WO2015026792A1 - Antiviral compounds - Google Patents

Antiviral compounds Download PDF

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Publication number
WO2015026792A1
WO2015026792A1 PCT/US2014/051642 US2014051642W WO2015026792A1 WO 2015026792 A1 WO2015026792 A1 WO 2015026792A1 US 2014051642 W US2014051642 W US 2014051642W WO 2015026792 A1 WO2015026792 A1 WO 2015026792A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
unsubstituted
hydrogen
Prior art date
Application number
PCT/US2014/051642
Other languages
French (fr)
Inventor
Guangyi Wang
Leonid Beigelman
Anh Truong
Carmela NAPOLITANO
Daniele Andreotti
Haiying He
Karin Ann Stein
Original Assignee
Alios Biopharma, Inc.
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=52484091&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2015026792(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CA2921294A priority Critical patent/CA2921294C/en
Priority to JP2016536372A priority patent/JP6485817B2/en
Priority to NZ716822A priority patent/NZ716822A/en
Priority to CN202210267361.7A priority patent/CN114716426A/en
Priority to UAA201601391A priority patent/UA123854C2/en
Priority to CN201480055176.5A priority patent/CN105636936B/en
Priority to EA201690224A priority patent/EA038819B1/en
Priority to KR1020167007035A priority patent/KR102455034B1/en
Priority to AU2014308991A priority patent/AU2014308991B2/en
Priority to SG11201600977XA priority patent/SG11201600977XA/en
Application filed by Alios Biopharma, Inc. filed Critical Alios Biopharma, Inc.
Priority to EP14837913.4A priority patent/EP3036220A4/en
Priority to BR112016003348-5A priority patent/BR112016003348B1/en
Priority to MX2016002199A priority patent/MX2016002199A/en
Publication of WO2015026792A1 publication Critical patent/WO2015026792A1/en
Priority to IL244163A priority patent/IL244163A0/en
Priority to PH12016500332A priority patent/PH12016500332B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/4353—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
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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
    • A61K31/4353—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
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    • 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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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/4427—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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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • 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
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    • A61P31/12—Antivirals
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
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    • 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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    • 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
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—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 three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18511—Pneumovirus, e.g. human respiratory syncytial virus

Definitions

  • the present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are new antiviral compounds, together with pharmaceutical compositions, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection with one or more small molecule compounds.
  • Respiratory viral infections including upper and lower respiratory tract viral infections, are a leading cause of death of millions of people each year.
  • Upper respiratory tract viral infections involve the nose, sinuses, pharynx and/or larynx.
  • Lower respiratory tract viral infections involve the respiratory system belo the vocal cords, including the trachea, primary bronchi and lungs.
  • Human respiratory syncytial virus (RSV) is a common cause of respiratory tract infections. Up to 60% of human infants are infected with RSV within their first year of life. Children and adults are also infected with RSV, where it is often manifesting as a lower respiratory tract infection with possible complications of bronchiolitis. RSV infections can be particularly severe in infants and elderly patients.
  • RSV is a negative-sense, single-stranded RNA virus classified within the Paramyxoviridae family, which also includes viruses that cause Newcastle disease, parainfluenza, mumps, measles, and canine distemper.
  • Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include administering to a subject suffering from the paramyxovirus viral infection an effective amount of one or more compounds of Formula ( ⁇ ), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition that includes one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof.
  • Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a paramyxov irus viral infection.
  • Still other embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a paramyxovirus viral infection.
  • Yet still other embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include contacting a cell infected with the paramyxovirus with an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein relate to a method of inhibiting the replication of a paramyxovirus that can include contacting a cell infected w ith the paramyxovirus with an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof.
  • the paramyxovirus viral infection can be caused by a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus (including a respiratory syncytial viral infection), a metapneumovirus, hendravirus, nipahvirus, measles, sendai virus, mumps, a human parainfluenza virus (HPIV- 1 , HPIV-2, HPIV-3 and HPIV-4) and/or a metapneumovirus.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include administering to a subject suffering from the viral infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein.
  • a compound described herein or a pharmaceutically acceptable salt thereof for example, one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include contacting a cell infected with the paramyxovirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein.
  • a compound described herein or a pharmaceutically acceptable salt thereof for example, one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof
  • Figure 1 illustrates examples of compounds of Formula (I), or pharmaceutically acceptable salt of any of the foregoing compounds.
  • Paramyxoviridae family is a family of single stranded RNA viruses.
  • Several genera of the paramyxoviridae family include henipavirus, morbillivirus. respirovirus, rubulavirus, pneumovirus and metapneumovirus. These viruses can be transmitted person to person via direct or close contact with contaminated respiratory droplets or fomites.
  • Species of henipavirus include hendravirus and nipahvirus.
  • a species of morbillivirus is measles.
  • Species of respirovirus include sendai virus and human parainfluenza viruses 1 and 3 ; and species of rubulavirus include mumps virus and human parainfluenza viruses 2 and 4.
  • a species of metapneumovirus is human metapneumovirus.
  • RSV Human Respiratory Syncytial Virus
  • Symptoms of an RSV infection include coughing, sneezing, runny nose, fever, decrease in appetite, and wheezing.
  • RSV is the most common cause of bronchiolitis and pneumonia in children under one year of age in the world, and can be the cause of tracheobronchitis in older children and adults. In the United States, between 75.000 and 125,000 infants are hospitalized each year with RSV. Among adults older than 65 years of age. an estimated 14.000 deaths and 177,000 hospitalizations have been attributed to RSV.
  • Treatment options for people infected with RSV are currently limited. Antibiotics, usually prescribed to treat bacterial infections, and over-the-counter medication are not effective in treating RSV. In severe cases, a nebulized bronchodilator, such as albuterol, may be prescribed to relieve some of the symptoms, such as wheezing.
  • RespiGram® RSV-1G1V, Medlmmune, approved for high risk children younger than 24 months of age
  • Synagis® palivizumab, Medlmmune. approved for high risk children younger than 24 months of age
  • Virzole® ribavirin by aerosol, ICN pharmaceuticals
  • Symptoms of the measles include fever, cough, runny nose, red eyes and a generalized rash. Some individuals with measles can develop pneumonia, ear infections and bronchitis. Mumps leads to swelling of the salivary glands. Symptoms of mumps include fever, loss of appetite and fatigue. Individuals are often immunized against measles and mumps via a three-part MMR vaccine (measles, mumps, and rubella). Human parainfluenza virus includes four serotypes types, and can cause upper and lower respiratory tract infections.
  • Human parainfluenza virus 1 can be associated with croup; human parainfluenza virus 3 (HPIV-3) can be associated with bronchiolitis and pneumonia. According to the Centers of Disease Control and Prevention (CDC), there are no vaccines against human parainfluenza virus.
  • any "R" group(s) such as, without limitation, R , R ⁇ , R ⁇ R ⁇ R 5 , R 6 , R 7 , R 8 . R 9 . R 10 . R 1 1 . R 12 . R 13 . R 14 . R 15 R u ⁇ R 1 7 , R 18 , R 19 . R 20 . R 21 . R 22 . R 23 . and R A represent substituents that can be attached to the indicated atom.
  • An R group may be substituted or unsubstituted. If tw o "R" groups are described as being “taken together" the R groups and the atoms they are attached to can form a cycloalkyl.
  • R d and R b of an NR d R b group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:
  • R groups are not limited to the variables or substituents defined previously.
  • sulfinyl sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
  • C a to Ct in which "a” and “b” are integers refer to the number of carbon atoms in an alky l, alkeny l or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl.
  • alkcnyl, alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the ary l, ring(s) of the heteroary l or ring(s) of the heteroalicycly l can contain from "a" to "b". inclusive, carbon atoms.
  • a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -. CH 3 CH 2 -. CH 3 CH 2 CH 2 -. (CIT ⁇ CH-. CH 3 CH 2 CH 2 CH 2 -.
  • alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g. , "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom. 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl " where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alky l group of the compounds may be designated as "C f -C 4 alky l" or similar designations.
  • “C 1 -C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl. n-butyl. iso-buty l, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl. butyl, i so butyl, tertiary butyl, pentyl and hexyl.
  • the alkyl group may be substituted or unsubstituted.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted.
  • cycloalkyl' ' refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s).
  • ⁇ cycloalky l group may be unsubstituted or substituted.
  • Typical cycloalkyl groups include, but are in no way limited to. cyclopropyl, cyclobutyl. cyclopentyl. cyclohexyl. cycloheptyl and cyclooctyl.
  • cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be "aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a C 6 -C[4 aryl group, a C 6 -Cio aryl group, or a C 6 aryl group.
  • Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one, two. three or more heteroatoms. that is. an element other than carbon, including but not limited to. nitrogen, oxygen and sulfur.
  • the number of atoms in the ring(s) of a heteroaryl group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, those described herein and the following: furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1 ,2,3- oxadiazole, 1 ,2,4-oxadiazole, thiazole.
  • heterocyclyl' refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- s stems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such "heterocyclyl' " or "heteroalicyclyl” groups include, but are not limited to.
  • tetrahydropyran 4H-pyran, tetrahydrothiopyran, thiamorphoiine, thiamorphoiine sulfoxide, thiamorphoiine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).
  • aralkyi and “aiyl(alkyl) refer to an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phcnylalkyl and naphthylalkyl.
  • heteroarylky l and “heteroaryl(alkyl) " ' refer to a heteroaryl group connected, as a substituent. via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl. 3-thienylalkyl. furylalkyl. thienylalkyl. pyrrolylalkyl. pyridylalkyl. isoxazolylalkyl, imidazolylalkyl and their benzo-fused analogs.
  • heteroalicyclyl(alkyl) and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent. via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a heteiOalicyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl). tetrahydro-2H-thiopyran-4-yl (methyl), and 1 ,3-thiazinan-4-yi(methyl).
  • Lower alkylene groups' are straight-chained -CH?- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (- CH 2 CH 2 CH 2 -), and butylene (-CH 2 CH 2 CH 2 CH 2 -).
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of "substituted.”
  • alkoxy refers to the formula -OR wherein R is an alkyl. an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl, aryl. heteroaryl. heterocyclyl. cycloalkyl(alkyl). aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • R is an alkyl. an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl, aryl. heteroaryl. heterocyclyl. cycloalkyl(alkyl). aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • a non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n- butoxy, iso-but
  • acyl refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyi). heteroaryl(alkyi) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl. acetyl, propanoyi, benzoyl and acryl. An acyi may be substituted or unsubstituted.
  • alkoxyalkyp refers to an alkoxy group connected, as a substituent, via a lower alkylene group. Examples include C alkyl-0-(CH 2 ) strig- ,w herein n is an integer in the range of 1 to 6.
  • aminoalkyl refers to an optionally substituted amino group connected, as a substituent. via a lower alkylene group.
  • examples include H 2 N(CH 2 ) strig- , wherein n is an integer in the range of 1 to 6.
  • hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
  • exemplary hydroxyalkyl groups include but are not limited to. 2-hydroxyethyl. 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl.
  • a hydroxyalkyl may 7 be substituted or unsubstituted.
  • 'haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g.. mono-haloalkyl, di-haloalkyl and tri- haloalkyl).
  • a halogen e.g.. mono-haloalkyl, di-haloalkyl and tri- haloalkyl.
  • groups include but are not limited to, chloromethyl, iluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-ditluoroalkyl and 2- fluoroisobutyl.
  • a haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy , di- haloalkoxy and tri- haloalkoxy).
  • a halogen e.g., mono-haloalkoxy , di- haloalkoxy and tri- haloalkoxy.
  • groups include but are not limited to. chloromethoxy. fluoromethoxy, difluoromethoxy, trifluoromethoxy. chloro-fluoroalkyl. chloro- difluoroalkoxy and 2-fluoroisobutoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • a “sulfenyl” group refers to an "-SR" group in which R can be hydrogen, an alkyl. an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl, aryl. heteroaryl. heterocyclyl. cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R can be hydrogen, an alkyl. an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl, aryl. heteroaryl. heterocyclyl. cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a sulfenyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an "SO?R” group in which R can be the same as defined with respect to sulfenyl. A sulfony l may be substituted or unsubstituted.
  • An O-carboxy may be substituted or unsubstituted.
  • An ester and C-carboxy may be substituted or unsubstituted.
  • a thiocarbonyl may be substituted or unsubstituted.
  • a "trihalome hanesulfonyl” group refers to an "X 3 CSO?-" group wherein each X is a halogen.
  • a "trihalomethanesulfonamido” group refers to an "X 3 CS(0) 2 N(R A )-" group wiierein each X is a halogen, and A hydrogen, an alkyl, an alkenyl. an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alk i), aryl(alkyl), heteroaryl(alkyi) or heterocyclyl(alkyl).
  • amino refers to a -NH 2 group.
  • hydroxy refers to a -OH group.
  • a "cyano" group refers to a "-CN” group.
  • An "isocyanato” group refers to a "-NCO” group.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An “isothiocyanato” group refers to an " -NCS " ' group.
  • An "S-sulfonamido " group refers to a "-S0 2 N(R ⁇ R B ) " group in wfiich R A and R B can be independently hydrogen, an alkyl. an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl( alkyl) or heterocyclyi(alkyi).
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a "RS0 2 N( , ⁇ )-" group in which R and RA can be independently hydrogen, an alkyl, an alkenyl. an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocycly l, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R and RA can be independently hydrogen, an alkyl, an alkenyl. an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocycly l, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-sulfonamido may be substituted or unsubstituted.
  • An ' ⁇ -carbamy 1 " group refers to a
  • RB can be independently hydrogen, an alkyl. an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl, aryl, heteroaryl. heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyi may be substituted or unsubstituted.
  • An "O-thiocarbamy ' group refers to a "-OC ⁇ Si-NiR A R B ) ' " group in which RA and R
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • N-amido group refers to a group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl. aryl, heteroaryl, heterocyclyl. cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyi(alkyi).
  • R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl. aryl, heteroaryl, heterocyclyl. cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyi(alkyi).
  • An N-amido may be substituted or unsubstituted.
  • a urea may be substituted or unsubstituted.
  • ''halogen atom or "halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • interferon is used herein as is commonly understood by one of ordinary skill in the art.
  • types of interferons are known to those skilled in the art, such as Type 1 interferons, Type 2 interferons and Type 3 interferons.
  • a non-limiting list of examples include: alpha-interferons, beta- interferons, delta-interferons, gamma interferons, lambda interferons, omega-interferons, tau-interferons, x-interferons, consensus interferons and asialo-interferons.
  • Interferons can be pegylated.
  • types of type 1 interferons include interferon alpha 1 A, interferon alpha 1 B.
  • pegylated-interferon alpha 2b ABUFERON, Human Genome Sciences Novartis.
  • PEGINTRON Schering
  • recombinant interferon alpha 2b TNTRON A, Schering
  • pegylated interferon alpha 2b PEG-INTRON. Schering, V1RAFERONPEG, Schering), interferon beta- l a (REBIF, Serono, Inc.
  • type 2 interferons include interferon gamma 1. interferon gamma 2 and pegylated interferon gamma; and examples of type 3 interferons include interferon lambda 1 , interferon lambda 2 and interferon lambda 3.
  • substituents there may be one or more substituents present.
  • haloalkyi may include one or more of the same or different halogens.
  • C i -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • abbreviations for any protective groups, amino acids and other compounds are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 1 1 :942-944 ( 1972)).
  • amino acid' refers to any amino acid (both standard and non-standard amino acids), including, but not limited to. cc-amino acids, ⁇ - amino acids, ⁇ -amino acids and ⁇ -amino acids.
  • suitable amino acids include, but are not limited to. alanine, asparagine, aspartate, cysteine, glutamate, glutamine. glycine, proline, serine, tyrosine, arginine, histidine. isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
  • amino acids include, but are not limited to, ornithine, hypusine. 2-aminoisobutyric acid, dehydroalanine. gam ma-ami no butyric acid, citrulline, beta-alanine. alpha-ethyl-glycine. alpha-propyl-glycine and norleucine.
  • amino acid also includes amino acids wherein the main-chain carboxylic acid group has been converted to an ester group.
  • protecting group and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unw anted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way.
  • protecting groups include benzyl; substituted benzyl: alkylcarbonyls and alkoxycarbonyls (e.g.. t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylearbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g..).
  • alkylcarbonyls and alkoxycarbonyls e.g. t-butoxycarbonyl (BOC), acetyl, or isobutyryl
  • arylalkylearbonyls and arylalkoxycarbonyls e.g., benzyloxycarbonyl
  • substituted methyl ether e
  • esters e.g. benzoate ester
  • carbonates e.g. methoxymethylcarbonate
  • sulfonates e.g. tosylate or mesylate
  • acyclic ketal e.g.
  • cyclic ketals e.g., 1 ,3-dioxane, 1 ,3-dioxolanes, and those described herein
  • acyclic acctal e.g., those described herein
  • acyclic hemiacetal e.g., cyclic hemiacetal
  • cyclic dithioketals e.g., 1 ,3-dithiane or 1 ,3-dithiolane
  • orthoesters e.g., those described herein
  • triarylmethyl groups e.g., trityl; monomethoxytrityl (MMTr); 4.4'-dimethoxytrityl (DMTr); 4.4'.4"-trimethoxytrityl (TMTr); and those described herein).
  • salts refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamme, N-methyl-D-glucamine. tris(hydroxymethy l)methylamine, C]-C 7 alkylamine. cyclohexylamine. triethanolamine. ethylenediamine. and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamme, N-methyl-D-glucamine. tris(hydroxymethy l)methylamine, C]-C 7 alkyl
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • a group of items linked with the conjunction “and " should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or ' unless expressly stated otherwise.
  • a group of items linked with the conjunction Or should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or * unless expressly stated otherwise.
  • each center may independently be of -configuration or S-conllguration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • valencies are to be filled with hydrogens or isotopes thereof, e.g.. hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol. or the like.
  • the compounds described herein exist in unsolvated form.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as w 7 ell as solvated forms.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [0077] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
  • Some embodiments disclosed herein relate to a compound of Formula (1). or a pharmaceutically acceptable salt thereof, having the structure:
  • L can be selected from:
  • A can be selected from an optionally substituted cycloalkyl.
  • Y can be selected from an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroarvl and an optionally substituted heterocvclvl:
  • R , a , R , b , R l c and R l cl can be each independently hydrogen or an unsubstituted C alkyl; R 2a , R 2al , R 2b , R 2b l .
  • R 2c , R 2c l , R 2d and R 2d l can be each independently selected from hydrogen, an optionally substituted Ci -4 alkyl, an optionally substituted aryl(Ci -6 alkyl), an optionally substituted heterocyclyl(C i_ 6 alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl and hydroxy; or R 2a l can be hydrogen, and R l a and R 2a can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl.
  • R 2b l can be hydrogen, and R l b and R 2b can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl; -------- between X L A and X 2D represents a single or double bond between X L A and
  • X 2 ' 1 ; between X 2A and X 3A represents a single or double bond between X 2A and X JA ; provided that -------- between X L A and X 2A and between X 2 ' 1 and X JA cannot be both double bonds and at least one of is a double bond; when between X L D and X A represents a double bond and between X 2A and X 3A is a single bond, then X a can be N
  • R and R can be each independently selected from hydrogen, hydroxy, halogen, amino, an optionally substituted C M alkyl, an optionally substituted C 2 - 4 alkenyl, an optionally substituted C 2 - 4 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C i. 4 alkoxy, -O-carboxy, an optionally substituted heteroaryl, an optionally substituted
  • R 4a , R 4al , R 4 '' 2 and R 4dJ can be each independently hydrogen or an unsubstitutcd C 1 -4 alkyl;
  • R ' a and R ' " ] can be each independently be hydrogen or an unsubstituted C alkyl;
  • R 6a and R 6a l can be each independently hydrogen, an optionally substituted C alkyl or an optionally substituted alkoxyalkyl;
  • R 6a2 and R 6aj can be each independently hydrogen or an
  • L can be Formula (la):
  • X L A can be CR 4A L or CR 4A2 R 4A3
  • X A can be N (nitrogen)
  • X can be CR A or CR 6A2 R 6AJ .
  • Formula (la) In some embodiments of Formula (la), X L A can be CR 4A L or CR 4A2 R 4A3 , X A can be N (nitrogen), and X , can be CR A or CR 6A2 R 6AJ .
  • R SA L can be hydrogen.
  • L of Formula (la) can be Formula (lal ):
  • X 2A and X 3A are uncharged.
  • X L A can be C.
  • X 2A can be N and
  • X "' can be C.
  • between X L A and X 2A can be a single bond.
  • between X A and X JA can be a double bond, X L A can be C, X 2A can be N and X ',A can be C.
  • between X and X 2A can be a double bond, between X 2A and X 3D can be a single bond.
  • X L D can be C.
  • X 2A can be
  • N and X '1 ' 1 can be C.
  • X L D and X L D can be C.
  • X 2D can be a single bond, -------- between X 2A and X ⁇ ' D can be a single bond, X 1 ' 1 can be C, X 2A can be O and X ',D can be C.
  • the valencies of X L A , X 2A and X A can be each independently satisfied with hydrogen or an unsubstituted C alkyl, such as CFF 3 ⁇ 4 .
  • the ring or ring system of Formula (lal) can be an optionally substituted aryl. In other embodiments, the ring or ring system of Formula (lal ) can be an optionally substituted mono-cyclic heteroaryl. In still other embodiments, the ring or ring system of Formula (lal ) can be an optionally substituted bi-cyclic heteroaryl. In some embodiments, the ring or ring system of Formula (lal ) can be an optionally substituted monocyclic heterocyclyl. In some embodiments, the ring or ring system of Formula (lal ) can be an optionally substituted bi-cyclic heterocyclyl.
  • R A3 and R A4 can be each independently hydrogen or an unsubstituted C i -6 alkvl. 2a
  • substituted be substituted with one or more substituents selected from amino, mono-substituted amino, di-substituted amino, hvdroxyalkyl, alkyl and alkoxy. In some embodiment can be
  • R ja can e hydroxy and R jal can be selected from amino, an unsubstituted C alkyl. an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C 3-6 cycloalkyl (for example, cyclopropyl). an unsubstituted C M alkoxy (such as OCH 3 ). hydroxy, halogen and an unsubstituted heteroary l (for example, thiazole).
  • R 3a l is OH. then is not an unsubstituted In other embodiments, when one of R 3a and R 3a l is H, then the other of R 3a and R 3al is not OH.
  • L of Formula (la) can be Formula (Ia2):
  • R 7a l , R' 1 ' 2 and R' 11J can be each independently selected from hydrogen, halogen, hydroxy, an optionally substituted C i -8 alkyl, an optionally substituted C2-8 alkenyl, an optionally substituted C2-8 alkynyl. an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl. an optionally substituted heteroaryl, an optionally substituted heterocyclyl.
  • R 7a l can be an unsubstituted C
  • R 7al can be a substituted C
  • R 7a l can be hydrogen
  • R /a2 can be an optionally substituted C
  • R /a3 can be hydrogen.
  • R 7d l can be hydrogen
  • R 7d2 can be a substituted C 3-6 cycloalkyl
  • R" can be hydrogen.
  • R 7al can be hydrogen.
  • R' a2 can be a mono- substituted amino
  • R 7d3 can be hydrogen.
  • the mono-substituted amino of R 7a l or R 7a2 can be -N(Ci-4 alkyl). such as -NCH 3 .
  • R 7a l can be a substituted Ci -8 alky 1 (such as an amino substituted Ci -8 alkyl) and R 7a2 and R 7aj can be both hydrogen.
  • R 7a l and R 7a2 can be both hydrogen and R 7aj can be halogen.
  • R 7d l and R 7a3 can be both hydrogen and R 7a2 can be an optionally substituted heterocyclyl, such as an optionally substituted mono-cyclic heterocyclyl.
  • optionally substituted mono-cyclic heterocyclyl at R 7a2 include, but are not limited to, an optionally substituted azetidine, an optionally substituted pyrrolidine, an optionally substituted pyrrolidinone, an optionally substituted piperidine and an optionally substituted oxetane.
  • R 7al , R 7a2 and/or R 7a3 are substituted, possible substituent(s) includes those provided in the list of "substituted *' along with urea, amidine and acetylurea.
  • the C alkyl, C 3-6 cycloalkyl and mono-cyclic heterocyclyl of R 7a2 can be substituted with various substituent(s), such as, halo, hydroxy, C M alkoxy, an optionally substituted aryl(C i _4 alkyl), an optionally substituted C-carboxy, amino, an optionally substituted mono-substituted amino, an optionally substituted di -substituted amino, an optionally substituted C-amido, an optionally substituted N-amido, an optionally substituted N-carbamyl, an optionally substituted N-sulfonamido, an optionally substituted urea, an optionally substituted amidine and an optionally substituted
  • L of Formula (la) can be Formula (Ia3):
  • R 8aj can be selected from hydrogen, halogen, hydroxy, an optionally substituted Ci-s alkyl, an optionally substituted C 2 - x alkenyl. an optionally substituted C 2 -8 alkynyl. an optionally substituted C3-6 cycloalkyl. an optionally substituted aryl. an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered cycloalkyl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered cycloalkyl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted aryl (for example, phenyl).
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heteroaryl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered heteroaryl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heterocyclyl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6- membered heterocyclyl.
  • the bicyclic ring system can be selected from an
  • each R A? . each R rt °. each R A ' can be halogen, an unsubstituted C
  • -6 alkyl, hydroxy, amino, an optionally substituted mono-substituted amino, an optionally substituted di- substituted amino, -(CH 2 )i_ 4 0H, -(CH 2 )i -4NH2 or N-sulfmamido (for example, -NH- S( 0)C alkyl), or two R A ⁇ two R A6 or two R A7 are taken together to form an optionally substituted 5- membered ring to an optionally substituted 6-membered ring (such as an optionally substituted cvcloalkvl or an optionally substituted heterocyclyl); and R A8 can be hydrogen or an unsubstituted C i -6 alkyl.
  • At least two R A: ⁇ groups can be an unsubstituted Ci -6 alkyl (for example, CH 3 ).
  • at least two R A6 groups can be an unsubstituted C
  • R a can be hydrogen.
  • R l d can be an unsubstituted C i -4 alkyl.
  • both R 2a and R 2a l can be hydrogen.
  • R 2a can be hydrogen and R 2al can be an unsubstituted C alkyl.
  • R 2a can be hydrogen and R 2a l can be a substituted C M alkyl.
  • R 2a can be hydrogen and R 2al can be an optionally substituted aryl(C
  • R 2a can be hydrogen and R 2dl can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl.
  • R 2d can be hydrogen and R 2al can be hydroxy .
  • R 2a l can be hydrogen, and R l a and R 2 can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl (for example, pyrrolidinyl) or an optionally substituted 6 membered heterocyclyl (for example, piperdinyl).
  • R and both can be an optionally substituted C alkyl.
  • R 3a can be hydrogen, and R "ia l can be selected from amino, an unsubstituted C M alkyl, an unsubstituted C2-4 alkenyi. an unsubstituted C2-4 alkynyl, an unsubstituted C3.6 cycloalkyl (for example, cyclopropyl), an unsubstituted C alkoxy (such as OCH 3 ).
  • R ja can be hydrogen, and R jal can be unsubstituted C alkyl.
  • R jal can be unsubstituted C alkyl.
  • R"' can be hydroxy, and R 3d l can be selected from amino, an unsubstituted C alkyl, an unsubstituted C2-4 alkenyl.
  • R ja can be hydroxy
  • R ⁇ 1dl can be an unsubstituted C alkyl.
  • R ja can be hydroxy
  • R ,al can be an unsubstituted C 2-4 alkenyl (such as ethenyl or propenyl) or an unsubstituted C 2-4 alkynyl (such as ethynyl or propynyl).
  • R ,a can be hydroxy
  • R ' dl can be CF 3 .
  • R ja can be hydroxy, and R 3a l can be CHF 2 .
  • R' a can be halogen, and R ,al can be CF 3 or CHF 2 .
  • R ia can be halogen
  • R ja l can be CHF2.
  • R"' can be hydroxy
  • R 3d l can be an unsubstituted C 3-6 cycloalkyl. for example, an unsubstituted cyclopropyl.
  • R" 1 can be halogen
  • R ⁇ 1d l can be an unsubstituted C 3-6 cycloalkyl, for example, an unsubstituted cyclopropyl.
  • R' d can be an unsubstituted C M alkoxy (such as methoxy)
  • R ",a l can be an unsubstituted C alkyl (such as methyl).
  • R 1d and R ial can be both an unsubstituted C M alkyl, for example, R ja and R ,al can be both methyl.
  • one of R ia and R' dl can be an optionally substituted mono-cyclic heteroaryl; and the other of R 3a and R a I can be hydroxy.
  • R 3a and R 3al are a substituted C alkyl
  • the C M alkyl can be substituted with various substituents.
  • one of R ,a and R is a substituted C ] _ 4 alkyl substituted with substituent selected from halogen, hydroxy, amino, mono-substituted amino (for example, -NH(C M alkyl)). di-substituted amino, -N- amido. mono-cyclic heteroaiyl and mono-cyclic heterocyclyl.
  • one of R' a and R j l can be an optionally substituted mono-cyclic heteroaryl or an optionally substituted mono-cyclic heterocyclyl and the other of R 3a and R '1 ' 1 ' can be hydroxy.
  • the mono-cyclic heteroaryl substituted on the C alkyl of one of R 3a and R ja l can be 5- membered or 6-membered heteroaryl.
  • the mono-cyclic heterocyclyl substituted on the C alkyl of one of R ia and R '1 ' 1 ' can be 4-membered, 5-membered or 6-membered heterocyclyl.
  • one of R ja and R ,a l can be a substituted C alkyl substituted with substituent selected from an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperazinc, an optionally substituted morpholine, an optionally substituted triazole, an optionally substituted piperazinone and an optionally substituted azetidine.
  • R ',d and R '1 ' 1 ' can join together with the atom to which they are attached to form an optionally substituted 3 to 6 membered ring.
  • the 3 to 6 membered ring can be a C 3-6 cycloalkyi.
  • the ring can be a 3 to 6 membered heterocyclyl, for example, an optionally substituted oxetane or an optionally substituted oxazolidinone.
  • the carbon to which R ,a and R ,dl are attached can be a chiral center.
  • the carbon to which R ja and R ia l are attached a chiral center
  • the carbon to which R ja and R ia l are attached can have a (R)-configuration.
  • the carbon to which R ,a and R' al are attached can have a (S)-configuration.
  • L of Formula (I) can be Formula (lb):
  • X B and X JB can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C i_4 alkyl; and X L B , X 2B and X 3B are uncharged.
  • the valencies of X l b , X 2b and X jb can be each independently satisfied with a substituent selected from hydrogen and an unsubstituted C alkyl.
  • the valencies of X L B , X 2B and X 3B can be each independently satisfied with hydrogen or methyl.
  • the bi-cyclic ring can be an optionally substituted 9-membered bi-cyclic heteroaryl. In other embodiments of Formula (lb), the bi-cyclic ring can be an optionally substituted 9-membered bi-cyclic heterocyclyl. In still other embodiments of Formula (lb), the bi-cyclic ring can be an optionally substituted 10-membered bi-cyclic heteroaryl. In yet still some embodiments of Formula (lb), the bi- cyclic ring can be an optionally substituted 10-membered bi-cyclic heterocyclyl.
  • the bi-cyclic ring can be an optionally substituted bi-cyclic heteroaryl ring.
  • X 2b when X l b can be C, X 2b can be N and X 3b can be C, the bi-cyclic ring can be an optionally substituted bi-cyclic heterocyclyl ring.
  • L of Formula (lb) can be Formula (Ibl ):
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl; and R 4b3 can be selected from hydrogen, halogen, hydroxy, an optionally substituted Ci -8 alkyl, an optionally substituted C 2- 8 alkenyl, an optionally substituted C 2- 8 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl. an optionally substituted heteroaryl. an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl.
  • Ci -8 alkoxy an optionally substituted Ci -8 alkoxy, an optionally substituted alkoxyalkyl. amino, mono-substituted amino, di-substituted amino. halo(C ] _8 alkyl), haloalkyl and an optionally substituted C-carboxy.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered cycloalkenyl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered cycloalkenyl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted aryl (for example, pheny l). In some embodiments of Formula (Ib l ).
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heteroaryl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered heteroary .
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heterocyclyl.
  • the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6- membered heterocyclyl.
  • the bi-c scrap rin s stem can be selected from an
  • At least two R B2 groups can be an unsubstituted C
  • at least two R Bj groups can be an unsubstituted Ci -6 alkyl (for example, CII ). Examples of these bi- cyclic groups include the following:
  • R lb can be hydrogen
  • both R 2 and R 2bl can be hydrogen.
  • R 2b can be hydrogen and R 2bl can be an unsubstituted CM alkyl.
  • R 2b can be hydrogen and R bl can be a substituted C alkyl.
  • R 2b can be hydrogen and R 2bl can be an optionally substituted aryl(Ci-6 alkyl) or an optionally substituted heterocyclyl(Ci -6 alkyl).
  • R b can be hydrogen and R bl can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl.
  • R 2b can be hydrogen and R 2bl can be hydroxy.
  • R bl can be hydrogen, and R l b and R 2b can be joined together with the atoms to which they are attached to form an optionally substituted 5 mcmbercd hcterocyclyl or an optionally substituted 6 membered heterocyclyl.
  • R L C can be hydrogen.
  • R K can be an unsubstituted C alkyl.
  • both R 2 and R 2 L can be hy drogen.
  • R 2C can be hydrogen and R C L can be an unsubstituted C M alkyl.
  • R 2 ° can be hydrogen and R C L can be a substituted C M alkyl.
  • R 2l can be hydrogen and R 2U can be an optionally substituted aryl(C i_ 6 alkyl) or an optionally substituted heterocyclyl(C i -6 alkyl).
  • R 2l can be hydrogen and R 2C L can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl.
  • R 2c can be hydrogen and R 2c 1 can be hydroxy.
  • R' c and R- c l both can be an optionally substituted C alkyl.
  • R ,c can be hydrogen, and R ,c l can be selected from amino, an unsubstituted C alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 2-4 alkynyl, an unsubstituted C 3-6 cycloalkyl (for example, cyclopropyl), an unsubstituted C M alkoxy (such as OCH 3 ), hydroxy, halogen and an unsubstituted heteroaryl (for example, thiazole).
  • R ' c can be hydrogen, and R JC
  • R JC and R ,c l can be both halogen.
  • R JC can be hydrogen
  • R ' cl can be unsubstituted C M alkyl.
  • R JL can be hydroxy
  • R JL l can be selected from amino, an unsubstituted C M alkyl.
  • R J can be hydroxy
  • R jU can be an unsubstituted C alkyl.
  • R JC and R jc l can join together with the atom to which they are attached to form an optionally substituted 3 to 6 membered ring.
  • the 3 to 6 membered ring can be a C 3-6 cycloalkyl.
  • the ring can be a 3 to 6 membered heterocyclyl. for example, an optionally substituted oxetane.
  • the carbon to which R '1L and R ⁇ 1L l are attached can be a chiral center. When the carbon to which R 3t and R 3e 1 are attached a chiral center, in some embodiments, the carbon can have a ( Reconfiguration. In other embodiments, the carbon to which R 1C and R ",c l are attached can have a (S)-configuration.
  • Z c can be N. In some embodiments of Formula (Ic), Z c can be CH.
  • R 4c and R '1C can be taken together to form an unsubstituted aryl (for example, pheny l).
  • R 4c and R 5c can be taken together to form an unsubstituted heteroaryl, such as piperdinyl.
  • R 4 and R ? can be taken together to form an optionally substituted heterocyclyl.
  • the optionally substituted heterocyclyl can be an optionally substituted tricyclic heterocyclyl, such as an optionally
  • L can be Formula (Id):
  • l d can be hydrogen. In other embodiments of Formula (Id ). R l d can be an unsubstituted C alkyl.
  • both R 2d and R 2d l can be hydrogen.
  • R 2d can be hydrogen and R 2c " can be an unsubstituted C
  • R 2d can be hydrogen and R d l can be a substituted C alkyl.
  • R d can be hydrogen and R 2d l can be an optionally substituted aryl(Ci -6 alkyl) or an optionally substituted hctcrocyclyl(C i -6 alkyl).
  • R 2d can be hydrogen and R 2 " can be an alkoxyalkyl. an aminoalkyl or a hydroxyalkyl. In other embodiments of Formula (Id). R 2d can be hydrogen and R 2d l can be hydroxy. In still other embodiments of Formula (Id), R 2d and R 2d l both can be an optionally substituted C alky l.
  • m d can be 0. In other embodiments of Formula (Id). m d can be 1 .
  • ring B d can be an optionally substituted C 5 cycloalkyl.
  • ring D d can be an optionally substituted
  • ring B d l can be an optionally
  • substituted pyridinyl having the structure
  • the C 5 cycloalkyl and/or pvridinyl ring can be unsubstituted or substituted with one or more substituents.
  • Suitable substituents include, but are not limited to, amino, mono-substituted amino, di-substituted amino, hydroxyalkyl, alkyl and alkoxy. [0118]
  • A can be substituted.
  • A can be unsubstituted.
  • possible substituent(s) includes those provided in the list of "substituted" along with those described herein.
  • A can be an optionally substituted aryl.
  • A can be an optionally substituted phenyl.
  • A can be a para- substituted phenyl, a meta-substituted phenyl or an ortho-substituted phenyl.
  • A can be unsubstituted phenyl. In some embodiments, A can be an optionally substituted naphthyl.
  • A can be a phenyl substituted with one or more substituents selected from an unsubstituted C alkyl, an optionally substituted C M alkyl, cycloalkyl, hydroxy, an optionally substituted C alkoxy, C M alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, mono- substituted amino, di-substituted amino, -O-amido, sulfenyl, alkyoxyalkyl, an optionally substituted aryl (for example, an optionally substituted phenyl), an optionally substituted monocyclic heteroaryl.
  • substituents selected from an unsubstituted C alkyl, an optionally substituted C M alkyl, cycloalkyl, hydroxy, an optionally substituted C alkoxy, C M alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, mono
  • an optionally substituted monocyclic heterocyclyl an optionally substituted aryl (C alky l), an optionally substituted monocyclic heteroaryl(C
  • the optionally substituted C M alkoxy can be further substituted, for example, further substituted with a substituent selected from C alkyl, halo, hydroxy, C- carboxy, C-amido. amino, mono-alkyl amine, di-alkyl amine and an amino acid.
  • the optionally substituted haloalkoxy can be further substituted, for example. further substituted with an C
  • the optionally substituted heteroaryl can be further substituted, for example, further substituted with an C alkyl.
  • substituents include, but are not limited to, methyl, ethyl, propyl (n-propyl and iso-propyl). butyl (n-butyl, iso-butyl and t-butyl). hydroxy, methoxy , ethoxy . propoxy (n-propoxy and iso-propoxy), butoxy (n-butoxy , iso-butoxy and t- butoxy ). phenoxy. bromo, chloro, fluoro, trifluoromethyl, difluoromethoxy , trifluoromethoxy. cyano, N,N-di-methyl-amine, N.N-di-ethyl-amine.
  • N-methyl-N-ethyl-amine N-methyl- amino.
  • alkylthio such as CH 3 CH 2 S-
  • N-sulfonamido for example, -NH-S(0) 2 C M alkyl
  • an optionally substituted phenyl an optionally substituted imidazole, an optionally substituted morpholinyl, an optionally substituted pyrazole, an optionally substituted pyrrolidinyl.
  • an optionally substituted pyridinyl an optionally substituted piperidinyl, an optionally substituted piperidinone, an optionally substituted pyrrolidinone, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted 1 ,2,4-oxadiazole, -(CH 2 ) M-OH, - (CH 2 )i- -NH(CH 3 ), an optionally substituted -(CH )i -2 -imidazole, an optionally substituted - (CH2) i-2-pyn * olidinone, an optionally substituted -(CH 2 ) i -2 -imidazolidinone.
  • an optionally substituted -O(CH 2 ) 0-2 -imidazole an optionally substituted -O(CH 2 ) 0-2 -pyrazole, an optionally substituted -O(CH 2 ) 0-2 -tetrahydrofuran, an optionally substituted - 0 CH 2 )o -2 -pyrrolidinone, an optionally substituted -O(CH 2 ) 0-2 -tetrazole, an optionally
  • A can be an optionally substituted cycloalkyl. Suitable examples of optionally substituted cycloalkyls include, but are not limited to, an optionally substituted cyclohexyl and an optionally substituted cycloheptyl. In other embodiments, A can be an optionally substituted cyeloalkenyl, for example, an optionally substituted cy embodiments, A can be an optionally substituted bi-cyclic
  • A can be an optionally substituted aryl(C i-2 alkyl). In some embodiments. A can be an optionally substituted benzyl.
  • A can be an optionally substituted mono-cyclic heteroaryl. In some embodiments, A can be an optionally substituted mono-cyclic 5- membered heteroaryl. In other embodiments, A can be an optionally substituted mono-cyclic 6-membered heteroaryl. In some embodiments, A can be an optionally substituted bi-cyclic heteroaryl.
  • the optionally substituted heteroaryl can be selected from an optionally substituted imidazole, an optionally substituted thiazole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted pyridine, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted quinoline, an optionally substituted imidazole, an optionally substituted oxazole, an optionally substituted isoxazole, an optionally substituted benzoimidazole.
  • A can be an optionally substituted benzooxazole, an optionally substituted benzothiazole and an optionally substituted imidazo[l ,2-a]pyrimidine.
  • A can be an optionally substituted thiophene.
  • A can be an optionally substituted thiazole.
  • A can be an optionally substituted pyridine.
  • A can be an optionally substituted pyrimidine.
  • A can be an optionally substituted pyrazine.
  • A can be an optionally substituted imidazole.
  • A can be an optionally substituted benzoimidazole. an optionally substituted benzooxazole or an optionally substituted benzothiazole.
  • A can be an optionally substituted heterocyclyl, for example, an optionally substituted mono-cyclic heterocyclyl or an optionally substituted bi- cyclic heterocyclyl. In some embodiments, A can be an optionally substituted
  • A can be an optionally substituted
  • A can be an optionally substituted
  • A can be an optionally substituted In some embodiments.
  • A can be an optionally substituted . In other embodiments, A can be an optionally s In still other embodiments. A can be an
  • A can be an
  • A can be an optionally e embodiments.
  • A can be an optionally
  • A can be substituted with one or more R 's.
  • one R A can be present.
  • two R A" s can be present.
  • three R A 's can be present.
  • four or more R A, s can be present.
  • two or more R A* s are present, two or more R A, s can be the same or two or more R A, s can be different.
  • at least two R A, s can be the same.
  • at least two R A" s can be different.
  • all the R A, s can be the same. In other embodiments, all the R A, s can be different. In some embodiments.
  • R can be each independently selected from an unsubstituted C alkyl, an optionally substituted C M alkyl, cycloalkyl, hydroxy, an optionally substituted C alkoxy, C M alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, mono-substituted amino, di-substituted amine, sulfenyl, alkyoxyalkyl, aryl, monocyclic heteroaryl. monocyclic heterocycly l and aminoalky l.
  • -4 alkoxy can be further substituted, for example, further substituted with a substituent selected from C alkyl, halo, hydroxy, C-carboxy, C- amido. N-amido. amino, mono-alkyl amine, di-alkyl amine and an amino acid.
  • the optionally substituted haloalkoxy can be further substituted, for example, further substituted with an C M alkoxy.
  • the optionally substituted heteroaryl can be further substituted, for example, further substituted with an C M alkyl.
  • each R A can be an alkyl. such as methyl, ethyl, propyl (n -propyl and iso-propyl) and/or butyl (n-butyl. iso-butyl and t-butyl).
  • each R A can be an optionally substituted alkoxy. for example, methoxy, ethoxy, propoxv (n-propoxy and iso-propoxy). butoxy (n-butoxy. iso- butox and t-butoxy), phenoxy, -0(CH 2 ) 2 -NH 2 , -0(CH 2 ) 2 -NH(CH 3 ), -0(CH 2 ) 2 -N(CH 3 ) 2 , -O-
  • an optionally substituted -O(CH 2 ) 0-2 -morpholinyl an optionally substituted -O(CH 2 ) 0-2 - triazole, an optionally substituted -0(CH2)o-2-iniidazole, an optionally substituted -O(CH 2 ) 0 _ 2 - cyclopentanone, an optionally substituted -0(CH 2 )o -2 pyiTolidinone, an optionally substituted - 0(CH 2 )o- 2 -pyrazole, an optionally substituted -O(CH 2 ) 0-2 -tetrahydrofuran, an optionally substituted -0(CH 2 )o- 2 -pynOlidinone, an optionall substituted -0(CH?)o- 2 -tetrazole.
  • R can be substituted C i -6 alkoxy substituted by one or more of the following: halo, hydroxy, CV 4 alkyi. cyano, amino, mono-substituted amino, di-substituted amino, sulionamidocarbonvl, hydroxamidine, C-amido, acyi, C-carboxy, O-carboxy, sulfonyl, S-sulfonamido, O-linked amino acid and carbonate ester.
  • each R A can be haloalkyl, for example, trifluoromethyl.
  • each R A can be an optionally substituted haloalkox for example, difluoromethoxy, trifluoromethoxy, ? ,
  • each R A can be halogen, for example, chloro. bromo and/or fluoro.
  • each R A can be amino, a mono-substituted amine or a di-substituted amine.
  • R A can be N,N-di-methyi-amine.
  • each R A can be hydroxy.
  • each R A can be alkylthio, for example ethvlthio.
  • each R A can be aminoalkyl, such as -(CH 2 ) i -2 - NH(CH 3 ).
  • each R A can be alkoxyalkyl. for example, -CH 2 -O-
  • each R A can be an optionally substituted aryl(C
  • Non-limiting examples include an optionally substituted -(CH2)i-2-imidazole, an optionally substituted -(CH2)i-2-pynOlidinonc, an optionally substituted -(CH?)i-2-imidaz.olidinone.
  • each R A can be hydroxyalkyl. for example. -(CH 2 )i_
  • each R A can be -O-amido, for example, H 2 N f ,
  • each R can be -N-amido. for example, O
  • each R A can be -N-sulfonamido, for example,
  • each R A can be aminoalkyl. for example, -CH 2 - NH 2 and/or -CH 2 -N(CH 3 )H.
  • each R A can be an optionally substituted aryl, for example, an optionally substituted phenyl.
  • each R A can be an optionally substituted monocyclic heteroaryl, such as an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted pyridinyl, an optionally substituted pyrimidine, an optionally substituted pyrazine and/or an optionally substituted 1 ,2,4-oxadiazole.
  • an optionally substituted monocyclic heteroaryl such as an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted pyridinyl, an optionally substituted pyrimidine, an optionally substituted pyrazine and/or an optionally substituted 1 ,2,4-oxadiazole.
  • each R A can be an optionally substituted monocyclic heterocyclyl, for example, an optionally substituted pyrrolidinyl, an optionally substituted piperidinyl, an optionally substituted morpholinyl and/or an optionally substituted pyrrolidinone.
  • Y can be an optionally substituted ary l.
  • Y can be a para-substituted phenyl, a meta-substituted phenyl or an ortho- substituted phenyl.
  • Y can be a mono-substituted phenyl, such as a mono-halo substituted phenyl.
  • Y can be a di-substituted pheny l, for example a di-halo substituted phenyl.
  • mono-halo substituted phenyls and di- an be di-substituted
  • Y can be a substituted phenyl that is substituted with 3 more substituents.
  • Y can be unsubstituted phenyl.
  • Y can be a substituted naphthyl.
  • Y can be an unsubstituted naphthyl.
  • Y can be an optionally substituted cycloalkyl (e.g., an optionally substituted cyclohexyl and an optionally substituted cycloheptyl).
  • Y can be an optionally substituted cycloalkenyl, for example, an optionally substituted cyclohexenyl.
  • Y can be an optionally substituted bi-cyclic
  • Y can be an optionally substituted mono-cyclic heteroarvl.
  • Y can be selected from an optionally substituted imidazole, an optionally substituted furan. an optionally substituted thiophene. an optionally substituted pyrrole, an optionally substituted pyrimidine. an optionally substituted pyrazine. an optionally substituted pyridine, an optionally substituted pyrazole, an optionally substituted oxazole and an optionally substituted isoxazole.
  • Y can be a substituted mono-cyclic heteroarvl, including those described herein.
  • Y can be an unsubstituted mono-cyclic heteroarvl, including those described herein. [0151] In some embodiments, Y can be an optionally substituted bi-cyclic heteroaryl. In some embodiments, Y can be selected from an optionally substituted benzothiophene. an optionally substituted benzofuran, an optionally substituted indole, an optionally substituted quinoline, an optionally substituted isoquinoline. an optionally substituted benzooxazole. an optionally substituted benzoisoxazole. an optionally substituted benzoisothiazole. an optionally substituted benzothiazole, an optionally substituted benzoimidazole. an optionally substituted benzotriazole. an optionally substituted 1 H- indazole and an optionally substituted 2H-indazole. In some embodiments, Y can be selected from an optionally substituted benzothiophene. an optionally substituted benzofuran, an optionally substituted indole
  • Y can be an unsubstituted bi-cyclic heteroaryl, including those described herein.
  • Y can be an optionally substituted heterocyclyl. In some embodiments. Y can be an optionally substituted mono-cyclic heterocyclyl, such as an optionally substituted pyridinone. In other embodiment, Y can be an optionally substituted disrupt heterocyclyl.
  • each R u can be independently selected from cyano, halogen, an optionally substituted C alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 2 - 4 alkynyl. an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroaryl. an optionally substituted 5 or 6 membered heterocyclyl, hydroxy, C alkoxy. alkoxyalkyl, C 1 .
  • the phenyl when Y is an optionally substituted phenyl, the phenyl can be substituted 1 , 2, 3 or more times with cyano, halogen, an optionally substituted C M alkyl- an unsubstituted C 2-4 alkenyl, an unsubstituted C7- 4 alkynyl, an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroary l, an optionally substituted 5 or 6 membered heterocyclyl. hydroxy. C alkoxy, C M haloalky l (such as CF 3 . CHF 2 ), haloalkoxy (such as OCF 3 ), an unsubstituted acyl. an optionally substituted -C- carboxy, an optionally substituted -C-amido. sulfonyl, amino, mono-C i- 4 alkyl amine, di-Ci -4
  • alkyl amine an when Y is an optionally substituted mono-cyclic heteroaryl, the mono-cyclic heteroaryl can be substituted 1 , 2, 3 or more times with halo, an optionally substituted C alkyl, an optionally substituted phenyl and/or an unsubstituted acyl.
  • the bi-cyclic heteroaryl when Y is an optionally substituted bi-cyclic heteroaryl, can be substituted 1 , 2, 3 or more times with halo, an optionally substituted CM alkyl, an optionally substituted phenyl, hydroxy, CV 4 alkoxy, an unsubstituted acyl. carbonyl, cyano, amino, mono-C i-4 alkyl amine and/or di-Ci -4 alkyl amine.
  • Y can be an optionally substituted benzothiophene. In some embodiments, Y can be a substituted benzothiophene. In other embodiments, Y can be an unsubstituted benzothiophene. In some embodiments, the benzothiophene can be substituted with one or more of the following: halogen (such as fluoro. chloro and/or bromo), carbonyl. C M alkyl, hydroxy. C alkoxy, NH 2 and/or mon -substituted amine. For
  • Y can be an optionally substituted benzofuran.
  • Y can be an optionally substituted indole. In some embodiments, Y can be a substituted indole. In some embodiments, the indole can be substituted 1. 2, 3 or more time with phenyl (substituted or unsubstituted). C alkyl and/or halo. In other embodiments. Y can be an unsubstituted indole.
  • Y can be substituted with one or more halogen. In some embodiments, Y can be substituted with one or more unsubstituted C alkyl. In some embodiments, Y can be substituted with more or more hydroxy. In some embodiments, Y can be substituted with one or more optionally substituted phenyl. In some embodiments, Y can be substituted with one or more alkoxy. In some embodiments, Y can be substituted with one or more acyl. In some embodiments, Y can be substituted with one or more amino, mono-substituted amino, or di-substitutcd amino. In some embodiments, Y can be substituted with one or more haloalkyl.
  • Y can be substituted with one or more haloalkoxy. In some embodiments, Y can be substituted with one or more C- carboxy. In some embodiments. Y can be substituted with one or more C-amido. In some embodiments, Y can be substituted with one or more hydroxyalkyl.
  • a compound of Formula (I) can be selected from the following compounds: 1, 1 -1, 100.101, 102.103.105, 106.107, 108, 109.110, 111. 112, 113, 114, 115, 116, 116a, 116 b, 117.
  • a compound of Formula (1) can be selected from: 149, 150, 156. 157, 160, 217, 220, 222, 229, 287, 302, 303, 304, 305, 31 1, 401 , 473 and 474. or a pharmaceutically acceptable salt of the foregoing.
  • a compound of Formula (1) can be selected from: 130, 135, 140 and 141 , or a pharmaceutically acceptable salt of the foregoing.
  • a compound of Formula (I) can be 104 or 161 , or a pharmaceutically acceptable salt of the foregoing.
  • a compound of Formula (I) can be 136 or 137, or a pharmaceutically acceptable salt of the foregoing.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof cannot be a compound provided in PCT Publication WO 2014/031784, published February 27. 2014.
  • compositions that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • compositions refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethancsulfonic acid, p-toluencsulfonic acid, and salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • physiologically acceptable defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
  • an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc.. to the composition.
  • a “diluent” is a type of excipient.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
  • the pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterfoils.
  • a targeted drug delivery system for example, in a liposome coated with a tissue-specific antibody.
  • the liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory infection may be desirable.
  • compositions may. if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use. or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary 7 administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Methods of Use
  • Some embodiments described herein relate to a method for ameliorating, treating and/or preventing a paramyxovirus viral infection, which can comprise administering an effective amount of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof).
  • Some embodiments described herein relate to a method for inhibiting viral replication of a paramyxovirus, which can comprise contacting a cell infected with the virus with an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Some embodiments described herein relate to a method for contacting a cell infected with a paramyxovirus, which can comprise contacting a cell infected with the virus with an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof).
  • the paramyxovirus infection is a human respiratory syncytial virus infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a respiratory syncytial viral infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a respiratory syncytial viral infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the replication a respiratory syncytial virus.
  • an effective amount of one or more compounds of Formula (1). or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutical ly acceptable salt thereof) can be used to inhibit the RSV polymerase complex.
  • the RSV can be RSV A.
  • the RSV can be RSV B.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a hendraviral infection and/or nipahviral infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to prevent a hendraviral infection and/or nipahviral infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the replication a hendravirus and/or nipahvirus.
  • an effective amount of one or more compounds of Formula ( ⁇ ), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula ( ⁇ ), or a pharmaceutically acceptable salt thereof) can be used to inhibit the hendravirus polymerase complex and/or nipahvirus polymerase complex.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to treat and/or ameliorate a measles.
  • an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to prevent a measles.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the measles polymerase complex.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to treat and/or ameliorate mumps.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to prevent mumps.
  • an effective amount of one or more compounds of Formula ( ⁇ ), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the replication a mumps virus.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the mumps polymerase complex.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to treat and/or ameliorate a sendai viral infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to prevent a sendai viral infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a sendai virus.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be used to inhibit the sendai virus polymerase complex.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to treat and/or ameliorate a HPIV-1 infection and/or HPIV-3 infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to prevent a HPIV- 1 infection and/or HPIV-3 infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the replication of a HPIV-1 and/or HPIV-3.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the HPIV-1 polymerase complex and/or HPIV-3 polymerase complex.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to treat and/or ameliorate a HPIV-2 infection and/or HPIV-4 infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to prevent a HPIV-2 infection and/or FIPIV-4 infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the replication of a HPIV-2 and/or HPIV-4.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the HPIV-2 polymerase complex and/or HPIV-4 polymerase complex.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to treat and/or ameliorate a human metapneumoviral infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to prevent a human metapneumoviral infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the replication of a human metapneumovirus.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the human metapneumovirus polymerase complex.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used treat and/or ameliorate an upper respiratory viral infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus. and a metapneumovirus.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein e.g..
  • a compound of Formula (1) can be used treat and/or ameliorate a lower respiratory viral infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, and a metapneumovirus.
  • a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, and a metapneumovirus.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate one or more symptoms of an infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, and a metapneumovirus (such as those described herein).
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate an upper respiratory viral infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus.
  • an effective amount of one or more compounds of Formula (1) can be used treat and/or ameliorate an upper respiratory viral infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus.
  • a pharmaceutical composition that includes one or more compounds described herein can be used treat and/or ameliorate a lower respirator ⁇ 7 viral infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus.
  • an effective amount of one or more compounds of Formula ( ), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate one or more symptoms of an infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus (such as those described herein).
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitis due to a RSV infection and/or human parainfluenza virus 3 (HPIV-3) infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate pneumonia due to a RSV infection and/or human parainfluenza virus 3 (HPIV-3) infection
  • an effective amount of one or more compounds of Formula (f), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate croup due to a RSV infection and/or human parainfluenza virus 1 (HPIV- 1 ) infection.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be used treat and/or ameliorate due to fever, cough, runny nose, red eyes, a generalized rash, pneumonia, an ear infection and/or bronchitis due to measles.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate due to swelling of the salivary 7 glands, fever, loss of appetite and/or fatigue due to mumps.
  • an effective amount of one or more compounds of Formula ( ⁇ ), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a human parainfluenza viral infection.
  • the human parainfluenza viral infection can be a human parainfluenza virus 1 (HPIV-1 ).
  • the human parainfluenza viral infection can be a human parainfluenza virus 2 (HPIV-2).
  • the human parainfluenza viral infection can be a human parainfluenza virus 3 (HPIV-3).
  • the human parainfluenza viral infection can be a human parainfluenza virus 4 (HPIV-4).
  • one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof can be used to treat and/or ameliorate one or more subtypes of human parainfluenza virus.
  • one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof can be used to treat HPIV- 1 and/or HPIV-3.
  • the one or more compounds of Formula ( ⁇ ) or a pharmaceutically acceptable salt thereof, that can be used to treat, ameliorate and/or prevent a paramyxovirus viral infection can he a compound of Formula (I), or pharmaceutically acceptable salt thereof, provided in any of the embodiments described in paragraphs [0078]-[0159J.
  • a "subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal' includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes. and. in particular, humans.
  • the subject is human.
  • prevention means lowering the efficiency of viral replication and/or inhibiting viral replication to a greater degree in a subject who receives the compound compared to a subject who does not receive the compound.
  • forms of prevention include prophylactic administration to a subject who has been or may be exposed to an infectious agent, such as a paramyxovirus (e.g., RSV).
  • treatment does not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy.
  • treatment may include acts that may worsen the subject ' s overall feeling of well-being or appearance, and may positively affect one or more symptoms or aspects of the disease while having effects on other aspects of the disease or on unrelated systems that may be considered undesireable.
  • a therapeutically effective amount of compound can be the amount needed to prevent, treat, alleviate or ameliorate one or more symptoms or conditions of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • Suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in viral RNA, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and/or other indicator of disease response.
  • an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is an amount that is effective to reduce viral titers to essentially undetectable or very 7 low 7 levels, for example, to less than 1.7 logio plaque forming units equivalents (PFUe)/mL, or less than 0.3 logi 0 plaque forming units equivalents (PFUe)/mL.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can reduce the viral load compared to the viral load before administration of the combination (for example, 60 hours after receiving the initial dosage of the combination).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein can reduce the viral load to lower than 1 .7 logio (PFUe)/mL, or lower than 0.3 logio (PFUe)/mL.
  • a combination of compounds described herein can achieve a reduction in viral titer in the serum of the subject in the range of about 1 .5-log to about a 2.5-log reduction, about a 3-log to about a 4-log reduction, or a greater than about 5 -log reduction compared to the viral load before administration of the combination.
  • the viral load is measure before administration of the combination, and several hours after receiving the initial dosage of the combination (for example, 60 hours after receiving the initial dosage of the combination).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can result in at least a 1 , 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of a paramyxovirus relative to pre-treatment levels in a subject, as determined several hours after receiving the initial dosage of the combination (for example, 60 hours after receiving the initial dosage of the combination).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein can result in a reduction of the replication of a paramyxovirus relative to pre -treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold.
  • a compound of Formula (T). or a pharmaceutically acceptable salt thereof can result in a reduction of a paramyxovirus replication in the range of 1 to 1 .5 log. 1 .5 log to 2 log. 2 log to 2.5 log. 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction of a paramyxovirus replication compared to the reduction of a paramyxovirus reduction achieved by ribavirin (Virazole®), or may achieve the same reduction as that of ribavirin (Virazole®) therapy in a shorter period of time, for example, in one day, two days, three days, four days, or five days, as compared to the reduction achieved after 5 days of ribavirin (Virazole®) therapy.
  • infectious agents can develop resistance to one or more therapeutic agents.
  • resistance refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s).
  • the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered to a subject infected with RSV that is resistant to one or more different anti-RSV agents (for example, ribavirin).
  • development of resistant RSV strains is delayed when subjects are treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of RSV strains resistant to other RSV drugs.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can decrease the percentage of subjects that experience complications from a RSV viral infection compared to the percentage of subjects that experience complication being treated with ribavirin.
  • the percentage of subjects being treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that experience complications can be 10% , 25%, 40%, 50%, 60%, 70%, 80% and 90% less compared to subjects being treated with ribavirin.
  • a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein can be used in combination with one or more additional agent(s). In some embodiments, a compound of Formula (1).
  • additional agent can be ribavirin, palivizumab. and RSV-IGIV.
  • additional anti-RSV agents include but are not limited to an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, a RSV polymerase inhibitor, an IMPDH inhibitor, an interferon and an other compound that inhibits the RSV virus, or a pharmaceutically acceptable salt of any of the foregoing.
  • additional agents is provided herein.
  • an anti-RSV nanobody e.g., ALX-0171 (a trivalent nanobody,
  • a peptide fusion inhibitor such as a peptide having the sequence DEFDASISQVNEKTNQSLAFTRKSDELL (T-67) a peptide having the sequence
  • Pegylated interferon-alpha-2a PEGASYS®
  • Pegylated interferon-alpha-2b PEG-INTRON ⁇
  • RNA oligonucleotide a double stranded RNA oligonucleotide
  • AFN-RSV01 an siRNA agent with the sense strand sequence (5' to 3') GGC U C U U AGC AAAGU C AAGdFdF (SEQ ID NO. 3) and the antisense strand sequence (5' to 3')
  • ALN-RSV01 and/or ALN-RSV02 can be found in U.S. Publication No. 2009/0238772. filed Dec. 15, 2008 (Alnylam Pharmaceuticals).
  • the additional agents can be administered in amounts that have been shown to be effective for those additional agents. Such amounts are known in the art; alternatively, they can be derived from viral load or replication studies using the parameters for "effective amount" set forth above. Alternatively, the amount used can be less than the effective monotherapy amount for such additional agents. For example, the amount used could be between 90% and 5% of such amount, e.g., 90%, 80%, 70%, 60%. 50%, 40%. 30%, 20%, 10%, or 5%, or intermediate values between those points.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered with one or more additional agent(s) together in a single pharmaceutical composition.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition.
  • one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered prior to all additional agents.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered prior to at least one additional agent.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered concomitantly with one or more additional agent(s).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered subsequent to the administration of at least one additional agent.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered subsequent to the administration of all additional agents.
  • a potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof, may be a reduction in the required amount(s) of one or more compounds of paragraphs [0198]-[01 9] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof) that is effective in treating a disease condition disclosed herein (for example, RSV), as compared to the amount required to achieve same therapeutic result when one or more compounds described in paragraphs [0198] -[0199] (including the table), including pharmaceutically acceptable salts thereof, are administered without a compound of Formula (1), or a pharmaceutically acceptable salt thereof.
  • a disease condition disclosed herein for example, RSV
  • the amount of a compound described in paragraphs [0198]-[0199] (including the table), including a pharmaceutically acceptable salt and prodrug thereof can be less compared to the amount of the compound described in paragraphs [0198]-[0199] (including the table), including a pharmaceutically acceptable salt and prodrug thereof, needed to achieve the same viral load reduction when administered as a monotherapy.
  • Another potential advantage of utilizing a compound of Formula (1) can be less compared to the amount of the compound described in paragraphs [0198]-[0199] (including the table), including a pharmaceutically acceptable salt and prodrug thereof, needed to achieve the same viral load reduction when administered as a monotherapy.
  • Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) described in paragraphs [0198] -[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof, may include little to no cross resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof); different routes for elimination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agcnt(s) described in paragraphs [0198]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof): little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) described in paragraphs [0 98]-[0199] (including the table) (
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.
  • the dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg. e.g. 5 to 200 mg.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED 50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • dosages may be calculated as the free base.
  • the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assay-s or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary- according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may 7 be used in veterinary medicine.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • Compound 100 was prepared using 1 -12 and 4-(cyclopropylmethoxy)-3- methoxybenzoic acid, and by following a synthetic route, which closely follows that described for the preparation of 1. 100: +ES1-MS: m/z 483. 1 [M+H]+.
  • Compound 106 was prepared using 2.6-dibromopyridine. 2-(7- fluoiObenzo[b]thiophen-3-yl)-4.4,5.5-tetramethyl-L3,2-dioxabo 1 Olane and 3,4- dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparati -MS: m/z 452.9 [M+H] + .
  • Compound 107 was prepared using 3.4-dimethoxybenzoic acid and 3- bromo-5-(7-iluorobenzo[b]thiophen-3-yl)-l-propyl-lH-l ,2,4-triazole, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ES1-MS: m/z 485.0 [M+ + .
  • Compound 108 was prepared using 2,4-dibromothiazole, 2-(7- fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-l ,3.2-dioxaborolane and 3,4- dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ES1-LCMS: m/z 459.0 [M+H]+.
  • Compound 109 was prepared using 2,4-dichloro-5-methoxypyrimidine. (3- chloro-4-fluorophenyi) boronic acid and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for preparation of 1. +ESl-MS:m/z 506.1 [M+ + .
  • Compound 110 was prepared using 2-hydroxy-4,5-dimethoxybenzoic acid and 2-amino- l-(6-(7-fluoiObenzo[b]thiophen-3-yr)-4-methoxypyridin-2-yl) ethanol, and by following a synthetic route, which closely follows that described for preparation of 1. Compound 110 was obtain .9[M+I I] + .
  • Compound 11 1 was obtained by closely following the procedure for obtaining 1 by using 2,4-dibromothiazole, 2-(7-fluorobenzo[b]thiophen-3-yl)-4,4.5,5- tetramethyl-l ,3.2-dioxaborolane and 3,4-dimethoxybenzoic acid.
  • Compound 1 11 was obtained as a white solid. +ESI-LCMS: m/z 466.9 [M+H] + .
  • Compound 116 was obtained by closely following the procedures for obtaining 100 and 114 using 7-fluoro-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-l -((2- (trimethylsilyl)ethoxy)methyl)- lH-indole and 4-ethoxy-3-methoxybenzoic acid.
  • Compound 116 was obtained as a white solid. +ESI-MS: m/z 494.2 M+H] + .
  • Compound 117 was obtained by closely following the procedures for obtaining 100 and 114 using 7-fluoro-3-(4,4,5.5-tetramethyl- l ,3,2-dioxaborolan-2-yl)- l -((2- (trimcthylsilyl)ethoxy )methyl)- l H-indolc and 4-(2-hydroxyethoxy )-3-methoxybenzoic acid.
  • Compound 117 was obtained as a white solid. +EST-MS: m/z 510.2 [M+H] + .
  • Compound 118 was prepared using l -amino-2-(6-(3-bromo-4- fluorophenyl)-5-methoxypyridin-2-yl)propan-2-ol and 4-(2-fluoroethoxy)-3-methoxybenzoic acid and 4-(2-fluoroethoxy)-3-methoxybenzoic acid, and by following a synthetic route, which closely follows that described for preparation of 100 and 1 14.
  • Compound 120 was prepared using N-(2-(6-(3-chloro-4-fluorophenyl)-5- methoxypyridin-2-yl)-2-oxoethyl)-4-(2-hydroxyethoxy)-3-niethoxybeiizamide with MeMgBr in THF, and by closely following a synthetic route, which closely follows that described for preparation of 119.
  • Compound 121 was prepared using N-(2-(6-(3-chloro-4- fluorophenyl)pyridin-2-yl)-2-oxoethyl)-3-methoxy-4-(2-(methylamino)-2- oxoethoxy)benzamide with MeMgBr in THF. and by following a synthetic route, which cl
  • Compound 128 was prepared using N-(2-(6-(3-chloro-4-fluorophenyl)-5- methoxypyridin-2-yl)-2-oxoethyl)-3-methoxy-4-(] H-pyrazol-1 -yl)benzamide with MeMgBr in THF. and by following a synthetic route, which closely follows that described for preparation of 119.
  • Compound 130 was obtained following the procedure for obtaining 129 by using 10-2, 1 J -dibromoimidazo[ 1 , -a] pyridine and 2-(7-fluorobenzo[b]thiophen-3-yl)- 4,4.5,5-tetramethyl- l ,3,2-dioxaborolane as the starting materials, and then the oxidizing reagent DMP. Compound 130 was obtained as a white solid. +ES1-MS: m/z 489.8 [M+H] + .
  • Compound 11 -1 was prepared using 10-2, 2,4,5-tribromo- l -((2- (trimethylsilyl)cthoxy)mcthyl)- l H-imidazole and 3,4-dimcthoxy-N-(2- (methoxy(methyl)amino)-2-oxoethyl)benzaiTiide, and by following a synthetic route, which closely follows that described for preparation of 129.
  • Compound 133 was prepared using 2.4,5-tribromo-l -methyl- l H-imidazole and 3.4-dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzamide. and by following a synthetic route, which closely follows that described for preparation of 129. +ESI-MS:m/z 455.9[M+H] + .
  • Compound 134 was prepared using 2,4-dibromothiazole and 3,4- dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzarnide, and by following a synthetic route, which closely follows that described for preparation of 129. +ESI-MS: m/z 459.0 [M+HJ + .
  • Dess-Martin periodinane (4.55 g. 10.7 mmol) was added to a solution of 12-2 (2.98 g, 7.16 mmol) in DCM (50 mL). The mixture was stirred at r.t. for 1 .5 h. A 1 : 1 mixture of 10% aq. Na 2 S?0 3 solution and sat. aq. NaHCOs solution was added, and the mixture w r as stirred for 40 mins. The layers were separated and the organic portion was dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure.
  • ft-Butyllithium (1.6M solution in hexane. 1.50 mL, 2.42 mmol) was added dropwise to a stirred solution of 12-4 (760 mg, 2.42 mmol) in toluene (15 mL), which had been pre-cooled to -78°C. After 20 mins, a solution of 12-3 (500 mg, 1 .21 mmol) in THF (10 mL) was added. The mixture was stirred at -78°C for 30 mins. The mixture was allowed to warm to r.t. and then quenched with MeOH. The volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water.
  • Compound 13-1 was obtained following the procedure for obtaining 1 by using 2,4,6-trichloropyridine, 2-(7-fluo 1 Obenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-l ,3,2- dioxaborolane and 3.4-dimethoxybenzoic acid.
  • Compound 15-2 was prepared starting from 2-chloro-6-(hydroxymethyl)- 4-iodopyridin-3-ol (15-1) according to procedures provided in PCT Publication No. WO 2004/039366, published May 13, 2004, which is hereb incorporated by reference for the limited purpose of its disclosure of the preparation of 15-2.
  • Dess-Martin pcriodinane 1 72 mg, 0.404 mmol was added to a solution of 15-6 (90 mg. 0.162 mmol) in DCM (4 mL). The mixture was stirred at r.t. for 1 h. A 1 : 1 sat. aq. NaHCOi solution-sat. aq. Na 2 S 2 0 3 solution was added. The mixture was stirred at r.t. for 30 mins and the layers were separated. The organic portion was washed with water, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure.
  • Compound 150 was prepared using 6-(2-bromo- l , l -difluoroethyl)-2-(3- chloro-4-fluorophenyl)-3-methoxypyridine, and by following a synthetic route, which closely follows that described for preparation of 149.
  • Compound 157 was prepared using N-(2-(6-(7-fluorobenzo[b]thiophen-3- yl)pyridin-2-yl)-2-oxoethyl)-3,4-dimethoxybenzamide and hydroxylamine hydrochloride, and by following a synthetic route, which closely follows that described for preparation of 156.
  • Dess-Martin periodinane (1.49 g, 3.52 mmol) was added to a stirred solution of 32-1 (300 mg, 1.40 mmol) in dry DCM (6.5 mL). The mixture was stirred at r.t. for 1 h and quenched with a 1 : 1 mixture of 2M aq. Na 2 S 2 0 3 solution and sat. aq. NaHC ( 3 ⁇ 4 solution (10 mL). The mixture was stirred vigorously for 30 mins and the layers were separated. The organic portion was washed with brine, dried filtered and concentrated under reduced pressure. The crude aldehyde was progressed to the next step without further purification.
  • Compound 170 was prepared using 2.6-dichloro-3-methylpyridine, 2-(7- fluorobenzo[b]thiophen-3-y] )-4,4,5,5-tetramethyl-1.3,2-dioxaborolane and 3,4- dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ESI-MS:m/z 464.9 [M+H] + .
  • Trimethylsulfoxonium iodide 1 .19 g, 5.41 mmol was added to a solution of potassium /crr-butoxide (551 mg. 4.92 mmol) in DMSO ( 10 mL). The mixture was stirred at r.t. for 30 mins. A solution of N- ⁇ 2-[6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl]- 2-oxoethyl) -3-methoxy-4- ⁇ 2-[(4-methoxyphenyl)methoxy]ethoxy ⁇ benzamide (1 , 3.00 g. 4.92 mmol) in DMSO (20 mL) was added.
  • Method A A mixture of epoxide 2 ( 100 mg, crude) and an amine ( 10 eq.) in MeOH ( 1 mL) was stirred at r.t. or heated to 100 °C. When complete, the reaction was concentrated under reduced pressure. The residue was dissolved in a 10: 1 DCM:TFA mixture (2.2 mL). After 30 mins of stirring at r.t., a 2M aq. NaOI I solution was added. The mixture was stirred at r.t. for 10 mins. The layers were separated, and the aqueous portion extracted with DCM. The combined organic portions were dried with Na 2 S0 4 , filtered and concentrated under reduced pressure. Chromatography of the residue afforded the aminol.
  • Method B A mixture of epoxide 2 (150 mg, crude), an amine (2 eq.) and K 2 C0 3 (66.0 mg. 2 eq.) in DMF (2 mL) was stirred at 50 °C. When complete, the reaction was diluted with EtOAc. The organic portion was washed twice with water, dried with Na 2 S0 4 , filtered and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and treated with TFA (300 uL). After 1 h, the reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue afforded the aminol.
  • Method C ⁇ (270 uL, 1.93 mmol) and MsCl (150 uL, 1.93 mmol) were added to a solution of 3 (600 mg, 0.964 mmol) in DCM (4 mL). The mixture was stirred at r.t. for 2 h. The mixture was poured into 1M aq. HCT solution and extracted with DCM. The combined organic portions were dried with Na ⁇ SC ⁇ and filtered. The volatiles were removed under reduced pressure to afford the crude mesylate 4, which was directly used in the next step. A mixture of 4 (80 mg) and an amine (50 uL) in MeOH (2 mL) was heated to 85 °C in a sealed vial.
  • Method D A mixture of epoxide 2 (50 mg, crude) and an amine ( 10 eq.) was heated to 60 °C under microwave irradiation. When complete, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and treated with TFA (300 uL). After 1 h. the reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue afforded the aminol.
  • Epoxide 2 (200 mg, crude) was dissolved in a 1 : 1 MeOH:6M aq. HC1 solution (2 mL), and the mixture was stirred at 60 °C for 2 h. The mixture was basified with 6M aq. NaOH solution and purified by reverse phase chromatography (water:CH 3 CN, 100:0 to 50:50) to afford 176 as an off-white solid (40.2 mg).
  • TMSCF 3 (810 uL, 5.50 mmol) was added to a solution of 2-5 (1.40 g, 4.60 mmol) in dry DCM (25 mL). The mixture was cooled 0 °C and TBAF (1 M sol in TI IF, 5.5 mL, 5.50 mmol) was added dropwise. The mixture was allowed to gradually reach r.t. and stirring was continued for 1 h. Water and DCM were added. The layers were separated, and the organic portion was dried with Na 2 S0 4 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 80:20) afforded 2-6 ( 1 .43 g, 82%). UPLC/MS(ES + ): m/z 376.16 [M+H] + .
  • Dess-Martin periodinane (3.25 g, 7.68 mmol) was added to a stirred solution of 2-6 (1 .43 g. 3.84 mmol) in dry DCM (1 7 mL). The mixture was stirred at r.t. for 1 h. A 1 : 1 2M aq. Na 2 S 2 0 3 :sat. aq. NaHC0 3 solution was added. The mixture was stirred at r.t. for 30 mins. The layers were separated, and the aqueous portion was extracted with DCM (2x). The combined organic portions were dried with Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • 14.5 min). UPLC and ⁇ NMR analyses for the two enantiomers were superimposible.
  • 2-9a and 2-9b were separately coupled with 2-10 according to Method B. Each diastereomeric mixture was resolved by chiral HPLC.
  • mobile phase n-Hexanc/(Ethanol+0.1 % isopropylamine) 30/70 % v/v, flow rate: 17 mL/min. UV detection DAD 220 nm].
  • 2-9b provided a mixture of 201 and 203 (t R 6.4 min and 12.3 min) [Whelk 01 (R.R) (25 x 2.0 cm), 5 ⁇ , mobile phase: n-Hexane/(Ethanol+0.1 % isopropylamine) 30/70 % v/v, flow rate: 17 mL/min, UV detection DAD 220 nm].
  • Acrolein (21.8 mL, 326 mmol) was added to a mixture of 4-amino-3- hydroxybenzoic acid (5.00 g, 33.0 mmol) in 12 N aq. HQ solution (50 mL). The mixture was refluxed for 1 h. After cooling to r.t., the mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH 3 CN 100:0 to
  • Crotonaldehyde (4.01 g. 48.9 mmol) was added dropwise to a mixture of 4-amino-3-hydroxybenzoic acid (5.00 g. 33.1 mmol) and 6M aq. HC1 solution (60 mL. 360 mmol). The mixture was refluxed for 1 8 h. After cooling to r.t. a precipitate formed. The solid was filtered off, dried and collected. Acid 2-21 (3.44 g) was used in the next step without further purification. UPLC/MS(ES + ): m/z 204.10 [M+H] + .
  • Lithium hydroxide monohydrate (0.272 g, 6.49 mmol) was added to a stirred suspension of 2-22 (500 mg. 2.16 mmol) in a 2: 1 :2 THF:MeOH:H20 mixture. The mixture was stirred at r.t. for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH 3 CN 100:0 to 0: 100) to afford 2-20 (291 mg). UPLC/MS(ES + ): m/z 218.10 [M+H] + .
  • Ester 2-22 (1.50 g, 6.48 mmol) was added to a suspension of selenium dioxide ( 1.44 g, 13.0 mmol) in pyridine (24 mL). The mixture was refluxed for 3 h. The volatiles were removed under reduced pressure, and the residue was triturated with EtOAc. The solid was dried and collected to provide 2-24 (595 mg, 35%).
  • Lithium hydroxide monohydrate (44.0 mg, 1.05 mmol) was added to a stirred suspension of 2-25 (91 .0 mg, 0.350 mmol) in a 2: 1 :2 THF:MeOH:H 2 0 mixture. The mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (watenCLLsCN 100:0 to 0: 100) to afford 2-23 (76 mg, 89%). UPLC/MS(ES + ): m/z 247.20 [M+H] + .
  • Triethylamine (0.240 mL, 1 .72 mmol) was added to a mixture of 3- methoxy-4-[(2-oxopyrrolidin-3-yl)oxy]benzoic acid (130 mg, 0.517 mmol).
  • HOBT 87.3 mg. 0.646 mmol.
  • EDC 124 mg, 0.646 mmol
  • 2-30 104 mg, 0.431 mmol
  • the mixture was warmed to 45 °C and stirred at 45 °C for 18 h. A 1M aq. HQ solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated.
  • Dess-Martin periodinane (453 mg, 1 .07 mmol ) was added to a stirred solution of 2-31 (203 mg) in dry DCM ( 10 mL). The mixture was stirred at r.t. for 2 h. and the reaction was quenched with a 1 : 1 1 M aq. Na 2 S?0 3 :sat. aq. NaHC0 3 solution (3 mL). The mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na 2 SC> 4 , filtered and concentrated under reduced pressure.
  • Trimethylsulfoxonium iodide (21 .0 mg, 0.097 mmol) was added to a solution of potassium tert-butoxide (9.8 mg, 0.086 mmol) in DMSO (0.6 mL). The mixture was stirred at r.t. for 30 mins. A solution of 218-1 (50.0 mg, 0.088 mmol) in DMSO (0.6 mL) was added, and the mixture was stirred at r.t. for a further 30 mins. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc.
  • Epoxide 2-33 (60 mg, crude) was dissolved in a 1 : 1 3M aq. HCl sol:MeOH mixture (5 mL). The mixture was heated to 50 °C for 3 h. After cooling to r.t., the mixture was basified with I M aq. NaOH solution and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH CN 95:5 to 0: 100) to afford 219 as a white solid ( 1 8 mg. 26% over two steps). UPLC/MS(ES + ): m/z 600.36 [M+H] + .
  • Triethylamine (0.35 mL, 2.51 mmol) was added to a mixture of 8- methoxyquinoline-6-carboxylic acid (286 mg, 1.18 mmol), HOBT (223 mg, 1.65 mmol), EDC (316 mg, 1.65 mmol) and 2-30 (239 mg, 1.18 mmol) in DCM (7 mL). The mixture was stirred at r.t. for 60 h. A I M aq. HCl solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with I M aq.
  • Trimethylsulfoxonium iodide 18.3 mg, 0.087 mmol was added to a solution of potassium tert-butoxide (9.3 mg, 0.083 mmol) in DMSO (0.3 mL). The mixture was stirred at r.t. for 30 mins. A solution of 220 (43.0 mg, 0.083 mmol) in DMSO (0.7 mL) was added, and the mixture was stirred at r.t. for a further 30 mins. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine, dried with Na?S0 4 .
  • Lithium hydroxide monohydrate (95.0 mg, 2.26 mmol) was added to a stirred mixture of 2-36 in 2: 1 : 1 TLTF ⁇ MeOLLLLO (8 mL). The reaction was stirred at r.t. for 3 h. Additional lithium hydroxide monohydrate (95 mg) was added and stirring was continued for 2 h. The mixture was poured in to 6M aq. HCl solution. The aqueous portion was saturated with NaCl and extracted with EtOAc and DCM. The combined organic portions were dried with Na 2 S0 4 , and filtered. The volatiles were removed under reduced pressure to afford crude 2-37, which was in the next step without further purification. UPLC7MS(ES + ): m/z

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Abstract

Disclosed herein are new antiviral compounds, together with pharmaceutical compositions that include one or more antiviral compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection with one or more small molecule compounds. Examples of paramyxovirus infection include an infection caused by human respiratory syncytial virus (RSV).

Description

ANTIVIRAL COMPOUNDS
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6.
REFERENCE TO SEQUENCE LISTING
[0002] The present application is filed with a Sequence Listing in Electronic format. The Sequence Listing is provided as a file entitled ALIOS079.txt created August 19. 2014, which is approximately 4 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.
BACKGROUND
Field
[0003] The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are new antiviral compounds, together with pharmaceutical compositions, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection with one or more small molecule compounds.
Description
[0004] Respiratory viral infections, including upper and lower respiratory tract viral infections, are a leading cause of death of millions of people each year. Upper respiratory tract viral infections involve the nose, sinuses, pharynx and/or larynx. Lower respiratory tract viral infections involve the respiratory system belo the vocal cords, including the trachea, primary bronchi and lungs. Human respiratory syncytial virus (RSV) is a common cause of respiratory tract infections. Up to 60% of human infants are infected with RSV within their first year of life. Children and adults are also infected with RSV, where it is often manifesting as a lower respiratory tract infection with possible complications of bronchiolitis. RSV infections can be particularly severe in infants and elderly patients. RSV is a negative-sense, single-stranded RNA virus classified within the Paramyxoviridae family, which also includes viruses that cause Newcastle disease, parainfluenza, mumps, measles, and canine distemper.
SUMMARY
[0005] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0006] Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include administering to a subject suffering from the paramyxovirus viral infection an effective amount of one or more compounds of Formula (Γ), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition that includes one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a paramyxov irus viral infection. Still other embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a paramyxovirus viral infection. Yet still other embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include contacting a cell infected with the paramyxovirus with an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein relate to a method of inhibiting the replication of a paramyxovirus that can include contacting a cell infected w ith the paramyxovirus with an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof. For example, the paramyxovirus viral infection can be caused by a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus (including a respiratory syncytial viral infection), a metapneumovirus, hendravirus, nipahvirus, measles, sendai virus, mumps, a human parainfluenza virus (HPIV- 1 , HPIV-2, HPIV-3 and HPIV-4) and/or a metapneumovirus.
[0007] Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include administering to a subject suffering from the viral infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein. Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include contacting a cell infected with the paramyxovirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] Figure 1 illustrates examples of compounds of Formula (I), or pharmaceutically acceptable salt of any of the foregoing compounds.
DETAILED DESCRIPTION
[0009] Paramyxoviridae family is a family of single stranded RNA viruses. Several genera of the paramyxoviridae family include henipavirus, morbillivirus. respirovirus, rubulavirus, pneumovirus and metapneumovirus. These viruses can be transmitted person to person via direct or close contact with contaminated respiratory droplets or fomites. Species of henipavirus include hendravirus and nipahvirus. A species of morbillivirus is measles. Species of respirovirus include sendai virus and human parainfluenza viruses 1 and 3 ; and species of rubulavirus include mumps virus and human parainfluenza viruses 2 and 4. A species of metapneumovirus is human metapneumovirus. [0010] Human Respiratory Syncytial Virus (RSV), a species of pneumovirus, can cause respiratory infections, and can be associated with bronchiolitis and pneumonia. Symptoms of an RSV infection include coughing, sneezing, runny nose, fever, decrease in appetite, and wheezing. RSV is the most common cause of bronchiolitis and pneumonia in children under one year of age in the world, and can be the cause of tracheobronchitis in older children and adults. In the United States, between 75.000 and 125,000 infants are hospitalized each year with RSV. Among adults older than 65 years of age. an estimated 14.000 deaths and 177,000 hospitalizations have been attributed to RSV.
[0011] Treatment options for people infected with RSV are currently limited. Antibiotics, usually prescribed to treat bacterial infections, and over-the-counter medication are not effective in treating RSV. In severe cases, a nebulized bronchodilator, such as albuterol, may be prescribed to relieve some of the symptoms, such as wheezing. RespiGram® (RSV-1G1V, Medlmmune, approved for high risk children younger than 24 months of age), Synagis® (palivizumab, Medlmmune. approved for high risk children younger than 24 months of age), and Virzole® (ribavirin by aerosol, ICN pharmaceuticals) have been approved for treatment of RSV.
[0012] Symptoms of the measles include fever, cough, runny nose, red eyes and a generalized rash. Some individuals with measles can develop pneumonia, ear infections and bronchitis. Mumps leads to swelling of the salivary glands. Symptoms of mumps include fever, loss of appetite and fatigue. Individuals are often immunized against measles and mumps via a three-part MMR vaccine (measles, mumps, and rubella). Human parainfluenza virus includes four serotypes types, and can cause upper and lower respiratory tract infections. Human parainfluenza virus 1 (HPIV-1 ) can be associated with croup; human parainfluenza virus 3 (HPIV-3) can be associated with bronchiolitis and pneumonia. According to the Centers of Disease Control and Prevention (CDC), there are no vaccines against human parainfluenza virus.
Definitions
[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary7 skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0014] As used herein, any "R" group(s) such as, without limitation, R , R~, R\ R\ R5, R6 , R7, R8. R9. R10. R1 1. R12. R13. R14. R15 Ru\ R1 7, R18, R19. R20. R21. R22. R23. and RA represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If tw o "R" groups are described as being "taken together" the R groups and the atoms they are attached to can form a cycloalkyl. cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if Rd and Rb of an NRd Rb group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:
Figure imgf000007_0001
In addition, if two "R" groups are described as being "taken together" with the atom(s) to which they are attached to form a ring as an alternative, the R groups are not limited to the variables or substituents defined previously.
[0015] Whenever a group is described as being "optionally substituted'' that group may be unsubstituted or substituted w ith one or more of the indicated substituents. Likew ise, when a group is described as being "unsubstituted or substituted" if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more group(s) individually and independently selected from alkyl. alkenyl. alkynyl. cycloalkyl, cycloalkenyl, acylalkyl. hydroxy, alkoxy. alkoxyalkyl, aminoalkyl. amino acid, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyi(alkyi), hydroxyalkyi, acyi, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N -sulfonamide C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocvanato, azido, nitro, silyi, sulfenyl. sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
[0016] As used herein. "Ca to Ct," in which "a" and "b" are integers refer to the number of carbon atoms in an alky l, alkeny l or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl. alkcnyl, alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the ary l, ring(s) of the heteroary l or ring(s) of the heteroalicycly l can contain from "a" to "b". inclusive, carbon atoms. Thus, for example, a "Ci to C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-. CH3CH2-. CH3CH2CH2-. (CIT^CH-. CH3CH2CH2CH2-. CH3CH2CH(CH3)- and (CH3)3C-. If no "a" and "b" are designated with regard to an alkyl. alkenyl, alkynyl. cycloalkyl cycloalkenyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these definitions is to be assumed.
[0017] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g. , "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom. 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alky l group of the compounds may be designated as "C f -C4 alky l" or similar designations. By way of example only. "C 1 -C4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl. n-butyl. iso-buty l, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl. butyl, i so butyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.
[0018] As used herein, "alkenyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.
[0019] As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted. [0020] As used herein, "cycloalkyl'' refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). Λ cycloalky l group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to. cyclopropyl, cyclobutyl. cyclopentyl. cyclohexyl. cycloheptyl and cyclooctyl.
[0021 ] As used herein, "cycloalkenyl" refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be "aryl," as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.
[0022] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C[4 aryl group, a C6-Cio aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.
[0023] As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one, two. three or more heteroatoms. that is. an element other than carbon, including but not limited to. nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term "heteroaryl" includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, those described herein and the following: furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1 ,2,3- oxadiazole, 1 ,2,4-oxadiazole, thiazole. 1 ,2,3-thiadiazole, 1 ,2,4-thiadiazole, benzothiazole, imidazole, benzimidazolc, indole, indazole, pyrazolc, benzopyrazole, isoxazole, benzoisoxazole. isothiazole. triazole. benzotriazole, thiadiazole, tetrazole. pyridine, pyridazine. pyrimidine, pyrazine, purine, pteridine. quinoline, isoquinoline. quinazoline. quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.
[0024] As used herein, "heterocyclyl'"' or "heteroalicyclyl" refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- s stems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such "heterocyclyl'" or "heteroalicyclyl" groups include, but are not limited to. those described herein and the following: 1 ,3-dioxin, 1.3-dioxane, 1 ,4-dioxane, 1.2-dioxolane, 1 ,3-dioxolane. 1 ,4- dioxolane, 1 ,3-oxathiane, 1 ,4-oxathiin. 1.3-oxathiolane. 1.3-dithiole. 1 ,3-dithiolane, 1 ,4- oxathiane, tetrahydro-l ,4-thiazine. 1.3-thiazinane, 2H-1 ,2-oxazine, maleimide. succinimide. barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane. hexahydro-l ,3.5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine. oxazoline. oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N- Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine. tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorphoiine, thiamorphoiine sulfoxide, thiamorphoiine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).
[0025] As used herein, "aralkyi" and "aiyl(alkyl)" refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phcnylalkyl and naphthylalkyl.
[0026] As used herein, "heteroaralky l" and "heteroaryl(alkyl)"' refer to a heteroaryl group connected, as a substituent. via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl. 3-thienylalkyl. furylalkyl. thienylalkyl. pyrrolylalkyl. pyridylalkyl. isoxazolylalkyl, imidazolylalkyl and their benzo-fused analogs.
[0027] A "heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent. via a lower alkylene group. The lower alkylene and heterocyclyl of a heteiOalicyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl). tetrahydro-2H-thiopyran-4-yl (methyl), and 1 ,3-thiazinan-4-yi(methyl).
[0028] "Lower alkylene groups'" are straight-chained -CH?- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of "substituted."
[0029] As used herein, "alkoxy" refers to the formula -OR wherein R is an alkyl. an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl, aryl. heteroaryl. heterocyclyl. cycloalkyl(alkyl). aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.
[0030] As used herein, "acyl" refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyi). heteroaryl(alkyi) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl. acetyl, propanoyi, benzoyl and acryl. An acyi may be substituted or unsubstituted. [0031] As used herein, "acylalkyl" refers to an acyl connected, as a substituent, via a lower alkylene group. Examples include aryl-C(=0)-(CI I2)N- and heteroaryl-C(=0)- (CH2)N-. where n is an integer in the range of 1 to 6.
[0032] As used herein, "alkoxyalkyp refers to an alkoxy group connected, as a substituent, via a lower alkylene group. Examples include C alkyl-0-(CH2)„- ,w herein n is an integer in the range of 1 to 6.
[0033] As used herein, "aminoalkyl" refers to an optionally substituted amino group connected, as a substituent. via a lower alkylene group. Examples include H2N(CH2)„- , wherein n is an integer in the range of 1 to 6.
[0034] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to. 2-hydroxyethyl. 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkyl may7 be substituted or unsubstituted.
[0035] As used herein, "'haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g.. mono-haloalkyl, di-haloalkyl and tri- haloalkyl). Such groups include but are not limited to, chloromethyl, iluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-ditluoroalkyl and 2- fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
[0036] As used herein, "haloalkoxy"' refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy , di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to. chloromethoxy. fluoromethoxy, difluoromethoxy, trifluoromethoxy. chloro-fluoroalkyl. chloro- difluoroalkoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.
[0037] A "sulfenyl" group refers to an "-SR" group in which R can be hydrogen, an alkyl. an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl, aryl. heteroaryl. heterocyclyl. cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.
[0038] A "sulfinyl" group refers to an "-S(=0)-R" group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted. [0039] A "sulfonyl" group refers to an "SO?R" group in which R can be the same as defined with respect to sulfenyl. A sulfony l may be substituted or unsubstituted.
[0040] An "O-carboxy" group refers to a "RC(=0)0-" group in which R can be hydrogen, an alkyl. an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl. aryl, heteroaryl. heterocyclyl, cycloalkyl(alkyl), aryl(alkyl). heteroaryl(alkyl) or hetei cyclyl(alkyl). as defined herein. An O-carboxy may be substituted or unsubstituted.
[0041 ] The terms "ester" and "C-carboxy" refer to a "-C(=0)OR" group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.
[0042] A "thiocarbonyl" group refers to a "-C(=S)R" group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.
[0043] A "trihalome hanesulfonyl" group refers to an "X3CSO?-" group wherein each X is a halogen.
[0044] A "trihalomethanesulfonamido" group refers to an "X3CS(0)2N(RA)-" group wiierein each X is a halogen, and A hydrogen, an alkyl, an alkenyl. an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alk i), aryl(alkyl), heteroaryl(alkyi) or heterocyclyl(alkyl).
[0045] The term "amino" as used herein refers to a -NH2 group.
[0046] As used herein, the term "hydroxy" refers to a -OH group.
[0047] A "cyano" group refers to a "-CN" group.
[0048] The term "azido" as used herein refers to a -N3 group.
[0049] An "isocyanato" group refers to a "-NCO" group.
[0050] A "thiocyanato" group refers to a "-CNS" group.
[0051 ] An "isothiocyanato" group refers to an " -NCS"' group.
[0052] A "carbonyl" group refers to a C=0 group.
[0053] An "S-sulfonamido" group refers to a "-S02N(R \RB)" group in wfiich RA and RB can be independently hydrogen, an alkyl. an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl( alkyl) or heterocyclyi(alkyi). An S-sulfonamido may be substituted or unsubstituted. [0054] An "N-sulfonamido" group refers to a "RS02N( ,\)-" group in which R and RA can be independently hydrogen, an alkyl, an alkenyl. an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocycly l, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.
[0055] An 'Ό-carbamy 1" group refers to a
Figure imgf000014_0001
and RB can be independently hydrogen, an alkyl. an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl, aryl, heteroaryl. heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.
[0056] An "N-carbamyl" group refers to an "ROC(=0)N(RA)-" group in w hich R and RA can be independently hydrogen, an alkyl. an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl( alkyl) or heterocyclyi(alkyi). An N-carbamyi may be substituted or unsubstituted.
[0057] An "O-thiocarbamy ' group refers to a "-OC^Si-NiRARB)'" group in which RA and R|¾ can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteiOaryl(alk ) or heterocyclyl(alk i). An O-thiocarbamyl may be substituted or unsubstituted.
[0058] An "N-thiocarbamy " group refers to an "ROC(=S)N(RA)-" group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl, aryl, heteroaryl. heterocyclyl. cycloalkyl(alkyl), aryl(alkyl). heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.
[0059] A "C-amido" group refers to a "-C(=0)N(RARB)" group in which RA and RB can be independently hydrogen, an alkyl. an alkenyl. an alkynyl. a cycloalkyl, a cycloalkenyl, aryl. heteroaryl. heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyi). A C-amido may be substituted or unsubstituted.
[0060] An "N-amido" group refers to a
Figure imgf000014_0002
group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl. a cycloalkenyl. aryl, heteroaryl, heterocyclyl. cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyi(alkyi). An N-amido may be substituted or unsubstituted. [0061] A "urea" group refers to "N(R)-C(=0)-NRARB group in which R can be hydrogen or an alky l, and R,\ and RB can be independently hydrogen, an alkyl, an alkenyl, an alkyny l, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocycly l, cycloalkyl(alkyl), ary l(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A urea may be substituted or unsubstituted.
[0062] The term ''halogen atom" or "halogen" as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
[0063] As used herein. " indicates a single or double bond, unless stated otherwise.
[0064] The term "interferon" is used herein as is commonly understood by one of ordinary skill in the art. Several types of interferons are known to those skilled in the art, such as Type 1 interferons, Type 2 interferons and Type 3 interferons. A non-limiting list of examples include: alpha-interferons, beta- interferons, delta-interferons, gamma interferons, lambda interferons, omega-interferons, tau-interferons, x-interferons, consensus interferons and asialo-interferons. Interferons can be pegylated. Examples of type 1 interferons include interferon alpha 1 A, interferon alpha 1 B. interferon alpha 2A, interferon alpha 2B, pegylated- interferon alpha 2a (PEGASYS, Roche), recombinant interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX. Aradigm). pegylated-interferon alpha 2b (ALBUFERON, Human Genome Sciences Novartis. PEGINTRON. Schering), recombinant interferon alpha 2b (TNTRON A, Schering), pegylated interferon alpha 2b (PEG-INTRON. Schering, V1RAFERONPEG, Schering), interferon beta- l a (REBIF, Serono, Inc. and Pfizer), consensus interferon alpha (INFERGEN, Valeant Pharmaceutical). Examples of type 2 interferons include interferon gamma 1. interferon gamma 2 and pegylated interferon gamma; and examples of type 3 interferons include interferon lambda 1 , interferon lambda 2 and interferon lambda 3.
[0065] Where the numbers of substituents is not specified (e.g. haloalkyi), there may be one or more substituents present. For example "haloalkyi" may include one or more of the same or different halogens. As another example, "C i -C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three atoms. [0066] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 1 1 :942-944 ( 1972)).
[0067] As used herein, the term "amino acid'" refers to any amino acid (both standard and non-standard amino acids), including, but not limited to. cc-amino acids, β- amino acids, γ-amino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to. alanine, asparagine, aspartate, cysteine, glutamate, glutamine. glycine, proline, serine, tyrosine, arginine, histidine. isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusine. 2-aminoisobutyric acid, dehydroalanine. gam ma-ami no butyric acid, citrulline, beta-alanine. alpha-ethyl-glycine. alpha-propyl-glycine and norleucine. As used herein, "amino acid" also includes amino acids wherein the main-chain carboxylic acid group has been converted to an ester group.
[0068] The terms "protecting group" and "protecting groups" as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unw anted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way. that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl: alkylcarbonyls and alkoxycarbonyls (e.g.. t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylearbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g.. trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tn-iso- propylsilyloxymethyi. [2-(trimethylsilyl)ethoxy]methyl or t-butyidiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1 ,3-dioxane, 1 ,3-dioxolanes, and those described herein); acyclic acctal; cyclic acctal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1 ,3-dithiane or 1 ,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4.4'-dimethoxytrityl (DMTr); 4.4'.4"-trimethoxytrityl (TMTr); and those described herein).
[0069] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamme, N-methyl-D-glucamine. tris(hydroxymethy l)methylamine, C]-C7 alkylamine. cyclohexylamine. triethanolamine. ethylenediamine. and salts with amino acids such as arginine and lysine.
[0070] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term 'including' should be read to mean "including, without limitation,' 'including but not limited to,' or the like; the term "comprising1 as used herein is synonymous with "including," 'containing," or 'characterized by,' and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term 'having' should be interpreted as 'having at least;' the term 'includes* should be interpreted as 'includes but is not limited to;* the term 'example* is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like 'preferably, " 'preferred,* 'desired," or 'desirable,' and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term "comprising" is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction "and" should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise. Similarly, a group of items linked with the conjunction Or" should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or* unless expressly stated otherwise.
