H), 3.20 (s, 3 H), 3.17-3.06 (m, 1 H)
    272
    Figure US20190015377A1-20190117-C00368
         		[M + H] 368 (400 MHz, CDCl3): δ 7.84-7.80 (m, 1H), 7.19-7.16 (m, 1H), 7.10 (d, 1H), 7.08-7.06 (m, 1H), 7.00-6.96 (m, 1H), 5.40 (d, 1H), 4.48-4.36 (m, 1H), 3.49- 3.27 (m, 2H), 2.93 (s, 3H)
    273
    Figure US20190015377A1-20190117-C00369
         		[M + formate − H] 418 (400 MHz, CDCl3): δ 7.63 (d, 1H), 7.21-7.18 (m, 1H), 7.11-7.09 (m, 1H), 7.03-6.97 (m, 2H), 5.29 (d, 1H), 3.51- 3.28 (m, 2H), 2.76 (br s, 1H)
    274
    Figure US20190015377A1-20190117-C00370
         		(M + H) 401 (400 MHz, CDCl3): δ 7.95 (d, 1H), 7.28-7.25 (m, 1H), 7.17-7.15 (m, 1H), 7.06 (dt, 1H), 7.00 (d, 1H), 5.62-5.56 (m, 1H), 5.37 (dd, 1H), 5.24 (dd, 1H), 4.26 (d, 1H), 3.57-3.34 (m, 2H), 3.20 (br d, 1H)
    275
    Figure US20190015377A1-20190117-C00371
         		(M + H) 401 (400 MHz, CDCl3): δ 7.96 (d, 1H), 7.28-7.25 (m, 1H), 7.18-7.16 (m, 1H), 7.06 (dt, 1H), 7.01 (d, 1H), 5.42 (dd, 1H), 5.27 (dd, 1H), 5.15 (dd, 1H), 5.04-5.02 (m, 1H), 3.62-3.38 (m, 2H), 3.33 (br s, 1H)
    276
    Figure US20190015377A1-20190117-C00372
         		(M + H) 408 (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.30 (ddd, 1H), 7.21-7.19 (m, 1H), 7.09 (dt, 1H), 6.99 (d, 1H), 5.92 (dd, 1H), 5.76-5.69 (m, 1H), 5.65 (dd, 1H), 5.55-5.37 (m, 1H), 3.43-3.18 (m, 2H), 3.22 (dd, 1H)
    277
    Figure US20190015377A1-20190117-C00373
         		(M + H) 408 (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.31 (ddd, 1H), 7.24-7.22 (m, 1H), 7.11 (dt, 1H), 7.00 (d, 1H), 6.27 (dd, 1H), 5.75-5.69 (m, 1H), 5.55 (dd, 1H), 5.56-5.39 (m, 1H), 3.45-3.22 (m, 2H), 3.12 (t, 1H)
    278
    Figure US20190015377A1-20190117-C00374
         		(M + Cl−) 551, 553 (400 MHz, CDCl3): δ 7.97 (d, 1H), 7.27-7.23 (m, 1H), 7.17-7.13 (m, 1H), 7.07 (dt, 1H), 7.02 (d, 1H), 5.54 (dd, 1H), 5.49-5.41 (m, 1H), 5.12 (br d, 1H), 3.33 (br s, 1H), 2.73-2.64 (m, 1H), 2.22 (d, 1H), 1.35 (s, 9H)
    279
    Figure US20190015377A1-20190117-C00375
         		(M + H) 417 (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.31 (ddd, 1H), 7.26-7.24 (m, 1H), 7.16 (dt, 1H), 6.94 (d, 1H), 5.53 (d, 1H), 4.59 (d, 1H), 2.69-2.61 (m, 1H), 2.35-1.95 (m, 4H)
    280
    Figure US20190015377A1-20190117-C00376
         		(M + H) 369, 371 (400 MHz, CDCl3): δ 7.79 (d, 1H), 6.98 (ddd, 1H), 6.91 (d, 1H), 6.91- 6.89 (m, 1H), 6.74 (dt, 1H), 5.97 (t, 1H), 5.68 (dt, 1H), 5.41 (t, 1H), 3.75 (d, 1H), 3.26-3.17 (m, 1H), 3.20 (s, 3H), 2.91-2.84 (m, 1H)
    281
    Figure US20190015377A1-20190117-C00377
         		(M + H) 387, 389 (400 MHz, CDCl3): δ 7.85 (d, 1H), 6.95 (ddd, 1H), 6.92 (d, 1H), 6.88- 6.85 (m, 1H), 6.70 (dt, 1H), 5.65 (d, 1H), 4.24-4.06 (br m, 1H), 4.08 (dd, 1H), 3.88 (dd, 1H), 3.64-3.59 (m, 1H), 3.26 (s, 3H), 2.69 (ddd, 1H), 2.66-2.48 (br m, 1H), 2.12 (d, 1H)
    282
    Figure US20190015377A1-20190117-C00378
         		(M + H) 390 (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.27 (ddd, 1H), 7.20-7.18 (m, 1H), 7.08 (dt, 1H), 7.00 (d, 1H), 5.98 (dd, 1H), 5.80-5.75 (m, 1H), 5.49 (dd, 1H), 3.17 (dt, 1H), 2.94 (ddd, 1H), 2.86 (d, 1H), 2.62-2.51 (m, 1H), 2.29- 2.20 (m, 1H)
    283
    Figure US20190015377A1-20190117-C00379
         		(M + H) 390 (400 MHz, CDCl3): δ 7.91 (d, 1H), 7.27 (ddd, 1H), 7.19-7.16 (m, 1H), 7.06 (dt, 1H), 6.98 (d, 1H), 5.85-5.79 (m, 1H), 5.72 (dd, 1H), 5.61 (dd, 1H), 3.15 (ddd, 1H), 2.97 (d, 1H), 2.89 (ddd, 1H), 2.62-2.52 (m, 1H), 2.27- 2.18 (m, 1H)
    284
    Figure US20190015377A1-20190117-C00380
         		(M + H) 479 (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.30 (ddd, 1H), 7.22-7.19 (m, 1H), 7.10 (dt, 1H), 7.01 (d, 1H), 5.97 (dd, 1H), 5.70 (dd, 1H), 5.60 (dd, 1H), 3.68 (d, 1H), 3.61-3.39 (m, 2H), 3.23 (s, 3H)
    285
    Figure US20190015377A1-20190117-C00381
         		(M + H) 426 (400 MHz, CDCl3): δ 8.01 (d, 1H), 7.34 (ddd, 1H), 7.25-7.22 (m, 1H), 7.12 (dt, 1H), 7.01 (d, 1H), 5.75 (dd, 1H), 5.71-5.65 (m, 1H), 5.61 (dd, 1H), 3.64-3.45 (m, 2H), 3.14 (dd, 1H)
    286
    Figure US20190015377A1-20190117-C00382
         		(M + H) 426 (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.34 (ddd, 1H), 7.26-7.24 (m, 1H), 7.14 (dt, 1H), 7.02 (d, 1H), 6.02 (dd, 1H), 5.65-5.59 (m, 1H), 5.54 (dd, 1H), 3.66-3.48 (m, 2H), 3.30 (dd, 1H)
    287
    Figure US20190015377A1-20190117-C00383
         		392 (M + HCO2 −) (400 MHz, CDCl3): δ 7.83 (d, 1H), 7.19-7.16 (m, 1H), 7.09-7.07 (m, 1H), 7.01-6.96 (m, 2H), 5.71-5.67 (m, 1H), 3.64 (d, 1H), 3.21 (s, 3H), 3.12-3.02 (m, 1H), 2.84-2.75 (m, 1H), 2.52-2.42 (m, 1H), 2.27-2.18 (m, 1H)
    288
    Figure US20190015377A1-20190117-C00384
         		428 (M + HCO2 −) (400 MHz, CDCl3): δ 8.08 (d, 1H), 7.29-7.23 (m, 1H), 7.19 (brs, 1H), 7.15-7.08 (m, 1H), 7.02 (d, 1H), 5.78- 5.70 (m, 1H), 3.89 (d, 1H), 3.23 (s, 3H), 3.17-3.02 (m, 1H), 2.80-2.64 (m, 1H)
    289
    Figure US20190015377A1-20190117-C00385
         		384 (M + H) (400 MHz, CDCl3): δ 8.13 (d, 1H), 7.31-7.25 (m, 1H), 7.23-7.19 (m, 1H), 7.14-7.09 (m, 1H), 7.04 (d, 1H), 6.09- 5.91 (m, 1H), 5.87-5.80 (m, 1H), 5.25-5.05 (m, 1H), 3.32 (s, 3H), 2.95 (d, 1H)
    290
    Figure US20190015377A1-20190117-C00386
         		437 (M + H) (400 MHz, CDCl3): δ 7.92 (d, 1H), 7.34-7.30 (m, 1H), 7.24-7.22 (m, 1H), 7.14-7.10 (m, 1H), 6.94 (d, 1H), 4.85 (d, 1H), 3.65-3.41 (m, 2H)
    291
    Figure US20190015377A1-20190117-C00387
         		481 (M + H) (400 MHz, CDCl3): δ 7.95 (d, 1H), 7.35-7.31 (m, 1H), 7.24-7.22 (m, 1H), 7.14-7.10 (m, 1H), 6.95 (d, 1H), 4.59 (d, 1H), 3.77-3.52 (m, 2H), 3.42 (t, 2H), 3.06 (t, 2H)
    292
    Figure US20190015377A1-20190117-C00388
         		419 (M + NH4 +) (400 MHz, CDCl3): δ 8.14-8.11 (m, 1H), 7.33-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.16-7.12 (m, 1H), 7.05 (d, 1H), 5.91-5.75 (m, 1H), 5.71-5.65 (m, 1H), 3.39 (d, 1H), 3.25 (s, 3H)
    293
    Figure US20190015377A1-20190117-C00389
         		419 (M + NH4 +) (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.32-7.28 (m, 1H), 7.23-7.20 (m, 1H), 7.15-7.10 (m, 1H), 7.02 (d, 1H), 6.07-5.90 (m, 1H), 5.87-5.80 (m, 1H), 3.95 (d, 1H), 3.26 (s, 3H)
    294
    Figure US20190015377A1-20190117-C00390
         		384 (M + H) (400 MHz, CDCl3): δ 8.09-8.06 (m, 1H), 7.27-7.24 (m, 1H), 7.19-7.17 (m, 1H), 7.10-7.07 (m, 1H), 7.04 (d, 1H), 6.30-6.12 (m, 1H), 5.96-5.89 (m, 1H), 5.46-5.27 (m, 1H), 3.53-3.51 (m, 1H), 3.27 (s, 3H)
    295
    Figure US20190015377A1-20190117-C00391
         		383 (M + NH4 +) (400 MHz, CDCl3): δ 8.04-8.01 (m, 1H), 7.25-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.11-7.06 (m, 1H), 7.00 (d, 1H), 6.09-5.79 (m, 1H), 5.69-5.61 (m, 1H), 3.54 (d, 1H), 3.23 (s, 3H), 2.94-2.80 (m, 1H), 2.52-2.41 (m, 1H)
    296
    Figure US20190015377A1-20190117-C00392
         		399 (M + NH4 +) (400 MHz, CDCl3): δ 8.05 (d, 1H), 7.26-7.22 (m, 1H), 7.19-7.17 (m, 1H), 7.12-7.07 (m, 1H), 7.05 (d, 1H), 5.76- 5.70 (m, 1H), 5.30-5.24 (m, 1H), 5.18-5.01 (m, 1H), 3.29 (s, 3H)
    297
    Figure US20190015377A1-20190117-C00393
         		426 (M + H) (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.34-7.30 (m, 1H), 7.25-7.22 (m, 1H), 7.23 (t, J = 54 Hz, 1H), 7.14-7.10 (m, 1H), 7.00 (d, 1H), 5.71-5.63 (m, 1H), 5.56-5.52 (m, 0.5H), 5.43-5.39 (m, 0.5H), 3.59 (t, 1H), 3.46-3.18 (m, 2H)
    298
    Figure US20190015377A1-20190117-C00394
         		397 (M + NH4) (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.22-7.19 (m, 1H), 7.12-7.09 (m, 1H), 7.03-6.98 (m, 2H), 5.29-5.23 (m, 1H), 3.57-3.53 (m, 1H), 3.26-3.04 (m, 2H), 3.19 (s, 3H), 1.70 (d, J = 22 Hz, 3H)
    299
    Figure US20190015377A1-20190117-C00395
         		426 (M + H) (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.34-7.30 (m, 1H), 7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 7.01 (t, J = 53 Hz, 1H), 6.99 (d, 1H), 5.73-5.66 (m, 1H), 5.56-5.52 (m, 0.5H), 5.43-5.39 (m, 0.5H), 3.45-3.34 (m, 1H), 3.35-3.19 (m, 2H)
    300
    Figure US20190015377A1-20190117-C00396
         		397 (M + NH4) (400 MHz, CDCl3): δ 7.90 (d, 1H), 7.21-7.19 (m, 1H), 7.10-7.08 (m, 1H), 6.99 (dt, 1H), 6.98 (d, 1H), 5.40-5.35 (m, 1H), 3.79-3.77 (m, 1H), 3.36-3.27 (m, 1H), 3.32 (s, 3H), 2.95-2.84 (m, 1H), 1.70 (d, 3H)
    301
    Figure US20190015377A1-20190117-C00397
         		379 (M + NH4) (400 MHz, CDCl3): δ 7.84 (d, 1H), 7.19-7.15 (m, 1H), 7.07-7.06 (m, 1H), 6.98 (d, 1H), 6.97 (dt, 1H), 5.46-5.43 (m, 1H), 3.12 (s, 3H), 3.08 (d, 1H), 2.97-2.91 (m, 1H), 2.68-2.53 (m, 2H), 1.25 (d, 3H)
    302
    Figure US20190015377A1-20190117-C00398
         		390 (M + H) (400 MHz, CDCl3): δ 8.00 (d, J = 8.7 Hz, 0.5H), 7.95 (d, J = 8.7 Hz, 0.5H), 7.29-7.25 (m, 1H), 7.19-7.16 (m, 1H), 7.10-7.05 (m, 1H), 7.01 (d, 1H), 5.78- 5.69 (m, 1H), 5.54-5.50 (m, 0.5H), 5.40-5.37 (m, 0.5H), 3.50 (d, J = 42 Hz, 3H), 3.39-3.11 (m, 3H)
    303
    Figure US20190015377A1-20190117-C00399
         		[M + H] = 357 (400 MHz, CDCl3): δ 8.72 (s, 1H), 8.64 (s, 1H), 7.64 (d, 1H), 7.59-7.57 (m, 1H), 6.97 (d, 1H), 5.33-5.28 (m, 1H), 3.55-3.32 (m, 2H), 2.86-2.82 (m, 1H)
    304
    Figure US20190015377A1-20190117-C00400
         		437, 439 (M + H+) (400 MHz, CDCl3): δ 7.88 (d, 1 H), 7.17-7.13 (m, 1 H), 7.04-7.02 (m, 1 H), 6.98 (d, 1 H), 6.77-6.74 (m, 1 H), 5.61-5.56 (m, 1 H), 3.57-3.36 (m 3 H), 3.22 (s, 3 H)
    305
    Figure US20190015377A1-20190117-C00401
         		(M + H) 437 (400 MHz, CDCl3): δ 8.01 (d, 1H), 7.32 (ddd, 1H), 7.24-7.22 (m, 1H), 7.12 (dt, 1H), 6.99 (d, 1H), 5.35 (dd, 1H), 4.73-4.71 (m, 1H), 3.97 (br s, 1H), 3.63-3.46 (m, 2H)
    306
    Figure US20190015377A1-20190117-C00402
         		(M + H) 437 (400 MHz, CDCl3): δ 8.07 (d, 1H), 7.30 (ddd, 1H), 7.23-7.21 (m, 1H), 7.11 (dt, 1H), 6.98 (d, 1H), 5.59 (ddd, 1H), 3.97 (d, 1H), 3.81 (br s, 1H), 3.61-3.39 (m, 2H)
    307
    Figure US20190015377A1-20190117-C00403
         		(M + H) 477 (400 MHz, CDCl3): δ 7.99 (d, 1H), 7.30 (ddd, 1H), 7.23-7.20 (m, 1H), 7.10 (dt, 1H), 6.98 (d, 1H), 6.04-5.93 (m, 1H), 5.35-5.28 (m, 2H), 5.21 (dq, 1H), 4.87 (br s, 1H), 4.16-4.09 (m, 1H), 4.04-3.96 (m, 1H), 3.61-3.44 (m, 2H)
    308
    Figure US20190015377A1-20190117-C00404
         		(M + H) 477 (400 MHz, CDCl3): δ 8.04 (d, 1H), 7.29 (ddd, 1H), 7.21-7.19 (m, 1H), 7.09 (dt, 1H), 6.97 (d, 1H), 5.98 (ddt, 1H), 5.58 (dd, 1H), 5.34 (dq, 1H), 5.19 (dq, 1H), 4.13-4.05 (m, 1H), 4.03-3.95 (m, 1H), 3.59-3.33 (m, 3H)
    309
    Figure US20190015377A1-20190117-C00405
         		(M + H) 414 (400 MHz, CDCl3): δ 8.49 (d, 1H), 8.37 (d, 1H), 7.93 (d, 1H), 7.26 (dt, 1H), 6.95 (d, 1H), 5.44 (dd, 1H), 3.67-3.48 (m, 2H), 3.42 (d, 1H).
    310
    Figure US20190015377A1-20190117-C00406
         		(M + H) 430 (400 MHz, CDCl3): δ 8.11-8.08 (m, 1H), 8.01-7.97 (m, 2H), 7.14 (d, 1H), 6.90 (dt, 1H), 5.43 (dd, 1H), 3.95 (d, 1H), 3.62-3.41 (m, 2H)
    311
    Figure US20190015377A1-20190117-C00407
         		400 (M + H) (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.27-7.25 (m, 1H), 7.20-7.18 (m, 1H), 7.12-7.07 (m, 1H), 7.03 (d, 1H), 5.81- 5.74 (m, 1H), 5.43-5.36 (m, 1H), 3.81 (d, 1H), 3.25 (s, 3H), 2.71 (m, 1H)
    312
    Figure US20190015377A1-20190117-C00408
         		400 (M + H) (400 MHz, CDCl3): δ 8.05 (d, 1H), 7.29-7.20 (m, 2H), 7.15-7.10 (m, 1H), 7.05 (d, 1H), 5.63-5.57 (m, 1H), 5.22- 5.15 (m, 1H), 3.53-3.48 (m, 1H), 3.24 (s, 3H), 2.73 (d, 1H)
    313
    Figure US20190015377A1-20190117-C00409
         		349 (M + H) (400 MHz, CDCl3): δ 8.75-8.72 (m, 1H), 8.66-8.64 (m, 1H), 7.92 (d, 1H), 7.61-7.59 (m, 1H), 6.95 (d, 1H), 5.73- 5.65 (m, 1H), 5.51-5.47 (m, 0.5H), 5.38-5.34 (m, 0.5H), 3.71-3.68 (m, 1H), 3.36-3.38 (m, 2H), 3.31 (s, 3H)
    314
    Figure US20190015377A1-20190117-C00410
         		(M + H) 420 (400 MHz, CDCl3): δ 8.83 (d, 1H), 8.72 (d, 1H), 8.02 (d, 1H), 7.73 (dd, 1H), 6.95 (d, 1H), 5.35 (dd, 1H), 4.73-4.70 (m s, 1H), 3.99 (br s, 1H), 3.67-3.49 (m, 2H)
    315
    Figure US20190015377A1-20190117-C00411
         		(M + H) 420 (400 MHz, CDCl3): δ 8.82 (d, 1H), 8.71 (d, 1H), 8.08 (d, 1H), 7.72 (dd, 1H), 6.93 (d, 1H), 5.63-5.57 (m, 1H), 3.97 (d, 1H), 3.82 (br s, 1H), 3.65- 3.43 (m, 2H)
    316
    Figure US20190015377A1-20190117-C00412
         		[M + H] 426 (400 MHz, CD3OD): δ 8.21 (dd, 1H), 7.59-7.56 (m, 1H), 7.54-7.53 (m, 1H), 7.46 (dt, 1H), 7.25 (d, 1H), 6.00 (dd, 1H), 5.60-5.56 (m, 1H), 3.64 (s, 3H)
    317
    Figure US20190015377A1-20190117-C00413
         		[M + H] 426 (400 MHz, CDCl3): δ 8.23-8.20 (m, 1H), 7.38-7.34 (m, 1H), 7.30-7.28 (m, 1H), 7.21-7.17 (m, 1H), 7.09 (d, 1H), 5.90 (dd, 1H), 5.71-5.66 (m, 1H), 3.90-3.88 (m, 1H), 3.64 (s, 3H)
    318
    Figure US20190015377A1-20190117-C00414
         		[M + H] 426 (400 MHz, CDCl3): δ 8.13 (dd, 1H), 7.37-7.33 (m, 1H), 7.28-7.27 (m, 1H), 7.19-7.15 (m, 1H), 7.05 (d, 1H), 6.08-5.84 (m, 2H), 4.08 (d, 1H), 3.54 (s, 3H)
    319
    Figure US20190015377A1-20190117-C00415
         		[M + H] 409 (400 MHz, CD3COCD3): δ 8.95 (d, 1H), 8.94 (d, 1H), 8.34-8.32 (m, 1H), 8.23-8.20 (m, 1H), 7.45 (d, 1H), 6.43- 6.40 (m, 1H), 6.15 (dd, 1H), 5.72-5.66 (m, 1H), 3.69 (s, 3H)
    320
    Figure US20190015377A1-20190117-C00416
         		[M + H] 409 (400 MHz, CD3COCD3): δ 8.96-8.95 (m, 1H), 8.94-8.92 (m, 1H), 8.34-8.32 (m, 1H), 8.24-8.20 (m, 1H), 7.44-7.41 (m, 1H), 6.51-6.31 (m, 2H), 5.90-5.83 (m, 1H), 3.81 (s, 3H)
    321
    Figure US20190015377A1-20190117-C00417
         		[M + H] 409 (400 MHz, CD3COCD3): δ 8.97-8.96 (m, 1H), 8.96-8.94 (m, 1H), 8.35 (dd, 1H), 8.25 (dd, 1H), 7.45 (d, 1H), 6.50 (brs, 1H), 6.16 (dd, 1H), 5.68-5.30 (m, 1H), 3.80 (s, 3H)
    322
    Figure US20190015377A1-20190117-C00418
         		[M + H] 409 (400 MHz, CD3COCD3): δ 8.95-8.94 (m, 1H), 8.94-8.92 (m, 1H), 8.33 (dd, 1H), 8.19 (dd, 1H), 7.41 (d, 1H), 6.50-6.28 (m, 2H), 5.90-5.85 (m, 1H), 3.70 (s, 3H)
    323
    Figure US20190015377A1-20190117-C00419
         		418, 420 (M + H) (400 MHz, CD3COCD3): δ 8.65-8.63 (m, 1H), 8.60-8.59 (m, 1H), 8.15-8.12 (m, 1H), 8.02-8.00 (m, 1H), 7.60-7.57 (m, 1H), 3.86-3.79 (m, 2H), 3.39 (s, 3H)
    324
    Figure US20190015377A1-20190117-C00420
         		420, 422 (M + H) (400 MHz, CDCl3): δ 8.61-8.59 (m, 1H), 8.41-8.39 (m, 1H), 7.91-7.87 (d, 1H), 7.61-7.58 (m, 1H), 6.95-6.9 (d, 1H), 5.63-5.57 (m, 1H), 3.61-3.40 (m, 3H), 3.23 (s, 3H)
    325
    Figure US20190015377A1-20190117-C00421
         		367 (M + H) (400 MHz, CDCl3): δ 8.76-8.75 (m, 1H), 8.67-8.66 (m, 1H), 7.95 (d, 1H), 7.70-7.68 (m, 1H), 6.98 (d, 1H), 5.60 (d, 1H), 3.57-3.35 (m, 3H), 3.22 (s, 3H)
    326
    Figure US20190015377A1-20190117-C00422
         		402, 404 (M + H) (400 MHz, CDCl3): δ 8.57-8.56 (m, 1H), 8.39-8.38 (m, 1H), 7.88 (d, 1H), 7.56-7.54 (m, 1H), 6.91 (d, 1H), 5.72- 5.65 (m, 1H), 5.51-5.47 (m, 0.5H), 5.38-5.34 (m, 0.5H), 3.71-3.69 (m, 1H), 3.38-3.09 (m, 3H), 3.29 (s, 3H)
    327
    Figure US20190015377A1-20190117-C00423
         		402 (M + H) (400 MHz, CDCl3): δ 8.10-8.06 (m, 1H), 7.44-7.32 (m, 3H), 6.91 (d, 1H), 5.95-5.91 (m, 0.5H), 5.81-5.78 (m, 0.5H), 5.70-5.64 (m, 1H), 4.00-3.97 (m, 1H), 3.24 (s, 3H)
    328
    Figure US20190015377A1-20190117-C00424
         		420, 422 (M + H) (400 MHz, CDCl3): δ 8.63-8.61 (m, 1H), 8.45-8.43 (m, 1H), 8.11-8.07 (m, 1H), 7.66-7.64 (m, 1H), 6.96 (d, 1H), 6.13-6.11 (m, 0.5H), 5.99-5.97 (m, 0.5H), 5.86-5.82 (m, 1H), 5.24-5.04 (m, 1H), 3.30 (s, 3H), 3.03-3.00 (m, 1H)
    329
    Figure US20190015377A1-20190117-C00425
         		378 (M + H) (400 MHz, CDCl3): δ 8.49-8.47 (m, 1H), 8.39-8.37 (m, 1H), 8.11-8.07 (m, 1H), 7.29-7.25 (m, 1H), 7.00 (d, 1H), 5.96-5.93 (m, 0.5H), 5.83-5.79 (m, 0.5H), 5.71-5.65 (m, 1H), 3.65-3.63 (m, 1H), 3.24 (s, 3H)
    330
    Figure US20190015377A1-20190117-C00426
         		378 (M + H) (400 MHz, CDCl3): δ 8.49-8.46 (m, 1H), 8.39-8.36 (m, 1H), 8.08-8.04 (m, 1H), 8.28-8.24 (m, 1H), 6.98 (d, 1H), 6.12-6.08 (m, 0.5H), 5.99-5.95 (m, 0.5H), 5.88-5.81 (m, 1H), 4.10-4.06 (m, 1H), 3.26 (s, 3H)
    331
    Figure US20190015377A1-20190117-C00427
         		394, 396 (M + H) (400 MHz, CDCl3): δ 8.56-8.55 (m, 1H), 8.44-8.43 (m, 1H), 8.11-8.08 (m, 1H), 7.54-7.52 (m, 1H), 6.99 (d, 1H), 5.96-5.92 (m, 0.5H), 5.83-5.79 (m, 0.5H), 5.71-5.65 (m, 1H), 3.66-3.64 (m, 1H), 3.25 (s, 3H)
    332
    Figure US20190015377A1-20190117-C00428
         		394, 396 (M + H) (400 MHz, CDCl3): δ 8.56-8.54 (m, 1H), 8.43-8.41 (m, 1H), 8.08-8.04 (m, 1H), 7.52-7.50 (m, 1H), 6.96 (d, 1H), 6.12-6.08 (m, 0.5H), 5.98-5.94 (m, 0.5H), 5.88-5.81 (m, 1H), 4.02-3.99 (m, 1H), 3.26 (s, 3H)
    333
    Figure US20190015377A1-20190117-C00429
         		367 (M + H) (400 MHz, CD3COCD3): δ 8.88-8.86 (m, 1H), 8.82-8.80 (m, 1H), 8.13-8.08 (m, 2H), 7.33 (d, 1H), 6.21-6.18 (m, 0.5H), 6.07-6.04 (m, 0.5H), 5.83-5.79 (m, 1H), 5.36-5.29 (m, 0.5H), 5.25- 5.16 (m, 0.5H), 5.07-5.04 (m, 1H), 3.33 (s, 3H)
    334
    Figure US20190015377A1-20190117-C00430
         		365 (M − H) (400 MHz, CD3OD): δ 7.87 (d, 1H), 7.42-7.35 (m, 1H), 7.26-7.13 (m, 2H), 7.08 (d, 1H), 5.63-5.51 (m, 1H), 5.40- 5.18 (m, 1H), 3.20-3.15 (m, 2H)
    335
    Figure US20190015377A1-20190117-C00431
         		383 (M − H) (400 MHz, CD3OD): δ 8.04 (d, 1H), 7.45-7.41 (m, 1H), 7.31-7.29 (m, 1H), 7.26-7.21 (m, 1H), 7.18 (d, 1H), 6.30- 6.11 (m, 1H), 5.80 (t, 1H), 5.37-5.17 (m, 1H)
    336
    Figure US20190015377A1-20190117-C00432
         		383 (M − H)
    337
    Figure US20190015377A1-20190117-C00433
         		399 (M − H) (400 MHz, CD3OD): δ 8.00 (d, 1H), 7.44-7.41 (m, 1H), 7.35-7.32 (m, 1H), 7.29-7.24 (m, 1H), 7.14 (d, 1H), 5.46 (d, 1H), 5.06 (d, 1H)
    338
    Figure US20190015377A1-20190117-C00434
         		401 (M − H) (400 MHz, CD3OD): δ 8.03-8.00 (m, 1H), 7.24-7.20 (m, 1H), 7.17-7.15 (m, 1H), 7.08-7.04 (m, 1H), 6.96 (d, 1H), 5.82-5.65 (m, 1H), 5.54-5.48 (m, 1H)
    339
    Figure US20190015377A1-20190117-C00435
         		401 (M − H) (400 MHz, CD3OD): δ 8.09-8.05 (m, 1H), 7.50-7.46 (m, 1H), 7.39-7.38 (m, 1H), 7.33-7.29 (m, 1H), 7.14 (d, 1H), 6.19-6.02 (m, 1H), 5.72-5.65 (m, 1H)
    340
    Figure US20190015377A1-20190117-C00436
         		384 (M − H) (400 MHz, CD3OD): δ 8.81 (d, 1H), 8.73 (d, 1H), 8.11-8.07 (m, 1H), 8.06- 8.04 (m, 1H), 7.18 (d, 1H), 6.04-5.86 (m, 1H), 5.57-5.51 (m, 1H)
    341
    Figure US20190015377A1-20190117-C00437
         		377 (M − H) (400 MHz, CD3OD): δ 8.43 (d, 1H), 8.35 (d, 1H), 8.10-8.06 (m, 1H), 7.59- 7.54 (m, 1H), 7.15 (d, 1H), 6.03-5.85 (m, 1H), 5.56-5.50 (m, 1H)
    342
    Figure US20190015377A1-20190117-C00438
         		(M + H) 385 (400 MHz, CDCl3): δ 8.82 (d, 1H), 8.74 (d, 1H), 8.14 (dd, 1H), 7.74 (dd, 1H), 7.02 (d, 1H), 5.87 (dd, 1H), 5.73-5.66 (m, 1H), 3.58 (d, 1H), 3.26 (s, 3H)
    343
    Figure US20190015377A1-20190117-C00439
         		(M + H) 385 (400 MHz, (CD3)2CO): δ 8.89 (dd, 1H), 8.86 (d, 1H), 8.21 (dd, 1H), 8.11 (dd, 1H), 7.36 (d, 1H), 6.36 (ddd, 1H), 6.10 (d, 1H), 5.87-5.80 (m, 1H), 3.31 (s, 3H)
    344
    Figure US20190015377A1-20190117-C00440
         		(M + H) 403 (400 MHz, CDCl3): δ 8.84 (d, 1H), 8.75 (d, 1H), 8.15 (dd, 1H), 7.77 (dd, 1H), 7.02 (d, 1H), 5.83 (dd, 1H), 5.68-5.62 (m, 1H), 5.43 (dd, 1H), 5.31 (dd, 1H), 3.43 (dd, 1H)
    345
    Figure US20190015377A1-20190117-C00441
         		(M + H) 403 (400 MHz, (CD3)2CO): δ 8.93 (dd, 1H), 8.90 (dd, 1H), 8.26 (dd, 1H), 8.13 (dd, 1H), 7.38 (d, 1H), 6.39 (ddd, 1H), 5.73 (dd, 1H), 5.80 (ddd, 1H), 5.61 (dd, 1H)
    346
    Figure US20190015377A1-20190117-C00442
         		(M + H) 401 (400 MHz, CDCl3): δ 8.14 (dd, 1H), 7.30 (ddd, 1H), 7.24-7.22 (m, 1H), 7.14 (dt, 1H), 6.98 (d, 1H), 5.77 (dd, 1H), 5.10-5.01 (m, 1H), 3.45 (s, 3H), 1.82 (br d, 2H)
    347
    Figure US20190015377A1-20190117-C00443
         		(400 MHz, CDCl3): δ 7.86 (d, 1H), 7.27 (d, 1H), 7.27-7.24 (m, 1H), 7.13- 7.11 (m, 1H), 7.04-7.00 (m, 1H), 5.41-5.37 (m, 1H), 3.06 (d, 1H)
    348
    Figure US20190015377A1-20190117-C00444
         		352, 354 (M − H) (CDCl3, 400 MHz) δ 7.89 (d, 1H), 7.13 (d, 1H), 7.09-7.06 (m, 1H), 6.96-6.94 (m, 1H), 6.80 (dt, 1H), 5.78-5.74 (m, 1H), 3.91 (dd, 1H), 3.65 (dd, 1H), 3.41 (d, 1H)
    349
    Figure US20190015377A1-20190117-C00445
         		404 (M − H) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.33-7.30 (m, 1H), 7.23 (t, 1H), 7.22- 7.18 (m, 2H), 7.10-7.06 (m, 1H), 5.69-5.65 (m, 1H), 3.23 (d, 1H)
    350
    Figure US20190015377A1-20190117-C00446
         		391, 393, 395 (M + H) (400 MHz, CDCl3): δ 7.70 (d, 1H), 7.10 (d, 1H), 6.93 (ddd, 1H), 6.78- 6.76 (m, 1H), 6.63 (dt, 1H), 3.62-3.58 (m, 2H), 3.42-3.37 (m, 2H)
    351
    Figure US20190015377A1-20190117-C00447
         		336, 338 (M + H) (400 MHz, CDCl3): δ 7.87 (d, 1H), 7.06 (dt, 1H), 7.03 (d, 1H), 6.94-6.92 (m, 1H), 6.78 (dt, 1H), 3.66-3.61 (m, 2H), 3.60-3.55 (m, 2H)
    352
    Figure US20190015377A1-20190117-C00448
         		424, 426, 428 (M + NH4) (400 MHz, CDCl3): δ 7.72 (d, 1H), 7.19 (d, 1H), 6.98-6.94 (ddd, 1H), 6.82-6.80 (m, 1H), 6.67 (dt, 1H), 5.60 (td, 1H), 3.80 (dd, 1H), 3.68 (dd, 1H), 2.89 (d, 1H)
    353
    Figure US20190015377A1-20190117-C00449
         		352, 354 (M − H) (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.13 (d, 1H), 7.07 (ddd, 1H), 6.97- 6.94 (m, 1H), 6.80 (dt, 1H), 5.79-5.72 (m, 1H), 3.91 (dd, 1H), 3.64 (dd, 1H), 3.57 (br d, 1H)
    354
    Figure US20190015377A1-20190117-C00450
         		(400 MHz, CDCl3): δ 7.89 (d, 1H), 7.50 (d, 1H), 7.06 (ddd, 1H), 6.89- 6.86 (m, 1H), 6.73 (dt, 1H)
    355
    Figure US20190015377A1-20190117-C00451
         		425, 427, 429 (M − OH) (400 MHz, CDCl3): δ 7.80 (d, 1H), 7.22 (d, 1H), 7.01 (dt, 1H), 6.87-6.85 (m, 1H), 6.71 (dt, 1H), 5.38 (d, 1H), 2.98 (br s, 1H)
    356
    Figure US20190015377A1-20190117-C00452
         		388, 390 (M − H) (400 MHz, CDCl3): δ 7.97 (d, 1H), 7.19 (d, 1H), 7.12 (ddd, 1H), 6.99- 6.97 (m, 1H), 6.83 (dt, 1H), 5.58-5.51 (m, 1H), 3.51 (br d, 1H)
    357
    Figure US20190015377A1-20190117-C00453
         		397, 399 (M − H) (400 MHz, CDCl3): δ 7.76 (d, 1H), 7.26 (d, 1H), 7.01 (ddd, 1H), 6.87- 6.85 (m, 1H), 6.71 (dt, 1H), 5.44 (dd, 1H), 2.94 (d, 1H)
    358
    Figure US20190015377A1-20190117-C00454
         		364, 366 (M + H) (400 MHz, CDCl3): δ 7.81 (d, 1H), 7.36 (dd, 1H), 7.20 (ddd, 1H), 6.99 (ddd, 1H), 6.89-6.86 (m, 1H), 6.71 (dt, 1H), 4.73-4.61 (m, 1H), 1.79 (br d, 2H)
    359
    Figure US20190015377A1-20190117-C00455
         		377, 379 (M − H) (400 MHz, CDCl3): δ 7.70 (d, 1H), 7.16 (d, 1H), 6.95 (ddd, 1H), 6.80- 6.78 (m, 1H), 6.64 (dt, 1H), 5.30 (dd, 1H), 2.72 (dd, 1H), 2.43 (s, 3H)
    360
    Figure US20190015377A1-20190117-C00456
         		431, 433 (M − H) (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.29 (d, 1H), 7.04 (ddd, 1H), 6.91- 6.89 (m, 1H), 6.74 (dt, 1H), 5.58 (d, 1H), 3.16 (br s, 1H)
    361
    Figure US20190015377A1-20190117-C00457
         		377, 379 (M − H) (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.22 (t, 1H), 7.14 (dt, 1H), 7.01 (ddd, 1H), 6.87-6.85 (m, 1H), 6.71 (dt, 1H), 5.90-5.85 (m, 1H), 3.77 (ddd, 1H), 3.67 (dd, 1H), 2.87 (t, 1H)
    362
    Figure US20190015377A1-20190117-C00458
         		363, 365 (M − H) (400 MHz, CDCl3): δ 7.84 (d, 1H), 7.27-7.23 (m, 2H), 7.01 (dt, 1H), 6.90-6.88 (m, 1H), 6.72 (dt, 1H), 5.35 (q, 1H), 2.79 (dd, 1H)
    363
    Figure US20190015377A1-20190117-C00459
         		378, 380 (M + H) (400 MHz, CDCl3): δ 7.80 (d, 1H), 7.22 (t, 1H), 7.06 (dt, 1H), 7.00 (dt, 1H), 6.87-6.84 (m, 1H), 6.70 (dt, 1H), 5.16-5.03 (br s, 1H), 3.75 (dd, 1H), 3.49 (dd, 1H), 2.20-1.97 (br s, 2H)
    364
    Figure US20190015377A1-20190117-C00460
         		413, 415 (M − H) (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.25 (t, 1H), 7.21-7.17 (m, 1H), 7.06 (ddd, 1H), 6.92-6.89 (m, 1H), 6.75 (dt, 1H), 5.67 (dd, 1H), 3.10 (dd, 1H)
    365
    Figure US20190015377A1-20190117-C00461
         		398 (M + H) (400 MHz, CDCl3): δ 7.90 (d, 1H), 7.28 (dd, 1H), 7.18-7.14 (m, 1H), 6.76 (tt, 1H), 6.67-6.60 (m, 2H), 4.98 (dt, 1H), 2.01 (br d, 2H)
    366
    Figure US20190015377A1-20190117-C00462
         		380 (M + H) (400 MHz, CDCl3): δ 7.87 (d, 1H), 7.44 (dd, 1H), 7.15 (d, 1H), 6.73 (tt, 1H), 6.64-6.57 (m, 2H), 5.58 (dd, 1H), 5.17-5.07 (m, 1H), 2.02-1.93 (m, 2H)
    367
    Figure US20190015377A1-20190117-C00463
         		362 (M + H) (400 MHz, CDCl3): δ 7.81 (d, 1H), 7.22 (t, 1H), 7.10-7.06 (m, 1H), 6.72 (tt, 1H), 6.63-6.56 (m, 2H), 5.14-5.07 (m, 1H), 3.75 (dd, 1H), 3.49 (dd, 1H), 2.12-2.04 (m, 2H)
    368
    Figure US20190015377A1-20190117-C00464
         		397 (M − H) (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.25 (t, 1H), 7.23-7.19 (m, 1H), 6.78 (tt, 1H), 6.68-6.61 (m, 2H), 5.67 (dd, 1H), 3.09 (dd, 1H)
    369
    Figure US20190015377A1-20190117-C00465
         		379 (M − H) (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.29 (t, 1H), 7.19 (d, 1H), 6.74 (tt, 1H), 6.65-6.58 (m, 2H), 5.87-5.80 (m, 1H), 5.66 (dd, 1H), 2.98 (ddd, 1H)
    370
    Figure US20190015377A1-20190117-C00466
         		363 (M + H) (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.25 (t, 1H), 7.16 (dt, 1H), 6.73 (tt, 1H), 6.63-6.56 (m, 1H), 5.90-5.86 (m, 1H), 5.90-5.85 (m, 1H), 3.78 (ddd, 1H), 3.67 (dd, 1H), 2.89 (t, 1H)
    371
    Figure US20190015377A1-20190117-C00467
         		414, 416 (M − H) (400 MHz, CDCl3): δ 7.95-7.92 (m, 1H), 7.25 (t, 1H), 7.21-7.17 (m, 1H), 7.06 (ddd, 1H), 6.92-6.89 (m, 1H), 6.75 (dt, 1H), 3.07 (d, 1H)
    372
    Figure US20190015377A1-20190117-C00468
         		405 (M + H) (400 MHz, CDCl3): δ 7.95 (d, 1H), 7.31-7.27 (m, 1H), 7.30 (dd, 1H), 7.19-7.14 (m, 2H), 7.07 (dt, 1H), 5.00-4.92 (m, 1H), 2.03 (d, 2H)
    373
    Figure US20190015377A1-20190117-C00469
         		385 (M + H) (400 MHz, CDCl3): δ 11.26-11.22 (m, 1H), 8.09 (dd, 1H), 8.06 (d, 1H), 7.04 (d, 1H), 7.27-7.23 (m, 1H), 7.15-7.13 (m, 1H), 7.06 (dt, 1H), 5.87 (dd, 1H)
