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WO2013127268A1 - Dérivés sulfonamides et sulfones amido-benzyliques - Google Patents

Dérivés sulfonamides et sulfones amido-benzyliques Download PDF

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Publication number
WO2013127268A1
WO2013127268A1 PCT/CN2013/000215 CN2013000215W WO2013127268A1 WO 2013127268 A1 WO2013127268 A1 WO 2013127268A1 CN 2013000215 W CN2013000215 W CN 2013000215W WO 2013127268 A1 WO2013127268 A1 WO 2013127268A1
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WO
WIPO (PCT)
Prior art keywords
pyridine
mmol
equiv
carboxylic acid
benzylamide
Prior art date
Application number
PCT/CN2013/000215
Other languages
English (en)
Inventor
Kenneth W. Bair
Timm R. Baumeister
Alexandre J. Buckmelter
Kanl H. CLODFELTER
Peter Dragovich
Bingsong Han
Jian Lin
Xiongcai LIU
Dominic J. Reynolds
Chase C. Smith
Zhongguo Wang
Po-Wai Yuen
Mark Zak
Yamin ZHANG
Xiaozhang Zheng
Guiling Zhao
Original Assignee
Genentech,Inc.
Forma Tm, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Genentech,Inc., Forma Tm, Llc filed Critical Genentech,Inc.
Publication of WO2013127268A1 publication Critical patent/WO2013127268A1/fr

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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
    • A61K31/33—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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Definitions

  • the present invention relates to certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, and methods of treating cancer, including leukemias and solid tumors, inflammatory diseases, osteoporosis, atherosclerosis, irritable bowel syndrome, and other diseases and medical conditions, with such compounds and pharmaceutical compositions.
  • the present invention also relates to certain amido-benzyl sulfone and sulfonamide compounds for use in inhibiting nicotinamide phosphoribosyltransferase ("NAMPT").
  • Nicotinamide adenine dinucleotide plays a fundamental role in both cellular energy metabolism and cellular signaling. NAD plays an important role in energy metabolism, as the pyridine ring in the NAD molecule readily accepts and donates electrons in hydride transfer reactions catalyzed by numerous
  • NAMPT nicotinamide phosphoribosyltransferase
  • NMPRT NMPRTase
  • NAmPRTase International nomenclature: E.C. 2.4.2.12
  • NAMPT is implicated in a variety of functions, including the promotion of vascular smooth muscle cell maturation, inhibition of neutrophil apoptosis, activation of insulin receptors, development of T and B lymphocytes, and reduction of blood glucose.
  • small molecule NAMPT inhibitors have potential uses as therapies in a variety of diseases or conditions, including cancers involving solid and liquid tumors, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer, central nervous system (CNS) cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.
  • NAMPT inhibitors also have potential uses as therapies for diseases or conditions such as cancer, rheumatoid arthritis, diabetes, atherosclerosis, sepsis, or aging.
  • NAMPT is implicated in the regulation of cell viability during genotoxic or oxidative stress, and NAMPT inhibitors may therefore be useful as treatments for inflammation.
  • NAMPT may also have effects on the reaction of endothelial cells to high glucose levels, oxidative stress, and aging.
  • NAMPT inbhitors may enable proliferating endothelial cells to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity.
  • NAMPT inhibitors have been shown to interfere with NAD biosynthesis and to induce apoptotic cell death without any DNA damaging effects or primary effects on cellular energy metabolism, and thus have important anti-tumor effects.
  • the NAMPT inhibitor FK866 has these biochemical effects, and has also been shown to reduce NAD levels, induce a delay in tumor growth and enhance tumor radiosensitivity in a mouse mammary carcinoma model. See, e.g., Hasmann M. and I. Schemainda, "FK866, a Highly Specific Noncompetitive Inhibitor of Nicotinamide Phosphoribosyltransferase, Represents a Novel Mechanism for Induction of Tumor Cell Apoptosis," Cancer Res.
  • CHS-828 another NAMPT inhibitor, CHS-828, has been shown to potently inhibit cell growth in a broad range of tumor cell lines. See Olesen, U.H. et al., "Anticancer agent CHS-828 inhibits cellular synthesis of NAD,” Biochem.
  • amido-benzyl sulfone and sulfonamide derivatives have been found in the context of this invention to have NAMPT- modulating activity.
  • the invention is directed to compounds selected from the group consisting of:
  • the invention is directed to compounds selected from the group consisting of: N-[[4-(8- azabi cy clo [3.2.1 ] octan -3 - ylsulfamoyl)phenyl]meth yl]thieno[2,3-c]pyndine- 2-carboxamide (isomer
  • compositions each comprising an effective amount of at least one compound listed above or a pharmaceutical ly acceptable salt of such a compound.
  • Pharmaceutical compositions according to the invention may further comprise at least one pharmaceutically acceptable excipient.
  • the invention is directed to a method of treating a subject suffering from a disease or medical condition mediated by NAMPT activity, comprising administering to the subject in need of such treatment an effective amount of at least one compound listed above or a pharmaceutically acceptable salt of such a compound, or comprising administering to the subject in need of such treatment an effective amount of a pharmaceutical composition comprising an effective amount of at least one compound listed above or a pharmaceutically acceptable salt of such a compound.
  • An aspect of the present invention concerns the use of compound listed abovev for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer.
  • An aspect of the present invention concerns the use of a compound listed above for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer, where the cancer is selected from leukemia, lymphoma, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, CNS cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.
  • An aspect of the present invention concerns the use of a compound listed abocev for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer, where the cancer is selected from cancers with solid and liquid tumors, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer, CNS cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.
  • the compounds listed above and pharmaceutically acceptable salts thereof are useful as NAMPT modulators.
  • the invention is directed to a method for modulating NAMPT activity, including when NAMPT is in a subject, comprising exposing NAMPT to an effective amount of at least one compound of the invention or a pharmaceutically acceptable salt of a compound listed abovec.
  • the present invention is directed to methods of making compounds as listed above and pharmaceutically acceptable salts thereof.
  • the compound of the invention is a compound selected from those species described or exemplified in the detailed description below, or is a pharmaceutically acceptable salt of such a compound.
  • alkyl refers to a saturated, straight- or branched-chain hydrocarbon group having from 1 to 1 0 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methy 1- 1 -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2- dimethy 1-1 -propyl, 2-methyl-l -pentyl, 3-methyl- l -pentyl, 4-methyl- l -pentyl, 2- methyl-2-pentyl, 3 -methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3 ,3 - dimethy 1- 1 -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,
  • amino refers to an -NH ⁇ group.
  • Any atom that is represented herein with an unsatisfied valence is assumed to have the sufficient number of hydrogen atoms to satisfy the atom' s valence.
  • Numerical ranges are intended to include sequential whole numbers. For example, a range expressed as “from 0 to 4" or "0-4" includes 0, 1 , 2, 3, and 4.
  • arylacyl- refers to a moiety in which an oxygen atom is the point of attachment to the core molecule while aryl is attached to the oxygen atom.
  • the term "subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans; non-human primates such as chimpanzees, and other apes and monkey species; farm an imals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • “Patient” includes both human and animals.
  • the term “inhibitor” refers to a molecule such as a compound, a drug, an enzyme activator, or a hormone that blocks or otherwise interferes with a particular biologic activity.
  • modulator refers to a molecule, such as a compound of the present invention, that increases or decreases, or otherwise affects the activity of a given enzyme or protein.
  • an "effective amount” or “therapeutically effective amount” refer to a sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease or medical condition, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic use is the amount of a compound, or of a composition comprising the compound, that is required to provide a clinically relevant change in a disease state, symptom, or medical condition.
  • An appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the expression “effective amount” generally refers to the quantity for which the active substance has a therapeutically desired effect.
  • preventative and curative treatment are meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom.
  • “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomers, including optical isomers, enantiomers, and diastereomers, of the compounds of the general formula, and mixtures thereof, are considered to fall within the scope of the formula.
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. All such isomeric forms, and mixtures thereof, are contemplated herein as part of the present invention.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more tautomeric or atropisomeric forms, and mixtures thereof.
  • Diastereomeric mixtures may be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers may be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride, or formation of a mixture of diastereomeric salts), separating the diastereomers and converting (e.g., hydrolyzing or de-salting) the individual diastereomers to the corresponding pure enantiomers.
  • Enantiomers may also be separated by use of chiral HPLC column.
  • the chiral centers of compounds of the present invention may be designated as "R" or "S” as defined by the lUPAC 1974 Recommendations.
  • the compounds of the invention can form pharmaceutically acceptable salts, which are also within the scope of this invention.
  • a "pharmaceutically acceptable salt” refers to a salt of a free acid or base of a compound of the invention that is nontoxic, is physiologically tolerable, is compatible with the pharmaceutical composition in which it is formulated, and is otherwise suitable for formulation and/or administration to a subject.
  • Reference to a compound herein is understood to include reference to a pharmaceutically acceptable salt of said compound unless otherwise indicated.
  • Compound salts include acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a given compound contains both a basic moiety, such as, but not limited to, a pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid
  • a zwitterion inner salt
  • such salts are included within the term "salt” as used herein.
  • Salts of the compounds of the invention may be prepared, for example, by reacting a compound with an amount of a suitable acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate ("mesylate”),
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the countenon may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counterions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,
  • camphorsulfonates fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates,
  • toluenesulfonates also known as tosylates, and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • any compound described herein is intended to refer also to any unsolvated form, or a hydrate, solvate, or polymorph of such a compound, and mixtures thereof, even if such forms are not listed explicitly.
  • “Solvate” means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Suitable solvates include those formed with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvent is water and the solvates are hydrates.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Methods for the preparation of solvates are generally known.
  • M. Caira et al., J. Pharmaceutical Sci., 93(3), 601 -61 1 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water
  • Similar preparations of solvates, hemisolvate, hydrates, and the like are described by E. C. van Tonder et al, A APS PharmSciTech., 5(1 ), article 12 (2004); and A. L. Bingham et al, Chem.