[0071 ] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article "a" or '"an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
[00721 It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry' is not expressly indicated, then each center may independently be of -configuration or S-conllguration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.
[0073] Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.
[0074] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g.. hydrogen- 1 (protium) and hydrogen-2 (deuterium).
[0075] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
[0076] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol. or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as w7ell as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [0077] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
Compounds
Formula (1)
[0078] Some embodiments disclosed herein relate to a compound of Formula (1). or a pharmaceutically acceptable salt thereof, having the structure:
(I)
wherein: L can be selected from:
Figure imgf000020_0001
A can be selected from an optionally substituted cycloalkyl. an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted aryl(C i-2 alkyl), an optionally substituted heteroarvl and an optionally substituted heterocyclyl; Y can be selected from an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroarvl and an optionally substituted heterocvclvl: R, a, R, b, Rl c and Rl cl can be each independently hydrogen or an unsubstituted C alkyl; R2a, R2al , R2b, R2b l. R2c, R2c l , R2d and R2d l can be each independently selected from hydrogen, an optionally substituted Ci-4 alkyl, an optionally substituted aryl(Ci -6 alkyl), an optionally substituted heterocyclyl(C i_6 alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl and hydroxy; or R2a l can be hydrogen, and Rl a and R2a can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl. R2b l can be hydrogen, and Rl b and R2b can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl; -------- between XL A and X2D represents a single or double bond between XL A and
X2'1; between X2A and X3A represents a single or double bond between X2A and XJA; provided that -------- between XL A and X2A and between X2'1 and XJA cannot be both double bonds and at least one of is a double bond; when between XL D and X A represents a double bond and between X2A and X3A is a single bond, then X a can be N
(nitrogen) or CR4a l, X2A can be N (nitrogen) or CR5a and X A can be NR6a l, C(=0) or CR6a R6i"; and when -------- between XL A and X2A represents a single bond and -------- between X A and X3a is a double bond, then XL A can be NR4a or CR4a2R4a3, X2A can be N (nitrogen) or CR5a and X3a can be N (nitrogen) or CR6a; or X, A, X2A and X A can be each independently C (carbon), N (nitrogen), O (oxygen) or C(=0), and form a ring or ring system selected from an optionally substituted aryl, an optionally substituted hctcroaryl and an optionally substituted heterocyclyl by joining XL A and XJA together; with the proviso that the valencies of XLA, X2A and XJA can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C alkyl. and X L , X2A and X ,A are uncharged; R and R can be each independently selected from hydrogen, hydroxy, halogen, amino, an optionally substituted C M alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C i. 4 alkoxy, -O-carboxy, an optionally substituted heteroaryl, an optionally substituted
heterocyclyl. CHF2, CF3 and
Figure imgf000021_0001
provided that R',a and R3al cannot be both hydrogen; or R,a and R"1' can together form =N-ORa; or R3a and R,a l can together with the atom to which they are attached can be joined to form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, an optionally substituted 5 membered ring or an optionally substituted 6 membered ring; R4a, R4al, R4''2 and R4dJ can be each independently hydrogen or an unsubstitutcd C 1 -4 alkyl; R' a and R' "] can be each independently be hydrogen or an unsubstituted C alkyl; R6a and R6a l can be each independently hydrogen, an optionally substituted C alkyl or an optionally substituted alkoxyalkyl; R6a2 and R6aj can be each independently hydrogen or an unsubstituted C M alky l; Xl b. X2'1 and X3h can be each independently C (carbon), N (nitrogen). O (oxygen) or C(=0). and form a bi-cyclic ring selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl by joining Xl b and X3b together; provided that at least one of Xl , X2 and Xjb comprises a nitrogen atom; with the proviso that the valencies of Xl b, X2b and X'lb can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C M alkyl, and Xl b, X2b and X3b are uncharged; R,c and R~lU can be each independently selected from hydrogen, hydroxy, halogen, amino, an optionally substituted C alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted€"2-4 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C alkoxy, -O- carboxy, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, CHF2,
CF3 and
Figure imgf000022_0001
provided that R,c and R 'c l cannot be both hydrogen; or R 'c and R,c l can together form =N-ORc; or R ' and R ,c l can together with the atom to which they are attached can be joined to form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, an optionally substituted 5 membered ring or an optionally substituted 6 membered ring; Ra and R1" can be each independently hydrogen or an unsubstituted C alkyl; R4c and R5c can be taken together to form an unsubstituted aryl, an unsubstituted heteroaryl or an optionally substituted heterocyclyl; ZL can be N or CH; m l can be 0 or 1 ; and ring Bd can be an optionally substituted C5 cycloalkyl; ring Bc" can be an optionally substituted pyridinyl; and provided that when L is Formula (11c), then Y is absent. Formula (la)
[0079] In some embodiments, L can be Formula (la):
Figure imgf000023_0001
[0080] In some embodiments of Formula (la), XL A can be CR4A L or CR4A2R4A3, X A can be N (nitrogen), and X, can be CR A or CR6A2R6AJ. In some embodiments of Formula
(la), between XL D and X2 can be a single bond, between X2 and XJA can be a double bond, X L A can be CR4A2R4A3, X2A can be N (nitrogen), and X B can be CR6A. In other embodiments of Formula (la), -------- between X L A and X2A can be a double bond, -------- between X2A and XJA can be a single bond, XL A can be CR4 L . X2B can be N (nitrogen), and XJB can be CR6A2R6 '. In some embodiments, including those of this paragraph, R?A can be hydrogen. In some embodiments including those of this paragraph. RSA L can be hydrogen. In some embodiments, -XL A X2A X3a- can be -CH2-N=CH- or -CH=N-CH2-. In other embodiments, -X L A- X2A X3A- can be -N=N-CH2-. -N=CH-CH2- or -N=CH-NH-. In still other embodiments, -XL A -X A X3A- can be -CH2-CH=N-, -NH-CH=NH- or -NH-
N=CH-. In some embodiments, XL A, X2A and X'1'1 can be each independently C (carbon), N (nitrogen), O (oxygen) or C(=0), and form a ring or ring system selected from an optionally substituted aryi, an optionally substituted heteroaryl and an optionally substituted heterocyclyi by joining XL A and X",A together; with the proviso that the valencies of XL A, X2A and X,A can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C alkyi; and XL A, X2A and XJ are uncharged.
Formula (lal )
[0081 ] In some embodiments, L of Formula (la) can be Formula (lal ):
Figure imgf000024_0001
wherein: X, A, X2A and X3A can be each independently C (carbon), N (nitrogen), O (oxygen) or C(=0), and form a ring or ring system selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl by joining XL D and X3D together; with the proviso that the valencies of X L D, X2D and X3a can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C alkyl; and XL A. X2A and X3A are uncharged.
[0082] In some embodiments of Formula (lal ). XL A can be C. X2A can be N and
X "' can be C. In some embodiments of Formula (lal ). between XL A and X2A can be a single bond. between X A and XJA can be a double bond, XL A can be C, X2A can be N and X',A can be C. In other embodiments of Formula (lal ). between X and X2A can be a double bond, between X2A and X3D can be a single bond. XL D can be C. X2A can be
N and X'1'1 can be C. In still other embodiments of Formula (lal ), between XL D and
X2D can be a single bond, -------- between X2A and X~'D can be a single bond, X1 '1 can be C, X2A can be O and X',D can be C. In some embodiments, the valencies of XL A, X2A and X A can be each independently satisfied with hydrogen or an unsubstituted C alkyl, such as CFF¾.
[0083] In some embodiments, the ring or ring system of Formula (lal) can be an optionally substituted aryl. In other embodiments, the ring or ring system of Formula (lal ) can be an optionally substituted mono-cyclic heteroaryl. In still other embodiments, the ring or ring system of Formula (lal ) can be an optionally substituted bi-cyclic heteroaryl. In some embodiments, the ring or ring system of Formula (lal ) can be an optionally substituted monocyclic heterocyclyl. In some embodiments, the ring or ring system of Formula (lal ) can be an optionally substituted bi-cyclic heterocyclyl.
Figure imgf000025_0001
[0084] In some embodiments of Formula (lal ). can be uted uted uted uted
Figure imgf000025_0002
, an optionally substituted an optionally substituted , an
optionally substituted
optionally substituted
Figure imgf000025_0003
and an optionally substituted
wherein RA I , RA2. RA3 and RA4 can be each independently hydrogen or an unsubstituted C i -6 alkvl. 2a
X 1 X 3a
[008 embodiments, an optionally
substituted
Figure imgf000026_0001
. In some embodiments, be substituted with one or more substituents selected from amino, mono-substituted amino, di-substituted
Figure imgf000026_0002
amino, hvdroxyalkyl, alkyl and alkoxy. In some embodiment can be
In other embodiments, can be a
substituted e embodiments,
Figure imgf000026_0003
an optionally substituted or an optionally
substituted
Figure imgf000026_0004
Rja can e hydroxy and Rjal can be selected from amino, an unsubstituted C alkyl. an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C3-6 cycloalkyl (for example, cyclopropyl). an unsubstituted C M alkoxy (such as OCH3). hydroxy, halogen and an unsubstituted heteroary l (for example, thiazole).
[0086] In so n one of and R'a' is H and the other of R"1
and R3a l is OH. then
Figure imgf000026_0005
is not an unsubstituted In other embodiments, when one of R3a and R3a l is H, then the other of R3a and R3al is not OH.
Figure imgf000027_0001
In some embodiments, is not an optionally substituted pyrimidine. In ompound of Formula (1) cannot
Figure imgf000027_0002
Formula (Ia2)
[0087] In some embodiments. L of Formula (la) can be Formula (Ia2):
Figure imgf000027_0003
(Ia2)
wherein R7a l , R'1'2 and R'11J can be each independently selected from hydrogen, halogen, hydroxy, an optionally substituted C i -8 alkyl, an optionally substituted C2-8 alkenyl, an optionally substituted C2-8 alkynyl. an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl. an optionally substituted heteroaryl, an optionally substituted heterocyclyl. an optionally substituted hydroxyalkyl, an optionally substituted C i -8 alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino, halo(C i -8 alkyl), haloalkyl, an optionally substituted O-amido and an optionally substituted C-carboxy. In some embodiments, R7a lcan be an unsubstituted C | -4 alkoxy, and R7a2 and R7'1'1 can be both hydrogen. In other embodiments, R7a'can be a substituted C | - alkoxy, and R7a2 and R7a'' can be both hydrogen. For example, R7alcan be a substituted C | -4 alkoxy substituted with an amino, mono-substituted amino or a di-substituted amino. In some embodiments, R7a l can be hydrogen, R/a2 can be an optionally substituted C | - alkyl, and R/a3 can be hydrogen. In other embodiments, R7d l can be hydrogen, R7d2 can be a substituted C3-6 cycloalkyl, and R" can be hydrogen. In still other embodiments, R7al can be hydrogen. R'a2 can be a mono- substituted amino, and R7d3 can be hydrogen. In yet still other embodiments, R7d l can be a mono-substituted amino or an optionally substituted O-amido (such as -C(=0)NH2) and R'd2 and R dJ can be both hydrogen. For example, the mono-substituted amino of R7a l or R7a2 can be -N(Ci-4 alkyl). such as -NCH3. In some embodiments, R7a l can be a substituted Ci-8 alky 1 (such as an amino substituted Ci-8 alkyl) and R7a2 and R7aj can be both hydrogen. In other embodiments, R7a l and R7a2 can be both hydrogen and R7aj can be halogen. In other embodiments, R7d l and R7a3 can be both hydrogen and R7a2 can be an optionally substituted heterocyclyl, such as an optionally substituted mono-cyclic heterocyclyl. Examples of optionally substituted mono-cyclic heterocyclyl at R7a2 include, but are not limited to, an optionally substituted azetidine, an optionally substituted pyrrolidine, an optionally substituted pyrrolidinone, an optionally substituted piperidine and an optionally substituted oxetane.
[0088] When R7al , R7a2 and/or R7a3 are substituted, possible substituent(s) includes those provided in the list of "substituted*' along with urea, amidine and acetylurea. For example, the C alkyl, C3-6 cycloalkyl and mono-cyclic heterocyclyl of R7a2 can be substituted with various substituent(s), such as, halo, hydroxy, C M alkoxy, an optionally substituted aryl(C i _4 alkyl), an optionally substituted C-carboxy, amino, an optionally substituted mono-substituted amino, an optionally substituted di -substituted amino, an optionally substituted C-amido, an optionally substituted N-amido, an optionally substituted N-carbamyl, an optionally substituted N-sulfonamido, an optionally substituted urea, an optionally substituted amidine and an optionally substituted acetylurea (e.g.. halogenated acetylurea). Non-limiting examples of substituted C alkyls and substituted C3.6 cycloalkyls of R7a2 are as follows:
NH, ,NH(CH3) N(CH3)2
-(CH2)-NH(=0)C N H
Figure imgf000028_0001
Figure imgf000029_0001
Formula (la3)
[0089] In some embodiments, L of Formula (la) can be Formula (Ia3):
Figure imgf000029_0002
Ia3) wherein: the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted cycloalkyl an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl; and R8aj can be selected from hydrogen, halogen, hydroxy, an optionally substituted Ci-s alkyl, an optionally substituted C2- x alkenyl. an optionally substituted C2-8 alkynyl. an optionally substituted C3-6 cycloalkyl. an optionally substituted aryl. an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl. an optionally substituted C i- alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino. h lo(C i.8 alkyl), haloalkyl and an optionally substituted C-carboxy.
[0090] In some embodiments of Formula (la3), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered cycloalkyl. In other embodiments of Formula (Ia3), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered cycloalkyl. In still other embodiments of Formula (Fa3). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted aryl (for example, phenyl). In some embodiments of Formula (Ia3), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heteroaryl. In other embodiments of Formula (Ia3). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered heteroaryl. In still other embodiments of Formula (la3). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heterocyclyl. In yet still other embodiments of Formula (la3). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6- membered heterocyclyl.
[0091| In some embodiments, the bicyclic ring system can be selected from an
optionally substituted
Figure imgf000030_0001
, an optionally substituted an optionally substituted
Figure imgf000031_0001
; wherein each - can be independently absent
, A6 . A7
or a bond; each RA?. each Rrt°. each RA' can be halogen, an unsubstituted C|-6 alkyl, hydroxy, amino, an optionally substituted mono-substituted amino, an optionally substituted di- substituted amino, -(CH2)i_40H, -(CH2)i -4NH2 or N-sulfmamido (for example, -NH- S(=0)C alkyl), or two RA\ two RA6 or two RA7 are taken together to form an optionally substituted 5- membered ring to an optionally substituted 6-membered ring (such as an optionally substituted cvcloalkvl or an optionally substituted heterocyclyl); and RA8 can be hydrogen or an unsubstituted C i-6 alkyl. In some embodiments of this paragraph. can be absent. In some embodiments of this paragraph, - can be a bond such that a double bond is present between the between carbons. In some embodiments, at least two RA:< groups can be an unsubstituted Ci-6 alkyl (for example, CH3). In some embodiments, at least two RA6 groups can be an unsubstituted C|-6 alkyl (for example, CH3). Examples of these bi-cyclic groups include the following:
Figure imgf000032_0001
[0092] In some embodiments of Formulae (la), (lal ). (Ia2) and/or (Ia3). R a can be hydrogen. In other embodiments of Formulae (la). (lal ). (Ia2) and/or (Ia3), Rl d can be an unsubstituted C i-4 alkyl.
[0093] In some embodiments of Formulae (Ta), (lal ), (Ia2) and/or (Ia3). both R2a and R2a l can be hydrogen. In other embodiments of Formulae (la). (lal ), (Ia2) and/or (Ia3). R2a can be hydrogen and R2al can be an unsubstituted C alkyl. In still other embodiments of Formulae (la), (lal), (Ia2) and/or (Ia3 ), R2a can be hydrogen and R2a l can be a substituted C M alkyl. In yet still other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), R2a can be hydrogen and R2al can be an optionally substituted aryl(C| -6 alkyl) or an optionally substituted heterocyclyl(C|- alkyl). In some embodiments of Formulae (la), (lal), (Ia2) and/or (la3), R2a can be hydrogen and R2dl can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), R2d can be hydrogen and R2al can be hydroxy . In still other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3). R2a l can be hydrogen, and Rl a and R2 can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl (for example, pyrrolidinyl) or an optionally substituted 6 membered heterocyclyl (for example, piperdinyl). In yet still other embodiments of Formulae (la), (lal ), (la2) and/or (Ia3). R and both can be an optionally substituted C alkyl.
[0094] In some embodiments of Formulae (la), (lal ). (Ia2) and/or (Ia3). R3a can be hydrogen, and R"ia l can be selected from amino, an unsubstituted C M alkyl, an unsubstituted C2-4 alkenyi. an unsubstituted C2-4 alkynyl, an unsubstituted C3.6 cycloalkyl (for example, cyclopropyl), an unsubstituted C alkoxy (such as OCH3). an unsubstituted -O- carboxy (such as -OC(=0)C |-4 alkyl), hydroxy, halogen, an unsubstituted heteroaryl (for example, thiazole) and an optionally substituted hctcrocyclyl (for example, azetidinc). In some embodiments of Formulae (la). (lal ), (Ia2) and/or (Ia3). R'a can be hydrogen, and Rja l can be hydroxy. In other embodiments or Formulae (la). (lal ). (Ia2) and/or (Ia3). R3a and Rja l can be both halogen. In still other embodiments of Formulae (la). (lal ). (Ia2) and/or (Ia3), Rja can be hydrogen, and Rjal can be unsubstituted C alkyl. In yet still other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), R"' can be hydroxy, and R3d l can be selected from amino, an unsubstituted C alkyl, an unsubstituted C2-4 alkenyl. an unsubstituted C2-4 alkynyl, an unsubstituted C3-6 cycloalkyl (for example, cyclopropyl), an unsubstituted C i-4 alkoxy (such as OCH3), hydroxy, halogen, an unsubstituted heteroaryl (for example, thiazole) and an optionally substituted heterocyclyl (for example, azetidine). In some embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), Rja can be hydroxy, and R~1dl can be an unsubstituted C alkyl. In other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), Rja can be hydroxy, and R,al can be an unsubstituted C2-4 alkenyl (such as ethenyl or propenyl) or an unsubstituted C2-4 alkynyl (such as ethynyl or propynyl). In still other embodiments of Formulae (la), (lal ). (Ia2) and/or (Ia3), R,a can be hydroxy, and R 'dl can be CF3. In yet still other embodiments of Formulae (la), (lal ), (Fa2) and/or (Ia3), Rja can be hydroxy, and R3a l can be CHF2. In some embodiments of Formulae (la). (lal ), (Ia2) and/or (Ia3), R'a can be halogen, and R,al can be CF3 or CHF2. In other embodiments of Formulae (la). (lal ), (Ta2) and/or (la3 ), Ria can be halogen, and Rja l can be CHF2. In some embodiments of Formulae (la). (lal ), (Ia2) and/or (Ia3), R"' can be hydroxy, and R3d l can be an unsubstituted C3-6 cycloalkyl. for example, an unsubstituted cyclopropyl. In some embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), R"1 can be halogen, and R~1d l can be an unsubstituted C3-6 cycloalkyl, for example, an unsubstituted cyclopropyl. In other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3 ), R'd can be an unsubstituted C M alkoxy (such as methoxy), and R",a l can be an unsubstituted C alkyl (such as methyl). In still other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), R1d and Rial can be both an unsubstituted C M alkyl, for example, Rja and R,al can be both methyl. In yet sill other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), one of Ria and R'dl can be an optionally substituted mono-cyclic heteroaryl; and the other of R3a and R a I can be hydroxy. In some embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3 ), one of Rja and RJdl can be an unsubstitutcd C1 -4 alkyl (such as methyl) ; and the other of R3a and R'a l can be an unsubstituted -O-carboxy (such as -OC(=0)Ci -4 alkyl).
[0095] When one of R3a and R3al is a substituted C alkyl, the C M alkyl can be substituted with various substituents. For example, in some embodiments, one of R,a and R is a substituted C ] _4 alkyl substituted with substituent selected from halogen, hydroxy, amino, mono-substituted amino (for example, -NH(C M alkyl)). di-substituted amino, -N- amido. mono-cyclic heteroaiyl and mono-cyclic heterocyclyl. In some embodiments, one of R'a and Rj l can be an optionally substituted mono-cyclic heteroaryl or an optionally substituted mono-cyclic heterocyclyl and the other of R3a and R'1'1' can be hydroxy. The mono-cyclic heteroaryl substituted on the C alkyl of one of R3a and Rja l can be 5- membered or 6-membered heteroaryl. The mono-cyclic heterocyclyl substituted on the C alkyl of one of Ria and R'1'1' can be 4-membered, 5-membered or 6-membered heterocyclyl. For example, one of Rja and R,a l can be a substituted C alkyl substituted with substituent selected from an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperazinc, an optionally substituted morpholine, an optionally substituted triazole, an optionally substituted piperazinone and an optionally substituted azetidine.
[0096] In some embodiments of Formulae (la). (lal ). (Ia2) and/or (Ia3). R,a and R,a l can together form N=ORa. In some embodiments of Formulae (la), (lal ). (Ia2) and/or (Ia3), Ria and R,al together form N=OH. In other embodiments of Formulae (la), (lal ). (Ia2) and/or (Ia3), Rja and R",al can together form N=OCH3. In some embodiments of Formulae (la). (lal ), (Ia2) and/or (Ia3). R',d and R'1'1' can join together with the atom to which they are attached to form an optionally substituted 3 to 6 membered ring. In some embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), the 3 to 6 membered ring can be a C3-6 cycloalkyi. In other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), the ring can be a 3 to 6 membered heterocyclyl, for example, an optionally substituted oxetane or an optionally substituted oxazolidinone. In some embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), the carbon to which R,a and R,dl are attached can be a chiral center. When the carbon to which Rja and Ria l are attached a chiral center, in some embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3). the carbon can have a (R)-configuration. In other embodiments of Formulae (la), (lal ), (Ia2) and/or (Ia3), the carbon to which R ,a and R'al are attached can have a (S)-configuration.
Formula (lb)
[0097] In some embodiments, L of Formula (I) can be Formula (lb):
Figure imgf000035_0001
(lb).
wherein the dotted curved line between XL B and X 'B indicates a bi-cyclic ring selected from an optionally substituted bi-cyclic heteroaryl and an optionally substituted bi-cyclic heterocyclyl by joining XL B and XJB together, wherein between XL B and X2 represents a single or double bond between XL B and X2B; between X2B and X~LB represents a single or double bond between X2B and X B; wherein XL , X2B and X3B can be each independently C (carbon), N (nitrogen), O (oxygen) or C(=0); and provided that at least one of XL H, X2B and X,B comprises a nitrogen atom and both -------- cannot be double bonds; with the proviso that the valencies of XL B. X B and XJB can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C i_4 alkyl; and XL B, X2B and X3B are uncharged. In some embodiments, the valencies of Xl b, X2b and Xjb can be each independently satisfied with a substituent selected from hydrogen and an unsubstituted C alkyl. In some embodiments, the valencies of XL B, X2B and X3B can be each independently satisfied with hydrogen or methyl.
[0098] In some embodiments of Formula (lb), the bi-cyclic ring can be an optionally substituted 9-membered bi-cyclic heteroaryl. In other embodiments of Formula (lb), the bi-cyclic ring can be an optionally substituted 9-membered bi-cyclic heterocyclyl. In still other embodiments of Formula (lb), the bi-cyclic ring can be an optionally substituted 10-membered bi-cyclic heteroaryl. In yet still some embodiments of Formula (lb), the bi- cyclic ring can be an optionally substituted 10-membered bi-cyclic heterocyclyl. [0099] In some embodiments of Formula (lb), Xl b can be C, X2b can be N and X3b can be C. In other embodiments of Formula (lb), Xl b can be N, X2b can be N and X3b can be C. In still other embodiments of Formula (lb), Xl b can be N, X2b can be C(=0) and X'b can be N. In yet still other embodiments of Formula (lb), Xl b can be C, X2b can be O and X'b can be C.
[0100] In some embodiments of Formula (lb), when Xl b can be C, X b can be N and X'b can be C, the bi-cyclic ring can be an optionally substituted bi-cyclic heteroaryl ring. In other embodiments of Formula (lb), when Xl b can be C, X2b can be N and X3b can be C. the bi-cyclic ring can be an optionally substituted bi-cyclic heterocyclyl ring.
Formula (lb 1 )
[0101] In some embodiments, L of Formula (lb) can be Formula (Ibl ):
Figure imgf000036_0001
(Ib l )
wherein: the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl; and R4b3 can be selected from hydrogen, halogen, hydroxy, an optionally substituted Ci -8 alkyl, an optionally substituted C2- 8 alkenyl, an optionally substituted C2-8 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl. an optionally substituted heteroaryl. an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl. an optionally substituted Ci-8 alkoxy, an optionally substituted alkoxyalkyl. amino, mono-substituted amino, di-substituted amino. halo(C ] _8 alkyl), haloalkyl and an optionally substituted C-carboxy.
[0102] In some embodiments of Formula (Ibl ), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered cycloalkenyl. In other embodiments of Formula (Ibl), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered cycloalkenyl. In still other embodiments of Formula (Ibl ). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted aryl (for example, pheny l). In some embodiments of Formula (Ib l ). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heteroaryl. In other embodiments of Formula (Ibl ), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered heteroary . In still other embodiments of Formula (Ibl ). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heterocyclyl. In yet still other embodiments of Formula (Ibl ), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6- membered heterocyclyl.
[0103| In some embodiments the bi-c clic rin s stem can be selected from an
optionally substituted
optionally substituted
Figure imgf000037_0001
an optionally substituted and an optionally
substituted
Figure imgf000037_0002
; wherein each can be independently absent or a bond; each RB I . each RB2 and each RB3 can be an unsubstituted C i-6 alkyl. halogen, hydroxy, amino, mono-substituted amino, di-substituted amino or -NH-S(=0)C i.4 alkyl; and RB4 can be hydrogen or an unsubstituted C i-6 alkyl,. In some embodiments of this paragraph, can be absent. In some embodiments of this paragraph, can be a bond such that a double bond is present between the between carbons. In some embodiments, at least two RB2 groups can be an unsubstituted C | -6 alkyl (for example, CH3). In some embodiments, at least two RBj groups can be an unsubstituted Ci-6 alkyl (for example, CII ). Examples of these bi- cyclic groups include the following:
Figure imgf000038_0001
[0104] In some embodiments of Formulae (lb) and (Ibl ), Rlb can be hydrogen.
[0105] In some embodiments of Formulae (lb) and (Ibl), both R2 and R2bl can be hydrogen. In other embodiments of Formulae (lb) and (Ibl), R2b can be hydrogen and R2bl can be an unsubstituted CM alkyl. In still other embodiments of Formulae (lb) and (Ibl), R2b can be hydrogen and Rbl can be a substituted C alkyl. In yet still other embodiments of Formulae (lb) and (Ibl), R2b can be hydrogen and R2bl can be an optionally substituted aryl(Ci-6 alkyl) or an optionally substituted heterocyclyl(Ci-6 alkyl). In some embodiments of Formulae (lb) and (Ibl), R b can be hydrogen and R bl can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In other embodiments of Formulae (lb) and (Ibl), R2b can be hydrogen and R2bl can be hydroxy. In still other embodiments of Formulae (lb) and (Ibl), R bl can be hydrogen, and Rl b and R2b can be joined together with the atoms to which they are attached to form an optionally substituted 5 mcmbercd hcterocyclyl or an optionally substituted 6 membered heterocyclyl.
Formula (lc)
[0106] In so
Figure imgf000039_0001
(Ic).
[0107] In some embodiments of Formula (Ic), RL C can be hydrogen. In other embodiments of Formula (Ic), RK can be an unsubstituted C alkyl.
[0108] In some embodiments of Formula (Ic), both R2 and R2 L can be hy drogen. In other embodiments of Formula (lc), R2C can be hydrogen and R C L can be an unsubstituted C M alkyl. In still other embodiments of Formula (Ic), R2° can be hydrogen and R C L can be a substituted C M alkyl. In yet still other embodiments of Formula (Ic). R2l can be hydrogen and R2U can be an optionally substituted aryl(C i_6 alkyl) or an optionally substituted heterocyclyl(C i-6 alkyl). In some embodiments of Formula (lc), R2l can be hydrogen and R2C L can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In other embodiments of Formula (Ic), R2c can be hydrogen and R2c 1 can be hydroxy. In still other embodiments of Formula (Ic), R'c and R-c l both can be an optionally substituted C alkyl.
[0109] In some embodiments of Formula (Ic), R,c can be hydrogen, and R,c l can be selected from amino, an unsubstituted C alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C3-6 cycloalkyl (for example, cyclopropyl), an unsubstituted C M alkoxy (such as OCH3), hydroxy, halogen and an unsubstituted heteroaryl (for example, thiazole). In some embodiments, R 'c can be hydrogen, and RJC | can be hydroxy. In other embodiments. RJC and R,c l can be both halogen. In still other embodiments, RJC can be hydrogen, and R 'cl can be unsubstituted CM alkyl. In yet still other embodiments of Formula (Ic). RJL can be hydroxy , and RJL l can be selected from amino, an unsubstituted C M alkyl. an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C3-6 cycloalkyl (for example, cyclopropyl), an unsubstituted C alkoxy (such as OCH3), hydroxy, halogen and an unsubstituted heteroaryl (for example, thiazole). In some embodiments of Formula (Ic). RJ can be hydroxy, and RjU can be an unsubstituted C alkyl. In some embodiments of Formula (Ic). R ' and RJC | can together form N=ORc. for example, N=OH or N=OCH3. In some embodiments of Formula (Ic). RJC and Rjc l can join together with the atom to which they are attached to form an optionally substituted 3 to 6 membered ring. In some embodiments, the 3 to 6 membered ring can be a C3-6 cycloalkyl. In other embodiments, the ring can be a 3 to 6 membered heterocyclyl. for example, an optionally substituted oxetane. In some embodiments, the carbon to which R'1L and R~1L l are attached can be a chiral center. When the carbon to which R3t and R3e 1 are attached a chiral center, in some embodiments, the carbon can have a ( Reconfiguration. In other embodiments, the carbon to which R1C and R",c l are attached can have a (S)-configuration.
[0110] In some embodiments of Formula (Ic), Zc can be N. In some embodiments of Formula (Ic), Zc can be CH.
[0111] In some embodiments of Formula (Ic), R4c and R'1C can be taken together to form an unsubstituted aryl (for example, pheny l). In other embodiments of Formula (Ic), R4c and R5c can be taken together to form an unsubstituted heteroaryl, such as piperdinyl. In still other embodiments of Formula (Ic), R4 and R? can be taken together to form an optionally substituted heterocyclyl. In some embodiments, the optionally substituted heterocyclyl can be an optionally substituted tricyclic heterocyclyl, such as an optionally
Figure imgf000040_0001
substituted, O wherein * each indicate a point of attachment to the 6-membered ring.
Formula (Id)
[0112] In some embodiments, L can be Formula (Id):
Figure imgf000041_0001
[0113] In some embodiments of Formula (Id), l d can be hydrogen. In other embodiments of Formula (Id ). Rl d can be an unsubstituted C alkyl.
[0114] In some embodiments of Formula (Id), both R2d and R2d l can be hydrogen. In other embodiments of Formula (Id), R2d can be hydrogen and R2c" can be an unsubstituted C| _4 alkyl. In still other embodiments of Formula (Id), R2d can be hydrogen and R d l can be a substituted C alkyl. In yet still other embodiments of Formula (Id), R d can be hydrogen and R2d l can be an optionally substituted aryl(Ci-6 alkyl) or an optionally substituted hctcrocyclyl(C i-6 alkyl). In some embodiments of Formula (Id), R2d can be hydrogen and R2 " can be an alkoxyalkyl. an aminoalkyl or a hydroxyalkyl. In other embodiments of Formula (Id). R2d can be hydrogen and R2d l can be hydroxy. In still other embodiments of Formula (Id), R2d and R2d l both can be an optionally substituted C alky l.
[01 15] In some embodiments of Formula (Id), md can be 0. In other embodiments of Formula (Id). md can be 1 .
[01 16] In some embodiments of Formula (Id), ring Bd can be an optionally substituted C5 cycloalkyl. In some embodiments, ring Dd can be an optionally substituted
Figure imgf000041_0002
[0117] In some embodiments of Formula (Id), ring Bd l can be an optionally
substituted pyridinyl having the structure
Figure imgf000041_0003
The C5 cycloalkyl and/or pvridinyl ring can be unsubstituted or substituted with one or more substituents. Suitable substituents include, but are not limited to, amino, mono-substituted amino, di-substituted amino, hydroxyalkyl, alkyl and alkoxy. [0118] In some embodiments, A can be substituted. In other embodiments, A can be unsubstituted. When A is substituted, possible substituent(s) includes those provided in the list of "substituted" along with those described herein.
[01 19] In some embodiments, A can be an optionally substituted aryl. For example, A can be an optionally substituted phenyl. In some embodiments, A can be a para- substituted phenyl, a meta-substituted phenyl or an ortho-substituted phenyl. In some
Figure imgf000042_0001
substituted with 3 more substituents. In other embodiments, A can be unsubstituted phenyl. In some embodiments, A can be an optionally substituted naphthyl.
[0120] In some embodiments and without limitation, A can be a phenyl substituted with one or more substituents selected from an unsubstituted C alkyl, an optionally substituted C M alkyl, cycloalkyl, hydroxy, an optionally substituted C alkoxy, C M alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, mono- substituted amino, di-substituted amino, -O-amido, sulfenyl, alkyoxyalkyl, an optionally substituted aryl (for example, an optionally substituted phenyl), an optionally substituted monocyclic heteroaryl. an optionally substituted monocyclic heterocyclyl, an optionally substituted aryl (C alky l), an optionally substituted monocyclic heteroaryl(C| _4 alkyl), an optionally substituted monocyclic heterocyclyl(C M alkyl). hydroxyalkyl and aminoalkyl. In some embodiments, the optionally substituted C M alkoxy can be further substituted, for example, further substituted with a substituent selected from C alkyl, halo, hydroxy, C- carboxy, C-amido. amino, mono-alkyl amine, di-alkyl amine and an amino acid. In some embodiments, the optionally substituted haloalkoxy can be further substituted, for example. further substituted with an C | - alkoxy. In some embodiments, the optionally substituted heteroaryl can be further substituted, for example, further substituted with an C alkyl.
[0121 ] Examples of suitable substituents include, but are not limited to, methyl, ethyl, propyl (n-propyl and iso-propyl). butyl (n-butyl, iso-butyl and t-butyl). hydroxy, methoxy , ethoxy . propoxy (n-propoxy and iso-propoxy), butoxy (n-butoxy , iso-butoxy and t- butoxy ). phenoxy. bromo, chloro, fluoro, trifluoromethyl, difluoromethoxy , trifluoromethoxy. cyano, N,N-di-methyl-amine, N.N-di-ethyl-amine. N-methyl-N-ethyl-amine, N-methyl- amino. N-ethyl-amino, amino, N-amido (for example, -NH-C(=0)C M alkyl). alkylthio (such as CH3CH2S-), N-sulfonamido (for example, -NH-S(0)2C M alkyl), an optionally substituted phenyl, an optionally substituted imidazole, an optionally substituted morpholinyl, an optionally substituted pyrazole, an optionally substituted pyrrolidinyl. an optionally substituted pyridinyl, an optionally substituted piperidinyl, an optionally substituted piperidinone, an optionally substituted pyrrolidinone, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted 1 ,2,4-oxadiazole, -(CH2) M-OH, - (CH2)i- -NH(CH3), an optionally substituted -(CH )i-2-imidazole, an optionally substituted - (CH2) i-2-pyn*olidinone, an optionally substituted -(CH2) i -2-imidazolidinone. -0(CH2) -NH2, - 0(CH2)2-NH(CH3), -0(CH2)2-N(CH3)2, -0-(CH2)2^OH, -0(CH2)2OCH3. an optionally substituted -O(CH2)0-2-cyclopentanone. an optionally substituted -0(CH2)o-2pyrrolidinone. an optionally substituted -0(CH2)o-2-morpholinyl. an optionally substituted -0(CH2)o-2-triazole. an optionally substituted -O(CH2)0-2-imidazole, an optionally substituted -O(CH2)0-2- pyrazole, an optionally substituted -O(CH2)0-2-tetrahydrofuran, an optionally substituted - 0 CH2)o-2-pyrrolidinone, an optionally substituted -O(CH2)0-2-tetrazole, an optionally
Figure imgf000043_0001
Figure imgf000044_0001
[0122] In some embodiments, A can be an optionally substituted cycloalkyl. Suitable examples of optionally substituted cycloalkyls include, but are not limited to, an optionally substituted cyclohexyl and an optionally substituted cycloheptyl. In other embodiments, A can be an optionally substituted cyeloalkenyl, for example, an optionally substituted cy embodiments, A can be an optionally substituted bi-cyclic
Figure imgf000044_0002
cyeloalkenyl, such as
[0123] In some embodiments, A can be an optionally substituted aryl(C i-2 alkyl). In some embodiments. A can be an optionally substituted benzyl.
[0124] In some embodiments. A can be an optionally substituted mono-cyclic heteroaryl. In some embodiments, A can be an optionally substituted mono-cyclic 5- membered heteroaryl. In other embodiments, A can be an optionally substituted mono-cyclic 6-membered heteroaryl. In some embodiments, A can be an optionally substituted bi-cyclic heteroaryl. [0125] In some embodiments, the optionally substituted heteroaryl can be selected from an optionally substituted imidazole, an optionally substituted thiazole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted pyridine, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted quinoline, an optionally substituted imidazole, an optionally substituted oxazole, an optionally substituted isoxazole, an optionally substituted benzoimidazole. an optionally substituted benzooxazole, an optionally substituted benzothiazole and an optionally substituted imidazo[l ,2-a]pyrimidine. In some embodiments, A can be an optionally substituted thiophene. In other embodiments, A can be an optionally substituted thiazole. In still other embodiments, A can be an optionally substituted pyridine. In yet still other embodiments, A can be an optionally substituted pyrimidine. In some embodiments, A can be an optionally substituted pyrazine. In other embodiments, A can be an optionally substituted imidazole. In still other embodiments, A can be an optionally substituted benzoimidazole. an optionally substituted benzooxazole or an optionally substituted benzothiazole.
[0126] In some embodiments, A can be an optionally substituted heterocyclyl, for example, an optionally substituted mono-cyclic heterocyclyl or an optionally substituted bi- cyclic heterocyclyl. In some embodiments, A can be an optionally substituted
Figure imgf000045_0001
. In other embodiments, A can be an optionally substituted
In still other embodiments, A can be an optionally substituted In yet still
other embodiments. A can be an optionally substituted
Figure imgf000045_0002
In some
embodiments, A can be an optionally substituted
Figure imgf000045_0003
. In other embodiments, A can be an optionally s In still other embodiments. A can be an
optionally still other embodiments. A can be an
optionally e embodiments. A can be an optionally
substituted
Figure imgf000046_0001
[0127] In some embodiments, A can be substituted with one or more R 's. In some embodiments, one RA can be present. In some embodiments, two RA"s can be present. In some embodiments, three RA's can be present. In some embodiments, four or more RA,s can be present. When two or more RA*s are present, two or more RA,s can be the same or two or more RA,s can be different. In some embodiments, at least two RA,s can be the same. In some embodiments, at least two RA"s can be different. In some embodiments, all the RA,s can be the same. In other embodiments, all the RA,s can be different. In some embodiments.
can have one of the following structures
Figure imgf000046_0002
Figure imgf000046_0003
[0128] In some embodiments, R can be each independently selected from an unsubstituted C alkyl, an optionally substituted C M alkyl, cycloalkyl, hydroxy, an optionally substituted C alkoxy, C M alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, mono-substituted amino, di-substituted amine, sulfenyl, alkyoxyalkyl, aryl, monocyclic heteroaryl. monocyclic heterocycly l and aminoalky l. In some embodiments, the optionally substituted C | -4 alkoxy can be further substituted, for example, further substituted with a substituent selected from C alkyl, halo, hydroxy, C-carboxy, C- amido. N-amido. amino, mono-alkyl amine, di-alkyl amine and an amino acid. In some embodiments, the optionally substituted haloalkoxy can be further substituted, for example, further substituted with an C M alkoxy. In some embodiments, the optionally substituted heteroaryl can be further substituted, for example, further substituted with an C M alkyl.
[0129] In some embodiments, each RA can be an alkyl. such as methyl, ethyl, propyl (n -propyl and iso-propyl) and/or butyl (n-butyl. iso-butyl and t-butyl).
[0130] In some embodiments, each RA can be an optionally substituted alkoxy. for example, methoxy, ethoxy, propoxv (n-propoxy and iso-propoxy). butoxy (n-butoxy. iso- butox and t-butoxy), phenoxy, -0(CH2)2-NH2, -0(CH2)2-NH(CH3), -0(CH2)2-N(CH3)2, -O-
Figure imgf000047_0001
an optionally substituted -O(CH2)0-2-morpholinyl, an optionally substituted -O(CH2)0-2- triazole, an optionally substituted -0(CH2)o-2-iniidazole, an optionally substituted -O(CH2)0_2- cyclopentanone, an optionally substituted -0(CH2)o-2pyiTolidinone, an optionally substituted - 0(CH2)o-2-pyrazole, an optionally substituted -O(CH2)0-2-tetrahydrofuran, an optionally substituted -0(CH2)o-2-pynOlidinone, an optionall substituted -0(CH?)o-2-tetrazole. an optionally substituted -0(CH2)o-2-tetrazolone and/or
Figure imgf000048_0001
. In some embodiments, R can be substituted C i-6 alkoxy substituted by one or more of the following: halo, hydroxy, CV 4 alkyi. cyano, amino, mono-substituted amino, di-substituted amino, sulionamidocarbonvl, hydroxamidine, C-amido, acyi, C-carboxy, O-carboxy, sulfonyl, S-sulfonamido, O-linked amino acid and carbonate ester.
[0131] In some embodiments, each RA can be haloalkyl, for example, trifluoromethyl.
[0132] In some embodiments, each RA can be an optionally substituted haloalkox for example, difluoromethoxy, trifluoromethoxy,
Figure imgf000048_0002
? ,
Figure imgf000048_0003
[0133] In some embodiments, each RA can be halogen, for example, chloro. bromo and/or fluoro.
[0134] In some embodiments, each RA can be amino, a mono-substituted amine or a di-substituted amine. For examples. RA can be N,N-di-methyi-amine. N,N-di -ethyl -amine. N-methyi-N-ethyl-amine. N-methyl-amino, N-ethyl-amino and/or amino.
[0135] In some embodiments, each RA can be hydroxy.
[0136] In some embodiments, each RA can be alkylthio, for example ethvlthio.
[0137] In some embodiments, each RA can be aminoalkyl, such as -(CH2) i -2- NH(CH3).
[0138] In some embodiments, each RA can be alkoxyalkyl. for example, -CH2-O-
CH3.
[0139] In some embodiments, each RA can be an optionally substituted aryl(C | .4 alkyl). In some embodiments, each RA can be an optionally substituted monocyclic heteroaryl(Ci -4 alkyi). In some embodiments, each RA can be an optionally substituted monocyclic heterocyclyl(C|_4 alkyl). Non-limiting examples include an optionally substituted -(CH2)i-2-imidazole, an optionally substituted -(CH2)i-2-pynOlidinonc, an optionally substituted -(CH?)i-2-imidaz.olidinone.
[0140] In some embodiments, each RA can be hydroxyalkyl. for example. -(CH2)i_
4-OH.
O
[0141 ] In some embodiments, each RA can be -O-amido, for example, H2N f ,
H
[0142] In some embodiments, each R can be -N-amido. for example, O
[0143] In some embodiments, each RA can be -N-sulfonamido, for example,
Figure imgf000049_0001
[0144] In some embodiments, each RA can be aminoalkyl. for example, -CH2- NH2 and/or -CH2-N(CH3)H.
[0145] In some embodiments, each RA can be an optionally substituted aryl, for example, an optionally substituted phenyl.
[0146] In some embodiments, each RA can be an optionally substituted monocyclic heteroaryl, such as an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted pyridinyl, an optionally substituted pyrimidine, an optionally substituted pyrazine and/or an optionally substituted 1 ,2,4-oxadiazole.
[0147] In some embodiments, each RA can be an optionally substituted monocyclic heterocyclyl, for example, an optionally substituted pyrrolidinyl, an optionally substituted piperidinyl, an optionally substituted morpholinyl and/or an optionally substituted pyrrolidinone.
[0148] In some embodiments, Y can be an optionally substituted ary l. In some embodiments, Y can be a para-substituted phenyl, a meta-substituted phenyl or an ortho- substituted phenyl. In some embodiments. Y can be a mono-substituted phenyl, such as a mono-halo substituted phenyl. In some embodiments. Y can be a di-substituted pheny l, for example a di-halo substituted phenyl. For example, mono-halo substituted phenyls and di- an be di-substituted
Figure imgf000050_0001
can be a substituted phenyl that is substituted with 3 more substituents. In other embodiments, Y can be unsubstituted phenyl. In some embodiments, Y can be a substituted naphthyl. In other embodiments, Y can be an unsubstituted naphthyl.
[0149| In some embodiments, Y can be an optionally substituted cycloalkyl (e.g., an optionally substituted cyclohexyl and an optionally substituted cycloheptyl). In other embodiments, Y can be an optionally substituted cycloalkenyl, for example, an optionally substituted cyclohexenyl. In some embodiments, Y can be an optionally substituted bi-cyclic
cycloalkenyl, s
Figure imgf000050_0002
[0150] In some embodiments. Y can be an optionally substituted mono-cyclic heteroarvl. In some embodiments, Y can be selected from an optionally substituted imidazole, an optionally substituted furan. an optionally substituted thiophene. an optionally substituted pyrrole, an optionally substituted pyrimidine. an optionally substituted pyrazine. an optionally substituted pyridine, an optionally substituted pyrazole, an optionally substituted oxazole and an optionally substituted isoxazole. In some embodiments, Y can be a substituted mono-cyclic heteroarvl, including those described herein. In some embodiments, Y can be an unsubstituted mono-cyclic heteroarvl, including those described herein. [0151] In some embodiments, Y can be an optionally substituted bi-cyclic heteroaryl. In some embodiments, Y can be selected from an optionally substituted benzothiophene. an optionally substituted benzofuran, an optionally substituted indole, an optionally substituted quinoline, an optionally substituted isoquinoline. an optionally substituted benzooxazole. an optionally substituted benzoisoxazole. an optionally substituted benzoisothiazole. an optionally substituted benzothiazole, an optionally substituted benzoimidazole. an optionally substituted benzotriazole. an optionally substituted 1 H- indazole and an optionally substituted 2H-indazole. In some embodiments, Y can be selected
Figure imgf000051_0001
a substituted bi-cyclic heteroaryl, including those described herein. In some embodiments, Y can be an unsubstituted bi-cyclic heteroaryl, including those described herein.
[0152] In some embodiments, Y can be an optionally substituted heterocyclyl. In some embodiments. Y can be an optionally substituted mono-cyclic heterocyclyl, such as an optionally substituted pyridinone. In other embodiment, Y can be an optionally substituted clic heterocyclyl. an
optionally substituted
Figure imgf000052_0001
or an opt ona y su st tute
[0153] When Y is substituted, Y can be substituted with one or more Ru "s. In some embodiments, each Ru can be independently selected from cyano, halogen, an optionally substituted C alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl. an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroaryl. an optionally substituted 5 or 6 membered heterocyclyl, hydroxy, C alkoxy. alkoxyalkyl, C1.4 haloalkyl, haloalkoxy, an unsubstituted acyl, an optionally substituted -C-carboxy, an optionally substituted -C-amido, sulfonyl, carbonyl. amino, mono-substituted amine, di-
substituted amine and
Figure imgf000052_0002
[0154] In some embodiments, when Y is an optionally substituted phenyl, the phenyl can be substituted 1 , 2, 3 or more times with cyano, halogen, an optionally substituted C M alkyl- an unsubstituted C2-4 alkenyl, an unsubstituted C7-4 alkynyl, an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroary l, an optionally substituted 5 or 6 membered heterocyclyl. hydroxy. C alkoxy, CM haloalky l (such as CF3. CHF2), haloalkoxy (such as OCF3), an unsubstituted acyl. an optionally substituted -C- carboxy, an optionally substituted -C-amido. sulfonyl, amino, mono-C i-4 alkyl amine, di-Ci-4
alkyl amine an
Figure imgf000052_0003
. In other embodiments, when Y is an optionally substituted mono-cyclic heteroaryl, the mono-cyclic heteroaryl can be substituted 1 , 2, 3 or more times with halo, an optionally substituted C alkyl, an optionally substituted phenyl and/or an unsubstituted acyl. In still other embodiments, when Y is an optionally substituted bi-cyclic heteroaryl, the bi-cyclic heteroaryl can be substituted 1 , 2, 3 or more times with halo, an optionally substituted CM alkyl, an optionally substituted phenyl, hydroxy, CV4 alkoxy, an unsubstituted acyl. carbonyl, cyano, amino, mono-C i-4 alkyl amine and/or di-Ci -4 alkyl amine.
[0155] In some embodiments, Y can be an optionally substituted benzothiophene. In some embodiments, Y can be a substituted benzothiophene. In other embodiments, Y can be an unsubstituted benzothiophene. In some embodiments, the benzothiophene can be substituted with one or more of the following: halogen (such as fluoro. chloro and/or bromo), carbonyl. C M alkyl, hydroxy. C alkoxy, NH2 and/or mon -substituted amine. For
example, an
optionally an
Figure imgf000053_0001
optionally substituted
[0156] In some embodiments, Y can be an optionally substituted benzofuran.
[0157] In some embodiments, Y can be an optionally substituted indole. In some embodiments, Y can be a substituted indole. In some embodiments, the indole can be substituted 1. 2, 3 or more time with phenyl (substituted or unsubstituted). C alkyl and/or halo. In other embodiments. Y can be an unsubstituted indole.
[0158] In some embodiments, Y can be substituted with one or more halogen. In some embodiments, Y can be substituted with one or more unsubstituted C alkyl. In some embodiments, Y can be substituted with more or more hydroxy. In some embodiments, Y can be substituted with one or more optionally substituted phenyl. In some embodiments, Y can be substituted with one or more alkoxy. In some embodiments, Y can be substituted with one or more acyl. In some embodiments, Y can be substituted with one or more amino, mono-substituted amino, or di-substitutcd amino. In some embodiments, Y can be substituted with one or more haloalkyl. In some embodiments, Y can be substituted with one or more haloalkoxy. In some embodiments, Y can be substituted with one or more C- carboxy. In some embodiments. Y can be substituted with one or more C-amido. In some embodiments, Y can be substituted with one or more hydroxyalkyl.
[0159] In some embodiments, a compound of Formula (I) can be selected from the following compounds: 1, 1 -1, 100.101, 102.103.105, 106.107, 108, 109.110, 111. 112, 113, 114, 115, 116, 116a, 116 b, 117. 117a, 117b, 118, 118a, 118b, 119, 120, 120a, 120 b, 121, 122, 122a, 122b, 123, 124, 125, 126, 127, 128, 129, 131, 132, 133, 134, 138, 139, 142, 143, 144, 145, 146, 147, 148, 151, 152, 153, 154, 155, 158. 159. 162. 163, 164. 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178. 179. 180. 181, 182. 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196. 197. 198. 199, 200.201, 202.203, 204, 205.206, 207.208.209.210, 211, 212, 213, 214.215.216.218.219.221, 223, 224, 225, 226, 227, 228, 230, 231, 232, 233, 234, 235, 236.237, 238, 239, 240, 241, 242, 243, 244.245, 246, 247, 248, 249.250, 251, 252, 253, 254.255, 256, 257, 258.259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279.280, 281.282.283, 284, 285, 286, 288.289.290.291, 292, 293, 294, 295, 296. 297, 298.299, 300.301.306, 307, 308, 309, 310.312.313.314, 315, 316, 317, 318, 319. J U, J21. J>22, J2J. J24. J>2 J26, J>2/, J2O, J2V. JJ>U. JJI. JJ>2, JJJ, JJ>4, JJ5, JJ>6, JJ>/. 338, 339.340, 342.343.344, 345, 346, 347, 348.349.350.351, 352, 353, 354, 355, 356. 357, 358.359, 360, 361.362, 363, 364, 365.366.367.368, 369, 370, 371, 372, 373, 374. 375, 376.377, 378, 379.380, 381, 382, 383.384.385.386.387.388, 389, 390, 391, 392. 393, 394, 395, 396, 397, 398, 399, 400, 402.403.404.405.406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424.425.426.427, 428.429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442.443.444.445, 446.447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460.461.462.463, 464.465, 466, 467, 468, 469, 470, 471, 472, 475, 476, 477, 478, 479, 480.481.482.483, 484.485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498a, 498b, 498c, 498d, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521 , 522, 523, 524, 525, 526, 527, 528, 529, 530, 531 , 532, 533. 534, 535, 536, 537, 538, 539, 540, 541 , 542, 543, 544, 545, 546, 547, 548, 549, 550, 551 , 552, 553, 554, 555. 556, 557. 558. 559, 560, 561 , 562, 563. 564. 565. 567, 568, 569, 570, 571 . 572. 573, 574. 575, 576. 577. 578, 579, 580, 581 , 582. 583. 584. 585, 586, 587, 588, 589, 590. 591 , 592, 593, 594, 595. 596. 597. 598. 599. 600. 601 , 602, 603. 604a. 604b. 604c. 604d. 605a, 605b, 605c, 605d, 606, 607, 608, 609, 610, 61 1 , 612. 613. 614, 61 5. 616, 617, 618. 619, 620. 621 , 622, 623a, 623b. 624a, 624b, 625. 626, 627, 628. 629, 630. 631 , 632. 633a. 633b. 634. 635. 636, 637, 638, 639, 640. 641. 642, 643. 644. 645, 646, 647. 648, 649, 650. 651 , 652. 653, 654, 655. 656, 657, 658, 659. 660. 661. 662. 663, 664, 665, 666, 667, 668. 669, 670, 671 , 672, 673, 674, 675, 676, 677, 678, 680, 681 and 682, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (1) can be selected from: 149, 150, 156. 157, 160, 217, 220, 222, 229, 287, 302, 303, 304, 305, 31 1, 401 , 473 and 474. or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (1) can be selected from: 130, 135, 140 and 141 , or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (I) can be 104 or 161 , or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (I) can be 136 or 137, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be a compound provided in PCT Publication WO 2014/031784, published February 27. 2014.
Pharmaceutical Compositions
[0160] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
[01611 The term "pharmaceutical composition'" refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethancsulfonic acid, p-toluencsulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
[0162] The term "physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.
[0163] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
[0164] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
[0165] As used herein, an "excipient" refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc.. to the composition. A "diluent" is a type of excipient.
[0166] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. [0167] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterfoils.
[0168] Multiple techniques of administering a compound exist in the art including, but not limited to. oral, rectal, pulmonar}7. topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary7 injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
[0169] One may also administer the compound in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory infection may be desirable.
[0170] The compositions may. if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use. or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary7 administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Methods of Use
[0171 ] Some embodiments described herein relate to a method for ameliorating, treating and/or preventing a paramyxovirus viral infection, which can comprise administering an effective amount of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof).
[0172] Some embodiments described herein relate to a method for inhibiting viral replication of a paramyxovirus, which can comprise contacting a cell infected with the virus with an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
[0173] Some embodiments described herein relate to a method for contacting a cell infected with a paramyxovirus, which can comprise contacting a cell infected with the virus with an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof).
[0174] In some embodiments, the paramyxovirus infection is a human respiratory syncytial virus infection.
[0175] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a respiratory syncytial viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a respiratory syncytial viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a respiratory syncytial virus. In some embodiments, an effective amount of one or more compounds of Formula (1). or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutical ly acceptable salt thereof) can be used to inhibit the RSV polymerase complex. In some embodiments, the RSV can be RSV A. In some embodiments, the RSV can be RSV B.
[01761 In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a hendraviral infection and/or nipahviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a hendraviral infection and/or nipahviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a hendravirus and/or nipahvirus. In some embodiments, an effective amount of one or more compounds of Formula (Γ), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (Γ), or a pharmaceutically acceptable salt thereof) can be used to inhibit the hendravirus polymerase complex and/or nipahvirus polymerase complex.
[0177] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a measles. In some embodiments, an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be used to prevent a measles. In some embodiments, an effective amount of one or more compounds of Formula (1). or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a measles virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the measles polymerase complex.
[0178] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate mumps. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent mumps. In some embodiments, an effective amount of one or more compounds of Formula (Γ), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a mumps virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the mumps polymerase complex.
[0179] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a sendai viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a sendai viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a sendai virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be used to inhibit the sendai virus polymerase complex.
[0180] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a HPIV-1 infection and/or HPIV-3 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a HPIV- 1 infection and/or HPIV-3 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication of a HPIV-1 and/or HPIV-3. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the HPIV-1 polymerase complex and/or HPIV-3 polymerase complex.
[0181] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a HPIV-2 infection and/or HPIV-4 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (f), or a pharmaceutically acceptable salt thereof) can be used to prevent a HPIV-2 infection and/or FIPIV-4 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication of a HPIV-2 and/or HPIV-4. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the HPIV-2 polymerase complex and/or HPIV-4 polymerase complex.
[01821 In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a human metapneumoviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a human metapneumoviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication of a human metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (Γ), or a pharmaceutically acceptable salt thereof) can be used to inhibit the human metapneumovirus polymerase complex.
[0183] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate an upper respiratory viral infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus. and a metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate a lower respiratory viral infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, and a metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate one or more symptoms of an infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, and a metapneumovirus (such as those described herein). [0184] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate an upper respiratory viral infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (1). or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate a lower respirator}7 viral infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula ( ), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate one or more symptoms of an infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus (such as those described herein).
[0185] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitis due to a RSV infection and/or human parainfluenza virus 3 (HPIV-3) infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate pneumonia due to a RSV infection and/or human parainfluenza virus 3 (HPIV-3) infection, in some embodiments, an effective amount of one or more compounds of Formula (f), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate croup due to a RSV infection and/or human parainfluenza virus 1 (HPIV- 1 ) infection.
[0186] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate due to fever, cough, runny nose, red eyes, a generalized rash, pneumonia, an ear infection and/or bronchitis due to measles. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate due to swelling of the salivary7 glands, fever, loss of appetite and/or fatigue due to mumps.
[0187] In some embodiments, an effective amount of one or more compounds of Formula (Γ), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a human parainfluenza viral infection. Tn some embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 1 (HPIV-1 ). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 2 (HPIV-2). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 3 (HPIV-3). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 4 (HPIV-4). In some embodiments, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can be used to treat and/or ameliorate one or more subtypes of human parainfluenza virus. For example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can be used to treat HPIV- 1 and/or HPIV-3.
[0188] The one or more compounds of Formula (Γ) or a pharmaceutically acceptable salt thereof, that can be used to treat, ameliorate and/or prevent a paramyxovirus viral infection can he a compound of Formula (I), or pharmaceutically acceptable salt thereof, provided in any of the embodiments described in paragraphs [0078]-[0159J.
[0189] As used herein, a "subject" refers to an animal that is the object of treatment, observation or experiment. "Animal'" includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes. and. in particular, humans. In some embodiments, the subject is human.
[0190] As used herein, the terms "prevent" and "preventing," mean lowering the efficiency of viral replication and/or inhibiting viral replication to a greater degree in a subject who receives the compound compared to a subject who does not receive the compound. Examples of forms of prevention include prophylactic administration to a subject who has been or may be exposed to an infectious agent, such as a paramyxovirus (e.g., RSV).
[0191] As used herein, the terms "treat." "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance, and may positively affect one or more symptoms or aspects of the disease while having effects on other aspects of the disease or on unrelated systems that may be considered undesireable.
[0192] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to prevent, treat, alleviate or ameliorate one or more symptoms or conditions of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
[0193] Various indicators for determining the effectiveness of a method for treating a viral infection, such as a paramyxovirus, are known to those skilled in the art. Example of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in viral RNA, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and/or other indicator of disease response.
[01941 In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral titers to essentially undetectable or very7 low7 levels, for example, to less than 1.7 logio plaque forming units equivalents (PFUe)/mL, or less than 0.3 logi0 plaque forming units equivalents (PFUe)/mL. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can reduce the viral load compared to the viral load before administration of the combination (for example, 60 hours after receiving the initial dosage of the combination). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein can reduce the viral load to lower than 1 .7 logio (PFUe)/mL, or lower than 0.3 logio (PFUe)/mL. In some embodiments, a combination of compounds described herein can achieve a reduction in viral titer in the serum of the subject in the range of about 1 .5-log to about a 2.5-log reduction, about a 3-log to about a 4-log reduction, or a greater than about 5 -log reduction compared to the viral load before administration of the combination. For example, the viral load is measure before administration of the combination, and several hours after receiving the initial dosage of the combination (for example, 60 hours after receiving the initial dosage of the combination).
[0195] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in at least a 1 , 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of a paramyxovirus relative to pre-treatment levels in a subject, as determined several hours after receiving the initial dosage of the combination (for example, 60 hours after receiving the initial dosage of the combination). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein can result in a reduction of the replication of a paramyxovirus relative to pre -treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formula (T). or a pharmaceutically acceptable salt thereof, can result in a reduction of a paramyxovirus replication in the range of 1 to 1 .5 log. 1 .5 log to 2 log. 2 log to 2.5 log. 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction of a paramyxovirus replication compared to the reduction of a paramyxovirus reduction achieved by ribavirin (Virazole®), or may achieve the same reduction as that of ribavirin (Virazole®) therapy in a shorter period of time, for example, in one day, two days, three days, four days, or five days, as compared to the reduction achieved after 5 days of ribavirin (Virazole®) therapy.
[0196] After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term "resistance"' as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject infected with RSV that is resistant to one or more different anti-RSV agents (for example, ribavirin). In some embodiments, development of resistant RSV strains is delayed when subjects are treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of RSV strains resistant to other RSV drugs.
[0197] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can decrease the percentage of subjects that experience complications from a RSV viral infection compared to the percentage of subjects that experience complication being treated with ribavirin. For example, the percentage of subjects being treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that experience complications can be 10% , 25%, 40%, 50%, 60%, 70%, 80% and 90% less compared to subjects being treated with ribavirin. [0198] In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, can be used in combination with one or more additional agent(s). In some embodiments, a compound of Formula (1). or a pharmaceutically acceptable salt thereof, can be used in combination with one or more agents currently used in a conventional standard of care for treating RSV. For example, the additional agent can be ribavirin, palivizumab. and RSV-IGIV. For the treatment of RSV, additional anti-RSV agents include but are not limited to an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, a RSV polymerase inhibitor, an IMPDH inhibitor, an interferon and an other compound that inhibits the RSV virus, or a pharmaceutically acceptable salt of any of the foregoing. A non-limiting list of examples of additional agents is provided herein.
Figure imgf000069_0001
BTA-C286
N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-l -yl)-6-methylpyrazolo[l ,5- a]pyrimidin-2-yl)piperidine- 1 -carbonyl)-4- chlorophenyl)methanesulfonamide (GS-5806)
an anti-RSV nanobody (e.g., ALX-0171 (a trivalent nanobody,
Ablynx)
a peptide fusion inhibitor (such as a peptide having the sequence DEFDASISQVNEKTNQSLAFTRKSDELL (T-67) a peptide having the sequence
FDASISQVNEKI QSLAFIRKSDELLHNVNAGKST (T-1 18)
(S)- 1 -(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro- 1H- benzo[cJ [ l ,4]diazepin-3-yl)urca (RSV-604)
N -protein
STP-92 (siRNA delivered through nanoparticle based delivery inhibitors
systems, Sirnaomics)
iKT-041 (Inhibikase)
6- {4-[(biphenyl-2-ylcarbonyl) amino] benzoyl) -N-cyclopropyl-5,6- dihydiO-4H-thieno[3,2-d] [l]benzazepine-2-carboxamide (YM-53403 )
N-cyclopropyl-5-(4-(2-(pyrrolidin-l -yl)benzamido)benzoyl)-5,6.7,10- tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide
6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-
RSV polymerase
cyclopropyl-5.6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2- inhibitors
carboxamide, 4-amino-8-(3- { [2-(3,4- dimethoxyphenyl)ethy l]amino} piOpy l)-6,6-dimethyl-2-(4-meth\ -3- nit1Ophenyl)-lH-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione (CAS Reg. No. 851658- 10- 1 )
AZ27
ribavirin
5-ethynyl- 1 -beta-D-ribofuranosylimidazole-4-carboxamide (EICAR)
4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide
(pyrazofurin)
1 - ((2R.3R.4S,5R)-3.4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)- 1 H- 1.2,4-triazole-3-carboximidamide (Taribavirin, viramidine)
1MPDH 1 ,3,4-thiadiazol-2-ylcyanamide (LY253963)
inhibitors tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5- yl)phenyl)ureido)benzylcarbamate (VX-497)
(4E)-6-(4-Hydroxy-6-methoxy-7-mcthyl-3-oxo- l ,3-dihydro-2- benzofutan-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid)
2- morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo- l H-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate ofetil)
Type 1 interferon
Type 2 interferon
Interferons Type 3 interferon
an alpha-interferon (IFN-a)
Pegylated interferon-alpha-2a (PEGASYS®) Pegylated interferon-alpha-2b (PEG-INTRON©)
interferon alfacon-1 (INFERGEN®)
beta-interferon (lFN-β)
lambda-interferon (IFN-λ)
a double stranded RNA oligonucleotide
5-methyl-N-[4-(trifluoromethyl) phenyl] -isoxazole-4-carboxamide (leflumomidc), N-(2-chloro-4-methylphcnyl)-2-((l -(4- methoxyphenyl)-l H-benzo[d]imidazol-2-yl)thio)propanamide (JMN3- 003)
an intratracheal formulation of recombinant human CC 10 (CG-100) other compounds high titer, human immunoglobulin (Rl-001, ADMA Biologies Inc.) a non-neutralizing mAb against the G protein (mAb 131 -2G)
AFN-RSV01 (an siRNA agent with the sense strand sequence (5' to 3') GGC U C U U AGC AAAGU C AAGdFdF (SEQ ID NO. 3) and the antisense strand sequence (5' to 3')
CUUGACUUUGCUAAGAGCCdTdT (SEQ ID NO. 4)
ALN-RSV02
Medi-559
Medi-534
Medi-557
ALN-RSV01 and/or ALN-RSV02 can be found in U.S. Publication No. 2009/0238772. filed Dec. 15, 2008 (Alnylam Pharmaceuticals).
ALX-01 71 described in U.S. Publication No. 2012/0128669, filed June 7, 2010.
T-67. SEQ ID NO: 1. U.S. Patent No. 6,623.741. filed Feb. 29. 2000.
F-l 18, SEQ ID NO: 2, U.S. Patent No. 6,623.741 , filed Feb. 29, 2000.
[0199] Other examples of compounds that can be used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt, include those provided in WO 2013/186333, published December 19, 2013; WO 2013/186332, published December 19, 2013; WO 2013/186335, published December 19, 2013; WO 2013/186334, published December 19, 2013; WO 2012/080447, published June 21 , 2012; WO 2012/080449, published June 21 , 2012; WO 2012/080450, published June 21 , 2012; WO 2012/080451 , published June 21 , 2012; WO 2012/080446, published June 21 , 2012; WO 2010/103306, published September 16, 2010; WO 2012/068622, published May 31 , 2012; WO 2005/042530, published May 12, 2005; WO 2006/136561 , pubhshed December 28, 2006; WO 2005/058869. published June 30. 2005; U.S. 2013/0090328. published April 1 1. 2013; WO 2014/009302. published January 16. 2014; WO 201 1 /005842. published January 13. 201 1 ; U.S. 2013/0273037. published October 17. 2013; U.S. 2013/0164280. published June 27. 2013; U.S. 2014/0072554. published March 13, 2014; WO 2014/031784, published February 27. 2014 and WO 2014/031 784. published February 27, 2014, all of which are hereby incorporated by reference.
[0200] In combination therapy, the additional agents can be administered in amounts that have been shown to be effective for those additional agents. Such amounts are known in the art; alternatively, they can be derived from viral load or replication studies using the parameters for "effective amount" set forth above. Alternatively, the amount used can be less than the effective monotherapy amount for such additional agents. For example, the amount used could be between 90% and 5% of such amount, e.g., 90%, 80%, 70%, 60%. 50%, 40%. 30%, 20%, 10%, or 5%, or intermediate values between those points.
[02011 in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
[0202] The order of administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one or more additional agent(s) can vary. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered prior to all additional agents. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered prior to at least one additional agent. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered concomitantly with one or more additional agent(s). In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of at least one additional agent. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of all additional agents.
[0203] A potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof, may be a reduction in the required amount(s) of one or more compounds of paragraphs [0198]-[01 9] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof) that is effective in treating a disease condition disclosed herein (for example, RSV), as compared to the amount required to achieve same therapeutic result when one or more compounds described in paragraphs [0198] -[0199] (including the table), including pharmaceutically acceptable salts thereof, are administered without a compound of Formula (1), or a pharmaceutically acceptable salt thereof. For example, the amount of a compound described in paragraphs [0198]-[0199] (including the table), including a pharmaceutically acceptable salt and prodrug thereof, can be less compared to the amount of the compound described in paragraphs [0198]-[0199] (including the table), including a pharmaceutically acceptable salt and prodrug thereof, needed to achieve the same viral load reduction when administered as a monotherapy. Another potential advantage of utilizing a compound of Formula (1). or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) described in paragraphs [01 8]-[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof, is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.
[0204] Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) described in paragraphs [0198] -[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof, may include little to no cross resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof); different routes for elimination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agcnt(s) described in paragraphs [0198]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof): little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) described in paragraphs [0 98]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof); little to no significant effects on cytochrome P450; and/or little to no pharmacokinetic interactions between a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof).
[02051 As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.
[0206] The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg. e.g. 5 to 200 mg. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
[0207] In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly- discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
[0208] In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art. in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
[0209] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assay-s or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0210] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary- according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may7 be used in veterinary medicine. [0211] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
Synthesis
[0212] Compounds of Formula (I), and those described herein may be prepared in various ways. Some compounds of Formula (1) can be obtained commercially and/or prepared utilizing known synthetic procedures. General synthetic routes to the compounds of Formula (I ), and some examples of starting materials used to synthesize the compounds of Formula (I) are shown and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.
EXAMPLES
[0213] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. EXAMPLE 1
Preparation of Compound 1
Figure imgf000077_0001
10214] To a mixture of 1-1 (3.65 g, 20 mmol) in NMP:THF (2 mL/20 mL), Fe(acac)j (622 mg, 2 mmol) was added. The solution was cooled to 0°C and i-PrMgCl (20 mL, 2N) was added slowly at 0°C. The solution was stirred for 2 h at 0°C. The solution was extracted with EA, and washed with brine. The organic phase was concentrated to give crude 1-2 as a colorless solid (2.4 g, 63.5%). +ESI-MS: m/z 190.1 [M+H]+.
[0215] To a mixture of 1-2 (1 g. 5.29 mmol) and 1-3 (1.03 g, 5.29 mmol) in DMF (30 mL) were added Pd(dppf)Cl2 (420 mg, 0.529 mmol) and a freshly prepared F solution (2.57 g in 10 mL of water). The system was degassed and then charged with nitrogen 3 times. The mixture was stirred under nitrogen at 70°C using an oil bath for 8 h. The reaction solution was cooled to r.t.. diluted with EA and separated from the water layer. The EA solution was washed with brine, dried over Na2S04 and concentrated. The residue was purified on a silica gel column to give 1-4 as a colorless solid (0.5 g, 31%). +ESI- S: m/z 306.0 [M+I I] ' .
[0216] To a mixture of 1-4 (900 mg, 2.95 mmol). 1-5 (1 .07 g, 2.95 mmol) and KF (0.684 g. 1 1 .8 mmol) in DMF ( 10 mL) was added Pd(dppf)Cl2 (228 mg, 0.295 mmol). The system was degassed and then charged with nitrogen 3 times. The mixture was stirred under nitrogen at 70°C using an oil bath for 8 h. The reaction solution was cooled to r.t., diluted with EA and H2O. The organic phase was washed with brine, dried over Na2S04 and concentrated to give crude 1-6 (1 g). +ES1-MS: m/z 342.1 [M+H]+.
[0217] A mixture of 1-6 (1 g, 2.9 mmol) and NBS (516 mg, 2.9 mmol) in a mixture of THF (10 mL) and FLO (1 mL) was stirred at r.t. for 30 mins. The solution was diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a sat. Na2S203 solution, followed by brine. The solution was dried over Na2S04 and evaporated to give crude 1-7 (1 g). +E SI-MS: m/z 392.0 [M+H]+.
[0218] To a solution of 1-7 (1 g, 2.55 mmol) in a mixture of THF (5 mL) and MeOH (0.5 mL) was added NaBH4 (193 mg, S. lmmol) at 0°C. The mixture was stirred at 0°C for 30 mins with TLC monitoring. The reaction was quenched by the addition of H?0 and extracted with EA. The combined organic layers were washed with brine, dried over NaTS04 and concentrated. The residue was purified on a silica gel column to give 1-8 (200 mg, 20%). +ESI-MS: m/z 394.0 [M+H]+.
[0219] A mixture of 1-8 (200 mg, 0.50 mmol) and sat. NH4OH/EtOH (1 mL/5 mL) in a sealed tube was heated to 70°C for 6 h. The solution was removed under reduced pressure to give crude 1 -9 (160 mg, 90.0%), which was used for next step directly without purification. +ESI-MS: m/z 331 .1 | M+H]+.
[0220] To a solution of 1-9 (65 mg, 0.363 mmol). HATU ( 172 mg, 0.45 mmol) and DIPEA ( 1 1 7 mg. 0.909 mmol) in anhydrous DMF ( 1 mL) was added 1 -10 ( 100 mg 0.303 mmol) at 25°C. The solution was stirred for 10 h at r.t. The solution was diluted with 1 .0 N aqueous NaHC03 solution (2 x 40 mL) and extracted with EA (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified on a silica gel column to give 1 (100 mg. 67.1 %). +ESI-MS: m/z 495.1 [M+H]+. EXAMPLE 2
Preparation of Compound 100
Figure imgf000079_0001
[0221] A solution of 2,4,6-trichloropyridine (6.5 g, 36 mmol) in anhydrous methanol (20 mL) was added MeONa (2.9 g, 54 mmol) at 0°C. The reacton mixture was stirred at r.t. for 12 h. The reaction was quenched with dry ice, and the mixture was filtered. The solution was concentrated under reduced pressure, and the residue was dissolved in EA. The mixture was washed with water, and the organic layers were dried over NaS04. The solvent was concentrated to give 1-12 (4.2 g, 67%).
[0222] Compound 100 was prepared using 1 -12 and 4-(cyclopropylmethoxy)-3- methoxybenzoic acid, and by following a synthetic route, which closely follows that described for the preparation of 1. 100: +ES1-MS: m/z 483. 1 [M+H]+.
EXAMPLE 3
Preparation of Compound 101
Figure imgf000079_0002
Figure imgf000080_0001
[0223] To a solution of 2-1 (3 g, 14 mmol) and the boronic acid (2.5 g, 14 mmol) in dioxane/H20 (30 mL/5 mL) was added Pd(dppf)Cl2 ( 1.02 g, 1.4 mmol) and Cs2C03 (6.8 g, 21 mmol). The system was degassed and then charged with nitrogen for 3 times. The mixture was stirred under nitrogen at 80°C in an oil bath for 2 h. The solution was cooled to r.t., diluted with EA and separated from the water layer. The EA solution was washed by brine, dried over Na?SC>4 and concentrated. The residue was purified on a silica gel column to give 2-2 (2 g, 47.9%).
[0224] To a solution of 2-2 (2 g, 6.7 mmol) in eOl I/DCM (20 niL/20 mL) was added NaB¾ (510 mg. 13.4 mmol) slowly at 0°C. The solution was stirred for 10 mins and heated to 50°C and stirred for 2 h. The solution was quenched with H20 and extracted with EA. The solution was concentrated to give crude 2-3 ( 1.81 g, 100 %).
[0225] To a solution of 2-3 (1 .81 g. 6.7 mmol) in DMF was added imidazole (1 .36 g, 1 .34 mmol) at r.t. TBSCl (201 mg, 1 .34 mmol) was added. The solution was stirred for 1 8 h. The solution was wrashed with water and extracted with EA. The organic phase was concentrated to give 2-4 (1 .8 g, 70.0%). ESI-LCMS: m/z 385.9 [M+H]+.
[0226] Compound 2-10 was prepared using 2-4 and 4-(cyclopropylmethoxy)-3- methoxybenzoic acid, and by following a synthetic route, which closely follows that described for the preparation of 1. Ή-NMR (400 MHz, CDC13), δ = 8.00 (d, J=5.51 Hz, 1 H) 7.87 (br. s., 1 H) 7.78 (s, 1 H) 7.81 (s, 1 H) 7.34 (s, 1 H) 7.26 (d, ,/=8.38 Hz, 1 H) 7.14 (t, J=8.71 Hz, 1 H) 6.92 (br, 1 H) 6.74 (d, .7=8.38 Hz, 1 H) 5.13 (d, J=4.41 Hz, 2 H) 4.72 (s, 2 IT) 3.71 -3.85 (m, 5 H) 1 .09 (br, 1 H), 0.83 (s, 10 IT) 0.46-0.56 (m, 2 H), 0.19-0.30 (m, 2 H), 0.00 (s, 7 H).
[0227] To a solution of 2-10 ( 100 mg, 0.163 mmol) in dioxane (2 mL) was added concentrated HC1 (2 mL) at r.t. and the mixture was stirred for 30 mins. The solution was quenched by aqueous NaHC03 solution and extracted by EA. The combined organic layers were washed by brine, dried over Na?S04 and concentrated. The residue was purified by prep-HPLC(FA) to give 2-1 1 (30 mg, 37.0%) as a white solid. +ES1-MS: m/z 498.9 [M+H]+.
[0228] The solution of 2-11 ( 100 mg, 0.20 mmol) in THF (2 mL) was added
MeMgBr (1 mL, 3 mmol) at r.t. and the mixture was stirred for 2 h. The solution was quenched with H20 and extracted with EA. The combined organic layers were washed by brine, dried over a SC and concentrated. The residue was purified by prep-TLC
(PE:EA=1 : 1) to give 101 (20 mg, 19.4%) as a white solid. +ES1-MS: m/z 514.9 [M+H]+.
EXAMPLE 4
Preparation of Compound 102
Figure imgf000081_0001
[0229] To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was added NBS ( 14 g, 80 mmol). The mixture was stirred for 1 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=2: 1 ) provided 3-2 as white solid (9.6 g, 99%). +E SI-MS: m/z 239.0 [M+H]+
[0230] To a solution of 3-2 (9.6 g. 40 mmol) and K2C03 (5.4 g. 40 mmol) in DMF (50 mL) at 40°C was added CH3I (6 g, 40 mmol). The mixture was stirred for 2 h at r.t. The solution was poured into water and extracted with EtOAc. The organic phase was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA=20: 1 ) to provide 3-3 (3 g, 30%). +ES1-MS: m/z 253.0 [M+H]+.
[0231] Compound 102 was obtained by closely following the procedure for obtaining 1 using 3-3 and 3,4-dimethoxybenzoic acid. Compound 102 was obtained as a white solid. +ES1-MS: m/z 470.1 [M+H]+. EXAMPLE 5
Preparation of Compound 103
Figure imgf000082_0001
[0232] To a stirring mixture of 2,6-dichloropyridine (270 mg, 1.82 mmol) and 7- fluoro-lH-benzo[d]imidazole (248 mg, 1.82 mmol) in DMF (3 mL) was added Cs2C03 (709 mg, 2. 2 mmol). The mixture was reacted at 120°C for 2 h and then cooled to r.t. The mixture was diluted with EtOAc and washed with a sat. NaCT solution. The layers were separated. The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure. Chromatography of the residue afforded 4-1 (300 mg) as a white solid. LCMS: m/z 248.1 [M+H]+.
[0233] Compound 103 was obtained as a yellow oil (100 mg) by closely following the procedure for obtaining 1 using 4-1 and 3,4-dimethoxybenzoic acid. LCMS: m/z 437.25 [M+H]+.
EXAMPLE 6
Figure imgf000082_0002
Figure imgf000083_0001
[0234] To a solution of 5-1 (10 g. 44.0 mmol) in DMF ( 150 raL) was added NaH (7.0 g, 0.1 77 mol), and the mixture was stirred at 0°C for 30 mins. The solution wras treated with PMBC1 (1 1.67 g, 0.0748 mol), and stirred at r.t. overnight. After complete conversion, the reaction was quenched with MeOH and H2O, and extracted with EA. The organic phase was concentrated to give 5-2 (1 1 g, 87.2%). +ES1-MS: m/z 375.9 [M+H]+.
[0235] To a solution of 5-2 (36 g, 96 mmol) in toluene (400 mL) was added (CH3)6Sn2 (47.0 g, 144.0 mmol). The mixture was bubbled with nitrogen gas and stirred at 100°C for 3 h. The mixture was concentrated in vacuum to give the crude product, wd ich was purified by column chromatography to give 5-3 (22 g). +ES1-MS: m/z 414.0 [M+H]+.
[0236] To a solution of 5-8 (30 g, 134 mmol) in anhydrous THF (500 mL) was added L1AIH4 (7.6 g, 200 mmol) in portions at 0°C, and the mixture was stirred at r.t. for 2 h (monitored by TLC). The reaction was quenched with a sat. NH4CI solution, and extracted with EA to give the crude product, which was purified by column chromatography to give 5- 9 (22 g). +ESI-MS: m/z 1 83.0 [M+H]+.
[0237] To a solution of 5-9 (22 g, 121 mmol ) in THF (400 mL) was added NBS (25.7 g. 145 mmol). and the mixture was stirred at r.t. overnight (monitored by TLC). The reaction was quenched with a sat. Na2S?03 solution, and extracted with EA to give the crude product . which was purified by column chromatography to give 5-10 (23 g). +ES1-MS: m/z 460.9 [M+H]+. [0238] To a solution of 5-10 (22 g, 84.6 mmol) in anhydrous THF (200 mL) was added Nal I (8.12 g, 33.85 mmol) in portions at 0°C, and the mixture was stirred at 0°C for 30 mins. MOMC1 (27.08 g, 338.5 mmol) was added, and the mixture was stirred at r.t. for 4 h. The reaction was quenched with water and extracted with EA. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give the crude product, which was purified by column chromatography to give 5-4 (21 g). +ESI-MS: m/z 304.9 [M+H]+.
[0239] To a solution of 5-3 (6.36 g, 15.4 mmol) in DMF (50 mL) were added 5-4 (4.7 g. 15.4 mmol). KF (3.7 g, 61 .6 mmol) and Pd(PPh3)2Cl2 (324 mg, 0.46 mmol). The mixture was bubbled with nitrogen gas and stirred at 100°C overnight. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give the crude product, which was purified by column chromatography to give 5-5 (3.8 g). +ESI-MS: m/z 474.1 [M+H]+.
[0240] To a solution of 5-5 (4.5 g, 9. 1 mmol) in THF (30 mL) was added 10% HC1 (30 mL), and stirred 1 10°C overnight. The mixture was cooled to r.t., and the pH was adjusted to 7.0 by adding a sat. NaHCO^ solution. The mixture was extracted with EA. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give 5-6 (2.0 g), which was used in the next step without purification. +ES1-MS: m/z 310.0 [M+H]+.
[0241] To a solution of 5-6 ( 1 .3 g, 4.2 mmol) in THF (100 mL) was added PPh (1 .32 g, 5.05 mmol), and the mixture was stirred at r.t. for 10 mins. DIAD ( 1 .01 g. 5.05 mmol) was added in portions, and the mixture stirred at refluxed for 4 h. The mixture was concentrated in vacuum to give the crude product, which was purified by column chromatography to give 5-7 (0.7 g). +ESI-MS: m/z 292.0 [M+H]+.
[0242] Compound 104 was obtained as a white solid (50 mg) by closely following the procedure for obtaining 1 by using 5-7 and 3,4-dimethoxybenzoic acid. +ES1-MS: m/z 481 .1 [M+H]+.
EXAMPLE 7
Preparation of Compound 105
Figure imgf000084_0001
[0243] To a solution of 6-1 (1 96 mg, 1 .0 mmol), l ,4-dibromobutane-2,3-dione (241 mg, 1 .0 mmol) in DCM (3 mL) was added AgOTf (255mg. 1 .0 mmol). The reaction was carried out at 80°C under microwave irradiation for 15 mins. The mixture was concentrated at low pressure. The residue was purified by silica gel column (PE/EA) to 6-2 (270 mg. 80%). +ESI-MS: m/z 339. 9 [M+H]+.
[0244] Compound 105 was obtained (100 mg, 48 %) by closely following the procedure for obtaining 1 using 6-2 and 3,4-dimethoxybenzoic acid. +ESI-MS: m/z 442. 9 [M+H]+.
Figure imgf000085_0001
[0245] Compound 106 was prepared using 2.6-dibromopyridine. 2-(7- fluoiObenzo[b]thiophen-3-yl)-4.4,5.5-tetramethyl-L3,2-dioxabo1Olane and 3,4- dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparati -MS: m/z 452.9 [M+H]+.
Figure imgf000085_0002
[0246] Compound 107 was prepared using 3.4-dimethoxybenzoic acid and 3- bromo-5-(7-iluorobenzo[b]thiophen-3-yl)-l-propyl-lH-l ,2,4-triazole, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ES1-MS: m/z 485.0 [M+ +.
Figure imgf000085_0003
[0247] Compound 108 was prepared using 2,4-dibromothiazole, 2-(7- fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-l ,3.2-dioxaborolane and 3,4- dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ES1-LCMS: m/z 459.0 [M+H]+.
Figure imgf000086_0001
[0248] Compound 109 was prepared using 2,4-dichloro-5-methoxypyrimidine. (3- chloro-4-fluorophenyi) boronic acid and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for preparation of 1. +ESl-MS:m/z 506.1 [M+ +.
Figure imgf000086_0002
[0249] Compound 110 was prepared using 2-hydroxy-4,5-dimethoxybenzoic acid and 2-amino- l-(6-(7-fluoiObenzo[b]thiophen-3-yr)-4-methoxypyridin-2-yl) ethanol, and by following a synthetic route, which closely follows that described for preparation of 1. Compound 110 was obtain .9[M+I I]+.
Figure imgf000086_0003
[0250] Compound 11 1 was obtained by closely following the procedure for obtaining 1 by using 2,4-dibromothiazole, 2-(7-fluorobenzo[b]thiophen-3-yl)-4,4.5,5- tetramethyl-l ,3.2-dioxaborolane and 3,4-dimethoxybenzoic acid. Compound 1 11 was obtained as a white solid. +ESI-LCMS: m/z 466.9 [M+H]+.
Figure imgf000087_0001
[02511 Compound 112 was prepared using 4-chloro-2-iodo-6-methoxypyrimidine,
2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetran ethyl- 1 , 3,2-dioxaborolane and 3,4- dimethoxybenzoic acid, and by following a synthetic route, which closely follows that described for preparation of 1. +ESI-MS: m/z 484.1 [M+H]+.
EXAMPLE 8
Preparation of Compound 1 13
Figure imgf000087_0002
[0252] To a solution of 7-1 (7.5 g, 27.17 mmol) in THF (100 mL) was added i-PrMgCl (25 mL, 2M in THF) at r.t., and the mixture stirred for 10 mins. The solution was quenched with MeOH and diluted with DCM (20 mL). The solution was washed by brine, dried over Na?SC>4 and concentrated to give crude 7-2 (5 g, 94.3 %).
[0253] To a solution of 7-2 (1 g, 5.1 mmol), the tin reagent (3.71 g, 10.2 mmol) and KF ( 1 .1 8 g. 20.4 mmol) in DMF ( 10 niT) was added Pd(dppf)Cl2 (372 mg, 0.51 mmol). The system was degassed and then charged with nitrogen for 3 times. The mixture was stirred under nitrogen at 80°C in an oil bath for 15 h. The solution was cooled to r.t. The mixture was diluted with EA. The EA solution was washed by brine, dried over Na2SC»4 and concentrated to give crude 7-3 (360 mg. 44.2%)
[0254] To a solution of 7-3 (360 mg, 2.25 mmol) in DCM (5 niL) was added NBS (480 mg, 2.7 mmol). The mixture was stirred at r.t. for 30 mins with TLC monitoring. The solution was quenched by aqueous Na2S203 solution and extracted by EA. The combined organic layers were dried over Na2SC>4 and concentrated. The residue was purified by prep- HPLC(FA) to give 7-4 (250 mg, 46.2%) .
[0255] To a solution of 7-4 (480 mg, 2 mmol) and the dioxaborolane reagent (558 mg, 2 mmol) in dioxane/EL;0 (10 mL/2 mL) were added Pd(dppf)Cl2 ( 146 mg, 0.2 mmol) and CS2CO3 (975 mg, 3 mmol). The system was degassed and then charged with nitrogen for 3 times. The mixture was stirred under nitrogen at 80°C in an oil bath for 15 h. The solution was cooled to r.t., diluted with EA and separated from the water layer. The EA solution was washed by brine, dried over Na2SC»4 and concentrated. The residue was purified on a silica gel column to give 7-5 (400 mg, 64.5%).
[0256] To a solution of 7-5 (550 mg, 1.77 mmol) in DCM (5 mL) was added DIPEA (685 mg, 5.3 1 mmol) and TMSOTf (589 mg, 2.65 mmol) at 0°C. The solution was stirred for 2 h at r.t. The solution was concentrated and the residue was dissolved in THF (10 mL) and LLO (1 mL). NBS (471 mg, 2.65 mmol) was added at r.t., and stirred for 1 .5 h. The solution was evaporated at low pressure. The residue was purified by chromatography (PE:EA=3 : 1 ) to give 7-6 (600 mg. 86.9%).
[0257] Compound 1 13 was prepared from 7-6 and 3.4-dimethoxy benzoic acid by following a synthetic route, which closely follows that described for the preparation of 1. Compound 113 was obtained as white solids. +ESI-MS: m/z 492.0 [M+H]+.
Figure imgf000089_0001
[0258] To a solution of 8-1 (90 mg, 0.19 mmol) in THF (5 niL) was added CH3MgBr (3 M. 0.64 M) at 0°C, and stirred at r.t. overnight. The reaction was quenched with NH4CI solution and extracted with EA. The organic layer was dried over sodium sulfate, then concentrated in vacuum to give the crude product , which was purified by prep- -MS: m/z 498.1 [M+H]+.
Figure imgf000089_0002
10260] Compound 116 was obtained by closely following the procedures for obtaining 100 and 114 using 7-fluoro-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-l -((2- (trimethylsilyl)ethoxy)methyl)- lH-indole and 4-ethoxy-3-methoxybenzoic acid. Compound 116 was obtained as a white solid. +ESI-MS: m/z 494.2 M+H]+.
[0261] Individual enantiomers of 116 (116a and 116b) were obtained by SEC separation of a racemic .
Figure imgf000089_0003
[0262] Compound 117 was obtained by closely following the procedures for obtaining 100 and 114 using 7-fluoro-3-(4,4,5.5-tetramethyl- l ,3,2-dioxaborolan-2-yl)- l -((2- (trimcthylsilyl)ethoxy )methyl)- l H-indolc and 4-(2-hydroxyethoxy )-3-methoxybenzoic acid. Compound 117 was obtained as a white solid. +EST-MS: m/z 510.2 [M+H]+.
[0263] Individual enantiomers of 1 17 (117a and 117b) were obtained by SFC separation of a racemic mixture of 117. +ESI-MS: m/z 510.1 [M+H]+.
Figure imgf000090_0001
[0264] Compound 118 was prepared using l -amino-2-(6-(3-bromo-4- fluorophenyl)-5-methoxypyridin-2-yl)propan-2-ol and 4-(2-fluoroethoxy)-3-methoxybenzoic acid and 4-(2-fluoroethoxy)-3-methoxybenzoic acid, and by following a synthetic route, which closely follows that described for preparation of 100 and 1 14. +ES1-MS: m/z 551 .9 [M+H]+.
[0265] Individual enantiomers of 1 18 (118a and 118b) were obtained by SFC separation of a racemic mixture of 118. +ESI-MS: m/z 551.9 [M+H]+.
Figure imgf000090_0002
[0266] To a stirring mixture of N-(2-(6-(3-chloro-4-fluorophenyl)-5- methoxypyi din-2-yl)-2-oxoethyl)-4-(2-fluoroethoxy)-3-methoxybenzamide (50 mg. 0.1 mmol) in THF at r.t. under argon was added a solution of MeMgCl in THF (0.5 mL, 1 .0 mmol). The mixture was reacted at r.t. for 2 h. The mixture was diluted w ith EtOAc and slowly quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 10 mins and then the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (NaiSC ), filtered and concentrated under reduced pressure. The crude mixture was purified via silica gel column and further purified via prep-HPTC to afford 119 as a white solid. TCMS: m/z 507.1 [M+H]+.
Figure imgf000091_0001
[0267| Compound 120 was prepared using N-(2-(6-(3-chloro-4-fluorophenyl)-5- methoxypyridin-2-yl)-2-oxoethyl)-4-(2-hydroxyethoxy)-3-niethoxybeiizamide with MeMgBr in THF, and by closely following a synthetic route, which closely follows that described for preparation of 119. LCMS: m/z 505.15 [M+H]+.
[0268] Individual enantiomers of 120(120a and 120b) were obtained by SFC separation of a racemi -MS: :m/z 505.1 [M+H]+.
Figure imgf000091_0002
[0269] Compound 121 was prepared using N-(2-(6-(3-chloro-4- fluorophenyl)pyridin-2-yl)-2-oxoethyl)-3-methoxy-4-(2-(methylamino)-2- oxoethoxy)benzamide with MeMgBr in THF. and by following a synthetic route, which cl
Figure imgf000091_0003
[0270] Compounds 122, 123, 124, 125, 126 and 127 were prepared using N-(2-(6- (3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-2-oxoethyl)-4-(2-fluoroethoxy)-3- methoxybenzamide with different Grignard reagents in THF, and by following a synthetic route, which closely follows that described for preparation of 119. 122: LCMS: m/z 521 .1 5 [M+H]+. 123: LCMS: m/z 533.1 5 [M+H]+. 124: LCMS: m/z 531.10 [M+H]+. 125: LCMS: m/z 535.15 [M+H]+. 126: LCMS: m/z 519.15 [M+H]+. 127: LCMS: m/z 517.05 [M+H]+.
[0271 ] Individual enantiomers of 122 (122a and 122b) were obtained by SFC separation of a racemic mixture of 122.
Figure imgf000092_0001
[0272] Compound 128 was prepared using N-(2-(6-(3-chloro-4-fluorophenyl)-5- methoxypyridin-2-yl)-2-oxoethyl)-3-methoxy-4-(] H-pyrazol-1 -yl)benzamide with MeMgBr in THF. and by following a synthetic route, which closely follows that described for preparation of 119. LCMS: m/z 51 1.10 [M+H]+.
EXAMPLE 9
Preparation of Compound 129
Figure imgf000093_0001
[0273] A 50 mL flask with a magnetic stirring bar was charged with 10-1 (223 mg. 1 .0 mmol). Weinreb amide (10-2, 282 mg. 1.0 mmol), and THF (10 mL) under N2 atmosphere. The solution was treated w ith i-PrMgCl ( 1.3 . 2.0 eq.) dropwise at r.t. The mixture was stirred for 1 h at r.t. Water (50 mL) and EA (50 mL) were added. The organic layer wras separated and the aqueous phase extracted with EA. The combined organic layers were dried with MgS04 and the volatiles were removed under reduced pressure. The residue was purified by column chromatography on silica gel (PE) to provide 10-3 as a solid (332 mg, 90%). +ESI-MS: m/z 367.0, 369.0 [M+H]+.
[0274] To a stirred solution of 10-3 (368 mg, 1.0 mmol) in MeOH/THF (5 mL/5 mL) was added NaBTL; (380 mg, 10 mmol) in portions until the starting materials was consumed. The volatiles were removed under reduced pressure. The residue was puritied by column chromatography on silica gel (PE: EtOAc=2: l ) to give 10-4 as a colorless oil (370 mg, 100%). +ESI-MS: m/z 369.0, 371 .0 [M+H]+.
[0275] A 50 mL flask with a magnetic stirring bar was charged with 10-4 ( 165 mg. 0.5 mmol). 2-(7-fluorobenzo[b]thiophen-3-yl)-dioxaborolane (278 mg. 1 .0 mmol). Pd(dppf)Cl2 (8 mg, 1 mol%), K.F (1 80 mg, 3.0 mmol), and dioxane/I I2O(20 mL/5 mL) under N? atmosphere. The mixture was stirred for 10 h at 100°C. Water (50 mL) and EA (50 mL) were added. The organic layer was separated and the aqueous phase extracted with EA. The combined organic phases were dried with MgS04 and the volatiles were removed under reduced pressure. The residue was purified by column chromatography on silica gel to provide 129 as a white sol +ES1-MS: m/z 463.9 [M +Na]+.
Figure imgf000094_0001
[0276| Compound 130 was obtained following the procedure for obtaining 129 by using 10-2, 1 J -dibromoimidazo[ 1 , -a] pyridine and 2-(7-fluorobenzo[b]thiophen-3-yl)- 4,4.5,5-tetramethyl- l ,3,2-dioxaborolane as the starting materials, and then the oxidizing reagent DMP. Compound 130 was obtained as a white solid. +ES1-MS: m/z 489.8 [M+H]+.
Figure imgf000094_0002
[0277] Compound 131 (176 mg. 80%) was obtained following the procedure for obtaining 129 by using 10-2. 4-chloro-2-iodo-6-methoxypyrimidine and 2-(7- fluorobenzo[b]thiophen-3-yl)-4,4,5.5-tetramethyl-l .3,2-dioxaborolane. +ES1-MS: m/z 483.9 [M+H]+.
EXAMPLE 10
Preparation of Compound 132
Figure imgf000094_0003
[0278] Compound 11 -1 was prepared using 10-2, 2,4,5-tribromo- l -((2- (trimethylsilyl)cthoxy)mcthyl)- l H-imidazole and 3,4-dimcthoxy-N-(2- (methoxy(methyl)amino)-2-oxoethyl)benzaiTiide, and by following a synthetic route, which closely follows that described for preparation of 129.
[0279] Compound 11 -1 (402 mg, 0.62 mmol) was dissolved in TFA/DCM (1 /1 , 6 niL). and stirred at r.t. for 3 h. The solvent was removed and the residue was purified by column (DCM /MeOH= 50: 1 to 20: 1 ) on silica gel to give 132 (149 mg, 72.4%). +ES1- MS:m/z 442.1 [M+H]+.
Figure imgf000095_0001
[0280] Compound 133 was prepared using 2.4,5-tribromo-l -methyl- l H-imidazole and 3.4-dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzamide. and by following a synthetic route, which closely follows that described for preparation of 129. +ESI-MS:m/z 455.9[M+H]+.
Figure imgf000095_0002
[0281] Compound 134 was prepared using 2,4-dibromothiazole and 3,4- dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzarnide, and by following a synthetic route, which closely follows that described for preparation of 129. +ESI-MS: m/z 459.0 [M+HJ+.
Figure imgf000095_0003
[0282] +ESI-MS: m/z 502.9 [M+Hf. EXAMPLE 11
Preparation of Compound
Figure imgf000096_0001
136 & 137
[0283] A mixture of 12-1 (3.26 g, 9.80 mmol), ( lR,2R)-2-aminocyclopentan-l-ol hydrochloride ( 1.04 g, 7.55 mmol), EDC (2.17 g, 1 1.3 mmol), HOBT ( 1.53 g, 1 1.3 mmol) and TEA (2.60 mL, 1 8.9 mmol) in DCM (50 mL) was stirred at r.t. for 18 h. The mixture was washed twice with 1 M aq. HCl solution, dried (Na2S04), filtered and concentrated under reduced pressure. Chromatography of the residue (eyclohexane-EtOAc. 100:0 to 0: 100) afforded 12-2 as a white solid (2.98 g. 95%). UPLC/MS(ES+): m/z 416.29 [M+H]+.
[0284] Dess-Martin periodinane (4.55 g. 10.7 mmol) was added to a solution of 12-2 (2.98 g, 7.16 mmol) in DCM (50 mL). The mixture was stirred at r.t. for 1 .5 h. A 1 : 1 mixture of 10% aq. Na2S?03 solution and sat. aq. NaHCOs solution was added, and the mixture wras stirred for 40 mins. The layers were separated and the organic portion was dried (Na2S04), filtered and concentrated under reduced pressure. Chromatography of the residue (eyclohexane-EtOAc, 100:0 to 0: 100) afforded 12-3 as a white solid (2.86 g. 96%). UPLC/MS(ES+): m/z 413.18 [M+H]+.