    374
    Figure US20190015377A1-20190117-C00470
         		370 (M − H) (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.28-7.25 (m, 1H), 7.20 (t, 1H), 7.17- 7.13 (m, 2H), 7.04 (dt, 1H), 5.90-5.85 (m, 1H), 3.79 (dd, 1H), 3.69 (dd, 1H), 2.93 (t, 1H)
    375
    Figure US20190015377A1-20190117-C00471
         		404 (M − H) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.31 (ddd, 1H), 7.23 (t, 1H), 7.22-7.18 (m, 2H), 7.08 (dt, 1H), 5.66 (dd, 1H), 3.23 (d, 1H)
    376
    Figure US20190015377A1-20190117-C00472
         		426, 428 (M + H) (400 MHz, CDCl3): δ 7.78 (d, 1H), 7.18 (d, 1H), 6.72 (tt, 1H), 6.63-6.54 (m, 2H), 4.70 (dt, 1H), 1.92 (d, 2H)
    377
    Figure US20190015377A1-20190117-C00473
         		426, 428 (M + H) (400 MHz, CDCl3): δ 7.88 (d, 1H), 7.22 (d, 1H), 6.71 (tt, 1H), 6.62-6.55 (m, 2H), 5.31 (dd, 1H), 3.43 (br s, 1H), 3.03 (d, 1H)
    378
    Figure US20190015377A1-20190117-C00474
         		426, 428 (M + H) (400 MHz, CDCl3): δ 7.81 (d, 1H), 7.22 (d, 1H), 6.70 (tt, 1H), 6.61-6.54 (m, 2H), 5.35 (t, 1H), 3.75 (br s, 1H), 3.27 (d, 1H)
    379
    Figure US20190015377A1-20190117-C00475
         		484, 486 (M + H) (400 MHz, CDCl3): δ 7.75 (d, 1H), 7.16 (d, 1H), 6.71 (tt, 1H), 6.62-6.55 (m, 2H), 4.60 (dd, 1H), 3.55 (t, 2H), 3.35 (s, 3H), 3.21-3.06 (m, 2H), 2.10- 2.03 (m, 1H)
    380
    Figure US20190015377A1-20190117-C00476
         		404 (M − H) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.31 (ddd, 1H), 7.23 (t, 1H), 7.22-7.18 (m, 2H), 7.08 (dt, 1H), 5.66 (dd, 1H), 3.23 (d, 1H)
    381
    Figure US20190015377A1-20190117-C00477
         		398, 400 (M + H) (400 MHz, CDCl3): δ 8.55 (d, 1H), 8.38 (d, 1H), 7.96 (d, 1H), 7.46 (t, 1H), 7.29 (t, 1H), 7.16-7.13 (m, 1H), 5.67 (dd, 1H), 3.24 (dd, 1H)
    382
    Figure US20190015377A1-20190117-C00478
         		463 (M + H) (400 MHz, CDCl3): δ 7.91 (d, 1H), 7.39 (t, 1H), 7.29-7.24 (m, 1H), 7.19- 7.14 (m, 2H), 7.05 (dt, 1H), 4.94-4.87 (m, 1H), 3.53 (t, 2H), 3.37 (s, 3H), 3.17-3.07 (m, 2H), 2.28-2.20 (m, 1H)
    383
    Figure US20190015377A1-20190117-C00479
         		389 (M + H) (400 MHz, CD3OD): δ 8.81 (d, 1H), 8.71 (d, 1H), 8.08 (d, 1H), 8.04 (dd, 1H), 7.42 (d, 1H), 7.38 (t, 1H), 5.69 (d, 1H)
    384
    Figure US20190015377A1-20190117-C00480
         		405 (M + H) (400 MHz, CDCl3): δ 7.95 (d, 1H), 7.31-7.27 (m, 1H), 7.30 (dd, 1H), 7.19-7.14 (m, 2H), 7.07 (dt, 1H), 5.01-4.91 (dd, 1H), 2.06-1.99 (m, 2H)
    385
    Figure US20190015377A1-20190117-C00481
         		(400 MHz, (CD3)2SO): δ 8.79 (s, 2H), 8.27 (d, 1H), 7.78-7.73 (m, 1H), 7.72 (t, 1H), 7.55-7.47 (m, 3H)
    386
    Figure US20190015377A1-20190117-C00482
         		405 (M − H) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.33-7.30 (m, 1H), 7.23 (t, 1H), 7.22- 7.18 (m, 2H), 7.08 (dt, 1H), 3.12 (s, 1H)
    387
    Figure US20190015377A1-20190117-C00483
         		405 (M + H) (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.30 (d, 1H), 7.31-7.27 (m, 1H), 7.19- 7.14 (m, 2H), 7.08 (dt, 1H), 5.02-4.89 (m, 1H), 2.12-1.92 (m, 2H)
    388
    Figure US20190015377A1-20190117-C00484
         		405 (M + NH4) (400 MHz, CDCl3): δ 7.90 (d, 1H), 7.29-7.25 (m, 1H), 7.19 (d, 1H), 7.16- 7.14 (m, 1H), 7.06-7.01 (m, 1H), 5.75 (d, 2H), 5.58 (br d, 1H), 3.30-3.22 (m, 1H)
    389
    Figure US20190015377A1-20190117-C00485
         		405 (M − H) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.33-7.30 (m, 1H), 7.23 (t, 1H), 7.22- 7.18 (m, 2H), 7.08 (dt, 1H), 3.12 (s, 1H)
    390
    Figure US20190015377A1-20190117-C00486
         		373 (M + NH4) (400 MHz, CD3CN): δ 8.02 (d, 1H), 7.27 (d, 1H), 7.01-6.87 (m, 3H), 5.88- 5.73 (m, 2H), 4.91 (d, 1H)
    391
    Figure US20190015377A1-20190117-C00487
         		(400 MHz, CDCl3): δ 8.13 (d, 1H), 7.67 (t, 1H), 7.53 (d, 1H), 7.43 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 2.45 (s, 3H)
    392
    Figure US20190015377A1-20190117-C00488
         		419 (M + NH4) (400 MHz, CDCl3): δ 7.91 (d, 1H), 7.41 (s, 1H), 7.27 (t, 1H), 7.21 (s, 1H), 7.13 (s, 1H), 7.10 (d, 1H), 5.71- 5.64 (m, 1H), 3.04 (br d, 1H), 2.44 (s, 3H)
    393
    Figure US20190015377A1-20190117-C00489
         		467, 469 (M + H2O + NH4) (400 MHz, CDCl3): δ 8.05 (d, 1H), 7.55 (d, 1H), 7.30 (d, 1H), 7.13 (s, 1H), 7.07-7.02 (m, 1H)
    394
    Figure US20190015377A1-20190117-C00490
         		387 (M + H) (400 MHz, CDCl3): δ 8.01 (d, 1H), 7.28 (t, 1H), 7.21 (d, 1H), 6.83-6.76 (m, 1H), 6.69-6.63 (m, 2H), 6.03-5.97 (m, 1H), 4.20 (dd, 1H), 3.88 (dd, 1H), 3.15-3.11 (m, 1H)
    395
    Figure US20190015377A1-20190117-C00491
         		387 (M + H) (400 MHz, CDCl3): δ 7.97 (d, 1H), 7.26 (t, 1H), 7.21 (d, 1H), 6.83-6.76 (m, 1H), 6.70-6.63 (m, 2H), 5.99 (t, 1H), 4.08-4.02 (m, 1H), 3.98 (dd, 1H), 3.20-3.15 (m, 1H)
    396
    Figure US20190015377A1-20190117-C00492
         		362 (M + H) (400 MHz, CDCl3): δ 7.80 (d, 1H), 7.17 (t, 1H), 7.12 (d, 1H), 6.74-6.67 (m, 1H), 6.62-6.55 (m, 2H), 5.80-5.74 (m, 1H), 3.80 (dd, 1H), 3.75-3.69 (m, 2H), 3.41-3.34 (m, 1H)
    397
    Figure US20190015377A1-20190117-C00493
         		423 (M + H) (400 MHz, CDCl3): δ 8.07-8.00 (m, 1H), 7.42-7.13 (m, 2H), 6.87-6.80 (m, 1H), 6.73-6.66 (m, 2H), 5.83-5.76 (m, 1H), 3.78-3.66 (m, 1H)
    398
    Figure US20190015377A1-20190117-C00494
         		398 (M + H) (400 MHz, CDCl3): δ 8.02 (d, 1H), 7.22 (t, 1H), 7.19 (d, 1H), 6.79-6.72 (m, 1H), 6.66-6.59 (m, 2H), 5.60 (t, 1H), 3.39 (br s, 1H), 3.12 (d, 1H)
    399
    Figure US20190015377A1-20190117-C00495
         		398 (M + H) (400 MHz, CDCl3): δ 7.95 (d, 1H), 7.23 (t, 1H), 7.19 (d, 1H), 6.79-6.72 (m, 1H), 6.66-6.59 (m, 2H), 5.64 (t, 1H), 3.68 (br s, 1H), 3.33 (d, 1H)
    400
    Figure US20190015377A1-20190117-C00496
         		387 (M + H) (400 MHz, CD3OD): δ 7.99 (d, 1H), 7.57 (d, 1H), 7.26 (t, 1H), 5.57-5.52 (m, 1H), 4.95-4.88 (m, 1H), 3.98-3.91 (m, 2H), 3.67-3.60 (m, 2H), 2.32-2.03 (m, 2H), 1.86-1.76 (m, 2H)
    401
    Figure US20190015377A1-20190117-C00497
         		398 (M + H) (400 MHz, CDCl3): δ 7.90 (d, 1H), 7.29 (t, 1H), 7.16 (d, 1H), 6.76 (tt, 1H), 6.67-6.60 (m, 2H), 5.02-4.93 (m, 1H), 2.01 (br d, 2H)
    402
    Figure US20190015377A1-20190117-C00498
         		394 (M + NH4) (400 MHz, CDCl3): δ 8.08 (d, 1H), 7.31 (t, 1H), 7.10 (d, 1H), 6.71 (tt, 1H), 6.61-6.54 (m, 2H), 5.52-5.48 (m, 1H), 4.05 (td, 1H), 3.32 (ddd, 1H), 2.84-2.74 (m, 1H), 2.73-2.64 (m, 2H)
    403
    Figure US20190015377A1-20190117-C00499
         		441, 443, 445 (M − H) (CDCl3, 400 MHz) δ: 7.80 (d, 1H), 7.22 (d, 1H), 7.02-7.00 (m, 1H), 6.87-6.86 (m, 1H), 6.72 (dt, 1 H), 5.38 (d, 1H)
    404
    Figure US20190015377A1-20190117-C00500
         		475, 477, 479 (M + HCO2−) (CDCl3, 400 MHz) δ: 8.00 (d, 1H), 7.46 (d, 1H), 6.99-6.96 (m, 1H), 6.81-6.80 (m, 1H), 6.67 (dt, 1H), 2.08-2.04 (m, 2H), 1.96-1.93 (m, 2H)
    405
    Figure US20190015377A1-20190117-C00501
         		441, 443, 445 (M − H) (CDCl3, 400 MHz): δ 7.80 (d, 1H), 7.22 (d, 1H), 7.02-7.00 (m, 1H), 6.87-6.86 (m, 1H), 6.72 (dt, 1H), 5.38 (d, 1H)
    406
    Figure US20190015377A1-20190117-C00502
         		479, 481, 483 (M + HCO2 −) (CDCl3, 400 MHz): δ 7.73 (dd, 1H), 7.16 (d, 1H), 6.98-6.95 (m, 1H), 6.83-6.82 (m, 1H), 6.66 (dt, 1H), 1.65 (s, 3H), 1.40 (s, 3H)
    407
    Figure US20190015377A1-20190117-C00503
         		352, 354 (M − H) (CDCl3, 400 MHz): δ 7.89 (d, 1H), 7.13 (d, 1 H), 7.09-7.06 (m, 1H), 6.96-6.94 (m, 1H), 6.80 (dt, 1 H), 5.78-5.74 (m, 1H), 3.91 (dd, 1H), 3.65 (dd, 1H), 3.41 (d, 1H)
    408
    Figure US20190015377A1-20190117-C00504
         		380, 382 (M − H) (CDCl3, 400 MHz): δ 7.91 (d, 1H), 7.10-7.06 (m, 2H), 6.97-6.96 (m, 1H), 6.81 (dt, 1H), 1.55 (s, 3H), 1.49 (s, 3H)
    409
    Figure US20190015377A1-20190117-C00505
         		397 (M + NH4) (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.27-7.23 (m, 2H), 7.15 (s, 1H), 7.04 (d, 1H), 5.46 (dd, 1H), 3.69 (s, 1H), 3.13 (d, 1H)
    410
    Figure US20190015377A1-20190117-C00506
         		410 (M − H) (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.28-7.25 (m, 1H), 7.23 (d, 1H), 7.16- 7.14 (m, 1H), 7.05 (dt, 1H), 5.43 (d, 1H), 5.19 (d, 2H), 3.27 (s, 1H)
    411
    Figure US20190015377A1-20190117-C00507
         		394 (M + NH4) (400 MHz, CDCl3): δ 7.92 (d, 1H), 7.46-7.10 (m, 7H), 5.61 (d, 1H), 5.26 (s, 2H), 3.00 (s, 1H)
    412
    Figure US20190015377A1-20190117-C00508
         		407, 409 (M + H) (400 MHz, CDCl3): δ 7.89-7.81 (m, 1H), 7.31-7.26 (m, 1H), 6.78 (t, 1H), 6.65 (d, 2H), 5.59-5.51 (m, 1H), 4.60- 4.38 (br s, 1H)
    413
    Figure US20190015377A1-20190117-C00509
         		(400 MHz, CDCl3): δ 7.72 (d, 1H), 7.21 (d, 1H), 6.71-6.64 (m, 1H), 6.57- 6.52 (m, 2H), 5.60 (t, 1H), 3.83-3.78 (m, 1H), 3.71-3.67 (m, 1H), 2.88 (d, 1H)
    414
    Figure US20190015377A1-20190117-C00510
         		(400 MHz, CDCl3): δ 7.89 (d, 1H), 7.15 (d, 1H), 6.83-6.76 (m, 1H), 6.71- 6.67 (m, 2H), 5.78-5.74 (m, 1H), 3.94-3.89 (m, 1H), 3.67-3.63 (m, 1H), 3.27-3.24 (m, 1H)
    415
    Figure US20190015377A1-20190117-C00511
         		(400 MHz, CDCl3): δ 7.77 (d, 1H), 7.25 (d, 1H), 7.22-7.19 (m, 1H), 7.06- 7.05 (m, 1H), 6.99-6.96 (m, 1H), 5.62-5.59 (m, 1H), 3.85-3.80 (m, 1H), 3.71-3.69 (m, 1H), 2.90 (d, 1H)
    416
    Figure US20190015377A1-20190117-C00512
         		(400 MHz, CDCl3): δ 7.94 (d, 1H), 7.35-7.31 (m, 1H), 7.24-7.22 (m, 1H), 7.16 (d, 1H), 7.16-7.12 (m, 1H), 5.80- 5.73 (m, 1H), 3.96-3.90 (m, 1H), 3.68-3.63 (m, 1H), 3.48-3.46 (m, 1H)
    417
    Figure US20190015377A1-20190117-C00513
         		(400 MHz, CDCl3): δ 8.24 (d, 1H), 7.89-7.86 (dd, 1H), 7.11 (d, 1H), 6.70-6.65 (m, 1H), 6.59-6.51 (m, 2H), 3.10 (s, 2H)
    418
    Figure US20190015377A1-20190117-C00514
         		(400 MHz, CDCl3): δ 7.72 (d, 1H), 7.20 (d, 1H), 6.70-6.65 (m, 1H), 6.58- 6.52 (m, 2H), 5.62-5.58 (m, 1H), 3.83-3.78 (m, 1H), 3.71-3.67 (m, 1H), 2.93 (d, 1H)
    419
    Figure US20190015377A1-20190117-C00515
         		(400 MHz, CDCl3): δ 7.66 (d, 1H), 7.40-7.35 (m, 1H), 7.10 (d, 1H), 6.97- 6.93 (m, 1H), 6.83-6.76 (m, 2H), 5.62-5.59 (m, 1H), 3.82-3.77 (m, 1H), 3.70-3.66 (m, 1H), 2.96 (d, 1H)
    420
    Figure US20190015377A1-20190117-C00516
         		(400 MHz, CDCl3 + CD3OD): δ 8.69 (d, 1H), 8.61-8.60 (d, 1H), 7.79 (d, 1H), 7.55-7.54 (m, 1H), 7.29 (d, 1H), 5.57 (d, 1H), 3.84-3.79 (m, 1H), 3.70- 3.66 (m, 1H)
    421
    Figure US20190015377A1-20190117-C00517
         		(400 MHz, CDCl3): δ 8.50 (s, 1H), 8.33 (s, 1H), 7.81 (d, 1H), 7.41-7.40 (m, 1H), 7.19 (d, 1H), 5.41-5.37 (m, 1H), 3.45-3.40 (m, 1H)
    422
    Figure US20190015377A1-20190117-C00518
         		(400 MHz, CDCl3): δ 7.83 (d, 1H), 7.48-7.42 (m, 1H), 7.08-7.03 (m, 1H), 7.06 (d, 1H), 6.94-6.87 (m, 2H), 5.78- 5.73 (m, 1H), 3.93-3.88 (m, 1H), 3.66-3.62 (m, 1H), 3.56 (d, 1H)
    423
    Figure US20190015377A1-20190117-C00519
         		(400 MHz, CDCl3): δ 8.43 (d, 1H), 8.29 (d, 1H), 7.82 (d, 1H), 7.21 (d, 1H), 7.18-7.14 (dt, 1H), 5.41-5.37 (m, 1H), 3.29-3.28 (m, 1H)
    424
    Figure US20190015377A1-20190117-C00520
         		(400 MHz, CDCl3): δ 8.76 (s, 1H), 8.64 (d, 1H), 7.87 (d, 1H), 7.59-7.58 (m, 1H), 7.27 (d, 1H), 5.42-5.36 (m, 1H), 3.36-3.32 (m, 1H)
    425
    Figure US20190015377A1-20190117-C00521
         		407 (M + HCOOH − H) (400 MHz, CDCl3): δ 7.81 (d, 1H), 7.28 (d, 1H), 7.24-7.21 (m, 1H), 6.76- 6.70 (1H), 6.65-6.95 (m, 2H), 2.80 (m, 1H), 1.75 (m, 3H)
    426
    Figure US20190015377A1-20190117-C00522
         		437, 439 (M − H) (400 MHz, CDCl3) δ 7.75 (d, 1H), 7.17 (d, 1H), 6.56-6.51 (m, 1H), 6.42- 6.37 (m, 2H), 5.42-5.35 (m, 1H), 3.80 (s, 3H), 2.99-2.95 (m, 1H)
    427
    Figure US20190015377A1-20190117-C00523
         		384 (M − H) (400 MHz, CDCl3) δ 7.92 (d, 1H), 7.17 (d, 1H), 6.64-6.60 (m, 1H), 6.50- 6.45 (m, 2H), 6.57-6.51 (m, 1H), 3.82 (s, 3H), 3.80-3.74 (m, 1H)
    428
    Figure US20190015377A1-20190117-C00524
         		(400 MHz, CDCl3): δ 8.38-8.36 (m, 1H), 8.14 (d, 1H), 7.72 (d, 1H), 7.24- 7.22 (m, 1H), 7.01 (d, 1H), 5.41-5.37 (m, 1H), 4.14-4.08 (m, 1H), 2.40 (s, 3H)
    429
    Figure US20190015377A1-20190117-C00525
         		(400 MHz, CDCl3): δ 8.26-8.23 (m, 1H), 7.95-7.93 (m, 1H), 7.73 (d, 1H), 7.06 (d, 1H), 6.95-6.92 (m, 1H), 5.42- 5.35 (m, 1H), 4.03-3.97 (m, 1H), 3.88 (s, 3H)
    430
    Figure US20190015377A1-20190117-C00526
         		(400 MHz, CDCl3): δ 7.80 (d, 1H), 7.59-7.54 (m, 2H), 7.37-7.35 (m, 1H), 7.32-7.27 (m, 1H), 7.15 (d, 1H), 5.42- 5.37 (m, 1H), 3.11 (d, 1H)
    431
    Figure US20190015377A1-20190117-C00527
         		388, 390 (M − H) (400 MHz, CDCl3): δ 7.82 (d, 1H), 7.32 (d, 1H), 7.25-7.23 (m, 1H), 7.12- 7.10 (m, 1H), 7.03-7.00 (dt, 1H), 5.44 (d, 1H), 3.39-3.25 (m, 1H)
    432
    Figure US20190015377A1-20190117-C00528
         		(400 MHz, CDCl3): δ 8.50 (d, 1H), 8.33 (d, 1H), 7.78 (d, 1H), 7.41-7.40 (m, 1H), 7.22 (d, 1H), 5.47-5.42 (m, 1H), 3.45 (d, 1H)
    433
    Figure US20190015377A1-20190117-C00529
         		430 (M + HCOOH − H) (400 MHz, CDCl3): δ 7.62 (d, 1H), 7.32 (d, 1H), 7.21-7.18 (m, 1H), 7.08- 7.06 (m, 1H), 6.97-6.93 (m, 1H), 5.47-5.43 (m, 1H), 4.02 (s, 3H), 3.10- 3.08 (m, 1H)
    434
    Figure US20190015377A1-20190117-C00530
         		418 (M + HCOOH − H) (400 MHz, CDCl3): δ 7.72 (d, 1H), 7.44-7.40 (m, 1H), 7.25-7.22 (m, 1H), 7.13-7.10 (m, 1H), 7.05-7.01 (m, 1H), 5.51 (d, 1H)
    435
    Figure US20190015377A1-20190117-C00531
         		(400 MHz, CDCl3): δ 7.92 (d, 1H), 7.62-7.57 (m, 2H), 7.42-7.40 (m, 1H), 7.35-7.31 (m, 1H), 7.28 (t, J = 53 Hz, 1H), 7.11 (d, 1H), 5.69-5.65 (m, 1H), 3.33-3.32 (m, 1H)
    436
    Figure US20190015377A1-20190117-C00532
         		(400 MHz, CDCl3 + CD3OD): δ 7.80 (d, 1H), 7.23-7.15 (m, 1H), 7.20 (t, 1H), 7.02 (d, 1H), 6.94-6.88 (m, 1H), 6.80-6.75 (m, 1H), 5.50 (d, 1H)
    437
    Figure US20190015377A1-20190117-C00533
         		(400 MHz, CDCl3 + CD3OD): δ 7.83 (d, 1H), 7.33-7.23 (m, 3H), 7.18 (t, 1H), 7.01 (d, 1H), 5.51-5.48 (m, 1H)
    438
    Figure US20190015377A1-20190117-C00534
         		(400 MHz, CDCl3): δ 7.93 (d, 1H), 7.24 (d, 1H), 7.21 (t, 1H), 5.63-5.58 (m, 1H), 4.23 (q, 2H), 2.94-2.89 (m, 1H), 1.51 (t, 3H)
    439
    Figure US20190015377A1-20190117-C00535
         		(400 MHz, CDCl3): δ 7.92 (d, 1H), 7.26 (t, 1H), 7.21 (d, 1H), 5.63-5.59 (m, 1H), 4.01-3.98 (m, 2H), 2.95-2.92 (m, 1H), 1.37-1.27 (m, 1H), 0.74-0.70 (m, 2H), 0.42-0.38 (m, 2H)
    440
    Figure US20190015377A1-20190117-C00536
         		(400 MHz, CDCl3): δ 7.85 (d, 1H), 7.78 (d, 1H), 7.50 (d, 1H), 7.47 (t, 1H), 7.42 (t, 1H), 7.17 (dd, 1H), 7.05 (dd, 1H), 6.96 (d, 1H), 5.73-5.67 (m, 1H), 3.20-3.13 (br s, 1H)
    441
    Figure US20190015377A1-20190117-C00537
         		(400 MHz, CDCl3): δ 8.17 (s, 1H), 7.83 (d, 1H), 7.72 (d, 1H), 7.42 (t, 1H), 7.22 (t, 1H), 7.12-7.07 (m, 2H), 5.69 (d, 1H)
    442
    Figure US20190015377A1-20190117-C00538
         		418 (M − H) (400 MHz, CDCl3): δ 7.95-7.90 (d, 1H), 7.65 (t, 1H), 7.25-7.22 (m, 1H), 7.22-7.18 (d, 1H), 7.13-7.11 (m, 1H), 7.08-7.04 (m, 1H), 3.73 (brd s, 1H), 1.91-1.88 (m, 3H)
    443
    Figure US20190015377A1-20190117-C00539
         		372 (M − H) (400 MHz, CDCl3): δ 7.97 (d, 1H), 7.20 (d, 1H), 6.87-6.81 (m, 1H), 6.76- 6.69 (m, 2H), 5.55 (dd, 1H)
    444
    Figure US20190015377A1-20190117-C00540
         		439, 441 (M − H) (400 MHz, CDCl3): δ 7.78 (d, 1H), 7.16 (d, 1H), 6.75-6.69 (m, 1H), 6.62- 6.54 (m, 2H), 3.04-2.98 (m, 1H), 1.95 (d, 3H)
    445
    Figure US20190015377A1-20190117-C00541
         		472 (M − H) (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.57 (t, 1H), 7.37 (d, 1H), 7.29-7.25 (m, 1H), 7.17-7.14 (m, 1H), 7.08 (dt, 1H), 5.40-5.10 (m, 1H)
    446
    Figure US20190015377A1-20190117-C00542
         		386 (M − H) (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.13 (d, 1H), 6.83 (tt, 1H), 6.75-6.68 (m, 2H), 3.54 (s, 1H), 1.97 (d, 3H)
    447
    Figure US20190015377A1-20190117-C00543
         		457, 459 (M − H) (400 MHz, CDCl3): δ 7.79 (d, 1H), 7.27 (d, 1H), 6.72 (tt, 1H), 6.62-6.55 (m, 2H), 4.71 (s, 1H), 4.16 (d, 1H), 3.83 (d, 1H)
    448
    Figure US20190015377A1-20190117-C00544
         		404 (M − H) (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.26 (d, 1H), 6.83 (tt, 1H), 6.76-6.69 (m, 2H), 4.26 (br s, 1H), 4.18 (d, 1H), 3.81 (d, 1H)
    449
    Figure US20190015377A1-20190117-C00545
         		464, 466 (M − H) (400 MHz, CDCl3): δ 7.84 (d, 1H), 7.30 (d, 1H), 7.27-7.24 (m, 1H), 7.12- 7.10 (m, 1H), 7.00 (dt, 1H), 4.63 (s, 1H), 4.18 (d, 1H), 3.85 (d, 1H)
    450
    Figure US20190015377A1-20190117-C00546
         		411 (M − H) (400 MHz, CDCl3): δ 7.99 (d, 1H), 7.38-7.34 (m, 1H), 7.29-7.24 (m, 2H), 7.20-7.16 (dt, 1H), 4.75 (br s, 1H), 4.20 (d, 1H), 3.82 (d, 1H)
    451
    Figure US20190015377A1-20190117-C00547
         		393 (M − H) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.39-7.35 (m, 1H), 7.27-7.25 (m, 1H), 7.17 (dt, 1H), 7.13 (d, 1H), 3.27 (d, 1H), 1.99 (d, 3H)
    452
    Figure US20190015377A1-20190117-C00548
         		401 (M + NH4 +) (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.27-7.24 (m, 1H), 7.21 (t, 1H), 7.16- 7.11 (m, 2H), 7.06-7.02 (m, 1H), 5.34 (br s, 1H), 3.66-3.58 (m, 1H), 3.13 (br s, 1H), 1.55 (d, 3H)
    453
    Figure US20190015377A1-20190117-C00549
         		401 (M + NH4 +) (400 MHz, DMSO-d6): δ 7.99 (d, 1H), 7.75-7.71 (m, 1H), 7.52-7.49 (m, 1H), 7.48-7.44 (m, 1H), 7.36 (d, 1H), 7.29 (t, 1H), 6.23 (d, 1H), 5.52 (t, 1H), 3.76-3.68 (m, 1H), 1.35 (d, 3H)
    454
    Figure US20190015377A1-20190117-C00550
         		347 (M + NH4 +) (400 MHz, CDCl3): δ 7.84 (d, 1H), 7.31 (t, 1H), 7.09 (d, 1H), 5.87-5.79 (m, 1H), 4.17-4.04 (m, 2H), 3.75-3.68 (m, 1H), 3.65-3.59 (m, 1H), 2.91-2.84 (m, 1H), 1.54-1.48 (m, 2H), 1.22-1.14 (m, 2H)
    455
    Figure US20190015377A1-20190117-C00551
         		410 (M + HCO2 −) (400 MHz, CDCl3): δ 7.86 (d, 1H), 7.19 (t, 1H), 7.14 (d, 1H), 5.47 (d, 1H), 4.15-4.03 (m, 2H), 3.15 (s, 1H), 1.47-1.39 (m, 2H), 1.19-1.12 (m, 2H)
    456
    Figure US20190015377A1-20190117-C00552
         		316 (M − H) (400 MHz, CDCl3): δ 7.92 (d, 1H), 7.18 (d, 1H), 4.81 (m, 1H), 3.18 (s, 1H), 1.92 (d, 3H), 1.48 (t, 6H)
    457
    Figure US20190015377A1-20190117-C00553
         		393 (M − H) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.39-7.35 (m, 1H), 7.27-7.25 (m, 1H), 7.17 (dt, 1H), 7.13 (d, 1H), 3.27 (d, 1H), 1.99 (d, 3H)
    458
    Figure US20190015377A1-20190117-C00554
         		393 (M − H) (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.39-7.35 (m, 1H), 7.27-7.25 (m, 1H), 7.17 (dt, 1H), 7.13 (d, 1H), 3.27 (d, 1H), 1.99 (d, 3H)
    459
    Figure US20190015377A1-20190117-C00555
         		410 (M + HCO2−) (400 MHz, (CD3)2CO): δ 8.23 (d, 1H), 7.74 (d, 1H), 7.57 (d, 2H), 7.48- 7.36 (m, 3H), 6.54 (d, 1H), 5.54 (s, 2H), 1.86 (d, 3H)
    460
    Figure US20190015377A1-20190117-C00556
         		405 (M − H) (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.39-7.35 (m, 1H), 7.26-7.24 (m, 1H), 7.18-7.13 (m, 2H), 6.12 (ddd, 1H), 5.86 (d, 1H), 5.73 (d, 1H), 3.45 (d, 1H)
    461
    Figure US20190015377A1-20190117-C00557
         		364 (M − H) (400 MHz, CDCl3): δ 7.97 (d, 1H), 7.02 (d, 1H), 4.90-4.81 (m, 1H), 3.29- 3.17 (m, 2H), 3.10 (d, 1H), 3.02-2.87 (m, 2H), 1.93 (d, 3H)
    462
    Figure US20190015377A1-20190117-C00558
         		486, 488, 490 (M + H) (400 MHz, (CD3)2SO): δ 8.15 (d, 1H), 7.48 (d, 1H), 7.47 (ddd, 1H), 7.29- 7.27 (m, 1H), 7.18 (dt, 1H), 5.04 (d, 1H)
    463
    Figure US20190015377A1-20190117-C00559
         		342 (M − H) (400 MHz, (CD3)2CO): δ 7.99 (d, 1H), 7.66-7.61 (m, 2H), 7.56 (dt, 1H), 7.42 (d, 1H), 5.03 (br s, 1H), 3.95 (dd, 1H), 3.48 (dd, 1H), 2.40 (br s, 2H)
    464
    Figure US20190015377A1-20190117-C00560
         		380 (M + H) (400 MHz, (CD3)2CO): δ 8.20 (d, 1H), 7.62 (ddd, 1H), 7.55-7.53 (m, 1H), 7.45 (dt, 1H), 7.39 (d, 1H), 5.14- 5.04 (m, 1H), 2.42 (br d, 2H)
    465
    Figure US20190015377A1-20190117-C00561
         		(M + H) 328 (400 MHz, CDCl3): δ 8.04 (s, 1H), 5.46-5.26 (m, 2H), 4.89-4.79 (m, 1H), 3.36-3.08 (m, 4H), 2.91-2.74 (m, 2H), 2.60 (dd, 1H)
    466
    Figure US20190015377A1-20190117-C00562
         		(M + H) 310 (400 MHz, CDCl3): δ 7.98 (s, 1H), 5.59-5.54 (m, 1H), 4.88-4.79 (m, 1H), 3.24-3.07 (m, 3H), 2.89 (dd, 1H), 2.89-2.74 (m, 2H), 2.44-2.34 (m, 1H), 2.28-2.21 (m, 1H), 2.12-2.09 (m, 1H)
    467
    Figure US20190015377A1-20190117-C00563
         		(M + H) 357 (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.22 (ddd, 1H), 7.10-7.08 (m, 1H), 6.99 (dt, 1H), 5.54-5.46 (m, 1H), 5.46-5.28 (m, 1H), 3.26 (ddd, 1H), 3.11 (ddd, 1H), 2.67 (dd, 1H)
    468
    Figure US20190015377A1-20190117-C00564
         		(M + H) 367 (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.25 (ddd, 1H), 7.14 (m, 1H), 7.03 (dt, 1H), 5.69 (dt, 1H), 5.53-5.36 (m, 1H), 4.24 (d, 1H), 3.34 (s, 3H), 3.31- 3.24 (m, 1H), 3.09 (ddd, 1H)
    469
    Figure US20190015377A1-20190117-C00565
         		326/328 (M + H)
    470
    Figure US20190015377A1-20190117-C00566
         		362 (M + H) (400 MHz, CDCl3): δ 7.49 (s, 1H), 6.80-6.71 (m, 3H), 6.19 (t, 1H), 3.36 (t, 2H), 3.06 (t, 2H), 2.31-2.23 (m, 2H)
    471
    Figure US20190015377A1-20190117-C00567
         		(M + H) 341 (400 MHz, CDCl3): δ 8.65 (s, 1H), 7.53-7.48 (m, 2H), 7.40 (ddd, 1H), 5.56-5.48 (m, 1H), 5.35 (ddt, 1H), 3.41 (ddd, 1H), 3.21 (ddd, 1H), 2.65 (dd, 1H)
    472
    Figure US20190015377A1-20190117-C00568
         		339 (M + H)
    473
    Figure US20190015377A1-20190117-C00569
         		302 (M + H)
    474
    Figure US20190015377A1-20190117-C00570
         		284 (M + H)
    475
    Figure US20190015377A1-20190117-C00571
         		338 (M + H)
    476
    Figure US20190015377A1-20190117-C00572
         		338 (M + H)
    477
    Figure US20190015377A1-20190117-C00573
         		333 (M + H)
    478
    Figure US20190015377A1-20190117-C00574
         		310 (M + H)
    479
    Figure US20190015377A1-20190117-C00575
         		340 (M + H)
    480
    Figure US20190015377A1-20190117-C00576
         		(M + HCO2 −) 445 (400 MHz, CDCl3): δ 7.92 (d, 1H), 7.52 (d, 1H), 5.40 (dd, 1H), 4.33-4.28 (m, 1H), 3.59 (ddd, 1H), 3.49 (t, 1H), 3.22-3.13 (m, 2H), 1.97-1.82 (m, 4H), 1.75-1.58 (m, 3H), 1.46 (dd, 1H), 1.42-1.37 (m, 1H)
    481
    Figure US20190015377A1-20190117-C00577
         		(M − OH) 381 (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.50 (d, 1H), 5.91-5.88 (m, 1H), 5.39 (dd, 1H), 4.49-4.43 (m, 1H), 3.64 (ddd, 1H), 3.39 (t, 1H), 3.18 (dd, 1H), 2.49-2.39 (m, 1H), 2.22-2.11 (m, 1H), 2.09-1.92 (m, 2H), 1.81-1.59 (m, 3H)
    482
    Figure US20190015377A1-20190117-C00578
         		(M + HCO2 −) 445 (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.55 (d, 1H), 5.41 (dd, 1H), 3.82-3.72 (m, 1H), 3.56 (ddd, 1H), 3.42 (t, 1H), 3.20 (dd, 1H), 2.67 (tt, 1H), 2.17-2.08 (m, 2H), 2.01-1.94 (m, 1H), 1.82-1.75 (m, 1H), 1.60-1.42 (m, 3H), 1.40-1.27 (m, 2H)
    483
    Figure US20190015377A1-20190117-C00579
         		(M + HCO2 −) 445 (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.55 (d, 1H), 5.41 (dd, 1H), 3.82-3.72 (m, 1H), 3.58 (ddd, 1H), 3.40 (t, 1H), 3.18 (d, 1H), 2.67 (tt, 1H), 2.16-2.06 (m, 2H), 2.02-1.95 (m, 1H), 1.86-1.78 (m, 1H), 1.58-1.28 (m, 5H)
    484
    Figure US20190015377A1-20190117-C00580
         		366 (M + H)
    485
    Figure US20190015377A1-20190117-C00581
         		(M − H) 411/ 413
    486
    Figure US20190015377A1-20190117-C00582
         		(M − H) 420
    487
    Figure US20190015377A1-20190117-C00583
         		(M − H) 377
    488
    Figure US20190015377A1-20190117-C00584
         		(M + H) 420
    489
    Figure US20190015377A1-20190117-C00585
         		(M − H) 435
    490
    Figure US20190015377A1-20190117-C00586
         		(M + H) 388
    491
    Figure US20190015377A1-20190117-C00587
         		(M + Na) 449
    492
    Figure US20190015377A1-20190117-C00588
         		(M + Na) 422
    493
    Figure US20190015377A1-20190117-C00589
         		453/455 (M + HCO2 −)
    494
    Figure US20190015377A1-20190117-C00590
         		346 (M − H)
    495
    Figure US20190015377A1-20190117-C00591
         		309 (M − H)
    496
    Figure US20190015377A1-20190117-C00592
         		345 (M − H)
    497
    Figure US20190015377A1-20190117-C00593
         		320 (M − H)
    498
    Figure US20190015377A1-20190117-C00594
         		345 (M − H)
    499
    Figure US20190015377A1-20190117-C00595
         		337 (M − H)
    500
    Figure US20190015377A1-20190117-C00596
         		373 (M − H)
    501
    Figure US20190015377A1-20190117-C00597
         		356 (M − H)
    502
    Figure US20190015377A1-20190117-C00598
         		381 (M − H)
    503
    Figure US20190015377A1-20190117-C00599
         		391 (M − H)
    504
    Figure US20190015377A1-20190117-C00600
         		408 (M − H)
    505
    Figure US20190015377A1-20190117-C00601
         		399 (M − H)
    506
    Figure US20190015377A1-20190117-C00602
         		392 (M − H)
    507
    Figure US20190015377A1-20190117-C00603
         		1HNMR (300 MHz, CDCl3): δ 7.83 (d, 1H), 7.30 (d, 1H), 6.77 (m, 2H), 6.67 (m, 1H), 6.10 (s, 1H), 5.36 (m, 1H), 3.45 (m, 1H), 3.27 (m, 2H).
    508
    Figure US20190015377A1-20190117-C00604
         		361 (M − H)
    509
    Figure US20190015377A1-20190117-C00605
         		397 (M − H)
    510
    Figure US20190015377A1-20190117-C00606
         		355 (M − H)
    511
    Figure US20190015377A1-20190117-C00607
         		391 (M − H)
    512
    Figure US20190015377A1-20190117-C00608
         		1HNMR (300 MHz, CDCl3): δ 8.76 (d, 1H), 6.97 (d, 1H), 5.62 (m, 1H), 3.29 (m, 1H), 3.09 (m, 1H), 3.05 (m, 1H), 2.36 (m, 2H), 1.98 (m, 1H), 1.17 (m, 2H), 0.85 (m, 2H).
