WO2019209948A1 - Compounds and uses thereof - Google Patents

Compounds and uses thereof Download PDF

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Publication number
WO2019209948A1
WO2019209948A1 PCT/US2019/028910 US2019028910W WO2019209948A1 WO 2019209948 A1 WO2019209948 A1 WO 2019209948A1 US 2019028910 W US2019028910 W US 2019028910W WO 2019209948 A1 WO2019209948 A1 WO 2019209948A1
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WIPO (PCT)
Prior art keywords
mmol
mixture
oxadiazol
piperidine
give
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PCT/US2019/028910
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French (fr)
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WO2019209948A9 (en
WO2019209948A8 (en
Inventor
Matthew Lucas
Bertrand Le Bourdonnec
Iwona WRONA
Bhaumik PANDYA
Parcharee Tivitmahaisoon
Kerem OZBOYA
Benjamin Vincent
Daniel TARDIFF
Jeff Piotrowski
Eric SOLIS
Robert Scannevin
Chee-Yeun Chung
Rebecca Aron
Kenneth Rhodes
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Yumanity Therapeutics, Inc.
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Publication of WO2019209948A1 publication Critical patent/WO2019209948A1/en
Publication of WO2019209948A8 publication Critical patent/WO2019209948A8/en
Publication of WO2019209948A9 publication Critical patent/WO2019209948A9/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep

Definitions

  • This disclosure provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:
  • B is absent or has the structure:
  • Het is -C(0)NH- or an optionally substituted C2-C9 heteroaryl
  • n 0 or 1 ;
  • n 0, 1 , or 2;
  • o is O, 1 , 2, 3, 4, 5, 6, 7, or 8;
  • p, p’, r, and r’ are, independently, 0 or 1 ;
  • X 1 and X 2 are each, independently, N or CR 6 ;
  • L 1 is -0-, -SO2-, NR 2 , optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkenylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, an optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heterocycle;
  • L 2 is absent, -0-, -SO2-, NR 2 , or -CR 2 R 3 -;
  • R 1 is hydrogen, amino, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkyl C1 -C6 alkyl, optionally substituted C2- C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heterocycle C1 -C6 alkyl;
  • R 2 and R 3 are each, independently, hydrogen, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, or combine with the carbon to which they are attached to form a carbonyl or an optionally substituted C3-C7 cycloalkyl;
  • each R 4 is, independently, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, or two R 4 combine with the carbon two which they are attached to form a carbonyl or optionally substituted C3-C7 cycloalkyl;
  • R 5 is optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocycle, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle C1 -C6 alkyl, or optionally substituted C2-C9 heteroaryl C1 -C6 alkyl; and
  • each R 6 is, independently, hydrogen, halogen, hydroxy, optionally substituted C1 -C6 heteroalkyl, or optionally substituted C1 -C6 alkyl.
  • B is absent.
  • B has the structure of Formula lb:
  • X 1 is N and X 2 is CR 6 .
  • o is 0, 1 , or 2.
  • R 4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R 4 combine with the carbon two which they are attached to form a carbonyl.
  • R 6 is hydrogen.
  • R 6 is halogen (e.g., fluoro).
  • R 6 is optionally substituted C1-C6 alkyl (e.g., methyl).
  • the dashed line represents a double bond. In some embodiments, both dashed lines represent a single bond.
  • p is 1 and r is 1 .
  • p is 1 and r is 0.
  • p is 0 and r is 0. In some embodiments,
  • B has the structure:
  • X 1 is CR 6 and X 2 is N.
  • o is 0, 1 , or 2.
  • R 4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R 4 combine with the carbon two which they are attached to form a carbonyl.
  • R 6 is hydrogen.
  • R 6 is halogen (e.g., fluoro).
  • R 6 is optionally substituted C1-C6 alkyl (e.g., methyl).
  • the dashed line represents a double bond.
  • the dashed line represents a single bond.
  • p is 1 and r is 1 .
  • p is 1 and r is 0.
  • p is 0 and r is 0.
  • B has the structure:
  • X 1 is N and X 2 is N.
  • o is 0, 1 , or 2.
  • R 4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R 4 combine with the carbon two which they are attached to form a carbonyl.
  • the dashed line represents a double bond. In some embodiments, the dashed line represents a single bond.
  • p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, p is 1 and r is 2.
  • B has the structure:
  • o is 0, 1 , or 2.
  • R 4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R 4 combine with the carbon two which they are attached to form a carbonyl.
  • the dashed line represents a double bond. In some embodiments, the dashed line represents a single bond.
  • p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0.
  • B has the structure:
  • B has the structure of Formula lc:
  • X 1 is N and X 2 is N. In some embodiments, o is 0. In some
  • p, p’, r, and r’ are 0. In some embodiments, p and r are each 1 and p’ and r’ are 0. In some embodiments, B has the structure:
  • B has the structure of Formula Id: In some embodiments, X 1 is N and X 2 is N. In some embodiments, o is 0. In some embodiments, B has the structure:
  • B has the structure of Formula le:
  • X 1 is N and X 2 is N. In some embodiments, o is 0. In some
  • B has the structure:
  • B has the structure of Formula If:
  • Het is -C(0)NH- or:
  • X 3 is O or S.
  • L 2 is absent. In some embodiments, L 2 is -NR 2 - (e.g., -NH-). In some embodiments, L 2 is -0-. In some embodiments, L 2 is -SO2-. In some embodiments, L 2 is -CR 2 R 3 -. In some embodiments, R 2 and R 3 combine with the carbon to which they are attached to form a carbonyl. In some embodiments, R 2 and R 3 combine with the carbon to which they are attached to form an optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 2 and R 3 are both hydrogen. In some embodiments, R 2 is hydrogen and R 3 is optionally substituted C1 -C6 alkylene (e.g., methylene).
  • C1 -C6 alkylene e.g., methylene
  • n is 0. In some embodiments, n is 1 .
  • L 1 is -NR 2 - (e.g., -NH- or -N(Et)-). In some embodiments, L 1 is -0-. In some embodiments, L 1 is -SO2-. In some embodiments, L 1 is optionally substituted C1-C6 alkylene (e.g., methylene or hydroxy-methylene). In some embodiments, L 1 is optionally substituted C1-C6 heteroalkylene (e.g., -NH-CH2-, -O-CH2-, -O-CH2- some embodiments, L 1
  • R 1 is cyano, optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, pentafluoro-ethyl, 2-chloro-ethyl, 1 -chloro-3-hydroxy- isopropyl, 2-methoxy-ethyl, or hexafluoro-isopropyl).
  • C1-C6 alkyl e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, pentafluoro-ethyl, 2-chloro-ethyl, 1 -chloro-3-hydroxy- isopropyl, 2-methoxy-ethyl, or hexafluoro-isopropyl.
  • R 1 is optionally substituted C6-C10 aryl (e.g., phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-trifluoromethyl-phenyl, 3- trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3- isopropyl-phenyl, 4-isopropyl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-difluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 2-chloro-5-fluoro-phenyl, 2-fluoro-4-chloro-phenyl, 3-fluoro-4-chloro-phenyl, 2-bromo-4-methoxy-phenyl, 2-bromo-4
  • R 1 is optionally substituted C6-C10 aryl C1 -C6 alkyl (e.g., naphthylmethyl).
  • R 1 is optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl, cyclohexyl, 6-methoxy-cyclohexyl, 1 -cyano- cyclopropyl, bicycle[1 .1 .1 ]pentane, 1 -methyl-cyclopropyl, 1 -ethyl-cyclopropyl, 1 -fluoro-cyclopropyl, 1 - methoxy-cyclopropyl, 1 -hydroxy-cyclopropyl, 2,2-dimethyl-cyclopropyl, 2,2-difluoro-cyclopropyl,
  • R 1 is optionally substituted C3-C7 cycloalkyl C1 -C6 alkyl (cyclopropylmethyl). In some embodiments, R 1 is optionally substituted C2-C9 heteroaryl
  • R 1 is optionally substituted C2-C9 heterocycle C1-C6 alkyl (e.g.,
  • R 5 is optionally substituted C6-C10 aryl (e.g., phenyl, 3,4-dimethoxy- phenyl, 3-methoxy-4-ethoxy-phenyl, 3,5-dimethoxy-phenyl, 3-methoxy-4-cyclopropoxy-phenyl, 3-
  • C6-C10 aryl e.g., phenyl, 3,4-dimethoxy- phenyl, 3-methoxy-4-ethoxy-phenyl, 3,5-dimethoxy-phenyl, 3-methoxy-4-cyclopropoxy-phenyl, 3-
  • R 5 is optionally substituted C2-C9 heteroaryl
  • R 5 is an optionally substituted indazole. In some embodiments, R 5 is optionally substituted
  • C2-C9 heterocycle e.g., a nitrogen containing heterocycle such as
  • R 5 is a bicyclic heterocyle.
  • a bicyclic heterocycle such as an indazole.
  • R 5 is an indazole having the structure:
  • R 5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R 5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl).
  • B has the sturucture:
  • R 1 is optionally substituted C1 -C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl), optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl.
  • C1 -C6 alkyl e.g., methyl, ethyl, iso-propyl, or tert-butyl
  • C6-C10 aryl optionally substituted C2-C9 heteroaryl.
  • n is 1
  • n is 1
  • L 2 is 0, and L 2 is -C(O)-. In some embodiments, , and L 2 is -C(O)-. In some embodiments,
  • R 5 is an indazole having the structure:
  • R 5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R 5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl);
  • B has the sturucture:
  • R 1 is optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl), optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl; and
  • n is 1
  • L 1 is -O-
  • L 2 is -C(O)-
  • R 1 is optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl).
  • optionally substituted C6-C10 aryl In some embodiments, optionally substituted C6-C10 aryl.
  • -C(O)-, and R 1 is optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl.
  • m is 1
  • n is 1
  • L 1 is 1
  • L 2 is -C(O)-
  • R 1 is optionally substituted C6-C10 aryl.
  • the compound has the structure of Formula Ig:
  • Het is an optionally substituted oxadiazole
  • o is O, 1 , 2, 3, 4, 5, 6, 7, or 8;
  • X 2 is N or CR 6 ;
  • R 1 is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkyl C1 -C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heterocycle C1 -C6 alkyl;
  • each R 4 is, independently, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, or two R 4 combine with the carbon two which they are attached to form a carbonyl or optionally substituted C3-C7 cycloalkyl;
  • R 5 is optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocycle, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heterocycle C1-C6 alkyl, or optionally substituted C2-C9 heteroaryl C1-C6 alkyl; and
  • each R 6 is, independently, hydrogen, halogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted C1-C6 alkyl.
  • Het is V
  • X 2 is N or CH. In some embodiments, X 2 is N. In some embodiments, X 2 is CH.
  • R 1 is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, or optionally substituted C6-C10 aryl.
  • R 5 is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl (e.g., bicyclic heteroaryl such as an indazole). In some embodiments, R 5 has the structure:
  • R 5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R 5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl).
  • R 5a is hydrogen.
  • R 5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl).
  • C1 -C6 alkyl e.g., methyl or iso-propyl
  • C2-C9 heterocyclyl e.g., oxetane
  • C3-C7 cycloalkyl e.g., cyclopropyl
  • Het is an optionally substituted optionally substituted C2-C9 heteroaryl
  • n 0 or 1 ;
  • n 0, 1 , or 2;
  • o is O, 1 , 2, 3, 4, 5, 6, 7, or 8;
  • X 1 and X 2 are each, independently, N or CR 6 ;
  • L 1 is optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkenylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocycle;
  • R 1 is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocycle;
  • R 2 and R 3 are each, independently, hydrogen, optionally substituted C1-C6 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
  • each R 4 is, independently, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or two R 4 combine with the carbon two which they are attached to form a carbonyl;
  • R 5 is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl
  • each R 6 is, independently, hydrogen or optionally substituted C1 -C6 alkyl.
  • R 2 and R 3 combine with the carbon to which they are attached to form a carbonyl. In some embodiments of any of the foregoing compounds, R 2 and R 3 are both hydrogen.
  • Het is:
  • X 3 is O or S.
  • the compound has the structure of Formula II or I la:
  • X 3 is O. In some embodiments of any of the foregoing compounds, X 3 is S.
  • X 1 is N and X 2 is CR 6 . In some embodiments of any of the foregoing compounds, X 1 is N and X 2 is N. In some embodiments of any of the foregoing compounds, X 1 is CR 6 and X 2 is N. In some embodiments of any of the foregoing compounds, R 6 is hydrogen.
  • R 5 is optionally substituted C6-C10 aryl.
  • R 5 is a C6-C10 aryl substituted with 1 , 2, 3, or 4 substituents independently selected from C1-C6 alkyl (e.g., methyl), halogen (e.g., fluoro, chloro, or bromo), C1-C6 alkoxy (e.g., methoxy or ethoxy), nitrile, or two substituents combine to form a 5 or 6-membered heterocycle (e.g., 2,2-difluoro-1 ,3-benzodioxole).
  • R 5 is phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, 2- methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxy-phenyl, 2-fluoro-phenyl, 3- fluoro - phenyl, 4- fluoro -phenyl, 3,4-di fluoro -phenyl, 3,4-dichloro-phenyl, 3-methoxy-4-ethoxy-phenyl, 3-chloro- 4-ethoxy-phenyl, 3-fluoro-4-ethoxy-phenyl, 3-bromo-4-ethoxy-phenyl, 3-cyano-4-ethoxy-phenyl, or 2,2- difluoro-1 ,3-benzodioxole.
  • the compound has the structure of Formula III or Ilia:
  • p is 1 , 2, 3, 4, or 5;
  • each R 7 is, independently, halogen, nitrile, OR 8 , or optionally substituted C1-C6 alkyl ; and each R 8 is, independently, hydrogen or optionally substituted C1-C6 alkyl.
  • the compound has the structure of Formula IV or IVa:
  • each R 7 is OR 8 .
  • each R 8 is optionally substituted Ci-C 6 alkyl (e.g., methyl or ethyl).
  • R 5 is optionally substituted C2-C9 heteroaryl (e.g., bicyclic heteroaryl). In some embodiments of any of the foregoing compounds, R 5 is:
  • R 5 is:
  • R 1 is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl.
  • R 1 is optionally substituted C6-C10 aryl.
  • R 1 is 2-methoxy-phenyl, 3-methoxy-phenyl, 4- methoxy-phenyl, 3,4-dimethoxy-phenyl, phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-methyl-phenyl, 4- iso-propyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, or 4-chloro-phenyl.
  • R 1 is a bicyclic C6-C10 aryl (e.g., naphthalene).
  • R 1 is C3-C7 cycloalkyl (e.g., cyclohexyl). In some embodiments of any of the foregoing compounds, R 1 is optionally substituted C2-C9 heteroaryl or optionally substituted C2-C9 heterocycle. For example, in some embodiments, R 1 is:
  • the compound has the structure of Formula V or Va:
  • q is 1 , 2, 3, 4, or 5;
  • Ft 9 is halogen or optionally substituted C1-C6 alkyl.
  • the compound has the structure of
  • n is 1 . In some embodiments of any of the foregoing compounds, n is 0.
  • L 1 is optionally substituted C1-C6 alkyl.
  • L 1 has the structure:
  • L 1 is optionally substituted C1-C6 alkenylene (e.g., ethenylene).
  • L 1 is optionally substituted C2-C9 heterocyclene or optionally substituted C2-C9 heteroarylene.
  • L 1 is optionally substituted C1-C6 heteroalkylene.
  • L 1 is:
  • L 1 is -NH-(CR 10 R 11 )r, wherein r is 1 , 2, 3, 4, 5, or 6, and each R 10 and R 11 is, independently, hydrogen or optionally substituted C1-C6 alkyl.
  • L 1 is -NH-CH2-, -NH-CR 10 R 11 -, wherein each of R 10 and R 11 is methyl, or -NH-CHR 11 -, wherein R 11 is methyl.
  • n is 1. In some embodiments of any of the foregoing compounds, m is 0.
  • the disclosure provides a compound, or pharmaceutically acceptable salt thereof, having the structure of any one of compounds 1-1195 in Table 1 , Table 2A, and Table 2B.
  • the compound is any one of compounds 1 -264, 266-271 , 274-276, 278-299, 302- SI 8, 320-329, 331-340, 344-354, 358, 362-364, 367, 369, 371-378, 385, 388-392, 396, 397, 399-401,
  • the compound is any one of compounds 1 -347, 349, 350, or 354-746 in Table 1.
  • the compound is any one of compounds 1-387, 389, 393-405, 407-430, 432-439, 441-449, 452, 454-457, 459-472, 475, 477- 480, 482-487, or 489-746 in Table 1 , In some embodiments, the compound is any one of compounds 1 - 483 or 491 -746 in Table 1. In some embodiments, the compound is any one of compounds 747-966.
  • the compound is any one of compounds 27, 40, 96, 128, 140, 168, 184, 204, 226, 244, 265, 268, 269, 284, 286291 , 294, 302, 305, 306, 308, 317, 319, 343, 344, 345, 346, 349, 355-357, or 359-364. In some embodiments, the compound is any one of compounds 244, 265, 269, 319, 345, 349, 355-357, 361 , or 364.
  • the compound is any one of compounds 750, 767, 775-778, 780, 784, 785, 789-792, 795, 799, 812, 813, 817, 828, 838, 839, 842-844, 846, 848, 850, 851, 853, 854, 861, 862, 865, 874-881 , 884-888, 890-898, 902, 903, 907, 910, 916, 928, 932, 934, 953, 957, 960, 964, or 965.
  • the compound is any one of compounds 967-1195.
  • the compound is any one of compounds 970, 971 , 974, 975, 979-982, 986, 988, 990, 992, 997, 999, 1000, 1003-1006, 1010, 1012, 1013, 1015-1026, 1028, 1029, 1031 , 1034-1037, 1039-1050, 1052-1062, 1065-1073, 1075-1080, 1082-1087, 1090, 1092, 1093, 1096-1098, 1100, 1104, 1105, 1107, 1109-1114, 1125, 1131, 1134-1141, 1144, 1146, 1149, 1151-1154, 1156, 1161, 1162, 1164, 1170, 1171,
  • the compound is any one of compounds 970, 971 , 974, 975, 979, 981, 982, 986, 988, 990, 992, 997, 999, 1005, 1012, 1016-1020, 1022, 1024, 1025, 1028, 1029, 1036, 1039, 1041-1043, 1046-1050, 1053-1062, 1065-1073, 1075, 1078, 1082-1084, 1086, 1087, 1092, 1093, 1096-1098, 1104, 1107, 1109-1112, 1114, 1134-1137, 1139, 1140, 1144, 1149, 1152, 1154,
  • the compound is any one of compounds 970, 971 , 974, 975, 986, 988, 990, 997, 999, 1005, 1012, 1016-1019, 1022, 1024, 1025, 1028, 1029, 1036, 1039, 1041, 1043, 1046-1050, 1053-1059, 1061, 1062, 1065-1073, 1075, 1078, 1083, 1084, 1086, 1087, 1092, 1093, 1096, 1097, 1104, 1107, 1109, 1110, 1134, 1136, 1137, 1139, 1140,
  • the compound is any one of compounds 970, 1053-1056, 1058, 1059, 1065-1069, 1071 -1073, 1093, or 1096. Table 1 . Compounds of the Invention
  • the disclosure provides pharmaceutical composition comprising any of the foregoing compounds, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a neurological disorder in a subject in need thereof, the method comprising administering an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions.
  • the disclosure provides a method of inhibiting toxicity in a cell (e.g., a mammalian neural cell) related to a protein (e.g., toxicity related to protein misfolding and/or aggregation such as protein aggregation related to misfolding of proteins such as a-synuclein or ApoE4), the method comprising administering, or contacting the cell with, an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof.
  • the toxicity is a- synuclein-related toxicity.
  • the toxicity is ApoE4-related toxicity.
  • Non-limiting exemplary neurological disorders include, but are not limited to Alexander disease, Alper' s disease, AD, amyotrophic lateral sclerosis, ataxia telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado-Joseph disease, multiple sclerosis, PD, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Ref sum's disease, Sandhoff disease, Schilder' s disease, Steele-Richardson-Olszewski disease, tabes dorsalis, frontal temporal dementia, vascular dementia, Down’s syndrome, and Guillain-Barre Syndrome.
  • Alexander disease Alper' s disease
  • AD amyotrophic lateral sclerosis
  • ataxia telangiectasia Canavan disease
  • the disclosure provides a method of treating a stearoyl-CoA desaturase (SCD)- associated disorder in a subject in need thereof, the method comprising administering, or contacting the cell with, an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof.
  • SCD stearoyl-CoA desaturase
  • Non-limiting exemplary SCD-associated disorders include, but are not limited to metabolic disorders (e.g., diabetes (e.g., Type I diabetes and Type II diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hypertension), cancer, cardiovascular diseases, cerebrovascular diseases, kidney diseases, liver diseases, skin disorders (e.g., acne (e.g., acne vulgaris)), central nervous system (CNS) disorders, dementia, multiple sclerosis, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, and dementia associated with Down Syndrome.
  • metabolic disorders e.g., diabetes (e.g., Type I diabetes and Type II diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hypertension
  • metabolic disorders e.g., diabetes (e.g
  • acyl represents a hydrogen or an alkyl group, as defined herein, that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl.
  • exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 1 1 1 , or from 1 to 21 carbons.
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms).
  • An alkylene is a divalent alkyl group.
  • alkenyl refers to a straight- chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • alkynyl refers to a straight- chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • amino represents -N(R N1 )2, wherein each R N1 is, independently, H, OH, NO2, N(R N2 )2, S020R N2 , S02R N2 , SOR N2 , an /V-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited R N1 groups can be optionally substituted; or two R N1 combine to form an alkylene or heteroalkylene, and wherein each R N2 is, independently, H, alkyl, or aryl.
  • the amino groups of the invention can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2).
  • aryl refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring.
  • groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1 H-indenyl.
  • arylalkyl represents an alkyl group substituted with an aryl group.
  • exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -6 alkyl Ce-io aryl, C1 -10 alkyl Ce-io aryl, or C1 -20 alkyl Ce-io aryl), such as, benzyl and phenethyl.
  • the akyl and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • azido represents a -IM3 group.
  • cyano represents a -CN group.
  • Carbocyclyl refers to a non-aromatic C3-12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms.
  • Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.
  • cycloalkyl refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.
  • halogen means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heteroalkyl groups are an“alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy).
  • a heteroalkylene is a divalent heteroalkyl group.
  • heteroalkenyl refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups.
  • heteroalkenyl groups are an“alkenoxy” which, as used herein, refers alkenyl-O-.
  • a heteroalkenylene is a divalent heteroalkenyl group.
  • heteroalkynyl refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups.
  • heteroalkynyl groups are an“alkynoxy” which, as used herein, refers alkynyl-O-.
  • a heteroalkynylene is a divalent heteroalkynyl group.
  • heteroaryl refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N,
  • heteroaryl group is pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.
  • heteroarylalkyl represents an alkyl group substituted with a heteroaryl group.
  • exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -6 alkyl C2-9 heteroaryl, C1 -10 alkyl C2-9 heteroaryl, or C1 -20 alkyl C2-9 heteroaryl).
  • the akyl and the heteroaryl each can be further substituted with 1 , 2,
  • heterocyclyl denotes a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing one, two, three, or four ring heteroatoms selected from N, O or S, wherein no ring is aromatic.
  • heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl.
  • heterocyclylalkyl represents an alkyl group substituted with a heterocyclyl group.
  • exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -6 alkyl C2-9 heterocyclyl, C1 -10 alkyl C2-9 heterocyclyl, or C1 -20 alkyl C2-9 heterocyclyl).
  • the akyl and the heterocyclyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • hydroxyl represents an -OH group.
  • /V-protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley &
  • /V-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p- toluenesulfonyl; carbamate forming groups such as benz
  • diisopropylmethoxycarbonyl isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl.
  • Preferred /V-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • nitro represents an -NO2 group.
  • thiol represents an -SH group.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified.
  • Substituents include, for example: aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol.
  • aryl e.g., substituted and unsubstituted phenyl
  • carbocyclyl e.g., substituted and unsubstituted cycloalkyl
  • halogen e.g., fluoro
  • hydroxyl hydroxyl
  • heteroalkyl e.g., substituted and unsubstituted
  • Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).
  • Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms.
  • Stereoisomers are compounds that differ only in their spatial arrangement.
  • Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon.
  • Racemate or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system.
  • Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • "R,” “S,” “S * ,” “R * ,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.
  • Certain of the disclosed compounds may exist in atropisomeric forms.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9%) by weight relative to the other
  • stereoisomers When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure.
  • the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure.
  • Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.
  • percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer.
  • diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers The invention embraces all of these forms.
  • pharmaceutically acceptable salt thereof is administered via any of the usual and acceptable methods known in the art, either singly or in combination.
  • compositions represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup) ; for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
  • A“pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C,
  • the term“pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of formula (I).
  • pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCFI, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • SCD-associated disorder refers to an undesired physiological condition, disorder, or disease that is associated with and/or mediated at least in part by an SCD protein.
  • SCD-associated disorders are associated with excess SCD levels and/or activity.
  • SCDs introduce a double bond in the C9-C10 position of saturated fatty acids such as palmitoyl-CoA and stearoyl-CoA which are converted to palmitoleoyl-CoA and oleoyl-CoA, respectively.
  • SCD1 One SCD gene, SCD1 , has been characterized in humans for which there are two isoforms, SCD1 and SCD5.
  • An SCD-associated disorder may be associated with and/or mediated at least in part by SCD1 and/or SCD5.
  • Exemplary SCD-associated disorders include SCD-associated disorders include, but are not limited to metabolic disorders (e.g., diabetes (e.g., Type I diabetes and Type II diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hypertension), cancer, cardiovascular diseases, cerebrovascular diseases, kidney diseases, liver diseases, skin disorders (e.g., acne (e.g., acne vulgaris)), central nervous system (CNS) disorders, dementia, multiple sclerosis, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, and dementia associated with Down Syndrome. Additional SCD-associated disorders are described herein or known in the art.
  • the term“subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • animal e.g., mammals such as mice, rats, rabbits, non-human primates, and humans.
  • a subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • FIGS. 1 A and 1 B are graphs showing that growth inhibition by 1 ,2,4-oxadiazoles occurs through same mechanism as the rescue of toxicity in the apolipoprotein E4 (ApoE4) Alzheimer’s disease yeast model.
  • Fig. 1 A Compound 7, a representative 1 ,2,4-oxadiazole, was profiled in ApoE4 (top) and control (bottom) non-inducing conditions at 12-point dose (x-axis). The Y-axis shows raw O ⁇ boo. Compound 7 exhibited a bell-shaped dose-response curve (DRC) in the ApoE4 model. Rescue decreased at concentrations just above the maximal efficacy (Emax). In the control condition (bottom panel), growth decreased at this same concentration.
  • DRC dose-response curve
  • FIG. 1 B The relationship between Emax (rescue in ApoE4) and growth inhibition (in control condition) correlated across 34 tested 1 ,2,4-oxadiazoles.
  • the maximal rescue dose (EC100) is shown on the y-axis for ApoE4 and minimal inhibitory dose (IC100) in the control condition is shown on the x-axis. This correlation indicates that growth inhibition is caused by the same on-target activity that rescues ApoE4 toxicity.
  • FIGS. 2A and 2B are graphs showing that exogenous oleic acid reverses growth inhibition and model rescue by Ole1/SCD-targeting 1 ,2,4-oxadiazoles. Growth was measured by reading O ⁇ boo in a microplate reader and normalized to solvent control DMSO samples.
  • Fig. 2A Growth inhibition (24 h) of strain GM yap1 flr1 by Ole1 /SCD-targeting 1 ,2,4-oxadiazoles is reversed by exogenous 0.5 mM oleic/palmitoleic acid, which did not affect growth inhibition by other compounds (black dots indicate other scaffolds tested). Maximal growth inhibition across a dose range from 33 nM to 33 mM is plotted.
  • FIGS. 3A and 3B are graphs showing that point mutations in yeast OLE1 confer resistance to growth inhibition and alpha-synuclein model rescue by 1 ,2,4-oxadiazoles. Growth was measured by reading O ⁇ boo in a microplate reader. (Fig.
  • Yeast cells deleted for the chromosomal copy of OLE1 and expressing OLE1 (wild-type), ole1P123T, or ole1E188Q mutants from a pRS316-based plasmid were grown in complete synthetic medium (CSM)-glucose media at the indicated doses of 1 ,2,4-oxadiazole Compound 95 for 24 h. Growth was normalized to samples treated with the solvent control dimethyl sulfoxide (DMSO), set as“1 (Fig.
  • DMSO dimethyl sulfoxide
  • Yeast cells deleted for the chromosomal copy of OLE1 and expressing OLE1 (Wild-type), ole1P123T, or ole1E188Q mutants from a pRS316-based plasmid were grown in CSM-galactose media (inducing expression of alpha-Synuclein) at the indicated doses of the 1 ,2,4-oxadiazole Compound 95 for 40 h. Growth was normalized to samples treated with the solvent control DMSO, where rescue is set as“1”.
  • FIG. 4 is a graph showing that a ole1A deletion mutant is resistant to the growth-inhibitory effects of 1 ,2,4-oxadiazoles, but not other compounds. Twenty-four hour growth (presented as raw O ⁇ boo) of the ole1A deletion strain in yeast extract-peptone-dextrose (YPD) media is shown, with drugs added at the indicated concentrations.
  • YPD yeast extract-peptone-dextrose
  • FIG. 5 is a graph showing that reducing OLE1 expression by deleting MGA2 rescues the growth of the ApoE4 yeast model.
  • Yeast cells expressing ApoE4 were deleted for the MGA2gene and their growth was assessed over time (compared to their isogenic, MGA2 wild-type counterpart). Growth was assessed by O ⁇ boo. Where indicated, 0.08 or 0.32 mM of oleic and palmitoleic acids (each) as added to the growth media in 0.01 % tween (final).
  • FIG. 6 is a series of graphs showing that commercial Scd inhibitors target human SCD1/SCD5 in yeast. Yeast surviving solely on yeast OLE1, or human SCD1 or SCD5, were treated with four commercial Scd inhibitors at indicated concentrations. Data are expressed as a percent of the DMSO- treated condition. All four compounds potently reduced growth of both SCD1 -expressing yeast and SCD5-expressing yeast, but not the strain expressing Ole1 . This growth inhibition was reversed by oleic/palmitoleic acid competition, similar to the results shown in Figs. 2A and 2B.
  • FIG. 7 is a series of graphs showing that 1 ,2,4-oxadiazoles target human SCD1 and SCD5.
  • Three“SCD” strains expressing yeast OLE1 or human SCD1 or SCD5 were treated with five
  • FIGS. 8A-8D are graphs showing that treatment of yeast cells with the 1 ,2,4-oxadiazole
  • Compound 95 inhibits lipid desaturation.
  • Exponentially-growing wild-type yeast cells were treated with the indicated doses of the 1 ,2,4-oxadiazole Compound 95 for the indicated times before cellular lysis, lipid extraction, and analysis by global LC-MS/MS profiling.
  • the relative abundance after 1 .5 h and 8 h drug treatment of the most abundant lipid with 2 or more degrees of unsaturation, phosphatidylcholine 16:1 ; 18:1 is depicted in Figs.
  • the data indicate a >300-fold increase in the abundance of the saturated lipid phosphatidylcholine 26:0 after 8 h treatment with Compound 95, and a >12-fold decrease in the abundance of the unsaturated lipid phosphatidylcholine 16:1 , 18:1 , indicating that Compound 95 blocks cellular fatty acid desaturase activity (Ole1 is the only fatty acid desaturase in yeast).
  • FIG. 9 shows OLE1 mutations conferring resistance to growth inhibition to 1 ,2,4-oxadiazoles identified by genome sequencing of resistant mutants.
  • Cells were plated on media containing 10 mM of the 1 ,2,4-oxadiazole Compound 155 and resistant colonies that emerged were isolated, and genomic DNA was prepared from mutants and the parental, drug-sensitive control strain. Genomic DNA sequence was aligned to the Saccharomyces cerevisiae reference and unique mutations in the 1 ,2,4-oxadiazole- resistant mutants were identified. The position of the mutations, the amino acid changes they encode, and the fold resistance (increase in minimal inhibitory concentration) of Compound 155 are shown.
  • the invention features compounds useful for the treatment of neurological disorders, e.g., by inhibiting a-synuclein toxicity in a cell such as a neural cell.
  • exemplary compounds described herein include compounds having a structure according to formula I or formula la:
  • the compound has the structure of any one of compounds 1 -746 in Table 1 . In some embodiments, the compound has the structure of any one of compounds 747-966 in Table 2A. In some emobdiments, the compound has the structure of any one of compounds 967-1 195 in Table 2B.
  • the compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to inhibit toxicity caused by protein aggregation, e.g., a-synuclein aggregation, in a cell.
  • Another aspect of the present invention relates to methods of treating and/or preventing a neurological disorder such as neurodegenerative diseases in a subject in need thereof.
  • a neurological disorder such as neurodegenerative diseases
  • the pathology of neurodegenerative disease may be characterized by the presence of inclusion bodies in brain tissue of affected patients.
  • neurological disorders that may be treated and/or prevented by the inventive methods include, but are not limited to, Alexander disease, Alper' s disease, AD, amyotrophic lateral sclerosis, ataxia telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado-Joseph disease, multiple sclerosis, PD, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Ref sum's disease, Sandhoff disease, Schilder' s disease, Steele- Richardson-Olszewski disease, tabes dorsalis, and Guillain-Barre Syndrome.
  • Alexander disease Alper' s disease
  • AD amyotrophic lateral sclerosis
  • ataxia telangiectasia Canavan disease
  • Cockayne syndrome corticobasal degeneration
  • SCD stearoyl-CoA desaturase
  • SCD inhibitors are known in the art to be useful in methods of treating and/or preventing SCD-associated disorders.
  • SCD-associated disorders are described, for example, in U.S. Patent No. 8,148,378, and in International Patent Application Publication Nos. WO 201 1 /047481 ,
  • Another aspect of the present invention relates to methods of treating and/or preventing an SCD-associated disorder in a subject in need thereof.
  • SCD-associated disorders include metabolic disorders (e.g., insulin resistance, diabetes mellitus (e.g., Type I diabetes, Type II diabetes, non-insulin-dependent diabetes mellitus, gestational diabetes, and diabetic complications (e.g., diabetic peripheral neuropathy, diabetic nephropathy diseases, diabetic retinopathy, diabetic macroangiopathy, vascular complications of diabetes, and diabetic arteriosclerosis)), hyperglycemia, metabolic syndrome, hyperinsulinanemia, glucose intolerance, impaired glucose tolerance, body weight disorders (e.g., obesity (e.g., abdominal obesity), overweight, cachexia, body mass index, and anorexia), lipid disorders (e.g., abnormal lipid levels (e.g., elevated lipid levels, for example, in plasma), dyslipidemia (e.g., diabetic dyslipidemia), mixed dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, atherosclerosis,
  • metabolic disorders
  • hypercholesterolemia e.g., familial hypercholesterolemia
  • low HDL high LDL
  • diseases related to accumulation of lipids in liver familial histiocytic reticulosis, lipoprotein lipase deficiency
  • polyunsaturated fatty acid (PUFA) disorder e.g.
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • microalbuminemia leptin related diseases
  • hyperleptinaemia hyperleptinaemia
  • appetite disorder essential fatty acid deficiency
  • adverse weight gain associated with a drug therapy adverse weight gain associated with a drug therapy.
  • Additional SCD-associated disorders include cancer, including solid tumors or hematological malignancies (e.g., esophageal cancer, pancreatic cancer, endometrial cancer, kidney cancer, hepatoma, thyroid cancer, gallbladder cancer, prostate cancer, leukemia (e.g., lymphomas and myelomas), ENT- related cancer, brain cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, skin cancer, and prostate cancer), neoplasia, malignancy, metastases, tumors (benign or malignant), carcinogenesis, and hepatomas.
  • cancer including solid tumors or hematological malignancies (e.g., esophageal cancer, pancreatic cancer, endometrial cancer, kidney cancer, hepatoma, thyroid cancer, gallbladder cancer, prostate cancer, leukemia (e.g., lymphomas and myelomas), ENT- related cancer, brain cancer
  • cardiovascular disease e.g., heart disease, atherosclerosis, hypertension, lipidemia, dyslipidemia, elevated blood pressure, microalbuminemia, hyperuricaemia, hypercholesterolemia, hyperlipidemias, hypertriglyceridemias, arteriosclerosis, coronary artery disease, myocardial infarction, vascular complications of diabetes, and diabetic arteriosclerosis
  • inflammation sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis
  • hepatitis e.g., sexual hepatitis
  • meibomitis cystic fibrosis
  • pre-menstrual syndrome osteoporosis
  • thrombosis cardiovascular risks, weight loss, angina, high blood pressure, ischemia, cardiac ischemia, reperfusion injury, angioplastic restenosis, infertility
  • liver disease e.g., fatty liver, cirrhosis, nonalcoholic steatohepatitis, liver fibrosis,
  • SCD-associated disorders include central nervous system (CNS) disorders, dementia, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, dementia associated with Down Syndrome, other neurodegenerative diseases, psychiatric disorders, eye diseases, immune disorders, multiple sclerosis, neuropathy, and depression.
  • CNS central nervous system
  • Additional SCD-associated disorders include skin disorders (e.g., acne (e.g., acne vulgaris), psoriasis, hirsutism, rosacea, seborrheic skin, oily skin (syn seborrhea), seborrheic dermatitis, hyperseborrhea, eczema, keloid scar, skin ageing, diseases related to production or secretions from mucous membranes, wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration, insufficient sebum secretion, oily hair, shiny skin, greasy-looking skin, greasy-looking hair, and other skin conditions caused by lipid imbalance).
  • skin disorders e.g., acne (e.g., acne vulgaris), psoriasis, hirsutism, rosacea, seborrheic skin, oily skin (syn seborrhea), seborrheic dermatitis, hyperseborrhea, e
  • An SCD-associated disorder can also include a disease or condition which is, or is related to, viral diseases or infections.
  • the SCD-associated disorder is acne (e.g., acne vulgaris).
  • the SCD-associated disorder is diabetes (e.g., type II diabetes, including diabetes with inadequate glycemic control).
  • the SCD-associated disorder is nonalcoholic fatty liver disease (NAFLD).
  • NAFLD nonalcoholic fatty liver disease
  • the SCD-associated disorder is cancer. In some embodiments, the SCD- associated disorder is obesity. In some embodiments, the SCD-associated disorder is metabolic syndrome (e.g., dyslipidemia, obesity, insulin resistance, hypertension,
  • microalbuminemia, hyperuricaemia, and hypercoagulability syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (e.g., obesity, overweight, cachexia, and anorexia), weight loss, body mass index, leptin related diseases, or a skin disorder (e.g., eczema, acne, psoriasis, and keloid scar).
  • the SCD-associated disorder is diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease.
  • the compounds of the invention can be combined with one or more therapeutic agents.
  • the therapeutic agent can be one that treats or prophylactically treats any neurological disorder described herein.
  • a compound of the invention can be used alone or in combination with other agents that treat neurological disorders or symptoms associated therewith, or in combination with other types of treatment to treat, prevent, and/or reduce the risk of any neurological disorders.
  • the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect.
  • the compounds of the invention are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.
  • the compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention.
  • the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • a compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.
  • a compound of the invention may also be administered parenterally.
  • Solutions of a compound of the invention can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003, 20 th ed.) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders.
  • Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine.
  • a carrier such as sugar, acacia, tragacanth, gelatin, and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.
  • the compounds of the invention may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
  • the dosage of the compounds of the invention, and/or compositions comprising a compound of the invention can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the invention are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form).
  • Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered. Preferred dose ranges include, for example, between 0.05-15 mg/kg or between 0.5-1 5 mg/kg.
  • the dosage amount can be calculated using the body weight of the patient.
  • the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1 -50 mg/kg (e.g., 0.25-25 mg/kg).
  • the dose may range from 0.5-5.0 mg/kg (e.g., 0.5, 1 .0, 1 .5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from 5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).
  • An appropriately substituted carboxylic acid I can be coupled with an appropriately substituted piperidine II to provide ester III. This can be hydrolysed under variety of conditions to provide carboxylic acid intermediate IV. This can be condensed with a substituted N-hydroxyimidamide V to give the desired 1 ,2,4-oxadiazole compound VI.
  • acyl halide XV (where X is a halogen atom, e.g., chlorine) can be coupled with an appropriately substituted piperidine XIII to provide the desired heterocyclic compound
  • An appropriately substituted alkyl intermediate XVI (where X is a good leaving group, e.g., a halogen atom or triflate) can undergo nucleophilic displacement with an appropriately substituted piperidine XIII to provide the desired heterocyclic compound XIV.
  • X is a good leaving group, e.g., a halogen atom or triflate
  • An appropriately substituted carboxylic acid IV can be coupled with an appropriately substituted ketone XVII (where X is a leaving group, e.g., bromine) to provide the intermediate compound XVII.
  • This compound can be condensed with ammonium acetate to provide oxazole IXX.
  • An appropriately protected and substituted thiomide XX can be coupled with an appropriately substituted ketone XVII (where X is a leaving group, most commonly bromine) to provide the protected (where PG is an amine protecting group, such as tert-butoxycarbonyl) thiazole compound XXI.
  • This compound can be deprotected under appropriate conditions to give intermediate piperidine XXII.
  • This can be coupled with and appropriately substituted carboxylic acid IV to provide thiazole XXIII.
  • An appropriately substituted carboxylic acid IV can be couple with and appropriately substituted piperidine compound XXVII to give a compound XXVIII.
  • This compound can be converted to the corresponding hydroxyimidamide compound XXIX.
  • An appropriately substituted oxadiazolone XXXII can be converted to the appropriately substituted compound XXXIII.
  • This compound can be coupled with the appropriate protected piperazine compound XXXIV (where PG is an /V-protecting group, for example, a tert-butyloxycarbonyl group) to give compound XXXV.
  • This compound can be deprotected under the appropriate conditions to give piperazine compound XXXVI.
  • This can be coupled with a carboxylic acid IV to provide 1 ,2,4-oxadiazole XXXVII.
  • the compounds of the invention can be synthesized according to the following procedures.
  • Step 2 Preparation of methyl 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylate
  • Step 4 Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-phenyl- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin-2-one
  • the mixture was purified by prep-HPLC (Waters X bridge 1 50x25 5 pm column; 36-66 % acetonitrile in a 1 0 mM ammonium acetate solution in water, 12 min gradient) to give 1 - (3,4-dimethylphenyl)-4-(4-(3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (73 mg, 164 pmol, 22 %) as a white solid.
  • Step 2 Preparation of methyl 1-(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin-2-one
  • Step 2 Preparation of 1 -(3,4-dimethylphenyl)-4-(4-(3-(m-tolyl)- 1 ,2,4-oxadiazoi-5-yi)piperidine- 1 - carbonyl)pyrrolidin-2-one
  • Step 1 Preparation of 3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile
  • N,N-dimethylformamide (10 mL) was added morpholine (136 mg, 1 .57 mmol, 138 pL), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1 .31 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (338 mg, 2.62 mmol, 457 mI_). The mixture was stirred at 20 °C for 16 h, then quenched with water (10 ml_) and extracted with ethyl acetate (20 ml_ x 4).
  • Step 3 Preparation of 3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5(4H)-one.
  • 3-(3,4-Dimethoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one 500 mg, 2.25 mmol was added to a mixture of phosphoryl chloride (13.2 g, 86.1 mmol, 8 ml_) and N,N-dimethylformamide (1 ml_).
  • the mixture was equipped with a calcium chloride tube and heated at 100 °C for 16 h, at which time the mixture was cooled and concentrated in vacuo at 45 °C.
  • Step 2 Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
  • Step 4 Preparation of (E)-N-((3-fluorophenyl)(hydroxyimino)methyl)-1-(4-isopropylbenzoyl)piperidine-4- carboxamide.
  • Step 5 Preparation of (4-(3-(3-fluorophenyl)- 1,2,4-oxadiazoi-5-yi)piperidin-1-yi)(4- isopropylphenyl)methanone.
  • reaction mixture was cooled and purified by direct injection and prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 50%-80%,12 min) to give (4-(3-(3-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)(4- isopropylphenyl)methanone (82 mg, 210 mitioI, 25 %) as a yellow oil.
  • reaction mixture was then stirred at 20 °C for 2 h, quenched by addition of water (5 mL), and extracted with ethyl acetate (20 mL x4). The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to provide a crude residue.
  • N,N- dimethylformamide (4 mL), and the resulting mixture was stirred at 120 ⁇ for 2 h, concentrated under vacuum, and purified by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-(2-oxo-2-(4-(3-phenyl-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)ethyl)benzamide (74 mg, 189 mitioI, 27 %) as a white solid.
  • Step 2 Preparation of N-(2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.
  • Step 2 Preparation of N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
  • Example 13 N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-4- methyl-benzamide.
  • Step 1 Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-4- methylbenzamide.
  • Example 14 N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3- methylbenzamide.
  • the mixture was stirred at 20 °C for 16 h.
  • the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3).
  • the combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.
  • N,N-Dimethylformamide (2 mL) was added, then the mixture was heated to 120 °C and stirred for a further 4 h.
  • the mixture was cooled to 25 °C, then water (5mL) was added, and the mixture extracted with ethyl acetate (1 0 mL x 3).
  • Step 3 Preparation of methyl 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate.
  • the mixture was treated with water (30 ml_) at 0 °C, extracted with ethyl acetate (50 ml_ x 3).
  • the combined organic phase was washed with water (20 ml_), 1 N hydrochloric acid (30 ml_), saturated aqueous sodium hydrogen carbonate solution (30 ml_), saturated aqueous sodium chloride solution (30 ml_), and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product.
  • Step 5 Preparation of N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.
  • Example 17 N-(2-(4-(3-(3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.
  • Step 1 Preparation of 4-(4-(3-(3,4-dimethoxyphenyt)- 1, 2, 4-oxadiazol-5-yl)piperidine- 1 -carbonyl)- 1- phenylpyrrolidin-2-one.
  • Example 19 4-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -(3,4- dimethylphenyl)pyrrolidin-2-one.
  • the mixture was stirred at 20 °C for 12 h.
  • the reaction mixture was diluted with water (5mL) and extracted with ethyl acetate (10 mL x 3).
  • the combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.
  • the residue was dissolved in N,N- dimethylformamide (2 mL) then heated at 120 °C for 5 h.
  • the mixture was cooled to 25 °C then diluted with water (5mL) and extracted with ethyl acetate (10 mL x 3).
  • Step 2 Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1 -carbonyl)pyrrolidin-2-one.
  • reaction mixture was cooled and purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 36%-66%,12 min) to give 1 -(3,4-dimethylphenyl)-4-(4-(3-(4- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (101 mg, 213 mitioI, 29 %) as a light yellow solid.
  • Example 21 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)pipe idine-1- carbonyl)pyrrolidin-2-one.
  • the mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h.
  • the reaction mixture was purified directly by prep-HPLC (column: Luna C8 1 00x30 5pm; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 40%-60%,12 min) to give 1 -(3,4-dimethylphenyl)-4-(4-(3-(3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (80 mg, 168 mitioI, 29 %) as a
  • Step 2 Preparation of N-(2-(4-(3-(3,4-dichlorophenyl)- 1 ,2,4-oxadiazol-5-yl)pipericlin- 1 -yl)-2- oxoethyl)benzamide.
  • Step 2 Preparation of N-(2-(4-(3-(3,4-difiuorophenyi)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
  • Step 1 Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)carbamate.
  • Step 2 Preparation of 2-amino-1-(4-(3-(3,4-dimethoxyphenyi)- 1 ,2,4-oxadiazoi-5-yi)piperidin-1 - yl)ethanone.
  • Step 3 Preparation of 2-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
  • the mixture was stirred at 20 °C for 2 h.
  • the reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,12 min) to give 3-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (126 mg, 261 mitioI, 58 %) as a white solid.
  • Step 1 Preparation of 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
  • the mixture was stirred at 20 °C for 2 h.
  • the reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (144 mg, 294 mitioI, 66 %) as a white solid.
  • Example 29 N-( 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2-methyl-1- oxopropan-2-yl)benzamide.
  • Example 31 2-(benzyloxy)-1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1- yl)ethanone.
  • Step 1 Preparation of tert-butyl (2-(4-(3J3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1- yl)ethyl)carbamate
  • Step 3 Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 - yl)ethyl)benzamide
  • Step 2 Preparation of 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-((2,2,2-trifluoro- 1 -phenylethyl)amino)ethanone
  • reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give 1 -(4-(3- (3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-((2,2,2-trifluoro-1 - phenylethyl)amino)ethanone (52 mg, 101 mitioI, 29 %) as a yellow solid.
  • Step 2 Preparation of tert-butyl 4-(3-(3,4-dimethoxyphenyl)- 1,2,4-thiadiazol-5-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate
  • Step 5 Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-thiadiazol-5-yl)piperidin- 1 -yl)-2- oxoethyl)benzamide
  • reaction mixture purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-thiadiazol- 5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (10 mg, 22 pmol, 10 %) as a yellow solid.
  • Step 4 Preparation of N-(2-(4-(5-(3,4-dimethoxyphenyi)- 1,2,4-oxadiazol-3-yl)piperidin- 1-yl)-2- oxoethyl)benzamide
  • reaction mixture was concentrated in vacuo to give crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-55%,12 min) to give N- (2-(4-(4-(3,4-dimethoxyphenyl)oxazol-2-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (55 mg, 120 mitioI, 31 %) as a pink solid.
  • Step 1 Preparation of tert-butyl 4-carbamothioylpiperidine- 1-carboxylate.
  • Step 2 Preparation of tert-butyl 4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate.
  • reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-(2-(4- (4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (1 1 1 mg, 239 mitioI, 43 %) as a yellow solid.
  • ⁇ NMR (400 MHz, CDCh) d 7.91 -7.85 (m, 2H), 7.57-7.42 (m, 5H), 7.39 (br.
  • Step 2 Methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate.
  • Step 3 N-(2-(4-(hydrazinecarbonyl)piperidin- 1-yl)-2-oxoethyl)benzamide.
  • Example 40 N-(2-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.
  • Step 1 Preparation of 1 ,3-dimethyl- 1 H-indazole-6-carbonitrile.
  • Step 2 Preparation of (Z)-N'-hydroxy- l ,3-dimethyl- 1 H-indazole-6-carboximidamide.
  • reaction mixture cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-65%,12 min) to give N-(2-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (46 mg, 101 mitioI, 25 %) as a yellow solid.
  • Step 2 Preparation of N-(2-(4-(3-(4-fluorophenyl)- 1 ,2, 4-oxadiazol-5-yl)piperidin- 1 -yl)-2- oxoethyl)benzamide.
  • Step 1 Preparation of N-(2-(4-(3-(3-fluorophenyl)- 1 ,2,4-oxadiazoi-5-yi)piperidin- 1 -yi)-2- oxoethyl)benzamide.
  • Example 43 N-(2-(4-(3-(2-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.
  • Step 1 Preparation of 1 -(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2- phenylethanone.
  • Step 2 Preparation of 2-(6-methylpyrazin-2-yl)acetic acid.
  • Step 3 Preparation of 1 -(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-(6- methylpyrazin-2-yl) ethanone.
  • the mixture was stirred at 20 °C for 4 h.
  • the reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-50%,12 min) to give 1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-(6-methylpyrazin-2- yl)ethanone (26 mg, 62 mitioI, 15 %) as a yellow solid.
  • Example 46 N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)acetamide.
  • Example 47 N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)isobutyramide.
  • Example 48 N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)cyclohexanecarboxamide.
  • Step 1 Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)cyclohexanecarboxamide.
  • reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 23%-53%,12 min) to give N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)cyclohexanecarboxamide (78 mg, 171 mitioI, 39 %) as a white solid.
  • Step 2 Preparation of N-phenethylpiperidine-4-carboxamide.
  • Step 4 Preparation of 1-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-4- carboxamide.
  • Example 50 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1- carbonyl)pyrrolidin-2-one.
  • reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow oil (1 .6 g).
  • a portion of the crude product (0.3 g) was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carbonitrile for analysis (144 mg). The remainder of the crude product was used directly without purification.
  • Step 2 Preparation of (Z)- 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hydroxypiperidine-4- carboximidamide.
  • Step 3 Preparation of 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)- 1 ,2,4-oxadiazoi-3-yi)piperidine- 1 - carbonyl)pyrrolidin-2-one.
  • reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Luna C18 100 * 30 5pm; mobile phase: [water (0.225%TFA)-acetonitrile]; B%: 45%-75%,12 min) to give the racemic of 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carbonyl)pyrrolidin-2-one (106 mg, 0.23 mmol, 28 %) as a white solid.
  • reaction mixture was cooled and concentrated in vacuo to give a crude product that was purified by prep- HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-75%,12 min) to give the racemic of 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carbonyl)pyrrolidin-2-one (156 mg, 0.34 mmol, 44 %) as a white solid.
  • Example 52 (4-(5-(3-fluorophenyl)- 1,2,4-oxadiazol-3-yl)piperidin-1-yl)(4- isopropylphenyl)methanone.
  • reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (40 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give yellow oil (1 .8 g).
  • Step 3 Preparation of (4-(5-(3-fluorophenyl)- 1 , 2, ⁇ 4-oxadiazol-3-yl)piperidin- 1-yl)(4- isopropylphenyljmethanone.
  • reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 50%-80%,12 min) to give (4-(5-(3-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)piperidin-1 -yl)(4-isopropylphenyl)methanone (76 mg, 193.5 mitioI, 28 %) as a yellow oil.
  • Example 53 (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1- yl)methanone.
  • Step 1 Preparation of 4-ethoxy-3-methoxybenzonitrile.
  • Step 3 Preparation of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carboxylate.
  • Step 5 Preparation of (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)(piperidin- 1- yl)methanone
  • reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give (4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)(piperidin-1 -yl)methanone (65 mg, 158 pmol, 24 %) as a yellow solid.
  • Example 54 (4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1- yl)methanone.
  • Step 1 Preparation of (4-(3-(3,4-dimethoxyphenyi)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)(piperidin- 1- yijmethanone.
  • reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give (4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)(piperidin-1 - yl)methanone (81 mg, 202 mitioI, 58 %) as a white solid.
  • Example 55 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2-(isoquinolin-1- ylamino)ethanone.
  • Step 1 Preparation of 1 -(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-(isoquinolin- 1 - ylamino)ethanone.
  • Step 4 Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperazin- 1-yl)-2- oxoethyl)benzamide.
  • the mixture was stirred at 20 °C for 5 h.
  • the reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-60%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperazin-1 -yl]-2-oxo-ethyl]benzamide (55 mg, 121 mitioI, 39 %) as a yellow solid.
  • Step 1 Preparation of tert-butyl 4-(piperidine- 1 -carbonyl)piperidine- 1 -carboxylate.
  • Step 4 Preparation of 5-chloro-3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazole.
  • Step 5 Preparation of (1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin- 1- yl)methanone.
  • reaction mixture was purified directly by prep-HPLC (column: Luna C8 100 * 30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give (1 - (3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1 -yl)methanone (61 mg, 147.6 mitioI, 29 %) as a yellow solid.
  • Example 58 N-(2-(4-(3-(2-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.
  • Step 1 N-(2-(4-(3-(2-methoxyphenyt)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.
  • Example 61 (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-1-yl)phenyl)methylium, Enantiomer 1 and Example 62: (2-methyl-4-(2-oxo-4-(4- (3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 -yl)phenyl)methylium,
  • Step 1 Preparation of (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin- 1-yl)phenyl)methylium, Enantiomer 1 and (2-methyi-4-(2-oxo-4-(4-(3-(p-toiyi)- 1,2,4- oxadiazol-5-yl)piperidine- 1 -carbonyl)pyrrolidin- 1 -yl)phenyl)methylium, Enantiomer 2
  • N-hydroxy-4-methylbenzimidamide 300 mg, 2.0 mmol
  • (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) 834 mg, 2.20 mmol
  • 1 -(1 -(3,4- dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (688 mg, 2.00 mmol) in N,N- dimethylformamide (10 ml_) were added N-ethyl-N-(propan-2-yl)propan-2-amine (516 mg, 4.00 mmol, 698 mI_) at 0 °C.
  • tetrahydrofuran 80 ml_ dropwise.
  • the mixture was stirred at 0 °C for 1 h, quenched by addition of a sodium sulfate solution in water (10 ml_) at 0 °C, and made basic (pH 1 1 ) by addition of an aqueous sodium carbonate solution.
  • the mixture was extracted with ethyl acetate (100 ml_), acidified to pH 2 using 1 M HCI, and extracted again with ethyl acetate (100 ml_).
  • the organic layers were washed with a saturated aqueous sodium chloride solution (100 ml_), dried over sodium sulfate, filtered and
  • Step 5 (4S)-4-[4-[3-(3,4-dimethoxyphenyl)- 1, 2, 4-oxadiazol-5-yl]piperidine- 1 -carbonyl]- 1 -phenyl-pyrrolidin- 2-one
  • Example 69 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-2-one, Enantiomer 1 and Example 70 1-(3,4-dimethylphenyl)-4-(4-(3-(3- methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, Enantiomer 2
  • Step 2 Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine- 1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 and 1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, Enantiomer 2
  • Example 71 (1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1- carbonyl)pyrrolidin-2-one), Enantiomer 1 and Example 72 (1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-
  • Racemic 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one (80 mg) was purified by SFC separation (column: AD (250x30mm, 5pm); mobile phase: [CO2 base-isopropanol]; B%: 50%-50%,min) to give firstly 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-
  • Racemic 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one 120 mg was purified by SFC separation (column: OJ(250mmX30mm,5mm); mobile phase: [CO2 base-ethanol]; B%: 30%-30%,min) to give firstly 1 -(3,4-dimethylphenyl)-4-(4-(5-(m- tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 (39 mg, 86.7 mitioI, 1 1 %) as a pink solid and secondly 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 --
  • Step 1 Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)carbamate.
  • Step 2 Preparation of 2-amino- 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1- yl)ethanone
  • a small amount (0.1 g) of the crude product was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrilej; B%: 2Q%-50%,12 min) to give a pure sample for analysis: 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethanone (32 mg).
  • the mixture was stirred at 20 °C for 2 h, and then heated at 120 °C for 2 h.
  • the reaction mixture was quenched with water (10 ml_), then the mixture was extracted with ethyl acetate (30 ml_ x 3).
  • the combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product.
  • the crude product was extracted with petroleum ether (30 ml_ x 2).
  • Step 3 Preparation of 5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 - yi)ethoxy)choman-4-one
  • reaction mixture was concentrated under reduced pressure and the resulting residue purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 45%-75%,12 min) to give 5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4- (3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethoxy)choman-4-one (120 mg, 250.6 mitioI, 44 %) as a white solid.

Abstract

The present invention features compounds useful in the treatment of neurological disorders. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders.

Description

COMPOUNDS AND USES THEREOF
Background
An incomplete understanding of the molecular perturbations that cause disease, as well as a limited arsenal of robust model systems, has contributed to a failure to generate successful disease modifying therapies against common and progressive neurological disorders, such as Parkinson's Disease (PD) and Alzheimer's Disease (AD). Progress is being made on many fronts to find agents that can arrest the progress of these disorders. However, the present therapies for most, if not all, of these diseases provide very little relief. Accordingly, a need exists to develop therapies that can alter the course of neurodegenerative diseases. More generally, a need exists for better methods and compositions for the treatment of neurodegenerative diseases in order to improve the quality of the lives of those afflicted by such diseases.
Summary of the Invention
This disclosure provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:
Figure imgf000002_0001
Formula la
wherein B is absent or has the structure:
Figure imgf000002_0002
Formula lb Formula lc Formula Id Formula le Formula If the dashed lines represent an optional double bond;
Het is -C(0)NH- or an optionally substituted C2-C9 heteroaryl;
m is 0 or 1 ;
n is 0, 1 , or 2;
o is O, 1 , 2, 3, 4, 5, 6, 7, or 8;
p, p’, r, and r’ are, independently, 0 or 1 ;
X1 and X2 are each, independently, N or CR6;
L1 is -0-, -SO2-, NR2, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkenylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, an optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heterocycle;
L2 is absent, -0-, -SO2-, NR2, or -CR2R3-; R1 is hydrogen, amino, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkyl C1 -C6 alkyl, optionally substituted C2- C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heterocycle C1 -C6 alkyl;
R2 and R3 are each, independently, hydrogen, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, or combine with the carbon to which they are attached to form a carbonyl or an optionally substituted C3-C7 cycloalkyl;
each R4 is, independently, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, or two R4 combine with the carbon two which they are attached to form a carbonyl or optionally substituted C3-C7 cycloalkyl;
R5 is optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocycle, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle C1 -C6 alkyl, or optionally substituted C2-C9 heteroaryl C1 -C6 alkyl; and
each R6 is, independently, hydrogen, halogen, hydroxy, optionally substituted C1 -C6 heteroalkyl, or optionally substituted C1 -C6 alkyl.
In some embodiments, B is absent.
In some embodiments, B has the structure of Formula lb:
Figure imgf000003_0001
In some embodiments, X1 is N and X2 is CR6. In some embodiments, o is 0, 1 , or 2. In some embodiments, R4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R4 combine with the carbon two which they are attached to form a carbonyl. In some embodiments, R6 is hydrogen. In some embodiments, R6 is halogen (e.g., fluoro). In some embodiments, R6 is optionally substituted C1-C6 alkyl (e.g., methyl). In some embodiments, the dashed line represents a double bond. In some embodiments, both dashed lines represent a single bond. In some embodiments, p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some
embodiments, B has the structure:
Figure imgf000003_0002
In some embodiments, X1 is CR6 and X2 is N. In some embodiments, o is 0, 1 , or 2. In some embodiments, R4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R4 combine with the carbon two which they are attached to form a carbonyl. In some embodiments, R6 is hydrogen. In some embodiments, R6 is halogen (e.g., fluoro). In some embodiments, R6 is optionally substituted C1-C6 alkyl (e.g., methyl). In some embodiments, the dashed line represents a double bond.
In some embodiments, the dashed line represents a single bond. In some embodiments, p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, B has the structure:
Figure imgf000004_0001
In some embodiments, X1 is N and X2 is N. In some embodiments, o is 0, 1 , or 2. In some embodiments, R4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R4 combine with the carbon two which they are attached to form a carbonyl. In some embodiments, the dashed line represents a double bond. In some embodiments, the dashed line represents a single bond. In some embodiments, p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, p is 1 and r is 2. In some embodiments, B has the structure:
In some embodiments,
Figure imgf000004_0002
, o is 0, 1 , or 2. In some embodiments, R4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R4 combine with the carbon two which they are attached to form a carbonyl. In some embodiments, the dashed line represents a double bond. In some embodiments, the dashed line represents a single bond. In some embodiments, p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, B has the structure:
Figure imgf000004_0003
In some embodiments, B has the structure of Formula lc:
Figure imgf000004_0004
In some embodiments, X1 is N and X2 is N. In some embodiments, o is 0. In some
embodiments, p, p’, r, and r’ are 0. In some embodiments, p and r are each 1 and p’ and r’ are 0. In some embodiments, B has the structure:
Figure imgf000004_0005
In some embodiments, B has the structure of Formula Id:
Figure imgf000004_0006
In some embodiments, X1 is N and X2 is N. In some embodiments, o is 0. In some embodiments, B has the structure:
Figure imgf000005_0001
In some embodiments, B has the structure of Formula le:
Figure imgf000005_0002
In some embodiments, X1 is N and X2 is N. In some embodiments, o is 0. In some
embodiments, B has the structure:
Figure imgf000005_0003
In some embodiments, B has the structure of Formula If:
Figure imgf000005_0004
In some embodiments of any of the foregoing compounds, Het is -C(0)NH- or:
Figure imgf000005_0005
wherein X3 is O or S.
In some embodiments, Het
In some embodiments, Het
Figure imgf000005_0006
In some embodiments, Het i
Figure imgf000005_0007
In some embodiments, Het i
Figure imgf000005_0008
In some embodiments, Het i
Figure imgf000005_0009
In some embodiments, L2 is absent. In some embodiments, L2 is -NR2- (e.g., -NH-). In some embodiments, L2 is -0-. In some embodiments, L2 is -SO2-. In some embodiments, L2 is -CR2R3-. In some embodiments, R2 and R3 combine with the carbon to which they are attached to form a carbonyl. In some embodiments, R2 and R3 combine with the carbon to which they are attached to form an optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl). In some embodiments, R2 and R3 are both hydrogen. In some embodiments, R2 is hydrogen and R3 is optionally substituted C1 -C6 alkylene (e.g., methylene).
In some embodiments, n is 0. In some embodiments, n is 1 . In some embodiments, L1 is -NR2- (e.g., -NH- or -N(Et)-). In some embodiments, L1 is -0-. In some embodiments, L1 is -SO2-. In some embodiments, L1 is optionally substituted C1-C6 alkylene (e.g., methylene or hydroxy-methylene). In some embodiments, L1 is optionally substituted C1-C6 heteroalkylene (e.g., -NH-CH2-, -O-CH2-, -O-CH2-
Figure imgf000006_0001
some embodiments, L1
is optionally substituted C2-C9 heterocycle
Figure imgf000006_0002
Figure imgf000006_0003
In some embodiments, R1 is cyano, optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, pentafluoro-ethyl, 2-chloro-ethyl, 1 -chloro-3-hydroxy- isopropyl, 2-methoxy-ethyl, or hexafluoro-isopropyl). In some embodiments, R1 is optionally substituted C6-C10 aryl (e.g., phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-trifluoromethyl-phenyl, 3- trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3- isopropyl-phenyl, 4-isopropyl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-difluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 2-chloro-5-fluoro-phenyl, 2-fluoro-4-chloro-phenyl, 3-fluoro-4-chloro-phenyl, 2-bromo-4-methoxy-phenyl, 2-trifluoromethyl-5-fluoro-phenyl, 2-trifluoromethyl-
5-chloro-phenyl,
Figure imgf000006_0004
some embodiments, R1 is optionally substituted C6-C10 aryl C1 -C6 alkyl (e.g., naphthylmethyl). In some embodiments, R1 is optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl, cyclohexyl, 6-methoxy-cyclohexyl, 1 -cyano- cyclopropyl, bicycle[1 .1 .1 ]pentane, 1 -methyl-cyclopropyl, 1 -ethyl-cyclopropyl, 1 -fluoro-cyclopropyl, 1 - methoxy-cyclopropyl, 1 -hydroxy-cyclopropyl, 2,2-dimethyl-cyclopropyl, 2,2-difluoro-cyclopropyl,
cyclobutyl,
Figure imgf000006_0005
some embodiments, R1 is optionally substituted C3-C7 cycloalkyl C1 -C6 alkyl (cyclopropylmethyl). In some embodiments, R1 is optionally substituted C2-C9 heteroaryl
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0004
Figure imgf000007_0003
Figure imgf000008_0001
some embodiments, R1 is optionally substituted C2-C9 heterocycle C1-C6 alkyl (e.g.,
Figure imgf000008_0002
In some embodiments, R5 is optionally substituted C6-C10 aryl (e.g., phenyl, 3,4-dimethoxy- phenyl, 3-methoxy-4-ethoxy-phenyl, 3,5-dimethoxy-phenyl, 3-methoxy-4-cyclopropoxy-phenyl, 3-
methoxy-4-trifluoromethoxy-phenyl, 3-isopropoxy-4-methoxy-phenyl,
Figure imgf000008_0003
Figure imgf000008_0004
some embodiments,
R5 is optionally substituted C2-C9 heteroaryl
Figure imgf000008_0005
Figure imgf000008_0006
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
embodiments, R5 is an optionally substituted indazole. In some embodiments, R5 is optionally substituted
C2-C9 heterocycle (e.g., a nitrogen containing heterocycle such as
Figure imgf000011_0002
Figure imgf000012_0001
Figure imgf000012_0006
In some embodiments, R5 is a bicyclic heterocyle. For example, a bicyclic heterocycle such as an indazole. In some embodiments, R5 is an indazole having the structure:
Figure imgf000012_0002
wherein R5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl).
In some embodiments, B has the sturucture:
Figure imgf000012_0003
In some embodiments, R1 is optionally substituted C1 -C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl), optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl.
In some embodiments, m is 0, n is 1 , some embodiments, m is 0, n
is 0, and L2 is -C(O)-. In some embodiments,
Figure imgf000012_0007
, and L2 is -C(O)-. In some embodiments,
Figure imgf000012_0004
In some embodiments, R5 is an indazole having the structure:
Figure imgf000012_0005
wherein R5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl); B has the sturucture:
Figure imgf000013_0001
R1 is optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl), optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl; and
Figure imgf000013_0002
In some embodiments, m is 0, n is 1 , L1 is -O-, L2 is -C(O)- and R1 is optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl).
In some embodiments, optionally substituted C6-C10 aryl.
In some embodiments,
Figure imgf000013_0003
-C(O)-, and R1 is optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl.
In some embodiments, m is 1 , n is 1 , L1 is
Figure imgf000013_0004
, L2 is -C(O)-, and R1 is optionally substituted C6-C10 aryl.
In some embodiments, the compound has the structure of Formula Ig:
Figure imgf000013_0005
Formula Ig
wherein Het is an optionally substituted oxadiazole;
o is O, 1 , 2, 3, 4, 5, 6, 7, or 8;
X2 is N or CR6;
R1 is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkyl C1 -C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heterocycle C1 -C6 alkyl;
each R4 is, independently, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, or two R4 combine with the carbon two which they are attached to form a carbonyl or optionally substituted C3-C7 cycloalkyl;
R5 is optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocycle, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C2-C9 heterocycle C1-C6 alkyl, or optionally substituted C2-C9 heteroaryl C1-C6 alkyl; and
each R6 is, independently, hydrogen, halogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted C1-C6 alkyl.