[0285] ft-Butyllithium (1.6M solution in hexane. 1.50 mL, 2.42 mmol) was added dropwise to a stirred solution of 12-4 (760 mg, 2.42 mmol) in toluene (15 mL), which had been pre-cooled to -78°C. After 20 mins, a solution of 12-3 (500 mg, 1 .21 mmol) in THF (10 mL) was added. The mixture was stirred at -78°C for 30 mins. The mixture was allowed to warm to r.t. and then quenched with MeOH. The volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The layers were separated and the organic portion was dried with Na2S04. filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromathography (water:CH3CN 100:0 to 95:5) to afford 12-5 as a 2: 1 diastereomeric mixture (470 mg. 65%). UPLC/MS(ES+): m/z 601 .22 [M+H]+.
[0286] A mixture of (3-chloro-4-fluorophenyl)boronic acid (50.5 mg. 0.290 mmol), 12-5 (70 mg, 0.1 16 mmol), Pd(dppf)Cl2 (4.3 mg, 0.006 mmol) and aq. Na2C03 (2M solution, 174 uL, 0.348 mmol) in DCE (2 mL) was degassed and heated to 85°C. After 1 h, water was added and the aqueous phase was extracted with DCM. The organic phase was dried with Na?S04, filtered and concentrated under reduced pressure. The residue was dissolved in a 10: 1 DCM-TFA solution (3 mL) and the mixture was stirred at r.t. for 30 mins. A 1M aq. NaOH solution was added and the mixture was stirred for further 30 mins. The phases were separated and the organic portion was dried with Na^SC^, filtered and concentrated under reduced pressure. Chromatography of the residue (DCM-MeOH, 98:2) afforded compounds 136 and 137. 136: UPLC/MS(ES+): m/z 531 .26 [M+I I]+. 137: UPLC/MS(ES+): m/z 531 .26 [M+H]+.
EXAMPLE 12
Preparation of Compound 138
Figure imgf000097_0001
13-1
[0287] Compound 13-1 was obtained following the procedure for obtaining 1 by using 2,4,6-trichloropyridine, 2-(7-fluo1Obenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-l ,3,2- dioxaborolane and 3.4-dimethoxybenzoic acid.
[0288] To a solution of 13-1 (972 mg, 2 mmol) in DME (1 mL) was added 13-2 (616 mg, 4 mmol), Pd(dppf)G?(146 mg, 0.2 mmol) and 0¾ΟΌ3(1 .3 g, 4 mmol). The mixture was stirred for 16 h at 120"C under N2. The reaction solution was filtered and to give a clear solution. The solution was extracted with EtOAc (80 mL) and washed with brine (3 x 20 mL). Compound 138 was purification by silica column chromatography using EA:PE = 1 : 1 as the elute (900 mg, 94%). ESI-MS: m/z 478.9 [M+H]+.
EXAMPLE 13
Preparation of Compound 139
Figure imgf000098_0001
[0289] To a solution of 14-1 (495 mg. 1 .0 mmol) in MeOH (10 mL) was added aqueous NaOH (10 mL, 1M). The mixture was stirred for 4 h at 60°C. The solution was cooled to r.t., acidified to pH=3 using IN HC1 solution and extracted with EtOAc. The organic phase was dried with anhydrous Na2S04 and concentrated under reduced pressure to provide 139 (490 mg, 99 %). +ESI-MS: m/z 497.1 [M+H]+.
EXAMPLE 14
Preparation of Compounds 140 and 141
Figure imgf000099_0001
[0290] Compound 15-2 was prepared starting from 2-chloro-6-(hydroxymethyl)- 4-iodopyridin-3-ol (15-1) according to procedures provided in PCT Publication No. WO 2004/039366, published May 13, 2004, which is hereb incorporated by reference for the limited purpose of its disclosure of the preparation of 15-2.
[0291 ] Dess-Martin periodinane (2.00 g, 4.21 mmol) was added to a stirred solution of 15-2 (835 mg) in dry DCM (5 mL). The mixture was stirred at r.t. for 40 mins. and quenched with a 1 : 1 mixture of 2M aq. Na?S2C»3 solution-sat. aq. NaHC03 sol (10 mL). After 30 mins., the layers were separated. The organic portion was washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 100:0 to 60:40) afforded 15-3 as a white solid (250 mg). Ή NMR (400 MHz, CDCb) δ ppm 1.44 (s. 6 H). 4.53 (s, 2 H). 7.79 (s. 1 H), 9.92 (s. 1 H). [0292] Nitromethane ( 191 uL, 3.54 mmol) and K2C03 (32.5 mg, 0.236 mmol) were added to a solution of 15-3 (250 mg, 1 .1 8 mmol) in dry THF (5 mL). The mixture was stirred at r.t. for 30 h and EtOAc was added. The organic portion was washed with water and brine, dried (Na2S04). filtered and concentrated under reduced pressure to afford crude 15-4 (343 mg). which was used in the next step. Ή NMR (400 MHz, CDC13) δ ppm 1 .36 - 1 .49 (m, 6 H). 4.45 (s, 2 H). 4.68 (dd, J= 13.6, 8.5 Hz. 1 H). 4.85 (dd. J= 13.4. 3.4 Hz, 1 H). 5.43 (dd. J=8.5. 3.3 Hz. 1 H). 7.26 (s, 1 H).
[0293] NaBH4 (21 .0 mg. 0.550 mmol) was added to a solution of NiCl2-6H20 (43.0 mg. 0.183 mmol) in MeOH (3 mL). After 30 mins. 15-4 (100 mg. 0.367 mmol) dissolved in MeOH (2 mL) w¾s added, followed by additional solid NaBH4 (28.0 mg. 0.730 mmol). The reaction was monitored by UPLC. When complete, the mixture was filtered through a pad of celite and the organic portion was concentrated under reduced pressure. The residue was eluted through a SCX-cartridge using MeOH and 2M NH^-MeOH solution to afford 15-5. UPLC/MS(ES+): m/z 243.10 [M+H]+.
[0294] A mixture of 15-5, 3-methoxy-4- {2-[(4- methoxyphenyl)methoxylethoxy}benzoic acid ( 146 mg, 0.440 mmol), EDC (106 mg, 0.550 mmol), HOBT (74 mg, 0.550 mmol) and TEA (101 uL, 0.730 mmol) in DCM (4 mL) was stirred at r.t. for 18 h. The mixture was washed twice with 1M aq. HCl solution. The organic portion was dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane: EtOAc, 80:20 to 0: 100) afforded 15-6 as a pale yellow wax (90 mg, 44% over two steps). UPLC/MS(ES 1 ): m/z 557.30 [M+H]" .
[0295] Dess-Martin pcriodinane ( 1 72 mg, 0.404 mmol) was added to a solution of 15-6 (90 mg. 0.162 mmol) in DCM (4 mL). The mixture was stirred at r.t. for 1 h. A 1 : 1 sat. aq. NaHCOi solution-sat. aq. Na2S203 solution was added. The mixture was stirred at r.t. for 30 mins and the layers were separated. The organic portion was washed with water, dried (Na2S04), filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 50:50 to 10:90) afforded 15-7 as a pale yellow wax (70 mg. 78%). Ή NMR (400 MHz, CDC13) δ ppm 1 .45 (s. 6 H), 3.83 (s. 3 H). 3.86 -3.92 (m, 2 H). 3.96 (s, 3 H), 4.27 (t, J=5.0 Hz, 2 H). 4.52 (s. 2 H), 4.60 (s. 2 H), 5.1 1 (d, J=4.5 Hz, 2 H), 6.91 (d. J=8.5 Hz. 2 H), 6.95 (d, J=8.5 Hz, 1 H), 7.02 (s, 1 H), 7.32 (d, J=8.5 Hz, 2 H), 7.41 (dd, J=8.3, 1 .8 Hz, 1 H), 7.51 (d, J=1 .8 Hz, 1 H), 7.90 (s, 1 H).
[0296] A mixture of 15-7 (90.0 mg, 0.126 mmol), (3-chIoro-4- fluorophenyl)boronic acid (55.0 mg. 0.316 mmol), Pd(dppf)Cl2 (6.0 mg. 0.008 mmol) and aq. NaiCOs (2M solution. 190 uL. 0.378 mmol) in DCE (3 mL) was degassed and heated to 85°C. After 20 h, the volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 80:20 to 0: 100) afforded the PMB-ether (51 mg). The PMB-ether was dissolved in DCM ( 1.5 mL) and treated with TFA (200 uL). The mixture was stirred at r.t. for 30 mins and quenched with 2M aq. NaOH solution. The layers were separated and the aqueous portion was extracted with DCM. The combined organic portions were dried (Na2S04), filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 80:20 to 0: 100) afforded 140 as a white solid (20 mg, 30% over two steps). Ή NM (400 MHz, CDCI3) δ ppm UPLC/MS(ES+): m/z 529.1 [M+H]+.
[0297] Coupling of 15-7 with 7-fluoiO-3-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l- { [2-(trimethylsilyl)ethoxy]-methyl}-lH-indole followed removal of all protecting groups (TFA-DCM) afforded 141 as an off-white solid (9% over two steps). UPLC/MS(ES+): m/z 534.33 [M+H]+.
EXAMPLE 15
Preparation of Compound 142
Figure imgf000101_0001
[0298] MeMgBr (0.7 mL, 2 mmol) was added dropwise to a stirred solution of 16-1 (700 mg, 0.3 mmol) in THF (5 mL) at -78°C. After 1 h, the mixture was allowed to warm to r.t. (approx. 2 h). The reaction was quenched with IN HCT and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and concentrated. The residue was purified by column on silica gel (PE:EA=10: 1 ) to give 16-2 (350 mg. 41 %).
[0299] A solution of 16-2 (350 mg. 0.96 mmol) in ammonia (6 mL) and EtOH (3 mL) was stirred at 90°C for 10 h. The solvent was removed and the crude product was used in next step without purification.
[0300] To a solution of 16-4 (73 mg, 0.4 mmol) in DIPEA (0.2 mL) and DMF (1 mL) was added HATU ( 1 52 mg, 0.4 mmol), and stirred at 40HC for 30 mins. Compound 16-
3 (100 mg, 0.33 mmol) was added. The mixture was stirred at 40°C for 10 h. The mixture was diluted with water and extracted w ith EtOAc. The organic layers w¾s washed w ith brine. dried over Na2S04, and concentrated. The crude product was purified by prep-HPLC to give
142 (60 mg, 39%). +ESI-MS:m/z 488.9 [M +Na]+.
EXAMPLE 16
Preparation of Compound 143
Figure imgf000102_0001
[0301] To a solution of 17-2 (132 mg, 0.4 mmol) in DIPEA (0.2 mL) and DMF (1 mL) was added I IATU (152 mg, 0.4 mmol), and the mixture stirred at 40°C for 30 mins. Compound 17-1 ( 100 mg, 0.33 mmol) was added. The mixture was stirred at 40°C for 10 h. The mixture was diluted with water and extracted with EtOAc. The organic layers was washed with brine, dried over Na2S04, and concentrated. The crude product was purified by column on silica gel (PE:EA=1 : 1 ) to give 17-3 (60 mg. 32%). [0302] To a solution of 17-3 (60 mg, 0.1 mmol) in DCM (2 mL) and H20 (0.2 mL) was added DDQ (45 mg, 0.2 mmol). The mixture was stirred for 2 h. at r.t. The mixture was dissolved in DCM (30 mL). The solution was washed with sat. NaHC0 , dried over Na2S04, and concentrated. The residue was purified by prep-HPLC to give 143 (30 mg. 60%). +ESI-MS:m/z 496.9 [M+H]+.
EXAMPLE 17
Preparation of Compound 144
Figure imgf000103_0001
Figure imgf000104_0001
[0303] To a solution of 4(5)-methylimidazole (2 g, 24 mmol) in CH2C12 (1 50 mL) was added bromine (2.5 mL, 48 mmol) at 0°C. The solution was stirred for 1 H at r.t. The product was filtered and partitioned between EA and sat. NaHCOs. The product was precipitated from MeOH/CLLCL to provide 18-1 (4.3 1 g, 75 %). Ή NMR (400 MHz. DMSO-d6): δ 2.06 (s, 3H).
[0304] To a solution of 18-1 (3.6 g, 15 mmol) and K2C03 (4.1 g, 30 mmol) in DMF ( 18 mL) was added iodomethane ( 1 .4 mL, 23 mmol) at 25°C. The solution was stirred for 1 5 h. The mixture was poured into water and extracted with EA The combined organic phase was dried over anhydrous Na?S04, and the residue was purified by chromatography on silica gel (EA/hexane) to giv e 18-2 (1 .6 g, 41 %). Ή NMR (400 MHz, CDC13): δ 3.52 (s. 3H). 2.21 (s, 3H).
[0305] To a solution of methyl vanillate (7.06 g, 39 mmol) and K2C03 (10.7 g, 78 mmol) in DMF (25 mL) was added l -bromo-2-fluoroethane (4.3 mL, 58 mmol) at 25°C. The solution was stirred for 2 days. The mixture was poured into water and extracted with EA. The combined organic layers were dried over anhydrous Na2SC>4, and concentrated. The residue w7as purified by chromatography on silica gel (EA/hexane) to give 18-3 (8.92 g, 103 %).). Ή NMR (400 MHz, CDCL,): δ 7.63 (dd, J=2.15, 8.41 , IH), 7.55 (d, J=8.41, IH), 4.72- 4.86 (m, 2H), 4.27-4.35 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H).
[03061 To a solution of 18-3 (8.92 g, 39 mmol) in MeOH ( 150 mL) was added 2 N NaOH (40 mL, 78 mmol). The solution was stirred for 2 h at 70°C. The mixture was concentrated, acidified with 2N HQ and extracted with EA to provide 18-4. (5.0 g, 30 %). Ή NMR (400 MHz, DMSO-d6): δ 7.47 (dd, J=1.96, 8.41, IH), 7.38 (d, J=1.96, IH), 6.99 (d, J=8.41. IH), 4.61 -4.76 (m, 2H), 4.17-4.27 (m, 2H).
[0307] To a solution of 18-4 (3.07 g, 14.3 mmol), glycine methyl ester HCT salt (3.6 g, 29 mmol), HATU (6.5 g, 17 mmol) in DMF (15 mL) was added DIEA (10 mL, 57 mmol). The solution was stirred for 1 8 h at r.t. The mixture was diluted with EA. The organic phase was washed with water, I N HC1, NaHC03 and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 18-5 (2.02 g, 51 %). Ή NMR (400 MHz, CDC13): δ 7.43 (d, J=2.15, IH), 7.30 (dd, J=2.15, 8.42), 6.90 (d, J-8.42, I H), 6.57 (br. t, I H), 4.72-4.85 (m, 2H), 4.22- 4.35 (m, 2H), 4.25 (d, J= 5.08, 2H) 3.85 (s, 3H), 3.79 (s. 3H).
[0308] To a solution of 18-5 (2.02 g, 7.1 mmol) in MeOH (50 mL) was added 2 N NaOH ( 10 mL. 20 mmol). The solution was stirred for 2 h at r.t. The mixture was concentrated, acidified with 2N HC1 and extracted with EA to provide 18-6. (1 .38 g, 72 %). Ή NMR (400 MHz, CD OD): δ 7.49 (m, 2H), 7.04 (d, J=8.42. I H). 4.62-4.85 (m. 2H). 4.25- 4.34 (m, 2H), 4.08 (s. 2H), 3.90 (s, 3H).
[0309] To a solution of 18-6 (0.52 g. 1.9 mmol). Ν,Ο-dimethylhydroxylamine hydrochloride (0.23g, 3.8 mmol), EDCl (0.38g. 2.3 mmol) in DMF (3 mL) was DIE A (1.0 mL, 5.8 mmol). The solution was stirred for 2 h at r.t. The mixture was diluted with EA. The organic phase was washed with water, IN HC1, NaHC03 and brine, dried over anhydrous a2SC>4, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 18-7 (0.28 g, 47%). Ή NMR (400 MHz, CDC13): δ 7.43 (d, .1=1.96, IH), 7.33 (dd, J=1.96, 8.22, IH), 6.90 (d, J=8.22, IH), 4.71 -4.84 (m, 2H), 4.26-4.36 (m, 4H), 3.91 (3, 3H), 3.76 (s, 3H), 3.25 (s, 3H).
[0310] Isopropylmagnesium chloride (2.0M, 0.48 mL, 0.95 mmol) was added dropwise to a solution of 18-7 (0.12 g, 0.38 mmol) and 18-2 (0.13 g, 0.50 mmol) in LHF (1.0 mL). The solution as stirred for 2 h at r.t. The reaction was quenched with IN HQ, diluted with EA and washed with brine. The organic solution was filtered to 18-8 (0.030 g, 20%). Ή NMR (400 MHz, CDC1 ): δ 7.49 (d, J =2.15, IH), 7.38 (dd, .1=2.15, 8.21 , IH), 7.03 (t, .1=5.09, I H), 4.93 (d, .1=5.09, 2H), 4.74-4.96 (m, 2H), 4.28-4.37 (m, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.22 (s, 3H).
[0311 ] A solution of 18-8 (30 mg, 0.070 mmol), 3-chloro-4-fluorophenylboronic acid (24 mg, 0.14 mmol), potassium acetate (21 mg. 0.21 mmol) and Pd(dppf)Cl2 ( 10 mg. 0.014 mmol) was heated under microwave irradiation for 1 h at 1 10°C. The mixture was concentrated and purified by chromatography on silica gel (EA/hexane) to give 18-9 (24 mg. 72%). LCMS: m/z 478.10 [M+H]+. [0312] Methylmagnesium bromide (0.33 mL, 0.46 mmol) was added to a solution of 18-9 (22 mg, 0.046 mmol) in THF ( 1 .0 mL). The mixture was stirred for 2 h at r.t.. and then quenched with 1 M HC1. The mixture was extracted with EA, washed with brine, dried and concentrated. The residue purified by reverse phase HPLC to give 144 (3.8 mg, 1 7%). LCMS: m/z 494.15 [M+H]+.
EXAMPLE 18
Preparation of Compound 145
Figure imgf000106_0001
[0313] To a solution of 4(5)-methylimidazole (2 g. 24 mmol) in CH2C12 ( 150 mL) was added bromine (2.5 mL. 48 mmol) at 0°C. The solution was stirred for 1 H at r.t. The product was filtered and partitioned between EA and sat. NaHCO . The product was precipitated from MeOH/CLLCL to provide 19-1 (4.31 g. 75 %). Ή NMR (400 MHz. DMSO-d6): δ 2.06 (s, 3H).
[0314] To a solution of 19-1 (3.6 g, 15 mmol) and K2C03 (4.1 g, 30 mmol) in DMF (18 mL) was added iodomethane (1.4 mL, 23 mmol) at 25°C. The solution was stirred for 15 h. The mixture was poured into water and extracted with EA The combined organic phase was dried over anhydrous NaiSC>4, and the residue was purified by chromatography on silica gel (EA/hexane) to give 19-2 (1.6 g, 41%). Ή NMR (400 MHz, CDCT3): δ 3.52 (s, 3H), 2.21 (s, 3H).
[0315] Compound 145 was prepared using iodoethane and closely following the procedure for preparing of 144. LCMS: m/z 476.10 [M+H]+.
EXAMPLE 19
Preparation of Compound 146
Figure imgf000107_0001
[0316] To a solution of 3-methoxy-4-iodobenzoic acid (0.45 g. 1 .6 mmol). 20-1 (0.485 g, 1 .6 mmol), HATU (0.75 g. 2.0 mmol) in DMF (3 mL) was added DIEA (0.71 mL. 4.1 mmol). The solution was stirred for 18 h at r.t. The mixture was diluted with EA. The organic phase was washed with water, IN HCL NaHCOs and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by chromatography on silica gel (MeOH/CH2Cl2) to give 20-2 (0.176 g. 51%). Ή NMR (400 MHz, CDC13): δ 7.99 (dd, J=2.15, 7.24, IH), 7.81 -7.85 (m, IH), 7.75 (d. J=8.02, IH), 7.37-7.42 (m, 2H), 7.26-7.27 (m, IH), 7.25 (t, J=8.71 , IH), 6.93 (dd, J=1.96. 8.02), 6.83-6.86 (m, IH), 4.97-4.99 (m, IH), 3.99-4.13 (m, IH), 3.90 (s, 3H), 3.89 (s, 3H), 3.54-3.72 (m, IH). [0317] A solution of 20-2 (25 mg, 0.045 mmol), pyridine-3-boronic acid (1 1 mg, 0.09 mmol), potassium acetate (13 mg, 0.13 mmol) and Pd(dppf)Cl2 (6 mg, 0.009 mmol) in DME (0.5 mL) and H?0 (0.05 mL) was heated under microwave irradiation for 1 h at 1 10°C. The mixture was concentrated and purified by chromatography on silica gel (MeOH/CH2Cl2) to give 20-3 (22 mg. 88%). Ή NMR (400 MHz, CDC13): δ 8.74-8.90 (br. s. 1 H). 8.60-8.72 (br. s, 1 H), 8.00, dd, J=2.1 5. 7.24). 7.85-7.88 (m, 2H), 7.34-7.45 (m. 5H). 7.1 7. (t. .1=8.80. lH). 6.94-6.97 (m, l H). 4.98-5.01 (m. 1 H), 4.00-4.09 (m. 1 H), 3.88 (s. 3H), 3.82 (s, 3H0. 3.68-3.75 (m. 1 H).
[0318] Dess-Martin periodinane (25 mg. 0.061 mmol) was added to a solution of 20-3 (22 mg. 0.043 mmol) in CLLCL. and stirred for 2 h. The mixture was diluted with CH2CI2, washed with sat. Na2CC>3, and brine, dried over MgS(D4. and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (EA/hexane) to give 20-4 (6.1 mg, 28%). LCMS: m/z 506.10 [M+H]+.
[0319] Methylmagnesium bromide ( 1.4 M in THF, 0.39 mL. 0.39 mmol) was added to a solution of 20-4 (20 mg. 0.039 mmol) in THF (1.0 mL) and stirred for 2 h. The mixture was diluted with quenched with IN HC1 and extracted with EA. The organic extracts were washed with brine, dried over MgS04, and concentrated under reduced pressure. The crude product purified by reverse phase HPLC to provide 146 (0.9 mg, 4%). LCMS: m/z 522.15 [M +.
Figure imgf000108_0001
[0320] Compound 147 was prepared using pyridine-4-boronic acid pinacol ester in the Suzuki reaction and by following a synthetic route, which closely follows that described for preparation of 146. LCMS: m/z 522.15 [M+Hj 1 . EXAMPLE 20
Preparation of Compound 148
Figure imgf000109_0001
148
[0321] To a solution of 21-1 (100 mg, 0.549 mmol), HATU (208 mg, 0.549 mmol) and D1PEA (142 mg, 1.1 mmol) in anhydrous DMF (2 mL) was added 21-2 (100 mg 0.347 mmol) at 25"C. The solution was stirred for 10 h at this temperature and then diluted with 1 .0 N aqueous NaHC03 solution (2 x 40 mL). extracted with EA (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na?S04, and concentrated under reduced pressure. The residue was purified on a silica gel column to give 21 -3 ( 100 mg, 40.3%). +ES1-MS: m/z 433.1 [M+H]+.
[0322] To a solution of 21-3 ( 100 mg, 0.22 mmol) in THF (2 mL) were added Ag20 (20 mg) and CH3I ( 100 mg. 0.72 mmol). The mixture was stirred for 15 h at 40°C. The solid was removed, and the filtrate was concentrated. The residue was purified by prep- HPLC (FA) to give 148 as a white solid (40 mg, 38.8 %). +ES1-MS: m/z 466.9 [M+H]+.
EXAMPLE 21
Preparation of Compound 149
Figure imgf000110_0001
[0323] To a solution of 22-1 (1 .1 g, 3.1 mmol) in DCM (3 niT) was added DAST (1 .4 g; 8.7 mmol). The solution was stirred at r.t. for 1 h with TLC monitoring. The reaction was quenched with aq. NaHCOj at 0°C and extracted with DCM. The combined organic solution was dried over anhydrous MgSC>4, and evaporated under reduced pressure. The residue was purified on a silica gel column (PE:EA=20: 1 to 6: 1 ) to give 22-2 (0.8 g).
[0324] To a solution of 22-2 (0.8 g, 2.2 mmol) in DMSO (5 mL) was added NaN3 (300 mg 4.6 mmol). The solution was stirred at 60°C for 3 h with LCMS monitoring. The reaction was quenched with aq. NaHCO and extracted with EA. The combined organic solution was dried over anhydrous MgS04. and evaporated under reduced pressure to give crude 22-3 (0.7 g), which was used in next step directly without purification.
[0325] To a solution of 22-3 (0.7 g, 2.1 mmol) in EtOH ( 10 mL) and HC1 (2 drops, 1.0 N) was added Pd/C (10%, 400 mg) under N2. The suspension was degassed under vacuum and purged with EE 3 times. The mixture was stirred under EL (40 psi) at r.t. for 1 h. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOH. The combined filtrates were concentrated to give crude 22-4 (0.4 g) used for next step directly without purification [0326] To a solution of 4-(2-hydrox ethoxy)-3-methoxybenzoic acid (212 mg, 1.0 mmol), I IATU (570 mg, 1 .5 mmol) and DIPEA (322 g, 2.5 mmol) in anhydrous DCM (5 niL) was added 22-4 (298 mg, 1 .0 mmol) at 25°C. The solution was stirred for 3 h. at this temperature, diluted with 1 .0 N aqueous NaHC03 solution, and extracted with DCM. The combined organic layers were washed by brine, dried over anhydrous Na2SC»4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 149 (180 mg) as a white solid. +ESI-MS::m/z 493.0 [M+H]+.
Figure imgf000111_0001
[0327] Compound 150 was prepared using 6-(2-bromo- l , l -difluoroethyl)-2-(3- chloro-4-fluorophenyl)-3-methoxypyridine, and by following a synthetic route, which closely follows that described for preparation of 149. +ES1-MS: :m/z 510.9 [M+H]+.
EXAMPLE 22
Preparation of Compound 151
Figure imgf000111_0002
[0328] To a solution of methyl 3-methoxy-4-iodobenzoate (250 mg, 0.85 mmol) in toluene (2 mL) was added pyrrolidinone (150 mg. 1.7 mmol), potassium phosphate (0.55 g, 2.2 mmol), xantphos (25 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.43 mmol). The mixture was heated at 1 10°C for 3 h. The mixture was then diluted with EA. The organic phase was washed with water, IN HCl, NaHC03 and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 23-1 (0.178 g, 83%). LCMS: m/z 478.10 [M+H]+.
[0329] To a solution of 23-1 (0.178 g. 0.72 mmol) in methanol (6 raL) was added NaOH (2.0 M, 2.0 mL) at 25°C. The solution was stirred for 1 5 h, acidified with 2N HCl and extracted with EA. The combined organic phase was dried over anhydrous Na2S04 to give 23-2 (0.152 g, 90%). Ή NMR (400 MHz, CDC13): δ 7.52 (dd, J=1.77. 8.22 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H), 7.30 (d, J=8.22 Hz, 1H), 3.82 (s, 3H), 3.75 (t, J=7.04 Hz, 2H), 2.55 (t, J=8.02 Hz, 2H), 2.0-2.3 (m, 2H).
[0330] To a solution of 23-2 (0.152 g, 0.65 mmol), 23-3 (0.19 g, 0.65 mmol), HATU (0.37 g, 0.97 mmol) in DMF ( 1 mL) was added DIEA (0.23 mL, 1.3 mmol). The solution was stirred for 2 h at r.t. The mixture w7as diluted with EA. The organic phase was washed with water. IN HCl, NaHCO^ and brine, dried over anhydrous a2S04, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 23-4 (0.1 72 g, 51 %). LCMS: m/z 478.10 [M+H]+.
[0331 ] Dess-Martin periodinane (220 mg, 0.50 mmol) was added to a solution of 23-4 ( 1 72 mg, 0.34 mmol) in CH2C12, and the mixture was stirred for 2 h. The mixture was diluted with CH2CI2 and washed with sat. Na2C03. and brine, dried over MgS04, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (EA/hexane) to give 23-5 (77 mg. 45%) as white solid. LCMS: m/z 512.10 [M+H]+.
[0332] Methyimagnesium bromide (1 .0 mL. 1 .4 mmol) was added to a solution of 23-5 (72 mg. 0.14 mmol) in THF (1 .0 mL). The mixture was stirred for 2 h at r.t.. and then quenched with I N HCl. The mixture was extracted with EA. washed with brine, dried and concentrated. The residue purified by reverse phase HPLC to give 151 (6.5 mg. 17%) as white solid. LCMS: m/z 528.15 [M+H]+. EXAMPLE 23
Preparation of Compound 152
Figure imgf000113_0001
[0333] To a stirring mixture of 24-1 (44 mg, 0.197 mmol) in DMF were added HATU (83 mg, 0.218 mmol) and DIPEA (51 mg, 0.4 mmol). The mixture was stirred at r.t. for 10 mins and a solution of 2-amino- l -(6-bromo-5-methoxypyridin-2-yl)ethan-l -ol was added. The mixture was stirred at r.t. for 1 h, diluted with EtOAc and quenched with a sat. NaHCOi solution. The mixture was stirred at r.t. for 10 mins and the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na2S04). filtered and concentrated under reduced pressure. The crude product was purified via silica gel chromatography to afford 24-2. LCMS: m/z 451 .05 [M+H]+.
[0334] To a stirring mixture of 24-2 (28 mg. 0.062 mmol) in DME/water (10: 1. 2.2 ml) were added CS2CO3 (60 mg, 0.19 mmol). PdCl2dppf(1 0 mg. 0.012 mmol), and (3- chloro^-fluoropheny boronic acid (1 1 mg, 0.062 mmol). The mixture was stirred under microwave conditions at 1 10°C for 1 h. The crude product mixture was cooled to r.t. and concentrated under reduced pressure. The crude mixture was purified via silica gel chro +.
Figure imgf000113_0002
[0335] Compounds 153 and 154 were prepared using commercially available benzoic acids and 2-amino- l -(6-bromo-5-methoxypyridin-2-y l)ethan-l -ol in 2 or 3 steps, and by following a synthetic route, which closely follows that described for preparation of the compound of Example 23. 153: LCMS: m/z 497.05 [M+I I] ' . 154: LCMS: m/z 475.10 [M+H]+.
EXAMPLE 24
Preparation of Compound 155
Figure imgf000114_0001
[0336] To a solution of 25-1 (1.82 g, 10 mmol) and K2C0 (2.76 g, 20 mmol) in CH3CN (20 mL) at r.t. was slowly added 2-bromoacetonitrile (2.4 g, 20 mmol). The mixture was heated to reflux and stirred for 15 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=3: 1 ) provided 25-2 (2 g, 90%).
[0337] To a solution of 25-2 (2.21 g, 10 mmol) in methanol (10 mL) was added NaOH aqueous ( 10 mL. 1 M). The mixture was stirred for 4 h at 60°C. The solution was cooled to r.t., acidified to pH=4 using IN HC1 solution and extracted with EtOAc. The organic phase was dried with anhydrous Na2S04 and concentrated under reduced pressure to provide 25-3 (1 .1 g. 50%).
[0338] To a solution of 25-3 (226 mg. 0.1 mmol) in DMF (3 mL) were added HATU (570 mg. 1.5 mmol) and D1PEA (387 mg. 3 mmol) at r.t. The solution was stirred for 10 mins at r.t. Compound 25-4 (287 mg, 1 mmol) was added and stirred for 1 h. The solution was extracted with EtOAc and washed with LLO. The organic phase was concentrated and purified by prep-TLC to give 155 (200 mg, 40%). +ES1-MS: m/z 495.9 [M+I I]+.
EXAMPLE 25
Preparation of Compound 156
Figure imgf000115_0001
[0339] To a stirring mixture of N-(2-(6-(7-fluorobenzo[b]thiophen-3-yl)-4- methylpyridin-2-yl)-2-oxoethyl)-3.4-dimethoxybenzamide (20 mg, 0.043 mmol) in LtOH (0.25 mL) were added methoxy amine hydrochloride (4 mg, 0.048 mmol) followed by an addition of pyridine (34 mg, 0.43 mmol). The mixture was heated at 80°C for 30 mins and then cooled to r.t. The mixture was concentrated under reduced pressure. The crude mixture was purified via prep-HPL [M+H]+.
Figure imgf000115_0002
[0340] Compound 157 was prepared using N-(2-(6-(7-fluorobenzo[b]thiophen-3- yl)pyridin-2-yl)-2-oxoethyl)-3,4-dimethoxybenzamide and hydroxylamine hydrochloride, and by following a synthetic route, which closely follows that described for preparation of 156. LCMS: m/z 466.25 [M+H]+.
EXAMPLE 26
Preparation of Compound 158
Figure imgf000115_0003
[0341] To a stirring mixture of 158 (20 mg, 0.036 mmol) in THF (1 mL) were added bis(tri-/er/-butylphosphine)palladium(0) (3.6 mg, 0.008 mmol), and a solution of MeZnCl in THF (0.055 mL. 0.1 1 mmol). The mixture was stirred under microwave condition at 100°C for 1 h. The mixture was cooled to r.t.. diluted with EtOAc and slowly quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 20 mins and then the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na?S04). filtered and concentrated under reduced pressure. The crude product mixture was purified via silica gel column to afford 159 as a colorless oil. LCMS: m/z 495.1 [M+H]+.
EXAMPLE 27
Preparation of Compound 160
Figure imgf000116_0001
[0342] To a stirring mixture of 26-1 (50 mg, 0.082 mmol) in MeOH ( 1 mL) were added amonium acetate (94 mg, 1.23 mmol), NaCNBLL (7.7 mg. 0.12 mmol). The mixture was heated at 70°C for 1 h and then cooled to room temperture. The mixtue was diluted wtih EtOAc and slowly quenched with a sat. NI I4CI solution. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na?S04), filtered and concentrated under reduced pressure. The crude product mixture was purified via silica gel chromatography to afford 26-2. The PMB ether was removed using ΤΓΑ in DCM at r.t. The crude product was concentrated under reduced pressure and purified via prep-HPLC to afford 160 (3.1 mg) as a white solid. LCMS: m/z 490.15 [M+H]+.
EXAMPLE 28
Preparation of Compound 161
Figure imgf000117_0001
[0343] To a solution of 3-methoxy-4-(2-((4-raethoxybenzyl)oxy)ethoxy)benzoic acid (205 mg, 0.62 mmol ) in DMT (15 niL) were added DIPEA (320 mg, 2.48 mmol) and HATU (235.6 mg, 0.62 mmol). The mixture was stirred at r.t. for 30 mins, and 27-1 (195 mg, 0.62 mmol) was added. The mixture was stirred at r.t. overnight. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give the crude product, which was purified by column chromatography to give 27-2 ( 180 mg). +ESI-MS: m/z 631.1 [M+H]+.
[0344] Compound 27-2 (180 mg, 0.286 mmol) was dissolved in TFA/DCM ( 10 niL). The mixture was stirred at r.t. for 1 h (monitored by TLC). The mixture was extracted with EA, and washed with a sat. NaHCOj solution. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give the crude product, which was purified by prep- HPLC to give 161 (50mg) as a white solid. +ESI-MS: m/z 51 1 .1 [M+H]+.
EXAMPLE 29
Preparation of Compound 162
Figure imgf000118_0001
[0345] A solution of 28-1 (2.59 g, 0.01 mol) in NHy'MeOH (20 mL) was stirred at r.t. for 30 mins. The solvent was removed by rotary evaporator. The residue. 28-2. was used in next step.
[0346] A mixture of 28-2 (2.44 g, 0.01 mol) 28-3 (2.73 g, 0.01 mol) and AgSbF6 (5.14 g, 0.01 5 mol) in DME (20 mL) was stirred for 2 h at 120°C under microwave irradiation. The mixture was filtered. The filtrate was concentrated by rotary evaporator to give crude 28-4 (5 g), which was used in next step without further purification.
[0347] To a solution of 28-4 (5 g) in EtOAc (10 mL) was added HCl-EtOAc (30 mL). The solution was stirred for 10 h. The solvent was concentrated by rotary evaporator. The product was purified by prep-HPLC to give 28-5 (250 mg). ESl-MS: m/z 278.8 [M+H]+.
[0348] To a solution of 28-5 ( 145 mg, 0.8 mmol) in DMF (10 mL) was added HATU (343 mg, 0.9 mmol). DIEA ( 155 mg. 1 .2 mmol), and stirred for 5 mins. 3,4- dimethoxybenzoic acid (250 mg. 0.8 mmol) was added and the mixture was stirred for 5 h. Water ( 100 mL) was poured into the solution, and a solid precipitated. The solid was purified by silica column chromatography (PE:EA=1 : 1 ) to give 162 (158 mg, 45%). ESI- MS: m/z 442.9 [M+H]+. EXAMPLE 30
Preparation of Compound 163
Figure imgf000119_0001
[0349] A 50 mL three-necked round bottle flask was charged with a solution of 2,6-dibromopyridine ( 1 .15 g, 5 mmol, 5.0 eq.) in THF under nitrogen. The solution was cooled to -78°C. and «-BuLi (2 mL, 5 mmol. 5.0 eq.) was added dropwise. After addition, the mixture was stirred for 30 mins. A solution of 29-1 (1 15 mg, 1 .0 mmol, 1 .0 eq.) (prepared according to Wuitschik et al., J. Med. ( 'hem. (2010) 53(8):3327-3246. which hereby is incorporated by reference for the limited purpose of preparing 29-1 ) in THF (3-5 mL) was added dropwise. After addition, the mixture was stirred for 30 mins. The reaction was quenched with sat. NH4CT. and the mixture was extracted by EA (3 x 10 mL). The combined organic phase was concentrated to dryness, and the residue was purified by prep- TLC to give 29-2 as a yellow oil (80 mg). Ή-NM (400MHz, CDCI3), δ = 7.67 - 7.60 (m, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 5.23 (s, 2H), 4.99 (d, J=7.0 Hz. 2H), 4.89 (d, J=7.0 Hz, 2H).
[0350] A 50 mL round bottom flask was charged with a mixture of 29-2 (0.4 g. 1.46 mmol), boric ester (0.6 g, 2.16 mmol, 1.5 eq.), Pd(dppf)Ci2 ( 107 mg, 0.146 mmol, 0.1 eq.) and Na C03 (320 mg, 3.0 mmol, 3.0 eq.) in dioxane/H?0 (10 n L/2 mL). The mixture was degassed and refilled with nitrogen. The mixture was heated to reflux overnight. The mixture was cooled to r.t. and concentrated to dryness. The residue was purified by column on silica gel (5-10% EA in PE) to give 29-3 as a pink oil (0.44 g, 87% yield). Ή-NMR (400MHz, CDC13), δ = 8.02 (d, J=8.5 Hz, 1H), 7.92 (t, .1=7.8 Hz, l H), 7.81 (s, 1H), 7.67 (dd, .1=7.8, 14.3 Hz. 2H), 7.42 (dt, .1=5.5, 8.0 Hz, 1 H), 7.16 - 7.07 (m, 1 H), 5.33 (s, 2H), 5.10 (d, .1=7.0 Hz, 2H), 5.00 (d, .1=6.5 Hz, 2H).
[0351 ] A 250 mL round bottom flask was charged with a solution of 29-3 (0.4 g, 1.1 7 mmol) in EtOH ( 100 mL) and Pd/C (0.2 g). The mixture was stirred under hydrogen balloon overnight. The mixture was filtered, and concentrated to dryness. Crude 29-4 was used in the next step without further purification.
[0352] To a solution of 29-4 (270 mg. 0.86 mmol, 1 .0 eq.), acid (31 3 mg, 0.942 mmol, 1 .1 eq.) and D1EA (0.33 g, 3.0 eq.) in DMF (10 mL) was added HATU (360 mg. 0.942 mmol. 1 .1 eq.). and the mixture was stirred at r.t. overnight. The mixture was diluted with EA and water. The organic phase was washed with brine, dried over anhydrous MgSCu, and concentrated to dryness. The residue was purified by silica gel column (60% EA in PE) to give 29-5 as a pale yellow oil (0.4 g. 74%).
[0353] To a solution of 29-5 (0.35 g) in DCM (25 mL) was added TEA (5 mL), and the mixture was stirred at r.t. for 10 mins. The mixture was neutralized with sat. Na2C03 solution. The organic phase was concentrated and purified by prep-TLC to give 163 as a white solid (70 mg). +ES1-MS: m/z 509.0 [M+H]+.
EXAMPLE 31
Preparation of Compound 164
Figure imgf000120_0001
[0354] To a solution of 30-1 (190 mg. OJOmmol) in THF (5 mL) was added NaB¾ (20 mg. 0.6 mmol) at r.t. MeOH (lmL) was added, and the mixture was stirred at 20°C for 1 h. The residue was purified by column chromatography on silica gel (PE) to provide 30-2 ( 190 mg, 99 %).
[0355] To a solution of 30-2 (190 mg, 0.3 mmol) in DCM (3 mL) was added TFA (0.5mL) and EEC1? (0.2 mL, 30%. 2eq). and the mixture was stirred for 30 mins. The mixture was neutralized with a sat. NaHCOs solution, and extracted with DCM (3 x l OmL). The solution was concentrated to give 164 in crude form (200 mg), +ES1-MS: m/z 625.0 [M+H]+.
EXAMPLE 32
Preparation of Compound 165
Figure imgf000121_0001
[0356] Compound 31-2 (106 mg, 0.5 mmol), 31-1 ( 140 mg, 0.5 mmol) and triethylamine (1 mmol) were dissolved in DMF (5 mL). HATU (380 mg, 1 mmol) was added to the solution. After 1 5-30 mins, the mixture was treated with sat. NaCT solution ( 100 mL), and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with 2N HC1 solution and 5%o NaHCO solution. The organic layer were dried over anhydrous MgSC , and concentrated in vacuum to give the crude product. The crude product was purified by silica gel column chromatography eluting with EtOAc/PE ( 1 /1 ) to give 165 as a white solid (24 mg. 10%). +ESI-MS: m/z 483.0 [M+H]+.
EXAMPLE 33
Preparation of Compound 166
Figure imgf000122_0001
[0357] Dess-Martin periodinane (1.49 g, 3.52 mmol) was added to a stirred solution of 32-1 (300 mg, 1.40 mmol) in dry DCM (6.5 mL). The mixture was stirred at r.t. for 1 h and quenched with a 1 : 1 mixture of 2M aq. Na2S203 solution and sat. aq. NaHC(¾ solution (10 mL). The mixture was stirred vigorously for 30 mins and the layers were separated. The organic portion was washed with brine, dried
Figure imgf000122_0002
filtered and concentrated under reduced pressure. The crude aldehyde was progressed to the next step without further purification. The aldehyde was dissolved in fcrt-butanol (21 mL). To the solution, 2-methyl-2-butene (1 .1 3 mL, 13.5 mmol) and a solution of sodium chlorite (244 mg, 2.70 mmol) and sodium phosphate monobasic di hydrate ( 1 .36 g, 8.70 mmol) in water (21 mL) were added. The mixture was stirred at r.t. for 18 h. Brine was added and the mixture was extracted 3 times with EtOAc. The combined organic portions were dried ( aiSC ) and filtered. The volatiles were removed under reduced pressure. Acid 32-2 (310 mg) was progressed to the next step without further purification. UPLC/MS(ES+): m/z 228.07 [M+H]+.
[0358] l . -Carbonyldiimidazole (1.17 g, 7.21 mmol) wras added to a solution of 32-2 (250 mg) in THF (9.6 mL). The mixture was stirred at r.t. for 30 mins and then nitromethane (671 mg, 1 1 .0 mmol) and potassium carbonate (608 mg, 4.40 mmol) were added. After 3 h, the volatiles were removed under reduced pressure. The residue was taken up with EtOAc. The organic portion was washed with water, dried with Na2S04, filtered and concentrated under reduced pressure. Crude 32-3 (300 mg) was progressed to the next step without further purification. UPLC/MS(ES+): m/z 271 .05 [M+H]+.
[0359] Methylmagnesium bromide (3M solution in Et20, 204 uT, 0.612 mmol) was added to a solution of 32-3 (300 mg) in THF (8 mL), which had been pre-cooled to - 40°C. The mixture was stirred at -40°C for 1 h, allowed to reach r.t. and then quenched with 1M aq. HC1 solution. The aqueous portion was extracted twice with EtOAc. The combined organic portions were dried with Na2SC»4, filtered and concentrated under reduced pressure. Crude 32-4 was progressed to the next step without further purification. UPLC7MS(ES+): m/z 287.10 [M+H]+.
10360] NaBH4 (52.0 mg, 1.38 mmol) was added to a solution of NiCl2-6H20 ( 109 mg, 0.460 mmol) in MeOH ( 10 mL). After 30 mins, nitro-derivative 32-4 (250 mg) dissolved in MeOH (2 mL) was added, followed by additional solid NaBELi (70 mg). The reaction was monitored by UPLC. When complete, the mixture was filtered through a pad of celite and the organic portion was concentrated under reduced pressure. Crude 32-5 (235 mg) was progressed to the next step without further purification. UPLC/MS(ES+): m/z 257.17 [M+H]\
[0361 ] A mixture of 32-5 (235 mg), 3-mcthoxy-4-{2-[(4- methoxyphenyl)methoxy]ethoxy} benzoic acid (365 mg. 1 .10 mmol), EDC (263 mg. 1 .38 mmol), HOBT (186 mg, 1 .38 mmol) and TEA (255 uL. 1 .84 mmol) in DCM (8 mL) was stirred at r.t. for 3 h. The mixture was washed twice with 1 M aq. HC1 solution. The organic portion was dried (Na2SC>4). filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc. 60:40 to 1 0:90) afforded 32-6 as an off- white solid (60 mg. 12% starting from 32-1). UPLC/MS(ES+): m/z 571.20 [M+H]+.
[0362] A mixture of 32-6 (60 mg. 0.100 mmol), (3-chloro-4-fluorophenyl)boronic acid (91 .0 mg, 0.500 mmol). Pd(dppf)Cl2 (3.6 mg, 0.005 mmol) and aq. Na2C03 (2M solution, 0.500 mmol, 250 uL) in DCE (1 mL) was degassed and then stirred with heat to 85 °C for 4 h. Water and DCM were added, and the layers were separated. The organic phase was dried with Na2S04. filtered and evaporated. Chromatography of residue (cyclohexane:EtOAc, 100:0 to 20:80) afforded 32-7 (46 mg, 69%). UPLC/MS(ES+): m/z 665.47 [M+H]+.
[0363] A solution of 32-7 (46.0 mg. 0.069 mmol) in 10: 1 DCM-TFA (1 .1 mL) was stirred at room temperatire for 1 h. 1 M aq. NaOH solution was added and the mixture was stirred for 15 mins. The layers were separated. The organic portion was dried (Na2S04). filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN. 100:0 to 50:50) to afford 166 as a white solid (racemic mixture, 18 mg, 33%). UPLC/MS(ES+): m/z 545.33 [M+H]+.
EXAMPLE 34
Preparation of Compound 167
Figure imgf000124_0001
[0364] To a stirring mixture of 33-1 (40 mg. 0.061 mmol) in THF (1 .0 mL) at r.t. under argon was added a solution of MeMgBr (1 .4 M) in THF (0.5 mL) dropwise. The mixture was reacted at r.t. for 1 h. The mixture was diluted with EtOAc and quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 10 mins and the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. The crude mixture was purified via silica gel column to afford 33-2 as a white solid. LCMS: m/z 669.1 [M+H]+.
[0365] To a stirring mixture of 33-2 (20 mg, 0.0299 mmol) in DCM ( 1.0 mL) at r.t. was added dropwise TFA (0.2 mL). The mixture was stirred at r.t. for 10 mins and then concentrated under reduced pressure. The crude product mixture was purified via prep- HPLC to afford 167. LCMS: m/z 549.05 [M+H]+. EXAMPLE 35
Preparation of Compound 168
Figure imgf000125_0001
[0366] To a stirring mixture of 2-bromothiazole (0.2 g. 1 .22 mmol) in THF under
Ar at -78°C was added dropwise a solution of n-BuLi (2.5 M) in hexane (0.49 mL. 1 .22 mmol). The mixture was stirred at -78°C for 1 5 mins and then a solution of 34-1 (40 mg.
0.081 mmol) in THF (0.5 mL) was added. The mixture was stirred at -78°C for 1 h and then warmed to r.t. for 10 mins. The mixture was diluted with EtOAc and quenched with a sat.
NH4CT solution. The mixture was stirred at r.t. for 10 mins and then the layers were separated. The aqueous layer was extracted with EtOAc (2 x 15 mL). The organic layers were dried (Na?S04 , filtered and concentrated under reduced pressure. The crude mixture was purified via silica gel chromatography and further purified via prep-HPLC to afford 168 as a tan solid. LCMS: m/z 576.1 [M+H]+.
EXAMPLE 36
Preparation of Compound 169
Figure imgf000125_0002
[0367] To a solution of 34-2 ( 100 mg, 0.442 mmol ), HATU (251 mg, 0.66 mmol) and DIPEA (170 mg, 1 .32 mmol) in anhydrous DMF (2 mL) was added 34-3 ( 127 mg 0.442 mmol) at 25°C. The solution was stirred for 10 h at r.t. and then diluted with 1 .0 N aqueous NaHCO solution (2 x 40 mL), extracted with EA (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified on a silica gel column to give 169 ( 120 mg, 54.8%). +ESI-MS: m/z 497.1 [M+H]+. EXAMPLE 37
Preparation of Compound 170
Figure imgf000126_0001
[0368] Compound 170 was prepared using 2.6-dichloro-3-methylpyridine, 2-(7- fluorobenzo[b]thiophen-3-y] )-4,4,5,5-tetramethyl-1.3,2-dioxaborolane and 3,4- dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ESI-MS:m/z 464.9 [M+H]+.
EXAMPLE 38
Preparation of Compounds 171 and 172
Figure imgf000126_0002
[0369] To a solution of 3-methoxy-4-iodobenzoic acid (0.45 g. 1 .6 mmol). 35-1 (0.485 g, 1 .6 mmol), HATU (0.75 g. 2.0 mmol) in DMF (3 mL) was added DIEA (0.71 mL. 4.1 mmol). The solution was stirred for 18 h at r.t. The mixture was diluted with FA. The organic phase was washed with water, IN HCL NaHCOs and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by chromatography on silica gel (MeOH/CH2Cl2) to give 171 (0.176 g, 51%). Ή NMR (400 MHz, CDClj): δ 7.99 (dd, J=2.15. 7.24, IH). 7.81 -7.85 (m, IH), 7.75 (d, J=8.02, IH), 7.37-7.42 (m, 2H). 7.26-7.27 (m, IH), 7.25 (t, J=8.71 , IH), 6.93 (dd, J=1.96, 8.02), 6.83-6.86 (m, IH), 4.97-4.99 (m, IH), 3.99-4.13 (m, IH), 3.90 (s, 3H), 3.89 (s, 3H), 3.54-3.72 (m, IH). [0370] A solution of 171 (25 mg, 0.045 mmol), pyridine-3-boronic acid (1 1 mg, 0.09 mmol), potassium acetate (13 mg, 0.13 mmol) and Pd(dppf)Cl2 (6 mg, 0.009 mmol) in DME (0.5 mL) and H?0 (0.05 mL) was heated under microwave irradiation for 1 h at 1 10°C. The mixture was concentrated and purified by chromatography on silica gel (MeOH/CH2Cl2) to give 172 (22 mg. 88%). Ή NMR (400 MHz. CDC13): δ 8.74-8.90 (br. s. 1 H). 8.60-8.72 (br. s, 1 H), 8.00, dd, J=2.1 5. 7.24). 7.85-7.88 (m, 2H), 7.34-7.45 (m. 5H). 7.1 7. (t. .1=8.80. 1H). 6.94-6.97 (m, l H). 4.98-5.01 (m. 1 H), 4.00-4.09 (m. 1 H), 3.88 (s. 3H), 3.82 (s, 3H0. 3.68-3.75 (m. 1 H).
EXAMPLE 39
Preparation of Compound 173
Figure imgf000127_0001
[0371] To a solution of methyl 3-methoxy-4-iodobenzoate (250 mg, 0.85 mmol) in toluene (2 mL) was added pyrrolidinone ( 150 mg, 1.7 mmol), potassium phosphate (0.55 g, 2.2 mmol), xantphos (25 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.43 mmol). The mixture was heated at 1 10"C for 3 h. The mixture was then diluted with EA. The organic phase was washed with water, IN HCl, NaHC03 and brine, dried over anhydrous a2S04, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 36-1 (0.178 g, 83%). LCMS: m/z 478. 1 0 [M+H]+.
[0372] To a solution of 36-1 (0.178 g, 0.72 mmol) in methanol (6 mL) was added NaOH (2.0 M, 2.0 mL) at 25°C. The solution was stirred for 1 5 h. acidified with 2N HCl and extracted with EA. The combined organic phase was dried over anhydrous Na2SC>4 to give 36-2 (0.1 52 g. 90%). "H NMR (400 MHz. CDC13): δ 7.52 (dd, .1=1 .77. 8.22 Hz. 1 H). 7.5 1 (d. .1=1 .77 Hz, 1 H), 7.30 (d, .1=8.22 Hz, 1 H), 3.82 (s, 3H), 3.75 (t, .1=7.04 Hz, 2H), 2.55 (t, J=8.02 Hz, 2H), 2.0-2.3 (m, 2H).
[0373] To a solution of 36-2 (0.152 g, 0.65 mmol), 36-3 (0.19 g, 0.65 mmol), HATU (0.37 g. 0.97 mmol) in DMF ( 1 mL) was added DIEA (0.23 mL, 1 .3 mmol). The solution was stirred for 2 h at r.t. The mixture was diluted with EA. The organic phase was washed with water, IN HC1, NaHCOs and brine, dried over anhydrous Na2SC>4, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 173 (0.172 g. 51 %). LCMS: m/z 478.10 [M+H]+.
EXAMPLE 40
Preparation of Compound 174
Figure imgf000128_0001
[0375] Addition of MeMgBr to 175-1 afforded 175 as a white solid ( 10%). UPLC/MS(ES+): m/z 497.1 [M+H]+.
EXAMPLE 42
Figure imgf000129_0001
[0376] Trimethylsulfoxonium iodide ( 1 .19 g, 5.41 mmol) was added to a solution of potassium /crr-butoxide (551 mg. 4.92 mmol) in DMSO ( 10 mL). The mixture was stirred at r.t. for 30 mins. A solution of N- {2-[6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl]- 2-oxoethyl) -3-methoxy-4- {2-[(4-methoxyphenyl)methoxy]ethoxy} benzamide (1 , 3.00 g. 4.92 mmol) in DMSO (20 mL) was added. The mixture was stirred at r.t. for 10 mins. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic extracts were washed with brine, dried with Na2S04 and concentrated under reduced pressure to afford the crude epoxide 2 (3.34 g). Epoxide 2:UPLC/MS(ES+): m/z 623.40 [M+H+]. With chromatography (cyclohexane-EtOAc, 75:25 to 50:50), epoxide 2 quantitatively rearranged to oxazoline 3 (1.92 g recovered from 3 g of crude 2). Oxazoline 3: UPLC7MS(ES+): m/z 623.29 [M+H+].
[0377] Method A: A mixture of epoxide 2 ( 100 mg, crude) and an amine ( 10 eq.) in MeOH ( 1 mL) was stirred at r.t. or heated to 100 °C. When complete, the reaction was concentrated under reduced pressure. The residue was dissolved in a 10: 1 DCM:TFA mixture (2.2 mL). After 30 mins of stirring at r.t., a 2M aq. NaOI I solution was added. The mixture was stirred at r.t. for 10 mins. The layers were separated, and the aqueous portion extracted with DCM. The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue afforded the aminol.
[0378] Method B: A mixture of epoxide 2 (150 mg, crude), an amine (2 eq.) and K2C03 (66.0 mg. 2 eq.) in DMF (2 mL) was stirred at 50 °C. When complete, the reaction was diluted with EtOAc. The organic portion was washed twice with water, dried with Na2S04, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and treated with TFA (300 uL). After 1 h, the reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue afforded the aminol.
[0379] Method C: ΊΈΑ (270 uL, 1.93 mmol) and MsCl (150 uL, 1.93 mmol) were added to a solution of 3 (600 mg, 0.964 mmol) in DCM (4 mL). The mixture was stirred at r.t. for 2 h. The mixture was poured into 1M aq. HCT solution and extracted with DCM. The combined organic portions were dried with Na^SC^ and filtered. The volatiles were removed under reduced pressure to afford the crude mesylate 4, which was directly used in the next step. A mixture of 4 (80 mg) and an amine (50 uL) in MeOH (2 mL) was heated to 85 °C in a sealed vial. When complete, the reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (1 .5 mL) and treated with a 6M aq. HC1 solution ( 1 .5 mL). The mixture was heated to 65 °C for 2 h. After cooling to r.t., the mixture was purified by reverse phase chromatography to afford the aminol.
[0380] Method D: A mixture of epoxide 2 (50 mg, crude) and an amine ( 10 eq.) was heated to 60 °C under microwave irradiation. When complete, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and treated with TFA (300 uL). After 1 h. the reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue afforded the aminol.
EXAMPLE 43
Preparation of Compound 176
Figure imgf000130_0001
[0381] Epoxide 2 (200 mg, crude) was dissolved in a 1 : 1 MeOH:6M aq. HC1 solution (2 mL), and the mixture was stirred at 60 °C for 2 h. The mixture was basified with 6M aq. NaOH solution and purified by reverse phase chromatography (water:CH3CN, 100:0 to 50:50) to afford 176 as an off-white solid (40.2 mg). UPLC/MS(ES+): m/z 521 .10 [M+H]+.
EXAMPLE 44
Preparation of Compound 177
Figure imgf000131_0001
1 77
[0382] Reaction of epoxide 2 with a 2M MeNl l2-MeOH solution followed by
PMB-group removal according to Method A afforded 177 as a white solid (13% over 3 steps). UPLC/MS(ES+): m/z 534.30 [M+H]+.
EXAMPLE 45
Preparation of Compound 178
Figure imgf000131_0002
178
[0383] Reaction of epoxide 2 with a 2M Me2NH-MeOH solution followed by
PMB-group removal according to Method A afforded 178 as a white solid (37% over 3 steps). UPLC/MS(ES+): m/z 548.30 [M+H]+.
EXAMPLE 46
Preparation of Compound 179
Figure imgf000131_0003
1 79
[0384] Reaction of epoxide 2 with a 7M NH3-MeOH solution followed by PMB- group removal according to Method A afforded 179 as a white solid (24% over 3 steps). UPLC/MS(ES ( ): m/z 520.40 [M+llj 1 . EXAMPLE 47
Preparation of Compound 180
Figure imgf000132_0001
[0385] A solution of 179 ( 10.0 mg, 0.019 mmol) and triphosgene (5.0 mg, 0.019 mmol) in a 1 : 1 5% aq. NaHC03:MeOH mixture (1 mL) was stirred and heated at 40 °C for 3 h. The volatiles were removed under reduced pressure to afford a 30:70 mixture of 180 and the corresponding methyl carbamate. This mixture was dissolved in DMT (0.5 mL) and treated with NaH (60% oil dispersion, 1 mg). After 30 mins, the reaction was quenched with MeOH, and the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (0.1 % HCOOH:water-0.1 % HCOOH:CH3CN, 100:0 to 30:70) to afford 180 as a white solid (4.0 mg. 39%). UPLC/MS(ES+): m/z 546.30 [M+H]+.
EXAMPLE 48
Preparation of Compound 181
Figure imgf000132_0002
[0386] Reaction of epoxide 2 with morpholine followed by PMB-group removal according to Method B afforded 181 as a white solid (10% over 3 steps). UPLC/MS(ES+): m/z 590.40 [M+H]+.
EXAMPLE 49
Preparation of Compound 182
Figure imgf000132_0003
[0387] A mixture of epoxide 2 ( 100 mg, crude), ketopiperazine (80 mg. 0.80 mmol) and K2C03 (155 mg, 1.13 mmol) in DMF (2 mL) was stirred at 60 °C for 18 h. The mixture was diluted with EtOAc, and the organic portion was washed with water (2x), dried with Na?S04, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and treated with 3M aq. HCl solution (500 uL). The mixture was heated to 80 °C and stirred at 80 °C for 30 mins. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water-CHiCN, 100:0 to 0: 100) to afford 182 as a light yellow solid (14% over 3 steps). UPLC/MS(ES+): m/z 603.30 [M+H]+.
EXAMPLE 50
Preparation of Compound 183
Figure imgf000133_0001
183
[0388] Reaction of epoxide 2 with ketopiperazine followed by PMB-group removal according to Method B afforded 183 as a light yellow solid (10% over 3 steps). UPLC/MS(ES+): m/z 621 .40 [M+H]+.
EXAMPLE 51
Preparation of Compounds 184, 185 and 186
Figure imgf000133_0002
[0389] Reaction of epoxide 2 with pyrazole followed by PMB-group removal according to Method B afforded 184 as a racemic mixture (32% over 3 steps). This mixture was resolved by using a prep-HPLC separation [Chiralpak AD-H (25 x 2.0 cm), 5 μΜ; mobile phase: Ethanol + 0.1 % isopropylamine 30%, flow rate: 46 mL/min, UV detection DAD 220 nm] to afford the two separated enantiomers 185 (t| = 1 1.0 min) and 186 (t«= 12.5 min). Analytical data for the single enantiomers: white solid. UPLC/MS(ES+): m/z 571.36 [M+H]+. EXAMPLE 52
Preparation of Compound 187
Figure imgf000134_0001
[0390] Reaction of mesylate 4 with pyrrolidine followed by PMB-group removal according to Method C afforded 187 as a white solid (55% over 3 steps). UPLC/MS(ES+): m/z 574.20 [M+H]+.
EXAMPLE 53
Preparation of Compound 188
Figure imgf000134_0002
188
[0391] Reaction of mesylate 4 with piperidine followed by PMB-group removal according to Method C afforded 188 as a white solid (6% over 3 steps). UPLC/MS(ES+): m/z 588.20 [M+H]+.
EXAMPLE 54
Preparation of Compound 189
Figure imgf000134_0003
189
[0392] Reaction of epoxide 2 with cyclopropylamine followed by PMB-group removal according to Method D afforded 189 as a white solid ( 11% over 3 steps). UPLC/MS(ES+): m/z 560.10 [M+H]+. EXAMPLE 55
Preparation of Compound 190
Figure imgf000135_0001
190
[0393] Reaction of epoxide 2 with 1 -Boc-piperazine followed by PMB-group removal according to Method C afforded 190 (17% over 3 steps). UPLC7MS(ES+): m/z 589.30 [M+H]+.
EXAMPLE 56
Preparation of Compound 191
Figure imgf000135_0002
191
[0394] Reaction of epoxide 2 with imidazole followed by PMB-group removal according to Method B afforded 191 as a white solid (12% over 3 steps). UPLC/MS(ES+): m/z 571.30 [M+H]+.
EXAMPLE 57
Figure imgf000135_0003
[0395] Reaction of epoxide 2 with l H-1.2,3-triazole followed by PMB-group removal according to Method B afforded compounds 192 ( 10% over 3 steps) and 193 (18% over 3 steps). 192: UPLC/MS(ES+): m/z 572.30 [M+H]+. 193: UPLC/MS(ES+): m/z 572.30 [M+H]+.
- 1 JJ>- EXAMPLE 58
Preparation of Compound 194
Figure imgf000136_0001
1 94
[0396] Reaction of epoxide 2 with l H-1.2,4-triazole followed by PMB-group removal according to Method B afforded compound 194 (24% over 3 steps). UPLC/MS(ES+): m/z 572.30 [M+H]+.
EXAMPLE 59
Preparation of Compound 195
Figure imgf000136_0002
[0397] A mixture of epoxide 2 (80 mg. crude) and 7M NI I3-MeOI I (1 .5 mL) in MeOH (2 mL) was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure. The resulting crude 195-1 was dissolved in DCM ( 1 mL) and treated with TEA ( 1 5 uL) and AcCl (1 1 uL). The mixture was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. Deprotection of the PMB-ether using TTArDCM afforded 195 as a white solid (7% overall). UPLC/MS(ES+): m/z 562.30 [M+H]+. EXAMPLE 60
Preparation of Compound 196
Figure imgf000137_0001
[0398] tt-BuLi (1 .6M solution in hexanes. 650 yiL, 1 .04 mmol) was added to a suspension of tert-butyl 3-oxopiperazine- l -carboxylate (160 mg. 0.800 mmol) in dry THF (2 mL), which had been pre-cooled to 0 °C. The mixture was stirred for 5 mins at 0 °C and then warmed to r.t. After 5 mins, a solution of epoxide 2 (200 mg, crude) in THF ( 1 mL) was added. The mixture was heated to 50 °C and stirred at 50 °C for 12 h. Water and EtOAc were added. The layers were separated, and the aqueous portion was extracted with EtOA. The combined organic portions were dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. The crude 6 was dissolved in MeOH (5 mL) and treated with 6M aq. HCl solution (2 mL). The mixture was heated to 60 °C and stirred at 60 °C for 1 .5 h. A majority of the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (watenCTLCN 100:0 to 40:60) to afford 196 as a white solid (3 1 mg, 16% over 3 steps). UPLC/MS(ES+): m/z 603.30 [M+H]+.
EXAMPLE 61
Preparation of Compound 197
Figure imgf000138_0001
[0399] Bromo(ethynyl)magnesium (4.90 niL, 2.46 mmol) was added to a solution of 1 (300 mg, 0.493 mmol) in THF (15 mL), which had been warmed to 55 °C. The mixture was stirred for 30 mins and quenched with sat. aq. NH4C1 solution. The aqueous portion was extracted with EtOAc (2x). The combined organic portions were dried with Na?SO_(, filtered and concentrated under reduced pressure. Chromatography of the residue (DCMrEtOAc. 100:0 to 80:20) afforded 7 as a light yellow solid ( 130 mg. 41 %). UPLC/MS(ES+): m/z 635.20 [M+H]+.
[0400] A mixture of aq formaldehyde (37% solution. 630 uL. 0.780 mmol) and glacial AcOH (7 uL, 0.1 17 mmol) in THF (500 uL) was stirred at r.t. for 15 mins. Sodium azide (7.6 mg. 0.1 1 7 mmol) and 7 (50.0 mg, 0.078 mmol) were sequentially added. After 10 mins, aq. sodium ascorbate (0.5 M solution, 32 uT. 0.016 mmol) and C11SO4 (1.2 mg. 0.008 mmol) were added. The mixture was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure. The residue was treated with a 3 : 1 MeOH:2N aq NaOH solution (4 mL), and the mixture was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure, and the residue was partitioned between EtOAc and water. The layers were separated, and the organic portion was dried with Na?S04, filtered and concentrated under reduced pressure to afford crude 8 (34 mg), which was used in next step without further purification. UPLC/MS(ES+): m/z 678.25 [M+H]+.
[0401 ] A solution of 8 (34 mg) in 10: 1 DCM-TFA (5 mL) was stirred at r.t. for 20 mins. The reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN. 95:5 to 0: 100) to afford 197 as a white solid (5.5 mg, 13% over 2 steps). UPLC/MS(ES ' ): m/z 558.1 1 [M+I I]+.
EXAMPLE 62
Preparation of Compounds 198 and 199
Figure imgf000139_0001
[0402] Potassium carbonate (40.0 mg, 0.295 mmol) and Mel (20.0 mg, 0.141 mmol) were added to a solution of 8 (80.0 mg, 0.1 18 mmol) in CH3CN (4 mL). The mixture was stirred at r.t. for 4 h, diluted with water and extracted with EtOAc (3x). The combined organic portions were dried with Na?S04, filtered and concentrated under reduced pressure. Chromatography of the residue (DCM:EtOAc, 70:30 to 0: 100) afforded the two separated regioisomers 9 (21 mg, 25%) and 10 (24 mg, 29%). 9: LJPLC/MS(ES+): m/z 692.29 [M+H]+. 10: UPLC/MS(ES+): m/z 692.28 [M+H] h.
[0403] General procedure for PMB-removal: A solution of PMB-cther (0.1 mmol) in 10: 1 DCM:TFA (3 mL) was stirred at r.t. for 30 mins. The reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue (EtOAc:MeOH, 100:0 to 90: 10) afforded the product. 198. (derived from 9) UPLC/MS(ES+): m/z 572.38 [M+H]+. 199: (derived from 10) UPLC/MS(ES+): m/z 572.43 [M+H]+. EXAMPLE 63
Preparation of Compounds 200, 201, 202, 203 and 204
Figure imgf000140_0001
[0404] Sodium hydride (1.80 g, 44.7 mmol) was added to a stirred solution of 2-1 (1 1.6 g, 40.7 mmol) in dry DMF (75 mL), which had been pre-cooled to 0° C. The mixture was stirred at 0° C for 10 mins, and then warmed to r.t. The mixture was then stirred for 30 mins. The reaction was cooled to 0° C and 3-bromo-2-methylprop- l -ene (5.70 g, 42.7 mmol) was added dropwise. The mixture was allowed to gradually reach r.t., and stirring was continued for 20 h. EtOAc and sat. aq. NH4CI solution were added. The layers were separated, and the organic portion was washed with brine, dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc. 100:0 to 50:50) afforded 2-2 (12.1 g, 87%). UPLC/MS(ES+): m/z 339.80 [M+H]+.
[0405] A mixture of 2-2 ( 12.0 g, 35.4 mmol), sodium formate (2.70 g. 40.7 mmol), tetrabutylammonium chloride (9.80 g. 35.4 mmol), Pd(OAc)2 (396 mg . 1.7 mmol) and TEA (14.7 mL. 106 mmol) in dry DMF (300 mL) was degassed and heated to 100 °C for 3 h. EtOAc and sat. aq. NH4CI solution were added. The layers were separated, and the organic portion was washed with brine, dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane.LtOAc, 100:0 to 50:50) afforded 2-3 as a pale yellow wax (6.15 g, 81%). UPLC/MS(ES+): m/z 213.91 M+H]+. [0406] A mixture of 2-3 ( 1.80 g, 8.45 mmol). (3-chloro-4-lluorophenyl)boronic acid (2.94 g, 16.9 mmol), [l , -bis(diphenylphosphino)†errocene]dichloropalladium(II) (61 8 mg, 0.84 mmol) and aq. Na2C0 (2M solution, 8.45 mL, 16.9 mmol) in DCE (80 mL) was degassed and heated to 100 °C under microwave irradiation. Water and DCM were added. The layers were separated, and the organic phase was dried with Na2S04. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 50:50) afforded 2-4 as a white solid ( 1 .97 g, 76%). UPLC/MS(ES+): m/z 307.1 8 [M+H]+.
[0407] Dess-Martin periodinane (6.8 g, 16.0 mmol ) was added to a stirred solution of 2-4 ( 1.97 g, 6.40 mmol) in dry DCM (28 mL). The mixture was stirred at r.t. under N2 atmosphere for 1 h. The reaction w-as quenched with a 1 : 1 2M aq. Na2S203:sat. aq. NaHC03 solution (30 mL), the mixture was vigorously stirred for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na2SC»4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 70:30) afforded 2-5 as a white solid ( 1.40 g. 72%). UPLC7MS(ES+): m/z 306.15 [M+H]+.
[0408] TMSCF3 (810 uL, 5.50 mmol) was added to a solution of 2-5 (1.40 g, 4.60 mmol) in dry DCM (25 mL). The mixture was cooled 0 °C and TBAF (1 M sol in TI IF, 5.5 mL, 5.50 mmol) was added dropwise. The mixture was allowed to gradually reach r.t. and stirring was continued for 1 h. Water and DCM were added. The layers were separated, and the organic portion was dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 80:20) afforded 2-6 ( 1 .43 g, 82%). UPLC/MS(ES+): m/z 376.16 [M+H]+.
[0409] Dess-Martin periodinane (3.25 g, 7.68 mmol) was added to a stirred solution of 2-6 (1 .43 g. 3.84 mmol) in dry DCM (1 7 mL). The mixture was stirred at r.t. for 1 h. A 1 : 1 2M aq. Na2S203:sat. aq. NaHC03 solution was added. The mixture was stirred at r.t. for 30 mins. The layers were separated, and the aqueous portion was extracted with DCM (2x). The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 70:30) afforded 2-7 as a white solid (1.20 g, 84%). UPLC/MS(ES+): m/z 392.16 [M+H30]+ [0410] Trimethylsulfoxonium iodide (695 mg, 3.16 mmol) was added to a solution of potassium tert-butoxide (354 mg, 3.16 mmol) in DMSO (6 mL). The mixture was stirred at r.t. for 30 mins. A solution of 2-7 (1 .1 8 g, 3.16 mmol) in DMSO (20 mL) was added, and the mixture was stirred at r.t. for 30 mins. EtOAc and water were added, and the layers were separated. The aqueous portion was extracted with EtOAc. The combined organic extracts were washed with brine, dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 70:30) afforded 2-8 as a colourless wax (530 mg, 43%). UPLC/MS(EST): m/z 388.1 8 [M+H]+.
[0411] A solution of 2-8 (530 mg. 1.37 mmol) in 7M NH3-MeOH (50 mL) was stirred at 45 °C for 1 h. The volatiles were removed under reduced pressure. The crude was purified by reverse phase chromatography (water:CLL,CN 95:5 to 0: 100) to afford 2-9 as a white solid (498 mg, 90%). UPLC/MS(ES+): m/z 405.21 [M+H]+.
[0412] Racemate 2-9 was resolved by using a prep-HPLC separation [Chiralpak AD-H (25 x 3 cm, 5 um), mobile phase: n-Hexane/(EtOH/MeOH+0.1 % ipa) 96/4 % v/v, flow rate: 32 mL/min, UV detection DAD 220 nm] to obtain the two separated enantiomers 2-9a (tR=10.9 min) and 2-9b (t| =14.5 min). UPLC and Ή NMR analyses for the two enantiomers were superimposible.
[0413] General amide coupling conditions-Method A: A mixture of 2-9 (50.0 mg, 0.124 mmol), EDC (31 .0 mg, 0.161 mmol), HOBT (22.0 mg, 0.161 mmol) and acid (0.124 mmol) in DGVLDMF (5: 1. 6 mL) was stirred at 45 °C for 2 h. DCM was added. The organic portion was washed with sat. aq. NH4C1 solution and brine, dried with Na?S04. filtered and concentrated under reduced pressure. Chromatography of the residue afforded the product.
[0414] General amide coupling conditions-Method B: DIPEA (281 uL, 1 .62 mmol) was added to a solution of acid (1.06 mmol) and HATIJ (461 mg, 1.21 mmol) in dry DMF (5 mL). After 20 mins, a solution of 2-9 (330 mg. 0.81 mmol) in DMF (5 mL) was added. The mixture was stirred at r.t. until complete. EtOAc and sat. aq. NH4C1 solution were added. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue afforded the product.
[0415] Coupling of 2-9 with acid 2-10 according to Method A afforded 200 as a white solid (30%. mixture of 4 isomers). UPLC/MS(ES+): m/z 638.1 8 [M+H]+. Racemate 200 was resolved by using a prep-HPLC separation [Chiralpak AD-H (25 x 2 cm. 5 um). mobile phase: Ethanol+0.1 % isopropylamine 20% v/v. flow rate: 45 mL/min. UV detection DAD 220 nm] to obtain the four separated isomers 201 (tR=12.9 min), 203 (tR=14.8 min). 202 (tR=16.6 min) and 204 (tR=23.6 min).
[0416] Alternatively, 2-9a and 2-9b were separately coupled with 2-10 according to Method B. Each diastereomeric mixture was resolved by chiral HPLC. 2-9a provided a mixture of 204 (tR=6.5 min) and 202 (tR=14.1 min) [Whelk 01 (R,R) (25 x 2.0 cm), 5 μ. mobile phase: n-Hexanc/(Ethanol+0.1 % isopropylamine) 30/70 % v/v, flow rate: 17 mL/min. UV detection DAD 220 nm]. 2-9b provided a mixture of 201 and 203 (tR 6.4 min and 12.3 min) [Whelk 01 (R.R) (25 x 2.0 cm), 5 μ, mobile phase: n-Hexane/(Ethanol+0.1 % isopropylamine) 30/70 % v/v, flow rate: 17 mL/min, UV detection DAD 220 nm].
EXAMPLE 64
Preparation of 2-10
Figure imgf000143_0001
[0417| Compound 2-12 (4.86 g, 26.7 mmol) was added to a stirring suspension of cesium carbonate (1 5.4 g, 47.5 mmol) in DCM ( 120 mL). A solution of 2-11 (3.13 g. 19.0 mmol) in DCM (20 mL) was added. The mixture was stirred at r.t. for 5 h. The mixturew was filtered through a pad of Celite, washed thoroughly with DCM and concentrated. The residue was dissolved in EtOAc. The organic portion was washed with water and brine, dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane: EtOAc 100:0 to 0: 100) afforded 2-13 as a white solid (4.50 g. 89%). UPLC/MS(ES+): m/z 266.15 [M+H]+. [0418] Lithium hydroxide monohydrate (258 mg. 6.10 mmol) was added to a suspension of 2-13 (1 .50 g. 5.60 mmol) in a 1 : 1 :6 THF:MeOH:H20 mixture (40 mL). The mixture was stirred at r.t. for 3 h, loaded on a reverse phase cartridge and eluted with water to afford 2-10 as a white solid ( 1 .10 g. 78%). UPLC/MS(ES+): m/z 252.13 [M+H]+.
EXAMPLE 65
Preparation of Compounds 205 and 206
Figure imgf000144_0001
[0419] Coupling of 2-9a with 3,4-dimethoxybenzoic acid according to Method A afforded 205 as a white solid (51%). UPLC/MS(ES+): m/z 569.40 [M+H]+. Using 2-9b and 3,4-dimethoxybenzoic acid according to Method A afforded 206 as a white solid (50%). UPLC/MS(ES+): m/z 569.40 [M+H]+.
EXAMPLE 66
Preparation of Compounds 207
Figure imgf000144_0002
207
[0420] Coupling of 2-9 with 2-14 according to Method A afforded 207 as a white solid (43%). UPLC/MS(ES+): m/z 576.32 [M+H]+.
EXAMPLE 67
-14
Figure imgf000144_0003
[0421] Acrolein (21.8 mL, 326 mmol) was added to a mixture of 4-amino-3- hydroxybenzoic acid (5.00 g, 33.0 mmol) in 12 N aq. HQ solution (50 mL). The mixture was refluxed for 1 h. After cooling to r.t., the mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to
50:50) to afford 2-14 (561 mg, 9%). UPLC/MS(ES+): m/z 1 90.04 [M+I I]+.
EXAMPLE 68
Preparation of Compound 208
Figure imgf000145_0001
208
[0422] Coupling of 2-9 with 2-15 according to Method A afforded 208 as a white solid (67%). UPLC/MS(ES+): m/z 590.25 [M+H]+.
EXAMPLE 69
Preparation of 2-15
Figure imgf000145_0002
[0423] Cesium carbonate (2.58 g, 7.92 mmol) and Mel (822 uL, 13.2 mmol) were sequentially added to a solution of 2-14 (500 mg. 2.64 mmol) in DMF (30 mL). The mixture was stirred at r.t. for 18 h. EtOAc was added. The organic portion was washed with 2M aq. HC1 solution and water, dried with Na2S04, filtered and concentrated under reduced pressure. Crude 2-16 was dissolved in a 2: 1 : 1 THF:MeOH:H20 mixture (8 mL). Lithium hydroxide monohydrate (332 mg, 7.92 mmol) was added, and the mixture was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. The residue was dissolved in water, and the pH of the solution was adjusted to 6 with 1M aq. HC1 solution. The aqueous portion was extracted with DCM (2x). The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure to afford crude 2-15 (227 mg), which was used in the next step without further purification. UPLC/MS(ES+): m/z 204.10 [M+H]+. EXAMPLE 70
Preparation of Compound 209
Figure imgf000146_0001
209
[0424] Coupling of 2-9 with 4-cyclopropoxy-3-methoxybenzoic acid according to
Method A afforded 209 as a white solid (41%). UPLC/MS(ES+): m/z 595.30 [M+H] \
EXAMPLE 71
Preparation of Compound 210
Figure imgf000146_0002
210
[0425] Coupling of 2-9 with 4-(carbamoylmethoxy)-3-methoxybenzoic acid according to Method B afforded 210 as a white solid (51 %). UPLC/MS(ES+): m/z: 612.21 [M+H]+.
EXAMPLE 72
Preparation of Compound 211
Figure imgf000146_0003
[0426] Coupling of 2-9 with 4-[(2R)-2-hydroxypropoxy]-3-methoxybenzoic acid according to Method B afforded 211 as a white solid (45%). UPLC/MS(ES+): m/z 613.27 [M+H]+. EXAMPLE 73
Preparation of Compound 212
Figure imgf000147_0001
[0427] Coupling of 2-9 with 2-17 according to Method B afforded 212 as a white solid (33%). UPLC/MS(ES+): m/z 636.00 [M+H]+.
EXAMPLE 74
Preparation of 2-17
Figure imgf000147_0002
[0428] LDA (2M solution in THF. 1 .05 mL. 2.10 mmol) was added to a stirred solution of l -(tert-butoxycarbonyl)-2-pyrrolidinone (276 uL, 1 .62 mmol) in THF ( 1 mL). which had been pre-cooled to -78 °C. After 15 mins. a solution of methyl 4-(bromomethyl)- 3-methoxybenzoate (460 mg, 1.78 mmol) in THF ( 1 mL) was added dropwise to the mixture and stirring at 78 °C was continued for 1 h. The reaction was quenched with water. The aqueous portion was extracted with EtOAc (2x). The combined organic portions were dried with a2SC>4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 70:30) afforded 2-18 ( 199 mg, 34%). UPLC/MS(ES+): m/z 364.20 [M+H]+.
[0429] A solution of 2-18 (199 mg, 0.547 mmol) in 5 : 1 DCM:TFA (3 mL) was stirred at r.t. for 5 mins. The mixture was diluted with DCM. The organic portion was washed with a sat. aq. NaHCC solution, dried with Na2S04, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (0.1 % I ICOOI I:water:0.1 % I ICOOI LCI I3CN 100:0 to 0: 100) to afford 2-19.
[0430] Compound 2-19 was dissolved in a 2: 1 : 1 THF:MeOH:H20 mixture (10 mL). Lithium hydroxide monohydrate (45 mg, 1 .10 mmol) was added. The mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford crude 2- 17. which was directly used in the next step without further purification. UPLC/MS(ES+): m/z 250.20 [M+H]+.
EXAMPLE 75
Preparation of Compound 213
Figure imgf000148_0001
[0431 ] Coupling of 2-9 with 2-20 according to Method B afforded 213 as a white solid (73%). UPLC/MS(ES+): m/z 604.00 [M+H]+.
EXAMPLE 76
-20
Figure imgf000148_0002
[0432] Crotonaldehyde (4.01 g. 48.9 mmol) was added dropwise to a mixture of 4-amino-3-hydroxybenzoic acid (5.00 g. 33.1 mmol) and 6M aq. HC1 solution (60 mL. 360 mmol). The mixture was refluxed for 1 8 h. After cooling to r.t. a precipitate formed. The solid was filtered off, dried and collected. Acid 2-21 (3.44 g) was used in the next step without further purification. UPLC/MS(ES+): m/z 204.10 [M+H]+.
[0433] Cesium carbonate (15.8 g, 48.6 mmol) and Mel (5.88 mL, 94.5 mmol) were sequentially added to a solution of 2-21 (3.04 g) in DMF (80 mL). The mixture was stirred at r.t. for 12 h. DMF was removed under reduced pressure, and the residue was taken up with EtOAc. The organic portion was washed with water, dried with Na2SC>4, filtered and concentrated under reduced pressure to afford crude 2-22 (2.76 g), which was used in the next step without further purification. UPLC/MS(ES 1 ): m/z 232.10 [M+I I]+.
[0434] Lithium hydroxide monohydrate (0.272 g, 6.49 mmol) was added to a stirred suspension of 2-22 (500 mg. 2.16 mmol) in a 2: 1 :2 THF:MeOH:H20 mixture. The mixture was stirred at r.t. for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 0: 100) to afford 2-20 (291 mg). UPLC/MS(ES+): m/z 218.10 [M+H]+.
EXAMPLE 77
Preparation of Compound 214
Figure imgf000149_0001
214
[0435] Coupling of 2-9 with 2-23 according to Method B afforded 214 as a white solid (49%). UPLC/MS(ES+): m/z 633.26 [M+H]+.
EXAMPLE 78
-23
Figure imgf000149_0002
[0436] Ester 2-22 (1.50 g, 6.48 mmol) was added to a suspension of selenium dioxide ( 1.44 g, 13.0 mmol) in pyridine (24 mL). The mixture was refluxed for 3 h. The volatiles were removed under reduced pressure, and the residue was triturated with EtOAc. The solid was dried and collected to provide 2-24 (595 mg, 35%). UPLC/MS(ES+): m/z 262.10 [M+H]+.
[0437] Oxalyl chloride (100 uL, 1 .14 mmol) and DMF (1 drop) were added to a solution of 2-24 (230 mg, 0.880 mmol) in DCM (7 mL). The mixture was stirred at r.t. for 30 mins. HMDS (400 uL, 1 .89 mmol) and then MeOH were added. The mixture was concentrated under reduced pressure. Chromatography of the residue (EtOAc-DCM. 100:0 to 0: 100) afforded 2-25. UPLC/MS(ES+): m/z 261 .10 [M+H]+. [0438] Lithium hydroxide monohydrate (44.0 mg, 1.05 mmol) was added to a stirred suspension of 2-25 (91 .0 mg, 0.350 mmol) in a 2: 1 :2 THF:MeOH:H20 mixture. The mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (watenCLLsCN 100:0 to 0: 100) to afford 2-23 (76 mg, 89%). UPLC/MS(ES+): m/z 247.20 [M+H]+.
EXAMPLE 79
Preparation of Compound 215
Figure imgf000150_0001
215
[0439] Coupling of 2-9 with 2-26 according to Method B afforded 215 as a white solid (41 %). UPLC/MS(ES+): m/z 615.26 [M+H]+.
EXAMPLE 80
Preparation
Figure imgf000150_0002
[0440] SOCT2 (420 uL, 5.76 mmol) and TEA (800 uL, 5.76 mmol) were added to a solution of 2-25 (150 mg, 0.576 mmol) in DCE (10 niL), which had been prc-cooled to 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction was quenched with a sat. aq. NaHCO solution. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 0: 100) to afford 2-27 (100 mg, 71 %). UPLC/MS(ES+): m/z 243.1 8 [M+H]+.
[0441] Lithium hydroxide monohydrate (21.0 mg, 0.49 mmol) was added to a stirred suspension of 2-27 (100 mg, 0.413 mmol) in a 2:2: 1 THF:MeOH:H20 mixture (10 niL). The mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure. Crude 2-26 was used in the next step without further purification. UPLC/MS(ES m/z 229.14 [M+I I]+.
EXAMPLE 81
Preparation of Compound 216
Figure imgf000151_0001
216
[0442| Coupling of 2-9 with 2-28 according to Method B afforded 216 as a white solid (46%). UPLC7MS(ES+): m/z 637.30 [M+H]+.
EXAMPLE 82
Preparation of 2-28
Figure imgf000151_0002
[0443] NaH (153 mg, 3.83 mmol) was added to a solution of imidazolidin-2-one (300 mg. 3.48 mmol) in THF (3 niL), which had been pre-cooled to 0 °C. After 1 h. methyl 4-(bromomethyl)-3-methoxybenzoate (899 mg, 3.48 mmol) was added. The mixture was stirred at r.t. for 18 h, poured in to water and extracted with EtOAc (3x). The combined organic portions were dried with Na2SC»4, filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAcMeOH 100:0 to 80:20) afforded 2-29 as a white solid (40 mg, 4%). UPLC/MS(ES+): m/z 265.20 [M+H]+.
[0444| Lithium hydroxide monohydrate (19.0 mg, 0.454 mmol) was added to a stirred suspension of 2-29 (40.0 mg, 0.151 mmol) in a 2:2: 1 THF:MeOH:H20 mixture (8 niL). The mixture was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure. The residue was taken up with water, and the aqueous portion was extracted with EtOAc (2x). The combined organic portions were dried with NaaSO.}, filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAcMeOH 100:0 to 80:20) afforded 2-28 as a white solid (32 mg, 84%). υΡΙΟ/Μ8(Ε8 ( ): m/z 251 .20 [M+H]+. EXAMPLE 83
Preparation of Compound 217
Figure imgf000152_0001
[0445] Triethylamine (0.240 mL, 1 .72 mmol) was added to a mixture of 3- methoxy-4-[(2-oxopyrrolidin-3-yl)oxy]benzoic acid (130 mg, 0.517 mmol). HOBT (87.3 mg. 0.646 mmol). EDC ( 124 mg, 0.646 mmol) and 2-30 (104 mg, 0.431 mmol) in a 4: 1 DCJVLDMF (5 mL). The mixture was warmed to 45 °C and stirred at 45 °C for 18 h. A 1M aq. HQ solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with 1M aq. HQ solution, dried with
Figure imgf000152_0002
filtered and concentrated under reduced pressure to afford crude 2-31 (203 mg), which was used in the next step without further purification. UPLC/MS(ES+): m/z 476.30 [M+I I] \
[0446] Dess-Martin periodinane (453 mg, 1 .07 mmol ) was added to a stirred solution of 2-31 (203 mg) in dry DCM ( 10 mL). The mixture was stirred at r.t. for 2 h. and the reaction was quenched with a 1 : 1 1 M aq. Na2S?03:sat. aq. NaHC03 solution (3 mL). The mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na2SC>4, filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAc:MeOH, 100:0 to 75:25) afforded 2-32 (80 mg, 39% over two steps). UPTC/MS(ES+): m/z 474.30 [M+H]+.
[0447] A mixture of 2-32 ( 10.0 mg, 0.021 mmol), (3-chloro-4- †luorophenyl)boronic acid (1 8.4 mg, 0.105 mmol), Pd(dppf)Cl2 (2.0 mg, 0.003 mmol) and aq. Na2COj (2M solution, 0.105 mmol, 0.05 mL) in DCE (0.3 mL) was degassed and stirred while heated to 85 °C under microwave irradiation (4 cycles for 10 mins each). After each run. a further aliquot of Pd(dppf)Cl2 (2.0 mg, 0.003 mmol) was added. The reaction was diluted with water, and DCM were added. The layers were separated, and the organic portion was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 0: 100) to afford 217. UPLC/MS(ES+): m/z 568.30 [M+H]+.
EXAMPLE 84
Preparation of Compound 218
Figure imgf000153_0001
[0448] Trimethylsulfoxonium iodide (21 .0 mg, 0.097 mmol) was added to a solution of potassium tert-butoxide (9.8 mg, 0.086 mmol) in DMSO (0.6 mL). The mixture was stirred at r.t. for 30 mins. A solution of 218-1 (50.0 mg, 0.088 mmol) in DMSO (0.6 mL) was added, and the mixture was stirred at r.t. for a further 30 mins. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine, dried with Na?S04, filtered and concentrated under reduced pressure to afford crude 2-33 (50 mg), which was used next step without further purification. UPLC/MS(ES+): m/z 582.34 M+H]+.
[0449] A mixture of 2-33 (50 mg), potassium carbonate (24.0 mg, 0.170 mmol) and pyrazole (24.0 mg, 0.350 mmol) in DMF ( 1 mL) was stirred at 40 °C for 18 h. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2SO_i, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 50:50) to afford 218 as a white solid (10 mg. 1 7% over two steps). UPLC/MS(ES+): m/z 650.40 [M+H]+. EXAMPLE 85
Preparation of Compound 219
Figure imgf000154_0001
[0450] Epoxide 2-33 (60 mg, crude) was dissolved in a 1 : 1 3M aq. HCl sol:MeOH mixture (5 mL). The mixture was heated to 50 °C for 3 h. After cooling to r.t., the mixture was basified with I M aq. NaOH solution and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH CN 95:5 to 0: 100) to afford 219 as a white solid ( 1 8 mg. 26% over two steps). UPLC/MS(ES+): m/z 600.36 [M+H]+.
EXAMPLE 86
Preparation of Compound 220
Figure imgf000154_0002
[04511 Triethylamine (0.35 mL, 2.51 mmol) was added to a mixture of 8- methoxyquinoline-6-carboxylic acid (286 mg, 1.18 mmol), HOBT (223 mg, 1.65 mmol), EDC (316 mg, 1.65 mmol) and 2-30 (239 mg, 1.18 mmol) in DCM (7 mL). The mixture was stirred at r.t. for 60 h. A I M aq. HCl solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with I M aq. HCl solution, dried with Na2SC>4, filtered and concentrated under reduced pressure to afford crude 2-34, which was used in the next step without further purification. UPLC/MS(ES+): m/z 428.30 [M+H]+. [0452] Dess-Martin periodinane ( 1 .20 g, 2.82 mmol ) was added to a stirred solution of 2-34 in dry DCM (6 mL). The mixture was stirred at r.t. for 2 h, and the reaction quenched with a 1 : 1 1 M aq. Na2S 03:sat. aq. NaHC(¾ solution. The mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na2S04. filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 80:20 to 0: 100) to afford 2-35 (1 1 .0 mg, 2% overall). UPLC/MS(ES+): m/z 426.20 [M+H]+.
[0453] A mixture of 2-35 ( 1 1 .0 mg, 0.026 mmol), (3-chloro-4- fluorophenyl)boronic acid ( 1 1.2 mg. 0.065 mmol), Pd(dppf)Cl2 (1 .3 mg. 0.002 mmol) and aq. Na2C03 (2M solution, 39 uL, 0.078 mmol) in DCE (1 mL) was degassed and heated to 85 °C for 24 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 30:70) to afford 220 as an off-white solid (2.3 mg, 17%). UPLC7MS(ES+): m/z 520.30 [M+H]+.
EXAMPLE 87
Preparation of Compound 221
Figure imgf000155_0001
[0454] Trimethylsulfoxonium iodide ( 18.3 mg, 0.087 mmol) was added to a solution of potassium tert-butoxide (9.3 mg, 0.083 mmol) in DMSO (0.3 mL). The mixture was stirred at r.t. for 30 mins. A solution of 220 (43.0 mg, 0.083 mmol) in DMSO (0.7 mL) was added, and the mixture was stirred at r.t. for a further 30 mins. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine, dried with Na?S04. filtered and concentrated under reduced pressure. The residue was dissolved in a 1 : 1 3M aq. HCl sohMeOH mixture (3 mL). and the mixture was heated to 50 °C for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 0: 100) to afford 221 as an off-white solid. UPLC/MS(ES+): m/z 552.38 [M+H]+. EXAMPLE 88
Preparation of Compound 222
Figure imgf000156_0001
[0455] NaH (59.0 mg, 1.47 mmol) was added to a solution of 2-13 (300 mg, 1.13 mmol) in dry THF (4.5 mL). After 5 mins of stirring at r.t., Mel (192 mg, 1 .35 mmol) was added. The reaction was stirred at r.t. for 3 h. EtOAc and 1 M aq. HCl solution were added. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2S04 and filtered. The volatiles were removed under reduced pressure to afford crude 2-36, which was in the next step without further purification. Lithium hydroxide monohydrate (95.0 mg, 2.26 mmol) was added to a stirred mixture of 2-36 in 2: 1 : 1 TLTF^MeOLLLLO (8 mL). The reaction was stirred at r.t. for 3 h. Additional lithium hydroxide monohydrate (95 mg) was added and stirring was continued for 2 h. The mixture was poured in to 6M aq. HCl solution. The aqueous portion was saturated with NaCl and extracted with EtOAc and DCM. The combined organic portions were dried with Na2S04, and filtered. The volatiles were removed under reduced pressure to afford crude 2-37, which was in the next step without further purification. UPLC7MS(ES+): m/z
Figure imgf000156_0002
[0456] A mixture of 2-37, 2-30 (273 mg, 1.13 mmol), EDC (282 mg, 1.47 mmol), HOBT ( 198 mg. 1.47 mmol) and TEA (267 uL, 1.92 mmol) in DMF (8 mL) was stirred at r.t. for 18 h. EtOAc and 2M aq. HCl solution were added. The layers were separated, and the organic portion was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (watenCI CN 100:0 to 0: 100) to afford 2-38 as a colorless wax (90 mg, 16% over 3 steps). UPLC/MS(ES+): m/z 490.30 [M+H]+. [0457] Dess-Martin periodinane ( 1 5 mg, 0.46 rnmol) was added to a stirred solution of 2-38 (90.0 mg, 0.1 84 mmol) in dry DCM (2 mL). The mixture was stirred at r.t. for 2 h. The reaction was quenched with a 1 : 1 1 M aq. Na2S 03:sat. aq. NaHC03 solution. The mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na2SC>4, filtered and concentrated under reduced pressure to afford crude 2-39 (92 mg). which was in the next step without further purification. UPLC/MS(ES+): m/z 488.30 [M+H]+.
[0458] A mixture of 2-39 (92 mg). (3-chloro-4-fluorophenyl)boronic acid (83.0 mg, 0.475 mmol). Pd(dppf)Cl2 (27.6 mg, 0.038 mmol) and aq. Na2C03 (2M solution, 285 uL. 0.570 mmol) in DCE (3 mL) was degassed and heated to 100 °C under microwaive irradiation for 1.5 h. Water and DCM were added. The layers were separated, and the organic portion was dried wtih Na2S04, filtered and concentrated under reduced pressure. The residue w7as purified by reverse phase chromatography (w7ater:CH3CN 100:0 to 0: 100) to afford 222 as an off-white solid (27.0 mg. 25% over two steps). UPLC/MS(ES+): m/z 582.30 [M+H]+.
EXAMPLE 89
Figure imgf000157_0001
[0459] 2-Methyl-2-butene (16.9 mL, 33.7 mmol, 2M solution in THE) was added to a solution of 2-5 (1 .03 g, 3.37 mmol) in tert-butanol (60 mL). A solution of sodium chlorite (609 mg, 6.74 mmol) and sodium phosphate monobasic dihydratc (3.41 g, 21 .9 mmol) in water (60 mL) was then added. The mixture was stirred at r.t. for 18 h. Brine was added, and the aqueous portion was extracted with EtOAc (3x). The combined organic portions were were dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane. 'EtOAc 100:0 to 0: 100) afforded 2-40 as an off- white solid (688 mg, 63%). UPLC/MS(ES h): m/z 322.10 [M+I I]+.
[0460] Triethylamine (0.160 mL, 1 .12 mmol) was added to a mixture of 2-40 (200 mg, 0.622 mmol), HOBT (151 mg, 1.12 mmol), EDC ( 167 g, 0.870 mmol) and Ν, Ο- dimethylhydroxylamine hydrochloride (91 .1 mg. 0.934 mmol) in DCM ( 1 5 mL). The mixture was stirred at r.t. for 1 8 h. A I M aq. HC1 solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with 1M aq. HC1 solution, dried with Na2S04. filtered and concentrated under reduced pressure to afford crude 2-41 (255 mg) which was used in the next step without further purification. UPLC/MS(ES+): m/z found 365.20 [M+H]+.
[0461] Cyclopropylmagnesium bromide ( 1M solution in 2-methyl tetrahvdroiuran, 1.96 mL, 1.96 mmol) was added to a solution of 2-41 (255 mg) in THF (10 mL). The mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. aq. NH4CT solution and extracted with DCM (3x). The combined organic portions were dried with Na?S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 100:0 to 50:50) afforded 2-42 (146 mg, 68% over 2 steps). UPLC/MS(ES+): m/z: 346.20 [M+H]+.
[0462] A mixture of trimethylsulfoxonium iodide (93.0 mg, 0.423 mmol) and NaH ( 16.9 mg, 0.423 mmol) in 1 : 1 DMSO:THF ( 1 mL) was stirred at r.t. for 1 h. A solution of 2-42 ( 146 mg, 0.423 mmol) in THF ( 1 mL) was added, and the mixture was stirred at r.t. for 1 8 h. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure to afford crude 2-43 ( 180 mg), w hich was used in the next step without further purification.
[0463] A solution of 2-43 ( 180 mg) in 7M NH3:MeOH (4 mL) was stirred at r.t. for 18 h and at 35 °C for an addition 24 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (watenCH CN 100:0 to 0: 1 00) to afford 2-44 (13 mg, 8% over 2 steps). UPLC/MS(ES+): m/z 377.20 [M+H]+.
[0464] A mixture of 2-10 (39.9 mg 0.159 mmol), HOBT (25.8 mg, 0.191 mmol), EDC (28.4 mg, 0.148 mmol), TEA (0.027mL, 0.191 mmol) and 2-44 (40.0 mg, 0.106 mmol) in DMF (2 mL) was stirred at r.t. for 18 h. A I M aq. HC1 solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with 1 M aq. HC1 solution, dried with Na?S04, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 0: 100) to afford 223 (8 mg, 12%). UPLC/MS(ES+): m/z 610.50 [M+H]+.
EXAMPLE 90
Preparation of Compound 224
Figure imgf000159_0001
[0465] Coupling of 2-44 with 2-14 using conditions reported for the preparation of 223 (EDC, HOBT) afforded 224 as a white solid. UPLC/MS(ES+): m/z 562.40 [M+H]+.
EXAMPLE 91
Preparation of Compound 225
Figure imgf000159_0002
[0466] Trimethylsulfoxonium iodide (21.5 mg, 0.098 mmol) was added to a mixture of potassium tert-butoxide (9.98 mg. 0.089 mmol) in DMSO (2 mL). After 30 mins. 2-45 (57.8 mg, 0.089 mmol) was added, and the mixture was stirred at r.t. for 1.5 h. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na?S04, filtered and concentrated under reduced pressure to afford crude 2-46, which was used in the next step without purification. Crude 2-46 was dissolved in DMF (1 mL). K2C03 (24.6 mg, 0.1 78 mmol) and imidazole ( 12.1 mg, 0, 1 78 mmol) were then sequentially added. The mixture was heated to 80 °C and stirred at 80 °C for 48 h. The volatiles were removed under reduced pressure to afford crude 2-47, which was used in the next step without purification.