  • a typical, non-limiting process involves dissolving the compound of the invention in a suitable amounts of the solvent (organic solvent or water or a mixture thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example, infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the invention also relates to pharmaceutically acceptable prodrugs of the compounds described herein, and treatment methods employing such
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the specific compound described herein).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise suitable for formulation and/or administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci -C 8 )alkyl, (C2-Ci 2)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- 1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
  • alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 - (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N- (alkoxycarbony])amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yi, di-N,N-(Ci-C2)alkylamino(C 2 -C3)alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(G-G)alkyl, N,N-di(G- C 2 )alkylcarbamoyl-(Ci-C2)al
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C 6 )alkanoyloxymethyl, 1 -((G- C6)alkanoyloxy)ethyl, 1 -methyl- l-((G-C6)alkanoyloxy)ethyl, (G- C f ,)alkoxycarbonyloxymethyl, N-(G-G,)alkoxycarbonylaminomethyl, succinoyi, (G - G)alkanoyl, a-amino(G-C4)alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl- a- aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, ⁇ (0)( ⁇ ) 2 , -P(0)(0(Ci)
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (G-Go)alkyl, (G-G) cycloalkyl, benzyl, or R- carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, -C(OH)C(0)OY' wherein Y 1 is H, (C-G,)alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C,-C 4 ) alkyl and Y 3 is (G- G)alkyl, carboxy(G-C6)alkyl, amino(G-G)alkyl or mono-N- or di-N,N-(G- G)alkylaminoalkyl, -C
  • the present invention also relates to pharmaceutically active metabolites of compounds of the invention, and uses of such metabolites in the methods of the invention.
  • a "pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound as described herein or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertohni et al., J. Med. hem.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, "C, , 3 C, , C, , 5 N, , 8 0, , 7 0, 31 P, 32 P, 5 S, , 8 F, 36 C1, and , 5 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (for example with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 1 8 F or "C labeled compound may be particularly suitable for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the
  • the use of the terms “salt,” “solvate,” “polymorph,” “prodrug,” and the like, with respect to the compounds described herein is intended to apply equally to the salt, solvate, polymorph, and prodrug forms of enantiomers, stereoisomers, rotamers, tautomers, atropisomers, and racemates of the compounds of the invention.
  • the compounds of the present invention are:
  • dosage forms of the present invention may contain a mixture of one or more compounds of this invention, and may include additional materials known to those skilled in the art as pharmaceutical excipients.
  • Excipient includes any excipient commonly used in pharmaceutics and should be selected on the basis of compatibility and the release profile properties of the desired dosage form.
  • Exemplary excipients include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.
  • Exemplary exipients include, e.g., acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lacrylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.
  • excipients include: stabilizing additives such as gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine; acidifying agents (acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid, nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid, tartaric acid); aerosol propellants (butane, dichlorodifluoro-methane, dichlorotetrafluoroethane, isobutane, propane,
  • stabilizing additives such as gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine
  • acidifying agents acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid, nitric acid, phosphoric acid
  • alkalizing agents strong ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine
  • anticaking agents see “glidant” below
  • antifoaming agents diimethicone, simethicone
  • antimicrobial preservatives benzalkonium chloride, benzalkonium chloride solution, benzelthonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium
  • anticaking agents calcium silicate, magnesium silicate, colloidal silicon dioxide, talc
  • humectants glycol, hexylene glycol, propylene glycol, sorbitol
  • plasticizers (castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono- and di-acetylated monoglycerides, polyethylene glycol, propylene glycol, tnacetin, tnethyl citrate); polymers (e.g., cellulose acetate, alkyl celloloses,
  • hydroxyalkylcelloloses acrylic polymers and copolymers
  • solvents acetone, alcohol, diluted alcohol, amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol,
  • carbon dioxide sorbents barium hydroxide lime, soda lime
  • stiffening agents
  • hydrophilic castor oil cetostearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat, paraffin, polyethylene excipient, stearyl alcohol, emulsifying wax, white wax, yellow wax
  • suspending and/or viscosity-increasing agents acacia, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, magma bentonite, carbomer 934p, carboxymethylcellulose calcium, carboxymethylcellulose sodium,
  • tablet binders acacia, alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methycellulose, polyethylene oxide, povidone, pregelatinized starch, syrup
  • tablet and/or capsule diluents calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, confectioner's sugar
  • tablet disintegrants alginic acid, microcrystalline cellulose, croscarmellose sodium, cor
  • the invention relates to methods of treating diseases or conditions mediated by elevated levels of NAMPT, or which are generally mediated by NAMPT activity.
  • diseases or condition is one or more selected from the group consisting of cancer, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, bladder cancer, pancreatic 15
  • cancer leukemia, lymphoma, Hodgkin's disease, viral infections, Human
  • Immunodeficiency Virus hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, dermatitis, atoptic dermatitis, psoriasis, systemic lupus erythematosis, multiple sclerosis,
  • psoriatic arthritis ankylosing spodylitis
  • graft-versus-host disease Alzheimer's disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephirihs, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamous cell cancers, kidney cancer, uretral and bladder cancers, cancers of head and neck, and cancers of the brain and central nervous system (CNS).
  • CNS central nervous system
  • the compounds of the invention can be useful in the therapy of proliferative diseases such as, but not limited to cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease
  • proliferative diseases such as, but not limited to cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease
  • the compounds can be useful in the treatment of a variety of cancers, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, non- small cell lung cancer, head and neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;
  • carcinoma including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, non- small cell lung cancer, head and neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;
  • hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma,
  • Hodgkins lymphoma Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic
  • tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas
  • other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • the compounds of the invention may induce or inhibit apoptosis.
  • the compounds of the invention may also be useful in the chemoprevention of cancer.
  • Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse
  • a further aspect of the invention is a method of inhibiting a NAMPT pathway in a subject, said method comprising administering to said subject a pharmaceutically acceptable amount of a compound of the invention to a subject in need thereof
  • Another embodiment of the invention comprises a pharmaceutical formulation of the invention, wherein the pharmaceutical formulation, upon administration to a subject (e.g., a human), results in a decrease in tumor burden.
  • a subject e.g., a human
  • Still another embodiment of the invention is a pharmaceutical formulation comprising at least one compound of the invention and a pharmaceutically acceptable excipient, and further comprising one or more adjunctive active agent.
  • the pharmaceutical formulations of the invention may further comprise a therapeutic effective amount of an adjunctive active agent.
  • the compounds of the present invention are also useful in combination
  • therapies with at least one adjunctive active agent include regimes in which the compound of the invention and the at least one adjunctive active agent are administered simultaneously or sequentially. Also useful are pharmaceuticals.
  • compositions in which at least one compound of the present invention and at least one adjunctive active agent are combined in a single formulation are combined in a single formulation.
  • adjunctive active agent generally refers to agents which targets the same or a different disease, symptom, or medical condition as the primary therapeutic agent. Adjunctive active agents may treat, alleviate, relieve, or ameliorate side effects caused by administration of the primary therapeutic agents. Examples of adjunctive active agents include, but are not limited to, antineoplastic agents,
  • adjunctive active agent include those which modify blood cell growth and maturation.
  • adjunctive active agent include those which modify blood cell growth and maturation.
  • adjunctive active agents include those which inhibit nausea associated with administration of chemotherapeutic agents, such as a 5-HT 3 receptor inhibitor (e.g., dolansetron, granisetron, or ondansetron), with or without dexamethasone.
  • chemotherapeutic agents such as a 5-HT 3 receptor inhibitor (e.g., dolansetron, granisetron, or ondansetron), with or without dexamethasone.
  • the invention also describes one or more uses of the compounds of the present invention with an adjunctive active agent such as TNF, GCSF, or other chemotherapeutic agents.
  • adjunctive active agents include those that mediate cytotoxicity of
  • NAMPT inhibitors such as nicotinic acid rescue agents, or other compounds that play a role in the NAMPT pathway, such as niacin (nicotinic acid), nicotinamide, or related compounds, or modified release formulations of such compounds, for example, NIASPAN ® .
  • chemotherapeutic agent and “antineoplastic agent” generally refer to agents, which treat, prevent, cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect malignancies and their metastasis.
  • agents include, but are not limited to, prednisone, fluorouracil (e.g., 5-fluorouracil (5- FU)), anastrozole, bicalutamide, carboplatin, cisplatin, chlorambucil, cisplatin, carboplatin, docetaxel, doxorubicin, flutamide, interferon-alpha, letrozole, leuprolide, megestrol, mitomycin, oxaliplatin, paclitaxel, plicamycin (Mithracin rM ), tamoxifen, thiotepa, topotecan, valrubicin, vinblastine, vincristine, and any combination of any of the foregoing.
  • the invention is also directed to a method of treating or preventing a disorder associated with excessive rate of growth of cells in a subject (e.g., a mammal) comprising administering to the subject an effective amount of the pharmaceutical formulation of the invention.
  • a disorder associated with excessive rate of growth of cells in a subject (e.g., a mammal) comprising administering to the subject an effective amount of the pharmaceutical formulation of the invention.
  • disorder include cancer or metastasis from malignant tumors.
  • Another aspect of the invention is a method of inhibiting tumor cell growth and rate of division in a subject (e.g., a mammal) with cancer, or other disorder associated with abnormally dividing cells comprising administering to the subject an effective amount of the pharmaceutical formulation of this invention.
  • Another embodiment of the invention is a method of treating bone pain due to excessive growth of a tumor or metastasis to bone in a subject (e.g., a mammal) in need thereof comprising administering to the subject an effective amount of the pharmaceutical formulation of this invention. 5
  • composition comprising mixing at least one compound of the present invention, and, optionally, one or more pharmaceutically acceptable excipients.
  • the invention is also directed to methods of synthesizing compounds of the present invention.
  • Still another aspect of this invention is to provide a method for treating, preventing, inhibiting or eliminating a disease or condition in a patient by inhibiting NAMPT in said patient by administering a therapeutically effective amount of at least one compound of this disclosure, wherein said disease or condition is selected from the group consisting of cancer, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin's disease, viral infections, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, dermatitis, atoptic dermatitis, psoriasis, systemic lupus erythematosis, multiple sclerosis,
  • psoriatic arthritis ankylosing spodylitis
  • graft-versus-host disease Alzheimer's disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephiritis, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamous cell cancers, kidney cancer, uretral and bladder cancers, cancers of head and neck, cancers of the brain and central nervous system.
  • the compounds of the invention can be used in the treatment of solid and liquid tumors, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer,
  • CNS cancer bladder cancer, pancreatic cancer and Hodgkin's disease.
  • the compounds of the invention can be used in the treatment of solid and liquid tumors, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.