,0.
Figure imgf000014_0001
N"
In some embodiments, Het is V
In some embodiments, Het
Figure imgf000014_0002
In some embodiments, X2 is N or CH. In some embodiments, X2 is N. In some embodiments, X2 is CH.
In some embodiments, R1 is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, or optionally substituted C6-C10 aryl.
In some embodiments, R5 is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl (e.g., bicyclic heteroaryl such as an indazole). In some embodiments, R5 has the structure:
Figure imgf000014_0003
wherein R5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl). In some embodiments, R5a is hydrogen.
In some embodiments, Het i
Figure imgf000014_0004
optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl (e.g., C1-C6 alkoxy or C1-C6 alkylamino), or optionally substituted C6-C10 aryl ; and R5 has the structure:
Figure imgf000014_0005
wherein R5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl).
In some embodiments the compound has the structure of Formula I:
Figure imgf000014_0006
Formula I wherein Het is an optionally substituted optionally substituted C2-C9 heteroaryl;
m is 0 or 1 ;
n is 0, 1 , or 2;
o is O, 1 , 2, 3, 4, 5, 6, 7, or 8;
X1 and X2 are each, independently, N or CR6;
L1 is optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkenylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocycle;
R1 is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocycle;
R2 and R3 are each, independently, hydrogen, optionally substituted C1-C6 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
each R4 is, independently, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or two R4 combine with the carbon two which they are attached to form a carbonyl;
R5 is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl; and
each R6 is, independently, hydrogen or optionally substituted C1 -C6 alkyl.
In some embodiments of any of the foregoing compounds, R2 and R3 combine with the carbon to which they are attached to form a carbonyl. In some embodiments of any of the foregoing compounds, R2 and R3 are both hydrogen.
In some embodiments of any of the foregoing compounds, Het is:
Figure imgf000015_0001
wherein X3 is O or S.
In some embodiments, the compound has the structure of Formula II or I la:
Figure imgf000015_0002
Formula II Formula lla
In some embodiments of any of the foregoing compounds, X3 is O. In some embodiments of any of the foregoing compounds, X3 is S.
In some embodiments of any of the foregoing compounds, X1 is N and X2 is CR6. In some embodiments of any of the foregoing compounds, X1 is N and X2 is N. In some embodiments of any of the foregoing compounds, X1 is CR6 and X2 is N. In some embodiments of any of the foregoing compounds, R6 is hydrogen.
In some embodiments of any of the foregoing compounds, R5 is optionally substituted C6-C10 aryl. For example, in some embodiments, R5 is a C6-C10 aryl substituted with 1 , 2, 3, or 4 substituents independently selected from C1-C6 alkyl (e.g., methyl), halogen (e.g., fluoro, chloro, or bromo), C1-C6 alkoxy (e.g., methoxy or ethoxy), nitrile, or two substituents combine to form a 5 or 6-membered heterocycle (e.g., 2,2-difluoro-1 ,3-benzodioxole). In some embodiments of any of the foregoing compounds, R5 is phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, 2- methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxy-phenyl, 2-fluoro-phenyl, 3- fluoro - phenyl, 4- fluoro -phenyl, 3,4-di fluoro -phenyl, 3,4-dichloro-phenyl, 3-methoxy-4-ethoxy-phenyl, 3-chloro- 4-ethoxy-phenyl, 3-fluoro-4-ethoxy-phenyl, 3-bromo-4-ethoxy-phenyl, 3-cyano-4-ethoxy-phenyl, or 2,2- difluoro-1 ,3-benzodioxole.
In some embodiments, the compound has the structure of Formula III or Ilia:
Figure imgf000016_0001
wherein p is 1 , 2, 3, 4, or 5;
each R7 is, independently, halogen, nitrile, OR8, or optionally substituted C1-C6 alkyl ; and each R8 is, independently, hydrogen or optionally substituted C1-C6 alkyl.
In some embodiments, the compound has the structure of Formula IV or IVa:
Figure imgf000016_0002
Formula IV Formula IVa
In some embodiments, each R7 is OR8. In some embodiments, each R8 is optionally substituted Ci-C6 alkyl (e.g., methyl or ethyl).
In some embodiments of any of the foregoing compounds, R5 is optionally substituted C2-C9 heteroaryl (e.g., bicyclic heteroaryl). In some embodiments of any of the foregoing compounds, R5 is:
Figure imgf000016_0003
Figure imgf000017_0001
In some embodiments of any of the foregoing compounds, R5 is:
Figure imgf000017_0002
In some embodiments of any of the foregoing compounds, R1 is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl. In some embodiments, R1 is optionally substituted C6-C10 aryl. For example, phenyl or a C6-C10 aryl substituted with 1 , 2, 3, 4, or 5 substituents independently selected from C1 -C6 alkyl (e.g., methyl or iso-propyl), C1 -C6 alkoxy (e.g., methoxy), or halogen (e.g., chloro). In some embodiments of any of the foregoing compounds R1 is 2-methoxy-phenyl, 3-methoxy-phenyl, 4- methoxy-phenyl, 3,4-dimethoxy-phenyl, phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-methyl-phenyl, 4- iso-propyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, or 4-chloro-phenyl. In some embodiments of any of the foregoing compounds, R1 is a bicyclic C6-C10 aryl (e.g., naphthalene). In some embodiments of any of the foregoing compounds, R1 is C3-C7 cycloalkyl (e.g., cyclohexyl). In some embodiments of any of the foregoing compounds, R1 is optionally substituted C2-C9 heteroaryl or optionally substituted C2-C9 heterocycle. For example, in some embodiments, R1 is:
Figure imgf000017_0003
In some embodiments of any of the foregoing compounds, the compound has the structure of Formula V or Va:
Figure imgf000017_0004
Formula V Formula Va
wherein q is 1 , 2, 3, 4, or 5; and
Ft9 is halogen or optionally substituted C1-C6 alkyl.
In some embodiments of any of the foregoing compounds, the compound has the structure of
Formula VI or Via:
Figure imgf000018_0001
Formula VI Formula Via
In some embodiments of any of the foregoing compounds, n is 1 . In some embodiments of any of the foregoing compounds, n is 0.
In some embodiments of any of the foregoing compounds, L1 is optionally substituted C1-C6 alkyl. For example, L1 has the structure:
Figure imgf000018_0002
In some embodiments of any of the foregoing compounds, L1 is optionally substituted C1-C6 alkenylene (e.g., ethenylene).
In some embodiments of any of the foregoing compounds, L1 is optionally substituted C2-C9 heterocyclene or optionally substituted C2-C9 heteroarylene. For example,
Figure imgf000018_0003
,
In some embodiments of any of the foregoing compounds, L1 is optionally substituted C1-C6 heteroalkylene. For example, in some embodiments, L1 is:
Figure imgf000018_0004
In some embodiments of any of the foregoing compounds, L1 is -NH-(CR10R11)r, wherein r is 1 , 2, 3, 4, 5, or 6, and each R10 and R11 is, independently, hydrogen or optionally substituted C1-C6 alkyl. For example, in some embodiments, L1 is -NH-CH2-, -NH-CR10R11-, wherein each of R10 and R11 is methyl, or -NH-CHR11-, wherein R11 is methyl.
In some embodiments of any of the foregoing compounds, m is 1. In some embodiments of any of the foregoing compounds, m is 0.
In another aspect, the disclosure provides a compound, or pharmaceutically acceptable salt thereof, having the structure of any one of compounds 1-1195 in Table 1 , Table 2A, and Table 2B. In some embodiments, the compound is any one of compounds 1 -264, 266-271 , 274-276, 278-299, 302- SI 8, 320-329, 331-340, 344-354, 358, 362-364, 367, 369, 371-378, 385, 388-392, 396, 397, 399-401,
403, 406-411 , 414, 418-420, 422, 425-432, 434-436, 438, 440-444, 446, 450-454, 456, 458, 460, 461 , 464, 466, 470, 472-474, 476, 477, or 481 -746 in Table 1. In some embodiments, the compound is any one of compounds 1 -347, 349, 350, or 354-746 in Table 1. In some embodiments, the compound is any one of compounds 1-387, 389, 393-405, 407-430, 432-439, 441-449, 452, 454-457, 459-472, 475, 477- 480, 482-487, or 489-746 in Table 1 , In some embodiments, the compound is any one of compounds 1 - 483 or 491 -746 in Table 1. In some embodiments, the compound is any one of compounds 747-966. In some embodiments, the compound is any one of compounds 27, 40, 96, 128, 140, 168, 184, 204, 226, 244, 265, 268, 269, 284, 286291 , 294, 302, 305, 306, 308, 317, 319, 343, 344, 345, 346, 349, 355-357, or 359-364. In some embodiments, the compound is any one of compounds 244, 265, 269, 319, 345, 349, 355-357, 361 , or 364. In some embodiments, the compound is any one of compounds 750, 767, 775-778, 780, 784, 785, 789-792, 795, 799, 812, 813, 817, 828, 838, 839, 842-844, 846, 848, 850, 851, 853, 854, 861, 862, 865, 874-881 , 884-888, 890-898, 902, 903, 907, 910, 916, 928, 932, 934, 953, 957, 960, 964, or 965. In some embodiments, the compound is any one of compounds 967-1195. In some embodiments, the compound is any one of compounds 970, 971 , 974, 975, 979-982, 986, 988, 990, 992, 997, 999, 1000, 1003-1006, 1010, 1012, 1013, 1015-1026, 1028, 1029, 1031 , 1034-1037, 1039-1050, 1052-1062, 1065-1073, 1075-1080, 1082-1087, 1090, 1092, 1093, 1096-1098, 1100, 1104, 1105, 1107, 1109-1114, 1125, 1131, 1134-1141, 1144, 1146, 1149, 1151-1154, 1156, 1161, 1162, 1164, 1170, 1171,
1175-1182, 1190, or 1192. In some embodiments, the compound is any one of compounds 970, 971 , 974, 975, 979, 981, 982, 986, 988, 990, 992, 997, 999, 1005, 1012, 1016-1020, 1022, 1024, 1025, 1028, 1029, 1036, 1039, 1041-1043, 1046-1050, 1053-1062, 1065-1073, 1075, 1078, 1082-1084, 1086, 1087, 1092, 1093, 1096-1098, 1104, 1107, 1109-1112, 1114, 1134-1137, 1139, 1140, 1144, 1149, 1152, 1154,
1161 , 1162, 1171 , 1176, 1180, 1190, or 1192. In some embodiments, the compound is any one of compounds 970, 971 , 974, 975, 986, 988, 990, 997, 999, 1005, 1012, 1016-1019, 1022, 1024, 1025, 1028, 1029, 1036, 1039, 1041, 1043, 1046-1050, 1053-1059, 1061, 1062, 1065-1073, 1075, 1078, 1083, 1084, 1086, 1087, 1092, 1093, 1096, 1097, 1104, 1107, 1109, 1110, 1134, 1136, 1137, 1139, 1140,
1144, 1149, 1152, 1154, 1161 , 1162, 1171 , 1180, 1190, or 1192. In some embodiments, the compound is any one of compounds 970, 1053-1056, 1058, 1059, 1065-1069, 1071 -1073, 1093, or 1096. Table 1 . Compounds of the Invention
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Table 2A. Compounds of the Invention
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Table 2B. Compounds of the Invention
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
In another aspect, the disclosure provides pharmaceutical composition comprising any of the foregoing compounds, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
In another aspect, the disclosure provides a method of treating a neurological disorder in a subject in need thereof, the method comprising administering an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions.
In another aspect, the disclosure provides a method of inhibiting toxicity in a cell (e.g., a mammalian neural cell) related to a protein (e.g., toxicity related to protein misfolding and/or aggregation such as protein aggregation related to misfolding of proteins such as a-synuclein or ApoE4), the method comprising administering, or contacting the cell with, an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof. In some embodiments, the toxicity is a- synuclein-related toxicity. In some embodiments, the toxicity is ApoE4-related toxicity.
Non-limiting exemplary neurological disorders include, but are not limited to Alexander disease, Alper' s disease, AD, amyotrophic lateral sclerosis, ataxia telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado-Joseph disease, multiple sclerosis, PD, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Ref sum's disease, Sandhoff disease, Schilder' s disease, Steele-Richardson-Olszewski disease, tabes dorsalis, frontal temporal dementia, vascular dementia, Down’s syndrome, and Guillain-Barre Syndrome.
In another aspect, the disclosure provides a method of treating a stearoyl-CoA desaturase (SCD)- associated disorder in a subject in need thereof, the method comprising administering, or contacting the cell with, an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof.
Non-limiting exemplary SCD-associated disorders include, but are not limited to metabolic disorders (e.g., diabetes (e.g., Type I diabetes and Type II diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hypertension), cancer, cardiovascular diseases, cerebrovascular diseases, kidney diseases, liver diseases, skin disorders (e.g., acne (e.g., acne vulgaris)), central nervous system (CNS) disorders, dementia, multiple sclerosis, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, and dementia associated with Down Syndrome.
Chemical Terms
It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.
The term“acyl,” as used herein, represents a hydrogen or an alkyl group, as defined herein, that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 1 1 , or from 1 to 21 carbons.
The term“alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). An alkylene is a divalent alkyl group.
The term“alkenyl,” as used herein, alone or in combination with other groups, refers to a straight- chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
The term“alkynyl,” as used herein, alone or in combination with other groups, refers to a straight- chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
The term“amino,” as used herein, represents -N(RN1)2, wherein each RN1 is, independently, H, OH, NO2, N(RN2)2, S020RN2, S02RN2, SORN2, an /V-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1 groups can be optionally substituted; or two RN1 combine to form an alkylene or heteroalkylene, and wherein each RN2 is, independently, H, alkyl, or aryl. The amino groups of the invention can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN1 )2).
The term“aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1 H-indenyl.
The term“arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -6 alkyl Ce-io aryl, C1 -10 alkyl Ce-io aryl, or C1 -20 alkyl Ce-io aryl), such as, benzyl and phenethyl. In some embodiments, the akyl and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
The term“azido,” as used herein, represents a -IM3 group.
The term“cyano,” as used herein, represents a -CN group.
The terms“carbocyclyl,” as used herein, refer to a non-aromatic C3-12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.
The term“cycloalkyl,” as used herein, refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.
The term“halogen,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
The term“heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an“alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group.
The term“heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an“alkenoxy” which, as used herein, refers alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group.
The term“heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups. Examples of heteroalkynyl groups are an“alkynoxy” which, as used herein, refers alkynyl-O-. A heteroalkynylene is a divalent heteroalkynyl group.
The term“heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N,
O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.
The term“heteroarylalkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -6 alkyl C2-9 heteroaryl, C1 -10 alkyl C2-9 heteroaryl, or C1 -20 alkyl C2-9 heteroaryl). In some embodiments, the akyl and the heteroaryl each can be further substituted with 1 , 2,
3, or 4 substituent groups as defined herein for the respective groups.
The term“heterocyclyl,” as used herein, denotes a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing one, two, three, or four ring heteroatoms selected from N, O or S, wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl.
The term“heterocyclylalkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -6 alkyl C2-9 heterocyclyl, C1 -10 alkyl C2-9 heterocyclyl, or C1 -20 alkyl C2-9 heterocyclyl). In some embodiments, the akyl and the heterocyclyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
The term“hydroxyl,” as used herein, represents an -OH group. The term“/V-protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley &
Sons, New York, 1999). /V-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p- toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3.4.5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, a,a-dimethyl-
3.5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl. Preferred /V-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
The term“nitro,” as used herein, represents an -NO2 group.
The term“thiol,” as used herein, represents an -SH group.
The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).
Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.“Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9%) by weight relative to the other
stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.
Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other
diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.
Definitions
In the practice of the methods of the present invention, an“effective amount” of any one of the compounds of the invention or a combination of any of the compounds of the invention or a
pharmaceutically acceptable salt thereof, is administered via any of the usual and acceptable methods known in the art, either singly or in combination.
The term“pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup) ; for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
A“pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
As used herein, the term“pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of formula (I). For example pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCFI, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.
The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
As used herein, the term“stearoyl-CoA desaturase (SCD)-associated disorder” refers to an undesired physiological condition, disorder, or disease that is associated with and/or mediated at least in part by an SCD protein. In some instances, SCD-associated disorders are associated with excess SCD levels and/or activity. SCDs introduce a double bond in the C9-C10 position of saturated fatty acids such as palmitoyl-CoA and stearoyl-CoA which are converted to palmitoleoyl-CoA and oleoyl-CoA, respectively. One SCD gene, SCD1 , has been characterized in humans for which there are two isoforms, SCD1 and SCD5. An SCD-associated disorder may be associated with and/or mediated at least in part by SCD1 and/or SCD5. Exemplary SCD-associated disorders include SCD-associated disorders include, but are not limited to metabolic disorders (e.g., diabetes (e.g., Type I diabetes and Type II diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hypertension), cancer, cardiovascular diseases, cerebrovascular diseases, kidney diseases, liver diseases, skin disorders (e.g., acne (e.g., acne vulgaris)), central nervous system (CNS) disorders, dementia, multiple sclerosis, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, and dementia associated with Down Syndrome. Additional SCD-associated disorders are described herein or known in the art.
As used herein, the term“subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
As used herein, the terms "treat," "treated," or "treating" mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e. , not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
Brief Description of the Drawings
FIGS. 1 A and 1 B are graphs showing that growth inhibition by 1 ,2,4-oxadiazoles occurs through same mechanism as the rescue of toxicity in the apolipoprotein E4 (ApoE4) Alzheimer’s disease yeast model. (Fig. 1 A) Compound 7, a representative 1 ,2,4-oxadiazole, was profiled in ApoE4 (top) and control (bottom) non-inducing conditions at 12-point dose (x-axis). The Y-axis shows raw Oϋboo. Compound 7 exhibited a bell-shaped dose-response curve (DRC) in the ApoE4 model. Rescue decreased at concentrations just above the maximal efficacy (Emax). In the control condition (bottom panel), growth decreased at this same concentration. (Fig. 1 B) The relationship between Emax (rescue in ApoE4) and growth inhibition (in control condition) correlated across 34 tested 1 ,2,4-oxadiazoles. The maximal rescue dose (EC100) is shown on the y-axis for ApoE4 and minimal inhibitory dose (IC100) in the control condition is shown on the x-axis. This correlation indicates that growth inhibition is caused by the same on-target activity that rescues ApoE4 toxicity.
FIGS. 2A and 2B are graphs showing that exogenous oleic acid reverses growth inhibition and model rescue by Ole1/SCD-targeting 1 ,2,4-oxadiazoles. Growth was measured by reading Oϋboo in a microplate reader and normalized to solvent control DMSO samples. (Fig. 2A) Growth inhibition (24 h) of strain GM yap1 flr1 by Ole1 /SCD-targeting 1 ,2,4-oxadiazoles is reversed by exogenous 0.5 mM oleic/palmitoleic acid, which did not affect growth inhibition by other compounds (black dots indicate other scaffolds tested). Maximal growth inhibition across a dose range from 33 nM to 33 mM is plotted. (Fig.
2B) Rescue (40 h) of the yeast alpha-synuclein (“aSyn”) model by 1 ,2,4-oxadiazoles was reversed by exogenous 0.5 mM oleic/palmitoleic acid, which did not affect rescue by other scaffolds. Maximal model rescue across a dose range from 33 nM to 33 pM is plotted. FIGS. 3A and 3B are graphs showing that point mutations in yeast OLE1 confer resistance to growth inhibition and alpha-synuclein model rescue by 1 ,2,4-oxadiazoles. Growth was measured by reading Oϋboo in a microplate reader. (Fig. 3A) Yeast cells deleted for the chromosomal copy of OLE1 and expressing OLE1 (wild-type), ole1P123T, or ole1E188Q mutants from a pRS316-based plasmid were grown in complete synthetic medium (CSM)-glucose media at the indicated doses of 1 ,2,4-oxadiazole Compound 95 for 24 h. Growth was normalized to samples treated with the solvent control dimethyl sulfoxide (DMSO), set as“1 (Fig. 3B) Yeast cells deleted for the chromosomal copy of OLE1 and expressing OLE1 (Wild-type), ole1P123T, or ole1E188Q mutants from a pRS316-based plasmid were grown in CSM-galactose media (inducing expression of alpha-Synuclein) at the indicated doses of the 1 ,2,4-oxadiazole Compound 95 for 40 h. Growth was normalized to samples treated with the solvent control DMSO, where rescue is set as“1”.
FIG. 4 is a graph showing that a ole1A deletion mutant is resistant to the growth-inhibitory effects of 1 ,2,4-oxadiazoles, but not other compounds. Twenty-four hour growth (presented as raw Oϋboo) of the ole1A deletion strain in yeast extract-peptone-dextrose (YPD) media is shown, with drugs added at the indicated concentrations.
FIG. 5 is a graph showing that reducing OLE1 expression by deleting MGA2 rescues the growth of the ApoE4 yeast model. Yeast cells expressing ApoE4 were deleted for the MGA2gene and their growth was assessed over time (compared to their isogenic, MGA2 wild-type counterpart). Growth was assessed by Oϋboo. Where indicated, 0.08 or 0.32 mM of oleic and palmitoleic acids (each) as added to the growth media in 0.01 % tween (final).
FIG. 6 is a series of graphs showing that commercial Scd inhibitors target human SCD1/SCD5 in yeast. Yeast surviving solely on yeast OLE1, or human SCD1 or SCD5, were treated with four commercial Scd inhibitors at indicated concentrations. Data are expressed as a percent of the DMSO- treated condition. All four compounds potently reduced growth of both SCD1 -expressing yeast and SCD5-expressing yeast, but not the strain expressing Ole1 . This growth inhibition was reversed by oleic/palmitoleic acid competition, similar to the results shown in Figs. 2A and 2B.
FIG. 7 is a series of graphs showing that 1 ,2,4-oxadiazoles target human SCD1 and SCD5.
Three“SCD” strains expressing yeast OLE1 or human SCD1 or SCD5 were treated with five
representative 1 ,2,4-oxadiazoles and a cycloheximide toxicity control at concentrations indicated on the logio x-axis. The y-axis indicates the percent of the DMSO-treated condition. All of the 1 ,2,4-oxadiazole compounds potently inhibited Ole1 -expressing yeast and showed variable growth inhibition of the SCD1 or SCD5 yeast strains. These data confirm that 1 ,2,4-oxadiazoles target the human protein and link Scd inhibition to rescue of neurodegenerative disease models. Approximately one half of all (250) 1 ,2,4- oxadiazoles tested inhibited SCD1 or SCD5 in a manner that was reversed by oleic/palmitoleic acid treatment. Cyclohexamide, a translation inhibitor (top left panel), inhibited growth of all three strains with the same potency, indicating differences in growth inhibition was due to targeting the human protein.
FIGS. 8A-8D are graphs showing that treatment of yeast cells with the 1 ,2,4-oxadiazole
Compound 95 inhibits lipid desaturation. Exponentially-growing wild-type yeast cells were treated with the indicated doses of the 1 ,2,4-oxadiazole Compound 95 for the indicated times before cellular lysis, lipid extraction, and analysis by global LC-MS/MS profiling. The relative abundance (fraction of total cellular lipid signal) after 1 .5 h and 8 h of the most abundant saturated lipid, phosphatidylcholine 26:0, is depicted in Figs. 8A and 8B, respectively. The relative abundance after 1 .5 h and 8 h drug treatment of the most abundant lipid with 2 or more degrees of unsaturation, phosphatidylcholine 16:1 ; 18:1 , is depicted in Figs. 8C and 8D, respectively. The data indicate a >300-fold increase in the abundance of the saturated lipid phosphatidylcholine 26:0 after 8 h treatment with Compound 95, and a >12-fold decrease in the abundance of the unsaturated lipid phosphatidylcholine 16:1 , 18:1 , indicating that Compound 95 blocks cellular fatty acid desaturase activity (Ole1 is the only fatty acid desaturase in yeast).
FIG. 9 shows OLE1 mutations conferring resistance to growth inhibition to 1 ,2,4-oxadiazoles identified by genome sequencing of resistant mutants. Cells were plated on media containing 10 mM of the 1 ,2,4-oxadiazole Compound 155 and resistant colonies that emerged were isolated, and genomic DNA was prepared from mutants and the parental, drug-sensitive control strain. Genomic DNA sequence was aligned to the Saccharomyces cerevisiae reference and unique mutations in the 1 ,2,4-oxadiazole- resistant mutants were identified. The position of the mutations, the amino acid changes they encode, and the fold resistance (increase in minimal inhibitory concentration) of Compound 155 are shown.
Detailed Description of the Invention
The invention features compounds useful for the treatment of neurological disorders, e.g., by inhibiting a-synuclein toxicity in a cell such as a neural cell. Exemplary compounds described herein include compounds having a structure according to formula I or formula la:
Figure imgf000098_0001
Formula I Formula la or pharmaceutically acceptable salts thereof.
In some embodiments, the compound has the structure of any one of compounds 1 -746 in Table 1 . In some embodiments, the compound has the structure of any one of compounds 747-966 in Table 2A. In some emobdiments, the compound has the structure of any one of compounds 967-1 195 in Table 2B.
Other embodiments, as well as exemplary methods for the synthesis or production of these compounds, are described herein.
Pharmaceutical Uses
The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to inhibit toxicity caused by protein aggregation, e.g., a-synuclein aggregation, in a cell.
Another aspect of the present invention relates to methods of treating and/or preventing a neurological disorder such as neurodegenerative diseases in a subject in need thereof. The pathology of neurodegenerative disease, may be characterized by the presence of inclusion bodies in brain tissue of affected patients.
In certain embodiments, neurological disorders that may be treated and/or prevented by the inventive methods include, but are not limited to, Alexander disease, Alper' s disease, AD, amyotrophic lateral sclerosis, ataxia telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado-Joseph disease, multiple sclerosis, PD, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Ref sum's disease, Sandhoff disease, Schilder' s disease, Steele- Richardson-Olszewski disease, tabes dorsalis, and Guillain-Barre Syndrome.
The compounds described herein are useful as inhibitors of stearoyl-CoA desaturase (SCD), including SCD1 and/or SCD5. SCD inhibitors are known in the art to be useful in methods of treating and/or preventing SCD-associated disorders. SCD-associated disorders are described, for example, in U.S. Patent No. 8,148,378, and in International Patent Application Publication Nos. WO 201 1 /047481 ,
WO 2010/1 12520, WO 2010/045374, WO 2010/028761 ; WO 2009150196, and WO
2009/106991 . Accordingly, another aspect of the present invention relates to methods of treating and/or preventing an SCD-associated disorder in a subject in need thereof.
SCD-associated disorders include metabolic disorders (e.g., insulin resistance, diabetes mellitus (e.g., Type I diabetes, Type II diabetes, non-insulin-dependent diabetes mellitus, gestational diabetes, and diabetic complications (e.g., diabetic peripheral neuropathy, diabetic nephropathy diseases, diabetic retinopathy, diabetic macroangiopathy, vascular complications of diabetes, and diabetic arteriosclerosis)), hyperglycemia, metabolic syndrome, hyperinsulinanemia, glucose intolerance, impaired glucose tolerance, body weight disorders (e.g., obesity (e.g., abdominal obesity), overweight, cachexia, body mass index, and anorexia), lipid disorders (e.g., abnormal lipid levels (e.g., elevated lipid levels, for example, in plasma), dyslipidemia (e.g., diabetic dyslipidemia), mixed dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, atherosclerosis,
hypercholesterolemia (e.g., familial hypercholesterolemia), low HDL, high LDL, diseases related to accumulation of lipids in liver, familial histiocytic reticulosis, lipoprotein lipase deficiency, polyunsaturated fatty acid (PUFA) disorder, fatty acid desaturation index (e.g. the ratio of 18:1 /1 8:0 fatty acids, or other fatty acids), and abnormal lipid metabolism disorders), disorders of abnormal plasma lipoprotein, disorders of pancreatic beta cell regeneration, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), hypertension, and microalbuminemia, leptin related diseases, hyperleptinaemia, appetite disorder, essential fatty acid deficiency, and adverse weight gain associated with a drug therapy).
Additional SCD-associated disorders include cancer, including solid tumors or hematological malignancies (e.g., esophageal cancer, pancreatic cancer, endometrial cancer, kidney cancer, hepatoma, thyroid cancer, gallbladder cancer, prostate cancer, leukemia (e.g., lymphomas and myelomas), ENT- related cancer, brain cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, skin cancer, and prostate cancer), neoplasia, malignancy, metastases, tumors (benign or malignant), carcinogenesis, and hepatomas.
Further SCD-associated disorders include cardiovascular disease (e.g., heart disease, atherosclerosis, hypertension, lipidemia, dyslipidemia, elevated blood pressure, microalbuminemia, hyperuricaemia, hypercholesterolemia, hyperlipidemias, hypertriglyceridemias, arteriosclerosis, coronary artery disease, myocardial infarction, vascular complications of diabetes, and diabetic arteriosclerosis), inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, hepatitis (e.g., sexual hepatitis), meibomitis, cystic fibrosis, pre-menstrual syndrome, osteoporosis, thrombosis, cardiovascular risks, weight loss, angina, high blood pressure, ischemia, cardiac ischemia, reperfusion injury, angioplastic restenosis, infertility, liver disease (e.g., fatty liver, cirrhosis, nonalcoholic steatohepatitis, liver fibrosis, and hepatitis C related steatosis), kidney disease (e.g., tubulointerstitial fibrosis, kidney lipid accumulation, glomerular sclerosis, and proteinuria), osteoarthritis (e.g., osteoarthritis of the knee), gastro-esophageal disease, sleep apnea, secondary hyperparathyroidism of renal osteodystrophy, peripheral vascular disease, cerebrovascular disease (e.g., stroke, ischemic stroke and transient ischemic attack (TIA), and ischemic retinopathy), hyperandrogenism, malignant syndrome, extrapyramidal symptoms, hyperuricemia, hypercoagulability, syndrome X, cataract, polycystic ovary syndrome, breathing abnormalities, sleep-disordered breathing, low back pain, gout, gallstone disease, myopathies, lipid myopathies (e.g., carnitine palmitoyltransferase deficiency (CPT I or CPT II)), autoimmune diseases (e.g., lupus, host versus graft rejection, and rejection of organ transplants), asthma, inflammatory bowel diseases, nephropathy, retinopathy, erythrohepatic protoporphyria, iron overload disorders, and hereditary hemochromatosis.
Still further SCD-associated disorders include central nervous system (CNS) disorders, dementia, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, dementia associated with Down Syndrome, other neurodegenerative diseases, psychiatric disorders, eye diseases, immune disorders, multiple sclerosis, neuropathy, and depression.
Additional SCD-associated disorders include skin disorders (e.g., acne (e.g., acne vulgaris), psoriasis, hirsutism, rosacea, seborrheic skin, oily skin (syn seborrhea), seborrheic dermatitis, hyperseborrhea, eczema, keloid scar, skin ageing, diseases related to production or secretions from mucous membranes, wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration, insufficient sebum secretion, oily hair, shiny skin, greasy-looking skin, greasy-looking hair, and other skin conditions caused by lipid imbalance).
An SCD-associated disorder can also include a disease or condition which is, or is related to, viral diseases or infections.
In some embodiments, the SCD-associated disorder is acne (e.g., acne vulgaris). In some embodiments, the SCD-associated disorder is diabetes (e.g., type II diabetes, including diabetes with inadequate glycemic control). In some embodiments, the SCD-associated disorder is nonalcoholic fatty liver disease (NAFLD). In some embodiments, the SCD-associated disorder is nonalcoholic
steatohepatitis (NASH). In some embodiments, the SCD- associated disorder is cancer. In some embodiments, the SCD- associated disorder is obesity. In some embodiments, the SCD-associated disorder is metabolic syndrome (e.g., dyslipidemia, obesity, insulin resistance, hypertension,
microalbuminemia, hyperuricaemia, and hypercoagulability), syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (e.g., obesity, overweight, cachexia, and anorexia), weight loss, body mass index, leptin related diseases, or a skin disorder (e.g., eczema, acne, psoriasis, and keloid scar). In some embodiments, the SCD-associated disorder is diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease.
Combination Formulations and Uses Thereof
The compounds of the invention can be combined with one or more therapeutic agents. In particular, the therapeutic agent can be one that treats or prophylactically treats any neurological disorder described herein.
Combination Therapies
A compound of the invention can be used alone or in combination with other agents that treat neurological disorders or symptoms associated therewith, or in combination with other types of treatment to treat, prevent, and/or reduce the risk of any neurological disorders. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect.
Pharmaceutical Compositions
The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.
The compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
A compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.
A compound of the invention may also be administered parenterally. Solutions of a compound of the invention can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003, 20th ed.) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.
Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.
The compounds of the invention may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
Dosages
The dosage of the compounds of the invention, and/or compositions comprising a compound of the invention, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the invention are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered. Preferred dose ranges include, for example, between 0.05-15 mg/kg or between 0.5-1 5 mg/kg.
Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1 -50 mg/kg (e.g., 0.25-25 mg/kg). In exemplary, non-limiting embodiments, the dose may range from 0.5-5.0 mg/kg (e.g., 0.5, 1 .0, 1 .5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from 5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).
EXAMPLES
The synthesis of compounds of this invention can be synthesized according to one or more of the general schemes 1 -10 shown below. The variables recited in the general schemes below are as defined for Formulae I, II, III, and IV.
General scheme 1
Figure imgf000103_0001
An appropriately substituted carboxylic acid I can be coupled with an appropriately substituted piperidine II to provide ester III. This can be hydrolysed under variety of conditions to provide carboxylic acid intermediate IV. This can be condensed with a substituted N-hydroxyimidamide V to give the desired 1 ,2,4-oxadiazole compound VI.
General Scheme 2
Figure imgf000104_0001
An appropriately substituted carboxylic acid VII can be coupled with an appropriately protected (where PG is an /V-protecting group) and substituted piperidine carboxylic acid VIII to provide intermediate IX. This can be deprotected using a variety of conditions to provide free amine intermediate X. This compound can be coupled using metal catalysis or under thermal conditions with a halogenated heterocycle such as XI to give the desired 1 ,2,4-oxadiazole (X3 = O) or 1 ,2,4-thiadiazole (X3 = S) compound XII. General scheme 3
Figure imgf000104_0002
An appropriately substituted carboxylic acid I can be coupled with an appropriately substituted piperidine XIII to provide the desired heterocyclic compound XIV. General scheme 4
Figure imgf000104_0003
An appropriately substituted acyl halide XV (where X is a halogen atom, e.g., chlorine) can be coupled with an appropriately substituted piperidine XIII to provide the desired heterocyclic compound
XIV.
General scheme 5
Figure imgf000105_0001
An appropriately substituted alkyl intermediate XVI (where X is a good leaving group, e.g., a halogen atom or triflate) can undergo nucleophilic displacement with an appropriately substituted piperidine XIII to provide the desired heterocyclic compound XIV.
General scheme 6
Figure imgf000105_0002
An appropriately substituted carboxylic acid IV can be coupled with an appropriately substituted ketone XVII (where X is a leaving group, e.g., bromine) to provide the intermediate compound XVII. This compound can be condensed with ammonium acetate to provide oxazole IXX.
General scheme 7
Figure imgf000105_0003
An appropriately protected and substituted thiomide XX can be coupled with an appropriately substituted ketone XVII (where X is a leaving group, most commonly bromine) to provide the protected (where PG is an amine protecting group, such as tert-butoxycarbonyl) thiazole compound XXI. This compound can be deprotected under appropriate conditions to give intermediate piperidine XXII. This can be coupled with and appropriately substituted carboxylic acid IV to provide thiazole XXIII. General scheme 8
Figure imgf000106_0001
An appropriately protected and substituted ester III can be treated with hydrazine to provide the hydrazide compound XXIV. This compound can coupled with an appropriately substituted acetimidate XXV to provide 1 ,3,4-oxadiazole XXVI.
General scheme 9
Figure imgf000106_0002
An appropriately substituted carboxylic acid IV can be couple with and appropriately substituted piperidine compound XXVII to give a compound XXVIII. This compound can be converted to the corresponding hydroxyimidamide compound XXIX. This is can be treated with an appropriately substituted acid halide (most commonly an acid chloride, where X=CI) XXX to provide 1 ,2,4-oxadiazole
XXXI.
General scheme 10
Figure imgf000107_0001
An appropriately substituted oxadiazolone XXXII can be converted to the appropriately substituted compound XXXIII. This compound can be coupled with the appropriate protected piperazine compound XXXIV (where PG is an /V-protecting group, for example, a tert-butyloxycarbonyl group) to give compound XXXV. This compound can be deprotected under the appropriate conditions to give piperazine compound XXXVI. This can be coupled with a carboxylic acid IV to provide 1 ,2,4-oxadiazole XXXVII. Experimental procedures
The compounds of the invention can be synthesized according to the following procedures.
In the examples below, when purification by preparative HPLC was performed, a Gilson 281 semi-preparative HPLC system was used, using a variety of stationary and mobile phases which are described in the experimental section. For example, (column: Waters X bridge 150x2.5mm 5pm; mobile phase: [water (10 mM NH40Ac)-acetonitrile]; B%: 36%-66%,12 min) indicates that the following purification conditions were used:
Mobile phase: A: 10mM NH4OAC in H2O; B: acetonitrile
Column: Waters Xbridge 150x2.5mm dimensions, 5 pm particle size
Flow rate: 25mL/min
Monitor wavelength: 220&254nm
Gradient:
Figure imgf000107_0002
Example 1. Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-2-one
Figure imgf000108_0001
A mixture of 2-methylenesuccinic acid (2.0 g, 1 .27 ml_, 15.37 mmol) and 3,4-dimethylaniline (1 .86 g, 15.37 mmol) in water (20 ml_) was stirred at 120 °C (reflux) for 16 h. The mixture was cooled to 25 °C and filtered. The filter cake was washed with cold water (5 ml_) to give 1 -(3,4-dimethylphenyl)-5- oxopyrrolidine-3-carboxylic acid (3.0 g, 12.9 mmol, 84 %) as a yellow solid. This material was used directly in the next step without further purification. 1H NMR (400MHz, DMSO-d6) d 7.40-7.35 (m, 2H), 7.13-7.1 1 (d, 1 H), 4.01 -3.93 (m, 2H), 3.34-3.30 (m, 1 H), 2.75-2.67 (m, 2H), 2.22 (s, 3H) 2.19 (s, 3H); LCMS (ESI) m/z: [M-H]- = 232.1 .
Step 2: Preparation of methyl 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylate
Figure imgf000108_0002
To a stirred solution of 1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (1 .0 g, 4.29 mmol) and methyl piperidine-4-carboxylate (737 mg, 5.15 mmol) in N,N-dimethylformamide (10 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 .63 g, 4.29 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 .1 1 g, 8.58 mmol, 1 .50 ml_). After stirring at 15 °C for 16 h, to the mixture was added water (20 ml_) and the mixture extracted with ethyl acetate (20 ml_ x 4). The organic layer was washed with water (10 ml_), saturated aqueous sodium chloride solution (10 ml_), then dried over anhydrous sodium sulfate, filtered and concentrated to give crude product that was purified by chromatography on silica gel eluted with Petroleum ether/ethyl acetate from 1/1 to 0/1 to give methyl 1 -(1 - (3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylate (1 .90 g, 5.30 mmol, quantitative) as a red oil. LCMS (ESI) m/z: [M+H]+ = 359.3.
Figure imgf000109_0001
To a stirred solution of methyl 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylate (400 mg, 1 .12 mmol) in tetrahydrofuran (4 ml_) was added aqueous sodium hydroxide (2 M,
1 .68 ml_). The mixture was stirred at 40 °C for 2 h, then the mixture was acidified with concentrated hydrochloric acid until pH 1 . The mixture was extracted with dichloromethane (20 ml_ x 3), then the organic layer was washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3- carbonyl)piperidine-4-carboxylic acid (300 mg, 871 mitioI, 78 %) as a white solid that was used directly without further purification.
Step 4: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-phenyl- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin-2-one
Figure imgf000109_0002
To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylic acid (253 mg, 734 pmol) in N,N-dimethylformamide (1 ml_) was added (2-(1 H-benzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (279 mg, 734 pmol) and N-ethyl-N-(propan-2- yl)propan-2-amine (285 mg, 2.20 mmol, 384 mI_). The mixture was stirred at 25 °C for 5 min, then N- hydroxybenzimidamide (100 mg, 734 mitioI) was added. The mixture was warmed to 25 °C, stirred for 16 h, then the mixture was diluted with water (5 ml_) and extracted with ethyl acetate (20 ml_ x 3). The organic layers were combined and washed with water (5 ml_ x 2) and saturated aqueous sodium chloride solution (5 ml_), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was dissolved in N,N-dimethylformamide (2 ml_) and then heated at 120 °C for 3 h.
Without any additional work-up, the mixture was purified by prep-HPLC (Waters X bridge 1 50x25 5 pm column; 36-66 % acetonitrile in a 1 0 mM ammonium acetate solution in water, 12 min gradient) to give 1 - (3,4-dimethylphenyl)-4-(4-(3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (73 mg, 164 pmol, 22 %) as a white solid. Ή NMR (400MHz, CDCh) d 8.1 0-8.09 (m, 2H), 7.55-7.49 (m, 3H), 7.39 (s, 1 H), 7.30 (s, 1 H), 7.15-7.13 (d, 1 H), 4.54-4.53 (m, 1 H), 4.31 -4.27 (m, 1 H), 3.98-3.90 (m., 2H), 3.60-3.56 (m, 1 H), 3.42-3.36 (m, 2H).3.15-2.95 (m, 2H), 2.86-2.79 (m, 1 H), 2.29-2.26(m, 8H), 2.03-1 .97 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 445.3.
Figure imgf000110_0001
To a stirred solution of 4-methylbenzonitrile (1 .0 g, 8.54 mmol, 1 .02 ml_) in ethanol (10 ml_) and water (1 ml_) was added hydroxylamine hydrochloride (1 .19 g, 17.1 mmol) and triethylamine (1 .73 g, 1 7.1 mmol, 2.37 ml_). The mixture was heated at 75 °C for 16 h, then the reaction mixture was concentrated under reduced pressure to give a residue that was diluted with water (5 ml_), and then extracted with dichloromethane (8 ml_ x 10). The combined organic layers were washed with saturated aqueous sodium chloride solution (8 ml_ x 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a N-hydroxy-4-methylbenzimidamide (900 mg, 5.99 mmol, 70 %) as a light green solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.49 (d, J=8.2 Hz, 2H), 7.18 (d, J=7.9 Hz, 2H), 2.33 (s, 3H).
Step 2: Preparation of methyl 1-(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin-2-one
Figure imgf000110_0002
To a stirred solution of methyl 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylate (229 mg, 666 pmol) in N,N-dimethylformamide (1 ml_) was added (2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (253 mg, 666 pmol) and N-ethyl-N-(propan-2- yl)propan-2-amine (258 mg, 2.00 mmol, 349 mI_). The mixture was stirred at 25 °C for 5 mins, then N- hydroxy-4-methylbenzimidamide (100 mg, 666 pmol) was added. After 16 h, the reaction mixture was extracted with ethyl acetate (5 ml_ x 3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 ml_ x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150x25 5pm; mobile phase: [water(10mM NhUHCOsl-acetonitrile]; B%: 40%-70%,12min) to give 1 -(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (38 mg, 81 mitioI, 12%, 98.4% purity) as a white solid. Ή NMR (400MHz, CHLOROFORM-d) d = 7.89 (d, J=7.1 Hz, 2H), 7.29 (s, 1 H), 7.22 (t, J=7.9 Hz, 3H), 7.05 (d, J=8.2 Hz, 1 H), 4.50 - 4.38 (m, 1 H), 4.20 (t, J=8.4 Hz, 1 H), 3.95 - 3.79 (m, 2H), 3.49 (td, J=8.5, 1 6.9 Hz, 1 H), 3.36 - 3.20 (m, 2H), 3.12 - 2.97 (m, 1 H), 2.89 (id, J=8.7, 17.1 Hz, 1 H), 2.79 - 2.69 (m, 1 H), 2.35 (s, 3H), 2.18 (d, J=13.0 Hz, 7H), 2.00 - 1 .82 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3.
Figure imgf000111_0001
To a stirred solution of 3-methylbenzonitrile (1 .0 g, 8.54 mmol, 1 .02 ml_) in ethanol (10 ml_) and water (1 ml_) was added hydroxylamine hydrochloride (1 .19 g, 17.1 mmol) and triethylamine (1 .73 g, 17.1 mmol, 2.37 ml_). The mixture was heated at 75 °C for 16 h and then concentrated under reduced pressure to give a residue that was then diluted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution (5mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give N-hydroxy-3-methyl-benzamidine (1 .05 g, solid) as a crude solid that was used directly in the next step without further purification. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.42 - 7.31 (m, 2H), 7.24 - 7.12 (m, 2 FI), 4.93 - 4.71 (s, 1 H), 3.67 - 3.58 (m, 1 H), 2.97 (q, J=7.3 Hz, 1 H), 2.30 (s, 3H), 1 .32 - 1 .23 (m, 1 H), 1 .18 - 1 .1 1 (m, 1 H).
Step 2: Preparation of 1 -(3,4-dimethylphenyl)-4-(4-(3-(m-tolyl)- 1 ,2,4-oxadiazoi-5-yi)piperidine- 1 - carbonyl)pyrrolidin-2-one
Figure imgf000111_0002
To a stirred solution of 1 -[1 -(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidine-4- carboxylic acid (229 mg, 666 pmol) in N,N-dimethylformamide (1 ml_) was added (2-(1 H-benzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (253 mg, 666 pmol) and N-ethyl-N-(propan-2- yl)propan-2-amine (258 mg, 2.00 mmol, 349 mI_). The mixture was stirred at 25 °C for 5 mins then N- hydroxy-3-methyl-benzamidine (100 mg, 666 pmol) was added. After 16 h, the reaction mixture was diluted with water (1 ml_) extracted with ethyl acetate (5 ml_ x 3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 ml_ x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue that was purified by prep-HPLC (Waters X bridge 150x25 5pm column, 41 %-71 % acetonitrile in an a 10 mM ammonium acetate solution in water, 12 min gradient) to give 1 -(3,4-dimethylphenyl)-4-[4-[3-(m-tolyl)-1 ,2,4-oxadiazol- 5-yl]piperidine-1 -carbonyl]pyrrolidin-2-one (1 18 mg, 266 mitioI, 38 %) as a yellow solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.93 - 7.83 (m, 1 H), 7.40 - 7.30 (m, 3H), 7.16 - 7.07 (m, 1 H), 4.58 - 4.45 (m, 1 H), 4.29 - 4.25 (m 1 H), 4.00 -3.90 (m, 2H), 3.59 - 3.55 (m, 1 H), 3.43 - 3.24 (m, 2H), 3.19 - 3.01 (m, 1 H), 3.01 - 2.89 (m, 1 H), 2.87 - 2.74 (m, 1 H), 2.43 (s, 3H), 2.27 - 2.22 (m, 8H), 2.07 - 1 .90 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3.
Figure imgf000112_0001
Step 1: Preparation of 3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile
Figure imgf000112_0002
To a stirred solution of 6-bromo-2H-benzo[b][1 ,4]oxazin-3(4H)-one (3.0g, 13.2 mmol) in N,N- dimethylformamide (35 ml_) was added zinc cyanide (1 .24 g, 10.5 mmol, 668 mI_) and
tetrakis(triphenylphosphine)palladium(0) (760 mg, 658 pmol) under nitrogen. The mixture was then stirred at 80 °C for 16 h, cooled to room temperature, and extracted with ethyl acetate (60 ml_ x 4). The combined organic layers were washed with saturated aqueous sodium chloride solution (15 ml_) and dried over anhydrous sodium sulfate. The combined organic layers were concentrated to dryness to give the crude product. The crude product was further purified by trituration in ethyl acetate and used in the next step without further purification. 3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile (3.40 g) was obtained as a white solid. LCMS (ESI) m/z: [M+H]+ = 1 75.0.
Figure imgf000112_0003
To a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile (3.30 g, 19.0 mmol) in N,N-dimethylformamide (35 mL) was added sodium hydride (758 mg, 19 mmol, 60% dispersion in mineral oil) and iodoethane (3.84 g, 25 mmol, 1 .97 mL) at 0 °C. The mixture was warmed to 20 °C. After 3 h, the mixture was cooled to 0 °C, quenched by addition of water (50 ml_), and extracted with ethyl acetate (60 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50:1 to 5:1 ) to give 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile (1 .30 g, 6.43 mmol, 34 %) as a white solid. 1 H NMR (400 MHz, CDCte) d 7.25 (dd, J = 1 .8, 8.3 Hz, 1 H), 7.17 (d, J = 1 .8 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H), 4.62 (s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 1 .23 (t, J = 7.2 Hz, 3H); LCMS (ESI) m/z = 203.1
[M+H]+.
Step 3: Preparation of 4-ethyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboximidamide
Figure imgf000113_0001
To a stirred solution of 4-ethy!-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitri!e (1 .20 g, 5.93 mmol) In ethanol (20 mi_) was added hydroxylamine hydrochloride (825 mg, 1 1 .9 mmol), triethylamine (1 .20 g, 1 1 .9 mmol, 1 .64 mL) and water (2 mL), then the mixture was heated at 75 °C. After 5 h, the mixture was cooled to 20 °C and water (20 mL) added. The mixture was extracted with ethyl acetate (30 mL x 3), then the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-ethyl- N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carboximidamide (1 .20 g, 5.10 mmol, 86 %) as a white solid that was used directly without further purification. Ή NMR (400 MHz, DMSO-d6) d 9.61 (s,
1 H), 7.44 (d, J = 1 .6 Hz, 1 H), 7.35 (dd, J = 1 .8, 8.4 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 5.87 (s, 2H), 4.66 (s, 2H), 3.96 (q, J = 7.0 Hz, 2H), 1 .18 (t , J = 7.0 Hz, 3H).
Figure imgf000113_0002
To a stirred solution of 4-ethyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6- carboximidamide (150 mg, 638 pmol) in N,N-dimethylformamide (5 mL) was added 1 -(1 -(3,4- dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (220 mg, 638 pmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (242 mg, 638 pmol) and N-ethyl-N-
(propan-2-yl)propan-2-amine (247 mg, 1 .91 mmol, 334 pL). After 16 h at 20 °C, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 4), then the combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (E)-1 -(1 -(3,4-dimethylphenyl)-5- oxopyrrolidine-3-carbonyl)-N-((4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)(hydroxyimino)methyl)piperidine-4-carboxamide (450 mg) as a yellow oil. This material was used directly without further purification. LCMS (ESI) m/z = 562.3 [M+H]+.
Figure imgf000114_0001
(E)-1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N-((4-ethyl-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)(hydroxyimino)methyl)piperidine-4-carboxamide (450 mg, 801 pmol) was heated in N,N-dimethylformamide (3 mL) at 120 °C for 3 h. The mixture was cooled and purified directly by prep- HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-65%,12 min) to give 6-(5-(1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidin-4-yl)- 1 ,2,4-oxadiazol-3-yl)-4-ethyl-2H-benzo[b][1 ,4]oxazin-3(4H)-one (142 mg, 255 pmol, 32 %) as a white solid. Ή NMR (400 MHz, CDCh) d 7.70-7.60 (m, 2H), 7.29 (s, 1 H), 7.22-7.1 9 (m, 1 H), 7.03 (dd, J = 8.3, 16.9 Hz, 2H), 4.60 (s, 2H), 4.56-4.40 (m, 1 H), 4.21 (d, J = 7.3 Hz, 1 H), 4.00 (d, J = 6.5 Hz, 2H), 3.96-3.78 (m, 2H), 3.49 (quin, J = 8.3 Hz, 1 H), 3.37-3.19 (m, 2H), 3.09-2.82 (m, 2H), 2.81 -2.69 (m, 1 H), 2.18 (d, J = 12.8 Hz, 8H), 1 .98-1 .82 (m, 2H), 1 .26 (t, J = 6.8 Hz, 3H); LCMS (ESI) [M+H]+ = 544.2.
Figure imgf000114_0002
To a stirred solution of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1 .31 mmol) in
N,N-dimethylformamide (10 mL) was added morpholine (136 mg, 1 .57 mmol, 138 pL), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1 .31 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (338 mg, 2.62 mmol, 457 mI_). The mixture was stirred at 20 °C for 16 h, then quenched with water (10 ml_) and extracted with ethyl acetate (20 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 4-(morpholine-4-carbonyl)piperidine-1 - carboxylate (700 mg) as a yellow oil. This material was used directly without further purification. 1 H NMR (400 MHz, CDCh) d 3.72-3.51 (m, 5H), 3.45 (br. s., 1 H), 3.1 8-3.05 (m, 1 H), 2.93-2.86 (m, 3H), 2.81 (s, 3H), 2.75-2.71 (m, 2H), 2.59-2.48 (m, 1 H), 1 .39 (s, 9H).
Figure imgf000115_0001
To a stirred solution of tert-butyl 4-(morpholine-4-carbonyl)piperidine-1 -carboxylate (700 mg, 2.35 mmol) in methanol (5 ml_) was added 4N hydrochloric acid in methanol (15 ml_). The mixture was stirred at 20 °C for 16 h then concentrated under reduced pressure to give morpholino(4-piperidyl)methanone (300 mg) as a colorless oil that was used directly without further purification. LCMS (ESI) [M+H]+ = 199.1 .
Figure imgf000115_0002
To a stirred solution of N-hydroxybenzamidine (2.0 g, 14.69 mmol) in dioxane (10 ml_) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (2.46 g, 16 mmol, 2.44 ml_) and 1 ,1’-carbonyldiimidazole (3.57 g, 22 mmol). The mixture was stirred at 1 10 °C for 16 h, then cooled and quenched with water (10 ml_). The mixture was extracted with dichloromethane (50 ml_ x 4), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 : 1 ) to give 3-phenyl-1 ,2,4-oxadiazol-5(4H)-one (1 .30 g, 8.02 mmol, 55 %) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 7.83-7.75 (m, 2H), 7.66-7.52 (m, 3H); LCMS (ESI) m/z = 163.2 [M+H]+.
Step 4: Preparation of 5-chloro-3-phenyl- 1 ,2,4-oxadiazole
Figure imgf000115_0003
To a stirred solution of 3-phenyl-1 ,2,4-oxadiazol-5(4H)-one (500 mg, 3.08 mmol) equipped with calcium chloride tube was added N,N-dimethylformamide (1 ml_). Phosphoryl chloride (10 ml_) was added dropwise, and the resulting mixture was heated at 1 10 Ό for 16 h. The reaction mixture was cooled to 20 °C and poured onto ice water (100 ml_), and the resulting mixture was stirred for 30 min. The mixture was extracted with dichloromethane (20 ml_ x 5), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50:1 ) to give 5-chloro-3-phenyl-1 ,2,4-oxadiazole (180 mg, 997 mitioI, 32 %) as a yellow oil. 1 H NMR (400 MHz, CDC ) 6 8.10-7.98 (m, 2H), 7.57-7.46 (m, 3H).
Figure imgf000116_0001
To a stirred solution of morpholino(piperidin-4-yl)methanone (180 mg, 908 pmol) in N-methyl-2- pyrrolidone (5 ml_) was added 5-chloro-3-phenyl-1 ,2,4-oxadiazole (163 mg, 908 pmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (234 mg, 1 .82 mmol, 317 mI_). The mixture was stirred at 120 °C for 16 h then cooled and purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm; mobile phase: [water (1 0 mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give morpholino(1 -(3- phenyl-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)methanone (130 mg, 380 mitioI, 42 %) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 8.00-7.94 (m, 2H), 7.55-7.45 (m, 3H), 4.26 (d, J = 13.3 Hz, 2H), 3.74- 3.59 (m, 8H), 3.32-3.26 (m, 2H), 3.08-2.98 (m, 1 H), 1 .92-1 .75 ppm (m, 4H); LCMS (ESI) [M+H]+ = 343.2.
Example 6: ( 1-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1- yl)methanone
Figure imgf000116_0002
To a mixture of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1 .31 mmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1 .31 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (338 mg, 2.62 mmol, 457 mI_) in N,N-dimethylformamide (1 ml_) was added piperidine (133 mg, 1 .57 mmol, 155 mI_) at 0°C. The mixture was stirred at 25 °C for 2 h. The residue was poured into water (5 ml_). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 4-(piperidine-1 - carbonyl)piperidine-1 -carboxylate (600 mg) as a yellow oil. This material was used directly without further purification. 1 H NMR (400MHz, CDCL) d 3.73 (dd, J = 6.4, 9.9 Hz, 1 H), 3.55 (br. s., 2H), 3.44 (br. s., 2H), 3.29-3.15 (m, 2H), 2.68-2.57 (m, 1 H), 1 .96-1 .83 (m, 1 H), 1 .77-1 .62 (m, 8H), 1 .56 (br. s., 4H), 1 .46 (s, 9H); LCMS (ESI) m/z = 297.3 [M+H]+.
Figure imgf000117_0001
To a mixture of tert-butyl 4-(piperidine-1 -carbonyl)piperidine-1 -carboxylate (500 mg, 1 .69 mmol) in methanol (5 ml_) was added 4M methanolic hydrochloric acid (10 ml_) at 0Ό. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give piperidin-1 -yl(piperidin-4-yl)methanone (300 mg) as a yellow oil which was used in the next step directly without further purification. LCMS (ESI) [M+H]+ = 197.3.
Step 3: Preparation of 3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5(4H)-one.
Figure imgf000117_0002
A mixture of N-hydroxy-3,4-dimethoxybenzimidamide (1 .0 g, 5.10 mmol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (853 mg, 5.61 mmol, 845 pL) and 1 ,1’-carbonyldiimidazole (1 .24 g, 7.65 mmol) in dioxane (10 mL) was prepared at 15°C. The mixture was warmed to 1 1 0Ό for 12 h. The mixture was cooled to 15°C and then poured into water (5 mL). The aqueous phase was extracted with dichloromethane (10 mL x 5), then the combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (800 mg) as a yellow solid. 1 H NMR (400MHz, CDCh) d 7.60-7.52 (m, 2H), 6.88 (d, J = 8.8 Hz, 1 H), 3.91 (d, J = 6.1 Hz, 6H); LCMS (ESI) m/z = 223.2 [M+H]+.
Figure imgf000117_0003
3-(3,4-Dimethoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (500 mg, 2.25 mmol) was added to a mixture of phosphoryl chloride (13.2 g, 86.1 mmol, 8 ml_) and N,N-dimethylformamide (1 ml_). The mixture was equipped with a calcium chloride tube and heated at 100 °C for 16 h, at which time the mixture was cooled and concentrated in vacuo at 45 °C. The residue was poured into ice-water (w/w = 10/1 ) (1 1 ml_) and stirred for 10 min. The mixture was extracted with dichloromethane (10 ml_ x 5), then the combined organic phases were washed with saturated aqueous sodium chloride solution (2 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by
chromatography (silica, petroleum ether: ethyl acetate = 5:1 to 1 :1 gradient) to afford 5-chloro-3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazole (200 mg, 0.83 mmol, 37 %) as a yellow solid. 1 H NMR (400MHz, CDCb) d 7.67 (dd, J = 2.0, 8.4 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 3.96 (d, J = 2.4 Hz, 6H) ; LCMS (ESI) m/z =241 .1 [M+H]+. Step 5: Preparation of (1-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin- 1- yl)methanone.
Figure imgf000118_0001
To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazole (200 mg, 831 pmol) and triethylamine (252 mg, 2.49 mmol, 345 mI_) in dichloromethane (2 ml_) was added piperidin-1 - yl(piperidin-4-yl)methanone (1 63 mg, 831 pmol) at 0 °C. The mixture was warmed to 1 5 °C and stirred for 2h, then concentrated in vacuo to afford crude product. The residue was purified by prep-HPLC (column : Luna C8 1 00x30 5pm ; mobile phase: [water (1 0 mM ammonium carbonate)-acetonitrile]; B%: 20%- 55%, 1 2 min) to give (1 -(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1 - yl)methanone (36 mg, 89.7 mitioI, 1 1 %) as a yellow solid. 1 H NMR (400MHz, CDCb) d 7.61 (d, J = 8.4 Hz, 1 H), 7.51 (s, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 4.28 (d, J = 13.2 Hz, 2H), 3.95 (d, J = 8.8 Hz, 6H), 3.65- 3.41 (m, 4H), 3.30-3.1 5 (m, 2H), 2.85-2.69 (m , 1 H), 2.01 -1 .89 (m, 2H), 1 .88-1 .79 (m , 2H), 1 .68 (d, J = 4.9 Hz, 2H), 1 .61 (br. s. , 1 H) ; LCMS (ESI) m/z = [M+H]+ : 401 .2.
Figure imgf000118_0002
To a stirred solution of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (5.0 g, 1 6.4 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide (2 M, 1 6.4 mL). The mixture was stirred at 20 °C for 2 h and then acidified by the addition of concentrated hydrochloric acid until pH 1 . The mixture was extracted with dichloromethane (80 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (3.25 g, 1 1 .2 mmol, 68 %) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 7.87 (d, J= 7.5 Hz, 2H), 7.59 - 7.42 (m, 3H), 4.39 - 4.20 (m, 3H), 3.92 (d, J=14.1 Hz, 1 H), 3.24 (t, J=1 1 .5 Hz, 1 H), 2.98 - 2.88 (m, 1 H), 2.62 (s,
1 H), 2.08 - 1 .89 (m, 2H), 1 .81 - 1 .53 (m, 2H).
Step 2: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000119_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (2.0 g, 6.89 mmol) in N,N-dimethylformamide (30 ml_) was added N-hydroxy-3,4-dimethoxybenzimidamide (1 .62 g, 8.27 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (2.67 g, 20.67 mmol, 3.61 ml_) and 1 -
[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2.62 g, 6.89 mmol). The mixture was stirred at 20 °C for 2 h and then warmed at 120 °C for 2 h. The reaction mixture was quenched by addition of water (40 ml_), then the mixture was extracted with ethyl acetate (80 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 20 : 1 to 1 : 2) to give a yellow solid. The yellow solid was washed with ethyl acetate (30 ml_), then the mixture was filtered, and the filter cake was dried in vacuo to give N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (1 .29 g, 2.86 mmol, 42 %) as a white solid. 1 H NMR (400 MHz, CDCI3) d 7.92 - 7.84 (m, 2H), 7.80 (s, 1 H), 7.58 - 7.44 (m, 3H), 7.41 - 7.35 (m, 1 H), 7.28 - 7.26 (m, 2H), 6.92 (d, J= 8.9 Hz, 1 H), 4.58 - 4.47 (m, 1 H), 4.32 (d, J= 3.9 Hz, 2H), 3.99 - 3.88 (m, 7H), 3.37 - 3.06 (m, 3H), 2.28 - 2.13 (m, 2H), 2.07 - 1 .89 (m, 2H); LCMS (ESI) [M+H]+ = 451 .3.
Figure imgf000120_0001
To a stirred solution of 4-isopropylbenzoic acid (250 mg, 1 .52 mmol) in N,N-dimethylformamide (10 mL) was added methyl piperidine-4-carboxylate (261 mg, 1 .82 mmol), (2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (576 mg, 1 .52 mmol) and N-ethyl-N-(propan-2- yl)propan-2-amine (392 mg, 3.04 mmol, 530 mI_). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product methyl 1 -(4- isopropylbenzoyl)piperidine-4-carboxylate (900 mg) as a yellow oil. LCMS (ESI) m/z: 290.3 [M+H]+.
Figure imgf000120_0002
To a stirred solution of methyl 1 -(4-isopropylbenzoyl)piperidine-4-carboxylate (900 mg, 3.1 1 mmol) in tetrahydrofuran (10 mL) was added aqueous sodium hydroxide (2 M, 3.1 1 mL). The mixture was stirred at 20 °C for 16 h. The mixture was acidified to pH 1 by dropwise addition of concentrated hydrochloric acid. The mixture was extracted with dichloromethane (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 1 -(4-isopropylbenzoyl)piperidine-4- carboxylic acid (400 mg) as a yellow solid. LCMS (ESI) [M+H]+ = 276.2.
Step 3: Preparation of 3-fluoro-N-hydroxybenzimidamide.
Figure imgf000121_0001
To a stirred solution of 3-fluorobenzonitrile (1 .0 g, 8.26 mmol, 884 mI_) in ethanol (10 ml_) were added hydroxylamine hydrochloride (1 .15 g, 16.5 mmol), triethylamine (2.09 g, 20.7 mmol, 2.86 ml_), and water (1 ml_). Then the mixture was heated at 75 °C for 16 h. After cooling to 20 °C, water (10 ml_) was added to the solution. The mixture was extracted with ethyl acetate (20 ml_ x 5). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-fluoro-N-hydroxybenzimidamide (2.0 g) as a green solid that was used directly in the next step without further purification. LCMS (ESI) m/z: 155.1 [M+H]+.
Step 4: Preparation of (E)-N-((3-fluorophenyl)(hydroxyimino)methyl)-1-(4-isopropylbenzoyl)piperidine-4- carboxamide.
Figure imgf000121_0002
To a stirred solution of 1 -(4-isopropylbenzoyl)piperidine-4-carboxylic acid (400 mg, 1 .45 mmol) in N,N-dimethylformamide (10 ml_) were added 3-fluoro-N-hydroxybenzimidamide (223 mg, 1 .45 mmol), (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (550 mg, 1 .45 mmol) and N- ethyl-N-(propan-2-yl)propan-2-amine (563 mg, 4.36 mmol, 761 mI_). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (10 ml_) and then extracted with ethyl acetate (20 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give (E)-N-((3- fluorophenyl)(hydroxyimino)methyl)-1 -(4-isopropylbenzoyl)piperidine-4-carboxamide (350 mg) as a yellow oil. LCMS (ESI) m/z: 412.3 [M+H]+.
Step 5: Preparation of (4-(3-(3-fluorophenyl)- 1,2,4-oxadiazoi-5-yi)piperidin-1-yi)(4- isopropylphenyl)methanone.
Figure imgf000121_0003
(E)-N-((3-Fluorophenyl)(hydroxyimino)methyl)-1 -(4-isopropyl benzoyl)piperidine-4-carboxamide (350 mg, 851 mitioI) was added to N,N-dimethylformamide (3 mL), and the mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled and purified by direct injection and prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 50%-80%,12 min) to give (4-(3-(3-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)(4- isopropylphenyl)methanone (82 mg, 210 mitioI, 25 %) as a yellow oil. 1 H NMR (400 MHz, Methanol-d4) d 7.92 (d, J = 7.8 Hz, 1 H), 7.79 (d, J = 9.7 Hz, 1 H), 7.57 (d, J = 5.6 Hz, 1 H), 7.42-7.28 (m, 5H), 4.69-4.50 (m, 1 H), 3.89 (br. s., 1 H), 3.53-3.42 (m, 1 H), 3.39-3.34 (m, 1 H), 3.32-3.28 (m, 1 H), 2.99 (td, J = 6.9, 13.8 Hz, 1 H), 2.43-2.09 (m, 2H), 2.07-1 .83 (m, 2H), 1 .30 (s, 3H), 1 .29 (s, 3H); LCMS (ESI) m/z [M+H]+ = 394.2
Figure imgf000122_0001
To a stirred solution of 2-benzamidoacetic acid (3.0 g, 16.7 mmol) in N,N-dimethylformamide (30 mL) were added methyl piperidine-4-carboxylate (2.88 g, 20.09 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (6.35 g, 16.7 mmol), and N-ethyl-N-(propan-2-yl)propan-2- amine (6.49 g, 50.2 mmol, 8.77 mL). The mixture was stirred at 20 °C for 3 h and then quenched by addition of water (40 mL). The mixture was extracted with ethyl acetate (80 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 5:1 to 1 :1 ) to give methyl 1 -(2- benzamidoacetyl)piperidine-4-carboxylate (7.0 g, 23.0 mmol, quantitative), as a yellow oil. LCMS (ESI) m/z = 305.1 [M+H]+.
Figure imgf000122_0002
To a stirred solution of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (7.0 g, 23.0 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide (2 M, 23 mL). The mixture was then stirred at 20 °C for 16 h. The mixture was then acidified to pH 1 using concentrated hydrochloric acid and then extracted with dichloromethane (80 mL x 4). The organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (4.20 g, 14.47 mmol, 63 %) as a yellow solid. This was used directly in the next step without further purification. 1 H NMR (400 MHz, Methanol-d4) d 7.93-7.85 (m, 2H), 7.59-7.54 (m, 1 H), 7.52-7.46 (m, 2H), 4.42-4.33 (m, 1 H), 4.29 (s, 2H), 4.01 -3.87 (m, 1 H), 3.30-3.20 (m, 1 H), 2.97-2.88 (m, 1 H), 2.63-2.52 (m, 1 H), 2.06-1 .92 (m, 2H), 1 .80-1 .55 (m, 2H).