[0467] A solution of 2-47 in 1 : 1 TFA:DCM (0.9 mL) was stirred at r.t. for 1 h. The reaction was quenched with a 1 M aq. NaOH solution. After 30 mins of stirring at r.t.. the layers were separated. The organic portion was dried with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford 225 as a white solid ( 1 mg, 2% overall). UPLC/MS(ES ): m/z 61 1.30 [M+H]+.
EXAMPLE 92
Preparation of Compound 226
Figure imgf000160_0001
[0468] NaH (9.0 mg, 0.226 mmol) was added to a solution of trimethylsulfoxonium iodide (49.7 mg, 0.226 mmol) in DMSO (2 mL). After 40 mins a solution of 220 ( 1 17 mg. 0.226 mmol) in THF (2 mL) was added, and the mixture was stirred at r.t. for 6 h. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with NaiSO,}, filtered and concentrated under reduced pressure to afford crude 2-48. which was used in the next step w ithout purification. UPLC/MS(ES+): m/z 534.30 [M+H]+.
[0469] Potassium carbonate (31.3 mg, 0.452 mmol) and imidazole (30.8 mg, 0.452 mmol) were sequentially added to a solution of 2-48 in DMF (2 mL). The mixture was heated to 120 °C for 18 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 0: 100) to afford 226 as a white solid ( 10 mg, 7% over 2 steps). UPLC/MS(ES+): m/z 602.50 [M+H]+. EXAMPLE 93
Preparation of Compound 227
Figure imgf000161_0001
[0470] A mixture of 2-49 (1 10 mg, 0.0 mmol), HOBT (86.0 mg, 0.640 mmol). EDC ( 1 22 mg. 0.640 mmol), TEA (120 uE. 0.860 mmol) and 4-(2-fluoroethoxy)-3- methoxybenzoic acid (1 10 mg, 0.510 mmol) in DCM (4 mL) was stirred at r.t. for 3 h. The reaction was quenched with 1M aq. HCl solution, and the mixture was stirred at r.t. for 10 mins. The layers were separated, and the organic portion was washed with 1M aq. HCl solution, dried with Na2SC> , filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 60:40 to 10:90) afforded 2-50 as a white solid (95 mg, 48%). UPLC/MS(ES+): m/z 453.09 [M+H]+.
[0471] A mixture of 2-50 (45.0 mg, 0.100 mmol), (3-chloro-4- fluorophenyl)boronic acid (87.0 mg, 0.500 mmol), Pd(dppf)Cl2 (3.6 mg, 0.005 mmol) and aq.
Na COs (2M solution, 250 uL, 0.500 mmol) in DCE ( 1 mL) was degassed and stirred with heating to 85 °C for 3 h. Water and DCM were added. The layers were separated, and the organic phase was dried with Na?S04, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (watenCH^CN 100:0 to 50:50) to afford 227 (10.5 mg. 19%). UPLC/MS(ES+): m/z 547.30 [M+H]+.
EXAMPLE 94
Preparation of Compound 228
Figure imgf000161_0002
[0472] A mixture of 2-50 (50.0 mg. 0.1 10 mmol), 7-fluoro-3-(tetramethyl-l,3,2- dioxaborolan-2-yl)- l -{ [2-(trimethylsilyl)ethoxy]methyl} -lH-indole (108 mg, 0.270 mmol), Pd(dppf)Cl2 (4.0 mg, 0.005 mmol) and aq. Na2C03 (2M solution, 135 uL, 0.270 mmol) in DCE (1 mL) was degassed and stirred with heating to 85 °C for 5 h. Water and DCM were added, and the layers were separated. The organic phase was dried with
Figure imgf000162_0001
filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 0: 100) to afford 2-51.
[0473] A solution of 2-51 in 10: 1 DCM:TFA (1 .1 mL) was stirred at r.t. for 3 h. A 1 M aq. NaOH solution was added, and the mixture was stirred at r.t. for 1 8 h. The layers were separated, and the organic phase was dried with Na2S04, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 50:50) to afford 228 (4.2 mg, 7% over 2 steps). UPLC/MS(ES+): m/z 552.40 [M+H]+.
EXAMPLE 95
Preparation of Compound 229
Figure imgf000162_0002
[0474] A mixture of 4-amino-3-hydroxybenzoic acid (2.01 g. 13.1 mmol). 12M aq. HC1 solution (20mL, 240 mmol) and 3-buten-2-one (1.59 mL, 19.6 mmol) was refluxed for 4 h. The volatiles were removed under reduced pressure, and the residue was purified by reverse phase chromatography (water:CLL,CN 100:0 to 0: 100) to afford 8-hydroxy-4- methylquinoline-6-carboxylic acid (830 mg, 3 1%). This w7as dissolved in DMT (35 mL). Cesium carbonate (4.42 g, 13.6 mmol) and iodomethane (1.28 mL, 20.5 mmol) were sequentially added to the solution. The mixture was stirred at r.t. for 4 h. The volatiles were removed under reduced pressure, and the residue was taken up with EtOAc. The organic portion was washed with water, dried with Na2S04, filtered and concentrated under reduced pressure to afford crude 2-52 (860 mg), which was used in the next step without further purification. UPLC/MS(ES+): m/z 232.10 [M+H]+. [0475] Lithium hydroxide monohydrate (280 mg. 6.73 mmol) was added to a stirred suspension of 2-52 (220 mg) in a 2: 1 : 1 TI IF:MeOH:H20 mixture (4 mL). The mixture was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. The residue was dissolved in water, and the pH of the aqueous portion was adjusted to 6 with 1 M aq. HCl solution. The mixture was purified by reverse phase chromatography (water:CH CN 100:0 to 0: 100) to afford 2-53 (80 mg, 31 %). UPLC/MS(ES+): m/z 21 8.10 [M+H]+.
[0476] Coupling of 2-53 with 2-30 according to Method A afforded 2-54, which was used in the next step without further purification.
[0477] Dess-Martin periodinane (127 mg. 0.299 mmol) was added to a stirred solution of 2-54 (66 mg) in dry DCM (32 mL). The mixture was stirred at r.t. for 1 h. The reaction was quenched with a 1 : 1 1M aq. Na2S203:sat. aq. NaHCOi solution, and the mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na2SC>4, filtered and concentrated under reduced pressure to afford crude 2-55, which was used in the next step without further purification.
[0478] A mixture of 2-55, (3-chloi -4-fluorophenyi)boronic acid (52.0 mg, 0.299 mmol), Pd(dppf)CT2 (16.0 mg, 0.022 mmol) and aq. Na2C03 (2M solution, 222 uL, 0.447 mmol) in DCE (3 1 mL) was degassed and heated to 100 °C under microwave irradiation. After 2.5 h, the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN 100:0 to 50:50) to afford 229 (10.0 mg). UPLC MS(ES f ): m/z 534.30 [M+Hj 1 .
EXAMPLE 96
Preparation of Compound
Figure imgf000163_0001
[0479] Methyl magnesiumbromide (3M solution in hexane, 300 uL, 0.892 mmol) was added to a solution of 3-1 (185 mg, 0.297 mmol) in dry THF (5 mL). The mixture was stirred at r.t. for 1 h. The reaction was quenched with 1 M aq. HO solution and EtOAc was added. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure to afford crude 3-2 (201 mg). which was used in the next step without further purification.
[0480] A solution of 3-2 (201 mg) in a 10: 1 DCM:TFA (3 mL) was stirred at r.t. for 40 mins. The reaction was quenched with 1 M aq. NaOH solution, and the mixture was stirred at r.t. for 10 mins. The layers were separated, and the aqueous portion was extracted with DCM. The combined organic portions were dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (EtOAc:MeOH 100:0 to 80:20) afforded the two separated diastereomers (each as a racemic mixture, relative stereochemistry arbitrarily assigned). 230: white solid ( 10 mg, 7% overall) and UPLC/MS(ES+): m/z 519.30 [M+H]+. 231: white solid (37 mg, 24% overall) and UPLC/MS(ES+): m/z 519.30 [M+H]+.
EXAMPLE 97
Preparation of Compound 232
Figure imgf000164_0001
[0481] To a solution of 232-1 (21.8 g, 69.9 mmol) and ethyl 2,2,2-trifiuoroacetate (12.9 g, 90.8 mmol) in THF (500 mL) was added isopropyl-magnesium chloride (46.0 mL, 2.3 N in THF) at 0°C. The mixture was stirred at 0°C for 30 mins. The reaction was quenched with sat. NH4CI solution and extracted with EA. The combined organic phases were dried over anhydride MgS04 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA, 5 : 1 ) to give 232-2 as an oil (16.5 g, 83.8%).
[0482] To a solution of 232-2 (16.5 g, 58.5 mmol), (3-chloro-4- fluorophenyl)boronic acid (10.51 g. 58.6 mmol). KF (7.1 g, 1 17 mmol) in dioxane (300 niL) and H?0 (30 mL) was added Pd(dppf)Cl2 (4.7 g, 5.8 mmol). The mixture was degassed and then charged with nitrogen (3x). The mixture was stirred at 70 °C in an oil bath for 6 h under N2. The mixture was cooled to r.t., diluted with EA and separated from the water layer. The organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA. 10: 1 ) to give 232-3 as a white solid (17.0 g, 87.2%). ESI-MS: m/z 351.8 [M+H20]+.
[0483] A mixture of 232-3 (17.0 g, 51.1 mmol) and K2C03 (13.8 g, 100 mmol) in nitro-me thane (100 mL) was stirred at r.t. for 10 h. The solution was extracted with EA (3 x 200 mL). The combined organic phases were dried over anhydrous MgSC and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 15% EA in PE to give 232-4 as a white solid (16.0 g, 80.0%).
[0484] To a solution of 232-4 (16.0g, 40.6 mmol) and NiCl2.6H20 (9.5 g, 40.4 mmol) in anhydrous MeOH (150 mL) and anhydrous THE (150 mL) was added NaBLL; (15.2 g, 400.6 mmol) in portions at 0 °C. After addition was complete, the solution was stirred at 0 °C for 1 h. The reaction was quenched with H20 and then extracted with EA (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na?S04. and concentrated under reduced pressure. The residue was purified by column chromatography using EA to give 232-5 as an oil ( 1 1 .0 g, 74.8%). ESI-MS: m/z 365 [M+H]+.
[0485] To a solution of (R)-3-chloro-4-(2-hydroxypropoxy)benzoic acid (1 15 mg. 0.5 mmol), HATU (260 mg. 0.7 mmol) and DIPEA (320 mg. 2.5 mmol) in anhydrous DCM (5 mL) was added 232-5 (1 80 mg, 0.5 mmol) at 25 °C. The solution was stirred for 1 h at 25 °C. The mixture was diluted with 1 .0 N aqueous NaHCO solution, and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 232 as a white solid (80 mg, 27.5%). ESI-MS: m/z 576.9 [M+H]+. EXAMPLE 98
Preparation of Compound 233
Figure imgf000166_0001
[0486] To a solution of 233-1 (1.8 g, 10.0 mmol) and F3CCH2I (2 g, 10.0 mmol) in DMF (100 mL) was added K2C0 (2.6 g, 20.0 mmol). The mixture was stirred at 80 °C for 3 h. The mixture was concentrated at low pressure, and the reidue was dissolved in EA (50 mL). The mixture was washed with brine, dried over anhydrous Na2SC>4 and concentrated to dryness. The crude product was purified by column chromatography using 10% EA in PE to give 233-2 (1 .6 g, 60%).
[0487] To a solution of 233-2 (1 .5 g. 5.7 mmol) in CH3OH and water (120 mL and 30 mL) was added LiOH (270 mg, 1 1 .3 mmol). The mixture was stirred at 70 °C for 2 h. and then cooled to r.t. The mixture was extracted with EA. and the residue was neutralized using 2.0 N HC1 solution. The mixture was extracted with EA (3 x 30 mL). The organic layer was washed with brine and dried over anhydrous Na2S04. The solution w¾s concentrated at low pressure to give 233-3 as a white solid (1.3 g, 85%).
[0488] Compound 233 was prepared essentially as described in the preparation of 232 by using 233-3 and 232-5. Compound 233 was obtained as a white solid. (100 mg, 67%) +ESl-MS:m/z 596.1 [M+H]+. EXAMPLE 99
Preparation of Compound 234
Figure imgf000167_0001
[0489] To a solution of 234-1 (1 .0 g, 5.4 mmol) in MeCN (10 mL) were added 1 - chloro-2-propanone ( 1 .0 g, 10.0 mmol) and K2C03 (3.5 g, 20.0 mmol). The mixture was stirred at 80 °C for 1 h. After filtration, the filtrate was concentrated at lo pressure. The residue was purified by chromatography to give 234-2 (850 mg, 65.4%).
[0490] A mixture of 234-2 (500 mg, 2.1 mmol) and DAST (5 mL) was stirred at 50 °C for 12 h. The reaction was quenched with sat. NaHC03 solution, and extracted with EA (3 x 20 mL). The organic layer was washed with brine, dried over anhydrous Na2SC>4. and concentrated to dryness. The residue was purified by column chromatography using 10% EA in PE to give 234-3 (310 mg, 56.8%).
[0491] Compound 234-4 was prepared essentially as described in the preparation of 233-3. Compound 234 was prepared essentially as described in the preparation of 232 by using 234-4 and 232-5. Compound 234 was obtained as white solid (58 mg, 24.1%). +ES1- MS:m/z 593.1 [M+H]+.
EXAMPLE 100
Preparation of Compound 235
Figure imgf000168_0001
10492] To a solution of 235-1 ( 1.82 g, 10.0 mmol), tetrahydrofuran-3-ol (880 mg, 10.0 mmol) and PPh3 (2.62 g, 10.0 mmol) in THF (30 mL) at 0 °C was added DIAD (2.02 g, 10.0 mmol) dropwise. The mixture was stirred at 0 °C for 2 h, and the reaction was then quenched with sat. NaHC03 solution. The aqueous layer was extracted by DCM (3x). The combined organic layers were dried over MgSC>4, filtered and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel to give 235-2 (2.4 g, 89.6%).
[0493] Compound 235-3 was prepared essentially as described in the preparation of 233-3. Compound 235 was prepared essentially as described in the preparation of compound 232 by using 235-3 and 232-5. Compound 235 was obtained as white solid (75 mg. 62.3%). +ESl-MS:m/z 585.2 [M+H]+.
EXAMPLE 101
Preparation of Compound 236
Figure imgf000168_0002
[0494] Compound 236 was prepared essentially as described in the preparation of compound 235 by using methyl 4-hydroxy-3-methoxybenzoate. Compound 236 was obtained as white solid (56 mg, 22.7 %). +ESl-MS:m/z 583.1 [M+U] EXAMPLE 102
Preparation of Compound 237
Figure imgf000169_0001
[0495] To a solution of 237-1 (0.93 g. 5 mmol) in acetone (30 mL) was added K2C03 (2.08 g, 15 mmol) and 2-iodoacetamide ( 1 .39 g. 7.5 mmol). The mixture was stirred at r.t. overnight. The mixture was diluted with water and extracted with EA (4 x 100 mL). The combined organic layers were dried over anhydrous Na SC^ and concentrated in vacuum to give crude 237-2, which was further purified by column chromatography on silica gel (PE:EA= 2: 1) to 237-2 (1.01 g, 83.1 %) as a white solid.
[0496] Compound 237-3 was prepared essentially as described in the preparation of 233. Compound 237 was prepared essentially as described in the preparation of 236 by using 237-3 and 232-5. Compound 237 was obtained as white solid (32 mg, 22.2%). +ES1- MS:m/z 576.1 [M+H]+.
EXAMPLE 103
Figure imgf000169_0002
[0497] Compound 240 was prepared essentially as described in the preparation of 232 by using 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid and 232-5. Compound 240 was obtained as a white solid (300 mg, 52.5%).
[0498] Compound 240 (300 mg, 0.53 mmol) was separated via SFC to give two enantiomers: 238 (140 mg, 93.3%) and 239 ( 100 mg, 66.7%). Compound 238: +ES1- MS:m/z 572.1 [M+H]+. Compound 239: +ESl-MS:m/z 572.0 [M+H]+.
EXAMPLE 104
Preparation of Compounds 241, 242 and 243
Figure imgf000170_0001
[0499] To a solution of 243-1 (714 mg, 2.0 mmol) in THF (4 mL) was added cyclopropylmagnesium bromide (4 mL, 0.5 M in TI IF). The mixture was stirred at 0 "C for 1 h. The reaction was quenched with water, and extracted with EA (3 x 20 mL). The combined organic layers was washed with brine, dried over anhydrous Na2SC>4, and concentrated at low pressure. Crude 243-2 was directly used in the next step. +ES1-MS: m/z 399.0 [M+H]+.
[0500] Compound 243-2 (600 mg), NH3 · H20 (10 mL) and ethanol ( 10 mL) were put in an autoclave. After sealing, the reaction was stirred at r.t. for 10 h. The mixture was extracted by EA (3 x 10 mL), dried over anhydrous Na2S04, and concentrated at low pressure to give 243-3, which was used without further purification. +ES1-MS: m/z 336.1 [M+H]+.
[0501 ] Compound 243 was prepared essentially as described in the preparation of 232 by using 4-(2-hydroxyethoxy)-3-methoxybenzoic acid and 243-3. Compound 243 was obtained as a white solid (152 mg, 23%). +ESI-MS: m/z 531.2 [M+H]+. [0502] Compound 243 ( 1 52 mg, 0.28 mmol) was separated via SFC to give two isomers: 242 (40.0 mg, 26%) and 241 (43.0 mg, 26%). 241 : +ESI-MS: m/z 53 1 . 1 [M+H]+. 242 : +ESI-MS: m/z 53 1 .1 |_M+H]+.
EXAMPLE 105
Preparation of Compound 244
Figure imgf000171_0001
[0503] Compound 244-2 was prepared as described in Franc k et al., Bioorganic & Medicinal Chemistry, (201 3) 21 (3):643-652. Compound 244-3 was prepared essentially as described in the preparation of 235 by using 244-4 and methyl 4-hydroxy-3- methoxybenzoate. Compound 244-3 was obtained as a white solid (2.8 g. 73.7%).
[0504] To a solution of 244-3 (2.8 g, 8.2 mmol) in methanol ( 1 5 mL) was added Pd(OH)2 on charcoal ( 1 0%, 500 mg) under N2. The suspension was degassed under vacuum and purged with H2 (3x). The mixture was stirred under H2 (40 psi) at r.t. for 3 h. The suspension was filtered through a pad of Celite, and the pad cake was washed with methanol. The combined filtrates were concentrated to give crude 244-4 ( 1.7 g, 84.5%), which was used in the next step without purification.
[0505] To a solution of 244-4 ( 1 .3 g, 5.2 mmol) in DCM ( 10 mL) was added DMP (3.4 g. 8.0 mmol). The mixture was stirred at r.t. for 40 mins. The reaction was quenched by sat. solution and extracted with EA. The combined organic layers were washed with sat. NaHC(¾ solution, brine and dried over anhydrous a2SC>4. The solution was concentrated to dryness, and the residue was purified by column chromatography on a silica gel column (PE:EA, 5 : 1 ) to give 244-5 as a white solid (0.8 g, 61 .6%).
[0506] Compound 244-5 (500 mg, 2.0 mmol) was treated with DAST (5 mL), and stirred at 0 °C for 30 mins. The reaction was quenched by a sat. NaHC03 solution at 0 °C. and then extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EA, 10: 1 ) to give 244-6 as a white solid (605 mg. 81 .2%). +ESI-MS: ni / 273.1 | \1 I I | .
[0507] To a solution of 244-6 (300 mg, 1.1 mmol) in MeOH (35 mL) was added NaOH solution (2 N. 35 mL). The reaction was stirred under reflux for 1 h. The mixture was neutralized with 2.0 N HC1 solution, and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous MgS04 and evaporated under reduced pressure to give 244-7 as a white solid (250 mg, 88.1 %). +ES1-MS: m/z 259 [M+Hf .
[0508] Compound 244 was prepared essentially as described in the preparation of compound 232 by using 244-7 and 232-5. Compound 244 was obtained as a white solid (60 mg, 25.5%). +ES1-MS: m/z 606.1 [M+Hf.
EXAMPLE 106
Preparation of Compound 245
Figure imgf000172_0001
[0509] Compound 245 was prepared essentially as described in the preparation of 235. Compound 245 was obtained as a white solid (70 mg. 54.8%). +ESI-MS:m/z 569.1 [M+H]+.
EXAMPLE 107
Preparation of Compound 248
Figure imgf000173_0001
[0510] Compound 248-2 was prepared as described in Rye ct al.„ Eur. J. Med. Chem. (2013) 60:240-248. To a solution of 248-2 (6.0 g, 29.41 mmol) and K2C03 (5.28 g. 38.23 mmol) in DMF (50 mL) was added methyl 2,4-dibromobutanoate (9.86 g. 38.23 mmol). The mixture was stirred at 80 °C for 12 h, and then diluted with water and extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum. The residue was purified by column chromatography on silica gel crude 248-3 (9.8 g).
[0511] To a solution of 248-3 (9.8 g, 25.8 mmol) in THF (100 mL) was added t- BuOK (28.37 mL, 28.37 mmol, 1 N in THF) at 0 "C. The mixture was stirred at r.t. for 3 h. The mixture was diluted with water and extracted with EA (3 x 60 mL). The combined organic layer was dried over anhydrous Na2S04 and concentrated at low7 pressure. The residue was purified by column chromatography to give 248-4 (6.0 g. 78.0%).
[0512] To a solution of 248-4 (6.0 g, 20.0 mmol) in EtOH (20 mL) was added NaBFL; (2.10 g, 30.0 mmol) at r.t. The mixture was stirred at r.t. for 10 mins. The mixture was heated to reflux for 10 h and then cooled to r.t. The mixture was diluted with EA (60 mL) and washed with brine. The combined organic layer was dried over anhydrous Na?S04 and concentrated at low pressure. The residue was purified by chromatography to give 248-5 (4.5 g) as a white solid.
[0513] To a solution of 248-5 (500 mg, 1 .84 mmol) in DCM ( 10 mL) was added Et3N (370 mg, 3.68 mmol) and DMAP (10.0 mg. 0.082 mmol). TsCl (459 mg. 2.41 mmol) was added portionwise. The mixture was stirred at r.t. overnight. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The combined organic layer were dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 248-6 as a white solid (730 mg, 93.1%).
[0514] To a solution of 248-6 (730 mg, 1.80 mmol) in anhydrous ΤΗΓ (10 mL) was added TBAF (1M in THF) (5.0 mL, 5.0 mmol). The mixture was stirred at r.t. overnight. The mixture was diluted with EA (20 mL) and washed with brine. Lhe combined organic layer was dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 248-7 as a white solid (330 mg, 67.0%).
[0515] To a solution of 248-7 (330 mg, 1.2 mmol) in anhydrous THF (10 mL) was added n-BuLi (0.63 mL, 1.6 mmol) at -78 °C dropwise. The mixture was stirred at -78 °C for 0.5 h. CICOOCH3 (0.69 g, 7.2 mmol) was added in one portion and stirred at -78 °C for 1 h. The mixture was diluted with EA (20 mL) and washed with brine. The combined organic layer was dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by chromatography to give 248-8 as a white solid (203 mg, 66.0%).
[0516] Compound 248-9 was prepared essentially as described in the preparation of 233. Compound 248 was prepared essentially as described in the preparation of 232 by using 248-9 and 248-10. Compound 248 was obtained as a white solid (12 mg. 3.7%). +ESI-MS:m/z 587.1 [M+H]+. EXAMPLE 108
Preparation of Compound 249
Figure imgf000175_0001
[0517] Compound 249-2 was prepared essentially as described in the preparation of 248. To a solution of 249-2 (1.02 mg. 2.5 mmol) in DMSO (10 mL) was added NaBH4 (285 mg. 7.5 mmol) at r.t. under N2 atmosphere. The solution was heated to 80 °C and stirred for 1 h. The solution was cooled to r.t. The reaction was quenched with water (20 mL) and extracted with EA (2 x 20 mL). The organic phase was concentrated at low pressure, and the residue was purified by column chromatography on silica gel (PE:EA=20: 1 ) to give 249-3 as a colorless oil (280 mg, 47.4%)
10518] Compound 249-4 was prepared essentially as described in the preparation of 233. Compound 249 was prepared essentially as described in the preparation of 232 by using 249-4 and 232-5. Compound 249 was obtained as a white solid (7 mg, 13.7%). +ES1- MS: m/z 569.0[M+H]+.
EXAMPLE 109
Preparation of Compound 250
Figure imgf000175_0002
[0519] Compound 250 was prepared essentially as described in the preparation of 235 by using methy l 4-hydroxy-3-methoxybenzoate and 232-5. Compound 250 was obtained as white solid (19.8 mg. 8.7%). +ESI-MS: m/z 571 .0[M+H]+. EXAMPLE 110
Preparation of Compound 251
Figure imgf000176_0001
[0520] To a suspension of [lrCl(cod)]2 (18 mg, 0.03 mmol) and sodium carbonate (171 mg, 1.6 mmol) in toluene ( 10 mL) was added 251-1 (500 mg, 2.68 mmol) and vinyl acetate (457 mg, 5.38 mmol) under Ar. The mixture was stirred at 100 °C for 2 h. The mixture was cooled to r. , and treated with PE. The precipitate was removed by filtration, and the organic phase was concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA = 30: 1) to give 251-2 (410 mg, 72%).
[0521] TEA (468 mg, 4.1 mmol) was slowly added to anhydrous DCM (5 mL) and Et2Zn (4.2 mL, 4.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 mins, followed by the addition of CH I2 (1 .9 g, 7.1 mL). The resulting solution was stirred at 0 °C for 10 mins, and then 251 -2 (300 mg, 1 .42 mmol) was added. The mixture was allowed to warm to r.t., and stirred at r.t. overnight. The reaction was quenched with sat. NH4C1 solution and extracted with EA (3 x 20 mL). The organic layer was dried over anhydrous MgS04 and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA=20: 1 ) to give 251 -3 (210 mg, 65.8%).
[0522] Compound 251-4 was prepared essentially as described in the preparation of 233. Compound 251 was prepared essentially as described in the preparation of 232 by using 251-4 and 232-5. Compound 251 wras obtained as white solid (23 mg, 10.1%). +ES1- MS: m/z 559.0[M+H]+. EXAMPLE 111
Preparation of Compound 252
Figure imgf000177_0001
[0523] Compound 252 was prepared essentially as described in the preparation of
232 by using quinoline-6-carboxylic acid and 232-5. Compound 252 was obtained as a white solid (70 mg. 33%). +ESI-MS:m/z 520.1 [M+H]+.
EXAMPLE 112
Preparation of Compound 253
Figure imgf000177_0002
[0524] Compound 253 was prepared essentially as described in the preparation of
232 by using 1 H-benzo[d]imidazole-5-carboxylic acid and 232-5. Compound 253 was obtained as a white solid (70 mg, 28%). +ESI-MS:m/z 509.1 [M+H]+.
EXAMPLE 113
Preparation of Compound 254
Figure imgf000177_0003
[0525] Compound 254 was prepared essentially as described in the preparation of 232 by using benzo[d]thiazole-6-carboxylic acid and 232-5. Compound 254 was obtained as a white solid (38 mg, 33%). +ESl-MS:m/z 525.9 [M+H]+.
EXAMPLE 114
Preparation of Compounds 255, 256 and 398
Figure imgf000178_0001
[0526] To a solution of 255-1 (5 g, 27 mmol) and (R)-2-methyloxirane (4.7 g, 82 mmol) in DMF ( 100 mL) was added K2C03 (7.4 g, 54 mmol). The mixture was stirred at 80 °C for 3 h. The reaction was quenched with water and extracted by ΕΛ (3 x 50 mL). The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 255-2 (6.5 g, 95%).
[0527] Compound 255-3 was prepared essentially as described in the preparation of 233. Compound 398 was prepared essentially as described in the preparation of 232 by using 255-3 and 232-5. Compound 398 was obtained as a w hite solid (687 mg. 68%).
[0528] Compound 398 (350 mg, 1.14 mmol) was separated via SFC to give two diastereomers: 255 (1 13 mg) and 256 (107 mg). 255: +ESI-MS:m/z 573.1 [M+H]+. 256: +ESl-MS:m/z 573.1 [M+H]+.
EXAMPLE 115
Preparation of Compound 257
Figure imgf000179_0001
[0529] Compound 257-2 was prepared according to the procedure provided in Xu et al., Angew. Chein. Int. Ed. (201 1 ) 50(51): 12249- 12252. Compound 257 was prepared essentially as described in the preparation of 234 by using 257-2 and 232-5. Compound 257 was obtained as a white solid (51 mg, 23.8%). +ESl-MS:m/z 597.1 [M+H]+.
EXAMPLE 116
Preparation of Compound 258
Figure imgf000179_0002
[0530] Compound 258 was prepared essentially as described in the preparation of 232 by using 3-oxo-3,4-dihydro-2H-benzo[b] [ l ,4]oxazine-6-carboxylic acid and 232-5. Compound 258 was obtained as a white solid (80 mg. 41 %). +EST-MS:m/z 540.0 [M+H]+.
EXAMPLE 117
Preparation of Compounds 259, 260 and 261
Figure imgf000180_0001
[0531] Compound 259-2 was prepared according to the procedure provided in Chinese Patent No. CN 1 869008, published Nov. 29, 2006, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 259-2. Compound 259-3 was prepared according to the procedure provided in Barbayianni et al., J. Org. hem. (2005) 70(22):8730-8733. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 259-3. Compound 259-4 was prepared essentially as described in the preparation of 235 by using 259-3 and methy l 3-chloro-4-hydroxybenzoate. Compound 259-4 was obtained as a white solid (4 g. 90%).
[0532] Under H2 atmosphere, a mixture of 259-4 (4g, 9 mmol) and Pd/C (200 mg) in MeOH (45 mL) was stirred at 30 °C for 10 h. Purification by column chromatography on silica gel provided 259-4 (2 g. 80%). +EST-MS:m/z 269.8[M+H]+.
[0533] To a solution of 259-4 and 259-4A (2 g, 7.4 mmol) in THF/H20 (10 mL/l mL) was added NaOH (400 mg. 10 mmol) in portions until the starting material was consumed completely. The mixture was neutralized by addition of 2 N HC1 solution. The mixture was extracted with EA (3 x 40 mL). The organic phase was washed with brine, dried over anhydrous MgSC^ and concentrated at low pressure to give 259-5 and 259-5A.
[0534] Compound 259-6 and 261 were prepared essentially as described in the preparation of 232 by using 259-5 and 232-5. Compound 259-6 (100 mg) and 261 (30 mg) were each obtained as a w hite solid. 261 : +ESl-MS:m/z 568. 1 [M+H]+.
[0535] Compound 259-6 ( 100 mg. 0.16 mmol) was separated by SFC to give 259 (80 mg, 80%) and 260 (20 mg, 20%). 259: +ESI-MS:m/z 602.1 [M+H]+. 260: +ES1- MS:m/z 602.1 [M+H]+.
EXAMPLE 118
Preparation of Compound 262
Figure imgf000181_0001
[0536] Compound 262 was prepared essentially as described in the preparation of
237 by using 2-oxo-2.3-dihydro-l H-benzo[d]imidazole-5-carboxylic acid and 232-5.
Compound 262 was obtained as a white solid (58 mg. 24.5%). +ESl-MS:m/z 563.0 [M+H]+.
EXAMPLE 119
Preparation of Compounds 264 and 265
Figure imgf000181_0002
[0537] Compounds 264 and 265 were prepared essentially as described in the preparation of 232 by using 1 -methyl- l H-bcnzo[dJimidazole-6-carboxylic acid or 1 -methyl- lH-benzo[d]imidazole-5-carboxylic acid, and 232-5. respectively. Compounds 264 (47 mg. 26%) and 265 (51 mg, 28%) were each obtained as a white solid. 264: +ESI-MS:m/z 522.9 [M+H]+. 265: +ESl-MS:m/z 523.0 [M+H]+.
EXAMPLE 120
Preparation of Compound 266
Figure imgf000181_0003
[0538] Compound 266 was prepared essentially as described in the preparation of 232 by using benzo[d]oxazole-6-carboxylic acid and 232-5. Compound 266 was obtained as a white solid (60 mg, 23%). +ESl-MS:m/z 509.9 [M+HJ+.
EXAMPLE 121
Preparation of Compound 267
Figure imgf000182_0001
[0539] Compound 267 was prepared essentially as described in the preparation of 232 by using 3-methyl-2-oxo-2.3-dihydro-l H-benzo[d]imidazole-5-carboxylic acid and 232- 5 as start material. Compound 267 was obtained as a white solid (10.7 mg, 7.6%). +ES1- MS:m/z 539.0 [M+H]+.
EXAMPLE 122
Preparation of Compound 268
Figure imgf000182_0002
[0540] Compound 268 was prepared essentially as described in the preparation of 232 by using l -methyl-2-oxo-2.3-dihydro-l H-benzo[d]imidazole-5-carboxylic acid and 232- 5. Compound 268 was obtained as a white solid (14 mg, 8.4%). +ESI-MS:m/z 539.0 [M+H]+.
EXAMPLE 123
Preparation of Compound 269
Figure imgf000183_0001
[0541| To a stirred solution of 269-1 (20.0 g, 130.68 mmol) in acetone (400 mL) was added KOH (18.4 g, 15 mmol) and (CH3)2S04 (29.4 mL, 318.9 mmol). The mixture was stirred at r.t. overnight. The solvent was evaporated at low pressure, and the residue was dissolved in hot water. The pH was adjusted to 9 with 1 N NaOH solution. After cooling to r.t., the precipitate was filtered off and thoroughly washed with cold EtOAc to give 269-2 as a light yellow powder (23.66 g, 63.4%). +ESl-MS:m/z 181.8 [M+H]+.
[0542] To a solution of 269-2 (14.4 g, 8 mmol) in EtOH (120 mL) was added acetic anhydride (9.0 g, 88 mmol). The mixture was allowed to stir at 50 °C for 2 h. The mixture was cooled to r.t., and neutralized with aqueous NaHC03 solution. The mixture was extracted with EA (3 x 60 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel (PE:EA 1 : 1 ) to give 269-3 (15.0 g. 84.1 %). +ESI-MS:m/z 223.9 [M+H]+.
[0543] To a solution of 269-3 (4.46 g, 20 mmol), PdOAc (0.45 g, 2 mmol) and Cu(OAe)2 (7.26 g, 40 mmol) in 1.2-dichloroethane ( 150 mL) was added anhydrous CuBr2 (8.93 g. 40 mmol) under N2 atmosphere. The mixture was stirred at 90 °C for 72 h. After cooling to r.t., the reaction was quenched by water, and filtered through a celite pad. The solution was washed with brine, dried by anhydrous Na2S04 and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel (PE:EA 1 : 1 ) to give 269-4 (6.04 g, 51 .3%). +ESI-MS:m/z 303.7 [M+I I]\
[0544] To a solution of 269-4 (4.53 g, 15 mmol) in ethanol (60 mL) and water (60 mL) was added NaOH (6.0 g, 1 50 mmol), and the mixture was stirred at 70 °C overnight. After cooling to 0°C, the mixture was neutralized with 5% aqueous HC1. The precipitate was filtered and concentrated to give 269-5 as a light yellow powder (3.1 g. 82.0%), which was used without further purification. +EST-MS:m/z 247.6[M+H]+.
[0545] A mixture of 269-5 (2.44 g. 10 mmol), glycerol (1 .5 mL. 20 mmol). and 3-nitrobenzensulfonate ( 10 g, 45 mmol) were treated with cone. H1SO4 (25 mL) and FLO (8.3 mL). The mixture was heated at 100 °C for 3 h.. and then stirred at 140 °C for 1 h. The mixture was slowly cooled to 60 °C. Ethanol (15 mL) was added, and the mixture was stirred overnight. The mixture was neutralized with ammonia water, and extracted with EA (3 x 50 mL). The solution was dried over anhydrous Na?S04 and concentrated at low7 pressure. The residue was purified by flash column chromatography on silica gel (PE:EA 10: 1 ) to give 269-
6 (0.50 g, 16.9%o). +ESl-MS:m/z 295.9 [M+H]+.
[0546] To a stirred solution of 269-6 (0.295 g, 1 mmol) in DMF (3 mL) was added K2C03 ( 145 mg, 1.05 mmol) and CH 1 (149 mg, 1.05 mmol). The mixture was stirred at r.t. overnight, and then concentrated at low pressure. The residue was dissolved in EA (20 mL). The solution was washed with brine, dried over Na2S04 and concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE:EA= 5: 1 ) to give 269-
7 (216 mg. 70.0%) as a white solid. +ESI-MS:m/z 31 1 .9 [M+H]+.
[0547] To a stirred solution of 269-7 (240 g. 0.77 mmol) in methanol (30 mL) was added Pd/C (15 mg). The mixture was stirred at r.t. under LL (balloon) for 1 h. The mixture was filtered, and the filtrate was concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA= 5: 1 ) to give 269-8 (101 mg. 56.0%) as a white solid. +EST-MS:m/z 231 .9 [M+H]+.
[0548] To a solution of 269-8 (0.1 g, 0.44 mmol) in CH3OH (2 ml.) and water (2mL) was added NaOH (80 mg, 2 mmol), and the mixture was stirred at 50 "C for 0.5 h. The mixture was cooled to 0 °C, and the pH was adjusted to 5 using 5%> HC1 solution. The mixture was extracted with EA (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated at low pressure to give crude 269-9 (66 mg, 75.8%) as a white solid, which was used without further purification.
[0549] To a solution of 269-9 (66 mg, 0.325 mmol) in DCM (5 mL) were added DMF ( 1 drop) and (COCl)? (0.23 mL, 1 .3 mmol). The mixture was stirred at r.t. for 2 h, and then concentrated at low pressure. The residue was treated with a solution of 232-5 ( 1 17 mg. 0.325 mmol) and TEA (0.28 mL) in DCM (5 mL) at 50 °C. The mixture was allowed to stir at r.t. overnight. The mixture was diluted with water, and extracted with EA (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by HPLC to give 269 as a white solid (25 mg. 14.0%). +ESI- MS:m/z 550.0 [M+H]+.
EXAMPLE 124
Preparation of Compound 270
Figure imgf000185_0001
270-8
[0550] Compound 270-2 was prepared according to the procedure provided in Rye et al., Eur. J. Med. Chem. (2013) 60:240-248, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 270-2. To a stirred solution of 270-2 ( 18.0 g, 89.1 mmol) in acetone (200 mL) were added ethyl 2-bromoacetate (29.6 g, 178.2 mmol) and 2CO3 (36.9 g, 270 mmol). The mixture was stirred at 80 °C for 12 h. The mixture was diluted with water and extracted with EA. The organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give crude 270-3 (25 g yield: 98%). [0551] To a solution of 270-3 ( 1 1 g, 38.2 mmol) in anhydrous THF (100 mL) was added Ti(i-PrO)4 (10.85 g. 38.2 mmol) under N2 at 0 °C, and then EtMgBr (34.4 mL, 103.14 mmol) was added dropwise. The mixture was stirred at r.t. overnight. The reaction was quenched with water, and extracted with ΕΛ (3 x 60 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 270-4 (4.2 g. 40.4%).
[0552] To a solution of 270-4 (2.5 g. 9.19 mmol) in DCM (20 mL) were added DHP (1 .54 g. 18.38 mmol) and TsOH (158.2 mg. 0.92 mmol). The mixture was stirred at r.t. overnight. The reaction was quenched with water, and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated at lowr pressure. The residue was purified by column chromatography on silica gel to give 270-5 as a white solid (2.6 g, yield: 74.0%).
[0553] To a solution of 270-5 (1.5 g, 4.21 mmol) in anhydrous THF ( 15 mL) was added w-BuLi (2.0 mL, 5.0 mmol) at -78 °C dropwise. After the mixture was stirred at -78 °C for 0.5 h, CICOOCH3 (2.39 g. 25.28 mmol) was added in one portion. The mixture was stirred at -78 °C for 1 h, and then diluted with EA (50 mL) and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by chromatography to generate 270-6 as a white solid (820 mg, yield: 58%).
[0554] To a stirred solution of 270-6 (410 mg. 1 .22 mmol) in EtOH/H20 (3: 1 , 10 mL) was added NaOH ( 195 mg, 4.88 mmol), and the mixture was stirred at 50 °C for 1 h. The mixture was diluted with water and extracted with EA. The pH of aqueous layers was adjusted to 4.0 by adding 5% HC1 solution. The aqueous phase was extracted with EA. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum to give crude 270-7 (198 mg).
[0555] To a solution of 270-7 (200 mg, 0.62 mmol) in DMF (1 5 mL) were added DIPEA (240 mg, 1.86 mmol) and HATU (236 mg, 0.62 mmol). The mixture was stirred at r.t. for 30 mins, and then 232-5 (226 mg, 0.62 mmol) was added. The mixture wras stirred at r.t. for 2 h, and then diluted with water and extracted with EA (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated at lo pressure. The residue was purified by column chromatography on silica gel to give 270-8 (250 mg, 60.4%).
[0556] To a solution of 270-8 (250 mg, 0.37 mmol) in EtOH (10 mL) was added PPTS (19.4 mg. 0.075 mmol). The mixture was stirred at 70 "C for 2 h, and then diluted with EA (50 mL) and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by prep-HPLC to give 270 as a white solid (80 mg, 37.0%). +ESI-MS:m/z 585.1 [M+H]+.
EXAMPLE 125
Preparation of Compounds 271, 272 and 314
Figure imgf000187_0001
[0557] A 1 L round bottom flask was charged with a mixture of 271 -1 ( 1 5 g. 86.71 mmol). (3-chloro-4-fluorophenyl) boronic acid ( 15 g. 86.03 mmol). [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(TT) (1.0 g, 1.37 mmol) and K2C<¾ (23.7g, 172 mmol) in dioxane/LLO (450 mL/50 mL) under N2 atmosphere. The mixture was heated to 100 °C for 2 h. The mixture was cooled to r.t. and dioxane was evaporated under reduced pressure. The residue was diluted with EA and water. The organic layer was dried over anhydrous Na?S04 and concentrated under reduced pressure. Chromatography of the residue (PErEtOAc 100: 1 to 40: 1 ) afforded 271 -2 as a white solid (1 1 g, 47.8%).
[0558] To a solution of 271-2 (7.2 g, 26.9 mmol) in toluene (200 mL) was added MeMgBr (27 mL. 81 mmol) in 5 mins. The solution was stirred for 30 mins at r.t. Ti(OiPr)4 (8 mL. 27.3 mmol) was added slowly at r.t. The solution was bathed in 100 °C oil and stirred for 20 mins. The mixture was cooled to r.t.. and the reaction was quenched with a sat. aq. Na2C03 solution. The mixture was separated by filtration, and the cake was washed with EA. The organic phase was concentrated to dryness, and crude 271-3 (7.0 g, brown oil) was used directly in the next step.
[0559] To a solution of 271-3 (7.0 g. 23.4 mmol) in toluene ( 100 mL), Et3N (7.09 g, 70.2 mmol) and B0C2O (5.6 g, 25.7 mmol) were added at r.t. The solution was bathed in 100 "C oil and stirred for 3 h. The solution was cooled to r.t., and separated between EA (300 mL) and water (200 mL). The organic phase was washed with brine and dried over Na?S04. The organic phase was concentrated, and the residue was purified by chromatography on silica gel (PE:EA 20: 1 -10: 1) to give 271-4 as a yellow7 solid (7.05 g, 75.5%). +ES1-MS: m/z 398.9 [M+H]+.
[0560] To a solution of 271-4 (7.0 g. 17.5 mmol) in EtOH (70 mL) were added 2CO3 (3.62 g, 26.2 mmol) and potassium trifluoro(vinyl)borate (2.8 g, 21 .0 mmol) at r.t. Pd(dppf)Cl? (256 g, 0.35 mmol) was added under N? atmosphere. The mixture was bathed in 100 °C oil and stirred for 3 h. The solution was concentrated at lo pressure, and the residue was separated between EA ( 100 mL) and water (50 mL). The organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by chromatography on silica gel (PE:EA 20: 1 -10: 1 ) to give 271 -5 as a yellow oil (6.1 g, 89.3%). +ES1-MS: m/z 391 .0 [M+H]+.
[0561] A solution of 271-5 (6.1 g, 15.6 mmol) in DCM ( 150 mL) was bubbled with O3 at -78 °C until the solution turned blue. The solution was then bubbled with N2 until the blue colour disappeared. PPI13 (4.9 g, 18.72 mmol) was added at -78 °C, and stirred for 2 h at -78 °C. The mixture was concentrated at low pressure, and the residue was purified by chromatography on silica gel (PE:EA 10: 1 -5: 1) to give 271-6 as a white solid (4.8 g, 78.4%). [0562] To a solution of 271-6 (4.86 g, 12.38 mmol) in dry D F (25 niL) was added TMSCF3 (4.4 g, 31 .0 mmol). The mixture was cooled down to -78 °C, and TBAF (1 M in THF, 7.3 mL, 7.3 mmol) was added dropwise. The mixture was allowed to gradually warm to r.t, and stirred for 0.5 h. The mixture was diluted with water and EtOAc. The organic layers was dried over anhydrous Na2S04 and concentrated under reduced pressure. Chromatography of the residue (PE:EtOAc 100:0 to 80:20) afforded 271 -7 (4.1 g. 72%).
[0563] To a stirred solution of 271 -7 (4.1 g, 8.86 mmol) in dry DCM (45 mL) was added Dess-Martin periodinane (4.96 g, 17.7 mmol). The mixture was stirred at r.t. for 10 h. The mixture was concentrated under reduced pressure and chromatography of the residue (PE:EtOAc 100:0 to 70:30) afforded 271-8 (3.8 g, 93%).
[0564] To a solution of 271-8 (3.8 g, 8.25 mmol) in MeNCb (10 mL) was added Et3N (2 mL, 14mmol), and the mixture was stirred at r.t. for 30 mins. The mixture was concentrated under reduced pressure, and the residue was dissolved in co-solvent of EtOH:H2O( 0 mL:5 mL). The mixture was treated with iron powrder ( 1.85 g, 33mmol) and NH4CI (1.8 g, 33mmol), and then heated to 80 °C for 2 h. After filtration, the solution was concentrated under reduced pressure. The residue was purified by chromatography to give 271-10 (2.5 g, 61.7%). +ES1-MS: m/z 491.9 [M+H]+.
[0565] A 100 mL round bottom flask was charged with a solution of 4- cyclopropoxy-3-mcthoxybenzoic acid (208 mg, 1 .0 mmol), D1PEA ( 193 mg, 1 .5 mmol) and HATU (380 mg. 1 .0 mmol) in anhydrous DMF ( 10 mL). The mixture was stirred at r.t. for 30 mins. Compound 271 -10 (490 mg, 1 .0 mmol) was added in one portion, and the mixture was stirred at r.t. for 2-3 h. The mixture was diluted with EA and water, and the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 1 : 1 ) to give 271 -1 1 as a pale yellow oil (610 mg. 88%).
[0566] A 50 mL round bottom flask was charged with a solution of 271-1 1 (610 mg, 0.88 mmol) in EA ( 10 mL). The solution was treated with HC1 in EA (10 mL, 4.0 M). The mixture was stirred at r.t. for 1-2 h. The mixture was concentrated at low pressure to give crude 314 (550 mg). [0567] Compound 314 (550 mg) was separated via SFC separation to give two enantiomers. The two enantiomers were treated with 2 M I IC1 in EA and then concentrated to give 271 (120 mg) and 272 (124 mg). 271 : +EST-MS:m/z 582.1 [M+H]+. 272: +ES1- MS:m/z 582.1 [M+H]+.
EXAMPLE 126
Preparation of Compound 273
Figure imgf000190_0001
[0568] Compound 273 was prepared essentially as described in the preparation of compound 272 by 273-1 and 273-2. Compound 273 was obtained as a white solid (41 mg, 52.2%). +ESl-MS:m/z 554.0 [M+H]+.
EXAMPLE 127
Preparation of Compounds 274-285
[0569] The following compounds in Table 1 were prepared essentially as described in the preparation of 272 by using the listed acid and amine.
Table 1
Figure imgf000190_0002
Figure imgf000191_0001
Figure imgf000192_0001
EXAMPLE 128
Preparation of Compound 286
Figure imgf000193_0001
[0570] Compound 286-2 was prepared according to the procedure provided in PCT Publication No. WO 2009/005638, published Jan. 8, 2009, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 286-2.
10571] To a solution of 286-2 (1.83 g, 7 mmol) in THF (15 mL) was added n- BuLi (7 mL, 2.5 M in THF) at -78 °C. After 5 mins, TMEDA (1 .624g, 14 mmol) was added at -78 °C. The solution was warmed slowly to -30 °C, and stirred for 30 mins at -30 "C. The solution was cooled to -78 °C and oxirane (0.7 mL, 14 mmol) was added. The solution was stirred at -78 °C for 2 h.. and stirred overnight at r.t. The reaction was quenched with H2O and extracted with EA (2 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous a?S04 and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 10: 1 ) to give 286-3 (0.7 g, 32.7 %).
[0572] To a solution of 286-3 (4.5 g, 14.7 mmol) in DCM (100 mL) was added TEA (4.45 g, 44.1 mmol). After cooled to 0 °C, MsCl (3.36 g, 29.4 mmol) was added slowly. The solution was stirred for 30 mins. The reaction was quenched with H20, and extracted with DCM (3 x 100 mL). The organic phase was washed with brine, dried over anhydrate sodium sulfate and concentrated at low pressure to give crude 286-4 (5.6 g, 99.2%). +ESI-MS:m/z 384.8 [M+I I] h.
[0573] To a solution of 286-4 (5.6 g, 14.5 mmol) in DMT (50 mL) was added K2CO3 (4.02 g, 29.2 mmol). The mixture was heated up to 50-60 °C. and stirred for 1 h. The solution was cooled to r. , poured into cold water and extracted with EA (2 x 100 mL). The combined organic phase w as w ashed w ith brine, dried over anhydrous Na2SC>4 and concentrated at low pressure. The residue was purified by chromatography (PE:EA 10: 1 ) to give 286-5 (3.1 g. 74.3%).
[0574] To a solution of 286-5 ( 1 .68 g. 5.83 mmol). 286-6 (860 mg. 5.83 mmol) and K2CO3 ( 1.61 g, 1 1.66 mmol) in MeOH (50 mL) was added Pd(dppf)Cl2 (426 mg. 0.583 mmol). The mixture was degassed and then refilled with N2 (3 times). The mixture was stirred under nitrogen at 70 °C for 15 h, and then cooled to r.t., and extracted with EA (3 x 50 mL). The organic phase was washed by brine, dried over anhydrous Na2SC* and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 5 : 1 ) to give 286-7 as a white solid ( 1.2 g, 70%).
[0575] To a solution of 286-7 (2.94 g, 10 mmol) in DCM (50 mL) were added NMO (2.4 g, 20 mmol) and Os04 (500 mg, 0.2 mmol) at r.t. The mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. aq. Na2S03, and stirred for 2 h. The m ixture was extracted with DCM (2 x 1 00 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 3 : 1 ) to give 286-8 (2.94 g. 89.6%). +ESl-MS:m/z 328.9 [M+H]+.
[0576] To a solution of 286-8 (3.28 g. 10 mmol) and TEA (4.45 g, 44.1 mmol ) in DCM (20 mL) was added MsCl (2.2 g, 20 mmol) slowly at 0°C. The solution was stirred for 30 mins, and then diluted with DCM (20 mL). The solution was washed with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated at lowr pressure to give crude 286-9 (4.06 g, 100.0%).
[0577] A solution of 286-9 (4.0 g, 10 mmol) in ammonia water and ethanol ( 10 mL: 10 mL) in a seal tube was stirred for 1 h at r.t. The solution was heated to 40 °C for 15 h. The mixture was concentrated to dryness under reduced pressure to give crude 286-10 (1.6 g, 50%), which was used without purification. +ESI-MS:m/z 327.9 [M+I I]+.
[0578] To a solution of 4-(2-fluoroethoxy)-3-methoxybenzoic acid (214 mg, 1 mmol), HATU (456 mg. 1 .2 mmol) and DTPEA (258 mg. 2 mmol) in anhydrous DMT (5 niL) was added 286-10 (327 mg, 1 mmol) at 25 "C. The solution was stirred for 2 h at 25 °C. The reaction was quenched by a sat. aq. NaHC03 solution (40 niT), and then extracted with EA (2 x 20 niL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 3 : 1 ) to give 286-11 (201 mg. 38.2%). +ESl-MS:m/z 524.0 [M+H]+.
[0579] To a solution of 286-11 (150 mg, 0.3 mmol), (3-chloro-4- fluorophenyl)boronic acid (105 mg, 0.6 mmol) and K2C03 (84 mg, 0.6 mmol) in dioxane (6 niL) was added Pd(dppf)Cl2 (22 mg, 0.03 mmol). The mixture was degassed and then refilled with 2 (3 times). The mixture was heated to 120 °C by microwave under N? for 2 h. The solution was cooled to r.t. and diluted with EA (20 mL). The solution was washed with brine, dried over anhydrous Na?S04 and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 1 : 1) to give 286-12 ( 123 mg, 65%).
[0580] To a solution of 286-12 ( 123 mg, 0.2 mmol) in DCM (2 mL) was added TFA (4 mL) at r.t. The mixture was stirred for 30 mins, concentrated to dryness and dissolved in EA (20 mL). The solution was washed with a sat. NaHCCh solution. The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by prep-HPLC to give 286 (80 mg. 77.6%) as a yellow solid. +ES1- MS:m/z 518.1 [M+H]+.
EXAMPLE 129
Preparation of Compound 287
Figure imgf000195_0001
[0581] Compound 287 was prepared essentially as described in the preparation of 286 by using 7-fluoro-3-(4,4,5.5-tetramethyl- l ,3,2-dioxaborolan-2-yl)- l -((2- (trimethylsilyl)cthoxy)mcthyl)- l H-indole and 287-1. Compound 287 was obtained as white solid. +ESl-MS:m/z 507.9 [M+H]+.
EXAMPLE 130
Preparation of Compounds 288 and 289
Figure imgf000196_0001
10582] To a solution of 135 (400 mg, 0.80 mmol) in THP (10 mL) was added MeMgBr (3 mL, 1.3 N in THF) under N2. The mixture was stirred at r.t. for 1 h under N2. The reaction was quenched with sat. aq. NH4C1 and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by prep-HPLC to give 288-1 ( 150 mg).
[0583] Compounds 288 (39 mg) and 289 (41 mg) were obtained by SFC separation of 288-1. 288: +ESI-MS:m/z 519.3 [M+H]+. 289: +ESI-MS: m/z 519.3 [M+H]+.
EXAMPLE 131
Preparation of Compound 290
Figure imgf000196_0002
[0584] To a solution of 286 (400 mg, 0.77 mmol) in DCM (20 mL) was added Μηθτ (336 mg, 3.86 mmol) at r.t. The mixture was stirred for 2 h. The precipitate was removed by filtration, and the filtrate was concentrated at low pressure. The residue was purified by prep-HPLC to give 290 ( 150 mg, 37.5%) as a yello solid. +ESl-MS:m/z 515.9 [M+H]+. EXAMPLE 132
Preparation of Compounds 291 and 292
Figure imgf000197_0001
[0585| Compounds 291 and 292 were prepared essentially as described in the preparation of 288 and 289 by using 291-1. Compound 291 (31 mg) and 292 (30 mg) were obtained as white solids. 291: +ESl-MS:m/z 524.1 [M+Hf. 292: +ESl-MS:m/z 524.1 [M+H]+.
EXAMPLE 133
Preparation of Compounds 293 and 294
Figure imgf000197_0002
[0586] Compound 286 (60 mg) was separated via SFC separation to obtain two enantiomers: 293 (24 mg) and 294 (22 mg). 293: +ESl-MS:m/z 517.9 [M+H]+. 294: +ES1- MS:m/z 517.9 [M+H]+.
EXAMPLE 134
Preparation of Compounds 295 and 296
Figure imgf000197_0003
[0587] Compound 290 (65 mg) was separated via SFC separation to obtain two enantiomers: 295 (21 mg) and 296 (18 mg). 295: +ESl-MS:m/z 515.9 [M+H]+. 296: +ES1- MS:m/z 515.9 [M+H]+. EXAMPLE 135
Preparation of Compound 297
Figure imgf000198_0001
10588] To a solution of 297-1 ( 1.4 g, 5.0 mmol) and 2-chloro-N-methoxy-N- methylacetamidein (700 mg, 5.0 mmol) in THF (20 mL) was added -PrMgCl (3 mL, 2.0 M in THF) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extrcted with EA (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuum. The residue was purified by column chromatography on silical gel to give 297-2 (1 .0 g, 87%). +ESI- MS:m/z 232.0 [M+H]+.
[0589] To a solution of 297-2 (460 mg, 2.0 mmol) in THF (4 mL) was added cyclopropylmagnesium bromide (4 mL, 0.5 M in THF) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuum. Compound 297-3 was used without furthur purification.
[0590] Compound 297 was prepared essentially as described in the preparation of 286 by using 297-3. Compound 297 was obtained as white solid (98 mg). +ESl-MS:m/z 548.3 [M+H]+. EXAMPLE 136
Preparation of Compound 298
Figure imgf000199_0001
[0591 ] Compound 298-2 was prepared according to the procedure provided in PCT Publication No. WO 2009/016460, published Feb. 5, 2009. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 298- 2. To a solution of 298-2 ( 1 .8 g, 8.3 mmol) in DCM ( 10 niL) was added DAST (2 niL) dropwise at 0°C. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with sat. NaHCOs solution at 0 °C and extracted with EA (3 x 30 mL). The combined organic layers were washed by brine, dried over anhydrous Na2S04 and concentrated in vacuum. The residue was purified by column chromatography on silica gel column (PE:EA 30: 1 ) to give 298-3 as a white solid (1.4 g. 77.8%).
[0592] To a solution of 298-3 (1.4 g, 6.4 mmol) in THF (10 mL) was added n- BuLi (3.3 mL, 2.5 N in hexane) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for 30 mins. 2-isopropoxy-4,4,5,5-tetramethyi- l ,3,2-dioxaborolane (1.6 g, 9.4 mmol) was added at -78 °C, and the mixture was allowed to warm to r.t., and stirred 10 mins. The reaction was quenched with sat. NH4C1 solution and extracted with EA. The combined organic solutions were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 50: 1 ) to give 298-4 as an oil (1 .0 g, 58.9%). [0593] Compound 298 was prepared essentially as described in the preparation of 286 by using 298-4. Compound 298 was obtained as a white solid (70 mg). +ESl-MS:m/z 555.1 [M+HJ+.
EXAMPLE 137
Preparation of Compound 299
Figure imgf000200_0001
[0594] Compound 299 was prepared essentially as described in the preparation of
288 and 289 by using 298 and cyclopropylmagnesium bromide. Compound 299 (30 mg) was obtained as a white solid. +ESI-MS:m/z 597.2 [M+H]+.
EXAMPLE 138
Preparation of Compounds 300 and 301
Figure imgf000200_0002
[0595] Compound 229 (28 mg, 0.047 mmol) was separated via SFC separation to give two enantiomers: 300 (3.8 mg) and 301 (4.5 mg) as white solids. 300: +ESl-MS:m/z 595.0 [M+H]+. 301: +ESl-MS:m/z 595.0 [M+H]+.
EXAMPLE 139
Preparation of Compound 335
Figure imgf000200_0003
[0596] To a solution of 335-1 (5.2 g, 20 mmol) in THF (30 mL) was added n- BuLi (16 mL, 20mmol, 2.5M) at -78 °C under N2. After stirred at -78°C for 0.5 h, a solution of I? (5.1 g 20 mmol) in THF (25 mL) was added slowly. The mixture was stirred at -78 °C for 1 h. The reaction was quenched with water and extracted with ΕΛ (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 10: 1 ) to give 335-2 (7.5 g. 95 %). +ES1-MS: m/z 388.9 [M+H]+.
[0597] To a solution of 335-2 (3.88 g, 10.0 mmol) in DMF (50 mL) was added sodium hydride (480 mg, 10 mmol, 60% in the mineral oil) at r.t. The mixture was stirred for 0.5 h and 3-chloro-2-methylprop-l -ene ( 1.0 g, 1 1 mmol) was added dropwise. The mixture was stirred for 2 h. The reaction was quenched with wrater and extracted with EA (2 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure to give crude 335-3 (4.4 g, 99%), which w7as used without further purification.
[0598] Under N2 atmosphere, a mixture of 335-3 (4.4 g, 10 mmol), LiCl (420 mg, 10 mmol), sodium formate ( 1.36 g, 20 mmol) and Pd(OAc)2 (1 1 1 mg, 0.1 mmol) in DMF (95 mL) was stirred at 100 °C for 2 h. After cooling to r.t, the mixture was diluted with EA (50 mL). The solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 10: 1 ) to give 335-4 (1 .5 g. 50%). +ESI-MS: m/z 316.9 [M+H]+.
[0599] Under N? atmosphere, a mixture of 335-4 (1 .5 g. 5 mmol). tributyl( l - ethoxyvinyl)stannane (3.6 g. 10 mmol) and Pd(dppf)Cl2 (180 mg, 0.25 mmol) in toluene ( 1 5 mL) was stirred at 140 "C for 0.5 h. After cooling to r.t., the mixture was concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 10: 1 ) to give 335-5 ( 1 .5 g. 88%). +ESI-MS:m/z 352.9 [M+H]+.
[0600] To a solution of 335-5 (1.5 g, 1.35 mmol) in THF/H20 (30mL/l mL) was added NBS (2.70 g, 15 mmol) in portions. The mixture was diluted with water and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low7 pressure. The residue was purified by column chromatography on silica gel (PE:EA 10: 1) to give 335-6 ( 1.5 g, 75 %). [0601] To a solution of 335-6 (400 mg, 1 .0 mmol) in DMF (5mL) was added CF3TMS (1 mL) and LiOAc (10 mg 0.02 eq.). After addition, the mixture was stirred at r.t. until 335-6 was consumed. The mixture was treated with ammonia water (5 mL), and then stirred at r.t. for 0.5 h. The mixture was diluted with EA (50 mL). The solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 1 : 1 ) to give 335-7 (205 mg, 50%). +ESI-MS:m/z 410.0 [M+H]+.
[0602] Compound 335 was prepared essentially as described in the preparation of 286 by using 4-cyclopropoxy-3-methoxybenzoic acid and 335-7. Compound 335 was obtained as a white solid (25 mg). +ESl-MS:m/z 594.1 [M+H]+.
EXAMPLE 140
Preparation of Compound 302
Figure imgf000202_0001
[0603] To a stirring mixture of 302-1 (460 mg, 1.6 mmol) in DMF (2 mL, deoxygenated prior to use) were added PdCl2(PPh3)2 (1 14 mg, 0.16 mmol) and tributyl(vinyl)stannane (500 mg, 1.6 mmol). The reaction was carried out under microwave irradiation at 80 ('C for 2 h. The mixture was cooled to r.t. and diluted with EtOAc. The mixture was washed with brine:water:NaHC03. The mixture was dried over MgSC>4, filtered and concentrated under reduced pressure. Crude 302-2 was purified via a silica gel column. LCMS: m/z 186.05 [M+H]+. [0604] To a stirring mixture of 302-2 (170 mg. 0.915 mmol) in DMF (3mL) was added Nai l (37 mg, 0.91 5 mmol). The mixture was stirred for 10 mins before allyl bromide (96 μΤ, 1 .09 mmol) was added. The mixture was stirred for 1 h at r.t., and then diluted with EtOAc and a 10% NaHC0 aq. solution. The mixture was worked- up with EtOAc. The crude was purified via a silica gel column to afford 302-3 as a yellow oil. LCMS: m/z 226.05 [M+H]+.
[0605] To a stirring mixture of 302-3 (100 mg, 0.44 mmol) in CH2C12 at r.t. (3.5 mL) was added benzylidene-bis(tricyclohexylphosphine) dichlororuthenium (12 mg, 0.014 mmol). The mixture was stirred for 3 h and then concentrated under reduced pressure. The crude was purified via a silica gel column to afford 302-4 as a tan solid. LCMS: m/z 198.0 [M+H]+.
[0606] To a stirring mixture of 302-4 (70 mg. 0.35 mmol) in DME (2 mL. deoxygenated prior to use) were added (3-chloro-4-fluorophenyl)boronic acid (74 mg, 0.43 mmol), PdCl?(PPh3)2, a solution of CS2CO3 (0.4 mL, 2.65 M). The mixture was carried out under microwave irradition at 1 10 °C for 1 h and then diluted with EtOAc and water. A normal aqueous workup was followed. The crude was purified via a silica gel column to afford 302-5 as a white solid. LCMS: m/z 292.0 [M+H]+.
[0607] To a stirring mixture of 302-5 (70 mg, 0.24 mmol) in CH2C12 (2 mL) at r.t. were added NaHC03 (1 14 mg, 1.7 mmol) and Dess-Martin periodinane (509 mg, 1.2 mmol). The mixture was stirred at r.t. until the alcohol was consumed. The reaction was quenched with 5% NaHS03 and sat. NaHCC»3 solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried Na2S04), filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 302-6. LCMS: m/z 290.0 [M+H]+.
[0608] To a stirring mixture of 302-6 (40 mg. 0.138 mmol) in THF (2 mL) were added K2C03 and nitromethane (25 mg, 0.42 mmol). The mixture was stirred overnight at r.t. The reaction was diluted with EtOAc and quenched with water and brine. The aqueous layer was extracted with EtOAc (2 x 25mL). The crude was purified via a silica gel chromatography to afford 302-7 as a white solid; LCMS: m/z 351.0 [M+H] . [0609] To a stirring mixture of 302-7 (55 mg, 0.1 58 mmol) in EtOAc (0.5 mL) was added SnCl2. 2I I20 ( 106 mg, 0.47 mmol). The mixture was heated at reflux for 1 h. The mixture was cooled and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 302-8 as a colorless oil. LCMS: m/z 321 .0 [M+H]+.
[0610] To a stirring mixture of 4-(2-fluoroethoxy)-3-methoxybenzoic acid (33.8 mg. 0.156 mmol) in DMF (0.5 mL) were added HATU (59.3 mg, 0.156 mmol) and D1PEA (40 mg, 0.26 mmol). The mixture was stirred at r.t. for 10 mins. Compound 302-8 (50 mg. 0.1 56 mmol) in DMF (0.5 mL) was added, and then the mixture was stirred for 10 mins. The reaction was quenched with a 10% aq. solution of NaHC03 ( 10 mT). The mixture was diluted with DCM and a normal aqueous work up with DCM was followed. The crude was purified via prep-HPLC to afford 302-9 as a white solid. LCMS: m/z 517.10 [M+H].
[0611] To a stirring mixture of 302-9 (30 mg, 0.058 mmol) in DCM (1 mL) at r.t. was added Dess-Martin periodinane (172 mg, 0.41 mmol). The mixture was stirred at r.t. for 1 h and the reaction quenched with 5% NaHS03 and a sat. NaHC03 solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. The crude product was purified via HPLC to afford 302 as a white solid. LCMS: m/z 515.05 [M+H].
EXAMPLE 141
Preparation of Compound 303
Figure imgf000204_0001
[0612] Compound 303 was synthesized by reacting 302 under hydrogenation reaction conditions using Pd/C in EtOAc/EtOH. LCMS: m/z 517.1 [M+H]. EXAMPLE 142
Preparation of Compound 304
Figure imgf000205_0001
[0613] To a stirring mixture of 3-methoxy-4-(2-((4- methoxybenzyl)oxy)ethoxy)benzoic acid (40 mg, 0.12 mmol) in DMT (0.5 mL) were added HATU (36 mg. 0.096 mmol) and D1PEA (25 mg. 0.192 mmol). The mixture was stirred at r.t. for 10 mins. Compound 304-1 (31 mg, 0.096 mmol) in DMF (0.5 mL) was added, the mixture was stirred for 10 mins. The reaction was quenched with 10% NaHC03 (3 mL). The mixture was diluted with DCM and a normal aqueous workup with DCM was followed. The crude was purified via prep- HPLC to afford 304-2 as a white solid. LCMS: m/z 635.1 [M+H].
[0614] To a stirring mixture of 304-2 (30 mg, 0.047 mmol) in DCM (1 mL) at r.t. was added Dess-Martin periodinane (200 mg, 0.47 mmol). The mixture was stirred at r.t. for 1 h, and the reaction was quenched with 5% NaHS03 and a sat. NaHC03 solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried (Na SC ). filtered and concentrated under reduced pressure. The crude was purified via HPLC to afford 304-3 as a white solid; LCMS: m/z 633.15 [M+H]+.
[0615] To a stirring mixture of 304-3 (20 mg. 0.031 mmol) in EtOH/EtOAc (1 : 1. 10 mL) was added Pd/C ( 10 mg). The mixture was reacted under H2 balloon. The mixture was filtered through a plug of celite, and the filtrate was concentrated under reduced pressure. Crude 304-4 was used without further purification; LCMS: m/z 635.15 [M+I I]+.
[0616] To a stirring mixture of 304-4 in DCM ( 1 mL) at 0 °C was added TFA (0.3 mL) dropwise. The mixture was stirred at r.t. for 10 mins and then diluted with EtOAc. The reaction was quenched sat. NaHCOs. The aqueous layer was extracted with EtOAc. dried over Na2S04, filtered and concentrated under reduced pressure. The product was purified via prep-HPLC to afford 304 as a w hite solid. LCMS: m/z 515.10 [M+H]+.
EXAMPLE 143
Preparation of Compound 305
Figure imgf000206_0001
[0617] To a stirring mixture of 305-1 (500 mg. 1 .75 mmol) in DMF (8.8 mL) at 0 °C was added NaH (144 mg. 3.6 mmol). The mixture was stirred at 0 °C for 5 mins. Allyl bromide (222 mg, 1.75 mmol) was added, and the mixture was stirred at 0 "C for 20 mins. The mixture was warmed to r.t. and stirred for 5 mins. The mixture was diluted with EtOAc and quenched with water. The aqueous layer was extracted with EtOAc, dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified via a silica gel chromatography to afford 305-2. LCMS: m/z 325.9 [M+H1+.
[06181 To a stining mixture of 305-2 (280 mg, 1.4 mmol) and A1BN (23 mg, 0.14 mmol) in toluene (3.5 mL) under Ar at reflux was added a solution of tributyltin hydride (407 mg, 1.4 mmol) in toluene ( 1 mL) dropwise over 5 mins. The mixture was stirred at reflux for 2 h. and then concentrated under reduced pressure. The crude was purified via a silica gel column to afford 305-3 as a colorless oil. LCMS: m/z 200.05 [M+I I]+.
[0619] To a stirring mixture of 305-3 (170 mg. 0.85 mmol) in DME (2.4 mL, deoxygenated prior to use) were added (3-chloro-4-fluorophenyl)boronic acid ( 163 mg, 0.94 mmol), PdCl2(PPh )2 (93 mg, 0.13 mmol) and a solution of Cs2C0 (0.6 mL, 4.25 M). The reaction was carried out under microwave irradition at 1 10 °C for 1 h. The mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. dried over
Na2S04, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 305-4 as a white solid. LCMS: m/z 294.0 [M+H].
[0620] Compound 305-7 was prepared in three steps similarly to the methods described for the synthesis of 302. Coupling of 305-7 with 3-methoxy-4-(2-((4- methoxybenzyl)oxy)ethoxy)benzoic acid followed by alcohol oxidation and deprotection afforded 305. LCMS: m/z 51 5.10 [M+H]+.
EXAMPLE 144
Preparation of Compound 306
Figure imgf000207_0001
[0621] To a stirring mixture of 306-1 (30 mg, 0.047 mmol) in THE (0.45 mL) at r.t. under Ar was added cyclopropyl magnesium bromide (1.9 mL, 0.95 mmol). The mixture was stirred for 30 mins and then diluted with EtOAc. The reaction was quenched with a sat. NH4CT solution. A normal aqueous workup with EtOAc was followed. The crude was purified via a silica gel column to afford 306-2. LCMS: m/z 675.20 [M+H]+.
[0622] To a stirring mixture of 306-2 (30 mg, 0.052 mmol) in DCM (1 mL) was added TEA (0.2 mL) at r.t. The mixture was stirred for 10 mins, and then quenched with a cold sat. NaI IC03 solution. The aqueous solution was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The crude was purified via prep-HPLC to afford 306 as a white solid. LCMS: m/z 555.10 [M+H]+. EXAMPLE 145
Preparation of Compounds 307-312
Tabic 2
Figure imgf000208_0001
EXAMPLE 146
Preparation of Compound 313
Figure imgf000209_0001
[0623] To a stirring mixture of 313-1 (45 mg, 0.092 mmol) in THF( 1 mL) at r.t. under Ar was added a solution of /-BuMgCl in THF (0.91 mL, 0.91 mmol). The mixture was cooled to r.t.. diluted with EtOAc and quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 20 mins and the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. The crude was purified via silica gel column and further purified via prep-HPLC to afford 313 as a white solid. LCMS: m/z 549.15 [M+H]+.
EXAMPLE 147
Preparation of Compound 314
Figure imgf000209_0002
[0624] Methylmagnesium bromide (27 mL, 3.2 M in THF. 87 mmol) was added to a solution of 314-1 (5.0 g. 29 mmol) in Et20 (80 mL) at 0 °C. After 1 h of stirring, titanium isopropoxide (8.2 mL, 29 mmol) was added, and the reaction was heated at 50 °C for 2 h. Copious quantities of celite were added to the mixture which was cooled to r.t. The mixture was basified with 2N NaOH and filtered through celite and washing with CH2C12. The layers were separated, and the organic layer was concentrated. The mixture was rc- dissolved in CH2C12 and extracted with IN HC1 (3x). The aqueous extracts were basified with solid K2C03 and back-extracted with EA. The combined organic layers were washed with brine, dried and concentrated to provide crude 314-2 (3.25 g).
[0625] Crude 314-2 (3.28 g, 16 mmol) was dissolved in CH2C12. Benzyl chloroformate (2.3 mL, 16 mmol) and DIPEA (3.0 mL, 18 mmol) were added, and the reaction was stirred at r.t. for 3 h. The mixture was washed with IN HC1. brine, dried (Na2S04) and concentrated. The crude wras purified via a silica gel chromatography to afford 314-3 as a white solid.
[0626] To a stirring mixture of 314-3 (2 g, 5.9 mmol) in DME (10 mL, deoxygenated prior to using) were added 4.4,6-trimethyl-2-(3,3,3-trifluoroprop-l -en-2-yl)- 1 ,3.2-dioxaborinane (1.32 g, 5.9 mmol) and a solution of Cs2C03 (6M, 3 mL), PdCL dppf) (461 mg, 0.59 mmol). The mixture was stirred at 1 10 °C under microwave reaction conditions for 1 h. The mixture was diluted with EtOAc and water. A normal aqueous workup with EtOAc was followed. The crude was purified via a silica gel chromatography (EtOAc:hex 0-20%) to afford 314-4 ( 1.3 g), which was used without further purification.
[0627] To a stirring mixture of 314-4 ( 1 .3 g, 3.2 mmol) in DME (5 mL, deoxygenated prior to using) were added 3-chloro-4-fluorophenylboronic acid (550 mg, 3.2 mmol), a solution of Cs2C0 (6M, 1 .5 mL). and PdCL(dppf) (230 mg, 0.32 mmol). The mixture was stirred at 1 10 "C under microwave reaction conditions for 1 h. The mixture was diluted with EtOAc and water. A normal aqueous workup with EtOAc was followed. The crude was purified via a silica gel chromatography (EtOAc:hex 0-20%) to afford 314-5. LCMS: m/z 493.05 [M+H]+.
[0628] To a stirring mixture of tert-butyl hydroxycarbamate (2 g, 15 mmol) in THF (10 mL) at 0 °C was added TsCl (2.8 g. 15 mmol) and TEA (2.2 mL. 15.8 mmol). The mixture was stirred at 0 "C for 20 mins, and then warmed to r.t. for 5 mins. The mixture was diluted with DCM and washed with water. A normal aqueous workup with DCM was followed. The crude was purified via a silica gel to afford tert-butyl tosyloxycarbamate as a white solid. [0629] To a stirring mixture of 314-5 (950 mg. 1.9 mmol) in t-BuOH:water (3: 1 , 3 mL total volume) at r.t. were added potassium osmate di hydrate (105 mg, 0.3 mmol) and tert-butyl tosyloxycarbamate (1 g, 3.8 mmol). The mixture was stirred at r.t. overnight, and then diluted with water and DCM. Λ normal aqueous work up with DCM was followed. The crude was purified via a silica gel chromatography to afford 314-6 ( 1 .3 g, 80% pure). LCMS: m/z 626.20 [M+H]+.
[0630] Compound 314-6 was dissolved in a solution of HCl (4N) in dioxane ( 10 mL) at r.t. The mixture was stirred at r.t. The mixture was concentrated under reduced pressure to afford crude 314-7, which was used without further purification. LCMS: m/z 526.05 [M+H]+.
[0631] To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid (350 mg, 1.69 mmol) in DMF (1.5 mL) were added HATU (642 mg. 1.69 mmol) and DIPEA (735 mL, 4.2 mmol). The mixture was stirred at r.t. for 10 mins. Compound 314-7 in DMF (2 mL) was added, and then stirred for 10 mins. The reaction was quenched with a 10% aqueous solution of NaHC(¾ (10 mL), and then diluted with DCM. A normal aqueous work up with DCM was followed. The crude was purified via prep-HPLC to afford 314-8 as a white solid. LCMS: m/z 716.2 [M+H]+.
[0632] To a stirring mixture of 314-8 (602 mg, 0.84 mmol) in AcCN (3 mL) at r.t. were added Nal (630 mg, 4.2 mmol) and TMSC1 (453 mg, 4.2 mmol). The mixture was warmed to 60 "C until the starting material disappeared. The mixture was cooled to r.t. and purified by silica gel chromatography (EtOAc:hex 0-50% and then MeOLLDCM 0-20%). The product was further purified via prep-HPLC and then converted to the HCl salt to afford 314. LCMS: m/z 582.2 [M+H]+.
EXAMPLE 148
Preparation of Compounds 315-317
Tabic 3
Figure imgf000212_0002
EXAMPLE 149
Preparation of Compound 318
Figure imgf000212_0001
[0633] To a stirring solution of 318-1 (40 mg, 0.028 mmol) in EtOAc:EtOH:HOAc (5 mL: 1 .0 mL:0.1 mL) was added Pd/C (20 mg). The mixture was placed under a H2 balloon. The mixture was stirred for several hours until the starting material was consumed. The mixture was filtered through a plug of celite, and the plug was washed with EtOAc (2 x 10 mL). The mixture was concentrated under reduced pressure and purified via prep-HPLC to afford 318 as a white solid. LCMS: m/z 548.15 [M+H]+. EXAMPLE 150
Preparation of Compounds 319-322
Tabic 4
Figure imgf000213_0001
EXAMPLE 151
Preparation of Compound 323
Figure imgf000214_0001
10634] To a solution of 323-1 (2.5 g, 14.2 mmol) in THT ( 10 mL) and MeOH ( 10 niL) was added NaBH4 (1.6 g, 42.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 mins. The reaction was quenched with 1.0 N HCl and extracted with EtOAc. The combined organic solutions were dried (MgS04) and evaporated under reduced pressure. The residue was purified on a silica gel column (PE:EA 5: 1 ) to give 323-2 as a colorless oil (2.0 g, 79.1 %).
[0635] A solution of 323-2 (2.0 g, 1 1 .2 mmol), methyl 4-hydroxy-3- methoxybenzoate (2.1 g, 1 1 .5 mmol) and PP1¾ (4.5 g, 17.3 mmol) was stirred in dry THT (40 mL) at 0 °C under a N2 atmosphere. D1AD (3.5 g. 1 7.5 mmol) added dropwise over a period of 5 mins. and the solution was allowed to stir at 50°C for 3 h. After disappearance of the starting material, the solvent was evaporated under reduced pressure. The residue was purified on by column chromatography on silica gel (PE:EA 10: 1 ) to give 323-3 as a white solid (2.8 g. 73.7%): Ή-NMR (CDC13, 400 MHz). δ = 7.62-7.60 (dd. J = 1 .6 Hz, J = 10.0 Hz, 1 H), 7.53 (s, 1 H). 7.34-7.25 (m, 5H), 6.66 (d, J= 8.4 Hz, 1 H). 4.96-4.93 (m, 1 H), 4.44 (s. 2H). 4.36-4.32 (m, 1H), 3.93 (s. 3H), 3.87 (s. 3H),2.59-2.54 (m, 4H).
[0636] To a mixture of 323-3 (2.8 g, 8.2 mmol) in MeOH (15 mL) was added Pd(OH)? on carbon ( 10%, 500 mg) under N2. The suspension was degassed under vacuum and purged with Hi (3x). The mixture was stirred under H2 (40 psi) at r.t. for 3 h. The suspension was filtered through a pad of Cclite, and the cake was washed with MeOH. The combined filtrates were concentrated to give crude 323-4 ( 1 .7 g, 84.5%) which was used without purification.
[0637] To a mixture of 323-4 ( 1 .7 g, 6.7 mmol) in DCM (10 mL) was added DAST (3 mL) at 0 °C. The mixture was stirred at 0 °C for 30 mins. The reaction was quenched by sat. aq. NaHC03 at 0 °C and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EA 1 5: 1 ) to give 323-5 as a white solid (800 mg, 47.1 %).
[0638] A solution of 323-5 (254 mg, 1.0 mmol) and aq. lithium hydroxide (2 N, 1 mL) in THT (5 mL) was stirred at r.t. for 1 h. The mixture was neutralized by using 2N HCT and extracted with EtOAc. The combined organic solutions were dried (MgS04), and evaporated under reduced pressure to give 323-6 as a white solid ( 100 mg, 41.6%).
[0639] Compound 323 was prepared similarly to the preparation of 314. LCMS: m/z 614.15 [M+H]+.
EXAMPLE 152
Preparation of Compound 324
Figure imgf000215_0001
[0640] To a stirring mixture of 324-1 (360 mg, 1 .73 mmol) and NaF (7.3 mg. 0.1 73 mmol) in toluene (2 mL) at reflux was added trimeth\isilyl-2,2-difluoro-2- (fluorosulphonyl)acetate dropwise over 1 h. The mixture was heated at reflux for 1 h and then cooled to r.t. The mixture was concentrated under reduced pressure and loaded into a silica gel column to afford 324-2. LCMS: m/z 259.05 [M+H]+. [0641] To a stirring mixture of 324-2 (320 mg, 1.24 mmol) in THFtwater ( 1.0 mL:0.2 mL) at r.t. was added aq. LiOI I (155 mg, 3.7 mmol). The mixture was stirred for 2 d. The mixture was diluted with EtOAc and acidified with 10% aqueous HC1 solution. A normal aqueous work up with EtOAc was followed. Crude 324-3 was used without further purification.
[0642] Compound 324 was prepared similarly to the preparation of 314. LCMS: m/z 61 8.15 [M+H]+.
EXAMPLE 153
Preparation of Compound 325
Figure imgf000216_0001
[0643] To a stirring mixture of 325-1 (0.5 g, 2.75 mmol) in DMF (7 mL) were added Cs2C03 (1.35 g. 4.12 mmol), and 2.2,2-trifluoroethyl 1 , 1 ,2.2,3.3,4.4,4- nonafluorobutane- 1 -sulfonate (837 mg, 2.2 mmol). The mixture was heated at 55 °C overnight, and then diluted with EtOAc, and washed with water. The aqueous layer was extracted with EtOAc, dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 325-2 as a white solid; LCMS: m/z 265.05 [M+H]+.
[0644] To a stirring mixture of 325-2 (300 mg. 1.13 mmol) in THF: water (1 mL:0.1 mL) was added aq. LiOH. The mixture was stirred at r.t. overnight. The mixture was diluted with EtOAc and acidified with a I N HC1 aqueous solution. The aqueous layer was extracted with EtOAc, dried over a2S04. filtered and concentrated under reduced pressure. Crude 325-3 was used without further purification.
[0645] Compound 325 was prepared similarly to the preparation of 314. LCMS: m/z 624.1 [M+H]+. EXAMPLE 154
Preparation of Compound 326
Figure imgf000217_0001
[0646] To a stirring mixture of acetic acid (5 mg. 0.083 mmol) in DMF (0.2 mL) were added HATU (3.1 mg, 0.083) and D1PEA (17 mg, 0.13 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 326-1 in DMF (0.8 mL) was added, and the mixture was stirred for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCOa ( 10 mL). The mixture was diluted with DCM, and a normal aqueous work up with DCM was followed. Crude product was purified via prep-HPLC to afford 326 as a white solid. LCMS: m/z 624.15 [M+H]+.
EXAMPLE 155
Preparation of Compounds 327-329
Table 5
Figure imgf000217_0002
Figure imgf000218_0001
Figure imgf000219_0001
EXAMPLE 156
Preparation of Compound 330
Figure imgf000220_0001
[0647] To a stirring mixture of 330-1 (20 mg, 0.034 mmol) in DCM (0.4 mL) were added TEA (7 mg, 0.069 mmol) and MsCl (1 drop). The mixture was stirred for 20 mins and slowly warmed to r.t. The mixture was diluted with DCM. and the reaction was quenched with a sat. NaHC03 solution. The aqueous layer was extracted w ith DCM. The organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. Crude product was purified via prep-HPLC to afford 330 as a white solid. LCMS: m/z 660.10 [M+H]+.
EXAMPLE 157
Preparation of Compound 332
Figure imgf000220_0002
[0648] To a stirring mixture of 332-1 (8 mg. 0.014 mmol) in DMF (0.2 mL) was added DMF.DMA (0.2 mL). The mixture was stirred at 90 °C until the starting material was consumed. The crude mixture was concentrated under reduced pressure and used without further purification.
[0649] To a stirring mixture of crude product from the previous step in DCM (0.5 mL) at 0 °C were added hydrazine monohydrate (0.1 mL) and HOAc (0.05 mL). The mixture was warmed to r.t. and then reflux for 30 mins. The mixture was cooled to r.t., and the reaction was quenched with a sat. NaHC03 solution. The aqueous layer was extracted with DCM, dried over Na2S04, filtered and concentrated under reduced product. Crude product was purified via prep-HPLC to afford 332 as a white solid. LCMS: m/z 595.1 [M+H]+. EXAMPLE 158
Preparation of Compound 342
Figure imgf000221_0001
[0650] To a stirring mixture of 342-1 (50 mg, 0.15 mmol) in t-BuOH:watcr (3: 1 , 1.3 mL) at 0 "C were added NMO (26 mg. 0.23 mmol) and potassium osmate dehydrate (5.5 mg. 0.016 mmol). The mixture was warmed to r.t. overnight, and then diluted with DCM and water. The aqueous layer was extracted with DCM, dried over Na?S04. filtered and concentrated under reduced pressure. The crude was purified on a silica gel column to afford 342-2 as a brownish oil (50 mg, 91 % yield). LCMS: m/z 366.0 [M+H]+.
[0651] To a stirring mixture of 342-2 (50 mg. 0.136 mmol) in DCM (1 mL) at 0 °C were added TsCl (52 mg. 0.273 mmol), TEA (60 μί, 0.41 mmol) and DMAP (2 crystals). The mixture was warmed to r.t. for 1 h and then diluted w ith DCM. The reactino was quenched with sat. NaHCCb solution. The aqueous layer was extracted with DCM, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 342-3 (65 mg, 92% yield). LCMS: m/z 520.0 [M+H]+.
[0652] To a stirring mixture of 342-3 ( 128 mg. 0.246 mmol) in acetone ( 1 mL) was added LiBr (64 mg, 0.74 mmol). The mixture was stirred at reflux for 2 h and loaded into a silica gel column to afford 342-4 as a colorless oil (75 mg, 71% yield). LCMS: m/z 427.95 [M+H]+.
[0653] To a stirring mixture of 342-4 in DCM (1 mL) at 0 °C was added DAST (58 mL, 0.44 mmol). The mixture was stirred at 0 °C for 30 mins and then warmed to r.t. for 5 mins. The reaction was quenched with a cold aq. NaHC(¾ solution. The aqueous layer was extracted w ith DCM, dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 342-5 (56 mg, 74% yield). LCMS: m/z 429.95 [M+H]+.
[0654] To a stirring mixture of 342-5 (50 mg. 0.1 16 mmol) in DMF (2 mL) were added tetrabutyl ammonium azide (330 mg, 1 .2 mmol) and tetrabutylammonium iodide (5 mg). The mixture was stirred at 95 °C for 4 h. The mixture was loaded onto a silica gel column, eluting with hexane:EtOAc to afford 342-6 as a colorless oil. LCMS: m/z 393.0 [M+H]+.
[0655] To a stirring mixture of 342-6 (25 mg. 0.064 mmol) in THF:water (10: 1. 1.1 mL) was added triphenylphosphine (polymer-bound, 167 mg, 0.64 mmol). The mixture was stirred at 70 °C for 30 mins. cooled to r.t. and filtered through a plug of celite. The plug was washed several times with EtOAc. The mixture was concentrated under reduced pressure and 342-7 used without further purification. LCMS: m/z 367.0 [M+H]+.
[0656] To a stirring mixture of (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid (18 mg, 0.079 mmol) in DMF (0.5 mL) were added HATU (36 mg, 0.095 mmol) and DIPEA (35 μΐ^, 0.191 mmol). The mixture was stirred at r.t. for 10 mins. A solution of 342-7 in DMF (0.5 mL) was added, and the mixture was stirred at for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCOs ( 10 mL). The mixture was diluted with DCM and a normal aqueous work up with DCM was followed. The crude was purified via prep- HPLC to afford 342 as a white solid. LCMS: m/z 575.1 5 LM+HJ+.
EXAMPLE 159
Preparation of Compound 343
Figure imgf000222_0001
[0657] Compound 343 was prepared according to the method described for 342.
LCMS: m/z 574.10 [M+H] . EXAMPLE 160
Preparation of Compound 344
Figure imgf000223_0001
[0658] To a stirring mixture of 3-methoxy-4-((4-methoxybenzyl)oxy)benzoic acid (35 mg, 0.095 mmol) in DMF (0.5 mL) were added HATU (45 mg, 0.1 14 mmol) and D1PEA (35 pL, 0.19 mmol). The mixture was stirred at r.t. for 10 mins. A solution of 344-1 in DMF (0.5 mL) was added, and the mixture was stirred for 10 mins. The reaction was quenched with a 10% aq. solution of NaHC03 (5 mL). The mixture was diluted with DCM and a normal aqueous work up with DCM was followed. The crude was purified via a silica gel column to afford 344-2 as a colorless oil. LCMS: m/z 637.15 [M+H]+.
[0659] To a stirring mixture of 344-2 in DCM (1 mL) was added TFA (0.4 mL). The mixture was stirred at r.t. until 344-2 was consumed. The reaction was quenched with a cold sat. NaHCOi solution. The aqueous layer was extracted with DCM. dried over Na2S04. filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to give 344-3 as a colorless oil. LCMS: m/z 517.1 [M+H]+.
[0660] To a stirring mixture of 344-3 (30 mg, 0.058 mmol) in DCM was added CS2CO3 (47 mg. 0.145 mmol) and 3-bromopyrrolidin-2-one ( 1 1.4 mg. 0.07 mmol). The mixture was heated under microwave irradiation at 70 °C for 1 h. The mixture was filtered through a plug of celite and washed several times with DCM. The mixture was concentrated under reduced pressure and further purified via HPLC to afford 344 as a white solid. LCMS: m/z 600.15 M+H]+. EXAMPLE 161
Preparation of Compound 350
Figure imgf000224_0001
10661] To a stirring mixture of 350-1 (57 mg, 0.21 mmol) in THF ( 1 niL) at 0 °C was added NaH ( 17 mg, 0.43 mmol). The mixture was stirred at 0 °C for 5 mins, and then methyl iodide (61 mg, 0.43 mmol) was added. The mixture was warmed to r.t. and then diluted with EtOAc. The reaction was quenched with a sat. NH4CI solution. The aqueous layer was extracted with EtOAc. dried over Na?S04, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to give 350-2. LCMS: m/z 280.05 [M+H] ( .
[0662] To a stirring mixture of 350-2 (50 mg, 0.1 7 mmol) in THF :MeOH: water ( 1 :0.4:0.1 ) at r.t. was added aq. LiOH (36 mg, 0.86 mmol). The mixture was stirred overnight at r.t. The mixture was diluted with EtOAc and acidified with a IN HCl solution. The aqueous layer was extracted with EtOAc, dried over Na2S04, filtered and concentrated under reduced pressure. Crude 350-3 was used without further purification. LCMS: m/z 266.05 [M+H]+.
[0663] Compound 350 was prepared similarly according to the methods for 349. LCMS: m/z 612.1 [M+H]+.
EXAMPLE 162
Preparation of Compound 351
Figure imgf000224_0002
[0664] To a stirring mixture of 351-1 (15 mg, 0.0295 mmol) in DCM (1 mL) at 0 °C were added acetic anhydride ( 10 mg, 0.09 mmol), TEA (20 μΐ) and DMAP ( 1 crystal). The mixture was stirred at r.t. until the alcohol was consumed. The reaction was quenched with a sat. NaHCO (5 mL). The aqueous layer was extracted with EtOAc, dried over NaiSC , filtered and concentrated under reduced pressure. The crude was purified via HPLC to afford 352 as a white solid. LCMS: m/z 549.10 [M+H]+.
EXAMPLE 163
Preparation of Compound 352
Figure imgf000225_0001
[0665] To a stirring mixture of 352-1 (25 mg, 0.047 mmol) in DMF (0.1 mL) was added DMF. DMA (0.1 mL). The mixture was stirred at 60 °C until the starting material was consumed. The mixture was cooled to r.t. and concentrated under reduced pressure. The crude used was without further purification. To the stirring crude in DCM at 0 °C were added HOAc (3 drops) and methyl hydrazine (3 drops). The mixture was warmed to r.t. for
20 mins and heated to reflux. The mixture was cooled to r.t., diluted with DCM and quenched with a cold sat. Nal lCOs solution. The aqueous layer was extracted with DCM (3 x 10 mL). dried over Na7SC>4, filtered and concentrated under reduced pressure. The crude was purified via prep-HPLC to afford 352 as a white solid. LCMS: m/z 582.15 [M+H]+.
EXAMPLE 164
Preparation of Compound 353
Figure imgf000225_0002
[0666] To a solution of 353-1 (53 mg, 0.1 1 mmol) in TI IF (4 mL) was added MeMgCl ( 1 mL). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with a sat. NH4CI solution. The organic layers was washed with brine, dried over Na^SC^ and concentrated. The crude was purified by prep-HPLC to give 353 (20 mg, 40%) as a white solid. LCMS: m/z 469.3 [M+I I]+.
EXAMPLE 165
Preparation of Compound 354
Figure imgf000226_0001
[0667] A solution of i-PrMgCl (2.75 mL, 3.84 mmol) in THF was added dropwise to a stirring mixture of 354-1 ( 1 g. 3.66 mmol) at -45 "C over 5 mins. The mixture was stirred for 1 h, and then cyclobutanone (256 mg, 3.66 mmol) in THF ( 1 mL) was added. The mixture was warmed to r.t. and stirred overnight. The mixture was diluted with EtOAc, and the reaction quenched with a sat. NH4C1 solution. The aqueous layer was extracted with EtOAc. dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 354-2 as a colorless oil. LCMS: m/z 21 8 [M+H]+.
[0668] To a stirring mixture of 354-2 (0.4 g. 1.83) in CH3CN (4 mL) at 0 °C was added dropwise LLSO4 (cone.) (490 μί, 9.2 mmol) over 5 mins. The mixture was warmed to r.t. for 1 h and then warmed to 80 °C for 30 mins. The mixture was cooled to r.t., and then diluted with EtOAc. The reaction was quenched with a sat. NaHCO solution. The aqueous layer was extracted with EtOAc. dried over Na?S04, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 354-3 as a white solid. LCMS: m/z 258.95 [M+H]+.
[0669] Steps 3-6 were conducted in a similar manner as 314 to provide 354. LCMS: m/z 636.15 [M+H]+. EXAMPLE 166
Preparation of Compound 355
Figure imgf000227_0001
[0670] To a stirring mixture of 354 (16 mg, 0.025 mmol) in 4N HC1 in dioxane (2 niL) was added a 6N HC1 aqueous solution. The mixture was heated under microwave irradiation at 120 °C for 1 h. The mixture was cooled to r. , diluted with DCM and neutralized with a cold sat. NaHCO^ solution. The aqueous layer was extracted with DCM, dried over Na2SC>4 and concentrated under reduced pressure. The crude was purified via prep-I IPLC to afford 355 as a white solid. LCMS: m/z 594.10 [M+H] h.
EXAMPLE 167
Preparation of Compound 356
Figure imgf000227_0002
[0671 ] To a stirring mixture of 356-1 (0.3 g, 1 mmol) in DMF at r.t. were added CS2CO3 (488 mg, 1 .5 mmol), Nal (1 5 mg) and l -bromo-2-fluorocthanc (127 mg, 1 mmol). The mixture was heated to 45 °C overnight. The mixture was diluted with EtOAc and quenched with water. The aqueous layer was extracted with EtOAc. dried over Na2S04 and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 356-2. LCMS: m/z 345.1 [M+H]+.
[0672] Compound 356 was prepared in 4 steps using the similar methods as 314. LCMS: m/z 628.15 [M+H]+. EXAMPLE 168
Preparation of Compounds 357-361 and 363
Tabic 6
Figure imgf000228_0001
EXAMPLE 169
Preparation of Compound 362
Figure imgf000229_0001
[0673] To a stirring mixture of 336 (20 mg, 0.035 mmol) in DCM (1 mL) at r.t. was added Dess-Martin periodinane ( 150 mg, 0.175 mmol). The mixture was stirred at r.t. for 1 h and then quenched with 5% NaHSO and a sat. NaHCO^ solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. The crude was purified via HPLC to afford 362 as a white solid. LCMS: m/z 571 .1 [M+H]+ .
EXAMPLE 170
Preparation of Compound 364
Figure imgf000229_0002
[0674] Methylmagnesium bromide ( 1.4 M in THT, 0.50 mL, 0.68 mmol) was added to a solution of bromoketone (0.163g, 0.45 mmol) in THF (2 mL) at 0 °C. After 30 mins, the reaction was quenched with NH4CI and extracted with EA, dried over anhydrous NaoS04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 364-2 (0.1 1 5 g, 68%). LCMS: m/z 375.95 [M+HJ 1 .
[0675] To a solution of 364-2 (0.1 15 g, 0.31 mmol) in CLLCL (3 mL) at 0 °C was added DAST (81 uL. 0.61 mmol). The solution was stirred for 1 h. The mixture was diluted with sat. NaHCOs and extracted with EA. The combined organic phase was dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 364-3 (0.071 g, 61 %). LCMS: m/z 377.95 [M+I I]+.
[0676] To a solution of 364-3 (0.071 g, 0.19 mmol) in DMT (1 mL) was added tetrabutylammonium azide (0.7 g, 0.94 mmol). The solution was stirred for 3 h at 90 °C and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous NaiSC^ and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 364-4 (0.054 g. 84%). LCMS: m/z 339.05 [M+H]+.
[0677] To a solution of 364-4 (0.054 g. 0.16 mmol) in THT ( 1 mL) and water ( 1 drop) was added polymer supported triphenylphosphine (0.5 g, 1 .5 mmol). The solution was stirred for 2 h at 60 "C. The mixture was diluted with EA and filtered to remove resin. The organic phase was washed with brine, dried over anhydrous Na2SC»4 and concentrated to provide crude 364-5 (0.032g. 63%), which w7as used without further purification. LCMS: m/z 313.00 [M+H]+.
[0678] Diisopropylethylamine (52 uL, 0.3 1 mmol) was added to a solution of 4- (2-fluoroethoxy)-3-methoxybenzoic acid (33 mg, 0.15 mmol), 364-5 (32 mg, 0.10 mmol) HBTU (62 mg, 0.16 mmol) in DMT (1 mL). The solution was stirred at r.t. for 3 h. The mixture was diluted with EtOAc, and washed with IN HC1, sat. Na2C03 and brine, dried over MgSC>4 and concentrated under reduced pressure. The crude was purified by reverse phase I IPLC to give 364 ( 10.4 mg. 20%). LCMS: m/z 509.05 [M+I I]+.
EXAMPLE 171
Preparation of Compound 365
Figure imgf000230_0001
[0679] Diisopropylethylamine (0.13mL, 0.75 mmol) was added to a solution of 3- methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid (33 mg. 0.15 mmol). 365-1 (78 mg, 0.25 mmol) HATIJ (0.15 g, 0.40 mmol) in DMF (1 mL). The solution was stirred at r.t. for 3 h. The mixture was diluted with EtOAc, and washed with I N HCl, sat. Na2C03 and brine, dried over MgS04 and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (EA:hexane) to give 365-2. LCMS: m/z 627.20 [M+H]+.
[0680] Compound 365-2 was deprotected using TFA (0.25 mL) in CH2C12 (1 .0 mL) at r.t. for 8 mins. The reaction was quenched with cold NaHC03 and extracted with CH2C12. The crude was purified by reverse phase HPLC to give 365 (10.4 mg, 8%). LCMS: m/z 507.01 [M+H]+.