  • Another embodiment is a pharmaceutical formulation comprising a pharmaceutically acceptable compound of the present invention, which provides, upon administration to a subject (e.g., a human), a decrease in tumor burden and/or metastases.
  • the pharmaceutical formulation can be administered by oral means or other suitable means.
  • Yet another embodiment is a method of treating ovarian cancer in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention.
  • NSCLC NSCLC in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention.
  • Yet another embodiment is a method of treating colon cancer in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention
  • Yet another embodiment is a method of treating breast cancer in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the pharmaceutical formulation of the present invention.
  • Yet another embodiment is a method of treating leukemia in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention.
  • Yet another embodiment is a method of treating colon cancer before or after surgical resection and/or radiation therapy, in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention.
  • Yet another embodiment is a method of treating cancer before or after surgical resection and/or radiation therapy, in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the
  • adjunctive therapy to treat nausea, with or without dexamethasone.
  • the compounds of the invention described herein may be administered and/or formulated in combination with an adjunctive active agent.
  • the adjunctive active agent is niacin, nicotinamide, nicotinic acid, nicotinamide mononucleotide (NMN), or variations thereof, including modified release formulations of niacin, such as NIASPAN ® .
  • Niacin, nicotinamide, nicotinic acid, nicotinamide mononucleotide (NMN), or variations thereof have also been described in the literature as "rescue agents” or “rescuing agents” and these terms have been used herein.
  • the role of nicotinamide and/or nicotinic acid as a rescuing or rescue agent has for example been described by Beauparlant et al. in Anti-Cancer Drugs 2009, 20:346-354 and by Rongvaux et al. in The Journal of Immunology, 2008, 1 81 : 4685 ⁇ 69
  • These two references describe the role of a rescuing or rescue agent with regards to ameliorating possible toxic effects of NAMPT inhibitors.
  • Yet another embodiment is a method of treating cancer before or after surgical resection and or radiation therapy, in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the
  • cytotoxic agents such as for example, but not limited to, DNA interactive agents (such as cisplatin or doxorubicin)); taxanes (e.g.
  • topoisomerase ⁇ inhibitors such as etoposide
  • topoisomerase I inhibitors such as irinotecan (or CPT-1 1 ), camptostar, or topotecan
  • tubulin interacting agents such as paclitaxel, docetaxel or the epothilones
  • hormonal agents such as tamoxifen
  • thymidilate synthase inhibitors such as 5-fluorouracil or 5-FU
  • anti-metabolites such as methoxtrexate
  • alkylating agents such as temozolomide, cyclophosphamide
  • Farnesyl protein transferase inhibitors such as, S ARASARTM.(4-[2-[4-[(l 1 R)-3 , 10-dibromo-8-chloro- 6, 1 1 -dihydro-5H-benzo[5,- 6]cyclohepta[ l ,2-b]pyridin-l l
  • BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.); signal transduction inhibitors (such as, Iressa ® (from Astra Zeneca Pharmaceuticals, England), Tarceva* (EGFR kinase inhibitors), antibodies to EGFR (e.g., C225), GLEEVEC 8 (C-abl kinase inhibitor from Novartis Pharmaceuticals, East Hanover, N.J.); interferons such as, for example, intron ® (from Merck &
  • Peg-Intron ® from Merck & Company
  • hormonal therapy combinations include aromatase combinations; ara-C, adriamycin, Cytoxan, and gemcitabine.
  • anti-cancer agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, Floxuridine, Cytarabine, 6- Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATIN ® from Sanofi-Synthelabo Pharmaceuticals, France), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide
  • Testolactone Megestrolacetate, Methylprednisolone, Methyltestosterone,
  • Prednisolone Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
  • Fulvestrant Exemestane, Ifosfomide, Rituximab, C225, and Campath, 5-fluorouracil and leucovorin, with or without a 5-HT$ receptor inhibitor (e.g., dolansetron, granisetron, ondansetron) with or without dexamethasone.
  • 5-HT$ receptor inhibitor e.g., dolansetron, granisetron, ondansetron
  • such combination products employ the compounds of this invention within the dosage range described herein (or as known to those skilled in the art) and the other pharmaceutically active agents or treatments within its dosage range.
  • the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., ( 1995) 108, 2897).
  • the compounds of the invention may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of the disclosed Formulas may be administered either prior to or after administration of the known anticancer or cytotoxic agent.
  • cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research (1997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
  • any of the aforementioned methods may be augmented by administration of fluids (such as water), loop diuretics, one or more adjunctive active agents, such as a chemotherapeutic or antineoplastic agent, such as leucovorin and fluorouracil, or an adjunctive chemotherapeutic agent (such as filgrastim and erythropoietin), or any combination of the foregoing.
  • fluids such as water
  • loop diuretics such as a chemotherapeutic or antineoplastic agent, such as leucovorin and fluorouracil
  • an adjunctive chemotherapeutic agent such as filgrastim and erythropoietin
  • Yet another embodiment is a method for administering a compound of the instant invention to a subject (e.g., a human) in need thereof by administering to the subject the pharmaceutical formulation of the present invention.
  • a subject e.g., a human
  • Yet another embodiment is a method of preparing a pharmaceutical formulation of the present invention by mixing at least one pharmaceutically acceptable compound of the present invention, and, optionally, one or more pharmaceutically acceptable additives or excipients.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral
  • compositions and formulations of the invention can be administered as sterile compositions and sterile formulations.
  • Sterile pharmaceutical formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards (e.g., United States Pharmacopeia Chapters 797, 1072, and 121 1 , California Business & Professions Code 4127.7; 16 California Code of Regulations 1751 , 21 Code of Federal Regulations 21 , or ex -U. S. counterparts to such regulations) known to those of skill in the art.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of this invention may also be delivered subcutaneously.
  • the compound can be administered orally or intravenously.
  • the pharmaceutical preparation can be in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 1000 mg, for example from about 1 mg to about 500 mg, in particular from about 1 mg to about 250 mg, or from about 1 mg to about 25 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing compounds according to the invention and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art.
  • Additional particularly useful reactions in preparing compounds of the present invention include alkylation, reductive amination, oxidation, reduction, and hydrolysis reactions. Such transformations are well within the ordinary skill in the art.
  • Compounds according to the invention may be prepared singly or as compound libraries comprising, for example, at least two, or 5 to 1 ,000 compounds, or 10 to 100 compounds.
  • Libraries of compounds of the invention may be prepared by a combinatorial "split and mix” approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least two compounds of the invention, or
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse- phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical;
  • SMB simulated moving bed
  • preparative thin or thick layer chromatography as well as techniques of small scale thin layer and flash chromatography.
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), N2013/000215
  • a single stereoisomer e.g., an enantiomer, substantially free of its
  • stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E.
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1 ) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: “Drug Stereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
  • diastereomeric salts can be formed by reaction of
  • enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a- methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate of the racemic mixture and analyzing the ⁇ NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers (Jacob ID.
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/151 1 1 ).
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J Chromatogr., (1990) 513 :375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • LC Parameters Column: Shim-pack XR-ODS, 2.2 urn, 3.0*50mm; Mobile Phase A : Water/0.05% TFA; Mobile Phase B: Acetonitnle; Gradient: 5% to 1 00% B in 2.0 min, 100% B for 1 .1 min, 1 00% to 5% B in 0.2 min, then stop; Flow Rate: l .O mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation : 1 mg/mL in Methanol; Injection Volume: 1 ⁇ .
  • Interface ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas: 1 .50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1 .7 kv.
  • LC Parameters Column: Shim-pack XR-ODS, 2.2 urn, 3.0* 50 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitri le/0.05% TFA, Gradient: 5% to 100% B in 2.0 min, 100% B for 1 . 1 min, 100% to 5% B in 0.2 min, then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation: 1 mg/mL in Methanol, Injection Volume: 1 ⁇ .
  • Interface ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1.5 kv.
  • LC Parameters Column: Shim-pack XR-ODS, 50 mm*3.0 mm, 2.2 um; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% B in 2. 1 min, 100% B for 0.8 min, 100% to 5% B in 0. 1 min, then stop; Flow Rate: 1 .0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample
  • Interface ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas. 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage. 1.05 kv.
  • LC Parameters Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 5% to 100% B in 2.0 min, 100% B for 1 .2 min, 1 00% to 5% B in 0. 1 min, then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation: 1 mg/mL in Methanol; Injection Volume: 1 ⁇ .
  • LC Parameters Column: Shim-pack XR-ODS, 50*3.0 nm, 2.2 um; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 5% B to 100% B for 2.0 min, 100% B for 1 .2 min, 100% B to 5% B in 0.1 min, then stop; Flow Rate: 1 .0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation: 1 mg/mL in Methanol, Injection Volume: 1 ⁇ L ⁇ .
  • Interface ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 70-900 (m/z); Detector voltage: 1 .05 kv.
  • Interface ESI (Positive & Negative); Interface Voltage: 4.0 kv; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1.5 kv
  • Interface ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 200 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1 05 kv
  • LC Parameters Column: Shim-pack XR-ODS 50 mm*3.0 mm, 2.2 um; Mobile Phase A: Water /0.05% TFA; Mobile Phase B: Acetonitrile /0.05% TFA; Gradient: 5% to 100% B in 1 .2 minutes, 100% B for 0.9 minutes, 100% to 5% B in 0.2 minutes, then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40 °C; Detector: PDA and ELSD; Sample Preparation: 1 mg/mL in Acetonitrile; Injection Volume: 1 ⁇ ; Report.
  • Interface ESI (Positive); Interface Voltage: Tuning File; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z), Detector voltage: 1 . 10 kv Method Q
  • LC Parameters Column: Shim-pack XR-ODS 50 mm*2.0 mm, 1 .6 um; Mobile Phase A: Water /0.1 % formic acid; Mobile Phase B: Acetonitnle /0.05% formic acid;
  • Detector PDA and ELSD; Sample Preparation: 1 mg/mL in Acetonitrile; Injection Volume: 1 ⁇ ; Report: Area Normalized Purity
  • Interface ESI (Positive); Interface Voltage: Tuning File; Heat Block: 250 °C; Nebulizing Gas: 1 .50 L/min; Scan Range: 90-900(m/z); Detector voltage: 0.85 kv
  • Step 1 Ethyl 3-hydroxyisonicotinate.