Figure imgf000123_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 689 mitioI) in N,N-dimethylformamide (4 mL) were added /V-hydroxybenzamidine (1 12 mg, 826 mitioI), N,N,N',N'- tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate (261 mg, 689 mitioI), and N,N- diisopropylethylamine (267 mg, 2.07 mmol, 360.96 mI_). The reaction mixture was then stirred at 20 °C for 2 h, quenched by addition of water (5 mL), and extracted with ethyl acetate (20 mL x4). The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to provide a crude residue. To the residue was added N,N- dimethylformamide (4 mL), and the resulting mixture was stirred at 120 Ό for 2 h, concentrated under vacuum, and purified by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-(2-oxo-2-(4-(3-phenyl-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)ethyl)benzamide (74 mg, 189 mitioI, 27 %) as a white solid. 1 H NMR (400 MHz, CDCh) d 8.13-8.08 (m, 2H), 7.88 (d, J = 7.2 Hz, 2H), 7.55-7.46 (m, 6H), 7.36 (br. s., 1 H), 4.51 (d, J = 13.7 Hz, 1 H), 4.33 (d, J = 3.8 Hz, 2H), 3.94 (d, J = 13.3 Hz, 1 H), 3.42-3.32 (m, 2H), 3.20 (t, J = 1 0.5 Hz,
1 H), 2.28 (br. s., 2H), 2.1 1 -1 .96 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 391 .1 .
Figure imgf000123_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) and N-hydroxy-4-methoxybenzimidamide (82 mg, 496 mitioI) in N,N-dimethylformamide (2 mL) were added N,N-diisopropylamine (106 mg, 827 mitioI, 144 mί) and (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (156 mg, 413 pmol) at 15 °C, then the mixture was stirred for 15h. The mixture was heated to 1 1 0 °C and stirred for 5h. After cooling, the mixture was purified directly by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 30%-65%,12 min) to give N-(2-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)benzamide (87 mg, 205 pmol, 50 %) as a yellow solid. 1 H NMR (400 MHz, Methanoi-d4) d 7.98 (d, J=8.8 Hz, 2H), 7.88 (d, J=7.5 Hz, 2H), 7.60 - 7.51 (m, 1 H), 7.51 - 7.38 (m, 2H), 7.04 (d, J=8.4 Hz, 2H), 4.46 (d, J=13.2 Hz, 1 H), 4.38 - 4.21 (m, 2H), 4.04 (d, J=13.7 Hz, 1 H), 3.86 (s, 3H), 3.47 - 3.34 (m, 2H), 3.07 (t, J=1 1 .9 Hz, 1 H), 2.31 - 2.15 (m, 2H), 2.05 - 1 .80 (m, 2H); LCMS (ESI) m/z [M+H]+ = 421 .1 .
Example 11
Figure imgf000124_0001
To a stirred solution of 3-methoxybenzonitrile (2.0 g, 1 5.0 mmol, 1 .83 mL) in ethanol (20 mL) was added hydroxylamine hydrochloride (2.09 g, 30.0 mmol), triethylamine (3.04 g, 30.0 mmol, 4.16 mL) and water (2 mL). Then the mixture was heated at 75 °C for 5 h. After cooling to 20 °C, water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL x 4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The combined organic phases were concentrated in vacuo to give N-hydroxy- 3-methoxybenzimidamide (2.60 g) as a white solid. This was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 9.67 (s, 1 H), 7.37-7.24 (m, 3H), 7.10-6.88 (m, 1 H), 5.84 (br. s., 2H), 3.82 (s, 3H).
Step 2: Preparation of N-(2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.
Figure imgf000124_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 pmol) in N,N-dimethylformamide (3 mL) were added N-hydroxy-3-methoxybenzimidamide (82 mg, 496 pmol), (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 pmol), and N- ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 pL). The mixture was stirred at 20 °C for 2 h, then heated at 120 Ό for 2 h. The reaction mixture was cooled and purified directly by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-60%,12 min) to give N-(2-(4-(3-(3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (83 mg, 198 mitioI, 48 %) as a yellow solid. 1 H NMR (400 MHz, CDCh) d 7.91 -7.85 (m, 2H), 7.72-7.68 (m, 1 H), 7.62 (dd, J = 1 .5, 2.5 Hz, 1 H), 7.57-7.52 (m, 1 H), 7.51 -7.45 (m, 2H), 7.42 (t, J = 8.0 Hz, 1 H), 7.38-7.32 (m, 1 H), 7.08 (ddd, J = 0.9, 2.6, 8.3 Hz, 1 H), 4.52 (d, J = 13.6 Hz, 1 H), 4.33 (d, J = 4.0 Hz, 2H), 3.95 (br. s., 1 H), 3.91 (s, 3H), 3.42-3.32 (m, 2H), 3.25-3.13 (m, 1 H), 2.33-2.22 (m, 2H),
2.1 1 -1 .94 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 421 .2.
Figure imgf000125_0001
Step 1: Preparation of N-hydroxy-2-methoxybenzimidamide.
Figure imgf000125_0002
To a stirred solution of 2-methoxybenzonitrile (2.0 g, 1 5.0 mmol, 1 .83 ml_) in ethanol (20 ml_) were added hydroxylamine hydrochloride (2.09 g, 30.0 mmol), triethylamine (3.04 g, 30.0 mmol, 4.16 ml_), and water (2 ml_), then the mixture was heated to 70 °C for 15h. The mixture was cooled and quenched with water (20 ml_), extracted with dichloromethane (30 ml_ x 3), and the combined organic phases were washed with water (20 ml_), saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give N-hydroxy-2-methoxybenzimidamide (2.80 g) as a light green solid, which was used in next step directly. 1 H NMR (400 MHz, Methanol-d4) d 7.47 - 7.30 (m, 2H), 7.06 (d, J=8.4 Hz, 1 H), 6.95 (t, J=7.5 Hz, 1 H), 3.86 (s, 3H).
Step 2: Preparation of N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000125_0003
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 pmol) and N-hydroxy-2-methoxybenzimidamide (68 mg, 413 pmol) in N,N-dimethylformamide (2 ml_) were added N- ethyl-N-(propan-2-yl)propan-2-amine (106 mg, 826 mitioI, 144 mI_) and (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI), and the mixture was stirred for 15 h at 15 °C. The mixture was then heated to 1 1 0 °C and stirred for 5h. After cooling, the mixture was purified directly by prep-HPLC (column: Luna C8 100x30 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%-60%,12 min) to give N-(2-(4-(3-(2-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (90 mg, 212 pmol, 51 %) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 7.96 (d, J=7.5 Hz, 1 H), 7.88 (d, J=7.9 Hz, 2H), 7.61 - 7.41 (m, 4H), 7.18 (d, J=8.8 Hz, 1 H), 7.09 (t, J=7.5 Hz, 1 H), 4.47 (d, J=13.2 Hz, 1 H), 4.37 - 4.23 (m, 2H), 4.12 - 4.00 (m, 1 H), 3.93 (s, 3H), 3.50 - 3.35 (m, 2H), 3.08 (t, J=1 1 .5 Hz, 1 H), 2.33 - 2.1 5 (m, 2H), 2.12 - 1 .79 (m, 2H); LCMS (ESI) m/z: [M+H]+
= 421 .1 .
Example 13: N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-4- methyl-benzamide.
Figure imgf000126_0001
Step 1: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-4- methylbenzamide.
Figure imgf000126_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 pmol) in N,N-dimethylformamide (2 ml_) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 mI_) and 2-[(4-methylbenzoyl)amino]acetic acid (105 mg, 544 pmol). The mixture was stirred at 20 °C for 5 h. The crude product was purified by prep-HPLC (column: Luna C8 100x30mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%:30%-60%,12 min) to give N-(2-(4-(3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)-4-methylbenzamide.
1 H NMR (400MHz, METHANOL-d4) d = 7.77 (d, J=7.5 Hz, 2H), 7.66 (d, J=8.2 Hz, 1 H), 7.59 (s, 1 H), 7.29 (d, J=7.7 Hz, 2H), 7.08 (d, J=8.4 Hz, 1 H), 4.47 (d, J=12.8 Hz, 1 H), 4.29 (m, J=6.0 Hz, 2H), 4.05 (d, J=14.1 Hz, 1 H), 3.89 (s, 6H), 3.50 - 3.34 (m, 3H), 3.06 (t, J=12.0 Hz, 1 H), 2.40 (s, 3H), 2.32 - 2.13 (t, 2H), 2.07 - 1 .79 (m, 3H); LCMS (ESI) m/z: [M+H]+ = 465.3.
Example 14: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3- methylbenzamide.
Figure imgf000127_0001
Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-oxoethyl)-3- methylbenzamide
Figure imgf000127_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (200 mg, 691 pmol) in N,N-dimethylformamide (2 ml_) was added N-ethyl-N-(propan-2-yl)propan-2-amine (268 mg, 2.07 mmol, 362 mI_), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (262 mg, 691 pmol) and 2-[(3-methylbenzoyl)amino]acetic acid (133 mg, 691 pmol). The mixture was stirred at 20 °C for 16 h. The crude product was purified by prep-HPLC (column: Luna C8 100x30 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]-3-methyl-benzamide (157 mg, 338 mitioI, 49 %) as a white solid. Ή NMR (400MHz, DMSO-d6) d = 8.48 (t, J=5.5 Hz, 1 H), 7.72 - 7.63 (m, 2H), 7.58 (dd, J=2.0, 8.4 Hz, 1 H), 7.46 (d, J=1 .8 Hz, 1 H), 7.34 (d, J=4.9 Hz, 2H), 7.1 1 (d, J=8.4 Hz, 1 H), 4.32 (br d, J=13.0 Hz, 1 H), 4.1 5 (dd, J=2.3, 5.4 Hz, 2H), 3.96 (d, J=13.7 Hz, 1 H), 3.87 - 3.77 (m, 6H), 3.51 - 3.39 (m,
1 H), 3.24 (s, 1 H), 2.90 (t, J=1 1 .6 Hz, 1 H), 2.35 (s, 3H), 2.20 - 2.04 (m, 2H), 1 .89 - 1 .75 (m, 1 H), 1 .72 - 1 .54 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 465.3.
Figure imgf000128_0001
Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-oxoethyl)-3,4- dimethylbenzamide
Figure imgf000128_0002
To a stirred solution of 1 -[2-[(3,4-dimethylbenzoyl)amino]acetyl]piperidine-4-carboxylic acid (200 mg, 628 mitioI) and N-hydroxy-3,4-dimethoxy-benzamidine (184 mg, 942 mitioI) in N,N-dimethylformamide (1 .50 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (238 mg, 628 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (243 mg, 1 .88 mmol, 329 mI_). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. N,N-Dimethylformamide (2 mL) was added, then the mixture was heated to 120 °C and stirred for a further 4 h. The mixture was cooled to 25 °C, then water (5mL) was added, and the mixture extracted with ethyl acetate (1 0 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. This residue was purified by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-65%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]- 3,4-dimethyl-benzamide (209 mg, 436 mitioI, 69 %) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) d = 8.40 (s, 1 H), 7.66 (s, 1 H), 7.59 (br d, J=7.9 Hz, 2H), 7.46 (s, 1 H), 7.21 (br d, J=7.7 Hz, 1 H), 7.1 1 (br d, J=8.4 Hz, 1 H), 4.32 (br d, J=12.6 Hz, 1 H), 4.14 (br s, 2H), 3.96 (br d, J=13.5 Hz, 1 H), 3.89 - 3.72 (m, 6H), 3.43 (br t, J=10.8 Hz, 1 H), 3.28 - 3.17 (m, 1 H), 2.90 (br t, J=1 1 .5 Hz, 1 H), 2.26 (s, 6H), 2.20-2.10 (m, 2H), 1 .80 (br d, J=10.4 Hz, 1 H), 1 .64 (br d, J=10.1 Hz, 1 H). (ESI) m/z: [M+H]+ = 479.3. Example 16: N-(2-(4-(3-(4-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide
Figure imgf000129_0001
To a stirred solution of 3,4-dimethylbenzoic acid (2.0 g, 13.3 mmol) and tert-butyl 2-aminoacetate (1 .92 g, 14.7 mmol) in N,N-dimethylformamide (20 ml_) were added N-ethyl-N-(propan-2-yl)propan-2- amine (3.44 g, 26.6 mmol, 4.65 ml_) and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (5.06 g, 13.3 mmol). After stirring at 1 5 °C for 3h, the mixture was treated with water (30 ml_), extracted with ethyl acetate (30 ml_ x 3), and the combined organic phases were washed with water (20 ml_), 1 N hydrochloric acid (30 ml_), saturated aqueous sodium hydrogen carbonate (30 ml_), saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 2-(3,4-dimethylbenzamido)acetate (4.0 g) as light brown oil, which was used in the next step directly without further purification. 1 H NMR (400 MHz, CDCh) d 7.52 (d, J=1 .6 Hz, 1 H), 7.46 (dd, J=1 .9, 7.9 Hz, 1 H), 7.1 1 (d, J=7.8 Hz, 1 H), 4.08 - 4.04 (m, 2H), 2.23 (s, 6H), 1 .44 (s, 9H).
Figure imgf000129_0002
A solution of tert-butyl 2-(3,4-dimethylbenzamido)acetate (4.0 g, 15.2 mmol) in TFA (20 ml_) and dichloromethane (20 ml_) was stirred for 20 h at 15 °C. The mixture was concentrated, and the residue was treated with water (1 0 ml_) and extracted with dichloromethane/methanol (20/1 , 20 ml_ x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2- (3,4-dimethylbenzamido)acetic acid (3.20 g) as a yellow oil, which was used in next step directly without further purification.
Step 3: Preparation of methyl 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate.
Figure imgf000130_0001
To a stirred solution of 2-(3,4-dimethylbenzamido)acetic acid (3.20 g, 15.4 mmol) and methyl piperidine-4-carboxylate (2.65 g, 18.5 mmol) in N,N-dimethylformamide (20 ml_) were added N-ethyl-N- (propan-2-yl)propan-2-amine (3.99 g, 30.9 mmol, 5.39 ml_) and (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (5.86 g, 15.4 mmol) at 0 °C, then the mixture was warmed slowly to 15 Ό and stirred for 15h. The mixture was treated with water (30 ml_) at 0 °C, extracted with ethyl acetate (50 ml_ x 3). The combined organic phase was washed with water (20 ml_), 1 N hydrochloric acid (30 ml_), saturated aqueous sodium hydrogen carbonate solution (30 ml_), saturated aqueous sodium chloride solution (30 ml_), and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Purification by chromatography (silica, petroleum ether/ethyl acetate from 10:1 to 1 :2) gave methyl 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate (3.50 g, 10.5 mmol, 68 %) as a white solid. 1 H NMR (400 MHz, CDCh) d 7.62 (s, 1 H), 7.57 (d, J= 7.9 Hz, 1 H), 7.28 (m, 1 H), 7.19 (d, J=7.5 Hz, 1 H), 4.39 (d, J=13.2 Hz, 1 H), 4.24 (d, J= 3.5 Hz, 2H), 3.78 (d, J=13.7 Hz, 1 H), 3.71 (s, 3H), 3.1 7 (t, J=1 1 .0 Hz, 1 H), 3.02 - 2.91 (m, 1 H), 2.67 - 2.54 (m, 1 H), 2.30 (s, 6H), 1 .98 (m, 2H), 1 .80 - 1 .64 (m,
2H).
Figure imgf000130_0002
To a stirred solution of methyl 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate (3.50 g, 10.5 mmol) in tetrahydrofuran (20 ml_) and methanol (20 ml_) was added aqueous sodium hydroxide (2 M, 7.90 ml_), and the mixture was stirred at 15 °C for 5h. The mixture was concentrated to remove tetrahydrofuran and methanol, then then residue was acidified by 1 N hydrochloric acid to pH = 2-3 at 0 °C. The mixture was then extracted with dichloromethane (20 ml_ x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (column: Phenomenex luna C18 250x50mm 10 pm ;mobile phase: [water (0.1 %TFA)-acetonitrile]; B%: 10%-40%, 20min) to give 1 -(2-(3,4- dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (1 .80 g, 5.65 mmol, 54 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) 68.39 (s, 1 H), 7.67 (s, 1 H), 7.61 (d, J= 7.7 Hz, 1 H), 7.24 (d, J= 7.7 Hz, 1 H), 4.21 (d, J=12.7 Hz, 1 H), 4.12 (d, J= 4.9 Hz, 2H), 3.85 (d, J=13.8 Hz, 1 H), 3.14 (t, J=1 1 .7 Hz, 1 H), 2.79 (t, J=1 1 .5 Hz, 1 H), 2.28 (s, 6H), 1 .86 (m, 2H), 1 .63 - 1 .32 (m, 2H).
Step 5: Preparation of N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.
Figure imgf000130_0003
To a stirred solution of 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 pmol) and N-hydroxy-4-methoxybenzimidamide (93 mg, 565 pmol) in N,N-dimethylformamide (2 ml_) was added N-ethyl-N-(propan-2-yl)propan-2-amine (121 mg, 942 mitioI, 164 pL) and (2-(1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (178 mg, 471 pmol) at 15 °C. After 15 h, the mixture was heated to 1 10 °C and stirred for 5 h. The mixture was cooled and directly purified by prep- HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 0mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give N-(2-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)-3,4-dimethylbenzamide (1 10 mg, 244 pmol, 52 %) as a light yellow solid. 1 H NMR (400 MHz, Methanol-d4) 67.98 (d, J=9.3 Hz, 2H), 7.66 (s, 1 H), 7.60 (d, J=7.5 Hz, 1 H), 7.23 (d, J=7.9 Hz, 1 H), 7.05 (d, J=9.3 Hz, 2H), 4.46 (d, J=13.2 Hz, 1 H), 4.34 - 4.23 (m, 2H), 4.04 (d, J=13.7 Hz, 1 H), 3.86 (s, 3H), 3.47 - 3.36 (m, 2H), 3.07 (t, J=1 1 .0 Hz, 1 H), 2.42 - 2.26 (s, 6H), 2.21 (d, J=17.6 Hz, 2H), 2.04 - 1 .82 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 449.2.
Example 17: N-(2-(4-(3-(3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.
Figure imgf000131_0001
To a stirred solution of 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 pmol) in N,N-dimethylformamide (3 ml_) were added N-hydroxy-3-methoxybenzimidamide (93 mg, 565 pmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 78 mg, 471 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (182 mg, 1 .41 mmol, 246 pL). The mixture was stirred at 20 °C for 2 h and then heated at 120 °C for 2 h. The reaction mixture was cooled and then purified directly by prep-HPLC (column: Luna C8 100x30 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give N-(2-(4-(3-(3-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)-3,4-dimethylbenzamide (1 19 mg, 263 pmol, 56 %) as a white solid. 1 H NMR (400MHz, CDCIs) d 7.63-7.47 (m, 4H), 7.32 (t, J = 7.9 Hz, 1 H), 7.23-7.20 (m, 1 H), 7.15-7.10 (m, 1 H), 6.98 (dd, J = 1 .8, 8.3 Hz, 1 H), 4.48-4.37 (m, 1 H), 4.22 (d, J = 3.9 Hz, 2H), 3.88-3.82 (m, 1 H), 3.81 (s, 3H), 3.31 -3.22 (m, 2H), 3.13-3.04 (m, 1 H), 2.24 (s, 6H), 2.22-2.12 (m, 2H), 2.00-1 .87 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 449.3.
Figure imgf000131_0002
Step 1: Preparation of 4-(4-(3-(3,4-dimethoxyphenyt)- 1, 2, 4-oxadiazol-5-yl)piperidine- 1 -carbonyl)- 1- phenylpyrrolidin-2-one.
Figure imgf000132_0001
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 pmol) in N,N-dimethylformamide (1 .5 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (196 mg, 518 pmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 mI_) and 5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (1 1 1 mg, 544 pmol). The mixture was stirred at 20 °C for 16 h. The mixture was filtered, and the filtrate was purified directly by prep-HPLC (column: Luna C8 100x30 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 30%-60%,12 min) to give 4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine- 1 -carbonyl]-1 -phenyl-pyrrolidin-2-one (86 mg, 181 pmol, 35 %) as a white solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.69 - 7.56 (m, 4H), 7.38 (br t, J=7.2 Hz, 2H), 7.22 - 7.16 (m, 1 H), 7.08 (br d, J=8.4 Hz, 1 H), 4.56 - 4.42 (m, 1 H), 4.19 - 4.04 (m, 3H), 3.89 (s, 6H), 3.86 - 3.81 (m, 1 H), 3.50 - 3.37 (m, 2H), 3.14 - 3.00 (m, 1 H), 2.94 - 2.78 (m, 2H), 2.31 - 2.16 (m, 2H), 2.01 - 1 .81 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 477.3.
Example 19: 4-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -(3,4- dimethylphenyl)pyrrolidin-2-one.
Figure imgf000132_0002
To a stirred solution of 1 -[1 -(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidine-4- carboxylic acid (200 mg, 581 pmol) in N,N-dimethylformamide (1 .5 mL) were added (2-(1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (220 mg, 581 pmol), N-ethyl-N-(propan-2- yl)propan-2-amine (225 mg, 1 .74 mmol, 304 pL), and N-hydroxy-3,4-dimethoxy-benzamidine (125 mg, 639 pmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (5mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in N,N- dimethylformamide (2 mL) then heated at 120 °C for 5 h. The mixture was cooled to 25 °C then diluted with water (5mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by prep- HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 0mM ammonium carbonate)- acetonitrile]; B%: 35%-65%,12 min), to give 4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine- 1 -carbonyl]-1 -(3,4-dimethylphenyl)pyrrolidin-2-one (7 mg, 15 mitioI, 3 %) as a pink solid. 1 H NMR
(400MHz, METHANOL-d4) d = 7.66 (br d, J=8.2 Hz, 1 H), 7.58 (s, 1 H), 7.36 (s, 1 H), 7.27 (br d, J=8.2 Hz,
1 H), 7.1 6 - 7.04 (m, 2H), 4.49 (br d, J=8.4 Hz, 1 H), 4.18 - 3.98 (m, 3H), 3.93 - 3.77 (m, 7H), 3.48 - 3.36 (m, 2H), 3.12 - 2.97 (m, 1 H), 2.92 - 2.78 (m, 2H), 2.32 - 2.14 (m, 8H), 2.01 - 1 .79 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 505.4.
Figure imgf000133_0001
To a stirred solution of 4-methoxybenzonitrile (2.0 g, 1 5.02 mmol) in ethanol (20 ml_) was added hydroxylamine hydrochloride (2.09 g, 30.0mmol) and triethylamine (3.04 g, 30.0mmol, 4.16 ml_) and water (2 ml_), then the mixture was heated to 70 °C for 15h. The mixture was treated with water (20 ml_) and extracted with dichloromethane (30 ml_ x 3). The combined organic phases were washed with water (20 ml_), saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude N-hydroxy-4-methoxybenzimidamide (2.50 g) as a white solid, which was used in the next step directly. 1 H NMR (400 MHz, Methanol-d4) d 7.61 - 7.48 (m, 2H), 6.98 - 6.85 (m, 2H), 3.81 (s, 3H).
Step 2: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1 -carbonyl)pyrrolidin-2-one.
Figure imgf000133_0002
To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylic acid (250 mg, 726 mitioI) and N-hydroxy-4-methoxybenzimidamide (120 mg, 726 mitioI) in N,N- dimethylformamide (3 ml_) was added N-ethyl-N-(propan-2-yl)propan-2-amine (187 mg, 1 .45 mmol, 253 mI_) and (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (275 mg, 726 mitioI), After 15h at 1 5 °C, the mixture was heated to 1 10 °C and stirred for 5 h. The reaction mixture was cooled and purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 36%-66%,12 min) to give 1 -(3,4-dimethylphenyl)-4-(4-(3-(4- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (101 mg, 213 mitioI, 29 %) as a light yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 7.98 (d, J=7.5 Hz, 2H), 7.36 (s, 1 H), 7.27 (d, J=7.9 Hz, 1 H), 7.13 (d, J=8.4 Hz, 1 H), 7.04 (d, J=8.4 Hz, 2H), 4.47 (m., 1 H), 4.19 - 3.96 (m, 3H), 3.86 (s, 3H), 3.84 - 3.78 (m, 1 H), 3.42 (m, 2H), 3.16 - 2.98 (m, 1 H), 2.93 - 2.74 (m, 2H), 2.37 - 2.10 (m, 8H), 2.02 - 1 .78 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 475.3.
Example 21 : 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)pipe idine-1- carbonyl)pyrrolidin-2-one.
Figure imgf000134_0001
To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylic acid (200 mg, 581 pmol) in N,N-dimethylformamide (3 mL) was added N-hydroxy-3- methoxybenzimidamide (96 mg, 581 pmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (220 mg, 581 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (225 mg, 1 .74 mmol, 304 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture was purified directly by prep-HPLC (column: Luna C8 1 00x30 5pm; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 40%-60%,12 min) to give 1 -(3,4-dimethylphenyl)-4-(4-(3-(3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (80 mg, 168 mitioI, 29 %) as a
Figure imgf000134_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 mitioI) in N,N-dimethylformamide (2 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 pL) and 2-[benzoyl(methyl)amino]acetic acid (105 mg, 544 pmol). The mixture was stirred at 20 °C for 5 h, then cooled and purified directly by prep-HPLC (column: Luna C8 100x30 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]-N-methyl-benzamide (133 mg, 282 mitioI, 54 %) as a white solid. Ή NMR (400MHz, DMSO-de) d = 7.59 (dd, J=1 .8, 8.4 Hz, 1 H), 7.49 - 7.32 (m,
5H), 7.27 (br d, J= 6.8 Hz, 1 H), 7.16 - 7.08 (m, 1 H), 4.44 - 4.24 (m, 2H), 4.21 - 4.03 (m, 1 H), 4.02 - 3.88 (m, 1 H), 3.88 - 3.74 (m, 6H), 3.56 (br d, J=13.7 Hz, 1 H), 3.48 - 3.33 (m, 1 H), 3.1 1 - 2.77 (m, 5H), 2.20 - 1 .99 (m, 2H), 1 .86 (br t, J=12.6 Hz, 1 H), 1 .74 - 1 .48 (m, 2H), 1 .43 - 1 .26 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 465.3.
Figure imgf000135_0001
To a stirred solution of 3,4-dichlorobenzonitrile (1 .0 g, 5.81 mmol) in ethanol (20 ml_) was added hydroxylamine hydrochloride (807 mg, 1 1 .6 mmol), triethylamine (1 .18 g, 1 1 .6 mmol, 1 .61 ml_) and water (2 ml_). The mixture was heated at 75 °C for 5 h, then cooled to 20 °C. Water (20 ml_) was added to the solution. The mixture was extracted with dichloromethane (40 ml_ x 4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml_) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 3,4-dichloro-N-hydroxybenzimidamide (1 .20 g) as a white solid. This was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 9.86 (s,
1 H), 7.87 (d, J = 1 .8 Hz, 1 H), 7.69-7.58 (m, 2H), 5.95 (s, 2H).
Step 2: Preparation of N-(2-(4-(3-(3,4-dichlorophenyl)- 1 ,2,4-oxadiazol-5-yl)pipericlin- 1 -yl)-2- oxoethyl)benzamide.
Figure imgf000135_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 688.92 mitioI) in N,N-dimethylformamide (4 ml_) was added 3,4-dichloro-N-hydroxybenzimidamide (169 mg, 826 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (261 mg, 688.92 mitioI) and N- ethyl-N-(propan-2-yl)propan-2-amine (267 mg, 2.07 mmol, 360 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture cooled then purified directly by prep-HPLC
(column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give N-(2-(4-(3-(3,4-dichlorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-oxoethyl)benzamide (92 mg, 201 mitioI, 29 %) as a white solid. 1 H NMR (400 MHz, CDCI3) d 8.14- 8.09 (m, 1 H), 7.85 (dd, J = 2.0, 8.2 Hz, 1 H), 7.78 (d, J = 7.1 Hz, 2H), 7.39 (s, 4H), 7.25 (br. s., 1 H), 4.43 (d, J = 13.7 Hz, 1 H), 4.24 (d, J = 3.5 Hz, 2H), 3.84 (d, J = 14.1 Hz, 1 H), 3.33-3.22 (m, 2H), 3.14-3.03 (m,
1 H), 2.23-2.13 (m, 2H), 1 .99-1 .86 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 459.1 .
Figure imgf000136_0001
To a stirred solution of 3,4-difluorobenzonitrile (1 .0 g, 7.19 mmol) in ethanol (20 ml_) were added hydroxylamine hydrochloride (999 mg, 14.4 mmol), triethylamine (1 .46 g, 14.4 mmol, 1 .99 ml_), and water (2 ml_). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 ml_) was added to the solution. The mixture was extracted with dichloromethane (30 ml_ x 4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, then filtered, and concentrated in vacuo to give 3,4-difluoro-N-hydroxybenzimidamide (1 .24 g) as a white solid. This was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 9.79 (s, 1 H), 7.68 (ddd, J = 2.0, 8.0, 12.2 Hz, 1 H), 7.55 (br. s., 1 H), 7.50-7.39 (m, 1 H), 5.92 (br. s., 2H).
Step 2: Preparation of N-(2-(4-(3-(3,4-difiuorophenyi)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000136_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) in N,N-dimethylformamide (4 ml_) were added 3,4-difluoro-N-hydroxybenzimidamide (85 mg, 496 mitioI), (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI), and N- ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 Ό for 2 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-60%,12 min) to give N-(2-(4-(3-(3,4-difluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (50 mg, 1 18 mitioI, 28 %) as a white solid. 1 H NMR (400 MHz, CDCh) d 7.78 (d, J = 7.1 Hz, 4H), 7.44 (d, J = 7.1 Hz, 1 H), 7.42-7.35 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 4.43 (d, J = 13.7 Hz,
1 H), 4.23 (d, J = 4.0 Hz, 2H), 3.84 (d, J = 13.7 Hz, 1 H), 3.32-3.21 (m, 2H), 3.13-3.03 (m, 1 H), 2.23-2.12 (m, 2H), 1 .99-1 .84 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 427.2.
Figure imgf000137_0001
Step 1: Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)carbamate.
Figure imgf000137_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (2.0 g, 6.91 mmol) in N,N-dimethylformamide (20 ml_) was added 2-(tert-butoxycarbonylamino)acetic acid (1 .21 g, 6.91 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (2.62 g, 6.91 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (2.68 g, 20.7 mmol, 3.62 ml_). The mixture was stirred at 15 °C for 2 h. The reaction mixture was quenched by addition of water (20 ml_), then the mixture was extracted with ethyl acetate (60 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue. Purification by chromatography (silica, petroleum ether : ethyl acetate = 5:1 to 1 :1 ) gave tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)carbamate (2.60 g, 5.82 mmol, 84 %) as a brown solid that was used directly without further purification. LCMS (ESI) m/z: [M+H]+ = 447.2.
Step 2: Preparation of 2-amino-1-(4-(3-(3,4-dimethoxyphenyi)- 1 ,2,4-oxadiazoi-5-yi)piperidin-1 - yl)ethanone.
Figure imgf000137_0003
To a stirred solution of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)carbamate (2.50 g, 5.60 mmol) in methanol (10 ml_) was added methanolic hydrogen chloride solution (4M, 30 ml_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give crude product. A part of crude product (0.1 g) was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (32 mg) for analysis. The remaining crude 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)ethanone (1 .90 g, 5.49 mmol, 98 %), obtained as a brown solid, was used directly. 1 H NMR (400 MHz, CDCIs) d 7.73-7.67 (m, 1 H), 7.58 (d, J = 1 .5 Hz, 1 H), 6.98 (d, J = 8.4 Hz,
1 H), 4.54 (d, J = 12.2 Hz, 1 H), 3.98 (d, J = 7.2 Hz, 6H), 3.84 (d, J = 12.0 Hz, 1 H), 3.54 (s, 2H), 3.34-3.21 (m, 2H), 3.08 (d, J = 12.3 Hz, 1 H), 2.21 (d, J = 13.1 Hz, 2H), 1 .98 (d, J = 9.4 Hz, 2H); LCMS (ESI) m/z: [M+H]+ = 347.1 .
Step 3: Preparation of 2-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000138_0001
To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (185 mg, 537 mitioI) in N,N-dimethylformamide (3 mL) was added 2-chlorobenzoic acid (70 mg, 447 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 mitioI), and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1 .79 mmol, 312 mI_). The mixture was stirred at 20 °C for 2 h, then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,12 min) to give 2-chloro-N-(2-(4- (3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (124 mg, 256 mitioI, 57 %) as a pink solid. 1 H NMR (400 MHz, CDCh) d 7.72 (ddd, J = 1 .9, 6.3, 7.9 Hz, 2H), 7.59 (d, J = 1 .9 Hz, 1 H), 7.49-7.33 (m, 4H), 6.98 (d, J = 8.4 Hz, 1 H), 4.52 (d, J = 13.6 Hz, 1 H), 4.36 (d, J = 4.0 Hz, 2H), 3.99 (d, J = 7.8 Hz, 6H), 3.92 (d, J = 13.8 Hz, 1 H), 3.41 -3.30 (m, 2H), 3.1 6 (t, J = 10.9 Hz, 1 H), 2.33-2.21 (m, 2H), 2.1 1 -1 .94 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 485.2.
Figure imgf000138_0002
To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (185 mg, 537 mitioI) in N,N-dimethylformamide (3 ml_) were added 3-chlorobenzoic acid (70 mg, 447 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 mitioI), and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1 .79 mmol, 312 mI_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,12 min) to give 3-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (126 mg, 261 mitioI, 58 %) as a white solid. NMR (400MHz, CDCh) d 7.89-7.86 (m, 1 H), 7.72 (d, J = 2.0 Hz, 2H), 7.59 (d, J = 1 .9 Hz, 1 H), 7.54-7.50 (m, 1 H), 7.45-7.39 (m, 1 H), 7.34 (br. s„ 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 4.53 (d, J = 14.3 Hz, 1 H), 4.31 (d, J = 3.9 Hz, 2H), 3.98 (d, J = 7.4 Hz, 6H), 3.96-3.87 (m, 1 H), 3.41 -3.30 (m, 2H), 3.18 (t, J = 10.9 Hz, 1 H), 2.33-2.22 (m, 2H), 2.10-1 .94 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 485.3.
Figure imgf000139_0001
Step 1: Preparation of 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000139_0002
To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (185 mg, 536.5 mitioI) in N,N-dimethylformamide (3 ml_) were added 4-chlorobenzoic acid (70 mg, 447 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1 .79 mmol, 312 mI_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (144 mg, 294 mitioI, 66 %) as a white solid.
Figure imgf000139_0003
NMR (400MHz, GDGb) d 7 82 (d, J = 8.5 Hz, 2H), 7.71 (dd, J = 1 .9, 8.3 Hz, 1 H), 7.59 (d, J = 1 .8 Hz, 1 H), 7.45 (d, J = 8.5 Hz, 2H), 7.33 (br. s., 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 4.52 (d, J = 14.2 Hz, 1 H), 4.31 (d, J = 3.9 Hz, 2H), 3.98 (d, J = 7.3 Hz, 6H), 3.92 (d, J = 13.7 Hz, 1 H), 3.41 -3.30 (m, 2H), 3.17 (t, J = 10.7 Hz, 1 H), 2.34-2.21 (m, 2H), 2.10-1 .94 (m, 2H); LCMS (ESI) m/z: [M÷H]+ = 485.2.
Figure imgf000139_0004
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 mitioI) in N,N-dimethylformamide (2 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 mitioI), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 mI_), and 2-benzamidopropanoic acid (105 mg, 544 mitioI). The mixture was stirred at 20 °C for 7 h, then the crude product was purified directly by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile; B%: 35%-60%,12 min] to give N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo-ethyl]benzamide (52 mg, 1 12 mitioI, 22 %) as a white solid. Ή NMR (400MHz, DMSO-d6) d = 8.63 (br dd, J=7.3, 16.1 Hz, 1 H), 7.88 (br d, J=7.3 Hz, 2H), 7.66 - 7.34 (m, 5H), 7.1 1 (br d, J=7.9 Hz, 1 H), 4.97 (br d, J=6.0 Hz, 1 H), 4.45 - 4.22 (m,
1 H), 4.08 - 3.94 (m, 1 H), 3.82 (s, 6H), 3.42 (br t, J=10.7 Hz, 1 H), 3.29 - 3.21 (m, 1 H), 3.00 - 2.80 (m, 1 H), 2.09 (br d, J=1 1 .9 Hz, 2H), 1 .87 - 1 .56 (m, 1 H), 1 .29 (s, 3H); LCMS (ESI) m/z: [M+H]+ = 465.3.
Example 29: N-( 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2-methyl-1- oxopropan-2-yl)benzamide.
Figure imgf000140_0001
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 pmol) in N,N-dimethylformamide (2 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 pmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 mI_) and 2-benzamido-2-methyl-propanoic acid (1 12 mg, 544 pmol). The mixture was stirred at 20 °C for 5 h. The crude product was purified directly by prep-HPLC (column: Waters Xbridge 1 50x25 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 27%-57%,12 min) to give N-[2-[4- [3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 ,1 -dimethyl-2-oxo-ethyl]benzamide (47 mg,
99 mitioI, 19 %) as a pale yellow solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.88 - 7.81 (m, 2H), 7.62 (dd, J=2.0, 8.4 Hz, 1 H), 7.57 - 7.51 (m, 2H), 7.49 - 7.42 (m, 2H), 7.06 (d, J=8.4 Hz, 1 H), 4.61 - 4.45 (m, 2H), 3.88 (d, J=5.1 Hz, 6H), 3.13 (s, 3H), 2.08 (br s, 2H), 1 .90 - 1 .74 (m, 2H), 1 .60 (s, 6H); LCMS (ESI) m/z: [M+H]+ = 477.1 .
Figure imgf000140_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 pmol) in N,N-dimethylformamide (1 .50 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (196 mg, 518 pmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 pL), and 2-(benzylamino)acetic acid (89 mg, 544 pmol). The mixture was stirred at 20 °C for 16 h and filtered, and the crude filtrate was purified directly by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%- 60%, 12 min) to give 2-(benzylamino)-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyljethanone (48 mg, 1 10 mitioI, 21 %) as a yellow solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.65 (dd, J=1 .8, 8.2 Hz, 1 H), 7.57 (d, J=1 .8 Hz, 1 H), 7.40 - 7.30 (m, 4H), 7.28 - 7.22 (m, 1 H), 7.06 (d, J=8.4 Hz, 1 H), 4.45 (br d, J=13.7 Hz, 1 H), 3.94 - 3.83 (m, 7H), 3.78 (s, 2H), 3.57 - 3.44 (m, 2H), 3.40 - 3.33 (m, 1 H), 3.27 - 3.20 (m, 1 H), 3.01 (t, J=1 1 .2 Hz, 1 H), 2.1 7 (dd, J=2.8, 13.3 Hz, 2H), 1 .93 - 1 .73 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 437.3.
Example 31 : 2-(benzyloxy)-1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1- yl)ethanone.
Figure imgf000141_0001
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 pmol) in N,N-dimethylformamide (2 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 pmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 pL), and 2-benzyloxyacetic acid (90 mg, 544 pmol, 77 pL). The mixture was stirred at 20 °C for 5 h. The crude product was purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 32%-62%,12 min) to give 2-benzyloxy-1 - [4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]ethanone (68 mg, 157 pmol, 30 %) as a white solid. 1 H NMR (400MHz, DMSO-d6) d = 7.60 (dd, J=1 .9, 8.3 Hz, 1 H), 7.48 (d, J=1 .9 Hz, 1 H), 7.40 - 7.35 (m, 4H), 7.34 - 7.26 (m, 1 H), 7.14 (d, J=8.4 Hz, 1 H), 4.54 (s, 2H), 4.33 (br d, J=13.2 Hz, 1 H), 4.25 (br d, J=7.8 Hz, 2H), 3.93 - 3.78 (m, 7H), 3.43 (tt, J=3.9, 1 1 .0 Hz, 1 H), 3.22 (br t, J=1 1 .7 Hz, 1 H), 2.90 (br t, J=1 1 .7 Hz, 1 H), 2.1 7 - 2.04 (m, 2H), 1 .88 - 1 .59 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 438.3.
Figure imgf000141_0002
Step 1: Preparation of tert-butyl (2-(4-(3J3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1- yl)ethyl)carbamate
Figure imgf000142_0003
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (750 mg, 2.59 mmol) in N,N-dimethylformamide (1 mL) were added cesium carbonate (844 mg, 2.59 mmol) and tert- butyl N-(2-bromoethyl)carbamate (871 mg, 3.89 mmol). The mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled then extracted with ethyl acetate (5 mL x 2). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]ethyl]carbamate (1 .30 g) which was used directly without further purification. LCMS (ESI) m/z = 433.3 [M+H]+.
Figure imgf000142_0001
A solution of tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]ethyl]carbamate (1 .0 g, 2.31 mmol) in hydrochloric acid/ethyl acetate (4M, 25 mL) was stirred at 25 °C for 30 mins. The reaction mixture was concentrated under reduced pressure to give 2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]ethanamine (750 mg) which was used directly without further purification. LCMS (ESI) m/z = 333.1 [M+H]+.
Step 3: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 - yl)ethyl)benzamide
Figure imgf000142_0002
To a mixture of 2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]ethanamine (200 mg, 602 pmol) and benzoyl chloride (109 mg, 782 mitioI, 90 pL) in dichloromethane (1 mL) was added triethylamine (182 mg, 1 .81 mmol, 250 pL) at 0 °C. The mixture was stirred at 20 °C for 5 h, then purified directly by prep-HPLC (column: Luna C8 100x30 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 35%-50%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol- 5-yl]-1 -piperidyl]ethyl]benzamide (25 mg, 56 pmol, 9 %) as a white solid. 1 H NMR (400MHz,
METHANOL-d4) d = 7.86 - 7.79 (m, 2H), 7.66 (dd, J=1 .8, 8.4 Hz, 1 H), 7.58 (d, J=1 .8 Hz, 1 H), 7.55 - 7.43 (m, 3H), 7.07 (d, J=8.6 Hz, 1 H), 3.89 (s, 6H), 3.58 (t, J=6.8 Hz, 2H), 3.1 6 - 3.09 (m, 2H), 2.67 (t, J=6.8 Hz, 2H), 2.37 - 2.29 (m, 2H), 2.18 (br d, J=1 1 .2 Hz, 2H), 2.07 - 1 .91 (m, 3H); LCMS (ESI) m/z: [M+H]+ =
437.3. Example 33: (E)-1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-4-phenylbut-2- ene-1 ,4-dione
Figure imgf000143_0001
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (250 mg, 864 pmol) in N,N-dimethylformamide (4 ml_) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (327 mg, 864 pmol), N-ethyl-N-(propan-2-yl)propan-2-amine (335 mg, 2.59 mmol, 452 mI_) and (E)-4-oxo-4-phenyl-but-2-enoic acid (152 mg, 864 pmol). The mixture was stirred at 20 °C for 5 h, then the crude mixture was purified directly by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give (E)-1 -[4-[3-(3,4- dimethoxyphenyl)-1 ,2, 4-oxadiazol-5-yl]-1 -piperidyl]-4-phenyl-but-2-ene-1 ,4-dione (1 18 mg, 251 pmol,
29 %) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) d = 8.03 (br d, J=7.3 Hz, 2H), 7.75 (d, J=15.4 Hz,
1 H), 7.71 - 7.65 (m, 1 H), 7.61 - 7.53 (m, 3H), 7.51 - 7.43 (m, 2H), 7.1 1 (d, J=8.4 Hz, 1 H), 4.41 (br d, J=13.2 Hz, 1 H), 4.1 1 - 3.99 (m, 1 H), 3.88 - 3.77 (m, 6H), 3.54 - 3.34 (m, 2H), 3.02 (br t, J=1 1 .2 Hz, 1 H), 2.15 (br d, J=13.0 Hz, 2H), 1 .88 - 1 .67 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 448.2.
Figure imgf000143_0002
To a stirred solution of 2,2,2-trifluoro-1 -phenylethanol (100 mg, 568 mitioI, 76 pL) in
dichloromethane (2 mL) were added 2,6-dimethylpyridine (121 mg, 1 .14 mmol, 132 pL) and
trifluoromethanesulfonic anhydride (288 mg, 1 .02 mmol, 168 pL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then diluted with dichloromethane (5 mL) and water (5 mL), and the phases separated. The aqueous phase was extracted with dichloromethane (1 5 mL x 2), then the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2,2,2-trifluoro-1 -phenylethyl trifluoromethanesulfonate (380 mg) as a brown oil. This material was used directly without further purification.
Step 2: Preparation of 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-((2,2,2-trifluoro- 1 -phenylethyl)amino)ethanone
Figure imgf000144_0001
To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (120 mg, 346 pmol) in dichloromethane (2.5 ml_) was added 2,2,2-trifluoro-1 -phenylethyl trifluoromethanesulfonate (213 mg, 692.88 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (179 mg, 1 .39 mmol, 242 mI_). The mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give 1 -(4-(3- (3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-((2,2,2-trifluoro-1 - phenylethyl)amino)ethanone (52 mg, 101 mitioI, 29 %) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 7.63-7.56 (m, 1 H), 7.51 -7.37 (m, 6H), 7.14 (d, J = 8.4 Hz, 1 H), 4.53-4.43 (m, 1 H), 4.30 (br. s., 1 H), 3.84
(s, 6H), 3.71 (d, J = 10.2 Hz, 1 H), 3.44-3.36 (m, 2H), 3.18-3.07 (m, 1 H), 2.99 (d, J = 5.5 Hz, 1 H), 2.87 (br. s., 1 H), 2.08 (d, J = 12.5 Hz, 2H), 1 .75-1 .56 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 505.3.
Figure imgf000144_0002
A mixture of 3-bromo-5-chloro-1 ,2,4-thiadiazole (500 mg, 2.51 mmol), tert-butyl 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (931 mg, 3.01 mmol), cesium fluoride (762 mg, 5.02 mmol, 1 85 mI_) in dioxane (3.5 ml_) was degassed and purged with nitrogen 3 times, then 4-ditert-butylphosphanyl-N,N-dimethyl-aniline;dichloropalladium (88 mg, 125.50 mitioI, 88 mI_, 0.05 eq) was added. The mixture was stirred at 80 °C for 2 h under an atmosphere of nitrogen. The mixture was cooled to 25 °C and concentrated in vacuo at 40 °C. The residue was poured into water (15 mL), the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford crude product. The crude product was purified by chromatography (silica, petroleum ether/ ethyl acetate (from 20/1 to 2/1 ) to give tert-butyl 4-(3-bromo- 1 , 2, 4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (260 mg, 750.92 mitioI, 30 %) as a yellow oil. LCMS (ESI) m/z: 368.3 [M+Na]+.
Step 2: Preparation of tert-butyl 4-(3-(3,4-dimethoxyphenyl)- 1,2,4-thiadiazol-5-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate
Figure imgf000145_0001
A mixture of tert-butyl 4-(3-bromo-1 ,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (260 mg, 751 mitioI), (3,4-dimethoxyphenyl)boronic acid (163 mg, 901 mitioI), and sodium carbonate (103 mg, 976 mitioI) in water (400 mI_) and dimethoxyethane(1 .2 mL) was degassed and purged with nitrogen 3 times, and then tetrakis(triphenylphosphine)palladium(0) (17 mg, 15 mitioI) was added. The mixture was stirred at 100 °C for 6 h under a nitrogen atmosphere. The mixture was cooled to 25 °C and concentrated in vacuo at 40 °C. The residue was poured into water (5 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford crude product. The crude residue was purified by prep-TLC (silica, petroleum ether/ ethyl acetate=3:1 ) to give tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridine-1 - carboxylate (122 mg, 303 mitioI, 40 %) as a yellow oil. LCMS (ESI) m/z: 404.1 [M+H]+.
Figure imgf000145_0002
To a stirred solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-thiadiazol-5-yl]-3,6-dihydro-2H- pyridine-1 -carboxylate (100 mg, 248 mitioI) in methanol (10 mL) was added palladium(O) on carbon (10%, 150 mg) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi) at 20 °C for 48 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- thiadiazol-5-yl]piperidine-1 -carboxylate (79 mg) that was used into the next step without further purification. LCMS (ESI) m/z: 406.2 [M+H]+.
Step 4: Preparation of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)- 1,2,4-thiadiazole
Figure imgf000146_0001
A solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-thiadiazol-5-yl]piperidine-1 -carboxylate (79 mg, 195 pmol) in hydrochloric acid/ethyl acetate (4M, 15 ml_) was stirred at 20 °C for 3 h. The reaction mixture was concentrated in vacuo to give 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4- thiadiazole (65 mg) that was used into the next step without further purification.
Step 5: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-thiadiazol-5-yl)piperidin- 1 -yl)-2- oxoethyl)benzamide
Figure imgf000146_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-thiadiazole (65 mg, 214 pmol) and 2-benzamidoacetic acid (46 mg, 257 pmol) in N,N-dimethylformamide (1 ml_) were added (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (81 mg, 214 pmol) and N-ethyl- N-(propan-2-yl)propan-2-amine (69 mg, 536 mitioI, 93 mI_). After 2 h, the reaction mixture purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-thiadiazol- 5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (10 mg, 22 pmol, 10 %) as a yellow solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.92 - 7.82 (m, 4H), 7.59 - 7.52 (m, 1 H), 7.51 - 7.44 (m, 2H), 7.06 (d, J=8.4 Hz, 1 H), 4.61 (d, J=12.9 Hz, 1 H), 4.41 - 4.24 (m, 2H), 4.1 1 (br d, J=14.9 Hz, 1 H), 3.98 - 3.84 (m, 6H), 3.63 - 3.52 (m, 1 H), 3.39 (br t, J=1 1 .7 Hz, 1 H), 2.99 (br t, J=1 1 .6 Hz, 1 H), 2.35 - 2.20 (m, 2H), 2.03 - 1 .74 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 467.2.
Figure imgf000146_0003
Figure imgf000147_0001
A mixture of tert-butyl 4-cyanopiperidine-1 -carboxylate (2.0 g, 9.51 mmol), hydroxylamine hydrochloride (1 .32 g, 19.0 mmol), and triethylamine (1 .92 g, 19.0 mmol, 2.64 ml_) in ethanol (20 ml_) and water (2 ml_) was heated at 75 °C for 16 h. The reaction mixture was cooled, diluted with water (1 0 ml_), and extracted with ethyl acetate (15 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1 - carboxylate (1 .90 g) which was used directly without further purification. 1 H NMR (400MHz, METHANOL- d4) d = 4.15 (br d, J=13.3 Hz, 2H), 2.78 (br s, 2H), 2.27 (tt, J=3.6, 12.1 Hz, 1 H), 1 .84 - 1 .70 (m, 2H), 1 .62 (dq, J=4.3, 12.6 Hz, 2H), 1 .53 - 1 .39 (m, 9H).
Figure imgf000147_0002
To a stirred solution of tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1 -carboxylate (750 mg, 3.08 mmol) in N,N-dimethylformamide (5 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (1 .17 g, 3.08 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (1 .19 g, 9.24 mmol, 1 .61 mL) and 3,4-dimethoxybenzoic acid (561 mg, 3.08 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (1 0 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Tetrahydrofuran (500 pL) and tetrabutylammonium fluoride / tetrahydrofuran (1 M, 4.62 mL) were added to the residue, and the resulting mixture was heated at 50 °C for 16 h. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=5:1 ) to give tert-butyl 4-[5-(3,4-dimethoxyphenyl)-1 ,2, 4-oxadiazol-3-yl]piperidine-1 -carboxylate (970 mg, 2.49 mmol, 81 %) as a white solid. LCMS (ESI) m/z: 412.3 [M+Na]+ = 334.2.
Figure imgf000147_0003
A solution of tert-butyl 4-[5-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl]piperidine-1 -carboxylate (750 mg, 1 .93 mmol) in hydrochloric acid / ethyl acetate (4M, 30 ml_) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 5-(3,4-dimethoxyphenyl)-3-(4-piperidyl)- 1 ,2,4-oxadiazole (683 mg) that was used directly without further purification. Step 4: Preparation of N-(2-(4-(5-(3,4-dimethoxyphenyi)- 1,2,4-oxadiazol-3-yl)piperidin- 1-yl)-2- oxoethyl)benzamide
Figure imgf000148_0001
To a stirred solution of 5-(3,4-dimethoxyphenyl)-3-(4-piperidyl)-1 ,2,4-oxadiazole (180 mg, 622 mitioI) in N,N-dimethylformamide (2 ml_) were added 2-benzamidoacetic acid (1 1 1 mg, 622 mitioI), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (235 mg, 622 mitioI), and N-ethyl-N- (propan-2-yl)propan-2-amine (241 mg, 1 .87 mmol, 325 mI_). The mixture was stirred at 20 °C for 16 h. The crude product was purified by prep-HPLC (column : Waters Xbridge 150x25 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-[2-[4-[5-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (169 mg, 376 mitioI, 60 %) as a white solid. Ή NMR (400MHz, DMSO-d6) d = 8.55 (br t, J=5.4 Hz, 1 H), 7.87 (br d, J=7.5 Hz, 2H), 7.70 (br d, J=8.4 Hz, 1 H), 7.57 - 7.41 (m, 4H), 7.17 (br d, J=8.4 Hz, 1 H), 4.34 (br d, J=12.3 Hz, 1 H), 4.16 (br d, J=4.2 Hz, 2H), 3.97 (br d, J=13.0 Hz, 1 H), 3.90 - 3.74 (m, 6H), 3.27 - 3.09 (m, 2H), 2.88 (br t, J=1 1 .6 Hz,
1 H), 2.03 (br t, J=1 1 .8 Hz, 2H), 1 .75 (br d, J=1 0.4 Hz, 1 H), 1 .59 (br d, J=9.9 Hz, 1 H); LCMS (ESI) m/z: [M+H]+ = 451 .2.
Figure imgf000148_0002
To a stirred solution of 1 -(3,4-dimethoxyphenyl)ethanone (1 .0 g, 5.55 mmol) in dichloromethane (6 mL) and methanol (3 ml_) was added benzyltrimethylammonium tribromide (2.1 6 g, 5.55 mmol). After 16 h, the mixture was diluted with dichloromethane (80 mL) and water (40 mL), the organic layer was separated, and the water phase was extracted with dichloromethane (80 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-bromo-1 -(3,4- dimethoxyphenyl)ethanone (1 .20 g, 4.63 mmol, 83 %) as a brown solid. 1 H NMR (400 MHz, CDCI3) d 7.63 (s, 1 H), 7.57 (d, J=2.1 Hz, 1 H), 6.94 (d, J=8.4 Hz, 1 H), 4.43 (s, 2H), 3.98 (d, J=8.4 Hz, 6H).
Figure imgf000149_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 689 pmol) in acetonitrile (6 ml_) was added 2-bromo-1 -(3,4-dimethoxyphenyl)ethanone (214 mg, 826 pmol) and triethylamine (209 mg, 2.07 mmol, 286 mI_) under nitrogen. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo to give 2-(3,4-dimethoxyphenyl)-2-oxoethyl 1 -(2- benzamidoacetyl)piperidine-4-carboxylate (233 mg, 497 mitioI, 72 %) as a yellow solid. This was used directly without further purification. LCMS (ESI) m/z: [M+H]+ = 469.3.
Figure imgf000149_0002
To a stirred solution of 2-(3,4-dimethoxyphenyl)-2-oxoethyl 1 -(2-benzamidoacetyl)piperidine-4- carboxylate (180 mg, 384 mitioI) in acetic acid (8 ml_) was added ammonium acetate (148 mg, 1 .92 mmol) under nitrogen, then the mixture was heated at 100 °C for 16 h. The reaction mixture was concentrated in vacuo to give crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-55%,12 min) to give N- (2-(4-(4-(3,4-dimethoxyphenyl)oxazol-2-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (55 mg, 120 mitioI, 31 %) as a pink solid. Ή NMR (400 MHz, CDCh) d 7.92 - 7.84 (m, 2H), 7.80 (s, 1 H), 7.58 - 7.44 (m, 3H), 7.41 - 7.35 (m, 1 H), 7.28 - 7.26 (m, 2H), 6.92 (d, J= 8.9 Hz, 1 H), 4.58 - 4.47 (m, 1 H), 4.32 (d, J= 3.9 Hz, 2H), 3.99 - 3.88 (m, 7H), 3.37 - 3.06 (m, 3H), 2.28 - 2.13 (m, 2H), 2.07 - 1 .89 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 450.3.
Figure imgf000149_0003
Step 1: Preparation of tert-butyl 4-carbamothioylpiperidine- 1-carboxylate.
Figure imgf000150_0001
To a stirred solution of tert-butyl 4-carbamoylpiperidine-1 -carboxylate (1 .0 g, 4.38 mmol) in a mixture of dimethoxyethane (16 ml_) and dichloromethane (8 ml_) was added 2,4-bis(4-methoxyphenyl)- 1 ,3, 2, 4-dithiadiphosphetane-2, 4-disulfide (885 mg, 2.19 mmol). The mixture was stirred at 20 °C for 16 h, then concentrated in vacuo. The residue dissolved in ethyl acetate and washed with saturated aqueous potassium carbonate (10 mL x 2). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 4-carbamothioylpiperidine-1 -carboxylate (1 .0 g) as a yellow solid. This was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 9.45 (br. s., 1 H), 9.17 (br. s., 1 H), 4.14-3.98 (m, 2H), 3.91 -3.79 (m, 1 H), 2.80-2.66 (m, 2H), 1 .74-1 .55 (m, 4H), 1 .46 (s, 9H).
Step 2: Preparation of tert-butyl 4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate.
Figure imgf000150_0002
To a stirred solution of tert-butyl 4-carbamothioylpiperidine-1 -carboxylate (200 mg, 818.5 pmol) in N,N-dimethylformamide (5 mL) was added 2-bromo-1 -(3,4-dimethoxyphenyl)ethanone (212 mg, 818.50 pmol) and potassium carbonate (124 mg, 900 pmol). The mixture was stirred at 1 10 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 4-(4-(3,4- dimethoxyphenyl)thiazol-2-yl)piperidine-1 -carboxylate (300 mg, 742 mitioI, 91 %) as a yellow solid. This was used directly without further purification. LCMS (ESI) m/z: [M+H]+ = 405.3.
Figure imgf000150_0003
To a stirred solution of tert-butyl 4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-1 -carboxylate (300 mg, 742 pmol) in methanol (3 mL) was added methanolic hydrogen chloride solution (4M, 10 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to provide 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)thiazole (260 mg) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 305.1 .
Figure imgf000150_0004
To a stirred solution of 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)thiazole (203 mg, 670 pmol) in N,N-dimethylformamide (4 ml_) were added 2-benzamidoacetic acid (100 mg, 558 pmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (21 1 mg, 558 pmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (288 mg, 2.23 mmol, 389 mI_). T he mixture was stirred at 20 °C for 16 h.
The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-(2-(4- (4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (1 1 1 mg, 239 mitioI, 43 %) as a yellow solid. Ή NMR (400 MHz, CDCh) d 7.91 -7.85 (m, 2H), 7.57-7.42 (m, 5H), 7.39 (br. s., 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 4.70 (d, J = 13.6 Hz, 1 H), 4.40-4.26 (m, 2H), 3.97 (d, J = 19.7 Hz, 7H), 3.43-3.26 (m, 2H), 3.05-2.95 (m, 1 H), 2.37-2.23 (m, 2H), 1 .98-1 .83 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 466.3.
Figure imgf000151_0001
To a stirred solution of 3,4-dimethoxybenzonitrile (2.0 g, 12.3 mmol) in dry ethanol (50 ml_) was added dropwise acetyl chloride (7.70 g, 98.1 mmol, 7.0 ml_) at 0 °C , after complete addition, the mixture was warmed to 15 °C and stirred for 30 h. The reaction was concentrated in vacuo, and then saturated hydrochloric acid in ethanol (50 ml_) was added. After 5h, the mixture was concentrated in vacuo to give crude ethyl 3,4-dimethoxybenzenecarboximidate (2.50 g) as a light yellow solid, which was used in next step directly.
Step 2: Methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate.
Figure imgf000151_0002
To a stirred solution of 2-benzamidoacetic acid (3.0 g, 16.7 mmol) and methyl piperidine-4- carboxylate (3.60 g, 25.1 mmol) in dry N,N-dimethylformamide (50 ml_) was added N-ethyl-N-(propan-2- yl)propan-2-amine (4.33 g, 33.5 mmol, 5.9 ml_) and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (7.0 g, 18.4 mmol) at 0 °C, then the mixture was warmed to 15 °C and stirred for 15h. The mixture was poured into ice water (100 ml_) then extracted with ethyl acetate (50 ml_ x 3). The combined organic phases were washed with 1 N hydrochloric acid (30 ml_ x 2), saturated aqueous sodium carbonate (30 ml_), and saturated aqueous sodium chloride solution (30 ml_), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude methyl 1 -(2- benzamidoacetyl)piperidine-4-carboxylate (5.30 g) as a brown oil, which was used in next step directly. 1 H NMR (400 MHz, Methanol-d4) d 7.87 (d, J=7.1 Hz, 2H), 7.58 - 7.51 (m, 1 H), 7.49 - 7.40 (m, 2H), 4.39 - 4.29 (m, 1 H), 4.28 - 4.17 (m, 2H), 3.96 - 3.84 (m, 1 H), 3.68 (s, 3H), 3.28 - 3.17 (m, 1 H), 2.96 - 2.86 (m,
1 H), 2.69 - 2.62 (m, 1 H), 2.00 - 1 .88 (m, 2H), 1 .78 - 1 .51 (m, 2H).
Step 3: N-(2-(4-(hydrazinecarbonyl)piperidin- 1-yl)-2-oxoethyl)benzamide.
Figure imgf000152_0001
A solution of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (500 mg, 1 .64 mmol) and hydrazine hydrate (328 mg, 6.56 mmol, 318 mI_) in methanol (3 ml_) was heated to 80 °C for 15 h. The mixture was concentrated in vacuo to give a crude residue that was washed with tert-butyl methyl ether (10 mL) to obtain N-[2-[4-(hydrazinecarbonyl)-1 -piperidyl]-2-oxo-ethyl]benzamide (500 mg) as a light yellow solid that was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 9.03 (s,
1 H), 8.54 (t, J=5.6 Hz, 1 H), 7.94 - 7.82 (m, 2H), 7.60 - 7.43 (m, 3H), 4.41 - 4.29 (m, 1 H), 4.13 (d, J=5.6 Hz, 2H), 3.93 (d, J=12.9 Hz, 1 H), 3.05 (t, J=1 1 .9 Hz, 1 H), 2.68 - 2.57 (m, 1 H), 2.34 (tdd, J=3.9, 7.5, 1 1 .2 Hz, 1 H), 1 .73 - 1 .34 (m, 4H).
Figure imgf000152_0002
A solution of N-[2-[4-(hydrazinecarbonyl)-1 -piperidyl]-2-oxo-ethyl]benzamide (200 mg, 657 mitioI) and ethyl 3,4-dimethoxybenzenecarboximidate (151 mg, 723 mitioI) in ethanol (4 ml_) was heated to 80 °C for 15h. The mixture was concentrated to give a crude product, which was purified by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-35%,12 min) to give N-[2-[4-[5-(3,4-dimethoxyphenyl)-1 ,3,4-oxadiazol-2-yl]-1 -piperidyl]-2-oxo- ethyl]benzamide (23 mg, 48 mitioI, 7 %) as a white solid. 1 H NMR (400 MHz, Methanol-d4) d 7.92 - 7.82 (m, 2H), 7.62 (dd, J=1 .8, 8.4 Hz, 1 H), 7.59 - 7.52 (m, 2H), 7.51 - 7.44 (m, 2H), 7.12 (d, J=8.4 Hz, 1 H),
4.49 (d, J=13.2 Hz, 1 H), 4.38 - 4.24 (m, 2H), 4.06 (d, J=13.7 Hz, 1 H), 3.97 - 3.80 (m, 6H), 3.48 - 3.34 (m, 2H), 3.06 (t, J=1 1 .2 Hz, 1 H), 2.33 - 2.1 5 (m, 2H), 2.06 - 1 .94 (m, 1 H), 1 .92 - 1 .75 (m, 1 H) ; LCMS (ESI) m/z: [M+H]+ = 451 .2.
Example 40: N-(2-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.
Figure imgf000153_0001
Step 1: Preparation of 1 ,3-dimethyl- 1 H-indazole-6-carbonitrile.
Figure imgf000153_0002
To a stirred solution of 6-bromo-1 ,3-dimethyl-1 H-indazole (400 mg, 1 .78 mmol) in N,N- dimethylformamide (5 ml_) was added zinc cyanide (209 mg, 1 .78 mmol, 1 12 mI_) and
tetrakis(triphenylphosphine)palladium(0) (205 mg, 1 78 mitioI, 0.1 0 eg) under nitrogen. The mixture was heated at 1 00 Ό for 1 6 h, then cooled to 20 °C, water (1 0 ml_) added, and the resulting mixture was extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (1 5 ml_) and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated in vacuo to give crude product. Petroleum ether (40 ml_) was added to the crude product, then the mixture was filtered, and the filter cake dried in vacuo to give 1 ,3-dimethyl-1 H- indazole-6-carbonitrile (250 mg, 1 .46 mmol, 82 %) as a white solid. 1 H NMR (400 MHz, CDCta) d 7.78 - 7.71 (m, 2H), 7.34 (dd, J= 1 .3, 8.3 Hz, 1 H), 4.07 (s, 3H), 2.61 (s, 3H).
Step 2: Preparation of (Z)-N'-hydroxy- l ,3-dimethyl- 1 H-indazole-6-carboximidamide.
Figure imgf000153_0003
To a stirred solution of 1 ,3-dimethyl-1 H-indazole-6-carbonitrile (1 00 mg, 584 mitioI) in ethanol (2 mL) was added hydroxylamine hydrochloride (81 mg, 1 .1 7 mmol), triethylamine (1 1 8 mg, 1 .1 7 mmol, 1 61 mI_) and water (200 mI_). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (5 mL) was added to the solution. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H- indazole-6-carboximidamide (140 mg) as a white solid. LCMS (ESI) m/z: [M+H]+ = 205.1 . Step 3: Preparation of N-(2-(4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2- oxoethyl)benzamide.
Figure imgf000154_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) in
N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (101 mg, 496 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg,
413 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 Ό for 2 h. The reaction mixture cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-65%,12 min) to give N-(2-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (46 mg, 101 mitioI, 25 %) as a yellow solid. 1 H NMR (400 MHz, CDC ) d 8.02 (s, 1 H), 7.81 - 7.73 (m, 3H), 7.66 (dd, J= 0.6, 8.4 Hz, 1 H), 7.48 - 7.42 (m, 1 H), 7.42 - 7.35 (m, 2H), 7.26 (br. s., 1 H), 4.46 (d, J=14.1 Hz, 1 H), 4.24 (d, J= 3.9 Hz, 2H), 4.01 (s, 3H), 3.86 (d, J=13.7 Hz, 1 H), 3.29 (ddd, J= 3.6, 10.5, 14.2 Hz, 2H), 3.13 - 3.04 (m, 1 H), 2.53 (s, 3H), 2.26 - 2.15 (m, 2H), 2.04 - 1 .89 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3.
Figure imgf000154_0002
To a stirred solution of 4-fluorobenzonitrile (1 .0 g, 8.26 mmol) in ethanol (1 0 ml_) was added hydroxylamine hydrochloride (1 .15 g, 16.5 mmol), triethylamine (1 .67 g, 16.52 mmol, 2.29 ml_) and water (1 ml_). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 ml_) was added to the solution. The mixture was extracted with dichloromethane (40 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 4-fluoro-N-hydroxybenzimidamide (1 .0 g, 6.49 mmol, 79 %) as a white solid. Ή NMR (400 MHz, DMSO-d6) d 9.64 (s, 1 H), 7.85-7.64 (m, 2H), 7.21 (t, J = 8.9 Hz, 2H), 5.84 (br. s., 2H).
Step 2: Preparation of N-(2-(4-(3-(4-fluorophenyl)- 1 ,2, 4-oxadiazol-5-yl)piperidin- 1 -yl)-2- oxoethyl)benzamide.
Figure imgf000155_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) in N,N-dimethylformamide (3 ml_) was added 4-fluoro-N-hydroxybenzimidamide (76 mg, 496 mitioI), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI) and N-ethyl-N- (propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture cooled then purified directly by prep-HPLC (column: Luna C18 1 50x2.5mm 5pm ; mobile phase: [water (0.225%FA)-acetonitrile]; B%: 35%-65%,12 min) to give N- (2-(4-(3-(4-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (56 mg, 135 mitioI,
33 %) as a white solid. 1 H NMR (400 MHz, CDCIs) d 8.13-8.07 (m, 2H), 7.90-7.86 (m, 2H), 7.58-7.52 (m,
1 H), 7.51 -7.45 (m, 2H), 7.35 (br. s., 1 H), 7.23-7.1 6 (m, 2H), 4.56-4.47 (m, 1 H), 4.33 (d, J = 3.9 Hz, 2H), 3.93 (d, J = 13.9 Hz, 1 H), 3.41 -3.31 (m, 2H), 3.23-3.13 (m, 1 H), 2.33-2.21 (m, 2H), 2.02 (ddq, J = 4.1 , 10.5, 14.2 Hz, 2H); LCMS (ESI) m/z: [M+H]+ = 409.2.
Figure imgf000155_0002
20-120 °C
Step 1: Preparation of N-(2-(4-(3-(3-fluorophenyl)- 1 ,2,4-oxadiazoi-5-yi)piperidin- 1 -yi)-2- oxoethyl)benzamide.
Figure imgf000155_0003
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) in N,N-dimethylformamide (4 ml_) was added 3-fluoro-N-hydroxybenzimidamide (76 mg, 496 mitioI), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI) and N-ethyl-N- (propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Luna C8 100*30 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-60%,12 min) to give N-(2-(4-(3-(3-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (59 mg, 145 mitioI, 35 %) as a yellow solid. Ή NMR (400MHz, CDCIs) 6 7.85-7.76 (m, 3H), 7.71 (d, J= 9 3 Hz,
1 H), 7.49-7.35 (m, 4H), 7.26 (br. s., 1 H), 7.15 (s, 1 H), 4.43 (d, J=13.7 Hz, 1 H), 4.24 (d, J= 3.5 Hz, 2H),
3.84 (d, J=14.1 Hz, 1 H), 3.33-3.22 (m, 2H), 3.14-3.04 (m, 1 H), 2.26-2.13 (m, 2H), 2.00-1 .85 ppm (m, 2H); LCMS (ESI) m/z: [M+H]+ = 409.2.
Example 43: N-(2-(4-(3-(2-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.
Figure imgf000156_0001
Step 1: Preparation of 2-fluoro-N-hydroxybenzimidamide.