EXAMPLE 172
Preparation of Compound 368
Figure imgf000231_0001
[0681] Compound 368-1 (5.0 g, 39 mmol) and solid NaHC03 (5.0 g, 60 mmol) were suspended in water (40 mL) and heated to 90 °C. Formaldehyde (10 mL) was added portionwise over 8 h and the reaction was heated at 90 °C overnight. The mixture was cooled to 0 °C and acidified to pH 1 with 6N HCL The solution was stirred at 0 °C for 1 h. The reaction was filtered, and the filtrate extracted with EA to provide 368-2 (4.9 g, 79%). Ή NM (400 MHz, CDCT3): δ 7.21 (d, J = 4.6, 1H), 7.20 (d, J = 4.6, 1H), 4.4 (s, 2H).
[0682] lodomethane (4.5 mL, 72 mmol) was added to a solution of 368-2 (7.7 g, 48 mmol) and potassium carbonate (13 g, 144 mmol) in DMF (60 mL). The mixture was stirred at 50 °C for 1 h. The mixture was diluted with EA, washed with brine, dried over anhydrous Na?S04 and concentrated. The residue was purified by chromatography on silica gel (EArhexane) to give 368-3 (2.57 g, 31%). Ή NMR (400 MHz, CDC1 ): δ 7.20 (s, 2H), 4.6 (d, J = 6.0, 2H).
[0683] Methanesulfonyl chloride (1 .4 mL, 0.1 8 mmol) was added to a solution of 368-3 (2.57 g, 15 mmol) and diisopropylethyl amine (3.9 mL, 22 mmol) in CI LCL (30 mL) at 0 °C. After 30 mins, the mixture was diluted with CLLCb, washed with IN HCl and brine, dried over anhydrous Na2S04 and concentrated. The residue was dissolved in DMF ( 10 mL) and treated with sodium cyanide (2.2 g. 44 mmol) at 80 °C for 3 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 368-4 (1 .13 g, 41 %). LCMS: m/z 1 83.03 [M+H]+.
[0684] Pd(dppf)Cl2 (0.45 g, 0.61 mmol) was added to a solution of 368-4 (0.56g. 3.1mmol), 3-chloro-4-fluorophenyl boronic acid (0.80g, 4.6 mmol) in CHjCN (10 mL) and 1M K2C03 (5 mL). Hie reaction vessel was heated under microwave irradiation for 3 h at 120 °C. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 368-5 (0.70 g, 81%). LCMS: m/z 277.05 [M+H]+.
[0685] Sodium hydride (76 mg, 1.9 mmol) was added to a solution of 368-5 (0.21 g, 0.76 mmol) in DMF (1 mL). After 5 mins, iodomethane (0.14 mL, 2.3 mmol) was added, and the mixture was stirred for 30 mins. The reaction was quenched with NI I4CI. diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 368-6 (0.19 g, 81 %). LCMS: m/z 305.00 [M+H]÷.
[0686] Lithium aluminum hydride ( 1 .8 mL, 1 M in THF. 1 .8 mmol) was added to a solution of 368-6 (0.19 g. 0.61 mmol) in THF (5 mL), and the mixture was stirred at r.t. for 2 h. The reaction was quenched by the addition of solid sodium sulfate decahydrate and stirred for 10 mins. The solids were filtered, and the filtrate was concentrated to yield 368-7 (0.16 g, 85%). LCMS: m/z 309.05 [M+H]+. [0687] Compounds 368-8 and 368 were prepared in the same manner as 365. Compound 368-8: LCMS: m/z 624.3 [M+H]+. Compound 368: LCMS: m/z 503.1 5 [M+HJ+.
EXAMPLE 173
Preparation of Compound 369
Figure imgf000233_0001
[0688] Methyl vanillate (0.25g, 1 .4 mmol) and vinyl acetate (0.25 mL, 2.7 mmol) were added to [IrCl(cod)]? (9 mg. 0.014) and sodium carbonate (52 mg. 0.49 mmol) in toluene ( 1 mL). The mixture was flushed with Ar and stirred at 1 10 °C for 1 .5 h and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 369-1 (0.159 g, 55%). Ή NMR (400 MHz, CDC13): δ 7.61 (dd. J = 1 .6. 8.0, 1 H), 7.0 (d. J = 8.4, 1 H), 6.63 (dd. J = 6.0, 14. 1 H), 4.87 (dd, J = 2.4. 14, 1 H). 4.55 (dd, J = 2.0, 6.0. 1 H), 2.92 (s. 2H), 3.91 (s, 3H).
[0689] Diethylzinc (9 mL, 9.0 mmol) was added dropwise to a solution of 369-1 (0.234 g, 1.1 mmol) and diiodoethane (0.72 mL, 9.0 mmol) in dichloroethane (3 mL) at 0 °C. The mixture was stirred at r.t. overnight, and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 369-2 (0.121 g. 55%). Ή NMR (400 MHz, CDCK): δ 7.61 (dd. J = 1.6. 8.0, 1H). 7.0 (d. J = 8.4, 1H), 6.63 (dd. J = 6.0, 14, 1H), 4.87 (dd, J = 2.4, 14, 1H), 4.55 (dd, J = 2.0, 6.0, 1H), 3.92 (s. 3H).
[0690] 2N Sodium hydroxide ( 1 mL) was added to a solution of 369-2 (58 mg) in methanol (3 mL), and the mixture was stirred at r.t. overnight. Lhe mixture was acidified with I N HC1 and extracted with EA to give 369-3 (50 mg, 86%). Ή NMR (400 MHz, CDCI3): δ 7.78 (d, J = 1.95, 1H), 7.58 (s, 1H), 7.30 (d, J = 1.95, 1H), 3.91 (s, 3H), 3.80-3.83 (m, 1 H), 0.85-0.89 (m, 4H).
[0691 ] Compound 369 was prepared in a similar manner as 364. LCMS: m/z 501 .1 | Μ+Η]+.
EXAMPLE 174
Preparation of Compound 371
Figure imgf000234_0001
[0692] Isobutylene (10 mL, 105 mmol) was added to a solution of methyl vanillate (1 g, 5.5 mmol) and H2SO4 (3 drops) in CH2C12 ( 15 mL) in a sealed vessel at -40 °C. The mixture was warmed to r.t. and stirred over 2-3 d. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EArhexane) to give 371-2 (0.161 g. 12%). Ή NMR (400 MHz. CDC13): δ 7.71 (d, J = 6.26, 1 H), 7.63 (d, J = 1.96, 1 H), 7.09 (d, .1 = 8.26, 1 H). 3.88 (s. 3H), 3.87 (s. 3H). 1 .41 (s, 9H).
[0693] Compound 371 prepared in a similar manner as 364. LCMS: m/z 517.2 [M+H]+.
EXAMPLE 175
Preparation of Compound 372
Figure imgf000234_0002
[0694] Potassium fluoride (0.10 g, 1 .7 mmol) and methyl vanillate (0.31 g, 1 .7 mmol) were mixed in methanol (5 mL) for 15 mins. The mixture was concentrated, co- evaporating with diethyl ether (2x). The residue was dissolved in DMSO (2.0 mL) and added to difluoroiodoethane (0.36 g, 1 .9 mmol) in a vial. The vial was flushed with Ar, sealed, and heated at 120 °C overnight. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 372-1 (0.060 g. 14%). Ή NMR (400 MHz, CDC13): δ 766 (dd, J = 1.95, 8.41 , 1 H), 7.59 (d. J = 1.95, 1 H), 6.92 (d, .1 = 8.41 , l H), 6.00-6.30 (m, 1 H), 4.24-4.3 1 (m, 2H), 3.91 (s, 3H). 3.91 (s, 3H).
[0695] Compound 372 was prepared in a similar manner as 364. LCMS: m/z 525.10 [M+H]+.
EXAMPLE 176
Preparation of Compound 374
Figure imgf000235_0001
[0696] Sodium iodide ( 1 mg) was added to a solution of methyl vanillate (0.26 g. 1.4 mmol), bromocyclobutane (0.40 mL, 4.3 mmol), potassium carbonate (0.98 g. 4.3 mmol) in NMP (1 .5 mL). The mixture was heated under microwave irradiation at 180 °C for 1 .5 h and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 374-1 (0.18 g, 54%). Ή NMR (400 MHz, CDC13): δ 7.3 (d. J = 8.41 , 1H), 7.53 (s, 1H), 6.74 (d, J = 8.41, 1H), 4.4-4.7 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H).
[0697] Compound 372-2 was hydrolyzed in a similar manner as 369, and 372 was prepared in a similar manner as 364. LCMS: m/z 568.9 [M+H]+.
EXAMPLE 177
Preparation of Compound 375
Figure imgf000235_0002
[0698] Tetrabutylammonium azide (0.33 g, 0.57 mmol) was added to 375-1 (60 mg, 0.16 mmol) in DMF (1 mL), and the mixture was heated at 80 °C for 5h. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 375-2 (0.052 g, 96%). LCMS: m/z 337.05 [M+I I]+.
[0699] NaH ( 12 mg, 0.31 mmol) was added to 375-2 (52 mg, 0.15 mmol) in DMF (1 mL). The mixture was stirred at r.t. for 15 mins. lodomethane (30 uL. 0.46 mmol) was added, and the mixture reaction was stirred for 2 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EArhexane) to give 375-3 (0.052 g, 98%). LCMS: m/z 351 .05 [M+Hf.
[0700] Compound 375 was prepared in a similar manner as 364. LCMS: m/z 539.15 [M+H]+.
EXAMPLE 178
Preparation of Compound 377
Figure imgf000236_0001
[0701 ] Pd(dppf)Cl2 (20 mg. 0.02 mmol) was added to a solution of 2,6-dichloro- 3-fluoropyridine (0.20 g, 0.78 mmol) and 1 -(trifluoromethyl)vinylboronic acid hexylene glycol ester (0.18 g, 0.86 mmol) in CH3CN (0.5 mL) and 1M K2C03 (0.25 mL). The mixture was heated under microwave irradiation for 1 h at 1 10 °C. The reaction was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 377-1 (0.10 g, 47%). LCMS: m/z 271.90 [M+H]+.
[0702] Pd(dppf)CT2 (75 mg. 0.091 mmol) was added to 377-1 (0.493 g, 1.8 mmol) and 3-chloro-4-fluorophenyl boronic acid (0.38 g, 2.7 mmol) in CH3CN (2 mL) and 1M 2CO3 (0.5 mL). The mixture was heated under microwave irradiation at 1 10 °C for 30 mins. The mixture was heated under microwave irradiation for 1 h at 1 10 °C. The mixture was diluted with EA. and the organic phase was washed with water and brine, dried over anhydrous Na2SC»4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 377-2 (0.286 g, 33%). LCMS: m/z 319.95 [M+I I]+.
[0703] Potassium osmate (50 mg, 0.13 mmol) was added to a suspension of 377-2 (0.286g, 0.89 mmol) and tert-butyl (tosyloxy)carbamate (0.36 g. 1 .3 mmol) in t-butanol (2 mL) and water (0.6 mL), and the mixture was stirred overnight at r.t. The crude was poured directly onto a silica gel column and chromatographed (EArhexane) to give 377-3. (0.162 g. 40%). LCMS: m/z 398.83 [M+H]+.
[0704] 4N HC1 in dioxane (2 mL) was added to 377-3 (0.16 g), and the mixture was stirred at r.t. for 1 h. The mixture was concentrated to give 377-4, which was used without further purification. Compound 377 was prepared in a similar manner as 364. LCMS: m/z 506.20 [M+H]+.
EXAMPLE 179
Preparation of Compound 378
Figure imgf000237_0001
[0705] NaH (0.13 g. 3.1 mmol) was added to a solution of methyl vanillate (0.44 g, 2.4 mmol) and 2-iodopropane ( 1 .2 mL. 12 mmol) in DMF (3.0 mL). and the mixture was heated at 65 °C for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 378-1 (0.50 g, 93%). Ή NMR (400 MHz, CDC ): δ 7.65 (dd, J = 1.95, 8.6, 1H), 7.55 (d, J = 1.96, 1H), 6.90 (d, J = 8.6, lH), 4.61 -4.66 (m, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H).
[0706] Compound 378-1 was hydrolyzed in a similar manner as 369 to give 378- 2. Ή NMR (400 MHz, CDC13): δ 7.74 (dd, J = 1.95, 8.6, 1H), 7.60 (d, J = 1.96, 1H), 6.92 (d, J = 8.6. lH), 4.65-4.68 (m, 1H), 3.92 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H). Compound 378 was prepared in a similar manner as 364. LCMS: m/z 557.10 [M+H]+. EXAMPLE 180
Preparation of Compound 379
Figure imgf000238_0001
[0707] NaH (0.13 g. 3.1 mraol) was added to a solution of methyl vanillate (0.44 g, 2.4 mmol) and chloromethylmethyl sulfide (0.24 mL, 2.8 mmol) in DMF (3.0 niL), and the mixture was stirred for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 379-1 (0.57 g, 92%).
[0708] MCPBA (0.9 g, 5.2 mmol) was added to 379-1 (0.576 g, 2.4 mmol) in CLLCl? (3 mL), and the mixture was stirred at r.t. for 1 h. The mixture was washed with Na?C03, dried over anhydrous Na^SC^ and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 379-2 (0.40 g, 70%).
[0709] Compound 379-2 was hydrolyzed in a similar manner as 369 to give 379- 3. Compound 379 was prepared in a similar manner as 364. LCMS: m/z 553.10 [M+I I] h.
EXAMPLE 181
Preparation of Compound 380
Figure imgf000238_0002
[0710] 2-Bromoacetamide (0.46 g, 3.4 mmol) was added to methyl 3-fluoro-4- hydroxybenzoate (0.29 g, 1.7 mmol) and potassium carbonate (0.70 g, 5.0 mmol) in DMF (1 mL), and the mixture was heated to 65 °C for lh. The mixture was diluted with EA. and the organic phase was washed with water and brine, dried over anhydrous Na2S0 and concentrated. Compound 380-1 was crystallized from EA and collected by filtration (0.27 g, 71%). Ή NMR (400 MHz, dmso-i/6): δ 7.67-7.42 (m, 2H), 7.50 (br. s, 1H), 7.38 (br. s, 1H), 7.1 1 (t, J = 8.62, l H), 4.62 (s, 2H), 3.79 (s, 3H).
[0711 ] Compound 380-1 was hydrolyzed in a similar manner as 369 to give 380- 2. Ή NMR (400 MHz, dmso-J6): δ 7.63-7.69 (m, 2H). 7.49 (br. s, 1 H), 7.38 (br. s, 1 H), 7.08-7.1 1 (m, l H). 4.61 (s, 2H). Compound 380 was prepared in a similar manner as 364. LCMS: m/z 560.05 [M+H] ( .
EXAMPLE 182
Preparation of Compound 381
Figure imgf000239_0001
[0712] 2-Bromoacetamide (0.46 g, 3.4 mmol) was added to methyl 3-bromo-4- hydroxybenzoate (0.46 g, 1.7 mmol) and potassium carbonate (0.70 g, 5.0 mmol) in DMF (1 niL), and the mixture was heated to 65 °C for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 381 -1 (0.091 g. 24%). Ή NMR (400 MHz, dmso-d6): δ 7.95 (d, J = 2.34, 1H), 7.90 (dd, J = 2.34, 8.61 , 1H), 7.45 (br. s, lH), 7.34 (br. s, lH). 7.06 (d, J = 8.61 , 1H), 4.65 (s, 2H), 3.78 (s, 3 H).
[0713] 381 -1 was hydrolyzed in a similar manner as 369-2 to give 381-2. Ή NMR (400 MHz, dmso-t/6): δ 8.12 (d, J = 2.34, I I I), 7.87 (dd, J = 2.35. 6.0, I I I), 7.15 (d, J = 6.0, 1 H), 4.87 (s, 2H).
[0714] Compound 381 was prepared in a similar manner as 364. LCMS: m/z 621 .76 [M+H]+. EXAMPLE 183
Preparation of Compound 382
Figure imgf000240_0001
[0715] Diisopropylethylamine (0.15 mL, 0.84 mmol) was added to a solution of 382-1 (0.10 g, 0.34 mmol), 3-methoxy-4-(2-((methosybenzyl)oxy)ethoxy)benzoic acid (0.15 g, 0.51 mmol) and HATU (0.25 g, 0.67 mmol) in DMF (1 mL). The mixture was stirred at r.t. for 2 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na^SC and concentrated. The residue was purified by chromatography on silica gel (EArhexane) to give 382-2 (0.15 g. 76%). LCMS: m/z 581 .1 5 [M+H]+.
[0716] Compound 382-2 was deprotected in a similar manner as 368 to give 382- 3 LCMS: m/z 461 .10 [M+H]+.
[0717] Cesium carbonate (0.1 1 g, 0.33 mmol) was added to a solution of 382-3 (0.050 g, 0.1 1 mmol) and 2-(Boc-amino)ethyl bromide (0.048 g. 0.22 mmol) in DMF (1 mL). The mixture was heated under microwave irradiation at 70 "C for 1 h. The mixture wras diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 382-4 (39 mg, 60%). LCMS: m/z 604.20 [M+H]+.
[0718] Hydrochloric acid in dioxane (1.5 mL, 4N) was added to 382-4 (39 mg, 0.077 mmol). The mixture was stirred at r.t. for 1 h and then concentrated under reduced pressure. The crude was purified by reverse phase HPLC to give 382 (8 mg, 25%). LCMS: m/z 503.95 [M+I I]+.
EXAMPLE 184
Preparation of Compound 383
Figure imgf000241_0001
[0719] Compound 383-1 was prepared in a similar manner as 364 to give 383-2. LCMS: m/z 487.10 [M+H]+.
[0720] Dess-Martin periodinane (0.58 g, 1.4 mmol) was added to 383-2 (0.337 g, 0.69 mmol) in CH2C12 (10 mL), and the mixture was stirred at r.t. for 1 h. The mixture was diluted with CH2C12, washed with Na2C(¾ and brine, dried over anhydrous a?S04 and concentrated. The crude was purified by chromatography on silica gel (EA:hexane) to provide 383-3 (0.144 g, 43%). LCMS: m/z 485.10 [M+H]+.
[0721] Potassium tert-butoxide (40 mg, 0.36 mmol) was added to trimethylsulfoxonium iodide (65 mg, 0.30 mmol) in DIV1SO (1 mL), and the mixture was stirred at r.t. for 30 mins. Compound 383-3 (0.144 g, 0.30 mmol) in DMSO (0.5 mL) was added, and the mixture was stirred for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 383-4 (0.050 g. 33%). TCMS: m/z 499.15 [M+H]+. [0722] Compound 383-4 (0.050 g, 0.10 mmol) was dissolved in 6N HC1 (1 mL) and MeOI I (1 mL) and heated at 60 °C for 2 h. The mixture was concentrated, and the crude was purified by reverse phase HPLC to give 383 (14 mg, 28%). LCMS: m/z 51 7.10 [M+H]+.
EXAMPLE 185
Preparation of Compound 384
Figure imgf000242_0001
[0723] Potassium tert-butoxide (81 mg. 0.72 mmol) was added to trimethylsulfoxonium iodide (0.13 g, 0.60 mmol) in DMSO (1 mL), and the mixture was stirred at r.t. for 30 mins. Compound 384-1 (0.329 g. 0.60 mmol) in DMSO (0.5 mL) was added, and the mixture was stirred for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 384-2 (0.1 1 g, 37%). LCMS: m/z 499.15 [M+H]+.
[0724] Compound 384-2 (0.1 1 g, 0.22 mmol) was dissolved in 6N HC1 ( 1 mL) and MeOH (1 mL) and heated at 60 °C for 2 h. The mixture was concentrated and treated with 2N NaOH (2 mL) in MeOH (2 mL) for 2 h. The crude was purified by reverse phase I IPLC to give 384 ( 17 mg, 5%). LCMS: m/z 51 7.10 [M+H]+.
EXAMPLE 186
Preparation of Compound 385
Figure imgf000243_0001
[0725] LDA (2 M in THF, 1.4 niL. 2.8 mmol) was added dropwise to a solution of 385-1 (0.93 g, 2.5 mmol) in THF ( 10 mL) at -78 °C, and the mixture was stirred at -78 °C for 15 mins. N-fluorobenzenesulfonimide (1 .2 g, 3.8 mmol) was added, and the mixture was stirred for 3 h. The mixture was warmed to r.t, and the reaction was quenched with IN HCl. The mixture was extracted with EA. and the organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 385-2 (0.57 g, 59%). LCMS: m/z 386.10 [M+H]+.
[0726] Sodium borohydride (0.12 g, 3.1 mmol) was added to a solution of 385-2 (0.14 g, 0.36 mmol) in EtOH. The mixture was stirred at r.t. for 2 h. The reaction was quenched with IN HCl and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 385-3 (0.040 g, 33%). LCMS: m/z 330.00 [M+H]+.
[0727] Compound 385-3 (25 mg, 0.076 mmol) in THF (1 mL) was added to NaH (3.0 mg, 0.076 mmol) in THF (0.5 mL), and the mixture solution was stirred for 30 mins. TBDMSC1 ( 1 1 mg, 0.076 mmol) was added, and the mixture was stirred at r.t. for 2 h. The reaction was quenched with IN HCl and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (EAthexane) to give 385-4 (0.014 g, 41%). LCMS: m/z 444.10 [M+I I]+.
[0728] Triflic anhydride (45 uL, 0.27 mmol) was added to a solution of 385-4 (60 mg. 0. 14 mmol) and 2,6-lutidine (47 uL. 0.40 mmol) in CH2C12 (1 mL) at -78 °C. The mixture was warmed to r.t. The reaction was quenched with IN HC1 and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude triflate was immediately dissolved in NMP (0. 5 mL) and tetrabutylammonium azide (0.39 g. 1 .4 mmol) was added, and the mixture was heated at 65 °C for 1 h. The mixture was diluted with EA, and organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography on silica gel (EA:hexane) to give 385-5 (0.057 g, 1 14%). LCMS: m/z 355.05 [M+H]+.
[0729| Compound 385-5 was reduced in a similar manner as 364 to give 385-6. LC/MS: [M+H] 329.00. Diisopropylethylamine (62 uL, 0.36 mmol) was added to a solution of 385-6 (54 mg, 0.12 mmol), 4-cyclopropoxy-3-methoxybenzoic acid (37 mg, 0.18 mmol) and HBTU (81 mg, 0.21 mmol) in DMF (1 mL), and the mixture was stirred at r.t. for 1 h. The mixture was diluted with EA and washed with 1 N HC1. sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. The crude was purified by reverse phase HPLC to give 385 ( 14 mg, 22%). LCMS: m/z 520.15 [M+H]+.
EXAMPLE 187
Preparation of Compound 386
Figure imgf000244_0001
[0730] Methyl magnesium bromide (1 .4 M in THF, 6.0 mL, 8.4 mmol) was added to a solution of ethyl 2,6-dichloroisonicotinate (0.74 g, 3.4 mmol) in TI IF (20 mL) at 0 °C. The mixture was stirred at r.t. for 2 h. The reaction was quenched with IN HCl and extracted with ΕΛ. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography on silica gel (EArhexane) to give 386-2 (0.63 g. 88%). LCMS: m/z 206.00 [M+H]+.
[0731 ] TBDMSOTf (2.6 mL. 12 mmol) was added dropwise to a solution of 386- 2 (0.80 g. 3.9 mmol) and 2,6-lutidine (2.3 mL, 19 mmol) in CH2C12 (20 mL). and the mixture was stirred at r.t. for 3 h. The reaction was quenched with IN HCl and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography on silica gel (EA:hexane) to give 386-3 (1.2 g, 96%). LCMS: m/z 320.05 [M+H]+.
[0732] Compounds 386-4, 386-5, 386-6, 386-7 and 386-8 were prepared in a similar manner as 377. 386-4: LCMS: m/z 350.10 [M+H]+. 386-5: LCMS: m/z 474.15 [M+H]+. 386-6: LCMS: m/z 607.20 [M+H]+. 386-7: LCMS: m/z 507.15 [M+H]+. 386-8: LCMS: m/z 697.25 [M+H]+.
[0733] TBAF ( 1 M in THF, 0.13 mL, 0.13 mmol) was added to a solution of 386-8 (25, mg, 0.043 mmol), and the mixture was stirred at r.t. for 1 h. The mixture was concentrated, and 386 was purified by reverse phase HPLC (5 mg, 20%). LCMS: m/z 583.20 [M+I I]+.
EXAMPLE 188
Preparation of Compound 387
Figure imgf000245_0001
[0734] Compound 314 (10 mg. 0.021 mmol) was dissolved in CH2C12 ( 1 mL). Ethyl isocyanate (10 uL, 0.12 mmol) was added, and the mixture was stirred at r.t. for 5 h. The reaction was quenched with methanol (2 mL) and concentrated. Compound 314 was purified by HPLC (4.1 mg, 40%). LCMS: m/z 653.20 [M+H]+. EXAMPLE 189
Preparation of Compound 388
Figure imgf000246_0001
[0735] Sodium triacetoxyborohydride (48 mg. 0.23 mmol) was added to a solution of 318 (28 mg. 0.051 mmol) and acetaldehyde (9 uL. 0.16 mmol) in CH2C12 ( 1 mL).
Additional acetaldehyde and reducing agent were added every 30 mins for 5 h. The reaction was quenched with ammonium chloride and extracted with CH2CI2. Compound 388 was purified by reverse phase HPLC ( 14 mg. 50%) LCMS: m/z 576.20 [M+H]+.
EXAMPLE 190
Preparation of Compound 393
Figure imgf000246_0002
[0736] NaH (9 mg, 0.22 mmol) was added to a solution of 393-1 (72 mg, 0.15 mmol) in DMF (1 mL) and stirred for 15 mins. lodomethane (18 uL, 0.29 mmol) was added, and the mixture was stirred at r.t. for 3 h. The reaction was quenched with sat. NH4CI and extracted with EA. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography on silica gel (EA:hexane) to give 393-2 (5 1 mg. 66%). LCMS: m/z 507.10 [M+H]+.
[0737] Potassium osmate (6 mg, 0.015 mmol) was added to a solution of 393-2 (51 mg. 0.10 mmol) and tert-butyl (tosyloxy)carbamate (41 mg, 0.15 mmol) in t-butanol ( 1 mL) and water (0.33 mL). and the solution was stirred overnight at r.t. The crude was purified by chromatography on silica gel (EA:hexane) to give 393-3 (0.025 g, 50%). LCMS: m/z 640.20 [M+I I]+.
[0738] HC1 (4N in dioxane. 1 mL) was added to 393-3 (0.025 g, 0.039 mmol), and the mixture was stirred for 1 h. The solvent was removed by evaporation and 4- cyclopropoxy-3-methoxy benzoic acid (24 mg, 0.12 mmol), HATU (60 mg. 0.16 mmol). and diisopropylethylamine (40 uL. 0.23 mmol) were added, and the mixture was stirred at r.t. for 1.5 h. The crude was diluted with EA and washed with IN HC1. sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude was purified by reverse phase HPLC to provide 393-4 (12 mg. 41 %). LCMS: m/z 730.15 [M+H]+.
[0739] Pd/C (10%, 3 mg) was added to a solution of 393-4 (12 mg, 0.025 mmol) in EtOH (3 mL), and the mixture was stirred under hydrogen atmosphere for 2 h. The catalyst was removed by filtration, and the crude was purified by reverse phase HPLC to provide 393 (2.5 mg, 28%) LCMS: m/z 563.20 [M+H]+.
EXAMPLE 191
Preparation of Compound 394
Figure imgf000247_0001
[0740] Sodium iodide (40 mg, 0.27 mmol) was added to a solution of 393-4 (40 mg, 0.55 mmol) and chlorotrimethylsilane (35 uL, 0.27 mmol) in acetonitrile (3 mL), and the mixture was stirred at r.t. for 2 h. The reaction mixture was diluted with EA and washed with sat. Na2(S02)j, and brine, dried over Na2S04 and concentrated. The product was purified by reverse phase HPLC to provide 394. LCMS: m/z 597.15 [M+H]+. EXAMPLE 192
Preparation of Compound 395
Figure imgf000248_0001
EXAMPLE 193
Preparation of Compound 396
Figure imgf000248_0002
[0742] Compound 396-2 was prepared in a similar manner as 364. LC/MS:m/z 714.20 [M+H]. HC1 (4N in dioxane, 2 mL) was added to 396-2 (80 mg. 0.1 1 mmol.) and the mixture was stirred for 2 h. The mixture was concentrated to remove volatile components, and 396 was purified by reverse phase HPLC (1 1 mg. 15%). LCMS: m/z 615.15 [M+H]+. EXAMPLE 194
Preparation of Compound 397
Figure imgf000249_0001
[0743] Methanesulfonyl chloride (0.30 mL. 4.0 mmol) was added dropwise to a solution of 397-1 (0.70 g. 2.7 mmol) and diisopropylethylamine (0.93 mL, 5.3 mmol) in CH2CI2 (30 mL) at 0 °C for 30 mins. The mixture was washed with IN HCl, and brine, dried over Na2S04 and concentrated. The crude was purified by silica gel chromatography (EA:hexane) to provide 397-2 (0.59 g. 85%). LCMS: m/z 349.95 [M+H]+.
[0744| Sodium cyanide (0.14 g, 2.8 mmol) was added to a solution of 397-2 (0.59 g, 2.3 mmol) in ethanol (10 mL) and water (2 mL). The mixture was heated at 50 °C for 30 mins. The mixture was diluted with EA and washed with water and brine, dried over Na^SC^ and concentrated. The crude was purified by silica gel chromatography (EA:hexane) to provide 397-3 (0.15 g, 23%). LCMS: m/z 280.95 [M+H]+.
[0745] NaH (65 mg, 1.6 mmol) was added to a solution of 397-3 (0.15 g, 0.54 mmol) in DMF (1 mL) and stirred for 5 mins. lodomethane (0.16 mL, 3.0 mmol) was added dropwise, and the mixture was stirred at r.t. for 1 h. The reaction was quenched with NH4CI and extracted with EA. The organic extracts were washed with water and brine, dried over Na2S04 and concentrated. The crude was purified by silica gel chromatography (eluent: EA:hexane) to provide 397-4 (0.123 g. 72%). LCMS: m/z 308.95 [M+H]+.
[0746] Borane-dimethylsulfide (0.1 1 mL, 0.1 1 mmol) was added dropwise to a solution of 397-4 (0.123 g, 3.9 mmol) in THF (2 mL). and the mixture was heated at 55 °C for 1 h. The reaction was quenched with 6N HC1 and heated at 55 °C for 15 mins. The volatile components were removed by evaporation, and 397-5 was used without further purification. LCMS: m/z 313.00 [M+H]+.
[0747] Benzy l chloroformate (85 uL. 0.59 mmol) was added dropwise to a solution of 397-5 (3.9 mmol) and diisopropylethylamine (0.20 mL, 1 .2 mmol) in CH2CI? (2 mL). and the mixture was stirred at r.t. for 1 h. The mixture was diluted with EA and washed with water and brine, dried over Na2SC>4 and concentrated. The crude was purified by silica gel chromatography (EA:hexane) to provide 397-6 (0.15 g, 87%). LCMS: m/z 447.05 [M+H]+.
[0748] Compound 397-7 was prepared in a similar manner as 364. LCMS: m/z 507.10 [M+H]+. Compound 397-8 was prepared in a similar manner as 377. LCMS: m/z 640.15 [M+H] . Compound 397-9 was prepared in a similar manner as 377. LCMS: m/z 730.15 [M+H] . Compound 397 was prepared in a similar manner as 394. LCMS: m/z 597.20 [M+H]+.
EXAMPLE 195
Preparation of Compounds 366, 367, 370, 373, 376, 389, 390, 391 and 392
Table 7
Figure imgf000250_0001
Figure imgf000251_0001
Example
Structure LCMS: m/z
Method
Compound
625.15 [M+H]+ 388 0 392
H
EXAMPLE 196
Preparation of Compounds 246 and 247
Figure imgf000252_0001
[0749| Compound 370 (270 mg, 0.49 mmol) was separated via SFC to give two enantiomers: 246 ( 100 mg, 74.0%) and 247 (1 10 mg, 81.5%). 246: +ESI-MS:m/z 555.1 [M+H]+. 247: +ESl-MS:m/z 555.1 [M+H]+.
EXAMPLE 197
Preparation of Compound 398
Figure imgf000252_0002
[0750] To a stirring mixture of 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid (70 mg, 0.31 mmol) in DMF (1.5 mL) were added HATU (90 mg, 0.237 mmol) and D1PEA (84 μΤ, 0.474 mmol). The mixture was stirred at r.t. for 10 mins. 2-amino-l-(6-(3-chloro-4- lluorophenyl)-5-methoxypyridin-2-yl)-l-cyclopi pylethan-l-ol in DMT (0.5 mL) as added. The mixture was stirred at for 10 mins, and then quenched with a 10% aq. solution of NaHCO (10 mL). The mixture was diluted with DCM, and a normal aqueous work up with DCM was followed. The crude was purified via prep-HPLC to afford 398 as a white solid. LCMS: m/z 544.15 [M+H]+. EXAMPLE 198
Preparation of Compound 399
Figure imgf000253_0001
[0751 ] Compound 399 was prepared in a manner similar to 398. LCMS: m/z 716.2 [M+H]+.
EXAMPLE 199
Preparation of Compound 400
Figure imgf000253_0002
[0752] To a stirring mixture of 400-1 (50 mg. 0.088 mmol, obtained during the preparation of 314) in DMF (2.0 mL) were added Cs2C03 (143 mg. 0.44 mmol) and Mel (38 mg. 0.264 mmol). The mixture was stirred at r.t. until the starting material was consumed. The crude was diluted EtOAc and water. The aqueous layer was extracted with EtOAc, dried over Na2S04. filtered and concentrated under reduced pressure. Compound 400 was purified via HPLC to afford 400 as a white solid. LCMS: m/z 61 0.15 [M+H]+.
EXAMPLE 200
Preparation of Compound 401
Figure imgf000254_0001
[0753] To a stirring mixture of 401-1 (460 mg, 1.6 mmol) in DMF (2.5 mL. deoxygenated) were added PdCl2(PPh3)2 (32 mg. 0.045 mmol), Cul (26 mg, 0.136 mmol), piperidine (0.35 mL) and trimethyl(prop-2-yn-l -yl)silane (180 mg, 1.6 mmol). The mixture subjected to microwave irradiation at 60 °C for 3 h. The mixture was cooled to r.t. and diluted with EtOAc. The mixture was washed with brine, water and NaHC03. The mixture was dried over MgSC>4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 401-2 as a yellow solid. LCMS: m/z 198.05 [M+H]+.
[0754] To a stirring mixture of 401 -2 (1 10 mg, 0.56 mmol) in DME (3 mL, deoxygenated) were added (3-chloro-4-fluorophenyl)boronic acid (191 mg, 1 .1 mmol), PdCl9(dppf)2 and a solution of Cs2C03 (0.6 mL, 3.7 M). The mixture subjected to under microwave irradition at 1 10 °C for 4 h. The mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, dried over MgSO. , filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 401 -3 as a white solid. LCMS: m/z 292.0 [M+H]+.
[0755] Compound 401 -6 was prepared in 3 steps using methods similar to those for preparing 302. LCMS: m/z 321 .0 [M+Hf. Compound 401 -6 was coupled with 3- methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid followed by alcohol oxidation and deprotection to afford 401. LCMS: m/z 513. 05 [M+I I]+.
EXAMPLE 201
Preparation of Compound 402
Figure imgf000255_0001
[0756| Diisopropylethylamine (24 uL, 0.14 mmol) was added to a solution of 402-1 (21 mg. 0.045 mmol), 3-methoxy-4-[(methylcarbamoyl)methoxy]benzoic acid (22 mg, 0.090 mmol) and HATU (38 mg, 0.099 mmol) in DMF ( 1 mL), and the mixture was stirred at r.t. for 2 h. The mixture was diluted with EA, washed with IN HCl, water and brine, dried over Na2SC>4 and concentrated. The crude was purified by reverse-phase HPLC to provide 402 (7.5 mg). LCMS: m/z 586.05 [M+H]+.
EXAMPLE 202
Preparation of Compounds 403, 404 and 405
Figure imgf000255_0002
[0757] To a solution of 403-1 (6.0 g. 32.97 mmol) and K2C03 (9.12 g, 66.1 mmol) in DMF (50 mL) was added 2-bromoacetonitrile (4.98 g, 39.52 mmol) dropwise. The mixture was stirred at 80 °C for 4 h. The mixture was diluted with water, and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (5-10% EA:PE) to give 402-2 as a colorless oil (5.1 g, 70 %).
[0758] To a solution of 402-2 (8.0 g, 36.2 mmol) in McOH:H20 (2: 1 , 90 mL) was added NaOH (2.9 g, 72.4 mmol), and the mixture stirred at 50 °C for 1 h. The mixture was diluted with water and extracted with EA (2 x 50 mL). The aqueous layer was acidified to pH 4.0 using 2.0 M HCl solution. The aqueous phase was extracted with EA (2 x 150 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated at low pressure to give 403-3 (5.6 g, 70%).
[0759] To a solution of 403-3 (530 mg, 2.35 mmol) in DMT (15 mL) were added DIPEA (590 mg, 7.04 mmol) and HATU (885 mg. 2.35 mmol). and the mixture was stirred at r.t. for 30 mins. The mixture was treated with 2-amino-l-(6-(3-bromo-4-fluorophenyl)-5- methoxypyridin-2-yl)ethanol (403-4, 800 mg, 2.35 mmol), and the mixture was stirred at r.t. for 2 h. The mixture was diluted with water, and extracted with EA (3 x 20 mL). The combined organic layer was w¾shed with brine, dried over anhydrous sodium sulfate and concentrated at low7 pressure. The residue was purified by column chromatography on silica gel (PE:EA 1 : 1) to give 403-5 ( 1.0 g, 77.5%). +ESI-MS:m/z 547.9 [M+H]+.
[0760] To a solution of 403-5 (600 mg, 1.10 mmol) in DCM (20 mL) was added DMP (948 mg, 2.2 mmol) in portions, and the mixture was stirred at r.t. for 1 h. The mixture was washed with sat. Na2S2(¾ solution and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by chromatography to give 403-6 as a white solid (400 mg, 66.7%). +ESI-MS:m/z 546.1 [M+H]+.
[0761 ] To a solution of 403-6 (400 mg. 0.73 mmol) in THF (20 mL) was added CH3MgBr (2.4 mL, 7.3 mmol) dropwise, and the mixture was stirred at r.t. for 30 mins. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The organic layer was washed w ith brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by prep-HPLC to give 403 (60 mg) as a white solid. +ESl-MS:m/z 562.1 [M+H]+. [0762] Compound 403 (~45 mg) was separated via SFC separation to give two isomers: 404 (10.0 mg) and 405 (12.5 mg). 404: +ESI-MS:m/z 562.1 [M+H]+. 405: +ESI- MS:m/z 562.0 [M+H]+.
EXAMPLE 203
Preparation of Compounds 406 and 407
Figure imgf000257_0001
[0763] To a solution of 406-1 (540 mg. 1 .53 mmol) in THF (4 mL) was added cyclopropylmagnesium bromide (4 mL, 0.5M in THF) dropwise at 0 "C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na SC^ and concentrated at low pressure. The residue was purified by chromatography (PE:EA 10: 1 ) to give 406-2 (400 mg, 70%).
[0764] Compound 406-2 (400 mg, 1.0 mmol) was treated with concentrated ammonia water (10 mL) and ethanol ( 10 mL) in an autoclave. After sealing, the mixture was heated to 80 °C for 10 h with stirring. The mixture was cooled to r.t., and diluted with EA (30 mL). The mixture was washed with brine, dried over anhydrous Na2S04 and concentrated at low pressure to give 406-3, which was used without further purification. +ESI-MS:m/z 337.1 [M+HJ+.
[0765] Compound 406-6 was prepared essentially as described in the preparation of 403 by using 4-(2-fluoroethoxy)-3-methoxybenzoic acid and 406-3. The crude was purified by column chromatography (EA:PE 1 : 1 ) to give 406-4 as a white solid (201 mg. 73%). +ESI-MS:m/z 533.1 [M+H]+. Compound 406-4 was separated via SFC separation to give two isomers: 406 (60 mg) and 407 (65 mg). 406: +ESl-MS:m/z 533.1 [M+H]+. 407: +ESI-MS:m/z 533.1 [M+H]+.
Figure imgf000258_0001
[0766] To a solution of 408-1 (560 mg, 0.2 mmol) in THF (4 mL) was added eMgCl ( 1 mL, 3 M in EtiO). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with CBra (5 g) in THF (10 mL). The mixture was diultcd with EA (50 mL). The solution was washed with brine, dried over anhydrous
Figure imgf000258_0002
and concentrated at low pressure. The residue was purified by silical gel to give 408-2 (402 mg, 70%). +ESI-MS:m/z 577.1 [M+H]+.
[0767] Under N2 atmosphere, a 50 mL flask with a magnetic stirring bar was charged with 208-3 (300 mg. 0.75 mmol), 408-2 (290 mg, 0.5 mmol). Pd(dppf)Cl2 (8 mg, 1 mmol%), KF ( 180 mg. 3.0 mmol). and dioxaneiFFO (20 mL:5mL). The mixture was stirred for 10 h at 100 °C. The mixture was cooled to r.t. and diluted with water (50 mL) and FA (50 mL). The organic layer was separated, and the aqueous phase was extracted with EA (2 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous Na?SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 10: 1) to give 408-3 as a solid (280 mg, 70%). +ESl-MS:m/z 774.5 [M+H]+. [0768] To a solution of 408-3 (280 mg, 0.36 mmol) in dioxane (8 n L) wad added conc. I ICl (2 mL). The mixture was stirred at 80 "C for 1 h. The mixture was cooled to r.t. and diuted with water ( 15 mL) and EA (20 mL). The organic phase was washed with brine, dried over anhydrous Na^SC^ and concentrated at lo pressure. The residue was purified by prep-HPLC to give 408-4 (189 mg).
[0769] Compound 408-4 (189 mg) was separated via SFC separation to give two enantiomers: 408 (60 mg) and 409 (65 mg). 408: +ESl-MS:m/z 524.1 [M+H]+. 409: +ESI- MS:m/z 524.1 [M+H]+.
EXAMPLE 205
Figure imgf000259_0001
[0770] Compound 410-3 was prepared essentially as described in the preparation of 403 by using 410-1 and 410-2. The crude was purified by column chromatography on silica gel (PE:acetone 5: 1 ) to give 410-3 (1.8 g. 89 %). +ESl-MS:m/z 628.1 [M+H]+.
[0771] Compound 410-4 was prepared essentially as described in the preparation of 403. Crude 410-4 was obtained (0.8 g, 52.3%). +ESI-MS:m/z 626.1 [M+H]+. Compound 410-5 was prepared essentially as described in the preparation of 403. Crude 410-5 was purified by column chromatography on silica gel (PE:acetone 5: 1 ) to give 410-5 (496 g. 51 %). +ESI-MS:m/z 642.1 [M+H]+. Compound 410-5 was prepared essentially as described in the preparation of 403. Crude 410-6 was purified by prep-HPLC to give 410-6 (302 mg, 70 %). +ESI-MS:m/z 512.1 [M+H] . Compound 410-5 was separated via SFC separation to give 410 (30 mg) and 411 (28 mg). 410: +ESI-MS:m/z 512.1 [M+H]+. 411 : +ESI-MS:m/z 12.1 [M+HJ+.
Figure imgf000260_0001
[0772] Compounds 412 and 413 were prepared essentially as described in the preparation of 403 by using 412-1 and ethynyl magnesium bromide. The product was purified by prep-HPLC and SFC separation. 412 (30 mg) and 413 (32 mg) were obtained as white solids. 412: +ESI-MS:m/z 516.9 [M+H]+. 413: +EST-MS:m/z 516.9 [M+H]+. Prep 416
Figure imgf000260_0002
414, 415 & 416
[0773] Racemic 414 was prepared essentially as described in the preparation of 403 by using 412-1 and ( ?^-4-(2-hydroxypropoxy)-3-methoxybenzoic acid. Compound 414 was obtained as a wrhite solid (150 mg). Compound 414 was separated via SFC separation to give two enantiomers: 415 (35 mg) and 416 (38 mg). 415: +ESI-MS:m/z 519.1 [M+H]+. 416: +ESI-MS:m/z 519.0 [M+H]+.
EXAMPLE 208
P 8
Figure imgf000260_0003
[0774] Compounds 417 and 418 were prepared essentially as described in the preparation of 403 by using 412-1 and (¾-4-(2-hydroxypropoxy)-3-methoxybenzoic acid. Compounds 417 (36 mg) and 418 (39 mg). 417: +ESI- S:m/z 51 8.9 [M+H] . 418: +ESI- S:m/z 518.9 [M+I lf.
Figure imgf000261_0001
[0775] To a solution of 419-1 (1.0 g, 2.32 mmol) in dioxane:H20 (4: 1. 20 niL) was added NaHC(¾ (584.6 mg, 6.96 mmol) in one portion and B0C2O (657.5 mg, 3.02 mmol) in portions. The mixture was stirred at r.t. for 2 h, and then diluted with water (50 niL) and EA (50 mL). The aqueous phase w7as extracted by EA (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE:EA 4: 1 ) to give 419-2 (1.2 g, 97%). +ESI-MS:m/z 532.3 [M+H] ".
[0776] To a solution of 419-2 (1.2 g, 2.26 mmol) in DCM (20 mL) was added DMP ( 1.95 g. 4.52 mmol) in portions. The mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. Na2S(¾ solution (50 mL), and extracted with CH2CI2 (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by chromatography to give 419-3 as a white solid ( 1.0 g, 83.3%). +ESI-MS:m/z 530.3 [M+H]+.
[0777] To a solution of 419-3 (1 .0 g, 1 .89 mmol) in ΤΗΓ (15 mL) was added CLfjMgBr (6.30 mL. 18.90 mmol) dropwise at 0 °C. and the mixture was stirred at r.t. for 30 mins. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated at low pressure. The crude was purified by column chromatography (PE:EA 3 : 1 -2: 1 ) to give 419-4 as a white solid (605 mg. 58.3%). +ESl-MS:m/z 546.2 [M+H]+.
[0778] To a solution of 419-4 (600 mg, 1.1 mmol) in dioxane (16 mT) was added cone. HC1 (8 mL). The mixture was stirred at 80 °C overnight. After cooled to r.t.. the mixture was neutralized by sat. NaHC(¾ solution, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure to give 419-5 (301 mg. 87%).
[0779] Compound 419 was prepared essentially as described in the preparation of 403 by using 419-5 and 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid. Compound 491 was obtained as a white solid (90 mg). +ESI-MS:m/z 523.1 [M+H]+.
[0780] Compound 419 (90 mg, 0.172 mmol) was separated via SFC separation to give two enantiomers: 420 (15.0 mg) and 421 (22.0 mg). 420: +ESI-MS:m/z 523.1
[M+H]+. 421: +ESl-MS:m/z 523.1 [M+H]+.
EXAMPLE 210
Preparation of Compounds 422 and 423
Figure imgf000262_0001
[0781] To a solution of 422-1 ( 100 mg, 0.575 mmol) in THT (10 mL) was NaBH4 (44 mg, 1.1 mmol) was added, and the mixture was stirred at r.t. for 30 mins. The reaction was quenched by water, and extracted with EA (3 x 20 mL). The organic phase was washed with brine, dried over anhydrous Na?SC»4 and concentrated at low pressure. The crude was purified by chromatography (PE:EA 20: 1 to 5: 1 ) to afford 422-2 (90 mg. 89.1 %).
[0782] To a solution of 422-2 (534 mg, 3.0 mmol), methyl 4-hydroxy-3- methoxybenzoate (546 mg, 3.0 mmol) and PPI13 (786 mg. 3.0 mmol) in THT (15 mL) at 0 °C was added D1AD (606 mg. 3.0 mmol) dropwise. The mixture was stirred at r.t. for 2 h. The reaction was quenched with sat. NaHC(¾ solution. The mixture wras extracted with DCM (3 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel to give 422-3 (667 mg, 66%).
[0783] A solution of 422-3 (2.0 g, 5.85 mmol) and Pd(OH)2 (0.2 g) in MeOH (20 mL) was stirred under ¾ atmosphere (50 psi) at r.t. overnight. The mixture was filtered, and the filtrate was evaporated to give crude 422-4 (1.5 g), which was used without further purification.
[0784] To a solution of 422-4 (150 mg. 0.597 mmol) in THF ( 10 mL) at 0 °C was added NaH (47.8 mg, 1.1 95 mmol), and the mixture was stirred at 0 "C for 0.5 h. The mixture was treated with SE C1 (149 mg. 0.896 mmol), and the mixture was allowed to warm to r.t. over 30 mins. The reaction was quenched with water, and extracted with EA (2 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 20: 1 ) to give 422-5 ( 1 10 mg, 48.2 %).
[0785] To a solution of 422-5 (600 mg, 1.57 mmol) in co-solvent THF:H20 (1 : 1. 10 mL) was added NaOH (126 mg. 3.14 mmol in 2 mL water). The mixture was stirred at r.t. for 1 h. The organic solvent was evaporated under reduced pressure, and the aqueous layer was acidified to pH 4-5 with 1M HCl solution. The mixture was extracted with EA (2 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated at low7 pressure to give 422-6 (480 mg, 83.0 %). [0786] Compound 422-8 was prepared essentially as described in the preparation of 403 by using 422-6 and 422-7. Compound 422-8 was obtained as a white solid (180 mg, 66.9 %). +EST-MS:m/z 661 .0 LM+HJ+.
[0787] A suspension of 422-8 ( 1 80 mg, 0.273 mmol) in HCkdioxane (4M. 15 mL) was stirred at r.t. for 30 mins. The mixture was concentrated under reduced pressure to give crude 422-9. The residue was diluted with sat. NaHCC>3 ( 10 mL). and extracted with EA (2 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 5: 1 to 1 : 1 ) to give 422-9 (90 mg, 62.3 %).
[0788] Compound 422-9 (90 mg) was separated by SFC separation to give two enantiomers: 422 (25 mg) and 423 (27 mg). 422: +ESI-MS:m/z 531.0 [M+H]+. 423: +ESI- MS:m/z 531.0 [M+H]+.
EXAMPLE 211
Figure imgf000264_0001
[0789] To a solution of 424-1 (1.05 g, 3.0 mmol) and 18-crowm-6 (800 mg. 3.1 mmol) in CHjCN (50 mL) was added CsF (900 mg. 6.0 mmol). The mixture was heated to reflux for 1 h and the concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10: 1 ) to provide 424-2 as a white sol id (360 mg. 40 %).
[0790] A 50 mL round bottom flask with a magnetic stirring bar was charged with 424-2 (360 mg, 1.2 mmol), MeN02 (5 mL) and Et N (303 mg, 3.0 mmol). The mixture was stirred at r.t. for 10 h and then concentrated under reduced pressure. The residue was purified by column chromatography (PE:DCM 2: 1) to give 424-3 (270 mg, 63%).
[0791] To a stirred mixture of 424-3 (271 mg, 0.75 mmol) and NiCl2 (127 mg, 1 mmol) in MeOH ( 10 mL) was added NaBLL (380 mg, 1.0 mmol) in portions until the starting materials was consumed. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:EtOH 10: 1 ) to give 424-4 as a colorless oil (130 mg, 50%). +ESI-MS:m/z 328.8 [ +I I] h.
[0792] Compound 424 was prepared essentially as described in the preparation of 403 by using the 424-4 and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid. The product was purified by prep-HPLC. Compound 424 was obtained as a white solid (180 mg, 66.9 %). +ES!-MS:m/z 523.2 [M+H]+.
EXAMPLE 212
Figure imgf000265_0001
[0793] Compound 425-3 was prepared essentially as described in the preparation of 403 by using 425-1 and 425-2. The crude was purified by column chromatography (PE:EA 1 : 1 ) to give 425-3 ( 190 mg). +ESl-MS:m/z 654.9 [M+H]+.
[0794] To a solution of 425-3 (190 mg, 0.29 mmol) in dioxane (15 mL) was added cone. HC1 (5.0 mL). The mixture was stirred at r.t. for 1 h, neutralized with sat. NaHC(¾ solution and extracted with EA (3 x 10 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by prep-HPLC to give 425 (21 mg, 13.5%) as a white solid. +ESl-MS:m/z 534.9 [M+H]+.
EXAMPLE 213
Preparation of Compound 426
Figure imgf000265_0002
[0795] To a stirred solution of 426-1 (16.2 g, 90mmol) in HCl (6 N, 300 mL) at 0 °C was added a solution of NaNOi (6.90 g, 99 mmol) in water ( 1 5 mL) dropwise. The mixture was stirred at 0 °C for 1 h and then treated with a solution of Kl (75 g, 450 mmol) in water ( 150 mL). The mixture was stirred for 30 mins and then extracted w ith ΕΛ (4 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 10: 1 ) to give 426-2 (21 .2 g. 80.5%) as a light yellow solid.
[0796] To a suspension of 426-2 (8.77 g, 30 mmol), Cul (1 .14 g. 6 mmol). PdCl2(PPh3)2 (1 -05 g, 1.5 mmol) and NEt3(2 l mL, 150 mmol) in THF( 150 mL) was added propiolic alcohol (3.36 g, 60 mmol) under N2 atmosphere. The mixture was stirred at r.t. overnight and then filtered through a celite pad. The filtrate was concentrated to dryness and the residue was diluted with EA (200 mL). The solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue w¾s purified by column chromatography on silica gel (PE:EA 1 : 1 ) to give 426-3 (5.1 g, 77.3%) as a light yellow solid.
[0797] To a solution of 426-3 (2.2 g, 10 mmol) in MeOH ( 100 mL) was added Pd/C (0.5 g) under N?. The mixture was degassed and refilled with hydrogen (3x). The mixture was stirred under I L atmosphere (40 psi) overnight. The mixture was filtered through a celite pad and the filtrate was concentrated in vacuum to give crude 426-4. The residue was purified by column chromatography on silica gel (PE:EA 1 : 1 ) to give 426-4 ( 1 .62 g, 72.3%) as a light yellow oil.
[0798] To a solution of 426-4 (0.67 g. 3 mmol) in EtOH (7.5 mL) and water (2.5 mL) was added NaOH (0.48 g. 12 mmol). The mixture was stirred at 50 °C for 1 h, cooled to 0 °C. and acidified to pH 5 with HCl (2 M) solution. The mixture was extracted with EA (4 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum to give 426-5 (0.50 g. 80.0%) as a yel low solid, which wras used without further purification.
[0799] Compound 426 was prepared essentially as described in the preparation of 403 by using 426-5 and 2-amino-l -(6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)- l - cyclopropylethanol. The crude was purified by prep-HPLC to give 426 (35 mg, 13.3%) as a white solid. +ESI-MS:m/z 529.0 [M+U] h.
Figure imgf000267_0001
[0800| To a suspension of 427-1 (1.0 g, 4.67 mmol) in dioxane (30 mL) were added 427-2 (2.37 g, 9.346 mmol), AcOK (1.37 g, 14.0 mmol) and Pd(dppf)Cl2 (0.346 g, 0.467 mmol). The mixture was stirred at 80 °C under Ντ atmosphere for 16 h. The mixture was cooled to r.t.. poured into water (100 mL), and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 50: 1 ) to give 427-3 (1 .4 g. contain 0.3-0.4 g of 427-2).
[0801] To a solution of 427-4 (3 10 mg, 0.554 mmol) in THF (10 mL) at 0 °C was added cyclopropyl-magnesium bromide (1 1 mL, 0.5 M in THF) dropwise. The mixture was stirred for 1 h and then warmed to r.t. The reaction was quenched with sat. NH4CI (10 mL) solution, and extracted with EA (2 x 20 mL). The combined organic phase was washed with sat. NaHCOj solution, and brine. The organic layer was dried over anhydrous Na2SC>4 and concentrated at low pressure. The residue was purified by column chromatography on silica gel (30% EA in PE) to give 427-5 ( 170 mg, 51.0 %). +ESI-MS:m/z 601.1 [M+H]+.
[0802] To a suspension of 427-5 (120 mg, 0.2 mmol) in a mixture of dioxane and H20 (9: 1, 10 mL) were added Cs2C03 (195.6 mg, 0.6 mmol), 427-3 (108.6 mg, 0.3 mmol) and Pd(dppf)Cl ( 16.3 mg, 0.02 mmol) under N? atmosphere. The mixture was stirred at 70 °C for 2 h. The mixture was cooled to r.t., poured into water (50 niL) and extracted with EA (2 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous and concentrated at low pressure. The residue was purified by column chromatography ( 10-30% ΕΛ in PE) to give 427-6 ( 121 mg. 92.2 %). +ESI-MS:m/z 657.1 [M+H]+.
[0803] A suspension of 427-6 ( 121 mg, 0.1 84 mmol) and Pd/C (20 mg) in MeOH (20 mL) was stirred under H2 atmosphere (balloon) at r.t. overnight. The solution was filtered, and the filtrate was concentrated in vacuum. The residue was purified by prep- HPLC to give 427 (17 mg, 10.1%) as a white solid. HSI-\IS:m / 539.1 [M+H]+.
EXAMPLE 215
Figure imgf000268_0001
[0804] Compound 428-2 was prepared as provided in Mello et al., J. Am. Chem. Soc. (2005) 127(29):10124-10125, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 428-2. Compound 428-3 was prepared as provided in PCT Publication No. WO 2002/034745. published May 2. 2002. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 428- 3.
[0805] To a solution of 428-3 (8 g, 38 mmol) in DMF (100 mL) were added K7CO (9.5 g. 69 mmol) and NaN3 (3 g. 46 mmol) at r.t. The solution was stirred for 2 h. poured into H2O (100 mL) and extracted with EA (3 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 10: 1 ) to give 428-4 (5.1 g, 66.1 %).
[0806] To a solution of 428-4 (5 g, 23.4 mmol) in EtOH (50 mL) were added B0C2O (6.1 1 g. 28 mmol) and Pd/C (1 g) at r.t. under N2. The solution was degassed and refilled with ¾ (3x). The mixture was stirred at r.t. under H2 atmosphere (balloon) for 18 h. The solution was filtered, and the filtrate was concentrated to dryness. The residue was purified by chromatography on silica gel (PE:EA 10: 1) to give 428-5 (2.2 g, 34.4%).
[0807] To a solution of 428-5 (2.2 g, 7.9 mmol) and (3-chloro-4- fluoro phenyl )boronic acid (1.39 g, 7.9 mmol) in a mixture of dioxane and LEO (20 mL/5 mL) were added Pd(dppi)CT? (289 g.0.395 mmol) and K2C<¾ (1.63 g. 1 1.85 mmol). The mixture was degassed and refilled with N? (3x). The mixture was stirred under N? at 40 °C for 3 h. The mixture was cooled to r.t., and diluted with EA ( 100 mL) and water ( 100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 10: 1 ) to give 428-6 (2.923 g, 100%) as a white solid. +ESI-MS:m/z 370.8 [M+H]+.
[0808] To a solution of 428-6 (1 .2 g, 3.24 mmol), tributyl( 1 -ethoxyvinyl)stannane (2.34 g, 6.48 mmol) and KF (751 mg, 12.96 mmol) in DMF ( 15 mL) was added Pd(dppf)Cl2 (237 mg. 0.324 mmol) under N2. The mixture was stirred at 80 °C for 2 h. After cooling to r.t., the mixture was diluted with EA (1 00 mL) and water (50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure to give crude 428-7 (1.35 g crude), which wras used in the next step directly. +ESI-MS:m/z 407.1 [M+H]+.
[0809] Compound 428-7 (1.315 g, 3.24 mmol) was dissolved in THF (20 mL) and FLO (2 mL). The solution was treated with NBS (1.13 g, 6.4 mmol) at r.t., and stirred for 20 mins. The mixture was concentrated at low pressure, and the residue was purified by column chromatography on silica gel (PE:EA 10: 1 ) to give 428-8 (1.4 g, 94.5%). +ESI- MS:m/z 459.1 [M+H]+.
[0810] Compound 428-9 was prepared essentially as described in the preparation of 406 by using 428-8. Crude 428-9 (410 mg, 63%) was used directly in the next step. Compound 428-10 was prepared essentially as described in the preparation of 406 by using crude 428-9. Crude 428-10 (205 mg, 57.6%) was used directly in the next step. +ESI- MS:m/z 436.3 [M+H] \ Compound 428-11 was prepared essentially as described in the preparation of 406 by using crude 428-10 and 3-methoxy-4-(2-((4- methoxybenzyl)oxy)ethoxy)benzoic acid. Crude 428-11 was purified by column chromatography on silica gel (50% EA in PE) to give purified 428-1 1 ( 106 mg, 30.1 %).
[0811 ] To a solution of 428-11 ( 100 mg, 0.13 mmol) in dioxane (2 mL) was added cone. HC1 (2 mL) at r.t, and the mixture w¾s stirred for 30 mins. The mixture was neutralized using a sat. NaaCO , solution, and extracted with EA (3 x 10 mL). The combined organic layer was washed with brine, dried over anhydrous NaoSC^ and concentrated at low pressure. The residue was purified by prep-HPLC to give 428 ( 15 mg, 21.2%) as a white solid. +ESl-MS:m/z 530.0 [M+H]+.
EXAMPLE 216
Prep and 431
Figure imgf000270_0001
429, 430 & 431
[0812] Compound 429 was prepared essentially as described in the preparation of 403 by using 403-3 and 406-3. Compound 429 was obtained as a white solid (50 mg). +ESI- MS:m/z 544.1 [M+H]+.
[0813] Compound 429 was separated via SEC separation to give two enantiomers: 430 (3.22 mg, 12.9%) and 431 (3.45 mg, 13.8%). 430: +ESl-MS:m/z 544.1 [M+H]+. 431: +ESl-MS:m/z 544.1 [M+H]+.
Figure imgf000271_0001
[0814] To a solution of 432-1 (2.0 g, 10.99 mmol) in DMF (20 mL) were added ClCF2COONa (3.0 g, 19.74 mmol) and K2C03 (4.4 g, 31.88 mmol). The mixture was stirred at 95 °C for 5 h. After cooling to r.t, the mixture was poured into water ( 100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (5-20% EA in PE) to give 432-2 (1 .3 g, 51 .0%).
[0815] Compound 432-3 was prepared essentially as described in the preparation of 426 using 432-2. Compound 432-3 was obtained as a white solid ( 1.19 g. 97.5%). Compound 432 was prepared essentially as described in the preparation of 406 by using 432- 3 and 432-4. Compound 432 was obtained after purification by prep-HPLC as a white solid (70 mg, 21.7%). +ESl-MS:m/z 537.1 [M+H]+.
EXAMPLE 218
Figure imgf000271_0002
[0816] To a solution of 433-1 (2 g, 6.8 mmol), potassium trifluoro(vinyl)borate (0.917 mg, 6.8 mmol) and Et3N (1.73 g, 17.12 mmol) in MeOH (30 mL) was added Pd(dppf)Cl2 (497 mg, 0.68 mmol) under N2. The mixture was stirred under N2 at 70 °C for 15 h. The solution was cooled to r.t, and diluted with EA (100 mL) and water (50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (3% EA in PE) to give 433-2 as a colorless oil ( 1 .1 g, 84.6%).
[0817] To a solution of 433-2 (730 mg. 3.84 mmol) in THF (15 mL) was added BHj · THF (4 mL, 1 M) at 0 "C, and the reaction was stirred at 0 °C for 1 h. The solution was treated with NaOH ( 10 mL, 1 M in water) and H1O2 (3 mL) at 0 "C. The mixture was stirred at r.t. for 1 h, and extracted with ΕΛ (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 5:1 ) to give 433-3 (320 mg. 40.4%).
[0818] Compound 433-4 was prepared essentially as described in the preparation of 426 using 433-3. Compound 433-4 obtained as a white solid (210 mg, 70.7%).
Compound 433 was prepared essentially as described in the preparation of 406 by using 433-
4 and 433-5. Compound 433 was obtained after purification by prep-HPLC as a white solid
(32 mg, 8.2%). +ESi-MS:m/z 515.0 [M+H]+.
EXAMPLE 219
Figure imgf000272_0001
[0819] Compound 434-2 was prepared as described in PCT Publication No. WO 2009/055077, published on April 30, 2009, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 434-2.
[0820] To a suspension of 1, 2, 4-triazole (0.52 g, 7.51 mmol), and 2CO3 (2.57 g, 20.49 mmol) in DMF ( 15 mL) was added 434-2 ( 1.77 g, 6.83 mmol) at 0 °C, and stirred at r.t. overnight. The mixture was poured into water ( 100 mL), and extracted by EA (4 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated at lo pressure. The residue was purified by column chromatography
[0821] Compound 434-4 was prepared essentially as described in the preparation of 426 by using 434-3. Compound 434-4 was obtained as a white solid (0.4 g. 57.2%).
Compound 434 was prepared essentially as described in the preparation of 406 by using 434-
4 and 434-5. Compound 434 was obtained after purification by prep-HPLC as a white solid
( 135 mg, 27.2%). +EST- S:m/z 552.1 [M+Hf.
EXAMPLE 220
Figure imgf000273_0001
[0822] To a solution of 435-1 (270 mg, 0.75 mmol) in DCM ( 10 mL) was added BAST (220 mg, 1.0 mmol) at r.t. The mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. NaHCCb solution (20 mL). extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Crude 435-2 (271 mg, 99 %) was used without further purification.
[0823] To a solution of 435-2 (271 mg, 0.75 mmol) and NiCL ( 127 mg, 1 mmol) in MeOH ( 10 mL) was added NaBLL; (380 mg, 1.0 mmol) in portions until the starting materials was consumed. The reaction was quenched by water (10 mL), and extracted with EA (3 x 30 mL). The organic phase was washed with brine, dried over anhydrous
Figure imgf000273_0002
and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10% EtOH in EA) to give 435-3 as a colorless oil ( 130 mg, 50%). +ESI-MS:m/z 331.1 [M+HJ+. [0824] Compound 435 was prepared essentially as described in the preparation of
406 by using 435-4 and 435-5. Compound 435 was obtained after purification by prep-
HPLC as a white solid (85 mg, 47%). +ESI-MS:m/z 525.2 LM+HJ+.
Figure imgf000274_0001
[0825] To a stirred solution of 436-1 (800 mg, 2.02 mmol) and PhS02CHF2 (465 mg, 2.42 mmol) in THF ( 10 mL) w7as added LDA (2 mL, 4 mmol) dropwise at -78 °C under NT atmosphere. The mixture was stirred at -78 "C for 2 h, and warmed to 0 "C for 30 mins. The reaction was quenched with sat. NH4CI solution, and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous a2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 3 : 1 ) to give 436-2 (610 mg, 51 .6%). +ESI-MS:m/z 587.1 [M+IIJ 1 .
[0826] To a solution of 436-2 (610 mg, 1 .04 mmol) in DMF (5 mL) were added HO Ac ( 1 mL) and H?0 (1 mL) at r.t. The mixture was treated with magnesium (250 mg. 10.4 mmol) in portions. After stirring at r.t. for 6 h, the mixture was poured into ice-water (50 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give 436-3 (320 mg, 68.9 %). +ESl-MS:m/z 446.9 [M+H]+.
[0827] To a solution of 436-3 (320 mg, 0.72 mmol) in EA (3 mL) was added HC1/EA (3 mL. 4M). The solution was stirred at r.t. for 30 mins, and then concentrated to dryness. Crude 436-4 (220 mg, 90.9%) was used without purification.
[0828] Compound 436 was prepared essentially as described in the preparation of 406 by using 436-4 and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid. Compound 436 was obtained after purification by prep-HPLC as white solid (40 mg, 1 1 .7%). +ESI-MS:m/z 541.0 LM+H]+.
Figure imgf000275_0001
[0829] To a solution of 437-1 (1.0 g, 5.5 mmol) and 2C03 (1.0 g, 7.3 mmol) in a mixture of CH3CN (10 mL) and LLO (2 mL) was added 2-bromo- L 1 -difluoroethene ( 10.0 mL, ~2 M in acetonitrile) at 0 °C. The mixture was stirred at 50 °C for 10 h. After cooling to r.t. the mixture was poured into w7ater (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10: 1 ) to give 437-2 as an oil (0.4 g crude).
[0830] To a solution of 437-2 (0.4 g, 1 .2 mmol) in McOH (20 mL) was added Pd/C (0.3 g) under N2. The suspension was degassed and refilled with H2 (3x). The mixture was stirred under H2 (50 psi) at r.t. for 5 h. The suspension was filtered through a Celite pad. and the filtrate was concentrated to dryness. The residue was purified by column chromatography (ΡΕ.ΈΑ 9:1 ) to give 437-3 as a white solid (250 mg, 84.7%).
[0831] Compound 437-4 was prepared essentially as described in the preparation of 426 by using 437-3. Compound 437-4 was obtained as a white solid (201 mg, 85.1 %). Compound 437 was prepared essentially as described in the preparation of 406 by using 437- 4 and 437-5. Compound 437 was obtained after purification by prep-HPLC as white solid (50 mg, 36.4%). +ESl-MS:m/z 551.2 [M+H]+.
Figure imgf000276_0001
[0832] Compound 438-1 was prepared in a similar manner as 434. Compound 438-4 was prepared in a similar manner as 406. Compound 438 was prepared essentially as described in the preparation of 434 by using 438-3 and 438-4. Compound 438 was obtained after purification by prcp-HPLC as white solid (230 mg, 23%). +ESI-MS:m/z 551.0 [M+HJ 1 .
Figure imgf000276_0002
[0833] To a solution of 439-6 (2.334 g, 6 mmol) in DMF (20 mL) were added N,0-dimethyl-hydroxylamine hydrochloride (873 mg, 9 mmol), DIPEA (2.322 g. 18 mmol) and HATU (3.42 g, 9 mmol), and the mixture was stirred at r.t. for 1 h. The mixture was poured into water (50 mL), and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na?S04 and concentrated under reduced pressure. The residue was purified by column chromatography (20-50% EA in PE) to give 439-7 (2.4 g. 92.7 %). +ESI-MS:m/z 433.1 [M+H]+.
[0834] Compound 439-2 was prepared essentially as described in the preparation of 428 by using 439-1 and 3-chloro-4-fluorophenylboronic acid. Compound 439-2 was obtained as a white solid (0.61 g. 69.0 %). Compound 439-3 was prepared essentially as described in the preparation of 426 by using 439-2. Compound 439-3 was obtained as a white solid (0.97 g, 58.8%).
[0835] To a solution of 439-3 (1.6 g. 4.8 mmol) and 439-7 (2.1 g. 4.8 mmol) in anhydrous THF (20 mL) was added isopropyl-magnesium chloride ( 18.5 mL. 24.1 mmol) dropwise at 0 °C, and the mixture was stirred at r.t. for 1 h. The mixture was quenched with water, and extracted with EA (2 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous
Figure imgf000277_0001
and concentrated under reduced pressure. The residue was purified by column chromatography (10-50% EA in PE) to give 439-4 (1.2 g, 64 %). +ESl-MS:m/z 578.0 [M+H]+.
[0836] Compound 439-5 was prepared essentially as described in the preparation of 403 by using 439-4. Compound 439-5 was obtained as a white solid (160 mg, 27.0 %). +ESl-MS:m/z 594.0 [M+H]+. Compound 439 was prepared essentially as described in the preparation of 425 by using 439-5. Compound 439 was obtained as a white solid (101 mg, 79.2 %). +EST-MS:m/z 473.8 LM+HJ+.
Figure imgf000277_0002
[0837] Compound 440 was prepared essentially as described in the preparation of 406 by using 2-bromo-l-(6-(3-chloiO-4-fluorophenyl)-4-ethylpyridin-2-yl)ethanone. Compound 440 was obtained as a white solid (197 mg, 73%). +LSl-MS:m/z 523.1 [M+H]+. EXAMPLE 226
Preparation of Compound 441
Figure imgf000278_0001
[0838] Compound 441 was prepared essentially as described in the preparation of
428 by using 2,4-dibromothiazole. Compound 441 was obtained as a white solid (60 mg.
35.7 %). +ESI-MS:m/z 480.8 [M+H]+.
EXAMPLE 227
Preparation of Compound 442
Figure imgf000278_0002
[0839] Compound 442-1 was prepared as essentially described in the preparation of 436. Compound 442-2 was prepared as essentially described in the preparation of 403.
Compound 442 was prepared essentially as described in the preparation of 406 by using 442-
1 and 442-2. Crude 442 was purified by prep-HPLC to give 442 as a white solid (65 mg.
13.3%). +ESI-MS:m/z 554.1 [M+H]+.
EXAMPLE 228
Figure imgf000278_0003
[0840] To a solution of 443-1 (51 1 mg, 1.27 mmol) in anhydrous DMF (5 mL) were added TMS-CF (21 7 mg, 1.53 mmol) and LiOAc (8.4 mg, 0.127 mmol) at r.t., and the mixture was stirred for 24 h. The mixture was treated with HCl (1.5 mL, 1 M) solution, and stirred at r.t. for 1 h. The mixture was diluted with water (20 rtiL), and extracted with EA (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous and concentrated under reduced pressure. The residue was purified by flash column chromatography (ΡΕ.ΈΛ 5: 1 ) to give 443-2 (131 mg, 21.8%).
[0841] Compound 443 was prepared essentially as described in the preparation of 428 by using 443-2 and 442-2. Compound 443 was obtained as a white solid (92 mg. 53.2%). +ESI-MS:m/z 616.0 [M+H]+.
EXAMPLE 229
Preparation of Compound 444
Figure imgf000279_0001
[0842] Compound 444 was prepared essentially as described in the preparation of 406 by using 444-1 and 444-2. Compound 444 was purified by prep-HPLC to give 444 as a white solid (55 mg, 25.4%). +ESl-MS:m/z 555.0 [M+H]+.
EXAMPLE 230
Preparation of Compound 445
Figure imgf000279_0002
[0843] Compound 445 was prepared essentially as described in the preparation of
406 by using 445-1 and 445-2. Compound 445 was purified by prep-HPLC to give 445 as a white solid (56 mg, 36.3%). +ESI-MS:m/z 537.0 [M+HJ .
EXAMPLE 231
Preparation of Compounds 446 and 447
Figure imgf000279_0003
[0844] Compound 442 (60 mg) was separated via SFC separation to give two isomers: 446 (25 mg) and 447 (25 mg). 446: +ESI-MS:m/z 554.0 [M+H]+. 447: +ESI- MS:m/z 554.1 [M+H]+.
Figure imgf000280_0001
[0845] Compound 448-2 was prepared essentially as described in Jang et al., Tel. Lett. (2006) 47(50):8917-8920, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 448-2. To a suspension of 448-2 (6.0 g, 22.9 mmol) and K2C03 (6.3 g, 45.6 mmol) in CH3CN (40 mL) was added Mel (6.5 g. 45.6 mmol) at r.t. The solution was heated to 80 °C and stirred for 8 h. The precipitate was removed by filtration, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 20: 1 ) to give 448-3 (5.5 g, 87.3%) as a white solid.
[0846] Compound 448 was prepared essentially as described in the preparation of 428 and 443 by using 448-3 and 448-4. Crude 448 was purified by prcp-HPLC to give 448 as a white solid (40 mg, 51 .9%). +ESI-MS:m/z 554.0 [M+H]+.
Figure imgf000281_0001
[0847] Step 1 and step 3 were conducted as essentially as described in the preparation of 232. Step 2 was conducted as essentially as described in the preparation of 426. To a solution of 449-4 (1 .0 g, 2.06 mmol) in AcOH (10 niL) was added Fe (576 mg. 10.3 mmol) powder in portions. The mixture was stirred at 80 °C for 2 h. After cooling to r.t, the mixture was neutralized with sat. Na CO , solution, and extracted with EA (3 x 50 mL). The combined organic phase wras washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column (PE:EA 3: 1) to give 449-5 (435 mg, 46.4%). +ESI-MS:m/z 457.0 [M+H]+.
[0848] Compound 449-6 was prepared essentially as described in the preparation of 406 by using 449-5 and (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid. Crude 449-6 was purified by prep-HPLC to give 449-6 (92 mg, 40.4%). +ES1-MS :m/z 665.0 [M+H]+. Compound 449-6 (92 mg) was separated via SFC separation to give two isomers: 449 (32 mg) and 450 (33 mg). 449: +ESI-MS:m/z 665.0 [M+Hf . 450: +ESl-MS:m/z 665.1 [M+H]+.
EXAMPLE 234
Preparation of Compound 451
Figure imgf000281_0002
[0849] Compound 451 was prepared essentially as described in the preparation of
443 and 448 by using 451-1. Crude 451 was purified by prep-HPLC to give 451 as a white solid (42 mg, 16.0%). +ESI-MS:m/z 553.9 [M+H]+.
Figure imgf000282_0001
[0850] Compound 452-1 was prepared essentially as described in the preparation of 259. Compound 452-2 was prepared essentially as described in the preparation of 471. Compound 452 was prepared essentially as described in the preparation of 406 by using 452- 1 and 452-2. Crude 452 was purified by prep-HPLC to give 452 as a white solid (90 mg, 19 %). +ESl-MS:m/z 564.0 [M+H]+.
EXAMPLE 236
Figure imgf000282_0002
[0851] To a solution of 453-1 ( 100 mg, 0.493 mmol) in SOCl2 (3 mL) was added DMF (one drop) at 0 °C. and stirred at r.t. for 1 h. The mixture was co-evaporated with toluene (2x), and re-dissolved in anhydrous DCM (5 mL). The solution was treated with TEA (99.6 mg. 0.986 mol) and 453-3 ( 164.2 mg. 0.493 mol). The mixture was stirred at r.t. for 1 h. The mixture was diluted with DCM (20 mL) and washed with brine (20 mL). The organic phase was dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 453 (42 mg, yield: 16.7%). +ESI-MS:m/z 512.1 [M+H]+.
Figure imgf000283_0001
[0852] Compound 454-2 was prepared essentially as described in the preparation of 406 by using 454-1 and prop-l -en-2-ylmagnesium bromide. Crude 454-2 was purified by column chromatography (PE:EA 8: 1 ) to give 454-2 as a solid (0.8 g). +ESl-MS:m/z 401 .9 [M+H]+.
[0853] To a solution of 454-2 (800 mg, 2.0 mmol) in DMSO (10 mL) was added a (650 mg, 10.0 mmol) at r.t.. and the mixture was stirred for 5 h. The reaction was quenched with water (30 mL), and extracted by EA (3 x 20 mL). The combined organic layers were wrashed with brine, dried over anhydrous a^SC^ and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 6: 1 ) to give 454-3 (402 mg, 55.1 %) as a white solid. +ESI-MS:m/z 362.9 [M+H]+.
[0854] Ozone wras bubbled into a solution of 454-3 (402 mg, 1.1 mmol) in anhydrous methanol (20 mL) at -78 °C for 10 mins. After excess ozone was purged by nitrogen, NaBLL; (125 mg, 3.3 mmol) was added. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with water and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5: 1 ) to give 454-4 as an oil (303 mg. 74.6%). [0855] Compound 454 was prepared essentially as described in the preparation of 428 from 454-4 and 454-7. Crude 454 was purified by prep-HPLC to give 454 as a white solid (40 mg, 31.4%). +ESI-MS:m/z 531 .0 [M+H]+.
Figure imgf000284_0001
[0856] Compound 455-2 was prepared essentially as described in PCT Publication No. WO 2012/057247, published May 3, 2012, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 455-2. To a solution of 455-2 (2.0 g. 9.17 mmol) in DCM (50 mL) was added DAST (6.0 g, 36 mmol) at 0 °C, and the mixture was stirred at r.t. for 1 h. The reaction was quenched with water (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by colomn chromatography (PE:EA 100: 1 ) to give 455-3 (1.2 g, 60%).
[0857] To a solution of 455-3 (1 .2 g, 5.4 mmol) in anhydrous THF (40 mL) was added w-BuLi (3 mL. 2.5M in hexane) dropwise at -78 °C. and the solution was stirred for 1 h. 2-isopropoxy-4A5,5-tetramethyl-l ,3.2-dioxaborolane ( 1.5 g, 8.1 mmol) was added dropwise, and the mixture was stirred at -78 "C for 1 h. The reaction was quenched with water (50 mL). and extracted with EA (2 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC»4 and concentrated under reduced pressure. The residue was purified by colomn chromatography (PE:EA 100: 1 ) to give 455-4 (0.4 g, 28%).
[0858] Compounds 455-5 to 455-7 was prepared essentially as described in the preparation of 449 by using 455-4. Crude 455-7 was purified by gel colomn to give 455-7 (0.9 g, 67%). A suspension of 455-7 (1.0 g. 2.9 mmol) and SnCT2-2H20 (2.6 g, 12 mmol) in EA (15 mL) was stirred at 70 °C overnight. After cooling to r.t., ΝΗ3 Ή2Ο (5 mL) was added, and the mixture was stirred for 30 mins. A white precipitate wras formed and removed by filtration. The filtrate was washed with brine, dried over anhydrous Na?S04 and concentrated under reduced pressure. Compound 455-8 (0.8 g) was used without further purification.
[0859] Compound 455-9 was prepared essentially as described in the preparation of 406 by using 455-8 and 4-(2-amino-2-oxoethoxy)-3-mcthoxybenzoic acid. Crude 455-9 was purified by prep-HPLC to give 455-9 as a white solid (570 mg, 41 %). +ESI-MS:m/z 521.8 [M+H]+. Compound 455-9 (570 mg. 1 .09 mmol) separated via SFC separation to give two enantiomers: 455-10 (230 mg) and 455-1 1 (220 mg, 42%).
[0860] To a solution of 455-10 (100 mg, 0.19 mmol) and 455-4 (150 mg. 0.56 mmol) in co-solvent dioxane (4 mL) and LEO (0.5mL) were added Pd(dppf)Cl2 (10 mg. 0.012 mmol) and K2CO3 (55 mg. 0.4 mmol). The mixture was degassed and then refilled with N2 (3x). The mixture was heated to 150 °C by microwave for 50 mins. The mixture was cooled to r.t., and diluted with EA (30 mL) and water (30 mL). The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 455-12 as a white solid (80 mg, 70%). [0861] Compound 455-12 (80 mg, 0.15 mmol) was separated via SFC separation to give two isomers: 457 (30 mg) and 458 (29 mg). 457: +ESI-MS:m/z 584.1 [M+Hf. 458: +ESI-MS:m/z 584.1 [M+HJ+.
[0862] Compound 456 was prepared by using 455-11 and 455-4. Crude 456 was purified by prep-HPLC to give 456 as a white solid (75 mg, 65%). +ESl-MS:m/z 584.1 [M+H]+. Compound 455 was prepared by using 455-9 and 455-4. Crude 455 was purified by prep-HPLC to give 455 as a white solid (40 mg. 23.3%). +ESI-MS:m/z 584.1 [M+H]+.
Figure imgf000286_0001
[0863] Compound 459-2 was prepared essentially as described in Hay et al., J. Med. Chem. (2010) 53(2):787-797. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 459-2. Compound 459-3 was prepared essentially as described in PCT Publication No. WO 2012/020786, published Feb. 16, 2012, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 459-3.
[0864] To a solution of NaB¾ (60 mg, 1.58 mmol) in a mixture of THF (5 mL) and eOH ( 1 mL) was added 459-3 (150 mg, 0.794 mol) in portions. The mixture was stirred at r.t. for 1 h. The reaction was quenched with water ( 10 mL), and extracted with EA (3 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na S04 and concentrated under reduced pressure. The residue was purified by colomn chromatography (10-20% EA in PE) to give 459-4 (97 mg, 63.8 %). [0865] To a solution of 459-4 (573 mg, 3.0 mmol), isoindoline-l,3-dione (441 mg, 3.0 mmol) and PPh3 (943 mg, 3.0 mmol) in anhydrous TI IF (15 mL) was added DIAD (727 mg, 3.0 mmol) dropwise at 0 °C under N2. The mixture was stirred for 2 h at r.t. The reaction was quenched by sat. NaHC03 solution (30 mL). The mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10: 1 ) to give 459-5 (604 mg, 62.9%).
[0866] Compounds 459-5 to 459-12 was prepared essentially as described in the preparation of 428. Crude 459-12 was purified by flash column chromatography (10-20% EA in PE) to give 459-12 (127 mg, 65.8%). A suspension of 459-12 ( 127 mg, 0.326 mmol) in Ν2Η4Ή2Ο (10 mL) was stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give 459 (35 mg, 33,9%), +ESI- MS:m/z 568.0 [M+H]+.
EXAMPLE 240
Figure imgf000287_0001
[0867] Compounds 460-1 to 460-6 were prepared essentially as described in the preparation of 272 and 403. Crude 460-6 was purified by prep-HPLC to give 460-6 as a white solid (67 mg, 50%). To a solution of 460-6 ( 100 mg, 0.16 mmol) in DCM (5mL) was added TFA (1 niL). The mixture was stirred at r.t. for 1 h. and then concentrated under reduced pressure. The residue was purified by prep-I IPLC to give 460 (30 mg, 60%). +ESI- MS:m/z 528.1 [M+H]+.
Figure imgf000288_0001
[0868] Compound 461-2 was prepared essentially as described in PCT Publication No. WO 2013/055645, published April 18, 2013, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 461-2. Compound 461-3 was prepared essentially as described in Podlech et al., Helv. Chimi a Acta (1995) 78(5): 1238- 1246, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 461-3. Compound 461-4 was prepared essentially as described in PCT Publication No. WO 2009/154780, published Dec. 23. 2009, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 461 -4.
[0869] To a solution of 461 -4 (9.0 g, 39.3 mmol) in anhydrous DMF (50 mL) were added DIPEA (15.2 g. 1 17.9 mmol) and HATU ( 14.9 g, 39.3 mmol), and the mixture was stirred at r.t. for 30 mins. N,0-dimethvlhydroxylamine (3.85 g, 39.3 mmol) was added, and the mixture was stirred at r.t. for 2 h. The mixture was diluted with water (100 mL), and extracted with EA (3 x 100 mL). The combined organic phase was washed brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10: 1 ) to give 461-5 (8.5 g, 70.7%).
[0870] To a solution of 461-5 (8.0 g, 31.0 mmol) and 2-bromo-6-iodo-3- methoxypyridine (9.7 g, 31.0 mmol) in anhydrous THE (120 mL) was added i-PrMgCl (23.5 mL, 46.51 mmol) dropwise at 0 °C, and the mixture was stirred at r.t. for 2 h. The reaction was quenched with water (50 mL) and extracted with EA (3 x 150 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue wras purified by column chromatography (PE:EA 8: 1 ) to give 461-6 (6.0 g, 49.6 %). +ESl-MS:m/z 385.01 [M+H]+.
[0871] Compound 461-7 was prepared as essentially as described in the preparation of 428 by using 461-6. Compound 461-7 (4.2 g) was obtained after purification by column chromatography .
[0872] To a suspension of CH3P+Ph3Br" (2.46 g, 6.92 mmol) in toluene (20 mL) was added NaHMDS (6.92 mL, 1 M in THF) dropwise at 0 °C under N2. The mixture was stirred for 30 mins. The mixture was cooled to -78 °C and 461 -7 (2.0 g. 4.6 mmol) was added, and then stirred at -78 "C to reflux overnight. The reaction was quenched by water (30 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5: 1 ) to give 461-8 (1.2 g, 61.0%).
[0873] To a solution of 461-8 (1.3 g, 3.0 mmol) in DCM (20 mL) were added NMO (1.05 g, 9.0 mmol) and Os04 (38.4 mg, 0.15 mmol), and the mixture was stirred at r.t. overnight. The reaction was quenched with sat. Na?S03 solution (50 mL) and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na S04 and concentrated under reduced pressure. The residue was purified by column chromatography (ΡΕ.ΈΑ 3: 1 ) to give 461-9 (0.85 g, 60.7%).
[0874] To an ice-cold solution of 461-9 (265 mg, 0.725 mmol) and TEA (220 mg, 2.2 mmol) in anhydrous DCM (20 mL) was added MsCl ( 1.0 g. 8.7 mmol) dropwise. and the mixture was stirred at r.t. for 1 h. The mixture was washed with brine (20 mL). dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5: 1 ) to give 461-10 (250 mg, 63.4%).
[0875] Compound 461 was prepared essentially as described in the preparation of 428 from 461-10. Crude 461 was purified by prep-HPLC to give 461 as a white solid (36 mg. 20.2%). +F,SI-MS:m/z 556.1 [M+H]+.
EXAMPLE 242
Figure imgf000290_0001
[0876] To a solution of 462-1 (3.56 g, 10.0 mmol) in DMSO (30 mL) was added NaN (1.95 g, 30.0 mmol) at 25 °C in portions, and the mixture was stirred for 30 mins. The mixture was poured into water (50 mL), and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous a2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5: 1 ) to give 462-2 (2.4 g. 75.1 %) as a white solid. +ESI-MS:m/z 320.9 [M+H]+.
[0877] To a solution of 462-2 (2.4 g, 7.5 mmol) in anhydrous THF (30 mL) was added vinyl-magnesium bromide (7.5 mL, 1 .0M in THP) dropwise at -30 °C under N2, and the mixture was stirred for 30 mins. The reaction was quenched with sat. NH4CI solution (50 mL). The mixture was allowed to warm to r.t. and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaiSC and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5: 1 ) to give 462-3 as a white solid (2.0 g. 76.9%). +ESI-MS:m/z 349.0 [M+H]+.
[0878] Ozone was bubbled into a solution of 462-3 (2.0 g, 5.7 mmol) in anhydrous MeOH (20 mL) at -78 °C for 10 mins. After excess Ozone was purged by N2„ NaBLL (800 mg, 21.1 mmol) wras added at r.t. in portions. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with wrater (30 mL) and extracted with EA (2 x 50 mL). The combined organic phase was wrashed with brine, dried over anhydrous NaiS04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 1 : 1) to give 462-4 as an oil ( 1.6 g, 80.1%). +ESI-MS:m z 352.9 [M+H]+.
|0879] To a solution of 462-4 ( 1.6 g, 4.5 mmol) and TEA (900 mg, 8.9 mmol) in anhydrous DCM (20 mL) was added MsCl (500 mg, 4.4 mmol) dropwise at 0 °C. The solution was stirred at r.t. for 30 mins. The reaction was quenched with HiO (30 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 4: 1 ) to give 462-5 as a solid ( 1.6 g. 84.2%»). +ESI- MS:m/z 431 [M+H]+.
[0880] To a solution of 462-5 ( 1.6 g. 3.7 mmol) in CH3CN (20 mL) was added azetidine hydrochloride ( 1 .6 g, 17.2 mmol) at r.t. The solution was heated to 70 °C and stirred for 8 h. After cooling to r.t., the reaction was quenched with H20 (30 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 1 : 1 ) to give 462-6 as an oil (500 mg, 35.7%). +ES1- MS:m/z 391.9 [M+H]+.
[0881 ] Compound 462 was prepared essentially as described in the preparation of 428 by using 462-6. Crude 462 was purified by prep-HPLC to give 462 as a white solid (10 mg, 6.5%). +ESl-MS:m/z 556.1 [M+H]+.
Figure imgf000292_0001
[0882] Compound 463 was prepared essentially as described in the preparation of 461 by using l -(tcrt-butoxycarbonyl)azetidinc-3-carboxylic acid. Compound 463 was obtained as white solid (40 mg. 40%). +ESI-MS:m/z 542.1 [M+H]+.
Figure imgf000292_0002
[0883] Compound 464-2 was prepared essentially as described in Zornik et aL Chem. Eur. J. (201 1) 1 7(5): 1473-1484 and S 1473/1 -S 1473/121, which is hereby incorporated by reference for the 1 united purpose of its description of the preparation of 464-2. Compound 464-10 was prepared essentially as described in the preparation of 272 by using 464-2. Compound 464-10 was obtained as white solid (300 mg, 68.5%). +ESI-MS:m/z 582.9 [M+H]+. [0884] To a solution of 464-10 (50 mg, 0.086 mmol) in 1.4-dioxane (5 mL) was added ammonia water (2 mL) in a sealed tube. The mixture was then stirred at 100 °C overnight. After cooling to r.t., tire mixture was concentrated to dryness, and the residue was purified by prep-HPLC to give 464 ( 15 mg, 30.8%) as a white solid. +ESI-MS:m/z 568.0 [M+H]+.
Figure imgf000293_0001
[0885] To a stirred solution of 465-1 (87.3 mg, 0.15 mmol) in THF (5 mL) at 0°C was added LAH (5.7 mg. 0.15 mmol) under N2. After stirring at 0 °C for 1 h, the reaction was quenched by water (10 mL). and extracted by EA (3 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated to dryness. The residue was purified by prep-HPLC to give 465 (50 mg, 60.2%) as a white solid. +ESI- MS:m/z 555.0 [M+H]+.
EXAMPLE 246
Preparation of Compound 466
Figure imgf000293_0002
[0886] Compound 466 was prepared essentially as described in the preparation of 459 by using l-(2,6-dichloropyridin-4-yl)ethanone. Compound 466 was obtained as white solid (20 mg, 18.5 %). +ESl-MS:m/z 582.1 [M+H]+. EXAMPLE 247
Preparation of Compound 467
Figure imgf000294_0001
[0887] To a solution of 467-1 (60 mg, 0.12 mmol) in THF (4 mL) was added
MeMgCl (1 mL, 3 M in ether) dropwise at 0 "C, and the mixture was stirred at for 1 h. The reaction was quenched with sat. NH4CI solution, and extracted with EA (3 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 467
(30 mg. 47%) as a white solid. +ESI-MS:m/z 531.3 [M+H]+.
EXAMPLE 248
Figure imgf000294_0002
10888] To a solution of 468-1 (2.4 g, 20 mmol) in anhydrous THF (50mL) was added w-BuLi (8 mL, 2.5M in hexane) at -78 °C under N2, and the mixture was stirred for 0.5 h. The mixture was treated with tributylchlorostannane (6.5 g, 20 mmol) in portions, and stirred at -78 "C for 1 h. The reaction was quenched by water (50 mL), and extracted with EA (3x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (ΡΕ.ΈΑ 10: 1 ) to give 468-2 (6 g, 74 %).
[0889] A mixture of 468-2 (2.02 g. 5.0 mmol). Pd(dppf)Cl2 (90 mg. 2% eq.) and l -(6-bromo-5-methoxypyridin-2-yl)-2.2,2-trifluoroethanone (1 .5 g, 5mL) was dissolved in dry DMF (10 mL) under N2. The mixture was heated to 130 °C by microwave and stirred for 0.5 h. After cooling to r.t., the mixture was poured into water (50 mL) and extracted with EA
(3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous and concentrated under reduced pressure. The residue was purified by column chromatography (ΡΕ.ΈΛ 5: 1 ) to give 468-3 (1 .4 g, 82 %).
[0890] Compound 468 was prepared essentially as described in the preparation of
424 by using 468-3. Crude 468 was purified by pre-HPLC to give 468 as a white solid (50 mg, 20 %). +ESI-MS:m/z 547.9 [M+H]+.
EXAMPLE 249
Preparation of Compound 469
Figure imgf000295_0001
[08911 Compound 469 was prepared according to the method described in the preparation of 176. LCMS: m/z 553.10 [M+H]+.
EXAMPLE 250
Figure imgf000295_0002
[0892] Compound 135-2 was prepared essentially as described in Granzhan et al.. Angew. Chem. Int l Ed. (2010) 49(32): 5515-5518. S5515/1 -S5515/30. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 135- 2.
[0893] To a solution of 135-2 ( 10.0 g, 57.8 mmol) in anhydrous THF (60 mL) was added «-BuLi (35 mL, 2.5 M in hexane) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for 30 mins. under Ντ and oxirane ( 15.5 mL. 289 mmol) was added. The mixture was warmed to r.t. and stirred for 2 h. The reaction was quenched with H20, and extracted with EA (3 x 100 mT). The combined organic phase was washed with brine, dried over anhydrous N 2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:F.A 3: 1 ) to give 135-3 (3.5 g, 28%). I Sl-MS:ir / 217.9 [M+H]+.
[0894] To a solution of 135-3 (3.5 g, 16.1 mmol) in MeOH (60 mL) was added cone. HO solution (15 mL, 12 N) at r.t., and stirred at 60 °C for 5 h. The reaction was quenched with sat. NaHC(¾ solution, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue w¾s purified by column chromatography (PE:EA 1 : 1 ) to give 135-4 ( 1.02 g, 36%).
[0895] To a solution of 135-4 ( 1.02 g, 5.7 mmol) and K2C0 (1.5 g, 1 1.5 mmol) in a mixture of THF (10 mL) and FLO ( 10 mL) was added L (1.5 g, 6.0 mmol) in portions, and the mixture was stirred at r.t. for 30 mins. The reaction was quenched with sat. NaS2<¾ solution, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous a2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 2: 1 ) to give 135-5 (1 .1 g. 62.5%).
[0896] To a solution of 135-5 ( 1.1 g. 3.7 mmol) and PPh3 (1.5 g. 5.7 mmol) in anhydrous THF (10 mL) was added DIAD (1 .2 g, 5.7 mmol) at r.t. under N2. The mixture was heated to 70 °C for 1 h and then cooled to r.t. The reaction was quenched with H2O, and extracted with EA (3 x 30 ml.). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 2: 1) to give 135-6 (0.8 g, 78%). +ESl-MS:m/z 281.8 [M+H]+. [0897] To a solution of 135-6 (0.8 g, 7.1 mmol) and 135-7 (2.2 g, 7.1 mmol) in TI IF (10 niL) was added i-PrMgBr (21 mL, 1.0 M in TI IF) dropwise under N2, and the mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. NH4CI solution and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 1 : 1 ) to give 135-8 (1 .2 g, 77%). +ESl-MS:m/z 408.9 [M+H]+.
[0898] To a solution of 135-8 (408 mg, 1 .0 mmol). (3-chIoro-4- fluorophenyl)boronic acid (1 75 mg, 1 .0 mmol) and CS2CO3 (276 mg, 2.0 mmol) in dioxane (5 mL) and water (1 mL) was added Pd(dppf)Ci2 (82 mg, 0.1 mmol) under N2. The mixture was heated to 120 °C under microwave irradiation and stirred for 30 mins. The mixture was cooled to r.t., poured into cold H20 and extracted with EA (3 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC> and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 135 (80 mg) as a w7hite solid. +ESl-MS:m/z 502.9 [M+H]+.
Figure imgf000297_0001
[0899] To a solution of 470-1 (1.7 g, 6.7 mmol) in DCM (10 mL) was added DAST (3 mL) at 0 °C, and the mixture wras stirred at 0°C for 30 mins. The resulting was quenched with sat. NaHC03 solution at 0 °C and extracted by EA (3 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous N 2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 15: 1) to give 470-2 as a white solid (800 mg, 47.1%). [0900] To a solution of 470-2 (254 mg, 1 .0 mmol) in MeOH (5 mL) was added NaOI I (5 mL, 2 V), and the mixture was stirred at reflux for 1 h. The mixture was cooled to r.t. and acidified to pH 4~5 using HC1 (2 M). The mixture was extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give 470-3 as s!ms solid ( 100 mg, 1 .h - h).
[0901] To a solution of 470-3 ( 100 mg, 0.42 mmol), HATU (190 mg. 0.5 mmol) and DIPEA ( 129 mg. 1.0 mmol) in anhydrous DCM (5 mL) was added 470-4 ( 140 mg, 0.39 mmol) at 25 °C. The solution was stirred for 1 h and then quenched with aq. NaHC0 solution. The aqueous phase was extracted with DCM (2 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na^SC^ and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 470 as a white solid (60 mg, 243%). +ESI-MS:m/z 586.9 [M+H]+.
EXAMPLE 252
Figure imgf000298_0001
[0902] To a solution of bromide 471-1 (5.0 g. 28.9 mmol) and (3-chloro-4- fluorophenyl)boronic acid (5.5 g, 31 .8 mmol) in dioxane (50 mL) were added Pd(dppf)CL (816 mg, 1.0 mmol) and a freshly prepared Cs2C03 solution (1 1 g in 50 mL of water) under N?. The mixture was stirred at 70 °C for 3 h. The solution was cooled to r.t.. poured into ice water and extracted with EA (3 x 100 mL). The combined organic phase wras washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10: 1-5 : 1 ) to give 471-2 (5.5 g) as a white solid.
[0903] To a solution of 471 -2 (3.9 g, 17.4 mmol) and K2C<¾ (3.0 g, 21.7 mmol) in DMF (50 mL) was added I? (1.4 g, 5.5 mmol) in portions at r.t., and the mixture was stirred for 2 h. The reaction was quenched with sat.
Figure imgf000299_0001
solution, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhyrous N 2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 50: 1-25: 1 ) to give 471-3 as a white solid (2.1 g, 50%). +ESI- MS:m/z 349.8 [M+H]+.
[0904] To a solution of 471-3 (2.0 g, 5.7 mmol) and K2C(¾ (790 mg. 5.7 mmol) in DMF (25 mL) was added Mel (1.5 g, 11 mmol) dropwise at 0 °C. The mixture was stirred at r.t. for 2 h. The reaction was quenched with water, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhyrous Na?S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 50: 1) to give 471-4 as a white solid (l . lg. 55%).
[0905] To a solution of 471-4 (1.1 g, 3.0 mmol), picolinic acid hydrochloride (240 mg, 1.5 mmol), Cs2C03 (2.8 g, 8.7 mmol) and Cul ( 165 mg, 0.75 mmol) in DMF (20 mL) was added ethyl 2-cyanoacetate (650 mg, 6.0 mmol) under N2. The mixture was heated to 130 °C under microwave irradiation and stirred for 30 mins. The mixture was cooled to r.t., poured into water and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhyrous a2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10: 1-5: 1 ) to give 471 -5 as a yellow solid (720 mg, 65%). +ESI-MS:m/z 348.8 [M+H]+.