  • a solution of 3-hydroxyisonicotinic acid (495 g, 3.56 mol) in ethanol (7 L) and concentrated H2SO4 (250 mL) was heated under reflux for 72 h and then cooled to rt and concentrated under reduced pressure to remove the solvent.
  • the residue was dissolved in water (3 L) and the pH was adjusted to 4 by addition of saturated aqueous NaHCOj solution.
  • the resulting precipitate was removed by filtration and the filtrate was extracted with DCM (2 L> ⁇ 3).
  • the combined organic phase was washed with brine, dried over anhydrous Na2SO and then concentrated under reduced pressure to give ethyl 3-hydroxyisonicotinate (414 g, 70%) as yellow oil.
  • the aqueous layer was separated and the organic phase was extracted by 1 N HC1 (1 L x 2).
  • the combined aqueous layers were slowly adjusted to pH 8 by addition of solid NaHCO;, and then extracted with ethyl acetate (2 Lx2).
  • the combined organic layers were dried over anhydrous Na2SC>4 and then concentrated under reduced pressure to give the title compound (380 g, 61 %) as a brown oil.
  • the precipitated solid was collected by filtration and washed with ethyl acetate (1 L).
  • the filtrate was washed with ethyl acetate ( 1 L> ⁇ 2) and the aqueous layer was combined with the solid and carefully acidified to a pH of 5 with acetic acid.
  • the resulting solid was collected by filtration and dried under vacuum to give the title compound (21 0 g, 68%) as a yel low solid.
  • Step 4 Ethyl 3-(((trifluoromethyl)sulfonynoxy)furo[2.3-c]pyridine-2- carboxylate.
  • ethyl 3-hydroxyfuro[2,3-c]pyridine-2-carboxylate 210 g, 1.01 mol
  • pyridine 107 mL, 1 .3 mol
  • TfiO 203 g, 1.2 mol
  • the reaction mixture was stirred at rt for 16 h and then quenched with ice water (1 L).
  • the aqueous layer was extracted with DCM ( 1 Lx2) and the combined organic layer was dried over anhydrous Na2SC>4 and then concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography eluting with 10% ethyl acetate/petroleum ether to give the title compound (298 g, 87%) as a white solid.
  • Step 6 To a solution of ethyl furo[2,3-c]pyridine-2-carboxylate ( 158 g, 0.83 mol) in water:THF:MeOH (1 : 1 : 1 , 2.4 L) was added KOH (1 39 g, 2.49 mol). The reaction mixture was stirred at rt for 16 h and then concentrated to a volume of 750 mL. To this residue was added acetic acid until pH ⁇ 4. The resulting solids were collected by filtration, washed with water (300 mL> ⁇ 2) and dried in a vacuum oven overnight to give the title compound ( 101 g, 75%) as a pale yellow solid.
  • Step 1 Imidazo[l ,2-a]pyridine-6-carboxylic acid hydrochloride salt.
  • Step 1 Sodium (Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-l -en-l -olate.
  • Methyl 3,3-dimethoxypropanoate 100 g, 675 mmol
  • methyl formate 81 g, 1350 mmol
  • Sodium hydride 60% dispersion; 32.4 g, 810 mmol, 1 .2 eq.
  • the reaction mixture was stirred at rt for 1 h, then was heated at 50 °C for 3 h. During this period, 3 ⁇ 4 evolution was observed.
  • the solvent was then removed under reduced pressure to give the crude product which was directly used in the next step without further purification.
  • Step 2 Methyl 2-aminopyrimidine-5-carboxylate.
  • the crude enolate from step 1 was dissolved in DMF (200 mL), and guanidine hydrochloride (64 g, 670 mmol) was added.
  • the mixture was heated at 100 °C under N2 for 3 h. After cooling to rt, water was added and the mixture was cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give the desired product (63 g, 61 % yield for 2 steps).
  • Step 3 Methyl imidazo[l ,2-a]pyrimidine-6-carboxylate.
  • 2- bromo-1 ,1 -diethoxyethane 100 6 g, 0.51 mol
  • methyl 2-aminopyrimidine-5- carboxylate 63 g, 0.41 mol
  • concentrated HBr 40%) (55 g).
  • the reaction mixture was heated to reflux for 3 h under N 2 . After cooling to rt, the mixture was further cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum overnight to give the desired product (92 g, 87%)
  • Step 1 I -(4-Methoxybenzyl)- l H-pyrazol-5-amine.
  • acrylonitrile 30 ml, 455 mmol
  • THF 250 mL
  • NH 2 NH 2 H 2 0 23.19 mL, 478 mmol
  • 4-methoxybenzaldehyde 55.4 mL, 455 mmol
  • the mixture was stirred at rt overnight, then at reflux for 2 h. After cooling to rt the mixture was quenched by addition of 300 mL of ice water.
  • the mixture was extracted with ethyl acetate (3 x), then the combined organic layers were extracted with 1 N HCI.
  • the aqueous layer was neutralized with aqueous 10 N NaOH solution, then extracted with ethyl acetate.
  • the organic layer was washed with H2O and brine, then dried over Na 2 S0 4 . Filtration, concentration, and recrystrallization with diethyl ether gave the target compound as a white solid (50 g, 60%).
  • Step 2 Ethyl 4-hvdroxy- l -(4-methoxybenzvD- l H-pyrazolo[ ,4-b1pyridine-5- carboxylate.
  • 1 -(4-Methoxybenzyl)-l H-pyrazol-5-amine (3.94 g, 1 9.39 mmol) followed by diethyl 2-(ethoxymethylene)malonate (4 mL, 20 mmol) was added to a 200 mL round bottom flask fitted with a distillation head to remove ethanol. The mixture was heated to 130 °C for 45 min, then 10 mL of diphenyl ether was added and the temperature was raised to 240 °C for 2 h. The reaction mixture was then cooled to rt and diethyl ether (100 mL) was added. The resulting precipitate was collected by vacuum filtration and dried under vacuum to afford the target compound as a white solid (4 g, 62%).
  • Step 3 Ethyl 4-chloro-l -(4-methoxybenzylVl H-pyrazolo[3.4-b]pyridine-5- carboxylate.
  • POCI3 (10 mL) was added to ethyl 4-hydroxy-l -(4-methoxybenzyl)-l H- pyrazolo[3,4-b]pyridine-5-carboxylate (7.5 g, 19.39 mmol). The mixture was stirred at 60 °C for 3 h. The mixture was poured into ice water and the resulting precipitate was collected by vacuum filtration and dried under vacuum to afford the target compound a light yellow solid (6.4 g, 80%).
  • Step 5 Ethyl 1 -(4-methoxybenzyl)-l H-pyrazolo[3,4-b]pyridine-5-carboxylate (4.4 g, 14 mmol) was dissolved in TFA (1 58 mL) and heated to 80 °C. The mixture was stirred at 80 °C for 4 h, then was concentrated to dryness. The residue was poured into ice water, then aqueous NaOH solution (2 M) was added until the pH was approximately 14. The solid formed was removed by filtration, and the aqueous layer was washed with ethyl acetate. To the aqueous layer was added concentrated HC1 was added until the pH was approximately 7.
  • Step l 3-Iodopyridin-4-amine.
  • a solution of 38 mL of concentrated sulfuric acid in 200 mL water was added to a 2 L 3-necked flask.
  • the solution was cooled with an ice-water bath, then 4-aminopyridine (200 g, 2.12 mol) and acetic acid (700 mL) were added in batches.
  • the mixture was then heated to reflux.
  • Iodine (1 89 g, 0.745 mol) and periodic acid dihydrate (97 g, 0.424 mol) were both equally divided into four parts.
  • One batch of iodine was added and then one batch of periodic acid dihydrate was added 1 5 min later.
  • Step 2 To a 2 L 3-necked flask was added DMF (700 mL), triethylene diamine ( 168 g, 1 .5 mol), and 4-amino-3-iodopyridine (24, 1 10 g, 0.5 mol). The mixture was cooled with an ice-water bath and pyruvic acid (1 32 g, 1 .5 mol) was slowly added, followed by palladium acetate (4.49 g, 0.02 mol). Under nitrogen atmosphere, the mixture was heated to 1 15 °C. The reaction generated effervescence. The reaction mixture was kept at 1 15-120 °C for 1 1 h. The mixture was concentrated under reduced pressure. The residue was poured into water (500 mL), and concentrated HC1 was added to adjust pH to ⁇ 1 . The mixture was cooled by adding ice and a filtration was performed. The cake thus obtained was a brownish black solid.
  • Step 1 3.5-Dibromoisonicotinaldehyde.
  • Lithium diisopropylamide (507 mmol, 1 .2 eq.) was added to 200 mL of dry THF at -78 °C under N 2 .
  • a solution of 3,5-dibromopyridine (100 g, 424 mmol) in 537 mL of dry THF was then added drop- wise over 30 min.
  • the reaction mixture was stirred at -78 °C for 1 h.
  • Ethyl formate (34.4 g, 465 mmol) was added drop-wise and stirred at -78 °C for 30 min, then the reaction mixture was poured into ice-cold saturated aqueous NaHCO ? solution.
  • Step 2 Methyl 4-bromothieno[2,3-c
  • Step 4 A three necked 2 L round bottom flask equipped with an overhead stirrer and thermocouple was charged with methyl thieno[2,3-c]pyridine-2- carboxylate (130 g, 674 mmol) and water (650 mL). Aqueous sodium hydroxide solution (1 0 N) was added with stirring at 20 °C. Over the next 20 min, the temperature rose to 25 °C and the solid dissolved. After 1 h, concentrated HC1 (1 .5 eq.) was slowly added to the reaction mixture with rapid stirring, generating a thick slurry. After stirring for 1 h, the slurry was filtered and the solid was dried under vacuum to give the title compound as a white solid ( 1 05.5 g, 88%).
  • Step 1 6-Chloro-imidazo[l ,2-b]pyridazine.
  • a solution of 6-chloro-l ,2- diazinan-3-amine (10 g, 73.75 mmol, 1 .00 equiv), 2-bromo-l ,l -dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), and HBr (40%, 45 mL) in ethanol (100 mL) was stirred overnight at 90 °C. The majority of the ethanol was removed under reduced pressure then the pH value of the solution was adjusted to 10 with 5% aqueous potassium carbonate solution. The resulting mixture was extracted with 6x500 mL of ethyl acetate.
  • Step 2 midazof 1 ,2-b1pyridazine-6-carboxylic acid methyl ester.