    513
    Figure US20190015377A1-20190117-C00609
         		341 (M − H)
    514
    Figure US20190015377A1-20190117-C00610
         		294 (M − H)
    515
    Figure US20190015377A1-20190117-C00611
         		307 (M − H)
    516
    Figure US20190015377A1-20190117-C00612
         		329 (M − H)
    517
    Figure US20190015377A1-20190117-C00613
         		343 (M − H)
    518
    Figure US20190015377A1-20190117-C00614
         		322 (M − H)
    519
    Figure US20190015377A1-20190117-C00615
         		214 (M + H)
    520
    Figure US20190015377A1-20190117-C00616
         		345 (M − H)
    521
    Figure US20190015377A1-20190117-C00617
         		375 (M − H)
    522
    Figure US20190015377A1-20190117-C00618
         		323 (M − H)
    523
    Figure US20190015377A1-20190117-C00619
         		322 (M − H)
    524
    Figure US20190015377A1-20190117-C00620
         		323 (M − H)
    525
    Figure US20190015377A1-20190117-C00621
         		323 (M − H)
    526
    Figure US20190015377A1-20190117-C00622
         		360 (M + H)
    527
    Figure US20190015377A1-20190117-C00623
         		360 (M + H)
    528
    Figure US20190015377A1-20190117-C00624
         		(400 MHz, CDCl3): δ 7.79 (d, 1H), 7.29 (d, 1H), 7.07-7.00 (m, 2H), 6.78 (d, 1H), 6.33 (t, 1H), 5.40 (d, 1H), 4.66 (d, 2H), 4.64-4.58 (m, 1H), 3.38- 3.24 (m, 2H), 3.14 (t, 1H)
    529
    Figure US20190015377A1-20190117-C00625
         		(400 MHz, CDCl3): δ 7.79 (d, 1H), 7.40 (s, 1H), 6.80 (d, 1H), 6.46-6.20 (m, 3H), 5.39 (d, 1H), 4.64 (t, 1H), 4.47 (d, 2H), 3.46-3.24 (m, 2H), 3.14 (t, 1H)
    530
    Figure US20190015377A1-20190117-C00626
         		(400 MHz, CDCl3): δ 7.79 (d, 1H), 7.28 (d, 1H), 7.01-6.94 (m, 3H), 6.35 (t, 1H), 5.38 (d, 1H), 4.61 (m, 2H), 3.70-3.58 (m, 1H), 3.52-3.44 (m, 1H), 3.23 (br s, 1H), 3.00 (s, 3H)
    531
    Figure US20190015377A1-20190117-C00627
         		[M − H]− 392
    532
    Figure US20190015377A1-20190117-C00628
         		[M + H]+ 343
    533
    Figure US20190015377A1-20190117-C00629
         		(400 MHz, CDCl3): δ 8.00 (dd, 1H), 7.84 (dd, 1H), 5.41 (dd, 1H), 5.00- 4.93 (m, 1H), 3.83 (ddd, 1H), 3.72- 3.43 (m, 4H)
    534
    Figure US20190015377A1-20190117-C00630
         		[M − H]− 382
    535
    Figure US20190015377A1-20190117-C00631
         		[M − H]− 382
    536
    Figure US20190015377A1-20190117-C00632
         		[M − H]− 382
    537
    Figure US20190015377A1-20190117-C00633
         		[M − H]− 331
    538
    Figure US20190015377A1-20190117-C00634
         		[M − H]− 406
    539
    Figure US20190015377A1-20190117-C00635
         		[M + H]+ 395
    540
    Figure US20190015377A1-20190117-C00636
         		[M + H]+ 428/ 430
    541
    Figure US20190015377A1-20190117-C00637
         		[M + H]+ 425
    542
    Figure US20190015377A1-20190117-C00638
         		[M + NH4]+ 444
    543
    Figure US20190015377A1-20190117-C00639
         		[M − OH]+ 409
    544
    Figure US20190015377A1-20190117-C00640
         		[M + Cl]− 463/ 465
    545
    Figure US20190015377A1-20190117-C00641
         		[M + Cl]− 463/ 465
    546
    Figure US20190015377A1-20190117-C00642
         		[M + NH4]+ 444
    547
    Figure US20190015377A1-20190117-C00643
         		[M + Cl]− 463/ 465
    548
    Figure US20190015377A1-20190117-C00644
         		[M + NH4]+ 446
    549
    Figure US20190015377A1-20190117-C00645
         		[M + NH4]+ 446
    550
    Figure US20190015377A1-20190117-C00646
         		[M + NH4]+ 446
    551
    Figure US20190015377A1-20190117-C00647
         		[M − OH]+ 409
    552
    Figure US20190015377A1-20190117-C00648
         		[M + NH4]+ 446
    553
    Figure US20190015377A1-20190117-C00649
         		[M + H]+ 366
    554
    Figure US20190015377A1-20190117-C00650
         		[M + NH4]+ 310
    555
    Figure US20190015377A1-20190117-C00651
         		[M + NH4]+ 346
    556
    Figure US20190015377A1-20190117-C00652
         		[M + NH4]+ 346
    557
    Figure US20190015377A1-20190117-C00653
         		[M + Na]+ 454
    558
    Figure US20190015377A1-20190117-C00654
         		[M + H]+ 380
    559
    Figure US20190015377A1-20190117-C00655
         		[M + H]+ 383
    560
    Figure US20190015377A1-20190117-C00656
         		[M + H]+ 369
    561
    Figure US20190015377A1-20190117-C00657
         		[M + H]+ 369
    562
    Figure US20190015377A1-20190117-C00658
         		[M + H]+ 397
    563
    Figure US20190015377A1-20190117-C00659
         		[M + Na]+ 436/ 438
    564
    Figure US20190015377A1-20190117-C00660
         		[M − H]− 393
    565
    Figure US20190015377A1-20190117-C00661
         		[M + Na]+ 436/ 438
    566
    Figure US20190015377A1-20190117-C00662
         		[M + H]+ 383
    567
    Figure US20190015377A1-20190117-C00663
         		[M + H]+ 434
    568
    Figure US20190015377A1-20190117-C00664
         		[M + H]+ 419
    569
    Figure US20190015377A1-20190117-C00665
         		[M − H]− 402
    570
    Figure US20190015377A1-20190117-C00666
         		[M + H]+ 405
    571
    Figure US20190015377A1-20190117-C00667
         		[M − H]− 381 (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.07 (d, 1H), 6.15 (tt, 1H), 5.38 (dd, 1H), 4.44-4.29 (m, 2H), 3.55-3.39 (m, 2H), 3.16 (d, 1H)
    572
    Figure US20190015377A1-20190117-C00668
         		[M − H]− 407 (400 MHz, CDCl3): δ 7.96 (d, 1H), 6.86 (d, 1H), 5.37 (dd, 1H), 4.86-4.76 (m, 1H), 3.53-3.35 (m, 2H), 3.27-3.14 (m, 3H), 2.92-2.78 (m, 2H)
    573
    Figure US20190015377A1-20190117-C00669
         		[M − H]− 405 (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.11 (d, 1H), 5.38 (dd, 1H), 4.92 (dd, 2H), 4.68 (dd, 2H), 4.59-4.46 (m, 2H), 3.54-3.36 (m, 2H), 3.19 (d, 1H)
    574
    Figure US20190015377A1-20190117-C00670
         		[M + H]+ 373 (400 MHz, (CD3)2CO): δ 8.11 (dd, 1H), 7.33 (d, 1H), 5.87 (dd, 1H), 5.65-5.59 (m, 1H), 5.17-5.08 (m, 1H), 3.40-3.26 (m, 2H), 3.27 (s, 3H), 2.98- 2.81 (m, 2H), 2.80 (t, 1H)
    575
    Figure US20190015377A1-20190117-C00671
         		[M + H]+ 373 (400 MHz, CDCl3): δ 8.06 (dd, 1H), 6.87 (d, 1H), 5.92 (dd, 1H), 5.78 (td, 1H), 4.86-4.76 (m, 1H), 3.98 (d, 1H), 3.25-3.14 (m, 2H), 3.22 (s, 3H), 2.95- 2.78 (m, 2H)
    576
    Figure US20190015377A1-20190117-C00672
         		[M + H]+ 391 (400 MHz, CDCl3): δ 8.13 (dd, 1H), 6.93 (d, 1H), 5.76 (dd, 1H), 5.59-5.53 (m, 1H), 5.47 (dd, 1H), 5.18 (dd, 1H), 4.90-4.80 (m, 1H), 3.29-3.16 (m, 2H), 3.16 (d, 1H), 2.97-2.81 (m, 2H)
    577
    Figure US20190015377A1-20190117-C00673
         		[M + NH4]+ 372 (400 MHz, (CD3)2CO): δ 8.05 (dd, 1H), 7.25 (d, 1H), 5.99 (dd, 1H), 5.74 (td, 1H), 5.16 (ddt, 1H), 5.13-5.03 (m, 1H), 4.84 (dd, 1H), 3.39-3.25 (m, 2H), 3.28 (s, 3H), 2.95-2.74 (m, 2H)
    578
    Figure US20190015377A1-20190117-C00674
         		[M + NH4]+ 390 (400 MHz, (CD3)2CO): δ 8.09 (dd, 1H), 7.12 (d, 1H), 5.95 (dd, 1H), 5.66 (dd, 1H), 5.61 (td, 1H), 5.34 (dd, 1H), 5.07 (ddt, 1H), 5.03-4.93 (m, 1H), 3.89 (dd, 1H), 3.33-3.18 (m, 2H), 2.95-2.72 (m, 2H)
    579
    Figure US20190015377A1-20190117-C00675
         		[M − H + formate] − 363 (400 MHz, CDCl3): δ 7.59 (d, 1H), 6.89 (d, 1H), 6.11 (tt, 1H), 5.25-5.20 (m, 1H), 4.33-4.20 (m, 2H), 3.50-3.30 (m, 2H), 2.62-2.59 (m, 1H)
    580
    Figure US20190015377A1-20190117-C00676
         		[M + H]+ 332 (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.69 (d, 1H), 6.90 (d, 1H), 6.12 (tt, 1H), 4.34-4.26 (m, 2H), 3.49 (t, 2H)
    581
    Figure US20190015377A1-20190117-C00677
         		[M − H]− 344 (400 MHz, CDCl3): δ 8.33 (d, 1H), 7.88-7.84 (m, 1H), 7.04 (d, 1H), 5.82 (dd, 1H), 4.67 (dt, 2H), 4.33-4.24 (m, 2H), 2.32-2.20 (m, 2H)
    582
    Figure US20190015377A1-20190117-C00678
         		(400 MHz, CDCl3): δ 7.80-7.77 (m, 1H), 7.05 (d, 1H), 5.74 (dd, 1H), 5.25-5.20 (m, 1H), 4.66 (dt, 2H), 4.33-4.22 (m, 2H), 2.52 (d, 1H), 2.32- 2.19 (m, 2H)
    583
    Figure US20190015377A1-20190117-C00679
         		(300 MHz, CDCl3): δ 7.87 (d, 1H), 6.95 (d, 1H), 5.58 (d, 1H), 4.08 (m, 2H), 2.06-3.17 (m, 2H), 2.84-2.94 (m, 1H), 2.37 (m, 1H), 2.27 (m, 1H), 1.86 (m, 2H), 1.07 (t, 3H)
    584
    Figure US20190015377A1-20190117-C00680
         		[M − H]− 359 (300 MHz, CDCl3): δ 7.95 (d, 1H), 7.04 (d, 1H), 5.36 (dd, 1H), 4.10 (m, 2H), 3.45 (m, 1H), 3.39 (m, 1H), 3.20 (m, 1H), 1.88 (m, 2H), 1.07 (t, 3H)
    585
    Figure US20190015377A1-20190117-C00681
         		[M + H]+ 337
    586
    Figure US20190015377A1-20190117-C00682
         		[M − H + HCOOH] − 345 (300 MHz, CDCl3): δ 7.57 (d, 1H), 7.00 (t, 1H), 6.85 (t, 1H), 6.13 (t, 1H), 5.32 (m, 1H), 4.24 (t, 2H), 3.25-3.48 (m, 2H), 2.45 (d, 1H)
    587
    Figure US20190015377A1-20190117-C00683
         		389 (M − H + HCOOH)
    588
    Figure US20190015377A1-20190117-C00684
         		(300 MHz, CDCl3): δ 7.90 (d, 1H), 6.97 (d, 1H), 5.58 (m, 1H), 3.97 (s, 3H), 3.17 (m, 1H), 3.12 (m, 1H), 2.87 (m, 1H), 2.37 (m, 1H), 2.27 (m, 1H).
    589
    Figure US20190015377A1-20190117-C00685
         		(300 MHz, CDCl3): δ 7.86 (d, 1H), 6.94 (d, 1H), 5.58 (m, 1H), 4.20 (m, 2H), 3.17 (m, 1H), 3.09 (m, 1H), 2.89 (m, 1H), 2.35 (m, 1H), 2.26 (m, 1H), 1.47 (t, 3H).
    590
    Figure US20190015377A1-20190117-C00686
         		331 (M − H)
    591
    Figure US20190015377A1-20190117-C00687
         		345 (M − H)
    592
    Figure US20190015377A1-20190117-C00688
         		(300 MHz, CDCl3): δ 7.85 (d, 1H), 6.94 (d, 1H), 5.57 (m, 1H), 4.72 (m, 1H), 3.18 (m, 1H), 3.11 (m, 1H), 2.86 (m, 1H), 2.35 (m, 1H), 2.25 (m, 1H), 1.41 (d, 6H).
    593
    Figure US20190015377A1-20190117-C00689
         		359 (M − H)
    594
    Figure US20190015377A1-20190117-C00690
         		389 (M − H)
    595
    Figure US20190015377A1-20190117-C00691
         		375 (M − H)
    596
    Figure US20190015377A1-20190117-C00692
         		(300 MHz, CD3OD): δ 7.89 (d, 1H), 7.28 (d, 1H), 5.44 (m, 1H), 5.27 (m, 1H), 5.14 (d, 1H), 3.77-3.96 (m 4H), 2.93 (m, 1H), 2.76 (m, 1H), 2.29 (m, 1H), 2.15 (m, 1H), 1.97 (m, 2H).
    597
    Figure US20190015377A1-20190117-C00693
         		(300 MHz, CDCl3): δ 7.85 (d, 1H), 6.92 (d, 1H), 5.57 (m, 1H), 3.96 (m, 2H), 3.17 (m, 1H), 3.08 (m, 1H), 2.94 (m, 1H), 2.36 (m, 1H), 2.26 (m, 1H), 1.28 (m, 1H), 0.68 (m, 2H), 0.39 (m, 2H).
    598
    Figure US20190015377A1-20190117-C00694
         		371 (M − H)
    599
    Figure US20190015377A1-20190117-C00695
         		(300 MHz, CDCl3): δ 7.87 (d, 1H), 6.99 (d, 1H), 5.57 (m, 1H), 4.27 (m, 2H), 3.80 (m, 2H), 3.45 (s, 3H), 3.15 (m, 1H), 3.11 (m, 1H), 2.93 (m, 1H), 2.36 (m, 1H), 2.27 (m, 1H)
    600
    Figure US20190015377A1-20190117-C00696
         		372 (M + NH4)
    601
    Figure US20190015377A1-20190117-C00697
         		(300 MHz, CDCl3): δ 7.82 (d, 1H), 6.79 (d, 1H), 5.57 (m, 1H), 4.78 (m, 1H), 3.17 (m, 1H), 3.09 (m, 1H), 2.89 (m, 1H), 2.50 (m, 2H), 2.20-2.28 (m, 4H), 1.77 (m, 1H), 1.55 (m, 1H).
    602
    Figure US20190015377A1-20190117-C00698
         		371 (M − H)
    603
    Figure US20190015377A1-20190117-C00699
         		(300 MHz, CDCl3): δ 7.85 (d, 1H), 6.95 (d, 1H), 5.56 (m, 1H), 4.91 (m, 1H), 3.18 (m, 1H), 3.10 (m, 1H), 2.87 (m, 1H), 2.32 (m, 1H), 2.25 (m, 1H), 1.56-1.99 (m, 8H).
    604
    Figure US20190015377A1-20190117-C00700
         		387 (M − H)
    605
    Figure US20190015377A1-20190117-C00701
         		385 (M − H)
    606
    Figure US20190015377A1-20190117-C00702
         		(300 MHz, CDCl3): δ 7.92 (d, 1H), 7.04 (d, 1H), 5.36 (d, 1H), 4.60 (m, 1H), 3.46 (m, 1H), 3.39 (m, 1H), 3.14 (m, 2H), 2.80 (m, 2H), 2.05 (m, 2H), 1.76 (m, 2H), 1.55 (m, 4H)
    607
    Figure US20190015377A1-20190117-C00703
         		402 (M + H)
    608
    Figure US20190015377A1-20190117-C00704
         		389 (M − H)
    609
    Figure US20190015377A1-20190117-C00705
         		(300 MHz, CDCl3): δ 7.90 (d, 1H), 6.94 (d, 1H), 5.60 (m, 1H), 4.04 (m, 2H), 3.20 (m, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.40 (m, 1H), 2.31 (m, 1H), 1.54 (s, 3H), 1.53 (s, 3H)
    610
    Figure US20190015377A1-20190117-C00706
         		398 (M − H)
    611
    Figure US20190015377A1-20190117-C00707
         		(300 MHz, CDCl3): δ 7.90 (d, 1H), 6.94 (d, 1H), 5.60 (m, 1H), 4.04 (m, 2H), 3.20 (m, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.40 (m, 1H), 2.31 (m, 1H), 1.54 (s, 3H), 1.53 (s, 3H)
    612
    Figure US20190015377A1-20190117-C00708
         		377 (M + H)
    613
    Figure US20190015377A1-20190117-C00709
         		371 (M − H + HCOOH)
    614
    Figure US20190015377A1-20190117-C00710
         		363 (M + H)
    615
    Figure US20190015377A1-20190117-C00711
         		425 (M − H + HCOOH)
    616
    Figure US20190015377A1-20190117-C00712
         		382 (M + NH4 +)
    617
    Figure US20190015377A1-20190117-C00713
         		399 (M − H)
    618
    Figure US20190015377A1-20190117-C00714
         		415 (M − H)
    619
    Figure US20190015377A1-20190117-C00715
         		406 (M − H + HCOOH)
    620
    Figure US20190015377A1-20190117-C00716
         		398 (M + H)
    621
    Figure US20190015377A1-20190117-C00717
         		411 (M − H + HCOOH)
    622
    Figure US20190015377A1-20190117-C00718
         		401 (M − H)
    623
    Figure US20190015377A1-20190117-C00719
         		415 (M − H)
    624
    Figure US20190015377A1-20190117-C00720
         		425 (M − H + HCOOH)
    625
    Figure US20190015377A1-20190117-C00721
         		372 (M + NH4)
    626
    Figure US20190015377A1-20190117-C00722
         		389 (M − H)
    627
    Figure US20190015377A1-20190117-C00723
         		444 (M + H)
    628
    Figure US20190015377A1-20190117-C00724
         		480 (M + H)
    629
    Figure US20190015377A1-20190117-C00725
         		430 (M + H)
    630
    Figure US20190015377A1-20190117-C00726
         		466 (M + H)
    631
    Figure US20190015377A1-20190117-C00727
         		439 (M + H)
    632
    Figure US20190015377A1-20190117-C00728
         		404 (M + H)
    633
    Figure US20190015377A1-20190117-C00729
         		377 (M + H)
    634
    Figure US20190015377A1-20190117-C00730
         		416 (M + H)
    635
    Figure US20190015377A1-20190117-C00731
         		362 (M + H)
    636
    Figure US20190015377A1-20190117-C00732
         		404 (M + H)
    637
    Figure US20190015377A1-20190117-C00733
         		440 (M + H)
    638
    Figure US20190015377A1-20190117-C00734
         		390 (M + H)
    639
    Figure US20190015377A1-20190117-C00735
         		389 (M − H)
    640
    Figure US20190015377A1-20190117-C00736
         		374 (M − H)
    641
    Figure US20190015377A1-20190117-C00737
         		390 (M + H)
    642
    Figure US20190015377A1-20190117-C00738
         		(300 MHz, CDCl3): δ 7.93 (d, 1H), 6.94 (d, 1H), 5.35 (m, 1H), 4.96 (m, 1H), 3.38-3.47 (m, 3H), 2.82-2.92 (m 3H), 2.52 (m, 1H), 2.43 (m 1H), 2.42 (s, 3H), 2.04 (m 1H)
    643
    Figure US20190015377A1-20190117-C00739
         		388 (M + H)
    644
    Figure US20190015377A1-20190117-C00740
         		433 (M − H + HCOOH)
    645
    Figure US20190015377A1-20190117-C00741
         		402 (M − H)
    646
    Figure US20190015377A1-20190117-C00742
         		389 (M − H)
    647
    Figure US20190015377A1-20190117-C00743
         		418 (M + H)
    648
    Figure US20190015377A1-20190117-C00744
         		(300 MHz, CDCl3): δ 7.92 (d, 1H), 6.87 (d, 1H), 5.36 (m, 1H), 4.93 (m, 1H), 3.80 (s, 3H), 3.44-3.60 (m, 2H), 3.22 (m, 1H), 1.71 (d, 3H)
    649
    Figure US20190015377A1-20190117-C00745
         		388 (M − H)
    650
    Figure US20190015377A1-20190117-C00746
         		376 (M + H)
    651
    Figure US20190015377A1-20190117-C00747
         		(400 MHz, CDCl3): δ 7.31 (m, 1H), 7.17 (d, 1H), 6.82 (d, 1H), 6.09 (t, 1H), 5.15 (m, 1H), 4.20 (m, 2H), 3.45 (m, 1H), 3.27 (m, 1H), 2.27 (m, 1H)
    652
    Figure US20190015377A1-20190117-C00748
         		313 (M − H + HCOOH)
    653
    Figure US20190015377A1-20190117-C00749
         		(400 MHz, CDCl3): δ 7.56 (d, 1H), 7.17 (d, 1H), 5.13 (m, 1H), 3.56 (m, 2H), 2.50 (s, 1H)
    654
    Figure US20190015377A1-20190117-C00750
         		359 (M − H)
    655
    Figure US20190015377A1-20190117-C00751
         		359 (M − H)
    656
    Figure US20190015377A1-20190117-C00752
         		371 (M − H)
    657
    Figure US20190015377A1-20190117-C00753
         		371 (M − H)
    658
    Figure US20190015377A1-20190117-C00754
         		442 (M + HCO2 −)
    659
    Figure US20190015377A1-20190117-C00755
         		389 (M − H)
    660
    Figure US20190015377A1-20190117-C00756
         		389 (M − H)
    661
    Figure US20190015377A1-20190117-C00757
         		424 (M + HCO2 −)
    662
    Figure US20190015377A1-20190117-C00758
         		265 (M − OH)
    663
    Figure US20190015377A1-20190117-C00759
         		(M + NH4) 426
    664
    Figure US20190015377A1-20190117-C00760
         		(M − H) 421
    665
    Figure US20190015377A1-20190117-C00761
         		(M + H) 410
    666
    Figure US20190015377A1-20190117-C00762
         		(400 MHz, CDCl3): δ 8.15 (s, 1H), 6.12 (t, 1H), 4.96-4.87 (1H), 4.22- 4.09 (2H), 3.62-3.50 (2H), 2.49 (1H)
    667
    Figure US20190015377A1-20190117-C00763
         		(M − OH) 467
    668
    Figure US20190015377A1-20190117-C00764
         		(M + NH4) 330
    669
    Figure US20190015377A1-20190117-C00765
         		(M + H) 350
    670
    Figure US20190015377A1-20190117-C00766
         		(400 MHz, CDCl3): δ 7.63 (d, 1H), 7.25 (d, 1H), 6.62 (t, 1H), 5.30-5.25 (m, 1H), 3.58-3.37 (m, 2H), 2.54-2.51 (m, 1H)
    671
    Figure US20190015377A1-20190117-C00767
         		(400 MHz, CDCl3): δ 7.59 (d, 1H), 7.18 (d, 1H), 6.60 (t, 1H), 5.40-5.23 (m, 2H), 3.40-3.12 (m, 2H), 2.55-2.51 (m, 1H)
    672
    Figure US20190015377A1-20190117-C00768
         		(M + H) 358
    673
    Figure US20190015377A1-20190117-C00769
         		[M − OH]+ 229
    674
    Figure US20190015377A1-20190117-C00770
         		[M − H + HCOOH]− 284
    675
    Figure US20190015377A1-20190117-C00771
         		[M − H + HCOOH]− 445
    676
    Figure US20190015377A1-20190117-C00772
         		[M + NH4]+ 360
    677
    Figure US20190015377A1-20190117-C00773
         		[M + NH4]+ 382
    678
    Figure US20190015377A1-20190117-C00774
         		[M + NH4]+ 346
    679
    Figure US20190015377A1-20190117-C00775
         		(400 MHz, CDCl3): δ 7.62 (d, 1H), 6.63 (d, 1H), 4.94 (dd, 1H), 3.81 (s, 3H), 3.46-3.38 (m, 2H), 2.43-2.40 (m, 1H)
    680
    Figure US20190015377A1-20190117-C00776
         		[M + Na]+ 289
    681
    Figure US20190015377A1-20190117-C00777
         		(400 MHz, CDCl3): δ 7.64 (d, 1H), 6.61 (d, 1H), 6.07 (tt, 1H), 4.94 (d, 1H), 4.19 (td, 2H), 3.50-3.42 (m, 2H), 2.41 (brs, 1H)
    682
    Figure US20190015377A1-20190117-C00778
         		(400 MHz, CDCl3): δ 7.59 (d, 1H), 6.61 (d, 1H), 4.98-4.91 (m, 1H), 3.92 (td, 2H), 3.48-3.39 (m, 2H), 2.40 (brs, 1H), 1.84-1.76 (m, 2H), 1.02 (t, 3H)
    683
    Figure US20190015377A1-20190117-C00779
         		(400 MHz, CDCl3): δ 7.58 (d, 1H), 6.57 (d, 1H) 5.26 (dq, 1H) 5.06-5.01 (m, 1H), 3.91 (t, 2H), 3.21 (dd, 2H), 2.42-2.38 (m, 1H), 1.84-1.74 (m, 2H), 1.03 (t, 3H)
    684
    Figure US20190015377A1-20190117-C00780
         		[M + H]+ 317
    685
    Figure US20190015377A1-20190117-C00781
         		[M + NH4]− 251
    686
    Figure US20190015377A1-20190117-C00782
         		[M − H + HCOOH]− 363
    687
    Figure US20190015377A1-20190117-C00783
         		(400 MHz, CDCl3): δ 7.42 (d, 1H), 6.73 (d, 1H), 6.07 (tt, 1H), 5.08 (d, 1H), 4.23-4.17 (m, 2H), 3.54-3.35 (m, 2H), 2.49 (brs, 1H)
    688
    Figure US20190015377A1-20190117-C00784
         		[M + H]+ 276
    689
    Figure US20190015377A1-20190117-C00785
         		(400 MHz, CDCl3): δ 7.78 (d, 1H), 7.09 (d, 1H), 6.17 (tt, 1H), 5.79 (dd, 1H), 5.24-5.18 (m, 1H), 4.42-4.31 (m, 2H), 2.47-2.44 (m, 1H)
    690
    Figure US20190015377A1-20190117-C00786
         		(400 MHz, CDCl3): δ 7.74 (d, 1H), 7.05 (d, 1H), 6.16 (tt, 1H), 6.02 (dd, 1H), 5.54-5.48 (m, 1H), 4.35 (td, 2H), 2.68 (brd, 1H)
    691
    Figure US20190015377A1-20190117-C00787
         		[M − H]− 290
    692
    Figure US20190015377A1-20190117-C00788
         		[M + H]+ 310
    693
    Figure US20190015377A1-20190117-C00789
         		[M + H]+ 286
    694
    Figure US20190015377A1-20190117-C00790
         		[M − H + HCOOH]− 343
    695
    Figure US20190015377A1-20190117-C00791
         		[M + H]+ 317
    696
    Figure US20190015377A1-20190117-C00792
         		(400 MHz, CDCl3): δ 7.56 (d, 1H), 6.84 (d, 1H), 6.11 (tt, 1H), 5.38-5.22 (m, 2H), 4.26 (td, 2H), 3.33-3.07 (m, 2H), 2.52-2.48 (m, 1H)
    697
    Figure US20190015377A1-20190117-C00793
         		(400 MHz, CDCl3): δ 7.56 (d, 1H), 6.87 (d, 1H), 6.12 (tt, 1H), 5.49-5.22 (m, 2H), 4.31-4.23 (m, 2H), 3.48-3.06 (m, 2H), 2.48 (brs, 1H)
    698
    Figure US20190015377A1-20190117-C00794
         		(400 MHz, CDCl3): δ 7.62 (d, 1H), 7.61 (s, 1H), 6.81 (d, 1H), 6.13 (tt, 1H), 4.28 (td, 2H), 3.09-2.97 (m, 4H)
    699
    Figure US20190015377A1-20190117-C00795
         		[M − H + HCOOH]− 381
    700
    Figure US20190015377A1-20190117-C00796
         		[M − H]− 344
    701
    Figure US20190015377A1-20190117-C00797
         		[M − H + HCOOH]− 377
    702
    Figure US20190015377A1-20190117-C00798
         		[M + H]+ 328
    703
    Figure US20190015377A1-20190117-C00799
         		[M + H]+ 310
    704
    Figure US20190015377A1-20190117-C00800
         		[M + Na]+ 320
    705
    Figure US20190015377A1-20190117-C00801
         		[M + H]+ 312
    706
    Figure US20190015377A1-20190117-C00802
         		363 (M − H)−
    707
    Figure US20190015377A1-20190117-C00803
         		472 (M + HCO2)−
    708
    Figure US20190015377A1-20190117-C00804
         		491 (M + HCO2)−
    709
    Figure US20190015377A1-20190117-C00805
         		373 (M − H)−
    710
    Figure US20190015377A1-20190117-C00806
         		373 (M − H)−
    711
    Figure US20190015377A1-20190117-C00807
         		355 (M − H)−
    712
    Figure US20190015377A1-20190117-C00808
         		377 (M − H)−
    713
    Figure US20190015377A1-20190117-C00809
         		387 (M − H)−
    714
    Figure US20190015377A1-20190117-C00810
         		401 (M − H)−
    715
    Figure US20190015377A1-20190117-C00811
         		401 (M − H)−
    716
    Figure US20190015377A1-20190117-C00812
         		385 (M − H)−
    717
    Figure US20190015377A1-20190117-C00813
         		387 (M − H)−
    718
    Figure US20190015377A1-20190117-C00814
         		413 (M − H)−
    719
    Figure US20190015377A1-20190117-C00815
         		416 (M + H)+
    720
    Figure US20190015377A1-20190117-C00816
         		416 (M + H)+
    721
    Figure US20190015377A1-20190117-C00817
         		495 (M + HCO2)−
    722
    Figure US20190015377A1-20190117-C00818
         		388 (M + H − CO2—C4H8)+
    723
    Figure US20190015377A1-20190117-C00819
         		451 (M − H)−
    724
    Figure US20190015377A1-20190117-C00820
         		388 (M + H)+
    725
    Figure US20190015377A1-20190117-C00821
         		430 (M + H)+
    726
    Figure US20190015377A1-20190117-C00822
         		510 (M + HCO2)−
    727
    Figure US20190015377A1-20190117-C00823
         		407 (M − H)−
    728
    Figure US20190015377A1-20190117-C00824
         		407 (M − H)
    729
    Figure US20190015377A1-20190117-C00825
         		439 (M + H)+
    730
    Figure US20190015377A1-20190117-C00826
         		401 (M − H)−
    731
    Figure US20190015377A1-20190117-C00827
         		401 (M − H)−
    732
    Figure US20190015377A1-20190117-C00828
         		439 (M + H)+
    733
    Figure US20190015377A1-20190117-C00829
         		436 (M + H)+
    734
    Figure US20190015377A1-20190117-C00830
         		344 (M + H)+
    735
    Figure US20190015377A1-20190117-C00831
         		353 (M + H)+
    736
    Figure US20190015377A1-20190117-C00832
         		355 (M + H)+
    737
    Figure US20190015377A1-20190117-C00833
         		355 (M + H)+
    738
    Figure US20190015377A1-20190117-C00834
         		353 (M + H)+
    739
    Figure US20190015377A1-20190117-C00835
         		402 (M + Na)+
    740
    Figure US20190015377A1-20190117-C00836
         		355 (M + H)+
    741
    Figure US20190015377A1-20190117-C00837
         		380 (M + H)+
    742
    Figure US20190015377A1-20190117-C00838
         		390 (M + NH4)+
    743
    Figure US20190015377A1-20190117-C00839
         		372 (M + NH4)+
    744
    Figure US20190015377A1-20190117-C00840
         		[M + NH4]+ 420
    745
    Figure US20190015377A1-20190117-C00841
         		[M + NH4]+ 384
    746
    Figure US20190015377A1-20190117-C00842
         		[M + NH4]+ 404
    747
    Figure US20190015377A1-20190117-C00843
         		[M + NH4]+ 422
    748
    Figure US20190015377A1-20190117-C00844
         		[M + NH4]+ 429
    749
    Figure US20190015377A1-20190117-C00845
         		[M + NH4]+ 445
    750
    Figure US20190015377A1-20190117-C00846
         		[M + NH4]+ 408
    751
    Figure US20190015377A1-20190117-C00847
         		[M + NH4]+ 382
    752
    Figure US20190015377A1-20190117-C00848
         		[M + NH4]+ 381
    753
    Figure US20190015377A1-20190117-C00849
         		[M + NH4]+ 354
    754
    Figure US20190015377A1-20190117-C00850
         		[M + NH4]+ 379
    755
    Figure US20190015377A1-20190117-C00851
         		[M + NH4]+ 364
    756
    Figure US20190015377A1-20190117-C00852
         		[M + NH4]+ 390
    757
    Figure US20190015377A1-20190117-C00853
         		[M + NH4]+ 407 (400 MHz, CDCl3): δ 8.09 (d, 1H), 7.07 (d, 1H), 5.82-5.66 (m, 1H), 5.61- 5.57 (m, 1H), 4.73 (m, 1H), 3.41 (d, 1H), 3.20 (s, 3H), 2.87 (m, 1H), 2.17- 1.80 (m, 8H)
    758
    Figure US20190015377A1-20190117-C00854
         		[M + NH4]+ 407 (400 MHz, CDCl3): δ 8.07 (dd, 1H), 7.04 (d, 1H), 5.85-5.70 (m, 1H), 5.62- 5.58 (m, 1H), 4.65 (m, 1H), 3.25 (d, 1H), 3.20 (s, 3H), 2.76-2.74 (m, 1H), 2.12-1.55 (m, 8H)
    759
    Figure US20190015377A1-20190117-C00855
         		[M + NH4]+ 404
    760
    Figure US20190015377A1-20190117-C00856
         		[M + NH4]+ 379 (400 MHz, CDCl3): δ 8.10 (dd, 1H), 6.86 (d, 1H), 5.82-5.66 (m, 1H), 5.61- 5.58 (m, 1H), 5.17-5.14 (m, 1H), 3.32-3.29 (m, 1H), 3.24 (d, 1H), 3.20 (s, 3H), 2.99-2.93 (m, 2H), 2.76-2.70 (m, 2H)
    761
    Figure US20190015377A1-20190117-C00857
         		[M + NH4]+ 379 (400 MHz, CDCl3): δ 8.08 (dd, 1H), 6.84 (d, 1H), 5.85-5.69 (m, 1H), 5.62- 5.58 (m, 1H), 4.86-4.79 (m, 1H), 3.24 (d, 1H), 3.20 (s, 3H), 3.07-3.00 (m, 2H), 2.96-2.87 (m, 1H), 2.76-2.66 (m, 2H)
    762
    Figure US20190015377A1-20190117-C00858
         		[M + NH4]+ 378
    763
    Figure US20190015377A1-20190117-C00859
         		[M + NH4]+ 397 (400 MHz, CDCl3): δ 8.06 (dd, 1H), 6.90 (d, 1H), 5.85-5.70 (m, 1H), 5.59- 5.56 (m, 1H), 5.39-5.32 (m, 2H), 4.79-4.76 (m, 1H), 3.24 (d, 1H), 3.20 (s, 3H), 2.83-2.74 (m, 3H), 2.63-2.55 (m, 2H)
    764
    Figure US20190015377A1-20190117-C00860
         		[M + NH4]+ 379 (400 MHz, CDCl3): δ 8.10 (dd, 1H), 7.09 (d, 1H), 5.91-5.76 (m, 1H), 5.58- 5.55 (m, 1H), 4.48-4.44 (m, 1H), 4.14-4.10 (m, 1H), 3.41 (d, 1H), 3.20 (s, 3H), 1.94-1.91 (m, 1H), 1.81-1.76 (m, 1H), 1.46-1.41 (m, 1H), 1.20-1.18 (m, 1H)
    765
    Figure US20190015377A1-20190117-C00861
         		[M + NH4]+ 379 (400 MHz, CDCl3): δ 8.12 (dd, 1H), 7.10 (d, 1H), 5.91-5.75 (m, 1H), 5.62- 5.58 (m, 1H), 4.39-4.29 (m, 2H), 3.26 (d, 1H), 3.21 (s, 3H), 1.90-1.86 (m, 1H), 1.79-1.76 (m, 1H), 1.45-1.39 (m, 1H), 1.26-1.22 (m, 1H)
    766
    Figure US20190015377A1-20190117-C00862
         		[M + NH4]+ 393 (400 MHz, CDCl3): δ 8.10 (dd, 1H), 6.88 (d, 1H), 5.82-5.66 (m, 1H), 5.61- 5.58 (m, 1H), 5.08-5.02 (m, 1H), 3.29 (d, 1H), 3.20 (s, 3H), 3.19-3.14 (m, 2H), 2.42-2.32 (m, 2H), 1.65 (s, 3H)
    767
    Figure US20190015377A1-20190117-C00863
         		[M + NH4]+ 393 (400 MHz, CDCl3): δ 8.05 (d, 1H), 6.81 (d, 1H), 5.87-5.71 (m, 1H), 5.61- 5.58 (m, 1H), 4.97-4.91 (m, 1H), 3.25 (d, 1H), 3.20 (s, 3H), 2.92-2.76 (m, 2H), 2.74-2.70 (m, 2H), 1.65 (s, 3H)
    768
    Figure US20190015377A1-20190117-C00864
         		[M + NH4]+ 390 (400 MHz, CDCl3): δ 8.11 (dd, 1H), 7.07 (d, 1H), 5.85-5.69 (m, 1H), 5.62- 5.58 (m, 1H), 4.36-4.32 (m, 1H), 4.21-4.17 (m, 1H), 3.27 (d, 1H), 3.20 (s, 3H), 2.18-2.10 (m, 1H), 1.72-1.67 (m, 2H), 1.41-1.33 (m, 1H)
    769
    Figure US20190015377A1-20190117-C00865
         		[M + NH4]+ 390 (400 MHz, CDCl3): δ 8.11 (dd, 1H), 7.06 (d, 1H), 5.87-5.72 (m, 1H), 5.61- 5.57 (m, 1H), 4.25-4.23 (m, 2H), 3.27 (d, 1H), 3.20 (s, 3H), 2.22-2.10 (m, 1H), 1.73-1.70 (m, 2H), 1.39-1.36 (m, 1H)
    770
    Figure US20190015377A1-20190117-C00866
         		[M + NH4]+ 379 (400 MHz, CDCl3): δ 8.10 (dd, 1H), 7.02 (d, 1H), 5.83-5.67 (m, 1H), 5.61- 5.58 (m, 1H), 4.25-4.22 (m, 1H), 4.14-4.09 (m, 1H), 3.32-3.29 (m, 1H), 3.21 (s, 3H), 2.06-2.04 (m, 1H), 1.59- 1.55 (m, 1H), 1.47-1.44 (m, 1H), 1.28-1.25 (m, 1H)
    771
    Figure US20190015377A1-20190117-C00867
         		[M + NH4]+ 418
    772
    Figure US20190015377A1-20190117-C00868
         		[M + NH4]+ 393
    773
    Figure US20190015377A1-20190117-C00869
         		[M + NH4]+ 340
    774
    Figure US20190015377A1-20190117-C00870
         		[M + NH4]+ 378
    775
    Figure US20190015377A1-20190117-C00871
         		[M + NH4]+ 366
    776
    Figure US20190015377A1-20190117-C00872
         		[M + NH4]+ 260
    777
    Figure US20190015377A1-20190117-C00873
         		[M + NH4]+ 296
    778
    Figure US20190015377A1-20190117-C00874
         		[M + NH4]+ 310
    779
    Figure US20190015377A1-20190117-C00875
         		[M + NH4]+ 336
    780
    Figure US20190015377A1-20190117-C00876
         		[M + NH4]+ 408
    781
    Figure US20190015377A1-20190117-C00877
         		[M + NH4]+ 372
    782
    Figure US20190015377A1-20190117-C00878
         		(400 MHz, CDCl3): δ 7.89 (d, 1H), 6.98 (d, 1H), 6.55 (t, J = 54 Hz, 1H), 5.41 (d, 1H), 4.68 (m, 1H), 3.98-3.88 (m, 2H), 3.66-3.54 (m, 2H), 3.48-3.26 (m, 2H), 1.87-1.74 (m, 2H), 1.62-1.51 (m, 2H)
    783
    Figure US20190015377A1-20190117-C00879
         		[M + NH4]+ 402
    784
    Figure US20190015377A1-20190117-C00880
         		[M + NH4]+ 392
    785
    Figure US20190015377A1-20190117-C00881
         		[M + NH4]+ 406
    786
    Figure US20190015377A1-20190117-C00882
         		[M + NH4]+ 415
    787
    Figure US20190015377A1-20190117-C00883
         		[M + NH4]+ 415
    788
    Figure US20190015377A1-20190117-C00884
         		[M + NH4]+ 429
    789
    Figure US20190015377A1-20190117-C00885
         		[M + NH4]+ 429
    790
    Figure US20190015377A1-20190117-C00886
         		[M + NH4]+ 429
    791
    Figure US20190015377A1-20190117-C00887
         		[M + HCl − H]− 508
    792
    Figure US20190015377A1-20190117-C00888
         		[M + H]+ 374
    793
    Figure US20190015377A1-20190117-C00889
         		[M + NH4]+ 469
    794
    Figure US20190015377A1-20190117-C00890
         		[M + NH4]+ 411
    795
    Figure US20190015377A1-20190117-C00891
         		[M + NH4]+ 411
    796
    Figure US20190015377A1-20190117-C00892
         		[M + NH4]+ 384
    797
    Figure US20190015377A1-20190117-C00893
         		402 (M + H)
    798
    Figure US20190015377A1-20190117-C00894
         		[M + NH4]+ 404
    799
    Figure US20190015377A1-20190117-C00895
         		[M + NH4]+ 354
    800
    Figure US20190015377A1-20190117-C00896
         		[M + NH4]+ 350
    801
    Figure US20190015377A1-20190117-C00897
         		(300 MHz, CDCl3): δ 8.25 (d, 1H), 7.27 (d, 1H), 4.18 (t, 2H), 3.50 (t, 2H), 1.94 (m, 2H), 1.11 (t, 3H)
    802
    Figure US20190015377A1-20190117-C00898
         		(300 MHz, CDCl3): δ 8.23 (d, 1H), 7.25 (d, 1H), 4.83 (m, 1H), 3.47 (t, 2H), 1.48 (d, 6H)
    803
    Figure US20190015377A1-20190117-C00899
    804
    Figure US20190015377A1-20190117-C00900
    805
    Figure US20190015377A1-20190117-C00901
         		(400 MHz, CDCl3): δ 8.21 (d, 1H), 7.40 (d, 1H), 4.88-4.83 (m, 1H), 3.67- 3.39 (m, 7H), 1.43 (d, 3H)
    806
    Figure US20190015377A1-20190117-C00902
         		(400 MHz, CDCl3): δ 8.13 (d, 1H), 7.34 (d, 1H), 4.82-4.76 (m, 1H), 3.60- 3.31 (m, 7H), 1.36 (d, 3H)
    807
    Figure US20190015377A1-20190117-C00903
         		405/407 (M + H) (400 MHz, CDCl3): δ 8.38 (d, 1H), 7.37-7.36 (m, 1H), 7.30 (ddd, 1H), 7.24 (dt, 1H), 6.09 (dddd, 1H), 6.00 (dddd, 1H)
    808
    Figure US20190015377A1-20190117-C00904
         		403/405 (M + H) (400 MHz, CDCl3): δ 8.36 (d, 1H), 7.37-7.35 (m, 1H), 7.29 (ddd, 1H), 7.25 (dt, 1H), 5.86 (dd, 1H), 5.11 (ddd, 1H), 2.73 (d, 1H)
    809
    Figure US20190015377A1-20190117-C00905
         		385 (M + H) (400 MHz, CDCl3): δ 8.75 (d, 1H), 7.39-7.37 (m, 1H), 7.34 (ddd, 1H), 7.29-7.25 (m, 1H), 6.25 (ddd, 1H), 5.94-5.87 (m, 1H), 5.44 (ddd, 1H), 3.66-3.58 (m, 1H), 3.29 (s, 3H)
    810
    Figure US20190015377A1-20190117-C00906
         		367 (M + H) (400 MHz, CDCl3): δ 8.60-8.59 (m, 1H), 7.35-7.33 (m, 1H), 7.31 (ddd, 1H), 7.24 (dt, 1H), 5.63 (ddd, 1H), 5.51 (dtd, 1H), 3.76 (dd, 1H), 3.47- 3.35 (m, 1H), 3.31 (s, 3H), 3.29-3.15 (m, 1H)
    811
    Figure US20190015377A1-20190117-C00907
         		403 (M + H) (400 MHz, CDCl3): δ 8.80 (d, 1H), 7.40-7.38 (m, 1H), 7.36 (ddd, 1H), 7.28 (dt, 1H), 5.88 (dd, 1H), 5.66-5.60 (m, 1H), 3.52 (dd, 1H), 3.28 (s, 3H)
    812
    Figure US20190015377A1-20190117-C00908
         		403 (M + H) (400 MHz, CDCl3): δ 8.77 (d, 1H), 7.39-7.37 (m, 1H), 7.35 (ddd, 1H), 7.27 (dt, 1H), 6.00 (dd, 1H), 5.83 (tdd, 1H), 3.97 (d, 1H), 3.29 (s, 3H)
    813
    Figure US20190015377A1-20190117-C00909
         		375 (M + H) (400 MHz, CDCl3): δ 8.42 (s, 1H), 7.28 (ddd, 1H), 7.20-7.18 (m, 1H), 7.09 (dt, 1H), 5.92 (dt, 1H), 5.53-5.46 (m, 1H), 5.19 (ddt, 1H), 2.66 (ddd, 1H)
    814
    Figure US20190015377A1-20190117-C00910
         		298 (M + H)
    815
    Figure US20190015377A1-20190117-C00911
         		298 (M + H)
    816
    Figure US20190015377A1-20190117-C00912
         		280 (M + H)
    817
    Figure US20190015377A1-20190117-C00913
         		280 (M + H)
    818
    Figure US20190015377A1-20190117-C00914
         		302 (M + H)
    819
    Figure US20190015377A1-20190117-C00915
         		349 (M + H) (400 MHz, CDCl3): δ 8.52-8.51 (m, 1H), 7.33 (ddd, 1H), 7.29 (ddd, 1H), 7.23 (dt, 1H), 5.71-5.66 (m, 1H), 3.64 (d, 1H), 3.26-3.17 (m, 1H), 3.22 (s, 3H), 2.99-2.90 (ddd, 1H), 2.66-2.56 (m, 1H), 2.32-2.22 (m, 1H)
    820
    Figure US20190015377A1-20190117-C00916
         		367 (M + H) (400 MHz, CDCl3): δ 8.60-8.59 (m, 1H), 7.35-7.33 (m, 1H), 7.31 (ddd, 1H), 7.24 (dt, 1H), 5.63 (ddd, 1H), 5.52 (dtd, 1H), 3.76 (dd, 1H), 3.47- 3.35 (m, 1H), 3.31 (s, 3H), 3.29-3.15 (m, 1H)
    821
    Figure US20190015377A1-20190117-C00917
         		310 (M + H)
    822
    Figure US20190015377A1-20190117-C00918
         		310 (M + H)
    823
    Figure US20190015377A1-20190117-C00919
         		339 (M + H) (400 MHz, CDCl3): δ 8.29-8.27 (m, 1H), 7.34-7.32 (m, 1H), 7.26 (ddd, 1H), 7.22 (dt, 1H), 5.57-5.10 (m, 1H), 3.22 (dt, 1H), 2.96 (ddd, 1H), 2.56- 2.45 (m, 1H), 2.33-2.25 (m, 1H), 2.22-2.18 (m, 1H)
    824
    Figure US20190015377A1-20190117-C00920
         		357 (M + H) (400 MHz, CDCl3): δ 8.36-8.34 (m, 1H), 7.35-7.32 (m, 1H), 7.28 (ddd, 1H), 7.23 (dt, 1H), 5.53-5.35 (m, 2H), 3.40 (ddd, 1H), 3.22 (ddd, 1H), 2.73- 2.68 (m, 1H)
    825
    Figure US20190015377A1-20190117-C00921
         		358 (M + H) (400 MHz, CDCl3): δ 8.79 (dd, 1H), 8.71 (d, 1H), 8.41 (s, 1H), 7.67 (dd, 1H), 5.94 (dt, 1H), 5.53-5.46 (m, 1H), 5.21 (ddt, 1H), 2.73 (ddd, 1H)
    826
    Figure US20190015377A1-20190117-C00922
         		298 (M + H) (400 MHz, CDCl3): δ 8.68 (s, 1H), 7.55-7.45 (m, 3H), 7.44-7.40 (m, 2H), 5.54-5.46 (m, 1H), 5.31 (ddt, 1H), 3.46 (ddd, 1H), 3.24 (ddd, 1H), 2.61 (dd, 1H)
    827
    Figure US20190015377A1-20190117-C00923
         		334 (M + H) (400 MHz, CDCl3): δ 8.65 (s, 1H), 6.99-6.91 (m, 3H), 5.54-5.47 (m, 1H), 5.33 (ddt, 1H), 3.44 (ddd, 1H), 3.23 (ddd, 1H), 2.63 (dd, 1H)
    828
    Figure US20190015377A1-20190117-C00924
         		346 (M + H) (400 MHz, CDCl3): δ 8.24 (s, 1H), 5.95 (ddd, 1H), 5.47-5.41 (m, 1H), 5.07 (ddt, 1H), 4.97-4.88 (m, 1H), 3.30-3.15 (m, 2H), 2.99-2.79 (m, 2H), 2.54-2.49 (m, 1H)
    829
    Figure US20190015377A1-20190117-C00925
         		315 (M + H) (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 6.26 (tt, 1H), 6.15 (ddd, 1H), 4.55 (td, 2H), 3.46-3.32 (m, 1H), 3.13 (ddd, 1H)
    830
    Figure US20190015377A1-20190117-C00926
         		324 (M + H) (400 MHz, CDCl3): δ 8.14 (s, 1H), 6.10 (tt, 1H), 5.58-5.30 (m, 1H), 4.39- 4.24 (m, 2H), 3.10 (dt, 1H), 2.87 (ddd, 1H), 2.37-2.27 (m, 1H), 2.20- 2.12 (m, 1H), 1.90-1.86 (m, 1H), 1.47-1.39 (m, 2H), 1.27-1.21 (m, 2H)
    831
    Figure US20190015377A1-20190117-C00927
         		351 (M + H)
    832
    Figure US20190015377A1-20190117-C00928
         		351 (M + H) (400 MHz, CDCl3): δ 8.75 (d, 1H), 8.65-8.62 (m, 1H), 6.17 (tt, 1H), 5.83 (dd, 1H), 4.83-4.64 (m, 2H)
    833
    Figure US20190015377A1-20190117-C00929
         		340 (M + H) (400 MHz, CDCl3): δ 7.43-7.41 (m, 1H), 7.33 (dt, 1H), 7.33-7.29 (m, 1H), 5.67-5.62 (m, 1H), 3.36-3.26 (m, 1H), 3.05 (ddd, 1H), 2.63-2.53 (m, 1H), 2.40-2.30 (m, 2H)
  • A composition of the present disclosure may be formulated in any suitable pharmaceutical formulation. A pharmaceutical composition of the present disclosure typically contains an active ingredient (e.g., a compound of the present disclosure or a pharmaceutically acceptable salt and/or coordination complex thereof), and one or more pharmaceutically acceptable excipients, carriers, including but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. A composition of the present disclosure may be formulated in any suitable pharmaceutical formulation. In some embodiments, the pharmaceutical acceptable carriers, excipients are selected from the group consisting of water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, and dimethyl sulfoxide (DMSO).
  • Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and/or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral intervention administration. For example, the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In some embodiments, the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi-solid, or solid form.
  • In some embodiments, the disclosure provides a pharmaceutical composition comprising an amount of a HIF-2α inhibitor, e.g. Compound 231, formulated for administration to a subject in need thereof. In some embodiments, the pharmaceutical composition comprises between about 0.0001-500 g, 0.001-250 g, 0.01-100 g, 0.1-50 g, or 1-10 g of HIF-2α inhibitor. In some embodiments, the pharmaceutical composition comprises about or more than about 0.0001 g, 0.001 g, 0.01 g, 0.1, 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g, 50 g, 100 g, 200 g, 250 g, 300 g, 350 g, 400 g, 450 g, 500 g, or more of a HIF-2α inhibitor. In some embodiments, the pharmaceutical composition comprises between 0.001-2 g of a HIF-2α inhibitor in a single dose. In some embodiments, the pharmaceutical composition comprises an amount between about 50-150 g of a HIF-2α inhibitor.
  • In some embodiments, a therapeutically effective amount of HIF-2α inhibitor, which can be a daily amount administered over the course of a period of treatment, can sufficiently provide any one or more of the therapeutic effects described herein. As an example, the therapeutic effective amount can be in the range of about 0.001-1000 mg/kg body weight, 0.01-500 mg/kg body weight, 0.01-100 mg/kg body weight, 0.01-30 mg/kg body weight, 0.1-200 mg/kg body weight, 3-200 mg/kg body weight, 5-500 mg/kg body weight, 10-100 mg/kg body weight, 10-1000 mg/kg body weight, 50-200 mg/kg body weight, 100-1000 mg/kg body weight, 200-500 mg/kg body weight, 250-350 mg/kg body weight, or 300-600 mg/kg body weight of a HIF-2α inhibitor. In some embodiments, the therapeutic amount can be about or more than about 0.001 mg/kg body weight, 0.01 mg/kg body weight, 0.1 mg/kg body weight, 0.5 mg/kg body weight, 1 mg/kg body weight, 2 mg/kg body weight, 3 mg/kg body weight, 4 mg/kg body weight, 5 mg/kg body weight, 6 mg/kg body weight, 7 mg/kg body weight, 8 mg/kg body weight, 9 mg/kg body weight, 10 mg/kg body weight, 15 mg/kg body weight, 20 mg/kg body weight, 25 mg/kg body weight, 50 mg/kg body weight, 100 mg/kg body weight, 200 mg/kg body weight, 250 mg/kg body weight, 300 mg/kg body weight, 350 mg/kg body weight, 400 mg/kg body weight, 450 mg/kg body weight, 500 mg/kg body weight, 600 mg/kg body weight, 800 mg/kg body weight, 1000 mg/kg body weight, or more of a HIF-2a inhibitor. In some embodiments, the effective amount is at least about 0.01 mg/kg body weight of a HIF-2α inhibitor. In some embodiments, the effective amount is an amount between about 0.01-30 mg/kg body weight of a HIF-2α inhibitor. In some embodiments, the therapeutic amount can be an amount between about 50-150 mg/kg body weight of a HIF-2α inhibitor.
  • In some embodiments, the composition is provided in one or more unit doses. For example, the composition can be administered in 1, 2, 3, 4, 5, 6, 7, 14, 30, 60, or more doses. Such amount can be administered each day, for example in individual doses administered once, twice, or three or more times a day. However, dosages stated herein on a per day basis should not be construed to require administration of the daily dose each and every day. For example, if the HIF-2α inhibitor is provided in a suitably slow-release form, two or more daily dosage amounts can be administered at a lower frequency, e.g., as a depot every second day to once a month or even longer. Most typically and conveniently for the subject, HIF-2α inhibitor can be administered once a day, for example in the morning, in the evening or during the day.
  • The unit doses can be administered simultaneously or sequentially. The composition can be administered for an extended treatment period. Illustratively, the treatment period can be at least about one month, for example at least about 3 months, at least about 6 months or at least about 1 year. In some cases, administration can continue for substantially the remainder of the life of the subject.
  • In some embodiments, the HIF-2α inhibitor is administered as part of a therapeutic regimen that comprises administering one or more second agents (e.g. 1, 2, 3, 4, 5, or more second agents), either simultaneously or sequentially with the HIF-2α inhibitor. When administered sequentially, the HIF-2α inhibitor may be administered before or after the one or more second agents. When administered simultaneously, the HIF-2α inhibitor and the one or more second agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising the HIF-2α inhibitor and the one or more second agents).
  • A variety of second agents and therapies suitable for combination therapy for the treatment of PAH are available, and may be combined with one or more HIF-2α inhibitors. Examples of second agents include, but are not limited to, mitotic kinesis inhibitors, JAK2 inhibitors, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, prostacyclin receptor agonists (e.g., selexipag), anticoagulants, diuretics, calcium channel blockers, digoxin, oxygen therapy, nitric oxide therapy, tyrosine kinases, statins, 5-hydroxytryptamine (5-HT) receptor antagonists, phosphatidylinositol 3-kinase inhibitors, soluble guanylate cyclase activators, adrenomedullin, platelet-derived growth factor (PDGF) inhibitors, Rho-kinase inhibitors, and mTOR inhibitors, treprostinil, bosentan, iloprost, ambrisentan, sildenafil, and tadalafil.
  • As an example, mitotic kinesin inhibitors are compounds that act to inhibit the activity of one or more mitotic kinesins. In general, inhibition refers to a decrease in mitotic kinesin activity as a direct or indirect response to the presence of a chemical entity (e.g., a mitotic kinesin inhibitor), relative to the activity of the mitotic kinesin in the absence of the chemical entity. In some embodiments, the decrease in activity is due to the direct interaction of the chemical entity with mitotic kinesin. In other embodiments, the decrease in activity is due to the interaction of the chemical entity with one or more other factors that affect mitotic kinesin activity. For example, the presence of the chemical entity may decrease mitotic kinesin activity by directly binding to the mitotic kinesin, by causing (directly or indirectly) another factor to decrease mitotic kinesin activity, or by (directly or indirectly) decreasing the amount of mitotic kinesin present in the cell or organism. As an example, mitotic kinesin inhibitors may act by increasing or decreasing spindle pole separation, causing malformation (e.g., splaying) of mitotic spindle poles, or otherwise causing morphological perturbation of the mitotic spindle or by interfering with the normal function of the mitotic spindle (e.g. misalignment and inappropriate segregation of chromosomes). Meiotic spindles may also be disrupted. Mitotic kinesin inhibitors may be reversible or irreversible, may bind to the kinesin's active site or an allosteric site, and may act as competitive, uncompetitive or non-competitive inhibitors. In all instances, mitotic kinesin inhibitors halt or slow the normal process of cell division and proliferation.
  • Non-limiting examples of JAK2 inhibitors include Pacritinib, CEP-33779, SB1578, TG101348, TG101209, AZD1480, AZ960, LY2784544, BMS911543, SGI-1252, MK0457, XL019, NVP-BSK805, Ruxolitinib, Baricitinib and CYT387. Further examples are described in WO2014161046A1 and U.S. Pat. No. 8,410,173.
  • A second agent can be a prostanoid. Examples of prostanoids include, but are not limited to, prostacyclin (epoprostenol, epoprostenol sodium) and prostacyclin analogs such as treprostinil sodium, iloprost, cisaprost, beraprost, and ciprostene sodium.
  • In some embodiments, a second agent is an endothelin receptor antagonist. The endothelin receptor antagonist can be an agent that selectively or preferentially inhibits type A endothelin receptor (ETA). In some embodiments, the endothelin receptor antagonist is an agent that selectively or preferentially inhibits type B endothelin receptor (ETB). In some embodiments, the endothelin receptor antagonist is an agent that inhibits both ETA and ETB. In some embodiments, pulmonary arterial hypertension is treated in a subject by administering to the subject a therapeutically effective amount of a mitotic kinesin inhibitor, an agent that selectively or preferentially inhibits ETA, and an agent that selectively or preferentially inhibits ETB. Examples of endothelin receptor antagonists include bosentan, tazosentan, BQ123, ambrisentan, atrasentan, sitaxsentan, BQ788 and macitentan.
  • Another example of a second agent is a phosphodiesterase (PDE) inhibitor. PDE inhibitors include selective and non-selective inhibitors of any of the PDE isoforms, including, for example, PDE1 and PDE5 inhibitors. Examples of PDE inhibitors include sildenafil, tadalafil, vardenafil, udenafil avanafil, dipyridamole, and vinpocetine.
  • Another example of a second agent is an anticoagulant. Anticoagulants can include, for example, coumarins (e.g., warfarin, acenocoumarol, phenprocoumon, phenindione), heparin, low molecular weight heparin, and direct thrombin inhibitors (e.g., argatroban, lepirudin, bivalirudin, dabigatran).
  • Another example of a second agent is a diuretic. Examples of diuretics include thiazide-like diuretics (e.g., chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone), loop diuretics (e.g., bumetanide, furosemide, torsemide) and potassium-sparing diuretics (e.g., amiloride hydrochloride, spironolactone, triamterene).
  • Another example of a second agent is calcium channel blocker. Examples of calcium channel blockers include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil.
  • Another example of a second agent is a tyrosine kinase. Tyrosine kinases include, for example, axitinib, bosutinib, cediranib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, neratinib, nilotinib, semaxanib, sorafenib, sunitinib, toceranib, vandetanib, and vatalanib.
  • In some embodiments, the second agent is a statin. Examples of statins include atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, simvastatin/ezetimibe, lovastatin/niacin, atorvastatin/amlodipine and simvastatin/niacin.
  • In some embodiments, a second agent is a 5-HT receptor antagonist. 5-HT receptor antagonists include selective and non-selective antagonists of any of the 5-HT receptor isoforms, including, for example, 5-HT1B, 5-HT2A and/or 5-HT2C receptor antagonists. Examples of 5-HT receptor antagonists include citalopram, clozapine, fluoxetine, ketanserin and paroxetine.
  • Another example of a second agent is a PDGF inhibitor. Examples of PDGF inhibitors can include imatinib, sorafenib, sunitinib, lefluonamide, midostaurin, semaxanib and vatalanib.
  • The second agent can be a phosphatidylinositol 3-kinase inhibitor. Examples of potential PI3 kinase inhibitor can include the class I PI 3-kinase, p110δ isoform specific inhibitors, IC486068 and IC87114, ICOS Corporation and GDC-0941.
  • In some embodiments, a second agent can be a soluble guanylate cyclase inhibitor. An example of a soluble guanylate cyclase activator is riociguat.
  • In some embodiments, a second agent can be a Rho-kinase inhibitor. An example of a Rho-kinase inhibitor is fasudil (fasudil hydrochloride).
  • In some embodiments, a second agent can be an mTOR inhibitor. Examples of mTOR inhibitors include rapamycin, temsirolimus and resveratrol.
  • When the method involves combination therapy, for example, wherein a secondary agent such as a vasodilator is co-administered with a HIF-2α inhibitor, the agents may be administered separately, at the same, or at different times of the day, or they may be administered in a single composition. In the combination therapies of the invention, each agent can be administered in an “immediate release” manner or in a “controlled release manner.” When the additional active agent is a vasodilator, for instance, any dosage form containing both active agents, such as both the HIF-2α inhibitor and the vasodilator, can provide for immediate release or controlled release of the vasodilator, and either immediate release or controlled release of the HIF-2α inhibitor.
  • As a general example, a combination dosage form for once-daily administration might contain in the range of about 0.001 mg/kg body weight to about 350 mg/kg body weight of a HIF-2α inhibitor, such as about 0.01 mg/kg body weight to about 50 mg/kg body weight of a HIF-2α inhibitor, or about 0.05 mg/kg body weight to about 15 mg/kg body weight of a HIF-2α inhibitor, or about 0.01 mg/kg body weight to about 30 mg/kg body weight in a controlled release (e.g., sustained release) or immediate release form, and either sildenafil in immediate release form, or in controlled release form, with the additional active agent present in an amount that provides a weight ratio of the HIF-2α inhibitor to sildenafil, or a weight ratio of the HIF-2α inhibitor to sildenafil, specified as above. In other formulations of the invention, two or more additional active agents, which may or may not be in the same class of drug (e.g., vasodilators), can be present in combination, along with the leukotriene inhibitor. In such a case, the effective amount of either or each individual additional active agent present will generally be reduced relative to the amount that would be required if only a single added agent were used.
  • Pharmaceutical Composition for Oral Administration
  • In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing a compound of the present disclosure, and a pharmaceutical excipient suitable for oral administration. The composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent.
  • Pharmaceutical composition of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient into association with the carrier. In general, the composition are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • This disclosure further encompasses anhydrous pharmaceutical composition and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical composition and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical composition and dosage forms of the disclosure which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous composition may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the composition for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Binders suitable for use in pharmaceutical composition and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • Examples of suitable fillers for use in the pharmaceutical composition and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the composition of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may alter the rate and extent of release of the active ingredient(s) from the dosage form. A sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactant which can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.
  • Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof polyoxyethylated vitamins and derivatives thereof polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for composition for non-oral use, e.g., composition for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.
  • Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. If present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
  • The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.
  • Pharmaceutical Composition for Topical (e.g., Transdermal) Delivery.
  • In some embodiments, the disclosure provides a pharmaceutical composition for transdermal delivery containing a compound of the present disclosure and a pharmaceutical excipient suitable for transdermal delivery. The composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent.
  • Composition of the present disclosure can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • The pharmaceutical composition also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Formulations for topical administration may include ointments, lotions, creams, gels (e.g., poloxamer gel), drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The disclosed compositions can be administered, for example, in a microfiber, polymer (e.g., collagen), nanosphere, aerosol, lotion, cream, fabric, plastic, tissue engineered scaffold, matrix material, tablet, implanted container, powder, oil, resin, wound dressing, bead, microbead, slow release bead, capsule, injectables, intravenous drips, pump device, silicone implants, or any bio-engineered materials.
  • Another exemplary formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present disclosure in controlled amounts, either with or without another agent.
  • The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Pharmaceutical Composition for Injection.
  • In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a compound of the present disclosure and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the composition are as described herein.
  • The forms in which the novel composition of the present disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Pharmaceutical Composition for Inhalation.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described vide supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder composition may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • Other Pharmaceutical Composition.
  • Pharmaceutical compositions may also be prepared from a composition described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.
  • In some embodiments, the compositions and methods further comprises administering, separately or simultaneously one or more additional agents (e.g. 1, 2, 3, 4, 5, or more). Additional agents can included those useful in wound healing. Non-limiting examples of additional agents include antibiotics (e.g. Aminoglycosides, Cephalosporins, Chloramphenicol, Clindamycin, Erythromycins, Fluoroquinolones, Macrolides, Azolides, Metronidazole, Penicillin's, Tetracycline's, Trimethoprim-sulfamethoxazole, Vancomycin), steroids (e.g. Andranes (e.g. Testosterone), Cholestanes (e.g. Cholesterol), Cholic acids (e.g. Cholic acid), Corticosteroids (e.g. Dexamethasone), Estraenes (e.g. Estradiol), Pregnanes (e.g. Progesterone), narcotic and non-narcotic analgesics (e.g. Morphine, Codeine, Heroin, Hydromorphone, Levorphanol, Meperidine, Methadone, Oxydone, Propoxyphene, Fentanyl, Methadone, Naloxone, Buprenorphine, Butorphanol, Nalbuphine, Pentazocine), chemotherapy (e.g. anti-cancer drugs such as but not limited to Altretamine, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Cyclophosphamide, Cytarabine, Dacarbazine, Diethylstilbesterol, Ethinyl estradiol, Etoposide, Floxuridine, Fludarabine, Fluorouracil, Flutamide, Goserelin, Hydroxyurea, Idarubicin, Ifosfamide, Leuprolide, Levamisole, Lomustine, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Paclitaxel, pentastatin, Pipobroman, Plicamycin, Prednisone, Procarbazine, Streptozocin, Tamoxifen, Teniposide, Vinblastine, Vincristine), anti-inflammatory agents (e.g. Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Decanoate; Deflazacort; Delatestryl; Depo-Testosterone; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab; Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lomoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Mesterolone; Methandrostenolone; Methenolone; Methenolone Acetate; Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Nandrolone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxandrolane; Oxaprozin; Oxyphenbutazone; Oxymetholone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Stanozolol; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Testosterone; Testosterone Blends; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium), or anti-histaminic agents (e.g. Ethanolamines (like diphenhydrmine carbinoxamine), Ethylenediamine (like tripelennamine pyrilamine), Alkylamine (like chlorpheniramine, dexchlorpheniramine, brompheniramine, triprolidine), other anti-histamines like astemizole, loratadine, fexofenadine, Bropheniramine, Clemastine, Acetaminophen, Pseudoephedrine, Triprolidine).
    • EXAMPLES
  • The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.
    • Example 1: Synthesis of 3-[(1S)-7-(difluoromethylsulfonyl)-2,2-difluoro-1-hydroxy-indan-4-yl]oxy-5-fluoro-benzonitrile (Compound 15)
  • Figure US20190015377A1-20190117-C00930
    • Step A: Preparation of 3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile
  • A mixture of 3-fluoro-5-hydroxy-benzonitrile (1.33 g, 9.7 mmol), 7′-(difluoromethylsulfonyl)-4′-fluoro-spiro[1,3-dioxolane-2,1′-indane] (1.0 g, 3.24 mmol), and cesium bicarbonate (1.26 g, 6.5 mmol) in 1-methyl-2-pyrrolidone (1.8 mL) was heated under N2 at 110° C. (microwave) for 1 hour and 5 minutes. The reaction was repeated ten times. The reaction mixtures were combined, diluted with EtOAc, and washed twice with 1 N NaOH. The combined aqueous layer was extracted with EtOAc. The EtOAc extracts were combined and washed with brine, dried over Na2SO4, filtered, and concentrated to about 100 mL to give a suspension. The suspension was filtered to give 3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile as an off-white solid (6.25 g). The filtrate was diluted with EtOAc, washed with brine (3×), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc/hexane (0% to 40%) to give additional 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile (3.3 g, 69% combined yield) as a white solid. LCMS ESI (+) m/z 426 (M+H).
    • Step B: Preparation of 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
  • A mixture of 3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile (10.9 g, 25.6 mmol) and PPTS (667 mg, 2.66 mmol) in acetone (100 mL)/water (15 mL) was heated at 82° C. for 5 hours and then 75° C. overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated. The residue was filtered and washed with water. The solid obtained was briefly dried under vacuum at 50° C. and then triturated with EtOAc/hexane to give 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (8 g). Flash column chromatography of the mother liquor on silica gel with EtOAc/hexane (0% to 80%) provided additional 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (1.3 g, combined 9.3 g, quant. yield). LCMS ESI (+) m/z 382 (M+H).
    • Step C: Preparation of (E,Z)-3-((1-(butylimino)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
  • A mixture of 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (1.42 g, 3.72 mmol), butylamine (6.0 mL) and 5 drops of trifluoroacetic acid (˜0.1 mL) in benzene (40 mL) was refluxed overnight with removal of water using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure, diluted with methyl tent-butyl ether, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was used in the next step without further purification.
    • Step D: Preparation of 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
  • A mixture of (E,Z)-3-((1-(butylimino)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (1.29 g, 3 mmol, crude from step C), Selectfluor® (2.62 g, 7.4 mmol) and sodium sulfate (4 g, 28.2 mmol) under N2 was heated at 82° C. for 4 hours. After cooling to room temperature, concentrated HCl (37%, 3 mL) was added. The mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. The residue was diluted with methyl t-butyl ether, washed with half saturated aqueous NaHCO3 and then brine, dried over Na2SO4, filtered, and triturated with EtOAc/hexane to give 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile as an off-white solid (0.5 g). The mother liquor was purified by flash column chromatography with EtOAc/hexane (5% to 40%) to give additional 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (0.13 g, 51% combined yield). LCMS ESI (+) m/z 418 (M+H) and 435 (M+NH4).
    • Step E: Preparation of (S)-3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (Compound 15)
  • An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.6 mg) in dichloromethane (0.2 mL) was added by syringe under nitrogen to an ice cold solution of 3-[7-(difluoromethylsulfonyl)-2,2-difluoro-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile (28 mg, 0.07 mmol), triethylamine (18.7 μL, 0.13 mmol) and formic acid (7.6 μL, 0.2 mmol) in dichloromethane (0.5 mL) and then placed in a refrigerator at 4° C. overnight. The reaction mixture was directly purified on preparative TLC with EtOAc/hexane (40%) to give Compound 15 (23.4 mg, 0.06 mmol, 83% yield). The ee was determined to be greater than 95% by 19F NMR analysis of the corresponding Mosher ester. LCMS ESI (+) m/z 420 (M+H); 1H NMR (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.33-6.98 (m, 4H), 6.44 (t, 1H), 5.51 (d, 1H), 3.61-3.45 (m, 2H).
    • Example 2: Synthesis of (S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (Compound 163)
  • Figure US20190015377A1-20190117-C00931
    • Step A: Preparation of 4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]
  • Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to 4′-fluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (100 mg, 0.37 mmol) and 3-bromo-5-fluoro-phenol (105 mg, 0.55 mmol) in 1-methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwave reaction vial equipped with a stir bar. The flask was flushed with nitrogen then sealed with a crimp cap. The reaction was heated to 150° C. for 7 hours, cooled to ambient temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording 4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (118 mg, 0.26 mmol, 72% yield).
    • Step B: Preparation of 3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile
  • Dichloro[1;1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (784 mg, 0.97 mmol) was quickly added to a degassed mixture of 4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (4.3 g, 9.7 mmol), zinc cyanide (1.14 g, 9.7 mmol) and zinc powder (761 mg, 11.6 mmol) in DMF (60 mL) under nitrogen. The reaction mixture was then warmed to 110° C. for 2 hours. After cooling, the mixture was filtered through a pad of celite. The filtrate was diluted with water (100 mL), extracted with MTBE (5×100 mL), washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified on silica gel (100 g SNAP, 14 CV, 15-100% EtOAc/hexanes) then purified again on silica gel (25 g Ultra SNAP, 14 CV, 0-20% dichloromethane/EtOAc) affording 3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile (3.77 g, 9.7 mmol, 100% yield).
    • Step C: Preparation of 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile
  • Pyridinium para-toluenesulfonate (354 mg, 1.4 mmol) was added all at once to a solution of 3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile (550 mg, 1.4 mmol) in acetone (6 mL)/water (2 mL) at room temperature and then warmed to reflux until completion. The mixture was concentrated in vacuo then purified on silica gel (10 g SNAP, 14 CV, 20-100% EtOAc/hexane) affording 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (450 mg, 1.3 mmol, 92% yield).
    • Step D: Preparation of 3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile
  • Butan-1-amine (5.15 mL, 52 mmol) was added to 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (450 mg, 1.3 mmol) and trifluoroacetic acid (19.96 μL, 0.26 mmol) in benzene (10 mL) at room temperature then warmed to reflux with the azeotropic removal of water by a Dean-Stark apparatus. Progress of the reaction was monitored by 1H-NMR. When complete, the reaction was cooled to room temperature then concentrated in vacuo. The residue was diluted with water (10 mL), extracted with MTBE (3×10 mL), washed with brine and dried over Na2SO4, filtered and concentrated. Crude 3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile was used immediately without purification in the next step.
    • Step E: Preparation of 3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile
  • Selectfluor® (1.15 g, 3.25 mmol) was added to crude 3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile (520 mg, 1.3 mmol) and sodium sulfate (369 mg, 2.6 mmol) in acetonitrile (10 mL) then warmed to reflux for 6 hours. The reaction was cooled to room temperature, concentrated HCl (1.0 mL, 12 mmol) was added and stirred for 15 minutes. The mixture was diluted with water (10 mL), extracted with EtOAc (3×10 mL), washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel (25 g SNAP, 14 CV, 20-100% EtOAc/hexane) afforded 3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile (437 mg, 1.2 mmol, 88% yield).
    • Step F: Preparation of (S)-3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (Compound 163)
  • An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (40.7 mg, 0.06 mmol) in CH2Cl2 (30 mL) was added by syringe under nitrogen to an ice cold solution of 3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile (2.44 g, 6.4 mmol), triethylamine (1.78 mL, 12.8 mmol) and formic acid (724 μL, 19.2 mmol) in CH2Cl2 (30 mL). The reaction was placed in a refrigerator at 4° C. for 16 hours. The mixture was concentrated to 10 mL then purified directly on silica gel (25 g SNAP ULTRA, 14 CV, 10-50% EtOAc/hexane) affording Compound 163 (2.15 g, 5.6 mmol, 87% yield). Enantiomeric excess (98%) was determined by chiral HPLC. Retention time for (S)-enantiomer:1.93 minutes; retention time for (R)-enantiomer: 2.32 minutes. LCMS ESI (−) 428 (M+HCO2 −). 1HNMR (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.07-7.03 (m, 1H), 7.00 (d, 1H), 5.63-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H).
    • Example 3: Synthesis of N-(3-Chlorophenyl-4,6-t2)-4-nitrobenzo[c][2,5]oxadiazol-5-amine (Compound 183)
  • Figure US20190015377A1-20190117-C00932
  • Step A: Synthesis of 3-chlorobenzen-4,6-t2-amine: 3-Chloro-4,6-diiodoaniline (100 mg) was dissolved in methanol (3 mL) and added with triethylamine (0.1 mL) and submitted for overnight tritiation using 50Ci of tritium gas, at room temperature. Labile tritium was removed by dissolving the crude reaction mixture in methanol (3 mL) and bringing to dryness under vacuum. Labile removal was done in duplicate. The crude tritiated material was purified by preparative TLC (Silica gel, 10000 using hexane:ethyl acetate:AcOH (85:14:1). The product band was eluted with ethyl acetate to give 3-chlorobenzen-4,6-t2-amine (yield=600 mCi, radiochemical purity was >98%).
  • Step B: Synthesis of Compound 183: A stirred mixture of 5-chloro-4-nitro-2,1,3-benzoxadiazole (20 mg, 0.1 mmol), 3-chlorobenzen-4,6-t2-amine (600 mCi) and Cs2CO3 (65 mg, 0.20 mmol) in DMF (1 mL) was heated at 60° C. for 1 h. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by preparative HPLC on an ACE-5 C18 Semi-prep column, 250×10 mm, 100 Å. Elution was carried out isocratically using 0.1% TFA in water/Acetonitrile (35:65) to give Compound 183 (478 mCi, 80%).
    • Example 4: Synthesis of Isomer 1 of N—((S)-7-(3-Cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ6-sulfanylidene)cyanamide (Compound 240)
  • Figure US20190015377A1-20190117-C00933
    • Step A: N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide
  • Sodium hydrogen carbonate (79.3 mg, 0.94 mmol) was added to a solution of 3-fluoro-5-hydroxy-benzonitrile (86.27 mg, 0.63 mmol) and N-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ6-sulfanylidene)cyanamide (80 mg, 0.31 mmol) in DMF (3 mL). The vial was sealed and heated at 100° C. over a weekend. The reaction mixture was partitioned between EtOAc and dilute aqueous NaOH. The EtOAc was washed with water, two portions of brine, dried over MgSO4, filtered, and evaporated. The residue was chromatographed on a Biotage 25M reverse phase column with a 20% to 90% ACN:water gradient to afford N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide (80 mg, 0.21 mmol, 69% yield). m/z (ES-API-pos) [M+H]=372.
    • Step B: N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide
  • Dess-Martin periodinane (192 mg, 0.45 mmol) was added to a solution of N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide (200 mg, 0.54 mmol) in dichloromethane (50 mL). After 10 minutes, the reaction mixture was evaporated and the residue was partitioned between EtOAc and aqueous sodium thiosulfate and saturated aqueous NaHCO3. The EtOAc layer was washed with water, brine, dried over MgSO4, filtered, and evaporated to afford N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide (174 mg, 0.47 mmol, 88% yield) as a colorless film. m/z (ES-API-pos) [M+H]=370.
    • Step C: (E/Z)-N-((7-(3-cyano-5-fluorophenoxy)-3-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide
  • Pivalic acid (9.4 mg, 0.09 mmol) was added to a mixture of N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide (170 mg, 0.46 mmol) and 3-methoxypropylamine (0.12 mL, 1.2 mmol) in cyclohexane (7 mL) and toluene (7 mL). The mixture was heated at reflux with a Hickman still attached. After 1 hour, the reaction mixture was evaporated and the residue was used as is in the next step.
    • Step D: N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide
  • 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (406 mg, 1.15 mmol) was added to a mixture of (E/Z)-N-((7-(3-cyano-5-fluorophenoxy)-3-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide (202 mg, 0.46 mmol) and sodium sulfate (162 mg, 1.15 mmol) in acetonitrile (5 mL). The mixture was heated at 70° C. After 3.5 hours, the reaction mixture was evaporated and the residue was partitioned between EtOAc and water. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated. The residue was taken up in EtOAc, absorbed on silica gel, and chromatographed on a Biotage 25 g SNAP column with a 50% to 100% EtOAc:hexane gradient to afford N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ6-sulfanylidene)cyanamide (48 mg, 0.118 mmol, 26% yield. m/z (ES-API-pos) [M+H]=406.
    • Step E: N-q(S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide (Compound 240)
  • RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.5 mg, 0.020 mmol) was added to a nitrogen-sparged, ice-cold solution of N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)λ6-sulfanylidene)cyanamide (49 mg, 0.120 mmol), triethylamine (0.022 mL, 0.16 mmol), and formic acid (0.01 mL, 0.24 mmol) in dichloromethane (5 mL). The flask was placed in a 4° C. refrigerator over a weekend. The reaction mixture was evaporated and the residue was chromatographed on a Biotage 10 g SNAP Ultra column with a 20% to 80% EtOAc:hexane gradient to afford a solid, which was triturated twice with chloroform to afford Compound 240 (8.6 mg, 0.021 mmol, 18% yield) as a single diastereomer in 93% d.e. by chiral chromatography. 1H NMR (400 MHz, CD3OD): δ 8.01 (d, 1H), 7.54-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.40-7.36 (m, 1H), 7.20-7.14 (m, 1H), 5.56 (d, 1H), 3.78-3.61 (m, 1H), 3.62 (s, 3H), 3.55-3.47 (m, 1H). m/z (ES-API-pos) [M+H]=408.