[0906] To a solution of 471-5 (720 mg. 2.04 mmol) in anhydrous DMF (15 mL) was added NaH ( 130 mg. 3.12 mmol) in portions at 0 °C. After stirring for 30 mins.. Mel (840 mg, 6 mmol) was added. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhyrous Na?S04 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 25: 1 ) to give 471-6 as a white solid (468 mg, 65%). +ESl-MS:m/z 362.8 [M+H]+. [0907] To a solution of 471-6 (460 mg, 1.27 mmol) in anhydrous THT (15 mL) was added LAI I (250 mg, 5 mmol) at 0 °C under N?, and the mixture stirred at 0 °C for 2 h. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhyrous Na2S04 and concentrated under reduced pressure. The residue was purified by prep-TLC to give 471-7 (150 mg. 36%). +ESI-MS:m/z 324.8 [M+H]+.
[0908] To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (60 mg, 0.3 mmol), HATU (70 mg. 0.5 mmol) and D1EA (300 mg. 0.7 mmol) in DCM (15 mL) was added amine 471-7 (100 mg. 0.3 mmol). After stirring at r.t. for 30 mins.. the reaction was quenched with sat. NaHCO^ solution, and extracted with DCM (3 x 10 mL). The combined organic phase was washed with brine, dried over anhyrous Na2S04 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 471 as a Avhite solid (55 mg, 32%). +ESI-MS:m/z 519.0 [M+H]+.
EXAMPLE 253
Preparation of Compounds 509-513
Figure imgf000301_0001
[0909] Potassium carbonate (29.8 g, 216 mmol) and trifluoroacetaldehyde ethyl hemiacetal (19 mL, 162 mmol) were sequentially added to a suspension of 509-1 ( 14.0 g, 108 mmol) in water (210 mL). The reaction was stirred at 100 °C overnight. Additional trifluoroacetaldehyde ethyl hemiacetal (19 mL, 162 mmol) was added. The reaction was stirred at 100 °C for 7 h, and further trifluoroacetaldehyde ethyl hemiacetal (19 mL, 162 mmol) was added. After 16 h at 100 °C, the reaction was cooled to 0 °C. neutralized with 1M aq. HCl solution and extracted with EtOAc. The organic portion was dried with Na2SC»4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 70:30) afforded 509-2 (24.0 g, 80% purity A/A UV). [0910] Iodine (40.1 g, 158 mmol) was added to a solution of 509-2 (24.0 g) and potassium carbonate (28.9 g, 210 mmol) in water (350 mL). The mixture was stirred at r.t. overnight. A 1 M aq. sodium thiosulfate solution was added. The mixture was treated with 3N aq. HCl until a white solid formed. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc (3x). The combined organic portions were dried with a2S(¾ and filtered. The solvents were removed under reduced pressure. Chromatography of the residue (cycIohexane:EtOAc, 100:0 to 70:30) afforded 509-3 as a white solid (21 .0 g, 50% over two steps). UPLC/MS(ES+) m/z: 354.03 [M+H]+.
[0911 ] Chloroacetone (2.6 mL, 32.8 mmol) was added to a solution of 509-3 ( 10.5 g, 29.8 mmol) and potassium carbonate (6.18 g, 44.8 mmol) in acetone (170 mL). The reaction was stirred at 50 °C overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The layers were separated, and the organic portion was dried with a2S04, filtered and concentrated under reduced pressure. The residue was tritrated with DCM, and the precipitate dried to afford 509-4 as a white solid (6.80 g, 55%). LIPLC/MS(ES+) m/z: 409.92 [M+H]+. The supernatant was concentrated under reduced pressure, and the residue chromatographed (cyclohexane:EtOAc, 100:0 to 0: 100) to afford unreacted 509-3 (1 .20 g, 1 1 %).
[0912] The reaction was performed in 8 batches. A mixture of 509-4 (841 mg, 2.05 mmol), 2-methylpropane-2-sulfmamide (273 mg, 2.26 mmol) and titanium(lV) ethoxide (1.03 g, 4.51 mmol) in THF ( 16 mL) was heated to 70 °C (sealed vial, degassed and purged with N2). The mixture was stirred at 70 °C for 3 h. The 8 batches were unified. EtOAc and water were added. The mixture was stirred for 5 mins, and then filtered through a pad of celite. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried writh Na2S04 and fdtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 50:50 to 0: 100) afforded 509-5 (5.36 g, 63%). UPLC/MS(ES+): m/z 513.10 [M+H]+.
[0913] w-Butliyllithium (1.6M solution in THF, 6.60 mL, 10.5 mmol) w<as added to a solution of EtMgBr (lM in THF, 5.23 mL, 5.23 mmol) in THF (15 mL), which had been pre-cooled to 0°C. After 10 mins, the mixture was cooled to -78 °C. A solution of 509-5 (2.68 g, 5.23 mmol) in THF (15 mL) w7as added dropwise. The reaction was stirred at -78°C for 15 mins. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with brine, and the aqueous portion extracted with EtOAc. The combined organic portions were dried with Na2SO_i. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 509- 6 as a yellow wax (2.60 g, 64%).
[0914] Dess-Martin periodinane (3.14 g, 7.46 mmol) was added to a stirred solution of 509-6 (2.60 g, 6.73 mmol) in DCM (36 mL). The reaction was stirred at r.t. under N2 atmosphere for 3 h. The reaction was quenched with a 1 : 1 mixture of 2M aq. Na2S203 and sat. aq. NaHC03. After 30 mins of vigorous stirring, the layers were separated. The organic portion was w7ashed with brine, dried with Na2SC> . filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane. 'EtOAc, 100:0 to 50:50) afforded 509-7 as a white solid (2.1 1 g, 81%). UPLC/MS(ES+): m/z 385.16 [M+H]+, 403.18
Figure imgf000303_0001
[0915] The reaction was performed in 2 batches. Trimethylsulfoxonium iodide (601 mg, 2.73 mmol) was added in 1 portion to a mixture of tBuOK (305 mg, 2.73 mmol) in CH3CN (50 mL), which had been previously degassed. The mixture w7as further degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution of 509-7 (1.05 g, 2.73 mmol) in CH3CN (50 mL), which had been previously degassed. The reaction was stirred at r.t. for 1 h. The 2 batches were combined, and the volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 50:50) afforded 509-8 as a colorless wax ( 1.45 g, 66%). UPLC/MS(ES+): m/z 399.14 [M+H]+.
[0916] A solution of 509-8 (1 .45 g. 3.64 mmol) in 7M NH3-MeOH (800 mL) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford 509-9 ( 1.43 g), which was used in the next step.
[0917] Method A: A mixture of 509-9 (750 mg). EDC (448 mg, 2.35 mmol). HOBT (317 mg. 2.35 mmol), TEA (500 uL. 3.60 mmol) and acid (1.80 mmol) in DCM (18 mL) was stirred at r.t. for 2 h. Water was added, and the mixture was stirred for 10 mins. The layers were separated, and the organic portion was dried with Na^SC The solvent was evaporated under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc) afforded 509-10.
[0918] Method B: A solution of acid (0.120 mmol), HATU (44 mg) and DIPEA (1 10 uL) in DMF or DCM ( 1 mL) was stirred at r.t. for 15 mins. A solution of 509-9 (50 mg) in DMF (or DCM, 1 mL) was added to the reaction. The mixture was stirred at r.t. for 20 mins. The majority of the volatiles were removed under reduced pressure. The residue was taken up with EtOAc, and the organic portion was washed with 1 M aq. NaOH and 1 M aq. HC1, dried with Na2SO.t, filtered and concentrated under reduced pressure to give 509-10.
[0919] A mixture of 509-10 (0.582 mmol), boronic acid (0.872 mmol), K?P04 (247 mg. 1.16 mmol), KH2P04 (158 mg, 1.16 mmol) and Pd(dbpf)Cl2 (1.3.8 mg, 0.029 mmol) in a DME:EtOH:H20 mixture (5:3: 1, 9 mL) was degassed and warmed to 50 °C for 6 h. DCM and water were added. The layers were separated, and the organic portion was dried with a2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane: EtOAc) afforded 509-11.
[0920] A 4M HCT-dioxane solution (1 mL) was added to a solution of 509-11 (0.508 mmol) in MeOH (5 mL). After 15 mins, the volatiles were removed under reduced pressure. The residue was dissolved in DCM. The organic portion was washed with 5% aq. NaHCO.i solution and water, dried with Na2S04, filtered and concentrated under reduced press
Figure imgf000304_0001
to Method A afforded 509-1 OA as a white solid (85%). UPLC/MS(ES+): m/z 606.24 [M+H] . Suzuki coupling of 509-10A with 4-fluorophenylboronic acid followed by sulfmamide hydrolysis afforded 509 as a white solid (53% over two steps). UPLC/MS(ES+): m/z 562.20 [M+H]+.
[0922] 509 (53 mg) was dissolved in DCM. The solution was washed with sat. aq. NaHC03 solution, dried with Na2S04, filtered and concentrated under reduced pressure. The amine was resolved by prep-HPLC [Chiralpak AD-H (25 x 3 cm, 5 um), mobile phase: n-hexane/(ethanol+0.1 % ipa) 80:20 % v/v. flow rate: 32mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: a mixture of 510, 512 and 513: tR= 21 .0 min; and 511 : white solid (7.3 mg, tR= 28.5 min). UPLC/MS(ES+): m/z 562.20 [M+H]+.
[0923] The mixture of 510, 512 and 513 was resolved by prep-HPLC [Chiralpak 1C (25 x 3 cm, 5 um), mobile phase: n-hexane/(ethanol + 0.1% ipa) 70/30 % v/v, flow rate: 32 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: a mixture of 512 and 513: tR= 8.2 min; and 510: white solid (7.1 mg. tR= 10.6 min). UPLC/MS(ES+): m/z 562.20 [M+H]+.
[0924] Lhe mixture of 512 and 513 was resolved by prep-HPLC [Chiralpak OJ-H (25 x 3 cm, 5 um). mobile phase: n-hexane/(ethanol/MeOH 1/1 + 0.1% ipa) 65/35 % v/v, flow rate: 38 mL/min, UV detection DAD 220 nm]. Lwo fractions were recovered based on retention times: 512: white solid (6.0 mg, tR= 7.2 min). IJPLC/ S(ES+): m/z 562.20 [M+I If; and 513: white solid (6.0 mg, tR= 1 1 .3 min). UPLC/MS(ES+): m/z 562.20 [M+I I] \
[0925] Alternatively, 509 (220 mg) was resolved by prep-HPLC [Chiralpak IC (25 x 2 cm. 5 um). mobile phase: n-hexane/(ethanol/methanol 1 /1 +0. 1 % ipa) 86/14% v/v. flow rate: 16 mL/min. UV detection DAD 220 nm]. Three fractions were recovered based on retention times: a mixture of 512 and 513: ( 104 mg. tR= 13.4 min); 511 : (40 mg. 14%, tR= 15.0 min). UPLC/MS(ES+): m/z 562.20 [M+H]+; and 510: (35 mg. 12%. tR= 17.5 min). UPLC/MS(ES+): m/z 562.20 [M+H]+.
[0926] The mixture of 512 and 513: was resolved by prep-HPLC [Chiralcel OJ-H (25 x 3 cm, 5 um). mobile phase: n-hexane/(ethanol/methanol 1 /1 +0.1% ipa) 65/35% v/v. flow rate: 40 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: 512 (41 mg, 14%, tR= 7.5 min). UPLC/MS(ES+): m/z 562.20 [M+H]+; and
513 (46.6 mg. 1 6%, tR= 12.0 min). UPLC7MS(ES+): m/z 562.20 [M+H]+.
EXAMPLE 254
Preparation of Compound 542
Figure imgf000306_0001
[0927] Suzuki coupling of 509-10A with 4-cyanophenylboronic acid followed by hydrolysis of the resulting sulimamide afforded 542 (78% over 2 steps). UPLC/MS(ES+):
Figure imgf000306_0002
EXAMPLE 255
Preparation of Compound 539
Figure imgf000306_0003
[0928] Coupling of 509-9 (50 mg) with 4-(2-(4-methoxybenzyloxy)ethoxy)-3- methoxybenzoic acid according to Method B afforded 509-l B. Suzuki coupling of 509-10B with 4-fIuorophenylboronic acid followed by sulfinamide hydrolysis and PMB-group removal afforded 539 as an off-white solid (10 mg). UPLC/MS(ES ' ): m/z 566.30 [M+H]+.
EXAMPLE 256
Preparation of Compound 543
Figure imgf000306_0004
[0929] Coupling of 509-9 (80 mg) with 4-(carbamoylmethoxy)-3-methoxybenzoic acid according to Method B afforded 509-10 C. Suzuki coupling of 509-l OC with 4- fluorophenylboronic acid followed by sulfinamide hydrolysis afforded 543 as an off-whitc solid (8.7 mg). UPLC/MS(ES+): m/z 579.40 [M+H]+.
EXAMPLE 257
Preparation of Compound 556
Figure imgf000307_0001
[0930] Coupling of 509-9 with 4-[(2 )-2-hydroxypropoxy]-3-methoxybenzoic acid according to Method A afforded 509-10D. UPLC/MS(ES+): m/z 624.20 [M+H]+. Suzuki coupling of 509-10D with 4-fluorophenylboronic acid followed by sulfinamide hydrolysis afforded 556 as an off-white solid (50% over 2 steps). UPLC/MS(ES+): m/z 580.33 [M+H]+.
Figure imgf000308_0001
[0931 J A mixture of 509-2 (5.00 g, 22.0 mmol). (3-chloro-4-fiuorophenyl)boronic acid (7.66 g„ 44.0 mmol), Pd(dppf)Ci2 ( 1.60 g, 2.20 mmol) and Na2C03 (2M aq solution. 22.0 mL. 44.0 mmol) in IX' i : (250 mL) was degassed and heated to reflux for 16 h. Additional Pd(dppf)Cl2 (0.05 eq), (3-chloro-4-fluorophenyl)boronic acid ( 1 eq.) and aq aoCO^ (1 eq) were added. The reaction was refluxed for 4 and then water was added. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2SC>4. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:DCM. 70:30 to 0: 100) afforded 494- 13 as a yellow solid (2.74 g). UPLC/MS(ES+): m/z 322.10 [M+H]+.
[0932] Iodine (1.77 g, 6.98 mmol) was added to a solution of 494-13 (2.24 g, 6.98 mmol) and potassium carbonate (2.89 g, 20.9 mmol) in water (100 mL). The mixture was stirred at r.t. for 30 mins. A 1 M aq. sodium thiosulfate solution was added. The mixture was treated with 3N aq. HC1 until a white solid formed. EtOAc was added, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic portions were dried with Na2S04 and filtered. The solvents were removed under reduced pressure. Chromatography of the residue (cvclohexanerEtOAc. 100:0 to 80:20) afforded 494-14 as a light yello solid (2.80 g, 90%). UPTC/MS(ES+): m/z 448.05 [M+Et .
[0933] Chloroacetone (548 μΕ. 6.89 mmol) was added to a solution of 494-14 (2.80 g. 6.26 mmol) and potassium carbonate (1.30 g, 9.40 mmol) in acetone (40 mL). The reaction was stirred at 50 °C for 24 h. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The layers were separated, and the organic portion was dried with N 2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:DCM, 60:40 to 30:70) afforded 494-15 as a white solid (2.38 g, 75%). UPLC/MS(ES+): m/z 504.27 [M+H]+.
|0934] A mixture of 494-15 (1.87 g. 3.72 mmol). 2-methylpropane-2-sulfinamide (495 mg, 4.09 mmol) and titanium(lV) ethoxide (1.86 g, 8.18 mmol) in THF (30 mL) was heated to 70 °C (sealed vial, degassed and purged with N2). The mixture wras stirred at 70 °C overnight. EtOAc and water were added. The mixture was filtered through a pad of celite. The layers were separated, and the organic portion was dried with Na9S04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 20:80) afforded 494-16 as a light yellow solid (1.00 g, 45%). UPLC/MS(ES+): m/z 607.07 [M+H]+.
[0935] n-Buthyllithium (1.6 M solution in THF. 2.07 mL, 3.32 mmol) was added to a solution of EtMgBr (1 M solution in THF, 1 .66 mL, 1 .66 mmol) in THF (5 mL), which had been pre-cooled to 0°C. After 10 mins. the mixture was cooled to -78°C. A solution of 494-16 (1.00 g, 1.66 mmol) in THF (5 mL) was added dropwise, and the reaction was stirred at -78 °C for 15 mins. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with brine, and the aqueous portion extracted with EtOAc. The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 50:50 to 0: 100) afforded 494- 17 (775 mg, 70% purity A/A UV). [0936] Dess-Martin periodinane (822 mg, 1 .94 mmol) was added to a stirred solution of 494-17 (775 mg) in DCM (7mL). The reaction was stirred at r.t. for 2 h and quenched with a 1 : 1 mixture of 2M aq. Na2S203 and sat. aq. NaHC(¾. After 20 mins of vigorous stirring, the layers were separated. The aqueous portion was extracted with DCM. The combined organic portions were dried with Na?S04. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 50:50 to 0:100) afforded 494-18 (480 mg, 60% over 2 steps).
[0937] Trimethylsulfoxonium iodide (57.5 mg. 0.261 mmol) was added in one portion to a mixture of tBuOK (29.2 mg, 0.261 mmol) in CH3CN (5 mL), which had been previously degassed. The mixture was further degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution 494-18 (125 mg. 0.261 mmol) in CH CN (4 mL), wTiich had been previously degassed. The reaction was stirred at r.t. for 15 mins. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 0: 100) afforded 494-19 as a colorless wax ( 1 mg, 40%). UPLC7MS(ES+): m/z 493.20 [M+H]+.
[0938] A solution of 494-19 (51 mg) in 7M NH3-MeOH (30 mL) was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure to afford 494-20 (62 mg), which was directly in the next step.
[0939] A mixture of acid (0.136 mmol), HATU (51 .7 mg, 0.136 mmol) and DIPEA (43 uL, 0.246 mmol) in DCM (2 mL) was stirred at r.t. for 30 mins. A solution of 494-20 (62 mg) in DCM (2 mL) was added, and the mixture was stirred at r.t. for 1 h. The reaction was partitioned between DCM and water, and the layers were separated. The organic portion was washed with brine, dried with Na^SC^. filtered and concentrated under reduced pressure. Chromatography of the residue afforded 494-21.
[0940] A 4M HCl-dioxane solution (1 mL) was added to a solution of 494-21 (0.060 mmol) in MeOH (5 mL). After 30 mins, the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography to afford 494-22.
Figure imgf000311_0001
[0941] Coupling of 494-20 with 3-chloro-4-ethoxybenzoic acid followed by hydrolysis of the resulting sulfinamide afforded 494 (42% over 3 steps). UPLC/MS(ES+): m/z 588.20 [ +H]+.
Figure imgf000311_0002
[0942] Coupling of 494-20 with 4-ethoxy-3-methoxybenzoic acid followed by hydrolysis of the resulting sulfinamide afforded 498 (28% over three steps). UPLC/MS(ES+): m/z 584.30 [M+H]+.
Figure imgf000311_0003
[0943] Coupling of 494-19 with 4-cyclopropoxy-3-methoxybenzoic acid afforded 482 (68% over 2 steps). UPLC/MS(ES+): m/z 700.32 [M+H]+.
Figure imgf000312_0001
[094 1 Hydrolysis of 482 according to general procedure afforded 483 as a white solid (formic acid salt, 76%). Alternatively. 483 was prepared by Suzuki coupling of 509- 10A with 3-chloro-4-fluorophenylboronic acid and subsequent hydrolysis of the resulting sulfmamide (53% over 2 steps). UPLC/MS(ES+): m/z 596.29 [M+H]+.
[0945] 483 (100 mg) was resolved by prep-HPLC [Chiralpak AD-H (25 x 2 cm, 5 urn), mobile phase: n-hexane/(ethanol+0.1 % ipa) 80/20% v/v, flow rate: 14 mL/min, UV detection DAD 220 ran]. Two fractions were recovered based on retention times: a mixture of 498a and 498b: 32 mg (tR= 14.3 min); and a mixture of 498c and 498d: 31 mg (tR= 19.0 min).
[0946] The mixture of 498a and 498b (32 mg) was resolved by prep-HPLC [Chiralcel OJ-H (25 x 2 cm, 5 um), mobile phase: n-hexane/(ethanol/methanol +0.1 % ipa) 55/45% v/v, flow rate: 17 mL/min, UV detection DAD 220 ran]. Two fractions were recovered based on retention times: 498a: 9.3 mg (IR= 5.7 min). UPLC/MS(ES+): m/z 596.25 [M+H]+; and 498b: 10.2 mg (tR= 8.8 min). UPLC/MS(T,S+): m/z 596.25 [M+H]+.
[0947] The mixture of 498c and 498d (31 mg) was resolved by prep-HPLC [Chiralpak IC (25 x 2 cm, 5 um), mobile phase: n-hexane/(2-propanol +0.1% ipa) 55/45% v/v, flow rate: 18 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: 498c: 10 mg (tR= 6.7 min). UPLC/MS(ES~): m/z 596.25 [M+H]+; and 498d: 8 mg (tR= 10.5 min). UPLC/MS(ES+): m/z 596.25 [M+H]+.
EXAMPLE 259
Preparation of Compound 499
Figure imgf000313_0001
[0948] A solution of 483 (30 mg) and chloroacetaldehyde (50% aq. solution, 30 uL) in MeOH (1.5 mL) was stirred at r.t. for 1 h. NaBH CN (2 mg) was added, and the mixture was stirred at r.t. for 1 8 h. The volatiles were removed under reduced pressure to afford a mixture of 499-1 and unreacted starting material (2: 1 ), which was dissolved in DMF (1.5 mL). NaN3 (10 mg) was added. The reaction was stirred at 70 °C for 20 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 80:20 to 0: 100) afforded 499-2 as a pale yellow oil (20 mg). UPLC/MS(ES+): m/z 665.30 [M+H]+.
[0949] A mixture of 499-2 (20 mg) and PPh3 (10 mg) in 2: 1 THF-H20 (1.5 mL) was stirred while heating to 60 °C for 2 h. The volatiles were removed under reduced pressure. The residue was loaded on to an SCX column and eluted with 2M NFL-MeOH to afford 499 (7 mg). UPLC/MS(ES+): m/z 639.30 [M+H]+.
Figure imgf000314_0001
[0950] Compounds 530 and 531 were prepared by using a strategy that follows the procedure described for 509.
[09511 l -Bromo-2-butanone (300 mg. 1.98 mmol) was added to a solution of 509- 3 (1.00 g, 2.84 mmol) and potassium carbonate (520 mg. 4.26 mmol) in acetone (16.5 rriL). The reaction was stirred at 50°C for 1 h. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The layers were separated. The organic portion was dried with Na2SO_i, filtered and concentrated under reduced pressure. The residue was triturated with DCM-cyclohexane to afford 530-1 as a white solid (1.02 g, 85%). UPLC/MS(ES+): m/z 423.93 [M+H]+. [0952] The reaction was performed in 2 batches. A mixture of 530-1 (510 mg, 1.20 mmol), 2-methylpropane-2-sulfinamide (160 mg, 1.32 mmol) and titanium(IV) ethoxide (602 mg, 2.64 mmol) in THF (9.5 mL) was heated to 70 °C (sealed vial, degassed and purged with N2). The mixture was stirred at 70 °C for 4 h. The 2 batches were unified, and EtOAc and water were added. The mixture was filtered through a pad of celite. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 95:5 to 60:40) afforded 530-2 (850 mg, 67%). UPLC/MS(ES+): m/z 527.00 [M+H]+.
[0953] EtMgBr (1M solution in THF, 1.61 mL, 1.61 mmol) was added to a solution of rt-BuLi ( 1.6M solution in THF, 2.01 mL, 3.23 mmol) in dry THF (5 mL), which had been pre-cooled to 0°C. After 30 mins, the mixture wras cooled to -78 °C. A solution of 530-2 (850 mg, 1.61 mmol) in dry THF (4 mL) was added dropwise, and the reaction was stirred at -78 °C for 20 mins. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with water and the aqueous portion extracted with EtOAc. The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 30:70) afforded 530-3 as a white foam (441 mg).
[0954] Dess-Martin pcriodinane (932 mg, 2.20 mmol) was added to a stirred solution of 530-3 (441 mg) in DCM (5 mL). The reaction was stirred at r.t. for 1 h and quenched with a 1 :1 mixture of 1 M aq. NaiS Os and 5% aq. NaHC03. After 20 min of vigorous stirring, the layers were separated. The aqueous portion was extracted with DCM. The combined organic portions were dried with Na2S04. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 0:100) afforded 530-4 as a white foam (320 mg, 50% over two steps). UPLC/MS(ES+): m/z 417.10 [M+H30]+.
[0955] Trimethylsulfoxonium iodide (175 mg, 0.790 mmol) was added in one portion to a mixture of tBuOK (88 mg, 0.790 mmol) in C¾CN (15 mL). which had been previously degassed. The mixture w7as further degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution 530-4 (317 mg, 0.790 mmol) in CH3CN (15 mL), which had been previously degassed. The reaction was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 530-5 as a colorless wax (207 mg. 64%). UPLC/MS(ES+): m/z 413.12 [M+H]+.
[0956] A solution of 530-5 (207 mg) in 7M NHi-MeOH (142 mL) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford crude 530-6 (203 mg) which was directly progressed to the next step.
[0957] A mixture of acid (0.233 mmol), HATU (86 mg. 0.252 mmol) and D1PEA (58 uL. 0.336 mmol) in DCM (2 mL) was stirred at r.t. for 30 mins. A solution of 530-6 (100 mg) in DCM (2 mL) was added. The mixture was stirred at r.t. for 1 h. The reaction wras partitioned between DCM and water, and the layers were separated. The organic portion was washed with brine, dried with Na?S04, filtered and concentrated under reduced pressure. The residue was purified by chromatography to give 530-7 or 530-8.
[0958] A mixture of 530-7 or 530-8 (0.134 mmol), 4-fluorophenylboronic acid (38 mg), K3PO4 (29 mg), H2P04 (18 mg) and Pd(dbpf)Cl2 (17 mg) in a DME:EtOH:H20 mixture (10:5:3, 3.6 mL) was degassed and wrarmed to 50 °C- 70 °C. DCM and w7ater w7ere added. The layers were separated. The organic portion was dried with a2S04, filtered and concentrated under reduced pressure. The residue was purified by chromatography. A solution of sulfmamide (80 mg) in 4M HCT-dioxane was stirred at r.t. for 10 mins. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography.
[0959] Coupling of 530-6 with 4-cyclopropoxy-3-methoxybenzoic acid afforded 530-7. which was subjected to Suzuki coupling and sulfmamide hydrolysis as described herein to afford 531 as a white solid (formic acid salt. 25% overall). UPLC/MS(ES+): m/z 576.30 [M+H]+.
[0960] Coupling of 530-6 with 4-(2-(4-methoxybenzyloxy)ethoxy)-3- methoxy benzoic acid afforded 530-8, which wras subjected to Suzuki coupling and protecting groups removal as described herein to afford 530 as a white powder (26% overall). UPLC/MS(LS+): m/z 580.34 [M+H]+.
Figure imgf000317_0001
[0961] Compounds 560, 565 and 531 were prepared by using a strategy that follows the procedure described for 509.
[0962] l -Bromo-3-methylbutan-2-one (659 mg. 3.99 mmol) was added to a solution of 509-3 (2.01 g, 5.71 mmol) and potassium carbonate ( 1.18 g, 8.56 mmol) in acetone (34 niL). The reaction was stirred at 50°C for 1 h. The volatiles were removed under reduced pressure and the residue was partitioned between water and EtOAc. The layers were separated. The organic portion was dried with Na2SC>4, filtered and concentrated under reduced pressure. The residue was tritured with cyclohexane and the precipitate dried to afford 560-1 as a white solid (1.38 g. 55%). UPLC/MS(ES+): m/z 438.10 [M+H]+. [0963] A mixture of 560-1 (1 .38 g, 3.15 mmol), 2-meth lpropane-2-sulfmamide (419 mg, 3.46 mmol) and titanium(IV) ethoxide (1.58 g, 6.93 mmol) in TI IF (25 mL) was heated to 70 °C (sealed vial, degassed and purged with N2) and stirred at 70 °C for 4 h. EtOAc and water were added. The mixture was filtered through a pad of celite. The layers were separated. The organic portion was dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexanerEtoO. 90: 10 to 60:40) afforded 560-2 (841 mg. 50%). UPLC/MS(ES+): m/z 541.10 [M+H]+.
[0964] n-Buthyllithiutn (1.6 M solution in THF. 1.93 mL, 3.10 mmol) was added to a solution of EtMgBr (1M solution in THF, 1 .55 mL, 1 .55 mmol) in THF (5 mL). which had been pre-cooled to 0°C. After 10 mins, the mixture was cooled to -78°C. A solution of 560-2 (841 mg, 1.55 mmol) in THF7 (4 mL) was added drop wise and the reaction was stirred at -78 °C for 20 min. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion w¾s washed with brine and the aqueous portion extracted with EtOAc. The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 30:70) afforded 560- 3 as a white foam (580 mg, 90%).
[0965] Dess-Martin periodinane (1.19 g, 2.80 mmol) was added to a stirred solution of 560-3 (580 mg, 1 .40 mmol) in DCM (10 mL). The reaction was stirred at r.t. for 1 h and quenched with a 1 : 1 mixture of 2M aq. Na2S203 and sat. aq. NaI IC03. After 20 mins vigorous stirring, the layers were separated. The aqueous portion was extracted with DCM. The combined organic portions were dried with Na?S04. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 0:100) afforded 560-4 as a white foam (520 mg. 90%).
[0966] Trimethylsulfoxonium iodide (277 mg, 1 .26 mmol) was added in one portion to a mixture of tBuOK ( 141 mg, 1.26 mmol) in CH3CN (20 mL). which had been previously degassed. The mixture was further degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution 560-4 (520 mg, 1.26 mmol) in CH3CN (20 mL), which had been previously degassed. The reaction was stirred at room temp for 15 min. Volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 50:50) afforded 560-5 as a colorless oil (31 1 mg, 58%). UPLC/MS(ES+): m/z 427.28 [M+I I] 1 .
[0967] A solution of 560-5 (31 1 mg, 0.730 mmol) in 7M NH3-McOH (140 mL) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford 560-6 (31 3 mg), which was directly progressed to the next step.
[0968] Method A: A mixture of 560-6 ( 155 mg. 0.350 mmol). acid (0.350 mmol), EDC (86.3 mg, 0.450 mmol). HOBT (61 .4 mg, 0.450 mmol) and TEA (97 iL, 0.700 mmol) in DCM (5 mL) was stirred at r.t. for 2 h. Water was added and the mixture was stirred at r.t. for 10 mins. The layers were separated, and the organic portion was washed with brine, dried th Na^SC^, filtered and concentrated under reduced pressure. Chromatography" of the residue (cyclohexane:EtOAc) afforded 560-7.
[0969] Method B: A mixture of acid (0.169 mmol), HATU (96.5 mg, 0.254 mmol), and DIPEA (59 uL, 0.338 mmol) in DMF (1 mL) was stirred at room temp for 30 min. A solution of aminol 560-6 (100 mg) in DMF (1 mL) was added and the reaction was stirred at room temp for lh. EtOAc was added and the organic portion w as washed twice with sat. aq. NH4CI solution, dried (Na^SC^), filtered and concentrated under reduced pressure to afford 560-7, which w7as directly progressed to the next step.
[0970] A mixture of 560-7 (0.250 mmol), 4-fluorophenylboronic acid (104 mg, 0.740 mmol), 3PO4 (106 mg, 0.500 mmol), KH2P04 (68 mg, 0.500 mmol) and Pd(dbpf)Cl2 ( 1 1 mg, 0.01 7 mmol) in a DME:EtOH:H20 mixture (5 :3 : 1 , 18 mL) was degassed and warmed to 80 °C. After 3 h, EtOAc was added. The organic portion was washed with sat. aq. NH4CI solution, dried with Na2SO_i, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 560-8.
[0971 ] Method A: Hydrochloric acid (4M solution in dioxane. 2 mL) was added to a solution of 560-8 (152 mg) in MeOH (4 mL). After 10 mins, the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography to afford 560-9.
[0972] Method B: A solution of 560-8 (0.089 mmol) in 4M HCl-dioxane (4 mL) was stirred at r.t. for 40 mins. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water-CPHCN, 100:0 to 50:50) to afford 560-9.
Figure imgf000320_0001
[0973] Coupling of 560-7 with 4-cyclopropoxy-3-methoxybenzoic acid according to Method A afforded 560-8A (70%). UPLC/MS(ES+): m/z 634.33 [M+H]+.
[0974] Suzuki coupling of 560-8A with 4-fluorophenylboiOnic acid followed by sulfmamide hydrolysis (Method A) afforded 560 as a white solid (43% over 2 steps). U +): m/z 590.40 [M+H]+.
Figure imgf000320_0002
[0975] Coupling of 560-7 with 4-(2-(4-methoxybenzyloxy)ethoxy)-3- methoxybenzoic acid according to Method B afforded 560-8B which was progressed to the next step without any purification.
[0976] Suzuki coupling of 560-8B with 4-fluorophenylboronic acid followed by sulfmamide hydrolysis (Method B) afforded 565 as an off-white solid ( 13% overall). UPLC/MS(ES+): m/z 594.40 [M+H]+.
Figure imgf000321_0001
[0977] Coupling of 560-7 with 4-[(2R)-2-hydroxypropoxy]-3-methoxybenzoic acid according to Method A afforded 560-8C (43%).
[0978] Suzuki coupling of 560-8C with 4-fluorophenylboronic acid followed by sulfmamide hydrolysis (Method A) afforded 568 (52% overall). UPLC/MS(ES+): m/z 608.50 [M+H]+.
Figure imgf000322_0001
[0979] Formaldehyde (37% aq. solution, 30.4 mL, 407 mmol) was added in 4 portions to a mixture of 473-1 ( 15.0 g. 116 mmol) and NaHC03 (14.6 g. 174 mmol) in water (120 mL) which had been pre-heated to 90°C. The reaction was stirred at 90 °C for 16 h. Additional formaldehyde (37% aq. solution, 232 mmol) was added and the reaction was stirred at 90°C for 1 h. After being cooled to r.t., the reaction was concentrated under reduced pressure. The crude 473-2 was directly used in the next step.
[0980] Iodine (25 g. 98.4 mmol) was added to a mixture of 473-2 ( 13 g) and K2C03 (22.0 g. 159 mmol) in water (100 mL). The mixture was stirred at r.t. for 4 h. The reaction was poured in to a 1M aq. HCl solution, which had been pre-cooled to 0 °C. The aqueous portion was extracted with EtOAc (3x). The combined organic portions were dried with Na2SC>4 and filtered. The volatilcs were removed under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc, 100:0 to 0: 100) afforded 473-3 as an off-white solid (5.4 g). Ή NMR (400 MHz. DMSO- ) δ ppm 4.41 (s, 2 H), 7.77 (s, 1 H), 10.37 (s. 1 H).
[0981] Chloroacetone (750 uL) was added to a mixture of 473-3 (2.41 g) and K2CO3 ( 1 .69 g) in acetone (50 mL). The mixture was warmed to 50 °C and stirred at 50 °C for 16 h. The volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na?S04 and filtered. The volatiles were removed under reduced pressure. Trituration of the residue with DCMxyclohexane afforded 473-4 as a white solid (2.33 g). UPLC/MS(ES+): m/z 342.00 [M+H]+.
[0982] EtMgBr (1M solution in 2-methyltetrahydrofuran, 4.39 mL, 4.39 mmol) was added to a solution of M-BuLi ( 1.6 M solution in hexane. 5.48 mL. 8.78 mmol) in THF (10 mL), which had been pre-cooled to 0 °C. After 10 mins, the mixture was cooled to -78 °C. A solution of 473-4 (1.35 g, 3.96 mmol) in THF (8 mL) was added dropwise and the reaction was stirred at -78 °C for 2 h. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with water, dried with Na2SO_j, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc, 70:30 to 0: 100) afforded 473-5 (619 mg, 72%). UPLC/MS(ES+): m/z 216.10 [M+H .
[0983] Alcohol 473-5 was split in 2 batches (2 x 305 mg) which were separately processed as described below. The 2 reactions were unified for work-up and purification procedures. A mixture of 473-5 (305 mg, 1.42 mmol). (3-chloro-4-fluorophenyl)boronic acid (617 mg, 3.54 mmol), Pd(dppf)Cl2 (104 mg, 0.142 mmol) and sodium carbonate (2M aq. solution, 2.49 mL, 5.00 mmol) in DCE (10 mL) was degassed and stirred with heating to 100°C under microwave irradiation for 1.5 h. DCM and water wrere added. The layers were separated and the aqueous portion was extracted with DCM. The combined organic portions were dried with NaiS04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 50:50 to 0: 100) afforded 473-6 (315 mg, 35%) and some unreacted 473-5 (94 mg). 473-6: Ή NMR (400 MHz, CDC¾) δ ppm 1.74 (s, 3 H), 4.48 (d, .7=10.3 Hz, 1 H), 4.66 (d, .7=10.3 Hz, 1 H), 4.75 (d, .7=14.1 Hz, 1 H), 4.79 (d, =14.1 I Iz, 1 1 1), 7.22 (s, 1 I I), 7.23 (t, =8.7 I Iz, 1 I I), 8.18 (ddd, J=8.7, 4.7. 2.3 I Iz, 1 H), 8.36 (dd, J=7.3, 2.3 Hz, 1 H).
[0984] Dess-Martin periodinane (365 mg. 0.861 mmol) was added to a stirred solution of 473-6 (315 mg, 1.02 mmol) in DCM (5 mL). The reaction was stirred at r.t. for 1.5 h. A 1 : 1 1 M aq. Na2S203:sat. aq. NaHC03 mixture was added to the reaction and the mixture was stirred at r.t. for 20 mins. The layers were separated and the aqueous portion was extracted with DCM. The combined organic portions were dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 90: 10 to 0: 100) afforded 473-7 (266 mg, 85%). Ή NMR (400 MHz. CDC ) δ ppm 1.57 (s, 3 H). 4.60 (d, J=10.3 Hz, 1 H), 4.82 (d. .7=10.3 Hz. 1 H), 7.30 (t, = 8.7 Hz, 1 H), 8.02 (s, 1 H), 8.32 (ddd, .7=8.7, 4.6, 2.3 Hz, 1 H), 8.50 (dd, ,7=7.3, 2.3 Hz, 1 H), 10.1 1 (s, 1 H).
[0985] Trimethylsulfoxonium iodide ( 191 mg, 0.866 mmol) was added to a solution of tBuOK (97 mg, 0.866 mmol) in DMSO (3 mL). The mixture was stirred at r.t. for 30 mins. A solution of 473-7 (266 mg, 0.866 mmol) in DMSO (3 mL) was added and the mixture was stirred at r.t. for 30 mins. The reaction was diluted with EtOAc and water. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine, dried with Na^SO. , filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 0: 100) afforded 473-8 (81 mg, 29%). Ή NMR (400 MHz, CDCb) δ ppm 1 .75 (2 x s, 3 H), 3.00- 3.04 (m, 1 H), 3.24 (dd. J=5.1 , 4.4 Hz, 1 H), 4.1 1 - 4.15 (m, 1 H) 4.48 (d. .7=10.0 Hz, 1 H), 4.68 (d. J=10.0 Hz. 1 H). 7.20 - 7.28 (m. 2 H). 8.21 - 8.28 (m. 1 H). 8.40 - 8.46 (m. 1 H).
[0986] A solution of 473-8 (81 mg. 0.252 mmol) in 7M NH3-MeOH (50 mL) was stirred at r.t. for 20 h. The volatiles were removed under reduced pressure. Crude 473-9 was directly used in to the next step.
[0987] A mixture of 4-cyclopropoxy-3-methoxy benzoic acid (63 mg. 0.302 mmol), HATU ( 144 mg. 0.378 mmol) and DIPEA (88 uL. 0.504 mmol) in DME (1 mL) was stirred at r.t. for 30 mins. A solution of 473-9 in DMF (2 mL) was added and the mixture was stirred at r.t. for 1 h. EtOAc was added The organic portion was washed with brine, dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAc:MeOLL 100:0 to 80:20) afforded 473-10 (82 mg). UPLC/MS(ES+): m/z 529.30 [M+H]+.
[0988] Dess-Martin periodinane (65 mg, 1 .57 mmol) was added to a solution of 473-10 (80 mg, 0.151 mmol) in DCM (5 mL). The reaction was stirred at r.t. for 10 mins. A 1 : 1 1 M aq. Na2S2C>3:sat. aq. NaHCO:, mixture was added. The mixture was stirred at r.t. for 20 mins. The layers were separated and the aqueous portion was extracted with DCM. The combined organic portions were dried with Na2SC>4 and filtered. The volatiies were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 70:30 to 0.T 00) afforded 473 (24 mg, 18% over 3 steps) and 474 (19 mg, 15% over 3 steps). 473: white solid; UPLC/MS(ES+): m/z 527.30 [M+H]+. 474: off-white solid; UPLC/MS(ES+): m/z 509.30 [M+H]+.
10989] MeMgBr (3M solution in Et20, 30 uL, 0.090 mmol) was added to a solution of 473 ( 16 mg, 0.030 mmol) in THF (2.5 mL). The reaction was stirred at r.t. under N2 atmosphere for 30 mins. EtOAc and water were added. The layers were separated and the aqueous portion extracted with EtOAc. The combined organic portions were dried with NaoSC and filtered. The volatiies were removed under reduced pressure. Chromatography of the residue (cyclohexane: EtOAc, 30:70 to 0: 100) afforded 475 as a white solid (6 mg, 37%). UPLC7MS(ES+): m/z 543.30 [M+H\
Figure imgf000326_0001
[0990] A mixture of 479-1 ( 1 .00 g. 7.75 mmol), (4-fluorophenyl) boronic acid (2.17 g, 1 5.5 mmol), Pd(dppf)Cl2 (566 mg, 0.775 mmol) and sodium carbonate (2M aq solution, 7.75 mL, 15.5 mmol) in DCE (70 mL) was degassed and stirred with heating to 85 °C overnight. Water and DCM were added. The layers were separated and the organic phase was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 50:50) afforded 479-2 as a white solid (990 mg, 67%). Ή NMR (400 MHz. DMSO-i&) δ ppm 7.16 - 7.29 (m, 3 H), 7.34 (dd, J=8.2, 1 .4 Hz, 1 H), 8.04 - 8.12 (m, 2 H), 8.1 5 (dd, J=4.4, 1.4 Hz, 1 H), 10.22 (s, 1 H).
[0991] Potassium carbonate (1 .15 g, 8.34 mmol) and trifluoroacetaldehyde ethyl hemiacetal (740 uL, 6.26 mmol) were added to a suspension of 479-2 (790 mg, 4.1 7 mmol) in water ( 15 mL). The mixture was stirred at 100 °C overnight. Additional trifluoroacetaldehyde ethyl hemiacetal (327 uL, 2.70 mmol) was added and the reaction was stirred at 100 °C overnight. The reaction was cooled to 0°, neutralized with 1M aq HCT solution and extracted with EtOAc. The organic portion was dried with a2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc, 100:0 to 50:50) afforded 479-3 as a white solid (1.08 g, 90%). Ί I NMR (400 M I Iz, DMSO- d6) δ ppm 5.00 - 5.14 (m, 1 I I), 6.83 (d, J=6.3 I Iz, 1 I I). 7.23 - 7.30 (m, 2 I I). 7.42 (s, 2 I I), 8.07 - 8.1 5 (m, 2 H), 10.48 (s, 1 H).
[0992] NaH (195 mg. 4.87 mmol) was added to a stirred solution of 479-3 ( 1 .08 g, 3.75 mmol) in DMF ( 1 1 mL). which had been pre-cooled to 0° C. The mixture was stirred at 0° C for 10 mins, then warmed to r.t. and stirred for 30 mins. The reaction was cooled to 0° C and chloroacetonitrile (260 uL, 4.1 3 mmol) was added dropwise. The mixture was allowed to gradually reach r.t. and stirring was continued for 20 h. EtOAc and sat. aq. NH4CI were added. The layers were separated. The organic portion was washed with brine, dried with N 2SC>4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:LtOAc, 100:0 to 50:50) afforded 479-4 as a colorless wax ( 1.10 g, 90%). Ή NMR (400 MHz, DMSO- ) δ ppm 5.12 - 5.25 (m, 1 H), 5.33 (s, 2 H), 7.02 (d, J=6.0 Hz, 1 H), 7.30 - 7.37 (m, 2 H), 7.67 (d, J=8.7 Hz, 1 H), 7.83 (d, .7=8.7 Hz, 1 H), 7.91 - 7.98 (m, 2 H).
10993] L1AIH4 (lM solution in THF. 3.17 mL, 3.17 mmol) was added dropwise to a stirred solution of 479-4 (940 mg, 2.80 mmol) in THF (20 mL) which had been pre-cooled to 0°C. The mixture was warmed to r.t. and stirred for 30 mins. The reaction was cooled to 0 °C. Water (3 mL) was slowly added, followed by IN aq. NaOH solution (3 mL) and more water (9 mL). EtOAc was then added, and the layers were separated. The organic portion was washed with brine, dried with
Figure imgf000327_0001
filtered and concentrated under reduced pressure. The crude 479-5 was directly used in the next step.
[0994] Di-tert-butyl dicarbonate (61 0 mg, 2.80 mmol) and DMAP (34.0 mg, 0.280 mmol) were added to a solution of 479-5 in DCM ( 10 mL). After 2 h, water was added and the layers were separated. The organic portion was dried with Na?SC>4. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 50:50) afforted a di-protected compound. This di-protected compound was dissolved in CH3CN (2 mL). A 1 M aq. NaOH solution (2 mL) was added and the reaction was stirred at 50 °C for 1 h. Most of the solvents were removed under reduced pressure and the pH of the resulting solution was adjusted to 7 with 1M aq. HC1. The aqueous portion was extracted with EtOAc. The organic layer was dried with Na2SC>4, filtered and evaporated under reduced pressure. Chromatography of the residue (cyclohcxanc:EtOAc, 100:0 to 50:50) afforted 479-6 as a white solid (235 mg). UPLC/MS(ES+): m/z 431.38 [M+H]+.
[0995] Dess-Martin periodinane (274 mg, 0.640 mmol) was added to a stirred solution of 479-6 (235 mg. 0.540 mmol) in DCM (9 mL). The reaction was stirred at r.t. under 2 atmosphere overnight and quenched with a 1 : 1 2M aq. Na2S203'.sat. aq. NaHCC^ mixture. After 30 mins, the layers were separated. The organic portion was washed with brine, dried with a2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 479-7 as a white solid (144 mg. 62%). UPLC/MS(ES+): m/z 447.29 [M+H30]+.
[0996] Trimethylsulfoxonium iodide (57.0 mg, 0.260 mmol) was added to a solution of tBuOK (29.0 mg, 0.260 mmol) in DMSO (3 mL). The mixture was stirred at r.t. for 30 mins. A solution of 479-7 (1 12 mg, 0.260 mmol) in THF (3 mL) was added, and the mixture was stirred at r.t. for 30 mins. The mixture was diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic portions were washed with brine, dried with Na2S0 , filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexanc.EtOAc, 100:0 to 50:50) afforded 479-8 (44 mg) and unreacted 479-7 (53 mg). 479-8: UPLC/MS(ES+): m/z 443.29 [M+H] 1.
[0997] A solution of 479-8 (44 mg) in 7M NELj-McOH (2 mL) was stirred with heating to 45° C for 40 mins. The volatiles were removed under reduced pressure. Crude 479-9 (45 mg) was directly used in the next step.
[0998] A mixture of 479-9 (45 mg), EDC (23 mg, 0.12 mmol), HOBT (17 mg, 0.12 mmol), TEA (33 uL, 0.24 mmol) and 4-cyclopropoxy-3-methoxybenzoic acid (20 mg. 0.098 mmol) in DCM (1 mL) was stirred at r.t. for 2 h. Water was added, and the mixture was stirred for 10 mins. The layers were separated. The organic portion was dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography (cyclohexane:EtOAc, 100:0 to 40:60) afforded 479-10 as a white solid (53 mg). UPLC/MS(ES+): m/z 650.40 [M+H]+. [0999] TFA (350 uL) was added to a solution of 479-10 (53 mg, 0.081 mmol) in DCM (2 niL). The mixture was stirred at r.t. for 30 mins. Water was added, and the layers were separated. The organic portion was dried with Na SO-i, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water: CH CN, 100:0 to 40:60) to afford 479 (A/1587/35/1 ) as a white solid (30 mg, 67%). UPTC/MS(ES+): m/z 550.32 [M+H]+.
[1000] Formaldehyde (37% aq. solution, 3 uL) was added to a solution of 479 (17 mg, 0.030 mmol) in MeOH (200 uL). The mixture was stirred at r.t. for 3 h. Sodium cyanoborohydride (1.8 mg, 0.030 mmol) wras added, and the reaction was stirred at r.t. for 10 mins. The solvents were removed under reduced pressure. Water and DCM were added. The layers were separated. The organic portion was dried with a?S04. filtered and concentrated under reduced pressure. Chromatography of the residue (DCM:MeOH, 100:0 to 90: 10) afforded 480 as a white solid (2 mg, 10%). UPLC/MS(ES+): m/z 578.40 [M+H]+.
Figure imgf000330_0001
[1001] LDA (2M solution. 39.4 mL. 78.7 mmol) was added to a solution of 507-1 (5.00 g, 39.4 mmol) in dry THF ( 100 mL). which had been pre-cooled to -78° C. The mixture was stirred at -78 °C for 1 h. Dimethylcarbonate (8.0 mL, 95.0 mmol) was added, and the temperature was raised to 0 °C. The reaction was stirred at 0 °C for 30 mins and then partitioned between EtOAc and sat. aq. NH4CI solution. The organic phase was purified by chromatography (cyclohexane:EtOAc, 100:0 to 80:20) to recover 507-2 as a yellow oil (4.8 g, 66%).
[1002] Tctrakis(triphenylphosphinc)-palladium(0) ( 1 . 1 8 g, 1 .03 mmol) was added to a mixture of 507-2 (3.8 g, 20.5 mmol), (4-fluorophenyl)boronic acid (4.30 g. 30.8 mmol) and Na2C03 (5.4 g, 51 .3 mmol) in 1 : 1 dioxane-H20 (60 mL). which had been previously degassed by bubbling N2. The reaction was stirred at 120 °C for 2 h. UPLC analysis of the reaction showed that Suzuki coupling was followed by hydrolysis of the methyl ester. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH and cone. H2SO4 was added. The reaction was warmed to 50 °C and stirred at 50 °C for 2 h. EtOAc was added. The mixture was cooled to 0 °C and quenched with a sat. aq. K2CO3 (final pH 8). The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue (DCMxyclohexane, 50:50) afforded 507-3 (2.66 g, 53%). UPLC/MS(ES+): m/z 246.20 [M+H .
[1003] LHMDS ( 1 M solution in THE, 1 1.9 mL, 1 1.9 mmol) was added dropwise to a solution of 507-3 (2.66 g, 10.8 mmol) in THE (40 mL), which had been pre-cooled to -78 °C. The mixture was stirred at -78 °C for 1 h. Methyl iodide (740 iL, 1 1.9 mmol) was added and the reaction was allowed to gradually reach r.t. After being stirred at r.t. for 16 h, the reaction was cooled to 0 °C and quenched with sat. aq. NaHCOi solution. The aqueous portion was extracted with EtOAc. The organic layer was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20) afforded 507-4 ( 1 .70 g, 61 %). UPLC/MS(ES+): m/z 260. 10 [M+HJ+.
[1004] LHMDS ( 1 M solution in THF, 7.22 mL. 7.22 mmol) was added dropwise to a solution of 507-4 ( 1 .70 g, 6.56 mmol) in THF (12 mL). which had been pre-cooled to -78 °C. The mixture was stirred at -78 °C for 1 h. A solution of bromoacetonitrile (503 uL. 7.22 mmol) in THF (12 mL) was added, and the reaction was allowed to gradually reach r.t. After being stirred at r.t. for 2 h, the reaction was cooled to 0 °C and quenched with sat. aq. NH4CI solution. The aqueous portion was extracted with EtOAc. The organic layer was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 50:50) afforded 507-5 ( 1.91 g, 98%). Ή NMR (400 MHz, DMSO-t¼) d ppm 1.76 (s, 3 H), 3.37 (d, 7=17.0 Hz, 1 H), 3.44 (d, .7=17.0 Hz, 1 H), 3.72 (s, 3 H), 7.31 - 7.40 (m, 3 H), 7.90 (d, J=1.5 Hz, 1 H), 8.15 - 8.23 (m, 2 H), 8.68 (d, J=5.3 Hz, 1 H).
[1005] Nickel Raney (0.600 mmol) was added to a solution of 507-5 (1.91 g, 6.40 mmol) in MeOH (50 mL). The reaction was stirred at 60 °C under H2 atmosphere (5 bar) for 3 h. The reaction was filtered through a pad of celite and the solution was refluxed for 4 h. DIPEA (1 eq.) was added, and the mixture was refluxed for 30 mins. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc. The organic portion was washed writh sat. aq. NaHC03 solution, dried and concentrated under reduced pressure. Chromatography of the residue (EtOAc:MeOH. 100:0 to 95:5) afforded 507-6 (870 mg. 50%). UPLC/MS(ES+): m/z 271.20 [M+H]+.
11006] LiAlH4 (2M solution in THE, 3.03 mL, 6.06 mmol) was added to a solution of 507-6 (820 mg, 3.03 mmol) in THF (18 mL), which had been pre-cooled to 0 °C. The reaction w7as stirred at r.t. for 1 h, then warmed to 70 °C and stirred at 70 °C for 30 mins. The reaction w7as cooled to 0 °C and Na2SO4*10 H?0 and EtiO were added. The mixture was filtered through a pad of celite, and the solution concentrated under reduced pressure. Crude 507-7 (720 mg) was directly used in the next step.
[1007] A mixture of 507-7 (720 mg) and sat. aq. NaHCOj solution (16 mL) in dioxane (9 mL) was cooled to 0 °C. A solution of FmocCl (764 mg, 2.95 mmol) in dioxane (9 mL) was added, and the reaction was allowed to reach r.t. After 1 h, the reaction was diluted with EtOAc. The organic portion was washed with water and brine, dried and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 50:50) afforded 507-8 (1.10 g. 49% over 2 steps). UPLC MS(ES+): m/z 479.40 [M+H]+.
[1008] /M-Chloroperbenzoic acid (797 mg. 4.62 mmol) was added to a solution of 507-8 ( 1.10 g, 2.31 mmol) in DCM (30 mL). The reaction was stirred at r.t. overnight. EtOAc was added. The organic phase was washed with sat. aq. K2C03 sol and concentrated under reduced pressure. Crude 507-9 ( 1.17 g) was directly used in the next step.
[1009] A mixture of 507-9 (1.17 g) and POCI3 (50 mL) was stirred at 60 °C for 12 h. The volatiles were removed under reduced pressure. EtOAc and water were added, and the mixture was basified by adding sat. aq. KHCO3 solution (final pH 8). The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc, 90: 10 to 0: 100, then EtOAc:MeOH, 80:20) afforded 507-10 (700 mg, 58%) and unreacted starting material 507-9 (300 mg). 507- 10: UPLC7MS(ES+): m/z 513.27 LM+Hf .
[1010] Tributyl[ l -ethoxyethenyl]stannane (552 uL. 1 .63 mmol) and Pd(PPh3)Cb (199 mg, 0.284 mmol) were sequentially added to a solution of 507-10 (700 mg, 1 .36 mmol) in dioxane (4 mL), which had been previously degassed by bubbling N2. The mixture was further degassed and stirred at 100 °C for 1 h. After being cooled to r.t.. the mixture was partitioned between EtOAc and sat. aq. KF solution. The layers were separated. The organic portion was washed with I M aq. HCI solution, dried and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 80:20) afforded 507-11 (670 mg, 95%). UPLC/MS(ES+): m/z 521.32 [M+H]+.
[1011 ] Hydrobromic acid (33% solution in AcOH, 377 uL, 2.08 mmol) and bromine (53 uL, 1.04 mmol) were added to a solution of 507-11 (541 mg, 1.04 mmol) in dioxane (10 mL), which had been pre-cooled to 0 °C. The reaction was stirred at r.t. for 2 h. Additional bromine (0.5 eq., 27 μΐ-L) was added and stirring was prolonged for 2 h. The reaction was quenched with water and neutralized with sat. aq. NaHC(¾ solution. The aqueous portion was extracted with DCM. The organic layer was dried with Na^SC^ and concentrated under reduced pressure. Chromatography of the residue (DCM:EtOAc, 60:40) afforded 507-12.
[1012] TMSCE3 (430 mg, 3.00 mmol) and CsF (91 mg) were sequentially added to a solution of 507-12 (90 mg) in THF (12 mL). The reaction was stirred at r.t. for 20 mins. The mixture was partitioned between EtOAc and I M aq. HCI solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Crude 507-13 was directly used in the next step.
[1013] A solution of 507-13 in ammonia (7M solution in MeOH, 5 mL) was stirred at r.t. for 1 .5 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc-MeOH, 60:30: 10) afforded 507-14 (44 mg). UPLC/MS(ES+): m/z 606.40 [M+H]+.
[1014] A solution of 4-cyclopropoxy-3-methoxybenzoic acid (20.0 mg. 0.095 mmol), DIPEA (50 uL, 0.270 mmol) and HATU (39.0 mg. 0.102 mmol) in DCM (4 mL) was stirred at r.t. for 30 mins. A solution of 507-14 (41.0 mg, 0.068 mmol) in DCM (1 mL) was added. The reaction was stirred for 16 h, quenched with MeOI I (10 mL) and stirred for 1 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 60:40) afforded 507-15 as a colorless oil (23 mg. 42%). UPLC/MS(ES+): m/z 796.50 [M+H]+.
[1015] Morpholine (1 mL) was added to a solution of 507-15 (23 mg. 0.029 mmol) in DMF (1 mL), and the solution was stirred for 1 h. The volatiles were removed under reduced pressure. Chromatography of the residue (NH-cartridge. cyclohexane:EtOAc:MeOH, 100:0:0 to 60:30: 10) afforded 507 (10 mg. 60%). UPLC/MS(ES+): m/z 574.30 [M+H]+.
[1016] Formaldehyde (37% aq. solution, 30 uL, 0.350 mmol) and NaBH(OAc)3 (22.0 mg, 0.105 mmol) were added to a solution of 507 (4.0 mg, 0.007mmol) in DCM (2 mL). The reaction was vigorously stirred overnight, quenched with 1M aq. NaOH solution and extracted with DCM. The volatiles were removed under reduced pressure. The residue was purified by SCX-chromatography to afford 506 as a colorless oil (2.4 mg, 58%). UPLC/MS(ES+): m/z 588.50 [M+H]+.
EXAMPLE 265
Figure imgf000334_0001
General Suzuki coupling conditions
[1017] Method A: A mixture of 519-1 (70 mg. 0.1 12 mmol), boronate/boronic acid (0.170 mmol), H2P04 (15.3 mg, 0.1 12 mmol), K3P04 (24.0 mg, 0.1 12 mmol) and Pd(dbpf)Cl2 (7.5 mg, 0.01 1 mmol) in DME:H20:EtOH (1 :0.5:0.3, 1.8 mL) was degassed and heated to 50 °C for 24 h. The mixture was partitioned between Et20 and water. The organic portion was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 519-2.
[1018] Method B: A mixture of 519-1 (90 mg. 0.145 mmol). boronic acid (0.322 mmol). Pd2(dba)3 ( 1 5 mg. 0.016 mmol), PCy3 (10 mg, 0.038 mmol) and K3P04 (85 mg. 0.402 mmol) in dioxane ( 1 mL)- water (300 uL) was degassed and heated to 100 °C for 12 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 519-2.
Protecting group(s)-removal:
[1019] Method A: Aqueous HC1 (6M solution, 4 mL) w¾s added to a solution of 519-2 (0.056 mmol) in isopropanol (2.5 mL). The reaction was heated to 95 °C for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography to afford 519-3.
[1020] Method B: A mixture of 519-2 (0.047 mmol) and Pd/C (9 mg) in MeOH (4.7 mL) was stirred under Hi atmosphere for 5 h. The mixture w7as filtered from the catalyst, and the solution was treated with 1M HC1 solution in EtiO. The volatiles were removed under reduced pressure. The residue was triturated with Et20 to afford 519-3 as its hydrochloride salt.
[1021 ] Method C: TMSC1 (32 uL) and Nal (39 mg) were sequentially added to a solution of 519-2 (0.089 mmol) in CI LCN (4 mL). The reaction was stirred at r.t. for 1 h, warmed to 45 °C and stirred at that temp for 1 6 h. Additional TMSC1 (64 uL) and Nal (80 mg) were added, and the reaction was stirred at 45 °C for 5 h. The volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and a 1 : 1 mixture of 5% aq. NaHCC^i l M aq. a2S2C>3. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with a2S04, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give 519-3.
[1022] Method D: Hydro bromic acid (33% solution in AcOH, 30 uL) was added to a solution of 519-2 (20 mg) in 4M HCl-dioxane (2 mL). The reaction was warmed to 70 °C. When complete Cbz-removal was observed by UPLC, the reaction was concentrated under reduced pressure. The residue purified by reverse phase chromatography to afford 519- 3.
[1023] Method E: A mixture of 519-2 (9.1 mg) in 4M HCl-dioxanc (2 mL) was warmed to 70 °C (or 1 00 °C). When complete Cbz-removal was observed by UPLC. the reaction was concentrated under reduced pressure, and the residue purified by reverse phase chromatography to afford 519-3.
Figure imgf000336_0001
[1024] Suzuki coupling of 519-1 with 1 -((2-(trimethylsilyl)ethoxy)methyl)-7- fluoro-3-(4.4,5.5-tetramethyl-l ,3.2-dioxaborolan-2-yl)-l H-indole (Method A) followed by protecting groups removal according to Method A afforded 519 as its hydrochloride salt (white solid, 16% overall). UPLC/MS(ES+): m/z 587.36 [M+H]+.
Figure imgf000336_0002
[1025] Suzuki coupling of 519-1 with 4-chlorophenylboronic acid (Method A) followed by Cbz-rcmoval according to Method A afforded 520 as its hydrochloride salt (white solid, 24% overall). UPLC/MS(ES+): m/z 564.30 [M+H]+.
Figure imgf000336_0003
[1026] Suzuki coupling of 519-1 with 4-fluoro-3-(trifluoromethyl)phenylboronic acid (Method A) followed by Cbz-removal according to Method B afforded 521 as its hydrochloride salt (45% overall). I PI C \ IS( I .S i: m/z 616.38 [M+H]+.
Figure imgf000337_0001
[1027| Suzuki coupling of 519-1 with 4-cyanophenyTboronic acid (Method A) followed by Cbz-removal according to Method C afforded 527 as its formic acid salt (white solid, 37% overall). UPLC7MS(ES+): m/z 555.40 [M+H]+.
Figure imgf000337_0002
[1028] Suzuki coupling of 519-1 with 4-(trifluoromethyl)phenylboronic acid (Method A) followed by Cbz-removal according to Method B afforded 523 (5% overall). UPLC/MS(ES+): m/z 598.30 [M+H]+.
EXAMPLE 266
Preparation of Compound 524
Figure imgf000337_0003
[1029] Suzuki coupling of 519-1 (310 mg) with 2-(4-fluoro-3-nitrophenyl)-5,5- dimethyl-l ,3,2-dioxaborinane (Method A of Example 265) afforded 519-2A (35 mg). UPLC/MS(ES+): m/z 727.30 [M+H]+.
[1030] Iron powder (8 mg, 0.144 mmol) was added to a solution of 519-2A (35 mg, 0.05 mmol) in 2:2: 1 EtOH:AcOH-H20 (2.5 mL). The mixture was heated to 80 °C for 1 h. The reaction was filtered through a pad of celite, and the volatiles were evaporated under reduced pressure. The crude was partitioned between EtOAc and aq. NaHCOj solution, and the organic portion was purified by chromatography to afford 519-4 (30 mg). UPLC/MS(ES+): m/z 697.40 [M+H]+.
[1031] Aniline 519-4 (30 mg) was dissolved in CH3CN (2 mL) under N2 atmosphere. f-BuONO (14 mg. 0.129 mmol) was added. The mixture was stirred at r.t. for 30 mins. CuBr (6.2 mg. 0.043 mmol) was added, and the mixture was stirred for 2.5 h. The reaction was partitioned between DCM and sat. aq. NH4C1 solution. The organic phase was purified by chromatography to recover 519-5 (12 mg).
[1032] Deprotection of 519-5 according to Method A of Example 265 afforded 524 as its hydrochloride salt (1.2 mg). UPLC/MS(ES+): m/z 626.30 [M+H]+.
EXAMPLE 267
Figure imgf000338_0001
[1033] Suzuki coupling of 519-1 with 2-chloropyridine-5-boronic acid (Method B of Example 265) followed by treatment of the resulting Cbz-protected amine with TMSCl/Nal according to Method C of Example 265 afforded 557 (5% overall). UPLC/MS(ES+): m z foun +.
Figure imgf000338_0002
[1034] Deprotection of 519-2B according to Method E of Example 265 afforded
567 (16%). UPLC/MS(ES+): m/z 565.40 [M+H]+.
Figure imgf000339_0001
[1035] Suzuki coupling of 519-1 with 2-chloropyridine-4-boronic acid (Method B of Example 265) followed by Cbz-removal according to Method D of Example 265 afforded 558 (3% overall). UPLC/MS(ES+): m/z 565.30 [M+H]+.
EXAMPLE 269
Preparation of Compound 559
Figure imgf000339_0002
[1036] Suzuki coupling of 519-1 with 3-cyano-4-fluorophenylboronic acid (Method A of Example 265) followed by Cbz-removal according to Method D of Example 265 afforded 559 (10% overall). UPLC/MS(ES+): m/z 573.42 [M+H]+. EXAMPLE 270
Preparation of Compound 514
Figure imgf000340_0001
[1037] NaBH4 (808 mg, 21.3 mmol) was added to a solution of 514-1 (3.10 g, 17.7 mmol) in MeOH (22 niL), which had been pre-cooled to 0 °C. The mixture was allowed to reach r.t. and stirring was prolonged for 30 mins. 1 M aq. HC1 solution was added, and the organic solvent was removed under reduced pressure. The aqueous phase was extracted with DCM (3x). The combined organic portions were dried with
Figure imgf000340_0002
and filtered. The volatiles were removed under reduced pressure to afford 514-2 (3.01 g). UPLC/MS(ES+): m/z 178.00 [M+H]+.
[1038] Chloromethyl methyl ether (704 μΐ,. 9.27 mmol) and TEA ( 1.75 mL, 12.6 mmol) were added to a solution of 514-2 (1 .5 g) in DCM (12 mL). The reaction was warmed to 45 °C. When complete conversion was observed by UPLC, the reaction was cooled to r.t.. diluted with DCM and washed with water. The organic portion was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 70:30) afforded 514- 3 (1.48 g). UPLC/MS(ES+): m/z 222.00 [M+H]+.
[1039] A mixture of 514-3 (1.38 g, 6.24 mmol), Pd(PPh )Cl2 (438 mg, 0.624 mmol) and tributyl[l -ethoxyethenyl]stannane (2.1 1 mL, 6.24 mmol) in dioxane (40 mL) was degassed, warmed to 90 °C and stirred at that temp for 3 h. After being cooled to r.t., the reaction was diluted with EtOAc. The organic portion was washed with a sat. aq. KF solution and water, dried with Na2SC>4, filtered and concentrated under reduced pressure to afford crude 514-4, which was directly used in the next step.
[1040] NBS (888 mg, 4.99 mmol) was added to a solution of 514-4 in THF (40 mL), which had been pre-cooled to 0 °C. The reaction w?as stirred at 0 °C for 1 h. then warmed to r.t., and stirred for 2 h. EtOAc was added. The organic portion was wrashed with water, dried with Na?S04. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 70:30) afforded 514-5 (1.1 1
[1041] CEjTMS (6 mL) was added to a solution of 514-5 (1.1 1 g) in THF (15 mL). CsF (2.74 g, 18.0 mmol) was added in 1 portion. After 1 h, the reaction was partitioned between EtOAc and sat. aq. NH4CI solution. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2S04, filtered and concentrated under reduced pressure. Crude 514-6 was directly used in the next step.
[1042] A solution of 514-6 and 7M NH3-MeOH (50 mL) was stirred at r.t. for 16 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN, 100: 0 to 50:50) to afford 514-7 (214 mg). UPLC/MS(ES+): m/z 315.30 [M+H]+.
[1043] A mixture of 514-7 (291 mg, 0.928 mmol), EDC (212 mg. 1.1 1 mmol). ΕΓΟΒΤ (150 mg, 1 .1 1 mmol), TEA (310 uL. 2.23 mmol) and 4-cyclopropoxy-3- methoxybenzoic acid (193 mg, 0.924 mmol) in DCM (6 mL) was stirred at r.t. for 2 h. A 1M aq. HC1 solution was added, and the mixture was stirred for 2 mins. The layers were separated. The organic portion was washed with 1M aq. NaOH solution, and concentrated under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc, 70:30) afforded 514-8 ( 140 mg, 30%). UPLC/MS(ES+): m/z 505.20 [M+[ I] h.
[1044] A mixture of 514-8 (67.6 mg, 0.134 mmol), 4-fluorophcnylboronic acid (28 mg. 0.201 mmol), KH2P04 (21 mg. 0.134 mmol), K3P04 (29.0 mg. 0.134 mmol) and Pd(dbpf)Cl2 (9 mg, 0.013 mmol) in DME-H20-EtOH (5:3: 1. 5 mL) was degassed and heated to 50 °C for 48 h. The mixture was partitioned between DCM and water. The organic portion was concentrated under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc. 70:30) afforded 514-9 (50.7 mg). Ή NMR (400 MHz. CDC13) δ ppm 0.80-0.90 (m, 4 H). 3.36 (s. 3 H). 3.72 - 3.81 (m. 1 H). 3.85 (s, 3 H). 3.97 (dd. J=14.0. 3.5 Hz, 1 H). 4.58 (s, 2 H), 4.62-4.73 (m. 3 H), 6.43 (dd. J=7.9. 3.5 Hz. 1 H). 6.67 (s, 1 H). 7.08 (dd. J=8.3. 1.8 Hz. 1 H), 7.14 - 7.22 (m, 3 H). 7.25 (d. J=1.8 Hz, 1 H), 7.53 - 7.61 (m. 2 H). 7.78 (d, J=8.1 Hz, 1 H), 8.05 (d, .7=8.1 Hz, 1 H).
[1045] A solution of 514-9 (50.7 mg, 0.09 mmol) in 1 : 1 DCM-TFA (700 pL) was stirred at r.t. for 12 h. The reaction was diluted with DCM. The organic portion was washed with 2M aq. NaOH solution and concentrated under reduced pressure. Crude 514-10 (45 mg) was directly used in the next step. UPLC/MS(ES+): m/z 521.30 [M+H .
[1046] TEA ( 19 pL, 0.136 mmol) and MsCl ( 10 pL, 0.133 mL) were sequentially added to a solution of 514-10 (45 mg) in DCM (1 mL), which had been pre-cooled to 0 °C. The reaction was allowed to reach r.t.. stirred for 12 h and diluted with DCM. The organic portion was washed with water, dried with Na2S04, filtered and concentrated under reduced pressure. Crude 514-11 (36 mg) was directly used in the next step.
[1047] A solution of 514-11 (36 mg) in 7M NH -MeOH ( 1 mL) was stirred at r.t. for 12 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH3CN, 100:0 to 67:33) to afford 514 (19.6 mg). UPLC/MS(ES+): m/z 520.30 [M+H]+.
Figure imgf000343_0001
[1048] A 0.2 M solution of 538-1 (465 mg, 1 .14 mmol) in toluene (5.7 mL) was degassed (raw vial). Pd(Q-phos)? (80 mg, 0.052 mmol) was added. The vial was sealed, purged with N2 and heated to 100 °C for 6 h. Additional Pd(Q-phos)2 (30 mg) was added. The vial was purged with N2 and heated to 100 °C for 4 h. The mixture w<as directly purified by chromatography on silica gel (cyclohexane:EtOAc, 95:5 to 70:30) to afford 538-2 (414 mg, 96%). UPLC/MS(ES+): m/z 408.10 [M+H]+.
11049] A mixture of 538-2 (340 mg) and NaN3 (288 mg) in DMT (4 mL) was heated to 65 °C and stirred at that temp for 16 h. The volatiles were removed under reduced pressure. The crude residue was partitioned between EtOAc and sat. aq. NH4CI solution. The layers were separate. The organic portion was dried with Na^SO,}. filtered and concentrated under reduced pressure to afford 538-3 (245 mg). UPLC7MS(ES+): m/z 323.10 [M+H]+.
[1050] Dess-Martin periodinane (484 mg, 1.14 mmol) was added to a solution of 538-3 (245 mg) in DCM (4 mL). The reaction was stirred at r.t. for 1 h and quenched with a 1 : 1 1 M aq. Na2S2(¾:5% aq. NaHC(¾. The mixture was vigorously stirred for 1 h. The layers were separated, and the aqueous portion was extracted with DCM. The combined organic portions were dried with Na^SO.;, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 538-4 (206 mg). UPLC7MS(ES+): m/z 339.10 [M+H30]+.
[1051] Trimethylsulfoxonium iodide ( 141 mg. 0.643 mmol) was added in one portion to a mixture of tBuOK (72 mg, 0.643 mg) in C¾CN (4 niL), which had been previously degassed. After 20 mins, the solution was filtered from the solid and added to a solution of 538-4 (206 mg) in CH3CN (4 mL), which had been previously degassed. The reaction was stirred at r.t. for 15 mins. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 538-5. UPLC/MS(ES+): m/z 335.10 [M+H]+.
[1052] A solution of 538-5 (100 mg) in 7M NH3-MeOH (60 mL) was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure to afford crude 538-6 (108 mg). which was directly used in the next step. UPLC/MS(ES+): m/z 352.10 [M+H]+.
[1053] A mixture of 538-6 ( 108 mg), EDC (89 mg, 0.462 mmol). HOBT (63 mg, 0.462 mmol). 4-cyclopropoxy-3-methoxybenzoic acid (64 mg, 0.307 mmol) and TEA (86 uL, 0.616 mmol) in DCM (4 mL) was stirred at r.t. for 16 h. The reaction wras diluted with DCM. The organic portion was washed with 1M aq. HC1 solution (2x), dried with aoSC^, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 538-7 ( 136 mg). UPLC/MS(ES+): m/z 542.20 [M+HJ+.
[1054] Pd(dbpf)Cl2 ( 16 mg. 0.025 mmol) was added to a mixture of 538-7 ( 136 mg), K3PO4 ( 107 mg, 0.503 mmol). KH2P04 (68 mg. 0.503 mg) and 4-fluorophenylboronic acid (74 mg, 0.503 mmol) in 5:3 : 1 DME:EtOH:H20 (2.7 mL), which had been previously degassed. The reaction was warmed to 65 °C and stirred at that temp for 10 h. The mixture was cooled to r.t. and stirred for 72 h. The reaction was diluted with EtOAc and washed with sat. aq. NH4CI solution. The organic portion was dried with N 2SC>4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water/0.1% HCOOH:CH3CN/0.1% HCOOH, 100:0 to 50:50) to afford 538 as a white solid (formic acid salt. 33 mg, dr 1 : 1). UPLC7MS(ES+): m/z 576.40 [M+H]+.
Figure imgf000345_0001
[1055] meto-Chloroperbenzoic acid (56.0 g. 328 mmol) was added in several portions to a solution of 2-chloro-4-methylpyridine (20.0 g. 156 mmol) in DCM (520 mL). The mixture was refluxed for 8 h and diluted with DCM. The organic portion w7as washed with sat. aq. K2CO3 solution. The aqueous portion was extracted with EtOAc. The combined organic portions were dried with
Figure imgf000345_0002
filtered and concentrated under reduced pressure. Chromatography of the residue (DCM:MeOH, 100:0 to 80:20) afforded 522-1 as a yellow oil (9.50 g. 42%). UPLC7MS(ES+): m/z 144.00 [M+H]+.
[1056] POCI3 (130 mL) was added to a solution of 522-1 (9.50 g. 66.0 mmol) in toluene (20 mL). The reaction was heated to 70 °C and stirred at that temp for 20 h. The volatiles were removed under reduced pressure. The residue was poured into ice. The mixture neutralized with sat. aq. K2CO3 solution and extracted with DCM (3x). The combined organic portions were dried with Na2SO_|, filtered and concentrated under reduced pressure. Chromatography of the residue afforded 522-2 (3.80 g, 36%). UPLC/MS(ES ): m/z 162.10 [M+I lf.
[1057] A freshly prepared solution of LDA solution (1 M in THF-hexanc, 44.6 mL. 44.6 mmol) was added to a solution of 522-2 (3.61 g. 22.3 mmol) in THF ( 1 10 mL). which had been pre-cooled to -78 °C. The reaction was stirred at -78 °C for 1 h. Dimethylcarbonate (4.5 mL, 53.5 mmol) was added. The reaction was allowed to reach 0 °C. stirred at that temp for 1 h and quenched with water. The volatiles removed under reduced pressure. The residue was taken up with EtOAc. The organic portion was washed with sat. aq. NH4CI solution, dried with Na^SO^, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 60:40) afforded 522-3 as a yellow oil (3.0 g, 61 %). UPLC/MS(ES+): m/z 220.0 [M+H]+.
[1058| A mixture of 522-3 (450 mg, 2.00 mmol), 3-chloro-4-fluorophenylboronic acid (285 mg, 1.60 mmol), NaHC03 (515 mg, 6.10 mmol) and Pd(PPhj)4 (95 mg, 0.080 mmol) in 2: 1 THF:water (9 mL) was degassed and heated to 50 °C. After 2 h, 3-chloro-4- fluorophenyl boronic acid (0.2 eq.) was added, and the mixture was stirred at 50 °C for 2 h. After being cooled to r.t., the reaction was diluted with DCM. The organic portion was washed with sat. aq. NaHC(¾ solution, dried with a2S04, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water :CI LCN, 70:30 to 10:90) to afford 522-4 as a yellow oil ( 1 0 mg, 29%). UPLC/MS(ES+): m/z 314.10 [M+H]+.
[1059] 522-4 (860 mg, 2.70 mmol) was dissolved in 7M NH3-MeOH ( 14 mL) at 0 °C. The reaction was stirred at r.t. for 3 h and at 40 °C for 20 h. The volatiles were removed under reduced pressure to afford crude 522-5 (775 mg), which was directly used in the next step.
[1060] Borane-THF complex (1 M solution in THF, 7.77 mL, 7.77 mmol) was added to a solution of 522-5 (775 mg) in THF ( 14 mL). The reaction was refluxed for 3 h. Additional borane-THF complex (4 eq., 2 aliquots) was added, and the mixture was refluxed overnight. The reaction was quenched with 2M aq. HC1 solution, and the mixture was stirred for 30 mins . The aqueous portion was basified with sat. aq. NaHC<¾ solution and extracted with EtOAc. The organic portion was washed with brine, dried with Na2S >4, filtered and concentrated under reduced pressure. The residue was loaded on to a SCX-column and eluted with 2M NH MeOI I to give 522-6 (610 mg, 82%). UPLC/MS(ES ): m/z 285.10 [M+H]+.
[1061] Triethylamine (590 uL, 4.26 mmol) and B0C2O (700 mg, 3.20 mmol) were sequentially added to a solution of 522-6 (610 mg. 2.13 mmol) in DCM (1 1 mL). The reaction was stirred at r.t. for 1 h, diluted with DCM and washed with 0.5M aq. HCl solution. The organic portion was dried with Na2SC>4. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 90:10 to 50:50) afforded 522- 7 as a white solid (580 mg, 71 %). UPLC/MS(ES+): m/z 385.20 [M+H]+.
[1062] A mixture of 522-7 (580 mg. 1.50 mmol). Pd(PPh3)Cl2 (105 mg. 0.150 mmol) and tributyl[l-ethoxyethenyl]stannane (560 uL. 1.65 mmol) in dioxane (8 mL) was degassed, warmed to 100 °C and stirred at that temp for 6 h. After being cooled to r.t., a sat. aq. KF solution was added. The mixture was stirred for 10 mins, and the aqueous portion was extracted with EtOAc. The organic phase was dried with N ?S04, filtered and concentrated under reduced pressure to afford crude 522-8, which was directly used in the next step.
[1063] Λ'-Bromosuccinimide (293 mg, 1.65 mmol) was added to a solution of 522-8 in THF (8 mL), which had been pre-cooled to 0 °C. The reaction was stirred at 0 °C for 1 h, quenched with water and extracted with EtOAc. The organic portion was dried with Na S , filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 90: 10 to 50:50) afforded 522-9 as a white solid (330 mg, 47% over 2 steps). Ή NMR (400 MHz, CDC13) δ ppm 1 .45 (s, 9 H), 3.00 (t, J=6.5 Hz, 2 H), 3.50 (q, J=6.5 Hz, 2 H). 4.58 - 4.69 (in. 1 H), 4.95 (s, 2 H). 7.30 (t. J=8.0 Hz. 1 H). 7.79 (br. s.. 1 H). 7.92 (s. 1 H), 7.95 - 8.02 (m, 1 H), 8.15 (dd, J=6.9, 2.1 Hz, 1 H).
[1064] CF3TMS (1.03 mL, 7.00 mmol) was added to a solution of 522-9 (330 mg. 0.700 mmol) in THF (5 mL). CsF (531 mg, 3.50 mmol) was added in one portion. After 1 h. the reaction was partitioned between EtOAc and sat. aq. NH4CI solution. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with a2S04, filtered and concentrated under reduced pressure. The crude 522-10 was directly used in the next step. [1065] A solution of 522-10 and 7M NH -MeOH (10 mL) was stirred at r.t. for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (waten.Cl¾CN, 95:5 to 30:70) to afford 522-11 (56 mg).
[1066] A mixture of 4-cyclopropoxy-3-methoxybenzoic acid (49.0 mg. 0.230 mmol), HATU (108 mg. 0.280 mmol) and DIPEA (122 uL, 0.700 mmol) in DCM ( 1 mL) was stirred at r.t. for 30 mins. A solution of 522-11 (56 mg) in DCM (1 mL) was added, and the reaction was stirred at r.t. for 2 h and quenched with water. EtOAc was added. The organic portion was washed with I M aq. HCl solution, 2M aq. NaOH solution and brine, dried with Na2SC>4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 90: 10 to 40:60) afforded 522-12 (65 mg).
[1067] A solution of 522-12 in 4M HCl-dioxane (1 mL) was stirred at 0 °C for 1 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (wrater:CH3CN, 95:5 to 40:60) to afford 522 ( 14 mg). UPLC/MS(ES+): m/z 568.30 [M+H]+.
EXAMPLE 273
Figure imgf000348_0001
[1068] A mixture of 271-10 (50 mg, 0.1 mmol), 477-1 (16 mg, 0.1 mmol) and TEA (1 mmol) was dissolved in anhydrous DCM (4 mL) with stirring. The mixture was treated with HATU (38 mg, 0.1 mmol) in 1 portion. After stirring at r.t. for 30 mins, TFA ( 1 mL) was added. The solution was stirred at r.t. for 2 h. The mixture w7as concentrated to dryness. The residue was purified by reverse prep-HPLC to afford 477 (28 mg, 48%) as a white solid. +ES1-MS: m/z 537.1 [M+H]+. EXAMPLE 274
Preparation of Compound 478
Figure imgf000349_0001
[1069] Compound 478 was prepared following the general procedure for preparing 477 by using 2-chlorooxazole-4-carboxylic acid and 271-10. Crude 478 was purified by prep-HPLC and obtained as a white solid (20 mg, 36%). +ESI-MS: m/z 520.9 [M+H]+.
EXAMPLE 275
Figure imgf000349_0002
[1070] To a solution of 485-1 (6 g, 15.4 mmol) in anhydrous DMF (95 mL) was added NaH (640 mg, 16 mmol, 60% in mineral oil) in small portions at r.t. After stirring for 10 mins, a solution of Mel (2.3 g, 16 mmol) in DMF (5 mL) was added dropwise, and the reaction was stirred for 1 h. After complete conversion of 485-1, the mixture was quenched with water, and extracted with EtOAc (150 mL x 2). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by chromatography using (PEtEtOAc: 100:0 to 80:20) to afford 485-2 (5.8 g, 93.5%). [1071] Compound 485 (white solid, 27 mg) was prepared following the general procedure for preparing 272 using 485-2 and (S)-3-methoxy-4-((2-oxopyrrolidin-3- yl)oxy)benzoic acid. +EST-MS: m/z 639.1 [M+HJ+.
Figure imgf000350_0001
[1072] Compound 486 (white solid, 34 mg) was prepared following the general procedure for preparing 485 by using 486-1 and 271-10. +ESI-MS: m/z 614.1 [M+H]+.
EXAMPLE 277
Figure imgf000350_0002
[1073] Compound 487 (wtiite solid, 27.5 mg) was prepared fol lowing the general procedure for preparing 485 by using 487-1 and 271-10. +ESI-MS: m/z 613.1 [M+H]+.
EXAMPLE 278
Preparation of Compound 488
Figure imgf000350_0003
[1074] Compound 488 (white solid, 26 mg) was prepared following the general procedure for preparing 485 by using 488-1 and 271-10. +ESI-MS: m/z 591.1 [M+H]+.
Figure imgf000351_0001
[1075] Compound 489 (white solid, 23 mg) was prepared following the general procedure for preparing 485 by using 489-1 and 271-10. +ES1-MS: m/z 586.0 [M+H]+.
EXAMPLE 280
Figure imgf000351_0002
[1076] Compound 490 (white solid, 41 mg) was prepared following the general dure for preparing 485 by using 490-1 and 271-10. +ESI-MS: m/z 656.0 [M+H]+.
Figure imgf000351_0003
[1077] Compound 491 (white solid, 25 mg, 44 %) was prepared following the general procedure for preparing 485 by using 491-1 and 491-2. +ES1-MS: m/z 600.1 [M+H]+.
Figure imgf000352_0001
11078] To a solution of 495-1 (850 mg, 1.73 mmol) in MeOH (50 mL) was added Pd/C (210 mg, 5%) under N at r.t. The suspension w7as purged with hydrogen for several times. The mixture was stirred under hydrogen (15 psi) at r.t. for 12 h. After complete conversion of 495-1, the mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness. The residue was 495-2 (750 mg, 94.6%), which was used directly without further purification. +ES1-MS: m/z 458.2 [M+H]+.
[1079] A mixture of 495-2 (750 mg, 1 .64 mmol), carboxyl acid 3 (340 mg, 1 .64 mmol) and TEA (1 mmol) is dissolved in anhydrous DMF (10 mL) with stirring. The solution was treated with HATU (623 mg, 1 .64 mmol) in one portion. After stirring at r.t. for 1-2 h, the mixture was poured into cold water and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous a?S04, and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=1 : 1 as the eluent to give 495-3 as an oil (910 mg. 86%). +E SI-MS: m/z 648.1 [M+H]+.
[1080] To a stirring solution of 495-3 (910 mg. 1.41 mmol) in DCM ( 10 mL) was added TFA (5 mL) dropwise at r.t. The reaction was stirred for 30 mins and concentrated to dryness under reduced pressure. The residue was neutralized by sat. sodium carbonate solution and extracted with EA (15 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified by prep-HPLC and separated by SFC to give 495 (93 mg) and 496 (82 mg) as a white solid.
495: +ESI-MS: m/z 548.1 [M+HJ+; and 496: +ES1-MS: m/z 548.1 [M+H]+.
Figure imgf000353_0001
[1081] To a stirring solution of 314 ( 1 16 mg, 0.2 mmol), 2-((tert- butoxycarbonyl)amino)acetic acid (35 mg. 0.20 mmol) and DIPEA (90 mg, 0.7 mmol) in anhydrous DCM (5 mL) was added HATU (76 mg. 0.2 mmol) in one portion at 25 °C. The solution was stirred for 1 h. The mixture was diluted with water and DCM. The organic layers were wrashed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give crude 497-1 (1 10 mg), which used directly without purification. +ESI-MS: m/z 739.1 [M+H]+.
[1082| To a stirring solution of crude 497-1 (1 10 mg) in EA (TO mL) was added HC1:EA (4 M, 5 mL) at r.t. The reaction was stirred for 30 mins with TLC monitoring. After conversion of 497-1, the reaction was quenched with sat. sodium bicarbonate solution, and extracted with EA (10 mL x 3). The combined organic layers w7ere washed with brine, dried over anhydrous NaiSCL and concentrated to dryness. The residue was purified by prep- HPLC to give 497 (50 mg, 52.6 ) as a white solid. +ES1-MS: m/z 639.2 [M+H]+.
Figure imgf000353_0002
[1083] To a solution of 314 (58 mg. 0.1 mmol) and 2C03 (27 mg, 0.2 mmol) in DMF ( 1 mL) was added methyl 2-bronioacetate (23 mg. 0.15 mmol) at r.t. The mixture was heated to 60 °C and stirred for 2 h. The reaction was cooled to r.t. and diluted with H2O and
EA. The combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 500 as a white solid (30 mg, l6. " o). +ESI-MS: m/z 654.1 [M+H]+.
EXAMPLE 285
Preparation of Compound 501
Figure imgf000354_0001
[1084] To a solution of 500 (90 mg. 0.14 mmol) in MeOH (10 mL) was added NH.¾: eOH (7M, 10 mL). The vial was sealed and heated to 60 °C for 2 h. The reaction was cooled to r.t. and diluted with H2O (20 mL) and EA (20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to dryness. The residue was purified by prep-HPLC to give 501 as a white solid (49 mg, 54/' ' ;»). +EST-MS: m/z 639.1 [M+H]+.
EXAMPLE 286
Preparation of Compound 502
Figure imgf000354_0002
[1085] To a solution of 500 (65 mg, 0.1 mmol) in co-solvent of THF (2 mL) and MeOH (2 mL) was added L1BH4 (10 mg. 0.5 mmol) at r.t. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with ¾0 and extracted with EA ( 10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to dryness at low pressure. The residue was purified by prep-HPLC to give 502 as a white solid (40 mg, 64.5%). +E SI-MS: m/z 626.0 [M+Hf.
Figure imgf000355_0001
[1086] To a solution of 503-1 (1 .0 g, 2.5 mmol) in toluene (8 mL) was added pyridine (590 mg. 7.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 mins and SOCL (820 mg, 7.0 mmol) was added dropwise. After addition, the mixture was stirred at 0 °C for 30 mins. The reaction was quenched with LLO and extracted with EA ( 10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to dryness. The residue was purified by column chromatography using PE:EA=5 : 1 as the eluent to give 503-2 as a solid (0.8 g, 85.1%). +ESI-MS: m/z 377.1 [M+H]+.
[1087] To a solution of 503-2 (0.8 g, 2.1 mmol) in DMSO (6 mL) was added ammonia water ( 1 mL) at 0 °C. The mixture was stirred at r.t. for 30 mins. The mixture was diluted with LLO and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated to dryness. The residue was purified by column chromatography using PE:EA= - as the eluent to give 503-3 as a solid , »50 nig. 7K.'7 ). +ESI-MS: m/z 394.1 [M+H]+.
[1088] To a solution of 503-3 ( 50 n¾, 1.7 mmol) in MeOH ( 10 mL) was added Raney Ni (0.7 g) under N2. The suspension was degassed under vacuum and purged with LL for several times. The reaction was stirred under H2 (balloon) at r.t. for 30 mins. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give 503-4 (550 mg), which was used directly without purification.
[1089] To a solution of 503-4 (37 mg, 0.10 mmol). 4-cyclopropoxy-3- methoxybenzoic acid (21 mg, 0.10 mmol) and DIPEA (39 mg, 0.3 mmol) in anhydrous DCM (3 mL) was added HATU (39 mg, 0.10 mmol) in one portion at 25 °C. The solution was stirred at this temperature for 1 h. The reaction was diluted with H20 and extracted with
DCM (10 mT x 2). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to dryness at low pressure. The residue was purified by prep-HPLC to give 503 as a white solid (35 mg, 63.6%). +ESI-MS: m/z 553.9 [M+H]+.
EXAMPLE 288
Preparation of Compound 504
Figure imgf000356_0001
Figure imgf000356_0002
[10911 Compound 505 (white solid, 9 mg) was prepared following the general procedure for preparing 500 by using 314 and 1 -bromo-2-methoxyethane as starting material. +ES1-MS: m/z 640.1 [M+H]+.
Figure imgf000357_0001
[1092] To a solution of 314 (290 mg, 0.5 mmol) in THF (5 mL) was added 2- chloroacetaldehyde (0.5 g, 40 % in H20) at r.t. The mixture was stirred for 30 mins and NaBH3CN ( 160 mg. 2.5 mmol ) was added. The mixture wras stirred at r.t. for 30 mins. The reaction was quenched with H20 and extracted with EA ( 10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous a2SC>4 and concentrated to dryness. The residue was purified by column chromatography using PE:EA= 1 : 1 as the eluent to give 508-1 as a solid (210 mg, 65.4%).
[1093] To a solution of 508-1 (1 V) 0.33 mmol) in DMSO (5 mL) was added NaN3 (6" mg, 0.92 mmol) at r.t. The mixture was stirred at 60 °C for 30 mins. The mixture was cooled to r.t. and diluted with H?0 and EA ( 10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na^SC and concentrated to give crude 508-2 (! vO as a pale yellow solid, which was used directly without purification. +ESI-MS: m/z 651 .1 [M+HJ+.
[1094] To a solution of 508-2 (? ¾) < MU. 0.29 mmol) in MeOH ( 1 5 mL) was added Pd/C (0.2 g) under τ at r.t. The suspension was degassed under vacuum and purged with H? for several times. The mixture was stirred under H2 balloon for 30 mins at r.t. The mixture was filtered through a pad of Celite. and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give 508 as a white solid ( 101 mg. >i.j¾). +ESI- MS: m/z 625.0 [M+H]+. EXAMPLE 291
Preparation of Compound 515
Figure imgf000358_0001
11095] To a solution of 500 (180 mg, 0.28 mmol) in MeOH (5 mL) was added a solution of NaOH (50 mg. 1.25 mmol) in H?0 (5 mL) at r.t. The mixture was stirred at 60 °C for 1 h. MeOH was evaporated, and the aqueous phase was acidified to pH = 1 by addition of 1 N HQ solution. The solution was extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous
Figure imgf000358_0002
and concentrated at low- pressure. The residue was purified by prep-HPLC to give 515 as a white solid (80 mg, 45.0%). +ESI-MS: m/z 640.0 [M+H]+.
Figure imgf000358_0003
[1096] To a solution of 314 (100 mg, 0.17 mmol) in DCM (2 mL) was added CCI3CONCO (36 mg, 0.1 89 mmol) at 0 °C. The solution was stirred for 20 mins. The solution was diluted with DCM (10 mL) and H2O (10 mL). The organic phase was separated and concentrated under reduced pressure to give crude 516-1 (78 mg. 60.0%). which was used directly without purification.
|1097] To a solution of 516-1 (78 mg, crude) in MeOH (1 mL) was added sat. NaHCO.i solution (1 mL) and stirred at r.t. for 1 h. The mixture was extracted with EA (lOmL x 3). The combined organic layers were washed by brine, dried over anhydrous Na?S04 and concentrated at low pressure. The residue was purified by prep-HPLC to give 516 (28 mg, 44.4%) as a white solid. +ES1-MS: m/z 625.1 [M+H]+.
Figure imgf000359_0001
[1098] Compound 517 (white solid, 87 mg, 35.3%) was prepared following the general procedure for preparing 232 and 504 by using 517-1 and ethyl 2,2-difluoroacetate. +ES1-MS: m/z 536.0 [M+H]+.
Figure imgf000359_0002
[1099] To a solution of 518-1 (3.56 g, 10.0 mmol) and CsF (3.0 g. 20.0 mmol) in MeCN (1 5 mL) was added 1 8-crown-6 (3.6 g. 13.6 mmol) at r.t. The mixture was heated to 100 °C and stirred at 100 °C for 5 h. The mixture was cooled to r.t., and the solid was removed by filtration. The filtrate was concentrated and purified by column chromatography using PE:EA=5: 1 as the eluent to give 518-2 as a solid (2.01 g, 67.3%). +ESI-MS: m/z 297.9 [ +I l .
[1100] Compound 518 (white solid, 21 mg, 45.3%) was prepared following the general procedure for preparing 503 by using 518-2. +ES1-MS: m/z 518.0 [M+H]+.
Figure imgf000360_0001
[1101] To a solution of 525-1 (2.8 g, 10.0 mmol) and AIBN (168 mg. 1.0 mraol) in CCI4 (20 mL) was added NBS (1.9 g, 10.7 mmol) at r.t. The mixture was heated to 70 °C and stirred for 3 h. The mixture was cooled to r.t. and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=15: 1 as the eluent to give 525-2 as a solid (2.5 g, 69.8%). +ESI-MS: m/z 359.9 [M+Hf.
[1102] To a solution of 525-2 (2.5 g, 7.0 mmol) in DMSO ( 15 mL) was added Na 3 ( 1.1 g, 16.9 mmol) at r.t. The reaction was heated to 60 °C and stirred for 1 h. The reaction was cooled to r.t. The mixlure was diluted with EEO and extracted with EA (60 mL x 3 ). The organic layers were dried over anhydrous aoSO^ and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=1 : 1 as the eluent to give 525-3 as a solid ( 1.8 g, 81.8%). +ESI-MS: m/z 322.8 [M+I I]
[1103] To a solution of 525-3 (1.8 g, 5.6 mmol) in McOH (15 mL) was added SnCl?-2H20 (2.5 g, 1 1.1 mmol) at r.t. The mixture was stirred for 1 h with TLC monitoring. After 525-3 was consumed, the reaction was quenched with sat. NaHC03 and extracted with EA (30 mL x 2). The combined organic solution was dried over anhydrous Na2SC>4. and concentrated under reduced pressure. Crude 525-4 (1 .0 g) was used directly without further purification.
[1 104] To a solution of 525-4 (1.0 g, 3.4 mmol) in DCM ( 1 5 mL) was added B0C2O (1.4 g, 6.4 mmol) at r.t. The mixture was stirred at r.t. for 3 h and then concentrated to dryness. The residue was purified by chromatography using PE:EA=5: 1 as the eluent to give 525-5 as a solid (0.8 g, 61.5%).
[1105] To a solution of 525-5 (0.8 g, 2.0 mmol) and CF3COOEt (1.7 g. 1 1.9 mmol) in THF (10 mL) was added isopropvlmagnesium chloride (4 mL, 2.0 M in THF) dropwise at r.t. under No. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with aq. NH4CI and extracted with EA (20 mL x 3). The combined organic solution was dried over anhydrous Na2S04, and concentrated under reduced pressure. Crude 525-6 (0.6 g) was used directly without purification.
[1106] Compound 525 (white solid, 130 mg) was prepared following the general procedure for preparing 272 using 525-6. +ESI- S: m/z 582.1 [M+I I]+.
Figure imgf000362_0001
|1107] To a solution of 526-1 (10 g, 0.05 mol) in anhydrous DCM (100 mL) was added oxalyl dichloride ( 12.7 g, 0.1 mmol) and several drops of DMF. The mixture was stirred for 1 h and evaporated under reduced pressure to give 526-2.
[1108] To a solution of 2-methylbut-3-yn-2-amine (4.4 g, 52.5 mmol) and Et3N (10.1 g, 0.1 mmol) in anhydrous DCM ( 100 mL) was added a solution of crude 526-2 in DCM (50 mL) dropwise at r.t. The solution was stirred for 1 h, washed with water and brine (50 mL). dried with anhydrous a?S04 and concentrated to give 526-3. The residue was used directly without further purification.
[1109] 526-3 (2.58 g. 10 mmol) in PhN02 ( 10 mL) was put in a microwave tube. The solution was heated to 210 °C by microwave irradiation and stirred for 5 mins. The reaction was cooled to r.t. and concentrated at low pressure. The residue was purified by column chromatography using PE:EA=10: 1~1 : 1 to give 526-4 (610 mg, 31 .1 %). +ES1-MS: m/z 197.1 [M+H]+. [1110] To a stirring solution of DMAE ( 1.068 g, 12 mmol) in THF (10 mL) was added n-BuLi ( 10 mL, 25 mmol) at -78 °C. After 5 mins, a solution of 526-4 (588 mg, 3 mmol) in anhydrous THF (3 mL) was added dropwise at -78 "C. The mixture was stirred for 10 mins and a solution of h (6.35g, 25 mmol) in THF was added dropwise at -78 °C. After 20 mins, the reaction was quenched with sat. aq. Na2SOj. The solution was extracted with EA (50 mL x 2). The organic phase was washed with brine and dried over anhydrous Na2S04. The organic phase was concentrated at low pressure, and the residue was purified by column chromatography using PE:EA=1 : 1 as the eluent to give 526-5 (650 mg, 51.0%). +ESI-MS: m/z 322.9 [M+H]+.