  • Step 1 N'-(5-Bromo-pyridin-2-yl)-N,N-dimethyl-formamidine.
  • a solution of 5-bromopyridin-2-amine (4 g, 23.12 mmol, 1 .00 equiv) and ⁇ , ⁇ -dimethylformamide dimethyl acetal (9.6 mL, 3.00 equiv) in DMF (30 mL) was stirred under nitrogen for 12 h at 130 °C. The reaction mixture was cooled to rt and then concentrated under vacuum to give 4 g (76%) of the title compound as an oil.
  • TLC: 1 :5 MeOH/DCM, Rf 0.6.
  • Step 4 A solution of [ l ,2,4]triazolo[l ,5-a]pyridine-6-carboxylic acid methyl ester (200 mg, 1 .13 mmol, 1 .00 equiv) in tetrahydrofuran (2 mL) was added to a solution of potassium hydroxide (1 g, 17.82 mmol, 1 5.79 equiv) in water (10 mL). The resulting mixture was stirred for 10 h at rt. After the reaction completed, the pH value of the solution was adjusted to 5-6 with 1 N HCl. The mixture was extracted with 3x50 mL of ethyl acetate.
  • Step 1 4H-Pyrazolo[L5-a]pyrimidin-5-one.
  • a solution of 1 H-pyrazol-3- ylamine (7 g, 84.24 mmol, 1.00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane (10 g, 1.21 equiv) was stirred under nitrogen overnight at 1 10 °C.
  • the reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36%) of the title compound as a light brown solid.
  • Step 3 Pyrazolo[1.5-a]pyrimidine-5-carboxylic acid methyl ester.
  • a mixture of 5-chloro-pyrazolo[ l ,5-a]pyrimidine (2 g, 1 3.02 mmol, 1 .00 equiv), tnethylamine (4 mL), MeOH (80 mL), and bis(triphenylphosphine)pa!ladium(II) dichloride ( 1 g, 1 .42 mmol, 0.1 1 equiv) was stirred in a 100-mL pressure reactor overnight at 100 °C under 10 atmospheres of carbon monoxide. The reaction mixture was cooled to rt then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 :5) to yield 1 .2 g (52%) of the title
  • Step 4 To a solution of methyl pyrazolo[l ,5-a]pyrimidine-5-carboxylic acid methyl ester (100 mg, 0.56 mmol, 1.00 equiv) in acetic acid (5 mL) was added
  • Step 1 Ethyl N-(prop-2-yn- 1 -yl Carbamate.
  • prop-2-yn- l - amine (1 1 .5 g, 208.79 mmol, 1 .00 equiv) and sodium hydroxide (9.1 g, 227.50 mmol, 1 .09 equiv) in water (40 mL) and toluene (1 10 mL) maintained under nitrogen was added ethyl chloroformate (23.9 g, 220.23 mmol, 1 .05 equiv) dropwise in 20 min with stirring at 10 °C. The resulting solution was stirred overnight at rt then extracted with 3x100 mL of toluene.
  • Step 3 Pyrimidin-5-ylmethanol.
  • a mixture of pyrimidine-5-carboxaldehyde (2 g, 1 8.50 mmol, 1 .00 equiv) and sodium borohydride (2 g) in MeOH (100 mL) was stirred at 0 - 10°C for 30 min.
  • the reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (50: 1 ) to yield 1 .2 g (59%) of pyrimidin-5-ylmethanol as a light yellow solid.
  • Step 5 Ethyl N-(prop-2-yn-l -yl)-N-(pyrimidin-5-ylmethyl)carbamate.
  • Step 7 2,3-Dihydro-l H-pyrrolo[3,4-clpyridine.
  • a mixture of ethyl lH,2H,3H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (400 mg, 2.4 mmol, 1 .00 equiv) and barium hydroxide (0.8 g) in water (100 mL) was stirred overnight at 120 °C.
  • the reaction mixture was cooled to rt and the solid material was collected by filtration.
  • the residue was stirred in hot ethyl acetate (1 50 mL) and then filtered to remove solid material. The filtrate was concentrated under vacuum to give 0.
  • Step 1 4-(Methoxycarbonyl)pyridine 1 -oxide.
  • a solution of methyl pyridine- 4-carboxylate (3 g, 21 .88 mmol, 1 .00 equiv) and m-chloroperbenzoic acid (5 g, 28.97 mmol, 1 .32 equiv) in DCM (30 mL) was stirred overnight at ty.
  • the precipitated product was collected by filtration to give 2.6 g (78%) of 4- (methoxycarbonyl)pyridine 1 -oxide as an off-white solid.
  • Step 2 Methyl 2-cyanopyridine-4-carboxylate.
  • Step 4 Methyl 2-(formamidomethyl)pyridine-4-carboxylate.
  • a solution of methyl 2-(aminomethyl)pyridine-4-carboxylate (2 g, 12.04 mmol, 1 .00 equiv) in formic acid (20 mL) was stirred for 2 h at 100 °C.
  • the resulting mixture was
  • Step 1 3-tert-Butylamino-imidazo[l ,2-a]pyridine-6-carboxylic acid methyl ester.
  • methyl 6-aminopyridine-3-carboxylate (3.8 g, 24.98 mmol, 1.00 equiv) and 2-oxoacetic acid hydrate (3.9 g, 42.39 mmol, 1 .70 equiv) in MeOH (120 mL) was added perchloric acid (250 mg, 2.50 mmol, 0.10 equiv).
  • perchloric acid 250 mg, 2.50 mmol, 0.10 equiv.
  • the reaction mixture was stirred for 30 min and 2-isocyano-2-methylpropane (2.08 g, 25.02 mmol,
  • Step 2 Sodium 3-tert-Butylamino-imidazo[l ,2-a]pyridine-6-carboxylate.
  • a solution of 3-tert-butylamino-imidazo[l ,2-a]pyridine-6-carboxylic acid methyl ester 300 mg, 1 .21 mmol, 1 .00 equiv
  • MeOH MeOH
  • a solution of sodium hydroxide 97 mg, 2.42 mmol, 2.00 equiv
  • the resulting solution was stirred for 1 .5 h at 46 °C.
  • the reaction mixture was cooled to rt and then quenched by the addition of 0.15 mL of HCl.
  • Step 3 Sodium 3-tert-butylamino-imidazo[l ,2-a]pyridine-6-carboxylate (300 mg, 1.17 mmol, 1.00 equiv) was dissolved in acetic acid (10 mL) and then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (20: 1 ) to give 150 mg (54%) of the title compound as a yellow solid.
  • Step 1 4-Benzenesulfonyl-benzonitrile.
  • a mixture of 4-fluorobenzonitrile (5 g, 41 .3 mmol) and sodium benzenesulfinate (7.45 g, 45.4 mmol) in DMSO (30 mL) was heated at 130 °C for 16 h.
  • the mixture was cooled to rt and poured onto 300 g of ice.
  • the precipitate was collected, washed with water, and dried to afford the title compound.
  • Step 2 4-Benzenesulfonyl-benzylamine.
  • a mixture of 4-benzenesulfonyl- benzonitnle (9.4 g, 38.64 mmol) and Raney Ni (500 mg) in 2 N NHi in MeOH ( 1 50 mL) was hydrogenated for 16 hours at 50 psi. Nitrogen gas was bubbled through the mixture, which was then filtered through a short pad of diatomaceous earth, and washed with MeOH. The filtrate was concentrated and triturated with ether to afford the title compound.
  • Step 3 Imidazo l ,2-b]pyridazine-6-carboxylic acid 4-benzenesulfonyl- benzylamide.
  • a solution of 4-benzenesulfonyl-benzylamine 100 mg, 0.40 mmol, 1 .00 equiv
  • imidazo[l ,2-b]pyridazine-6-carboxylic acid 900 mg crude
  • HOBt 66 mg, 0.49 mmol, 1 .21 equiv
  • EDCI 93 mg, 0.48 mmol, 1 .20 equiv
  • Step 1 4-Cyano-N-(tetrahydro-pyran-4-yl)-benzenesulfonamide.
  • Step 2 4-Aminomethyl-N-(tetrahydro-pyran-4-yn-benzenesulfonamide. To a solution of 4-cyano-N-(tetrahydro-pyran-4-yl)-benzenesulfonamide (800 mg, 3.00 mmol, 1 .00 equiv) in MeOH (50 mL) was added Raney Ni (3 g). The reaction
  • Step 3 A solution of furo[2,3-c]pyridine-2-carboxylic acid (73 mg, 0.45 mmol, 1 .50 equiv), 4-aminomethyl-N-(tetrahydro-pyran-4-yl)-benzenesulfonamide (80 mg, 0.30 mmol, 1 .00 equiv), EDCI (69 mg, 0.36 mmol, 1 .20 equiv), HOBt (49 mg, 0.36 mmol, 1.20 equiv), and diisopropylethylamine (1 16 mg, 3.00 equiv) in DMF (5 mL) was stirred for 10 h at rt. The resulting mixture was concentrated under vacuum.
  • Step 1 4-(3.5-Difluoro-phenylsulfanyl)-benzonitrile.
  • a mixture of 4- fluorobenzonitrile (1.5 g, 12.39 mmol, 1.00 equiv), 3,5-difluorobenzene-l -thiol (2.17 g, 14.85 mmol, 1.20 equiv), and potassium carbonate (5.13 g, 37.12 mmol, 3.00 equiv) were combined in DMF (50 mL).
  • the reaction mixture was stirred under nitrogen for 5 h at 1 00 °C.
  • the resulting solution was diluted with 150 mL of water and then extracted with 3x50 mL of ethyl acetate.
  • the combined organic layers were washed with 3x100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum.
  • the residue was purified on a silica gel column eluted with ethyl
  • Step 3 4-(3.5-Difluoro-benzenesulfonyl)-benzylamine.
  • Step 5 A mixture of 3-tert-butylamino-imidazo[ l ,2-a]pyridine-6-carboxylic acid 4-(3,5-difluoro-benzenesulfonyI)-benzylamide (80 mg, 0.16 mmol, 1 .00 equiv) in 12 N aqueous hydrochloric acid solution (5 mL) was stirred for 2 h at 65°C.
  • Example 33 Imidazo[ l ,2-a]pyridine-6-carboxylic acid 4-(3-hvdroxy-3-methyl- cyclobutanesulfonyl)-benzylamide
  • Step 1 l -Bromo-4-(3-methyl-but-3-ene-l -sulfonyl)-benzene.