    • Example 5: Synthesis of 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile (Compound 289)
  • Figure US20190015377A1-20190117-C00934
    • Step A: [(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate
  • To a stirred solution of 3-fluoro-5-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (2.00 g, 5.47 mmol) in DCM (27 mL) was added 4-(dimethylamino)pyridine (0.2 g, 1.64 mmol) and triethylamine (1.53 mL, 10.9 mmol). Acetic anhydride (1.00 mL, 10.9 mmol) was added dropwise at 0° C. under nitrogen. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-40% EtOAc/hexane) to give [(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (1.95 g, 87%). LCMS ESI (+) m/z 408 (M+H).
    • Step B: [(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate and [(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate
  • To a stirred solution of [(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (1.95 g, 4.79 mmol) in 1,2-dichloroethane (24 mL) was added N-bromosuccinimide (0.94 g, 5.27 mmol) and 2,2′-azobisisobutyronitrile (8 mg, 0.05 mmol). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (20-30% EtOAc/hexane) to give [(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (1.52 g, 65%). LCMS ESI (+) m/z 486, 488 (M+H). Further elution with 30-50% EtOAc/hexane gave the more polar product [(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate (0.583 g, 25%). LCMS ESI (+) m/z 486, 488 (M+H).
    • Step C: [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate
  • To a combined mixture of [(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate and [(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl]acetate prepared in Step B (2.05 g, 4.22 mmol) were added 1,2-dimethoxyethane (28 mL) and water (0.050 mL) followed by silver perchlorate hydrate (1.42 g, 6.32 mmol). The reaction mixture was heated at 70° C. for 2 hours. After cooling, the reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-50%) to give [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (0.416 g, 23%) as the less polar product. LCMS ESI (+) m/z 441 (M+NH4 +). Further elution with 60% EtOAc/hexane gave [(1S,2R,3R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (0.58 g, 32%). LCMS ESI (+) m/z 441 (M+NH4 +).
    • Step D: [(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate
  • To a stirred solution of [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (416 mg, 0.98 mmol) in DCM (10 mL) was added (diethylamino)sulfur trifluoride (DAST) (0.26 mL, 2.0 mmol) at −78° C. under nitrogen. The reaction mixture was allowed to warm to 0° C. and stirred for 15 minutes. The reaction was quenched by saturated aqueous NaHCO3. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-40% EtOAc/hexane) to give [(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate (310 mg, 74%). LCMS ESI (+) m/z 426 (M+H).
    • Step E: 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile (Compound 289)
  • To a stirred solution of [(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate (0.23 mmol) in tetrahydrofuran (1.5 mL) was added 0.5 N LiOH solution (0.68 mL, 0.34 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (30-70% EtOAc/hexane) to give Compound 289. LCMS ESI (+) m/z 384 (M+H); 1HNMR (400 MHz, CDCl3): δ 8.13 (d, 1H), 7.31-7.25 (m, 1H), 7.23-7.19 (m, 1H), 7.14-7.09 (m, 1H), 7.04 (d, 1H), 6.09-5.91 (m, 1H), 5.87-5.80 (m, 1H), 5.25-5.05 (m, 1H), 3.32 (s, 3H), 2.95 (d, 1H).
    • Example 6: Synthesis of 3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (Compound 292)
  • Figure US20190015377A1-20190117-C00935
    • Step A: [(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate and [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate
  • To a stirred solution of [(1S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-yl]acetate (1.0 g, 2.35 mmol) in DCE (24 mL) were added N-bromosuccinimide (0.46 g, 2.59 mmol) and 2,2′-azobisisobutyronitrile (4 mg, 0.02 mmol). The reaction mixture was heated at 80° C. overnight. After cooling, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The crude product was dissolved in 1,2-dimethoxyethane (11 mL) and water (0.11 mL). Silver perchlorate hydrate (0.35 g, 1.55 mmol) was added. The reaction mixture was heated at 70° C. overnight. After cooling, the reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-60% EtOAc/hexane) to give [(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (39 mg, 9% yield) as the less polar product. LCMS ESI (+) m/z 459 (M+NH4 +). Further elution gave [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate (80 mg, 18%). LCMS ESI (+) m/z 459 (M+NH4 +).
    • Step B: [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-yl]acetate
  • Prepared as described in Example 5 Step D substituting [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate with [(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate. LCMS ESI (+) m/z 444 (M+H).
    • Step C: 3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (Compound 292)
  • Prepared as described in Example 5 Step E substituting [(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate with [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-yl]acetate. LCMS ESI (+) m/z 419 (M+NH4 +); 1H NMR (400 MHz, CDCl3): δ 8.14-8.11 (m, 1H), 7.33-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.16-7.12 (m, 1H), 7.05 (d, 1H), 5.91-5.75 (m, 1H), 5.71-5.65 (m, 1H), 3.39 (d, 1H), 3.25 (s, 3H).
    • Example 7: Synthesis of (R)-3-((4-(Difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile (Compound 349)
  • Figure US20190015377A1-20190117-C00936
    • Step A: Preparation of 2-bromo-3-(difluoromethyl)-1,4-difluorobenzene
  • A solution of 2-bromo-3,6-difluorobenzaldehyde (40.0 g, 181 mmol) dissolved in dichloromethane (800 mL) was cooled to 0° C., then treated with (diethylamino)sulfur trifluoride (70.0 g, 454 mmol). After the addition, the reaction mixture was warmed to ambient temperature and stirred at this temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added slowly until the pH was 8-9. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-bromo-3-(difluoromethyl)-1,4-difluorobenzene (44.0 g, quant.) as solid which was used immediately in the next step without purification. 1H NMR (400 MHz, CDCl3): δ 7.28-7.22 (m, 1H), 7.17-7.10 (m, 1H), 7.04 (t, 1H).
    • Step B: Preparation of 2-(difluoromethyl)-3,6-difluorobenzonitrile
  • A suspension of 2-bromo-3-(difluoromethyl)-1,4-difluorobenzene (44.0 g, 181 mmol) and copper (I) cyanide (21.1 g, 235 mmol) in 1-methyl-2-pyrrolidinone (400 mL) was heated to 180° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate to give 2-(difluoromethyl)-3,6-difluorobenzonitrile as a solid (23 g, 67%). 1H NMR (400 MHz, CDCl3): δ 7.48-7.35 (m, 2H), 6.98 (t, 1H).
    • Step C: Preparation of 2-(difluoromethyl)-3-fluoro-6-(methylthio)benzonitrile
  • A solution of 2-(difluoromethyl)-3,6-difluorobenzonitrile (31.3 g, 65.5 mmol) in acetonitrile (500 mL) was cooled to −30° C., then treated with sodium methanethiolate (12.8 g, 174 mmol). After addition of the solid, the reaction mixture was stirred for 7 hours while maintaining the temperature between −30° C. and −40° C. A mixture of water (200 mL) and methyl t-butyl ether (500 mL) were added and the reaction mixture was warmed to ambient temperature. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-(difluoromethyl)-3-fluoro-6-methylsulfanyl-benzonitrile as yellow solid (36.3 g, 150 mmol, 91%). 1H NMR (400 MHz, CDCl3): δ 7.47-7.44 (m, 1H), 7.36-7.32 (m, 1H), 6.99 (t, 1H), 2.58 (s, 3H).
    • Step D: Preparation of 2-(difluoromethyl)-3-fluoro-6-(methylsulfonyl)benzonitrile
  • A slurry of 2-(difluoromethyl)-3-fluoro-6-methylsulfanyl-benzonitrile (36.3 g, 167 mmol) in acetonitrile (350 mL) and water (175 mL) was treated with Oxone® (257 g, 418 mmol), then the mixture was heated at 56° C. for 4 hours. After cooling to ambient temperature, the remaining solids were removed by filtration and washed with dichloromethane (300 mL). The filtrate was concentrated in vacuo to remove volatile solvents. The resulting aqueous solution was extracted with dichloromethane (400 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was suspended in 4:1 hexane/methyl t-butyl ether (200 mL) and stirred for 10 minutes at ambient temperature. The undissolved solid was collected by filtration and air-dried to give 2-(difluoromethyl)-3-fluoro-6-(methylsulfonyl)benzonitrile (29.9 g, 71%). 1H NMR (400 MHz, CDCl3): δ 8.41-8.37 (m, 1H), 7.66-7.61 (m, 1H), 7.11 (t, 1H), 3.34 (s, 3H).
    • Step E: Preparation of 3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile
  • A suspension of 2-(difluoromethyl)-3-fluoro-6-(methylsulfonyl)benzonitrile (9.52 g, 38.2 mmol), 3-fluoro-5-hydroxy-benzonitrile (5.23 g, 38.2 mmol), and cesium carbonate (7.77 g, 40.1 mmol) in N,N-dimethylformamide (76 mL) was heated to 45° C. for 3 hours. Additional cesium carbonate (0.46 g, 1.4 mmol) was added and the reaction mixture was heated at 45° C. for three hours, then stirred at ambient temperature for 54 hours. The reaction mixture was vigorously stirred while water (800 mL) was added. The resulting suspension was stirred for 30 minutes, then the solids were collected by filtration, washed with water (1.2 L), and dried under high vacuum to give 3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile as a white solid (13.3 g, 96%). LCMS ESI (+) m/z 384 (M+NH4). 1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, 1H), 7.86-7.82 (m, 1H), 7.72-7.62 (m, 3H), 7.49 (t, 1H), 3.44 (s, 3H).
    • Step F: Preparation of 3-((4-(difluoromethyl)-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile
  • A solution of 3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile (13.3 g, 36 mmol) was dissolved in tetrahydrofuran (380 mL) and treated with sodium hydride (60% in mineral oil, 2.26 g, 56 mmol) in two equal portions at five minute intervals. The resulting suspension was stirred at ambient temperature for 60 minutes. The reaction mixture was quenched by addition of a mixture of 4:1 methanol/10% aqueous HCl (200 mL) and the resulting suspension was stirred for 1 hour. The mixture was concentrated to remove volatile solvents, then the remaining slurry was diluted with additional water (800 mL) and stirred for an additional 30 minutes. The solids were recovered by filtration and washed with additional water and the resulting beige solid was dried under high vacuum in the presence of solid NaOH. 3-((4-(Difluoromethyl)-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile was obtained as a beige solid (13.3 g, quant.) and was used without further purification. LCMS ESI (−) m/z 366 (M−H). 1H NMR (400 MHz, DMSO-d6): δ 8.35 (d, 1H), 7.79 (d, 1H), 7.76 (t, 1H), 7.76-7.72 (m, 1H), 7.56-7.50 (m, 2H), 4.72 (s, 2H).
    • Step G: Preparation of 3-((4-(difluoromethyl)-2,2-difluoro-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile
  • A solution of 3-((4-(difluoromethyl)-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile (1.40 g, 3.82 mmol) dissolved in acetonitrile (38 mL) was treated at ambient temperature with sodium carbonate (890 mg, 8.4 mmol) followed by Selectfluor® (2.98 g, 8.4 mmol). The reaction mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was concentrated in vacuo to remove volatile solvents, then the residue was diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL portions). The combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo to give 3-((4-(difluoromethyl)-2,2-difluoro-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile as a solid (1.48 g, quant.). 1H NMR (400 MHz, DMSO-d6, sample exists as hydrate): δ 8.81 (s, 2H), 8.29 (d, 1H), 7.80-7.76 (m, 1H), 7.74 (t, 1H), 7.57-7.50 (m, 3H).
    • Step H: Preparation of 3-((4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile
  • A solution of 3-((4-(difluoromethyl)-2,2-difluoro-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile (1.48 g, 3.67 mmol) in methanol (37 mL) was cooled to 0° C., then treated with sodium borohydride (139 mg, 3.7 mmol) and stirred for 1 hour. The reaction was quenched by addition of water (0.5 mL) and saturated NH4Cl (0.25 mL). The reaction mixture was concentrated in vacuo to remove volatile solvents, then diluted with 0.5 M NaOH (10 mL). The aqueous was extracted three times with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexane to give 3-((4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile as a white solid (1.24 g, 83%).
    • Step I: Preparation of (R)-3-((4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile
  • 3-((4-(Difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile was resolved using preparative SFC chromatography under the following conditions: ChiralPak AS(—H) (2×15 cm) column, 20% ethanol with carbon dioxide at 100 bar, 60 mL/min flow rate, injection volume was 0.5 mL of a 20 mg/mL solution in ethanol, peak detection at 220 nm. Compound 349 was recovered as the first peak (1.50 minutes) to elute from the column. LCMS ESI (−) m/z 404 (M−H). 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 1H), 7.33-7.30 (m, 1H), 7.23 (t, 1H), 7.22-7.18 (m, 2H), 7.10-7.06 (m, 1H), 5.69-5.65 (m, 1H), 3.23 (d, 1H).
    • Example 8: Synthesis of (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465) and (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466)
  • Figure US20190015377A1-20190117-C00937
    • Step A: Preparation of 4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one
  • A suspension of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1.0 g, 4.72 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (4.69 g, 14.15 mmol) in a mixture of dichloromethane (30 mL) and water (15 mL) at 0° C. was treated with tert-butyl hydroperoxide (˜70% in water, 2.58 mL, 18.86 mmol, added via pipette using a plastic tip) and stirred overnight. Additional portions of bis(((trifluoromethyl)sulfinyl)oxy)zinc (2.35 g, 7.07 mmol) and tert-butyl hydroperoxide (2.58 mL, 18.86 mmol) were added sequentially to drive the reaction to completion. After stirring for an additional day, the reaction vessel was placed into a water bath and carefully quenched by the addition of saturated NaHCO3. Once effervescence ceased, the reaction mixture filtered through a pad of celite to remove. The pad of celite was rinsed with additional dichloromethane. The filtrate was separated and the aqueous portion extracted further with 2×20 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 30-90% CH2Cl2/hexane to afford 4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one as an off-white solid (390 mg, 30%). The desired regioisomer elutes first. LCMS ESI (+) (M+H) m/z 280/282.
    • Step B: Preparation of 4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] and 4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine
  • Trimethylsilyl trifluoromethanesulfonate (75.9 μL, 0.42 mmol) was added to a solution of 4-bromo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (389 mg, 1.39 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.37 mL, 5.56 mmol) in dichloromethane (13.6 mL) cooled in an ice bath. The mixture was allowed to slowly warm to ambient temperature. After 5 h, an additional 1.3 mL of trimethyl(2-trimethylsilyloxyethoxy)silane and 76 μL of trimethylsilyl trifluoromethanesulfonate were added. After another 16 h, the reaction mixture was treated with triethylamine (770 μL, 5.56 mmol), stirred for 10 min, and then concentrated. The residue was treated with 20 mL EtOAc and 20 mL of water and the layers separated. The aqueous portion was extracted further with 2×20 mL of EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and evaporated. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford 4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] as a shite solid (262 mg, 58%) and 4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine as a white solid (170 mg, 31%). Data for 4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: LCMS ESI (+) (M+H) m/z 324/326. Data for 4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine: 1H NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 5.59 (t, 1H), 4.10 (t, 2H), 3.96 (t, 2H), 3.36 (d, 2H), 0.15 (s, 9H).
    • Step C: Preparation of 4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]
  • A solution of 2-[[4-bromo-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-7-yl]oxy]ethoxy-trimethyl-silane (146.6 mg, 0.37 mmol) and sodium sulfate (262.7 mg, 1.85 mmol) in acetonitrile (3.7 mL) was stirred for 10 min and then treated with Selectfluor® (145.2 mg, 0.41 mmol) and stirred at 25° C. for 1 h. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford 4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] as a white solid (96.2 mg, 76%). LCMS ESI (+) (M+H) m/z 342/344.
    • Step D: Preparation of 6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol and 1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol
  • A solution of 4′-bromo-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (96.2 mg, 0.2800 mmol) and 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (3.4 mg, 0.007 mmol) in 1,4-dioxane (5.0 mL) was sparged with nitrogen for 3 mins. The reaction mixture was then treated sequentially with potassium hydroxide (47.3 mg, 0.84 mmol), water (101 μL, 5.62 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-t-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (6.0 mg, 0.007 mmol) under continuous nitrogen stream. The vessel was sealed and heated to 80 C for 1 h and 30 min. The reaction mixture was quenched by the addition of acetic acid (64.3 μL, 1.13 mmol). The reaction mixture was poured into 75 mL of water and extracted with 4×20 mL EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification (87 mg). During the reaction, some of the hydrodefluorinated product formed as an impurity. Data for 6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol: LCMS ESI (+) (M+H) m/z 280. Data for 1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol: LCMS ESI (+) (M+H) m/z 262.
    • Step E: Preparation of 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] and 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]
  • A solution of impure 6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (44.0 mg, 0.16 mmol), polymer supported triphenylphosphine (˜2.06 mmol/g, 306.2 mg, 0.63 mmol), and 3,3-difluoro-cyclobutanol (68.1 mg, 0.63 mmol) in tetrahydrofuran (3.2 mL) was treated with diisopropyl azodicarboxylate (120 μL, 0.61 mmol) and stirred at 60° C. for 2 h. The reaction mixture was filtered and the filter cake rinsed with 20 mL EtOAc. The filtrate was concentrated and purified by chromatography on silica using 10-30% EtOAc/hexane to afford a clear solid (39.0 mg, 67%) that was a 2:1 mixture of the fluorinated and hydrodefluorinated products. LCMS ESI (+) (M+H) m/z 370. Data for 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: LCMS ESI (+) (M+H) m/z 370. Data for 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: LCMS ESI (+) (M+H) m/z 352.
    • Step F: Preparation of 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one and 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one
  • A solution of impure 4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (39.0 mg, 0.106 mmol) in dichloromethane (2.0 mL) at 0 C was treated with perchloric acid (70% in water, 200 μL) and stirred at 0 C for 3 h. The reaction mixture was quenched by the addition of 5 mL of saturated aqueous NaHCO3. The resulting mixture was extracted with 3×15 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification as a 2:1 mixture of fluorinated and hydrodefluorinated ketones. LCMS ESI (+) (M+H) m/z 326. Data for 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one: LCMS ESI (+) (M+H) m/z 326. Data for 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one: LCMS ESI (+) (M+H) m/z 308.
    • Step G: Preparation of (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465) and (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466)
  • A solution of impure 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (33.8 mg, 0.10 mmol) in dichloromethane (4.0 mL) was cooled to 0° C. and sparged with nitrogen for 5 min. During this time formic acid (11.8 μL, 0.31 mmol) and triethylamine (28.8 μL, 0.21 mmol) were sequentially added. Once sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.3 mg, 0.002 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and placed into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 4-18% EtOAc/CH2Cl2 to afford (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465) as a clear solid (5.4 mg, 16%) and (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466) as a clear solid (7.4 mg, 23%). Data for (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465): Retention time HPLC (14 min)=3.59 min; LCMS ESI (+) (M+H) m/z 328; 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 5.46-5.26 (m, 2H), 4.89-4.79 (m, 1H), 3.36-3.08 (m, 4H), 2.91-2.74 (m, 2H), 2.60 (dd, 1H). Data for (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466): Retention time HPLC (14 min)=3.95 min; LCMS ESI (+) (M+H) m/z 310; 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 5.59-5.54 (m, 1H), 4.88-4.79 (m, 1H), 3.24-3.07 (m, 3H), 2.89 (dd, 1H), 2.89-2.74 (m, 2H), 2.44-2.34 (m, 1H), 2.28-2.21 (m, 1H), 2.12-2.09 (m, 1H).
    • Example 9: Synthesis of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 467)
  • Figure US20190015377A1-20190117-C00938
    • Step A: Preparation of 1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol
  • A solution of 4′-bromo-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (226.4 mg, 0.70 mmol) and 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (8.5 mg, 0.017 mmol) in 1,4-dioxane (7.0 mL) was sparged with nitrogen for 3 mins. The reaction mixture was then treated sequentially with potassium hydroxide (117.6 mg, 2.10 mmol), water (252 μL, 13.97 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (14.9 mg, 0.017 mmol) under continuous nitrogen stream. The vessel was sealed and heated to 80 C for 1 h and 30 min. The reaction mixture was quenched by the addition of acetic acid (160 μL, 2.79 mmol). The reaction mixture was poured into 75 mL of water and extracted with 4×20 mL EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. The brown solid was used without further purification. LCMS ESI (−) (M−H) m/z 260.
    • Step B: Preparation of 3-fluoro-5-((1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile
  • A suspension of potassium tert-butoxide (28.4 mg, 0.25 mmol) in tetrahydrofuran (1.5 mL) at 0 C was treated with 1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (60.0 mg, 0.23 mmol) and stirred at 0 C for 15 min. The resulting mixture was treated with (3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium; 4-methylbenzenesulfonate (144.8 mg, 0.28 mmol) and heated to 40 C. The reaction mixture was filtered through a plastic filter cup using EtOAc to rinse. Volatiles were removed by concentration under reduced pressure. Purification was achieved by chromatography on silica using 10-40% EtOAc/hexane to afford a solid (42 mg, 48%). LCMS ESI (+) (M+H) m/z 381.
    • Step C: Preparation of 3-fluoro-5-((7-oxo-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile
  • A solution of 3-fluoro-5-[1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile (42.0 mg, 0.11 mmol) in dichloromethane (2.0 mL) at 0 C was treated with perchloric acid (70% in water, 240 μL) and stirred at 0 C for 30 min. The reaction mixture was carefully quenched by the addition of 15 mL of saturated NaHCO3 and extracted with 3×15 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The solid residue was used immediately in the next step without further purification. LCMS ESI (+) (M+H) m/z 337.
    • Step D: Preparation of 3-((7-((tert-butyldimethylsilyl)oxy)-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile
  • A solution of triethylamine (122 μL, 0.88 mmol) and 3-fluoro-5-[[7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile (37.0 mg, 0.11 mmol) in dichloromethane (2.2 mL) at 0° C. was treated with tert-butyldimethylsilyl triflate (152 ul, 0.66 mmol). The ice bath was removed and the reaction mixture left to stir for 2 h. The reaction mixture was poured into 30 mL of saturated NaHCO3 and extracted with 3×20 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) (M+H) m/z 451.
    • Step E: Preparation of 3-fluoro-5-((6-fluoro-7-oxo-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile
  • A solution of 3-[[7-[tert-butyl(dimethyl)silyl]oxy-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl]oxy]-5-fluoro-benzonitrile (49.56 mg, 0.1100 mmol) in acetonitrile (2.2 mL) at 25° C. was treated with Selectfluor® (42.9 mg, 0.12 mmol) and stirred at 25° C. for 1 h. Volatiles were removed by concentration under reduced pressure The reaction mixture was poured into 30 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-25% EtOAc/hexane to afford a thin film (37.8 mg, 97%). LCMS ESI (+) (M+H) m/z 355.
    • Step F: Preparation of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 467)
  • A solution of 3-fluoro-5-[[6-fluoro-7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile (15.3 mg, 0.043 mmol) in dichloromethane (1.5 mL) was cooled to 0° C. and sparged with nitrogen for 5 min. During this time formic acid (4.9 μL, 0.13 mmol) and triethylamine (12.0 μL, 0.086 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.5 mg, 0.00086 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and placed into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 10-30% EtOAc/hexane to afford 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 467) as a clear solid (11.8 mg, 77%). Retention time HPLC (14 min)=4.19 min; LCMS ESI (+) (M+H) m/z 357; 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.22 (ddd, 1H), 7.10-7.08 (m, 1H), 6.99 (dt, 1H), 5.54-5.46 (m, 1H), 5.46-5.28 (m, 1H), 3.26 (ddd, 1H), 3.11 (ddd, 1H), 2.67 (dd, 1H).
    • Example 10: Synthesis of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 468)
  • Figure US20190015377A1-20190117-C00939
    • Step A: Preparation of 5-bromo-2-(methylthio)nicotinic Acid
  • A solution of 5-bromo-2-fluoro-pyridine-3-carboxylic acid (3.50 g, 15.91 mmol) in DMF (62 mL) at 0° C. was treated with potassium carbonate (2.42 g, 17.5 mmol) and vigorously stirred at 0° C. for 7 minutes. During this time, nitrogen was sparged through the solution. Then sodium thiomethoxide (1.23 g, 16.7 mmol) was added in one portion to the reaction vessel under continuous nitrogen stream. The reaction vessel was sealed and the ice bath removed. The solution turned from a tan color to faint yellow. The reaction mixture was left to stir overnight. The reaction mixture was poured onto 10% citric acid solution inducing precipitation of a white solid. The solid was filtered and rinsed exhaustively with water. Finally, the white solid was dried overnight under high vacuum in the presence of solid NaOH and used without further purification (3.63 g, 92%). LCMS ESI (+) (M+H) m/z 248/250.
    • Step B: Preparation of 5-bromo-4-formyl-2-(methylthio)nicotinic Acid
  • A solution of 2,2,6,6-tetramethyl-piperidine (3.26 mL, 19.35 mmol) in tetrahydrofuran (40.3 mL) at −50 C was treated with n-butyllithium (˜2.5M in hexanes, 7.09 mL, 17.73 mmol) and stirred for 5 min. Then 5-bromo-2-methylsulfanyl-pyridine-3-carboxylic acid (2.00 g, 8.06 mmol) was added via cannula over 30 min as a solution in 60 mL of THF. The resulting mixture stirred for 30 min at −50 C. The reaction mixture was quenched by the addition of N,N-dimethylformamide (0.94 mL, 12.09 mmol). 15 minutes following addition of the DMF, the reaction mixture was quenched by the addition of 40 mL of 10% citric acid solution (aqueous) and the reaction warmed to room temperature. After stirring for 30 min, excess THF removed by concentration under reduced pressure. The leftover mixture was poured into 120 mL of 3% citric acid (aqueous) and extracted with 3×50 mL EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. 2.41 g of an orange solid was isolated and used without further purification. The material was contaminated with about 22% citric acid based on proton integration of the unpurified NMR spectra. LCMS ESI (+) (M+H) m/z 276/278.
    • Step C: Preparation of methyl (E)-5-bromo-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-(methylthio)nicotinate
  • A solution of 7-bromo-1-hydroxy-4-methylsulfanyl-1H-furo[3,4-c]pyridin-3-one (2.21 g, 8.00 mmol), lithium chloride (anhydrous, 339.1 mg, 8.00 mmol) and ethyl 2-diethoxyphosphorylacetate (1.60 mL, 8.00 mmol) in acetonitrile (80 mL) at 25 C was treated with 1;8-Diazabicyclo[5.4.0]undec-7-ene (2.87 mL, 19.20 mmol) and stirred at 25 C for 2 h. Initially, the solution is heterogenous with the pyridine being insoluble. Upon addition of the DBU the solution becomes homogeneous and darkens in color. After 1 h, the reaction appears to be mostly complete. In addition a precipitate has formed. Volatiles were removed by concentration under reduced pressure. The product residue was solubilized with 25 mL of DMF and treated with dimethyl sulfate (1.89 mL, 20.00 mmol). After 2 h, the reaction mixture was poured into 300 mL of water and extracted with 4×40 mL Et2O. The combined organics were rinsed with 20 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford methyl (E)-5-bromo-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-(methylthio)nicotinate as a white solid (1.90 g, 66%). LCMS ESI (+) (M+H) m/z 360/362.
    • Step D: Preparation of methyl 5-bromo-4-(3-ethoxy-3-oxopropyl)-2-(methylthio)nicotinate
  • A solution of methyl 5-bromo-4-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2-methylsulfanyl-pyridine-3-carboxylate (1.87 g, 5.19 mmol) and cobalt(ii) chloride hexahydrate (123.5 mg, 0.52 mmol) in methanol (20.8 mL) at 0° C. was sparged with nitrogen for 3 min and treated with sodium borohydride (98.2 mg, 2.60 mmol) under continuous nitrogen stream. The vessel was sealed and the contents stirred at 0° C. for 10 min. LCMS at this time indicated partial consumption of the olefin. An additional portion of sodium borohydride (98.2 mg, 2.60 mmol) was added to drive the reaction to completion. The reaction mixture was quenched by the addition of 30 mL of saturated aqueous NH4Cl. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×40 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-15% EtOAc/hexane to afford the desired product as a solid (1.08 g, 57%). LCMS ESI (+) (M+H) m/z 362/364.
    • Step E: Preparation of ethyl 4-bromo-1-(methylthio)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one
  • A solution of methyl 5-bromo-4-(3-ethoxy-3-oxo-propyl)-2-methylsulfanyl-pyridine-3-carboxylate (1.08 g, 2.98 mmol) in tetrahydrofuran (29.8 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (˜1.0 M in THF, 7.16 mL, 7.16 mmol) by dropwise addition over 30 minutes. Once the addition was complete, LCMS indicated a small amount of starting material remained so an additional 1 mL of lithium bis(trimethylsilyl)amide was added and the reaction allowed to stir for a further 15 minutes. The reaction mixture was quenched by the addition of 30 mL of saturated aqueous NH4Cl. THF was removed by concentration under reduced pressure. The reaction mixture diluted with 60 mL of EtOAc and an additional 30 mL of water. A thick precipitate formed that could be eliminated by the addition of 10% citric acid solution. The reaction mixture was extracted with 3×30 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The intermediate product was transferred into a microwave tube using 9.1 mL of DMSO. The resulting mixture was diluted with 900 μL of water. The vessel was sealed and heated to 150 C by microwave irradiation for 40 min. The reaction mixture was diluted with 120 mL of water to induce precipitation of the product and vigorously stirred for 30 min. The precipitate was collected, dried overnight under high vacuum in the presence of solid NaOH, and used without further purification. Beige solid (705 mg, 92%). LCMS ESI (+) (M+H) m/z 258/260.
    • Step F: Preparation of 4-bromo-1-(methylsulfonyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one
  • A solution of 4-bromo-1-methylsulfanyl-5,6-dihydrocyclopenta[c]pyridin-7-one (364.5 mg, 1.41 mmol) in methanol (11.3 mL) at 0° C. was treated with a solution of Oxone® (1.91 g, 3.11 mmol) in water (11.3 mL). The reaction was left to stir for 24 h. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 40 mL of water and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The off white solid was used without further purification. LCMS ESI (+) (M+H) m/z 290/292.
    • Step G: Preparation of 4-bromo-1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]
  • Trimethylsilyl trifluoromethanesulfonate (331 μL, 1.83 mmol) was added to a solution of 4-bromo-1-methylsulfonyl-5,6-dihydrocyclopenta[c]pyridin-7-one (354 mg, 1.22 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.20 mL, 4.88 mmol) in dichloromethane (14 mL) cooled in an ice bath. The ice bath was removed. After 3 h, an additional portion of trimethyl(2-trimethylsilyloxyethoxy)silane (1.20 mL, 4.88 mmol) was added. The reaction was left to stir overnight. After stirring, for the rest of the day, the reaction was quenched by the addition of triethylamine (1.02 mL, 7.32 mmol). The reaction mixture stirred for 10 min. Volatiles were removed and the residue suspended into 30 mL of saturated aqueous NaHCO3 and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 15-50% EtOAc/hexane to afford 4-bromo-1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] as a white solid (74.5 mg, 18%). LCMS ESI (+) (M+H) m/z 334/336. The bulk of the product was isolated as the enol ether (295 mg, 59%).
    • Step H: Preparation of 1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol
  • A solution of 4′-bromo-1′-methylsulfonyl-spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (74.5 mg, 0.22 mmol) and 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (5.4 mg, 0.011 mmol) in 1,4-dioxane (1.5 mL) was sparged with nitrogen for 3 mins. The reaction mixture was then treated sequentially with potassium hydroxide (37.5 mg, 0.67 mmol), water (80.3 μl, 4.46 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (9.5 mg, 0.011 mmol) under continuous nitrogen stream. The vessel was sealed and heated to 80 C for 1 h and 30 min. The reaction mixture was quenched by the addition of acetic acid (51.0 μL, 0.89 mmol). The reaction mixture was poured into 75 mL of water and extracted with 4×20 mL EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification (77.9 mg). LCMS ESI (+) (M+H) m/z 272.
    • Step I: Preparation of 3-fluoro-5-((1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile
  • A suspension of potassium carbonate (30.6 mg, 0.22 mmol) in acetonitrile (1.5 mL) at 25 C was treated with 1′-methylsulfonylspiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (40.0 mg, 0.15 mmol) and stirred at 25 C for 10 min. The resulting mixture was treated with (3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium; 4-methylbenzenesulfonate (116.2 mg, 0.22 mmol) and heated to 50 C for 3 h. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 20-50% EtOAc/hexane to afford (3-fluoro-5-((1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile as a solid (25.1 mg, 44%). LCMS ESI (+) (M+H) m/z 391.
    • Step J: Preparation of 3-fluoro-5-((1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile
  • A solution of 4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-methylsulfonyl-spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (25.1 mg, 0.064 mmol) in dichloromethane (3.0 mL) at 0 C was treated with perchloric acid (70% in water, 330 μL) and stirred at 0 C for 2 h and then at room temperature for 30 min. The reaction mixture was carefully quenched with 5 mL of saturated NaHCO3/10 mL of water and extracted with 3×15 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) (M+H) m/z 347.
    • Step K: Preparation of 3-((7-((tert-butyldimethylsilyl)oxy)-1-(methylsulfonyl)-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile
  • A solution of triethylamine (71.4 μL, 0.51 mmol) and 3-fluoro-5-[[7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile (22.2 mg, 0.064 mmol) in dichloromethane (3.0 mL) at 0° C. was treated with tert-butyldimethylsilyl trifluoromethanesulfonate (58.2 μL, 0.38 mmol). The ice bath was removed and the reaction mixture stirred for 2 h. The reaction mixture was poured into 30 mL of saturated NaHCO3 and extracted with 3×20 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) (M+H) m/z 461.
    • Step L: Preparation of 3-fluoro-5-((6-fluoro-1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile
  • A solution of 3-[[7-[tert-butyl(dimethyl)silyl]oxy-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl]oxy]-5-fluoro-benzonitrile (29.5 mg, 0.064 mmol) in acetonitrile (2.6 mL) at 25° C. was treated with Selectfluor® (24.9 mg, 0.070 mmol) and stirred at 25° C. for 1 h. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-25% EtOAc/hexane to afford 3-fluoro-5-((6-fluoro-1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile as a thin film (11.1 mg, 48%). LCMS ESI (+) (M+H) m/z 365.
    • Step M: Preparation of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 468)
  • A solution of 6-fluoro-4-[(5-fluoro-3-pyridyl)oxy]-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (11.1 mg, 0.031 mmol) in dichloromethane (2.0 mL) was cooled to 0° C. and sparged with nitrogen for 5 min. During this time formic acid (3.4 μL, 0.091 mmol) and triethylamine (8.4 μL, 0.061 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.4 mg, 0.0006 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 20-60% EtOAc/hexane to afford 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 468) as a white solid (7.0 mg, 63%). Retention time HPLC (14 min)=3.16 min; LCMS ESI (+) (M+H) m/z 367; 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.25 (ddd, 1H), 7.14 (m, 1H), 7.03 (dt, 1H), 5.69 (dt, 1H), 5.53-5.36 (m, 1H), 4.24 (d, 1H), 3.34 (s, 3H), 3.31-3.24 (m, 1H), 3.09 (ddd, 1H).
    • Example 11: Synthesis of 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 469) and 4-(difluoromethylsulfonyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 470)
  • Figure US20190015377A1-20190117-C00940
    • Step A: 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine
  • A mixture of 4-bromo-2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-one (420 mg, 1.96 mmol) and POCl3 (2.20 mL, 23.6 mmol) was heated at reflux for 40 hours. After cooling, excess POCl3 was removed under reduced pressure. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (2-10% EtOAc/hexanes) to give 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine (207 mg, 45%). LCMS ESI (+) m/z 232/234/236 (M+H)+.
    • Step B: 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 469)
  • A mixture of 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine (62 mg, 0.27 mmol), 3,5-difluorophenol (38 mg, 0.29 mmol), cesium carbonate (130 mg, 0.400 mmol) and NMP (1.8 mL) was heated at 90° C. overnight under nitrogen. The reaction mixture was heated to 140° C. and stirred overnight again. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by Biotage C18 reverse phase flash chromatography (20-95% acetonitrile/water) to give 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 469, 21 mg, 24%) as a pale yellow solid. LCMS ESI (+) m/z 326/328 (M+H)+.
    • Step C: S-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate
  • To a vial containing a solution of 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (20 mg, 0.060 mmol) in 1,4-dioxane (0.3 mL) were added acetylsulfanylpotassium (8.8 mg, 0.080 mmol) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (4.3 mg, 0.010 mmol). The mixture was sparged with nitrogen. Then tris(dibenzylideneacetone)dipalladium(0) (3.4 mg, 0.004 mmol) was added, and the vial was sealed and heated at 110° C. for 4 hours. After cooling, the reaction mixture was filtered through Celite. The filtrate was concentrated. The residue was purified by Biotage C18 reverse phase flash chromatography (10-80% acetonitrile/water) to give S-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate (10 mg, 51%). LCMS ESI (+) m/z 322 (M+H)+.
    • Step D: 1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-thiol
  • To a stirred solution of S-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate (10 mg, 0.030 mmol) in MeOH (0.3 mL) was added 1 N LiOH solution (0.050 mL, 0.050 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then concentrated. To the residue was added water. The pH was added to 2-3 using 0.1 N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The crude was used in the next step without further purification. LCMS ESI (+) m/z 280 (M+H)+.
    • Step E: 4-(difluoromethylsulfanyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine
  • To a stirred solution of crude 1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-thiol (9 mg, 0.03 mmol) in acetonitrile (0.3 mL) was added potassium hydroxide (36 mg, 0.64 mmol) in water (0.3 mL). The reaction mixture was purged with nitrogen and then cooled to −78° C. Bromodifluoromethyl diethylphosphonate (17 mg, 0.060 mmol) was added. The resulting mixture was allowed to warm to ambient temperature and stirred for 3 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude was used in the next step without further purification. LCMS ESI (+) m/z 330 (M+H)+.
    • Step F: 4-(difluoromethylsulfonyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 470)
  • Sodium periodate (18 mg, 0.080 mmol) was added all at once to crude 4-(difluoromethylsulfanyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (11 mg, 0.030 mmol) and ruthenium(III) chloride (0.2 mg, 0.001 mmol) in acetonitrile (0.2 mL)/CCl4 (0.2 mL)/water (0.4 mL). The reaction mixture was stirred at ambient temperature for 3 hours. Solids were removed by filtration and rinsed with CH2Cl2. The organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (4-12% EtOAc/hexanes) affording Compound 470 (3 mg, 25% overall yield for three steps) as a white solid. LCMS ESI (+) m/z 362 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.49 (s, 1H), 6.80-6.71 (m, 3H), 6.19 (t, 1H), 3.36 (t, 2H), 3.06 (t, 2H), 2.31-2.23 (m, 2H).
    • Example 12: Synthesis of racemic 3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile (Compound 471)
  • Figure US20190015377A1-20190117-C00941
    • Step A: Preparation of racemic (6R,7S)-4-bromo-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol
  • A solution of 4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (6.7 mg, 0.022 mmol) in methanol (0.8 mL) at 0° C. was treated with sodium borohydride (0.9 mg, 0.022 mmol) and stirred at 0° C. for 10 min. The reaction mixture was quenched by the addition of 0.2 mL of saturated NH4Cl. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) (M+H) m/z 300/302.
    • Step B: Preparation of racemic 3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile (Compound 471)
  • A suspension of racemic (6R,7S)-4-bromo-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (6.7 mg, 0.022 mmol), 3-cyano-5-fluorophenylboronic acid (5.5 mg, 0.033 mmol), cesium fluoride (10.5 mg, 0.069 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.8 mg, 0.0011 mmol) in a mixture 1,4-dioxane (0.8 mL) and water (80 μL) was sparged with nitrogen for 3 mins. The vessel was sealed and heated to 80° C. for 1 h. LCMS indicates product formation. The reaction mixture was poured into 60 mL of water and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-30% EtOAc/hexane to afford racemic 3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile (Compound 471) as an orange solid (1.8 mg, 24%). Retention time HPLC (14 min)=3.80 min; LCMS ESI (+) (M+H) m/z 341; 1H NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 7.53-7.48 (m, 2H), 7.40 (ddd, 1H), 5.56-5.48 (m, 1H), 5.35 (ddt, 1H), 3.41 (ddd, 1H), 3.21 (ddd, 1H), 2.65 (dd, 1H).
    • Example 13: Synthesis of (S)-1-((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-3-ol (Compound 484)
  • Figure US20190015377A1-20190117-C00942
    • Step A: Preparation of 4,7-difluoro-1H-indene-1,3(2H)-dione
  • A solution of 3,6 difluorophthalic anhydride (4.25 g, 23.1 mmol), tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride (21.0 mL, 221.6 mmol) at 25° C. was treated with triethylamine (11.7 mL, 84.3 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was cooled to 0° C. and treated with 10% hydrochloric acid (65 mL, 211 mmol) by dropwise addition. Once the addition was complete, the ice bath was removed and the mixture stirred at ambient for 10 minutes. The mixture was then heated to 75° C. for 10 minutes. During this time gas evolution was observed. The suspension slowly broke up to form a clear red mixture. The reaction mixture was poured into 100 mL of water and extracted with 3×50 mL CH2Cl2. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification.