[1111] To a solution of 526-5 (642 mg, 2 mmol) and CF3COOEt (468 mg, 4 mmol) in anhydrous THF (5 mL) was added iPrMgCl (3 mL, 6 mmol) dropwise at r.t. The solution was stirred for 10 mins. The reaction was quenched with water and extracted with EA (20 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na?S04, and concentrated to dryness. The residue was purified by column chromatography using PE:EA=1 : 1 as the eluent to give 526-6 (302 mg, 51.3%).
[1112] To a solution of 526-6 (300 mg, 1.03 mmol) in DME/H20 (4 niL/1 mL), CS2CO3 (502 mg, 1.55 mmol), (3-chloiO-4-fluoiOplienyl)boronic acid (270 mg, 1.87 mmol) and Pd(dppf)Cl2 (50 mg, 65 mmol) were added at r.t. under N2. The vial was sealed and heated to 100 °C for 40 mins by microwave irradiation. After cooling to r.t., the mixture was diluted with EA (10 mL) and brine ( 10 mL). The aqueous layer was extracted with EA (10 mL x 2). The combined organic layers were washed with brine ( 10 mL), dried over anhydrous Na2S04. and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=1 : 1 as the eluent to give 526-7 (310 mg. 73.7%>). +ES1-MS: m/z 386.9 [M+H]+.
[11 13] To a solution of 526-7 (310 mg. 0.76 mmol) in diy THF (5 mL) was added BHvMe2S ( 1 mL. 10 mmol) at r.t. The solution was stirred in a pre -heated 80 °C oil bath for 2 h. The solution was cooled to r.t., and the reaction was quenched with H2O. The mixture was extracted with EA (20 mL x 2). The combined organic phase was w7ashed with brine, dried over anhydrous a?S04 and concentrated under reduced pressure. The residue was purified by column chromatography using EA as the eluent to give 526-8 ( 140 mg, 49.2%) as a gray solid.
[1114] To a solution of 526-8 (140 mg, 0.37 mmol) in toluene (3 niT) was added EtjN (75 mg. 0.74 mmol) and Boc?0 (87 mg, 0.44 mmol) at r.t. The solution was stirred in a pre-heated 100 "C oil bath for 3 h. The solution was cooled to r.t. and diluted with EA (20 mL) and water (20 mL). The organic phase was washed with brine, dried over anhydrous N 2S04 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=5: 1 as the eluent to give 526-9 (90 mg, 51.0%). +ES1-MS: m/z 474.9 [M+H]+.
[1115] To a stirred solution of 526-9 (90 mg, 0.189 mmol) in DMSO (2 mL) was added IBX (212 mg, 0.75 mmol) in one portion, and stirred at 40 °C for 2 h. The solution was poured into aq. NaHCO and extracted with EA (10 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography using 0-30% EA in PE as the eluent to give 526-10 (60 mg, 66.7%).
[1116] Compound 526 (white solid, 4 mg, 13.7%) was prepared following the general procedure for preparing 272 using 526-10. +ES1-MS: m/z 594.1 [M+H]+.
Figure imgf000365_0001
[1 117] To a stirred solution of 528-1 (50 g. 310 mmol) in anhydrous THF (1 .2 L) was added LDA (310 mL. 620 mmol) at -78 °C slowly under N2. and the mixture stirred at - 78 °C for 0.5 h. A solution of dimethyl carbonate (67.1 g, 750 mmol) in dry THF (150 mL) was added dropwise. The solution was allowed to warm to 0 °C and stirred for 1 h below 0 °C. The reaction was quenched with aq. NH4CI (500 mL), and extracted with EA (500 mL x 3). The combined organic phase w¾s washed with aqueous sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to dr ness, and the residue was purified by column chromatography (PE:EA = 20: 1 ) to give 528-2 (50 g, 73.5 %) as a colorless oil. [1118] To a solution of crude 528-2 (50 g, 230 mmol) in dioxane:H20 (6: 1 ) (1 L) was added (3-chloro-4-fluorophenyl) boronic acid (40 g, 230 mmol), Cs2COj (223.3 g, 680 mmol) and Pd(dppf)Cl2 ( 16.8 g, 23 mmol) under N2. The mixture was degassed for 3 times and refilled with N2. The reaction was stirred at 80 °C in a pre-heated oil bath for 4 h. After cooling to r.t.. the mixture was diluted with water ( 1 .5 L) and extracted with EA ( 1 L x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=20.T ~15: 1 ) to yield 528-3 (42 g. 58.7%) as a light yellow solid.
[1119] To a solution of 528-3 (9.39 g, 30.00 mmol) in HOAc (100 mL) was added Br2 (5.28 g, 33 mmol) dropwise at r.t. The mixture was heated at 60 °C for 5 h. The reaction was cooled to r.t. and concentrated under reduced pressure to di ness. The residue was used directly without further purification. +ES1-MS: m/z 393.7 [M+H]+.
[1120] To a solution of crude 528-4 (10.0 g) in MeOH ( 100 mL) was added NaN.¾ (3.3 g, 50.8 mmol) at 25 °C, and the mixture was stirred at 25°C for 1 h. The mixture was diluted with H20 (150 mL), and extracted with and EA (150 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S0 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA =20: 1-5 : 1 as the eluent to give 528-5 (8.02 g, 88%).
[1121] To a solution of 528-5 (8.02 g, 22.6 mmol) and Boc20 (14.8 g, 67.77 mmol) in MeOH (100 mL) was added Pd/C (3.0 g. 10%) under N?. The suspension was degassed and purged with H2 for several times. The mixture was stirred under H2 balloon at 25 °C for 3 h. TLC showed that the starting material was consumed completely. The mixture was filtered through a pad of Celite. and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=50:1~5: 1 ) to give 528- 6 (5.5 g). +EST-MS: m/z 428.9 [M+H]+.
[ 122] 528-13 (white solid. 80 mg) was prepared following the general procedure for preparing 272 using 528-6. +ESI-MS: m/z 712.1 [M+Hf.
[1123] To a solution of 528-13 (80.00 mg crude) in a co-solvent of MeOH (5 mL) and THF (5 mL) was added NaBH4 (40 mg, 1.05 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction w¾s quenched by H20 and extracted by EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na^SC^ and concentrated at lo pressure. The residue was purified by prep-TLC to give 528-14 (5 1 mg). +ESI-MS: m/z 684.1 [M+H]+.
[1 124] Compound 528 (white solid, 1 8 mg, 39.9%) was prepared following the general procedure for preparing 272 using 528-14. +ESI-MS: m/z 584.0 [M+H]+.
EXAMPLE 298
Preparation of Compound 529
Figure imgf000367_0001
[1125] To a solution of 529-1 (150.00 mg) in MeOH (50 niL) was added a- Ni (0.15 g) under N2. The suspension was degassed and purged with i for several times. The mixture was stirred under H? balloon at 25 °C for 2 H. TLC (PE:EA=1 : 1 ) showed that the starting material was consumed. The mixture was filtered, and the filtrate was concentrated to give 529-2 (90 mg. crude), which was used directly without further purification.
[1 126] Compound 529 (white solid, 13 mg) was prepared following the general procedure for preparing 528 by using 529-2. +EST-MS : m/z 550.1 [M+H]+.
Figure imgf000368_0001
[1 127] Compound 532 (white solid, 13 mg) was prepared following the general procedure for preparing 501 and 272 by using 532-1. +ES1-MS: m/z 597.1 [M+H]+.
Figure imgf000368_0002
[1128] To a solution of 533-1 (10 g, 3 1 .9 mmol) in anhydrous THF (1 00 mL) was added Lil l DS (63.9 mL, 63.9 mmol) dropwise. and stirred at -78 °C for 30 mins. A solution of Mel (9.07 g, 63.9 mmol) in dry THF (50 mL) was added dropwise. The mixture was warmed to 0 °C and stirred at 0 °C for 1 h. The reaction was quenched with water ( 100 mL) and extracted with EA ( 150 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=10: 1 ) to yield 533-2 (3.5 g. 32%) as a light yellow solid.
[1129] 533-4 (crude, yellow oi l) was prepared following the general procedure for preparing 501 by using 2. +ESI-MS: m/z 369.0 [M+H]+.
[1130] To a solution of 533-4 (500.00 mg, 1 .35 mmol) in MeOH (30 mL) was added S11CI2 · 21 O (760.40 mg, 3.39 mmol) in one portion at r.t. under N?. and the mixture was stirred for 2 h. TLC showed that the reaction was completed. The mixture was di luted with water (20 mL). The solution was extracted with EA (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous NaiSO.}, and concentrated under reduced pressure. The residue was used in the next step without purification.
[1131 ] To a solution of 533-5 (0.5 g, 1.46 mmol) and CbzCl (745.56 mg. 4.37 mmol) in DCM ( 15 mL) was added NaHC03 (489.61 mg, 5.83 mmol) in one portion, and the mixture was stirred at r.t. for 1 h. The solution was poured into ice-water (15 mL) and stirred for 20 mins. The aqueous phase was extracted with EA (40 mL x 3). The combined organic phase was washed with brine, dried over anhydrous NaaSO.}, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=30: 1 -1 0: 1 ) to afford 533-6 (0.4 g) as a yellow solid. +ESI-MS: m/z 477.1 [M+HJ+.
[1 132] To a solution of 533-6 (0.4 g, 0.84 mol) in THF (40 mL) was added LiBH4 (55 mg, 2.5 mmol) in one portion, and the mixture stirred at r.t. for 1 h. TLC showed that the reaction was completed. The mixture was poured into ice-water ( 15 mL) and stirred for 20 mins. The aqueous phase was extracted with EA (40 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, filtered and concentrated at low pressure. The residue wras purified by column chromatography (PE:EA=30: 1 ~2: 1 ) to afford 533-7 (320.00 mg, 85%) as a yellow solid. +E SI-MS: m/z 448.6 [M+H]+. [1133] To a solution of 533-7 (320 mg, 0.71 mmol) in DME (5 mL) and H20 (] mL) were added 4,4,6-trimethyl-2-[l -(trifluoromethyl)vinyl]- l ,3,2-dioxaborinane (320 mg, 1.42 mmol), Cs2C03 (0.7 g, 2.13 mmol), and Pd(dppf)CL (52 mg, 0.07mol) under N2. The reaction flask was sealed and stirred at 1 10 °C by microwave irradiation for 1 h. The reaction was cooled to r.t., and diluted with EA and water. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography using 3-20% of EA in PE as the eluent to give 533-8 (220 mg, 60%). +ESI-MS: m/z 508.9 [M+H]+.
[1 134] To a mixture of 533-8 (100.00 mg, 0.2 mmol) in t-BuOH ( 1.5 ml.) and H20 (0.5 mL), were added K20s04H20 (11 mg, 0.06 mmol) and BocHN-OTs (113 mg, 0.39 mmol), and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water, stirred for 20 mins and extracted with EA (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30: 1-20: 1 as the eluent to give 533-9 (50 mg, 40%) as a yellow solid. +E SI-MS: m/z 642.1 [M+H]+.
[1135] To a solution of 533-9 (50.00 mg, 0.078 mmol) in DCM (2 mL) was added TFA ( 1 mL). The mixture was stirred at r.t. for 1 h. The solution was poured into ice-water (5 mL) and neutralized with sat. Nal lCO solution. The aqueous phase was extracted with EA (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using EA as the eluent to give 533-10 (30.00 mg. 71 %) as a yellow solid. +ES1-MS: m/z 542.1 [M+H]+.
[1 136] 533-11 (yellow solid, 30 mg, 74%) was prepared following the general procedure for preparing 272 using 533-1 1. +E SI-MS: m/z 732.3 [M+Hf.
[1 137] To a solution of 533-1 1 (30 mg) in CH3CN (1 mL) was added one drop of TMSI at r.t. The mixture was stirred at r.t. for 10 mins. The mixture was poured into wrater. neutralized with sat. NaHCO? solution and extracted with EA ( 10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 533 (23.00 mg) as a white solid. +ESI-MS: m/z 597.9 [M+LLf.
Figure imgf000371_0001
[1138] To a solution of 534-1 (6 g. 1 8.3 mmol) and TEA ( 18.5 g, 183 mmol) in THF (60 mL) was added aq. HCHO ( 1 5 g. 183 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 2 h. TLC (PE:EA=5: 1 ) showed that the reaction was completed. The mixture was diluted with water and extracted with EA (100 mL x 3). The combined organic phase was washed with brine, dried over anhydrous N 2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30: 1-5: 1 as the eluent to afford 534-2 (5.1 g, 77%) as a white oil. +ESLMS: m/z 358.1 [M+H]+.
[11391 To a solution of 534-2 ( 1.76 g, 4.91 mmol) in DCM (20 mL) was added DAST (7.91 g, 49.10 mmol) dropwise at -78 °C under N2. The mixture was slowly warmed to 25 °C, and stirred for 12 h. TLC (PE:EA=5: 1) showed that the reaction was completed. The mixture was cooled to 0 °C and quenched with sat. NaHC(¾ solution. The aqueous phase was extracted with EA (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, filtered and concentrated at low pressure. The residue was purified by column chromatography using PE:EA=100: 1~ 60: 1 as the eluent to afford 534-3 (0.6 g. 34%) as a white oil. +ESI-MS: m/z 360.1 [M+H]+. [1140] To a solution of 534-3 (590 mg, 1 .64 mmol) in MeOH (6 mL) was added a solution of NaOI I (260 mg, 6.6 mmol) in I LO (6 mL) at r.t. The mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to r.t.. and the organic solvent was removed under reduced pressure. The pH of aqueous phase was adjusted to ~3 using 2M HC1 and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuum to give 534-4 (503 mg, 88%) as a white solid.
[1 141] To a solution of 534-4 (438 mg. 1.27 mmol), D1PEA (655 mg, 5.07 mmol) and BnOH (274 mg, 2.53 mmol) in toluene (5 mL) was added DPPA (698 mg, 2.54 mmol) at r.t. under N2. The mixture w¾s heated to 80 °C and stirred for 12 h. The mixture was cooled to r.t. and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30: 1-5: 1 as the eluent to afford 534-5 (450.00 mg, 78.52%) as a w7hite solid.
[1142] Compound 534 (white solid, 21 mg, 45.9%) was prepared following the general procedure for preparing 533 using 534-5. +ESI-MS: m/z 600.0 [M+H]+.
Figure imgf000372_0001
[1143] To a solution of 535-1 (2.0 g, 4.2 mmol) in eOH (20 mL) was added NaBI U (476 mg, 12.6 mmol) at r.t. in small portions. The solution was stirred for 30 mins and quenched with H?0. The mixture was extracted with EA (50 mL). The organic phase was washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography using PE:EA=1 : 1 to give 535-2 (1.6 g. 85%) as a white solid. +ESI-MS: m/z 449.1 [M+H]+.
[1 144] To a solution of 535-2 (1.40 g, 3.1 mmol) in THF (20 mL) were added Ag O (723 mg, 3.1 mmol) and Mel (1.77 g, 12.5 mmol) at r.t. The mixture was sealed and heated to 40 °C. The reaction was stirred overnight and concentrated to dryness at low pressure. The residue was purified by column chromatography using PE:EA=10: 1 as the eluent to give 535-3 (450 mg, 31%). +ESI-MS: m/z 463.1 [M+H]+.
[1145] Compound 535 (white solid, 1 1 mg. 22%) was prepared following the general procedure for preparing 533 using 535-3. +ESI-MS: m/z 612.1 [M+H]+.
EXAMPLE 303
Figure imgf000373_0001
[1146] Compound 536 (white solid, 65 mg. 83%) was prepared following the general procedure for preparing 533 and 501 using 536-1. +ES1-MS: m/z 61 1.2 [M+H]+.
Figure imgf000374_0001
[1147] To a solution of 537-1 (0.7 g, 2. 1 mmol) in THF (8 mL) was added LiHMDS (3.2 mL 1 M in THF) at -78 °C in a period of 1 minute under N2. After stirring at - 78°C for 10 minutes, a solution of MOMC1 (340 mg. 4.2 mmol) in THF (2 mL) was added at -78 °C in a period of 1 min under Ντ . The reaction mixture was wanned to room temperature and stirred for 20 minutes. LCMS showed that 537-1 was consumed completely. The reaction was quenched by water and extracted with EA (20 mL X 3). The combined organic phase was washed with brine, dried over anhydrous Na^SO-t, filtered and concentrated under reduced pressure to give 537-2 (720 mg, 82%) as colorless oil. +ESI-MS: m/z 372.1 [M+H]+.
[1 148] 537-8 (white solid. 45 mg. 78%) was prepared following the general procedure for preparing 533 using 537-2. +ESI-MS: m/z 746.1 [M+H]+.
[1149] To a solution of 537-8 (45 mg, 0.06 mmol) in TFA ( 1 mL) was added HBr/HOAc ( 1 mL, 40%) at r.t. The reaction mixture was stirred at room temperature until all starting material was consumed (followed by LCMS). The resulting mixture was concentrated under reduced pressure. The residue was neutralized with aqueous NaHCOj and extracted with EA. The combined organic phase was concentrated under reduced pressure. The residue was purified by Pre-1 1PLC to afford 537 (9 mg. 16.3%) as a white solid. +ESI- MS: m/z 654.1 [M+H]+.
Figure imgf000375_0001
[1 151] Compound 541 (white solid, 13 mg, 18.4%) was prepared following the 1 procedure for preparing 537 and 528 using 541 -1. +ES1-MS: m/z 616.0 [M+H]+.
Figure imgf000376_0001
544-9 544-10
[1152] To a solution of CI 13CN (24.6 g, 600 mmol) in toluene (200 mL) was added n-BuLi (120 mL, 2.5 M in hexane) dropwise at -78"C under N2. The mixture was stirred at -78 °C for 30 mins. The mixture was treated with a solution of 544-1 (36.0 g, 120 mmol) in toluene (200 mL). The mixture was warmed to r.t. and stirred for 2 h. The reaction was quenched with sat. aq. NH4C1, and extracted with EA (4 x 200 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated at low pressure. The residue was purified by column chromatography to give 544-2 as a white solid (31.5 g, 85.0%). +ES1-MS: m/z 308.9 [M+H]+.
[1153] To a solution of 544-2 (30.9 g. 100 mmol) in MeOH (600 mL) was added NaBFL (19 g, 500 mmol) in portions at 0 °C, and stirred at 0 "C for 4 h. The mixture was quenched with water, and extracted with EA (4 x 300 mL). The combined organic layer was washed with brine, dried over anhydrous a2SC>4, filtered and concentrated under reduced pressure. The residue was further purified by column chromatography to afford 544-3 as a light yellow solid (28.0 g, 90.0%). +ESI-MS: m/z 310.9 [M+H]+.
[1154] To a solution of 544-3 (5 g, 16.08 mmol) in MeOH (100 mL) was added SOCL (20 mL) at 0 °C dropwise. The mixture was heated to reflux and stirred for 48 h. The mixture was cooled to r.t. The solution was neutralized with sat. aq. NaHC03„ and extracted with EA (4 x 300 mL). The combined organic layer was washed with brine, dried over anhydrous
Figure imgf000377_0001
filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 544-4 as a light yellow solid (3.32 g. 60.0%).
[1 155] Compound 544-5 (light yellow solid, 2.65 g, 90%) was prepared was prepared following the general procedure for preparing 544-3 using 544-4. +ES1-MS: m/z 315.7 [M+H]+.
[1 156] To a solution of 544-5 (2.65 g. 8.38 mmol) and TEA (2.54 g, 25.15 mmol) in DCM (20 mL) was added MsCl (2.88 g. 25.15 mmol) at 0 °C. The mixture was stirred at r.t. for 2 h. The reaction was quenched with sat. aq. NaHCO and extracted with EA (4 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na SC , filtered and concentrated at low pressure. The residue w¾s purified by column chromatography to afford 544-6 as a light yellow solid (3.2 g, 80.8 %).
[1157] To a solution of 544-6 (3.2 g, 8.4 mmol) in toluene (50 mL) were added BnNLL (5.4 g. 50.3 mmol), K2C<¾ (6.9 g, 50.3 mmol), and l ( 100 mg) at r.t. The mixture was stirred at 160 °C for 6 h. The mixture was cooled to r.t. and diluted with water. The solution was extracted with EA (4 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO_t, filtered and concentrated at low pressure. The residue was purified by column chromatography to afford 544-7 as a light yellow solid (1 .1 g, 33.9%). +ESI-MS: m/z 386.9 [M+H]+.
[1 158] Compound 544 (white solid. 450 mg. 40.3%) was prepared was prepared following the general procedure for preparing 528 using 544-7. +ESI-MS: m/z 670.3 [M+H]+.
EXAMPLE 308
Preparation of Compounds 545 and 546
Figure imgf000378_0001
[1159] Compounds 545 (white solid, 1 12 mg) and 546 (white solid, 107 mg) was prepared following the general procedure for preparing 495 and 496 using 545-1 and 545-2. 545: +ESI-MS: m/z 566.2 [M+H]+; and 546: +ESI-MS: m/z 566.2 [M+H]+.
EXAMPLE 309
Preparation of Compounds 547 and 548
Figure imgf000379_0001
[1160] Compounds 547 (white solid, 45 mg) and 548 (wiiite solid, 48 mg) was prepared following the general procedure for preparing 271 and 272 using 547-1 and 547-2. 547: +ESI-MS: m/z 599.1 [M+H]+; and 548: +ES1-MS: m/z 599.1 [M+H]+.
Figure imgf000380_0001
[1161] Compounds 549 (white solid, 102 mg) and 550 (white solid, 108 mg) was prepared following the general procedure for preparing 271 and 272 using 549-1 and 549-2. 549: +ESI-MS: m/z 585.9 [M+H]+; and 550: +ESI-MS: m/z 586.0 [M+H]+.
Figure imgf000381_0001
[1162] Compounds 551 (white solid. 78 mg) and 552 (white solid, 72 mg) was prepared following the general procedure for preparing 271 and 272 using 551-1 and 551-2.
551: +ESI-MS: m/z 600.2 [M+H]+; and 552: +ES1-MS: m/z 600.2 [M+H]+.
Figure imgf000381_0002
[1163] Compounds 553 (white solid, 35 mg) and 554 (white solid, 45 mg) was prepared following the general procedure for preparing 495 and 496 using 553-1 and 553-2.
553: +ESI-MS: m/z 552.2 [M+HJ 1 ; and 554: +ES1-MS: m/z 552.1 [M+H]\
EXAMPLE 313
Figure imgf000382_0001
[1164] To a solution of 555-1 (2.74 g, 10 mmol) in anhydrous THF (30 mL) was added «-BuLi (4.8 mL. 2.5 M in hexane) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for 20 mins, and then treated with a solution of tcrt-butyl 3-oxoazetidine-l - carboxylate (1 .71 g, 10.00 mmol) in anhydrous THF (5 mL) at -78 °C. The solution was stirred for 30 mins at -78 °C. The reaction was quenched with water and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous N 2SC»4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=9: 1 as the eluent to afford 555-2 (1 .05 g. 33%). +ESI- MS: m/z 319.1 [M+H]+.
[1165] To a solution of 555-2 (0.8 g. 2.52 mmol) and (3-chloro-4-fluorophenyl) boronic acid (440 mg, 2.52 mmol) in dioxane:EL:0 (10:1 mL) were added CS7CO3 (1.23 g, 3.78 mmol) and Pd(dppf)Ci2 (185.00 mg, 0.25 mmol) under N2. The mixture was heated to 80 °C in an oil bath and stirred for 1 h. The mixture was cooled to r. , poured into H20 (20 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous aaSC^ and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=9: 1 as the eluent to afford 555-3 (780 mg). +ESl-MS: m/z 413.1 [M+H]+.
[1 166] To a solution of 555-3 (780 mg. 1.89 mmol) in DCM (8 mL) was added TFA (2 mL). and the mixture stirred at r.t. for 30 mins. The mixture was concentrated under reduced pressure, and the residue was dissolved in DCM ( 10 mL) and Et3N (572 mg, 5.65 mmol). CbzCl (643 mg. 3.77 mmol) was added slowly at r.t.. and the mixture was stirred for 2 h. The solution was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduce pressure. The residue was purified by column chromatography using PE:EA=4: 1 as the eluent to give 555-5 (720.00 mg). +ESI-MS: m/z 447.1 [M +H]+.
[1167] Compound 555 (white solid, 3.5 mg. 16.3%) was prepared following the general procedure for preparing 533 using 555-5. +ESI-MS: m/z 595.9[M+H]+.
EXAMPLE 314
Preparation of Compounds 561 and 562
o r
Figure imgf000383_0001
[1168] Compounds 561 (white solid, 50 mg) and 562 (white solid, 48 nig) was prepared following the general procedure for preparing 495 and 496 using 561-1 and 561-2.
561 : +ESI-MS: m/z 565.1 [M+HJ ' ; and 562: +ES1-MS: m/z 565.1 [M+H]\
EXAMPLE 315
Figure imgf000384_0001
[1169] A solution of 563-1 (3.00 g, 10.56 mmol) and tetraethoxytitanium (7.23 g, 3 1.68 mmol) in anhydrous THF (60 niL) was stirred for 5 mins. The solution was treated with 2-methylpropane-2-sulfmamide ( 1 .92 g, 15.84 mmol) and stirred at 70 °C for 5 h. The mixture was cooled to r.t., and the reaction was quenched with sat. aq. NaHCC^ until white titanium salts precipitate was formed. The suspension was filtered through a pad of Celite. and the cake was washed with EA. The aqueous was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous a2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 563-2 (3.50 g, 85.6%). +ES1-MS: m/z 387.0 [M+H]+. [1170] To a solution of 563-2 (3.50 g, 9.0 mmol) in anhydrous THT (15 mL) was added allylmagnesium bromide (13.6 mL, 1.0 M in TI IF) at -78 °C under N2, and the mixture was stirred at -78 °C for 1 h. The mixture was allowed to warm to 25 "C and stirred for another 1 h. The reaction was quenched with aq. NH4CI solution and extracted with ΕΛ (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04. filtered and concentrated under reduced pressure. The residue was purified column chromatography to afford 563-3 (1 .20 g. 31 %) as a yellow solid. +ESI-MS: m/z 429.1 [M+H]+.
[1171 ] Ozone was bubbled into a solution of 563-3 (1 .2 g, 2.8 mmol) in anhydrous MeOH (30 mL) at -78 °C for 10 mins. After excess O3 was purged by nitrogen, NaBLL; (420 mg 1 1.2 mmol) was added at 25 °C in portions. The solution was stirred for 30 mins at r.t. The reaction was quenched with HiO and extracted with EA (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous NaiSC>4 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA = 2: 1 as the eluent to give 563-4 ( 1.02 g. 83%) as a solid. +ES1-MS: m/z 433.1 [M+H]+.
[1172] To a solution of 563-4 (1.01 g, 2.5 mmol) and PPh3 (1 .0 g, 3.8 mmol) in anhydrous TI IF (20 mL) was added DIAD (870 mg, 4.3 mmol) dropwise at 25 "C under N2. The mixture was heated to 70 °C and stirred for 4 h. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by column chromatography to afford 563-5 (902 mg. 85%) as a solid.
[1 173] To a solution of 563-5 (902 mg 2.2 mmol) in dioxane (8 mL) was added cone. HC1 (1 mL, 12 M) in one portion, and stirred at 25 "C for 1 h. The mixture was concentrated to give 563-6 (750 mg), which was used for the next step without further purification.
[1174] 563-6 (750mg) and NaHC0 (607 mg, 7.2mmol) were dissolved in DCM ( 10 mL) and H20 ( 1 mL). The solution was treated with CbzCl (617 mg 3.6 mmol) at r.t. The mixture was stirred at r.t. for 1 h. The mixture was diluted with water and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na^SCu, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 563-7 (990 mg, 93%). +ESI-MS: m/z 444.9 [M+I I] h.
[1175] 563-8 (white solid, 1 .1 g, 16.3%) was prepared following the general procedure for preparing 533 using 563-7. +ES1-MS: m/z 595.9 [M+H]+. 563-9 (402 mg) was obtained by SFC separation of 563-8 (1.1 g).
[1176] Compound 563 (white solid. 20 mg, 33%) was prepared following the general procedure for preparing 533 using 563-9. +ESI-MS: m/z 593.9 [M+H]+.
Figure imgf000386_0001
[1 177] 564-3 was prepared as described in Franc k, D. et al., Bioorganic & Medicinal Chemistry (2013) 21 (3):643-652.
[1178] To a solution of 564-4 (1 1.22 g. 35.7 mmol) in anhydrous THF (200 mL) was added LiHMDS (286 mL 1 M in THF) in portions at -78 °C under N2. The mixture was stirred at -78 °C for 30 mins. The mixture was treated with a solution of 564-3 (22 g, 71.4 mmol) in anhydrous THF (50 mL) dropwise. The mixture was warmed to r.t. and stirred for 3 h. The reaction w7as quenched with ice-water (150 mL). The aqueous phase was extracted with EA (3 x 200 mL). The combined organic phase was washed with brine, dried over anhydrous Na7S04 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30: 1~10: 1 as the eluent to afford 564-5 (1 1 .0 g, 70% purity) as a light yellow oil. +ESI-MS: m/z 460.0 [M+I if.
[1179] To a solution of 564-5 (1 1.0 g, 23.9 mmol) in anhydrous THF (60 mL) was added L1AIH4 (907 mg, 23.9 mmol) in portions at 0 °C under N2. The mixture was stirred at 0 "C for 30 mins. The reaction was quenched by ice-water and filtered via a pad of Celite. The filtrate was extracted with EA (3 x 100 mL). The combined organic phase was washed with brine, dried with anhydrous Na2SC»4 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30: 1 -20: 1 as the eluent to afford 564-6 (3.8 g, 28% yield, 81% purity) as a light yellow oil. +ES1-MS: m/z 432.1 [M+H]+.
[1180] To a solution of 564-6 (0.8 g, 2.34 mmol) and TEA (0.71 g, 7.01 mmol) in DCM (10 mL) was added MSCT (270 mg, 2.34 mmol) dropwise at 0 °C, and the mixture was stirred at 20 °C for 30 mins. The mixture was poured into ice-water (50 mL) and extracted with EA (3 x 20 mL). The combined organic phase w7as washed with brine, dried with anhydrous Na2SC»4, filtered and concentrated under reduced pressure to afford 564-7 (0.6 g, crude) as a yellow oil, which was used for next step directly. +ES1-MS: m/z 509.9 [M+H]+.
[1181] To a solution of crude 564-7 (0.6 g, 1.43 mmol,) in DMSO (6 mL) was added NaBH4 (270 mg, 7.14 mmol) in one portion at r.t. under N2. The mixture was stirred at 50-60 "C for 12 h. The reaction was cooled to r.t., quenched with ice-water and extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30:1~8: 1 as the eluent to afford 564-8 (0.3 g, 78% purity) as a yellow solid. +ESI-MS: m/z 415.9 [M+H]+.
[1 182] Compound 564 (white solid. 2.7 mg) was prepared following the general procedure for preparing 533 using 564-8. +ESI-MS: m/z 609.1 [M+H]+.
Figure imgf000388_0001
[1 183] Compound 569 (white solid. 53 mg, 74%) was prepared following the general procedure for preparing 495 using 569-1 and 569-2. +ESI-MS: m/z 51 9.1 [M+H]+.
EXAMPLE 318
Preparation of Compound 570
Figure imgf000388_0002
[1 184] Compound 570 (white solid, 25 mg, 32%) was prepared following general procedure for preparing 495 using 570-1 and 570-2. +ESI-MS: m/z 5 1 7.1 [M+H]
EXAMPLE 319
Figure imgf000389_0001
[1185] Compound 571 (white solid, 21 mg. 23%) was prepared following the general procedure for preparing 495 using 571-1 and 571 -2. +ESI-MS: m/z 517.1 [M+H]+.
EXAMPLE 320
Preparation of Compounds 604a-d
Figure imgf000390_0001
[1 186] To a mixture of 604-1 (12.0 g, 92.6 mmol) and 2.2.2-trifluoroethane-l ,l - diol (32.3 g, 277.9 mmol) in H20 (25 mL) was added 2C03 (25.6 g. 185.2 mmol, 2.00 eq.) in one portion at r.t. The flask was sealed, heated to 125°C and stirred for 16 h. The mixture was cooled to 0 °C, neutralized with l HC1 solution, and extracted with EA (3 x 100 mL). The combined organic phase was dried over anhydrous a S04, filtered and concentrated under reduced pressure. The residue was washed with DCM and PE to afford 604-2 (17.0 g, 81 %) as a w hire solid.
[1 187] To a stirring solution of 604-2 (130 g, 571 .2 mmol) and Na2C03 (121 g. 1.1 mol) in LEO (800 mL) was added E ( 174 g. 685.5 mmol) in portions. The mixture was stirred at 25 °C for 48 h. A sat. sodium sulfite solution (500 mL) was used to quench the reaction. The mixture was acidified with 3M HC1 and diluted with EA (1 L). The organic phase wras separated, and the aqueous phase wras extracted with EA (3 x 500 mL). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography by using PE:EA=1 : 1 as the eluent to afford 604-3 (180 g, 89%) as a white solid.
[1188] To a solution of 604-3 (88 g, 249 mmol) and l -chloropropan-2-one (55.9 g. 605.0 mmol) in DMT (200 mL) was added NaHCC>3 (62.7 g, 746.1 mmol) in one portion at r.t. under N2. The mixture wras stirred at 25 °C for 25 h, and the solid wras removed by filtration. The filtrate was concentrated to dryness under reduced pressure, and the residue was dissolved in DCM and triturated with PE to afford 604-4 (66 g, 65%) as a white solid.
[1189] A mixture of 604-4 (9.0 g, 22 mmol), 2-methylpropane-2-sulfinamide (S- configuration, 2.66 g, 22 mmol) and titanium(IV) ethoxide (10.5 g, 46.1 mmol) in anhydrous THF (18.00 mL) was heated to 80 °C (sealed vial, degassed and purged with N2) and stirred for 1 h. EA (150 mL) and water ( 10 mL) were added with stirring. The mixture was stirred for 5 mins and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using EA:DCM=1 :9 as the eluent to afford 604-5 (6.8 g. 60%).
[1190] To a solution of EtMgBr (4.4 mL. 13.2 mmol. 3 M in ether) in dry THF (50 mL) was added w-BuLi ( 10.6 mL, 26.5 mmol, 2.5 M in hexane), and the mixture was stirred at 0 °C. After stirring for 10 mins, the mixture was cooled down to -78 °C. A solution of 604-5 (6.8 g, 13.26 mmol) in dry THF (50 mL) was added dropwise, and the reaction w7as stirred at -78 °C for 15 mins. The reaction was quenched with H20 (50 mL) and extracted with EA (2 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 0-10% EA in DCM) to afford 604-6 (3.1 0 g, 60%).
[1191] To a stirring solution of 604-6 (6.8, 17.6 mmol) in DCM (50 mL) was added Dess-Martin reagent (8.95 g, 21.1 mmol), and the mixture was stirred at r.t. under N2 for 1 h. The reaction was quenched with sat. aq. Na2S03 solution and sat. aq. NaI IC0 solution. After 30 mins of stirring vigorously, the organic layers were separated, and the aqueous layer was extracted with EA (2 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 0-10% EA in DCM) to afford 604-7 (5.1 g 75.4%).
[1 192] To a solution of /-BuOK (1.64 g, 14.58 mmol) in CH3CN (1 50 mL) was added Me3SOI (3.21 g, 14.58 mmol). The mixture was degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution of 604-7 (5.1 g, 13.25 mmol) in CH C (150 mL), which had been previously degassed. The reaction was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. The residue was purified by column chromatography using DCM:EA=9: 1 as the eluent to give 604-8 (3.2 g, 60.5%).
[1193] To a solution of 604-8 (3.2 g, 8.02 mmol) in MeOH (300 mL) was added ammonia water ( 10 mL) in one portion. The solution was stirred at 25 °C for 18 h. The volatiles were removed under reduced pressure to afford crude 604-9 (3. 1 g, 93%).
[1194] To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (460 mg, 2.1 7 mmol) in DCM (6 mL) was added I IATU (985 mg, 2.59 mmol) and DIPEA (558 mg, 4.32 mmol) in one portion at r.t. After stirring for 10 mins, 604-9 (900 mg, 2.1 6 mmol) was added. The mixture was stirred for 1 h at r.t. The solution was washed with brine, dried over anhydrous Na2S<¾, fi ltered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 10-100% EA in PE) to give 604-10 (890 mg. 67.5%).
[1 195] 604-10 (300 mg, 0.49 mmol). (4-cyanophenyl)boronic acid (88 mg, 0.6 mmol) and CsiCO:, (240 mg, 0.74 mmol) were taken up into a microwave tube in co-solvent DME:H20 (12 niL, v:v=5: l ). The solution was degassed and Pd(PPh3)4 (57 mg, 0.05 mmol, 0.10 cq.) was added. The scaled tube was heated to 1 10 °C by microwave irradiation and stirred for 1 h. The solution was cooled to r.t. and poured into water. The mixture was extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (20 mL). dried over anhydrous Na?S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using EA as the eluent to give 604-11 (320 mg. 96.2%).
[1 196] To a solution of 604-11 (300 mg, 0.44 mmol) in dioxane (3 mL) was added HCl/dioxane (1 mL, 4M) at r.t. The mixture was stirred at r.t. until all the starting material was consumed. The mixture was concentrated under reduced pressure. The residue was dissolved in EA, and basilied by a sat. NaHCO solution. The organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford crude 604-12 (-200 mg, 71% yield, 90% purity).
[1197] 604-12 (-200.00 mg, 90% purity) was separated by SFC ("Column: Chiralcel OJ-H 250*4.6ητηι I.D., 5um Mobile phase: methanol (0.05% DEA) in C02 from5% to 40% Flow rate: 2.35mL/min Wavelength: 220nm") to give peak 1 , peak 2, peak 3 and peak 4. The solution of peak 1 in CH3CN and water was treated with HCl (2 M, 0.2 mL) and lyophilized to give 604a (25 mg). +ESI-MS: m/z 573.1 [M+I I] '. The solution of peak 2 in CH3CN and water was treated with HCl (2 M, 0.2 mL) and lyophilized to give 604b (25 mg). +ESI-MS: m/z 573.1 [M+H]+ . The solution of peak 3 in CH3CN and water was treated with HCl (2 M. 0.2 mL) and lyophilized to give 604c (19 mg). +EST-MS: m/z 573.1 [M+H]+ The solution of peak 4 in CH CN and water was treated with HCl (2 M. 0.2 mL) and lyophilized to give 604d (22 mg). +ES1-MS: m/z 573.3 [M+H]+
EXAMPLE 321
Preparation of Compounds 605a-d
Figure imgf000394_0001
[1198] To a solution of 604-10 (400 mg, 0.66 mmol) and (4-fluorophenyl)boronic acid (138 mg. 984 mmol) in DME (3 mL) and LLO ( 1 mL) was added Pd(dppf)Cl2 (24 mg. 0.033 mmol) and CS2CO3 (641 mg, 2.0 mmol) in a microwave tube under N2. The reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and stirred for 5 mins. The aqueous phase was extracted with EA (30 mL X 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using EA as eluent to give 605-1 (310 mg) as a white solid. +ESI-MS: m/z 670.1 [M +H]+.
11199] Compounds 605a, 605b, 605c and 605d was prepared following the general procedure for preparing 605a using 605-1. The crude was purified by prep-HPLC and SFC separation. 605a (white solid, 20 mg): m/z 566.2 [M+H] , 605b (white solid, 18 mg): m/z 566.1 [M+H]+, 605c (white solid, 12.8 mg): m/z 566.1 [M+H]+ and 605d (white solid, 12.7 mg): m/z 566.2 [M+H]+.
EXAMPLE 322
Preparation of Compounds 629-632
Figure imgf000395_0001
[1200] Compounds 629, 630, 631 and 632 was prepared following the general procedure for preparing 605d using 604-10, 629-1 and (4-fluorophenyl)boronic acid. 629 (white solid, 14.1 mg): m/z 580.1 [M+H]+, 630 (white solid, 18.6 mg): m/z 580.1 [M+H]+, 631 (white solid, 25.8 mg): m/z 580.1 [M+H]+ and 632 (white solid, 34.5 mg): m/z 580.1 [M+H]+.
Figure imgf000396_0001
[1201] 633-1 (9.0 g, 25.5 mmol) and NaHC03 (6.4 g. 76.4 mmol) were dissolved in DMF (80 mL). 3-bromo-2-methylprop-l -ene (4.5 g. 33.1 mmol) was added by syringe, and the mixture was heated to 70 °C for 3 h. After cooling to r.t. the reaction was quenched with H20 and extracted with EA. The organic phase was washed with brine, dried over anhydrous MgS04. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: PE:EA = 30: 1-8: 1 ) to give 633-2 (8.02 g. 77%) as a white solid. +ESI-MS: m/z 407.8 [M+H]+.
[1202| A sealed tube was charged writh a solution of 633-2 (7.0 g, 17.2 mmol) in toluene (50 mL). Pd2(dba)3 (580.0 mg, 1.0 mmol) and Q-phos (1.0 g, 1.4 mmol) w7as added under N2. The sealed tube was stirred at 100 °C in an oil bath. After stirring for 7 h, the mixture was cooled to r.t. and concentrated at low7 pressure. The residue was purified by flash chromatography using 2~5% EA in PE as the eluent to afford 633-3 (3.5 g, 50%>) as a solid.
[1203] To a solution of 633-3 (3.5 g, 8.6 mmol) in DMF (50 mL) was added Na (12.4 g, 190.7 mmol) at r.t. The solution was heated to 70 °C and stirred for 16 h. The mixture was cooled to r.t. and quenched by pouring into water. The mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgS04. filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 5-12% ΕΛ in PE as the eluent to give 633-4 (2.4 g, 86.6%) as an oil. +ES1-MS: m/z 322.9 [M+H]+.
[1204] 633-8 was prepared following the general procedure for preparing 604a using 633-4.
[1205] 633-8 (500 mg. 0.92 mmol), (4-fluorophenyl)boronic acid ( 167 mg. 1 .2 mmol), CS2CO3 (450 mg. 1.4 mmol) and Pd(PPh?)4 (106 mg. 0.092 mmol) were taken up into a microwave tube in a co-solvent of dioxane ( 15 mL) and LLO (3 mL). The sealed tube was heated at 1 10 °C by micrcwave irradiation and stirred for 1 h. LCMS showed that -30%) of the desired product was formed. The solution was concentrated under reduced pressure, and the residue was purified by TLC and further purified by prep-HPLC to give pure 633a (-80 mg) and 633b (-70 mg). 633a: +ES1-MS: m/z 580.2 [M+H]+ and 633b: +ES1-MS: m/z 580.1 [M+H]+.
EXAMPLE 324
Preparation of Compound 638
Figure imgf000397_0001
[1206] Compound 638 (white solid, 15 mg) was prepared following the general procedure for preparing 604a using 604-10 and (3-chloro-4-fluorophenyl)boronic acid. +ES1-MS: m/z 600.1 [M+H]+. EXAMPLE 325
Preparation of Compounds 653 and 654
Figure imgf000398_0001
[1207] 2-chloro-4-iodo-6-(2,2,2-trifluoro-l -hydroxyethyl)pyridin-3-ol was prepared as provided in Henichart, J. et a\.. J. Het. Chem. (1986). 23(5):1531-1533.
[1208] To a solution of 2-chloro-4-iodo-6-(2,2.2-trifluoro-l- hydroxyethyl)pyridin-3-ol (16 g, 45.3 mmol) in C¾CN ( 150 mL) was added K2C03 (12.5 g, 90.5 mmol) in one portion. After stirring at r.t. for 5 mins, a solution of 653-3 (9.8 g, 54.3 mmol) in CH3CN (10 mL) was added slowly under N2. The mixture was stirred at 90 °C for 1 h in a pre-hcated oil bath. After cooling to r.t., the mixture was poured into water (150 mL) and stirred for 5 mins. The mixture was extracted with EA (2 x 150 mL). The combined organic phase was washed with brine, dried with anhydrous a2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography using 2-5% EA in PE as the eluent to afford 653-4 (10.9 g, 49%) as a yellow solid.
[1209] 653-8 was prepared following the general procedure for preparing 604a using 653-4.
[1210] To a solution of 653-8 ( 1 .0 g, 1.9 mmol) in CH3N02 ( 1 5 mL) was added TEA (2.0 mL) in one portion at r.t. The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography using 10-20% EA in PE as the eluent to afford 653-9 (0.8 g, 72%) as a yellow solid. +ESI- MS: m/z 593.9 [M+H]+.
[1211] To a solution of 653-9 (400 mg, 0.67 mmol) in EtOH ( 10 mL) and H20 (10 mL) was added Fe (188 mg, 3.4 mmol) powder and NH4CI (180 mg, 3.4 mmol) in one portion. The mixture w7as stirred at 80 °C for 2 h. After cooling to r.t., the mixture was poured into water (20 mL) and extracted with EA (3 x 10 mL). The combined organic phase was washed with brine, dried with anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography using EA as the clucnt to afford 653-10 (250 mg, 66%) as a yellow solid. +ESI-MS: m/z 564.1 [M+H]+.
[1212] To a solution of 4-cyclopropoxy-3-methoxybenzoic acid (75 mg. 0.36 mmol) in DMF (6.0 mL) was added HATU (137 mg, 0.36 mmol) and DTPEA (47 mg. 0.36 mmol). After stirring at r.t. for 5 mins, 653-10 (203 mg. 0.36 mmol) was added. The mixture was stirred for 1 h and then poured into water. The mixture was extracted with EA (2 x 10 mL). The combined organic phase was washed with brine, dried with anhydrous Na2S04. filtered and concentrated in vacuum. The residue wras purified by column chromatography using EA as the eluent to afford 653-11 ( 120 mg, 44.2 %) as a yellow solid. +ES1-MS: m/z 754.2 [M+H]+.
[1213] Ozone was bubbled into a solution of 653-11 ( 120 mg. 0.16 mmol) in anhydrous MeOH ( 10 mL) at -78 °C for 6 mins. After excess O3 was purged by N2, NaBLL; (18.1 mg, 0.48 mmol) was added at r.t. The reaction was stirred for 0.5 h and quenched with water. The mixture was extracted with EA (2 x 10 mL), dried over sodium sulfate, concentrated to give the crude product. The residue was purified by column chromatography using EA as the eluent to afford 653-12 (70 mg. 65%) as a yellow solid. +ESI-MS: m/z 682.1 [M+H]+.
[1214] To a solution of 653-12 (70 mg, 0.1 mmol) in MeOH ( 10 mL) was added HCl/dioxane (3 mL, 4 M). The mixture was stirred at r.t. for 20 mins. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford 653 ( 12 mg) and 654 (18 mg) as white solids. 653: +ESI-MS: m/z 578.1 [M+H]+ and 654: +ESI- MS: m/z 578.1 [M+H]+.
EXAMPLE 326
Figure imgf000400_0001
[1215] A mixture of 606-2 (45 mg. 0.1 mmol). 606-1 ( 16 mg, 0.1 mmol) and TEA (1 mmol) is dissolved in anhydrous DCM (4 mL) with stirring. The solution was treated with HATU (38 mg, 0.1 mmol) in one portion. After stirring at r.t. for 30 mins, TFA (1 mL) was added. The solution was stirred at r.t. for 2 h. The mixture was concentrated to dryness. The residue was isolated by acidic prep-HPLC to afford 606 (26 mg, 45%) as a white solid. +ES1-MS: m/z 452.0 [M+H]+.
Figure imgf000401_0001
[1216] Compound 607 was prepared following the general procedure for preparing 606 using 607-1 and 606-2. The crude product was purified by prep-HPLC to give
607 (66 mg, 75%) as a white solid (oo tl¾, ϊ *! «,). +ESI-MS: m/z 466.9 [ +H]+.
EXAMPLE 328
Figure imgf000401_0002
[1217] Compound 608 was prepared following the general procedure for preparing 606 using 608-1 and 606-2. The crude product was purified by prep-HPLC to give
608 (46.5 mg, 84%) as a white solid. +ES1-MS: m/z 466.9 [M+H]+.
Figure imgf000401_0003
[1218] Compound 609 was prepared following the general procedure for preparing 606 using 609-1 and 606-2. The crude product was purified by prep-HPLC to give 609 ( 13.5 mg, 34%) as a white solid. +ES1-MS: m/z 465.9 [M+H]+.
Figure imgf000402_0001
[1219] Compound 610 was prepared following the general procedure for preparing 606 using 610-1 and 606-2. The crude product was purified by prep-HPLC to give
610 (34 mg, 57%) as a white solid. +ESI-MS: m/z 51 8.9 [M+H]+.
EXAMPLE 331
Preparation of Compound 613
Figure imgf000402_0002
[1220] Compound 613 was prepared following the general procedure for preparing 606 using 613-1 and 606-2. The crude product was purified by prep-HPLC to give 613 (29 mg, 50%) as a white solid. +ESI-MS: m/z 451.9 [M+H]+.
Figure imgf000403_0001
[1221] To a solution of 623-1 (20 g, 1 16 mmol) in anhydrous toluene (200 mL) was added MeMgBr (3 M, 1 15.61 mL) slowly at 0°C under N2. After addition and stirring for 30 mins, Ti(i-PrO)4 (36.1 g, 127.2 mmol) was added dropwise The mixture was heated at 100 °C for 30 mins. After cooling to r. , copious quantities of diatomite was added to the mixture. The mixture was basified with aqueous NaOH solution (2 M) and filtered through a pad of diatomite. The cake was washed with EA, and the filtrate was separated and concentrated to provide crude 2-(2.6-dichloro-4-pyridyl)propan-2-amine (-25 g).
[1222] Crude 2-(2,6-dichloro-4-pyridyl)propan-2-amine was dissolved in anhydrous DCM (250 mL). The solution was treated with CbzCl (20.79 g, 121.90 mmol) and DIPEA (31.51 g, 243.80 mmol). The mixture was stirred at r.t. overnight. The mixture was washed with brine, dried over anhydrous Na2SC>4 and concentrated to dryness under reduced pressure. The residue was purified by column chromatography using 3—10% EA in PE as the eluent to give 623-2 (15 g, 36% yield over 3 steps) as a white solid. +ESI- S: m/z 338.8 [M+I I]+.
[1223] To a stirring solution of 623-2 (5.0 g, 14.7 mmol) in dioxanc (100 mL) and water (10 mL) were added (4-cyanophenyl)boronic acid (2.17 g. 14.7 mmol). CS2CO3 (9.6 g. 29.5 mmol). and Pd(dppf)C12 (1.08 g. 1.47 mmol) under N2. The mixture was stirred at 80 °C for 1 h under N2. After cooling to r.t.. the mixture was diluted with EA ( 100 mL) and water (100 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated to dryness under reduced pressure. The residue was purified by column chromatography using 3-20% EA in PE as the eluent to give 623-3 (2.0 g, 33% yield) as a white solid.
[1224] Compound 623-8 was prepared following the general procedure for preparing 533 using 623-3. Racemic 623-8 was separated by SFC and prep-HPLC to afford 623a (62 mg) and 623b (29 mg) as white solids. 623a: +ES1-MS: m/z 559.4 [M+H]+ and 623b: +ESI-MS: m/z 559.0 [M+H]+.
EXAMPLE 333
Figure imgf000404_0001
[1225] Compounds 624a (white solid, 62 mg) and 624b (white solid, 62 mg) were prepared following the general procedure for preparing 623a and 623b using 624-1 and 624-
2. 624a: +ES1-MS: m/z 573.1 [M+H]" and 624b: +ESI-MS: m/z 573.1 [M+HJ+.
EXAMPLE 334
Figure imgf000405_0001
[1226] Compound 625 (white solid, 32 mg) was prepared following the general procedure for preparing 623a and 623b using 625-1 and 624-2. +ES1-MS: m z 572.1 [M+H]+.
Figure imgf000406_0001
[1227] Compound 634 (white solid, 10 mg) was prepared following the general procedure for preparing 406 using 634-1 and 634-2. +ES1-MS: m/z 524.1 [M+H]+.
Figure imgf000407_0001
[1228] 639-6 was prepared as provided in Pascal, R., et al., Eur. J. Org. hem. (2000) 2000(22):3755-3761 .
[1229] To a solution of 639-6 (1 .1 g, 5.3 mmol) in 1120 (10 niL) was added NaOH (426 mg, 10.7 mmol) in one portion. The mixture was stirred at 25 °C for 1 7 h. The solid was formed upon acidification to pH 1 with concentrated HCl (37%). The precipitate was collected by filtration, washed with water and dried in vacuum to give 639-7 (0.5 g. 49%) as a white solid, which was used for the next step without further purification. +ESI- MS: m/z 193.1 [M+H]+.
[1230] Compound 639 (28 mg, 45%) was prepared following the general procedure for preparing 606 using 639-7. +ESI-MS: m/z 532.0 [M+H]+.
Figure imgf000408_0001
11231] To a solution of 643-1 (1.5 g, 6.9 mmol) in DMF (20 mL) was added 2- benzyloxyl ethanol (6.3 g, 41 mmol) at 25 °C. The solution wras stirred for 6 h and then poured into ¾0 (20 mL). The mixture was extracted with EA (2 x 40 mL). The combined organic phase was washed with brine, dried over anhydrous Na^SC^ and concentrated under reduced pressure. The residue was purified by column chromatography using 5-10% EA in PE as the eluent to give a mixture of 643-2 and 643-2 A ( 1 .50 g).
[1232] To a solution of 643-2A and 643-2 A (1.50 g. crude mixture) in EtOI I/I I20 (20/1 OmL) were added Fe ( 1 .5 g. 26.7 mmol) and NH4C1 (1 .5 g, 28 mmol) at 25 °C. The solution was heated to 80 °C and stirred for 2 h. The mixture was filtered, and the filtrate was concentrated to give a mixture of 643-3 and 643-3A ( 1.20 g, crude). The products were used for the next step without further purification.
[1233] A mixture of 643-3 and 643-3A (1.2 g, crude) in H2S04/H20 (1 : 1 ) (l OmL) was cooled to -5 °C. NaN02 (376 mg, 5.45 mmol) was added in portions at -5 °C. The solution wras stirred at -5 °C for 0.5 h. The solution was heated to 120 °C. After stirring 0.5 h at 120 °C, the solution was poured into ice water (20 mL) and extracted with EA (2 x 20 mL). The organic phase was concentrated at low pressure. The residue was purified by chromatography to give 643-4 (0.3 g, crude).
[1234] To a solution of 643-4 (0.3 g, crude) in DMF (5 mL), K2C03 (320 mg, 2.3 mmol) was added dropwise CHT (2.14 g. 15.1 mmol) at r.t. The solution was stirred for 3 h. The mixture was poured into LEO (10 mL) and extracted with EA (2 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give crude 643-5 (210 mg), which was used in the next step directly.
[1235] To a mixture of 643-5 (210 mg, crude) in MeOH (2 mL) was added an aq. NaOH solution (2 mL, 2 M) in one portion at 25 °C. The mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to r.t. and acidified to pH=3~4 by the addition of 1 M aqueous HC1. The mixture was extracted with EA (3 x lOmL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue w7as purified by prep-TLC (EA) to afford 643-6 ( 1 10 mg, 56%).
[1236] Compound 643 (white solid, 14 mg. 24%) w7as prepared following the general procedure for preparing 606 using 643-6. +ESI-MS: m/z 553.1 [M+H]+.
Figure imgf000409_0001
[1237] 644-2 was prepared as provided in PCT Publication No. WO 2013/007663, published January 17, 2013
[1238] 644-4 was prepared following the general procedure for preparing 272 using 644-2.
[1239] Λ mixture of 644-4 (1 .5 g, 5.5 mmol), potassium vinyl trifluoro borate ( 1.6g. 1 1.1 mmol), Cs2C03 (1.8 g, 5.5 mmol) and Pd(dppf)Cl2 (0.4 g, 0.5 mmol) in i-PrOH (10 mL) was de-gassed. The mixture was heated to 80 °C for 15 h under N2. After cooling to r.t, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography using 5-20% DCM in PE to give 644-5 (0.9 g, 74.5%).
[1240] Ozone was bubbled into a solution of 644-5 (0.87 g, 4 mmol) in anhydrous MeOH (10 mL) at -78 °C for 10 mins. After the excess ozone was purged by N2. NaBH.4 (304 mg, 8 mmol) was added at 25 °C. The solution was stirred at 25 °C for 30 mins. The reaction w7as quenched with H20 and extracted with EA (3 x 20 mL). The combined organic solutions were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography 10-25% DCM in PE to give 644-6 (0.7 g, 79%) as a solid.
[1241] To a solution of 644-6 (0.5 g, 2.3 mmol) in MeOH (3 mL) was added NaOH (0.5 g, 12.5 mmol) in H20 (3 mL). After stirring at 60 °C for 1 h, the mixture was acidified to pi 1=3—4 by addition of 2 M I Id solution. The mixture was extracted with EA (3 x 10 mL). The combined organic solutions were washed with brine, dried over Na2S04 and concentrated under reduced pressure to give 644-7 (0.4 g. 85.3%).
[1242] Compound 644 (while solid. 27 mg, 42%) was prepared following the general procedure for preparing 606 using 644-7. +ESI-MS: m/z 548.0 [M+H]+.
EXAMPLE 339
Preparation of Compound 657
Figure imgf000411_0001
[1243] 657-6 was prepared following the general procedure for preparing 606 using 657-1.
[1244] Lo a stirring solution of 657-6 (2 g. 4.3 mmol) in EtOH (40 mL) were added SnCl2-2H20 (3.9 g, 1 7.3 mmol) and cone. HCI (5.4 mL, 12 M). After stirring at 60 °C for 12 h, the mixture was cooled to r.t., and EtOH was removed under reduced pressure. The residue was diluted with water (10 mL) and neutralized by sat. aq. Na2C03 solution. The aqueous phase w7as extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 50-100% EA in PE as the eluent to afford 657-7 (0.82 g. 44%) as a yellow oil. +ES1-MS: m/z 432.3 [M+H]+.
[1245] To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (1.5 g, 7.2 mmol) in anhydrous DMF (30 mL) were added HATU (2.7 g, 7.2 mmol) and DIEA (2.3 g, 18 mmol). After stirring at 25 °C for 30 mins, a solution of 657-7 (2.5 g, 6.0 mmol) in DMF (5 mL) was added dropwise. The mixture was stirred at 25 °C for 1 -2 h. The solution was poured into water (50 mL). and extracted with EA (3 x 30 mL) . The combined organic phase was washed with brine, dried over anhydrous Na2SO_t. filtered and concentrated under reduced pressure. The residue was purified by column chromatography using DCMrMeOI 1=200: 1-80: 1 as the eluent to afford 657-8 (2.2 g, 59 %) as yellow oil.
[1246] 657-8 (100 mg, 0.16 mmol), 4-CT-phenyl boronic acid (50 mg, 0.32 mmol) and CS2CO3 ( 156 mg, 0.48 mmol) were taken up into a microwave tube in co-solvent dioxane:H?0 (1 .2 mL, v:v=5: l ). The solution was degassed and Pd(dppf)Cb (3.5 mg, 0.05 mmol) was added. The sealed tube was heated to 1 10 °C by microwave irradiation and stirred for 1 h. The solution was cooled to r.t. and poured into water (10 mL). The mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous N 2SC>4, filtered and concentrated under reduced pressure. The residue was purification by prep-TLC to give 657-9 (49 mg, 44%)
[1247] To a solution of 657-9 (49 mg) in CH3CN (1 mL) was added one drop of
TMS1 at r.t., and the mixture stirred at r.t. for 10 mins. The mixture was poured into water, neutralized with sat. NaHC03 solution, and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 657
(15 mg) as a white solid. +ES1-MS: m/z 567.9 [M+H]+.
Figure imgf000412_0001
[1248] Compound 658 (white solid, ni ) was prepared following the general procedure for preparing 657 using 658-1 and 4-CF3-phenyl boronic acid. The crude product was purified by prep-HPLC. +E SI-MS: m/z 602.1 [M+H]+.
Figure imgf000413_0001
[1249] Compound 659 (white solid, 1 1 mg) was prepared following the general procedure for preparing 657 using 659-1 and 2-methoxy-4-pyridyl boronic acid. The crude product was purified by prep-HPLC. +ES1-MS: m/z 565.1 [M+H]+.
EXAMPLE 342
Preparation of Compound 660
Figure imgf000413_0002
[1250] Compound 659 (white solid, 10 mg) was prepared following the general procedure for preparing 657 using 660-1 and 2-methoxy-4-pyridyl boronic acid. The crude product was purified by prep-HPLC. +ESI-MS: m/z 565.1 [M+H]+.
Figure imgf000414_0001
[1251] A mixture of 614-1 (23 mg, 0.1 mmol), 614-2 (50 mg, 0.1 mmol) and TEA (1 mmol) were dissolved in DCM (4 mL). HATU (38 mg, 0.1 mmol) was added, and the mixture was stirred for 30 mins. The mixture was diluted with brine (5mL), and the aqueous phase was extracted with DCM (2 x 5 mL). The combined organic layer was washed with brine, dried over anhydrous a?S0 and concentrated under reduced pressure. The residue was dissolved in MeOH ( 10 mL) and hydrogenated over Pd/C (10 mg, 10%) at 15 psi for 17 h. The catalyst was removed by filtration, and the cake was washed with MeOH (5 mL). The combined filtrates was concentrated and purified by prep-HPLC to give 614 (28 mg, 45 %). +ES1-MS: tn/z 584.0 [M+H]+.
EXAMPLE 344
Preparation of Compound 615
Figure imgf000414_0002
[1252] Compound 615 (white solid, 43 mg) was prepared following the general procedure for preparing 614 using 615-1 and 615-2. The crude product was purified by prep- HPLC. +ES1-MS: m/z 583.1 [M+H]+.
EXAMPLE 345
Preparation of Compound 626
Figure imgf000414_0003
[1253] To a solution of 540 (160 mg, 0.26 mmol) in MeOH (2 mL) was added Pd/C ( 150 mg) under Ντ. The suspension was degassed under vacuum and purged with I I2 several times. The mixture was stirred at 25 °C for 12 h. The mixture was filtered through a pad of Celite, and the pad was washed with MeOH. The combined filtrates were concentrated under reduced pressure. The residue was purified by prep-HPLC of acidity w ith HCl to give 626 (69 mg. 43%). +ESI-MS: m/z 570.0 [M+H]+.
Figure imgf000415_0001
[1254] A mixture of 627-1 (66 mg, 0.3 mmol). 627-2 ( 150 mg. 0.3 mmol) and TEA (1 mmol) were dissolved in DCM (4 mL). HATU (120 mg. 0.2 mmol) was added, and the mixture was stirred for 30 mins. The reaction was diluted with brine (5mL), and the aqueous phase was extracted with DCM (2 x 5 mL). The combined organic layer was washed with brine, dried over anhydrous N 2SC»4 and concentrated under reduced pressure to give crude 627-2, which was used in next step without further purification. +ESI-MS : m/z 764.1 [M+H]+.
[1255] To a solution of 627-2 (0.7 g, crude) in MeOH (20 mL) was added L1BH4 (59 mg, 2.8 mmol) in one portion at r.t. The mixture was stirred for 1 h. The reaction was quenched with 2N HCl solution and extracted with EA (3 x 20 mL). The combined organic layer wras washed with brine, dried over anhydrous Na2S0 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30: 1~3: 1 as the eluent to afford 627-3 (0.6, 89%) as an oil. +ES1-MS: m/z 736.0 [M+H]+. [1256] Compound 627 (white solid, 1 80 mg) was prepared following the general procedure for preparing 540 using 627-3. +ESI- S: m/z 568.1 [M+H]+.
Figure imgf000416_0001
[1257] Compound 615 (30 mg) was separated by SFC to give solutions of peak 1 and peak 2. The two peaks were acidified by aq. HC1 (2 M) and lyophilized to give 655 (9.2 mg) and 656 (8.9 mg) as a white solid. 655: +ES1-MS: m/z 583.1 [M+H]+ and 656: +ESI- MS: m/z 583.1 [M+I I] h.
Figure imgf000416_0002
[1258] 622-1 (white solid, 610 mg) was prepared following the general procedure for preparing 536. +ESI-MS: m/z 760.1 [M+H]+.
[1259] Compound 622 (12 mg,) was prepared following the general procedure for preparing 581 using 622-1. LCMS: m/z 592.15 [M+H]+.
Figure imgf000417_0001
[1260| 650-17 (white solid, 210 mg) was prepared following the general procedure for preparing 563 using 650-1 and 4-F-phenyl boronic acid. +ES1-MS: m/z 698.1
[1261] To a stirring mixture of 650-17 (200 mg, 0.28 mmol) in CH3CN (2 mL) were added Nal (215 mg, 1.4 mmol) and TMSCl (152 mg, 1.4 mmol). The mixture was stirred at 65 >C for 20 mins. The mixture was cooled to r.t. and diluted with EtOAc. The reaction was quenched with a 10% aqueous solution of Na2S203. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2S(¾, filtered and concentrated under reduced pressure. The crude product mixture was purified via prep-HPLC to afford 650 (10 mg) as a white solid. LCMS 564.20 m/z [M+H]+.
Figure imgf000418_0001
[1262] To a solution of 667-1 (100 mg, 0.16 mmol) in THF (1 mL) wras added cyclopropylmagnesium chloride (2 mL, 1 mmol) dropwise at r.t. The mixture was stirred for 2 h. The reaction was quenched with aq. NH4CI and extracted with EA (3 x 10 mL). The combined organic phase was washed with brine, dried over Na?S04 and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=1 : 1 ) to give 667-2 (62 mg, 58.4%).
[1263] To a solution of 667-2 (62 mg, 0.1 mmol) in DCM (2 mL) was added TFA (2 mL) at r.t. The mixture was stirred for 30 mins. The mixture was neutralized by aq. Nal lCOj solution and extracted by EA (3 x 10 mL). The combined organic layers were washed with brine, dried over Na7S04 and concentrated under reduced pressure. The residue was purified by prep-HPTC to give 667 (9 mg, 16.3%) as a white solid. +ESI-MS: m/z 554.0 [M+H]+.
Figure imgf000419_0001
[1264] Enantiomer 603-2 (270 mg) was obtained by SFC separation of raccmic 603-1 ( 1 .1 g).
[1265] To a stirring mixture of 603-2 (270 mg 0.8 mmol) in 2-methylpropan-2-ol (6 mL):H20 (2 mL) at 0 °C were added BocN-OTs (308 mg 1.07 mmol) and K20s04-H20 (60 mg, 0.16 mmol) at r.t. The mixture was stirred at r.t. for 30 h. The mixture was diluted with water and extracted with DCM (3 x 10 mL). The combined organic phase was washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=1 : 1 as the eluent to afford 603-3 (-200 mg, ~60%). +ESl-MS: m/z 638.1 [M+H]+.
[1266] To a mixture of 603-3 (200 mg, 0.32 mmol) in DCM (6 mL) was added TFA (3 mL) at r.t. The mixture was stirred for 30 mins, neutralized with aqueous NaHCOj and extracted with EA (3 x 10 mL). The combined organic layers were washed by brine, dried over
Figure imgf000419_0002
and concentrated under reduced pressure to give crude 603-4 (1 10 mg), which w7as used without further purification. +ESI-MS: m/z 538.1 [M+H]+. [1267] To a solution of 4-(cyclopropoxy)-3-methoxy-benzoic acid (37 mg, 0.17 mmol), I IATU (100 mg 0.26 mmol) and DIPEA (57 mg, 0.44 mmol) in anhydrous D F (3 mL) was added 603-4 (1 10 mg crude) at r.t. The solution was stirred for 5 h at r.t. with TLC monitoring. The mixture was diluted with 1 .0 N aqueous NaHC(¾ solution and extracted with EA (3 x 10 mL). The combined organic layers were washed by brine, dried over anhydrous Na2S04. and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA = 1 : 1 as the eluent and prep-HPLC to give 603-5 (43 mg, 28.7%). +ESl-MS: m/z 728.1 [M+Hf.
[1268] To a stirring mixture of 603-5 (15 mg, 0.041 mmol) in CH3CN ( 1 mL) at r.t. were added Nal (32 mg. 0.2 mmol) and TMSC1 (22 mg, 0.2 mmol). The mixture was stirred at 55 °C for 15 mins. The mixture was diluted with EtOAc and washed with a 10% aq. Na?S203 solution. The organic layer w7as washed with brine, dried over a2S04, liltered and concentrated under reduced pressure. The reaction was concentrated and the crude product was purified by prep-HPLC to provide 603. +ES1-MS: m/z 594.20 [M+H]+.
Figure imgf000420_0001
[1269] Cyclobutanone ( 17 ιΕ, 0.22 mmol) and sodium cyanoborohydride (47 mg, 0.22 mmol) were added to a solution of 314 (43 mg. 0.074 mmol) every 30 mins for 6 h. The mixture was diluted with EtOAc, washed with IN HCl and brine, dried over MgS04 and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 575 ( 14 mg. 23%). LCMS: m/z 637.20 [M+H]+.
Figure imgf000421_0001
[1270] Compound 577 was prepared following the general procedure for preparing 575. LCMS: m/z 639.1 0 [M+H]+.
EXAMPLE 354
Preparation of Compound 581
Figure imgf000421_0002
[1271] 577 ( 12 mg, 0.019 mmol) was hydrogenated over 10% Pd/C (3 mg) in EtOH (2 niL) for 1 h. The catalyst was removed by filtration and the crude product was purified by reverse-phase I IPLC to give 581 (8 mg, 66%). LCMS: m/z 604.20 [ +I i]+.
Figure imgf000422_0001
[1272] Pd(dppf)Cl2 (66 mg. 0.091 mmol) was added to a solution of 2,4-dichloro- 4-iodopyridine (0.50 g. 1 .8 mmol). ( l -(tert-Butoxycarbonyl)- 1 .2,3.6-tetrahydropyridin-4- yl)boronic acid (0.54 g. 1 .8 mmol) and cesium carbonate ( 1 .8 g. 5.5 mmol) in dimethoxyethane (10 mL) and water (1 mL). The mixture was heated under microwave irradiation at 1 1 0 "C for I h. The mixture was diluted with FA, washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 576-1 (0.47 g, 72%). LCMS: m/z 329.00 [Μ+ΗΓ.
[1273] A solution of 576-1 (0.83 g. 2.5 mmol) and platinum oxide (83 mg) in EtOH was stirred under Lb atmosphere for 1 h. The mixture was filtered to remove catalyst and concentrated. The product (0.80 g, 96%) was used without further purification. LCMS:
Figure imgf000422_0002
[1274] HC1 (4N in dioxane, 3 mL) was added to 576-2 (0.80 g, 2.4 mmol). The mixture was stirred at r.t. for 30 mins and concentrated under reduced pressure. The crude product was dissolved in Cl LCb (10 mL), and DI EA ( 1 .1 mL. 6.0 mmol) and benzyl chloroformatc (0.41 mL, 2.9 mmol) were added. The reaction was stirred at r.t. for 1 h. The mixture was diluted with EA, washed with I HCl and brine, dried over anhydrous Na^SC and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 576-3 (0.49 g. 54%). LCMS: m/z 365.05 [M+H]+.
[1275] Pd(dppf)Cl2 (0.45 g. 0.61 mmol) was added to a solution of 576-3 (0.49 g. 1.3 mmol), l -(trifluoromethyl)vinylboronic acid hexylene glycol ester (0.30 g. 1 .3 mmol). CS2CO3 (1.3 g, 4.0 mmol) in DME (3 niL) and water (0.3 ml). The reaction vessel was heated under microwave irradiation for 20 mins at 1 10 "C. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous NaiSCu and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 576-4 (0.23 g, 41%). LCMS: m/z 425.05 [M+H]+.
[1276] Pd(dppf)Ci2 (20 mg, 0.027 mmol) was added to a solution of 576-4 (0.23 g, 0.54 mmol), 3-chloi -4-fluorophenyl boronic acid (95 mg, 0.54 mmol), Cs2C03 (0.53 g, 1.6 mmol) in DME (2 mL) and water (0.2 mL). The reaction vessel was heated under microwave irradiation at 1 10 °C for 1 h. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous NaoSC^ and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 576-4 (0.1 1 g, 38%). LCMS: m/z 519.10 [M+H]+.
[1277] Potassium osmate (1 1 mg, 0.029 mmol) was added to a solution of 576-5 (0.1 1 g, 0.21 mmol) and tert-butyl (tosyloxy)carbamate (91 mg, 0.33 mmol) in t-butanol (1 mL) and water (0.33 mL). The solution was stirred overnight at r.t. The crude mixture was purified by chromatography on silica gel (EArhexane) to give 576-6 (0.12 g. 85%). LCMS: m/z 652.20 [M+H]+.
[1278] HCl (2 mL, 4N in dioxane) was added to 576-6 (0.12 g, 0.18 mmol), and the mixture was stirred at r.t. for 2 h. The solvent was removed by evaporation and the amine salt was re-dissolved in DMF (1 mL). 4-cyclopropoxy-3-methoxybenzoic acid (57 mg. 0.28 mmol), HATU (0.14 g. 0.37 mmol) and DIEA (0.14 mL. 0.74 mmol) were added, and the mixture was stirred at r.t. for 2 h. The mixture was diluted with EA. The organic phase was washed with IN HCl, water and brine, dried over anhydrous a2S04 and concentrated. The residue was purified by chromatography on silica gel (EAdiexane) to give 576-7 (35 mg, 26%). LCMS: m/z 742.20 [M+H]+. [1279] Chlorotrimethylsilane (23 μί, 0.24 mmol) was added dropwise to a solution of 576-7 (35 mg, 0.047 mmol) and Nal (28 mg, 0.24 mmol) in CH CN (1 mL). and the mixture was stirred for 30 mins. The mixture was diluted with EA, washed with NaiSoO.} and brine, dried and concentrated. The crude product was purified by reverse-phase HPLC to provide 576 (13 mg. 37%). LCMS: m/z 609.15 [M+H]+.
EXAMPLE 356
Preparation of Compound 579
Figure imgf000424_0001
[1280] Ethyl acetimidate hydrochloride (150 mg, 1.2 mmol) was added to a solution of 314 (50 mg, 0.086 mmol) in EtOH (3 mL). The mixture heated at reflux for 24 h. The mixture was diluted with EA, washed with brine, dried and concentrated. The crude product was purified by reverse phase HPLC to give 579 (8 mg, 16%). LCMS: m/z 624.15 [M+H]+.
Figure imgf000424_0002
[1281] Compound 585 was prepared following the general procedure for preparing 579 using 318 and ethy l acetimidate. LCMS: m/z 590.20 [M+H]+.
Figure imgf000425_0001
[1282] Benzyl(2-2(3-amino-l ,1 ,1 -trirluoro-2-hydroxypropan-2-yl)-6-(3-chloro-4- fluorophenyl)pyridine-4-yl)propan-2-yl)carbamate was coupled with 4-(2-amino-2- oxoethoxy)-3-methoxybenzoic acid following the general procedure for 576-7. 580-1 was hydrogenated following the general procedure for preparing 581. LCMS: m/z 565.15 [M+H]+.
Figure imgf000425_0002
[1283] 586-1 was prepared following the general procedure for 576-7. HC1 in dioxane (3 mL) was added to 568-1 (92 mg, 0.18 mmol), and the mixture was stirred at r.t. for 3 h. The mixture was concentrated, and the crude product purified by reverse-phase HPLC to provide 586 (43 mg, 47%). LCMS: m/z 566.20 [M+Hf.
Figure imgf000426_0001
[1284] Compound 592 was prepared following the general procedure for 586 using 4-acetamido-3-methoxybenzoic acid. LCMS: m/z 583.15 [M+H]+.
Figure imgf000426_0002
[1285] Compound 593 was prepared following the general procedure for 586.
LCMS: m/z 619.00 [M+Hf .
EXAMPLE 362
Figure imgf000426_0003
[1286] Compound 596 was prepared following the general procedure for 586 using 4-(3-hydroxycyclobutoxy)-3-methoxybenzoic acid. LCMS: m/z 578.20 [M+H]+.
Figure imgf000427_0001
[1287| To a stirring mixture of methyl 4-hydroxy-3-methoxybenzoate (1 g, 5.49 mmol) in DMF (5 mL) at r.t. were added K2C03 (1.14 g, 8.24 mmol) and 2- bromoacetonitrile. The mixture was stirred at r.t. for several hours and then diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over a2S(¾. filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel chromatography to afford 616-1 as a white solid.
[1288] To a stirring mixture of 616-1 ( 190 mg. 0.856 mmol) in DMF (2 mL) were added NaN3 (71.5 mg, 1 .1 mmol) and NH CI (59 mg, 1.1 mmol). The mixture was carried out under microwave irradiation for 45 mins at 100 °C. The mixture was diluted with EtOAc and water, and the layers were separated. To the aqueous layer was added a 10% aqueous HCl solution until a white precipitation was formed. The tetrazole-product was filtered off. and then dissolved directly in aq. NaOH solution (1.5 mL, 2N). The mixture was heated at 80 °C for 30 mins. The mixture was cooled to r.t. and acidified with a 10% aq. HCl solution. The white solid was filtered off and dry under reduced pressure. Crude 616-2 was used without further purification. LCMS: m/z 265.05 [M+H]+.
[1289| Compound 616 was prepared following the general procedure for 586 using 616-2. LCMS: m/z 624.15 [M+H .
Figure imgf000428_0001
[1290| 599-1 was prepared following the general procedure for 576-7. Pd(dppf)Cl2 (12 mg, 0.016 mmol) was added to a solution of 599-1 (0.23 g, 0.32 mmol), pyridine-4-boronic acid (65 mg, 0.016 mmol) and cesium carbonate (0.31 g, 0.96 mmol) in dimethoxyethane (2 mL) and water (0.2 mL). The mixture was heated under microwave irradiation at 1 10 °C for 20 mins. The mixture was diluted with EA. washed with brine, dried and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 599-2 (0.1 1 g, 50%).
[1291] 599-2 was prepared following the general procedure for 586 to give 599. LCMS: m/z 569.20 [M+I I] ' .
EXAMPLE 365
Preparation of Compound 601
Figure imgf000428_0002
[1292] DIEA (87 μΕ, 0.50 mmol) was added to a solution of 317 (0.10 g, 0.16 mmol), acetic acid (20 mL. 0.33 mmol) and HATU (0.14 g. 0.35 mmol) in DMF. The mixture was stirred at r.t. for 1 h. The crude product was purified by reverse phase HPLC to provide 601 (17 mg, 17%). LCMS: m/z 642.15 [M+H]+. EXAMPLE 366
Preparation of Compound 611
Figure imgf000429_0001
[1293] Compound 611 was prepared following the general procedure for 601 using 320. LCMS: m/z 594.20 [M+H]+.
Figure imgf000429_0002
[1294] Compound 612 was prepared following the general procedure for 601 using 322. LCMS: m/z 641 .15 [M+HJ+.
Figure imgf000429_0003
[1295] Compound 621 was prepared following the general procedure for 601 using 580. LCMS: m/z 607.20 [M+H]+.
Figure imgf000430_0001
[1296] Compound 620 was prepared following the general procedure for 601 using 586. LCMS: m/z 608.2 [M+H]+.
Figure imgf000430_0002
[1297] Isopropylmagnesium chloride (2M in THF, 2.0 mL. 4.0 mmol) was added dropwise to a solution of 2,6-dichloro-4-iodopyridine ( 1 .0 g, 3.7 mmol) at -40 °C. The solution was stirred for 30 mins. 3-Oxetanone (0.28 mL. 4.4 mmol) was added dropwise. The mixture was stirred and warmed to r.t. for 2 h. The reaction was quenched with IN HCI. extracted with EA, washed with brine, dried and concentrated. The residue was purified by chromatography on silica gel (HA:hexane) to give 595-1 (0.42 g, 51 %).
[1298] Methanesulfonylchloride ( 1 .1 mL. 15 mmol) was added dropwise to a solution of 595-1 (2.14 g, 9.7 mmol) and diisopropylethylamine (3.4 mL, 19 mmol) in CH2CI2. The mixture was stirred at 0 °C for 1 h. The mixture was washed with I N HCI and brine, dried and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 595-2 ( 1. 1 g, 66%).
[1299] Sodium azide (0.83 g, 1.3 mmol) was added to a soltuion of 595-2 (1.91 g, 0.64 mol) in DMSO (3 mL), and the mixture was stirred at 70 °C for 2 h. The mixture was diluted with EA, washed with water and brine, dried and concentrated. The product was purified by chromatography on silica gel (hexane:EA) to provide 595-3 (0. 67 g, 42%).
[1300] Trimethylphosphine ( 1 M in THF. 2.2 mL, 2.2 mmol) was added to a solution of 595-3 (0.357 g, 1.5 mmol) in EA (5 mL). The mixture was stirred for 20 mins. Water (0.5 mL) was added, and the mixture was stirred at 70 °C for 1 h. The mixture was washed with brine, dried and concentrated to provide 595-4 (0.31 g, 93%) which was used without further purification.
[1301] Benzyl chloroformate (0.98 mL. 6.9 mmol) was added to a solution of 595- 4 (4.6 mmol) in THF (15 mL) and sat. sodium carbonate (15 mL). The mixture was stirred at r.t. overnight, and the aqueous layers were separated. The organic layer was washed with brine, dried and concentrated. The product was purified by chromatography on silica gel (hexane:EA) to provide 595-5 (1.4 g, 87%).
[1302] Compound 595-6 was prepared following the general procedure for 576-4. LCMS: m/z 413.05 [M+H]+. Compound 595-7 was prepared following the general procedure for 576-5. LCMS: m/z 473.10 [M+H]+. Compound 595-8 was prepared following the general procedure for 576-6. LCMS: m/z 606.15 [M+H]+.
[1303] 595-8 (75 mg, 0.12 mmol) w7as dissolved in hexafluoroisopropanol (1.5 mL). The solution was heated under micro wave irradiation at 1 0 °C for 65 mins. The mixture w7as concentrated, and crude 595-9 was used without further purification. LCMS: m/z 505.46 [M+H]+.
[1304] 595-10 was prepared following the general procedure for 576-7. LCMS: m/z 696.20 [M+H]+. Compound 595 was prepared following the general procedure for 580 using 595-10. LCMS: m/z 562.15 [M+H]+.
Figure imgf000432_0001
[1305] Benzyl chloroformate (0.61 mL, 4.3 mmol) was added dropwise to a solution of 602-1 (0.86 g, 2.9 mmol) and diisopropylethylamme (1 .0 mL, 5.7 mmol) in CH2CI2 (10 mL). The mixture was stirred at r.t. overnight. The mixture was washed with IN HC1 and brine, dried and concentrated. Crude 602-2 (0.73 g. 58%) was purified by chromatography (hexanerEA). LCMS: m/z 433.05 [M+H]+.
[1306] 602-3 was prepared following the general procedure for 576-4. LCMS: m/z 439.10 [M+H] . 602-4 was prepared following the general procedure for 576-6. LCMS: m/z 572.15 [M+H]+. 602-5 was prepared following the general procedure for 576-7. LCMS: m/z 679.20 [M+H]+. Compound 602 was prepared following the general procedure for 580 using 602-5. LCMS: m/z 51 1 .1 5 [M+H]+.
EXAMPLE 372
Figure imgf000432_0002
[1307] Trifluoroacetic acid (0.3 mL) was added to 578-1 (55 mg, 0.069 mmol) in CI I2CI2, and the mixture was stirred at r.t. for 4 mins. The reaction was quenched with cold sodium bicarbonate and extracted with CH2CI2. The combined organic extracts were washed with brine, dried, concentrated and used without further purification.
[1308] Potassium carbonate (50 mg, 0.35 mmol) was added to a solution of 578-2 (0.069 mmol) and tert-butyl bromoacetate (30 μΐ^. 0.21 mmol) in DMF (1 mL). The mixture was heated at 55 °C for 1 h. The mixture was diluted with EA, and washed with water and brine. The crude product was purified by column chromatography (hexane:EA) to provide 578-3. LCMS: m/z 790.20 [M+H]+.
[1309] Compound 578 was prepared following the general procedure for 576 using 578-3. LCMS: m/z 600.15 [M+H]+.
EXAMPLE 373
Figure imgf000433_0001
[1310] 619-1 was prepared following the general procedure for 576. Compound /as prepared following the general procedure for 580. LCMS: m/z 525.15 [M+H]+.
Figure imgf000434_0001
[1311] DIE A (90 μί, 0.52 mmol) was added to a solution of 635-1 (72 mg, 0.17 mmol), 8-methoxyquinoline-6-carboxylic acid (45 mg, 0.21 mmol) and HATU (98 mg, 0.26 mmol). The mixture was stirred at r.t. for 2 h. The mixture was purified by reverse-phase HPLC to provide 635-2 (50 mg, 48%). LCMS: m/z 601.10 [M+H]+.
[1312] Pd(dppf)Cl2 (3 mg, 0.0041 mmol) was added to a solution of 635-2 (50 mg, 0.083 mmol), 4-fluorophenyl boronic acid (17 mg, 0.12 mmol), K3PO4 (0.1 1 mg, 0.22 mmol), KH2PO4 (45 mg. 0.22 mmol) in DME (1 mL), EtOH (0.6 niL) and water (0.2 mL). The solution was heated under microwave irradiation at 1 10 °C for 4 h. The mixture was diluted with EA, washed with brine, dried and concentrated. Crude 635-3 was purified by silica gel chromatography (MeOH:EtOAc). LCMS: m/z 661.20 [M+H]+.
[1313] 635-3 (27 mg) wras dissolved in MeOH (1 mL). To this stirring mixture was added a solution of HCT in dioxane (0.2 mL). The mixture was stirred at r.t. for 5 mins. The mixture was concentrated, and 635 (5 mg, 25%) was purified by reverse-phase HPLC. LCMS: m/z 557.15 [M+H]+.
Figure imgf000435_0001
[1314] Chloromethanesullbnyl chloride (0.4 mL, 4.4 mmol) was added dropwise to a solution of ammonia (0.5 M in dioxane. 8.8 mL, 4.4 mmol) and DIEA (0.92 mL, 5.3 mmol) at 0 °C. The solution was stirred for 1 h. The reaction was washed with I N I IC1 and brine, dried and concentrated. The crude product was used without further purification.
[1315] Potassium carbonate ( 1 .2 g. 8.8 mmol) was added to a solution of methyl vanillate (0.40 g, 2.2 mmol) and 637-1 (4.4 mmol) in DMF (2.0 mL). The mixture was stirred at 65 °C overnight. The reaction was diluted with EA. washed with water and brine, dried and concentrated. The crude product was purified by silica gel chromatography (hexane:EA) to provide 637-2 (50 mg. 8%).
[1316] NaOH (2N, 1 mL) was added to a solution of 637-2 (50 mg, 0.1 8 mmol) in MeOH (3 mL). The mixture wras stirred at r.t. overnight. The mixture was acidified by the addition of 2N HC1 and extracted with EA. The organic extracts were washed with brine, dried and concentrated. Crude 637-3 was used without further purification.
[1317] 637-4 was prepared following the general procedure for 576-7. Compound 637 was prepared following the general procedure for 586. LCMS: m/z 635.15 [M+H]+.
Figure imgf000436_0001
[1318] Cesium carbonate (1.0 g, 5.9 mmol) as added to vanillic acid (2.0 g. 12 mmol) suspended in 90% aq. MeOH (20 mL). The mixture was stirred at r.t. for 30 mins. The solvents were removed and the crude product was dried by co-evaporating (2x) with toluene. The cesium salt was re-dissolved in DMF (15 mL). Benzyl bromide was added, and the mixture was stirred at r.t. overnight. The mixture was diluted with LA, washed with water and brine, dried and concentrated. The product was purified by silica gel chromatography (hexane:EA) to yield 618-1 (0.4 g, 12%).
[1319] Ethyl bromoacetate (0.34 mL, 3.1 mmol) was added to a solution of 618-1 (0.4 g, 1.5 mmol) and potassium carbonate (0.64 g, 4,6 mmol) in DMF (3 mL). The mixture was stirred at r.t. for 3 h. The mixture was washed with water and brine, dried and concentrated. The crude product was purified by column chromatography (hexane:EA) to yield 618-2 (0.1 77 g, 34%).
[1320] 618-2 (0.1 77 g 0.51 mmol) was hydrogenated over 10% Pd/C (35 mg) in EtOH for 45 mins. The catalyst was removed by filtration, and the mixture was concentrated to yield 618-3 (0.13 g. 100%), which was used without further purification.
[1321] 618-4 was prepared following the general procedure for 576-7. LCMS: m/z 728.20 [M+H]+. NaOH (2N, 2 mL) was added to a solution of 618-4 (0.302 g, 0.43 mmol) in MeOH (10 mL). The mixture was stirred overnight at r.t. The mixture was acidified with I N HCl and extracted with EA. The organic extracts were washed with brine, dried and concentrated to yield 618-5 (0.29 g, 92%). LCMS: m/z 700.20 [M+H]+.
[1322] DMAP was added to a solution of 618-5 (50 mg, 0.071 mmol), methyl sulfonamide (10 mg. 0.1 1 mmol) and EDCI (16 mg, 0.086 mmol) in DMF (1 mL). The mixture was stirred at r.t. overnight. The product was purified by reverse-phase HPLC to yield 618-6 (27 mg). LCMS: m/z 777.05 [M+H]+. Compound 618 was prepared following the general procedure for 586. LCMS: m/z 677.05 [M+H]+.
EXAMPLE 377
Figure imgf000437_0001
[1323] Compound 617 was prepared following the general procedure for 586.
LCMS: m/z 628.15 [M+Hf .
EXAMPLE 378
Preparation of Compound 641
Figure imgf000437_0002
[1324] To a stirring mixture of 641-1 (950 mg, 1.9 mmol) in t-BuOH:water (3: 1 , 3 mL total volume) at r.t. were added potassium osmate dihydrate (105 mg, 0.3 mmol) and tert-butyl tosyloxycarbamate (1 g, 3.8 mmol). The mixture was stirred at r.t. overnight. The mixture was diluted with water and DCM. The aqueous layer was extracted with DCM. dried over Na2SC>4. filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 641 -3 as a minor product (200 mg, 1 0%); LCMS: m/z 527.2 [M+H]+.
[1325] tert-butyl tosyloxycarbamate was prepared as follows. To a stirring mixture of tert-butyl hydroxycarbamate (2 g, 15 mmol) in THF (10 mL) at 0 °C was added TsCl (2.8 g, 15 mmol) and TEA (2.2 mL, 15.8 mmol). The mixture was stirred at 0 °C for 20 mins and then quickly warmed to r.t. for 5 mins. The mixture was diluted with DCM and washed with wrater. An aqueous workup with DCM gave the crude product, which was purified via a silica gel to afford tert-butyl tosyloxycarbamate as a white solid.
[1326] To a stirring mixture of 641-3 (200 mg, 0.39 mmol) in CH2 T2 (2 mL) at r.t. were added TsCT (376 mg, 1.96 mmol) and TEA (320 ^iL, 2.34 mmol). The mixture was stirred at r.t. for 30 mins. The reaction was quenched with sat. NaHC(¾ solution. The layers were separated. The aqueous layer was extracted with EtOAc (2 x 25 mL). dried over NaoSC^, filtered and concentrated under reduced pressure. Chromatography of the crude product afforded 641 -4 (128 mg) as a colorless oil. LCMS: m/z 681 .10 [M+H]+.
[1327] To a stirring mixture of 641 -4 ( 128 mg, 0.188 mmol) in acetone (2 mL) at r.t. was added LiBr. The mixture was heated at reflux for 1 h and then cooled to r.t. The mixture was concentrated under reduced pressure. Chromatography of residue afforded 641 - 5 as a colorless oil (80 mg. 72% yield). LCMS: m/z 589 [M+H]+.
[1328] To a stirring mixture of 641 -5 (80 mg. 0.1 35 mmol) in DCM ( 1 .5 mL) at 0 °C was added DAST (58 μΕ, 0.41 mmol). The mixture was stirred at 0 °C for 30 mins and then quickly warmed to r.t. for 5 mins. The reaction was quenched with a cold aq. NaHC<¾ solution. The aqueous layer was extracted with DCM. dried over Na2S04. filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel column to afford 641-6 (56 mg. 74% yield). LCMS: m/z 591.0 [M+H]+. [1329] To a stirring mixture of 641-6 (50 mg, 0.084 mmol) in DMF (1 mL) were added tetrabutylammonium azide (240 mg, 0.84 mmol) and tetrabutylammonium iodide (12 mg). The mixture was stirred at 100 °C for several hours. The mixture was directly loaded onto a silica gel column, eluting with hexanerEtOAc to afford 641-7 (30 mg, 64%) as a colorless oil. LCMS: m/z 554.10 [M+H]+.
[1330] To a stirring mixture of 641 -7 (30 mg. 0.054 mmol) in THF: water ( 10: 1. 1.1 mL) was added triphenylphosphine, polymer-bound (142 mg. 0.54 mmol). The mixture was stirred at 70 °C for 30 mins and then cooled to r.t. The mixture was filtered through a plug of celite. The plug was washed several times with EtOAc. The crude mixture was concentrated under reduced pressure, and the crude product w<as used in the next step without further purification.
[1331] To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid in DMF (1 mL) were added HATU (21 mg, 0.054 mmol) and DIPEA (15 L, 0.1 1 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 641-8 in DMF (0.5 mL) was added. The mixture was stirred at r.t. for 10 mins. The reaction was quenched with a 10% aq. solution of NaHC<¾ (10 mL). The mixture was diluted with DCM, and an aqueous work up with DCM was followed. The crude product was purified via prep-HPLC to afford 641-9 (20 mg, 52%, 2 steps) as a white solid. LCMS: m/z 718.2 [M+H]+.
[1332] To a stirring mixture of 641-9 (20 mg, 0.0286 mmol) in AcCN ( 1 mL) at r.t. were added Nal (22 mg. 0.143 mmol) and TMSC1 ( 19 mg. 0.143 mmol). The mixture was warmed to 60 °C until the starting materials were consumed. The mixture was cooled to r.t. and diluted with CH2CI2. The mixture was washed with a 10% aq. solution of Na2S2(¾. The aqueous layer was extracted with DCM (2 x 10 mL). dried over Na2SC>4. filtered and concentrated under reduced pressure. The crude product was further purified via prep-HPLC to afford 641. LCMS: m/z 584.15 [M+H]+.
Figure imgf000440_0001
[1333] To a stirring solution of 573-1 (30 mg. 0.41 mmol) in EtOAc:Et01 I (5 mL:5niL) was added Pd/C (20 mg). The mixture was placed under a ¾ balloon. The mixture was stirred for several hours until the starting material was consumed. The crude mixture was filtered through a plug of celite, and the plug was washed with EtOAc (2 x 20 mL). The mixture was concentrated under reduced pressure, which was used without further purification.
[1334] The N-Boc protected amine was dissolved in a 4N HC1 in dioxane. The mixture was stirred overnight at r.t. The crude product mixture was concentrated under reduced pressure. The crude product mixture was purified via a prep-HPLC to afford 573 as a white solid. LCMS: m/z 590.15 [M+H]+.
EXAMPLE 380
Preparation of Compound 598
Figure imgf000440_0002
[1335] To a stirring mixture of 2,6-dichloroisonicotinoiiitrile (1 g, 5.78 mmol) in Et O at r.t. under Ar was added Ti(OiPr)4 ( 1.97 mL, 6.65 mmol). The mixture was stirred for 10 mins and then cooled to 0 °C. A solution of EtMgBr (3.54 mL, 12.14 mmol) in 2- methyltetrafuran was added over 10 mins. The mixture was stirred at r.t. for 1 h. and then cooled to 0 °C. BF3.OEt (1 .3 mL. 10.58 mmol) was added. The mixture was warmed to r.t. and stir for 30 mins. The reaction was quenched with IN HC1 (5 mL) and then 2N NaOH (10 mL). The mixture was diluted with DCM. The aqueous layer was extracted with DCM. dried over MgS04. filtered and concentrated under reduced pressure. Chromatography of the residue afford 598-1 (100 mg, 8.5%) as a colorless oil. LCMS: m/z 203.1 [M+H]+.
[1336] To a stirring mixture of 598-1 (100 mg, 0.49 mmol) in DCM ( 1 mL) at 0 °C were added CBzCl (84.2 mg. 0.49 mmol) and DIPEA (86 μΧ, 0.49 mmol). The mixture was warmed to r.t. for 20 mins. The reaction wras quenched with a cold sat. NaHC03 solution. The aqueous layer w7as extracted with DCM, dried over Na2S04, filltered and concentrated under reduced pressure. Chromatography of the residue afford N-CBz protected amine (100 mg, 60%). LCMS: m/z 337.0 [M+H]+.
[1337] To a stirring mixture of benzyl ( l-(2,6-dichloropyridin-4- yl)cyclopropyl)carbamate (100 mg. 0.297 mmol) in DME (2 mL. deoxygenated prior to using) were added 4,4,6-trimethyl-2-(3,3,3-trifluoroprop- l -en-2-yl)-l,3,2-dioxaborinane ( 132 mg, 0.59 mmol), a solution of Cs2C0 (290 mg, 0.89 mmol in 0.3 mL of water) and PdCL(dppf) (45 mg, 0.062 mmol). The mixture was heated under microwave irradiation for 1 h at 1 10 °C. The crude product mixture was diluted with EtOAc and water. An aqueous workup with EtOAc was followed. The crude product was purified via a silica gel chromatography to afford desired product. The mixtures was used in the next step without further purification (70 mg). LCMS: m/z 397.10 [M+H]+.
[1338] To a stirring mixture of products from the previous step (70 mg. 0.176 mmol) in DME ( 1.5 mL, deoxygenated prior to using) were added 4-fluorophenylboronic acid (36 mg, 0.259 mmol), a solution of Cs2C0 (171 mg, 0.52 mmol in 0.3 mL of water), and PdCl2(dppf) (26 mg, 0.035 mmol). The mixture was carried out under microwave irradiation at 1 10 "C for 1 h. The crude product was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, dried over MgS04, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to yield benzyl (l -(2-(4-fluorophcnyl)-6-(3,3,3-trifluoroprop-l -en-2-yl)pyridin-4- yl)cyclopropyl)carbamate as the desired product. LCMS: m/z 457. [M+H]+.
[1339] To a stirring mixture of 598-2 (50 mg, 0.085 mmol) in t-BuOH:water (3 : 1 , 1 .3 mL) at r.t. were added potassium osmate dihydrate (8 mg, 0.0215 mmol) and tert- butyl tosyloxycarbamate (62 mg, 0.215 mmol). The mixture was stirred at r.t. overnight, and then diluted with water and DCM. The aqueous layer was extracted with DCM. dried over MgSC>4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 598-3 (24 mg. 37%). LCMS: m/z 590.20 [M+H]+.
[1340] The N-Boc protected amine was dissolved in a solution of HC1 in dioxane (2 mL, 4N) at r.t. The mixture was stirred at r.t. until the starting material was consumed. The mixture was concentrated under reduced pressure to afford the crude amino alcohol, which w7as used without further purification. LCMS: m/z 490.10 [M+H]+.
[1341] To a stirring mixture of (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid (9 mg, 0.04 mmol) in DMF (0.5 mL) were added HATU (15.2 mg, 0.04 mmol) and D1PEA (17 μ]^, 0.1 mmol). The mixture was stirred at r.t. for 10 mins. A solution of the crude amino alcohol in DMF (0.2 mL) was added. The mixture was stirred at r.t. for 10 mins. The reaction was quenched with a 10% aq. NaHCOj solution (1 mL). The mixture was diluted with DCM, and an aqueous work up with DCM was followed. The crude product was purified via prcp-HPLC to afford benzyl ( l -(2-(4-fluoiOphenyl)-6-( 1 ,1 ,1 -trifl uoro-2-hydroxy- 3-(4-((R)-2-hydiOxypiOpoxy)-3-methoxybenzamiclo)propan-2-yl)pyridin-4- yl)cyclopropyl)carbamate (7 mg, 24% 2 steps) as a white solid. LCMS: m/z 698.2 [M+H]\
[1342] To a stirring mixture of 598-4 (7 mg, 0.01 mmol) in AcCN (0.5 mL) at r.t. were added Nal (7.5 mg, 0.05 mmol) and TMSCl (5.4 mg. 0.05 mmol). The mixture was warmed to 60 °C until the starting material was consumed. The mixture was cooled to r.t. and diluted with CH2CI2. The mixture was washed with a 1 0% aq. Na2S203 solution. The aqueous layer wras extracted with DCM (2 x 10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was further purified via prep-HPLC to afford 598. LCMS: m/z 564.20 [M+H]+.
Figure imgf000443_0001
11343] To a stirring solution of 533 (10 mg, 0.016 mmol) in EtOAc:EtOH (5 mL; l mL) was added Pd/C (15 mg). The mixture was placed under a H? balloon. The mixture was stirred for several hours until the starting material was consumed. The crude mixture was filtered through a plug of celite, and the plug was washed several times with
EtOAc (2 x 20 mL). The mixture was concentrated under reduced pressure and purified via prep-HPLC to afford 600 as a white solid (3 mg, 32%). LCMS: m/z 564.2 [M+H]+.
EXAMPLE 382
Preparation of Compound 594
Figure imgf000443_0002
[1344] Iodomethane (0.66 mL, 1 1 mmol) was added dropwise to a solution of 2- -3-hydroxy-6-(hydroxymethyl)-4-iodopyridine (2.03 g, 7.1 mmol) and potassium carbonate (2.0 g, 14 mmol) in DMF (8 mL). The mixture was stirred at r.t. for 1 h. The mixture was diluted with EA, washed with water and brine, dried and concentrated. The product ( 1 .77 g. 64%) crystallized upon standing.