  • THF diisopropylamine
  • n-butyllithium in hexanes 1 .6 M, 5.9 mL
  • Example 36 1.3-Dihydro-pyrrolo[3,4-c]pyridine-2-carboxylic acid 4-(6-methyl- pyndine-3-sulfonyl)-benzylamide
  • Step 1 [4-(6-Methyl-pyridine-3-sulfonyl)-benzyll-carbamic acid 4-nitro- phenyl ester.
  • a mixture of 4-nitrophenyl chloroformate (40 mg, 0.20 mmol, 1 .04 equiv) and 4-(6-methyl-pyridine-3-sulfonyl)-benzylamine (50 mg, 0.19 mmol, 1 .00 equiv) in toluene (5 mL) was heated to reflux for 1 h. The progress of reaction was monitored by TLC. After the reaction completed, the resulting mixture was concentrated under vacuum to afford 0 08 g (98%o) of the title compound as a light red solid. The residue was used directly without further purification.
  • Step 1 Lithium 6-methyl-pyndine-3-sulfinate.
  • 5- bromo-2-methylpyridine (17.1 g, 99.41 mmol, 1 .00 equiv) in THF (200 mL) maintained under nitrogen at -90 °C was added a solution of n-butyllithium (50 mL, 2.4 M in hexanes) dropwise.
  • the resulting solution was stirred for 30 min at -90 °C. Sulfur dioxide gas was then bubbled into the reaction mixture at this temperature.
  • Step 2 5-(4-Isocyano-benzenesulfonyl)-2-methyl-pyridine.
  • a solution of lithium 6-methyl-pyridine-3-sulfinate (3.26 g) and 4-bromobenzonitrile (3.64 g) in dimethylsulfoxide (50 mL) was stirred for 1 6 h at 130 °C. After the reaction completed, the mixture was cooled to rt and poured into 500mL of ice/water. The precipitated product was collected by filtration and washed with water. The filtrated was extracted with methylene chloride (3x100 mL).
  • Step 4 A solution of furo[2,3-c]pyndine-2-carboxylic acid (120 mg, 0.74 mmol, 1 .48 equiv), 4-(6-methyl-pyridine-3-suIfonyl)-benzyIamine ( 130 mg, 0.50 mmol, 1 .00 equiv), EDCI (125 mg, 0.65 mmol, 1 .32 equiv), HOBt (90 mg, 0.67 mmol, 1 .34 equiv), and diisopropylethylamine (0.5 mL) in DMF (5 mL) was stirred overnight at rt. After the reaction completed, the resulting solution was diluted with 100 mL of DCM.
  • Example 40 The title compounds were prepared as for Example 40. The resulting mixture of isomers was separated by chiral chromatography. The compounds displayed LC MS data comparable to Example 40.
  • Example 58 tert-Butyl 3-fluoro-4-[[4-[(imidazo[l ,2-a]pyridine-6- carbonylamino)methyl]phenyl]sulfonylamino]piperidine-l -carboxylate.
  • Step 1 lmidazo[l ,2-alpyridine-6-carboxylic acid benzylamide.
  • benzylamine 2.616 g, 23.93mmol
  • benzotriazol- l -yl- oxytripyrrolidinophosphonium hexafluorophosphate 6.420 g, 1 1.96 mmol
  • imidazo[l ,2-a]pyridine-6-carboxylic acid 2.000 g, 1 1 96 mmol
  • DCM 100 mL
  • triethylamine 10.50 mL, 59.82 mmol
  • Step 2 4- ⁇ [(Imidazo[l ,2-a]pyridine-6-carbonyl)-amino]-methyl ⁇ - benzenesulfonyl chloride.
  • Imidazo[l ,2-a]pyridine-6-carboxylic acid benzylamide (2.000 g, 7.80 mmol) was added slowly to a cooled flask containing chlorosulfonic acid (6.51 mL, 97.49 mmol). The reaction mixture was kept at ice bath for another 30 min, then was warmed to rt, and stirred for 2 h. The reaction mixture was poured slowly into ice water to give a milky suspension. After 30 min, the water layer was separated, washed twice with ether, and dried in vacuo to give title compound as glassy solid ( 1 .928 g, 70.7%). This material was used in the next step without further purification.
  • Example 64 7-Amino-N-[[4-(benzenesulfonyl)phenyl]methyl]furo[2.3-c]pyridine-2- carboxamide.
  • Step 1 Methyl furo[2.3-c]pyridine-2-carboxylate.
  • a solution of furo[2,3- c]pyridine-2-carboxylic acid (2 g, 12.26 mmol, 1.00 equiv), EDCI (2.8 g, 14.61 mmol, 1.20 equiv), HOBt (2 g, 14.80 mmol, 1.20 equiv) and DIPEA (4.7 g, 3.00 equiv) in MeOH (100 mL) was stirred for 20 h at rt. The resulting mixture was concentrated under vacuum.
  • Step 4 7-Aminofuro[2.3-c]pyridine-2-carboxylic acid.
  • Example 77 6-Amino-N-[[4-(benzenesulfonyl)phenyl " lmethyll- 1 ,3- dihydropyrrolo[3,4-c]pyridine-2-carboxamide.
  • Step 1 4-Nitrophenyl N-
  • a mixture of [4-(benzenesulfonyl)phenyl]methanamine (500 mg, 2.02 mmol, 1 .00 equiv) and 4-nitrophenyl chloroformate (500 mg, 2.48 mmol, 1 .23 equiv) in toluene (30 mL) was stirred under nitrogen at 120°C for 30 min. The reaction mixture was cooled to rt.
  • Step 2 6-Chloropyridine-3-carbonyl chloride.
  • a mixture of 6- chloropyridine-3-carboxylic acid (20 g, 126.94 mmol, 1 .00 equiv), DMF ( 1 g, 1 3.68 mmol, 0.1 1 equiv) and thionyl chloride (20 mL) in toluene (200 mL) was stirred under nitrogen for 3 h at 80°C. The resulting solution was cooled to rt and
  • Step 4 6-Chloro-4-formyl-N,N-bis(propan-2-yl)pyridine-3-carboxamide.
  • diisopropylamine (1 g, 9.88 mmol, 4.76 equiv) in ether (30 mL) at -50°C maintained under nitrogen was added a 2.5 M solution of n-BuLi (5 mL) in hexanes dropwise The reaction mixture was stirred for 30 min a -50°C then solid 6- chloro-N,N-bis(propan-2-yl)pyridine-3-carboxamide (500 mg, 2.08 mmol, 1 .00 equiv) was added in a single portion.
  • Step 5 6-Chloro-4-(hydroxymethyl)-N,N-bis(propan-2-yl)pyridine-3- carboxamide.
  • a mixture of 6-chloro-4-formyl-N,N-bis(propan-2-yl)pyridine-3- carboxamide (500 mg, 1 .86 mmol, 1 .00 equiv) and NaBH 4 (500 mg, 13.22 mmol, 7.10 equiv) in ethanol (50 mL) was stirred for 50 min at 30°C. The reaction was then quenched by the addition of 1 M HC1.
  • Step 7 [6-Chloro-4-(hvdroxymethyl)pyridin-3-yl]methanol.
  • a mixture of 6- chloro-1 H,3H-furo[3,4-c]pyridin-3-one (1 g, 5.90 mmol, 1 .00 equiv) and NaBR, (0.5 g) in ethanol (50 mL) was stirred for 60 min at 25 U C.
  • the pH value of the solution was adjusted to 1 with 6M hydrochloric acid.
  • the solid was removed by filiation and the filtrate was concentrated under vacuum.
  • Step 8 2-Chloro-4.5-bis(chloromethyl)pyridine hydrochloride.
  • a mixture of [6-chloro-4-(hydroxymethyl)pyridin-3-yl]methanol (100 mg, 0.58 mmol, 1 .00 equiv) and thionyl chloride (2 mL) in DCM (20 mL) was stirred under nitrogen at rt for 1 h.
  • the resulting mixture was concentrated under vacuum to give 0.1 g of crude 2- chloro-4,5-bis(chloromethyl)pyridine hydrochloride as a dark red solid.
  • Step 9 6-Chloro-2-[(2.4-dimethoxyphenynmethyl]-l H.2H.3H-pyrrolo[3.4- cjpyridine.
  • Step 1 1 . l H,2H,3H-Pyrrolo[3,4-c1pyridin-6-amine.
  • a solution of N, 2- bis[(2,4-dimethoxyphenyl)methyl]-l H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine (300 mg, 0.69 mmol, 1 .00 equiv) in TFA (20 mL) was stirred under nitrogen overnight at 90°C. The resulting mixture was concentrated under vacuum to remove most of the TFA. The pH value of the residue was adjusted to 8 with saturated sodium carbonate solution. The mixture was concentrated under vacuum and the residue was dissolved in hot ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to provide 0.15 g of crude lH,2H,3H-pyrrolo[3,4-c]pyridin-6-amine as a red oil.
  • Step 12 A mixture of 4-nitrophenyl N-[[4- (benzenesulfonyl)phenyl]methyl]carbamate (200 mg, 0.48 mmol, 1 .00 equiv) and l H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine (60 mg, 0.44 mmol, 0.92 equiv) in ethanol (20 mL) was stirred for 1 h at 90°C. The reaction was cooled to it and then concentrated under reduced pressure.
  • Example 82 6-Amino-N-[[4-(3,5-difluorophenvnsulfonylphenyllmethyl]-lH- pyrrolo[3.2-c]pyridine- -carboxamide.
  • Step 1 6-Chloro-N.N-bis (4-methoxyphenyl)methyl]pyridin-2-amine.
  • Step 2 6-Chloro-5-iodo-N.N-bis [(4-methoxyphenyl)methyllpyridin-2 -amine.
  • a solution of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2 -amine (10 g, 27.1 1 mmol, 1 .00 equiv) and N-iodosuccinimide (24 g, 137.94 mmol, 4.00 equiv) in acetonitrile (200 mL) was stirred at 30°C for 20 h. The reaction was then quenched by the addition of a solution of containing K 2 CCh (20 g) and Na 2 S203 (20 g) in water (30 mL).
  • Step 3 6-[bis (4-Methoxyphenyl)methyllaminol-2-chloropyridine-3- carbaldehvde.