    • Step B: Preparation of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione
  • A solution of the unpurified 4,7-difluoro-1H-indene-1,3(2H)-dione (4.2 g, 23.1 mmol) in acetonitrile (100 mL) cooled in a 25° C. water bath was treated with sodium carbonate (5.38 g, 50.7 mmol). Selectfluor® (17.97 g, 50.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were removed under reduced pressure and the residue was poured into 100 mL of 0.1% HCl and extracted with 3×50 mL EtOAc. The combined organics were rinsed with 40 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel 1:1 hexane/ethyl acetate to give 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.5 g, 70%) as a solid. 1H NMR (400 MHz, CDCl3): δ 7.70 (t, 2H).
    • Step C: Preparation of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one
  • To a solution of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.48 g, 16.0 mmol) in dichloromethane (150 mL) at 0° C. was added formic acid (600 μl, 16.0 mmol) and triethylamine (1.55 mL, 11.2 mmol). The resulting mixture was sparged with nitrogen for 5 minutes and then RuCl(p-cymene)[(S,S)-Ts-DPEN] (203.6 mg, 0.32 mmol) was added. The reaction vessel was sealed and put into a 4° C. refrigerator to stand for 18 hours. The reaction mixture was poured into 40 mL 1 N HCl. The CH2Cl2 layer was separated and the aqueous layer extracted with ethyl acetate (2×50 mL). The combined organics were dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 25% EtOAc/hexane to give (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2.9 g, 83%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.51 (ddd, 1H), 7.29-7.23 (m, 1H), 5.44 (dd, 1H), 2.79 (dd, 1H).
    • Step D: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one
  • A solution of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (966 mg, 4.39 mmol) in acetonitrile (40 mL) at 0° C. was sparged with nitrogen for 5 minutes and treated with sodium thiomethoxide (353.7 mg, 5.05 mmol). The ice bath was removed and the reaction mixture was allowed to stir at ambient temperature for 2 hours. The reaction mixture was evaporated and the residue partitioned between 40 mL of EtOAc and 40 mL of water. The aqueous layer was further extracted with 2×40 mL of EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica using 10-60% EtOAc/hexane to afford (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (870 mg, 80%) as a yellow solid. LCMS ESI (+) m/z 249 (M+H).
    • Step E: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (400 mg, 1.6 mmol) was dissolved in MeOH (10 mL) and the reaction was treated dropwise with a solution of Oxone® (2.18 g, 3.55 mmol) dissolved in water (10 mL). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was filtered, the solids were washed with ethyl acetate and the filtrate was concentrated in vacuo. The aqueous filtrate was extracted 3×30 mL of EtOAc and then the combined organics were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a yellow solid that was used without further purification (467 mg). LCMS ESI (+) m/z 281.1 (M+H).
    • Step F: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (450 mg, 1.6 mmol) was dissolved in dichloromethane (16 mL), cooled to 0° C. and treated dropwise with diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and the mixture was stirred at 0° C. for 2 hours, then the whole homogeneous reaction mixture was placed into the refrigerator overnight. The reaction was treated with additional diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and stirring continued for 6 hours at 0° C. The cold reaction was treated with saturated NaHCO3 (10 mL) and stirred vigorously for 20 minutes. The mixture was diluted with additional methylene chloride and the layers were separated. The aqueous was re-extracted with methylene chloride and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to a yellow solid. The crude material was chromatographed on SiO2 (Biotage SNAP Ultra) and eluted with a gradient of ethyl acetate/hexanes. The desired material was concentrated to a pale yellow solid (258 mg). LCMS ESI (+) m/z 283 (M+H).
    • Step G: Preparation of (R)-2,2,3-trifluoro-4-((S)-3-hydroxypiperidin-1-yl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • A solution of (3R)-2,2,3,4-tetrafluoro-7-methylsulfonyl-indan-1-one (28.7 mg, 0.10 mmol) and (3S)-3-piperidinol, hydrochloride (14.0 mg, 0.10 mmol) in DMF (700 μL) was treated with cesium bicarbonate (59.2 mg, 0.31 mmol) and stirred at 35° C. for 3 h. The reaction mixture was poured into 30 mL of water and extracted with 3×10 mL Et2O. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) m/z 364 (M+H).
    • Step H: Preparation of (S)-1-((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-3-ol (Compound 484)
  • A solution of (3R)-2,2,3-trifluoro-4-[(3S)-3-hydroxy-1-piperidyl]-7-methylsulfonyl-indan-1-one (36.3 mg, 0.10 mmol) in dichloromethane (4 mL) was cooled to 0° C. and sparged with nitrogen for 5 min. During this time formic acid (12.1 μL, 0.32 mmol) and triethylamine (27.9 μL, 0.20 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.3 mg, 2 mol %) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 45-75% EtOAc/hexane to afford (S)-1-((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-3-ol (Compound 484) as a white solid (23.9 mg, 65%). Retention time HPLC (14 min)=2.63 min; LCMS ESI (+) m/z 366 (M+H); 1H NMR (400 MHz, CDCl3): δ 7.97 (dd, 1H), 7.07 (d, 1H), 5.74 (dd, 1H), 5.55 (dd, 1H), 4.01-3.93 (m, 1H), 3.46-3.34 (m, 3H), 3.33 (d, 1H), 3.20-3.13 (m, 1H), 3.18 (s, 3H), 2.01-1.91 (m, 2H), 1.89 (d, 1H), 1.82-1.62 (m, 2H).
    • Example 14: Synthesis of (S)-2,2-difluoro-4-((1R,3R)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 480) and (1S)-2,2-difluoro-4-(3-hydroxycyclohex-1-en-1-yl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 481) and (S)-2,2-difluoro-4-((1R,3S)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 482) and (S)-2,2-difluoro-4-((1S,3R)-3-hydroxycyclohexyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 483)
  • Figure US20190015377A1-20190117-C00943
    • Step A: Preparation of (S)-3-(2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)cyclohex-2-en-1-one
  • A suspension of (1S)-4-bromo-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-1-ol (102.0 mg, 0.27 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (89.2 mg, 0.40 mmol), cesium fluoride (126.0 mg, 0.83 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9.5 mg, 0.013 mmol) in 1,4-dioxane (4.5 mL) was sparged with nitrogen for 3 mins. The vessel was sealed and heated to 80° C. for 1 h. The reaction mixture was poured into 60 mL of water and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 20-50% EtOAc/hexane. LCMS ESI (−) (M−H) m/z 395.
    • Step B: Preparation of (S)-2,2-difluoro-4-((1R,3R)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 480) and (1S)-2,2-difluoro-4-(3-hydroxycyclohex-1-en-1-yl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 481) and (S)-2,2-difluoro-4-((1R,3S)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 482) and (S)-2,2-difluoro-4-((1S,3R)-3-hydroxycyclohexyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 483)
  • A solution of 3-[(1S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]cyclohex-2-en-1-one (60.0 mg, 0.15 mmol) in methanol (3.0 mL) at 0° C. was treated with sodium borohydide (11.5 mg, 0.30 mmol) and stirred at 0° C. for 1 h. The reaction mixture was quenched by the addition of 0.5 mL of saturated NH4Cl. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Initial purification was achieved by chromatography on silica using 10-40% EtOAc/CH2Cl2 to isolate 2 components. A second purification was necessary on the first eluting component by chromatography on silica using 20-45% EtOAc/hexanes. Finally, each product was purified individually, as described in the characterization section. Data for (S)-2,2-difluoro-4-((1R,3R)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 480): Final purification was achieved by chromatography on silica using 30-70% EtOAc/hexanes to afford the desired product as a white solid (1.5 mg, 2%). Retention time HPLC (14 min)=4.69 min; LCMS ESI (−) (M+HCO2 −) m/z 445; 1H NMR (400 MHz, CDCl3): δ 7.92 (d, 1H), 7.52 (d, 1H), 5.40 (dd, 1H), 4.33-4.28 (m, 1H), 3.59 (ddd, 1H), 3.49 (t, 1H), 3.22-3.13 (m, 2H), 1.97-1.82 (m, 4H), 1.75-1.58 (m, 3H), 1.46 (dd, 1H), 1.42-1.37 (m, 1H). Data for (1S)-2,2-difluoro-4-(3-hydroxycyclohex-1-en-1-yl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 481): Final purification was achieved by chromatography on silica using 30-70% EtOAc/hexanes to afford the desired product as a clear solid (3.5 mg, 6%). Retention time HPLC (14 min)=4.70 min; LCMS ESI (+) (M−OH) m/z 381; 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.50 (d, 1H), 5.91-5.88 (m, 1H), 5.39 (dd, 1H), 4.49-4.43 (m, 1H), 3.64 (ddd, 1H), 3.39 (t, 1H), 3.18 (dd, 1H), 2.49-2.39 (m, 1H), 2.22-2.11 (m, 1H), 2.09-1.92 (m, 2H), 1.81-1.59 (m, 3H). Data for (S)-2,2-difluoro-4-((1R,3S)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 482): Final purification was achieved by chromatography on silica using 30-70% EtOAc/hexanes to afford the desired product as a clear solid (6.7 mg, 11%). Retention time HPLC (14 min)=4.27 min; LCMS ESI (−) (M+HCO2 −) m/z 445; 1H NMR (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.55 (d, 1H), 5.41 (dd, 1H), 3.82-3.72 (m, 1H), 3.56 (ddd, 1H), 3.42 (t, 1H), 3.20 (dd, 1H), 2.67 (tt, 1H), 2.17-2.08 (m, 2H), 2.01-1.94 (m, 1H), 1.82-1.75 (m, 1H), 1.60-1.42 (m, 3H), 1.40-1.27 (m, 2H). Data for (S)-2,2-difluoro-4-((1S,3R)-3-hydroxycyclohexyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 483): Final purification was achieved by chromatography on silica using 20-60% EtOAc/hexanes to afford the desired product as a white solid (8.6 mg, 14%). Retention time HPLC (14 min)=4.77 min; LCMS ESI (−) (M+HCO2 −) m/z 445; 1H NMR (400 MHz, CDCl3): δ 7.94 (d, 1H), 7.55 (d, 1H), 5.41 (dd, 1H), 3.82-3.72 (m, 1H), 3.58 (ddd, 1H), 3.40 (t, 1H), 3.18 (d, 1H), 2.67 (tt, 1H), 2.16-2.06 (m, 2H), 2.02-1.95 (m, 1H), 1.86-1.78 (m, 1H), 1.58-1.28 (m, 5H).
    • Example 15: (S)-3-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)amino)-5-fluorobenzonitrile (Compound 489)
  • Figure US20190015377A1-20190117-C00944
    • Step A: Preparation of 4-bromophenyl 3-chloropropanoate
  • A solution of 4-bromophenol (45.0 g, 260 mmol) in dichloromethane (1.0 L) was cooled to 0° C., treated with triethylamine (44.7 g, 442 mmol). A solution of 3-chloropropionyl chloride (36.3 g, 286 mmol) dissolved in dichloromethane (100 mL) was added dropwise to the reaction vessel. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. Saturated NaCl was added to the reaction mixture, (300 mL). After stirring for 1 hour, the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organics were washed with saturated NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was used without further purification.
    • Step B: Preparation of 4-bromo-7-hydroxy-2,3-dihydro-1H-inden-1-one
  • A flask containing crude (4-bromophenyl) 3-chloropropanoate (68.0 g, 258 mmol) was cooled to 0, then treated in several portions with aluminum trichloride (275 g, 2060 mmol). The reaction mixture was then heated at 155° C. under N2 for 3 hours. Stirring became difficult as the reaction proceeded. HCl (g) which was generated from the reaction was trapped by a beaker containing 1 N NaOH. After cooling to ambient temperature, the reaction mixture was further cooled in an ice bath. Water was added very carefully (dropwise initially and then added in small volumes) to the reaction to quench excess AlCl3. The mixture was then extracted with twice with ethyl acetate. The combined organic layers were washed with water and brine, dried and concentrated. The crude product was used without additional purification.
    • Step C: Preparation of O-(7-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl) dimethylcarbamothioate
  • A mixture of 4-bromo-7-hydroxy-2,3-dihydro-1H-inden-1-one (900 mg, 4.0 mmol) dissolved in DMF (15 mL) was treated with DABCO 33LV (1.3 mL, 12 mmol) and N,N-dimethylcarbamothioyl chloride (1.5 g, 12 mmoil) was stirred overnight at ambient temperature. The reaction was treated with water and ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate then the combined organic layers were washed with water and saturated NaCl. After drying, the organic layer was concentrated in vacuo and purified by chromatography on SiO2 eluting with a gradient of ethyl acetate/hexanes, (670 mg, 54%). 1H NMR (400 MHz, CDCl3): δ 7.78-7.76 (d, 1H), 6.97-6.95 (d, 1H), 3.44 (s, 3H), 3.41 (s, 3H), 3.08 (m, 2H), 2.76-2.69 (m, 2H).
    • Step D: Preparation of S-(7-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl) dimethylcarbamothioate
  • A mixture of O-(7-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl) dimethylcarbamothioate (670 mg, 2.1 mmol) and diphenyl ether (15 mL) was heated at 220° C. under N2 for 30 minutes. After cooling to ambient temperature, the mixture was diluted with hexanes and the mixture was applied to a pad of SiO2 and eluted with hexanes. After removal of the diphenyl ether, the desired product was eluted with ethyl acetate. After concentration in vacuo, the crude product was used without further purification.
    • Step E: Preparation of 4-bromo-7-mercapto-2,3-dihydro-1H-inden-1-one
  • A solution of S-(7-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl) dimethylcarbamothioate (670 mg, 2.1 mmol) dissolved in ethanol (25 mL) was treated with 3N sodium hydroxide) 10.7 mL, 32.1 mmol). The mixture was heated to reflux for 1 hour then cooled to 0° C. Aqueous HCl (3M) was added dropwise to neutralize the reaction. Ethanol was removed by concentration in vacuo followed by addition of aqueous HCl (1M) to adjust to pH 3-4. The aqueous was extracted twice with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried and concentrated in vacuo. The crude product was used without further purification.
    • Step F: Preparation of 4-bromo-7-((trifluoromethyl)thio)-2,3-dihydro-1H-inden-1-one
  • Methyl viologen dichloride hydrate (0.11 g, 0.41 mmol), 4-bromo-7-mercapto-2,3-dihydro-1H-inden-1-one (2.0 g, 8.2 mmol) and triethylamine (1.25 g, 12.3 mmol) were dissolved in DMF (50 mL) and cooled to −50° C. The flask was placed under gentle vacuum then trifluoromethyl iodide (3.2 g, 16 mmol) gas was introduced using a balloon. This reaction was warmed to ambient temperature and stirred at overnight. The reaction mixture was diluted with ethyl acetate and water, filtered through a celite pad, and the layers were partitioned. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and evaporated. The crude oil was then purified by flash column chromatography on SiO2 eluting with petroleum ether/ethyl acetate, (0.96 g, 51.7%). 1H NMR (400 MHz, CDCl3): δ 7.72 (d, 1H), 7.41 (d, 1H), 3.10-3.07 (m, 2H), 2.79-2.77 (m, 2H).
    • Step G: Preparation of 4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one
  • Ruthenium(III) chloride (19 mg, 0.09 mmol) was added to a mixture of 4-bromo-7-((trifluoromethyl)thio)-2,3-dihydro-1H-inden-1-one (0.96 g, 3.1 mmol) and sodium periodate (1.98 g, 9.26 mmol) in a mixture of carbon tetrachloride (20 mL), acetonitrile (20 mL), and water (40 mL). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on SiO2 eluting with petroleum ether/ethyl acetate, (1.7 g, 79%). 1H NMR (400 MHz, CDCl3): δ 8.05-8.02 (m, 2H), 3.21-3.18 (m, 2H), 2.89-2.86 (m, 2H).
    • Step H: Preparation of 4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]
  • Trimethylsilyl trifluoromethanesulfonate (177 mg, 0.80 mmol) was added dropwise to a pre-cooled (−78° C.) solution of 4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one and trimethyl(2-trimethylsilyloxyethoxy)silane (410 mg, 2.0 mmol) dissolved in dichloromethane (50 mL). The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction was quenched by addition of triethylamine then concentrated in vacuo. The residue was redissolved in ethyl acetate and washed twice with water, and saturated NaCl. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on SiO2 eluting with ethyl acetate/isohexane, (600 mg, 77%).
    • Step I: Preparation of 4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one
  • 4-Bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane] (3.5 g, 9.1 mmol) was dissolved in THF (72 mL) and treated with 10% aqueous HCl (27 mL, 27 mmol). The mixture was stirred for several minutes then warmed to 60° C. for 2 hours. The mixture was cooled, diluted with diethyl ether and separated. The aqueous was washed with diethyl ether and the combined organics were washed with water, saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a yellowish solid, (3.09 g, quant.). 1H NMR (400 MHz, CDCl3): δ 8.05-8.02 (m, 2H), 3.21-3.18 (m, 2H), 2.89-2.86 (m, 2H).
    • Step J: Preparation of (E. Z)-3-((4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)amino)propan-1-ol
  • 4-Bromo-7-(trifluoromethylsulfonyl)indan-1-one (3.09 g, 9.02 mmol] was slurried in toluene (35 mL) and cyclohexane (35 mL) then treated with 3-methoxypropylamine (2.15 mL, 27.1 mmol) and pivalic acid (46 mg, 0.45 mmol). The mixture was refluxed through a Dean-Stark trap (sidearm pre-filled with cyclohexane) for 8 hours. The reaction mixture was cooled and concentrated in vacuo. The crude material was taken directly into the fluorination.
    • Step K: Preparation of 4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one
  • Crude (E. Z)-3-((4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)amino)propan-1-ol (3.75 g, 9.1 mmol) was dissolved in dry acetonitrile (23 mL) and added dropwise to a warm (60° C.), suspension of Selectfluor (9.6 g, 27.2 mmol) and sodium sulfate (12.9 g, 90.5 mmol) slurried in acetonitrile (10 mL). After the addition, the mixture was heated to 60° C. for 10 minutes then cooled to ambient temperature and treated with 10% HCl (15 mL) and stirred for 20 minutes. The mixture was adjusted to pH 8 with solid NaHCO3 then diluted with ethyl acetate and separated. The aqueous was washed with ethyl acetate and the combined organics were washed with saturated NaHCO3, saturated NaCl, dried over Na2SO4 filtered, and concentrated in vacuo to dark oil. The crude material was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The desired product was concentrated to a light yellow solid, (2.27 g, 66%). 1H NMR (400 MHz, CDCl3): δ 8.22-8.14 (m, 2H), 3.60-3.55 (t, 2H).
    • Step L: Preparation of (S)-4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol
  • 4-Bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one (1.65 g, 4.35 mmol) was dissolved in isopropanol (21 mL) and treated with triethylamine (1.2 mL, 8.7 mmol), formic acid (0.49 mL, 13.1 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (27.7 mg, 0.040 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed in vacuo then the crude material was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The product was isolated as a more pure fraction (1.83 g) and a slightly less pure fraction. Both of these fractions were successfully utilized in the coupling reaction. 1H NMR (400 MHz, CDCl3): δ 7.88-7.80 (m, 2H), 5.50-5.45 (m, 1H), 3.66-3.58 (m, 1H), 3.20 (m, 1H).
    • Step M: Preparation of (S)-3-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)amino)-5-fluorobenzonitrile
  • (S)-4-Bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (98 mg, 0.26 mmol) was dissolved in 1,4-dioxane (0.80 mL) and treated with benzonitrile, 3-amino-5-fluoro-(42 mg, 0.31 mmol), palladium (II) acetate (2.9 mg, 0.010 mmol), and Xantphos (14.9 mg, 0.030 mmol). The mixture was heated to 120° C. for 1.5 hours in the microwave reactor. The reaction mixture was cooled, diluted with ethyl acetate and water then separated. The aqueous was washed with ethyl acetate and the combined organics were washed with saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude dark oil was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The desired material was recovered in a slightly impure form. This material was re-chromatographed on reversed-phase SiO2 eluting with a gradient of MeCN/water. A single fraction was collected and to light tan solid, (35 mg, 31%). LCMS ESI (−) m/z (M−H) 435; 1H NMR (400 MHz, CDCl3): δ 7.87 (d, 1H), 7.31-7.29 (m, 2H), 7.21-7.19 (m, 2H), 6.18 (m, 1H), 5.42-5.38 (m, 1H), 3.52-3.41 (m, 1H), 3.32-3.24 (m, 1H).
    • Example 16: Synthesis of (S)-5-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)amino)nicotinonitrile (Compound 488)
  • Figure US20190015377A1-20190117-C00945
  • (S)-4-Bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (23 mg, 0.060 mmol) was dissolved in 1,4-dioxane (0.20 mL) and treated with 3-pyridinecarbonitrile, 5-amino-(8.6 mg, 0.070 mmol), cesium carbonate (27.5 mg, 0.080 mmol), palladium (II) acetate (0.68 mg, 0.003 mmol), and Xantphos (3.5 mg, 0.010 mmol). After cooling, the mixture was diluted with water and ethyl acetate then separated. This mixture didn't separate well and there was insoluble yellow solid present, which was removed by filtration. The aqueous was washed with ethyl acetate and the combined organics were washed with saturated NaHCO3, saturated NaCl, dried over Na2SO4, and concentrated in vacuo to a dark residue. The crude material was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The product was recovered as light tan solid, (12 mg, 47%). LCMS ESI (+) m/z (M+H) 420; 1H NMR (400 MHz, CDCl3 plus CD3OD): δ 8.66 (s, 1H), 8.60 (s, 1H), 7.79-7.75 (m, 2H), 7.22-7.20 (m, 1H), 5.30 (d, 1H), 3.92-3.90 (m, 1H), 3.46-3.32 (m, 1H), 3.31-3.21 (m, 1H).
    • Example 17: Synthesis of (S)-2,2-difluoro-4-morpholino-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 490)
  • Figure US20190015377A1-20190117-C00946
    • Step A: Preparation of (S)-((4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane
  • (S)-4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (0.30 g, 0.78 mmol) was dissolved in methylene chloride (3.3 mL) and treated with 2,6-lutidine (0.40 mL, 3.1 mmol), cooled to 0° C., followed by treatment with t-butyldimethylsilyl triflate (0.45 mL, 1.9 mmol). The mixture was warmed to ambient temperature and stirred for two hours. The reaction mixture was re-cooled to 0° C. and cold 10% KHSO4 was added along with additional methylene chloride then the layers were separated. The organic layer was washed with 10% KHSO4, water, then with one-half saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated in vacuo to a light yellow oil. The crude product was chromatographed on SiO2 eluting with a gradient of methylene chloride/hexanes. The product was concentrated to colorless oil, (466 mg, 92%).
    • Step B: Preparation of (S)-4-(1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)morpholine
  • (S)-((4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane (0.030 g, 0.060 mmol) was dissolved in DMF (0.25 mL) and treated with sodium acetate (14 mg, 0.17 mmol) followed by morpholine (0.020 mL, 0.17 mmol). The mixture was heated at 120° C. for 1 hour in the microwave reactor. After cooling, the mixture was diluted with ethyl acetate then washed 7 times with water, saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The product was recovered as a colorless film, (17 mg, 58%). LCMS ESI (+) m/z (M+H) 502.
    • Step C: Preparation of (S)-2,2-difluoro-4-morpholino-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol
  • (S)-4-(1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)morpholine (0.02 g, 0.04 mmol) was dissolved in THF (0.25 mL) and treated with glacial acetic acid (2 μL, 0.04 mmol) followed by a solution of 1 M tetrabutylammonium fluoride in THF (0.04 mL, 0.04 mmol). The mixture was heated to 60° C. for 45 minutes. The darkened reaction mixture was cooled and added into saturated aqueous NaHCO3. The mixture was vortexed vigorously then diluted with ethyl acetate and separated. The organic layer was washed with saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude material was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. Compound 490 was recovered as light orange oil, (10.8 mg, 78%). LCMS ESI (+) m/z (M+H) 388; 1H NMR (400 MHz, CDCl3): δ 7.87 (d, 1H), 7.01 (d, 1H), 5.35-5.31 (m, 1H), 3.93-3.81 (m, 4H), 3.56-3.45 (m, 1H), 3.35-3.23 (m, 3H), 3.16-3.09 (m, 3H).
    • Example 18: Synthesis of (1S,3R)-4-((3-chloro-5-fluorophenyl)thio)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 491)
  • Figure US20190015377A1-20190117-C00947
    • Step A: Preparation of 4,7-difluoro-1H-indene-1,3(2H)-dione
  • (0.52 g, 2.8 mmol) was slurried acetic anhydride (2.5 mL, 27 mmol) and treated with tent-butyl 3-oxobutanoate (0.52 mL, 3.1 mmol) and triethylamine (1.4 mL, 10 mmol). The mixture was stirred at ambient temperature for 60 hours. The reaction was cooled to 0° C. and treated with 10% aqueous hydrochloric acid (8.6 mL, 25 mmol) by dropwise addition. After the addition, the mixture was warmed to ambient temperature then heated to 75° C. for 10 minutes. After cooling, the mixture was diluted with water (20 mL) and extracted three times with methylene chloride (20 mL portions). The combined organics were dried over Na2SO4 and concentrated in vacuo to crude orange solid. This material was carried forward without purification.
    • Step B: Preparation of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione
  • 4,7-difluoro-1H-indene-1,3(2H)-dione (0.51 g, 2.8 mmol) was dissolved in acetonitrile (27 mL), placed in an ambient temperature water bath then treated with solid sodium carbonate (950 mg, 9.0 mmol) followed by Selectfluor® (2.18 g, 6.2 mmol). The mixture was stirred at ambient temperature for 1 hour. The mixture was filtered to removed undissolved solids, the solids were washed with ethyl acetate and the filtrate was concentrated in vacuo. The residue was redissolved in water (ca. 20 mL) and extracted four times with ethyl acetate (20 mL each). The combined organics were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to orange solid. The crude solid was chromatographed on SiO2 eluting with an aggressive gradient of ethyl acetate/hexanes. The desired material concentrated to orange solid, (493 mg, 81%). 1H NMR (400 MHz, CDCl3): δ 7.70-7.65 (2H).
    • Step C: Preparation of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one
  • 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (5.81 g, 26.6 mmol) was suspended in methylene chloride (260 mL), cooled to 0° C., and treated with formic acid (1.01 mL, 26.6 mmol), triethylamine (2.60 mL, 18.6 mmol), then the reaction mixture was sparged with argon for 5 minutes. RuCl(p-cymene)[(S,S)-Ts-DPEN] (339 mg, 0.530 mmol) was added and the reaction was transferred to the refrigerator and allowed to stand at 4° C. for 20 hours. The cold reaction mixture was poured into cold 1N aqueous HCl (70 mL) and separated. The aqueous was washed twice with ethyl acetate then the combined organic layers were dried over Na2SO4 and concentrated in vacuo to a brown semi-solid. The crude material was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The product was recovered as yellow solid, (3.48 g, 59%). 1H NMR (400 MHz, CDCl3): δ 7.86-7.80 (m, 1H), 7.60-7.54 (m, 1H), 5.79-5.74 (m, 1H), 3.23-3.18 (m, 1H).
    • Step D: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one
  • (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (0.40 g, 1.8 mmol) was dissolved in dry acetonitrile (18 mL), cooled to 0° C., and sparged with argon for 5 minutes. The solution was treated in a single portion with sodium thiomethoxide (144 mg, 2.06 mmol) and after 5 minutes, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was redissolved in water and ethyl acetate. After separation, the aqueous was washed twice with ethyl acetate and the combined organics were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The orange residue was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The desired material was recovered as bright yellow solid, (314 mg, 70%). LCMS ESI (+) m/z (M+H) 249.
    • Step E: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (0.40 g, 1.6 mmol) was dissolved in MeOH (10 mL) and the reaction was treated dropwise with a solution of Oxone® (2.2 g, 3.6 mmol) dissolved in water (10 mL). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was filtered, the solids were washed with ethyl acetate and the filtrate was concentrated in vacuo to remove volatile solvents. The aqueous filtrate was extracted three times with ethyl acetate then the combined organics were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to yellow solid, (467 mg, quant.). LCMS ESI (+) m/z (M+H) 281.
    • Step F: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (0.45 g, 1.6 mmol) was dissolved in dichloromethane (16 mL), cooled to 0° C., and treated dropwise with diethylaminosulfur trifluoride (DAST) (0.32 mL, 2.4 mmol) and stirred at 0° C. for 14 hours. The reaction was treated with additional diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and stirring continued for 6 hours at 0° C. The cold reaction was treated with saturated NaHCO3 (10 mL) and stirred vigorously for 20 minutes. The mixture was diluted with additional methylene chloride and the layers were separated. The aqueous was re-extracted with methylene chloride and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to a yellow solid. The crude material was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The desired material was recovered as pale yellow solid, (258 mg, 53%). LCMS ESI (+) m/z (M+H) 283.
    • Step G: Preparation of (1S,3R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol
  • (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (0.098 g, 0.35 mmol) was suspended in methylene chloride (3.3 mL), cooled to 0° C., and treated with triethylamine (97 μL, 0.69 mmol), formic acid (39 μL, 1.0 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (2.2 mg, 0.003 mmol). The solution was allowed to stand at 4° C. in the refrigerator for 60 hours. The reaction mixture was concentrated in a stream of nitrogen gas then chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The desired fractions were concentrated to colorless film, (53 mg, 53%). LCMS ESI (+) m/z (M+H) 285.
    • Step H: Preparation of (1S,3R)-4-((3-chloro-5-fluorophenyl)thio)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol
  • (1S,3R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (0.005 g, 0.02 mmol) was treated with cesium bicarbonate (17 mg, 0.090 mmol) and suspended in DMF (0.1 mL) then stirred at ambient temperature for 1 hour. 3-Chloro-5-fluorothiophenol (14 mg, 0.090 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The reaction was concentrated in a stream of nitrogen gas to remove DMF. The residue was chromatographed on SiO2 eluting with a stepped gradient of ethyl acetate/hexanes. Compound 491 was concentrated to light pink oil, (7 mg, 93%). LCMS ESI (+) m/z (M+Na) 449; 1H NMR (400 MHz, CDCl3): δ 7.99-7.95 (m, 1H), 7.33-7.32 (m, 1H), 7.24-7.19 (m, 2H), 7.16-7.13 (m, 1H), 5.75 (dd, 1H), 5.68-5.65 (m, 1H), 3.37-3.36 (m, 1H), 3.23 (s, 3H).
    • Example 19: Synthesis of 3-(((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)thio)benzonitrile (Compound 492)
  • Figure US20190015377A1-20190117-C00948
  • (1S,3R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (0.0073 g, 0.030 mmol) was treated with cesium bicarbonate (25 mg, 0.13 mmol) and suspended in DMF (0.1 mL) then 3-mercapto-benzonitrile (17 mg, 0.13 mmol) was added and the mixture was stirred at ambient temperature for 60 hours. The reaction was concentrated in a stream of nitrogen gas to remove DMF. The residue was chromatographed on SiO2 eluting with a stepped gradient of ethyl acetate/hexanes. The product was concentrated to light oil, (7 mg, 91%). LCMS ESI (+) m/z (M+Na) 422; 1H NMR (400 MHz, CDCl3): δ 7.97-7.87 (m, 1H), 7.81 (m, 1H), 7.77-7.74 (m, 2H), 7.61-7.57 (m, 1H), 7.16-7.14 (m, 1H), 5.77 (dd, 1H), 5.69-5.65 (m, 1H), 3.40-3.39 (m, 1H), 3.23 (s, 3H).
    • Example 20: Synthesis of (S)-4-(3-chlorophenyl)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 485)
  • Figure US20190015377A1-20190117-C00949
    • Step A: Preparation of 4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]
  • A solution of 4′-fluoro-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (1.0 g, 3.07 mmol) and 4-methoxybenzyl alcohol (760 μL, 6.13 mmol) in acetonitrile (9.3 mL) at 25° C. was treated with potassium hydroxide (516 mg, 9.2 mmol) and stirred at 25° C. for 1.5 h. The reaction mixture was poured into 150 mL of water and extracted with 3×40 mL EtOAc. The combined organics were rinsed with 20 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-25% EtOAc/hexane to afford 4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane] as a solid (1.08 g, 79%). LCMS ESI (+) [M+H]+ m/z 445.
    • Step B: Preparation of 4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one
  • In a glass pressure vessel, a solution of 4′-[(4-methoxyphenyl)methoxy]-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (1.08 g, 2.43 mmol) in a mixture acetone (20 mL) and water (20 mL) was treated with pyridinium p-toluenesulfonate (122 mg, 0.49 mmol), sealed and stirred at 80° C. overnight. Volatiles were removed by concentration under reduced pressure. The residue was poured into 40 mL of saturated aqueous NaHCO3 and extracted with 3×50 mL EtOAc. The combined organics were rinsed with 30 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) [M+H]+ m/z 401.
    • Step C: Preparation of 2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one
  • 2,2-Dimethylpropanoic acid (50 mg, 0.46 mmol) was added to a flask containing a suspension of 4-[(4-methoxyphenyl)methoxy]-7-(trifluoromethylsulfonyl)indan-1-one (922 mg, 2.3 mmol) and 3-methoxypropan-1-amine (0.35 mL, 3.45 mmol) in a mixture of toluene (14 mL) and cyclohexane (14 mL). This was refluxed with a Dean-Stark trap attached at 104° C. After 2.5 h, the reaction mixture was cooled and volatiles removed by concentration under reduced pressure. The residue was dissolved in acetonitrile (24 mL) and treated sequentially with sodium sulfate (850 mg, 6.0 mmol) and and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (2.13 g, 6.0 mmol). The resulting suspension stirred at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was treated with concentrated hydrochloric acid (600 μl, 7.2 mmol) and water (10 mL). The resulting mixture stirred for 20 min. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with 3×30 mL EtOAc. The combined organics were rinsed with 20 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-40% EtOAc/hexane to afford 2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one as a solid (520 mg, 50%). LCMS ESI (+) [M+H]+ m/z 437.
    • Step D: Preparation of (S)-2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol
  • A solution of 2,2-difluoro-4-[(4-methoxyphenyl)methoxy]-7-(trifluoromethylsulfonyl)indan-1-one (520 mg, 1.19 mmol) in dichloromethane (11.9 mL) was cooled to 0° C. and sparged with nitrogen for 5 minutes. During this time, formic acid (130 μL, 3.58 mmol) and triethylamine (330 μl, 2.38 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (22.8 mg, 0.036 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Once complete, the reaction mixture was poured into 30 mL of saturated aqueous NaHCO3 and extracted with 3×30 mL CH2Cl2. The combined organics were rinsed with 20 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-40% EtOAc/hexane to afford (S)-2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol as a solid (370 mg, 71%). LCMS ESI (+) [M+NH4]+ m/z 456.
    • Step E: Preparation of (S)-tert-butyl((2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane
  • A solution of (1S)-2,2-difluoro-4-[(4-methoxyphenyl)methoxy]-7-(trifluoromethylsulfonyl)indan-1-ol (370 mg, 0.84 mmol) and 2,6-lutidine (780 μL, 7.76 mmol) in dichloromethane (8.4 mL) at −78° C. was treated with tert-butyldimethylsilyl trifluoromethanesulfonate (980 μL, 4.22 mmol) and allowed to warm to room temperature over 2 h. The reaction mixture was poured into 30 mL of saturated aqueous NaHCO3 and extracted with 3×20 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford (S)-tert-butyl((2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane (460 mg, quant). LCMS ESI (−) [M−H]−m/z 551.
    • Step F: Preparation of (S)-1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-ol
  • A solution of tert-butyl-[(1S)-2,2-difluoro-4-[(4-methoxyphenyl)methoxy]-7-(trifluoromethylsulfonyl)indan-1-yl]oxy-dimethyl-silane (460 mg, 0.83 mmol) in dichloromethane (3.0 mL) at 25° C. was treated with trifluoroacetic acid (3.0 mL) and stirred at 25° C. After 1 h, volatiles were removed by concentration under reduced pressure. To the resulting residue was added 6 mL of toluene and the organic volatiles were once again removed by concentration under reduced pressure. This process was repeated twice. Purification was achieved by chromatography on reverse phase by injection of a DMF solution of the product residue. 40-100% CH3CN/Water was used as eluent. (S)-1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-ol was isolated a thick orange oil (236 mg, 89%). LCMS ESI (−) [M−H]− m/z 431.
    • Step G: Preparation of (S)-2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yltrifluoromethanesulfonate
  • A solution of (S)-1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-ol (215 mg, 0.50 mmol) and 2,6-bis(1,1-dimethylethyl)-4-methyl-pyridine (408 mg, 1.99 mmol) in dichloromethane (10 mL) was cooled to −78° C. and treated with trifluoromethanesulfonic anhydride (0.17 mL, 0.99 mmol). The mixture was stirred at −78° C. for 1 h. The reaction mixture was poured into 20 mL of saturated NaHCO3 and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on SiO2 eluting with a gradient of ethyl acetate/hexanes.
  • Step H: Preparation of tributyl(3-chlorophenyl)stannane: A solution of 3-chlorophenylmagnesium bromide (0.5 M in THF) (1.40 mL, 0.70 mmol) was cooled to −78° C. and treated dropwise with a solution of tributyl(chloro)stannane (230 mg, 0.70 mmol) dissolved in THF (0.5 mL). The solution was stirred for 5 minutes then allowed to warm to ambient temperature slowly without the bath and stirred at ambient temperature for 45 hours. The reaction was quenched by addition of saturated NH4Cl and water. Diethyl ether was added and the mixture was separated. The aqueous was washed twice with diethyl ether and the combined organics were washed saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude material was chromatographed on SiO2 eluting with cyclohexane. The desired product was concentrated to colorless liquid, (234 mg, 84%). 1H NMR (400 MHz, CDCl3): δ 7.58-7.30 (m, 4H), 1.60-1.45 (m, 6H), 1.40-1.28 (m, 6H), 1.17-1.00 (m, 6H), 0.92-0.85 (m, 9H).
    • Step I: Preparation of (S)-tert-butyl((4-(3-chlorophenyl)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane
  • (S)-2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (17 mg, 0.030 mmol) was dissolved in toluene (0.4 mL) then tributyl-(3-chlorophenyl)stannane (23 mg, 0.060 mmol), tetrakis(triphenylphosphine)palladium (1.7 mg, 0.001 mmol), and lithium chloride (4 mg, 0.09 mmol) were added. The reaction mixture was sparged with argon then heated to reflux for 16 hours. After cooling, the mixture was concentrated in a stream of nitrogen gas. The crude material was chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The less polar UV-active spot was recovered as colorless oil, (9.8 mg, 63%).
    • Step J: Preparation of (S)-4-(3-chlorophenyl)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol
  • (S)-tert-butyl((4-(3-chlorophenyl)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane (9.8 mg, 0.020 mmol) was dissolved in THF (0.2 mL) containing glacial acetic acid (3.2 μL, 0.060 mmol) and the mixture was treated with a 1M solution of tetrabutylammonium fluoride in THF (28 μL, 0.030 mmol). The mixture was heated to 60° C. for 2 hours, then the reaction was cooled, treated with one-half saturated NaHCO3, diluted with ethyl acetate and separated. The aqueous was washed twice with ethyl acetate and the combined organics were washed with saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo to dark oil. The crude material was chromatographed on SiO2 eluting with a stepped gradient of ethyl acetate/hexanes. The desired product was concentrated to light yellow solid, (2.5 mg, 32%). LCMS ESI (−) m/z (M−H) 411/413; 1H NMR (400 MHz, CDCl3): δ 8.06-8.04 (d, 1H), 7.66-7.64 (d, 1H), 7.48-7.41 (m, 3H), 7.29-7.26 (m, 1H), 5.47-5.43 (m, 1H), 3.78-3.65 (m, 1H), 3.33 (t, 1H), 3.19-3.17 (m, 1H).
    • Example 21: Synthesis of (S)-2,2-difluoro-4-phenyl-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 487)
  • Figure US20190015377A1-20190117-C00950
  • (S)-4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (20 mg, 0.050 mmol) was dissolved in 1,4-dioxane (0.20 mL) and treated with phenylboronic acid (9.6 mg, 0.080 mmol), Pd(dppf)Cl2-DCM adduct (3 mg, 0.004 mmol), and potassium fluoride (6.1 mg, 0.10 mmol). The mixture was heated to 100° C. for 10 hours. After cooling, the reaction mixture was concentrated in a stream of nitrogen gas then chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The desired material was concentrated to white solid, (17 mg, 86%). LCMS ESI (−) m/z (M−H) 377; 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.67 (d, 1H), 7.54-7.47 (m, 3H), 7.42-7.39 (m, 2H), 5.47-5.43 (m, 1H), 3.80-3.67 (m, 1H), 3.40-3.31 (t, 1H), 3.22-3.21 (m, 1H).