Figure imgf000156_0002
To a stirred solution of 2-fluorobenzonitrile (1 .0 g, 8.26 mmol, 877 mI_) in ethanol (10 ml_) was added hydroxylamine hydrochloride (1 .15 g, 1 6.5 mmol), triethylamine (1 .67 g, 16.5 mmol, 2.29 ml_) and water (1 ml_). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 ml_) was added. The mixture was extracted with dichloromethane (40 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 2-fluoro-N-hydroxybenzimidamide (1 .20 g, 7.79 mmol, 94 %) as a white solid. LCMS (ESI) m/z: [M+H]+ = 1 55.1 . Step 2: Preparation of N-(2-(4-(3-(2-fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2- oxoethyl)benzamide.
Figure imgf000157_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 51 6.7 pmol) in N,N-dimethylformamide (4 ml_) was added 2-fluoro-N-hydroxybenzimidamide (95 mg, 620 pmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (195 mg, 51 6.7 pmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (200 mg, 1 .55 mmol, 270 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Luna C8 100*30 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-(2-(4-(3-(2-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (85 mg, 208.6 mitioI, 40 %) as a yellow solid. 1 H NMR (400 MHz, CDCh) d 7.98 (s, 1 H), 7.81 -7.75 (m, 2H), 7.48- 7.34 (m, 4H), 7.28-7.20 (m, 2H), 7.16 (d, J = 8.5 Hz, 1 H), 4.42 (d, J = 14.1 Hz, 1 H), 4.23 (d, J = 3.9 Hz, 2H), 3.84 (d, J = 13.9 Hz, 1 H), 3.29 (dt, J = 4.1 , 10.4 Hz, 2H), 3.14-3.04 (m, 1 H), 2.25-2.13 (m, 2H), 2.02- 1 .86 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 409.2.
Figure imgf000157_0002
Step 1: Preparation of 1 -(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2- phenylethanone.
Figure imgf000157_0003
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 mitioI) in N,N-dimethylformamide (1 .50 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (196 mg, 518 mitioI), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 pL) and 2-phenylacetic acid (74 mg, 544 mitioI, 68 pL). The mixture was stirred at 20 °C for 16 h. The crude product was purified directly by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give 1 -[4-[3- (3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-phenyl-ethanone (24 mg, 59 pmol, 1 1 %) as a white solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.63 (dd, J=2.0, 8.4 Hz, 1 H), 7.55 (d, J=1 .8 Hz, 1 H), 7.39 - 7.20 (m, 5H), 7.05 (d, J=8.4 Hz, 1 H), 4.49 (br d, J=13.5 Hz, 1 H), 4.04 (br d, J=13.2 Hz, 1 H), 3.88 (s, 6H), 3.82 (s, 2H), 3.34 (br d, J=2.6 Hz, 1 H), 3.29 - 3.23 (m, 1 H), 3.05 - 2.95 (m, 1 H), 2.19 - 2.1 1 (m, 1 H), 2.06 - 1 .98 (m, 1 H), 1 .83 - 1 .71 (m, 1 H), 1 .67 - 1 .54 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 408.3.
Figure imgf000158_0001
To a stirred solution of 2-chloro-6-methylpyrazine (1 .0 g, 7.78 mmol) in N,N-dimethylformamide (20 mL) was added diethyl malonate (3.12 g, 19.5 mmol, 2.94 ml_) and potassium carbonate (2.69 g,
19.5 mmol), then the mixture was stirred at 1 10 °C for 16 h. The reaction mixture was cooled to 20 °C, quenched with water (20 mL), and then extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 10 : 1 ) gave diethyl 2-(6-methylpyrazin-2-yl)malonate (180 mg, 713.5 mitioI, 9 %) as a green oil. 1 H NMR (400 MHz, CDCh) d 8.58 (s, 1 H), 8.44 (s, 1 H), 4.91 (s, 1 H), 4.20-4.15 (q, J = 7.2 Hz, 4H), 2.58 (s, 3H), 1 .25-1 .22 (t, J = 7.2 Hz, 6H); LCMS (ESI) m/z: 253.1 [M+H]+.
Step 2: Preparation of 2-(6-methylpyrazin-2-yl)acetic acid.
Figure imgf000158_0002
To a stirred solution of diethyl 2-(6-methylpyrazin-2-yl)malonate (180 mg, 713.5 pmol) in ethanol (10 mL) was added sodium hydroxide (2 M, 1 .96 mL) and the mixture warmed at 60 °C for 2 h. The reaction was cooled to 20 °C, and acidified with 1 M hydrochloric acid (5 mL). The mixture was concentrated in vacuo to give 2-(6-methylpyrazin-2-yl) acetic acid (1 .42 g) as a light yellow solid that was used directly without further purification.
Step 3: Preparation of 1 -(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-(6- methylpyrazin-2-yl) ethanone.
Figure imgf000159_0001
To a stirred solution of 2-(6-methylpyrazin-2-yl)acetic acid (1 .05 g, 415 mitioI, purity 6 %) in N,N- dimethylformamide (4 mL) was added 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (120 mg, 415 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 , 3, 3-tetramethyluronium hexafluorophosphate) (157 mg, 415 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (214 mg, 1 .66 mmol, 289 pL). The mixture was stirred at 20 °C for 4 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-50%,12 min) to give 1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-(6-methylpyrazin-2- yl)ethanone (26 mg, 62 mitioI, 15 %) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 8.41 (s, 2H), 7.68 (dd, J=1 .9, 8.3 Hz, 1 H), 7.61 (d, J=1 .8 Hz, 1 H), 7.10 (d, J=8.4 Hz, 1 H), 4.51 (d, J=13.4 Hz, 1 H), 4.22 (d, J=13.9 Hz, 1 H), 4.12 - 3.93 (m, 2H), 3.92 (s, 6H), 3.52 - 3.38 (m, 2H), 3.12 - 3.02 (m, 1 H), 2.57 (s,
3H), 2.28 - 2.17 (m, 2H), 2.04 - 1 .80 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 424.2.
Example 46: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)acetamide.
Figure imgf000159_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (250 mg, 864 pmol) in N,N-dimethylformamide (1 .5 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (327 mg, 864 pmol), N-ethyl-N-(propan-2-yl)propan-2-amine (335 mg, 2.59 mmol, 452 mI_) and 2-acetamidoacetic acid (106 mg, 907 pmol). The mixture was stirred at 20 °C for 16 h. The crude product was purified by prep-HPLC (column: Luna C8 100x30 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]acetamide (36 mg, 94 mitioI, 1 1 %) as a white solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.69 (dd, J=1 .9, 8.3 Hz, 1 H), 7.61 (d, J=1 .9 Hz, 1 H), 7.10 (d, J=8.4 Hz, 1 H), 4.47 (br d, J=14.2 Hz, 1 H), 4.21 - 4.06 (m, 2H), 3.98 (br d, J=13.1 Hz, 1 H), 3.92 (s, 6H), 3.47 - 3.38 (m, 2H), 3.13 - 3.00 (m, 1 H), 2.31 - 2.16 (m, 2H), 2.05 (s, 3H), 2.00 - 1 .79 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 389.2.
Example 47: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)isobutyramide.
Figure imgf000160_0001
To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (150 mg, 433 mitioI) in dichloromethane (3 ml_) was added isobutyryl chloride (55 mg, 520 mitioI, 54 mI_) and triethylamine (131 mg, 1 .30 mmol, 180 mI_) at 0 °C. The mixture was warmed and stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give crude product that was purified by HPLC prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 23%-53%,12 min) to give N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol- 5-yl)piperidin-1 -yl)-2-oxoethyl)isobutyramide (85 mg, 204 mitioI, 47 %) as a white solid. ¾ H NMR (400MHz, GDGh) d 7.74-7.68 (m, 1 H), 7 58 (d, J = 1 .9 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.63 (br. s , 1 H), 4.49 (d, J = 13.3 Hz, 1 H), 4.12 (d, J = 4.0 Hz, 2H), 3.98 (d, J = 7.3 Hz, 6H), 3.87 (d, J = 14.1 Hz, 1 H), 3.36-3.26 (m, 2H), 3.13 (t, J = 1 0.9 Hz, 1 H), 2.50 (td, J = 6.9, 13.8 Hz, 1 H), 2.23 (br. s., 2H), 2.06-1 .92 (m, 2H), 1 .22 (d, J = 6.9 Hz, 6H); LCMS (ESI) m/z: [M+H]+ = 41 7 3.
Example 48: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)cyclohexanecarboxamide.
Figure imgf000160_0002
Step 1: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)cyclohexanecarboxamide.
Figure imgf000160_0003
To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (150 mg, 433 mitioI) in dichloromethane (3 ml_) was added cyclohexanecarbonyl chloride (76 mg, 520 mitioI, 69 mI_) and triethylamine (131 mg, 1 .30 mmol, 180 mI_) at 0 °C. The mixture was warmed and stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 23%-53%,12 min) to give N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)cyclohexanecarboxamide (78 mg, 171 mitioI, 39 %) as a white solid. 1 H NMR (400MHz, GDGh) d 7.73-7 68 (m, 1 H), 7.60-7.57 (m, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.64-6.59 (m, 1 H), 4.53-4.45 (m, 1 H), 4.1 1 (d, J = 4.0 Hz, 2H), 3.98 (d, J = 7.2 Hz, 6H), 3.86 (d, J = 13.3 Hz, 1 H), 3.36-3.26 (m, 2H), 3.12 (t, J = 10.7 Hz, 1 H), 2.28-2.18 (m, 3H), 2.05-1 .89 (m, 4H), 1 .82 (d, J = 12.3 Hz, 2H), 1 .71 (d, J = 10.9 Hz, 1 H), 1 .54-1 .42 (m, 2H), 1 .37-1 .22 (m, 3H); LCMS (ESI) m/z: [M+H]+ = 457.3. Example 49: 1-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(2-phenylethyl)piperidine-4- carboxamide.
Figure imgf000161_0001
To a stirred solution of 1 -tert-butoxycarbonylpiperidine-4-carboxylic acid (1 .0 g, 4.36 mmol) in dichloromethane (15 mL) was added 2-phenylethanamine (528 mg, 4.36 mmol, 544 pL), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (835 mg, 4.36 mmol) and triethylamine (44 mg, 436 mitioI, 60 pL). The mixture was stirred at 20 °C for 5 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by chromatography (silica, petroleum ether / ethyl acetate from 10/1 to 1 /1 ) to give tert-butyl 4-(2-phenylethylcarbamoyl)piperidine-1 -carboxylate (800 mg, 2.41 mmol, 55 %) as a white solid. LCMS (ESI) m/z: 355.2 [M+Na]+.
Step 2: Preparation of N-phenethylpiperidine-4-carboxamide.
Figure imgf000161_0002
A solution of tert-butyl 4-(2-phenylethylcarbamoyl)piperidine-1 -carboxylate (800 mg, 2.41 mmol) in 4N hydrochloric acid / ethyl acetate (1 0 ml_) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give N-(2-phenylethyl)piperidine-4-carboxamide (720 mg) as a hydrochloric acid salt and as a white solid.
Figure imgf000161_0003
3-(3,4-dimethoxyphenyl)-4H-1 ,2,4-oxadiazol-5-one (900 mg, 4.05 mmol) was added to a mixture of N,N-dimethylformamide (2 ml_) and phosphoryl chloride (24.8 g, 161 .4 mmol, 15 ml_). The mixture was equipped with calcium chloride tube and the mixture was heated at 100 °C for 16 h. The mixture was cooled to 0°C and concentrated under reduced pressure. The residue was poured into ice-water (20 ml_) and stirred for 10 min, then the aqueous phase was extracted with dichloromethane (10 mL x 5). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=5/1 , 1/1 ) to give 5-chloro-3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazole (104 mg, 432 mitioI, 1 1 %) as a white solid.
Step 4: Preparation of 1-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-4- carboxamide.
Figure imgf000162_0001
To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazole (95 mg, 395 mitioI) in N-methyl-2-pyrrolidone (2 ml_) was added N-(2-phenylethyl)piperidine-4-carboxamide (1 10 mg, 474 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (102 mg, 790 mitioI, 137 pL) at 20 °C. Then the mixture was heated to 120 Ό and stirred for 5 h. The crude product was purified by prep-HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-65%,12 min), Compound 1 -[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-N-(2-phenylethyl)piperidine-4-carboxamide (1 17 mg, 266 mitioI, 67 %) as a white solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.57 (dd, J=2.0, 8.4 Hz, 1 H), 7.51 (d, J=1 .9 Hz, 1 H), 7.33 - 7.27 (m, 2H), 7.25 - 7.18 (m, 3H), 7.06 (d, J=8.4 Hz, 1 H), 4.22 (br d, J=13.3 Hz, 2H), 3.90 (s, 6H), 3.44 (t, J=7.3 Hz, 2H), 3.27 - 3.17 (m, 2H), 2.82 (t, J=7.2 Hz, 2H), 2.51 - 2.40 (m, 1 H), 1 .92 - 1 .67 (m, 4H); LCMS (ESI) m/z: [M+H]+ = 437.3.
Example 50: 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1- carbonyl)pyrrolidin-2-one.
Figure imgf000162_0002
To a stirred solution of 1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (1 .0 g, 4.29 mmol) in N,N-dimethylformamide (10 mL) was added piperidine-4-carbonitrile (567 mg, 5.15 mmol), (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 .63 g, 4.29 mmol) and N-ethyl- N-(propan-2-yl)propan-2-amine (1 .66 g, 12.87 mmol, 2.25 mL). The mixture was stirred at 20 °C for 16 h.
The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow oil (1 .6 g). A portion of the crude product (0.3 g) was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carbonitrile for analysis (144 mg). The remainder of the crude product was used directly without purification. 1 H NMR (400 MHz, Methanol-d4) d 7.37 (d, J = 2.5 Hz, 1 H), 7.31 -7.25 (m, 1 H), 7.15 (d, J = 8.2 Hz, 1 H), 4.08 (d, J = 7.0 Hz, 5H), 3.59-3.37 (m, 2H), 3.1 6-3.03 (m, 1 H), 2.91 -2.79 (m, 2H), 2.28 (d, J = 10.2 Hz, 6H), 2.10-1 .72 (m,
4H); LCMS (ESI) m/z: [M+H]+ = 326.2.
Step 2: Preparation of (Z)- 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hydroxypiperidine-4- carboximidamide.
Figure imgf000163_0001
To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carbonitrile (1 .30 g, 4.00 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (555 mg, 8.00 mmol), triethylamine (809 mg, 8.00 mmol, 1 .1 1 mL) and water (1 mL). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid (1 .4 g). A portion of crude product (0.3 g) was purified by prep-HPLC
(column: Luna C18 150x2.5mm 5pm; mobile phase: [water (0.225% TFA)-acetonitrile]; B%: 15%-40%,12 min) to give (Z)-1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hydroxypiperidine-4- carboximidamide. The remainder was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) d 8.86-8.77 (m, 1 H), 8.15 (s, 1 H), 7.45-7.33 (m, 2H), 7.12 (dd, J = 8.2, 2.4 Hz, 1 H), 5.36 (br. s., 2H), 4.47- 4.32 (m, 1 H), 4.06-3.86 (m, 3H), 3.75-3.60 (m, 1 H), 3.07 (br. s., 1 H), 2.80-2.57 (m, 3H), 2.36-2.24 (m,
1 H), 2.21 (d, J = 1 1 .8 Hz, 6H), 1 .83-1 .67 (m, 2H), 1 .56 ppm (br. s., 2H); LCMS (ESI) m/z: [M+H]+ = 359.3.
Step 3: Preparation of 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)- 1 ,2,4-oxadiazoi-3-yi)piperidine- 1 - carbonyl)pyrrolidin-2-one.
Figure imgf000163_0002
To a stirred solution of (Z)-1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'- hydroxypiperidine-4-carboximidamide (300 mg, 837 pmol) in tetrahydrofuran (8 mL) was added 4- methylbenzoyl chloride (155 mg, 1 .00 mmol, 132 pL) and triethylamine (254 mg, 2.51 mmol, 348 pL) at 0 °C, then the mixture was warmed at 20 °C. After 3 h, to the reaction mixture was added ethyl acetate and water and the organic phase was separated. The organic phase was washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. To the residue were added tetrahydrofuran (8 ml_) and a tetrabutylammonium fluoride in tetrahydrofuran (1 M, 2.51 ml_) solution, and the mixture warmed at 50 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Luna C18 100*30 5pm; mobile phase: [water (0.225%TFA)-acetonitrile]; B%: 45%-75%,12 min) to give the racemic of 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carbonyl)pyrrolidin-2-one (106 mg, 0.23 mmol, 28 %) as a white solid. 1 H NMR (400 MHz, CDCh) d 8.06-7.99 (m, 2H), 7.41 -7.33 (m, 3H), 7.31 (d, J = 2.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 4.60 (t, J = 13.2 Hz, 1 H), 4.30 (dd, J = 7.4, 9.5 Hz, 1 H), 4.04-3.88 (m, 2H), 3.60 (quin, J = 8.5 Hz, 1 H), 3.42-3.31 (m, 1 H), 3.25-3.14 (m, 1 H), 3.1 1 -2.94 (m, 2H), 2.88-2.78 (m, 1 H), 2.47 (s, 3H), 2.32-2.12 (m, 8H), 2.03- 1 .86 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3.
Figure imgf000164_0001
To a stirred solution of (Z)-1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'- hydroxypiperidine-4-carboximidamide (280 mg, 781 pmol) in tetrahydrofuran (8 mL) was added 3- methylbenzoyl chloride (144 mg, 937 mitioI, 123 pL) and triethylamine (237 mg, 2.34 mmol, 324 pL) at 0 °C, the mixture was stirred at 20 °C for 3 h. To the reaction mixture was added ethyl acetate and water and the organic phase was separated. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. To the residue were addded tetrahydrofuran (8 mL) and a tetrabutylammonium fluoride in tetrahydrofuran solution (1 M, 2.34 mL). The mixture was warmed to 50 °C and stirred for 16 h. The reaction mixture was cooled and concentrated in vacuo to give a crude product that was purified by prep- HPLC (column: Luna C8 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-75%,12 min) to give the racemic of 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carbonyl)pyrrolidin-2-one (156 mg, 0.34 mmol, 44 %) as a white solid. 1 H NMR (400 MHz, CDCh) d 7.99-7.91 (m, 2H), 7.43 (d, J = 1 .0 Hz, 3H), 7.32-7.29 (m, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 4.60 (t, J = 14.1 Hz, 1 H), 4.30 (dd, J = 7.3, 9.6 Hz, 1 H), 4.04-3.88 (m, 2H), 3.65-3.54 (m, 1 H), 3.37 (d, J = 7.0 Hz,
1 H), 3.21 (d, J = 3.5 Hz, 1 H), 3.1 1 -2.94 (m, 2H), 2.88-2.78 (m, 1 H), 2.48 (s, 3H), 2.32-2.13 (m, 8H), 1 .93 (d, J = 12.2 Hz, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3.
Example 52: (4-(5-(3-fluorophenyl)- 1,2,4-oxadiazol-3-yl)piperidin-1-yl)(4- isopropylphenyl)methanone.
Figure imgf000165_0001
To a stirred solution of 4-isopropylbenzoic acid (1 .0 g, 6.09 mmol) in N,N-dimethylformamide (10 mL) was added piperidine-4-carbonitrile (805 mg, 7.31 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (2.31 g, 6.09 mmol) and N-ethyl-N-(propan-2-yl)propan-2- amine (2.36 g, 1 8.27 mmol, 3.19 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (40 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give yellow oil (1 .8 g). A portion of crude product (0.2 g) was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%-55%,12 min) to give 1 -(4- isopropylbenzoyl)piperidine-4-carbonitrile (1 15 mg) as a sample for analysis. The remainder was used directly. Ή NMR (400 MHz, Methanol-d4) d 7.37 (s, 4H), 4.16-3.40 (m, 4H), 3.15-3.07 (m, 1 H), 3.02-2.93 (m, 1 H), 2.10-1 .76 (m, 4H), 1 .31 -1 .26 (m, 6H); LCMS (ESI) m/z: [M+H]+ = 257.2.
Figure imgf000165_0002
To a stirred solution of 1 -(4-isopropylbenzoyl)piperidine-4-carbonitrile (1 .60 g, 6.24 mmol) in ethanol (15 ml_) was added hydroxylamine hydrochloride (867 mg, 12.5 mmol), triethylamine (1 .26 g, 12.48 mmol, 1 .73 ml_) and water (1 .50 ml_). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 ml_) was added to the solution. The mixture was extracted with dichloromethane (40 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give N-hydroxy- 1 -(4-isopropylbenzoyl)piperidine-4-carboximidamide (1 .60 g, 5.53 mmol, 89 %) as a white solid that was used directly without further purification. 1 H NMR (400 MHz, Methanol-d4) d 7.40-7.33 (m, 4H), 4.78-4.58 (m, 1 H), 3.94-3.73 (m, 1 H), 3.22 (d, J = 7.3 Hz, 2H), 3.02-2.95 (m, 1 H), 2.50-2.35 (m, 1 H), 1 .96-1 .67 (m, 4H), 1 .31 -1 .27 (m, 6H).
Step 3: Preparation of (4-(5-(3-fluorophenyl)- 1 , 2,· 4-oxadiazol-3-yl)piperidin- 1-yl)(4- isopropylphenyljmethanone.
Figure imgf000166_0001
To a stirred solution of N-hydroxy-1 -(4-isopropylbenzoyl)piperidine-4-carboximidamide (200 mg, 691 mitioI) in tetrahydrofuran (5 ml_) was added 3-fluorobenzoyl chloride (131 mg, 829 mitioI, 99 mI_) and triethylamine (209 mg, 2.07 mmol, 287 mI_) at 0 °C. The mixture was warmed and then stirred at 20 °C for 16 h. To the reaction mixture was added ethyl acetate and water and the organic phase was separated.
The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. To the obtained residue were added tetrahydrofuran (5 ml_) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 2.07 ml_), then the mixture was warmed at 50 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 50%-80%,12 min) to give (4-(5-(3-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)piperidin-1 -yl)(4-isopropylphenyl)methanone (76 mg, 193.5 mitioI, 28 %) as a yellow oil. 1 H NMR (400 MHz, CDCh) d 7.85 (d, J = 7.7 Hz, 1 H), 7.78-7.72 (m, 1 H), 7.45 (dt, J = 5.6, 8.0 Hz, 1 H), 7.32-7.27 (m, 2H), 7.26-7.20 (m, 2H), 7.18 (s, 1 H), 4.76-3.64 (m, 2H), 3.20-2.97 (m, 3H), 2.86 (td, J = 6.9, 13.8 Hz, 1 H), 2.18-1 .74 (m, 4H), 1 .19 (d, J = 6.9 Hz, 6H); LCMS (ESI) m/z: [M+H]+ = 394.2.
Example 53: (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1- yl)methanone.
Figure imgf000166_0002
Step 1 : Preparation of 4-ethoxy-3-methoxybenzonitrile.
Figure imgf000166_0003
To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (5.0 g, 33.5 mmol) in N,N- dimethylformamide (50 ml_) was added iodoethane (6.27 g, 40.2 mmol, 3.22 ml_) and potassium carbonate (9.27 g, 67.0 mmol) at 0 °C, then the reaction was warmed and stirred at 40 °C for 16 h. The reaction mixture was quenched by addition of water (50 ml_) then the mixture was extracted with ethyl acetate (80 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (50 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-ethoxy-3- methoxybenzonitrile (5.80 g, 32.7 mmol, 98 %) as a white solid. 1 H NMR (400 MHz, CDCta) d 7.20-7.16 (m, 1 H), 7.00 (d, J = 1 .9 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 4.07 (q, J = 6.9 Hz, 2H), 3.82 (s, 3H), 1 .45-1 .39 (m, 3H).
Figure imgf000167_0001
To a stirred solution of 4-ethoxy-3-methoxybenzonitrile (5.80 g, 32.7 mmol) in ethanol (50 ml_) was added hydroxylamine hydrochloride (4.55 g, 65.5 mmol), triethylamine (6.62 g, 65.46 mmol, 9.07 ml_) and water (5 ml_). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, the solvents were evaporated under vacuum, and water (20 ml_) was added to the solution. The mixture was extracted with dichloromethane (60 ml_ x 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, and then filtered and
concentrated in vacuo to give (Z)-4-ethoxy-N'-hydroxy-3-methoxybenzimidamide (5.96 g, 28.4 mmol, 87 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 9.44 (br. s., 1 H), 7.28-7.14 (m, 2H), 6.90 (d, J = 8.4 Hz, 1 H), 5.73 (s, 2H), 4.00 (q, J = 6.9 Hz, 2H), 3.75 (s, 3H), 1 .31 (t, J = 7.1 Hz, 3H).
Step 3: Preparation of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carboxylate.
Figure imgf000167_0002
To a stirred solution of (Z)-4-ethoxy-N'-hydroxy-3-methoxybenzimidamide (1 .0 g, 4.76 mmol) in N,N-dimethylformamide (15 ml_) was added 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1 .09 g, 4.76 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 .81 g, 4.76 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 .85 g, 14.28 mmol, 2.49 ml_). The mixture was stirred at 20 °C for 16 h then heated at 120 Ό for 2 h. The reaction mixture was cooled then quenched by addition of water (40 ml_), then the mixture was extracted with ethyl acetate (80 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 4-(3-(4-ethoxy-3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carboxylate (2.56 g) as a yellow oil. LCMS (ESI) m/z: [M+H]+ = 404.3.
Figure imgf000167_0003
To a stirred solution of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine- 1 -carboxylate (1 .0 g, 2.48 mmol) in methanol (5 ml_) was added 4 M methanolic hydrochloric acid (20 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to provide the crude 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (900 mg) as a yellow solid that was used directly without further purification. LCMS (ESI) m/z: [M+H]+ = 304.1
Step 5: Preparation of (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)(piperidin- 1- yl)methanone
Figure imgf000168_0001
To a stirred solution of 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (200 mg, 659 pmol) in dichloromethane (3 mL) was added piperidine-1 -carbonyl chloride (1 16 mg, 791 mitioI, 98 pL) and triethylamine (200 mg, 1 .98 mmol, 274 pL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give (4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)(piperidin-1 -yl)methanone (65 mg, 158 pmol, 24 %) as a yellow solid. 1 H NMR (400 MHz, CDCh) d 7.71 -7.66 (m, 1 H), 7.59 (d, J = 1 .9 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.1 9 (q, J = 6.9 Hz, 2H), 3.98 (s, 3H), 3.75 (d, J = 13.6 Hz, 2H), 3.29-3.13 (m, 5H), 3.04-2.94 (m, 2H), 2.17 (dd, J = 3.1 , 13.3 Hz, 2H), 2.05-1 .93 (m, 2H), 1 .60 (d, J = 8.4 Hz, 6H), 1 .53 (t, J = 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ =
415.3.
Example 54: (4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1- yl)methanone.
Figure imgf000168_0002
Step 1: Preparation of (4-(3-(3,4-dimethoxyphenyi)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)(piperidin- 1- yijmethanone.
Figure imgf000168_0003
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (100 mg, 346 pmol) in dichloromethane (3 mL) was added piperidine-1 -carbonyl chloride (61 mg, 41 5 pmol, 51 pL) and triethylamine (104 mg, 1 .04 mmol, 143 pL) at 0 °C. The mixture was stirred at 20 Ό for 1 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give (4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)(piperidin-1 - yl)methanone (81 mg, 202 mitioI, 58 %) as a white solid. 1 H NMR (400MHz, CDCI3) d 7.74-7.68 (m, 1 H), 7.59 (d, J = 1 .9 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 3.98 (d, J = 8.4 Hz, 6H), 3.76 (d, J = 13.4 Hz, 2H), 3.29- 3.14 (m, 5H), 3.04-2.95 (m, 2H), 2.17 (dd, J = 13.3, 3.4 Hz, 2H), 2.05-1 .94 (m, 2H), 1 .60 ppm (d, J = 8.5 Hz, 6H); LCMS (ESI) m/z: [M+H]+ = 401 .3.
Example 55: 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2-(isoquinolin-1- ylamino)ethanone.
Figure imgf000169_0002
Step 1: Preparation of 1 -(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-(isoquinolin- 1 - ylamino)ethanone.
Figure imgf000169_0001
To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (150 mg, 433 mitioI) in toluene (2 ml_) was added 1 -chloroisoquinoline (70 mg, 433 mitioI), cesium carbonate (423 mg, 1 .30 mmol), (±)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthalene (26 mg, 43 mitioI, 0.1 0 eg), and palladium(ll) acetate (9 mg, 43 mitioI, 0.10 eg) under nitrogen. The mixture was stirred at 100 °C for 1 6 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Luna C8 100*30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give 1 -(4- (3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-(isoquinolin-1 -ylamino)ethanone (57 mg, 1 19 mitioI, 27 %) as a white solid. 1 H NMR (400MHz, CDCb) d 8.04-7.96 (m, 2H), 7.75-7.50 (m, 5H), 7.03- 6.95 (m, 2H), 6.66 (br. s., 1 H), 4.60 (d, J = 13.7 Hz, 1 H), 4.45 (br. s., 2H), 4.08 (d, J = 12.5 Hz, 1 H), 3.98 (d, J = 7.9 Hz, 6H), 3.46-3.30 (m, 2H), 3.24-3.13 (m, 1 H), 2.28 (br. s., 2H), 2.13-1 .97 (m, 2H); LCMS (ESI) m/z: [M÷H]+ = 474.3.
Figure imgf000170_0003
To a mixture of N,N-dimethylformarriide (1 ml_) and phosphoryl chloride (8.25 g, 53.8 mmol, 5 ml_) was added 3-(3,4-dimethoxyphenyl)-4H-1 ,2,4-oxadiazol-5-one (300 mg, 1 .35 mmol) at 25 °C under calcium chloride tube. The mixture was heated to 100 °C and stirred for 16 h. The mixture was cooled to 25 °C and concentrated in vacuo carefully. The residue was poured into ice-water (20 ml_) and stirred for 10 min. The aqueous phase was extracted with dichloromethane (10 ml_ x 5). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (petroleum ether / ethyl acetate=5/1 to 1 /1 ) to afford 5-chloro-3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazole (99 mg, 414 mitioI, 31 %) as a white solid. LCMS (ESI) m/z: 241 .1 [M+H]+.
Figure imgf000170_0001
To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazole (90 mg, 374 mitioI) and tert-butyl piperazine-1 -carboxylate (83 mg, 448.80 mitioI) in N-methyl-2-pyrrolidone (1 .50 ml_) was added N-ethyl-N-(propan-2-yl)propan-2-amine (96 mg, 748 mitioI, 130 mI_). The mixture was stirred at 120 °C for 2 h. The mixture was cooled to 25 °C and concentrated in vacuo at 40 °C. The residue was poured into water (10 ml_) then the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperazine-1 -carboxylate (900 mg) that was used directly without further purification.
Figure imgf000170_0002
A solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperazine-1 -carboxylate (146 mg, 374 mitioI) in hydrochloric acid / ethyl acetate (4M, 1 0 ml_) was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo to give 3-(3,4-dimethoxyphenyl)-5-piperazin-1 -yl-1 ,2,4- oxadiazole hydrochloride (900 mg) which was used directly without further purification.
Step 4: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperazin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000171_0001
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-piperazin-1 -yl-1 ,2,4-oxadiazole hydrochloride (667 mg, 306 mitioI,) and 2-benzamidoacetic acid (137 mg, 765 mitioI) in N,N-dimethylformamide (2 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 74 mg, 459 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 1 8 mg, 918.51 mitioI, 1 60 mI_) at 20 °C. The mixture was stirred at 20 °C for 5 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-60%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperazin-1 -yl]-2-oxo-ethyl]benzamide (55 mg, 121 mitioI, 39 %) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) d = 8.59 (br t, J=5.6 Hz, 1 H), 7.93 - 7.83 (m, 2H), 7.60 - 7.44 (m, 4H), 7.39 (d, J=1 .9 Hz, 1 H), 7.08 (d, J=8.5 Hz, 1 H), 4.20 (d, J=5.6 Hz, 2H), 3.81 (d, J=1 .1 Hz, 6H), 3.73 - 3.58 (m, 8H); LCMS (ESI) m/z: [M+H]+ = 452.2. Example 57: ( 1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1- yl)methanone.
Figure imgf000171_0002
Step 1: Preparation of tert-butyl 4-(piperidine- 1 -carbonyl)piperidine- 1 -carboxylate.
Boc
Figure imgf000172_0001
To a stirred solution of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1 .0 g, 4.36 mmol) in N,N- dimethylformamide (15 ml_) was added piperidine (445 mg, 5.23 mmol, 518 mI_), 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1 .99 g, 5.23 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 .69 g, 13.1 mmol, 2.29 ml_). The mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched by addition of water (20 ml_) then the mixture was extracted with ethyl acetate (40 ml_ x 4), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 4-(piperidine-1 -carbonyl)piperidine-1 -carboxylate (1 .90 g) as a yellow oil. This was used directly without further purification. LCMS (ESI) m/z: [M+H]+ = 297.2
Figure imgf000172_0002
To a stirred solution of tert-butyl 4-(piperidine-1 -carbonyl)piperidine-1 -carboxylate (500 mg, 1 .69 mmol) in methanol (5 ml_) was added 4N methanolic hydrogen chloride solution (15 ml_). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to provide piperidin-1 -yl(piperidin-4-yl)methanone (400 mg) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) d 3.51 - 3.36 (m, 4H), 3.28-3.18 (m, 2H), 2.90 (s, 4H), 1 .82-1 .68 (m, 4H), 1 .64-1 .37 (m, 6H).
Figure imgf000172_0003
To a stirred solution of 4-ethoxy-N-hydroxy-3-methoxybenzimidamide (800 mg, 3.81 mmol) in dioxane (8 ml_) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (638 mg, 4.19 mmol, 631 mI_) and 1 ,1’- carbonyldiimidazole (926 mg, 5.72 mmol). The mixture was stirred at 1 1 0 °C for 16 h. The reaction mixture was quenched with water (10 ml_), then the mixture was extracted with dichloromethane (50 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica, dichloromethane : methanol = 50 :1 ) gave 3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5(4H)- one (1 .20 g, quant.) as a yellow oil. LCMS (ESI) m/z: [M+H]+ = 237.1 .
Step 4: Preparation of 5-chloro-3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazole.
Figure imgf000173_0001
To a stirred mixture of 3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (500 mg, 2.12 mmol) and N,N-dimethylformamide (1 mL) was equipped with calcium chloride tube and phosphoryl chloride (10 mL) was added dropwise. The mixture was heated at 1 10 °C for 1 6 h. The reaction mixture was cooled to 20 °C, then poured onto ice water (1 00 mL), and stirred for 30 min. The mixture was extracted with dichloromethane (20 mL x 5), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazole (360 mg, 1 .41 mmol,
67 %) as a brown solid. LCMS (ESI) m/z: [M+H]+ = 255.1
Step 5: Preparation of (1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin- 1- yl)methanone.
Figure imgf000173_0002
To a stirred solution of piperidin-1 -yl(piperidin-4-yl)methanone (100 mg, 509 pmol) in N-methyl-2- pyrrolidone (4 mL) was added 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazole (194 mg, 764 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (131 mg, 1 .02 mmol, 177 pL). The mixture was stirred at 120 °C for 16 h. The reaction mixture was purified directly by prep-HPLC (column: Luna C8 100*30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give (1 - (3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1 -yl)methanone (61 mg, 147.6 mitioI, 29 %) as a yellow solid. 1 H NMR (400 MHz, CDCh) d 7.53-7.47 (m, 1 H), 7.42 (d, J = 1 .9 Hz,
1 H), 6.84 (d, J = 8.5 Hz, 1 H), 4.24-4.16 (m, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.87 (s, 3H), 3.50 (br. s., 2H), 3.40 (br. s., 2H), 3.19-3.09 (m, 2H), 2.69 (tt, J = 3.8, 10.7 Hz, 1 H), 1 .94-1 .71 (m, 4H), 1 .63-1 .48 (m, 6H),
1 .42 (t, J = 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 41 5.3.
Example 58: N-(2-(4-(3-(2-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.
Figure imgf000173_0003
Step 1: N-(2-(4-(3-(2-methoxyphenyt)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.
Figure imgf000174_0001
To a stirred solution of 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 mitioI) and N-hydroxy-2-methoxybenzimidamide (78 mg, 471 mitioI) in N,N-dimethylformamide (2 ml_) was added N-ethyl-N-(propan-2-yl)propan-2-amine (121 mg, 942 mitioI, 164 mI_) and (2-(1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (178 mg, 471 mitioI) at 15 °C. The mixture was stirred for 15 h, then the mixture was heated to 1 1 0 °C and stirred for 5 h. The mixture was cooled and then purified by prep-HPLC (column: Waters Xbridge 150x25 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 37%-67%,12 min) to obtain N-(2-(4-(3-(2-methoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)-3,4-dimethylbenzamide (1 10 mg, 244 mitioI, 52 %) as yellow solid. 1 H NMR (400 MHz, Methanol-d4) 67.96 (dd, J=1 .5, 7.7 Hz, 1 H), 7.66 (s, 1 H), 7.60 (d, J=7.9 Hz,
1 H), 7.56 - 7.49 (m, 1 H), 7.23 (d, J=7.5 Hz, 1 H), 7.1 8 (d, J=8.4 Hz, 1 H), 7.09 (t, J=7.5 Hz, 1 H), 4.47 (d, J=12.8 Hz, 1 H), 4.35 - 4.23 (m, 2H), 4.04 (d, J=13.7 Hz, 1 H), 3.92 (s, 3H), 3.49 - 3.35 (m, 2H), 3.07 (t,
J=1 1 .0 Hz, 1 H), 2.32 (s, 6H), 2.27 - 2.1 0 (m, 2H), 2.06 - 1 .83 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 449.3.
Figure imgf000174_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 mitioI) and 2-benzamidopropanoic acid (105 mg, 544 mitioI) in N,N-dimethylformamide (2 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 mitioI) and N- ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 mI_). The mixture was stirred at 20 °C for 5 h. The crude product was purified by prep-HPLC (column: Luna C18 150x25 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give rac-N-(1 -(4-(3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-1 -oxopropan-2-yl)benzamide then the product purified by SFC separation (column: AD(250x30mm, 5pm); mobile phase: [Neu-IPA]; B%: 42%-42%,min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo- ethyl]benzamide, Enantiomer 1 (63 mg, 134.93 mitioI, 26 %) as a white solid and N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo-ethyl]benzamide, Enantiomer 2 (56 mg, 120 mitioI, 23% as a white solid.
N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo- ethyl]benzamide, Enantiomer 1 :
1 H NMR (400MHz, DMSO-de) d = 8.63 (br dd, J= 7.3, 1 6.1 Hz, 1 H), 7.88 (br d, J= 7.5 Hz, 2H), 7.62 - 7.41 (m, 5H), 7.1 1 (br d, J= 8.2 Hz, 1 H), 4.97 (br d, J=6.4 Hz, 1 H), 4.43 - 4.24 (m, 1 H), 4.10 - 3.95 (m, 1 H), 3.82 (s, 6H), 3.42 (br t, J=10.8 Hz, 1 H), 3.30 - 3.21 (m, 1 H), 2.99 - 2.83 (m, 1 H), 2.09 (br d, J=1 1 .9 Hz, 2H),
1 .83 - 1 .60 (m, 2H), 1 .30 (br s, 3H); LCMS (ESI) m/z: [M+H]+ = 465.3. ee = 100%.
N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo- ethyl]benzamide, Enantiomer 2:
1 H NMR (400MHz, DMSO-de) d = 8.65 (br dd, J= 7.6, 1 6.1 Hz, 1 H), 7.98 - 7.86 (m, 2H), 7.70 - 7.41 (m, 5H), 7.13 (br d, J= 8.2 Hz, 1 H), 5.00 (br d, J= 5.5 Hz, 1 H), 4.49 - 4.24 (m, 1 H), 4.12 - 3.96 (m, 1 H), 3.85 (s, 6H), 3.45 (br t, J=10.7 Hz, 1 H), 3.27 (br s, 1 H), 3.05 - 2.83 (m, 1 H), 2.12 (br d, J=12.5 Hz, 2H), 1 .89 - 1 .61 (m, 2H), 1 .32 (br s, 3H); LCMS (ESI) m/z: [M+H]+ = 465.3. ee = 99.6
Example 61 : (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-1-yl)phenyl)methylium, Enantiomer 1 and Example 62: (2-methyl-4-(2-oxo-4-(4- (3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 -yl)phenyl)methylium,
Enantiomer 2
Figure imgf000175_0001
Step 1: Preparation of (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin- 1-yl)phenyl)methylium, Enantiomer 1 and (2-methyi-4-(2-oxo-4-(4-(3-(p-toiyi)- 1,2,4- oxadiazol-5-yl)piperidine- 1 -carbonyl)pyrrolidin- 1 -yl)phenyl)methylium, Enantiomer 2
Figure imgf000176_0001
To a stirred solution of N-hydroxy-4-methylbenzimidamide (300 mg, 2.0 mmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (834 mg, 2.20 mmol) and 1 -(1 -(3,4- dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (688 mg, 2.00 mmol) in N,N- dimethylformamide (10 ml_) were added N-ethyl-N-(propan-2-yl)propan-2-amine (516 mg, 4.00 mmol, 698 mI_) at 0 °C. Then the reaction was warmed to 25 °C. After 17 h, the reaction was warmed to 90 °C. After 3 h, the mixture was cooled, diluted with water (10 ml_), and extracted with ethyl acetate (30 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (40 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by prep-HPLC (column: Phenomenex luna(2) C18 250x50 10pm ; mobile phase: [water (0.1 %TFA)- acetonitrile]; B%: 40%-70%,20min) to give the racemic of 1 -(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1 ,2,4- oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (600 mg, 1 .31 mmol, 65 %). This was purified by SFC (column: AS(250x30mm, 5pm); mobile phase: [CO2 base-methanol]; B%: 40%-40%) to give (2- methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 - yl)phenyl)methylium, Enantiomer 1 (193 mg, 421 mitioI, 21 %) as a white solid, and (2-methyl-4-(2-oxo-4- (4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 -yl)phenyl)methylium, Enantiomer 2 (199 mg, 433 mitioI, 22 %) as a white solid.
(2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 - yl)phenyl)methylium, Enantiomer 1 :
1 H NMR (400MHz, DMSO-d6) d = 7.91 (br d, J=6.9 Hz, 2H), 7.43 (br s, 1 H), 7.38 (br d, J=8.0 Hz, 3H),
7.12 (br d, J=6.3 Hz, 1 H), 4.35 (br s, 1 H), 4.09 - 3.98 (m, 2H), 3.92 (td, J=5.0, 10.0 Hz, 1 H), 3.80 - 3.63 (m, 1 H), 3.45 (br t, J=10.8 Hz, 1 H), 3.36 (br s, 1 H), 3.00 - 2.90 (m, 1 H), 2.82 - 2.65 (m, 2H), 2.39 (s, 3H), 2.27 - 2.10 (m, 8H), 1 .91 - 1 .61 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3; ee = 98.6
(2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 - yl)phenyl)methylium, Enantiomer 2:
1 H NMR (400MHz, DMSO-d6) d = 7.91 (br d, J=6.9 Hz, 2H), 7.43 (br s, 1 H), 7.38 (br d, J=8.0 Hz, 3H), 7.12 (br d, J=6.4 Hz, 1 H), 4.35 (br s, 1 H), 4.1 1 - 3.97 (m, 2H), 3.92 (td, J=5.0, 9.9 Hz, 1 H), 3.81 - 3.68 (m, 1 H), 3.53 - 3.37 (m, 1 H), 3.36 (br s, 1 H), 3.02 - 2.90 (m, 1 H), 2.82 - 2.65 (m, 2H), 2.39 (s, 3H), 2.25 - 2.09 (m, 8H), 1 .89 - 1 .62 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3; ee = 99%.
Figure imgf000177_0001
To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylic acid (350 mg, 1 .02 mmol) and N-hydroxy-4-methoxybenzimidamide (168 mg, 1 .02 mmol) in N,N-dimethylformamide (3 ml_) was added N-ethyl-N-(propan-2-yl)propan-2-amine (262 mg, 2.03 mmol, 354 mI_) and (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (385 mg, 1 .02 mmol), then the mixture was stirred for 15 h at 15 °C. The the mixture was then heated to 1 10 °C and stirred for 5 h. The mixture was cooled and purified by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 37%-67%, 12 min) to give racemic 1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2- one (0.2 g) as a white solid. This was purified by SFC separation: (column: OJ(250x30mm,1 Opm); mobile phase: [CO2 base-ethanol]; B%: 45%-45%) to give ((1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 (84 mg, 177 mitioI, 1 7 %) as a white solid and 1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2 (96 mg, 198 mitioI, 19 %) as a yellow solid
1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 1 :
1 H NMR (400 MHz, Methanol-d4) d 7.98 (dd, J=2.2, 8.8 Hz, 2H), 7.36 (s, 1 H), 7.27 (d, J=7.9 Hz, 1 H), 7.13 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.1 Hz, 2H), 4.53 - 4.43 (m, 1 H), 4.18 - 3.99 (m, 3H), 3.95 - 3.73 (m, 4H), 3.49 - 3.36 (m, 2H), 3.14 - 3.01 (m, 1 H), 2.93 - 2.77 (m, 2H), 2.47 - 2.04 (m, 8H), 2.01 - 1 .80 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 475.3; ee = 100 %.
1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2: 1 H NMR (400 MHz, Methanol-d4) d 7.98 (dd, J=2.4, 9.0 Hz, 2H), 7.36 (s, 1 H), 7.27 (d, J=8.4 Hz, 1 H), 7.13 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.1 Hz, 2H), 4.48 (d, J=7.5 Hz, 1 H), 4.1 6 - 4.00 (m , 3H), 3.92 - 3.74 (m , 4H), 3.49 - 3.37 (m , 2H), 3.13 - 3.03 (m, 1 H), 2.91 - 2.80 (m , 2H), 2.34 - 2.1 1 (m, 8H), 1 .98 - 1 .83 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 475.3; ee = 1 00 %.
Figure imgf000178_0001
To a stirred solution of 5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (20.0 g, 97.5 mmol) in chloroform (1 00 ml_) was added (4R)-4-benzyloxazolidin-2-one (20.72 g, 1 1 7 mmol), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (20.74 g, 1 08.2 mmol) and DMAP (6.43 g , 52.6 mmol) at 0 °C. After addition, the mixture was stirred for 1 5 min, then warmed and stirred at 20 °C for 1 8 h. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=1 /1 to 1 :9) to give (4R)-4-benzyl-3- [(3S)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]oxazolidin-2-one (1 0.0 g, 27.4 mmol, 28 %) and (4R)-4- benzyl-3-[(3R)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]oxazolidin-2-one (1 0.0 g, 27 mmol, 28 %) each as a white solid. LCMS (ESI) m/z: 365.1 [M+H]+.
Figure imgf000178_0002
To a stirred solution of lithium hydroxide monohydrate (2.63 g, 62.8 mmol) in water (30 ml_) was added dropwise hydrogen peroxide (15.5 g, 456.6 mmol, 13.2 ml_) at 0°C. The mixture was stirred for 30 min. To the mixture was then added tetrahydrofuran (80 ml_), water (30 ml_) followed by a solution of 3- [(3S)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]-4-phenyl-oxazolidin-2-one (1 0.0 g, 28.5 mmol) in
tetrahydrofuran (80 ml_) dropwise. The mixture was stirred at 0 °C for 1 h, quenched by addition of a sodium sulfate solution in water (10 ml_) at 0 °C, and made basic (pH 1 1 ) by addition of an aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (100 ml_), acidified to pH 2 using 1 M HCI, and extracted again with ethyl acetate (100 ml_). The organic layers were washed with a saturated aqueous sodium chloride solution (100 ml_), dried over sodium sulfate, filtered and
concentrated under reduced pressure to give (3S)-5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (4.80 g, 23.39 mmol, 82 %) as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d 7.57 (dd, J=0.9, 8.6 Hz, 2H), 7.40 - 7.34 (m, 2H), 7.20 - 7.15 (m, 1 H), 4.18 - 4.13 (m, 1 H), 4.10 - 4.04 (m, 1 H), 3.45 - 3.35 (m, 1 H), 3.03 - 2.86 (m, 2H).
Figure imgf000179_0001
A mixture of (3S)-5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (4.50 g, 21 .93 mmol), methyl piperidine-4-carboxylate (3.77 g, 26.32 mmol), 2,4,6-tripropyM ,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide in ethyl acetate (27.91 g, 43.86 mmol, 26.08 ml_, 50% purity), triethylamine (44.38 g, 438.60 mmol, 60 ml_) in dichloromethane (60 ml_) was degassed, purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30 ml_) and extracted with dichloromethane (50 ml_). The organic layers were washed with saturated aqueous sodium chloride solution (50 ml_), dried over Na2SC>4, filtered, concentrated under reduced pressure and purified by chromatography (silica, petroleum ether / ethyl acetate=1 :1 ) to give methyl 1 -[(3S)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylate (4.70 g, 14.2 mmol, 65 %) as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d 7.56 (d, J=7.7 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.16 - 7.1 1 (m, 1 H), 4.47 - 4.34 (m, 1 H), 4.24 (dd, J=7.3, 9.5 Hz, 1 H), 3.91 - 3.81 (m, 2H), 3.69 (s, 3H), 3.52 (quin, J=8.5 Hz, 1 H), 3.24 - 3.12 (m, 1 H), 2.98 - 2.87 (m, 2H), 2.80 - 2.73 (m, 1 H), 2.64 - 2.52 (m,
1 H), 1 .97 (br dd, J=4.3, 8.3 Hz, 2H), 1 .73 - 1 .63 (m, 2H).
Figure imgf000179_0002
To a stirred solution of methyl 1 -[(3S)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4- carboxylate (3.00 g, 9.08 mmol) in tetrahydrofuran (60 mL) was added a solution of lithium hydroxide monohydrate (0.5 M, 21 .79 ml_) in water. The mixture was then stirred at 0 °C for 2 h. The mixture was acidified to pH 4-5 using 1 M HCI, and then extracted with dichloromethane (60 ml_; 30 ml_ x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution 40 ml_; 20 ml_ x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1 -[(3S)-5-oxo-1 - phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (2.70 g, 8.53 mmol, 94 %) as a white solid.
Step 5: (4S)-4-[4-[3-(3,4-dimethoxyphenyl)- 1, 2, 4-oxadiazol-5-yl]piperidine- 1 -carbonyl]- 1 -phenyl-pyrrolidin- 2-one
Figure imgf000180_0001
A mixture of N'-hydroxy-3,4-dimethoxy-benzamidine (1 .04 g, 5.32 mmol), 1 -[(3S)-5-oxo-1 -phenyl- pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (1 .40 g, 4.43 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (2.18 g, 5.76 mmol) and N-ethyl-N-(propan-2-yl)propan-2- amine (1 .72 g, 13.29 mmol, 2.32 ml_) in N,N-dimethylformamide (8.00 ml_), was stirred at 20 °C for 15h and at 1 10°C for 1 h. The mixture was cooled to room temperature, concentrated under reduced pressure to give a residue purified by prep-HPLC [column: Phenomenex luna C18 250x50mmx10 pm; mobile phase: water / ammonium carbonate (1 OmM) / acetonitrile]; B%: 30%-60%,30 min. The desired compound (4S)-4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -phenyl- pyrrolidin-2-one was isolated as a light yellow solid (608 mg, 1 .28 mmol, 29 %). 1 H NMR (400MHz, CHLOROFORM-d) d 7.68 (br d, J=8.2 Hz, 1 H), 7.61 - 7.53 (m, 3H), 7.40 - 7.33 (m, 2H), 7.18 - 7.12 (m,
1 H), 6.95 (d, J=8.4 Hz, 1 H), 4.61 - 4.46 (m, 1 H), 4.30 (dd, J=7.2, 9.6 Hz, 1 H), 4.01 - 3.92 (m, 8H), 3.57 (quin, J=8.4 Hz, 1 H), 3.43 - 3.26 (m, 2H), 3.14 - 2.91 (m, 2H), 2.86 - 2.80 (m, 1 H), 2.23 (br t, J=13.1 Hz, 2H), 2.02 - 1 .93 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 477.3.
Example 66 [(4R)-4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1- phenyl-pyrrolidin-2-one]
o
Figure imgf000180_0002
To a stirred solution of 1 -[(3R)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (1 15 mg, 363.52 pmol) and N'-hydroxy-3,4-dimethoxy-benzamidine (71 mg, 363.52 pmol) in N,N- dimethylformamide (500 mI_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 , 3, 3-tetramethyluronium
hexafluorophosphate) (137 mg, 363.52 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 727 mitioI, 126 mI_) at 25 °C. The mixture was then stirred at 25 °C for 2 h, and at 1 10 °C for 2h. The mixture was concentrated under reduced pressure and the resulting crude product was purified by
chromatography (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: water / ammonium carbonate (10mM) / acetonitrile]; B%: 25%-60%,12 min to give (4R)-4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol- 5-yl]piperidine-1 -carbonyl]-1 -phenyl-pyrrolidin-2-one (32 mg, 67.45 mitioI, 19 %) as a yellow solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.68 (br d, J= 8.2 Hz, 1 H), 7.61 - 7.55 (t, 3H), 7.37 (t, J= 7.8 Hz, 2H),
7.19 - 7.14 (t, 1 H), 6.95 (d, J=8.4 Hz, 1 H), 4.60 - 4.46 (m, 1 H), 4.31 (dd, J= 7.2, 9.6 Hz, 1 H), 3.98 - 3.94 (m, 7H), 3.98 - 3.92 (m, 1 H), 3.58 (quin, J= 8.5 Hz, 1 H), 3.43 - 3.26 (m, 2H), 3.16 - 2.91 (m, 2H), 2.88 - 2.79 (m, 1 H), 2.24 (br t, J=13.3 Hz, 2H), 2.06 - 1 .88 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 477.3.
Figure imgf000181_0001
To a stirred solution of 1 -[1 -(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidine-4- carboxylic acid (351 mg, 1 .02 mmol) in N,N-dimethylformamide (1 .50 ml_) was added (2-(1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (386 mg, 1 .02 mmol), N-ethyl-N-(propan-2- yl)propan-2-amine (395 mg, 3.06 mmol, 534 mI_) and N-hydroxy-3,4-dimethoxy-benzamidine (200 mg,
1 .02 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was then diluted with water (5mL) and extracted with ethyl acetate (1 0 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_ x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. N,N-dimethylformamide (2 ml_) was added to the residue and the resulting mixture was heated at 120 °C for 5 h. The mixture was cooled to 25 °C, diluted by addition of water (5mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150x25 pm; mobile phase: water / ammonium carbonate (1 OmM) / acetonitrile]; B%: 33%-63%,12 min) to give racemic 4-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carbonyl)-1 -(3,4-dimethylphenyl)pyrrolidin-2-one. This was separated by chiral-SFC (column: AS(250x30mm, 10pm); mobile phase: [CO2 base-methanol]; B%: 40%-40%,min) to give firstly 4- [4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -(3,4-dimethylphenyl)pyrrolidin-2- one, Enantiomer 1 (51 mg, 102 mitioI, 10 %) as a white solid. 1 H NMR (400MHz, DMSO-d6) d = 7.61 (br d, J=8.4 Hz, 1 H), 7.48 (s, 1 H), 7.43 (br s, 1 H), 7.38 (br d, J=7.5 Hz, 1 H), 7.16 - 7.10 (m, 2H), 4.37 (br s,
1 H), 4.08 - 3.99 (m, 2H), 3.96 - 3.88 (m, 1 H), 3.85 (s, 6H), 3.79 - 3.67 (m, 1 H), 3.45 (br t, J=10.8 Hz, 1 H), 3.32 - 3.28 (m, 1 H), 3.02 - 2.87 (m, 1 H), 2.82 - 2.70 (m, 2H), 2.24 - 2.18 (m, 6H), 2.18 - 2.10 (m, 2H), 1 .91 - 1 .61 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 505.4 and secondly 4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -(3,4-dimethylphenyl)pyrrolidin-2-one, Enantiomer 2 (48 mg, 95 mitioI, 9 %) also as a white solid. 1 H NMR (400MHz, DMSO-d6) d = 7.61 (br d, J=8.4 Hz, 1 H), 7.48 (s,
1 H), 7.43 (br s, 1 H), 7.41 - 7.35 (m, 1 H), 7.17 - 7.10 (m, 2H), 4.37 (br s, 1 H), 4.09 - 3.99 (m, 2H), 3.98 - 3.89 (m, 1 H), 3.85 (s, 6H), 3.78 - 3.68 (m, 1 H), 3.50 - 3.39 (m, 1 H), 3.35 (br s, 1 H), 3.00 - 2.88 (m, 1 H), 2.81 - 2.70 (m, 2H), 2.26 - 2.19 (m, 6H), 2.17 - 2.09 (m, 2H), 1 .88 - 1 .63 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 505.4
Example 69 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-2-one, Enantiomer 1 and Example 70 1-(3,4-dimethylphenyl)-4-(4-(3-(3- methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, Enantiomer 2
Figure imgf000182_0001
To a stirred solution of methyl 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylate (470 mg, 1 .31 mmol) in tetrahydrofuran (5 ml_) was added sodium hydroxide (2 M, 1 .31 ml_). The mixture was stirred at 20 °C for 16 h. The mixture was acidified with concentrated hydrochloric acid until pH = 1 . The mixture was extracted with dichloromethane (20 ml_ x 4). The organic layers were combined and washed with saturated aqueous sodium chloride solution (5 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3- carbonyl)piperidine-4-carboxylic acid (300 mg) as a brown solid. LCMS (ESI) m/z: [M+H]+ = 345.2.
Step 2: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine- 1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 and 1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, Enantiomer 2
Figure imgf000182_0002
To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4- carboxylic acid (300 mg, 871 pmol) in N,N-dimethylformamide (4 ml_) was added N-hydroxy-3-methoxy- benzamidine (173 mg, 1 .05 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (330 mg, 871 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (337 mg, 2.61 mmol, 456 mI_). The mixture was stirred at 20°C for 2 h and then at 120 °C for 2 h. The reaction mixture was cooled, concentrated under reduced pressure and purified directly by preparative HPLC (column: Luna C8 100*30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 45%-65%,12 min) to give (rac)- 1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl) pyrrolidin-2-one that was was purified by chiral-SFC (column: AD(250mm*30mm,5mm); mobile phase: [Base-isopropanol]; B%: 42%-42%,min) to give firstly 1 -(3,4-dimethylphenyl)-4-(4-(3-(3- methoxyphenyl)-1 ,2, 4-oxadiazol-5-yl)piperidine-1 -carbonyl) yrrolidin-2-one, Enantiomer 1 (75 mg, 158.7 mitioI, 18 %, ee 100 %) as a white solid, then 1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 2 (75 mg, 160 mitioI, 18 %, ee 99.7 %) as a yellow solid.
1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 , 2, 4-oxadiazol-5-yl)piperidine-1 -carbonyl) pyrrolidin-2-one, Enantiomer 1 .
1 H NMR (400 MHz, CDCh) d 7.63-7.57 (m, 1 H), 7.55-7.50 (m, 1 H), 7.31 (d, J = 12.3 Hz, 2H), 7.22-7.19 (m, 1 H), 7.05 (d, J = 8.2 Hz, 1 H), 7.00 (d, J = 1 .8 Hz, 1 H), 4.53-4.37 (m, 1 H), 4.21 (dd, J = 7.3, 9.6 Hz,
1 H), 3.95-3.77 (m, 5H), 3.49 (td, J = 8.6, 1 6.9 Hz, 1 H), 3.36-3.20 (m, 2H), 3.12-2.96 (m, 1 H), 2.89 (td, J = 8.3, 16.9 Hz, 1 H), 2.79-2.70 (m, 1 H), 2.18 (d, J = 13.1 Hz, 8H), 1 .99-1 .83 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 475.1 .
1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2.
1 H NMR (400 MHz, CDCh) d 7.63-7.57 (m, 1 H), 7.53 (s, 1 H), 7.36-7.27 (m, 2H), 7.21 (d, J = 2.0 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 4.53-4.37 (m, 1 H), 4.21 (dd, J = 7.3, 9.5 Hz, 1 H), 3.96- 3.77 (m, 5H), 3.55-3.44 (m, 1 H), 3.37-3.19 (m, 2H), 3.12-2.82 (m, 2H), 2.76 (d, J = 9.4 Hz, 1 H), 2.18 (d, J = 13.1 Hz, 8H), 1 .92 (br. s„ 2H); LCMS (ESI) m/z: [M+H]+ = 475.1 .
Example 71 (1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1- carbonyl)pyrrolidin-2-one), Enantiomer 1 and Example 72 (1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-
1.2.4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one), Enantiomer 2
Racemic 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one (80 mg) was purified by SFC separation (column: AD (250x30mm, 5pm); mobile phase: [CO2 base-isopropanol]; B%: 50%-50%,min) to give firstly 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-
1 .2.4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 (26 mg, 59 mitioI, 7 %) as a white solid and secondly 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2 as a white solid (23 mg, 52 mitioI, 6 %).
1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2- one, Enantiomer 1 .
1 H NMR (400 MHz, CDCh) d 8.06-8.00 (m, 2H), 7.41 -7.33 (m, 3H), 7.32-7.29 (m, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 4.66-4.54 (m, 1 H), 4.30 (dd, J = 7.4, 9.5 Hz, 1 H), 4.05-3.88 (m, 2H), 3.65-3.55 (m, 1 H), 3.43-3.30 (m, 1 H), 3.20 (d, J = 3.4 Hz, 1 H), 3.12-2.94 (m, 2H), 2.85 (d, J = 9.7 Hz, 1 H), 2.47 (s, 3H), 2.32-2.14 (m, 8H),
1 .94 (br. s., 2H); LCMS (ESI) m/z: [M+H]+ = 459.3. 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2- one, Enantiomer 2.
1 H NMR (400 MHz, CDCb) d 7.96-7.90 (m, 2H), 7.32-7.24 (m, 3H), 7.22-7.19 (m, 1 H), 7.05 (d, J=8.2 Hz,
1 H), 4.58-4.43 (m, 1 H), 4.20 (s, 1 H), 3.94-3.79 (m, 2H), 3.50 (quin, J = 8.5 Hz, 1 H), 3.28 (br. s., 1 H), 3.10 (d, J = 3.9 Hz, 1 H), 3.02-2.84 (m, 2H), 2.78-2.68 (m, 1 H), 2.38 (s, 3H), 2.23-2.03 (m, 8H), 1 .83 (d, J =
10.8 Hz, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3
Examples 73 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1- carbonyl)pyrrolidin-2-one, Enantiomer 1 and Example 74 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, Enantiomer 2
Racemic 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one (120 mg) was purified by SFC separation (column: OJ(250mmX30mm,5mm); mobile phase: [CO2 base-ethanol]; B%: 30%-30%,min) to give firstly 1 -(3,4-dimethylphenyl)-4-(4-(5-(m- tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 (39 mg, 86.7 mitioI, 1 1 %) as a pink solid and secondly 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2 (36 mg, 77.9 mitioI, 10 %) as a pink solid.
1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2- one, Enantiomer 1 :
1 H NMR (400 MHz, CDCb) d 7.94 (br. s., 2H), 7.39 (d, J = 15.0 Hz, 3H), 7.29 (br. s., 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 4.58 (t, J = 13.9 Hz, 1 H), 4.28 (f, J = 8.6 Hz, 1 H), 4.01 -3.87 (m, 2H), 3.62-3.53 (m, 1 H), 3.35 (br. s., 1 H), 3.19 (br. s., 1 H), 3.08-2.93 (m, 2H), 2.86-2.76 (m, 1 H), 2.45 (s, 3H), 2.32-2.1 1 (m, 8H), 1 .90 (d, J = 13.7 Hz, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3.
1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2- one, Enantiomer 2:
1 H NMR (400 MHz, Methanol-d4) 68.00-7.90 (m, 2H), 7.53-7.45 (m, 2H), 7.41 -7.37 (m, 1 H), 7.32-7.27 (m, 1 H), 7.1 9-7.13 (m, 1 H), 4.53 (dd, J=3.5, 13.2 Hz, 1 H), 4.19-4.03 (m, 3H), 3.90-3.80 (m, 1 H), 3.49-3.39 (m, 1 H), 3.30-3.20 (m, 1 H), 3.12-3.00 (m, 1 H), 2.94-2.82 (m, 2H), 2.47 (s, 3H), 2.35-2.1 1 (m, 8H), 1 .99-1 .77 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 459.3.
Figure imgf000184_0001
Step 1: Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)carbamate.
Figure imgf000184_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (2.0 g, 6.91 mmol) in N,N-dimethylformamide (20 ml_) was added 2-(tert-butoxycarbonylamino)acetic acid (1 .21 g,
6.91 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (2.62 g, 6.91 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (2.68 g, 20.7 mmol, 3.62 ml_). The mixture was stirred at 15 °C for 2 h. The reaction mixture was quenched by addition of water (20 ml_) then the mixture was extracted with ethyl acetate (60 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and
concentrated to give a crude material that was purified by chromatography (silica, petroleum ether : ethyl acetate = 5:1 to 1 :1 ) to give tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)- 2-oxoethyl)carbamate (2.60 g, 5.82 mmol, 84 %) as a brown solid. LCMS (ESI) m/z: [M+H]+ = 447.2.
Step 2: Preparation of 2-amino- 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1- yl)ethanone
Figure imgf000185_0001
To a stirred solution of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)carbamate (2.50 g, 5.60 mmol) in methanol (1 0 ml_) was added methanolic hydrogen chloride solution (30 ml_). The mixture was stirred at 20 °C for 1 h and then concentrated to give 2-amino- 1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethanone (1 .90 g, 5.49 mmol, 97.95 %), isolated as a brown solid and used for the next step without further purification. A small amount (0.1 g) of the crude product was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrilej; B%: 2Q%-50%,12 min) to give a pure sample for analysis: 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethanone (32 mg). 1 H NMR (400 MHz, GDGh) d 7.73-7.67 (m, 1 H), 7.58 (d, J = 1 .5 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 4.54 (d, J = 1 2.2 Hz, 1 H), 3.98 (d, J = 7.2 Hz, 6H), 3.84 (d, J = 12.0 Hz, 1 H), 3.54 (s, 2H), 3.34-3.21 (m, 2H), 3.08 (d, J = 12.3 Hz, 1 H), 2.21 (d, J = 13.1 Hz, 2H), 1 .98 (d, J = 9.4 Hz, 2H); LCMS (ESI) m/z: [M+H]+ = 347.1 .
Figure imgf000186_0001
To a stirred solution of (Z)-N'-hydroxybenzimidamide (214 mg, 1 .57 mmol) in N,N- dimethylformamide (5 ml_) was added 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1 .31 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1 .31 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (507 mg, 3.93 mmol, 686 mI_). The mixture was stirred at 20 °C for 2 h, and then heated at 120 °C for 2 h. The reaction mixture was quenched with water (10 ml_), then the mixture was extracted with ethyl acetate (30 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was extracted with petroleum ether (30 ml_ x 2). The combined organic extracts were concentrated under reduced pressure to give tert-butyl 4-(3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carboxylate (310 mg, 941 mitioI, 72 %) as a yellow oil. This product was used in the next step without further purification.
Figure imgf000186_0002
To a stirred solution of tert-butyl 4-(3-phenyl-1 , 2, 4-oxadiazol-5-yl)piperidine-1 -carboxylate (310 mg, 941 mitioI) in ethyl acetate (2 ml_) was added an anhydrous solution of hydrochloric acid in ethyl acetate (20 ml_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to provide the crude 3-phenyl-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (233 mg) as a yellow solid that was used for the next step without further purification. LGMS (ESi) m/z: [M+H]+ = 230.2.
Step 3: Preparation of 5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 - yi)ethoxy)choman-4-one
Figure imgf000187_0001
To a stirred solution of 2-((5-hydroxy-2,2-dimethyl-4-oxochoman-7-yl)oxy)acetic acid (150 mg,
563 gmol) in N,N-dimethylformamide (2 ml_) was added 3-phenyl-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (142 mg, 620 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (213 mg, 563 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (291 mg, 2.25 mmol, 393 mI_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 45%-75%,12 min) to give 5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4- (3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethoxy)choman-4-one (120 mg, 250.6 mitioI, 44 %) as a white solid. 1 H NMR (400 MHz, CDCh) d 12.00 (s, 1 H), 8.12 - 8.07 (m, 2H), 7.56 - 7.48 (m, 3H), 6.07 (d, J=2.4 Hz, 1 H), 6.04 (d, J=2.3 Hz, 1 H), 4.74 (s, 2H), 4.46 (d, J=13.8 Hz, 1 H), 3.98 (d, J=13.1 Hz, 1 H), 3.42 - 3.28 (m, 2H), 3.13 (t, J=1 1 .1 Hz, 1 H), 2.71 (s, 2H), 2.23 (br. s., 2H), 2.07 - 1 .92 (m, 2H), 1 .49 - 1 .46 (m, 6H); LCMS (ESI) m/z: [M+H]+ = 478.2.
Figure imgf000187_0002
To a stirred solution of 2-((5-hydroxy-2,2-dimethyl-4-oxochoman-7-yl)oxy)acetic acid (150 mg,
563 mitioI) in N,N-dimethylformamide (2 ml_) was added 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4- oxadiazole (195 mg, 676 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium
hexafluorophosphate) (213 mg, 563 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (291 mg, 2.25 mmol, 393 mI_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give 7- (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethoxy)-5-hydroxy-2,2- dimethylchoman-4-one (133 mg, 245.66 mitioI, 44 %) as a white solid. Ή NMR (400MHz, CDCI3) d 12.00 (s, 1 H), 7.71 (dd, J=1 .9, 8.3 Hz, 1 H), 7.58 (d, J=1 .9 Hz, 1 H), 6.98 (d, J=8 4 Hz, 1 H), 6.06 (d, J=2 4 Hz, 1 H), 6 03 (d, J=2.4 Hz, 1 H), 4 74 (s, 2H), 4.47 (d, J=14.2 Hz, 1 H), 4 01 - 3.94 (m, 7H), 3.41 - 3.26 (m, 2H), 3.1 1 (t, J=1 1 .0 Hz, 1 H), 2.71 (s, 2H), 2.22 (br. s., 2H), 2.06 - 1 .93 (m, 2H), 1 .47 (s, 6H); LCMS (ESI) m/z: [M÷H]+ = 538.3.