  • 6-chloro-5-iodo-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine 8 g, 1 6. 17 mmol, 1 .00 equiv
  • THF 100 mL
  • n-BuLi 8 mL, 1 .20 equiv
  • Step 4 Ethyl 2-azido-3-(6-[bis[(4-methoxyphenyl)methyl]aminol-2- chloropyridin-3-yl)prop-2-enoate.
  • 6-[bis[(4- methoxyphenyl)methyl]amino]-2-chloropyridine-3-carbaldehyde (640 mg, 1 .61 mmol, 1.00 equiv) and ethyl 2-azidoacetate (800 mg, 6.20 mmol, 3.00 equiv) in ethanol ( 100 mL) at 0°C was added sodium ethoxide (400 mg, 3.00 equiv) in several portions.
  • Step 6 6-[bis[(4-Methoxyphenyl)methyl] amino]-4-chloro-l H-pyrrolo[3.2- clpyridine-2-carboxylic acid.
  • ethyl 6-[bis[(4- methoxyphenyl)methyl]amino]-4-chloro-l H-pyrrolo[3,2-c]pyridine-2-carboxylate 400 mg, 0.83 mmol, 1 .00 equiv
  • ethanol 10 mL
  • potassium hydroxide 400 mg, 7.1 3 mmol, 8.55 equiv
  • Step 7. 6-[ " bisf(4-Methoxyphenyl)methyllamino]-4-chloro-N-([4-[(3,5- difluorobenzene)sulfonyl]phenyl]methyl)-l H-pyrrolo[3.2-c]pyridine-2-carboxamide.
  • Step 8 6-Amino-4-chloro-N-(j4-f(3.5- difluorobenzene)sulfonyl]phenyl]methyl)-1 H-pyrro1o[3,2-c]pyridine-2-carboxamide.
  • Step 9 To a mixture of 6-amino-4-chloro-N-([4-[(3,5- difIuorobenzene)sulfonyl]phenyl]methyl)-l H-pyrrolo[3,2-c]pyridine-2-carboxamide (60 mg, 0.13 mmol, 1.00 equiv) and potassium acetate (0.5 g) in MeOH (20 rtiL) was added 10% palladium on carbon catalyst (60 mg). The mixture was stirred under 1 atmosphere of H 2 for 20 h at rt. The catalyst was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (5 : 1 ).
  • the semi pure product was further purified by Prep- HPLC with the following conditions (IntelFlash-1 ): Column, silica gel; mobile phase, 18 to 38 % CH CN:H 2 0 within 20 min; Detector, UV 254 nm to give 7.4 mg (13%) of 6-amino-N-([4-[(3 ,5-difluorobenzene)sulfonyl]phenyl] methyl)- 1 H-pyrrolo[3,2- c]pyridine-2-carboxamide as an off-white solid.
  • Step 1 2-Chloro-5-(methoxymethoxy)pyridine.
  • 6- chloropyridin-3-ol 10 g, 77. 19 mmol, 1 .00 equiv
  • DMF 120 mL
  • NaH 3.8 g , 60%
  • the resulting solution was stirred at rt for 1 h.
  • 1 -Bromo-2-methoxyethane (1 3 g, 93.53 mmol, 1 .21 equiv) was then added dropwise with stirring to the reaction mixture while maintaining the reaction temperature at ⁇ 10°C.
  • the resulting solution was stirred at rt for another 2 h.
  • Step 4 Methyl 2-[(6-chloro-4-forrnylpyridin-3-y0oxy]acetate.
  • a solution of 2-chloro-5-hydroxypyridine-4-carbaldehyde (5.7 g, 36. 18 mmol, 1.00 equiv), methyl 2-bromoacetate (7.8 g, 50.99 mmol, 1 .41 equiv) and potassium carbonate (6.5 g) in DMF (100 mL) was stirred for 2 h at 50°C
  • the resulting solution was diluted with 400 mL of ethyl acetate and washed with 2x200 mL of FL .
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step 7 N-[[4-(Benzenesulfonyl)phenyl]methyl]-5-chlorofuro[2,3-c]pyridine- 2-carboxamide.
  • Step 8 N-[[4-(Benzenesulfonyl)phenyl1methyl]-5- [(diphenylmethylidene)amino]furo[2.3-c]pyridine-2-carboxamide.
  • Step 9 A solution of N-[[4-(benzenesulfonyl)phenyl]methyl]-5- [(diphenylmethylidene)amino]furo[2,3-c]pyridine-2-carboxamide (300 mg, 0.52 mmol, 1 .00 equiv) in THF (5 mL) and 1 8% HC1 (3 mL) was stirred for 30 min at rt. The pH value of the solution was adjusted to 7 with 5% aqueous sodium carbonate solution. The organic layer was collected and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step 1 4-Methoxypyridazine.
  • 3 ,6-dichloro-4- methoxypyridazine (30 g, 167.59 mmol, 1 .00 equiv) and ammonium formate (3 1 g, 491.63 mmol, 2.93 equiv) in MeOH (500 mL) was added 10% palladium on carbon (3 g) catalyst.
  • the mixture was stirred under 1 atmosphere of 3 ⁇ 4 at rt overnight.
  • the catalyst was removed by filtration and the filtrate was concentrated under vacuum. The residue was triturated in 500 mL of DCM MeOH ( 10: 1 ) and the solid material was filtered out.
  • Step 2 Methyl 5-methoxypyrazolo[1.5-b]pyridazine-3-carboxylate.
  • hydroxylamine-O-sulfonic acid 30.8 g, 272.57 mmol, 1 .50 equiv
  • potassium bicarbonate 29. 1 g, 290.67 mmol, 1 .60 equiv
  • the resulting mixture was stirred for 10 min then a solution of 4-methoxypyridazine (20 g, 181 .63 mmol, 1 .00 equiv) in water (1 00 mL) was added.
  • reaction mixture was stirred at 70°C for 5 h and then cooled back to rt.
  • a solution of methyl prop-2- ynoate (16.8 g, 199.83 mmol, 1.10 equiv) in DCM (500 mL) followed by a solution of potassium hydroxide (17.3 g, 308.32 mmol, 1 .70 equiv) in water (1 00 mL) were added to the reaction mixture.
  • the resulting solution was stirred overnight at rt then extracted with 4 L of DCM.
  • the organic layer was washed with 3x500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step 4 Pyrazolo[l ,5-b]pyridazin-3-yl trifluoromethanesulfonate.
  • pyrazolof l ,5-b]pyridazin-3-ol 450 mg, 3.33 mmol, 1 .00 equiv
  • pyridine 1 .1 g, 1 3.91 mmol, 3.00 equiv
  • trifluoromethanesulfonic anhydride (1 .9 g, 6.73 mmol, 2.02 equiv
  • Step 5 Methyl pyrazolo[1.5-b]pyridazine-3-carboxylate.
  • Step 6 Lithium pyrazolof 1 ,5-blpyridazine-5-carboxylate.
  • a solution of methyl pyrazolo[ l ,5-b]pyridazine-3-carboxylate (60 mg, 0.34 mmol, 1 .00 equiv) in THF (5 mL) was added a solution of LiOH (40 mg, 1 667mmol, 1.7 equiv) in water (1 mL).
  • the reaction mixture was stirred overnight at 50°C and then concentrated under vacuum to give 150 mg of crude lithium pyrazolo[l ,5-b]pyridazine-5- carboxylate as a dark red solid.
  • Step 7 N-([4-[(3,5-Difluorobenzene)sulfonyllphenyl]methyl)pyrazolo[l ,5- b]pyridazine-5-carboxamide.
  • reaction was then quenched by the addition of 1 00 mL of H2O and the resulting solution was extracted with 3x100 mL of ethyl acetate. The combined organic layers were washed with 3x100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuum.
  • Step 1 3.4-Dimethyl 2-chloropyridine-3.4-dicarboxylate.
  • Step 3 2-Chloro-3 ,4-bis(chloromethyl)pyridine.
  • a solution of [2-chloro-4- (hydroxymethyl)pyridin-3-yl]methanol (300 mg, 1.73 mmol, 1 .00 equiv) and thionyl chloride (20 mL) in DCM (20 mL) was stirred under nitrogen at rt for 1 h.
  • the resulting mixture was concentrated under vacuum.
  • Saturated aqueous sodium carbonate solution was added to the residue to adjust the pH value to 8.
  • the resulting solution was extracted with 2x100 mL of DCM.
  • Step 5 N,2-bis[(2,4-Dimethoxyphenyl)methyll- l H.2H,3H-pyrrolo[3,4- c]pyridin-4-amine.
  • a mixture of 4-chloro-2-[(2,4-dimethoxyphenyl)methyl]- l H,2H,3H-pyrrolo[3,4-c]pyridine 200 mg, 0.66 mmol, 1 .00 equiv
  • (2,4- dimethoxyphenyl)methanamine 300 mg, 1 .79 mmol, 2.73 equiv
  • Pd2(dba)i 1 00 mg, 0.1 1 mmol, 0.
  • Step 6 l H.2H.3H-Pyrroloi3.4-clpyridin-4-amine.
  • a solution of N,2-bis[(2,4- dimethoxyphenyl)methyl]- l H,2H,3H-pyrrolo[3 ,4-c]pyridin-4-amine (50 mg, 0.1 1 mmol, 1 .00 equiv) in TFA (20 mL) was reflux under nitrogen for 4 h.
  • the reaction mixture was cooled to rt and then concentrated under vacuum.
  • the residue was diluted in 10 mL of H 2 0 and the pH value of the solution was adjusted to 8 with potassium carbonate.
  • the resulting solution was washed with 2x60 mL of ether.
  • the compounds of Examples 69 and 78 were prepared according to the methods described in Examples 24 and 36.
  • the compounds of Examples 70, 73, 76, and 81 were prepared according to the methods described in Example 36.
  • the compounds of Examples 84 and 85 were prepared according to the methods described for Example 77.
  • the compounds of Examples 92 and 93 were prepared according to the methods described in Examples 10 and 37. Additional examples were prepared using methods analogous to those described above. The structures of all example compounds were confirmed by LC MS and/or H NMR analysis.
  • NAMPT protein purification Recombinant His-tagged NAMPT was produced in E.coli cells, purified over a Ni column, and further purified over a size- exclusion column by XTAL Biostructures.