    • Example 22: Synthesis of (S)-3-(2,2-difluoro-1-hydroxy-7((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-5-fluorobenzonitrile (Compound 486)
  • Figure US20190015377A1-20190117-C00951
  • (S)-4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (20 mg, 0.050 mmol) was dissolved in 1,4-dioxane (0.20 mL) and treated with 3-cyano-5-fluorophenylboronic acid (10 mg, 0.060 mmol), Pd(dppf)Cl2-DCM adduct (3 mg, 0.004 mmol), and potassium fluoride (6.1 mg, 0.10 mmol). The mixture was heated to 100° C. for 10 hours. After cooling, the mixture was concentrated in a stream of nitrogen gas, then directly chromatographed on SiO2 eluting with a gradient of ethyl acetate/hexanes. The desired product was recovered as colorless film, (12 mg, 54%). LCMS ESI (−) m/z (M−H) 420; 1H NMR (400 MHz, CDCl3): δ 8.09 (d, 1H), 7.65 (d, 1H), 7.61-7.60 (m, 2H), 7.40-7.37 (m, 1H), 5.49-5.46 (m, 1H), 3.78-3.65 (m, 1H), 3.33-3.25 (t, 1H), 3.20 (m, 1H).
    • Example 23: Synthesis of (R)-4-((3-chloro-5-fluorophenyl)thio)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 493)
  • Figure US20190015377A1-20190117-C00952
  • Sodium bicarbonate (18.9 mg, 0.23 mmol) was added all at once to (1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol (20.0 mg, 0.08 mmol) and 3-chloro-5-fluoro-benzenethiol (24.4 mg, 0.15 mmol) in 1-methyl-2-pyrrolidone (0.5 mL) at room temperature then the reaction vial was sealed with a threaded cap. The reaction mixture was then warmed to 90° C. and continued to stir at this temperature until complete as judged by LC-MS (4 h). Cooled to room temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording (1R)-4-(3-chloro-5-fluoro-phenyl)sulfanyl-7-(difluoromethylsulfonyl)indan-1-ol (25.5 mg, 0.062 mmol, 83% yield). LC-MS ESI (−) m/z 453/455 (M+HCO2 −). 1H-NMR (400 MHz, CDCl3): δ 7.84 (d, 1H), 7.19-7.17 (m, 1H), 7.08 (s, 1H), 7.00-6.97 (m, 2H), 5.71-5.68 (m, 1H), 3.64 (d, 1H), 3.21 (s, 3H), 3.12-3.04 (m, 1H), 2.84-2.76 (m, 1H), 2.52-2.43 (m, 1H), 2.27-2.19 (m, 1H).
    • Example 24: Synthesis of (1R)-7-(difluoromethylsulfonyl)-4-(tetrahydropyran-4-ylamino)indan-1-ol (Compound 494)
  • Figure US20190015377A1-20190117-C00953
  • 4-Piperidone (8.4 mg, 0.08 mmol) was added all at once to (1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol (22.0 mg, 0.08 mmol) in 1-methyl-2-pyrrolidone (0.5 mL) at room temperature. The reaction mixture was then stirred at 50° C. for 24 h. Additional 4-piperidone (8.4 mg, 0.08 mmol) was added at room temperature and then warmed to 90° C. for an additional 4 h. Cooled to room temperature and added additional 4-piperidone (8.4 mg, 0.08 mmol). Warmed to 90° C. for an additional 4 h. Cooled to room temperature then purified directly on reverse phase silica gel (12+M, 14 CV, 20-100% MeCN/water) affording (1R)-7-(difluoromethylsulfonyl)-4-(tetrahydropyran-4-ylamino)indan-1-ol (15.8 mg, 0.046 mmol, 55% yield). LC-MS ESI (−) m/z 346 (M−H). 1H-NMR (400 MHz, CDCl3): δ 7.69 (d, 1H), 6.64 (d, 1H), 6.26 (t, 1H), 5.57-5.56 (m, 1H), 4.14 (d, 1H), 4.06-4.01 (m, 2H), 3.72-3.62 (m, 1H), 3.58-3.51 (m, 2H), 3.32 (d, 1H), 2.95-2.84 (m, 1H), 2.61-2.55 (m, 1H), 2.47-2.38 (m, 1H), 2.28-2.20 (m, 1H), 2.09-2.03 (m, 2H), 1.62-1.52 (m, 2H).
    • Example 25: Synthesis of 4-(2-hydroxyethyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 495)
  • Figure US20190015377A1-20190117-C00954
    • Step A: Preparation of diethyl 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanedioate
  • Tetrahydrofuran (12.0 mL) was added all at once to sodium hydride (735.6 mg, 18.39 mmol) at 0° C. under nitrogen followed by the slow addition of diethyl malonate (1.86 mL, 12.26 mmol). Stirred for 15 min then a solution of 4′-fluoro-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (1.0 g, 3.07 mmol) in tetrahydrofuran (3.0 mL) was added by syringe over 2 minutes. The reaction mixture was then removed from the cooling bath and stirred at room temperature overnight. Additional sodium hydride (200 mg) was added as well as diethyl malonate (0.5 mL) and stirred an additional 6 h. Cooled to 0° C., quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purified on silica gel (25 g SNAP Ultra, 10-100% ethyl acetate/hexanes) affording diethyl 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanedioate (940.0 mg, 2.01 mmol, 66% yield).
    • Step B: Preparation of 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetic Acid
  • HCl (4.84 mL, 29.03 mmol) was added to diethyl 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanedioate (300.0 mg, 0.64 mmol) then warmed to 100° C. for 6 h. Cooled to room temperature, extracted with MTBE, washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo affording 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid (200.0 mg, 0.62 mmol, 96% yield). Used without further purification.
    • Step C: Preparation of 4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-ol
  • Borane dimethylsulfide complex (434.4 μL, 0.87 mmol) was added slowly to 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid (70.0 mg, 0.22 mmol) in tetrahydrofuran (1.5 mL) at room temperature and stirred for 2 h. Cooled to 0° C. and quenched with 1 N HCl, extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 60-100% ethyl acetate/hexanes) affording 4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-ol (36.0 mg, 0.12 mmol, 53% yield). Hexanes was added to the clear oil and then cooled to −78° C. with scratching until a white gum was observed, warmed to room temperature and continued scratching until a white powder formed. Hexanes was then removed under a stream of nitrogen to afford Compound 495. LC-MS (−) ESI m/z 309 (M−H). 1H-NMR (400 MHz, CDCl3): δ 7.83 (d, 1H), 7.47 (d, 1H), 5.61 (d, 1H), 3.95-3.92 (m, 1H), 3.27-3.18 (m, 1H), 3.10 (s, 1H), 2.99-2.96 (m, 3H), 2.41-2.26 (m, 2H).
    • Example 26: Synthesis of (S)-2,2-difluoro-4-(2-hydroxyethyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 496)
  • Figure US20190015377A1-20190117-C00955
  • Step A: Borane dimethylsulfide complex (439.0 μL, 0.88 mmol) was added dropwise to 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]acetic acid (268.0 mg, 0.73 mmol) in tetrahydrofuran (7.0 mL) at 0° C. under nitrogen then slowly warmed to room temperature. Stirred until complete as judged by LC-MS. Quenched carefully with saturated sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 40-100% ethyl acetate/hexanes) affording 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]ethanol (95.0 mg, 0.27 mmol, 37% yield).
  • Step B: HCl (1.0 mL, 1.0 mmol) was added all at once to 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]ethanol (95.0 mg, 0.27 mmol) in acetone (4.0 mL) at room temperature then stirred until complete as judged by LC-MS. Diluted with water, extracted with ethyl acetate, washed with saturated sodium bicarbonate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Used without further purification.
  • Step C: Tert-Butyldimethylsilyl chloride (46.9 mg, 0.31 mmol) was added all at once to a solution of 4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-one (80.0 mg, 0.26 mmol) and imidazole (53.0 mg, 0.78 mmol) in dichloromethane (2.0 mL) at room temperature then stirred overnight. Diluted with water, extracted with MTBE, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP, 12 CV, 5-60% ethyl acetate/hexanes) affording 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-7-(trifluoromethylsulfonyl)indan-1-one (89.0 mg, 0.21 mmol, 81% yield).
  • Step D: Pivalic acid (2.2 mg, 0.02 mmol) was added to a mixture of 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-7-(trifluoromethylsulfonyl)indan-1-one (89.0 mg, 0.21 mmol) and 3-methoxypropylamine (37.6 mg, 0.42 mmol) in cyclohexane (1.5 mL): toluene (1.5 mL) at room temperature then warmed to reflux with the azeotropic removal of water by Dean-Stark trap. Monitored by 1H-NMR. Cooled to room temperature then concentrated in vacuo. Used without further purification.
  • Step E: Crude 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-(3-methoxypropyl)-7-(trifluoromethylsulfonyl)indan-1-imine (103.0 mg, 0.21 mmol) in acetonitrile (1.5 mL) was added to 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (184.8 mg, 0.52 mmol) and sodium Sulfate (59.3 mg, 0.42 mmol) in acetonitrile (1.5 mL) at 60° C. and stirred for 1 h. Cooled to room temperature then 1 N HCl (3.0 mL) was added and stirred overnight. Extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified on reverse phase silica gel (12+M, 14 CV, 20-100% acetonitrile/water) affording 2,2-difluoro-4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-one (40.0 mg, 0.12 mmol, 56% yield).
  • Step F: Chloro{[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) (1.5 mg, 0.002 mmol) was added all at once to an ice cold solution of 2,2-difluoro-4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-one (40.0 mg, 0.12 mmol), triethylamine (32.4 μL, 0.23 mmol) and formic acid (13.2 μL, 0.35 mmol) in dichloromethane (1.0 mL) then sealed with a threaded teflon cap and placed in a 4° C. fridge over the weekend. Purified directly on silica gel (10 g SNAP Ultra, 14 CV, 25-100% ethyl acetate/hexanes) affording (1S)-2,2-difluoro-4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-ol (Compound 496) (28.0 mg, 0.081 mmol, 70% yield) as a clear oil. Swirled with hexanes to yield a white solid. LC-MS ESI (−) m/z 345 (M−H).
    • Example 27: Synthesis of 3-(2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)propane-1,2-diol (Compound 521)
  • Figure US20190015377A1-20190117-C00956
  • Step A: Tetrakis(triphenylphosphine)palladium(0) (59.69 mg, 0.0500 mmol) was added all at once to a degassed solution of 4′-bromo-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (200.0 mg, 0.52 mmol) and allyltributyltin (0.19 mL, 0.62 mmol) in DMF (5.0 mL) under nitrogen then warmed to 90° C. until complete as judged by LC-MS. Cooled to room temperature, saturated KF (5.0 mL) was added and stirred for 30 min, extracted with MTBE, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 5-50% ethyl acetate/hexanes) affording 4′-allyl-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (145.0 mg, 0.42 mmol, 81% yield).
  • Step B: HCl (2.0 mL, 2.0 mmol) was added all at once to a solution of 4′-allyl-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (145.0 mg, 0.42 mmol) in acetone (5.0 mL) then stirred overnight at room temperature. Diluted with water, extracted with MTBE, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Used without further purification.
  • Step C: Pivalic acid (2.6 mg, 0.02 mmol) was added all at once to 4-allyl-7-(trifluoromethylsulfonyl)indan-1-one (76.0 mg, 0.25 mmol) and 3-methoxypropylamine (76.4 μL, 0.75 mmol) in cyclohexane (1.5 mL): toluene (1.5 mL) at room temperature then warmed to reflux with azeotropic removal of water via a Dean-Stark trap until complete as judged by 1H-NMR. Cooled to room temperature then concentrated in vacuo. Used without further purification.
  • Step D: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (219.4 mg, 0.62 mmol) was added all at once to crude 4-allyl-N-(3-methoxypropyl)-7-(trifluoromethylsulfonyl)indan-1-imine (93.0 mg, 0.25 mmol) and sodium sulfate (70.4 mg, 0.50 mmol) in acetonitrile (3.0 mL) at 60° C. then stirred for 1 h. Cooled to room temperature, 1 N HCl was added (3.0 mL) and stirred for 15 min, extracted with MTBE, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Used without further purification.
  • Step E: Sodium borohydride (25.0 mg, 0.66 mmol) was added all at once to a solution of 4-allyl-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-1-one (75.0 mg, 0.22 mmol) and 2,2-difluoro-4-[(E)-prop-1-enyl]-7-(trifluoromethylsulfonyl)indan-1-one (75.0 mg, 0.22 mmol) in methanol (2.0 mL) at room temperature and stirred for 30 min. Quenched with 1 N HCl (2.0 mL), diluted with water, extracted with MTBE, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Used without further purification.
  • Step F: Osmium tetroxide, 4 wt. % solution (27.9 μL, 0.004 4 mmol) was added all at once to a solution of 4-allyl-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-1-ol (75.0 mg, 0.22 mmol), 4-methylmorpholine N-oxide (51.3 mg, 0.44 mmol) in acetone (2.0 mL) then stirred over the weekend in a sealed vial. Diluted with water, extracted with ethyl acetate, washed with brine dried over Na2SO4, filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 50-100% ethyl acetate/hexanes) affording Compound 521 (17.4 mg, 0.046 mmol, 21% yield). LC-MS ESI (−) m/z 375 (M−H)
    • Example 28: Synthesis of 4-(3-hydroxypropyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 522)
  • Figure US20190015377A1-20190117-C00957
  • Step A: 3-Ethoxy-3-oxopropylzinc bromide (0.77 mL, 0.39 mmol) was added to a solution of 4′-bromo-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (50.0 mg, 0.13 mmol), palladium(II) acetate (2.9 mg, 0.01 mmol) and SPhos (10.6 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) at room temperature under nitrogen in a sealed microwave vial then warmed to 60° C. until complete as judged by LC-MS. Cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 5-50% ethyl acetate/hexanes) affording ethyl 3-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanoate (25.0 mg, 0.061 mmol, 47% yield).
  • Step B: 1 N HCl (1.0 mL, 1.0 mmol) was added all at once to a solution of ethyl 3-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanoate (25.0 mg, 0.06 mmol) in acetone (2.0 mL) then stirred at room temperature until complete as judged by LC-MS (30 min). Diluted with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. Used without further purification.
  • Step C: Lithium borohydride solution (0.2 mL, 0.40 mmol) was added to a solution of crude ethyl 3-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]propanoate (22.0 mg, 0.06 mmol) in tetrahydrofuran (0.50 mL) at room temperature under nitrogen then stirred until complete as judged by LC-MS. Warmed to 75° C. after 5 h at room temperature and held for 3 h. Cooled to room temperature, poured into 1 N HCl, extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 50%-100% EtOAc/hexanes) affording Compound 522 (4.4 mg, 0.014 mmol, 22% yield). LC-MS ESI (−) m/z 323 (M−H).
    • Example 29: Synthesis of 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide (Compound 523)
  • Figure US20190015377A1-20190117-C00958
    • Step A: Preparation of 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]acetic acid
  • Sodium hydroxide (0.55 mL, 1.66 mmol) added by syringe to diethyl 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanedioate (515.0 mg, 1.10 mmol) in ethanol 95% (2.2 mL) at room temperature and stirred for 30 min. Warmed to 60° C. for 3 h. Added additional sodium hydroxide (0.55 mL, 1.66 mmol) and stirred until complete as judged by LC-MS. Acidified to pH 2 with 1 N HCl, diluted with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo affording 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]acetic acid (368 mg, 1.00 mmol, 91% yield). Used without further purification.
    • Step B: Preparation of 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide
  • N,N-Diisopropylethylamine (142.7 μL, 0.82 mmol) added all at once to 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]acetic acid (100.0 mg, 0.27 mmol), ammonium chloride (73.0 mg, 1.4 mmol) and HATU (156.1 mg, 0.41 mmol) in DMF (2.0 mL) at room temperature then stirred until complete as judged by LC-MS. Purified directly on reverse phase silica gel (12+M, 14 CV, 20-100% acetonitrile/water) affording 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide (12.0 mg, 0.037 mmol, 14% yield). LC-MS ESI (+) m/z 322 (M+H).
    • Step C: Preparation of 2-[1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide
  • Sodium borohydride (4.2 mg, 0.11 mmol) was added all at once to 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide (12.0 mg, 0.04 mmol) in methanol (1.0 mL) at room temperature and stirred for 20 min. Quenched with 1 N HCl, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. A portion was purified by preparative TLC (ethyl acetate) affording Compound 523 (1.6 mg, 0.005 mmol, 13% yield). LC-MS ESI (−) m/z 322 (M−H).
    • Example 30: Synthesis of (R)-2-(1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Compound 524)
  • Figure US20190015377A1-20190117-C00959
  • Chloro{[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) (2.0 mg, 0.003 mmol) was added all at once to an ice cold solution of 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid (102.0 mg, 0.32 mmol), triethylamine (88.2 μL, 0.63 mmol) and formic acid (35.8 μL, 0.95 mmol) in dichloromethane (3.0 mL), sealed with a teflon lined cap and placed in a 4° C. fridge overnight. Warmed to room temperature then stirred for an additional 3 days. Concentrated in vacuo then purified on reverse phase silica gel (25+M, 14 CV, 20-100% acetonitrile/water), diluted with ethyl acetate, washed with 1 N HCl to remove triethylamine, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo affording 2-[(1R)-1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid (45.0 mg, 0.14 mmol, 44% yield). LC-MS ESI (−) m/z 323 (M−H).
    • Example 31: Synthesis of (1S,3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 574) and (1S,3S)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 575)
  • Figure US20190015377A1-20190117-C00960
    • Step A: Preparation of 4,7-difluoro-1H-indene-1,3(2H)-dione
  • A solution of 3,6 difluorophthalic anhydride (4.25 g, 23.1 mmol), tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride (21.0 mL, 221.6 mmol) at 25° C. was treated with triethylamine (11.7 mL, 84.3 mmol) and stirred at ambient temperature for 18 h. The reaction mixture was cooled to 0° C. and treated with 10% hydrochloric acid (65 mL, 211 mmol) by dropwise addition. Once the addition was complete, the ice bath was removed and the mixture stirred at ambient for 10 minutes. The mixture was then heated to 75° C. for 10 minutes. During this time gas evolution was observed. The suspension slowly broke up to form a clear red mixture. The reaction mixture was poured into 100 mL of water and extracted with 3×50 mL CH2Cl2. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification.
    • Step B: Preparation of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione
  • A solution of the unpurified 4,7-difluoro-1H-indene-1,3(2H)-dione (4.2 g, 23.1 mmol) in acetonitrile (100 mL) cooled in a 25° C. water bath was treated with sodium carbonate (5.38 g, 50.7 mmol). Selectfluor® (17.97 g, 50.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were removed under reduced pressure and the residue was poured into 100 mL of 0.1% HCl and extracted with 3×50 mL EtOAc. The combined organics were rinsed with 40 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel 1:1 hexane/ethyl acetate to give 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.5 g, 70%) as a solid. 1H NMR (400 MHz, CDCl3): δ 7.70 (t, 2H).
    • Step C: Preparation of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one
  • To a solution of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.48 g, 16.0 mmol) in dichloromethane (150 mL) at 0° C. was added formic acid (600 μl, 16.0 mmol) and triethylamine (1.55 mL, 11.2 mmol). The resulting mixture was sparged with nitrogen for 5 minutes and then RuCl(p-cymene)[(S,S)-Ts-DPEN] (203.6 mg, 0.32 mmol) was added. The reaction vessel was sealed and put into a 4° C. refrigerator to stand for 18 hours. The reaction mixture was poured into 40 mL 1 N HCl. The CH2Cl2 layer was separated and the aqueous layer extracted with ethyl acetate (2×50 mL). The combined organics were dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 25% EtOAc/hexane to give (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2.9 g, 83%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.51 (ddd, 1H), 7.29-7.23 (m, 1H), 5.44 (dd, 1H), 2.79 (dd, 1H).
    • Step D: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one
  • A solution of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (966 mg, 4.39 mmol) in acetonitrile (40 mL) at 0° C. was sparged with nitrogen for 5 minutes and treated with sodium thiomethoxice (353.7 mg, 5.05 mmol). The ice bath was removed and the reaction mixture was allowed to stir at ambient temperature for 2 hours. The reaction mixture was evaporated and the residue partitioned between 40 mL of EtOAc and 40 mL of water. The aqueous layer was further extracted with 2×40 mL of EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica using 10-60% EtOAc/hexane to afford (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (870 mg, 80%) as a yellow solid. LCMS ESI (+)[M+H]+ m/z 249.
    • Step E: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (400 mg, 1.6 mmol) was dissolved in MeOH (10 mL) and the reaction was treated dropwise with a solution of Oxone® (2.18 g, 3.55 mmol) dissolved in water (10 mL). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was filtered, the solids were washed with ethyl acetate and the filtrate was concentrated in vacuo. The aqueous filtrate was extracted 3×30 mL of EtOAc and then the combined organics were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a yellow solid that was used without further purification (467 mg). LCMS ESI (+) [M+H]+ m/z 281.
    • Step F: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (450 mg, 1.6 mmol) was dissolved in dichloromethane (16 mL), cooled to 0° C. and treated dropwise with diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and the mixture was stirred at 0° C. for 2 hours, then the whole homogeneous reaction mixture was placed into the refrigerator overnight. The reaction was treated with additional diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and stirring continued for 6 h at 0° C. The cold reaction was treated with saturated NaHCO3 (10 mL) and stirred vigorously for 20 minutes. The mixture was diluted with additional methylene chloride and the layers were separated. The aqueous was re-extracted with methylene chloride and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to a yellow solid. The crude material was chromatographed on SiO2 (Biotage SNAP Ultra) and eluted with a gradient of ethyl acetate/hexane. The desired material was concentrated to a pale yellow solid (258 mg). LCMS ESI (+) [M+H]+ m/z 283.
    • Step G: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]
  • A solution of (3R)-2,2,3,4-tetrafluoro-7-methylsulfonyl-indan-1-one (2.03 g, 7.2 mmol) and 2-bromoethanol (1.53 mL, 21.6 mmol) in DMF (16 mL) at 25° C. was treated with potassium carbonate (2.98 g, 21.6 mmol) and stirred at 25° C. for 30 min. The reaction mixture was poured into 200 mL of water and extracted with 3×50 mL Et2O. The combined organics were rinsed with 30 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The off-white solid was used without further purification. LCMS ESI (+) [M+1-1]+ m/z 327.
    • Step H: Preparation of (R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]
  • A solution of (3′R)-2′,2′,3′,4′-tetrafluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (1.95 g, 5.98 mmol) and 3,3-difluoro-cyclobutanol (770 μL, 7.95 mmol) in acetonitrile (30 mL) at 25° C. was treated with potassium hydroxide (402.4 mg, 7.17 mmol) and stirred at 25° C. for 1 h. Excess acetonitrile was removed by concentration under reduced pressure. The reaction mixture was poured into 40 mL of water and extracted with 3×40 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 15-45% EtOAc/hexane to afford a white solid (2.2 g, 89%). LCMS ESI (+) [M+H]+ m/z 415.
    • Step I: Preparation of (R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one
  • A solution of (3′R)-4′-(3,3-difluorocyclobutoxy)-2′,2′,3′-trifluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (2.2 g, 5.31 mmol) in dichloromethane (30 mL) at 25° C. was treated with perchloric acid (70% in water, 10 mL) and left to stir for 2 days. The reaction mixture was carefully quenched by the addition of 100 mL of saturated aqueous NaHCO3 and extracted with 3×50 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 25-65% EtOAc/hexane to afford a solid (1.41 g, 72%). LCMS ESI (+) [M+1-1]+ m/z 371.
    • Step J: Preparation of (1S,3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 574) and (1S,3S)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 575)
  • A solution of (3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-one (1.41 g, 3.81 mmol) in dichloromethane (40 mL) was cooled to 0° C. and sparged with nitrogen for 5 minutes. During this time formic acid (430 μL, 11.42 mmol) and triethylamine (1.06 mL, 7.62 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (48.5 mg, 0.076 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 25-55% EtOAc/hexane. Additional purifications by chromatography on silica using 20-50% EtOAc/hexane were necessary to isolate material of sufficient purity. A flash crystallization was preformed from CHCl3. The sample was dissolved in a minimum of refluxing CHCl3 and then cooled to 0° C. The collected solid was rinsed with CHCl3 and dried under high vacuum overnight to afford Compound 574 as a white solid (550 mg, 39%). From the repeated purifications, Compound 575 was isolated as a white solid. Data for Compound 574: LCMS ESI (+) [M+H]+ m/z 373; 1H NMR (400 MHz, (CD3)2CO): δ 8.11 (dd, 1H), 7.33 (d, 1H), 5.87 (dd, 1H), 5.65-5.59 (m, 1H), 5.17-5.08 (m, 1H), 3.40-3.26 (m, 2H), 3.27 (s, 3H), 2.98-2.81 (m, 2H), 2.80 (t, 1H). Data for Compound 575: LCMS ESI (+) [M+H]+ m/z 373; 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, 1H), 6.87 (d, 1H), 5.92 (dd, 1H), 5.78 (td, 1H), 4.86-4.76 (m, 1H), 3.98 (d, 1H), 3.25-3.14 (m, 2H), 3.22 (s, 3H), 2.95-2.78 (m, 2H).
    • Example 32: Synthesis of (1S,3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 576)
  • Figure US20190015377A1-20190117-C00961
    • Step A: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one
  • A solution of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (402 mg, 1.62 mmol) in dichloromethane (16.2 mL) at 0° C. was treated with diethylaminosulfur trifluoride (390 μL, 2.92 mmol). The ice bath was removed from the resulting reaction mixture and the reaction mixture was stirred for 2 hours at room temperature. Volatiles were removed by concentration under reduced pressure. The residue was suspended in 30 mL of EtOAc, cooled to 0° C., and quenched by the addition of 20 mL of saturated aqueous NaHCO3. The reaction mixture was vigorously stirred for 30 minutes and then extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) [M+H]+ m/z 251.
    • Step B: Preparation of (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one
  • A solution of (R)-2,2,3,4-tetrafluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (393 mg, 1.57 mmol) in acetonitrile (15.7 mL) at 0° C. was treated with Selectfluor® (584.3 mg, 1.65 mmol) and stirred at 0° C. for 2 hours. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-30% EtOAc/hexane to afford (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one (153 mg, 36%) as a yellow oil. LCMS ESI (+) [M−F]+ m/z 249.
    • Step C: Preparation of (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one
  • A solution of (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one (91.8 mg, 0.34 mmol) in a mixture of methanol (3.4 mL) and water (3.4 mL) was treated with Oxone® (252.5 mg, 0.41 mmol). The resulting suspension was heated to 60° C. overnight. Additional Oxone® (252.5 mg, 0.41 mmol) was added and the reaction mixture heated for an additional 6 hours. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 100 mL of water and extracted with 3×25 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-40% EtOAc/hexane to afford (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one as a white solid (73 mg, 71%). LCMS ESI (+) [M+H]+ m/z 301.
    • Step D: Preparation of (1S,3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 576)
  • Prepared similarly as described in Example 31, Steps G-J. Purification was achieved by chromatography on silica using 15-30% EtOAc/hexane to afford Compound 576 (29.8 mg, 49%) as a white solid. Retention time HPLC (14 min)=4.63 min; LCMS ESI (+) [M+H]+ m/z 391; 1H NMR (400 MHz, CDCl3): δ 8.13 (dd, 1H), 6.93 (d, 1H), 5.76 (dd, 1H), 5.59-5.53 (m, 1H), 5.47 (dd, 1H), 5.18 (dd, 1H), 4.90-4.80 (m, 1H), 3.29-3.16 (m, 2H), 3.16 (d, 1H), 2.97-2.81 (m, 2H).
    • Example 33: HIF-2α Scintillation Proximity Assay (SPA)
  • The total assay volume was about 100 μL in the following configuration: 2 μL compound in 100% DMSO, 88 μL buffer with protein and probe and 10 μL of SPA beads. The compound was diluted in a master plate consisting of a 10-point dose response with a 3-fold compound dilution from 100 μM to 5 nM. Assays were run on a 96-well plate in which one column, designated as the high signal control, contained DMSO with no compound and another column, designated as the low signal control, contained no protein. Prior to plating out of compound, a buffer solution, consisting of 25 mM TRIS pH 7.5 (Sigma), 150 mM NaCl (Sigma), 15% Glycerol (Sigma), 0.15% BSA (Sigma), 0.001% Tween-20 (Sigma), 150 nM N-(3-Chlorophenyl-4,6-t2)-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine (Compound 183) and 100 nM HIF-2α HIS TAG-PASB Domain, was made and allowed to equilibrate for 30 minutes. Compounds that were to be tested were then plated in to a 96-well white clear bottom Isoplate-96 SPA plate (Perkin Elmer). To the compounds was added 88 μL of the buffer solution, then the plate covered with a plastic cover and aluminum foil, placed onto a shaker and equilibrated for 1 hour. After equilibration, 10 μL of a 2 mg/mL solution of YSi Cu His tagged SPA beads (Perkin Elmer) were then added to each well of the plate, covered and equilibrated for another 2 hours. The plates were then removed from the shaker, placed into a 1450 LSC and luminescence counter MicroBeta Trilux (Perkin Elmer) to measure the extent of probe displacement. The percent inhibition was determined and IC50 values were calculated using the Dotmatics system based on the following equation: % inhibition=[(high control−sample)/(high control−low control)]×100.
    • Example 34: VEGF ELISA Assay
  • About 7500 786-0 cells in 180 μL of growth medium were seeded into each well of a 96-well, white, clear bottom plate (07-200-566, Fisher Scientific) on day one in the
  • Four hours later, serial dilutions of 10× compound stocks were made in growth medium from 500×DMSO stocks, and 20 μL of those 10× stocks were added to each well to make final concentrations as follows (04): 20, 6.67, 2.22, 0.74, 0.25, 0.082, 0.027, 0.009, 0.003, 0.001, and 0. Each concentration was plated in duplicate. About 20 hours later, medium was removed by suction and each well was supplied with 180 μL of growth medium. About 20 μl freshly-made 10× compound stocks were added to each well. About 24 hours later, cell culture medium was removed and the VEGF concentration determined using an ELISA kit purchased from R&D systems, following the manufacturer's suggested method. The EC50 was calculated by GraphPad Prism using the dose-response-inhibition (four parameter) equation. The cell-seeded plate was then subjected to CellTiter-Glo luminescence cell viability assay (Promega) by adding 50 μL of Celltiter Glo reagent into each well and shaking the plate for 8 minutes at 550 rpm (Thermomixer R, Eppendorf) then the luminescence signal immediately read in a plate reader (3 second delay, 0.5 second/well integration time, Synergy 2 multi Detection Microplate reader).
    • Example 35: Luciferase Assay
  • 786-O-Hif-Luc single clone cells were obtained by infecting 786-O cells (ATCC® CRL-1932™) with commercial lentivirus that delivers a luciferase gene driven by multiple HIF responsive elements (Cignal Lenti HIF Reporter (luc): CLS-007L, Qiagen) at Multiplicity of Infection (MOI) of 25 for 24 hours. The cells were replenished with fresh medium (Dulbecco's Modified Eagle's Medium (DMEM, D5796, Sigma) supplemented with 10% FBS (F6178, Sigma), 100 units penicillin and 100 μg streptomycin/mL (P4333, Sigma)) for another 24 hours. A pool of infected cells were then selected against 2 μg/mL of puromycin (P8833, Sigma) for 10 days followed by limited dilution to select single clones. The clones were tested for their response to HIF-2 inhibitors and the ones that showed the biggest dynamic range (786-0-Hif-Luc) were expanded and used for the luciferase assay. For the luciferase assay, about 7500 786-O-Hif-Luc cells in 90 μL growth medium were seeded into each well of a 96-well white opaque plate (08-771-26, Fisher scientific) a day before treatment with the layout:
  • On treatment day, serial dilutions of 10× compound stocks were made in growth medium from 500×DMSO stocks, and 10 μL of the 10× stocks were added to each well to make final concentrations as follows (μM): 20, 6.67, 2.22, 0.74, 0.25, 0.08, 0.027, 0.009, 0.003, 0.001, and 0. Each concentration was tested in triplicate. After about 24 hours, luciferase activity was determined using ONE-Glo Luciferase Assay Reagent (E6110, Promega) following the manufacturer's recommended procedure. EC50 were calculated using Dotmatics software.
  • Table 3 shows biological activities of selected compounds in Luciferase, VEGF ELISA and Scintillation Proximity assays. Compound numbers correspond to the numbers and structures provided in Table 2 and Examples 1-32.
  • TABLE 3
    Less than 50 nM to 250 nM to Greater than
    50 nM (++++) 249 nM (+++) 1000 nM (++) 1000 nM (+)
    Scintillation 1, 2, 6, 7a, 8, 9, 17, 18, 21, 33, 38, 3, 5, 16, 22, 24, 4, 7b, 12, 13, 14,
    Proximity 11, 15, 25,26, 29, 39, 41, 50, 54, 74, 27, 31, 40, 42, 43, 19, 20, 23, 28, 35,
    Assay 30, 32, 34, 52, 55, 75, 90, 93, 94, 99, 46, 48, 53, 70, 71, 36, 37, 44, 45, 47,
    IC50 (nM) 56, 57, 58, 59, 60, 100, 102, 107, 72, 76, 78, 81, 91, 49, 51, 66, 68, 69,
    61, 62, 63, 64, 65, 116, 117, 118, 103, 104, 106, 73, 77, 79, 82, 83,
    67, 80, 92, 98, 119, 128, 136, 115, 120, 131, 84, 85, 86, 87, 88,
    101, 111, 112, 141, 145, 146, 132, 133, 134, 89, 95, 96, 97,
    123, 124, 140, 147, 148, 153, 135, 137, 152, 105, 108, 109,
    143, 144, 155, 156, 162, 165, 157, 172, 178, 110, 113, 114,
    158, 159, 160, 187, 192, 195, 182, 184, 190, 121, 122, 125,
    161, 163, 166, 203, 204, 214, 193, 197, 202, 126, 127, 129,
    167, 168, 179, 224, 237, 241, 207, 209, 212, 130, 138, 139,
    185, 186, 188, 242, 252, 254, 213, 218, 220, 142, 149, 150,
    191, 194, 196, 260, 265, 267, 243, 244, 249, 151, 154, 164,
    198, 200, 201, 270, 274, 275, 258, 261, 264, 169, 170, 171,
    206, 215, 221, 276, 277, 285, 269, 271, 281, 173, 174, 175,
    223, 225, 227, 295, 302, 308, 287, 293, 307, 176, 177, 180,
    228, 229, 230, 312, 324, 325, 339, 346, 369, 181, 189, 199,
    231, 232, 233, 333, 334, 336, 374, 411, 422, 205, 208, 210,
    234, 235, 236, 353, 358, 361, 423, 432, 433, 211, 216, 217,
    240, 245, 247, 370, 378, 381, 434, 471, 476, 219, 222, 226,
    251, 256, 263, 383, 387, 388, 481, 482, 487, 238, 239, 246,
    266, 273, 286, 399, 405, 409, 496, 505, 506, 248, 250, 253,
    289, 290, 292, 412, 414, 421, 511, 513, 522, 255, 257, 259,
    303, 304, 305, 424, 426, 427, 523, 531, 542, 262, 268, 272,
    306, 309, 310, 437, 442, 444, 575, 580, 591, 278, 279, 280,
    314, 315, 316, 462, 468, 477, 595, 601, 603, 282, 283, 284,
    317, 319, 321, 480, 488, 517, 612, 622, 637, 288, 291, 294,
    327, 328, 329, 545, 547, 551, 644, 648, 678, 296, 297, 298,
    331, 338, 340, 554, 563, 569, 703, 707, 711, 299, 300, 301,
    341, 342, 344, 584, 586, 598, 735, 748, 749, 311, 313, 318,
    347, 348, 349, 604, 609, 614, 750, 754, 762, 320, 322, 323,
    355, 356, 357, 616, 620, 660, 765, 770, 775, 326, 330, 332,
    359, 360, 364, 663, 669, 672, 781, 812, 816, 335, 337, 343,
    365, 368, 371, 676, 681, 682, 827 345, 350, 351,
    372, 375, 376, 686, 696, 697, 352, 354, 362,
    379, 386, 389, 700, 701, 706, 363, 366, 367,
    392, 397, 398, 714, 717, 718, 373, 377, 380,
    401, 403, 430, 730, 734, 737, 382, 384, 385,
    431, 435, 436, 747, 751, 755, 390, 391, 393,
    440, 443, 446, 759, 768, 769, 394, 395, 396,
    451, 458, 465, 771, 782, 784, 400, 402, 404,
    466, 467, 472, 788, 795, 808, 406, 407, 408,
    473, 478, 483, 815, 818 410, 413, 415,
    485, 486, 489, 416, 417, 418,
    491, 507, 509, 419, 420, 425,
    532, 549, 550, 428, 429, 438,
    557, 571, 572, 439, 441, 445,
    573, 574, 576, 447, 448, 449,
    577, 578, 579, 450, 452, 453,
    581, 582, 585, 454, 455, 456,
    587, 593, 594, 457, 459, 460,
    602, 605, 607, 461, 463, 464,
    608, 610, 617, 469, 470, 474,
    623, 626, 654, 475, 484, 490,
    655, 656, 657, 492, 493, 494,
    658, 659, 661, 495, 497, 498,
    675, 677, 699, 499, 500, 501,
    704, 709, 710, 502, 503, 504,
    712, 713, 715, 508, 510, 512,
    716, 727, 728, 514, 515, 516,
    731, 736, 739, 518, 519, 520,
    740, 741, 742, 521, 524, 525,
    743, 744, 746, 526, 527, 528,
    753, 756, 760, 529, 530, 533,
    761, 766, 774, 534, 535, 536,
    778, 783, 786, 537, 538, 539,
    787, 789, 790, 540, 541, 543,
    794, 796, 811, 544, 546, 548,
    813, 814, 825, 552, 553, 555,
    828, 831 556, 558, 559,
    560, 561, 562,
    564, 565, 566,
    567, 568, 570,
    583, 588, 589,
    590, 592, 596,
    597, 599, 600,
    606, 611, 613,
    615, 618, 619,
    621, 624, 625,
    627, 628, 629,
    630, 631, 632,
    633, 634, 635,
    636, 638, 639,
    640, 641, 642,
    643, 645, 646,
    647, 649, 650,
    651, 652, 653,
    662, 664, 665,
    666, 667, 668,
    670, 671, 673,
    674, 679, 680,
    683, 684, 685,
    687, 688, 689,
    690, 691, 692,
    693, 694, 695,
    698, 702, 705,
    708, 719, 720,
    721, 722, 723,
    724, 725, 726,
    729, 732, 733,
    738, 745, 752,
    757, 758, 763,
    764, 767, 772,
    773, 776, 777,
    779, 780, 785,
    791, 792, 793,
    797, 807, 809,
    810, 817, 819,
    820, 821, 822,
    823, 824, 826,
    829, 830, 833
    Mean 8, 9, 11, 15, 25, 2, 17, 67, 155, 1, 34, 41, 74, 78, 98, 133, 179, 274
    VEGF 55, 60, 63, 64, 166, 188, 191, 80, 99, 102, 124,
    ELISA 158, 159, 161, 225, 231, 234, 132, 165, 203,
    EC50 (nM) 163, 167, 185, 240, 245, 252, 267, 353, 387,
    186, 196, 228, 254, 256, 303, 424, 473, 495,
    230, 233, 235, 304, 310, 325, 577, 734
    236, 251, 273, 342, 347, 349,
    289, 292, 305, 355, 357, 360,
    306, 309, 316, 365, 372, 398,
    317, 364, 368, 399, 421, 431,
    375, 389, 403, 467, 507, 574,
    446, 451, 458, 576, 578, 605,
    465, 478, 489, 610, 620, 659,
    571, 572, 579, 706, 710, 713,
    617, 654, 655, 736, 740, 743,
    656, 657, 658, 760, 761, 783,
    709, 712, 742, 784, 825
    744, 813, 828
    Mean 8, 9, 11, 15, 25, 1, 2, 6, 17, 26, 27, 3, 5, 7a, 34, 38, 16, 18, 20,21, 22,
    Luciferase 55, 63, 64, 65, 56, 57, 58, 59, 60, 39, 41, 42, 43, 52, 31, 32, 33, 35, 40,
    EC50 (nM) 158, 159, 160, 61, 62, 67, 155, 54, 74, 80, 81, 90, 46, 50, 53, 75, 85,
    161, 163, 166, 162, 165, 187, 92, 93, 94, 99, 91, 98, 100, 103,
    167, 185, 186, 188, 191, 200, 101, 107, 112, 104, 110, 111,
    196, 215, 221, 206, 223, 224, 115, 124, 144, 114, 116, 117,
    225, 227, 228, 237, 241, 245, 145, 146, 156, 118, 119, 120,
    229, 230, 231, 251, 252, 254, 168, 192, 194, 128, 131, 132,
    232, 233, 234, 260, 267, 270, 198, 203, 207, 134, 135, 136,
    235, 236, 240, 274, 276, 277, 213, 242, 243, 140, 143, 147,
    247, 256, 266, 285, 286, 290, 263, 265, 271, 148, 151, 152,
    273, 289, 292, 302, 310, 314, 275, 287, 293, 157, 172, 181,
    303, 304, 305, 315, 334, 336, 294, 295, 308, 182, 190, 195,
    306, 309, 316, 342, 348, 355, 312, 324, 325, 201, 202, 209,
    317, 338, 347, 357, 360, 365, 339, 353, 359, 212, 214, 218,
    349, 364, 368, 369, 372, 381, 361, 370, 377, 220, 222, 226,
    371, 375, 380, 383, 387, 388, 378, 390, 411, 244, 249, 250,
    386, 389, 399, 392, 398, 401, 414, 416, 422, 253, 255, 258,
    403, 430, 431, 405, 409, 421, 426, 432, 434, 259, 261, 264,
    435, 446, 451, 423, 424, 436, 437, 440, 443, 268, 269, 272,
    458, 465, 467, 473, 477, 480, 444, 462, 466, 279, 291, 296,
    478, 489, 571, 486, 488, 507, 468, 471, 472, 300, 301, 307,
    572, 576, 579, 523, 547, 549, 482, 483, 505, 313, 352, 356,
    582, 584, 602, 573, 574, 578, 517, 531, 532, 358, 363, 374,
    605, 617, 654, 593, 594, 598, 550, 557, 563, 376, 379, 385,
    655, 656, 657, 604, 610, 620, 569, 577, 585, 394, 397, 400,
    658, 661, 675, 623, 626, 659, 591, 595, 608, 412, 427, 428,
    704, 709, 710, 676, 677, 681, 616, 622, 644, 433, 439, 441,
    712, 716, 727, 686, 696, 697, 660, 663, 669, 455, 456, 464,
    728, 742, 743, 699, 706, 713, 678, 682, 707, 470, 474, 476,
    744, 746, 783, 715, 717, 730, 711, 714, 718, 481, 485, 487,
    786, 787, 789, 731, 734, 736, 747, 748, 750, 491, 492, 495,
    790, 794, 813, 740, 760, 761, 753, 756, 759, 496, 506, 509,
    828, 831 781, 782, 784, 762, 766, 768, 511, 513, 516,
    795, 814, 818, 769, 771, 774, 534, 538, 542,
    825 775, 788, 796 545, 551, 554,
    558, 565, 570,
    575, 580, 581,
    586, 601, 603,
    607, 609, 612,
    614, 618, 619,
    637, 639, 665,
    670, 672, 683,
    692, 700, 701,
    703, 721, 722,
    723, 724, 725,
    726, 735, 737,
    739, 741, 749,
    751, 752, 754,
    755, 764, 765,
    767, 770, 778,
    779, 780, 808,
    811, 812, 833
    • Example 36: Prevention of PAH by a HIF-2α Inhibitor
  • The preventive effects of sildenafil and Compound 231 were evaluated in rats with hypoxia/semaxanib induced pulmonary arterial hypertension. Male Sprague-Dawley rats (n=10 in each group) were orally administered vehicle (0.5% methylcellulose, 0.5% Tween80 in water, administered once daily), Compound 231 (100 or 300 mg/kg, administered once daily), or sildenafil (30 mg/kg, administered twice daily) daily for 28 consecutive days. Two rats not exposed to either semaxanib or hypoxia served as hypertrophic sentinels for this study. Rats received a single injection of semaxanib (200 mg/kg, s.c.) on the same day as initiation of test article dosing and introduction to the hypoxic chamber. Rats were kept in hypoxic conditions for the duration of this study. On the twenty-eighth day of test article dosing, the rats were anesthetized with ketamine/xylazine for terminal monitoring of pulmonary and systemic arterial pressures along with heart rate. In addition, histopathology and muscularization of pulmonary arterioles were evaluated in lungs from thirty-eight male (Sprague Dawley) rats in groups 1 (seven rats), 2 (nine rats), 3 (ten rats), 4 (ten rats), and 5 (two rats). Table 4 is a summary of the experimental design. Compound 231 has the following formula:
  • Figure US20190015377A1-20190117-C00962
  • TABLE 4
    Experimental design of Example 36.