Example 78: (N-(2-oxo-2-(4-(3-(pyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide.
Figure imgf000188_0003
-
Step 1: Preparation of (Z)-N'-hydroxypicolinimidamide.
Figure imgf000188_0001
To a stirred solution of picolinonitrile (3.0 g, 28.8 mmol, 2.78 ml_) in ethanol (30 ml_) was added hydroxylamine hydrochloride (4.01 g, 57.6 mmol), triethylamine (5.83 g, 57.6 mmol, 8.0 ml_) and water (5 ml_). The mixture was heated at 75 °C for 5 h. The mixture was then concentrated to give a residue. The solid residue was triturated with water (30 ml_), filtered, and dried under reduced pressure to give (Z)-N'- hydroxypicolinimidamide (2.0 g, 14.6 mmol, 51 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 9.93 (s, 1 H), 8.57 (d, J=4.5 Hz, 1 H), 7.92 - 7.75 (m, 2H), 7.47 - 7.35 (m, 1 H), 5.85 (br. s., 2H).
Step 2: Preparation of N-(2-oxo-2-(4-(3-(pyridin-2-yi)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)ethyl)benzamide
0"N.
o ^ N / V V
To a stirred solution of 1 c^nr" acid (120 mg, 413 mitioI) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxypicolinimidamide (56 mg, 413 mitioI), N-ethyl-N- (propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_) and (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI). The mixture was stirred at 20 °C for 2 h, then heated at 120 Ό for 2 h. The reaction mixture was cooled, concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-55%,12 min) to give N-(2-oxo-2-(4-(3- (pyridin-2-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethyl)benzamide (75 mg, 192 mitioI, 47 %) as a yellow solid. Ή NMR (400 MHz, CDC ) d 8.84 (td, J= 0.8, 4.0 Hz, 1 H), 8.18 - 8.12 (m, 1 H), 7.93 - 7.84 (m, 3H), 7.58 - 7.43 (m, 4H), 7.35 (br. s., 1 H), 4.53 (d, J=13.6 Hz, 1 H), 4.32 (t, J= 3.5 Hz, 2H), 3.93 (d, J=14.1 Hz,
1 H), 3.45 - 3.31 (m, 2H), 3.21 - 3.10 (m, 1 H), 2.37 - 2.24 (m, 2H), 2.15 - 1 .98 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 392.2.
Figure imgf000188_0002
Step 1: Preparation of (Z)-N'-hydroxyquinoline-2-carboximidamide.
Figure imgf000189_0001
To a stirred solution of quinoline-2-carbonitrile (900 mg, 5.84 mmol) in ethanol (10 ml_) was added hydroxylamine hydrochloride (81 1 mg, 1 1 .7 mmol), triethylamine (1 .18 g, 1 1 .7 mmol, 1 .6 ml_) and water (1 ml_). The mixture was heated at 75 °C for 5 h. The reaction mixture was cooled and filtered, and the filter cake dried in vacuo to give (Z)-N'-hydroxyquinoline-2-carboximidamide (1 .0 g, 5.34 mmol, 91 %) as a light yellow solid. This was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 10.23 (s, 1 H), 8.34 (d, J= 8.7 Hz, 1 H), 8.10 - 7.93 (m, 3H), 7.80 (s, 1 H), 7.67 - 7.59 (m, 1 H), 6.02 (br. s., 2H).
Figure imgf000189_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxyquinoline-2-carboximidamide (77 mg, 413 mitioI), N-ethyl-N-(propan-2-yl)propan-2-amine (1 60 mg, 1 .24 mmol, 216 mI_) and (2-(1 H-benzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI). The mixture was stirred at 20 °C for 2 h firstly, then heated at 120 °C for 2 h. The reaction mixture was cooled and purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%:30%-60%,12 min) to give N-(2-oxo-2-(4-(3-(quinolin-2-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)ethyl)benzamide (66 mg, 150 mitioI, 36 %) as a yellow solid. 1 H NMR (400 MHz, CDCI3) d 8.26 (dd, J=2.1 , 8.5 Hz, 2H), 8.14 (d, J= 8.5 Hz, 1 H), 7.86 - 7.77 (m, 3H), 7.72 (dt, J=1 .3, 7.7 Hz, 1 H), 7.61 - 7.53 (m, 1 H), 7.49 - 7.34 (m, 3H), 7.27 (br. s., 1 H), 4.50 (d, J= 13.8 Hz, 1 H), 4.24 (d, J= 3.6 Hz, 2H), 3.87 (d, J=13.8 Hz, 1 H), 3.42 - 3.22 (m, 2H), 3.09 - 2.98 (m, 1 H), 2.31 - 2.16 (m, 2H), 2.10 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 442.2.
Figure imgf000189_0003
Step 1: (2-isocyanatocyclopropyl)benzene.
Figure imgf000190_0001
To a stirred solution of 2-phenylcyclopropanecarboxylic acid (1 .0 g, 6.17 mmol) in toluene (10 mL) was added diphenylphosphoryl azide (2.04 g, 7.40 mmol, 1 .60 ml_) and triethylamine (935 mg, 9.25 mmol, 1 .28 mL) under nitrogen. The mixture was stirred at 120 °C for 2 h. The reaction mixture was cooled then concentrated in vacuo to give (2-isocyanatocyclopropyl)benzene (2.0 g) as a yellow oil that was used directly without purification.
Step 2: Preparation of methyl 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate.
Figure imgf000190_0002
To a stirred solution of methyl piperidine-4-carboxylate (800 mg, 5.59 mmol) in toluene (10 mL) was added (2-isocyanatocyclopropyl)benzene (2.0 g, 12.58 mmol, 2.25 eg) and N-ethyl-N-(propan-2- yl)propan-2-amine (722 mg, 5.59 mmol, 975 pL). After 16 h, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (50 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a residue which was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 2 :1 ) to give methyl 1 -((2- phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate (820 mg, 2.71 mmol, 48 %) as a yellow oil. 1 H NMR (400 MHz, CDC ) d 7.22 - 7.19 (m, 1 H), 7.17 (s, 1 H), 7.1 0 (d, J=7.4 Hz, 3H), 4.75 (br. s., 1 H), 3.79 (d, J=13.3 Hz, 2H), 3.63 (s, 3H), 2.89 - 2.73 (m, 3H), 2.47 - 2.33 (m, 1 H), 2.02 - 1 .78 (m, 3H), 1 .61 (dd, J=2.1 , 13.1 Hz, 2H), 1 .1 6 - 1 .1 1 (m, 1 H), 1 .08 - 1 .03 (m, 1 H).
Figure imgf000190_0003
To a stirred solution of methyl 1 -((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate (770 mg, 2.55 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (1 M, 5.10 mL). After 2 h, the reaction was acidified with 1 M hydrochloric acid (8 mL). The mixture was extracted with dichloromethane (40 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 -((2- phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (660 mg, 2.29 mmol, 90 %) as a yellow solid that was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 12.22 (s, 1 H), 7.33 - 7.01 (m, 5H), 6.78 (d, J= 2.5 Hz, 1 H), 3.85 (d, J= 13.3 Hz, 2H), 2.81 - 2.66 (m, 3H), 2.40 (br. s., 1 H), 1 .95 - 1 .69 (m, 3H), 1 .39 (d, J= 12.0 Hz, 2H), 1 .21 - 1 .13 (m, 1 H), 1 .10 - 1 .04 (m, 1 H). Step 4: Preparation of 4-(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)-N-(2- pheny Icy clopropyl) piperidine- 1 -carboxamide.
Figure imgf000191_0001
To a stirred solution of 1 -((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (100 mg, 347 mitioI) in N,N-dimethylformamide (2 ml_) was added (Z)-4-ethoxy-N'-hydroxy-3- methoxybenzimidamide (72 mg, 347 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (131 mg, 347 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (134 mg, 1 .04 mmol, 181 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 Ό for 2 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 40 %-75 %,12 min) to give 4-(3-(4-ethoxy-3- methoxyphenyl)-1 , 2, 4-oxadiazol-5-yl)-N-(2-phenylcyclopropyl)piperidine-1 -carboxamide (81 mg, 173 mitioI, 50 %) as a yellow solid. 1 H NMR (400 MHz, CDC ) d 7.70 - 7.66 (m, 1 H), 7.58 (d, J=1 .9 Hz, 1 H), 7.31 (s, 1 H), 7.27 (s, 1 H), 7.23 - 7.17 (m, 3H), 6.97 (d, J= 8.5 Hz, 1 H), 4.91 (s, 1 H), 4.19 (q, J= 7.0 Hz, 2H), 3.98 (s, 5H), 3.25 - 3.16 (m, 1 H), 3.13 - 3.03 (m, 2H), 2.91 - 2.85 (m, 1 H), 2.1 8 (dd, J=3.5, 13.4 Hz, 2H), 2.07 (ddd, J= 3.3, 6.2, 9.5 Hz, 1 H), 2.03 - 1 .91 (m, 2H), 1 .53 (t, J= 7.0 Hz, 3H), 1 .28 - 1 .22 (m, 1 H), 1 .1 7 (td, J=5.0, 9.7 Hz, 1 H); LCMS (ESI) m/z: [M+H]+ = 463.2.
Example 81 : N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)-1 ,2, 4-oxadiazol-5-yl)piperidine-1- carboxamide.
Figure imgf000191_0002
Step 1: Preparation of N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carboxamide.
Figure imgf000191_0003
To a stirred solution of 1 -((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (130 mg, 451 mitioI) in N,N-dimethylformamide (1 ml_) was added (Z)-N'-hydroxypicolinimidamide (74 mg, 541 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (170 mg, 451 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (174 mg, 1 .35 mmol, 236 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 1 10 °C for 2 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 30%-60%,12 min) to give N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carboxamide (47 mg, 121 .6 mitioI, 27 %) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) d 8.76 (d, J=4.0 Hz, 1 H), 8.12 - 7.97 (m, 2H), 7.65 - 7.55 (m, 1 H), 7.30 - 7.19 (m, 2H), 7.18 - 7.05 (m, 3H), 6.87 (br. s., 1 H), 3.96 (d, J=13.2 Hz, 2H), 2.93 (t, J=1 1 .7 Hz, 2H), 2.71 (d, J= 3.1 Hz, 1 H), 2.06 (d, J=1 1 .5 Hz, 2H), 1 .89 (br. s., 1 H), 1 .68 (d, J= 1 1 .9 Hz, 3H), 1 .20 - 1 .04 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 390.1 .
Example 82: N-(2-phenylcyclopropyl)-4-(3-(quinolin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carboxamide
Figure imgf000192_0001
Step 1: Preparation of N-(2-phenylcyclopropyl)-4-(3-(quinolin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carboxamide.
Figure imgf000192_0002
To a stirred solution of 1 -[(2-phenylcyclopropyl)carbamoyl]piperidine-4-carboxylic acid (130 mg, 451 mitioI) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxyquinoline-2-carboximidamide (101 mg, 541 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (170 mg, 451 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (174 mg, 1 .35 mmol, 236 mI_). The mixture was stirred at 20 °C for 2 h, and then heated at 120 Ό for 2 h. The reaction mixture was cooled then purified by prep- HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give N-(2-phenylcyclopropyl)-4-(3-(quinolin-2-yl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carboxamide (34 mg, 77 mitioI, 17 %) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) d 8.60 (s, 1 H), 8.22 - 8.07 (m, 3H), 7.88 (br. s., 1 H), 7.74 (d, J= 7.5 Hz, 1 H), 7.30 - 7.20 (m, 2H), 7.18 - 7.06 (m, 3H), 6.89 (br. s., 1 H), 3.99 (d, J=13.7 Hz, 2H), 3.45 - 3.37 (m, 1 H), 2.94 (t, J=1 1 .7 Hz, 2H), 2.72 (d, J=3.5 Hz, 1 H), 2.10 (d, J=1 1 .0 Hz, 2H), 1 .89 (br. s., 1 H), 1 .72 (d, J=1 1 .5 Hz, 2H), 1 .18 (td, J= 4.6, 9.3 Hz,
1 H), 1 .1 1 - 1 .05 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 440.1 .
Example 83: 4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-1- carboxamide.
Figure imgf000192_0003
Step 1: Preparation of 4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine- 1- carboxamide.
Figure imgf000193_0001
To a stirred solution of (2-isocyanatoethyl)benzene (72 mg, 494 mitioI, 68 mI_) in toluene (2 mL) was added 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (150 mg, 494 mitioI) and N- ethyl-N-(propan-2-yl)propan-2-amine (63 mg, 494 mitioI, 86 pL). Then mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep- HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 35%-60%,12 min) to give 4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)-N- phenethylpiperidine-1 -carboxamide (58 mg, 130 mitioI, 26 %) as a white solid. 1 H NMR (400MHz, CDCI3) d 7.59 (dd, J-2.0, 8.4 Hz, 1 H), 7.49 (d, J=1 .9 Hz, 1 H), 7.28 - 7.22 (m, 2H), 7.18 - 7.12 (m, 3H), 6.87 (d, J=8.4 Hz, 1 H), 4.40 (br. s., 1 H), 4.10 (q, J= 7.0 Hz, 2H), 3.88 (s, 3H), 3.86 - 3.80 (m, 2H), 3.48 - 3.41 (m, 2H), 3.14 - 3.05 (m, 1 H), 2.97 - 2.88 (m, 2H), 2.78 (t, J= 6.8 Hz, 2H), 2.04 (dd, J= 3.2, 13.1 Hz, 2H), 1 .89 - 1 .77 (m, 2H), 1 .43 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 451 .3.
Example 84: 4-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1- phenylpyrrolidin-2-one, Example 85: (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5- yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, and Example 86: (S)-4-(4-(3-(4-ethoxy-3- methoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendine-1-carbonyl)-1-phenylpyrrolidin-2-one.
Figure imgf000193_0002
To a stirred solution of 5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (200 mg, 975 mitioI) in N,N dimethylformamide (4 mL) was added 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (295 mg, 975 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (369 mg, 975 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (377 mg, 2.92 mmol, 510 mI_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give racemic 4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one (151 mg, 31 %). A portion of this racemic mixture (140 mg) underwent SFC separation (column: OJ(250x30mm, 5pm);mobile phase: [CO2 base-isopropanol]; B%: 45%-45%, min]) to give (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one (64 mg, 132 mitioI, 14 %, 99.7% purity) as a white solid then (S)-4-(4-(3-(4-ethoxy- 3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one (65 mg, 133.9 mitioI, 14 %, 99.58% purity) also as a white solid.
4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one:
1 H NMR (400 MHz, DMSO-d6) d 7.68 (d, J= 8.0 Hz, 2H), 7.62 - 7.56 (m, 1 H), 7.48 (s, 1 H), 7.39 (t, J= 6.7 Hz, 2H), 7.19 - 7.09 (m, 2H), 4.38 (d, J=13.8 Hz, 1 H), 4.14 - 3.93 (m, 5H), 3.85 (s, 3H), 3.80 - 3.71 (m,
1 H), 3.51 - 3.40 (m, 1 H), 3.30 (br. s., 1 H), 3.00 - 2.89 (m, 1 H), 2.83 - 2.73 (m, 2H), 2.22 - 2.09 (m, 2H),
1 .90 - 1 .64 (m, 2H), 1 .37 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 491 .2.
(R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one:
1 H NMR (400 MHz, DMSO-d6) d 7.68 (d, J= 7.9 Hz, 2H), 7.62 - 7.56 (m, 1 H), 7.51 - 7.46 (m, 1 H), 7.39 (t, J=6.7 Hz, 2H), 7.19 - 7.09 (m, 2H), 4.38 (d, J=13.4 Hz, 1 H), 4.13 - 3.95 (m, 5H), 3.85 (s, 3H), 3.80 - 3.71 (m, 1 H), 3.44 (d, J=10.0 Hz, 2H), 2.94 (br. s., 1 H), 2.81 - 2.74 (m, 2H), 2.1 6 (t, J=13.6 Hz, 2H), 1 .91 - 1 .64 (m, 2H), 1 .37 (t, J= 6.9 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 491 .1 .
(S)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one.
1 H NMR (400 MHz, DMSO-d6) d 7.66 (d, J= 6.6 Hz, 2H), 7.57 (d, J= 8.4 Hz, 1 H), 7.46 (s, 1 H), 7.41 - 7.33 (m, 2H), 7.17 - 7.07 (m, 2H), 4.37 (d, J=12.8 Hz, 1 H), 4.12 - 3.92 (m, 5H), 3.83 (s, 3H), 3.78 - 3.69 (m,
1 H), 3.43 (t, J=10.6 Hz, 1 H), 3.28 (br. s., 1 H), 2.92 (t, J=13.0 Hz, 1 H), 2.81 - 2.70 (m, 2H), 2.14 (t, J=13.5 Hz, 2H), 1 .88 - 1 .78 (m, 1 H), 1 .74 - 1 .64 (m, 1 H), 1 .35 (t, J= 7.1 Hz, 3H); LCMS (ESI) m/z: C27H30N4O5 [M+H]+ = 491 .1
Alternatively, Example 85: (4R)-4-[4-[3-(4-ethoxy-3-methoxy-phenyl)- 1 ,2,4-oxadiazol-5-yl]piperidine- 1 - carbonyl]- 1-phenyl-pyrrolidin-2-one can be prepared in an enantioselective fashion as follows:
Figure imgf000194_0001
Step 1: Preparation of (4R)-4-[4-[3-(4-ethoxy-3-methoxy-phenyl)-1,2,4-oxadiazol-5-yl]piperidine-1- carbonyl]- 1 -phenyl-pyrrolidin-2-one.
Figure imgf000195_0001
To a stirred solution of 1 -[(3R)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (100 mg, 316 prnol) and 4-ethoxy-N'-hydroxy-3-methoxy-benzamidine (66 mg, 316 prnol) in DMF (1 .50 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 1 9 mg, 316 prnol) and N-ethyl-N-(propan-2-yl)propan-2-amine (81 mg, 632 prnol, 1 10 pL) 3ί 25Ό. After 12h, the mixture was heated and stirred at 1 10 °C for 1 h. The mixture was cooled then purified by prepJHPLC (Waters Xbridge 150x25 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%-65%,12 min) to give (4R)-4-[4-[3-(4-ethoxy-3-methoxy-phenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carbonyl]-1 -phenyl-pyrrolidin-2-one (59 mg, 122 pmol, 39 %) as a pink solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.66 (br d, J= 8.2 Hz, 1 H), 7.61 - 7.54 (m, 3H), 7.37 (m, J= 7.9 Hz, 2H), 7.19 - 7.14 (m, 1 H), 6.94 (d, J=8.4 Hz, 1 H), 4.59 - 4.46 (m, 1 H), 4.31 (dd, J= 7.3, 9.7 Hz, 1 H), 4.17 (q, J= 7.0 Hz, 2H), 3.99 - 3.90 (m, 5H), 3.58 (quin, J=8.4 Hz, 1 H), 3.43 - 3.26 (m, 2H), 3.16 - 2.92 (m, 2H), 2.88 - 2.79 (m,
1 H), 2.24 (br t, J=12.9 Hz, 2H), 2.05 - 1 .89 (m, 2H), 1 .50 (t, J= 6.9 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 491 .3.
Figure imgf000195_0002
To a stirred solution of 3-chloro-4-hydroxybenzonitrile (2.0 g, 13.0 mmol) in N,N- dimethylformamide (20 ml_) was added iodoethane (2.44 g, 15.6 mmol, 1 .25 ml_) and potassium carbonate (3.60 g, 26.1 mmol) at 0 °C. The reaction was warmed to 40 °C. After 16 h, the reaction mixture was quenched by addition of water (30 ml_) then the mixture was extracted with ethyl acetate (60 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude 3-chloro- 4-ethoxybenzonitrile (2.50 g) as a yellow solid. 1 H NMR (400 MHz, CDCta) d 7.57 (d, J= 1 .9 Hz, 1 H), 7.45 (dd, J-2.0, 8.7 Hz, 1 H), 6.88 (d, J= 8.5 Hz, 1 H), 4.10 (q, J= 7.0 Hz, 2H), 1 .43 (t, J= 7.0 Hz, 3H).
Figure imgf000196_0001
To a stirred solution of 3-chloro-4-ethoxybenzonitrile (2.40 g, 13.2 mmol) in ethanol (30 ml_) was added hydroxylamine hydrochloride (1 .84 g, 26.4 mmol), triethylamine (2.67 g, 26.4 mmol, 3.66 ml_) and water (3 ml_). The mixture was heated at 80 °C for 2 h. The reaction mixture was filtered and the filter cake dried in vacuo to give (Z)-3-chloro-4-ethoxy-N'-hydroxybenzimidamide (700 mg, 3.62 mmol, 69 %) as a brown oil. 1 H NMR (400 MHz, DMSO-d6) d 9.59 (s, 1 H), 7.72 (d, J= 2.0 Hz, 2H), 7.14 (d, J= 8.8 Hz,
1 H), 5.83 (s, 2H), 4.14 (q, J= 6.9 Hz, 2H), 1 .45 - 1 .30 (m, 3H).
Step 3: Preparation of N-(2-(4-(3-(3-chloro-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide
Figure imgf000196_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) in N,N-dimethylformamide (2 ml_) was added (Z)-3-chloro-4-ethoxy-N'-hydroxybenzimidamide (97 mg, 455 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 45%-80%,12 min) to give N-(2-(4-(3-(3-chloro-4-ethoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (104 mg, 223 mitioI, 54 %) as a yellow solid. 1 H NMR (400 MHz, CDCta) d 8.12 (d, J= 2.0 Hz, 1 H), 7.95 (dd, J=2.1 , 8.6 Hz, 1 H), 7.91 - 7.86 (m, 2H), 7.58 - 7.44 (m, 3H), 7.35 (br. s., 1 H), 7.02 (d, J= 8.7 Hz, 1 H), 4.51 (d, J= 13.7 Hz, 1 H), 4.33 (d, J= 3.9 Hz, 2H), 4.21 (q, J= 7.0 Hz, 2H), 3.93 (d, J= 13.9 Hz, 1 H), 3.41 - 3.29 (m, 2H), 3.18 (t, J= 10.8 Hz, 1 H), 2.33 - 2.20 (m, 2H), 2.09 - 1 .93 (m, 2H), 1 .53 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 469.3. Example 88: N-(2-(4-(3-(1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide
Figure imgf000197_0001
-
Step 1: Preparation of 1 H-indazole-6-carbonitrile
Figure imgf000197_0002
To a stirred solution of 6-bromo-1 H-indazole (1 .0 g, 5.08 mmol) in N,N-dimethylformamide (12 mL) was added zinc cyanide (595 mg, 5.08 mmol, 322 mI_) and tetrakis(triphenylphosphine)palladium(0) (586 mg, 508 mitioI), and the mixture was degassed with nitrogen three times. The mixture heated at 100 °C for 4 h under nitrogen. The reaction cooled to 20 °C, water (15 mL) was added, and the reaction mixture was extracted with ethyl acetate (40 mL x 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product. This was triturated with petroleum ether (30 mL) and dichloromethane (5 mL), and the mixture filtered. The filter cake was dried in vacuo to give 1 H-indazole- 6-carbonitrile (880 mg) as a yellow solid that was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 13.65 (br. s., 1 H), 8.33 - 8.12 (m, 2H), 7.99 (d, J=8.4 Hz, 1 H), 7.88 - 7.80 (m, 1 H).
Step 2: Preparation of (Z)-N'-hydroxy- 1H-indazole-6-carboximidamide.
Figure imgf000197_0003
To a stirred solution of 1 H-indazole-6-carbonitrile (800 mg, 5.59 mmol) in ethanol (1 ml_) was added hydroxylamine hydrochloride (776 mg, 1 1 .18 mmol), triethylamine (1 .13 g, 1 1 .1 8 mmol, 1 .55 ml_) and water (100 mI_). The mixture was heated at 80 °C for 2 h. The reaction mixture was cooled, concentrated under reduced pressure, and then diluted with water (5 ml_). The solid that formed was filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l H-indazole-6- carboximidamide (500 mg, 2.84 mmol, 51 %) as a yellow solid that was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 13.22 - 13.10 (m, 1 H), 9.68 (br. s., 1 H), 8.04 (s, 1 H), 7.78 (s, 1 H), 7.70 - 7.66 (m, 1 H), 7.47 - 7.42 (m, 1 H), 5.87 (br. s., 2H). Step 3: Preparation of N-(2-(4-(3-(1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000198_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 pmol) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxy-l H-indazole-6-carboximidamide (94 mg, 537 pmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 1 0 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Luna C18 100*30 5pm ; mobile phase: [water (0.225%TFA)-acetonitrile]; B%: 30%-55%,12 min) to give N-(2-(4-(3-(1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (21 mg, 44 mitioI, 1 1 %) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) d 13.34 (br s, 1 H), 8.55 (t, J= 5.6 Hz, 1 H), 8.18 - 8.16 (m, 1 H), 7.94 - 7.89 (m, 1 H), 7.88 - 7.83 (m, 2H), 7.72 (dd, J=1 .1 , 8.4 Hz, 1 H), 7.54 - 7.41 (m, 3H), 4.36 - 4.27 (m, 1 H), 4.16 (d, J= 5.7 Hz, 2H), 3.97 (br d, J=14.1 Hz, 1 H), 3.59 (br s, 1 H), 3.47 (s, 1 H), 3.34 - 3.24 (m, 1 H), 2.98 - 2.88 (m, 1 H), 2.20 - 2.08 (m, 2H), 1 .89 - 1 .77 (m, 1 H), 1 .66 (br d, J=1 1 .5 Hz,
1 H); LCMS (ESI) m/z: [M+H]+ = 431 .1 .
Example 89: 4-(4-(3-( 1 ,3-dimethyl-1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1- phenylpyrrolidin-2-one, example 90: 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5- yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, Enantiomer 1 and Example 91 : (R)-4-(4-(3-(1 ,3- dimethyl-1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, Enantiomer 2.
Figure imgf000198_0002
To a stirred solution of 6-bromo-1 ,3-dimethyl-1 H-indazole (480 mg, 2.13 mmol) in N,N- dimethylformamide (5 mL) was added zinc cyanide (250 mg, 2.13 mmol) and
tetrakis(triphenylphosphine)palladium(0) (246 mg, 213 pmol) under nitrogen, then the mixture was heated to 100 °C. After 16 h, the reaction was cooled to 20 °C, water (10 ml_) was added, and the reaction mixture extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 ml_), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give crude product. The residue was triturated with petroleum ether (30 ml_), then filtered and the filter cake dried in vacuo to give 1 ,3-dimethyl-1 H-indazole-6-carbonitrile (300 mg, 1 .75 mmol, 82 %) as a yellow solid. Ή NMR (400 MHz, CDCh) d 7.78 - 7.71 (m, 2H), 7.38 - 7.31 (m, 1 H), 4.08 (s, 3H), 2.61 (s, 3H).
Step 2: Preparation of (Z)-N'-hydroxy- l ,3-dimethyl- 1 H-indazole-6-carboximidamide.
Figure imgf000199_0001
To a stirred solution of 1 ,3-dimethyl-1 H-indazole-6-carbonitrile (300 mg, 1 .75 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (243 mg, 3.50 mmol), triethylamine (354 mg, 3.50 mmol, 485 mI_) and water (500 mI_). The mixture was heated at 80 °C for 5 h, then cooled and filtered, and the filter cake was dried in vacuo to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (290 mg, 1 .42 mmol, 81 %) as a white solid that was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) d 9.71 (s, 1 H), 7.86 (s, 1 H), 7.65 (d, J= 8.5 Hz, 1 H), 7.49 (d, J= 8.5 Hz, 1 H), 5.90 (s, 2H), 3.97 (s, 3H), 2.47 (s, 3H).
Figure imgf000199_0002
To a stirred solution of 5-oxo-1 -phenylpyrrolidine-3-carboxylic acid (500 mg, 2.44 mmol) in N,N- dimethylformamide (10 mL) was added methyl piperidine-4-carboxylate (349 mg, 2.44 mmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (925 mg, 2.44 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (946 mg, 7.32 mmol, 1 .28 mL). The mixture was stirred at 20 °C for 2 h.
The reaction mixture was quenched by addition of water (20 mL) then extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by
chromatography (silica, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1 ) gave methyl 1 -(5-oxo-1 - phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate (940 mg) as a yellow oil.
Figure imgf000199_0003
To a stirred solution of methyl 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate (900 mg, 2.72 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (2 M, 2.72 mL). Afterr 2 h, the reaction mixture was acidified to pH 1 with 1 M hydrochloric acid (6 mL). The mixture was extracted with ethyl acetate (40 mL x 3). The organic extracts were combined and washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (600 mg, 1 .90 mmol, 70 %) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 12.37 - 12.17 (m, 1 H), 7.66 (dd, J=5.8, 7.2 Hz, 2H), 7.38 (t, J=7.9 Hz, 2H), 7.19 - 7.09 (m, 1 H), 4.28 - 4.19 (m, 1 H), 4.04 (s, 1 H), 3.93 (br. s., 2H), 3.76 - 3.66 (m, 1 H), 3.18 (br. s., 1 H), 2.86 - 2.67 (m, 4H), 1 .87 (t, J=13.2 Hz, 2H), 1 .61 - 1 .35 (m, 2H).
Figure imgf000200_0001
To a stirred solution of 1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (150 mg, 474 pmol) in N,N-dimethylformamide (2 mL) was added N'-hydroxy-1 ,3-dimethyl-indazole-6- carboxamidine (96 mg, 474 pmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium
hexafluorophosphate) (179 mg, 474 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (183 mg, 1 .42 mmol, 248 pL). The mixture was stirred at 20 °C for 2 h, then heated at 120 Ό for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 30%-55%,12 min) to give the racemic of 4-(4-(3- (1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one (85 mg) as a white solid. A portion (25 mg, 53 mitioI, 1 1 %, 99.83% purity) was retained for analysis. The remainder (60 mg) was purified by SFC (column: OJ (250x30mm, 5pm); mobile phase: [CO2 base- methanol]; B%: 45%-45%,min) to give 4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one, Enatiomer 1 (27 mg, 56 mitioI, 12 %) as a brown solid then 4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin- 2-one, Enantiomer 2 (26 mg, 55 mitioI, 12 %) as a white solid.
4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one:
1 H NMR (400 MHz, CDCb) d 8.13 - 8.07 (m, 1 H), 7.83 (s, 1 H), 7.78 - 7.72 (m, 1 H), 7.61 (d, J= 8.0 Hz, 2H), 7.39 (t, J=7.9 Hz, 2H), 7.18 (s, 1 H), 4.65 - 4.50 (m, 1 H), 4.34 (t, J=7.3 Hz, 1 H), 4.09 (d, J= 3.3 Hz, 3H), 4.05 - 3.92 (m, 2H), 3.60 (quin, J=8.4 Hz, 1 H), 3.46 - 3.32 (m, 2H), 2.98 (d, J= 6.7 Hz, 2H), 2.91 - 2.81 (m,
1 H), 2.61 (s, 3H), 2.35 - 2.22 (m, 2H), 2.02 (d, J=6.1 Hz, 2H); LCMS (ESI) m/z: [M+H]+ = 485.2.
4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one, Enantiomer 1 :
1 H NMR (400 MHz, CDCb) d 8.12 (d, J=4.1 Hz, 1 H), 7.86 (br d, J= 8.5 Hz, 1 H), 7.80 - 7.74 (m, 1 H), 7.63 (d, J=7.9 Hz, 2H), 7.41 (t, J= 8.0 Hz, 2H), 7.23 - 7.18 (m, 1 H), 4.67 - 4.52 (m, 1 H), 4.36 (br t, J= 7.0 Hz,
1 H), 4.1 1 (d, J=3.4 Hz, 3H), 4.07 - 3.94 (m, 2H), 3.62 (quin, J= 8.5 Hz, 1 H), 3.49 - 3.35 (m, 2H), 3.22 - 2.96 (m, 2H), 2.93 - 2.81 (m, 1 H), 2.63 (s, 3H), 2.37 - 2.25 (m, 2H), 2.1 1 - 1 .97 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 485.3. 4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one, Enantiomer 2:
1 H NMR (400 MHz, CDCh) d 8.12 (d, J=3.9 Hz, 1 H), 7.86 (d, J=8.4 Hz, 1 H), 7.80 - 7.74 (m, 1 H), 7.63 (d, J=8.3 Hz, 2H), 7.41 (t, J= 8.0 Hz, 2H), 7.24 - 7.18 (m, 1 H), 4.66 - 4.53 (m, 1 H), 4.36 (br t, J= 7.3 Hz, 1 H), 4.1 1 (d, J=3.5 Hz, 3H), 4.07 - 3.94 (m, 2H), 3.62 (quin, J= 8.5 Hz, 1 H), 3.48 - 3.36 (m, 2H), 3.21 - 2.96 (m, 2H), 2.93 - 2.81 (m, 1 H), 2.63 (s, 3H), 2.36 - 2.26 (m, 2H), 2.06 (br d, J=13.4 Hz, 2H); LCMS (ESI) m/z: [M+H]+ = 485.3.
Examples 90 and 91 can be synthesized in an enantiospecific fashion using appropriate enantiopure starting materials, following the representative procedure below:
Figure imgf000201_0001
Preparation of (4R)-4-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1 ,2,4-oxadiazol-5-yl]piperidine- 1 -carbonyl]- 1 -phenyl- pyrrolidin-2-one.
Figure imgf000201_0002
To a stirred solution of 1 -[(3R)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (1 15 mg, 363.52 mitioI) and N'-hydroxy-1 ,3-dimethyl-indazole-6-carboxamidine (74 mg, 364 mitioI) in DMF (1 .50 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (137 mg, 364 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 727 mitioI, 126 mI_) at 25 °C. After 3 h, the mixture was warmed to 1 10 °C. After 1 h, the mixture was purified by chromatography (Waters Xbridge 150x25 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-60%,12 min) to give (4R)-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -phenyl- pyrrolidin-2-one (64 mg, 133 mitioI, 37 %) as a pink solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 8.09 (d, J=4.0 Hz, 1 H), 7.84 - 7.80 (d, 1 H), 7.75 - 7.71 (d, 1 H), 7.59 (d, J= 7.9 Hz, 2H), 7.38 (t, J= 7.9 Hz, 2H), 7.20 - 7.14 (t, 1 H), 4.62 - 4.49 (m, 1 H), 4.36 - 4.29 (m, 1 H), 4.07 (d, J= 3.3 Hz, 3H), 4.04 - 3.89 (m, 2H), 3.58 (quin, J=8.4 Hz, 1 H), 3.45 - 3.30 (m, 2H), 3.1 8 - 2.92 (m, 2H), 2.90 - 2.80 (m, 1 H), 2.59 (s, 3H), 2.27 (br t, J=13.2 Hz, 2H), 2.09 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 485.3.
Figure imgf000202_0001
To a stirred solution of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine- 1 -carboxylate (800 mg, 1 .98 mmol) in ethyl acetate (5 mL) was added 4M hydrochloric acid / ethyl acetate (20 mL). The mixture was stirred at 20 °C for 0.5 h . The reaction mixture was filtered and the filter cake was dried in vacuo to give 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (450 mg,
1 .48 mmol, 75 %) as a white solid. 1 H NMR (400 MHz, CDCI3) d 7.67 (dd, J=1 .6, 8.3 Hz, 1 H), 7.60 - 7.54 (m , 1 H), 6.97 (d, J=8.4 Hz, 1 H), 4.24 - 4.13 (m, 2H), 3.98 (s, 3H), 3.56 (br s, 2H), 3.39 (br s, 1 H), 3.33 - 3.1 5 (m, 2H), 2.51 (br s, 2H), 2.48 - 2.33 (m , 2H), 2.1 9 - 1 .83 (m, 1 H), 1 .53 (t, J= 7.0 Hz, 3H).
Step 2: Preparation of (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)(3- phenylisoxazol-5-yl)methanone.
Figure imgf000202_0002
To a stirred solution of 3-phenylisoxazole-5-carboxylic acid (75 mg, 396 gmol) in N,N- dimethylformamide (2 mL) was added 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (120 mg, 396 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate) (1 50 mg, 396 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 53 mg, 1 .1 9 mmol, 207 mI_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was then purified by prep-HPLC (column : Waters Xbridge 1 50x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%:40%-70%, 12 min) to give (4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)(3-phenylisoxazol-5- yl)methanone (41 mg, 87 mitioI, 22 %) as a white solid. 1 H NMR (400 MHz, CDCI3) d 7.87 (br s, 2H), 7.70 (br d, J=7.8 Hz, 1 H), 7.60 (br s, 1 H), 7.53 (br s, 3H), 7.1 4 (s, 1 H), 6.99 (br d, J= 7.5 Hz, 1 H), 4.59 (br s,
1 H), 4.36 (br d, J=1 2.5 Hz, 1 H), 4.21 (br d, J=6.4 Hz, 2H), 4.00 (s, 3H), 3.55 (br s, 1 H), 3.46 - 3.25 (m , 2H), 2.32 (br s, 2H), 2.1 5 (br s, 2H), 1 .54 (br t, J= 6.8 Hz, 3H) ; LCMS (ESI) m/z: [M+H]+ = 475.2. Example 93: N-(2-(4-(3-(3-methyl-1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)benzamide.
Figure imgf000203_0001
Step 1: Preparation of 3-methyl- 1 H-indazole-6-carbonitrile.
Figure imgf000203_0002
To a stirred solution of 6-bromo-3-methyl-1 H-indazole (440 mg, 2.08 mmol) in N,N- dimethylformamide (5 ml_) was added zinc cyanide (244 mg, 2.08 mmol) and
tetrakis(triphenylphosphine)palladium(0) (240 mg, 208 mitioI), then the mixture was degassed with nitrogen three times. The mixture stirred at 100 °C for 4 h under nitrogen, then cooled to 20 °C, water (10 ml_) added, and the reaction mixture was extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product. Petroleum ether (20 ml_) was added to the crude product, then the mixture was filtered and the filter cake dried in vacuo to give 3- methyl-1 H-indazole-6-carbonitrile (220 mg, 1 .40 mmol, 67 %) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) d 13.29 - 13.09 (m, 1 H), 8.09 - 8.05 (m, 1 H), 7.96 - 7.90 (m, 1 H), 7.41 (d, J= 8.3 Hz, 1 H), 2.54 (s, 3H).
Figure imgf000203_0003
To a stirred solution of 3-methyl-1 H-indazole-6-carbonitrile (200 mg, 1 .27 mmol) in ethanol (1 ml_) was added hydroxylamine hydrochloride (176 mg, 2.55 mmol), triethylamine (257 mg, 2.55 mmol, 352 mI_) and water (100 mI_). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled and then concentrated under reduced pressure to remove ethanol. The residue was diluted with water (5 ml_), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-3-methyl-1 H-indazole- 6-carboximidamide (150 mg, 789 mitioI, 62 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 12.73 (s, 1 H), 9.67 (s, 1 H), 7.73 (s, 1 H), 7.65 (d, J= 8.5 Hz, 1 H), 7.45 (d, J= 8.5 Hz, 1 H), 5.86 (s, 2H), 2.49 (s, 3H). Step 3: Preparation of N-(2-(4-(3-(3-methyl- 1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000204_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 pmol) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxy-3-methyl-1 H-indazole-6-carboximidamide (78 mg, 413 pmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20°C for 2 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-55%,12 min) to give N-(2-(4-(3-(3-methyl-1 H-indazol-6-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (93 mg, 209 pmol, 51 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 12.92 (s, 1 H), 8.59 - 8.53 (m, 1 H), 8.08 (s, 1 H), 7.86 (d, J=8.4 Hz, 3H), 7.71 - 7.65 (m, 1 H), 7.55 - 7.42 (m, 3H), 4.30 (d, J=13.2 Hz, 1 H), 4.16 (d, J= 5.7 Hz, 2H), 3.97 (d, J=14.6 Hz,
1 H), 3.49 - 3.43 (m, 1 H), 3.29 - 3.24 (m, 1 H), 2.92 (t, J=1 1 .2 Hz, 1 H), 2.50 (s, 3H), 2.14 (t, J= 13.0 Hz, 2H), 1 .88 - 1 .78 (m, 1 H), 1 .66 (d, J= 9.7 Hz, 1 H); LCMS (ESI) m/z: [M+H]+ = 445.3.
Example 94: N-(2-(4-(3-( 1 -methyl-1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)benzamide.
Figure imgf000204_0002
To a stirred solution of 6-bromo-1 -methyl-1 H-indazole (500 mg, 2.37 mmol) in N,N- dimethylformamide (8 ml_) was added zinc cyanide (278 mg, 2.37 mmol) and
tetrakis(triphenylphosphine)palladium(0) (273 mg, 236.90 pmol), the mixture was degassed with nitrogen three times. The mixture was stirred at 100 Ό for 4 h under nitrogen, then cooled to 20 °C, water (10 ml_) added, and the reaction mixture extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product. The mixture was triturated with petroleum ether (20 ml_) and dichloromethane (3 ml_), then filtered and dried in vacuo to give 1 -methyl- 1 H-indazole-6-carbonitrile (300 mg, 1 .91 mmol, 81 %) as a yellow solid. 1 H NMR (400 MHz, CDCI3) d 8.10 (s, 1 H), 7.88 - 7.83 (m, 1 H), 7.82 (s, 1 H), 7.39 (dd, J=1 .1 , 8.3 Hz, 1 H), 4.1 6 (s, 3H).
Step 2: Preparation of (Z)-N'-hydroxy- l -methyl- 1 H-indazole-6-carboximidamide.
Figure imgf000205_0001
To a stirred solution of 1 -methyl-1 H-indazole-6-carbonitrile (250 mg, 1 .59 mmol) in ethanol (1 ml_) was added hydroxylamine hydrochloride (221 mg, 3.1 8 mmol), triethylamine (321 mg, 3.18 mmol, 440 mI_) and water (100 mI_). The mixture was heated at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue then triturated with water (4 ml_), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l -methyl-1 H-indazole-6-carboximidamide (500 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 10.65 (br. s., 2H), 9.65-9.84 (m, 1 H), 7.98 (d, J=18.1 Hz, 2H), 7.67 (d, J= 8.8 Hz, 1 H), 7.46-7.52 (m, 1 H), 4.03 ppm (s, 3H).
Step 3: Preparation of N-(2-(4-(3J1 -methyl- 1 H-indazol-6-yl)- 1 ,2,4-oxadiazol-5-yl)pipericlin- 1 -yl)-2- oxoethyl)benzamide.
Figure imgf000205_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxy-l -methyl-1 H-indazole-6-carboximidamide (125 mg, 661 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified by prep- HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 33%-63%,12 min) to give N-(2-(4-(3-(1 -methyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (29 mg, 64 mitioI, 15 %) as a yellow solid. 1 H NMR (400 MHz, CDC ) d 8.19 (s, 1 H), 8.06 (s, 1 H), 7.92 - 7.82 (m, 4H), 7.58 - 7.45 (m, 3H), 7.36 (br. s., 1 H), 4.56 (d, J=14.2 Hz, 1 H), 4.34 (d, J= 3.9 Hz, 2H), 4.19 (s, 3H), 4.00 - 3.92 (m, 1 H), 3.44 - 3.34 (m, 2H), 3.19 (t,
J=10.9 Hz, 1 H), 2.36 - 2.26 (m, 2H), 2.14 - 1 .98 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 445.2.
Figure imgf000206_0001
Step 1: Preparation of 1 , 3-dimethyl- 1 H-indazole-5-carbonitrile.
Figure imgf000206_0002
To a stirred solution of 5-bromo-1 ,3-dimethyl-1 H-indazole (600 mg, 2.67 mmol) in N,N- dimethylformamide (10 ml_) was added zinc cyanide (313 mg, 2.67 mmol, 169 mI_) and
tetrakis(triphenylphosphine)palladium(0) (308 mg, 267 mitioI) under nitrogen. The mixture was stirred at 100 °C for 16 h, then cooled to 20 °C, and diluted with water (15 ml_). The reaction mixture was extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product. This was triturated with petroleum ether (30 ml_) and dichloromethane (5 ml_), filtered and the filter cake dried in vacuo to give 1 ,3-dimethyl-1 H-indazole-5-carbonitrile (340 mg, 1 .99 mmol, 74 %) as a brown solid. 1 H NMR (400 MHz, CDCh) d 8.02 (s, 1 H), 7.54 (d, J= 8.8 Hz, 1 H), 7.37 (d, J=8.8 Hz, 1 H), 4.02 (s, 3H), 2.57 (s, 3H).
Step 2: Preparation of (Z)-N'-hydroxy- l ,3-dimethyl- 1 H-indazole-5-carboximidamide.
Figure imgf000206_0003
To a stirred solution of 1 ,3-dimethyl-1 H-indazole-5-carbonitrile (340 mg, 1 .99 mmol) in ethanol (6 mL) was added hydroxylamine hydrochloride (276 mg, 3.97 mmol), triethylamine (401 mg, 3.97 mmol,
550 mI_) and water (600 mI_). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was triturated with water (4 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-5- carboximidamide (250 mg, 1 .22 mmol, 62 %) as a white solid.1 H NMR (400 MHz, DMSO-d6) d 9.50 (s,
1 H), 7.99 (s, 1 H), 7.72 (dd, J=1 .5, 9.0 Hz, 1 H), 7.48 (d, J= 8.8 Hz, 1 H), 5.82 (s, 2H), 3.92 (s, 3H), 2.46 (s, 3H). Step 3: Preparation of N-(2-(4-(3-( 1 ,3-dimethyl- 1 H-indazol-5-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000207_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 mitioI) in N,N-dimethylformamide (2 ml_) was added N'-hydroxy-1 ,3-dimethyl-indazole-5-carboxamidine (84 mg,
413 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 56 mg, 413 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 mI_). The mixture was stirred at 20 °C for 2 h, and then heated at 1 10 °C for 2 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-64%,12 min) to give N-(2-(4-(3-(1 ,3-dimethyl-1 H-indazol-5-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (54 mg, 1 18 mitioI, 29 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 8.55 (t, J= 5.5 Hz, 1 H), 8.34 (s, 1 H), 7.96 (dd, J=1 .3, 8.8 Hz, 1 H), 7.86 (d, J= 7.1 Hz, 2H), 7.70 (d, J= 8.8 Hz, 1 H), 7.55 - 7.42 (m, 3H), 4.31 (d, J=13.2 Hz, 1 H), 4.16 (dd, J= 2.2, 5.3 Hz, 2H), 4.03 - 3.92 (m, 4H), 3.49 - 3.40 (m, 1 H), 3.34 - 3.30 (m, 1 H), 2.92 (t, J=1 1 .5 Hz, 1 H), 2.52 (s, 3H), 2.14 (t, J=13.0 Hz, 2H), 1 .83 (d, J=10.1 Hz, 1 H), 1 .71 - 1 .62 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 459.3.
Figure imgf000207_0002
To a stirred solution of (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (180 mg, 881 mitioI) in dioxane (3 ml_) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (147 mg, 970 mitioI, 146 mI_) and 1 ,1’-carbonyldiimidazole (214 mg, 1 .32 mmol). The mixture was stirred at 1 10 °C for 16 h. The reaction mixture was concentrated in vacuo then purified by chromatography (silica, dichloromethane : methanol = 50 :1 ) to give 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5(4H)-one (220 mg) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 7.97 - 7.93 (m, 1 H), 7.82 - 7.77 (m, 1 H), 7.62 (d, J= 1 .1 Hz, 1 H), 4.05 (s, 3H), 2.57 (s, 3H).
Figure imgf000208_0001
A flask 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5(4H)-one (220 mg, 956 pmol) was charged with N,N-dimethylformamide (1 ml_) then phosphoryl chloride (10 ml_) was added dropwise. The mixture was heated at 1 10 °C for 16 h, then cooled and concentrated under reduced pressure, poured onto ice water (10 ml_), and stirred for 10 min. The mixture was extracted with dichloromethane (20 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-chloro-3-(1 ,3-dimethyl-1 H- indazol-6-yl)-1 ,2,4-oxadiazole (1 00 mg) as a brown solid.
Step 3: Preparation of tert-butyl 4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperazine- 1- carboxylate
Figure imgf000208_0002
To a stirred solution of 5-chloro-3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazole (100 mg, 402.1 mmitioI) in N-methyl-2-pyrrolidone (3 ml_) was added tert-butyl piperazine-1 -carboxylate (74 mg, 402 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (103 mg, 804 mitioI, 140 mI_). The mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled, quenched by addition of water (5 ml_) then the mixture was extracted with ethyl acetate (20 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and
concentrated. Purification by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ) gave tert-butyl 4-(3- (1 ,3-dimethyl-1 H-indazol-6-yl)-1 , 2, 4-oxadiazol-5-yl)piperazine-1 -carboxylate (65 mg, 163 mitioI, 41 %) as a brown solid.
Figure imgf000208_0003
To a stirred solution of tert-butyl 4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperazine-1 - carboxylate (65 mg, 163 pmol) in ethyl acetate (1 ml_) was added hydrochloric acid / ethyl acetate (4M, 5 ml_). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4-oxadiazole (40 mg, 134 pmol,
82 %) as a white solid. LCMS (ESI) m/z: [M+H]+ = 299.1 .
Step 5: Preparation of 4-(4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1 ,2,4-oxadiazol-5-yl)piperazine- 1 -carbonyl)- 1 -phenylpyrrolidin-2-one
Figure imgf000209_0001
To a stirred solution of 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4-oxadiazole (35 mg, 1 1 7 pmol) in N,N-dimethylformamide (1 ml_) was added 5-oxo-1 -phenylpyrrolidine-3-carboxylic acid (24 mg, 1 1 7 pmol), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate) (44 mg, 1 1 7 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (45 mg, 352 mitioI, 61 mI_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by prep-H PLC (column : Waters Xbridge 1 50x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give 4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazine-1 -carbonyl)-1 - phenylpyrrolidin-2-one (26 mg, 54.58 mitioI, 47 %) as a white solid. 1 H NMR (400 MHz, CDCI3) d 8.05 (s,
1 H), 7.83 - 7.69 (m , 2H), 7.63 (br d, J= 7.5 Hz, 2H), 7.42 (br t, J= 7.5 Hz, 2H), 7.22 (br d, J= 7.9 Hz, 1 H), 4.37 (br t, J=8.0 Hz, 1 H), 4.09 (s, 3H), 4.03 - 3.96 (m, 1 H), 3.93 - 3.72 (m , 8H), 3.63 (br d, J= 9.7 Hz, 1 H), 3.04 - 2.85 (m , 2H), 2.62 (s, 3H) ; LCMS (ESI) m/z: [M+H]+ = 486.3.
Figure imgf000209_0002
Step 1: Preparation of 4-ethoxy-3-fluorobenzonitrile
Figure imgf000209_0003
To a stirred solution of 3-fluoro-4-hydroxybenzonitrile (800 mg, 5.83 mmol) in N,N- dimethylformamide (1 0 ml_) was added iodoethane (1 .09 g, 7.00 mmol, 559 mI_) and potassium carbonate (1 .61 g, 1 1 .7 mmol) at 0 °C. The reaction was warmed at 40 °C for 1 6 h. The reaction mixture was quenched with water (1 0 ml_), then the mixture was extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (1 0 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give crude 4-ethoxy-3-fluorobenzonitrile (750 mg, 4.54 mmol, 78 %) as a yellow solid. 1 H NMR (400 MHz, CDCI3) d 7.43 - 7.30 (m , 2H), 6.98 (t, J= 8.3 Hz, 1 H), 4.1 5 (q, J= 7.0 Hz, 2H), 1 .47 (tt, J=1 .2, 7.0 Hz, 3H).
Figure imgf000210_0001
To a stirred solution of 4-ethoxy-3-fluorobenzonitrile (400 mg, 2.42 mmol) in ethanol (6 ml_) was added hydroxylamine hydrochloride (336 mg, 4.84 mmol), triethylamine (490 mg, 4.84 mmol, 671 mI_) and water (600 mI_). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled then concentrated under reduced pressure. The residue was triturated with water (5 ml_), filtered and the filter cake was dried under reduced pressure to give (Z)-4-ethoxy-3-fluoro-N'-hydroxybenzimidamide (300 mg,
1 .51 mmol, 63 %) as a white solid. Ή NMR (400 MHz, DMSO-d6) d 9.57 (s, 1 H), 7.47 - 7.39 (m, 2H),
7.12 (t, J=8.9 Hz, 1 H), 5.80 (s, 2H), 4.13 - 4.06 (m, 2H), 1 .34 - 1 .29 (m, 3H).
Step 3: Preparation of N-(2-(4-(3-(4-ethoxy-3-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide
Figure imgf000210_0002
To a stirred solution of 1 -(2-benzamidoacetyi)piperidine-4-carboxyiic acid (100 mg, 344 mitioI) in N,N-dimethylformamide (2 mL) was added (Z)-4-ethoxy-3-fluoro-N'-hydroxybenzimidamide (68 mg, 344 pmol), (2-(1 H-benzotriazol-1 -yi)-1 ,1 ,3,3-tetramethyluronlum hexafiuorophosphate) (130 g, 344 mitioI) and N-ethyi-N-(propan-2-yl)propan-2-amine (133 mg, 1 .03 mmol, 180 pL). The mixture was stirred at 20 °C for 1 h, then heated at 1 1 0 °C for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)- aceionitri!e]; B%: 40%-70%,12 min) to give N-(2-(4-(3-(4-ethoxy-3-fluorophenyl)-1 ,2,4-oxadiazo!-5- yl)piperidin-1 -yl)-2-oxoethy!)benzamide (43 mg, 96 pmol, 28 %) as a pink solid. ¾ H NMR (400 MHz, CDCb) d 7.88 (d, J= 7.0 Hz, 2H), 7.85 - 7.79 (m, 2H), 7.58 - 7.44 (m, 3H), 7.35 (br s, 1 H), 7.05 (t, J= 8.5 Hz, 1 H), 4.51 (br d, J= 13.6 Hz, 1 H), 4.33 (d, J=3.8 Hz, 2H), 4.20 (q, J= 7.0 Hz, 2H), 3.93 (br d, J= 13.7 Hz,
1 H), 3.41 - 3.29 (m, 2H), 3.23 - 3.13 (m, 1 H), 2.32 - 2.20 (m, 2H), 2.08 - 1 .93 (m, 2H), 1 .51 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M÷H]+ = 453.1 .
Example 98: [4-[3-(4-ethoxy-3-methoxy-phenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-(2-phenyl-1H- imidazol-5-yl)methanone
Figure imgf000211_0001
Figure imgf000211_0004
A mixture of 2-benzamidoacetic acid (1 .0 g, 5.58 mmol) and 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (953 mg, 6.14 mmol, 1 .08 ml_) in dichloromethane (25 ml_) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 6h under a nitrogen atmosphere. The mixture was concentrated in vacuum to get a crude product. The crude product, 2-phenyl-4H-oxazol-5-one (1 .20 g) was used directly without further purification.
Step 2: Ethyl 2-phenyl- 1 H-imidazole-5-carboxylate
Figure imgf000211_0002
A mixture of 2-phenyl-4H-oxazol-5-one (1 .0 g, 6.21 mmol), ethyl cyanoformate (676 mg, 6.83 mmol, 669 mI_) and tributylphosphine (753 mg, 3.72 mmol, 918 mI_) in dichloromethane (3 ml_) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 6h under a nitrogen atmosphere. The reaction mixture was quenched by addition of water (3 ml_), then extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (silica, petroleum ether / ethyl acetate = 2:1 ) to give ethyl 2-phenyl-1 H-imidazole-5-carboxylate (480 mg, 2.22 mmol, 36 %) as a white solid.
Step 3: 2-phenyl- 1 H-imidazole-5-carboxylic acid
Figure imgf000211_0003
A mixture of ethyl 2-phenyl-1 H-imidazole-5-carboxylate (300 mg, 1 .39 mmol) and sodium hydroxide (166 mg, 4.1 7 mmol) in tetrahydrofuran (3 mL) and water (1 .50 mL) was stirred at 20 °C for 2 h. The reaction mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-phenyl-1 H-imidazole-5-carboxylic acid (200 mg) that was used directly without further purification.
Step 4: [4-[3-(4-ethoxy-3-methoxy-phenyt)- 1,2, 4-oxadiazol-5-yl]- 1 -piperidyl]-(2-phenyl- 1 H-imidazol-5- yl)methanone
Figure imgf000212_0001
A mixture of 2-phenyl-1 H-imidazole-5-carboxylic acid (62 mg, 330 pmol), 3-(4-ethoxy-3-methoxy- phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (100 mg, 330 pmol), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (125 mg, 330 pmol) and diisopropylethylamine (85 mg, 659 mitioI, 1 15 mI_) in N,N-dimethylformamide (3 ml_) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 2 h under a nitrogen atmosphere. The mixture was purified by prep-HPLC (column: Waters Xbridge 150x25 5pm; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-65%,12 min) to give [4-[3-(4-ethoxy-3-methoxy-phenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]-(2-phenyl-1 H-imidazol-5-yl)methanone (25 mg, 105 mitioI, 16 %) as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.95 (br d, J=7.7 Hz, 2H), 7.65 (dd, J=1 .8, 8.4 Hz, 1 H), 7.54 (s, 2H),
7.47 - 7.32 (m, 3H), 6.92 (d, J=8.4 Hz, 1 H), 5.56 - 5.27 (m, 1 H), 4.77 - 4.46 (m, 1 H), 4.14 (q, J=6.8 Hz, 2H), 3.99 - 3.88 (m, 3H), 3.66 - 3.09 (m, 3H), 2.24 (br d, J=9.7 Hz, 2H), 2.07 (br s, 1 H), 1 .84 (br s, 1 H),
1 .47 (t, J=6.8 Hz, 3H); LCMS(ESI) m/z: [M+H]+ = 474.3.
Example 99: N-(2-(4-(3-(3-bromo-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)benzamide
Figure imgf000212_0002
Step 1: Preparation of N-(2-(4-(3-(3-bromo-4-ethoxyphenyt)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide
Figure imgf000212_0003
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (100 mg, 344 pmol) in N,N-dimethylformamide (2 ml_) was added (Z)-3-bromo-4-ethoxy-N'-hydroxybenzimidamide (89 mg, 344 mihoI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (130 mg, 344 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (133 mg, 1 .03 mmol, 180 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 45%-75%,12 min) to give N-(2-(4-(3-(3-bromo-4-ethoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (43 mg, 83 mitioI, 24 %) as a yellow solid. 1 H NMR (400MHz, CDC ) d 8.30 (d, J=2.1 Hz, 1 H), 8.00 (dd, J=2.1 , 8.6 Hz, 1 H), 7.91 - 7.85 (m, 2H), 7.58 - 7.44 (m, 3H), 7.35 (br s, 1 H), 6.98 (d, J= 8.7 Hz, 1 H), 4.50 (br d, J=14.1 Hz, 1 H), 4.33 (d, J= 3.9 Hz, 2H), 4.20 (q, J= 6.9 Hz, 2H), 3.93 (br d, J=13.8 Hz, 1 H), 3.41 - 3.29 (m, 2H), 3.18 (br t, J= 10.6 Hz, 1 H), 2.32 - 2.20 (m, 2H), 2.09 - 1 .93 (m, 2H), 1 .53 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 513.2.
Figure imgf000213_0001
To a stirred solution of 4-ethoxy-N-hydroxy-3-methoxybenzimidamide (1 .0 g, 4.76 mmol) in dioxane (10 ml_) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (796 mg, 5.24 mmol, 788 mI_) and 1 ,1’- carbonyldiimidazole (1 .16 g, 7.14 mmol). The mixture was heated at 1 10 °C for 1 6 h. The reaction mixture was cooled, quenched with water (10 ml_), and then extracted with dichloromethane (50 ml_ x 3). The combined organic phases were washed with 1 M aqueous hydrochloric acid (5 ml_ x 2), then with saturated aqueous sodium chloride solution (10 ml_), filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated to give 3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (1 .02 g, 4.32 mmol, 91 %) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) d 12.78 (br s, 1 H), 7.38 - 7.28 (m, 2H), 7.08 (d, J=8.4 Hz, 1 H), 4.05 (q, J= 7.1 Hz, 2H), 3.77 (s, 3H), 1 .30 (t, J= 6.9 Hz, 3H).
Figure imgf000213_0002
A flask 3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (1 .02 g, 4.32 mmol) was equipped with calcium chloride tube, then phosphoryl chloride (12 ml_) and pyridine (170 mg, 2.16 mmol, 174 mI_) were added dropwise and the mixture was heated at 1 10 °C for 16 h. The reaction mixture was cooled then concentrated under reduced pressure to remove phosphoryl chloride, and the residue added to ice water (20 ml_) and stirred for 10 min. The mixture was extracted with dichloromethane (40 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give crude 5-chloro-3-(4-ethoxy-3- methoxyphenyl)-1 ,2,4-oxadiazole (910 mg) as a yellow solid.
Step 3: Preparation of methyl 1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-4- carboxylate.
Figure imgf000214_0001
To a stirred solution of 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazole (600 mg, 2.36 mmol) in N-methyl-2-pyrrolidone (8 ml_) was added methyl piperidine-4-carboxylate (337 mg, 2.36 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (610 mg, 4.72 mmol, 824 mI_). The mixture was stirred at 120 °C for 16 h. The reaction mixture was quenched with water (10 ml_), then the mixture was extracted with ethyl acetate (40 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 10:1 ) to give methyl 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (510 mg, 1 .41 mmol, 60 %) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 7.47 (dd, J= 1 .9, 8.3 Hz, 1 H), 7.38 (d, J-2.0 Hz, 1 H), 7.06 (d, J=8.4 Hz, 1 H), 4.08 (q, J= 7.0 Hz, 2H), 4.00 (td, J=3.5, 13.2 Hz, 2H), 3.82 (s, 3H), 3.64 (s, 3H), 3.31 - 3.24 (m, 2H), 2.68 (tt, J= 3.9, 10.9 Hz, 1 H), 1 .98 (br dd, J= 3.2, 13.5 Hz, 2H), 1 .70 - 1 .58 (m, 2H), 1 .36 (t, J= 7.0 Hz, 3H).
Figure imgf000214_0002
To a stirred solution of methyl 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylate (490 mg, 1 .36 mmol) in tetrahydrofuran (1 0 ml_) was added lithium hydroxide (2 M, 2.04 ml_). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, then the mixture was acidified with concentrated hydrochloric acid until pH 1 . The mixture was extracted with dichloromethane (40 ml_ x 3). The organic layer was washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give crude 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylic acid (400 mg, 1 .15 mmol, 85 %) as a white solid. 1 H NMR (400 MHz, Methanol-d4) d 7.52 - 7.45 (m, 2H), 6.99 (d, J=8.4 Hz, 1 H), 4.15 - 4.05 (m, 4H), 3.86 (s, 3H), 3.32 (br d, J=3.1 Hz, 1 H), 3.28 - 3.25 (m, 1 H), 2.61 (tt, J= 3.8, 10.8 Hz, 1 H), 2.07 - 1 .98 (m, 2H), 1 .80 - 1 .68 (m, 2H), 1 .41 (t, J= 6.9 Hz, 3H). Step 5: Preparation of (1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(3- phenylpiperidin- 1 -yl)methanone.
Figure imgf000215_0001
To a stirred solution of 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylic acid (100 mg, 288 mitioI) in N,N-dimethylformamide (500 mI_) was added 3-phenylpiperidine (46 mg, 288 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (109 mg, 288 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 1 1 mg, 863.66 mitioI, 1 50 mI_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-60%,12 min) to give (1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(3-phenylpiperidin-1 - yl)methanone (80 mg, 162 mitioI, 56 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 7.45 - 7.40 (m, 1 H), 7.36 - 7.16 (m, 6H), 7.02 (d, J=8.4 Hz, 1 H), 4.49 - 4.36 (m, 1 H), 4.09 - 3.92 (m, 5H), 3.78 (s, 3H), 3.28 - 2.92 (m, 4H), 2.70 - 2.50 (m, 2H), 1 .89 (br d, J=1 1 .7 Hz, 1 H), 1 .82 - 1 .44 (m, 7H), 1 .31 (t, J= 6.9 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 491 .3.
Figure imgf000215_0002
To a stirred solution of 3-bromo-4-hydroxybenzonitrile (1 .0 g, 5.05 mmol) in N,N- dimethylformamide (10 ml_) was added iodoethane (945 mg, 6.06 mmol, 484 mI_) and potassium carbonate (1 .40 g, 10.1 mmol) at 0 °C. The reaction was warmed at 40 °C for 16 h. The reaction mixture was quenched by addition of water (15 ml_), then the mixture was extracted with ethyl acetate (40 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-bromo-4- ethoxybenzonitrile (1 .20 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) d 7.80 (d, J= 2.0 Hz, 1 H), 7.55 (dd, J-2.0, 8.6 Hz, 1 H), 6.89 (d, J= 8.6 Hz, 1 H), 4.14 (q, J= 7.0 Hz, 2H), 1 .49 (t, J= 6.9 Hz, 3H).
Step 2: Preparation of (Z)-3-bromo-4-ethoxy-N'-hydroxybenzimidamide.
Figure imgf000216_0001
To a stirred solution of 3-bromo-4-ethoxybenzonitrile (1 .15 g, 5.09 mmol) in ethanol (10 ml_) was added hydroxylamine hydrochloride (706 mg, 10.2 mmol), triethylamine (1 .03 g , 10.2 mmol, 1 .41 ml_) and water (1 ml_). The mixture was heated at 80 °C for 1 h, then cooled and concentrated under reduced pressure to remove ethanol. The residue was triturated with water (5 ml_) and filtered, and the filter cake was dried under reduced pressure to give (Z)-3-bromo-4-ethoxy-N'-hydroxybenzimidamide (1 .31 g, 5.06 mmol, 99 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 9.55 (br s, 1 H), 7.82 (d, J= 2.2 Hz, 1 H), 7.60 (dd, J-2.2, 8.6 Hz, 1 H), 7.05 (d, J= 8.8 Hz, 1 H), 5.79 (s, 2H), 4.12 - 4.05 (m, 2H), 1 .31 (t, J= 7.1 Hz, 3H).
Figure imgf000216_0002
To a stirred solution of zinc cyanide (226 mg, 1 .93 mmol, 122 mI_) in N,N-dimethylformamide (10 mL) was added (Z)-3-bromo-4-ethoxy-N'-hydroxybenzimidamide (500 mg, 1 .93 mmol) and
tetrakis(triphenylphosphine)palladium(0) (222 mg, 193 mitioI), then the mixture was degassed with nitrogen three times. The mixture was heated at 1 10 °C for 16 h under nitrogen then cooled to 20 °C, water (10 mL) was added, and the reaction mixture extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 13%-43%, 12 min) to give (Z)-3-cyano-4-ethoxy-N'-hydroxybenzimidamide (60 mg, 292 mitioI, 15 %) as a white solid.
Step 4: Preparation of N-(2-(4-(3-(3-cyano-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000216_0003
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (70 mg, 241 mitioI) in N,N-dimethylformamide (1 mL) was added (Z)-3-cyano-4-ethoxy-N'-hydroxybenzimidamide (49 mg, 241 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (91 mg, 241 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 723 mitioI, 126 pL). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-65%,12 min) to give N-(2-(4-(3-(3-cyano-4-ethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (20 mg, 43 mitioI, 18 %) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 8.55 (t, J= 5.5 Hz, 1 H), 8.26 - 8.1 7 (m, 2H), 7.84 (dd, J=1 .2, 8.3 Hz, 2H), 7.57 - 7.34 (m, 4H), 4.26 (q, J= 6.9 Hz, 3H), 4.14 (br d, J= 5.5 Hz, 2H), 3.94 (br d, J=14.6 Hz, 1 H), 3.48 - 3.40 (m, 1 H), 3.29 - 3.22 (m, 1 H), 2.90 (br t, J=1 1 .4 Hz, 1 H), 2.10 (br t, J= 12.8 Hz, 2H), 1 .87 - 1 .72 (m, 1 H), 1 .68 - 1 .55 (m, 1 H), 1 .37 (t, J= 6.9 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 460.2.
Example 102: N-(2-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazin-1-yl)-2- oxoethyl)benzamide
Figure imgf000217_0001
Step 1: Preparation of 1 ,3-dimethyl- 1 H-indazole-6-carbonitrile.
Figure imgf000217_0002
To a stirred solution of 6-bromo-1 ,3-dimethyl-1 H-indazole (1 .0 g, 4.44 mmol) in N,N- dimethylformamide (10 ml_) was added zinc cyanide (521 mg, 4.44 mmol, 281 mI_) and
tetrakis(triphenylphosphine)palladium(0) (513 mg, 444 pmol), then the mixture was degassed with nitrogen three times. The mixture was stirred at 100 °C for 16 h under nitrogen, then cooled to 20 °C, water (10 ml_) added, and the reaction mixture extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 10:1 ) to give 1 ,3-dimethyl-1 H-indazole- 6-carbonitrile (660 mg, 3.86 mmol, 87 %) as a white solid. 1 H NMR (400 MHz, CDCh) d 7.74 - 7.66 (m, 2H), 7.30 (d, J=8.4 Hz, 1 H), 4.03 (s, 3H), 2.57 (s, 3H).
Step 2: Preparation of (Z)-N'-hydroxy- l ,3-dimethyl- 1 H-indazole-6-carboximidamide.