[1345] DIPEA (2.0 mL. 12 mmol) was added dropwise to a solution of (6-chloro- 4-iodo-5-methoxypyridin-2-yl)methanol (1 .77 g. 5.91 mmol ). tert-butylchlorodimethylsilane (1 .3 g, 8.9 mmol) and a catalytic amount of imidazole in CH2C12 ( 10 mL). The mixture was stirred at r.t. overnight. The mixture was di luted with CH2C12, washed with IN HC1 and brine, dried and concentrated. The crude product was purified by column chromatography (hexane:EA) to yield the product (2.18 g. 75%) as a white solid.
[1346] Copper cyanide (1.0 g, 12 mmol) was added to a solution of 6-(((tert- butyldimethylsilyl)oxy)methyl)-2-chloro-4-iodo-3-methoxypyridine ( 1.0 g, 2.4 mmol) in dimethyl acetamide (3 mL). The mixture wras heated at 140 "C for 2 h, and then diluted with DCM. A 10% aq. solution of NH4OH was added. The mixture was stirred at r.t. for 20 mins, and the layers were separated. An aqueous work up with EtOAc was followed. Chromatography of residue afforded 6-(((tert-biityldimethylsilyl)oxy)methyl)-2-chloro-3- methoxyisonicotinonitrile (520 mg,70%) as a colorless oil.
[1347] To a stirring mixture of 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro- 3-mcthoxyisonicotinonitrile (520 mg, 1 .66 mmol) in E12O (3.9 mL) at 0 °C was added a solution of MeMgBr in 2-methyltetrafuran ( 1 .47 mL, 4.71 mmol). After 1 h of stirring at r.t.. Ti(OiPr)4 was added. The mixture was heated at reflux for 2 h and then diluted with CH?C12. The mixture was cooled to r.t., and copious quantities of Celite were added. The crude mixture was basified with a solution of NaOH (2 mL. 2N) and filtered through a plug of Celite. The plug was washed several times with DCM. The filtrate was washed with a 10% aq. HC1 solution. The layers were separated, and the organic layer was washed with sat. NaHCCr? solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried over Na?S04, filtered and concentrated under reduced pressure. Chromatography of residue afforded 594-1 (147 mg, 26%) as a colorless oil. LCMS: m/z
Figure imgf000444_0001
[1348] To a stirring mixture of 594-1 ( 147 mg, 0.45 mmol) in DCM ( 1.5 mL) at 0 °C were added CBzCT ( 1 14 mg, 0.67 mmol) and DIPEA (233 ^iL, 0.49 mmol). The mixture was warmed to r.t. for 10 mins. The reaction was quenched with a cold sat. NaHC0 solution. The aqueous layer was extracted with DCM, dried over Na2 04, filltered and concentrated under reduced pressure. Chromatography of the residue afford 594-2 ( 1 10 mg, 57%) as a white solid.
[1349] To a stirring mixture of 594-2 (1 10 mg. 0.25 mmol) in THF (762 μΐ,) at rt was added dropwise a solution of TBAF (0.85 mL) in THF. The mixture was stirred at r.t. until the starting material was consumed. Silica gel was added, and the mixture was stirred at r.t. for 10 mins. resulting mixture was concentrated under reduced pressure. Chromatography of the residue 594-3. which was used without further purification. LCMS: m/z 365.05 [M+H]+.
[1350] To a stirring mixture of 594-3 (1 10 mg. -0.3 mmol) in CH2C12 ( 1.3 mL) at r.t. was added and Dess-Martin periodinane (383 mg, 0.9 mmol). The mixture was stirred at r.t. until the alcohol was consumed. The reaction was quenched with a 5% NaHS03 solution and a sat. NaHC0 solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried with Na2S04, filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel column to afford 594-4 (90 mg, 55% 2 steps). LCMS: m/z 363.05 [M+H]+.
[1351] To a stirring mixture of 594-4 (90 mg, 0.248 mmol) in DMF (0.5 mL) were added T SCF (53 mg, 0.37 mmol) and a TBAF solution in THF (37 ^iL). The mixture was stirred at r.t. for 1 h. Silica gel was added, and the mixture was stirred for 10 mins. The crude mixture was concentrated under reduced pressure. Chromatography of the residue afford 594-5 (86 mg, 80%). LCMS: m/z 433.05 [M+H] h.
[1352] To a stirring mixture of 594-5 (86 mg, 0.198 mmol) in CH2C12 ( 1 .0 mL) at r.t. was added the Dess-Martin periodinane reagent (421 mg, 0.99 mmol). The mixture was stirred at r.t. until the alcohol was consumed. The reaction was quenched with a 5% aqueous solution of NaHS03 and a sat. NaHC0 solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried with Na2S04. filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel column to afford 594-6 (80 mg. 90%). LCMS: m/z 449.05 [M+H2OHT]+. [1353] To a stirring mixture of 594-6 (30 mg, 0.074 mmol) in MeNO? (0.5 mL) was added TEA (20 μ]^, 0.147 mmol). The mixture was stirred at r.t. for 30 mins, and then diluted with DCM and washed with water. The aqueous layer was extracted with DCM, dried over Na2S04, filltcred and concentrated under reduced pressure. Chromatography of the residue afford 594-7 (30 mg. 82%) as a white solid. LCMS : m/z 492.05 [M+H]+.
[1354] To a stirring mixture of 594-7 (30 mg. 0.061 mmol) in EtOAc (0.3 mL) at r.t. was added SnCl2.2H20 (166 mg, 0.74 mmol). The mixture was heated at reflux for 1 h and then cooled to r.t. The mixture was concentrated under reduced pressure. The crude product mixture was direcltv loaded into a silica gel column to afford 594-8. LCMS: m/z 462.05 [M+H]+.
[1355] To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid ( 12.6 mg. 0.06 mmol) in DMF (0.5 mL) were added HATU (23 mg. 0.06 mmol) and DIPEA (16 iL. 0.09 mmol). The mixture was stirred at r.t. for 10 mins. A solution of 594-8 in DMF (0.2 mL) was added, and the mixture was stirred at r.t. for 10 mins. The reaction was quenched with a 10% aq. NaHCC^ solution(10 mL). The mixture was diluted with DCM and an aqueous work up with DCM was followed. The crude product was purified via prep-HPLC to afford benzyl (2-(2-chloro-6-(3 -(4-cyclopropoxy-3 -methoxybenzamido )- 1 , 1 , 1 -trifluoro-2- hydiOxypropan-2-yl)-3-methoxypyridin-4-yi)propan-2-yl)carbamate (30 mg, quantitative) as a white solid. LCMS: m/z 652.15 [M+H]+.
[1356] To a stirring mixture of benzyl (2-(2-chloro-6-(3-(4-cyclopiOpoxy-3- methoxybenzamido)- l , l , l -triiluoro-2-hydroxypropan-2-yl)-3-methoxypyridin-4-yl)propaii-2- yl)carbamate (30 mg, 0.046 mmol) in DME (2 mL, deoxygenated prior to using) were added 4-fluoiOphenyl boronic acid (8 mg, 0.055 mmol), a solution of CS2CO3 (45 mg, 0.14 mmol in 0.3 mL of water) and PdCL(dppf) (5 mg. 0.007 mmol). The mixture was stirred at 1 10 °C under microwave reaction conditions for 1 h. The crude product mixture was diluted with EtOAc and water. An aqueous workup with EtOAc was followed. The crude product mixture was purified via a silica gel chromatography to afford the product and unreacted starting material (25 mg). LCMS: m/z 71 2.20 [M+H]+.
[1357] To a stirring solution of N-Cbz protected amine and unreacted starting material from the previous step (25 mg) in EtOAc:i-PrOH:HOAc (5 mL: l mL: l mL) was added Pd/C (20 mg). The mixture was placed under a ¾ balloon. The mixture was stirred for several hours until the starting material was consumed. The crude mixture was filtered through a plug of celite, and the plug was washed with EtOAc (2 x 20 mT). The mixture was concentrated under reduced pressure. The crude product mixture was purified via HPLC to afford 594 as a white solid. LCMS: m/z 578.15 [M+H]+.
Figure imgf000447_0001
11358] To a stirred solution of 582-1 (50 g, 310 mmol) in anhydrous THF (1.2 L) was added LDA (310 mL, 620 mmol) at -78 °C under N2. The mixture was stirred at -78 "C for 0.5 h. A solution of dimethyl carbonate (67.1 g, 750 mmol) in dry THF ( 150 mL) was added dropwise. The solution was warmed to 0 "C and stirred for 1 h below 0 °C. The reaction was quenched with aq. NH4CI (500 mL), extracted with EA (3 x 1 L). The combined organic phase was washed with a. sodium bicarbonate (1 L) and brine, and dried over sodium sulfate. The organic layer was concentrated to dryness, and the residue was purified by column chromatography (PE:EA = 20: 1) to give 582-2 (50 g, 73.5 %) as a colorless oil.
[1359] To a solution of crude 582-2 (50 g, 230 mmol) in dioxane:H20 (6: 1 ) (1 L) was added 4-fluoro-3-chloro-phenyl boronic acid (40 g, 230 mmol), CS2CO3 (223.3 g, 680 mmol) and Pd(dppf)Cl? (16.8 g. 23 mmol) under N2. The mixture was degassed (3x) and refilled with N2. The mixture was stirred at 80 °C in a pre-heated oil bath for 4 h. After cooling to r.t.. the mixture was diluted with water ( 1 .5 L) and extracted with EA (3 x 1 L). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=20: 1~15:1) to yield 582-3 (42 g, 58.7%) as a light yellow solid.
[1360] To a solution of 582-3 (10 g, 31.9 mmol) in anhydrous THE (100 mL) was added LiHMDS (63.9 mL, 63.9 mmol) dropwise at -78 °C. The mixture was stirred at -78 "C for 30 mins. A solution of Mel (9.07 g, 63.9 mmol) in dry THF (50 mL) w7as added dropwise. The mixture was warmed to 0 °C and stirred at 0 °C for 1 h. The reaction was quenched with water (100 mL) and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=10: 1 ) to yield 582-4 (3.5 g. 32%) as a light yellow solid.
[1361] To a solution of 582-4 (3.2 g, 10.22 mmol) in anhydrous THF (20 mL) was added NaHMDS (20.44 mL. 20.44 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 mins. A solution of BnOCH2Cl (3.19 g, 20.44 mmol) in dry THF (10 mL) was added dropwise. The mixture was warmed to 0 °C and stirred for 1 h. The reaction was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers wrere washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=10: 1 ) to yield 582-5 (2.7 g, 59%) as a yellow oil.
[1362] To a stirred solution of 582-5 (16.22 g, 36.29 mmol) in anhydrous THF ( 150 mL) was added L1AIH4 (1.38 g, 36.29 mmol) powder in portions under Ντ at 0 "C for a period of 10-15 mins. The mixture was stirred at 0 °C for 0.5 h. The reaction was quenched with water (100 mL) and filtered via a plug of celite. The filtrate wras extracted with EA (3 x 100 niL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=3 : 1 ) to give 582-6 (13.5 g. 89 %) as a yellow oil.
[1363] To a stirred solution of 582-6 (5 g, 1 1.93 mmol) in anhydrous DCM (50 mL) was added FeCl3 (19.4 g. 1 19.3 mmol) powder in one portion at r.t. The mixture was stirred at r.t. for 1 h. The mixture was diluted with water (100 mL) and filtered via a bed of celite bed. The filtrate was extracted with EA (2 x 150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=1 : 1 ) to give 582-7 (3.6 g, 92 %) as a brown oil.
[1364] To a stirred solution of 582-7 (3.5 g, 10.6 mmol) in anhydrous DCM (20 mL) was added TEA (5.4 g, 53 mmol) at r.t. MsCl (4.8 g, 42.4 mmol) was added dropwise, and the mixture was stirred at r.t. for 1 h. The solution was washed with water (20 mL) and brine (20 mL), and then concentrated to dryness. The residue was purified by column chromatography (PE:EA=5: 1) to give 582-8 (3.6 g. 69%) as a yellow oil.
[1365] 582-8 (480 mg, 0.987 mmol) was dissolved in benzyl amine (3 mL). The mixture was heated under microwave irradiation at 135 °C for 5 h. The crude mixture was cooled to r.t. and directly loaded into a silica gel column to afford a mixture of products. This mixture was further purified via prep-HPLC to afford 582-9 (100 mg, 25% yield) as a colorless oil: LCMS: m/z 401 .05 [M+H]+.
[1366] To a stirring mixture of 582-9 (100 mg. 0.249 mmol) in DME (2 mL. deoxygenated prior to using) were added 4,4,6-trimethyl-2-(3.3,3-trifluoroprop-l -en-2-yl)- 1 ,3,2-dioxaborinane (1 1 1 mg. 0.498 mmol), a solution of Cs2C03 (243 mg, 0.75 mmol in 0.5 mL of water) and PdCl2(dppf) (36 mg, 0.005 mmol). The mixture was stirred at 1 10 °C for 2 h under microwave reaction conditions. The crude product mixture was diluted with EtOAc and water. An aqueous workup with EtOAc was followed. The crude product mixture was purified via a silica gel chromatography to afford 582-10 (1 14 mg, quantitative yield). LCMS: m/z 461.05 [M+H]+.
[1367] To a stirring mixture of 582-10 (26 mg, 0.056 mmol) in t-BuOH:water (3 : 1, 1.3 mL total volume) at r.t. were added potassium osmate dihydrate (3 mg. 0.008 mmol) and tert-butyl tosyloxycarbamate (32 mg, 0.1 12 mmol). The mixture was stirred at r.t. overnight. The mixture was diluted with water and diluted with DCM. The aqueous layer was extracted with DCM. dried over NaiSO , filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel chromatography to afford 582-11 ( 15 mg. 45%). LCMS: m/z 594.2 [M+H]+.
[1368] The N-Boc protected amine was dissolved in HC1 in dioxane (3 mT, 4N). The mixture was stirred at r.t. for several hours until the starting material was consumed. The crude product was concentrated under reduced pressure and directly used in the next step without further purification. Coupling of the crude amine with 4-cyclopropoxy-3- methoxybenzoic acid following the general procedure for 598 afforded 589 as a white solid. LCMS: m/z 684.20 [M+Lif.
11369] To a stirring solution of 589 (38 mg, 0.064 mmol) in EtOAc:iPrOH:HOAc (5 mL: l niL: lmL) was added a 10% Pd/C (40 mg). The mixture was placed under a ¾ balloon. The mixture was stirred for several hours until the starting material was consumed. The crude mixture was filtered through a plug of celite, and the plug was wrashed with EtOAc (2 x 20 mL). The mixture was concentrated under reduced pressure and purified via prep- HPLC to afford 583 and 582. 583: LCMS: m/z 560.15 [M+H]+ and 582: LCMS: m/z 594.15 [M+I I] '.
EXAMPLE 384
Preparation of Compound 590
Figure imgf000450_0001
[1370] Compound 590 was prepared following the general procedure for 583 using (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid and HATU. LCMS: m/z 578.15
[M+H]+.
Figure imgf000451_0001
[1371] 584-1 was prepared following the general procedure for 583 using 3- methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid and HATU.
[1372] To a stirring mixture of 584-1 in DCM (1 mL) was added TFA (0.2 mL).
The mixture was stirred at r.t. for 5 mins, and then diluted with DCM. The reaction quenched with a cold NaHCC solution. The aqueous layer was extracted with DCM. dried with Na2S04, filtered and concentrated under reduced pressure. The crude product mixture was purified via prep-HPLC to afford 584 as a white solid. LCMS: m/z 606.25 [M+H]+.
EXAMPLE 386
Figure imgf000451_0002
[1373] To a stirring mixture of 2-(2-chloro-6-(3-chloro-4-fluorophenyl)pyridin-4- yl)propan-2-amine (200 mg, 0.67 mmol) in DCE (1 mL) at r.t. wrere added acetone (78 mg, 1.33 mmol), HOAc (10 mg) and Na(OAc)3BH (280 mg). The mixture was stirred at r.t. overnight. The mixture was diluted with DCM, and the reaction quenched with a cold NaHC(¾ solution. The aqueous layer was extracted with DCM. dried with Na2S04, filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel column to afford 588-1 (180 mg. 79%) as a colorless oil. LCMS: m/z 341 .0 [M+I I]
[1374] Compound 588 was prepared following the general procedure for 582 and 583. LCMS: m/z 607.2 [M+H]+.
Figure imgf000452_0001
[1375] To a stirring mixture of 4-(3-hydroxycyclobutoxy)-3-methoxybenzoic acid (70 mg, 0.168 mmol) in DMF (1 mL) were added HATU (64 mg, 0.168 mmol) and DIPEA (60 pL, 0.336 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 597-1 in DMF (0.5 mL) was added, and the mixture was stirred at r.t. for 10 mins. The reaction was quenched with a 10% aq. solution of NaHC0 ( 1 mL). The mixture was diluted with DCM, and an aqueous work up with DCM wras followed. The crude product was purified via prep-HPLC to afford 597-2 (80 mg, 75%) as a white solid. LCMS: m/z 636.15 [M+H]+.
[1376] To a stirring mixture of 597-2 (40 mg. 0.063 mmol) in DME:EtOH:H20 (1.5 mL:0.5 mL:0.2 mL, deoxygenated prior to using) w¾re added 4-fluorophenylboronic acid (9 mg, 0.063 mmol), K3P04. 7H20 (64 mg, 0.19 mmol), KH2P04 (25 mg. 0.16 mmol) and PdCl2(dppi) (7.5 mg. 0.01 mmol). The mixture was carried out under microwave irradiation at 1 10 °C for 5 h. The crude product mixture was diluted with EtOAc and water. An aqueous workup with EtOAc was followed. The crude product mixture was purified via a silica gel chromatography to afford 597-3. LCMS: m/z 696.20 [M+H]+. [1377] To a stirring mixture of 597-3 in MeOH (5 mL) at r.t. was added a solution of I IC1 in dioxane (4N, 1 mL). The mixture was stirred for 10 mins, and then concentrated under reduced pressure. The crude product was purified via HPLC to afford 597 (30 mg, 70%) as a white solid. LCMS: m/z 592.1 [M+H]+.
Figure imgf000453_0001
[1378] To a stirring mixture of 574-1 (130 mg. 0.21 mmol) in THF (2 mL) at r.t. was added dropwise a solution of MeMgBr in toluene (0.91 mL, 1.27 mmol). The mixture was stirred at r.t. for 2 h. and then diluted with EtOAc. The reaction quenched with a sat. NH4CI solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over a2SC>4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford a mixture that included 574-2. LCMS: m/z 628.20 [M+H]+.
[1379] 574-2 (40 mg) was hydrogenated over 10% Pd/C (35 mg) in EtOAc:EtOH (5 mL each) for 2 h. The catalyst wras removed by filtration, and the crude product was used in the next step without further purification. LCMS: m/z 594.25 [M+H]+.
[1380] To EtCl in dioxane (5 mL, 4N) was added 574-3 (20 mg), and the mixture was stirred at r.t. for 3 h. The mixture was concentrated, and the crude product was purified by prep-HPLC to provide 574. LCMS: m/z 494.20 [M+H] ' .
Figure imgf000454_0001
[1381] To a stirring mixture of 572-1 (25 mg. 0.0357 mmol) in pyridine ( 1 mL) was added a solution of isopropylchloroformate (1 10 pL, 0.101 mmol) in toluene. The mixture was stirred at r.t. for 2 h. The mixture was diluted with DCM. and the reaction quenched with a sat. NaHCO:, solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 572-2 as a colorless oil. LCMS: m/z 786.25 [M+H]+.
[1382] To a stirring mixture of 572-2 (22 mg, 0.032 mmol) in AcCN (1 mL) at 0 °C were added Nal (24 mg, 0.15 mmol) and TMSC1 (25 pL. 0.15 mmol). The mixture was stirred for an 10 mins, and then warmed to r.t. The mixture was diluted with EtOAc and washed with a 10% aq.
Figure imgf000454_0002
solution. The organic layer were washed with brine, dried over Na^SCLt, filtered and concentrated under reduced pressure. The mixture was concentrated, and the crude product purified by prep-HPLC to provide 572. LCMS: m/z 686.2 [M+H]+.
EXAMPLE 390
Preparation of Compound 591
Figure imgf000454_0003
[1383] To a stirring mixture of 544 (50 mg, 0.075 mmol) in HOAc: EtOAc (6 mL, 5: 1 ) was added Pd/C (30 mg). The mixture was placed under a L¾ balloon for several hours. The mixture was filtered through a plug of Celite, and the plug was washed several times with EtOAc. The fitrate was concentrated under reduced pressure and purified via prep-
I IPLC to afford 544. LCMS: m/z 582.10 [M+I I] 1.
Figure imgf000455_0001
[1384] Suzuki coupling of 640-1 (50 mg) with 4-chlorophenylboronic acid followed by sulfinamidc hydrolysis afforded 640 (20 mg) as a white solid. LCMS: m/z 582.15 [M+H]+.
EXAMPLE 392
Figure imgf000455_0002
[1385] Compound 646 (white solid, 1 1.6 mg) was prepared following the general procedure for 640 using 646-1 (25 mg). LCMS: m/z 596.10 [M+H]+.
Figure imgf000456_0001
[1386] Compound 666 (white solid. 6.7 mg) was prepared following the general procedure for 640 using 646-1 (20 mg) and 4-chloro-3-fluorophenyl boronic acid. LCMS: m/z 614.15 [M+H]+.
EXAMPLE 394
Figure imgf000456_0002
11387] Compound 649 (white solid, 19.6 mg) was prepared following the general procedure for 640 using 640-1 (40 mg) and (6-oxo- l ,6-dihydropyridin-3-yl)boronic acid. LCMS: m/z 565.15 [M+H]+.
Figure imgf000456_0003
[1388] Compound 649 (white solid, 9.2 mg) was prepared following the general procedure for 640 using 646-1 (35 mg) and (4-fluoro-3-(trifliioromcthyl)phenyl)boronic acid. LCMS: m/z 648.15 [M+H]+.
Figure imgf000457_0001
[1389] To a stirring mixture of methyl-4-methoxybenzoate ( 1 g, 5.49 mmol) in DMF (5 mL) at r.t. was added K2C0 (1.14 g, 8.24 mmol) and 2-bromoacetonitrile (653 mg, 5.49 mmol). The mixture was stirred at r.t. for 3 h, and then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The organic layers were dried over Na7S04, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 628-1 as a white solid.
[1390] To a stirring mixture of 628-1 (600 mg, 2.72 mmol) in THF (6 mL) was added dropwise a solution of borane and DMS complex in THF (0.26 mL, 2.72 mmol) at r.t. The mixture was slowly wrarmed to 60 °C for 1 h. The mixture was cooled to r.t. and diluted with EtOAc. The reaction was quenched with an aq. solution of HCl (I N). The mixture was stirred at r.t. for 10 mins and then neutralized with a sat. NaHCOs solution. The layers were separated, and the aquoues layer was extracted with EtOAc. The organic layers wrere dried over Na?S04, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 628-2 as a white solid. LCMS: m/z 226.1 [M+H]+.
[1391] To a stirring mixture of 628-2 (40 mg, 0.177 mmol) in DCM (0.6 mL) at 0 "C were added diphosgene (32 mg, 0. 177 mmol) and D1PEA (42 ^iL, 0.27 mmol). The mixture was warmed to r.t. for 20 mins and then concentrated under reduced pressure. The crude product was dissolved in toluene (0.5 mL), and azidotrimcthylsilanc (0.14 mL) and 1 drop of BF3. OEti were added. The mixture was heated at reflux for 1 h. The crude mixture was cooled to r.t. and diluted with DCM. The reaction was quenched with water, and extracted with DCM. The organic layers were dried over Na2S04. fi ltered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 628-3 as a white solid ( 18 mg. 36% in 2 steps).
[1392] 628-3 was dissolved in a solution of HC1 in dioxane (1 mL). An aqueous solution of HC1 (6N, 1 mL) was added, and the mixture was heated at 80 "C overnight. The mixture was cooled to r.t. and diluted with EtOAc. The aqueous layer was extracted with EtOAc. The organic layers were dried over N SC , filtered and concentrated under reduced pressure. The crude product was purified via prep-HPLC to afford 628-4 as a white solid. LCMS: m/z 302.85 [M+Na]+.
[1393] To a stirring mixture of tert-butyl (2-(2-(3-amino- 1 , 1 , 1 -trifluoro-2- hydroxypropan-2-yl)-6-(3-chloro-4-fluorophenyl)pyridin-4-yr)propaii-2-yl)cai'haniate (8 mg, 0.0163 mmol) and 628-4 (from the previous step) in DCM (0.3 mL) were added EDC1 (6.2 mg, 0.032 mmol). HOAt (4.5 mg, 0.033 mmol) and TEA (20 iL). The mixture was stirred for 5 mins, and the reaction was quenched with 2 drops of a solution of HC1 ( I N). The organic layer was transferred to a different flask and concentrated under reduced pressure. The crude product was purified via prep-HPLC to afford the desired product as a white solid; LCMS: m/z 754.20 [M+H]+.
[1394] 628-5 was dissolv ed in a solution of HC1 in dioxane (5 mL, 4N). The mixture was stirred at r.t. until the starting material was consumed. The crude mixture was concentrated under reduced pressure and purified via prep-HPLC to afford 628 as a white solid (8.5 mg). LCMS: m/z 654.1 [M+H]+.
Figure imgf000459_0001
[1395] To a stirring mixture of 636-1 (130 mg, 0.192 mmol) in DMF (1 mL) were added added K2C03 (80 mg, 0.576 mmol) and 2-bromoacetonitrile (46 mg. 0.38 mmol). The mixture was stirred at r.t. until the starting material was consumed. The mixture was diluted with EtOAc and washed with brine. The aqueous layer was extracted with EtOAc, dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 636-2 as a colorless oil (40 mg). LCMS: m/z 715.15 [M+H]+.
[1396] To a stirring mixture of 636-2 (20 mg, 0.028 mmol) in pyridine (0.3 mL) was added Η2θΗ·ΗΟ (10 mg). The mixture was stirred at reflux for several hours. The mixture was cooled to r.t., diluted with toluene and concentrated under reduced pressure. This process was repeated twice. The crude product was purified via a silica gel column to afford 636-3 as a colorless oil ( 10 mg).
[1397] To a stirring mixture of 636-3 (10 mg, 0.013 mmol) in EtOAc:HOAc:EtOH (5: 1 : 1 , 7 mL) wras added Pd/C (20 mg). Lhe mixture was placed under a HT balloon for several hours. The mixture was filtered through a plug of Celite, and the plug was washed several times with EtOAc. The titrate was concentrated under reduced pressure and purified via prep-HPLC to afford 636 (4.0 mg) as a white solid. LCMS: m/z 580.15 [M+H]+.
Figure imgf000460_0001
[1398] To a stirring mixture of 652-1 (750 mg. 2.12 mmol) were added 1- chloroliex-5-en-2-one (390 mg, 2.33 mmol) and potassium carbonate (410 mg, 2.97 mmol) in acetone (4.0 mL). The mixture was stirred at 50 °C for 2 h. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The layers were separated, and the organic layers were dried with Na2SC>4. filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 652-2 as a white solid (480 mg, 50%). LCMS: m/z 449.90 [M+H]+. [1399] A mixture of 652-2 (420 mg, 1.18 mmol), 2-meth lpropane-2-sulfmamide (157 mg, 1.31 mmol) and titanium(IV) ethoxide (770 μί, 2.6 mmol) in THF (7 mL) was heated to 70 °C (sealed vial, degassed and purged with N2). The mixture was stirred 70 °C for 3 h. The mixture was diluted with EtOAc and water was added. The mixture was stirred for 5 mins and then filtered through a pad of celite. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried with Na2S04 and filtered. The volatiles were removed under reduced pressure. Crude 652-3 was used in the next step without further purification. LCMS: m/z 552.95 [M +H]+.
[1 00] n-Buthyllithium (2.5 M solution in hexane, 0.64 mL, 1 .6 mmol) was added to a solution of ethylmagnesium bromide (3.42 M in 2-Me THF, 0.24 mL, 0.8 mmol) in THF (2.5 mL), which had been pre-cooled to 0°C. After 10 mins, the mixture was cooled to -78 °C. A solution of 652-3 (460 mg, 0.83 mmol) in THF (1 mL) was added dropwise, and the mixture was stirred at -78 °C for 15 mins. The reaction was quenched with MeOH and diluted with EtOAc. The organic layer w7as washed with brine, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2S0 , filtered and concentrated under reduced pressure. Chromatography of the residue afforded 652-4 as a brownish oil. LCMS: m/z 427.05 [M+H]+.
[1401] To a stirring mixture of 652-4 (180 mg, 0.42 mmol) in DCM (2 mL) was added Dess-Martin reagent (537 mg, 1 .26 mmol). The mixture was stirred at r.t. until the starting material was consumed. The mixture was diluted with EtOAc. The reaction quenched with 5% of NaHSO and a sat. NaHCOs solution. The layers were seperated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 652-5 as a white solid. LCMS: m/z 443.1 [M+H+H20]+.
[1402] To a stirring mixture of 652-5 (135 mg, 0.305 mmol) in nitromethane (0.5 mL) at r.t. was added TEA (63 μΕ. 0.46 mmol). The mixture was stirred at r.t. for 30 mins and then diluted with DCM. The reaction was quenched with a sat. NaHCO^ solution. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over a?S04, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 652-6 as a white solid ( 140 mg, 94%). LCMS: m/z 486.05 [M+I I] '\
[1403] To a stirring mixture of 652-6 (50 mg, 0.1 mmol) in EtOHtwater ( 10: 1 , 1 . 1 mL) was added Fe (28 mg. 0.5 mmol) and NH4CI (27 mg. 0.5 mmol). The mixture was heated at 80 °C for 30 mins and thens cooled to r.t. The mixture was diluted with DCM (5 mL). and the reaction was quenched with a solution of NaOH (2N„ 1 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 5 mL). The combined organic layers were dried over Na2SC>4, fi ltered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 652-7 as a white sol id. LCMS: m/z 456.1 [M+H]+.
[1404| To a stirring mixture of 3-methoxy-4-(2-((4- methoxybenzyl)oxy)ethoxy)benzoic acid (14.5 mg, 0.044 mmol) in DMF (0.2 mL) w7ere added HATU ( 17 mg, 0.044 mmol) and DIPEA (17 iL, 0.088 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 652-7 (20 mg. 0.044 mmol) in DMF (0.1 mL) was added, and the mixture was stirred at for 10 mins. The reaction w7as quenched with a 10% aq. solution of NaHCC>3 ( 1 mL). The mixture was diluted with DCM, and an aqueous work up with DCM was followed. The crude product was purified via prep-HPLC to afford 652-8 (6.5 mg, 19%) as a white solid. LCMS: m/z 770.25 [M+H .
[1405] To a stirring mixture of 652-8 (6.5 mg, 0.008 mmol) in DME:EtOH:H20 (1 .0 mL:0.3 mL:0.1 mL, deoxygenated prior to using) were added 4-fluorophenylboronic acid (9 mg, 0.063 mmol), Κ3Ρ04·7Η20 ( 14.3 mg, 0.04 mmol), KH2P04 (5.5 mg, 0.04 mmol) and PdCL(dppf) (6.0 mg, 0.008 mmol). The mixture was carried out under microwave irradiation at 1 10 °C for 5 h. The crude product was concentrated under reduced pressure and purified via a silica gel chromatography to afford 652-9. LCMS: m/z 830.2 [M+H]+.
[1406] To a stirring mixture of 652-9 in t-BuOLLLTO (3: 1 , 0.4 mL) were added K2OsO4 »2H20 ( 1 mg). The mixture was stirred for 2 h and NaI04 (5 mg) was added. The mixture was stirred at r.t. overnight. The mixture was loaded directly into a silica gel column to afford 652-10. LCMS: m/z 832.3 [M+H]+. [1407] To a stirring mixtue of 652-10 in MeOH (1 .0 mL) was added a solution of I ICl in dioxane (0.2 mL), The mixture was stirred for 10 mins at r.t. and concentrated under reduced pressure. Crude 652-11 was used in the next step without further purification.
[1408] 652-11 was dissolved in MeOH (0.5 mL) was added NaBH4 (1 .6 mg). The mixture was stirred at r.t. for 10 mins and then diluted with EtOAc. The reaction was quenched with a sat. NaHCO, solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2S04. filtered and concentrated under reduced pressure. Crude 652-12 was used in the next step without further purification.
[1409] To a stirring mixture of 652-12 in DCM ( 1.0 mL) was added TLA (0.1 mL). The mixture was stirred at r.t. until the starting material was consumed. The mixture was diluted with DCM, and the reaction was quenched with a cold sat. NaHC03 solution. The layers were separated, and the aqueous layer wras extracted with EtOAc. The The combined organic layers w7ere dried over a?S04, filtered and concentrated under reduced pressure. The crude product w7as purified via prep-HPLC to afford 652 as a w7hite solid (1.0 mg). LCMS: m/z 592.20 [M+H]+.
EXAMPLE 399
Figure imgf000463_0001
[1410] 645-2 was prepared following the general procedure for 635-2. LCMS: m/z 610.10 [M+H]+. 645-3 was prepared following the general procedure for 635-3. LCMS: m/z 720.20 [M+H] . Compound 645 ( 15.7 mg) was prepared following the procedure for 635 using 645-3 (45 mg, 0.063 mmol). LCMS: m/z 616.15 [M+I I]+.
Figure imgf000464_0001
[1411] Compound 662 (5.7 mg) was prepared following the general procedure for 645. LCMS: m/z 616.10 [M+H]+.
EXAMPLE 401
Figure imgf000464_0002
[1412] Compound 663 (1 1.4 mg) was prepared following the general procedure for 645. LCMS: m/z 584.15 [M+H]+.
EXAMPLE 402
Preparation of Compound 647
Figure imgf000465_0001
[1413] 647-3 was prepared following the general procedure for 635-3. LCMS: m/z 839.25 [M+Hf. 647-4 was prepared following the general procedure for 635. 647-4 (51 mg, 0.084 mmol) was treated with TBAF (1 M in THF, 0.1 mL. 0.1 mol) in THF (2 mL) at 70 °C for 2 h. The mixture was concentrated, and the crude product purified by silica gel chromatography (CH2Cl2:MeOH:NH3) to provide 647 ( 10 mg, 19%). LCMS: m/z 605.15 [M+H]+.
Figure imgf000466_0001
[1414] 648-2 was prepai'ed following the general procedure for 637-4. LCMS: m/z 629.05 [M+H]+. 648-3 was prepared following the general procedure for 635-3. LCMS: m/z 719.15 [M+H]+. Compound 648 (13.5 mg) was prepared following the general procedure for 635 using 648-3 (27 mg, 0.038 mmol). LCMS: m/z 61 5.15 [M+H]+.
Figure imgf000467_0001
[1415] 651-2 was prepared following the general procedure for 637-2. LCMS: m/z 730.20 [M+H]+. 651-3 was prepared following the general procedure for 637-3. LCMS: m/z 787.30 [M+HJ ' .
[1416] A solution of 651-3 ( 15 mg, 0.019 mmol) in CH3CN (0.5 mL) was added dropwise to a solution of isopentyl nitrite (4 uL, 0.029 mmol) and copper bromide (3 mg. 0.023 mmol) in CH CN (1 mL) at 65 °C. The mixture was stirred at 65 °C for 1 h and then cooled to 0 °C. The reaction was quenched with the addition of IN HC1. The aqueous layer was basified with sodium bicarbonate and extracted with EA. The product was used without further purification to provide 651 -4. LCMS: m/z 748.15 [M+H]+.
[1417] Trifluoroacetic acid (0.1 mL) was added to a solution of 651-4 in CH2CI2 (0.9 mL), and the reaction was stirred at r.t. for 5 mins. The mixture was cooled to 0 °C. The reaction was quenched with bicarbonate and extracted with EA. The product was purified by reverse-phase HPLC to yield 651 (4.0 mg). LCMS: m/z 628.05 [M+H]+.
Figure imgf000468_0001
[1418] Compound 661 was prepared following the general procedure for 651. m/z 563.15 [M+H]+.
EXAMPLE 406
Figure imgf000468_0002
[1419] Compound 493 was prepared following the general procedure for 397 using (S)-3-methoxy-4-((2-oxopyrrolidin-3-yl)oxy)benzoic acid. LCMS: m/z 640.15 [M+H] 1.
EXAMPLE 407
Preparation of Compound 587
Figure imgf000468_0003
[1420] To a stirring mixture of 587-1 (200 mg, 0.67 mmol) in DCE (1 mL) at r.t. were added acetone (78 mg, 1.33 mmol), HOAc (10 mg), and Na(OAc)3BH (280 mg). The mixture was stirred at r.t. overnight. The mixture was diluted with DCM, and the reaction was quenched with a cold NaHC(¾ solution. The aqueous layer was extracted with DCM, dried over
Figure imgf000469_0001
filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 587-1 (1 80 mg. 79%) as a colorless oil. LCMS: m/z 341.0 [M+H]+.
[1421] Compound 587 (35 mg) was prepared in 4 steps from 587-2 ( 180 mg). LCMS: m/z 641.15 [M+H]+.
Figure imgf000469_0002
[1422] Compound 664 is a single diastereomer of 626 and was obtained by chiral separation of 626 via SFC system. +ESI-MS: m/z 570.15 [M+H]+ .
EXAMPLE 409
Preparation of Compound 642
Figure imgf000469_0003
[1423] To a stirring mixture of 642-1 (540 mg, 1 .76 mmol) in DMF (5 mL, deoxygenated prior to use) were added Pd(OAc)? (1 19 mg, 0.1 7 mmol), PPh3 (102 mg. 0.387 mmol), TEA (0.3 mL, 2.1 1 mmol) and ethyl acrylate (0.42 mL, 3.87 mmol). The mixture was stirred at 85 °C overnight. The mixture was diluted with EtOAc and washed with brine. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 642-2 as a yellow solid (410 mg, 83%). LCMS: m/z 280.05 [M+H]+.
[1424] To a stirring mixture of 642-2 in a solution of HC1 in dioxane (3 mL) was added concentrated HC1 (1 mL). The mixture was stirred at 90 °C overnight. The crude product was cooled to r.t. and concentrated under reduced pressure to afford 642-3 as a brown solid. The solid w7as dissolved in toluene and concentrated under reduced pressure (2X). Crude 642-3 was used in the next step without further purification. LCMS: m/z 220.0
[1425] To a stirring mixture of 642-3 (63 mg, 0.144 mmol) in DMF (0.5 mL) were added EDCT (33 mg, 0.173 mmol). HO At (23 mg, 0.173 mmol) and TEA (41 ^iL. 0.088 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 642-4 (60 mg, 0.144 mmol) in DMF (0.5 mL) was added. The mixture was stirred r.t. for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCO ( 1 mL). The mixture was diluted with DCM, and an aqueous work up with DCM was followed. The crude product was purified via prep- HPLC to afford 642-5 (20 mg) as a white solid. LCMS: m/z 617.1 [M+HJ+.
[1426] To a stirring mixture of 642-5 (20 mg. 0.032 mmol) in DME:EtOH:H20 (1.0 mL:0.3 mL:0.1 mL. deoxygenated prior to using) were added 4-fluorophenylboronic acid (9 mg. 0.063 mmol), K3P04. 7H20 (43 mg, 0.128 mmol). KH2P04 ( 17.4 mg, 0.128 mmol) and PdCl2(dppf) (20 mg). The mixture was carried out under microwave irradiation at 1 10 °C for 5 h. The crude product was concentrated under reduced pressure, and then purified via a silica gel chromatography to afford 642-6 as a brownish oil. LCMS: m/z 677.15 [M+H]+.
[1427] To a stirring mixture of 642-6 in MeOH (1 mL) at r.t. was added a solution of HC1 in dioxane (0.2 mL, 4N). The mixture was stirred at r.t. for 5 mins and then concentrated under reduced pressure. The crude product was purified via prep-HPLC to afford 642 (8.5 mg ) as a white solid. LCMS: m/z 573.1 [M+I I] \
Figure imgf000471_0001
[1428] Diisopropylazadicarboxylate (0.29 mL, 1 .5 mmol) was added to a solution of methyl 3-fluoro-4-hydroxybenzoate (0.21 g, 1.2 mmol, ethyl glycol mono-to -butyl ether (0.32 mL, 2.5 mmol) and polymer bound triphenylphosphine ( 1.1 g, 1.9 mmol) in THT (5 mL). The mixture was stirred at r.t. for 1 h. The resin was removed by filtration, and the mixture was concentrated. The product was purified by column chromatography (hexane:EA) to 476-1 (0.34 g, 98%).
[1429] NaOH (2N. 3 mL) was added to a solution of 476-1 (0.34 g, 1.2 mmol) in MeOH (10 mL), and the mixture was heated at reflux for 1 .5 h. The mixture was acidified with IN HCl and extracted with FA. The organic extracts were washed with brine, dried and concentrated to obtain 476-2 (0.29 g, 91%).
[1430] 476-3 was prepared following the general procedure for 635-2 using 476- 2. 476-4 was prepared following the general procedure for 635-3 using 476-3.
[1431] HCl (4N in dioxane, 1 mL) was added to a solution of 476-4 (32 mg, 0.049 mmol) in CL CL (1 mL), and the mixture was stirred at r.t. for 5 h. The mixture was concentrated and the crude product purified by HPLC to yield 476. LCMS: m/z 555.05 [M+H]+. EXAMPLE 411
Preparation of Compound 481
Figure imgf000472_0001
[1432] Compound 481 (8.7 mg) was prepared following the general procedure for 645. LCMS: m/z 562.15 [M+H]X
EXAMPLE 412
[1433] The following compounds were prepared following one or more of the methods provided herein.
Figure imgf000472_0002
Figure imgf000473_0001
Figure imgf000474_0001
-472-
Figure imgf000475_0001
EXAMPLE A RSV Antiviral Assay
[1434] CPE reduction assays are performed as described by Sidwell and Huffman et aL Appl. Microbiol. ( 1971 ) 22(5):797-801 with slight modifications. HEp-2 cells (ATCC#, CCL-23) are seeded at a density of 1.500 cells/30 μΐ/well into the 384-well cell plate(s) (Corning#3701) one day prior to the assay. Compounds are added into 384-well cell plates by Labcyte POD 810 Plate Assembler system. Each of the test compounds is provided to duplicate wells of a 384-well cell plate at final concentrations starting from 100 μΜ or 1 μΜ using 1/3 stepwise dilutions for 9 points. Quick-thaw Respiratory Syncytial Virus (RSV) long strain (ATCC#VR-26) stock in a 37°C water bath. Place on ice until ready to use. Viruses are diluted to the concentration of 100 TCID3()/30 pL with medium and 30 μΐ diluted RSV are added into related wells of 384-well cell plates. For each plate, sixteen wells are set aside as uninfected, untreated cell controls (CC), and nine wells per test plate receive virus only as a control for virus replication (VC). The final DMSO concentration of all wells is 1%. Place the plates at 37°C, 5% C02 for 5 days.
[1435] After 5 days incubation, observe the CPE of cells in all wells. Cell controls should be natural and have no cell fusion; Cells in the virus control wells should exhibit signs of virus cytopathology (giant cell formation, syncytia). Six μΐ of cell counting kit-8 reagent (CCK-8. Dojindo Molecular Technologies Inc., CK04-20) are added to each well, which allows colorimetric assays to determine the number of viable cells through the dehydrogenase activity detection. After 3-4 hour incubation, the absorbance of each well is measured with a spectrophotometric plate reader at 450 nm wavelength, using a 630 ran filter as background according to manufacturer's instruction. The 50% effective concentration (E o) is calculated by using regression analysis, based on the mean O.D. at each concentration of compound.
[1436] Compounds of Formula (T) are active in the assay against the RSV virus as demonstrated in Tables A and B. Table A includes compounds with an EC50 value that is less than 1 μΜ. Table B includes compounds with an EC50 value that is equal to or higher than 1 μΜ and less than 50 μΜ. Other tested compounds disclosed herein had an EC50 value of 50 μΜ or greater.
Table A
Figure imgf000476_0001
Figure imgf000477_0001
Table B
Figure imgf000477_0002
Figure imgf000478_0001
EXAMPLE B
Cytotoxicity Determination
[1437] In order to determine the compound cytotoxicity, in parallel, each of the compounds is applied to duplicate wells in a 384-well cell plate at serial final concentrations starting from 100 μΜ using 1 /2 stepwise dilutions for 7 points without addition of virus. Incubate the cells at 37°C, 5% CO? for 5 days. Add 6 xL CCK-8 into each well and incubate in a CO? incubator at 37°C for 3-4 hours. Read the plates to obtain the optical densities which are used to calculate 50% cytotoxicity concentration (CC50).
[1438] Compounds of Formula (I) are not cytotoxic as shown in Tables C and D. Table C includes compounds with a CC50 value that is greater than 100 μΜ. Table D includes compounds with a CC50 value that is equal to or less than 100 μΜ and greater than 10 μΜ. Other tested compounds disclosed herein had a CC50 value of less than 10 μ .
Table C
Figure imgf000478_0002
Compound Compound Compound Compound Compound Compound
370 420 474 61 1 624a 670 -) / J 421 484 612 624b 671
387 427 492 613 625 672
403 439 561 615 627 673
404 441 562 616 628 674
405 446 580 620 634 675
406 447 604a 621 643
408 451 604b 623a 653
419 470 608 623b 655
Table D
Figure imgf000479_0001
Compound Compound Compound Compound Compound
357 431 482 540 598
359 432 483 541 599
360 433 485 542 604c
361 434 486 543 605a
362 435 487 545 605b
364 436 488 546 605c
365 437 489 547 605d
366 438 490 548 606
368 440 491 549 607
369 442 495 550 609
371 443 496 551 610
372 444 498 552 614
383 445 498d 553 617
384 448 500 554 619
385 449 501 556 626
386 450 502 557 629
388 452 503 558 630
391 453 504 559 631
392 454 507 560 632
396 455 510 563 633a
400 456 514 565 633b
407 457 515 568 635
409 458 516 569 637
410 459 517 570 638
41 1 460 518 571 639
412 461 525 574 640
413 462 526 575 642
414 463 527 577 644
41 5 464 528 578 645
416 465 529 579 646
41 7 466 530 583 650
41 8 467 531 586 654
422 468 532 587 656
423 469 5 590 662
424 471 534 592 663
425 473 535 593 664
426 475 536 594 665
428 476 537 595 666
429 477 538 596
430 479 539 597 EXAMPLE C
RSV Polymerase Inhibition Assay
[1439] Standard RSV polymerase assays were conducted in the presence of 10 nM recombinant RSV complex in a reaction buffer containing Tris-HCl pH7.5, 6 mM MgCli, and other additives and substrates including RNA oligonucleotides and radionucleotides. Standard reactions were incubated in 96-well plate format for 2 h at 30 °C. in the presence of increasing concentration of inhibitor. The reaction was stopped with 90 μί of 0.1 M EDTA, and the reaction product was transferred to a "reading" 96-well plate. After washing of the plate, radiolabeled RNA products were detected according to standard procedures with a Trilux Topcount scintillation counter. The compound concentration at which the enzyme-catalyzed rate was reduced by 50% (ICso) was calculated by fitting the data to a non-linear regression (sigmoidal). The IC50 values were derived from the mean of several independent experiments and are shown in Tables E and T.
[1440] Table E includes compounds with an IC50 of < 1 μΜ. Table T includes compounds with an ICso < 10 μΜ. Table G includes compounds with an IC50 value of < 100 μΜ.
Table E
Figure imgf000481_0001
Compound Compound Compound Compound Compound
250 307 354 405 470
251 308 355 406 473
252 309 356 409 474
254 310 357 41 1 475
255 31 1 358 413 476
256 312 359 415 479
257 314 360 418 481
258 315 361 419 482
259 316 362 421 483
260 317 364 423 485
261 318 365 424 486
262 319 366 425 487
263 320 367 428 488
264 321 369 431 489
266 322 370 432 491
267 323 371 434 493
270 324 372 435 494
271 325 373 436 495
272 326 375 437 496
273 327 376 440 497
274 328 378 442 498
275 329 379 443 498c
276 330 380 444 498d
278 J J 1 383 445 499
279 384 447 500
280 385 448 501
281 ~> » Λ 386 449 501
282 387 451 502
283 336 388 452 503
284 J J I 389 453 504
285 338 390 454 505
287 339 391 455 506
289 340 392 456 507
292 341 393 459 508
297 342 394 460 509
298 343 395 461 510
299 344 396 462 51 1
301 345 397 463 514
302 346 398 464 515
303 347 399 465 516
304 348 400 466 517
305 349 402 467 518
306 353 403 469 519 Compound Compound Compound Compound Compound
520 549 581 615 643
521 550 582 617 644
522 551 583 618 645
523 552 584 619 646
524 553 585 620 647
525 554 586 621 648
526 555 588 622 650
527 556 589 623 b 651
528 557 590 624b 652
529 558 591 625 653
530 559 593 626 654
531 560 594 627 655
532 562 595 628 656
533 563 596 629 657
534 565 598 630 658
535 567 599 631 662
536 568 600 632 663
537 569 601 633a 664
538 570 602 633b 665
539 571 603 634 666
540 573 604d 635 667
541 574 605a 636 668
452 575 605c 637 669
543 576 605d 638 676
545 577 610 639
546 578 61 1 640
547 579 612 641
548 580 614 642
Table F
Compound Compound Compound Compound Compound
109 153 247 350 477
1 14 154 253 352 478
120a 165 265 363 480
122b 168 268 377 484
124 174 277 404 490
145 175 286 416 492
146 177 290 417 498b
148 187 294 426 512
149 188 296 438 513
150 203 300 450 561
151 216 1 471 564 Compound Compound Compound Compound Compound
572 604b 609 624a 672 592 604c 613 659
597 607 616 660
604a 608 623a 672
Table G
Figure imgf000484_0001
EXAMPLE D RSV Assay
[1441 ] The RSV subgenomic replicon 395 HeLa and APC 1 26 were licensed from Apath (Brooklyn, NY) and were originally developed by Dr. Mark Meeplcs of Center for Vaccines & Immunity, the Research Institute at Nationwide Children's Hospital in Columbus. Ohio. To generate subgenomic RSV replicon, three glycoprotein genes, those for SH. G, and F. from a full-length recombinant GFP-expressing (rg) RSV antigenomic cDNA were deleted. In their place, a blasticidin S deaminase (bsd) gene was inserted. Through multiple steps, the RSV replicon was established in HeTa cells (395 Hela) or BHK cells (APC 126). Both 395 HeLa and APC 126 cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 4500 mg/L D-glucose, L-glutamine, and H O mg/L sodium pyruvate (Invitrogen, Cat. # 1 1995-040). The medium was further supplemented with 10% (v/v) fetal bovine serum (FBS) (Mediatech, Cat. #35-010-CV), 1% (v/v) penicillin/streptomycin (Mediatech. Cat. #30-002-CI), and 10 ng/mL of Blasticidin (BSD) (Invivogen, Cat. code ant- bl-1 ). Cells were maintained at 37 °C in a humidified 5% C0 atmosphere.
[1442] Determination of 50% inhibitory concentration (EC?o). 90% inhibitory concentration (EC90) and 50% cytotoxic concentration (CC 0) in RSV replicon cells were performed by the following procedure. On the first day, 5000 RSV replicon cells per well were plated in a 96-well plate. On the following day, compounds to be tested were solubilized in 100% DMSO to 100X the desired final testing concentration. Each compound was serially diluted ( 1 :3) up to 9 distinct concentrations. Compounds in 100% DMSO were reduced to 10% (v/v) DMSO by diluting 1 : 10 in cell culture media. A 10 μΐ^ sample of the compounds diluted to 10% (v/v) DMSO with cell culture media was used to treat the RSV replicon cells in 96-well format. The final DMSO concentration was 1 % (v/v). Cells were incubated with compounds for 7 days (for 395Hela) or 3 days (for APC126) at 37 °C in a 5% CO2 atmosphere. In each assay, positive control that was previously characterized in the RSV replicon assay was included.
[1443] The Renilla Luciferase Assay System (Promega, Cat. #E2820) was used to measure anti-RSV replicon activity. Assay plates were set up as stated above. Tuminescence was recorded using a Perkin Elmer multilabel counter Victor3V. EC50. the concentration of the drug required for reducing RSV replicon RNA by 50% in relation to the untreated cell control value, w7as calculated from the plot of percentage reductions of the optical density (OD) value against the drug concentrations using the Microsoft Excel forecast function.
[1444] 395 HeLa or APC 126 cell proliferation assay (Promega; CellTiter-Glo Luminescent Cell Viability Assay. Cat. #G7 72) was used to measure cell viability. The CellTiter-Glo*' Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells. Assay plates were set up in the same format as noted above for the replicon assay. CellTiter-Glo reagent (100 μί) was added to each well and incubated at room temperature for 8 minutes. Luminescence was recorded using a Perkin Elmer multilabel counter Victor3V. The CC50, the concentration of the drug required for reducing viable cells by 50% in relation to the untreated cell control value, was calculated from the plot of percentage reductions of the luminescence value against the drug concentrations using the Microsoft Excel forecast function.
[1445] Table H includes compounds with an EC50 value that is less than 1 μΜ. Table I includes compounds with an EC50 value that is equal to or higher than 1 μΜ and less than 50 μΜ. Other tested compounds disclosed herein had an EC o value of 50 μΜ or greater. Table H
Figure imgf000486_0001
Compound Compound Compound Compound Compound
505 JJJ 563 596 637
506 534 564 598 638
507 535 567 600 640
508 536 569 601 641
509 538 571 602 642
5 10 539 572 603 643
51 1 540 574 604d 644
514 542 575 605d 645
5 15 543 576 61 1 646
516 545 577 612 647
519 546 578 614 650
520 547 579 615 651
521 548 580 621 653
523 550 581 622 659
524 55 1 583 623b 663
525 552 584 624b 664
526 554 585 626 665
527 555 586 627 667
528 556 588 630 672
529 558 589 633 b 675
530 560 590 634
53 1 561 594 635
532 562 595 636
Table 1
Compound Compound Compound Compound
127 168 438
128 220 375 461
163 J 1 J 378
EXAMPLE 15
Combination Studies
RSV with Renilla Reporter
[1446] RSV expressing Renilla luciferase (A2-RL-linel 9F) was generated by Dr. Martin Moore of Emory University, Atlanta, GA. USA. The in vitro viral kinetics of A2-RL- linel 9F is similar to that of wild type RSV (See Hotard, A.L., Virology (201 2) 434(1 ): 1 29- 136). [1447] Host cell HEp-2 was purchased from ATCC (Cat. #CCL-23) and cells were cultured in DMEM/I lam's F- 12 50/50 I * containing L-glutamine and 15 mM HEPES (Mediatech, Cat. # 10-092-CM). The medium was further supplemented with 5% (v/v) FBS (Mediated!, Cat. #35-010-CV) and 1 % (v/v) penicillin/streptomycin (Mediatech. Cat. #30-002-0). HEp-2 cells were maintained at 37 °C in a humidified 5% CO2 atmosphere. Drug Treatment and Viral Dosing
[1448] To determine the effect of a combination of compounds, the following procedure was followed. On the first day, 20.000 HEp-2 cells were plated per well in a 96- well plate. On the following day. test articles were solubilized in 100% DMSO (for chemicals) or 1 x PBS (for biologies) to 200x the desired final testing concentration. Subsequently, Compound (A), or a pharmaceutically acceptable salt thereof, was serially diluted ( 1 :3) to 9 distinct concentrations "horizontally" in a 96- well plate, and Compound (B), or a pharmaceutically acceptable salt thereof, was serially diluted ( 1 :3) to 7 distinct concentrations "vertically" in 96-well plate. The serially diluted 200x test articles were then diluted 1 : 10 into cell culture media to generate 20x test articles. A 5 μΐ^ aliquot of the 20x test articles was added in a checkerboard fashion to the cells with 90 [iL existing media. Space was also allotted for titrations of each of the compounds alone to be used as reference controls. After 12 hour pre-incubation of test articles, A2-RL-linel 9F at an MOI of 0.5 was added to the plate and further incubated for 2 days at 37 °C in a 5% CO?.
Determination of Anti-RSV Activity
[1449] The Renilla Luciferase Assay System (Promega, Cat. # E2820) was used to measure anti-RSV replicon activity. Assay plates were set up as stated above. Luminescence was recorded using a Perkin Elmer multi label counter Victor3V.
Cell Viability Assay
[1450] Promega Cel lTiter-Glo Luminescent Cell Viability Assay, Cat. #G7572) was used to measure cell viability. The CellTiter-Glo " Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the adenosine triphosphate (ATP) present, wrhich signals the presence of metabolically active cells. Assay plates were set up in the same format the anti-RSV assay, except that no virus was added to the cell viability assay. A 100-pL aliquot of CellTiter-Glo reagent was added to each well and incubated at room temperature for 8 minutes. Luminescence was recorded using a Pcrkin Elmer multilabel counter Victor3V.
Data Analysis
[1451] Each experiment was performed at N=5 for both anti-RSV activity and cell viability. Mean percent inhibition of the replicon values from the 5 experiments was generated and for anti-RSV activity, it was analyzed using two drug interaction analysis models. Isobologram Analysis and/or Prichard's Model.
Isobologram Analysis
[1452] The effects of drug-drug combinations were evaluated by the Loewe additivity model in which the experimental data were analyzed using CalcuSyn (Biosoft, Ferguson, MO), a computer program based on the method of Chou and Talalay. The combination index (CI) value and the isobologram for each experimental combination wrere calculated. C values of <1, 1 , and >1 indicate synergy, additive effect, and antagonism, respectively. Under the synergy category, CT<0.1 is considered very strong synergism; CI 0.1-0.3 strong synergism; CI 0.3-0.7 synergism and CI 0.7-0.85 moderate synergism. The isobologram analysis, which graphically represents additive, synergistic, and antagonistic drug effects, was also used to model the interaction of antiviral activities. In this representation, an effective concentration (EC) value of one drug is plotted on one axis and corresponding EC value of a second drug is plotted on the second axis; the line connecting these two points represents the amount of each drug in a combination that would be required to reach the equivalent EC value, given that their effects are additive.
Prichard's Model (MacSynergy II)
[1453] MacSynergy Π software was kindly provided by Dr. M. Prichard (University of Michigan). This program allows the three-dimensional examination of drug interactions of all data points generated from the checkerboard combination of two inhibitors with Bliss-Independence model. Confidence bounds are determined from replicate data. If the 95% confidence limits (CL) do not overlap the theoretic additive surface, then the interaction between the two drugs differs significantly from additive. The volumes of synergy or antagonism can be determined and graphically depicted in three dimensions and represent the relative quantity of synergism or antagonism per change in the two drug concentrations. Synergy and antagonism volumes are based on the Bliss independence model, which assumes that both compounds act independently on different targets. A set of predicted fractional responses faA B under the Bliss independence model is calculated as faAB = faA +fdB - faA* faB with faA and faB representing the fraction of possible responses, e.g. % inhibition, of compounds A and B at amounts dA and dB, respectively, and describes the % inhibition of a combination of compounds A and B at amount (dA+dB). If 'faAB > faA + faB - faA* faB then we have Bliss synergy; if faAB < faA + faB - faA* faB then we have Bliss antagonism. The 95% synergy/antagonism volumes are the summation of the differences between the observed inhibition and the 95% confidence limit on the prediction of faAB under the Bliss independence model. MacSynergy II was used for data analysis.
11454] MacSynergy II Volume Descriptions: <25 μΜ2% = Additive; 25-50 μΜ~% = Minor synergism; 50-100 μΜ~% = Significant synergism; and >100 μΜ % = Strong synergism. For the combination of 574 and BMS-433771 (a fusion protein inhibitor) had a synergy volume of 24.9 μΜ2% (additive/minor synergism).
EXAMPLE F
Parainfluenza virus-3 (P1V-3) Plaque Assay
[1455] MA-104 cells are grown in 24-well plates to a confluency of 90% in the presence of minimal essential medium (MEM) supplemented with 10% fetal bovine serum and antibiotics (C-EMEM). The cells are then washed twice with non-complete minimal essential medium (NC-EMEM). Test articles are dissolved in DMSO to a stock concentration of 10 niM.
[1456] An aliquot of 0.5 mL of the test article at various concentrations are then inoculated in triplicate wells and are incubated for 60 mins at 37 °C with 5% C(¾ for the diffusion of test article into MA-104 cells. After the incubation period, a stock of human PIV type 3 are thawed and diluted with NC-EMEM to achieve a viral concentration of 104 pfu/mL. An aliquot of 0.1 mL are then inoculated into all the wells except for the negative and test article toxicity control wells. Upon infection, the plates are incubated for 72 h at 37 °C at 5% CO2. After incubation, the plates are examined under microscopy to record cytotoxicity. The supernatants are collected for viral quantification using a standard plaque assay using MA-104 cells as the indicator cells. [1457] To perform the plaques assay, MA- 104 cells are grown to confluence in 24-well plates. The cells are washed with serum-free medium prior to inoculation of duplicate wells with serial 10-fold dilutions of supernatant sample. After 1 h incubation at 37 °C, the samples are aspirated and 1 .0 mL of methyl cellulose overlay media are added to each well. After 6 days of culture, the cells are fixed and stained with 0.06% crystal violet in 1 % glutaraldehyde and viral plaques are enumerated. The data are analyzed with Prism software with EC 0 defined as drug concentration that reduced the viral load 50% from the viral control (VC).
EXAMPLE G
Human metapneumovirus (hMPV) TClDgo Assay
[1458| LLC-MK2 cells are grown in 24-w¾ll plates to a confluency of 90%» in the presence of minimal essential medium (MEM) supplemented with 10% fetal bovine serum and antibiotics (C-EMEM). The cells are then wrashed twice with non-complete minimal essential medium (NC-EMEM). Test articles are dissolved in DMSO to a stock concentration of 10 mM.
[1459] An aliquot of 0.5 mL of the test article at various concentrations are then inoculated in triplicate wells and are incubated for 60 mins at 37 °C with 5% C(¾ for the diffusion of test article into LLC-MK2 cells. After the incubation period, a stock of human metapneumovirus are thawed and diluted with NC-EMEM to achieve a viral concentration of 104 pfu/mL. An aliquot of 0.1 mL are then inoculated into all the wells except for the negative and test article toxicity control wells. Upon infection, the plates are incubated for 7 days at 37 °C at 5% CO2. After incubation, the plates are examined under microscopy to record cytotoxicity. The supernatants are collected for viral quantification using a standard TCID50 assay using LLC-MK2 cells as the indicator cells. The data are analyzed with Prism software with EC50 defined as drug concentration that reduced the viral load 50% from the viral control (VC).
[1460] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein arc illustrative only and arc not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

Claims

WHAT IS CLAI M ED IS :
1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, havin the structure:
Figure imgf000493_0001
A is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted cvcloalkenyl, an optionally substituted aryl, an optionally substituted aryl(C i-2 alkyl). an optionally substituted heteroaryl and an optionally substituted heterocyclyl:
Y is selected from the group consisting of an optionally substituted cycloalkyl. an optionally substituted cvcloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl:
RL A, RL H, RI l and RL D are each independently hydrogen or an unsubstituted C i .4 alkyl;
R2A, R2A L , R2B, R2B L , R C, R2C L , R D and R2D L are each independently selected from the group consisting of hydrogen, an optionally substituted C alkyl, an optionally substituted aryl(C | _6 alkyl), an optionally substituted heterocyclyl(C 1 -6 alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl and hydroxy; or R2A L is hydrogen, and R1 '1 and R2A is joined together with the atoms to which they are attached to form an optionally substituted 5 membered hctcrocyclyl or an optionally substituted 6 membered heterocyclyl, R2B L is hydrogen, and RL B and R2H is joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl;
between Xl a and X2a represents a single or double bond between Xl a and X2a; z between X~a and X~,a represents a single or double bond between X~a and X,a; provided that between Xi d and X2'1 and between X2d and X3d cannot be both double bonds and at least one of is a double bond;
wiien between Xia and X a represents a double bond and -------- between X2a and X3A is a single bond, then Xl a is N or CR4A L , X2a is N or CR5 A and X a is NR6A 1 , C(=0) or
CR6A R6IU; and when between Xl a and X2a represents a single bond and between X2a and X3a is a double bond, then Xl a is NR4A or CR4A2R4A3, X2a is N or CR5" and X3a is N or CR6A; or
Xl a, X2a and X3a are each independently C, N, 0 or C(=0), and form a ring or ring system selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl by joining Xl a and Xja together; with the proviso that the valencies of Xla. X2a and X a can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C alkyl, and Xla. X2 and Xja are uncharged:
R3A and R3A L are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, an optionally substituted C alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted cycloalkyl, an optionally substituted C M alkoxy, -O-carboxy, an optionally substituted heteroaryl, an
optionally substituted heterocyclyl. CHF9, CF3 and
Figure imgf000494_0001
, prov ided that R3A and RJA L cannot be both hydrogen; or RIA and R, A L together form =N-ORA; or R, A and R1dl together with the atom to which they are attached can be joined to form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, an optionally substituted 5 membered ring or an optionally substituted 6 membered ring;
R4a_ R4a l _ R4a2 &nd R4a3 are each independently hydrogen or an unsubstituted C alkyl;
R I and Ryd l are each independently be hydrogen or an unsubstituted C M alkyl;
R6A and R6AL are each independently hydrogen, an optionally substituted C alkyl or an optionally substituted alkoxyalkyl;
R6A2 and R6AJ are each independently hydrogen or an unsubstituted C1.4 alkyl;
Xi , X2b and X3b are each independently C. N. O or C(=0), and form indicates a bi- cyclic ring selected from an optionally substituted bi-cyclic heteroarvl and an optionally substituted bi-cyclic heterocyclyl by joining Xi b and X~'b together, wherein between
Xl b and X2b represents a single or double bond between Xl b and X2b; between X b and
Xjb represents a single or double bond between X2b and X,b; and provided that at least one of
Xl b, X b and Xj comprises a nitrogen atom and both cannot be double bonds; with the proviso that the valencies of Xl b, X2b and X3b can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C M alkyl; and Xl b, X2b and Xjb are uncharged;
R3C and R 'cl are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, an optionally substituted C M alkyl, an optionally substituted C2-4 alkenyl. an optionally substituted C2-4 alkynyl. an optionally substituted Cs-f, cycloalkyl, an optionally substituted CM alkoxy, -O-carboxy, an optionally substituted heteroaryl, an
Figure imgf000495_0001
cannot be both hydrogen; or RJE and R1l I togetlier form =N-ORC; or R'1C and R~,c l together with the atom to which they are attached can be joined to form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, an optionally substituted 5 membered ring or an optionally substituted 6 membered ring;
RD and RC are each independently hydrogen or an unsubstituted CM alkyl; R4c and R5t are taken together to form an unsubstituted aryl, an unsubstituted heteroaryl or an optionally substituted heterocyclyl;
Zc is N or CH;
md is 0 or 1 ; and
ring Bd is an optionally substituted C? cycloalkyl;
ring Bd l is an optionally substituted pyridinyl; and
provided that when L is Formula (lie), then Y is absent; and
provided that the compound is not
Figure imgf000496_0001
2. The compound of Claim 1 , wherein L is Formula (la).
3. The compound of Claim 2. wherein Xl a is CR4al or CR4ii2R4a3. X2a is N. and CR6a or CR6a2R6a3.
4. The compound of Claim 2, wherein between Xla and X2a is a single between X2a and X3a is a double bond. Xl a is CR4a R4a3. X a is N. and X3b is
CR0il.
5. The compound of Claim 2, wherein -------- between X a and X"a is a double bond, between X2a and Xja is a single bond, Xl a is CR4a l, X'b is N, and X
C R6a2R6a3_
6. The compound of Claim 2, wherein -X'a X'a X - is -CH2-N=CH- or■
CH=N-CH2-.
7. The compound of Claim 2, wherein -Xla X2a X i1- is -N=N-CH2-, ■
N=CH-CH2- or -N=CH-NH-.
8. The compound of Claim 2, wherein -Xla X2a X3a- is -CI I2-CI I=N-, ■
NH-CH=NH- or -NH-N=CH-.
9. The compound of Claim 1 , wherein L is Formula (Ial ):
Figure imgf000497_0001
10. The compound of Claim 9, wherein Xl a, X2a and X'a is a ring or ring system is an optionally substituted aryl.
1 1. The compound of Claim 9, wherein Xl a, X2a and Xja is a ring or ring sy stem is an optionally substituted mono-cyclic heteroaryl or an optionally substituted bi-cyclic heteroaryl.
12. The compound of Claim 9, wherein Xl a, X2" and Xyd is a ring or ring system is an optionally substituted mono-cyclic heterocyclyl or an optionally substituted bi-cyclic heterocyclyl.
13. The compound of Claim 9. wherein Xl a. X2a and Xja is a ring or ring system
selected from the gro an
optionally substituted
Figure imgf000497_0002
optionally substituted
optionally substituted
Figure imgf000497_0003
optionally substituted
optionally substituted an
optionally substituted
Figure imgf000497_0004
. an optionally substituted an optionally substituted substituted
substituted
substituted
Figure imgf000498_0001
optionally
substituted
Figure imgf000498_0002
wherein R , R R 3 and R is each independently hydrogen or an unsubstituted C | _6 alkyl; each is independently absent or a bond; each
RA\ each RA6, each RA7 is an unsubstituted C , alkyl, halogen, hydroxy, amino, mono- substituted amino, di-substitutcd amino or -NH-S(=0 )C | .4 alkyl; and R' is hydrogen or an unsubstituted C i -& alkyl.
14. The compou a2):
Figure imgf000498_0003
wherein R7A L , R7A2 and R7AJ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted CVs alkyl, an optionally substituted C2-8 alkenyl, an optionally substituted C?-s alkynyl, an optionally substituted C3.6 cycloalkyl. an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl. an optionally substituted hydroxyalkyl an optionally substituted CM alkoxy, an optionally substituted alkoxyalkyl. amino, mono-substituted amino, di-substituted amino. halo(C] _8 alkyl). haloalkyl, an optionally substituted O-amido and an optionally substituted C- carboxy.
1 5. The compound of Claim 14, wherein R7al is a C alkoxy. and R7a2 and R'aj are both hydrogen.
1 6. The compound of Claim 14. wherein R7a i is a hydrogen. R'd2 is an optionally substituted C alkyl. and R7aj is hydrogen
17. The compound of Claim 16, wherein the substituted C alkyl of R7a2 is substituted with a substituent selected from the group consisting of halo, hydroxy. C M alkoxy, an optionally substituted aryl(Ci.4 alkyl), an optionally substituted C-carboxy, amino, an optionally substituted mono-substituted amino, an optionally substituted di-substituted amino, an optionally substituted C-amido, an optionally substituted N-amido, an optionally substituted N-carbamyl, an optionally substituted N-sulfonamido, an optionally substituted urea, an optionally substituted amidine and an optionally substituted acetylurea.
1 8. The compound of Claim 14, wherein R7a l is a hydrogen, R7a2 is an optionally substituted heterocyclyl, and R7aj is hydrogen
19. The compound of Claim 14. wherein R7a l is a mono-substituted amino, and R7a2 and R7iU are both hydrogen.
20. The compoun (la3):
Figure imgf000499_0001
wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted cycloalkyl an optionally substituted aryl. an optionally substituted heteroaryl or an optionally substituted heterocyclyl; and R8'1'1 is selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted C i-8 alkyl, an optionally substituted Ci-g alkenyl, an optionally substituted Ci-s alkynyl, an optionally substituted C3 -6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl. an optionally substituted hydroxyalkyl. an optionally substituted Ci_8 alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino, halo(Ci-8 alkyl). haloalkyl and an optionally substituted C- carboxy.
21. The compound of Claim 20, wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optional ly substituted 5-membered cycloalkyl or an optionally substituted 6-membered cycloalkyl.
22. The compound of Claim 20, wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted aryl.
23. The compound of Claim 20. wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered heteroaryl or an optionally substituted 6-membered heteroaryl.
24. The compound of Claim 20, wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered heterocyclyl or an optionally substituted 6-membered heterocyclyl.
25. The compound of Claim 20, wherein the dashed semi-circ with the
two carbon atoms to wh
an optionally substituted
Figure imgf000500_0001
or an optionally substituted
wherein each is independently absent or a bond; each RA5. each
Figure imgf000500_0002
halogen, an unsubstituted C | _6 alkyl, hydroxy, amino, an optionally substituted mono- substituted amino, an optionally substituted di-substituted amino, -(CH2) | .40H. -(CH?) i- 4NH2 or N-sulfinamido (for example, -NH-S(=0)C alkyl). or two RA\ two RA6 or two RA7 are taken together to form an optionally substituted 5- membered ring to an optionally substituted 6-membcred ring; and RA8 is hydrogen or an unsubstituted Οι-6 alkyl.
26. The compound of any one of Claims 2-25, wherein R| J can be hydrogen.
27. The compound of any one of Claims 2-25. wherein Rl a can be an unsubstituted C 1 -4 alkyl.
28. The compound of any one of Claims 2-27. wherein R2iI and R2a i are both hydrogen.
29. The compound of any one of Claims 2-27, wherein R2a is hydrogen and R2d l is an optionally substituted C 1.4 alkyl.
30. The compound of any one of Claims 2-27, wherein R2a is hydrogen and R2a l is an optionally substituted aryl(C| .6 alkyl) or an optionally substituted heterocyclyl(C 1 -6 alkyl).
31. The compound of any one of Claims 2-27, wherein R2a is hydrogen and R2a l is an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl or hydroxy.
32. The compound of any one of Claims 2-27, wherein R2dl is hydrogen, and Rl a and R2d are joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl.
33. The compound of any one of Claims 2-27, wherein R2a and R2a l are both an optionally substituted C] _4 alkyl.
34. The compound of any one of Claims 2-33. wherein R'a is hydrogen, and R ' l is selected from the group consisting of amino, an unsubstituted Ci_4 alkyl, an unsubstituted C2-4 alkenyl. an unsubstituted C2-4 alkynyl. tin unsubstituted C3-6 cycloalkyl, an unsubstituted Ci-4 alkoxy, hydroxy, halogen and an unsubstituted heteroaryl.
35. The compound of any one of Claims 2-33, wherein R',a is hydrogen, and R'1'1' is hydroxy.
36. The compound of any one of Claims 2-33, wherein R"'a is hydroxy, and R~ia l is selected from the group consisting of amino, an unsubstituted C 1 -4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C3-6 cycloalkyl, an unsubstituted C |-4 alkoxy, hydroxy, halogen, -O-carboxy. an unsubstituted heteroaryl and an optionally substituted heterocyclyl.
37. The compound of any one of Claims 2-33, wherein RJd is hydroxy, and R a l is an unsubstitutcd C alkyl.
38. The compound of any one of Claims 2-33. wherein RJd is hydroxy, and R"'1 is an unsubstituted C2-4 alkynyl.
39. The compound of any one of Claims 2-33. wherein Rja is hydroxy, and R,a l is
CF3.
40. The compound of any one of Claims 2-33. wherein Rja is hydroxy, and R"'1 is
CHF2.
41. The compound of any one of Claims 2-33. wherein R3a is halogen, and R'al is
CF3.
42. The compound of any one of Claims 2-33, wherein R3a is halogen, and R',ai is
CHF2.
43. The compound of any one of Claims 2-33, wherein R,a is hydroxy, and R, l is an unsubstituted C3-6 cycloalkyl.
44. The compound of any one of Claims 2-33, wherein R3'1 is halogen, and R3dl is an unsubstituted C3-6 cycloalkyl.
45. The compound of any one of Claims 2-33, wherein R' and Kyd] are both halogen.
46. The compound of any one of Claims 2-33. wherein R'a is hydrogen, and R ' l is unsubstituted C M alkyl.
47. The compound of any one of Claims 2-33. wherein R3d is an unsubstituted C alkoxy. and Rjal is an unsubstituted C alkyl.
48. The compound of any one of Claims 2-33, wherein R'a and R'ia l are both an unsubstituted C alkyl.
49. The compound of any one of Claims 2-33. wherein one of R~ld and R''a l is a substituted C alkyl substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mono-substituted amino, di-substituted amino, -N-amido, an optionally substituted mono-cyclic heteroaiyl and an optionally substituted mono-cyclic heterocyclyl; and the other of R3a and R a l is hydroxy .
50. The compound of any one of Claims 2-33, wherein one of Rja and RJd l is an optionally substituted mono-cyclic heteroaryl or an optionally substituted mono-cyclic heterocyclyl; and the other of R"' and R"'1 is hydroxy.
51. The compound of Claim 50. wherein one of R'a and R '"1 is selected from the group consisting of an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperazine. an optionally substituted morpholine, an optionally substituted triazole, an optionally substituted piperazinone and an optionally substituted azetidine; and the other of R3a and R3al is hydroxy.
52. The compound of any one of Claims 2-33, wherein R',a and R'1Ji together form N=ORa.
53. The compound of any one of Claims 2-33, wherein R'1d and R"'al are join together with the atom to which they are attached to form an optionally substituted 3 to 6 membered ring.
54. The compound of Claim 1 , wherein L is Formula (lb):
Figure imgf000503_0001
55. The compound of Claim 54, wherein the bi-cyclic ring is an optionally substituted 9-membered bi-cyclic heteroaryl or an optionally substituted 10-membered bi- cyclic heteroaryl.
56. The compound of Claim 54. wherein the bi-cyclic ring is an optionally substituted 9-membered bi-cyclic heterocyclyl or an optionally substituted 10-membered bi- cyclic heterocyclyl.
57. The compound of any one of Claims 54-56. wherein Xl b is C, X2b is N and X3b is C.
58. The compound of any one of Claims 54-56, wherein Xi is N, X2b is N and X b is C.
59. The compound of any one of Claims 54-56, wherein X lh is N or C, X2b is or O and X3b is N or C.
60. d of Claim 54. wherein the bi-c clic ring is an optionally
substituted an optionally substituted optionally
substituted
Figure imgf000504_0001
and an optionally substituted ; wherein each is independently absent or a bond; each RB I , each RB2 and each RRl is an unsubstituted C| .6 alkyl, halogen, hydroxy, amino, mono- substituted amino, di-substituted amino or -NH-S(=0)C | .4 alkyl; and RB4 is hydrogen or an unsubstituted C | -6 alkyl.
61. The compound of Claim 1. wherein L is Tormula (Ibl ):
Figure imgf000504_0002
wherein: the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted cycloalkenyl an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl; and R kl is selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted CVs alkyl, an optionally substituted C?-8 alkenyl, an optionally substituted C?-g alkynyl. an optionally substituted C3 -6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl, an optionally substituted Ci_g alkoxy, an optionally substituted alkoxyalkyl. amino, mono-substituted amino, di-substituted amino, halo(C | -s alkyl), haloalkyl and an optionally substituted C- carboxy.
62. The compound of Claim 61 , wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-mcmbered cycloalkenyl or an optionally substituted 6-membered cycloalkenyl.
63. The compound of Claim 61. wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted aryl.
64. The compound of Claim 61. wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered heteroaryl or an optionally substituted 6-membered heteroaryl.
65. The compound of Claim 61. w ierein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered heterocyclyl or an optionally substituted 6-membered heterocyclyi.
66. The compound of any one of Claims 54-65. wherein RL B is hydrogen.
67. The compound of any one of Claims 54-65, wherein RL B is unsubstituted C alkyl.
68. The compound of any one of Claims 54-67, wherein R2B and R B L are both hydrogen.
69. The compound of any one of Claims 54-67, wherein R2B is hydrogen and R2B L is an optionally substituted C alkyl.
70. The compound of any one of Claims 54-67, wherein R2B is hydrogen and R2M is an optionally substituted aryl(C|_6 alkyl) or an optionally substituted heterocyclyl(Ci-6 alkyl).
71. The compound of any one of Claims 54-67. wherein R2B is hydrogen and R2B L is an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl or hydroxy.
72. The compound of any one of Claims 54-67, wherein R2B L is hydrogen, and RL B and R2 are joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl.
73. The compound of any one of Claims 54-67, wherein R2'1 and R2'1' are both an optionally substituted C 1-4 alkyl. Claim 1 , wherein L is Formula (Ic)
Figure imgf000506_0001
75. The compound of Claim 74, wherein 0 is hydrogen.
76. The compound of Claim 74, wherein Rl c is an unsubstituted C| _ alkyl.
77. The compound of any one of Claims 74-76, wherein R2° and R2 are both hydrogen.
78. The compound of any one of Claims 74-76, wherein R2t is hydrogen and R2 is an optionally substituted C alkyl.
79. The compound of any one of Claims 74-76. wherein R2c is hydrogen and R2 is an optionally substituted aryl(C]_(, alkyl) or an optionally substituted heterocyclyl(Ci_(, alkyl).
80. The compound of any one of Claims 74-76, wherein R2t is hydrogen and R2 I is an alkoxyalkyl. an aminoalkyl, a hydroxyalkyl or hydroxy.
81. The compound of any one of Claims 74-76, wherein R c and R ci are both an optionally substituted C 1 -4 alkyl.
82. The compound of any one of Claims 74-81, wherein R3 is hydrogen, and R'ic l is selected from the group consisting of amino, an unsubstituted C 1 -4 alkyl, an unsubstituted C?-4 alkenyl, an unsubstituted C?-4 alkynyl, an unsubstituted ¾-6 cycloalkyl. an unsubstituted C alkoxy. hydroxy, halogen and an unsubstituted heteroaryl.
83. The compound of any one of Claims 74-81 , wherein RJ is hydrogen, and R3 is hydroxy.
84. The compound of any one of Claims 74-81 , wherein RJC is hydroxy , and R ' is selected from the group consisting of amino, an unsubstituted C M alkyl, an unsubstituted C2-4 alkenyl. an unsubstituted C2-4 alkynyl. an unsubstituted C3- cycloalkyl, an unsubstituted C M alkoxy, hydroxy, halogen and an unsubstituted heteroaryl.
85. The compound of any one of Claims 74-81. wherein R 'c is hydroxy, and R 1L | is an unsubstituted C M alkyl.
86. The compound of any one of Claims 74-81 , wherein RIC and RJC L are both halogen.
87. The compound of any one of Claims 74-81. wherein RJC is hydrogen, and R ' is unsubstituted C|-4 alkyl.
88. The compound of any one of Claims 74-81 , wherein RJC and RJCL together form N=ORC.
89. The compound of any one of Claims 74-81. wherein RJT and RJT I join together with the atom to which they are attached to form an optionally substituted 3 to 6 membered ring.
90. The compound of any one of Claims 74-89, wherein ZL is N.
91. The compound of any one of Claims 74-89, wherein Zc is CH.
92. The compound of any one of Claims 74-91, wherein R4C and R^ are taken together to form an unsubstituted aryl or an unsubstituted heteroarvl.
93. The compound of any one of Claims 74-91 , wherein R4l and R^ are taken together to form an optionally substituted heterocyclyl.
94. aim 93, wherein the optionally substituted heterocyclyl is
an optionally
Figure imgf000507_0001
wherein * each indicate a point of attachment to the piperdinyl ring.
95. The compound of Claim 1, wherein L is Formula (Id):
Figure imgf000507_0002
96. The compound of Claim 95, wherein md is 0 or 1.
97. The compound of Claim 95. wherein ring Bd is an optionally substituted C5 cycloalkyl.
98. The compound of any one of Claims 95-97, wherein RL D is hydrogen.
99. The compound of any one of Claims 95-97, wherein Rl d is unsubstituted C M alkyl.
100. The compound of any one of Claims 95-99. wherein R2D and R2T" are both hydrogen.
101. The compound of any one of Claims 95-99, wherein R2D is hydrogen and R2D L is an optionally substituted C alkyl.
102. The compound of any one of Claims 95-99, wherein R2D is hydrogen and R2D L is an optionally substituted aryl(Ci.f, alkyl) or an optionally substituted heterocyclyl(Ci-6 alkyl).
103. The compound of any one of Claims 95-99. wherein R2D is hydrogen and R2D L is an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl or hydroxy.
104. The compound of any one of Claims 95-99. wrherein R2C and R2C L are both an optionally substituted C 1-4 alkyl.
105. The compound of any one of Claims 1 -104, wherein A is an optionally substituted aryl.
106. The compound of Claim 105, wherein A is an optionally substituted phenyl.
107. The compound of Claim 106, wherein A is a phenyl substituted with one or more substituents selected from the group consisting of: an unsubstituted C M alkyl, an optionally substituted C alkyl, cycloalkyl, hydroxy, an optionally substituted C alkoxy. C alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, mono- substituted amino, di-substituted amine, -O-amido, sulfenyl, alkyoxyalkyl, an optionally substituted aryl. an optionally substituted mono-cyclic heteroaryl, an optionally substituted mono-cyclic heterocyclyl, an optionally substituted aryl(C i_4 alkyl), an optionally substituted monocyclic heteroaryl(C alkyl), an optionally substituted monocyclic heterocyclyl(C alkyl), hydroxyalkyl and aminoalkyl.
108. The compound of Claim 106, wherein A is a phenyl substituted with one or more substituents selected from the group consisting of: methyl, ethyl, propyl, butyl, hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy. iso-butoxy, t-butoxy. phenoxy, bromo, chioro, fluoro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, N,N-di- methyl-amine, N,N-di-ethyl-amine, N-methyl-N-ethyl-amine, N-methyl-amino, N-ethyl- amino, amino, N-amido , N-sulfonamido, alkylthio, an optionally substituted phenyl, an optionally substituted imidazole, an optionally substituted morpholinyl, an optionally substituted pyrazole, an optionally substituted pyrrolidinyl, an optionally substituted pyridinyl. an optionally substituted piperidinyl. an optionally substituted piperidinone, an optionally substituted pyrrolidinone. an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted 1.2,4-oxadiazole, -(CH2) -OH, -(0¾)Ι -2- NH(CH3), an optionally substituted -(CH2)i-2-imidazole. an optionally substituted -(0¾)ι-2- pyrrolidinone, an optionally substituted -(CH2)i-2-imidazolidinone, -0(CH2)2-NH2, - 0(CH2)2-NH(CHj), -0(CH2)2-N(CHj)2. -0-(CH2)2^OH. -0(CH2)2OCHj, an optionally substituted -0(CH2)o-2-cyclopentanone, an optionally substituted -0(CH.2)o-2pyrrolidinone, an optionally substituted -0(CH2)o-2-morpholinyl, an optionally substituted -0(CH2)o-2-triazole, an optionally substituted -0(CH2)o-2-imidazole, an optionally substituted -0(CH.2)o-2- pyrazole, an optionally substituted -0(CH2)o-2-tetrahydrofuran, an optionally substituted - -pyrrolidinone, an optionally substituted -0(CH2)o-2-letrazole, an optionally
Figure imgf000509_0001
Figure imgf000510_0001
109. The compound of any one of Claims 106- 108, wherein A is a di-suhstituted phenyl.
1 10. The compound of any one of Claims 1 -104, wherein A is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
1 1 1. The compound of any one of Claims 1 -104, wherein A is an optionally substituted aryl(Ci_2 alkyl).
1 12. The compound of any one of Claims 1 -104, wherein A is an optionally substituted heteroaryl.
1 13. The compound of Claim 112, wherein the optionally substituted heteroaryl is selected from the group consisting of: an optionally substituted imidazole, an optionally substituted thiazoie, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted pyridine, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted quinolone, an optionally substituted imidazole, an optionally substituted oxazole, an optionally substituted isoxazole, an optionally substituted benzoimidazole. an optionally substituted benzooxazole, an optionally substituted benzothiazole and an optionally substituted imidazo[l ,2- a]pyrimidine.
1 14. The compound of any one of Claims 1 -104, wherein A is an optionally substituted heterocyclyl.
1 15. The compound of Claim 1 14, wherein the optionally substituted heterocyclyl
is selected from the group consisting of: an optionally substituted
Figure imgf000510_0002
, an
Figure imgf000511_0001
1 16. The compound of any one of Claims 1 -73 or 95-1 15, wherein Y is an optionally substituted aryl.
1 17. The compound of Claim 1 16. wherein Y is a mono-substituted phenyl.
1 18. The compound of Claim 1 17, wherein Y is a di-substituted phenyl.
1 19. The compound of any one of Claims 1 -73 or 95-1 15, wherein Y is an optionally substituted mono-cyclic heteroaryl.
120. The compound of Claim 1 19, wherein the optionally substituted mono-cyclic heteroaryl is selected from the group consisting of: an optionally substituted imidazole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted pyridine, an optionally substituted pyrazole, an optionally substituted oxazole, an optionally substituted isoxazole and an optionally substituted thiazole.
121. The compound of any one of Claims 1 -73 or 95-1 15, wherein Y is an optionally substituted bi-cyclic heteroaryl.
122. The compound of Claim 121. wherein the optionally substituted bi-cyclic heteroaryl is selected from the group consisting of: an optionally substituted benzothiophene. an optionally substituted benzofuran, an optionally substituted indole, an optionally substituted quinoline. an optionally substituted isoquinoline. an optionally substituted benzooxazole, an optionally substituted benzoisoxazole, an optionally substituted benzoisothiazole, an optionally substituted benzothiazole, an optionally substituted benzoimidazolc, an optionally substituted benzotriazole, an optionally 1 H-
indazole, an optionally substituted 2H-indazole, an optionally substituted
Figure imgf000512_0001
, an
optionally
optionally
substituted
substituted
Figure imgf000512_0002
123. The compound of any one of Claims 1 -73 or 95-1 15, wherein Y is an optionally substituted heterocyclyl.
124. The compound of Claim 123, wherein the optionally substituted heterocyclyl is selected from the group consisting of: an optionally substituted pyridinone, an optionally
substituted an optionally
substituted
Figure imgf000513_0001
and an optionally substituted
125. The compound of any one of Claims 1-73 or 95-115, wherein Y is an optionally substituted cycloalkyl.
126. The compound of any one of Claims 1-73 or 95-115, wherein Y is an optionally substituted cycloalkenyl.
127. The compound of any one of Claims 1-73.93-116 or 119-126, wherein Y is unsubstituted.
128. The compound of any one of Claims 1-73 or 95-126, wherein Y is substituted with one or more RB, wherein each RB is independently selected from the group consisting of: cyano, halogen, an optionally substituted Ομ alkyl, an unsubstituted Co-4 alkenyl, an unsubstituted C2. alkynyl. an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 5 or 6 membered heterocyclyf hydroxy, Cj_4 alkoxy. alkoxyalkyl, Ci_4 haloalkyl, haloalkoxy, an unsubstituted acyl, an optionally substituted -C-carboxy. an optionally substituted -C-amido, sulfonyl, carbonyl, amino,
mono-substituted amine, di-substituted amine and
Figure imgf000513_0002
129. The compound of any one of Claims 1-73.95-115 or 128, wherein Y is an optionally substituted benzothiophene.
130. The compound of any one of Claims 1-73, 95-115 or 128, wherein Y is an optionally substituted benzofuran or an optionally substituted indole.
131. The compound of Claim 1. wherein the compound of formula (I) is selected from the group consisting of: 1, 13-1, 100, 101, 102, 103, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 116a, 116b. 117. 117a, 117b, 118, 118a, 118b, 119, 120, 120a, 120b, 121 , 122, 122a, 122b, 123, 124, 125, 126, 127, 128, 129, 131 , 132, 133. 134, 138, 139, 142, 143, 144, 145, 146, 147, 148, 151 , 152, 153, 154, 155, 158, 159, 162, 163, 164, 165, 166, 167. 168, 169. 170. 171 , 172, 173, 174. 175. 1 76. 1 77. 178, 179, 180, 181 , 182. 183. 184, 1 85. 186, 187. 188. 189, 190, 191 , 192, 1 93. 194. 195. 196, 197, 198, 199, 200, 201. 202, 203. 204, 205. 206. 207, 208, 209, 210, 21 1. 212. 213. 214, 215, 216, 218, 219, 221. 223, 224. 225, 226, 227. 228, 230, 231 , 232. 233. 234. 235, 236. 237, 238, 239, 240, 241. 242, 243. 244, 245, 246. 247, 248, 249, 250. 251. 252. 253, 254, 255, 256, 257, 258, 259. 260, 261. 262, 263. 264. 265, 266, 267, 268. 269. 270. 271, 272. 273, 274, 275, 276, 277. 278, 279. 280, 281, 282. 283, 284, 285, 286. 288. 289. 290. 291 , 292, 293, 294, 295, 296. 297, 298, 299, 300. 301, 306, 307, 308, 309, 310, 312, 313, 314. 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332. 333. 334, 335, 336, 337, 338. 339, 340. 342, 343, 344. 345. 346. 347, 348, 349, 350, 351. 352. 353. 354, 355. 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369. 370, 371 , 372, 373, 374, 375, 376, 377, 378. 379, 380, 381 , 382, 383, 384, 385, 386, 387, 388, 389, 390, 391 , 392, 393, 394, 395, 396, 397, 398, 399, 400, 402, 403, 404, 405, 406. 407, 408, 409, 410, 41 1 , 412, 413, 414, 415, 416, 417, 418, 419, 420, 421 , 422, 423, 424, 425, 426, 427, 428, 429, 430, 431 , 432. 433, 434, 435, 436, 437, 438, 439, 440, 441 , 442, 443, 444, 445, 446, 447, 448, 449. 450, 451 , 452. 453, 454, 455, 456, 457. 458. 459. 460, 461 , 462, 463, 464, 465. 466, 467. 468, 469. 470. 471 , 472, 475, 476, 477. 478. 479. 480, 481 , 482, 483, 484, 485. 486, 487, 488, 489, 490, 491. 492. 493. 494. 495. 496, 497, 498a, 498b, 498c, 498d. 499. 500, 501. 502, 503, 504. 505, 506, 507, 508. 509. 510. 51 1 , 512, 513, 514, 515, 516, 517. 51 8, 51 9. 520, 521, 522. 523, 524, 525, 526, 527. 528. 529. 530. 531 , 532, 533, 534, 535. 536, 537, 538, 539, 540, 541 , 542, 543, 544. 545, 546, 547, 548, 549, 550, 551 , 552, 553, 554, 555, 556, 557, 558, 559, 560, 561 , 562, 563, 564, 565, 567, 568, 569, 570, 571 , 572, 573, 574, 575, 576, 577, 578, 579, 580, 581 , 582, 583, 584, 585. 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601 , 602, 603, 604a, 604b, 604c, 604d, 605a, 605b, 605c, 605d, 606, 607. 608. 609, 610, 61 1 , 612, 613, 614, 615, 616, 617, 618, 619. 620, 621. 622, 623a. 623b. 624a. 624b. 625, 626. 627, 628. 629. 630, 631 , 632. 633a, 633b, 634, 635, 636, 637, 638, 639, 640. 641 , 642, 643, 644, 645, 646, 647, 648, 649, 650, 651 , 652, 653. 654, 655, 656, 657, 658, 659, 660, 661 , 662, 663. 664, 665, 666, 667, 668, 669, 670, 671 , 672, 673, 674, 675, 676, 677, 678, 680, 681 and 682, or a pharmaceutically acceptable salt of the foregoing.
132. The compound of Claim 1. wherein the compound of Formula (I) is selected from the group consisting of: 149. 150. 156. 157, 160, 217. 220, 222, 229. 287, 302, 303. 304, 305, 31 1. 401. 473 and 474, or a pharmaceutically acceptable salt of the foregoing.
133. The compound of Claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 130, 135, 140 and 141 , or a pharmaceutically acceptable salt of the foregoing.
134. The compound of Claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 104 and 161, or a pharmaceutically acceptable salt of the foregoing.
135. The compound of Claim 1. wherein the compound of Formula (I) is selected from the group consisting of: 136 and 137, or a pharmaceutically acceptable salt of the foregoing.
136. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1 - 135, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
137. Use of an effective amount of a compound of any one of Claims 1 - 135. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 136 in the preparation of a medicament for ameliorating or treating a paramyxovirus infection.
138. Use of an effective amount of a compound of any one of Claims 1 -135. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 136 in the preparation of a medicament for inhibiting replication of a paramyxovirus.
139. Use of an effective amount of a compound of any one of Claims 1-135, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 136 in the preparation of a medicament for contacting a cell infected with a paramyxovirus.
140. The use of any one of Claims 137- 139, wherein the paramyxovirus infection is a human respiratory syncytial virus infection.
141. Use of an effective amount of a compound of any one of Claims 1- 135, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 136 in the preparation of a medicament for ameliorating or treating a paramyxovirus infection in combination with one or more agents comprising administering or contacting a cell with an effective amount of the compound of any one of Claims 1 -135. or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 136.
142. The use of Claim 141. wherein the paramyxovirus infection is a human respiratory syncytial virus infection; and wherein the one or more agents is selected from the group consisting of an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, a RSV polymerase inhibitor, an 1MPDH inhibitor, an interferon and an other compound that inhibits the RSV virus, or a pharmaceutically acceptable salt of any of the foregoing.
143. The use of Claim 142, w7herein the one or more agents is selected from the group consist of RSV-IGIV. palivizumab, motavizumab, l-cyclopropyl-3-[[l -(4- hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771). 4,4"- bis- { 4,6-bis- [3 -(bis-carbamoylmethyl-sulfamoyl )-phenylamino] -( 1 ,3 ,5 )triazin-2-ylamino } - biphenyl-2,2"-disulfonic-acid (RFI-641 ), 4,4'-Bis[4,6-di[3-aminophenyl-N,N-bis(2- carbamoylethyl)-SLilfonilimino]- l ,3,5-triazine-2-ylamino]-biphenyl-2,2'-disulfonic acid, disodium salt (CL387626), 2-[[2-[[l -(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-l 11- bcnzimidazol- 1 -yl]-6-methyl-3-pyridinol (JNJ-2408068), 2-[[6-[[[2-(3-Hydroxypropyl)-5- methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol- l - yl]methyl]-6-methylpyridin-3-ol (TMC-353121 ), 5,5'-bis[l -(((5-amino-l H- tetrazolyl)imino)methyl)]2,2',4"-methylidynetrisphenol (VP-14637. MDT-637), N-(2- hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[l ,2.4]triazolo[3.4-a]phth ilcizin-3- yl)benzenesulfonamide (PI 3), 2-((2-((l-(2-aminoethy[)piperidin-4-yl)amino)-4-methyl-lH- benzo[d]imidazol- 1 -yl)methyl)-6-methylpyridm-3-ol (Rl 70591 ), 1 ,4-bis(3-methylpyridin-4- yl)-l,4-diazepane (C I 5), (R)-9b-(4-chlorophenyl)-l-(4-fluoi benzoyl)-2,3-dihydro-lH- imidazo[l',2,: l ,2]pyrrolo[3,4-c]pyridin-5(9bH)-one (BTA9981), [2,2-bis(docosyloxy- oxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-0-(sodium-oxysulfonyl)-D- glycero-D-galacto-2-nonulopyranosid]onate (MBX-300), BTA-C286, N-(2-((S)-2-(5-((S)-3- aminopyrrolidin- 1 -yl)-6-methylpyrazolo [ 1 ,5 -a]pyrimidin-2-yl)piperidine- 1 -carbonyI)-4- chloiOphenvl)methanesulfonamide (GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor (such as a peptide having the sequence DEFDASISQVNEKINQSLAFIRKSDELL (T-67), a peptide having the sequence FDASISQVNE INQSLAFIR SDELLHNVNAGKST (T- l 18), (S)- l -(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro- l H-bcnzo[e][l ,4]diazepin-3- yl)urea (RSV-604), STP-92. iKT-041 , 6-{4-[(biphenyl-2-ylcarbonyl) amino] benzoyl }-N- cyclopropyl-5.6-dihydro-4H-thieno[3.2-d][l ]benzazepine-2-carboxaniide (YM-53403). N- cyclopropyl-5-(4-(2-(pyrrolidin-l -yl)benzaniido)benzoyl)-5,6.7, 10- tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide. 6-(4-(2-(2-oxa-7- azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5.6-dihydro-4H- benzo[b]thieno[2,3-d]azepine-2-carboxamide, 4-amino-8-(3-{ [2-(3,4- dimethoxyphenyl)ethyl] amino } propyl)-6,6-dimethyl-2-(4-metliyl-3 -nitrophenyl)- 1 H- imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione. AZ27, ribavirin. 5-ethynyl-l-beta-D- ribofuranosylimidazole-4-carboxamide (EICAR), 4-hydroxy-3-beta-D-ribofuranosylpyrazole- 5-carboxamide (pyrazofurin). 1 -((2R.3R.4S,5R)-3.4-dihydroxy-5-
(hydroxymethyl)tetrahydrofuran-2-yl)- 1 H- 1 ,2,4-triazole-3 -carboximidamide (Taribavirin, viramidine), l,3,4-thiadiazol-2-ylcyanamide (LY253963), tetrahydrofuran-3-yl-3-(3-(3- methoxy-4-(oxazol-5-yl)phenyl ureido)benzylcarbamate (VX-497), (4E)-6-(4-Hydroxy-6- methoxy-7-methyl-3-oxo-l ,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid), 2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo- lH-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil), a Type 1 interferon, a Type 2 interferon, a Type 3 interferon, a double stranded RNA oligonucleotide. 5-methyl- N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide (leflumomide), N-(2-chloro-4- methy1phenyl)-2-((l -(4-methoxypheny )-l H-benzo[d]imidazol-2-yl)thio)propanamide (JMN3-003), an intratracheal formulation of recombinant human CCI O (CG-100). high titer, human immunoglobulin (RI-001 ). a non-neutralizing mAb against the G protein (mAb 131- 2G), ATN-RSV01, ATN-RSV02, Medi-559, Medi-534 and Medi-557, or a pharmaceutically acceptable salt of the foregoing.
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