    Test Stock Dose
    Group/ Compound Concen- Vol- Number
    Test Dose Level tration ume Dose of Male
    Compound (mg/kg) (mg/mL) (mL/kg) Route Rats
    1-4/ 200 60 3.33 subcuta- 40
    Semaxanib1 neous
    1/  0 0 5 oral 5
    Vehicle2,3 gavage
    2/ 100 20 5 oral 10
    Compound 2313 gavage
    3/ 300 60 5 oral 10
    Compound 2313 gavage
    4/ 60/day 6 5/dose oral 10
    Sildenafil4 gavage
    5/NA NA NA NA NA 2
    1Single dose in DMSO (J. T. Baker, Catalog 9224-01) administered 28 days prior to terminal procedure.
    2Vehicle is 0.5% methylcellulose, 0.5% Tween80 in water.
    3Administered once daily for 28 days (Days 1 to 28). Hypoxia during Days 1-28.
    4Administered twice daily for 28 days (Days 1 to 28). Vehicle is saline. Hypoxia during Days 1-28.
  • There were substantive differences in systolic and mean pulmonary arterial pressures after 28 days in rats treated with Compound 231 compared to the vehicle group (Table 5). The low and high doses of Compound 231 showed a 38% and 56% reduction in systolic pulmonary arterial pressure—the variable used as the arbiter of protection. The 300 mg/kg QD Compound 231 systolic pulmonary artery pressures were also significantly reduced compared to sildenafil. The sildenafil group also showed protection versus vehicle. There was a significant protective effect with respect to right ventricular hypertrophy (as measured by Fulton's Index, RV/LV+S) in the Compound 231 cohort compared to vehicle. Rats treated with Compound 231 at 100 mg/kg QD presented with a 28% reduction in Fulton's right ventricular hypertrophy ratio, while animals treated with 300 mg/kg QD reduced this parameter by 40%. The 300 mg/kg QD dose was also superior to sildenafil with respect to Fulton's Index. Mean arterial pressure was also significantly increased in Compound 231 rats compared to vehicle treated animals, a finding that may represent improved health of the rats in the Compound 231 cohorts. No notable differences in heart rate were noted for rats treated with Compound 231 or sildenafil compared to vehicle. FIGS. 1-8 illustrate the bar graphs of systolic pulmonary artery pressure, mean pulmonary artery pressure, diastolic pulmonary artery pressure, heart rate, systolic arterial pressure, mean arterial pressure, diastolic arterial pressure, and Fulton's index, respectively. Bars from left to right correspond to groups listed in the legend from top to bottom.
  • Both histopathology evaluation and counts of completely, partially, and non-muscularized arterioles showed a dose-related decrease in pulmonary arteriolar smooth muscle hypertrophy in rats injected with Semaxanib, exposed to hypoxia, and treated with Compound 231 compared to those injected with Semaxanib, exposed to hypoxia, and treated with vehicle (compare FIGS. 9-13). In this study, Sildenafil treatment (FIG. 13) led to a slight decrease in pulmonary arteriolar smooth muscle hypertrophy compared to vehicle treatment (FIG. 10), based on histopathology evaluation.
  • TABLE 5
    Summary of endpoint parameters of Example 36.
    Treatment Cohort (mg/kg)
    Parameter Compound 231 Compound 231 Sildenafil Sentinel
    Mean ± SEM Vehicle 100 300 60/day bid n = 2
    Systolic PAP 71 ± 8  44 ± 7*  31 ± 4**,# 55 ± 5 
    (mm Hg)
    Mean PAP 47 ± 4  33 ± 4     23 ± 3***,# 38 ± 3 
    (mm Hg)
    MAP 78 ± 7  96 ± 3* 104 ± 3** 92 ± 2 
    (mm Hg)
    HR 271 ± 15  283 ± 6  283 ± 7  289 ± 11 
    (bpm)
    Heart Wt 1.41 ± 0.1  1.29 ± 0.05 1.24 ± 0.05 1.23 ± 0.03 1.04 ± 0.03
    (g)
    LV Wt 0.77 ± 0.05 0.80 ± 0.02 0.81 ± 0.03 0.71 ± 0.02 0.71. ± 0.00 
    (g)
    RV Wt 0.44 ± 0.04 0.34 ± 0.03  0.28 ± 0.02** 0.36 ± 0.03 0.21 ± 0.01
    (g)
    Lung Wt 2.30 ± 0.11 2.57 ± 0.10 2.31 ± 0.09 2.39 ± 0.07 1.60 ± 0.13
    (g)
    RV/LV + S 0.58 ± 0.05  0.42 ± 0.03*    0.35 ± 0.02***,# 0.52 ± 0.04 0.30 ± 0.02
    RV/BW 1.34 ± 0.12  0.93 ± 0.09*  0.79 ± 0.05** 1.12 ± 0.10 0.57 ± 0.00
    Body Weight 0.33 ± 0.01  0.37 ± 0.01# 0.36 ± 0.01 0.33 ± 0.01 0.38 ± 0.02
    (kg)
    *= p < 0.05, ANOVA - Turkey vs Vehicle
    **= p < 0.01, ANOVA - Turkey vs Vehicle
    ***= p < 0.001, ANOVA - Turkey vs Vehicle
    #=<0.05, ANOVA - Turkey vs Sildenafil
  • Histopathology evaluation showed that smooth muscle hypertrophy was greatest in Group 1 (Semaxanib/Vehicle) and there was a dose-related decrease in smooth muscle hypertrophy in Groups 2 (Semaxanib/100 mg/kg QD Compound 231) and 3 (Semaxanib/300 mg/kg QD Compound 231) compared to Group 1. There was a slight decrease in smooth muscle hypertrophy in Group 4 (Semaxanib/30 mg/kg BID Sildenafil) compared to Group 1. Group mean scores for smooth muscle hypertrophy were 3.7, 3.0, 2.2, 3.4, and 0 in Groups 1, 2, 3, 4, and 5, respectively.
  • Counts of completely, partially, or non-muscularized arterioles showed that the greatest percentage of completely muscularized arterioles and lowest percentages of non-muscularized and partially muscularized arterioles were in Group 1. Groups 2 and 3 showed dose-related decreases in completely muscularized arterioles and corresponding increases in non-muscularized and partially muscularized arterioles (FIG. 14). Muscularization of arterioles was similar in Groups 1 and 4. The mean percentages of completely muscularized arterioles were 59.6%, 40.6%, 23.8%, 58.7%, and 10.0% in Groups 1, 2, 3, 4, and 5. The mean percentages of partially muscularized arterioles were 39.6%, 57.8%, 71.7%, 40.2%, and 80.0% in Groups 1, 2, 3, 4, and 5, respectively. The mean percentages of non-muscularized arterioles were 0.9%, 1.7%, 4.5%, 1.1%, and 10.0% in Groups 1, 2, 3, 4, and 5, respectively.
    • Example 37: Effect of HIF-2α Inhibition in a Model of Active PAH
  • The interventional effects of sildenafil and Compound 231 were evaluated in rats with hypoxia/semaxanib induced pulmonary arterial hypertension. Male Sprague-Dawley rats (n=10 in each group) were orally administered vehicle (0.5% methylcellulose, 0.5% Tween80 in water, administered once daily), Compound 231 (300 mg/kg, administered once daily), or sildenafil (30 mg/kg, administered twice daily) daily for 14 consecutive days starting on Study Day 14 after the initiation of PAH. Four rats not exposed to either semaxanib or hypoxia served as hypertrophic sentinels for this study, while five rats served as a breakout group that were developing PAH only for 14 days. Rats in Groups 2-4 received a single injection of semaxanib (200 mg/kg, s.c.) 28 days prior to terminal assessment. Rats were kept in hypoxic conditions for the duration of this study. On the fourteenth day of test article dosing, the rats were anesthetized with ketamine/xylazine for terminal monitoring of pulmonary and systemic arterial pressures along with heart rate. In addition, lungs from thirty-one male (Sprague Dawley) rats in groups 1 (five rats), 2 (nine rats), 3 (eight rats), and 4 (ten rats) were provided to Seventh Wave for evaluation of histopathology and muscularization of pulmonary arterioles. Table 6 is a summary of the experimental design.
  • TABLE 6
    Experimental design of Example 37.
    Test Stock Dose
    Group/ Compound Concen- Vol- Number
    Test Dose Level tration ume Dose of Male
    Compound (mg/kg) (mg/mL) (mL/kg) Route Rats
    1-4/ 200 60 3.33 subcuta- 35
    Semaxanib1 neous
    1/ 0 0 5 oral 5
    Vehicle2 gavage
    2/ 0 0 5 oral 10
    Vehicle3 gavage
    3/ 300 60 5 oral 10
    Compound 2313 gavage
    4/ 60/day 6 5/dose oral 10
    Sildenafil4 gavage
    5/NA NA NA NA NA 4
    1Single dose in DMSO (J. T. Baker, Catalog 9224-01) administered 14 days (Group 1) or 28 days (Groups 2-4) prior to terminal procedure.
    2Vehicle is 0.5% methylcellulose, 0.5% Tween80 in water. Administered once daily for 14 days (Days 1 to 14). Hypoxia during Days 1-14. Terminal procedure on Day 14.
    3Vehicle is 0.5% methylcellulose, 0.5% Tween80 in water. Administered once daily for 14 days (Days 15 to 28). Hypoxia during Days 1-28. Terminal procedure on Day 28.
    4Administered twice daily for 14 days (Days 15 to 28). Vehicle is saline. Hypoxia during Days 1-28. Terminal procedure on Day 28.
  • Moderate reductions in systolic and mean pulmonary arterial pressures were observed after 14 days of interventional treatment with Compound 231 compared to the vehicle group (Table 7). The 300 mg/kg QD dose of Compound 231 showed a 29% reduction in systolic pulmonary arterial pressure—the variable used as the arbiter of protection. The 300 mg/kg QD Compound 231 systolic pulmonary artery pressures were not significantly different from sildenafil-treated rats. Rats treated with Compound 231 at 300 mg/kg QD presented with an 8% reduction in Fulton's right ventricular hypertrophy ratio. When correcting RV weight by body weight, 300 mg/kg QD Compound 231 rats only showed a 7% decrease in this ratio compared to vehicle. However, pulmonary hypertrophy was significantly reduced with Compound 231 treatment. Sildenafil rats presented with a 21% reduction (p<0.05) in RV/BW ratio, along with reductions in pulmonary hypertrophy. Mean arterial pressure was also significantly increased in Compound 231 rats compared to vehicle treated animals. No substantive differences in heart rate were noted for rats treated with Compound 231 or sildenafil compared to vehicle. FIGS. 15-21 illustrate the bar graphs of systolic pulmonary artery pressure, mean pulmonary artery pressure, diastolic pulmonary artery pressure, heart rate, systolic arterial pressure, mean arterial pressure, and diastolic arterial pressure. Bars from left to right correspond to groups listed in the legend from top to bottom.
  • TABLE 7
    Summary of endpoint parameters of Example 37.
    Treatment Cohort (mg/kg)
    Parameter Compound 231 Sildenafil
    Mean ± SEM Vehicle 300 60/day bid
    Systolic PAP 84 ± 11 60 ± 11 56 ± 6 
    (mm Hg)
    Mean PAP 52 ± 5  41 ± 6  36 ± 3*
    (mm Hg)
    MAP 77 ± 3  97 ± 10 93 ± 2 
    (mm Hg)
    HR 286 ± 8  274 ± 5  289 ± 6 
    (bpm)
    Heart Wt 1.41 ± 0.1  1.39 ± 0.07 1.25 ± 0.04
    (g)
    LV Wt 0.81 ± 0.04 0.83 ± 0.03 0.75 ± 0.02
    (g)
    RV Wt 0.39 ± 0.02 0.37 ± 0.04 0.35 ± 0.02
    (g)
    Lung Wt 2.40 ± 0.07  2.09 ± 0.08*,+ 2.36 ± 0.07
    (g)
    LW/BW 7.75 ± 0.30  6.26 ± 0.20* 6.68 ± 0.15
    RV/LV + S 0.48 ± 0.02 0.44 ± 0.04 0.46 ± 0.02
    RV/BW 1.24 ± 0.07 1.15 ± 0.08  0.98 ± 0.07*
    Body Weight 0.32 ± 0.01 0.34 ± 0.02 0.35 ± 0.01
    (kg)
    *= p < 0.05, ANOVA - Turkey vs Vehicle
    += p < 0.05, ANOVA - Turkey vs Sildenafil
  • Both histopathology evaluation and counts of completely, partially, and non-muscularized arterioles showed a similar decrease in pulmonary arteriolar smooth muscle hypertrophy in rats injected with Semaxanib, exposed to hypoxia, and treated for 14 days with 300 mg/kg/day Compound 231 or 60 mg/kg/day Sildenafil compared to those injected with Semaxanib, exposed to hypoxia, and treated with vehicle for 28 days. Rats in Group 2 (28 days of vehicle treatment, FIG. 23) also exhibited slightly more perivascular inflammation and perivascular fibrosis, based on severity scores and/or incidence, than those in other groups. Group 1 (14 days of vehicle treatment, FIG. 22) showed the least amount of pulmonary arteriolar smooth muscle hypertrophy based on histopathology and counts of arterioles in each category. FIGS. 24 and 25 show histopathology of Compound 231 and sildenafil treated rats, respectively. Histopathology scoring of pulmonary vascular muscularization are illustrated in FIG. 26. Lungs from rats in Group 1 did not exhibit perivascular inflammation or perivascular fibrosis.
  • Group mean scores for smooth muscle hypertrophy were 1.4, 3.8, 2.8, and 2.6 in Groups 1, 2, 3, and 4, respectively. The mean percentages of completely muscularized arterioles were 23.8, 61.0, 48.0, and 47.2 in Groups 1, 2, 3, and 4, respectively. The mean percentages of partially muscularized arterioles were 76.0, 38.9, 50.9, and 51.7 in Groups 1, 2, 3, and 4, respectively. The mean percentages of non-muscularized arterioles were 0.2, 0.1, 0.9, and 1.1 in Groups 1, 2, 3, and 4, respectively.
    • Example 38: Effects of HIF-2α Inhibition in a Human Subject with PAH
  • A HIF-2α inhibitor can be administered to a human subject suffering from PAH, such as about 0.05 to 50 mg/kg. Prior to administering the HIF-2α inhibitor, a baseline can be established for one or more of pulmonary vascular resistance, pulmonary arterial pressure, systemic arterial pressure, mixed venous oxygen saturation, arterial oxygen saturation, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six-minute walk distance, brain natriuretic peptide level, and lung diffusion capacity. Upon beginning treatment with the HIF-2α inhibitor, the parameters for which a baseline is established can be monitored over time for any improvement in one or more of these parameters (e.g. an increase in six-minute walk distance, or a decrease in pulmonary vascular resistance).
    • Example 39: Assay for Testing Inhibition of HIF-2α Dimerization
  • This example describes an example assay for testing inhibition of HIF-2a dimerization using co-immunoprecipitation.
  • Cell Culture and Compound Treatment
  • 786-O cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM, D5796, Sigma) supplemented with 10% FBS (F6178, Sigma), 100 units penicillin, and 100 μg/mL streptomycin (P4333, Sigma). About 5×105 cells were plated into 6-well cell culture plates (Corning Cat#3506) in 2 mL of media and were placed in a 37° C. cell culture incubator with atmospheric levels of oxygen and 5% CO2. As the cultures reached confluence, 2 μl of Compound 163 or 226 diluted in DMSO at 1000× of final concentration was added.
  • Co-Immunoprecipitation Analysis of HIF and ARNT
  • Cells in a 6-well plate were washed with 1 ml of DPBS and lysed in 1 ml of cell lysis buffer (Tris-HCl 20 mM, pH 7.5, Triton X100 1%, NaCl 150 mM, Glycerol 5%, EDTA 1 mM, DTT 1 mM and 1 tablet per 10 mls of Roche Proteinase Inhibitor Tablet Complete). The cell lysate was transferred to a 1.5 mL Eppendorf tube, and was incubated on ice for 15 to 20 min. The debris was spun down in an Eppendorf microfuge tube at 15,000 RPM for 15 min at 4° C., and the supernatant was transferred into a new tube. 1 μg of mouse mAb against human ARNT (Santa Cruz, sc-55526) or 1 μg of antibody against HIF-2α (Abcam Ab199) and 50 μl of Protein AG beads (Santa Cruse, 50% slurry in lysis buffer) were added. The tubes were rotated at 4° C. for 2 to 16 hours. The beads were spun down and washed three times with 1 ml cold lysis buffer and resuspended in 30 μl of SDS sample buffer (10% Glycerol, 60 mM Tri-HCl pH6.8, 2% Sodium Dodecyl Sulfate, 0.01% Bromophenol Blue and 1.25% β-mercaptoethanol). The tubes were boiled for 3 min. The beads were spun down, and supernatant was loaded on a denaturing acrylamide gel (Bio-Rad precasted gel) for electrophoresis. The proteins in the gels were then transferred to 0.2 μM PVDF membrane (Bio-Rad) using Bio-Rad Trans-Blot Turbo transfer system.
  • For Western Blotting, the membranes were incubated in TBST (10 mM Tris-HCl pH 7.4, 150 mM Sodium Chloride and 0.1% Tween 20) containing 5% dry milk for 1 hour. The membranes were incubated with antibody to HIF-2α (Abcam Ab199) at 1:500 dilutions in the blocking buffer overnight. The membrane was washed three times in TBST then incubated in TBST with 5% dry milk with HPR-conjugated goat anti rabbit (Bio-Rad 172-1019) at 1:5000 dilution for ARNT detection. The Western blot signals were developed using Thermo Super-Western Pico Lumino/Enhancer Solution following the protocol provided by the manufacturer.
  • Disruption of HIF-2α and ARNT Dimerization
  • Total protein was extracted from 786-O cells treated with the indicated concentration of Compound 163 and Compound 226. HIF-2α protein complex was immunoprecipitated with antibody to HIF-2a. The immunoprecipitants were blotted with antibody against ARNT. ARNT protein coprecipitated with HIF-2α was reduced in a lysate of cells treated with Compound 163 in a dose-dependent manner (FIG. 27). Compound 226 reduced ARNT protein in complex with HIF-2α only at the highest concentration (10 μM).
  • While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the appended claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (20)

What is claimed is:
1. A compound of Formula I:
Figure US20190015377A1-20190117-C00963
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X is CR5;
Y is CR6;
Z is O, S, or NRB;
R1 is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R2 and R3 taken together form a 5-membered heterocycle;
R4 is nitro, halo, cyano, alkyl, fluoroalkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl, or fluoroalkyl sulfonyl; and
R5, R6, and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl, or alkoxy.
2. The compound of claim 1, wherein Z is O.
3. The compound of claim 1, wherein R1 is phenyl substituted with at least one substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.
4. The compound of claim 3, wherein the halo is fluoro.
5. The compound of claim 1, wherein the 5-membered heterocycle contains an oxygen atom.
6. The compound of claim 5, wherein the 5-membered heterocycle is substituted with at least one substituent selected from the group consisting of halo, hydroxy, C1-C4 alkoxy, alkyl, heteroalkyl, and cyano.
7. The compound of claim 1, wherein Z is O, R1 is phenyl, and the 5-membered heterocycle contains an oxygen atom.
8. The compound of claim 7, wherein said 5-membered heterocycle is substituted with at least one substituent selected from the group consisting of halo and hydroxy.
9. The compound of claim 8, wherein said 5-membered heterocycle is substituted with fluoro.
10. The compound of claim 8, wherein R4 is selected from the group consisting of sulfonyl, fluoroalkyl sulfonyl, fluoroalkyl, and trifluoromethyl.
11. A compound of Formula I:
Figure US20190015377A1-20190117-C00964
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X is CR5;
Y is CR6;
Z is O, S, or NRB;
R1 is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R2 and R3 taken together form a cyclic moiety;
R4 is cycloalkyl or heteroaryl; and
R5, R6, and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl, or alkoxy.
12. The compound of claim 11, wherein Z is O.
13. The compound of claim 11, wherein R1 is phenyl substituted with at least one substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.
14. The compound of claim 13, wherein the halo is fluoro.
15. The compound of claim 11, wherein R2 and R3 taken together form a 5- or 6-membered carbocycle with at least one sp3 hybridized carbon.
16. The compound of claim 15, wherein the carbocycle is substituted with at least one substituent selected from the group consisting of halo, hydroxy, alkyl, heteroalkyl, C1-C4 alkoxy, cyano, cycloalkyl, heterocycloalkyl, and oxo.
17. The compound of claim 16, wherein the carbocycle is substituted with at least one substituent selected from the group consisting of fluoro and hydroxy.
18. The compound of claim 17, wherein R4 is heteroaryl.
19. The compound of claim 15, wherein the R4 is pyrazolyl and the carbocycle is substituted with fluoro and hydroxy.
20. The compound of claim 11, wherein R4 is selected from the group consisting of pyrazolyl, pyrrolyl, thiazolyl, and thiophenyl.
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Publication number Priority date Publication date Assignee Title
ES2784454T3 (en) 2013-09-09 2020-09-25 Peloton Therapeutics Inc Aryl ethers and their uses
EP3267792A4 (en) 2015-03-11 2018-09-26 Peloton Therapeutics, Inc. Compositions for use in treating pulmonary arterial hypertension
WO2016144825A1 (en) 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Aromatic compounds and uses thereof
WO2016145045A1 (en) 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Compositions for use in treating glioblastoma
US10155726B2 (en) 2015-03-11 2018-12-18 Peloton Therapeutics, Inc. Substituted pyridines and uses thereof
US10335388B2 (en) 2015-04-17 2019-07-02 Peloton Therapeutics, Inc. Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof
WO2018130174A1 (en) * 2017-01-11 2018-07-19 江苏豪森药业集团有限公司 Pyrrolo[2,3-c]pyridine derivative, preparation method therefor, and use thereof in medicine
US10953036B2 (en) 2017-11-20 2021-03-23 University Of Georgia Research Foundation, Inc. Compositions and methods of modulating HIF-2A to improve muscle generation and repair
WO2019191227A1 (en) * 2018-03-28 2019-10-03 Peloton Therapeutics, Inc. Methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha
CA3100399A1 (en) 2018-05-18 2019-11-21 Ryvu Therapeutics S.A. Thiophene derivatives
SG11202012616RA (en) 2018-08-21 2021-02-25 Kyorin Pharmaceutical Co Ltd Bicyclic heteroaromatic ring derivative
CA3113353A1 (en) * 2018-09-19 2020-03-26 Modernatx, Inc. High-purity peg lipids and uses thereof
CN109796332B (en) * 2019-03-08 2022-02-11 浙江师范大学 2-difluoroethyl-1-indanone derivative and preparation method thereof
MX2021012549A (en) 2019-04-18 2022-01-18 Nikang Therapeutics Inc Tetrahydro-1h-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors.
CN112812136B (en) * 2019-11-15 2022-04-12 武汉光谷亚太医药研究院有限公司 Novel 2, 3-indane derivative compound, preparation method and application
IL293305A (en) 2019-11-26 2022-07-01 Merck Patent Gmbh Thiophene derivatives, their preparation and their use
CA3173831A1 (en) * 2020-03-19 2021-09-23 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alpha
US11420936B2 (en) 2020-04-16 2022-08-23 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases
WO2021212062A1 (en) 2020-04-16 2021-10-21 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases
CN113582968A (en) * 2020-04-30 2021-11-02 江西济民可信集团有限公司 Sulfone imine compounds and preparation method and application thereof
US20220377951A1 (en) * 2020-06-11 2022-11-24 K-Tronics (Suzhou) Technology Co., Ltd. Shielding cover and display device
CN115667202A (en) * 2020-06-17 2023-01-31 贝达药业股份有限公司 Indenone compound and application thereof
WO2021254417A1 (en) * 2020-06-17 2021-12-23 贝达药业股份有限公司 Bicyclic compound and application thereof
WO2022082329A1 (en) * 2020-10-19 2022-04-28 Nikang Therapeutics, Inc. Processes of preparing 3-fluoro-5- ( ( (1s, 2ar) -1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) -benzonitrile
CN112755015A (en) * 2021-02-01 2021-05-07 中国人民解放军陆军军医大学 Application of PT2385 in preparation of medicine for preventing and treating pulmonary hypertension
TW202334083A (en) * 2021-11-02 2023-09-01 大陸商貝達藥業股份有限公司 Bicyclic compound and application thereof
CN116063211B (en) * 2023-02-14 2023-11-10 斯坦德药典标准物质研发(湖北)有限公司 Preparation method of Belzutifan

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120010207A1 (en) * 2010-07-12 2012-01-12 Pfizer Limited Chemical Compounds
US9908845B2 (en) * 2013-09-09 2018-03-06 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US10155726B2 (en) * 2015-03-11 2018-12-18 Peloton Therapeutics, Inc. Substituted pyridines and uses thereof
US10278942B2 (en) * 2015-03-11 2019-05-07 Peloton Therapeutics, Inc. Compositions for use in treating pulmonary arterial hypertension
US10335388B2 (en) * 2015-04-17 2019-07-02 Peloton Therapeutics, Inc. Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof

Family Cites Families (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE705530C (en) 1932-01-23 1941-04-30 Chem Fab Von Heyden Akt Ges Process for the preparation of polychloride substitution products of diphenyl ether
FR1574139A (en) 1968-05-06 1969-07-11
JPS4872169A (en) 1971-12-28 1973-09-29
GB1448696A (en) 1973-05-29 1976-09-08 Pfizer 2-phqnyl-astriazine-3,4-2h,4h-diones
GB2017087B (en) 1978-03-03 1982-09-02 Roussel Lab Ltd Process for the preparation of xanthone derivatives
US4214103A (en) 1978-11-30 1980-07-22 Great Lakes Chemical Corporation Purification of brominated organic products
DE2938595A1 (en) 1979-09-24 1981-04-23 Celamerck Gmbh & Co Kg, 6507 Ingelheim METHOD FOR PRODUCING DIPHENYL ETHERS
US4505929A (en) 1980-06-12 1985-03-19 The Dow Chemical Company Sulfur-substituted diphenyl ethers having antiviral activity
US4426385A (en) 1980-10-16 1984-01-17 Union Carbide Corporation Insecticidal bicyclooxyphenyl ureas
DE3110894A1 (en) 1981-03-20 1982-09-30 Celamerck Gmbh & Co Kg, 6507 Ingelheim NEW NITROANILINE
DE3239449A1 (en) 1981-10-27 1983-05-05 CIBA-GEIGY AG, 4002 Basel Phenoxyphenyl and pyridyloxyphenyl derivatives, their preparation, agents containing them, and their use
JPS58124758A (en) 1982-01-20 1983-07-25 Fujisawa Pharmaceut Co Ltd Benzenesulfonamide derivative
DE3209878A1 (en) 1982-03-18 1983-09-29 Celamerck Gmbh & Co Kg, 6507 Ingelheim METHOD FOR PRODUCING DIPHENYL ETHERS
US4665097A (en) 1983-03-31 1987-05-12 Union Carbide Corporation Novel bicyclooxyaryl thioureas and process for preparation
US4705955A (en) 1985-04-02 1987-11-10 Curt Mileikowsky Radiation therapy for cancer patients
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
JPS6351363A (en) 1986-08-21 1988-03-04 Tekukemu:Kk Production of amino group-containing diphenyl compound
US4992445A (en) 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5001139A (en) 1987-06-12 1991-03-19 American Cyanamid Company Enchancers for the transdermal flux of nivadipine
US5059609A (en) 1987-10-19 1991-10-22 Pfizer Inc. Substituted tetralins, chromans and related compounds in the treatment of asthma, arthritis and related diseases
IL105777A0 (en) 1992-06-04 1993-09-22 Great Lakes Chemical Corp Method for the isolation of a partially brominated diphenyl ether product
ATE185813T1 (en) 1993-08-27 1999-11-15 Hoffmann La Roche TETRAHYDRONAPHTHALINE PEPTIDE DERIVATIVES
DE69635874T2 (en) 1995-12-06 2006-12-14 Japan Science And Technology Agency, Kawaguchi Process for the preparation of optically active alcohols
US6887820B1 (en) 1995-12-06 2005-05-03 Japan Science And Technology Corporation Method for producing optically active compounds
WO1998042671A1 (en) 1997-03-20 1998-10-01 Basf Aktiengesellschaft Substituted 2-benz(o)ylpyridines, their preparation and their use as herbicides
CA2382789A1 (en) 1999-08-27 2001-03-08 Sugen, Inc. Phosphate mimics and methods of treatment using phosphatase inhibitors
US20050043227A1 (en) 2001-04-24 2005-02-24 Veerle Compernolle Use of hypoxia inducible factor 2alpha for curing neonatal respiratory distress syndrome and as a target for the treatment of pulmonary hypertension
US7230031B2 (en) 2002-01-30 2007-06-12 Kissei Pharmaceutical Co., Ltd. Thyroid hormone receptor ligand, medicinal compositions containing the same and use thereof
CA2463464A1 (en) 2003-04-28 2004-10-28 Auckland Uniservices Limited Methods of treatment and compositions therefor
SE0301906D0 (en) 2003-06-26 2003-06-26 Astrazeneca Ab New compounds
US7728025B2 (en) 2003-12-29 2010-06-01 Banyu Pharmaceutical Co., Ltd. 2-heteroaryl-substituted benzimidazole derivative
AR049388A1 (en) 2004-05-28 2006-07-26 Speedel Experimenta Ag HETEROCICLES AS INHIBITORS OF ALDOSTERONA SINTASA
BRPI0514675A (en) 2004-09-10 2008-06-17 Pfizer Prod Inc therapeutic diphenyl ether binders
AU2005316739A1 (en) 2004-12-13 2006-06-22 Galileo Pharmaceuticals, Inc. Spiro derivatives as lipoxygenase inhibitors
US7759493B2 (en) 2005-01-31 2010-07-20 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
TW200714597A (en) 2005-05-27 2007-04-16 Astrazeneca Ab Chemical compounds
KR20080056220A (en) 2005-10-19 2008-06-20 에프. 호프만-라 로슈 아게 Phenyl-acetamide nnrt inhibitors
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
GB0526445D0 (en) 2005-12-23 2006-02-08 Novartis Ag Organic compounds
WO2007079078A1 (en) 2005-12-29 2007-07-12 Bayer Schering Pharma Aktiengesellschaft Diamine derivatives as inhibitors of leukotriene a4 hydrolase
WO2007101232A2 (en) 2006-02-28 2007-09-07 Cytopia Research Pty, Ltd. Inhibition of jak2 as a treatment of pulmonary arterial hypertension
WO2007099423A1 (en) 2006-03-02 2007-09-07 Pfizer Products Inc. 1-pyrrolidine indane derivatives as histamine-3 receptor antagonists
US20070244071A1 (en) 2006-03-07 2007-10-18 Mount Sinai Hospital Treatment of proliferative diseases
AU2007254325B2 (en) 2006-05-15 2012-05-10 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
CN101506210A (en) 2006-08-23 2009-08-12 神经能质公司 2-phenoxy pyrimidinone analogues
MX2009010559A (en) 2007-03-30 2009-10-22 Nippon Shinyaku Co Ltd Heteroaryl derivative.
CN101058535B (en) 2007-05-25 2010-07-21 复旦大学 Di(7-hydrxyl-2,3-dihydro-1-1H-indeno)ether and the like, synthetic method and application
DE602008002205D1 (en) 2007-06-06 2010-09-30 Torrent Pharmaceuticals Ltd NOVEL CONNECTIONS
WO2008157273A1 (en) 2007-06-14 2008-12-24 Smithkline Beecham Corporation Chemical compounds
WO2009093133A1 (en) 2008-01-25 2009-07-30 Medichem, S.A. Method for determining the enantiomeric purity of indane derivatives
WO2009109477A1 (en) 2008-03-05 2009-09-11 F. Hoffmann-La Roche Ag 2-aminoquinolines
US8188098B2 (en) 2008-05-19 2012-05-29 Hoffmann-La Roche Inc. GPR119 receptor agonists
AR074210A1 (en) 2008-11-24 2010-12-29 Boehringer Ingelheim Int PIRIMIDINE DERIVATIVES AS INHIBITORS OF PTK2-QUINASA
WO2010068794A2 (en) 2008-12-10 2010-06-17 The General Hospital Corporation Hif inhibitors and use thereof
KR101345497B1 (en) 2009-01-12 2013-12-31 이카겐, 인코포레이티드 Sulfonamide derivatives
EP2406230A1 (en) 2009-03-11 2012-01-18 Pfizer Inc. Substituted indazole amides and their use as glucokinase activators
WO2010137620A1 (en) 2009-05-27 2010-12-02 武田薬品工業株式会社 Phenoxyethylamine derivative
WO2010141956A2 (en) 2009-06-05 2010-12-09 Caron Joan M Methods and compositions for the treatment of cancer
US8461164B2 (en) 2009-08-31 2013-06-11 Dow Agrosciences, Llc. Pteridines and their use as agrochemicals
EP2493874A1 (en) 2009-10-30 2012-09-05 Glaxo Group Limited Novel crystalline forms of (3r,6r) -3- (2, 3 -dihydro- 1h- inden- 2 -yl) - 1 - [ (1r) - 1 - (2, 6 - dimethyl - 3 - pyridinyl) - 2 - (4 -morpholinyl) -2-oxoethyl]-6- [(1s) - 1 -methylpropyl]-2,5- piperazinedione
WO2011066537A1 (en) * 2009-11-30 2011-06-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Nitroxide therapy for the treatment of von hippel - lindau disease (vhl) and renal clear cell carcinoma (rcc)
JP4902819B1 (en) 2010-02-26 2012-03-21 株式会社日本触媒 Phthalocyanine derivatives
GB201005589D0 (en) 2010-04-01 2010-05-19 Respivert Ltd Novel compounds
JP5787977B2 (en) 2010-04-08 2015-09-30 レスピバート・リミテツド P38 MAP kinase inhibitor
WO2011133659A2 (en) 2010-04-20 2011-10-27 Emory University Inhibitors of hif and angiogenesis
WO2011159769A2 (en) 2010-06-17 2011-12-22 Aragon Pharmaceuticals, Inc. Indane estrogen receptor modulators and uses thereof
AU2011283563C1 (en) 2010-07-29 2015-01-22 Astellas Pharma Inc. Condensed ring pyridine compound
EP2502917A1 (en) 2011-03-17 2012-09-26 Santhera Pharmaceuticals (Schweiz) AG Solid state crystalline forms of 4-(2-ethyl-5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole
CN103717214A (en) 2011-06-06 2014-04-09 阿克比治疗有限公司 Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
UY34200A (en) 2011-07-21 2013-02-28 Bayer Ip Gmbh 3- (FLUOROVINIL) PIRAZOLES AND ITS USE
WO2013043964A1 (en) 2011-09-22 2013-03-28 Merck Sharp & Dohme Corp. Acyclic cyanoethylpyrazoles as janus kinase inhibitors
CN104144925A (en) 2011-10-17 2014-11-12 拜耳知识产权有限责任公司 Substituted oxadiazolyl pyridinones and oxadiazolyl pyridazinones as hif inhibitors
BR112014010368A2 (en) 2011-10-31 2017-04-25 Xenon Pharmaceuticals Inc biaryl ether sulfonamides and their use as therapeutic agents
SG11201404217XA (en) 2012-01-28 2014-08-28 Merck Patent Gmbh Azaheterocyclic compounds
JP6198715B2 (en) 2012-03-06 2017-09-20 武田薬品工業株式会社 Tricyclic compounds
PL2865663T3 (en) * 2012-06-21 2017-09-29 Eisai R&D Management Co., Ltd. Novel indanesulfamide derivative
EP2888253A4 (en) 2012-08-24 2016-01-06 Univ Texas Heterocyclic modulators of hif activity for treatment of disease
WO2014031928A2 (en) 2012-08-24 2014-02-27 Philip Jones Heterocyclic modulators of hif activity for treatment of disease
US20140128365A1 (en) 2012-11-02 2014-05-08 Bristol-Myers Squibb Company Pyridone/hydroxypyridine 11-beta hydroxysteroid dehydrogenase type i inhibitors
CA2890897A1 (en) 2012-11-14 2014-05-22 The Board Of Regents Of The University Of Texas System Inhibition of hif-2.alpha. heterodimerization with hif 1.beta. (arnt)
SG11201503800QA (en) 2012-11-28 2015-06-29 Boehringer Ingelheim Int New indanyloxydihydrobenzofuranylacetic acids
JP6283862B2 (en) 2012-12-07 2018-02-28 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New indanyloxydihydrobenzofuranyl acetic acid
AU2014246667A1 (en) 2013-04-04 2015-11-19 Olivia Newton-John Cancer Research Institute Methods of treating diseases characterized by excessive Wnt signalling
WO2015095048A1 (en) 2013-12-16 2015-06-25 Peloton Therapeutics, Inc. Cyclic sulfone and sulfoximine analogs and uses thereof
WO2016145236A1 (en) 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Hif-2-alpha inhibitor polymorphs
WO2016144825A1 (en) 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Aromatic compounds and uses thereof
WO2016145045A1 (en) 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Compositions for use in treating glioblastoma
US9796697B2 (en) 2015-06-12 2017-10-24 Peloton Therapeutics, Inc. Tricyclic inhibitors of HIF-2-alpha and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120010207A1 (en) * 2010-07-12 2012-01-12 Pfizer Limited Chemical Compounds
US9908845B2 (en) * 2013-09-09 2018-03-06 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US10155726B2 (en) * 2015-03-11 2018-12-18 Peloton Therapeutics, Inc. Substituted pyridines and uses thereof
US10278942B2 (en) * 2015-03-11 2019-05-07 Peloton Therapeutics, Inc. Compositions for use in treating pulmonary arterial hypertension
US10335388B2 (en) * 2015-04-17 2019-07-02 Peloton Therapeutics, Inc. Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof

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