Figure imgf000217_0003
To a stirred solution of 1 ,3-dimethyl-1 H-indazole-6-carbonitrile (660 mg, 3.86 mmol) in ethanol (8 mL) was added hydroxylamine hydrochloride (536 mg, 7.72 mmol), triethylamine (781 mg, 7.72 mmol,
1 .07 mL) and water (800 pL). The mixture was heated at 80 °C for 2 h, then cooled and concentrated under reduced pressure. The residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (650 mg, 3.18 mmol, 82 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 9.72 (br. s., 1 H), 7.86 (s, 1 H), 7.65 (d, J=8.5 Hz, 1 H), 7.49 (dd, J=1 .1 , 8.5 Hz, 1 H), 5.91 (s, 2H), 3.97 (s, 3H), 2.47 (s, 3H).
Step 3: Preparation of 3-(1 ,3-dimethyl- 1 H-indazol-6-yl)- 1 ,2, 4-oxadiazol-5(4H)-one.
Figure imgf000218_0001
To a stirred solution of (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (510 mg, 2.50 mmol) in dioxane (8 ml_) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (418 mg, 2.75 mmol, 414 mI_) and 1 ,T-carbonyldiimidazole (608 mg, 3.75 mmol). The mixture was stirred at 1 10 °C for 16 h. The reaction mixture was cooled, quenched with water (1 0 ml_), and then extracted with dichloromethane (50 ml_ x 3). The combined organic layers were washed with 1 M hydrochloric acid (5 ml_ x 2), then washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5(4H)-one (430 mg, 1 .87 mmol, 75 %) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 13.29 - 12.78 (m, 1 H), 8.03 (s, 1 H), 7.87 (d, J=8.4 Hz, 1 H), 7.48 (dd, J= 1 .1 , 8.4 Hz, 1 H), 3.98 (s, 3H), 2.48 (br s, 3H).
Figure imgf000218_0002
A flask 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5(4H)-one (180 mg, 781 .86 mitioI) was equipped with calcium chloride tube then pyridine (123 mg, 1 .56 mmol, 126 mI_) and phosphoryl chloride (5 mL) were added dropwise. The mixture was heated at 1 1 0 °C for 16 h, then cooled and concentrated under reduced pressure to remove phosphoryl chloride, and then added to ice water (20 mL). The mixture was extracted with dichloromethane (40 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-chloro-3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2, 4-oxadiazole (250 mg) as a brown solid.
Step 5: Preparation of tert-butyl 4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperazine- 1- carboxylate.
Figure imgf000218_0003
To a stirred solution of 5-chloro-3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2, 4-oxadiazole (230 mg, 925 mitioI) in N-methyl-2-pyrrolidone (3 ml_) was added tert-butyl piperazine-1 -carboxylate (172 mg, 925 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (239 mg, 1 .85 mmol, 323 mI_). The mixture was heated at 120 °C for 2 h. The reaction mixture was cooled, quenched by addition of water (5 ml_), then the mixture was extracted with ethyl acetate (20 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. Purification by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ) gave tert- butyl 4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazine-1 -carboxylate (150 mg, 376 mitioI, 41 %) as a pink solid.
Step 6: Preparation of 3-( 1, 3-dimethyl- 1H-indazol-6-yl)-5-(piperazin- 1-yl)- 1 ,2,4-oxadiazole.
Figure imgf000219_0001
To a stirred solution of tert-butyl 4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5- yl)piperazine-1 -carboxylate (150 mg, 376 mitioI) in ethyl acetate (1 ml_) was added hydrochloric acid / ethyl acetate (4M, 5 ml_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was
concentrated under reduced pressure to give 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4- oxadiazole (1 10 mg, 369 mitioI, 98 %) as a pink solid. LCMS (ESI) m/z: [M+H]+ = 299.2.
Step 7: Preparation of N-(2-(4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1 ,2,4-oxadiazol-5-yl)piperazin- 1 -yl)-2- oxoethyl)benzamide.
Figure imgf000219_0002
To a stirred solution of 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4-oxadiazole (50 mg, 168 mitioI) in N,N-dimethylformamide (1 ml_) was added 2-benzamidoacetic acid (30 mg, 168 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (63 mg, 168 mitioI) and N- ethyl-N-(propan-2-yl)propan-2-amine (64 mg, 503 mitioI, 87 mI_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-(2-(4- (3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazin-1 -yl)-2-oxoethyl)benzamide (29 mg, 64 mitioI, 38 %) as a white solid. Ή NMR (400 MHz, CDCh) d 8.00 (s, 1 H), 7.84 (d, J= 7.7 Hz, 2H), 7.76 - 7.66 (m, 2H), 7.55 - 7.41 (m, 3H), 7.27 - 7.25 (m, 1 H), 4.33 (d, J= 3.7 Hz, 2H), 4.05 (s, 3H), 3.89 - 3.75 (m, 6H), 3.66 (br d, J=5.1 Hz, 2H), 2.57 (s, 3H); LCMS (ESI) m/z: [M+H]+ = 460.3.
Example 103: (4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazin-1-yl)(3- phenylisoxazol-5-yl)methanone.
Figure imgf000220_0001
Step 1: Preparation of (4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperazin- 1-yl)(3- phenylisoxazol-5-yl)methanone.
Figure imgf000220_0002
To a stirred solution of 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4-oxadiazole (50 mg, 168 mitioI) in N,N-dirnethylformarnide (1 ml_) was added 3-phenylisoxazole-5-carboxylic acid (31 mg, 168 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (63 mg, 168 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (64 mg, 502.8 mitioI, 87 mI_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-75%,12 min) to give (4- (3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazin-1 -yl)(3-phenylisoxazol-5-yl)methanone (26 mg, 56.9 mitioI, 34 %) as a white solid. Ή NMR (400MHz, CDCI.3) d 8.01 (s, 1 H), 7.83 (td, J= 2.8, 4.1 Hz, 2H), 7.76 - 7.73 (m, 1 H), 7.71 - 7.67 (m, 1 H), 7.51 - 7.47 (m, 3H), 7.18 (s, 1 H), 4.05 (s, 3H), 4.03 - 3.93 (m, 4H), 3.89 - 3 84 (m, 4H), 2 57 (s, 3H); LCMS (ESI) m/z: [M+H]+ = 470.3.
Example 104: N-(2-(4-(3-(benzo[c][1 ,2,5Jthiadiazol-5-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.
Figure imgf000220_0003
Step 1: Preparation of benzo[c][1 ,2,5]thiadiazole-5-carbonitrile.
Figure imgf000220_0004
To a stirred solution of 5-bromobenzo[c][1 ,2,5]thiadiazole (200 mg, 930 gmol) in N,N- dimethylformamide (2 ml_) was added zinc cyanide (109 mg, 930 gmol, 59 mI_) and
tetrakis(triphenylphosphine)palladium(0) (107 mg, 93 gmol), the mixture was degassed with nitrogen three times. The mixture was heated at 1 10 °C for 1 6 h under nitrogen. After cooling to 20 °C, water (5 ml_) was added to the reaction, and the mixture extracted with ethyl acetate (20 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product. The mixture was triturated with petroleum ether (20 ml_) and dichloromethane (2 ml_), then the mixture was filtered, and the filter cake dried in vacuo to give benzo[c][1 ,2,5]thiadiazole-5-carbonitrile (100 mg, 620 gmol, 67 %) as a red solid. LCMS (ESI) m/z: [M+H]+ = 162.0.
Step 2: Preparation of (Z)-N'-hydroxybenzo[c][1,2,5]thiadiazole-5-carboximidamide.
Figure imgf000221_0001
To a stirred solution of benzo[c][1 ,2,5]thiadiazole-5-carbonitrile (100 mg, 620 gmol) in ethanol (2 mL) was added hydroxylamine hydrochloride (86 mg, 1 .24 mmol), triethylamine (125 mg, 1 .24 mmol, 172 gl_) and water (200 gl_). The mixture was heated at 80 °C for 1 h. The reaction mixture was cooled and then concentrated under reduced pressure to remove ethanol. The residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'- hydroxybenzo[c][1 ,2,5]thiadiazole-5-carboximidamide (70 mg, 360 gmol, 58 %) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) d 10.13 (s, 1 H), 8.35 (d, J= 0.9 Hz, 1 H), 8.10 (dd, J=1 .5, 9.3 Hz, 1 H), 8.01 - 7.96 (m, 1 H), 6.08 (s, 2H).
Step 3: Preparation of N-(2-(4-(3-(benzo[c][1,2,5]thiadiazoi-5-yi)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2- oxoethyljbenzamide.
Figure imgf000221_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (80 mg, 276 gmol) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxybenzo[c][1 ,2,5]thiadiazole-5-carboximidamide (53 mg, 276 gmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (104 mg, 276 gmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (106 mg, 827 gmol, 144 gl_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was purified directly by prep- HPLC (column: Waters Xbridge 150x2.5mm 5gm; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 45%-65%,12 min) to give N-(2-(4-(3-(benzo[c][1 ,2,5]thiadiazol-5-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (30 mg, 67 gmol, 24 %) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) d 8.66 (t, J=1 .2 Hz, 1 H), 8.55 (t, J= 5.7 Hz, 1 H), 8.28 - 8.22 (m, 2H), 7.87 - 7.83 (m, 2H), 7.54 - 7.42 (m, 3H), 4.31 (br d, J=13.0 Hz, 1 H), 4.16 (dd, J=1 .5, 5.7 Hz, 2H), 3.98 (br d, J=13.5 Hz, 1 H), 3.54 - 3.51 (m, 1 H), 3.29 (br t, J=1 1 .5 Hz, 1 H), 2.93 (br t, J= 1 1 .2 Hz, 1 H), 2.16 (br t, J= 13.2 Hz, 2H), 1 .90 - 1 .78 (m, 1 H), 1 .73 - 1 .62 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 449.2.
Figure imgf000222_0001
Figure imgf000222_0002
To a stirred solution of 2-benzamidoacetic acid (5.0 g, 27.9 mmol) in N,N-dimethylformamide (50 ml_) was added methyl piperidine-4-carboxylate (4.40 g, 30.7 mmol), 1 -[bis(dimethylamino)methylene]- 1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1 0.6 g, 27.9 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (10.8 g, 83.7 mmol, 14.6 ml_). The mixture was stirred at 20 °C for 2 h, then quenched by addition of water (50 ml_). The mixture was extracted with ethyl acetate (100 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (40 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 5:1 to 1 :1 ) to give methyl 1 -(2- benzamidoacetyl)piperidine-4-carboxylate (9.17 g) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 7.88 - 7.83 (m, 2H), 7.55 - 7.49 (m, 1 H), 7.48 - 7.41 (m, 2H), 4.35 - 4.28 (m, 1 H), 4.24 (d, J= 5.3 Hz, 2H), 3.88 (d, J=14.1 Hz, 1 H), 3.66 (s, 3H), 3.20 (d, J= 2.2 Hz, 1 H), 2.92 - 2.84 (m, 1 H), 2.65 (tt, J=4.0, 10.8 Hz,
1 H), 1 .99 - 1 .87 (m, 2H), 1 .74 - 1 .64 (m, 1 H), 1 .62 - 1 .51 (m, 1 H). Step 2: Preparation of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid.
Figure imgf000223_0001
To a stirred solution of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (9.1 7 g, 30.1 mmol) in tetrahydrofuran (90 ml_) was added sodium hydroxide (2 M, 30.1 ml_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure then acidified with concentrated hydrochloric acid until pH 1 . The mixture was extracted with dichloromethane (80 ml_ x 4). The organic phases were combined and then washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue (8.85 g). A portion of crude product (2.5 g) was purified by prep-HPLC (column: Daiso 250*50mm, 10pm; mobile phase: [water (0.1 %TFA)-acetonitrile] ; B%: 1 %-30%, 20 min) to provide 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (0.95 g). The remaining crude product was used directly without purification. 1 H NMR (400 MHz, Methanol-d4) d 7.87 - 7.83 (m, 2H), 7.55 - 7.50 (m, 1 H), 7.48 - 7.42 (m, 2H), 4.36 (td, J= 3.2, 13.2 Hz, 1 H), 4.25 (d, J=3.3 Hz, 2H), 3.94 - 3.86 (m, 1 H), 3.22 - 3.14 (m, 1 H), 2.89 - 2.80 (m, 1 H), 2.46 (tt, J= 3.9, 1 1 .0 Hz, 1 H), 2.00 - 1 .87 (m, 2H), 1 .74 - 1 .52 (m, 2H).
Step 3: Preparation of 2-acetyl-4-chlorophenyl trifluoromethanesulfonate.
Figure imgf000223_0002
Triflic anhydride (9.92 g, 35.2 mmol, 5.80 ml_) was added dropwise at 0° C to a stirred solution of 1 -(5-chloro-2-hydroxy-phenyl)ethanone (5.0 g, 29.3 mmol) in pyridine (50 ml_) The reaction was warmed slowly to 15 Ό and stirred for 15 h. The reaction solution was diluted with dichloromethane (100 ml_), then poured into 1 N aqueous hydrochloric acid (100 ml_) at 0 °C and the phases separated. The organic phase was washed with 1 N hydrochloric acid (50 ml_ x 2), saturated aqueous sodium chloride solution (50 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue Purification by chromatography (silica, petroleum ether : ethyl acetate from 100/1 to 30/1 ) gave 2-acetyl- 4-chlorophenyl trifluoromethanesulfonate (7.50 g, 24.8 mmol, 85 %) as a yellow liquid.
Figure imgf000223_0003
To a stirred solution of 2-acetyl-4-chlorophenyl trifluoromethanesulfonate (3.0 g, 9.91 mmol) in N,N-dimethylformamide (30 ml_) was added 1 -vinyloxybutane (4.96 g, 49.6 mmol, 6.36 ml_), palladium(ll) acetate(1 1 1 mg, 495.5 pmol), 3-diphenylphosphanylpropyl(diphenyl)phosphane (245 mg, 594.6 pmol) and TEA (1 .20 g, 1 1 .9 mmol, 1 .65 ml_), then the mixture was degassed with nitrogen three times. The mixture was heated at 80 °C for 16 h under nitrogen. After cooling to 20 °C, 2M hydrochloric acid (20 ml_) was added and the solution stirred at 20 °C for 2 h. Water (30 ml_) was added and the mixture was extracted with ethyl acetate (80 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 10:1 ) to give 1 ,1 '-(4-chloro-1 ,2-phenylene)diethanone (800 mg, 4.07 mmol, 41 %) as a red oil. Ή NMR (400 MHz, CDCta) d 7.58 - 7.54 (m, 1 H), 7.51 - 7.47 (m, 1 H), 7.43 (t, J= 1 .9 Hz, 1 H), 2.52 (d, J= 2.0 Hz, 3H), 2.50 (d, J= 2.0 Hz, 3H).
Figure imgf000224_0001
1 ,1 '-(4-chloro-1 ,2-phenylene)diethanone (800 mg, 4.07 mmol) in ethanol (15 ml_) was added to hydrazine hydrate (224 mg, 4.48 mmol, 217 mI_) in ethanol (15 ml_) at 0 °C over a period of 5 min under argon. The mixture was stirred at 20 °C for 18 h. The reaction mixture was concentrated under reduced pressure to ~15 ml_, then extracted with dichloromethane (50 ml_ x 3). The combined organic phases were washed water (20 ml_ x 2), then the separated organic layer was washed saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 6-chloro- 1 ,4-dimethylphthalazine (662 mg, 3.44 mmol, 84 %) as a red solid. 1 H NMR (400 MHz, CDCta) d 7.98 - 7.93 (m, 2H), 7.75 (dd, J=2.1 , 8.8 Hz, 1 H), 2.88 (d, J= 5.1 Hz, 6H).
Step 6: Preparation of 1,4-dimethylphthalazine-6-carbonitrile.
Figure imgf000224_0002
To a stirred solution of 6-chloro-1 ,4-dimethylphthalazine (640 mg, 3.32 mmol) in N,N- dimethylformamide (10 ml_) was added zinc cyanide (390 mg, 3.32 mmol, 210 mI_) and
tetrakis(triphenylphosphine)palladium(0) (383 mg, 332 mitioI) under nitrogen. The mixture was heated at 1 10 °C for 16 h, then cooled to 20 °C. Water (15 ml_) was added then the reaction mixture was extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product. Trituration with petroleum ether (30 ml_) and dichloromethane (5 ml_) followed by filtration and drying the filter cake in vacuo gave 1 ,4-dimethylphthalazine-6-carbonitrile (400 mg, 2.18 mmol, 66 %) as a brown solid. 1 H NMR (400 MHz, CDCta) d 8.47 (s, 1 H), 8.21 (d, J= 8.5 Hz, 1 H), 8.09 (dd, J=1 .4, 8.5 Hz, 1 H), 3.04 (s, 6H).
Step 7: Preparation of (Z)-N'-hydroxy-l ,4-dimethylphthalazine-6-carboximidamide.
Figure imgf000225_0001
To a stirred solution of 1 ,4-dimethylphthalazine-6-carbonitrile (380 mg, 2.07 mmol) in ethanol (1 ml_) was added hydroxylamine hydrochloride (288 mg, 4.15 mmol), triethylamine (419 mg, 4.15 mmol, 575 mI_) and water (100 mI_). The mixture was heated at 80 °C for 1 h. The reaction mixture was cooled then concentrated under reduced pressure. The residue was triturated with water (5 ml_), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l ,4-dimethylphthalazine-6- carboximidamide (330 mg, 1 .53 mmol, 74 %) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) d 1 0.06 (s, 1 H), 8.38 (d, J=1 .3 Hz, 1 H), 8.28 (dd, J= 1 .7, 8.7 Hz, 1 H), 8.12 (d, J= 8.8 Hz, 1 H), 6.19 (s, 2H), 2.85 (d,
J=17.0 Hz, 6H).
Step 8: Preparation of N-(2-(4-(3-( 1 ,4-dimethylphthalazin-6-yl)- 1 ,2,4-oxadiazol-5-yl)pipericlin- 1 -yl)-2- oxoethyl)benzamide.
Figure imgf000225_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (100 mg, 344 mitioI) in N,N-dimethylformamide (2 ml_) was added N'-hydroxy-1 ,4-dimethyl-phthalazine-6-carboxamidine (74 mg, 344 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (130 mg, 344 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (133 mg, 1 .03 mmol, 180 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled, then purified by prep- HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 25%-55%,12 min) to give N-(2-(4-(3-(1 ,4-dimethylphthalazin-6-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (37 mg, 77 mitioI, 22 %) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 8.71 (d, J= 1 .5 Hz, 1 H), 8.59 (t, J= 5.6 Hz, 1 H), 8.54 (dd, J=1 .5, 8.6 Hz, 1 H), 8.39 (d, J= 8.6 Hz, 1 H), 7.90 - 7.86 (m, 2H), 7.57 - 7.45 (m, 3H), 4.37 (br d, J=13.2 Hz, 1 H), 4.25 - 4.13 (m, 2H), 4.02 (br d, J=13.5 Hz, 1 H), 3.55 (tt, J= 3.8, 1 1 .1 Hz, 1 H), 3.32 - 3.27 (m, 1 H), 2.96 (s, 3H), 2.98 - 2.91 (m, 1 H),
2.93 (s, 3H), 2.20 (br t, J= 13.7 Hz, 2H), 1 .95 - 1 .82 (m, 1 H), 1 .77 - 1 .65 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 471 .3.
Example 106: 2-(2-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)isoindolin-1-one.
Figure imgf000225_0003
Step 1: Preparation of 2-(2-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)isoindolin- 1 -one.
Figure imgf000226_0001
To a stirred solution of 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (50 mg,
165 mitioI) in N,N-dimethylformamide (1 ml_) was added 2-(1 -oxoisoindolin-2-yl)acetic acid (31 mg, 165 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (62 mg, 165 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (63 mg, 494 mitioI, 86 mI_). The mixture was stirred at 20 °C for 1 h, then the reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give 2- (2-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)isoindolin-1 -one (41 mg, 86 mitioI, 52 %) as a gray solid. 1 H NMR (400MHz, CDCI3) d 7.88 (d, J= 8.2 Hz, 1 H), 7.66 (dd, J= 1 .9, 8.3 Hz, 1 H), 7.59 - 7.54 (m, 2H), 7.48 (t, J=6.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 1 H), 4.59 (d, J=3.4 Hz, 2H), 4.53 - 4.40 (m, 3H), 4.18 (q, J= 7.0 Hz, 2H), 4.08 (br d, J= 13.7 Hz, 1 H), 3.96 (s, 3H), 3.43 - 3.24 (m, 2H), 3.1 1 - 3.02 (m, 1 H), 2.28 - 2.15 (m, 2H), 2.05 - 1 .90 (m, 2H), 1 .51 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 477.3.
Figure imgf000226_0002
Step 1: 2-bromo-6-iodo-pyridin-3-ol.
Figure imgf000226_0003
A mixture of 2-bromopyridin-3-ol (5.0 g, 28.7 mmol), iodine (8.02 g, 31 .6 mmol, 6.37 ml_), and potassium carbonate (7.94 g, 57.5 mmol) in water (66 ml_) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 1 6 h under a nitrogen atmosphere. Excess iodine was quenched by addition of solid sodium bisulfite. The pH of the solution was adjusted to 5-6 using glacial acetic acid, and the solid formed was collected by filtration and dried in vacuum to give 2-bromo-6-iodo- pyridin-3-ol (10.0 g) that was used directly without further purification. Step 2: 2-bromo-3-ethoxy-6-iodo-pyridine.
Figure imgf000227_0001
To a stirred solution of 2-bromo-6-iodo-pyridin-3-ol (10.0 g, 33.4 mmol) in tetrahydrofuran (200 mL) was added potassium carbonate (6.91 g, 50.0 mmol) and the mixture was stirred for 10 min at 0 Ό in an ice bath lodoethane (6.24 g, 40.0 mmol, 3.20 mL) was added dropwise, then the reaction mixture was warmed to 40 °C. After 16 h, the reaction mixture was quenched by addition of water (10 mL), and then extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-bromo-3-ethoxy-6-iodo-pyridine (7.50 g, 22.9 mmol, 69 %) that was used directly without further purification.
Step 3: 3-ethoxy-6-iodo-2-methoxy-pyridine.
Figure imgf000227_0002
A mixture of 2-bromo-3-ethoxy-6-iodo-pyridine (7.0 g, 21 .4 mmol) and sodium methoxide (1 .73 g, 32.0 mmol) in N,N-dimethylformamide (3 mL) was degassed and purged with nitrogen 3 times, and then the mixture was heated at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was quenched by addition of water (20 mL), then extracted with ethyl acetate (20 mL x 3). The organic layer phases were combined and then washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-ethoxy-6- iodo-2-methoxy-pyridine (5.0 g, 17.9 mmol). This was used directly without further purification.
Step 4: 5-ethoxy-6-methoxy-pyridine-2-carbonitrile.
Figure imgf000227_0003
A mixture of 3-ethoxy-6-iodo-2-methoxy-pyridine (2.50 g, 8.96 mmol) and coper(l) cyanide (962 mg, 10.75 mmol, 2.35 mL) in N,N-dimethylformamide (10 mL) was degassed and purged with nitrogen 3 times, and then the mixture was heated at 100 Ό for 1 6 h under a nitrogen atmosphere. The reaction mixture was quenched by addition of water (20 mL), then extracted with ethyl acetate (20 mL x 3). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-ethoxy-6- methoxy-pyridine-2-carbonitrile (1 .40 g). This was used directly without further purification.
Step 5: 5-ethoxy-6-methoxy-pyridine-2-carbonitrile. H0 V \
H2N^ ^ °e*
OMe
A mixture of 5-ethoxy-6-methoxy-pyridine-2-carbonitrile (1 .0 g, 5.61 mmol), hydroxylamine hydrochloride (857 mg, 12.34 mmol) and triethylamine (1 .25 g, 12.34 mmol, 1 .71 ml_) in ethanol (10 ml_) was heated at 75 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled, diluted with water (10 ml_), and filtered. The filter cake was dried in vacuo to give 5-ethoxy-N'-hydroxy-6-methoxy- pyridine-2-carboxamidine (950 mg, 4.50 mmol, 80 %) as a yellow solid. 1 H NMR (400MHz,
CHLOROFORM-d) d = 7.40 (d, J=8.2 Hz, 1 H), 6.99 (d, J=8.2 Hz, 1 H), 5.45 (br s, 2H), 4.05 (q, J=6.9 Hz, 2H), 3.98 (s, 3H), 1 .41 (t, J=7.0 Hz, 3H).
Step 6: N-[2-[4-[3-(5-ethoxy-6-methoxy-2-pyridyl)- 1 ,2,4-oxadiazol-5-yl]- 1 -piperidyl]-2-oxo- ethyljbenzamide.
Figure imgf000228_0001
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (100 mg, 344 mitioI) in N,N-dimethylformamide (2 ml_) was added 5-ethoxy-N'-hydroxy-6-methoxy-pyridine-2-carboxamidine (72 mg, 344 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (133 mg, 1 .03 mmol, 180 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The crude product was purified by prep-HPLC (column: Waters Xbridge 150x25 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%- 60%, 12 min) to give N-[2-[4-[3-(5-ethoxy-6-methoxy-2-pyridyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo- ethyl]benzamide (37 mg, 79.9 mitioI, 23 %) as a yellow solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.91 - 7.85 (m, 2H), 7.70 (d, J=8.0 Hz, 1 H), 7.57 - 7.52 (m, 1 H), 7.51 - 7.44 (m, 2H), 7.36 (br s, 1 H), 7.13 (d, J=8.2 Hz, 1 H), 4.57 - 4.48 (m, 1 H), 4.32 (d, J=3.9 Hz, 2H), 4.23 - 4.12 (m, 5H), 4.06 - 3.90 (m, 1 H), 3.42 - 3.32 (m, 2H), 3.20 - 3.1 1 (m, 1 H), 2.32 - 2.20 (m, 2H), 2.08 - 1 .95 (m, 2H), 1 .54 (t, J=7.0 Hz, 3H); LCMS(ESI) m/z: [M+H]+ = 466.3.
Figure imgf000228_0002
Step 1: 4-[4-[3-(5-ethoxy-6-methoxy-2-pyridyt)- 1, 2, 4-oxadiazol-5-yl]piperidine- 1 -carbonyl]- 1-phenyl- pyrrolidin-2-one.
Figure imgf000229_0001
To a stirred solution of 5-ethoxy-N'-hydroxy-6-methoxy-pyridine-2-carboxamidine (66 mg, 316 mitioI) in N,N-dimethylformamide (2 mL) was added 1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)piperidine-4- carboxylic acid (100 mg, 316 pmol), (2-(1 FI-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium
hexafluorophosphate) (143 mg, 379 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (122 mg, 948 mitioI, 165 pL). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The mixture was cooled and the crude product was purified by prep-FIPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-70%,12 min) to give 4-[4-[3-(5- ethoxy-6-methoxy-2-pyridyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -phenyl-pyrrolidin-2-one (47 mg, 96 mitioI, 3 %) as a yellow solid. 1 FI NMR (400MFIz, CFILOROFORM-d) d = 7.71 (dd, J=4.6, 8.0 Hz, 1 FI), 7.62 (dd, J=1 .1 , 8.7 Hz, 2H), 7.43 - 7.38 (m, 2H), 7.22 - 7.17 (m, 1 H), 7.13 (d, J=7.8 Hz, 1 H), 4.63 - 4.48 (m, 1 H), 4.34 (t, J=7.9 Hz, 1 H), 4.22 - 4.15 (m, 5H), 4.03 - 3.93 (m, 2H), 3.60 (m, 1 H), 3.46 - 3.33 (m, 2H), 3.15 - 2.95 (m, 2H), 2.91 - 2.82 (m, 1 H), 2.27 (m, 2H), 2.08 - 1 .94 (m, 2H), 1 .54 (t, J=7.0 Hz, 3H);
LCMS(ESI) m/z: [M+H]+ = 492.3.
Figure imgf000229_0002
Step 1: 2,2-difluoro- 1,3-benzodioxole-5-carbonitrile.
Figure imgf000229_0003
A mixture of 5-bromo-2,2-difluoro-1 ,3-benzodioxole (500 mg, 2.1 1 mmol), zinc cyanide (247 mg,
2.1 1 mmol, 133 mI_) and tetrakis(triphenylphosphine)palladium(0) (243 mg, 21 1 pmol) in N,N- dimethylformamide (4 mL) was degassed and purged with nitrogen 3 times, and then the mixture was heated at 100 Ό for 16 h under a nitrogen atmosphere. The reaction mixture was cooled, diluted with water (5 mL), and extracted with ethyl acetate (10 mL x 2 ). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2,2-difluoro-1 ,3-benzodioxole-5-carbonitrile (300 mg,
1 .64 mmol, 78 %) as a solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.38 (dd, J=1 .5, 8.3 Hz, 1 H), 7.27 (d, J=1 .5 Hz, 1 H), 7.08 (d, J=8.3 Hz, 1 H).
Step 2: 2,2-difluoro-N'-hydroxy- 1,3-benzodioxole-5-carboxamidine.
Figure imgf000230_0001
A mixture of 2,2-difluoro-1 ,3-benzodioxole-5-carbonitrile (300 mg, 1 .64 mmol), triethylamine (331 mg, 3.28 mmol, 454 mI_) and hydroxylamine hydrochloride (227 mg, 3.28 mmol) in water (500 mI_) and ethanol (5 ml_) was heated at 70 °C for 16 h. The reaction mixture was cooled, diluted with water (10 ml_) and filtered. The collected solid was dried in vacuo to give 2,2-difluoro-N'-hydroxy-1 ,3-benzodioxole-5- carboxamidine (210 mg) as a solid.
Step 3: N-[2-[4-[3-(2, 2-difluoro- 1 ,3-benzodioxol-5-yl)- 1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo- ethyljbenzamide,
Figure imgf000230_0002
A mixture of 2,2-dii!uoro-N'-hydroxy-1 ,3-benzodioxole-5-carboxamidine (74 g, 344 mitioI), 1 -(2- benzamidoacetyi)piperidine-4-earboxylic acid (100 mg, 344 mitioI), N-ethyl-N-(propan-2-yl)propan-2- amine (133 mg, 1 .03 mmol, 180 mI_) and (2-(1 H-benzotr!azo!-1 -y!)-1 ,1 ,3,3-tetramethy!uronium
hexafluorophosphate) (156 mg, 413 mitioI) in N,N-dimethyiformamide (2 mL) was stirred at 20 °C for 1 h under a nitrogen atmosphere. The mixture was heated at 120°C for 1 h, then cooled and purified by prep- HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 QmM ammonium carbonate)- acetonitriiej; B%: 40%-70%,12 min) to give N-[2-[4-[3-(2,2-dif!uoro-1 ,3-benzodioxol-5-yl)-1 ,2,4-oxadiazol- 5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (58 mg, 124 miho!, 36 %) as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.85 - 7.76 (m, 3H), 7.72 (d, J=1 .5 Hz, 1 H), 7.48 - 7.42 (m, 1 H), 7.41 - 7.35 (m, 2H), 7.26 (br s, 1 H), 7.10 (d, J=8.4 Hz, 1 H), 4.53 - 4.37 (m, 1 H), 4.23 (d, J=4.0 Hz, 2H), 3.84 (br d, J=13.9 Hz, 1 H), 3.35 - 3.21 (m, 2H), 3.12 - 3.02 (m, 1 H), 2.26 - 2.10 (m, 2H), 1 .98 - 1 .85 (m, 2H); LCMS (ESI) m/z: [M÷H]+:471 .2.
Example 110: N-(2-(4-(3-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4Joxazin-7-yl)-1,2,4-oxadiazol-5- yl)piperidin-1-yl)-2-oxoethyl)benzamide.
Figure imgf000231_0001
To a stirred solution of 7-bromo-4-ethyl-2H-benzo[b][1 ,4]oxazin-3(4H)-one (900 mg, 3.51 mmol) in tetrahydrofuran (1 0 ml_) was added a solution of borane in tetrahydrofuran (1 M, 12.28 ml_), and the mixture was stirred 20 °C for 1 h, then heated at 80 °C for 2 h. The reaction mixture was cooled then quenched by addition of methanol (15 ml_). The mixture was concentrated under reduced pressure, then diluted with water (20 ml_), extracted with ethyl acetate (60 ml_ x 2), and the combined organic phases washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 7-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine (750 mg, 3.10 mmol, 88 %) as a yellow oil. 1 H NMR (400 MHz, CDCh) d 6.86 - 6.80 (m, 2H), 6.45 (d, J= 8.3 Hz, 1 H), 4.19 - 4.13 (m, 2H), 3.28 - 3.18 (m, 4H), 1 .06 (t, J= 7.1 Hz, 3H).
Figure imgf000231_0002
To a stirred solution of 7-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine (80 mg, 330 pmol) in N,N-dimethylformamide (1 ml_) was added zinc cyanide (38 mg, 330 pmol) and
tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 pmol), then the mixture was degassed with nitrogen three times. The mixture was heated at 1 10 °C for 1 6 h under nitrogen, then cooled to 20 °C, and water (3 ml_) added. The reaction mixture was extracted with ethyl acetate (20 ml_ x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 ml_), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give a crude residue that was purified by prep- TLC (petroleum ether : ethyl acetate=2:1 ) to give 4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7- carbonitrile (60 mg, 319 mitioI, 96 %) as a brown solid. 1 H NMR (400 MHz, CDCh) d 7.1 0 (td, J=1 .4, 8.5 Hz, 1 H), 7.00 - 6.92 (m, 1 H), 6.59 (d, J=8.4 Hz, 1 H), 4.20 (dt, J=0.9, 4.5 Hz, 2H), 3.42 - 3.33 (m, 4H), 1 .16 (dt, J=0.9, 7.2 Hz, 3H).
Step 3: Preparation of (Z)-4-ethyl-N'-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboximidamide.
Figure imgf000232_0001
To a stirred solution of 4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7-carbonitrile (60 mg, 319 gmol) in ethanol (1 ml_) was added hydroxylamine hydrochloride (44 mg, 638 mitioI), triethylamine (64 mg, 638 gmol, 88 mI_) and water (100 mI_). The mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled, concentrated under reduced pressure, and then diluted with water (5 ml_). The mixture was extracted with ethyl acetate (20 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo to give crude (Z)-4-ethyl-N'-hydroxy-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7- carboximidamide (60 mg, 271 gmol, 85 %) as a white solid.
Step 4: Preparation of N-(2-(4-(3J4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)- 1 ,2,4-oxadiazol-5- yl)piperidin- 1-yl)-2-oxoethyl)benzamide.
Figure imgf000232_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (60 mg, 207 gmol) in N,N-dimethylformamide (1 ml_) was added (Z)-4-ethyl-N'-hydroxy-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7- carboximidamide (45 mg, 207 gmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium
hexafluorophosphate) (78 mg, 207 gmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (80 mg, 620 gmol,
108 gl_). The mixture was stirred at 20 °C for 1 h, then heated at 1 1 0 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Luna C1 8 1 50x2.5mm 5gm; mobile phase: [water (0.225% TFA)- acetonitrile]; B%: 40%-65%,16 min) to give N-(2-(4-(3-(4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-7-yl)- 1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (17 mg, 35.8 gmol, 17 %) as a brown solid. 1 H NMR (400 MHz, CDC ) d 7.89 - 7.84 (m, 2H), 7.58 - 7.43 (m, 5H), 7.35 (br s, 1 H), 6.72 (d, J= 8.5 Hz, 1 H), 4.45 (br d, J= 13.8 Hz, 1 H), 4.33 - 4.24 (m, 4H), 3.89 (br d, J=14.1 Hz, 1 H), 3.45 - 3.25 (m, 6H), 3.18 (br t, J=10.4 Hz, 1 H), 2.28 - 2.18 (m, 2H), 2.07 - 1 .92 (m, 2H), 1 .20 (t, J= 7.2 Hz, 3H); LCMS (ESI) m/z: [M+H]+
= 476.3.
Example 111: N-(2-(4-(3-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1,2,4-oxadiazol-5- yl)piperidin-1-yl)-2-oxoethyl)benzamide.
Figure imgf000233_0001
To a stirred solution of 7-bromo-4H-1 ,4-benzoxazin-3-one (2.0 g, 8.77 mmol) in N,N- dimethylformamide (20 ml_) was added iodoethane (1 .64 g, 10.52 mmol, 841 mI_) and potassium carbonate (3.64 g, 26.3 mmol) at 0 °C. The reaction was warmed at 40 °C for 2 h. The reaction mixture was cooled then quenched by addition of water (30 ml_), and then the mixture was extracted with ethyl acetate (60 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 7-bromo-4-ethyl- 2H-benzo[b][1 ,4]oxazin-3(4H)-one (2.06 g, 8.04 mmol, 92 %) as a yellow solid. 1 H NMR (400 MHz,
CDCta) d 7.1 1 - 7.05 (m, 2H), 6.78 (d, J= 8.9 Hz, 1 H), 4.52 (s, 2H), 3.89 (q, J= 7.2 Hz, 2H), 1 .20 (t, J= 7.2 Hz, 3H).
Figure imgf000233_0002
To a stirred solution of 7-bromo-4-ethyl-2H-benzo[b][1 ,4]oxazin-3(4H)-one (800 mg, 3.12 mmol) in N,N-dimethylformamide (10 ml_) was added copper(l) cyanide (559 mg, 6.25 mmol, 1 .36 ml_) and tetrakis(triphenylphosphine)palladium(0) (360 mg, 312 mitioI). The mixture was degassed with nitrogen, then heated at 1 10 °C for 1 6 h under nitrogen. The reaction mixture was cooled to 20 °C, then water (1 5 ml_) was added and the reaction mixture extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filetered and concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 5:1 ) to give 4-ethyl-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazine-7-carbonitrile (70 mg, 346 mitioI, 1 1 %) as a white solid. 1 H NMR (400 MHz, CDCta) d 7.38 (dd, J=1 .9, 8.4 Hz, 1 H), 7.30 - 7.29 (m, 1 H), 7.08 (d, J= 8.3 Hz, 1 H), 4.68 (s, 2H), 4.04 (q, J= 7.2 Hz, 2H), 1 .32 (t, J= 7.2 Hz, 3H).
Step 3: Preparation of (Z)-4-ethyl-N'-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboximidamide.
Figure imgf000234_0001
To a stirred solution of 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7-carbonitrile (70 mg, 346 gmol) in ethanol (1 mL) was added hydroxylamine hydrochloride (48 mg, 692 mitioI), triethylamine (70 mg, 692 gmol, 95 mI_) and water (100 mI_). The mixture was heated at 80 °C for 5 h. The reaction mixture was cooled then concentrated under reduced pressure. The residue was diluted with water (5 mL), then the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (Z)-4-ethyl-N'-hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazine-7-carboximidamide (60 mg, 255 gmol, 74 %) as a white solid.
Figure imgf000234_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (60 mg, 206.7 gmol) in N,N-dimethylformamide (1 mL) was added (Z)-4-ethyl-N'-hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazine-7-carboximidamide (48 mg, 206.7 gmol), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (78 mg, 206.7 gmol) and N-ethyl-N-(propan-2-yl)propan-2- amine (80 mg, 620 gmol, 108 gL). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Luna C1 8 1 00x30 5gm; mobile phase: [water (0.1 %TFA)-methanol]; B%: 38%-68%,12 min) to give N-(2-(4-(3-(4-ethyl-3-oxo-3,4-dihydro- 2H-benzo[b][1 ,4]oxazin-7-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (6 mg, 13 gmol,
6 %) as a white solid. Ή NMR (400 MHz, CDC ) d 7.86 (d, J= 7.2 Hz, 2H), 7.77 (dd, J=1 .8, 8.5 Hz, 1 H), 7.71 (d, J=1 .8 Hz, 1 H), 7.56 - 7.43 (m, 3H), 7.34 (br s, 1 H), 7.10 (d, J=8.4 Hz, 1 H), 4.66 (s, 2H), 4.50 (br d, J=13.7 Hz, 1 H), 4.31 (d, J= 3.8 Hz, 2H), 4.04 (q, J= 7.1 Hz, 2H), 3.92 (br d, J=14.7 Hz, 1 H), 3.40 - 3.29 (m, 2H), 3.17 (br t, J= 10.7 Hz, 1 H), 2.31 - 2.19 (m, 2H), 2.00 (br t, J=13.4 Hz, 2H), 1 .32 (t, J= 7.2 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 490.2.
Example 112: (1-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(2- phenylmorpholino)methanone.
Figure imgf000234_0003
To a stirred solution of 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylic acid (80 mg, 230 mitioI) in N,N-dimethylformamide (1 ml_) was added 2-phenylmorpholine (37 mg, 230 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (87 mg, 230 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (89 mg, 690.93 mitioI, 120 mI_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified by prep-HPLC (column: Waters Xbridge 150x2 5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-70%,12 min) to give (1 - (3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(2-phenylmorpholino)methanone (94 mg, 191 .6 mitioI, 83 %) as a yellow oil. 1 H NMR (400MHz, Methanoi-d4) d 7 55 - 7 41 (m, 3H), 7 40 - 7.26 (m, 4H), 6.99 (d, J=8.4 Hz, 1 H), 4.51 - 4.36 (m, 2H), 4.26 - 4.13 (m, 2H), 4.12 - 3.98 (m, 4H), 3.86 (s, 3H), 3.75 - 3.58 (m, 1 H), 3.46 - 3.30 (m, 1 H), 3.28 - 3.17 (m, 2H), 3.04 (br s, 1 H), 2.95 - 2.64 (m, 1 H), 1 .93 - 1 .68 (m, 4H), 1 .40 (t, J= 6.9 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 493.3.
Figure imgf000235_0002
Step 1: Preparation of (1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(4-methyl-3- phenylpiperazin- 1 -yl)methanone.
Figure imgf000235_0001
To a stirred solution of 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylic acid (70 mg, 201 .5 mitioI) in N,N-dimethylformamide (1 ml_) was added 1 -methyl-2- phenylpiperazine dihydrochloride (50 mg, 201 .5 mitioI,), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (76 mg, 201 .5 mitioI) and N-ethyl-N-(propan-2-yl)propan-2- amine (78 mg, 604.6 mitioI, 105 mI_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 38%-68%,12 min) to give (1 -(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(4-methyl-3-phenylpiperazin-1 -yl)methanone (60 mg, 1 17 mitioI, 58 %) as a yellow solid. 1 H NMR (400MHz, CDCb) d 7.57 (br d, J= 7.9 Hz, 1 H), 7.50 (br s, 1 H), 7.45 - 7.29 (m, 5H), 6.91 (d, J= 8.3 Hz, 1 H), 4.68 - 4.48 (m, 1 H), 4.35 - 4.1 1 (m, 4H), 3.94 (s, 3H), 3 92 - 3.69 (m, 1 H),
3.52 - 3.10 (m, 3H), 3.09 - 2.60 (m, 4H), 2.33 - 2.17 (m, 1 H), 2.07 (br d, J=4 9 Hz, 3H), 2.04 - 1 73 (m,
4H), 1 .49 (t, J= 7 0 Hz, 3H); LCMS (ESI) m/z: [M~H]+ = 506.4.
Example 114: N-(2-(4-(3-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)benzamide.
Figure imgf000236_0001
To a stirred solution of 4,6-dichloronicotinic acid (1 .0 g, 5.21 mmol) in N,N-dimethylformamide (15 ml_) was added N,O-dimethylhydroxylamine (1 .02 g, 10.42 mmol), hydroxybenzotriazole (1 .41 g, 10.4 mmol), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.0 g, 10.4 mmol) and N-ethyl-N-(propan-2- yl)propan-2-amine (2.02 g, 15.6 mmol, 2.73 ml_). The mixture was stirred at 20 °C for 48 h. The reaction mixture was quenched by addition of water (20 ml_) then the mixture was extracted with ethyl acetate (50 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 5:1 to give 4,6-dichloro-N- methoxy-N-methylnicotinamide (660 mg, 2.81 mmol, 54 %) as a yellow oil.1 H NMR (400 MHz, CDCI3) d 8.37 (s, 1 H), 7.45 (s, 1 H), 3.51 (br s, 3H), 3.40 (br s, 3H).
Figure imgf000236_0002
To a stirred solution of 4,6-dichloro-N-methoxy-N-methylnicotinamide (600 mg, 2.55 mmol) in tetrahydrofuran (1 0 ml_) was added methylmagnesium bromide (3 M, 2.16 ml_) at 0 °C, then the mixture was stirred at 0 °C for 2 h. After addition of saturated aqueous ammonium chloride (20 ml_), the mixture was concentrated to ~20 ml_ and the residue that remained was extracted with dichloromethane (40 ml_ x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1 -(4,6- dichloropyridin-3-yl)ethanone (430 mg, 2.26 mmol, 89 %) as a yellow oil. 1 H NMR (400 MHz, CDCI3) d 8.64 (s, 1 H), 7.48 (s, 1 H), 2.70 (s, 3H).
Step 3: Preparation of 6-chloro-3-methyl- 1H-pyrazolo[4,3-c]pyridine.
Figure imgf000237_0001
1 -(4,6-dichloropyridin-3-yl)ethanone (430 mg, 2.26 mmol) in hydrazine hydrate (10 mL) was stirred at 20 °C for 4 h. The reaction mixture was diluted with water (10 mL), then the mixture was extracted with dichloromethane (40 mL x 3). The combined organic phases were washed with water (10 mL x 2), then saturated aqueous sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give crude 6-chloro-3-methyl-1 H-pyrazolo[4,3-c]pyridine (370 mg,
2.21 mmol, 98 %) as a yellow solid.1 H NMR (400 MHz, DMSO-d6) d 13.23 (br s, 1 H), 8.95 (br s, 1 H), 7.59 (s, 1 H), 2.61 (br s, 3H).
Figure imgf000237_0002
To a stirred solution of 6-chloro-3-methyl-1 H-pyrazolo[4,3-c]pyridine (330 mg, 1 .97 mmol) in N,N- dimethylformamide (5 ml_) was added iodomethane (558 mg, 3.94 mmol, 245 mI_) and potassium carbonate (81 6 mg, 5.91 mmol) at 0 °C. The reaction was heated at 60 °C for 2 h. The reaction mixture was cooled then quenched with water (10 ml_), and the mixture was extracted with ethyl acetate (20 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (1 0 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by prep-TLC (Petroleum ether : ethyl acetate=1 :1 ) to give 6-chloro-1 ,3-dimethyl-1 H-pyrazolo[4,3- c]pyridine (120 mg, 661 mitioI, 34 %) as a yellow solid. 1 H NMR (400 MHz, CDCI3) d 8.77 (s, 1 H), 7.29 - 7.27 (m, 1 H), 3.98 (s, 3H), 2.63 (s, 3H).
Figure imgf000237_0003
To a stirred solution of 6-chloro-1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine (100 mg, 551 mitioI) in N,N-dimethylformamide (2 ml_) was added zinc cyanide (64 mg, 551 mitioI) and
tetrakis(triphenylphosphine)palladium(0) (63 mg, 55 mitioI), then the mixture was degassed with nitrogen three times. The mixture was stirred at 1 10 °C for 16 h under nitrogen. The reaction was cooled to 20 °C, then water (3 ml_) was added and the mixture was extracted with ethyl acetate (20 ml_ x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue that was purified by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ). 1 ,3-dimethyl-1 H-pyrazolo[4,3- c]pyridine-6-carbonitrile (50 mg, 290 mitioI, 53 %) as a white solid. LCMS (ESI) m/z: [M+H]+ = 173.1 . Step 6: Preparation of (Z)-N'-hydroxy- l, 3-dimethyl- 1H-pyrazolo[4,3-c]pyridine-6-carboximidamide.
Figure imgf000238_0001
To a stirred solution of 1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6-carbonitrile (50 mg, 290 mitioI) in ethanol (1 ml_) was added hydroxylamine hydrochloride (40 mg, 580.76 mitioI), triethylamine (58 mg, 580.76 mitioI, 80 mI_) and water (100 mI_). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure then diluted with water (5 ml_). The reaction mixture was extracted with ethyl acetate (20 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (50 ml_), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo to give crude (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6- carboximidamide (60 mg) as a white solid. LCMS (ESI) m/z: [M+H]+ = 206.2.
Step 7: Preparation of N-(2-(4-(3-( 1 ,3-dimethyl- 1 H-pyrazolo[4,3-c]pyridin-6-yl)- 1 ,2,4-oxadiazol-5- yl)piperidin- 1-yl)-2-oxoethyl)benzamide.
Figure imgf000238_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (35 mg, 120.6 mitioI) in N,N-dimethylformamide (1 ml_) was added (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6- carboximidamide (24 mg, 120.6 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium
hexafluorophosphate) (45 mg, 120.6 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (46 mg, 361 .7 mitioI, 63 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give N-(2-(4-(3-(1 ,3-dimethyl- 1 H-pyrazolo[4,3-c]pyridin-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (5 mg, 1 1 mitioI, 9 %) as a yellow solid. Ή NMR (400 MHz, CDC ) d 9.13 (d, J=1 .1 Hz, 1 H), 8.12 (d, J=1 .0 Hz, 1 H), 7.89 - 7.84 (m, 2H), 7.56 - 7.43 (m, 3H), 7.34 (br s, 1 H), 4.55 (br d, J= 13.7 Hz, 1 H), 4.32 (d, J= 3.9 Hz, 2H), 4.09 (s, 3H), 3.94 (br d, J= 13.8 Hz, 1 H), 3.44 - 3.32 (m, 2H), 3.14 (br t, J=10.9 Hz, 1 H), 2.68 (s, 3H), 2.37 - 2.24 (m, 2H), 2.16 - 1 .96 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 460.1 .
Example 115: N-[2-[4-[3-(1 ,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]- 2-oxo-ethyl]benzamide.
Figure imgf000239_0001
Step 1 : 2, 6-difluoro-N-methoxy-N-methyl-pyridine-3-carboxamide.
Figure imgf000239_0002
A mixture of 2,6-difluoropyridine-3-carboxylic acid (3.0 g, 18.9 mmol), N-methoxymethanamine hydrochloride (12.9 g, 132.0 mmol) hydroxybenzotriazole (10.2 g, 75.4 mmol), diisopropylethylamine (3.70 g, 28.7 mmol, 5.01 ml_) and 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (7.20 g, 37.5 mmol) in N,N-dimethylformamide (50 ml_) was stirred at 20 °C for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30 ml_) and extracted with dichloromethane (20 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_ x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2,6-difluoro-N- methoxy-N-methyl-pyridine-3-carboxamide (2.80 g, 13.9 mmol, 73 %) as a solid.
Step 2: 1-(2,6-difluoro-3-pyridyl)ethanone.
Figure imgf000239_0003
To a stirred solution of 2,6-difluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (3.0 g, 14.8 mmol) in tetrahydrofuran (60 ml_) was added dropwise methylmagnesium bromide (1 .77 g, 14.84 mmol) at 0°C. The resulting mixture was stirred at 0°C for 2 h, and then quenched by water at 0 °C. The mixture was diluted with ethyl acetate (60 ml_) and extracted with ethyl acetate (50 ml_ x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (25 ml_ x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
Purification by chromatography (silica, petroleum ether / ethyl acetate=2:1 ) gave 1 -(2,6-difluoro-3- pyridyl)ethanone (2.20 g, 14.0 mmol, 94 %) as a white solid.
Step 3: 3-ethoxy-6-iodo-2-methoxy-pyridine.
Figure imgf000239_0004
A solution of 1 -(2,6-difluoro-3-pyridyl)ethanone (1 .50 g, 9.55 mmol) in dichloromethane (55 ml_) was treated with titanium(IV) isopropoxide (10.37 g, 36.48 mmol, 10.80 ml_) at room temperature. The resulting mixture was stirred for 15 min, then hydrazine hydrate (2.06 g, 41 .16 mmol, 2 ml_) was added. Stirring continued for an additional 1 .5 h, then water (5 ml_) was added, and the resulting thick mixture was stirred vigorously for 20 min. The reaction mixture was filtered, and the solids were washed with dichloromethane (10 ml_). The filtrate was concentrated in vacuo to provide the crude hydrazone intermediate as an oil. The crude hydrazine was dissolved in ethanol (1 5 ml_), and the solution was heated at 80 °C for 24 h. The reaction mixture was quenched by addition of water (10 ml_) at 20°C, and then extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-fluoro-3-methyl-1 H-pyrazolo[3,4-b]pyridine (1 .20 g) which was used directly without further purification.
Figure imgf000240_0001
A mixture of 6-fluoro-3-methyl-1 H-pyrazolo[3,4-b]pyridine (1 .20 g, 7.94 mmol), dimethylsulfate (1 .20 g, 9.53 mmol, 903 mI_), sodium hydroxide (952 mg, 23.82 mmol) in water (30 ml_) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 70 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled, extracted with ethyl acetate (50 ml_ x 2), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_ x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=2:1 ) to give 6-fluoro- 1 ,3-dimethyl-pyrazolo[3,4-b]pyridine (400 mg, 2.42 mmol, 3 %) as a yellow solid.
Step 5: 1,3-dimethylpyrazolo[3,4-b]pyridine-6-carbonitrile.
Figure imgf000240_0002
A mixture of 6-fluoro-1 ,3-dimethyl-pyrazolo[3,4-b]pyridine (350 mg, 2.12 mmol), tetra-n- butylammonium bromide (1 .37 g, 4.24 mmol) and sodium cyanide (727 mg, 14.84 mmol) in
dimethylsulfoxide (10 ml_) was degassed and purged with nitrogen 3 times, and then the mixture was heated at 150 Ό for 2 h under a nitrogen atmosphere. The reaction mixture was cooled then extracted with ethyl acetate (5 ml_ x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=2:1 ) to give 1 ,3-dimethylpyrazolo[3,4-b]pyridine-6-carbonitrile (1 50 mg, 871 mitioI, 41 %) as a yellow solid.
Step 6: N'-hydroxy- 1,3-dimethyl-pyrazolo[3,4-b]pyridine-6-carboxamidine
Figure imgf000241_0001
A mixture of 1 ,3-dimethylpyrazolo[3,4-b]pyridine-6-carbonitrile (150 mg, 871 mitioI),
hydroxylamine hydrochloride (121 mg, 1 .74 mmol) and triethylamine (176 mg, 1 .74 mmol, 241 mI_) in ethanol (3 ml_) and water (300 mI_) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 70 °C for 5 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give N'-hydroxy-1 ,3-dimethyl-pyrazolo[3,4-b]pyridine-6- carboxamidine (120 mg, 584.7 mitioI, 67 %) as a yellow solid.
Step 7: N-[2-[4-[3-( 1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)- 1 ,2,4-oxadiazol-5-yl]- 1 -piperidyl]-2-oxo- ethyljbenzamide
Figure imgf000241_0002
A mixture of N'-hydroxy-1 ,3-dimethyl-pyrazolo[3,4-b]pyridine-6-carboxamidine (50 mg, 243.6 mitioI), 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (84 mg, 292 mitioI), (2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 10 mg, 292 mitioI) and N-ethyl-N-(propan-2- yl)propan-2-amine (94 mg, 730.92 mitioI, 127 mI_) in N,N-dimethylformamide (1 ml_) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 1 h under a nitrogen atmosphere. The mixture was stirred at 120 Ό for 1 h. The mixture was cooled then purified via Prep- HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 0mM ammonium carbonate)- acetonitrile]; B%: 20%-50%,12 min) to give N-[2-[4-[3-(1 ,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1 ,2,4- oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (14 mg, 31 .71 mitioI, 13 %) as a brown solid. 1 H NMR (400MHz, CHLOROFORM-d) d 8.17 - 8.15 (d, J=8.3 Hz, 1 H), 7.96 - 7.94 (d, J=8.2 Hz, 1 H), 7.90 - 7.86 (m, 2H), 7.57 - 7.52 (m, 1 H), 7.51 - 7.46 (m, 2H), 7.36 (br s, 1 H), 4.60 - 4.56 (br d, J=13.9 Hz, 1 H), 4.34 - 4.33 (d, J=4.0 Hz, 2H), 4.20 (s, 3H), 3.98- 3.95 (br d, J=13.3 Hz, 1 H), 3.49 - 3.33 (m, 2H), 3.22 - 3.10 (m,
1 H), 2.64 (s, 3H), 2.38 - 2.26 (m, 2H), 2.15 - 1 .99 (m, 2H); LCMS(ESI) m/z: [M+H]+ = 460.3.
Example 116: 4-[4-[3-(1, 3-dimethylpyrazolo[ 3, 4-b ]pyridin-6-yl)- 1, 2, 4-oxadiazol-5-yl]piperidine- 1 - carbonyl]-1-phenyl-pyrrolidin-2-one.
Figure imgf000241_0003
Prepared using a similar experimental procedure as for example 1 15. 4-[4-[3-(1 ,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -phenyl- pyrrolidin-2-one (4.06 mg, 8.36 mitioI, 3.43% yield) was obtained as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d 8.1 5-8.17 (d, J=8.4 Hz, 1 H), 7.96-7.93 (dd, J=3.2, 8.2 Hz, 1 H), 7.61 -7.63 (d, J=7.7 Hz, 2H), 7.42-7.40 (t, J=8.0 Hz, 2H), 7.23 - 7.17 (m, 1 H), 4.65-4.62 (br t, J=14.0 Hz, 1 H), 4.36-4.32 (dd, J=7.3, 9.6 Hz, 1 H), 4.21 (s, 3H), 4.07 - 3.94 (m, 2H), 3.69 - 3.58 (m, 1 H), 3.50 - 3.37 (m, 2H), 3.16 - 2.96 (m, 2H), 2.91 - 2.84 (m, 1 H), 2.64 (s, 3H), 2.33 (br t, J=13.9 Hz, 2H), 2.13 - 1 .97 (m, 2H); LCMS(ESI) m/z: [M+H]+ = 486.3.
Example 117: (4-(3-( 1,3-dimethyl-1H-indazol-5-yl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)(piperidin-1- yl)methanone.
Figure imgf000242_0001
Step 1: Preparation of tert-butyl 4-(3-( 1 ,3-dimethyl- 1 H-indazol-5-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carboxylate.
Figure imgf000242_0002
To a stirred solution of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (150 mg, 654 mitioI) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-5-carboximidamide (133 mg, 654 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (248 mg, 654 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (253 mg, 1 .96 mmol, 342 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 120 Ό for 1 h. The reaction mixture was quenched by addition of water (5 ml_) then the mixture was extracted with ethyl acetate (20 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ) to furnish tert-butyl 4-(3-(1 ,3-dimethyl-1 H-indazol-5-yl)-1 ,2,4- oxadiazol-5-yl)piperidine-1 -carboxylate (1 90 mg, 478 mitioI, 73 %) as a white solid.
Figure imgf000243_0001
To a stirred solution of tert-butyl 4-(3-(1 ,3-dimethyl-1 H-indazol-5-yl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carboxylate (190 mg, 478 mitioI) in methanol (3 ml_) was added methanolic hydrogen chloride solution (4M, 10 ml_). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to provide 3-(1 ,3-dimethyl-1 H-indazol-5-yl)-5-(piperidin-4-yl)-1 ,2,4- oxadiazole (140 mg, 471 mitioI, 98 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 9.04 (br s, 1 H), 8.33 (d, J=0.7 Hz, 1 H), 7.96 (dd, J= 1 .3, 8.8 Hz, 1 H), 7.71 (d, J= 8.8 Hz, 1 H), 3.98 (s, 3H), 3.53 - 3.43 (m,
1 H), 3.34 (br d, J= 12.6 Hz, 2H), 3.1 1 - 3.00 (m, 2H), 2.52 (s, 3H), 2.26 (br d, J= 10.8 Hz, 2H), 2.08 - 1 .95 (m, 2H).
Step 3: Preparation of (4-(3-(1, 3-dimethyl- 1H-indazol-5-yl)- 1, 2, 4-oxadiazol-5-yl)piperidin- 1-yl)(piperidin- 1- yljmethanone.
Figure imgf000243_0002
To a stirred solution of 3-(1 ,3-dimethyl-1 H-indazol-5-yl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (130 mg, 437 mitioI) in dichloromethane (500 mI_) was added piperidine-1 -carbonyl chloride (77 mg, 524.6 mitioI, 65 mI_) and triethylamine (132 mg, 1 .31 mmol, 181 mI_) at 0 °C. The mixture was warmed and then stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-70%,12 min) to give (4-(3-(1 ,3-dimethyl-1 H-indazol-5-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)(piperidin-1 -yl)methanone (68 mg, 166.6 mitioI, 38 %) as a pale yellow solid. 1 H NMR (400 MHz, CDC ) d 8.42 (s, 1 H), 8.08 (dd, J=1 .4, 8.8 Hz, 1 H), 7.40 (d, J=8.8 Hz, 1 H), 4.03 (s, 3H), 3.80 - 3.70 (m, 2H), 3.28 - 3.14 (m, 5H), 3.05 - 2.93 (m, 2H), 2.62 (s, 3H), 2.18 (br dd, J=3.3, 13.6 Hz, 2H), 2.07 - 1 .93 (m, 2H), 1 .60 (br s, 6H); LCMS (ESI) m/z: [M+H]+ = 409.1 .
Figure imgf000244_0001
Step 1: Preparation of 2-chloro-5-ethoxypyridine.
Figure imgf000244_0002
To a stirred solution of 6-chloropyridin-3-ol (3.0 g, 23.2 mmol) in N,N-dimethylformamide (30 ml_) was added iodoethane (4.33 g, 27.8 mmol, 2.22 ml_), and potassium carbonate (9.60 g, 69.6 mmol) at 0 °C. The reaction was warmed and stirred at 40 °C for 2 h. The reaction mixture was quenched by addition of water (30 ml_) then the mixture was extracted with ethyl acetate (60 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxypyridine (3.30 g, 20.9 mmol, 90 %) as a yellow solid. Ή NMR (400 MHz, CDC ) d 7.97 (d, J= 2.9 Hz, 1 H), 7.1 7 - 7.07 (m, 2H), 3.99 (q, J= 7.0 Hz, 2H), 1 .36 (t, J=7.0 Hz, 3H).
Step 2: Preparation of 2-chloro-5-ethoxypyridine 1 -oxide.
Figure imgf000244_0003
Hydrogen peroxide-urea adduct (3.82 g, 40.61 mmol) was added in one portion to a solution of 2- chloro-5-ethoxypyridine (3.20 g, 20.3 mmol) in dichloromethane (30 ml_) at 0 °C, trifluoroacetic anhydride (7.68 g, 36.6 mmol, 5.08 ml_) was added dropwise. The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by addition of saturated aqueous sodium thiosulfate (30 ml_). The mixture was extracted with dichloromethane (60 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxypyridine 1 -oxide (4.0 g) as a yellow oil. 1 H NMR (400 MHz, CDCI3) d 8.35 - 8.28 (m, 1 H), 7.44 (dt, J= 3.0, 6.0 Hz, 1 H), 7.13 - 7.04 (m, 1 H), 4.13 - 4.00 (m, 2H), 1 .50 - 1 .40 (m, 3H).
Figure imgf000244_0004
To a stirred solution of 2-chloro-5-ethoxypyridine 1 -oxide (1 .80 g, 10.37 mmol) in concentrated sulfuric acid (12 ml_) was added concentrated nitric acid (6.50 ml_) at 0 °C, the mixture was stirred at 25 °C for 1 hrs, then heated to 1 10 Ό and stirred for 16 hrs. After cooling to 20 °C, the mixture was poured onto ice, and then aqueous sodium hydroxide solution (40 wt.%) was added carefully to adjust the pH to 14. The mixture was extracted with dichloromethane (80 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-chloro-5-ethoxy-4-nitropyridine (810 mg, 4.00 mmol, 39 %) as a yellow solid. 1 H NMR (400 MHz, CDCta) d 8.32 (s, 1 H), 7.64 (s, 1 H), 4.30 (q, J= 6.9 Hz, 2H), 1 .51 (t, J=7.0 Hz, 3H).
Figure imgf000245_0003
To a stirred solution of 2-chloro-5-ethoxy-4-nitro-pyridine (770 mg, 3.80 mmol) in methanol (8 ml_) was added potassium tert-butoxide (644 mg, 4.18 mmol) at 0 °C, then the mixture was warmed and stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure then diluted with water (10 ml_) of water. The mixture was extracted with dichloromethane (60 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxy-4-methoxypyridine (660 mg, 3.52 mmol, 93 %) as a yellow solid. 1 H NMR (400 MHz, CDCta) d 7.85 (s, 1 H), 6.80 (s, 1 H), 4.13 (q, J=7.0 Hz, 2H), 3.95 - 3.88 (m, 3H), 1 .47 (t, J= 7.0 Hz, 3H).
Step 5: Preparation of 5-ethoxy-4-methoxypicolinonitrile.
Figure imgf000245_0001
To a stirred solution of zinc cyanide (368 mg, 3.14 mmol) in N,N-dimethylformamide (8 ml_) was added 2-chloro-5-ethoxy-4-methoxypyridine (590 mg, 3.14 mmol) and
tetrakis(triphenylphosphine)palladium(0) (362 mg, 314 pmol) under nitrogen. The mixture was heated at 120 °C for 16 h. The reaction was cooled to 20 °C, water (20 ml_) was added to the reaction, and then the mixture was extracted with ethyl acetate (60 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 5:1 ) to give 5-ethoxy-4-methoxypicolinonitrile (320 mg, 1 .80 mmol, 57 %) as a white solid. 1 H NMR (400 MHz, CDCta) d 8.19 (s, 1 H), 7.1 8 (s, 1 H), 4.25 (q, J= 6.9 Hz, 2H), 3.96 (s, 3H), 1 .52 (t, J=7.0 Hz, 3H).
Figure imgf000245_0002
To a stirred solution of 5-ethoxy-4-methoxypicolinonitrile (320 mg, 1 .80 mmol) in ethanol (5 ml_) was added hydroxylamine hydrochloride (250 mg, 3.60 mmol), triethylamine (364 mg, 3.60 mmol, 499 mI_) and water (0.50 ml_). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure then diluted with water (10 ml_). The mixture was extracted with ethyl acetate (60 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_) then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (Z)-5- ethoxy-N'-hydroxy-4-methoxypicolinimidamide (330 mg, 1 .56 mmol, 87 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 9.71 (s, 1 H), 8.1 0 (s, 1 H), 7.39 (s, 1 H), 5.75 (br s, 2H), 4.17 - 4.06 (m, 2H), 3.84 (s, 3H), 1 .34 (t, J=6.9 Hz, 3H).
Step 7: Preparation of 4-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)- 1 -phenylpyrrolidin-2-one.
Figure imgf000246_0001
To a stirred solution of 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (90 mg, 285 pmol) in N,N-dimethylformamide (2 ml_) was added (Z)-5-ethoxy-N'-hydroxy-4- methoxypicolinimidamide (60 mg, 285 pmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (107 mg, 285 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 10 mg, 854 pmol, 149 mI_). The mixture was stirred at 20 Ό for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled and then purified directly by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-55%,12 min) to give 4-(4-(3- (5-ethoxy-4-methoxypyridin-2-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one (34 mg, 70 mitioI, 24 %) as a yellow solid. Ή NMR (400 MHz, CDC ) d 8.29 (s, 1 H), 7.68 - 7.57 (m, 3H), 7.44 - 7.33 (m, 2H), 7.22 - 7.13 (m, 1 H), 4.63 - 4.50 (m, 1 H), 4.36 - 4.22 (m, 3H), 4.04 - 3.90 (m, 5H), 3.59 (td, J=8.6, 16.7 Hz, 1 H), 3.43 - 3.30 (m, 2H), 3.12 - 2.93 (m, 2H), 2.88 - 2.79 (m, 1 H), 2.33 - 2.20 (m, 2H), 2.13 - 1 .93 (m, 2H), 1 .52 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 492.1 .
Figure imgf000246_0002
Step 1: Preparation of methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-phenylpentanoate.
Figure imgf000247_0001
To a stirred solution of 01 -tert-butyl 02-methyl 5-oxopyrrolidine-1 ,2-dicarboxylate (1 .0 g, 4.1 1 mmol) in tetrahydrofuran (10 ml_) was added phenylmagnesium bromide (1 M in THF, 4.93 ml_) at -30 °C. The reaction mixture was slowly warmed to 20 °C and stirred for 16 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (1 0 ml_), and then extracted with ethyl acetate (40 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by chromatography (silica, petroleum ether : ethyl acetate =
1 :0 to 20:1 ) to give methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-phenylpentanoate (900 mg, 2.80 mmol, 68 %) as a white solid. Ή NMR (400 MHz, CDCh) d 7.95 (d, J= 8.0 Hz, 2H), 7.60 - 7.53 (m, 1 H), 7.50 - 7.43 (m, 2H), 5.17 (br s, 1 H), 4.40 (brs, 1 H), 3.75 (s, 3H), 3.19 - 2.99 (m, 2H), 2.37 - 2.26 (m, 1 H), 2.15 - 2.02 (m, 1 H), 1 .42 (s, 9H).
Step 2: Preparation of (2S/R,5R/S)-1 -tert-butyl 2-methyl 5-phenylpyrrolidine- 1 ,2-dicarboxylate.