  • the NAMPT enzymatic reaction The NAMPT enzymatic reactions were carried out in Buffer A (50mM Hepes pH 7.5, 50 mM NaCl, 5 mM MgCl 2 , and 1 mM THP) in 96- well V-bottom plates. The compound titrations were performed in a separate dilution plate by serially diluting the compounds in DMSO to make a 100X stock.
  • Buffer A (89 ⁇ ) containing 33 nM of NAMPT protein was added to 1 ⁇ , of 100X compound plate containing controls (e.g. DMSO or blank). The compound and enzyme mixture was incubated for 1 5 min at rt, then 10 ⁇ of 1 OX substrate and co- factors in Buffer A were added to the test well to make a final concentration of 1 ⁇ NAM, 1 00 ⁇ 5-Phospho-D-ribose 1 -diphosphate (PRPP), and 2.5 mM Adenosine 5'-triphosphate (ATP).
  • controls e.g. DMSO or blank
  • the compound and enzyme mixture was incubated for 1 5 min at rt, then 10 ⁇ of 1 OX substrate and co- factors in Buffer A were added to the test well to make a final concentration of 1 ⁇ NAM, 1 00 ⁇ 5-Phospho-D-ribose 1 -diphosphate (PRPP), and 2.5 mM Adenosine 5'-
  • reaction was allowed to proceed for 30 min at rt, then was quenched with the addition of 1 1 ⁇ L of a solution of formic acid and L- Cystathionine to make a final concentration of 1 % formic acid and 10 ⁇ L- Cystathionine. Background and signal strength was determined by addition (or non- addition) of a serial dilution of NMN to a pre-quenched enzyme and cofactor mix.
  • NMN ⁇ -nicotinamide mononucleotide
  • L-Cystathionine the internal control
  • NMN and L-Cystathionine were detected using the services of Biocius Lifesciences with the RapidFire system.
  • the NMN and L-Cystathionine were bound to a graphitic carbon cartridge in 0. 1 % formic acid, eluted in 30% acetonitrile buffer, and injected into a Sciex 4000 mass spectrometer. The components of the sample were ionized with electrospray ionization and the positive ions were detected.
  • the Ql (parent ion) and Q3 (fragment ion) masses of NMN were 334.2 and 123.2, respectively.
  • the Ql and Q3 for L- Cystathionine were 223.1 and 134.1 , respectively.
  • the fragments are quantified and the analyzed by the following method.
  • NMN signal was normalized to the L-Cystathionine signal by dividing the NMN signal by the L-Cystathionine signal for each well. The signal from the background wells were averaged and subtracted from the test plates. The compound treated cells were then assayed for percent inhibition by using this formula:
  • % Inh 100 - 100*x/y wherein x denotes the average signal of the compound treated wells and y denotes the average signal of the DMSO treated wells.
  • IC 50 10 A (LOG,o(X) + (((50-% Inh at Cmpd Concentration 1 )/(XX - YY)*(LOG,o(X)-LOGio(Y))))
  • X denotes the compound concentration 1
  • Y denotes the compound concentration 2
  • XX denotes the % inhibition at compound concentration 1
  • YY denotes the % inhibition at compound concentration 2 (Y).
  • the compounds of this invention have IC50 values that are preferably under ⁇ ⁇ , more preferably under 0.1 ⁇ , and most preferably under 0.01 ⁇ . Results for the compounds tested in this assay are provided in Table 2 below
  • A2780 cells were seeded in 96-well plates at 1 x 10 3 cells/well in 180 ⁇ _ of culture medium (10% FBS, 1 % Pen/Strep Amphotericin B, RPMT-1 640) with and without the addition of either NMN or nicotinamide (NAM). After overnight incubation at 37 °C and 5% CO 2 , the compound titrations were performed in a separate dilution plate by serially diluting the compounds in DMSO to make a 1000X stock. The compounds were then further diluted to 10X final concentration in culture media, whereupon 20 ⁇ _ of each dilution was added to the plated cells with controls (e.g.
  • DMSO and blank to make a final volume of 200 ⁇ _.
  • the final DMSO concentration in each well was 0.1 %.
  • the plates were then incubated for 72 hours at 37 °C in a 5% CO 2 incubator. The number of viable cells was then assessed using sulforhodamine B (SRB) assay. Cells were fixed at 4 °C for 1 hour with the addition of 50 ⁇ _ 30% trichloroacetic acid (TCA) to make a final concentration of 6 % TCA.
  • TCA trichloroacetic acid
  • the plates were washed four times with 3 ⁇ 40 and allowed to dry for at least 1 hour, whereupon 100 ⁇ of a 4% SRB in 1 % acetic acid solution was added to each well and incubated at rt for at least 30 min.
  • the plates were then washed three times with 1 % acetic acid, dried, and treated with 100 ⁇ of l OmM Tris-Base solution. The plates were then read in a microplate reader at an absorbance of 570 nm. Background was generated on a separate plate with media only. Determination of IC > Values. First, the signals from the background plate were averaged, then the background was subtracted from the test plates. The compound-treated cells were then assayed for % inhibition by using the following formula:
  • x denotes the average signal of the compound-treated cells and y denotes the average signal of the DMSO-treated cells.
  • X denotes the compound concentration 1
  • Y denotes the compound concentration 2
  • XX denotes the % inhibition at compound concentration 1
  • YY denotes the % inhibition at compound concentration 2 (Y).
  • the compounds of this invention have IC50 values that are preferably under 1 ⁇ , more preferably under 0.1 ⁇ , and most preferably under 0.01 ⁇ .

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Abstract

La présente invention concerne certains composés sulfonamides et sulfones amido-benzyliques, des compositions pharmaceutiques comprenant de tels composés, et des procédés de traitement utilisant ces composés.
PCT/CN2013/000215 2012-03-02 2013-03-01 Dérivés sulfonamides et sulfones amido-benzyliques WO2013127268A1 (fr)

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WO2018086703A1 (fr) 2016-11-11 2018-05-17 Bayer Pharma Aktiengesellschaft Dihydropyridazinones substituées par des phénylurées
CN109843334A (zh) * 2016-10-18 2019-06-04 西雅图基因公司 烟酰胺腺嘌呤二核苷酸补救途径抑制剂的靶向递送
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US11931414B2 (en) 2017-04-27 2024-03-19 Seagen Inc. Quaternized nicotinamide adenine dinucleotide salvage pathway inhibitor conjugates
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US11279687B2 (en) 2010-09-03 2022-03-22 Valo Health, Inc. Compounds and compositions for the inhibition of NAMPT
US10329275B2 (en) 2010-09-03 2019-06-25 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
US10647695B2 (en) 2010-09-03 2020-05-12 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
US20140294805A1 (en) * 2010-09-03 2014-10-02 Kenneth W. Bair Novel compounds and compositions for the inhibition of nampt
US10772874B2 (en) 2010-09-03 2020-09-15 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
US10272072B2 (en) 2010-09-03 2019-04-30 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
US11547701B2 (en) 2010-09-03 2023-01-10 Valo Health, Inc. Compounds and compositions for the inhibition of NAMPT
US10456382B2 (en) 2010-09-03 2019-10-29 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
US10730889B2 (en) 2012-03-02 2020-08-04 Forma Tm, Llc Amido spirocyclic amide and sulfonamide derivatives
US11485745B2 (en) 2012-03-02 2022-11-01 Valo Health, Inc. Amido spirocyclic amide and sulfonamide derivatives
US10696692B2 (en) 2012-03-02 2020-06-30 Forma Tm, Llc Amido-benzyl sulfone and sulfoxide derivates
US20130303511A1 (en) * 2012-05-11 2013-11-14 Abbvie Inc. Nampt inhibitors
US9187472B2 (en) * 2012-05-11 2015-11-17 Abbvie Inc. NAMPT inhibitors
WO2014111871A1 (fr) 2013-01-17 2014-07-24 Aurigene Discovery Technologies Limited Dérivés de 4,5-dihydroisoxazole utilisés comme inhibiteurs de nampt
US10323018B2 (en) 2015-01-20 2019-06-18 Millennium Pharmaceuticals, Inc. Quinazoline and quinoline compounds and uses thereof
US11464796B2 (en) 2015-08-05 2022-10-11 Metro International Biotech, Llc Nicotinamide mononucleotide derivatives and their uses
US11878027B2 (en) 2015-08-05 2024-01-23 Metro International Biotech, Llc Nicotinamide mononucleotide derivatives and their uses
US10548913B2 (en) 2015-08-05 2020-02-04 Metro International Biotech, Llc Nicotinamide mononucleotide derivatives and their uses
US11059847B2 (en) 2015-10-02 2021-07-13 Metro International Biotech, Llc Crystal forms of β-nicotinamide mononucleotide
US10392416B2 (en) 2015-10-02 2019-08-27 Metro International Biotech, Llc Crystal forms of beta-nicotinamide mononucleotide
CN109843334A (zh) * 2016-10-18 2019-06-04 西雅图基因公司 烟酰胺腺嘌呤二核苷酸补救途径抑制剂的靶向递送
US11638762B2 (en) 2016-10-18 2023-05-02 Seagen Inc. Targeted delivery of nicotinamide adenine dinucleotide salvage pathway inhibitors
WO2018086703A1 (fr) 2016-11-11 2018-05-17 Bayer Pharma Aktiengesellschaft Dihydropyridazinones substituées par des phénylurées
US11931414B2 (en) 2017-04-27 2024-03-19 Seagen Inc. Quaternized nicotinamide adenine dinucleotide salvage pathway inhibitor conjugates
US11180521B2 (en) 2018-01-30 2021-11-23 Metro International Biotech, Llc Nicotinamide riboside analogs, pharmaceutical compositions, and uses thereof
US11939348B2 (en) 2019-03-22 2024-03-26 Metro International Biotech, Llc Compositions comprising a phosphorus derivative of nicotinamide riboside and methods for modulation of nicotinamide adenine dinucleotide
US10618927B1 (en) 2019-03-22 2020-04-14 Metro International Biotech, Llc Compositions and methods for modulation of nicotinamide adenine dinucleotide
CN110183466A (zh) * 2019-07-19 2019-08-30 华东理工大学 一种稠环二吡咯烯及其合成方法
CN110183466B (zh) * 2019-07-19 2022-02-18 华东理工大学 一种稠环二吡咯烯及其合成方法
US11787830B2 (en) 2021-05-27 2023-10-17 Metro International Biotech, Llc Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use
US11952396B1 (en) 2021-05-27 2024-04-09 Metro International Biotech, Llc Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use

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