Figure imgf000247_0002
To a stirred solution of methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-phenylpentanoate (800 mg, 2.49 mmol) in dichloromethane (10 ml_) was added trifluoroacetic acid (5.68 g, 49.8 mmol, 3.69 ml_) at 20 °C. After 16 h, the solvent was removed under reduced pressure, then the residue was dissolved in methanol (10 ml_) and cooled to 0 °C. Sodium borohydride (188 mg, 4.98 mmol) was slowly added, then the mixture was warmed and stirred at 20 °C for 16 h. The mixture was concentrated in vacuo and the resulting orange oil was diluted with methanol (20 ml_) and concentrated again a total of four times. The residue was suspended in dichloromethane (1 0 ml_), then di-tert-butyl dicarbonate (815 mg, 3.74 mmol, 858 mI_), triethylamine (377 mg, 3.74 mmol, 517 mI_), 4-dimethylaminopyridine (3 mg, 24.90 mitioI) were added and stirred at 20 °C for 16 h. Sat. aq. ammonium chloride (20 ml_) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (50 ml_ x 3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 36%-66%,12min]) to give (2S/R,5R/S)-1 -tert-butyl 2-methyl 5- phenylpyrrolidine-1 ,2-dicarboxylate (230 mg, 753 mitioI, 30 %) as a white solid. 1 H NMR (400 MHz,
CDCh) d 7.56 (br d, J= 7.5 Hz, 2H), 7.33 (t, J= 7.5 Hz, 2H), 7.26 - 7.19 (m, 1 H), 5.00 (br d, J=3.4 Hz,
0.4H), 4.75 (br t, J= 7.0 Hz, 0.6H), 4.50 (br dd, J= 4.7, 8.0 Hz, 0.6H), 4.36 (br t, J=7.4 Hz, 0.4H), 3.82 (s, 3H), 2.38 - 2.28 (m, 1 H), 2.20 (ddd, J= 6.5, 7.8, 12.5 Hz, 1 H), 2.12 - 1 .91 (m, 2H), 1 .42 (s, 3.6H), 1 .15 (s, 5.4H).
Step 3: Preparation of (2S/R,5R/S)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid.
Figure imgf000248_0001
To a stirred solution of (2S/R,5R/S)-1 -tert-butyl 2-methyl 5-phenylpyrrolidine-1 ,2-dicarboxylate (180 mg, 589 pmol) in tetrahydrofuran (2 mL) was added lithium hydroxide (2 M, 589 mI_). The mixture was stirred at 20 °C for 16 h. The mixture was acidified to pH 1 by dropwise addition of concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (40 mL x 3). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (2S/R,5R/S)-1 -(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid (300 mg) as a white solid.
Figure imgf000248_0002
To a stirred solution of (2S,5R)-1 -(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid (270 mg, 927 pmol) in N,N-dimethylformamide (3 mL) was added 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4- yl)-1 ,2,4-oxadiazole (281 mg, 927 pmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium
hexafluorophosphate) (351 mg, 927 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (359 mg, 2.78 mmol, 485 pL). The mixture was stirred at 20 °C for 1 h. Water (15 mL) was added to the reaction, then the reaction mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (2S/R,5R/S)-tert-butyl 2-(4-(3-(4-ethoxy-3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-5-phenylpyrrolidine-1 -carboxylate (500 mg) as a yellow oil. This material was used directly without purficication.
Step 5: Preparation of (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)((2S/R,5R/S)- 5-phenylpyrrolidin-2-yl)methanone.
Figure imgf000248_0003
To a stirred solution of (2S/R,5R/S)-tert-butyl 2-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidine-1 -carbonyl)-5-phenylpyrrolidine-1 -carboxylate (500 mg, 867 pmol) in ethyl acetate (5 mL) was added 4N hydrochloric acid in ethyl acetate (20 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to provide the crude product. The crude product was purified by prep-HPLC (column : Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 45%-65%,12 min) to give (4-(3-(4-ethoxy-3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)((2S/R,5R/S)-5-phenylpyrrolidin-2-yl)methanone (78 mg, 161 .6 mitioI, 19 %) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 7.66 (ddd, J= 2.0, 3.5, 8.3 Hz, 1 H), 7.61 (br d, J= 2.5 Hz, 1 H), 7.48 (br d, J= 7.8 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.35 - 7.28 (m, 1 H), 7.1 1 - 7.04 (m, 1 H), 4.53 (br t, J=12.5 Hz, 1 H), 4.24 - 4.05 (m, 5H), 3.92 (d, J=1 .8 Hz, 3H), 3.49 - 3.38 (m, 2H), 3.1 8 - 3.06 (m, 1 H), 2.45 - 2.20 (m, 4H), 2.04 - 1 .66 (m, 4H), 1 .45 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 477.1 .
Figure imgf000249_0001
A solution of 4,6-dichloropyridine-3-carboxylic acid (13.5 g, 70.3 mmol) and 1 ,1
carbonyldiimidazole (17.10 g, 105.5 mmol) in tetrahydrofuran (200 ml_) was stirred for 0.5 h at 25 °C. N- ethyl-N-(propan-2-yl)propan-2-amine (18.1 7 g, 140.62 mmol, 24.55 ml_) and N,O-dimethylhydroxylamine hydrochloride (8.23 g, 84.4 mmol) were added and the resulting solution was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (200 ml_), then the mixture was extracted with ethyl acetate (200 ml_ x 3). The combined organic layer was washed with water (50 ml_ x 3) then saturated aqueous sodium chloride solution (50 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 4,6-dichloro-N-methoxy-N-methylnicotinamide (19.0 g) as a yellow oil. 1 H NMR (400 MHz, CDCI3) d 8.35 (s, 1 H), 7.44 (d, J=0.6 Hz, 1 H), 3.49 (br s, 3H), 3.38 (br s, 3H).
Figure imgf000249_0002
To a stirred solution of 4,6-dichloro-N-methoxy-N-methylnicotinamide (16.0 g, 68.1 mmol) in tetrahydrofuran (200 ml_) was added a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 57.6 ml_) at 0 °C, the mixture was stirred at 0 °C for 2 h. After addition of saturated aqueous ammonium chloride (100 ml_), the mixture was concentrated to ~ 200 ml_ and the residue was extracted with dichloromethane (200 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (60 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1 -(4,6-dichloropyridin-3-yl)ethanone (8.95 g, 47.1 mmol, 69 %) as a yellow oil. 1 H NMR (400 MHz, CDCh) d 8.62 (s, 1 H), 7.46 (s, 1 H), 2.68 (s, 3H).
Step 3: Preparation of 6-chloro-3-methyl- 1H-pyrazolo[4,3-c]pyridine.
Figure imgf000250_0001
1 -(4,6-dichloropyridin-3-yl)ethanone (8.40 g, 44.2 mmol) in hydrazine hydrate (60 ml_) was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (100 ml_), then the mixture was extracted with dichloromethane (150 ml_ x 3). The separated organic layer was washed water (40 ml_ x 3) and saturated aqueous sodium chloride solution (50 ml_), then dried over anhydrous sodium sulfate, filtered and concentrated to give 6-chloro-3-methyl-1 H-pyrazolo[4,3-c]pyridine (6.10 g, 36.4 mmol, 82 %) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 13.17 (br s, 1 H), 8.88 (s, 1 H), 7.53 (s, 1 H), 2.55 (s, 3H).
Figure imgf000250_0002
To a stirred solution of 6-chloro-3-methyl-1 H-pyrazolo[4,3-c]pyridine (5.90 g, 35.2 mmol) in N,N- dimethylformamide (80 ml_) was added iodomethane (9.99 g, 70.4 mmol, 4.38 ml_), and potassium hydroxide (7.90 g, 140.8 mmol) at 0 °C. The reaction was stirred at 60 °C for 2 h. The reaction mixture was cooled then quenched by addition of water (100 ml_). The mixture was extracted with ethyl acetate (150 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (100 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 5:1 )to give 6-chloro- 1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine (2.73 g, 15.0 mmol, 43 %) as a yellow solid. 1 H NMR (400 MHz, CDCta) d 8.70 (s, 1 H), 7.22 (s, 1 H), 3.93 (s, 3H), 2.58 (s, 3H).
Figure imgf000250_0003
To a stirred solution of 6-chloro-1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine (1 .70 g, 9.36 mmol) in N,N-dimethylformamide (20 ml_) was added zinc cyanide (1 .1 0 g, 9.36 mmol, 594 mI_) and tetrakis(triphenylphosphine)palladium(0) (1 .08 g, 936 pmol) under nitrogen. The mixture was stirred at 1 10 °C for 16 h. The reaction was cooled to 20 °C, water (30 ml_) was added to the reaction, and then the reaction mixture was extracted with ethyl acetate (80 ml_ x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50:1 to 1 :1 ) to give 1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6-carbonitrile (1 .06 g, 6.16 mmol, 66 %) as a white solid. Ή NMR (400 MHz, CDCI3) d 9.03 (d, J=1 .0 Hz, 1 H), 7.73 (d, J=1 .0 Hz, 1 H), 4.07 (s, 3H), 2.67 (s, 3H). Step 6: Preparation of (Z)-N'-hydroxy- 1 ,3-dimethyl- 1 H-pyrazolo[4,3-c]pyridine-6-carboximidamide.
Figure imgf000251_0001
To a stirred solution of 1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6-carbonitrile (1 .06 g, 6.16 mmol) in ethanol (15 ml_) was added hydroxylamine hydrochloride (855 mg, 12.3 mmol), triethylamine (1 .25 g, 12.3 mmol, 1 .71 ml_) and water (1 .50 ml_). The mixture was heated at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure then the residue was triturated with water (5 ml_), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3- c]pyridine-6-carboximidamide (1 .0 g, 4.87 mmol, 79 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 9.73 (s, 1 H), 9.02 (s, 1 H), 7.91 (s, 1 H), 5.91 (br s, 2H), 3.98 (s, 3H), 2.56 (s, 3H). Step 7: Preparation of methyl 1-(5-oxo- 1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate.
Figure imgf000251_0002
To a stirred solution of 5-oxo-1 -phenylpyrrolidine-3-carboxylic acid (3.0 g, 14.6 mmol) in dichloromethane (30 ml_) was added methyl piperidine-4-carboxylate (2.09 g, 14.6 mmol), 2,4,6-tripropyl- 1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (9.30 g, 14.6 mmol, 8.69 ml_, 50% purity in ethyl acetate) and triethylamine (1 .48 g, 14.6 mmol, 2.03 ml_). The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted by addition of water (20 ml_) then extracted with dichloromethane (60 ml_ x 3). The combined organic layer was washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 1 -(5-oxo-1 -phenylpyrrolidine-3- carbonyl)piperidine-4-carboxylate (4.02 g, 12.2 mmol, 83 %) as a yellow oil. 1 H NMR (400 MHz, CDCI3) d 7.59 (d, J=7.7 Hz, 2H), 7.38 (t, J=7.3 Hz, 2H), 7.21 - 7.12 (m, 1 H), 4.43 (m, 1 H), 4.29 (dd, J= 7.3, 9.6 Hz,
1 H), 3.97 - 3.81 (m, 2H), 3.72 (s, 3H), 3.55 (m, 1 H), 3.28 - 3.17 (m, 1 H), 3.01 - 2.75 (m, 3H), 2.62 (dt, J=6.3, 10.4 Hz, 1 H), 2.08 - 1 .94 (m, 2H), 1 .80 - 1 .64 (m, 2H). Step 8: Preparation of 1-(5-oxo- 1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid.
Figure imgf000252_0002
To a stirred solution of methyl 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate (4.0 g, 12.1 1 mmol) in tetrahydrofuran (30 ml_) was added aqueous lithium hydroxide (2 M, 12.1 1 ml_). After 1 h, the reaction mixture was cooled to 0 °C then acidified with 2 M hydrochloric acid (6 ml_). The mixture was extracted with ethyl acetate (80 ml_ x 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (3.60 g, 1 1 .38 mmol, 94 %) as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) d 7.59 (dd, J= 4.0, 7.7 Hz, 2H), 7.38 (t, J=7.6 Hz, 2H), 7.23 - 7.1 5 (m, 1 H), 4.41 - 4.30 (m, 1 H), 4.15 - 3.96 (m, 3H), 3.85 - 3.75 (m, 1 H), 3.30 - 3.22 (m, 1 H), 2.99 - 2.77 (m, 3H), 2.63 (m, 1 H), 2.06 - 1 .93 (m, 2H), 1 .74 - 1 .53 (m, 2H).
Step 9: Preparation of 4-(4-(3-( 1 ,3-di methyl- 1 H-pyrazolo[4,3-c]pyridin-6-yl)- 1 ,2,4-oxadiazol-5- yl)piperidine- 1 -carbonyl)- 1 -phenylpyrrolidin-2-one.
Figure imgf000252_0001
To a stirred solution of (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6-carboximidamide (84 mg, 410.9 pmol) in N,N-dimethylformamide (2 ml_) was added 1 -(5-oxo-1 -phenylpyrrolidine-3- carbonyl)piperidine-4-carboxylic acid (130 mg, 410.9 pmol), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (155 mg, 410.9 pmol) and N-ethyl-N-(propan-2-yl)propan-2- amine (159 mg, 1 .23 mmol, 215 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-40%,12 min) to give 4-(4-(3-(1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridin-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)-1 -phenylpyrrolidin-2-one (78 mg, 155 mitioI, 38 %) as a yellow solid. 1 H NMR (400 MHz, CDCI3) d 9.13 (d, J=1 .0 Hz, 1 H), 8.12 (br d, J= 3.9 Hz, 1 H), 7.60 (br d, J= 7.8 Hz, 2H), 7.39 (br t, J= 8.0 Hz, 2H),
7.18 (br t, J=7.4 Hz, 1 H), 4.59 (br t, J=13.8 Hz, 1 H), 4.36 - 4.27 (m, 1 H), 4.09 (d, J= 3.8 Hz, 3H), 4.03 - 3.92 (m, 2H), 3.60 (m, 1 H), 3.39 (br s, 2H), 3.14 - 2.94 (m, 2H), 2.90 - 2.80 (m, 1 H), 2.68 (s, 3H), 2.37 - 2.23 (m, 2H), 2.12 - 1 .96 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 486.1 .
Example 121: N-(2-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)benzamide.
Figure imgf000253_0001
Step 1: Preparation of 2-chloro-5-ethoxypyridine.
Figure imgf000253_0002
To a stirred solution of 6-chloropyridin-3-ol (21 .0 g, 1 62.1 mmol) in N,N-dimethylformamide (200 mL) was added iodoethane (30.34 g, 194.5 mmol, 15.6 ml_) and potassium carbonate (67.2 g, 486.3 mmol) at 0 °C, then the reaction was warmed and stirred at 40 °C for 2 h. The reaction mixture was quenched by addition of water (200 mL), then the mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxypyridine (26.0 g) as a yellow oil. This was used directly without further purification. 1 H NMR (400 MHz, CDCI3) d 7.95 (d, J-2.9 Hz, 1 H), 7.15 - 7.06 (m, 2H), 3.98 (q, J= 7.0 Hz, 2H), 1 .35 (t, J= 7.0 Hz, 3H).
Step 2: Preparation of 2-chloro-5-ethoxypyridine 1 -oxide.
Figure imgf000253_0003
Hydrogen peroxide-urea complex (31 .04 g, 330 mmol) was added in one portion to a solution of 2-chloro-5-ethoxypyridine (26.0 g, 165 mmol) in dichloromethane (250 ml_) at 0 °C, then trifluoroacetic anhydride (62.4 g, 297 mmol, 41 .3 0 ml_) was added dropwise. The mixture was stirred at 20 Ό for 16 h. The reaction mixture was quenched by addition of saturated aqueous sodium thiosulfate (150 ml_). The mixture was extracted with dichloromethane (200 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (100 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 1 :2) to give 2-chloro-5-ethoxypyridine 1 -oxide (22.0 g, 126.7 mmol, 77 %) as a yellow solid. 1 H NMR (400 MHz, CDC ) d 8.05 (d, J= 2.6 Hz, 1 H), 7.29 (d, J= 9.0 Hz, 1 H), 6.81 (dd, J-2.6, 9.1 Hz, 1 H), 3.97 (q, J= 6.9 Hz, 2H), 1 .37 (t, J= 7.0 Hz, 3H).
Step 3: Preparation of 2-chloro-5-ethoxy-4-nitropyridine.
Figure imgf000253_0004
To a stirred solution of 2-chloro-5-ethoxypyridine 1 -oxide (5.0 g, 28.8 mmol) in concentrated sulfuric acid (30 ml_) was added dropwise concentrated nitric acid (15 ml_) at 0 °C, then the mixture was warmed, stirred at 25 °C for 1 h, and then heated to 1 1 0 °C for 16 h. After cooling to 20 °C, the mixture was poured onto ice, and then aqueous sodium hydroxide solution (40 wt.%) was added carefully to adjust the pH to 14. The mixture was extracted with dichloromethane (100 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxy-4-nitropyridine (3.10 g,
15.3 mmol, 53 %) as a yellow solid. Ή NMR (400 MHz, CDC ) d 8.32 (s, 1 H), 7.64 (s, 1 H), 4.30 (q, J= 7.0 Hz, 2H), 1 .50 (t, J=7.0 Hz, 3H).
Step 4: Preparation of 2-chloro-5-ethoxy-4-methoxypyridine.
Figure imgf000254_0001
To a stirred solution of 2-chloro-5-ethoxy-4-nitro-pyridine (3.1 0 g, 15.3 mmol) in methanol (32 ml_) was added potassium tert-butoxide (2.60 g, 16.8 mmol) at 0 °C, the mixture was warmed and stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure then diluted with water (20 ml_).
The mixture was extracted with dichloromethane (60 ml_ x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxy-4-methoxypyridine (2.68 g, 14.28 mmol, 93 %) as a yellow solid. Ή NMR (400 MHz, CDCIs) d 7.88 - 7.81 (m, 1 H), 6.83 - 6.76 (m, 1 H), 4.18 - 4.07 (m, 2H), 3.91 (dd, J=2.1 , 2.8 Hz, 3H), 1 .46 (m, 3H).
Step 5: Preparation of 5-ethoxy-4-methoxypicolinonitrile.
Figure imgf000254_0002
To a stirred solution of zinc cyanide (1 .31 g, 1 1 .2 mmol) in N,N-dimethylformamide (25 ml_) was added 2-chloro-5-ethoxy-4-methoxypyridine (2.10 g, 1 1 .2 mmol) and
tetrakis(triphenylphosphine)palladium(0) (1 .29 g, 1 .12 mmol) under nitrogen. The mixture was heated at 1 10 °C for 16 h. The reaction was cooled to 20 °C, then water (40 ml_) was added and the reaction mixture extracted with ethyl acetate (80 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (50 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 5:1 ) to give 5-ethoxy-4-methoxypicolinonitrile (1 .20 g, 6.73 mmol, 60 %) as a white solid. Ή NMR (400 MHz, CDCIs) d 8.18 (s, 1 H), 7.18 (s, 1 H), 4.24 (q, J= 7.0 Hz, 2H), 3.96 (s, 3H), 1 .51 (t, J=7.0 Hz, 3H).
Step 6: Preparation of (Z)-5-ethoxy-N'-hydroxy-4-methoxypicoiinimidamide.
Figure imgf000255_0001
To a stirred solution of 5-ethoxy-4-methoxypicolinonitrile (1 .20 g, 6.73 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (935 mg, 13.5 mmol), triethylamine (1 .36 g, 13.5 mmol, 1 .87 mL) and water (1 .50 mL). The mixture was heated at 80 °C for 2 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-5-ethoxy-N'-hydroxy-4-methoxypicolinimidamide (1 .30 g, 6.15 mmol, 91 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d 9.70 (s, 1 H), 8.10 (s, 1 H), 7.38 (s,
1 H), 5.72 (s, 2H), 4.12 (q, J= 7.0 Hz, 2H), 3.84 (s, 3H), 1 .34 (t, J= 6.9 Hz, 3H).
Step 7: Preparation of N-(2-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000255_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 51 6.7 mitioI) in N,N-dimethylformamide (2 mL) was added (Z)-5-ethoxy-N'-hydroxy-4-methoxypicolinimidamide (109 mg, 516.7 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (195 mg, 51 6.7 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (200 mg, 1 .55 mmol, 270 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled and then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-40%,12 min) to give N-(2-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (32 mg, 67 mitioI, 13 %) as a yellow solid. 1 H NMR (400 MHz, CDCta) d 8.29 (s, 1 H), 7.90 - 7.82 (m, 2H), 7.64 (s, 1 H), 7.56 - 7.42 (m, 3H), 7.34 (br s, 1 H), 4.52 (br d, J=13.6 Hz, 1 H), 4.34 - 4.21 (m, 4H), 4.02 (s, 3H), 3.91 (br d, J=14.1 Hz, 1 H), 3.41 - 3.28 (m, 2H), 3.12 (br t, J=1 1 .0 Hz, 1 H), 2.33 - 2.21 (m, 2H), 2.13 - 1 .95 (m, 2H), 1 .52 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 466.3.
Example 122: N-[2-[4-[3-(1 ,3-dimethyl-2-oxo-benzimidazol-5-yl)-1 ,2,4-oxadiazol-5-yl]-1 -pipehdyl]-2- oxo-ethyl]benzamide:
Figure imgf000256_0001
Step 1: Preparation of 3,4-diaminobenzonitrile.
Figure imgf000256_0002
To a stirred solution of 4-amino-3-nitro-benzonitrile (2.00 g, 12.3 mmol) in methanol (20 ml_) was added Pd/C (500 mg, 10% purity), then the flask was degassed and filled with hydrogen three times, and the reaction mixture stirred vigorously under hydrogen (balloon) for 18 h at 25 °C. The mixture was evacuated and backfilled with nitrogen three times, then filtered through a pad of celite, and the filtrate concentrated in vacuo to give 3,4-diaminobenzonitrile (1 .47 g, 1 1 .04 mmol, 90 %) as a green oil that was used in next step directly.
Step 2: Preparation of 2-oxo- 1 ,3-dihydrobenzimidazole-5-carbonitrile
Figure imgf000256_0003
To a stirred solution of 3,4-diaminobenzonitrile (1 .40 g, 10.5 mmol) in tetrahydrofuran (70 ml_) at 0 °C was added 1 ,1’-carbonyldiimidazole (2.22 g, 13.7 mmol), then the mixture was warmed to 25 °C and stirred for 18 h. The mixture was treated with ethyl acetate (100 ml_), washed with 1 N HCI (20 ml_ x 2) and saturated aqueous sodium chloride solution (30 ml_), then dried over anhydrous sodium sulfate, filtered and concentrated to give 2-oxo-1 ,3-dihydrobenzimidazole-5-carbonitrile (1 .50 g) as a pale yellow solid, which was used in next step directly.
Step 3: Preparation of 1,3-dimethyl-2-oxo-benzimidazole-5-carbonitrile.
Figure imgf000256_0004
To a stirred suspension of sodium hydride (1 .13 g, 28.29 mmol, 47.15 ml_, 60% dispersion in mineral oil) in N,N-dimethylformamide (5 ml_) was added 2-oxo-1 ,3-dihydrobenzimidazole-5-carbonitrile (1 .50 g, 9.43 mmol) in N,N-dimethylformamide (5 ml_) at 25 °C. After 15 min, the mixture was cooled to 5 °C then methyl iodide (4.70 g, 33.1 mmol, 2.06 ml_) was added dropwise. The reaction mixture was warmed to 25°C and stirred for 1 h. The mixture was poured into ice-water (1 00 ml_), filtered and the residue dissolved in dichloromethane (10 ml_). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (5 ml_), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1 ,3-dimethyl-2-oxo-benzimidazole-5-carbonitrile (1 .26 g, 6.73 mmol, 71 %) as pale yellow solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.37 (dd, J= 1 .4, 8.2 Hz, 1 FI), 7.15 (s, 1 H), 6.95 (d, J= 8.2 Hz, 1 H), 3.38 (d, J= 3.3 Hz, 6H).
Figure imgf000257_0001
A mixture of 1 ,3-dimethyl-2-oxo-benzimidazole-5-carbonitrile (1 .25 g, 6.68 mmol), hydroxylamine hydrochloride (928 mg, 13.4 mmol) and triethylamine (1 .35 g, 13.4 mmol, 1 .85 ml_) in ethanol (15 ml_) and water (1 .50 ml_) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 70 °C for 5 h under a nitrogen atmosphere. The resulting suspension was filtered then the filter cake was dissolved in ethyl acetate (20 ml_), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give N'-hydroxy-1 ,3-dimethyl-2-oxo-benzimidazole-5-carboxamidine (1 .25 g, 5.68 mmol, 85 %) as a white solid.
Step 5: Preparation of N-[2-[4-[3-( 1,3-dimethyl-2-oxo-benzimidazol-5-yl)- 1 , 2, 4-oxadiazol-5-yl]- 1 -piper idyl]- 2-oxo-ethyl]benzamide.
Figure imgf000257_0002
To a stirred solution of N'-hydroxy-1 ,3-dimethyl-2-oxo-benzimidazole-5-carboxamidine (80 mg, 363 mitioI) and 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (105 mg, 363 mitioI) in N,N- dimethylformamide (1 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium
hexafluorophosphate) (137 mg, 363 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 726.5 mitioI, 126 mI_) at 25 °C. After stirring at 25 °C for 1 h, the mixture was warmed to 1 10 °C and stirred for 1 h. The mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-40%,12 min) to give N-[2-[4-[3-(1 ,3- dimethyl-2-oxo-benzimidazol-5-yl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (38 mg, 78.7 mitioI, 22 %) as pale yellow solid. 1 H NMR (400MHz, DMSO-d6) d = 8.55 (t, J=5.7 Hz, 1 H), 7.89 - 7.83 (m, 2H), 7.75 (dd, J=1 .5, 8.2 Hz, 1 H), 7.67 (d, J=1 .3 Hz, 1 H), 7.55 - 7.42 (m, 3H), 7.29 (d, J=8.2 Hz, 1 H), 4.31 (br d, J=13.0 Hz, 1 H), 4.16 (dd, J=3.6, 5.4 Hz, 2H), 3.97 (br d, J=13.9 Hz, 1 H), 3.48 - 3.40 (m, 1 H), 3.37 (d, J=10.4 Hz, 6H), 3.29 - 3.22 (m, 1 H), 2.91 (br t, J=1 1 .2 Hz, 1 H), 2.13 (br t, J=12.9 Hz, 2H), 1 .89 - 1 .58 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 475.3. Example 123: 1 ,3-dimethyl-5-[5-[1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)-4-piperidyl]-1 ,2,4- oxadiazol-3-yl]benzimidazol-2-one.
Figure imgf000258_0001
Step 1: Preparation of 1 ,3-dimethyl-5-[5-[1 -(5-oxo- 1 -phenyl-pyrrolidine-3-carbonyl)-4-piperidyl]- 1 ,2,4- oxadiazol-3-yl]benzimidazol-2-one.
Figure imgf000258_0002
To a stirred solution of N'-hydroxy-1 ,3-dimethyl-2-oxo-benzimidazole-5-carboxamidine (120 mg, 544.9 gmol) and 1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (206 mg, 653.9 mitioI) in N,N-dimethylformamide (2 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (206 mg, 544.9 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (140 mg, 1 .09 mmol, 190 mI_) at 25°C. After stirring at 25 °C for 2h, the mixture was heated at 120 °C for 1 h. The mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 25%-55%,12 min) to give 1 ,3-dimethyl-5-[5-[1 -(5- oxo-1 -phenyl-pyrrolidine-3-carbonyl)-4-piperidyl]-1 ,2,4-oxadiazol-3-yl]benzimidazol-2-one (57 mg, 1 10.5 mitioI, 20 %) as a yellow solid. 1 H NMR (400MHz, DMSO-de) d = 7.75 (td, J=1 .5, 8.2 Hz, 1 H), 7.69 - 7.62 (m, 3H), 7.38 - 7.32 (m, 2H), 7.29 (d, J=8.4 Hz, 1 H), 7.15 - 7.08 (m, 1 H), 4.35 (br d, J=12.8 Hz, 1 H), 4.07 - 3.91 (m, 3H), 3.77 - 3.68 (m, 1 H), 3.47 - 3.39 (m, 1 H), 3.39 - 3.34 (m, 6H), 3.34 - 3.32 (m, 1 H), 3.28 (s,
1 H), 2.98 - 2.88 (m, 1 H), 2.82 - 2.67 (m, 2H), 2.14 (br t, J=13.8 Hz, 2H), 1 .90 - 1 .63 (m, 2H).LCMS (ESI) m/z: [M+H]+ = 501 .3.
Example 124: 1-[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1,3-dimethylindazol-6-yl)-1,2,4-oxadiazol-5- yl]piperidine-1-carbonyl]pyrrolidin-2-one
Figure imgf000259_0001
Step 1: Preparation of 1-[1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carbonyl]piperidine-4- carboxylic acid
Figure imgf000259_0003
To a stirred solution of methyl 1 -[1 -[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3- carbonyl]piperidine-4-carboxylate (200 mg, 494 mitioI) in tetrahydrofuran (2 ml_) was added aqueous lithium hydroxide (2 M, 494 mI_). The mixture was stirred at 20 °C for 2 h, then the mixture was acidified with 2N hydrochloric acid to pH 1 . The mixture was extracted with ethyl acetate (20 ml_ x 3), then the organic extracts were combined and washed with saturated aqueous sodium chloride solution (1 0 ml_), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -[1 -[(2,4- dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (160 mg, 409.8 mitioI, 83 %) as a yellow solid.
Step 2: Preparation of 1-[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol- 5-yl]piperidine- 1 -carbonyl]pyrrolidin-2-one.
Figure imgf000259_0002
To a stirred solution of N'-hydroxy-1 ,3-dimethyl-indazole-6-carboxamidine (78 mg, 384 mitioI) in N,N-dimethylformamide (2 ml_) was added 1 -[1 -[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3- carbonyl]piperidine-4-carboxylic acid (150 mg, 384 pmol), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (145 mg, 384 pmol) and N-ethyl-N-(propan-2-yl)propan-2- amine (148 mg, 1 .15 mmol, 201 mI_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-50%,12 min) to give 1 -[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carbonyl]pyrrolidin-2-one (35 mg, 64 pmol, 17 %) as a pink solid. 1 H NMR (400 MHz, CDCh) d 8.09 (d, J=4.1 Hz, 1 H), 7.85 - 7.80 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.17 (d, J= 8.7 Hz, 1 H), 6.49 - 6.43 (m, 2H), 4.59 - 4.38 (m, 3H), 4.08 (d, J=1 .8 Hz, 3H), 3.98 - 3.86 (m, 1 H), 3.84 - 3.77 (m, 6H), 3.71 - 3.62 (m, 1 H), 3.46 - 3.24 (m, 4H), 3.13 - 2.96 (m, 1 H), 2.85 - 2.75 (m, 1 H), 2.67 (m, 1 H), 2.60 (s, 3H), 2.21 (br s, 2H), 2.04 - 1 .87 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 559.3.
Example 125: 1-cyclohexyl-4-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]piperidine-1- carbonyl]pyrrolidin-2-one
Figure imgf000260_0001
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (100 mg, 345.6 pmol) and 1 -cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (73 mg, 345.6 pmol) in N,N- dimethylformamide (1 .00 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (131 mg, 345.63 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (89 mg, 691 mitioI, 120 pL) at 25 °C. The mixture was then stirred for an additional 2h at 25 °C. The reaction mixture was concentrated under reduced pressure to give a residue further purified by chromatography [Waters Xbridge 150x25 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-50%,12 min]. The title product, 1 -cyclohexyl-4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carbonyl]pyrrolidin-2-one, was isolated as a white solid (97 mg, 201 .6 mitioI, 58 %). 1 H NMR (400MHz, CHLOROFORM-d) d = 7.69 (dd, J= 1 .7, 8.3 Hz, 1 H), 7.57 (d, J= 1 .8 Hz, 1 H), 6.97 (d, J= 8.4 Hz, 1 H), 4.60 - 4.44 (dd, 1 H), 3.97 (d, J= 7.9 Hz, 6H), 3.77 (br t, J= 7.0 Hz, 1 H), 3.51 - 3.21 (m, 4H), 3.14 - 2.97 (m, 1 H), 2.77 - 2.61 (m, 2H), 2.28 - 2.17 (m, 2H), 2.03 - 1 .89 (m, 2H), 1 .88 - 1 .64 (m, 7H), 1 .48 - 1 .32 (m, 4H), 1 .23 - 1 .04 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 483.3.
Example 126: 4-[4-[3-(1 ,3-dimethylindazol- 6-yl)-1,2,4-oxadiazol-5-yl]piperidine-1- carbonyl]pyrrolidin-2-one.
Figure imgf000261_0001
To a stirred solution of 6-bromo-1 ,3-dimethyl-indazole (3.0 g, 13.33 mmol) in N,N- dimethylformamide (30 mL) was added, under a nitrogen atmosphere, zinc cyanide (1 .57 g, 13.33 mmol, 846 pL) and tetrakis(triphenylphosphine)palladium(0) (1 .54 g, 1 .33 mmol). The mixture was then stirred at 1 10 °C for 16 h and then cooled to 20 °C. Water (50 mL) was added to the reaction mixture which was extracted with ethyl acetate (80 mL x 3). The organic extracts were combined, washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product further purified by chromatography (silica, petroleum ether: ethyl acetate = 50 : 1 to 1 0:1 . The title compound, 1 ,3-dimethylindazole-6-carbonitrile was isolated as a white solid (1 .92 g, 1 1 .21 mmol, 84 %) 1 H NMR (400 MHz, CDCb) d 7.78 - 7.67 (m, 2H), 7.33 (dd, J=1 .0, 8.3 Hz, 1 H), 4.05 (s, 3H), 2.59 (s, 3H) Step 2: Preparation of N'-hydroxy- 1,3-dimethyi-indazoie-6-carboxamidine.
Figure imgf000261_0002
To a stirred solution of 1 ,3-dimethylindazole-6-carbonitrile (2.50 g, 14.60 mmol) in ethanol (30 mL) was added hydroxylamine hydrochloride (2.03 g, 29.20 mmol), triethylamine (2.95 g, 29.20 mmol, 4.05 mL) and water (3 mL). The mixture was stirred at 80 °C for 2 h, and then concentrated under reduced pressure. Water (5mL) was added to the residue, the resulting solid was collected by filtration and used for the next step without further purification. The title compound, N'-hydroxy-1 ,3-dimethyl- indazole-6-carboxamidine, was isolated as a white solid (2.86 g, 14.00 mmol, 96 %); 1H NMR (400 MHz, DMSO-d6) d 9.70 (s, 1 H), 7.85 (s, 1 H), 7.63 (d, J=8.4 Hz, 1 H), 7.47 (dd, J= 1 .2, 8.5 Hz, 1 H), 5.89 (s, 2H), 3.96 (s, 3H), 2.46 (s, 3H).
Step 3: Preparation of methyl 1-[1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carbonyl]piperidine- 4-carboxylate.
Figure imgf000262_0001
To a stirred solution of 1 -[(2,4-dimethaxypheny!)methy!]-5-oxo-pyrro!idine-3-carbaxylic acid (1 .0 g, 3.58 mmol) in dichloromethane (15 mL) was added methyl piperidine-4-carboxylate (512 g, 3.58 mmol), 2,4,6-tripropyM ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (2.51 g, 3.94 mmol, 2 34 L, 50% purity), triethylamine (724 mg, 7.16 mmol, 992 pL), and the reaction mixture was stirred at 20 TD for 2 h. Water (30 mL) was added to the mixture which was extracted with dichloromethane (50 mL x 3)).
The organic extracts were combined, washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 1 -[1 -[(2,4-dimethoxypheny!)methy!]-5- oxo-pyrro!idine-3-carbony!]p!peridine-4-carboxylate isolated as a yellow oil (1 .37 g, 3.39 mmol, 95 %) and used for the next step without further purification. ¾H NMR (400 MHz, GDCta) d 7.15 (br d, J=8.5 Hz, 1 H), 6.51 - 6.39 (m, 2H), 4.50 - 4.33 (m, 3H), 3.80 (s, 6H), 3.75 (br d, J=5.Q Hz, 1 H), 3.70 (s, 3H), 3.65 - 3.55 (m, 1 H), 3.42 - 3.29 (m, 2H), 3.19 - 3.05 (m, 1 H), 2.94 - 2.71 (m, 2H), 2.64 - 2.49 (m, 2H), 1 .94 (br dd, J-3.3, 13.3 Hz, 2H), 1 .62 (br s, 2H).
Step 4: Preparation of 1-[1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carbonyl]piperidine-4- carboxylic acid.
Figure imgf000262_0002
To a stirred solution of methyl 1 -[1 -[(2,4-dimethoxypheny!)methy!]-5-oxo-pyrro!idine-3- carbonyl]plperidine-4-carboxylate (1 .17 g, 2.89 mmol) in tetrahydrofuran (15 mL) was added lithium hydroxide (2 M solution in tetrahydrofuran, 2.89 L). The reaction mixture was stirred at 20 °C for 1 h, and then acidified until pH 1 using a 2M aqueous solution of hydrochloric acid. The resulting mixture was extracted with ethyl acetate (80 mL x 3). The organic extracts were combined, washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -[1 -[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid isolated as a white solid (1 .0 g, 2.56 mmol, 89 %) and used for the next step without further purification.1 H NMR (400 MHz, Methano!-d4) d 7 09 (dd, J= 2.9, 8.4 Hz, 1 H), 6 52 (d, J= 2.2 Hz, 1 H), 6 47 (dd, J=2.3, 8.3 Hz, 1 H), 4 46 - 4.25 (m, 3H), 3.92 - 3.83 (m, 1 H), 3 80 (d, J= 1 .3 Hz, 3H), 3 78 - 3.75 (m, 3H), 3.65 - 3.36 (m, 3H), 3 25 - 3.1 1 (m, 1 H), 2.92 - 2.80 (m, 1 H), 2 71 - 2.52 (m, 3H), 1 .97 - 1 .87 (m, 2H), 1 .68 - 1 42 (m, 2H)
Step 5: Preparation of 1-[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)- 1 ,2,4-oxadiazol- 5-yl]piperidine- 1 -carbonyl]pyrrolidin-2-one.
Figure imgf000263_0001
To a stirred solution of N'-hydroxy-1 ,3-dlmethyi-indazoie-6-carboxamldlne (261 mg, 1 .28 mmoi) in N,N-dimethy!formamide (6 mL) was added 1 -[1 -[(2,4-dimethoxyphenyl)methyi]-5-oxo-pyrroiidine-3- carbonyi]p!peridine-4-carboxylie acid (500 mg, 1 .28 mmol), (2-(1 H-benzotrlazo!-1 -y!)-1 , 1 ,3,3- tetramethy!uronium hexafiuorophosphate) (485 mg, 1 .28 mmol) and N-ethy!-N-(propan-2-yl)propaR-2- amine (496 mg, 3.84 mmoi, 670 pL). The reaction mixture was stirred at 20 °C for 1 h, at 1 10 °C for 1 h. and then cooled to 20 °C. Water (10 L) was added to the mixture, which was extracted with ethyl acetate (40 mL x 3). The organic extracts were combined, washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product further purified by chromatography (Dichloromethane : Methanol = 1 :0 to 10:1 ). The title compound, 1 -[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4- oxadiazol-5-yl]piperidine-1 -carbony!]pyrrolidin-2-one was isolated as a yellow solid (500 mg, 895 mitioI, 70 %). 1 H NMR (400 MHz, GDGb) d 8.1 1 (d, J= 5.0 Hz, 1 H), 7.84 (d, J= 8.5 Hz, 1 H), 7.79 - 7.73 (m, 1 H), 7 17 (d, J= 8.9 Hz, 1 H), 6.50 - 6.44 (m, 2H), 4.58 - 4.41 (m, 3H), 4.10 (s, 3H), 3.97 - 3 88 (m, 1 H), 3.84 - 3 79 (m, 6H), 3.69 (br d, J=6.7 Hz, 1 H), 3.47 - 3.27 (m, 4H), 3.16 (q, J= 7 5 Hz, 1 H), 2.83 - 2 76 (m, 1 H), 2 71 - 2.64 (m, 1 H), 2.62 (s, 3H), 2.25 (br s, 2H), 2.03 - 1 .88 (m, 2H)
Step 6: Preparation of 4-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]piperidine- 1- carbonyl]pyrrolidin-2-one.
Figure imgf000263_0002
A mixture of 1 -[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carbonyl]pyrrolidin-2-one (150 mg, 268.51 pmol), anisole (58 mg, 537 mitioI, 58 pL) in trifluoro acetic acid (2 mL) was degassed, purged with nitrogen three times, and then stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product further purified by chromatography (column: Waters Xbridge 150x25 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 15%-35%,12min). The title compound, 4- [4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]pyrrolidin-2-one, was isolated as a white solid (50 mg, 122.8 pmol, 46 %) 1 H NMR (400 MHz, CDCh) d 8.10 (br s, 1 H), 7.86 - 7.80 (m,
1 H), 7.77 - 7.72 (m, 1 H), 5.74 (br s, 1 H), 4.55 (br t, J=14.1 Hz, 1 H), 4.08 (s, 3H), 3.95 (br d, J= 9.0 Hz,
1 H), 3.82 - 3.75 (m, 1 H), 3.66 - 3.53 (m, 2H), 3.43 - 3.29 (m, 2H), 3.15 - 3.02 (m, 1 H), 2.77 - 2.67 (m, 1 H), 2.60 (s, 3H), 2.59 - 2.52 (m, 1 H), 2.33 - 2.18 (m, 2H), 2.08 - 1 .92 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 409.3.
Example 127: [4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-(4- isopropylphenyl)methanone.
Figure imgf000264_0001
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (80 mg, 276.50 pmol) and 4-isopropylbenzoic acid (54 mg, 331 .80 pmol) in N,N-dimethylformamide (1 .00 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (125 mg, 331 .80 pmol) and N- ethyl-N-(propan-2-yl)propan-2-amine (71 mg, 553 mitioI, 96 pL) at 25 °C. The mixture was stirred at 25 °C for 2h and then concentrated under reduced pressure to provide a residue purified by
chromatography (Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12min. The title compound, [4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5- yl]-1 -piperidyl]-(4-isopropylphenyl)methanone was isolated as a yellow solid (83 mg, 191 .6 pmol, 69 %)
1 H NMR (400MHz, CHLOROFORM-d) d = 7.71 (dd, J= 1 .9, 8.3 Hz, 1 H), 7.59 (d, J= 1 .9 Hz, 1 H), 7.40 - 7.36 (dd, 2H), 7.31 - 7.26 (t, 2H), 6.97 (d, J=8.4 Hz, 1 H), 4.65 (br s, 1 H), 3.97 (d, J= 8.5 Hz, 6H), 3.36 - 3.15 (m, 3H), 2.95 (spt, J= 6.9 Hz, 1 H), 2.33 - 1 .62 (m, 4H), 2.36 - 1 .62 (m, 1 H), 1 .28 (d, J= 6.9 Hz, 6H); LCMS (ESI) m/z: [M+H]+ = 436.3.
Figure imgf000264_0002
To a stirred solution of 3-hydroxy-2-(1 -oxoisoindolin-2-yl)propanoic acid (120 g, 542 pmol) in N,N-dimethyiformamide (2 mL) was added 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyi)-1 ,2,4- oxadiazole (153 mg, 452 pmol, 1 .00 eg, hydrochloric acid), (2-(1 H-benzotriazo!-1 -y!)-1 ,1 ,3,3- tetramethy!uronium hexafluorophosphate) (205 mg, 542 pmol) and N-ethyi-N-(propan-2-y!)propan-2- amine (175 mg, 1 .36 mmol, 236 pL). The mixture was stirred at 20 °C for 1 h, and then purified directly by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (I QmM ammonium carbonatej-acetonitr!!e]; B%: 30%-60%,12min) The title compound, 2-[2-[4-[3-(4-ethoxy-3-methoxy- phenyi)-1 ,2,4-oxadiazoi-5-yl]-1 -piperidyl]-1 -(hydroxymethyl)-2-oxo-ethyl]isoindolin-1 -one was isolated as a white solid (139 g, 274.8 pmol, 61 %) 1H NMR (400 MHz, CDCb) d 7.88 (t, J= 6.8 Hz, 1 H), 7.68 - 7.44 (m, 5H), 6.92 (dd, J=8.4, 17.7 Hz, 1 H), 5.38 (t, J=4.6 Hz, 1 H), 4.84 (br d, J=17.2 Hz, 1 H), 4.48 - 4.35 (m, 2H), 4.21 - 3.98 (m, 5H), 3.94 (d, J=17.1 Hz, 3H), 3.77 - 3.41 (m, 1 H), 3.39 - 3.04 (m, 3H), 2.26 - 1 .78 (m, 4H), 1 .50 (q, J=6.8 Hz, 3H); LCMS (ESI) m/z: [M÷H]+ = 507.3.
Figure imgf000265_0001
To a stirred solution of 3-hydroxy-2-(1 -oxoisoindolin-2-yl)propanoie acid (120 mg, 542 mitioI) in N,N-dimethy!formamide (2 ml_) was added 3-(1 ,3-dlmethy!indazoi-6-yi)-5-(4-piperidy!)-1 ,2,4-oxadiazo!e, hydrochloride (150 g, 452 pmol), (2-(1 H-benzotriazol-1 -yl)-1 1 ,3,3-tetramethyluronium
hexafluorophosphate) (205 mg, 542 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (175 mg, 1 .36 nimoi, 236 m!_). The reaction mixture was stirred at 20 °C for 1 h and then purified directly by prep-HPLC (column: Waters Xbr!dge 150x25 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrilej; B%: 25%-55%,12min). The title compound, 2-[2-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazoi-5-y!]-1 - piperidyl]-1 -(hydroxymethyl)-2-oxo-ethyl]isoindolin-1 -one was isolated as a white solid (68 mg, 137 pmol, 30 %) Ή NMR (400 MHz, CDCb) d 8.1 0 - 7.97 (m, 1 H), 7.91 - 7.65 (m, 3H), 7.62 - 7.44 (m, 3H), 5.40 (t, J=4.9 Hz, 1 H), 4.82 (dd, J=3.0, 17.3 Hz, 1 H), 4.51 - 4.37 (m, 2H), 4.16 - 3.99 (m, 6H), 3 65 (br s, 1 H),
3 43 - 3.04 (m, 3H), 2.58 (d, J= 6.7 Hz, 3H), 2.27 - 1 .93 (m, 3.6H), 1 .62 - 1 .50 (m, 0.4H); LCMS (ESI) m/z: [M+H]+ = 501 .3.
Example 130: 4-[4-[3-(6-ethoxy-5-methoxy-3-pyridyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1- phenyl-pyrrolidin-2-one.
Figure imgf000265_0002
A solution of (Z)-6-ethoxy-N'-hydroxy-5-methoxynicotinimidamide (100 mg, 474 pmol) in N,N- dimethylformamide (2.00 mL) was added 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (150 mg, 474 pmol) N-ethyl-N-(propan-2-yl)propan-2-amine (183 mg, 1 .42 mmol, 248 pL), and (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (197 mg, 521 .58 pmol). The mixture was stirred at 25 °C for 12 h, and then at 1 10 °C for 1 h. The residue was purified directly by pre- HPLC (column: Waters Xbridge 150x2.5mm 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 30%-50%,12min) to give 4-[4-[3-(6-ethoxy-5-methoxy-3-pyridyl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carbonyl]-1 -phenyl-pyrrolidin-2-one (96 mg, 194.7 mitioI, 41 %), isolated as as a yellow solid. Ή NMR (400MHz, CHLOROFORM-d) d = 8.44 (s, 1 H), 7.64 - 7.57 (m, 3H), 7.41 - 7 34 (m, 2H), 7 21 - 7.14 (m, 1 H), 4.61 - 4.46 (m, 3H), 4.37 - 4.28 (m, 1 H), 4.02 - 3.90 (m, 5H), 3.58 (td, J=8.4, 16.6 Hz, 1 H), 3.44 - 3 26 (m, 2H), 3.17 - 2.91 (m, 2H), 2.89 - 2.78 (m, 1 H), 2 31 - 2.17 (m, 2H), 2.06 - 1 .87 (m, 2H), 1 47 (t, J=7 2 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 492.1
Example 131: 2-(2-(4-(3-(6-ethoxy-5-methoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)isoindolin-1-one.
Figure imgf000266_0001
A solution of 6-ethoxy-N'-hydroxy-5-methoxy-pyridine-3-carboxamidine (104 mg, 496 gmol) in N,N-dimethylformamide (2 mL) was added 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid (150 mg, 496 mitioI), N-ethyl-N-(propan-2-yl)propan-2-amine (192 mg, 1 .49 mmol, 259 mI_) and (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (206 mg, 545.77 mitioI). The mixture was stirred at 25 °C for 12 h, and then at 1 10 °C for 1 h. The mixture was purified by pre-HPLC (column: Waters Xbridge 150x25 5pm; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%- 50%,12min) to give 2-[2-[4-[3-(6-ethoxy-5-methoxy-3-pyridyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo- ethyl]isoindolin-1 -one (82 mg, 171 mitioI, 34 %), isolated as a pink solid. 1 H NMR (400MHz,
CHLOROFORM-d) d = 8.46 (d, J=1 .8 Hz, 1 H), 7.89 (d, J=7.8 Hz, 1 H), 7.65 (d, J=1 .5 Hz, 1 H), 7.62 - 7.56 (m, 1 H), 7.50 (t, J=6.7 Hz, 2H), 4.64 - 4.44 (m, 7H), 4.1 1 (br d, J=13.7 Hz, 1 H), 3.98 (s, 3H), 3.46 - 3.26 (m, 2H), 3.08 (br t, J=10.9 Hz, 1 H), 2.24 (br t, J=14.0 Hz, 2H), 2.09 - 1 .89 (m, 2H), 1 .50 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 478.1 .
Example 132: N-(2-(4-(3-(6-ethoxy-5-methoxypyndin-3-yl)-1,2,4-oxadiazol-5-yl)pipendin-1-yl)-2- oxoethyl)benzamide.
Figure imgf000266_0002
Figure imgf000267_0003
A solution of sodium (465 mg, 20.23 mmol, 479 mI_) in ethanol (5 mL) was stirred at 20 °C for 2 h. 5-Bromo-2-chloro-3-methoxypyridine (1 .50 g, 6.74 mmol) was then added to the mixture which was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was then added to the residue. The mixture was extracted with dichloromethane (60 mL x 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 5-bromo-2-ethoxy-3-methoxypyridinee, isolated as a white solid (1 .70 g, crude), and used for the next step without further purification. 1 H NMR (400MHz, METHANOL-d4) d = 7.70 (d, J=2.0 Hz, 1 H), 7.34 (d, J=2.2 Hz, 1 H), 4.34 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 1 .36 (t, J=7.1 Hz, 3H).
Step 2: Preparation of 6-ethoxy-5-methoxynicotinonitrile.
Figure imgf000267_0001
To a stirred solution of 5-bromo-2-ethoxy-3-methoxy-pyridine (1 .70 g, 7.33 mmol) in N,N- dimethylformamide (10 ml_) was added zinc cyanide (860 mg, 7.33 mmol, 464 mI_), and
tetrakis(triphenylphosphine)palladium(0) (847 mg, 733 mitioI, 0.10 eq), the mixture was degassed with nitrogen for three times. The resulting mixture was stirred at 1 10 °C for 12 h under nitrogen atmosphere and then poured into water (30 ml_). The mixture was then extracted with dichloromethane (50 ml_ x 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product purified by chromatography (silica, petroleum ether : ethyl acetate = 50:1 Rt= 0.6). The title compound, 6-ethoxy-5-methoxy-pyridine-3-carbonitrile was isolated as a white solid (820 mg, 4.60 mmol, 63 %) 1 H NMR (400MHz, METHANOL-d4) d = 8.08 (d,
J=1 .8 Hz, 1 H), 7.49 (d, J=1 .8 Hz, 1 H), 4.48 (q, J=7.1 Hz, 2H), 3.92 - 3.88 (m, 3H), 1 .42 (t, J=7.1 Hz, 3H) .
Figure imgf000267_0002
To a stirred solution of 6-ethoxy-5-methoxynicotinonitrile (820 mg, 4.60 mmol) in ethanol (20 ml_) and water (2 ml_) was added hydroxylamine hydrochloride (639 mg, 9.20 mmol) and triethylamine (931 mg, 9.20 mmol, 1 .28 ml_). The mixture was stirred at 80 °C for 2 h, cooled to room temperature, concentrated under reduced pressure and poured into water (5 ml_). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give (Z)-6-ethoxy-N'-hydroxy-5-methoxynicotinimidamide (1 .0 g, crude) as a white solid. 1 H NMR (400MHz, METHANOL-d4) d = 7.94 (d, J=2.0 Hz, 1 H), 7.44 (d, J=2.0 Hz, 1 H), 4.43 - 4.36 (m, 2H), 3.86 (s, 3H), 1 .38 (t, J=7.1 Hz, 3H).
Step 4: Preparation of N-(2-(4-(3-(6-ethoxy-5-methoxypyridin-3-yl)- 1,2,4-oxadiazol-5-yl)pipericlin- 1-yl)-2- oxoethyl)benzamide.
Figure imgf000268_0001
To a stirred solution of (Z)-6-ethoxy-N'-hydroxy-5-methoxynicotinimidamide (109 mg, 516.69 pmol) in N,N-dimethylformamide (2 ml_) was added 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 516.69 pmol), N-ethyl-N-(propan-2-yl)propan-2-amine (200 mg, 1 .55 mmol, 270 pL) and (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (215 mg, 568 pmol). The mixture was stirred at 25 Ό for 12 h, and at 1 1 0 °C for 1 h. The residue was purified directly by chromatography (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-50%,12min) to give N-(2-(4-(3-(6-ethoxy-5-methoxypyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)benzamide (83 mg, 177.7 pmol, 34 %) as a yellow solid. 1 H NMR (400MHz,
CHLOROFORM-d) d = 8.44 (d, J=1 .8 Hz, 1 H), 7.88 - 7.82 (m, 2H), 7.62 (d, J=2.0 Hz, 1 H), 7.55 - 7.49 (m, 1 H), 7.48 - 7.42 (m, 2H), 7.32 (br s, 1 H), 4.58 - 4.47 (m, 3H), 4.30 (d, J=4.0 Hz, 2H), 3.95 (s, 3H), 3.39 - 3.28 (m, 2H), 3.18 - 3.09 (m, 1 H), 2.30 - 2.19 (m, 2H), 2.07 - 1 .91 (m, 2H), 1 .47 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 466.1 .
Example 133: 3-methyl-5-[5-[1-[2-(1-oxoisoindoHn-2-yl)acetyl]-4-piperidyl]-1,2,4-oxadiazol-3-yl]-1H- benzimidazol-2-one.
Figure imgf000268_0002
A mixture of N'-hydroxy-3-methyl-2-oxo-1 H-benzimidazole-5-carboxamidine (81 .85 mg, 396.94 gmol, 1 .20 eq), 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid (100.00 mg, 330.78 pmol, 1 .00 eq), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (188.16 mg, 496.1 6 pmol, 1 .50 eq), N-ethyl-N-(propan-2-yl)propan-2-amine (128.25 mg, 992.33 pmol, 173.31 pL, 3.00 eq) in N,N-dimethylformamide (2.00 ml_) then the mixture was stirred at 20 °C for 15h then the mixture was stirred at 1 10 °C for 1 h. The product was purified by column: Waters Xbridge 150x25 5pm; mobile phase: [water (1 0 mM NH4HCC>3)-acetonithle]; B%: 20%-45%,12min to obtain compound 3-methyl-5-[5-[1 -[2-(1 - oxoisoindolin-2-yl)acetyl]-4-piperidyl]-1 ,2,4-oxadiazol-3-yl]-1 H-benzimidazol-2-one (53.58 mg, 1 13.40 pmol, 34.28 %) as a pink solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 9.60 (br s, 1 H), 7.79 (t, J=9.0 Hz, 2H), 7.61 (s, 1 H), 7.51 - 7.46 (m, 1 H), 7.42 - 7.37 (m, 2H), 7.10 (d, J=8.2 Hz, 1 H), 4.52 (s, 2H), 4.45 - 4.37 (m, 3H), 4.02 (br d, J=13.6 Hz, 1 H), 3.42 (s, 3H), 3.37 - 3.19 (m, 2H), 3.00 (br t, J=1 1 .0 Hz, 1 H), 2.21 - 2.10 (m, 2H), 1 .99 - 1 .85 (m, 2H); LCMS (ESI) m/z [M+H]+ = 473.3.
Example 134: 3-methyl-5-[5-[1-(5-oxo-1-phenyl-pyrrolidine-3-carbonyl)-4-piperidyl]-1,2,4-oxadiazol- 3-yl]-1H-benzimidazol-2-one.
Figure imgf000269_0001
Example 134 was synthesized according to the synthetic procedure reported for the preparation of Example 133. 1 H NMR (400MHz, CHLOROFORM-d) d = 9.82 (br s, 1 H), 7.79 (br d, J=8.2 Hz, 1 H), 7.62 (br s, 1 H), 7.52 (d, J=8.2 Hz, 2H), 7.34 - 7.29 (m, 2H), 7.14 - 7.08 (m, 2H), 4.57 - 4.40 (m, 1 H), 4.26 (br t, J=7.3 Hz, 1 H), 3.97 - 3.84 (m, 2H), 3.52 (quin, J=8.4 Hz, 1 H), 3.42 (d, J=1 .6 Hz, 3H), 3.37 - 3.23 (m, 2H), 3.13 - 2.86 (m, 2H), 2.83 - 2.76 (m, 1 H), 2.19 (br t, J=12.5 Hz, 2H), 2.00 - 1 .82 (m, 2H). LCMS (ESI) m/z: [M+H]+ = 487.3.
Figure imgf000269_0002
To a stirred solution of 1 -(4-bromo-2-hydroxy-phenyl)ethanone (10.00 g, 46.50 mmol) and pyridine (49.66 g, 627.75 mmol, 50.67 ml_) in ethanol (100 ml_) was added hydroxylamine hydrochloride (16.16 g, 232.50 mmol) at 25 °C. The mixture was heated to 90Ό for 4 h and was poured into a 2M aqueous solution of hydrochloric acid (250 ml_). The mixture was then extracted with ethyl acetate (1 00 ml_ x 4), washed with saturated aqueous sodium chloride solution (25 mL x 1 ), dried with anhydrous Na2SC>4, filtered and concentrated under vacuum to give 1 -(4-bromo-2-hydroxy-phenyl)ethanone oxime (12.49 g, crude), isolated as pale yellow solid, and used for the next step without further purification. (1 H
NMR (400MHz, CHLOROFORM-d) d = 1 1 .47 (br s, 1 H), 8.65 (br d, J= 4.3 Hz, 1 H), 7.94 (br s, 1 H), 7.31 - 7.28 (d, 1 H), 7.1 7 (d, J=1 .9 Hz, 1 H), 7.06 (dd, J= 2.0, 8.5 Hz, 1 H), 2.37 (s, 3H) Step 2: Preparation of [(E)- 1-(4-bromo-2-hydroxy-phenyl)ethylideneamino] acetate.
Figure imgf000270_0001
Acetic anhydride (25.50 ml_) was added to 1 -(4-bromo-2-hydroxy-phenyl)ethanone oxime (12.49 g, 54.29 mmol, 1 .00 eq) one portion at 25 °C, then the mixture was stirred at 25 °C for 30 mins. Water (100 mL) was then added to the suspension (a solid precipitated from the reaction mixture after 30 min stirring at room temperature), further stirred for 30 min at 25 °C. The suspension was filtered and the resulting solid was washed with water (1 0 mL x 3) and dissolved in ethyl acetate (20 mL). The organic solution was then dried with anhydrous Na2SC>4, filtered and concentrated under vacuum to give [(E)-1 -(4- bromo-2-hydroxy-phenyl)ethylideneamino] acetate (12.18 g, 44.8 mmol, 82 %) as pale white solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 1 1 .48 (s, 1 H), 7.34 (d, J= 8.7 Hz, 1 H), 7.24 (d, J= 1 .9 Hz, 1 H), 7.07 (dd, J=1 .9, 8.6 Hz, 1 H), 2.45 (s, 3H), 2.28 (s, 3H).
Step 3: Preparation of 6-bromo-3-methyl- 1,2-benzoxazole
Figure imgf000270_0002
[(E)-1 -(4-bromo-2-hydroxy-phenyl)ethylideneamino] acetate (1 1 .00 g, 40.4 mmol) was added in one portion to pyridine (100 mL) and the resulting solution was refluxed at 130 Ό for 15 h. The mixture was cooled to room temperature and poured into a 2M aqueous solution of hydrochloric acid (500 mL). The resulting mixture was extracted with methyl tert-butyl ether (200 mL x 3). The organic extracts were washed with saturated aqueous sodium chloride solution (20 mL x 1 ), dried with anhydrous Na2SC>4, filtered and concentrated under vaccum to give the crude product further purified by chromatography (silica, petroleum ether / ethyl acetate=200/1 to 1 00/1 ). The desired compound (6-bromo-3-methyl-1 ,2- benzoxazole) was obtained as a yellow solid (7.50 g). 1 H NMR (400MHz, DMSO-d6) d = 8.05 (s, 1 H), 8.08 - 8.03 (d, 1 H), 8.08 - 8.03 (, 1 H), 7.82 (d, J=8.4 Hz, 1 H), 7.56 (dd, J=1 .1 , 8.3 Hz, 1 H), 2.56 (s, 3H).
Step 4: Preparation of 3-methyl- 1 ,2-benzoxazole-6-carbonitrile.
Figure imgf000270_0003
To a stirred solution of 6-bromo-3-methyl-1 ,2-benzoxazole (2.50 g, 1 1 .8 mmol) and zinc cyanide (1 .38 g, 1 1 .8 mmol, 748 pL) in N,N-dimethylformamide (12 mL) was added
tetrakis(triphenylphosphine)palladium(0) (1 .36 g, 1 .18 mmol) at 25 °C ,the mixture was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 1 10 °C for 24 hrs under a nitrogen atmosphere. The suspension was filtered through a pad of Celite. The filtrate was then poured into water (50 mL), extracted with ethyl acetate (50 mL x 3) and the organic layer was washed with saturated aqueous sodium chloride solution (20 mL x 1 ), dried with anhydrous Na2SC>4, and concentrated in vacuo. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=1 00/1 to 50:1 ) to give 3-methyl-1 ,2-benzoxazole-6-carbonitrile (240 mg, 1 .52 mmol, 13 %), isolated as awhite solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.89 (t, J= 1 .0 Hz, 1 H), 7.76 (dd, J=0.7, 8.2 Hz, 1 H), 7.60 - 7.57 (m, 1 H), 2.63 (s, 3H).
Step 5: Preparation of N'-hydroxy-3-methyl- 1 ,2-benzoxazole-6-carboxamidine
Figure imgf000271_0001
To a stirred solution of 3-methyl-1 ,2-benzoxazole-6-carbonitrile (240 mg, 1 .52 mmol) in ethanol (4.00 mL) and water (400 pL) was added hydroxylamine hydrochloride (21 0 mg, 3.03 mmol) and triethylamine (307 mg, 3.03 mmol, 420 pL) at 25 °C. The mixture was then stirred at 70 °C for 5 h and concentrated in vacuo to give N'-hydroxy-3-methyl-1 ,2-benzoxazole-6-carboxamidine (265 mg, 1 .39 mmol, 91 .60 %) isolated as a white solid, and used for the next step without further purification.
Step 6: Preparation of N-[2-[4-[3-(3-methyl- 1 ,2-benzoxazol-6-yl)- 1 , 2, 4-oxadiazoi-5-yi]- 1 -piperidyi]-2-oxo- ethyljbenzamide.
Figure imgf000271_0002
To a stirred solution of N'-hydroxy-3-methyl-1 ,2-benzoxazole-6-carboxamidine (85 mg, 447.80 pmol) and 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (130 mg, 447.80 pmol) in N,N- dimethylformamide (2.00 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447.80 pmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 15 mg, 895.60 mitioI, 156 mI_) at 25 °C. The mixture was then stirred at 25 °C for 4 h and warmed to 1 10 °C for 1 h. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Boston Green ODS 150x30mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,1 1 .5 min) to give N-[2-[4-[3-(3-methyl-1 ,2-benzoxazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]-2-oxo-ethyl]benzamide (48 mg, 107.82 pmol, 24%, 99% purity), isolated as a pale yellow solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 8.28 (s, 1 H), 8.05 (d, J= 8.3 Hz, 1 H), 7.85 (d, J= 7.5 Hz, 2H), 7.74 (d, J=7.9 Hz, 1 H), 7.55 - 7.42 (m, 3H), 7.34 (br s, 1 H), 4.51 (br d, J=13.6 Hz, 1 H), 4.31 (d, J= 3.9 Hz, 2H), 3.93 (br d, J=14.0 Hz, 1 H), 3.41 - 3.32 (m, 2H), 3.16 (br t, J=10.7 Hz, 1 H), 2.63 (s, 3H), 2.33 - 2.22 (m, 2H), 2.09 - 1 .93 (m, 2H); LCMS (ESI) m/z: [M+H]+:446.2. Example 136: 4-[4-[3-(3-methyl- 1,2-benzoxazol-6-yl)- 1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1- phenyl-pyrrolidin-2-one.
Figure imgf000272_0001
To a stirred solution of N'-hydroxy-3-methyl-1 ,2-benzoxazole-6-carboxamidine (78 mg, 410.94 mitioI) and 1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (130 mg, 410.94 mitioI) in N,N-dimethylformamide (2.00 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (155 mg, 410.94 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (106 mg,
821 .88 mitioI, 143 mI_) at 25 °C. The mixture was then stirred at 25 °C for 4 h and warmed to 1 10 °C for 1 h. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Boston Green ODS 150x30 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,1 1 .5 min) to give 4-[4-[3-(3-methyl-1 ,2-benzoxazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carbonyl]-1 -phenyl-pyrrolidin-2-one (42 mg, 89.8 mitioI, 22 %) isolated as a yellow solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 8.28 (s, 1 H), 8.06 (d, J= 8.3 Hz, 1 H), 7.74 (d, J= 8.3 Hz, 1 H), 7.60 (d,
J= 7.9 Hz, 2H), 7.38 (t, J= 7.9 Hz, 2H), 7.20 - 7.14 (t, 1 H), 4.61 - 4.48 (t, 1 H), 4.35 - 4.29 (t, 1 H), 4.04 - 3.92 (dd, 2H), 3.59 (quin, J=8.4 Hz, 1 H), 3.46 - 3.31 (m, 2H), 3.20 - 3.05 (m, 1 H), 3.03 - 2.92 (m, 1 H), 2.89 - 2.80 (m, 1 H), 2.63 (s, 3H), 2.28 (br t, J=12.3 Hz, 2H), 2.08 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 472.2.
Figure imgf000272_0002
A 3M solution of ethylmagnesium bromide in tetrahydrofuran (4.97 ml_) was added at 0 °C to a stirred solution of 5-bromo-3-fluoropicolinonitrile (2.0 g, 9.95 mmol) in tetrahydrofuran (20 ml_). The mixture was then stirred at 25 °C for 1 h, and quenched by addition of an aqueous solution of ammonium hydroxide ammonium chloride solution (20 ml_). The resulting mixture was extracted with ethyl acetate (2 X 20 ml_). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 ml_), dried over anhydrous anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product further purified by chromatography (silica, petroleum ether : ethyl acetate = 20:1 to 1 :1 ). The desired compound (1 -(5-bromo-3-fluoropyridin-2-yl)ethanone) was isolated as a yellow solid (580 mg, 1 .49 mmol, 15 %). 1H NMR (400MHz, CHLOROFORM-d) d 8.56 (s, 1 H), 7.74 (dd, J=1 8, 9 8 Hz, 1 H), 2.68 (s, 3H).
Figure imgf000273_0001
To a stirred solution of 1 -(5-bromo-3-fluoropyridin-2-yl)ethanone (570 mg, 1 .46 mmol) in ethanol (5 mL), was added methylhydrazine (1 .68 g, 14.60 mmol, 1 .91 ml_), and the resulting mixture was heated at 80 °C for 2 h. The reaction mixture was then quenched with water (5 mL) and extracted with ethyl acetate (2X5 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product further purified by prep-TLC (silica, petroleum ether : ethyl acetate = 3:1 ). The title compound (6-bromo-1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine) was isolated as a yellow solid (280 mg,
1 .23 mmol, 84 %) ¾H NMR (400MHz, CHLOROFORM-d) d 8.54 (d, J= 1 .9 Hz, 1 H), 7.86 (d, J= 1 .9 Hz, 1 H), 3.99 (s, 3H), 2.64 (s, 3H).
Figure imgf000273_0002
A solution of 6-bromo-1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine (280 mg, 1 .24 mmol), tetrakis(triphenylphosphine)palladium(0) (214 mg, 186 pmol), and zinc cyanide (87 mg, 744 mitioI, 47 pL) in N,N-dimethylformamide (2 mL) under nitrogen was heated to 100 °C and stirred for 12 h at 100 °C.
The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated to give a residue poured into water (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL x 3). The combined organic extracts were then washed with saturated aqueous sodium chloride solution (5 mL x 1 ), dried over anhydrous anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-TLC (silica, petroleum ether : ethyl acetate = 1 : 1 ) to give 1 ,3-dimethyl-1 H-pyrazolo[4,3- b]pyridine-6-carbonitrile (190 mg, 805.5 mitioI, 65 %) as a light yellow solid. Ή NMR (400MHz,
CHLOROFORM-d) d 8.72 (d, J=1 .5 Hz, 1 H), 8.04 (d, J=1 .5 Hz, 1 H), 4.09 (s, 3H), 2.69 (s, 3H).
Figure imgf000274_0001
To a stirred solution of 1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine-6-carbonitrile (170 mg, 987 mitioI) in ethanol (2 ml_) was added hydroxylamine hydrochloride (137 mg, 1 .97 mmol), triethylamine (199 mg,
1 .97 mmol, 273 mI_) and water (200 mI_). The reaction mixture was then stirred at 80 °C for 2 h. and concentrated under reduced pressure. The residue was diluted with water (5 ml_). The resulting solid was filtered to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine-6-carboximidamide (160 mg, 779.7 mitioI, 79 %) isolated as a light yellow solid, and used for the next step without further purification. 1 H NMR (400MHz, DMSO-de) 6 9.93 (s, 1 H), 8.82 (d, J=1 .8 Hz, 1 H), 8.29 (d, J= 2.0 Hz, 1 H), 6.07 (br s, 2H), 4.00 (s, 3H), 2.51 (s, 3H).
Figure imgf000274_0002
To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 51 6.69 mitioI) in N,N-dimethylformamide (1 .50 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (215 mg, 568 mitioI), N-ethyl-N-(propan-2-yl)propan-2-amine (200 mg, 1 .55 mmol, 270 mI_) and (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine-6-carboximidamide (106 mg, 516.69 mitioI). The reaction mixture was stirred at 25 °C for 1 h, and then warmed to 1 10 °C for 1 h. The reaction mixture was concentrated under vacuum and the resulting residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-45%,12min) to give N-(2-(4-(3-(1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridin-6-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (1 16 mg, 252.7 mitioI, 49 %) isolated as a brown solid. 1 H NMR (400MHz, DMSO-de) d 9.05 (d, J= 1 .8 Hz, 1 H), 8.64 (d, J=1 .8 Hz, 1 H), 8.61 - 8.54 (m, 1 H), 7.88 (br d,
J=7.1 Hz, 2H), 7.57 - 7.45 (m, 3H), 4.35 (br d, J= 13.0 Hz, 1 H), 4.19 (br t, J= 5.6 Hz, 2H), 4.1 0 (s, 3H), 4.01 (br d, J=13.2 Hz, 1 H), 3.53 (br t, J= 1 0.9 Hz, 1 H), 3.58 - 3.48 (m, 1 H), 3.32 - 3.24 (m, 1 H), 2.96 (br t,
J=1 1 .8 Hz, 1 H), 2.56 (s, 3H), 2.18 (br t, J= 13.7 Hz, 2H), 1 .88 (br d, J=10.1 Hz, 1 H), 1 .81 - 1 .57 (m, 1 H); LCMS (ESI) m/z: [M+H]+ = 460.3.
Example 138: 4-(4-(3-(1,3-dimethyl-1H-pyrazolo[4,3-b ]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)pipendine-1- carbonyl)-1-phenylpyrrolidin-2-one.
Figure imgf000275_0001
To a stirred solution of 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (150 mg, 474 pmol) in N,N-dimethylformamide (1 .50 ml_) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (197 mg, 521 .58 pmol), N-ethyl-N-(propan-2-yl)propan-2-amine (183 mg, 1 .42 mmol, 248 mI_) and (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine-6- carboximidamide (97 mg, 474 pmol). The reaction mixture was stirred at 25 °C for 1 h and then warmed to 1 10 °C for 1 h. The reaction mixture was concentrated under vacuum and the resulting residue was purified by prep-HPLC (column: Waters Xbridge 1 50x25 5pm; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12min) to give 4-(4-(3-(1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridin-6- yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one (121 mg, 249 mitioI, 52 %) isolated as a yellow solid. Ή NMR (400MHz, DMSO-de) d 9.05 (s, 1 H), 8.64 (br s, 1 H), 7.66 (br d, J= 8.2 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.17 - 7.1 1 (m, 1 H), 4.39 (br d, J=13.5 Hz, 1 H), 4.10 (s, 3H), 4.06 (br d, J=9.0 Hz,
2H), 4.00 - 3.93 (m, 1 H), 3.80 - 3.71 (m, 1 H), 3 52 (br t, J= 10.9 Hz, 1 H), 3.40 - 3.34 (m, 1 H), 3.03 - 2.92 (m, 1 H), 2.85 - 2.71 (m, 2H), 2.56 (s, 3H), 2.19 (t, J=14.3 Hz, 2H), 1 .95 - 1 .82 (m, 1 H), 1 .80-1 .70 (m, 1 H); LG MS (ESi) m/z: [M+H]÷ = 486.3.
Figure imgf000275_0002
Step 1: Preparation of 4-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]piperidine- 1- carbonyl]pyrrolidin-2-one.
Figure imgf000275_0003
A mixture of 1 -[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carbonyl]pyrrolidin-2-one (350 mg, 626.53 pmol), anisole (135 mg, 1 .25 mmol, 135 pL) in trifluoroacetic acid (5 mL) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere and then concentrated under reduced pressure to to provide the crude product (500 mg) isolated as a yellow oil and used for the next step without further purification. Step 2: Preparation of 4-[4-[4-[3-(1,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]piperidine- 1-carbonyl]-2- oxo-pyrrolidin- 1 -yljbenzonitrile.
Figure imgf000276_0001
A mixture of 4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbony!jpyrroiidin- 2-one (200 mg, 489.68 pmo!), 4-iodobenzonitriie (1 12 g, 489.66 pmol), potassium phosphate tribasic (1 87 g, 881 pmol), copper iodide (18 mg, 97.93 pmol) and (1 S,2S)-cyclohexane-1 ,2-diamine (55 mg, 489.66 pmol, 60 pL) in dioxane (1 mL) and N,N-dimethy!formamide (1 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 1 10 ¾ for 1 6 h under a nitrogen atmosphere. After the reaction cooled to 20 °C, water (10 mL) was added to the mixture which was extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product further purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 15%-40%,12min). The title compound (4-[4-[4-[3-(1 ,3- dimethylindazol-6-yl)-1 ,2,4-oxadiazoi-5-yl]piperidine-1 -carbony!]-2-oxo-pyrro!idin-1 -yljbenzonitrile) was isolated as a pale yellow solid (1 7 g, 34 mitioI, 7 %) ' H NMR (400 MHz, GDGta) d 8.10 (br s, 1 H), 7.87 - 7.72 (m, 4H), 7.67 (d, J=8.8 Hz, 2H), 4.63 - 4.47 (m, 1 H), 4.36 (dd, J= 7.1 , 9.5 Hz, 1 H), 4.09 (s, 3H), 4.03 - 3.93 (m, 2H), 3.62 (m, 1 H), 3.48 - 3.32 (m, 2H), 3.20 - 3.04 (m, 1 H), 3.02 - 2.88 (m, 2H), 2.61 (s, 3H), 2.30 (br t, J=14.4 Hz, 2H), 2.10 - 1 .96 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 51 0.3.
Example 140: 2-[2-[4-[3-(4-ethoxy-3-methoxy-phenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2- oxo-ethyl]isoindolin-1-one.
Figure imgf000276_0002
Step 1: Preparation of 2-[2-[4-[3-(4-ethoxy-3-methoxy-phenyl)- 1 ,2,4-oxadiazoi-5-yi]- 1 -piperidyiJ- 1 -methyi- 2-oxo-ethyl]isoindolin- 1 -one.
Figure imgf000276_0003
To a stirred solution of 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazo!e (130 mg, 382.56 pmoi, 1 .00 eq, hydrochloric acid) in N,N-dimethy!formamide (2 mL) was added 2-(1 -oxoisoindolin- 2-y!)propanoic acid (78 mg, 382.56 pmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (174 mg, 459 mitioI) and N-ethyl-N-(propan-2-yl)propan-2-amine (148 mg, 1 .15 mol, 200 m!_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by prep-HPLG (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (1 GmM ammonium carbonate)-acetonitrilej; B%: 40%-70%,12min) to give 2-[2-[4-[3-(4-ethoxy-3- methoxy-phenyi}-1 ,2,4-oxadiazoi-5-yi]-1 -piperldyl]-1 -methyl-2-oxo-ethyl]isoindolin-1 -one (132 mg, 266 pmol, 70 %), isolated as a yellow solid. ¾ H NMR (400 MHz, CDC ) d 7 86 (br t, J=6.2 Hz, 1 H), 7.69 - 7.43 (m, 5H), 6.93 (dd, J=8.4, 15.4 Hz, 1 H), 5.55 (q, J= 6.8 Hz, 1 H), 4.57 - 4.36 (m, 3H), 4.29 - 4.1 1 (m, 3H), 3.95 (d, J=13.5 Hz, 3H), 3.42 - 3.19 (m, 2H), 3.14 - 3.00 (m, 1 H), 2.1 6 (br dd, J=4.4, 8.8 Hz, 2H),
2.06 - 1 .67 (m, 2H), 1 .54 - 1 .47 (m, 6H); LCMS (ESI) m/z: [M+H]+ = 491 .1 .
Example 141: 2-[2-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-ylJ-1-piperidyl]-1-methyl-2-oxo- ethyl]isoindolin-1 -one
Figure imgf000277_0001
To a stirred solution of 2-(1 -oxoisoindoiin-2-y!)propanoic acid (79 mg, 389 prnol) in N,N- dimethylformamide (2 mL) was added 3-(1 ,3-dimethylindazoi-6-y!)-5-(4-piperldyi)-1 ,2,4-oxadiazoie (130 g, 389 pmol), (2-(1 H-benzotriazoi-1 -y!)-1 ,1 ,3,3-tetramethyiuronium hexafluorophosphate) (177 mg, 467 pmol) and N-ethy!-N-(propan-2-y!)propan-2-amine (150 mg, 1 .17 mmol, 204 m!_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5pm ; mobile phase: [water (10mM ammonium carbonate)- acetonitrilej; B%: 40%-70%,12min) to give 2-[2-[4-[3-(1 ,3-dimethy!indazo!-8-y!)-1 ,2,4-oxadiazo!-5-yl]-1 - piperldyl]-1 -methyi-2-oxo-ethyl]isoindolin-1 -one (1 18 mg, 243.5 pmol, 63 %) Isolated as a white solid. 1 H NMR (400 MHz, GDGh) d 8.12 - 8.01 (m, 1 H), 7.90 - 7.67 (m, 3H), 7.60 - 7.44 (m, 3H), 5.56 (q, J=6.6 Hz, 1 H), 4.58 - 4.40 (m, 3H), 4.27 (br t, J=13.7 Hz, 1 H), 4.07 (d, J= 9.9 Hz, 3H), 3.45 - 3.24 (m, 2H), 3 14 - 3 03 (m, 1 H), 2.59 (d, J= 6.6 Hz, 3H), 2.21 (br d, J=12.8 Hz, 2H), 2.10 - 1 .70 (m, 2H), 1 .52 (br dd, J=4 3, 6 3 Hz, 3H); LCMS (ESI) m/z: [M~H]+ = 485.1 .
Figure imgf000277_0002
Example 142 was synthesized according to the synthetic procedure reported for the preparation of Example 147. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.87 (d, J=7.5 Hz, 1 H), 7.67 (d, J=8.3 Hz,
1 H), 7.58 - 7.53 (m, 1 H), 7.47 (t, J=6.8 Hz, 2H), 7.10 (d, J=7.9 Hz, 1 H), 4.58 (d, J=5.7 Hz, 2H), 4.52 (s, 1 H), 4.48 - 4.41 (m, 2H), 4.19 - 4.12 (m, 5H), 4.04 (s, 1 H), 3.44 - 3.26 (m, 2H), 3.05 (br t, J=1 1 .0 Hz, 1 H), 2.26 - 2.13 (m, 2H), 1 .96 (br dd, J=10.1 , 19.7 Hz, 2H), 1 .52 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z:
[M+H]+:478.1 .
Example 143: N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo- ethyl]piperidine-1 -carboxamide
Figure imgf000278_0001
Step 1: Preparation of tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1 , 2,4-oxadiazol-5-yl]- 1 -piperidyl]-2-oxo- ethyljcarbamate.
Figure imgf000278_0002
To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole hydrochloride (1 .00 g, 3.07 mmol, 1 .00 eq) and 2-(tert-butoxycarbonylamino) acetic acid (537 mg, 3.07 mmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 .16 g, 3.07 mmol) in N,N- dimethylformamide (10.00 ml_) was added N-ethyl-N-(propan-2-yl)propan-2-amine (793 mg, 6.14 mmol,
1 .07 ml_) at 25 °C. The mixture was then stirred at 25 °C for 1 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 ml_ x 3). The organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried with anhydrous Na2SC>4, filtered and concentrated under vacuum to provide the crude product further purified by chromatography (silica, petroleum ether / ethyl acetate=1 00/1 to 50:1 to 1 :1 ). The title compound (tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]carbamate)was isolated as a pale yellow oil (1 .70 g, crude) (contained some residual ethyl acetate and dimethylformamide, and was used without further purification).
Step 2: 2-amino- 1 J4-[3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl]- 1-piperidyl]ethanone.
Figure imgf000278_0003
To a stirred solution of tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]-2-oxo-ethyl]carbamate (800 mg, 1 .79 mmol) in ethyl acetate (5.00 mL) was added a 4M hydrochloric acid in ethyl acetate (1 5.00 mL). The mixture was then stirred at 25 °C fori h, and then concentrated under vacuum to give 2-amino-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyljethanone hydrochloride (660 mg, crude), isolated as a white solid and used for the next step without further purification.
Step 3: Preparation of N-[2-[4-[3-(3, 4-dimethoxyphenyl) - 1,2, 4-oxadiazol-5-yl]- 1 -piperidyl]-2-oxo- ethyljpiperidine- 1 -carboxamide.
Figure imgf000279_0001
To a stirred solution of 2-amino-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyljethanone (200 mg, 522 mitioI) and piperidine-1 -carbonyl chloride (77 mg, 522 mitioI, 65 pL) in dichloromethane (3.00 mL) was added triethylamine (158 mg, 1 .57 mmol, 217 pL) at 25 °C. The mixture was then stirred at 25 °C for 5 h. The reaction mixture was poured into 5mL water and extracted with dichloromethane (5 mL x 3). The combined organic extracts were concentrated under vacuum, dissolved in N,N-dimethylformamide (3 mL)and purified by chromatography (Boston Green ODS 150x30
5pm;mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-70%,1 1 5min to give N- [2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]piperidine-1 -carboxamide (1 13 mg, 248 pmol, 48 %) isolated as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.68 (dd, J=1 .8, 8.3 Hz, 1 H), 7.56 (d, J=1 .8 Hz, 1 H), 6.95 (d, J= 8.8 Hz, 1 H), 5.57 (br s, 1 H), 4.46 (br d, J=13.6 Hz,
1 H), 4.1 0 (d, J=3.5 Hz, 2H), 3.95 (d, J= 7.5 Hz, 6H), 3.86 (br d, J=14.0 Hz, 1 H), 3.40 - 3.35 (m, 4H), 3.32 - 3.23 (m, 2H), 3.08 (br t, J=1 1 .0 Hz, 1 H), 2.25 - 2.1 5 (m, 2H), 2.03 - 1 .88 (m, 2H), 1 .62 - 1 .51 (m, 6H); LCMS (ESI) m/z: [M+H]+ = 458.1 .
Example 144: N-[2-[4-[3-(3, 4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-2- methoxy-benzamide.
Figure imgf000279_0002
To a stirred solution of 2-amino-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyljethanone hydrochloride (200 mg, 522 pmol) and 2-methoxybenzoic acid (79 mg, 522 pmol) in dichloromethane (3.00 mL) was added 2,4,6-tripropyM ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (661 .8 mg,1 .04 mmol, 681 .51 mI_, 50% purity) and triethylamine (158 mg, 1 .57 mmol, 217 mI_) at 25 °C. The mixture was then stirred at 25 °C for 5 h. The reaction mixture was poured into water (5mL) and extracted with dichloromethane (5 mL x 3). The combined organic extracts were concentrated under vacuum. The resulting residue, dissolved in dimethylsulphoxide (3mL), was purified by chromatography (Boston Green ODS 150*30mm 5pm ;mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 42%-72%,1 1 .5 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]-2-methoxy-benzamide (83 mg, 169.3 mitioI, 32 %) isolated as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 9.01 (br s, 1 H), 8.21 (dd, J= 1 .8, 7.9 Hz, 1 H), 7.68 (dd, J=2.2, 8.3 Hz, 1 H), 7.56 (d, J=1 .8 Hz, 1 H), 7.49 - 7.43 (m, 1 H), 7.1 1 - 6.93 (m, 3H), 4.51 (br d, J=13.6 Hz, 1 H), 4.36 (d, J= 3.9 Hz, 2H), 4.04 (s, 3H), 3.95 (t, J= 7.9 Hz, 7H), 3.38 - 3.26 (m, 2H), 3.13 (br t, J=1 1 .0 Hz, 1 H), 2.28 - 2.17 (d, 2H), 2.07 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 481 .1 .
Example 145: N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo- ethyl]pyridine-2-carboxamide.
Figure imgf000280_0001
To a stirred solution of 2-amino-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyljethanone (200 mg, 522 pmol,1 .00 eg, HCI) and pyridine-2-carboxylic acid (64 mg, 522 mitioI) in dichloromethane (3.00 ml_) was added 2,4,6-tripropyM ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (661 .81 mg,1 .04 mmol, 681 .51 mI_, 50% purity, 2eq) and triethylamine (158 mg, 1 .57 mmol, 217 mI_) at 25 °C, then the mixture was stirred at 25 °C for 5 h. The reaction mixture was poured into water (5mL) and extracted with dichloromethane (5 ml_ x 3). The combined organic extracts were concentrated under vacuum. The resulting residue, dissolved in dimethylsulphoxide (3mL), was purified by prep-HPLC (Boston Green ODS 150x30mm 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,1 1 .5 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]pyridine-2-carboxamide (85 mg, 182.18 mitioI, 35 %) isolated as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 8.91 (br s, 1 H), 8.61 (d, J=3.9 Hz, 1 H), 8.17 (d, J=7.9 Hz, 1 H), 7.84 (dt, J=1 .8, 7.7 Hz, 1 H), 7.68 (dd, J=1 .8, 8.3 Hz, 1 H), 7.56 (d, J=1 .8 Hz, 1 H), 7.46 - 7.40 (dd, 1 H), 6.95 (d, J= 8.3 Hz, 1 H), 4.53 (br d, J=13.6 Hz, 1 H), 4.33 (d, J=4.4 Hz, 2H), 3.95 (d, J= 7.9 Hz, 6H), 3.91 (br s, 1 H), 3.39 - 3.26 (m, 2H), 3.12 (br t, J=1 1 .0 Hz, 1 H), 2.29 - 2.1 8 (t, 2H), 2.07 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 452.1 .
Example 146: 2-[2-[4-[3-(1 ,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]- 2-oxo-ethyl]isoindolin-1-one.
Figure imgf000280_0002
Example 146 was synthesized according to the synthetic procedure reported for the preparation of Example 147. 1 H NMR (400MHz, CHLOROFORM-d) d = 8.1 1 (d, J=8.4 Hz, 1 H), 7.89 (d, J=8.2 Hz,
1 H), 7.85 (d, J=8.2 Hz, 1 H), 7.56 - 7.50 (m, 1 H), 7.47 - 7.41 (m, 2H), 4.60 - 4.41 (m, 5H), 4.16 (s, 3H), 4.12 - 4.05 (m, 1 H), 3.41 - 3.31 (m, 2H), 3.06 - 2.98 (m, 1 H), 2.62 - 2.57 (m, 3H), 2.25 (br t, J=14.6 Hz, 2H), 2.05 - 1 .94 (m, 2H); LCMS(ESI) m/z: [M+H]+:472.3.
Figure imgf000281_0001
A mixture of 2-(1 -oxoisoindolin-2-yl)acetic acid (3.0 g, 15.69 mmol), methyl piperidine-4- carboxylate (2.47 g, 17.26 mmol), 2,4,6-tripropyM ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (12.98 g, 20.40 mmol, 12.13 ml_, 50% purity) and triethylamine (31 .76 g, 313.80 mmol, 43.51 ml_) in dichloromethane (60 ml_), was stirred at 20 °C for 16 h. The reaction mixture was then diluted with water (20 ml_) and extracted with dichloromethane (60 ml_). The organic layers were combined, washed with saturated aqueous sodium chloride solution (30 ml_ x 2), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give the crude product further purified by chromatography (silica, petroleum ether / ethyl acetate=1 :2). The title compound methyl 1 -[2-(1 - oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylate was isolated as a yellow solid (4.30 g, 13.6 mmol,
87 %).
Figure imgf000281_0002
A mixture of methyl 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylate (4.30 g, 13.59 mmol), Lithium hydroxide monohydrate (1 M, 13.59 mL) in tetrahydrofuran (50 mL) was stirred at 20 °C for 1 h, and then acidified to pH 3 by addition of a 1 M aqueous hydrochloric acid solution. The mixture was extracted with dichloromethane 20 mL. The organic layers were combined, washed with saturated aqueous sodium chloride solution (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid (2.50 g, 8.27 mmol, 60.85 %) isolated as a white solid, and used for the next step without further purification.
Step 3: 2-[2-[4-[3-(5-ethoxy-4-methoxy-2-pyridyt)- 1 ,2, 4-oxadiazol-5-yl]- 1 -piperidyl]-2-oxo-ethyl]isoindolin- 1-one.
Figure imgf000282_0001
A mixture of 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid (150 mg, 496 pmol), 5- ethoxy-N'-hydroxy-4-methoxy-pyridine-2-carboxamidine (125 mg, 595 pmol), (2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (282 mg, 744 pmol) and N-ethyl-N-(propan-2- yl)propan-2-amine (192 mg, 1 .49 mmol, 259 mI_) in N,N-dimethylformamide (2 ml_) was stirred at 20 °C for 5 h, and at 1 10°C for 1 h. The mixture was then cooled to room temperature and concentrated under vacuum to give a residue purified by chromatography (Boston Green ODS 150x30 5pm; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 25%-45%,1 1 .5min). The title compound 2-[2-[4- [3-(5-ethoxy-4-methoxy-2-pyridyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]isoindolin-1 -one was isolated as a white solid (76 mg, 160 mitioI, 32 %) as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) d = 8.26 (s, 1 H), 7.88 - 7.82 (m, 1 H), 7.62 (s, 1 H), 7.56 - 7.52 (m, 1 H), 7.48 - 7.43 (m, 2H), 4.56 (d, J=9.3 Hz, 2H), 4.52 - 4.40 (m, 3H), 4.24 (q, J=7.1 Hz, 2H), 4.07 (br d, J=13.7 Hz, 1 H), 4.00 (s, 3H), 3.40 - 3.26 (m, 2H), 3.05 - 2.97 (m, 1 H), 2.27 - 2.16 (m, 2H), 2.07 - 1 .93 (m, 2H), 1 .50 (t, J=6.9 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 478.3.
Example 148: (R)-5-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-3- phenyloxazolidin-2-one.
Figure imgf000282_0002
To a stirred solution of (R)-2-oxo-3-phenyloxazolidine-5-carboxylic acid (100 mg, 482.67 pmol) in dichloromethane (2 ml_) was added 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 1 1 mg, 579 pmol), HOBt (78 mg, 579 pmol), triethylamine (146 mg, 1 .45 mmol, 200 pL) and 3-(4-ethoxy-3-methoxyphenyl)- 5-(piperidin-4-yl)-1 ,2,4-oxadiazole hydrochloride (164 mg, 482.67 pmol). The reaction mixture was stirred at 25 °C for 12 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Boston Green ODS 150x30 5pm; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 45%-75%,1 1 .5min) to give (R)-5-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carbonyl)-3-phenyloxazolidin-2-one (139 mg, 280 pmol, 58 %) as a pale yellow solid. 1 H NMR. (400MHz, CHLOROFORM-d) d 7 67 (d, J=8.3 Hz, 1 H), 7 59 - 7.55 (m, 3H), 7.40 (t, J=7.7 Hz, 2H), 7 17 (t, J=6.9 Hz, 1 H), 6.95 (dd, J=1 .1 , 8.6 Hz, 1 H), 5.25 (ddd, J=3 1 , 6.2, 9.1 Hz, 1 H), 4.81 (dd, J=6 8, 8 6 Hz, 1 H), 4.58 (br d, J=14.0 Hz, 0.5H), 4.37 - 4.21 (m, 1 H), 4.17 (q, J=7.0 Hz, 2H), 4.07 (dt, J= 2.6, 9.0 Hz, 1 5H), 3.96 (d, J=2.2 Hz, 3H), 3.59 (ddd, J= 3.3, 10.3, 14.0 Hz, 0.5H), 3 41 - 3.17 (m, 2H), 3.09 - 3.00 (m, 0.5H), 2.34 - 1 .95 (m, 4H), 1 .54 - 1 .47 (m, 3H) ; LCMS (ESI) m/z: [M+H]+ = 493 3.
Figure imgf000283_0001
Step 1: Preparation of benzyl phenylcarbamate.
Figure imgf000283_0002
To a stirred solution of aniline (5.0 g, 53.69 mmol, 4.90 ml_) in tetrahydrofuran (100 ml_) at 0 °C was added saturated aqueous sodium hydrogen carbonate (4.96 g, 59.06 mmol, 2.30 ml_) followed by benzyl chloroformate (10.07 g, 59.06 mmol, 8.39 ml_). The reaction mixture was stirred for 0.25h at 0 °C, warmed to 25 °C and stirring was continued for 0.75 h at 25 °C. The reaction mixture was quenched with water (50 ml_) and extracted with ethyl acetate (3 X 50 ml_). The combined organic extracts were dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide benzyl phenylcarbamate (12.98 g, 53.7 mmol, 100 %) isolated as a white solid, and used for the next step without further purification 1 H NMR (400MHz, DMSO-de) d 9.76 (s, 1 H), 7.53 - 7.23 (m, 9H), 6.99 (t, J=7.1 Hz, 1 H), 5.15 (s, 2H).
Step 2: Preparation of (S)-5-(hydroxymethyl)-3-phenyloxazolidin-2-one.
O
G Ko
4¾ OH
A solution of benzyl phenylcarbamate (3.0 g, 13.20 mmol) in dry tetrahydrofuran (30 ml_) was cooled to -78 °C under dry nitrogen atmosphere. A solution of n-butyl lithium in tetrahydrofuran (2.5 M, 7.92 ml_) was slowly added to the reaction mixture which was stirred for 0.75h at -78 °C. A solution of (S)-oxiran-2-ylmethyl butyrate (2.28 g, 15.84 mmol) in dry tetrahydrofuran (1 0 ml_) was slowly added to the mixture which was stirred at -78 °C for 2 h and then slowly warmed to 25 °C. Stirring was continued for 12h at room temperature and the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (30 ml_). Ethyl acetate (30 ml_) and water (30 ml_) were added to the mixture and the layers were separated. The aqueous layer was further extracted with ethyl acetate (3 X30 ml_). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 ml_), dried over anhydrous anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :1 ). The title compound (S)-5-(hydroxymethyl)-3-phenyloxazolidin-2-one was isolated as a white solid (1 .70 g, 8.80 mmol, 67 %). 1 H NMR (400MHz, METHANOL-d4) d 7.57 (d, J= 7.8 Hz, 2H), 7.43 - 7.31 (m, 2H), 7 14 (t,
J= 7.2 Hz, 1 H), 4.78 - 4.71 (m, 1 H), 4.13 (t, J= 9.0 Hz, 1 H), 3 94 (dd, J=6.6, 8.8 Hz, 1 H), 3 85 (dd, J=3.4, 12.5 Hz, 1 H), 3.70 (dd, J=4.2, 12.6 Hz, 1 H).
Step 3: Preparation of (S)-2-oxo-3-phenyloxazolidine-5-carboxylic acid.
Figure imgf000284_0001
To an ice-cooled solution of NalC (3.88 g, 18.13 mmol, 1 .01 ml_) in water (30 ml_) was added a solution of (S)-5-(hydroxymethyl)-3-phenyloxazolidin-2-one (1 .0 g, 5.1 8 mmol) in a mixture of acetonitrile (20 ml_) and carbon tetrachloride (20 ml_). Solid RUCI3.H2O (58 mg, 259 pmol) was added to the reaction mixture which was stirred at 0 °C for 0.5 h, warmed to 25 °C and then stirred at 25 °C for an additional 12 h. The suspension was then filtered and the filtered solid was washed thoroughly with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure to provide a residue further dissolved in ethyl acetate (50mL). The organic solution was washed with saturated aqueous sodium carbonate (2 X 20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 X 30 mL). The combined organic phases were dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (850 mg) crude. 500 mg of this crude product was purified by prep-HPLC (column: Luna C18 1 50x25mm 5pm ; mobile phase: [water (0.225%FA)-acetonitrile]; B%: 30%-50%,12min) to give 1 50 mg of (S)-2-oxo-3-phenyloxazolidine-5-carboxylic acid as an off-white solid. 1 H NMR (400MHz, GHLOROFORM-d) d 7.57 - 7.45 (m, 2H), 7.44 - 7.34 (m, 2H), 7 24 - 7.1 0 (m, 1 H), 5.12 (dd, J= 5.3, 9.8 Hz, 1 H), 4.37 (t, J= 9.6 Hz, 1 H), 4 19 (dd, J= 5.3, 9.4 Hz, 1 H)
Step 4: Preparation of (S)-5-(4-(3-(1 ,3-dimethyl- 1 H-indazol-6-yl)- 1 ,2,4-oxadiazol-5-yl)piperidine- 1 - carbonyl)-3-phenyloxazolidin-2-one.
Figure imgf000284_0002
To a stirred solution of (S)-2-oxo-3-phenyloxazolidine-5-carboxylic acid (80 mg, 386 pmol) in hydroxybenzotriazole (62 mg, 463 pmol), triethylamine (1 17 mg, 1 .1 6 mmol, 160 pL) and 3-(1 ,3-dimethyl- 1 H-indazol-6-yl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole, hydrochloride (128 mg, 386 mitioI, hydrochloric acid). The reaction mixture was stirred at 25 °C for 12 h and was then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Boston Green ODS 1 50x30 5miti; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 43%-73%,1 1 5min) to give (S)-5-(4-(3-(1 ,3-dimethyl-1 H- indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-3-phenyloxazolidin-2-one (82 mg, 168.7 mitioI,
44 %) isolated as a white solid. 1 H NMR (40GMHz, CHLOROFORM-d) d 8 1 1 (d, J= 7.9 Hz, 1 H), 7 84 (d, J=8.8 Hz, 1 H), 7.74 (dd, J=3.5, 8.3 Hz, 1 H), 7.58 (d, J=8.3 Hz, 2H), 7.41 (t, J= 7.7 Hz, 2H), 7.20 - 7.16 (m, 1 H), 5.26 (dd, J-7.5, 8 3 Hz, 1 H), 4.83 (dd, J=6.4, 9 0 Hz, 1 H), 4.66 - 4 57 (m, 0.5H), 4.38 - 4 27 (m, 1 H), 4 09 (d, J= 3.1 Hz, 4.5H), 3.66 - 3 59 (m, 0.5H), 3.45 - 3 32 (m, 2H), 3.08 (br t, J=1 1 .2 Hz, 0.5H), 2.60 (s, 3H), 2.39 - 2.25 (m, 2H), 2.24 - 1 .97 (m, 2H); LCMS (ESI) m/z: [M+H]÷ = 487.3.
Example 150: N-[2-[4-[3-(1,3-dimethyUndazol-6-yl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-4- methoxy-pyridine-2-carboxamide.
Figure imgf000285_0001
To a stirred solution of 2-amino-1 -[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazoi-5-yl]-1 - piperidyl]ethanone (130 mg, 366.81 pmoi) in dichloromethane (3 mL) was added 4-methoxypyridine-2- carboxyiie acid (56 g, 366.81 pmol), 2,4,6-tripropyi-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethy! acetate (256 mg, 403 mitioI, 239 m!_, 50% purity) and triethyiamine (1 1 1 mg, 1 .10 mmol, 152 mI_).
The mixture was stirred at 20 °C for 1 h and then concentrated under reduced pressure. The resulting residue was purified by chromatography (column: Luna C18 100x30 5pm ; mobile phase: [water (10mM ammonium carbonate)-acetonitrilej; B%: 20%-60%,10min) to give N-[2-[4-[3-(1 ,3-dimethylindazoi-6-yl)- 1 ,2,4-oxad!azol-5-y!]-1 -piperidyl]-2-oxo-ethyi]-4-methoxy-pyridine-2-carboxamide (18 mg, 35 mitioI, 10 %) as a white solid. Ή NMR (400 MHz, GDGte) d 8.93 (br s, 1 H), 8.41 (d, J=5.5 Hz, 1 H), 8.10 (s, 1 H), 7.86 - 7.80 (m, 1 H), 7 77 - 7.69 (m, 2H), 6.93 (dd, J=2 4, 5.5 Hz, 1 H), 4.56 (br d, J=14.1 Hz, 1 H), 4.34 (d, J=4.4 Hz, 2H), 4.08 (s, 3H), 3.96 (br d, J=13.9 Hz, 1 H), 3.92 (s, 3H), 3.41 - 3.31 (m, 2H), 3.14 (br t, J=1 1 .6 Hz,
1 H), 2.60 (s, 3H), 2.33 - 2.22 (m, 2H), 2 1 1 - 1 .95 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 490.2.
Figure imgf000285_0002
Example 151 was synthesized according to a procedure similar to the one described in Example 154. 1 H NMR (400 MHz, CDCh) d 8.72 (br s, 1 H), 8.27 (d, J= 2.6 Hz, 1 H), 8.13 (d, J= 8.6 Hz, 1 H), 8.09 (s, 1 H), 7.85 - 7.79 (m, 1 H), 7.77 - 7.68 (m, 1 H), 7.29 (d, J= 2.6 Hz, 1 H), 4.55 (br d, J=13.7 Hz, 1 H), 4.33 (d, J=4.2 Hz, 2H), 4.08 (s, 3H), 3.96 (br d, J=13.9 Hz, 1 H), 3.91 (s, 3H), 3.40 - 3.30 (m, 2H), 3.13 (br t, J= 10.9 Hz, 1 H), 2.60 (s, 3H), 2.27 (br t, J= 1 1 .8 Hz, 2H), 2.09 - 1 .95 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 490.2.
Figure imgf000286_0001
Example 152 was synthesized according to a procedure similar to the one described in Example 154. 1 H NMR (400 MHz, CDCh) d 9.03 (br s, 1 H), 8.22 (dd, J=1 .4, 7.8 Hz, 1 H), 8.10 (s, 1 H), 7.87 - 7.80 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.51 - 7.43 (m, 1 H), 7.09 (t, J= 7.6 Hz, 1 H), 7.01 (d, J= 8.2 Hz, 1 H), 4.55 (br d, J=13.9 Hz, 1 H), 4.38 (d, J= 4.0 Hz, 2H), 4.08 (s, 3H), 4.05 (s, 3H), 3.96 (br d, J=14.1 Hz, 1 H), 3.41 - 3.31
(m, 2H), 3.15 (br t, J=1 1 .4 Hz, 1 H), 2.60 (s, 3H), 2.28 (br t, J=10.6 Hz, 2H), 2.10 - 1 .96 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 489.3.
Example 153: N-(2-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)picolinamide.
Figure imgf000286_0002
Example 153 was synthesized according to a procedure similar to the one described in Example 154. 1 H NMR (400 MHz, CDCL) d 8.93 (br s, 1 H), 8.63 (d, J= 4.0 Hz, 1 H), 8.19 (d, J= 7.7 Hz, 1 H), 8.10 (s, 1 H), 7.89 - 7.80 (m, 2H), 7.76 - 7.71 (m, 1 H), 7.47 - 7.41 (m, 1 H), 4.56 (br d, J= 13.7 Hz, 1 H), 4.35 (d, J=4.4 Hz, 2H), 4.09 (s, 3H), 3.96 (br d, J= 13.9 Hz, 1 H), 3.44 - 3.31 (m, 2H), 3.15 (br t, J=10.7 Hz, 1 H),
2.60 (s, 3H), 2.34 - 2.23 (m, 2H), 2.1 1 - 1 .95 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 460.2.
Figure imgf000287_0001
Step 1: Preparation of tert-butyl N-[2-[4-[3J 1 ,3-dimethylindazol-6-yl)- 1 , 2, 4-oxadiazol-5-yl]- 1 -piperidyt]-2- oxo-ethyl]carbamate.
Figure imgf000287_0002
To a stirred solution of 3-(1 ,3-dimethylindazol-6-yl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (1 .0 g, 3.00 mmol, 1 .00 eg, hydrochloric acid salt) in dichloromethane (20 ml_) was added 2-(tert- butoxycarbonylamino)acetic acid (525 mg, 3.00 mmol), 2,4,6-tripropyM ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (2.86 g, 4.50 mmol, 2.68 ml_, 50% purity) and triethylamine (1 .82 g, 18.00 mmol, 2.49 ml_, 6.00 eg). The mixture was stirred at 20 °C for 16 h. Water (30 ml_) was then added to the reaction mixture which was extracted with dichloromethane (60 ml_ x 3). The combined organic extracts were washed with saturated aqueous sodium chloride (30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product further purified by chromatography (silica, petroleum ether : ethyl acetate = 20:1 to 1 :4). The title compound (tert-butyl N-[2- [4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]carbamate) was isolated as a white solid (1 .0 g, 2.20 mmol, 73 %). 1 H NMR (400 MHz, CDCIs) d 8.1 0 (s, 1 H), 7.86 - 7.80 (m, 1 H), 7.77 - 7.72 (m, 1 H), 5.53 (br s, 1 H), 4.50 (br d, J=12.3 Hz, 1 H), 4.09 (s, 3H), 4.02 (br d, J= 3.5 Hz, 2H), 3.83 (br d, J=12.7 Hz, 1 H), 3.38 - 3.23 (m, 2H), 3.10 (br t, J=1 1 .6 Hz, 1 H), 2.60 (s, 3H), 2.23 (br s, 2H), 2.06 - 1 .94 (m, 2H), 1 .47 (s, 9H).
Step 2: Preparation of 2-amino- 1-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-ylJ 1- piperidyljethanone.
Figure imgf000287_0003
To a stirred solution of tert-butyl N-[2-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]-2-oxo-ethyl]carbamate (980 mg, 2.16 mmol) in ethyl acetate (5 ml_) was added a 4M solution of hydrochloric acid in ethyl acetate (50 ml_). The mixture was stirred at 20 °C for 0.5 h and then concentrated under reduced pressure to give 2-amino-1 -[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol- 5-yl]-1 -piperidyl]ethanone, hydrochloride (940 mg, crude)) isolated as a white solid and used for the next step without further purification. 1 H NMR (400 MHz, Methanoi-d4) d 8.19 (s, 1 H), 7.83 (d, J= 0.9 Hz, 2H), 4.48 (br d, J=13.9 Hz, 1 H), 4.06 (s, 3H), 4.04 - 3.95 (m, 2H), 3.86 (br d, J=13.9 Hz, 1 H), 3.53 - 3.43 (m,
1 H), 3.38 (br t, J=1 1 .5 Hz, 1 H), 3.13 (br t, J=1 1 .2 Hz, 1 H), 2.58 (s, 3H), 2.28 (br t, J= 9.3 Hz, 2H), 2.01 - 1 .84 (m, 2H).
Step 3: Preparation of N-[2-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1 ,2,4-oxadiazol-5-yl]- 1 -piperidyl]-2-oxo-ethyl]- 6-methoxy-pyridine-2-carboxamide.
Figure imgf000288_0001
To a stirred solution of 2-amino-1 -[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyljethanone (130 mg, 366.81 mitioI) in N,N-dimethylformamide (2 ml_) was added 6- methoxypyridine-2-carboxylic acid (56 mg, 366.81 mitioI), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (166 mg, 440 mitioI) and N-ethyl-N-(propan-2-yl)propan-2- amine (142 mg, 1 .10 mmol, 192 mI_). The mixture was stirred at 20 °C for 1 h and concentrated under reduced pressure. The resulting residue was purified by chromatography (column: Luna C18 100x30 5pm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-65%,10min) to give N- [2-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]-6-methoxy-pyridine-2- carboxamide (92 mg, 187.6 mitioI, 51 %) as a white solid. 1 H NMR (400 MHz, CDCI3) d 8.82 (br s, 1 H),
8.10 (s, 1 H), 7.86 - 7.69 (m, 4H), 6.92 (d, J= 8.2 Hz, 1 H), 4.55 (br d, J=13.9 Hz, 1 H), 4.34 (d, J= 4.2 Hz, 2H), 4.08 (s, 3H), 4.05 (s, 3H), 4.01 - 3.92 (m, 1 H), 3.43 - 3.32 (m, 2H), 3.17 (br t, J=1 1 .1 Hz, 1 H), 2.60 (s, 3H), 2.34 - 2.23 (m, 2H), 2.12 - 1 .97 (m, 2H); LCMS (ESI) m/z: [M+H]+ = 490.3.
Figure imgf000288_0002
Step 1: Preparation of 4-ethoxy-3-methoxy-benzonitriie.
Figure imgf000289_0001
To a 0 °C stirred solution of 4-hydroxy-3-methoxy-benzonitrile (20g, 134.09 mmol) in N,N- dimethylformamide (200 ml_) was added iodoethane (25.1 0 g, 160.91 mmol, 12.87 ml_), potassium carbonate (37.07 g, 268.18 mmol). The reaction mixture was stirred at 40 °C for 16 h and then quenched by addition of water (300 ml_). The mixture was extracted with ethyl acetate (200mL x 3) and the combined organic extracts were washed with saturated aqueous sodium chloride solution (100 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-ethoxy-3- methoxy-benzonitrile (25.0 g, crude), isolated as a yellow solid and used for the next step without further purification. 1 H NMR (400 MHz, CDC ) d 7.30 - 7.20 (m, 1 H), 7.07 (d, J=1 .8 Hz, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 4.14 (q, J= 7.0 Hz, 2H), 3.88 (s, 3H), 1 .49 (t, J= 7.0 Hz, 3H).
Figure imgf000289_0002
To a stirred solution of 4-ethoxy-3-methoxy-benzonitrile (25.0 g, 141 .08 mmol) in ethanol (200 ml_) was added hydroxylamine hydrochloride (19.61 g, 282.17 mmol), triethylamine (28.55 g, 282.17 mmol, 39.1 1 ml_) and water (20 ml_). The mixture was stirred at 80 °C for 2 h and then concentrated under reduced pressure. The resulting residue was diluted with water (30 ml_) and filtered to provide 4- ethoxy-N'-hydroxy-3-methoxy-benzamidine isolated as a white solid (24.0 g, 1 14.2 mmol, 81 %) and used for the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) d 9.47 (br s, 1 H), 7.25 (d, J-2.0 Hz, 1 H), 7.20 (dd, J= 2.0, 8.4 Hz, 1 H), 6.92 (d, J=8.4 Hz, 1 H), 5.75 (br s, 2H), 4.01 (q, J= 7.0 Hz,
2H), 3.76 (s, 3H), 1 .32 (t, J= 7.0 Hz, 3H).
Step 3: Preparation of tert-butyi 4-[3-(4-ethoxy-3-methoxy-phenyi)- 1,2,4-oxadiazol-5-yl]piperidine- 1- carboxylate.
Figure imgf000289_0003
To a stirred solution of 4-ethoxy-N'-hydroxy-3-methoxy-benzamidine (10.0 g, 47.57 mol) in N,N- dimethy!formamide (100 mL) was added 1 -tert-butoxycarbony!piperidine-4-carboxy!ic acid (1 0.91 g, 47.57 m ol), 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (18.04 g, 47.57 m ol) and N-bίί^!-N-^or3h-2·^!)r^r3h-2-3h'Ήhb (18.44 g, 142.71 mmol, 24.92 mL). The mixture was stirred at 20 °C for 16 h and at 1 10 °C for 1 h. The reaction mixture was then cooled to room temperature, quenched by addition of water (100 mL) and extracted with ethy! acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product further was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 10:1 ) The title compound, tert-butyl 4-[3- (4-ethoxy-3-methoxy-phenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carboxylate, was isolated as a yellow solid (13.30 g, 33 0 mmol, 69 %).
Figure imgf000290_0001
To a stirred solution of tert-butyl 4-[3-(4-ethoxy-3-methoxy-phenyl)-1 ,2,4-oxadlazoi-5-yl]piperidine- 1 -earboxy!ate (13.30 g, 32.96 mmol) in ethyl acetate (300 mL) was added a 4M solution of hydrochloric acid in methanol (30 mL). The mixture was stirred at 20 °C for 2 h and filtered to give 3-(4-ethoxy-3- methoxy-phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole hydrochloride (10.0 g, 29.4 mmol, 89 %), isolated as a white solid and used for the next step without further purification.
Step 5: Preparation of N-[2-[4-[3-(4-ethoxy-3-methoxy-phenyi)- 1,2,4-oxadiazol-5-ylJ 1-piperidyl]-2-oxo- ethyljbenzamide.
Figure imgf000290_0002
To a stirred solution of 2-benzamidoacetic acid (1 .16 g, 6.48 mmol) in dichloromethane (20 ml_) was added 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole hydrochloride (2.0 g, 5.89 mmol), 2,4,6-tripropyM ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (4.87 g, 7.65 mmol, 4.55 ml_, 50% in ethyl acetate) and triethylamine (2.38 g, 23.5 mmol, 3.26 ml_). The mixture was stirred at 20 °C for 16 h. Water (20 ml_) was then added to the mixture which was extracted with dichloromethane (80 ml_ x 2). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue dissolved in with ethyl acetate (40 ml_). The organic solution was washed with 1 N aqueous hydrochloric acid solution (15 mL x 2), saturated sodium carbonate (15 ml_ x 2), saturated aqueous sodium chloride solution (15 ml_ x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. To a solution of the crude product in methyl tert-butyl ether (20 mL) was added petroleum ether (2 mL). The precipitate, formed after 2 h stirring at room temperature, was collected by filtration, washed with methyl tert-butyl ether (5 mL x 2) and dried under reduced pressure to give N-[2-[4-[3-(4-ethoxy-3-methoxy- phenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (1 .68 g, 3.60 mmol, 61 %) as a white solid. Ή NMR (400 MHz, CDC ) d 7.89 - 7.83 (m, 2H), 7.66 (dd, J=1 .9, 8.3 Hz, 1 H), 7.58 - 7.42 (m, 4H), 7.35 (br s, 1 H), 6.95 (d, J=8.4 Hz, 1 H), 4.50 (td, J=3.8, 13.6 Hz, 1 H), 4.30 (d, J= 4.0 Hz, 2H), 4.17 (q,
J=7.0 Hz, 2H), 3.96 (s, 3H), 3.94 - 3.87 (m, 1 H), 3.38 - 3.27 (m, 2H), 3.19 - 3.08 (m, 1 H), 2.24 (m, 2H), 2.07 - 1 .91 (m, 2H), 1 .50 (t, J= 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H]+ = 465.2. Example 156. Characterization Data of Compounds of the Invention
The following compounds were synthesized by methods similar to those described above.
Figure imgf000291_0001
1 H NMR (400 MHz, DMSO-de) d 8.10-7.71 (m, 5H), 7.65-7.30 (m, 7H), 4.87 (br s, 2H), 4.26 (s, 2H), 3.69 (br s, 2H), 1 .23 (br s, 3H); LCMS (ESI) [M+H]+: 372.1 .
Figure imgf000291_0002
1 H NMR (400 MHz, DMSO-de) d 8.07-8.00 (m, 1 H), 7.99-7.91 (m, 1 H), 7.86 (d, J = 6.2 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.58-7.52 (m, 3H), 7.49 (br s, 2H), 7.20 (d, J = 8.4 Hz, 1 H), 4.92 (br s, 2H), 4.32 (s, 2H), 3.91 (d, J = 6.2 Hz, 6H), 3.74 (br s, 2H), 1 .28 (br s, 3H); LCMS (ESI) [M+H]+: 432.1 .
Figure imgf000291_0003
1 H NMR (400 MHz, DMSO-de) d 7.71 -7.59 (m, 1 H), 7.33 (br d, J = 8.6 Hz, 1 H), 7.1 8 (d, J = 8.4 Hz, 1 H), 6.89 (br d, J = 8.6 Hz, 2H), 4.76 (s, 2H), 4.06-3.91 (m, 2H), 3.74 (s, 3H), 1 .60-1 .49 (m, 2H), 1 .34 (br d, J = 2.2 Hz, 2H), 1 .16 (br t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 392.2.
Figure imgf000291_0004
1 H NMR (400 MHz, DMSO-de) d 7.73-7.63 (m, 2H), 7.44-7.39 (m, 2H), 7.37-7.25 (m, 3H), 7.21 -7.15 (m,
1 H), 4.84-4.69 (s, 2H), 4.05-3.91 (m, 2H), 1 .62-1 .54 (m, 2H), 1 .43-1 .36 (m, 2H), 1 .16 (s, 3H); LCMS (ESI) [M+H]+: 362.2.
Figure imgf000292_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.71 (dd, J = 1 .8, 8.3 Hz, 1 H), 7.63 (d, J = 1 .9 Hz, 1 H), 7.37- 7.31 (m, 2H), 7.27 (t, J = 7.5 Hz, 2H), 7.22-7.16 (m, 2H), 7.00 (d, J = 8.3 Hz, 1 H), 4.60 (s, 2H), 4.28 (q, J = 7.2 Hz, 1 H), 3.99 (q, J = 7.1 Hz, 2H), 1 .69 (d, J = 7.2 Hz, 3H), 1 .25 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 350.2.
Figure imgf000292_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09-8.1 1 (m, 2H), 7.51 -7.53 (m, 5H), 7.25-7.40 (m, 3H), 1 .72- 1 .74 (t, 2H), 1 .43-1 .46 (t, 2H); LCMS (ESI) [M+H]+: 263.1 .
Figure imgf000292_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 9.06 (br s, 1 H), 7.88-7.80 (m, 3H), 7.69 (s, 1 H), 7.53-7.44 (m, 3H), 7.40-7.30 (m, 1 H), 7.1 8-7.16 (d, J = 8.4 Hz, 1 H), 4.54-4.50 (m, 1 H), 4.33-4.32 (d, J = 4.0 Hz, 2H), 3.95-3.91 (m, 1 H), 3.49 (s, 3H), 3.39-3.13 (m, 1 H), 2.30-2.23 (m, 2H), 2.05-1 .98 (m, 2H); LCMS (ESI) [M+H]+: 461 .1 .
Figure imgf000292_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.64 (t, J = 1 .1 Hz, 1 H), 8.1 1 (dd, J = 1 .2, 9.4 Hz, 1 H), 7.96 (dd, J = 1 .0, 9.4 Hz, 1 H), 7.87-7.81 (m, 2H), 7.54-7.48 (m, 1 H), 7.47-7.41 (m, 2H), 7.31 (br s, 1 H), 4.57-4.48 (m, 1 H), 4.30 (d, J = 3.7 Hz, 2H), 3.92 (br d, J = 14.1 Hz, 1 H), 3.41 -3.31 (m, 2H), 3.20-3.09 (m, 1 H), 2.27 (dt, J = 3.7, 13.2 Hz, 2H), 2.00 (ddq, J = 4.1 , 1 0.6, 14.4 Hz, 2H); LCMS (ESI) [M+H]+: 433.1 .
Figure imgf000293_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.63 (s, 1 H), 8.10 (d, J = 9.3 Hz, 1 H), 7.95 (d, J = 9.3 Hz, 1 H), 7.57 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.18-7.12 (m, 1 H), 4.63-4.43 (m, 1 H), 4.30 (br t, J = 7.9 Hz, 1 H), 4.06-3.87 (m, 2H), 3.57 (quin, J = 8.6 Hz, 1 H), 3.45-3.28 (m, 2H), 3.1 7-2.75 (m, 3H), 2.36-2.20 (m, 2H), 2.07-1 .89 (m, 2H); LCMS (ESI) [M+H]+: 459.2.
Figure imgf000293_0002
1 H NMR (400 MHz, METHANOL-cU) d 8.14 (s, 1 H), 7.77-7.70 (m, 3H), 7.62-7.47 (m, 2H), 7.51 -7.46 (m, 1 H), 4.64-4.42 (m, 5H), 4.09-4.01 (m, 1 H), 4.01 (s, 3H), 3.48-3.37 (m, 2H), 3.06 (br t, J = 1 1 .0 Hz, 1 H), 2.53 (s, 3H), 2.32-2.18 (m, 2H), 2.07-1 .84 (m, 2H); LCMS (ESI) [M+H]+: 471 .3.
Figure imgf000293_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.18 (s, 1 H), 7.85 (d, J = 7.0 Hz, 2H), 7.54-7.42 (m, 3H), 7.32 (br s, 1 H), 4.51 (br d, J = 13.6 Hz, 1 H), 4.29 (t, J = 4.8 Hz, 2H), 4.26-4.17 (m, 5H), 3.90 (br d, J = 14.0 Hz, 1 H), 3.42-3.28 (m, 2H), 3.1 0 (br t, J = 1 1 .0 Hz, 1 H), 2.33-2.22 (m, 2H), 2.13-1 .95 (m, 2H), 1 .52 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 467.3.
Figure imgf000293_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.68 (dd, J = 1 .8, 8.3 Hz, 1 H), 7.56 (d, J = 1 .8 Hz, 1 H), 7.36- 7.27 (m, 3H), 7.24-7.20 (m, 1 H), 6.95 (d, J = 8.3 Hz, 1 H), 4.76-4.53 (m, 1 H), 3.86-3.93 (m, 1 H), 3.94-3.96 (d, J = 8.3 Hz, 6H), 3.34-3.14 (m, 2H), 3.34-3.1 1 (m, 1 H), 2.93 (quin, J = 7.0 Hz, 1 H), 2.97-2.89 (m, 1 H), 2.34-1 .88 (m, 4H), 1 .26 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 436.2.
Figure imgf000294_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (d, J = 3.1 Hz, 1H), 8.01-7.88 (m, 2H), 7.87-7.80 (m, 1H), 7.78-7.71 (m, 1 H), 7.53-7.42 (m, 2H), 4.63-4.49 (m, 1 H), 4.34 (dd, J = 7.1 , 8.8 Hz, 1 H), 4.09 (d, J = 2.6 Hz, 3H), 4.04-3.92 (m, 2H), 3.63 (quin, J = 8.2 Hz, 1H), 3.48-3.34 (m, 2H), 3.21-2.85 (m, 3H), 2.61 (s, 3H), 2.30 (br t, J = 14.3 Hz, 2H), 2.11-1.94 (m, 2H); LCMS (ESI) [M+H]+: 510.0.
Figure imgf000294_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.69 (br s, 1 H), 8.32 (dd, J = 1.5, 4.2 Hz, 1 H), 8.10 (s, 1 H), 7.86- 7.80 (m, 1 H), 7.77-7.71 (m, 1 H), 7.45-7.36 (m, 2H), 4.54 (br d, J = 13.9 Hz, 1 H), 4.37 (br d, J = 3.5 Hz, 2H), 4.09 (s, 3H), 4.00 (s, 3H), 3.96 (br s, 1H), 3.41-3.31 (m, 2H), 3.14 (br t, J = 11.1 Hz, 1H), 2.60 (s,
3H), 2.33-2.22 (m, 2H), 2.11 -1.94 (m, 2H); LCMS (ESI) [M+H]+: 490.2.
Figure imgf000294_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (brd, J = 7.1 Hz, 1H), 7.87-7.79 (m, 1H), 7.78-7.63 (m, 3H), 7.56-7.48 (m, 1 H), 7.46-7.38 (m, 1 H), 4.56 (br t, J = 13.6 Hz, 1 H), 4.32-4.22 (m, 1 H), 4.17-3.96 (m, 5H), 3.74 (quin, J = 8.2 Hz, 1H), 3.48-3.31 (m, 2H), 3.20-3.04 (m, 1H), 3.01-2.84 (m, 2H), 2.60 (s, 3H), 2.36- 2.21 (m, 2H), 2.10- 1.93 (m, 2H); LCMS (ESI) [M+H]+: 510.3.
Figure imgf000294_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.05 (s, 1 H), 7.87-7.78 (m, 4H), 7.54-7.42 (m, 2H),
7.35 (br s, 1H), 5.00-4.91 (spt, J = 6.8 Hz, 1H), 4.52-4.50 (brd, J = 13.7 Hz, 1H), 4.35-4.27 (d, J = 3.7 Hz, 2H), 3.94-3.91 (br d, J = 13.9 Hz, 1 H), 3.38-3.32 (m, 2H), 3.18-3.12 (br t, J = 1 1 .0 Hz, 1 H), 2.35-2.21 (m, 2H), 2.09-1 .96 (m, 2H), 1 .63-1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 473.2.
Figure imgf000295_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.67 (br d, J = 8.2 Hz, 1 H), 7.60-7.55 (m, 3H), 7.40 (t, J = 7.7 Hz, 2H), 7.18 (t, J = 6.9 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 5.28-5.22 (m, 1 H), 4.84-4.79 (m, 1 H), 4.59 (br d, J = 13.5 Hz, 0.5H), 4.36-4.22 (m, 1 H), 4.1 8 (q, J = 7.1 Hz, 2H), 4.13-4.03 (m, 1 .5H), 3.97 (d, J = 2.2 Hz, 3H), 3.64-3.54 (m, 0.5H), 3.41 -3.27 (m, 2H), 3.09-3.01 (m, 0.5H), 2.35-2.15 (m, 2.5H), 2.1 1 -1 .93 (m,
1 5H), 1 .51 (t, J = 6.8 Hz, 3H); LCMS (ESI) [M+H]+: 492.8.
Figure imgf000295_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (d, J = 7.5 Hz, 1 H), 7.84 (dd, J = 1 .3, 8.3 Hz, 1 H), 7.74 (dd, J = 3.9, 8.3 Hz, 1 H), 7.58 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1 H), 5.26 (t, J = 7.7 Hz, 1 H), 4.83 (dd, J = 6.6, 8.8 Hz, 1 H), 4.62 (d, J = 13.6 Hz, 0.5H), 4.38-4.26 (m, 1 H), 4.13-4.05 (m, 4.5H), 3.66-3.58 (m, 0.5H), 3.45-3.31 (m, 2H), 3.1 1 -3.04 (m, 0.5H), 2.60 (s, 3H), 2.40-2.25 (m, 2H), 2.24- 1 .96 (m, 2H); LCMS (ESI) [M+H]+: 487.3.
Figure imgf000295_0003
1 H NMR (400 MHz, DMSO-de) d 8.28 (s, 1 H), 8.1 7 (s, 1 H), 7.92-7.90 (d, J = 8.4 Hz, 1 H), 7.75-7.73 (d, J = 8.4 Hz, 1 H), 7.66-7.64 (br d, J = 8.2 Hz, 2H), 7.38-7.33 (dt, J = 3.7, 7.8 Hz, 2H), 7.13-7.1 1 (m, 1 H), 5.15- 5.1 1 (dt, J = 3.5, 6.5 Hz, 1 H), 4.39-4.35 (br d, J = 13.2 Hz, 1 H), 4.06-3.93 (m, 3H), 3.78-3.70 (m, 1 H), 3.50-3.45 (br t, J = 10.7 Hz, 1 H), 3.36-3.33 (m, 1 H), 2.98-2.93 (m, 1 H), 2.81 -2.71 (m, 2H), 2.20-2.13 (br t, J = 14.0 Hz, 2H), 1 .89-1 .65 (m, 2H), 1 .49-1 .48 (d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 499.2.
Figure imgf000296_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.69-7.62 (m, 2H), 7.55 (d, J = 1 .8 Hz, 1 H), 7.45 (dt, J = 4.6, 7.7 Hz, 1 H), 7.27-7.24 (m, 1 H), 7.27-7.19 (m, 1 H), 6.94 (d, J = 8.6 Hz, 1 H), 4.63 (d, J = 2.9 Hz, 2H), 4.55-4.39 (m, 3H), 4.16 (q, J = 6.9 Hz, 2H), 4.02 (br d, J = 13.7 Hz, 1 H), 3.95 (s, 3H), 3.43-3.23 (m, 2H), 3.06 (br t, J = 10.9 Hz, 1 H), 2.29-2.15 (m, 2H), 2.08-1 .88 (m, 2H), 1 .50 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 495.1 .
Figure imgf000296_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.85 (dd, J = 5.3, 8.4 Hz, 1 H), 7.65 (dd, J = 1 .8, 8.4 Hz, 1 H), 7.56 (d, J = 1 .8 Hz, 1 H), 7.20-7.13 (m, 2H), 6.95 (d, J = 8.4 Hz, 1 H), 4.57 (d, J = 3.7 Hz, 2H), 4.51 -4.41 (m, 3H), 4.18 (q, J = 7.0 Hz, 2H), 4.05 (br d, J = 13.9 Hz, 1 H), 3.96 (s, 3H), 3.42-3.24 (m, 2H), 3.07 (br t, J = 1 0.9 Hz, 1 H), 2.29-2.15 (m, 2H), 2.07-1 .89 (m, 2H), 1 .51 (t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 495.1 .
Figure imgf000296_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.53 (dd, J = 2.0, 8.4 Hz, 1 H), 7.46-7.39 (m, 2H), 7.30 (dd, J = 4.4, 8.2 Hz, 1 H), 7.18-7.10 (m, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 4.52-4.27 (m, 5H), 4.05 (q, J = 7.0 Hz, 2H), 3.92 (br d, J = 13.7 Hz, 1 H), 3.84 (s, 3H), 3.32-3.10 (m, 2H), 2.94 (br t, J = 10.8 Hz, 1 H), 2.1 0 (br t, J =
15.0 Hz, 2H), 1 .95-1 .76 (m, 2H), 1 .39 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 495.1 .
Figure imgf000296_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.66 (dd, J = 2.0, 8.4 Hz, 1 H), 7.58-7.49 (m, 2H), 7.24 (d, J = 7.5 Hz, 1 H), 7.10 (t, J = 8.8 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 4.59 (d, J = 5.1 Hz, 2H), 4.53-4.38 (m, 3H), 4.17 (q, J = 6.9 Hz, 2H), 4.07 (br d, J = 13.9 Hz, 1 H), 3.96 (s, 3H), 3.45-3.22 (m, 2H), 3.12-3.02 (m, 1 H), 2.22 (br dd, J = 14.2, 18.2 Hz, 2H), 2.09-1 .88 (m, 2H), 1 .51 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 495.3.
Figure imgf000297_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.56 (dd, J = 2.3, 7.2 Hz, 1 H), 8.13-8.02 (m, 2H), 7.86-7.79 (m, 1 H), 7.77-7.71 (m, 1 H), 7.1 7 (d, J = 8.6 Hz, 1 H), 4.64-4.47 (m, 1 H), 4.32 (ddd, J = 3.3, 6.6, 9.5 Hz, 1 H), 4.08 (d, J = 2.2 Hz, 3H), 4.04-3.91 (m, 2H), 3.63 (quin, J = 8.3 Hz, 1 H), 3.46-3.32 (m, 2H), 3.19-3.04 (m, 1 H), 3.01 -2.81 (m, 2H), 2.60 (s, 3H), 2.54 (s, 3H), 2.28 (br t, J = 13.3 Hz, 2H), 2.1 1 -1 .95 (m, 2H); LCMS (ESI) [M+H]+: 500.3.
Figure imgf000297_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.51 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 2H), 7.59-7.57 (br d, J = 8.2 Hz, 2H), 7.38-7.34 (t, J = 7.9 Hz, 2H), 7.17-7.13 (m, 1 H), 4.85-4.77 (m, 1 H), 4.50-4.42 (br t, J = 14.9 Hz,
1 H), 4.33-4.23 (m, 1 H), 4.01 -3.89 (m, 2H), 3.62-3.54 (quin, J = 8.5 Hz, 1 H), 3.45-3.27 (m, 2H), 3.22-2.90 (m, 2H), 2.87-2.75 (m, 1 H), 2.31 -2.17 (m, 2H), 2.07-1 .91 (m, 2H), 1 .67-1 .66 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 499.3.
Figure imgf000297_0003
1 H NMR (400 MHz, DMSO-de) d 8.57-8.52 (m, 2H), 8.27 (s, 1 H), 7.88-7.84 (t, J = 7.6 Hz, 3H), 7.62-7.60 (dd, J = 1 .2, 8.7 Hz, 1 H), 7.55-7.43 (m, 3H), 4.92-4.82 (spt, J = 6.7 Hz, 1 H), 4.34-4.31 (br d, J = 13.5 Hz,
1 H), 4.1 8-4.1 6 (d, J = 5.5 Hz, 2H), 4.00-3.96 (br d, J = 13.9 Hz, 1 H), 3.50-3.43 (m, 1 H), 3.29-3.25 (m, 1 H), 2.95-2.90 (br t, J = 1 1 .2 Hz, 1 H), 2.18-2.12 (br t, J = 12.3 Hz, 2H), 1 .88-1 .80 (q, J = 1 0.6 Hz, 1 H), 1 .73- 1 .63 (m, 1 H), 1 .60-1 .55 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 473.3.
Figure imgf000298_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.63 (t, J = 1 .1 Hz, 1 H), 8.1 1 (dd, J = 1 .3, 9.3 Hz, 1 H), 7.96 (dd, J = 1 .0, 9.4 Hz, 1 H), 7.88-7.83 (m, 1 H), 7.59-7.53 (m, 1 H), 7.50-7.43 (m, 2H), 4.58 (s, 2H), 4.53-4.43 (m, 3H), 4.1 1 (br d, J = 14.1 Hz, 1 H), 3.45-3.28 (m, 2H), 3.12-3.01 (m, 1 H), 2.25 (br t, J = 14.1 Hz, 2H), 2.07- 1 .87 (m, 2H); LCMS (ESI) [M+H]+: 445.2.
Figure imgf000298_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.44 (br d, J = 5.5 Hz, 1 H), 8.09 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.71 (m, 1 H), 7.50 (br s, 1 H), 7.40 (br d, J = 5.3 Hz, 1 H), 4.64-4.48 (m, 1 H), 4.29 (dd, J = 6.9, 9.6 Hz, 1 H), 4.08 (s, 3H), 4.04-3.90 (m, 2H), 3.61 (quin, J = 8.4 Hz, 1 H), 3.40 (br d, J = 10.8 Hz, 2H), 3.21 -3.04 (m, 1 H), 3.02-2.82 (m, 2H), 2.60 (s, 3H), 2.56 (s, 3H), 2.29 (br t, J = 14.7 Hz, 2H), 2.1 1 -1 .96 (m, 2H); LCMS (ESI) [M+H]+: 500.2.
Figure imgf000298_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.27 (br dd, J = 4.7, 8.3 Hz, 1 H), 8.1 5 (br s, 1 H), 8.10 (br s, 1 H), 7.86-7.79 (m, 1 H), 7.78-7.71 (m, 1 H), 7.52 (br d, J = 8.4 Hz, 1 H), 4.57 (br t, J = 12.7 Hz, 1 H), 4.41 (dd, J = 9.0, 1 0.8 Hz, 1 H), 4.22-4.14 (m, 1 H), 4.09 (s, 3H), 4.04 (br d, J = 14.1 Hz, 1 H), 3.57 (quin, J = 8.2 Hz,
1 H), 3.47-3.32 (m, 2H), 3.25 (br dd, J = 7.7, 17.2 Hz, 1 H), 3.16-3.04 (m, 1 H), 2.86-2.76 (m, 1 H), 2.60 (s, 3H), 2.36-2.21 (m, 5H), 2.12-1 .93 (m, 2H); LCMS (ESI) [M+H]+: 500.3.
Figure imgf000298_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.85-7.80 (m, 2H), 7.66 (br t, J = 8.8 Hz, 1 H), 7.58-7.49 (m, 3H), 7.47-7.41 (m, 2H), 6.94 (t, J = 7.9 Hz, 1 H), 5.1 8 (br d, J = 2.6 Hz, 1 H), 4.54-4.38 (m, 1 H), 4.18 (br t, J = 14.0 Hz, 1 H), 3.97-3.92 (m, 7H), 3.89-3.83 (m, 1 H), 3.46-3.36 (m, 1 H), 3.34-3.23 (m, 1 H), 3.19-3.03 (m,
1 H), 2.23 (br s, 2H), 2.1 1 -1 .92 (m, 2H); LCMS (ESI) [M+H]+: 481 .3.
Figure imgf000299_0001
1 H NMR (400 MHz, METHANOL-d4) d 8.14 (br d, J = 1 1 .0 Hz, 1 H), 7.89-7.84 (m, 2H), 7.77 (br d, J = 7.0 Hz, 2H), 7.55-7.43 (m, 3H), 5.23 (t, J = 6.1 Hz, 1 H), 4.58-4.45 (m, 1 H), 4.28 (br t, J = 14.9 Hz, 1 H), 4.02 (br d, J = 5.3 Hz, 3H), 3.93-3.82 (m, 2H), 3.54-3.40 (m, 2H), 3.16-3.03 (m, 1 H), 2.54 (s, 3H), 2.34-2.18 (m, 2H), 2.08-1 .86 (m, 2H); LCMS (ESI) [M+H]+: 489.3.
Figure imgf000299_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.86 (d, J = 7.1 Hz, 2H), 7.58-7.42 (m, 3H), 7.35 (br s, 1 H), 7.23 (d, J = 2.2 Hz, 2H), 6.61 (t, J = 2.2 Hz, 1 H), 4.50 (br d, J = 13.7 Hz, 1 H), 4.31 (d, J = 4.0 Hz, 2H), 3.91 (br d, J = 14.3 Hz, 1 H), 3.86 (s, 6H), 3.39-3.29 (m, 2H), 3.1 5 (br t, J = 10.7 Hz, 1 H), 2.30-2.20 (m, 2H), 2.08- 1 .93 (m, 2H); LCMS (ESI) [M+H]+: 451 .3.
Figure imgf000299_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (d, J = 4.9 Hz, 1 H), 7.87-7.80 (m, 1 H), 7.79-7.72 (m, 1 H), 7.57 (br dd, J = 4.6, 8.6 Hz, 2H), 7.08 (t, J = 8.6 Hz, 2H), 4.65-4.48 (m, 1 H), 4.36-4.29 (m, 1 H), 4.09 (d, J = 3.3 Hz, 3H), 4.05-3.87 (m, 2H), 3.60 (quin, J = 8.3 Hz, 1 H), 3.48-3.32 (m, 2H), 3.20-3.03 (m, 1 H), 3.01 - 2.82 (m, 2H), 2.61 (s, 3H), 2.29 (br t, J = 13.7 Hz, 2H), 2.10-1 .94 (m, 2H); LCMS (ESI) [M+H]+: 503.3.
Figure imgf000300_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.34 (d, J = 0.9 Hz, 1 H), 7.93 (d, J = 1 .1 Hz, 1 H), 7.83-7.75 (m, 4H), 7.49-7.35 (m, 3H), 7.27 (br s, 1 H), 4.52-4.43 (m, 1 H), 4.25 (dd, J = 2.4, 3.7 Hz, 2H), 4.02 (br d, J = 6.4 Hz, 2H), 3.91 -3.81 (m, 2H), 3.34-3.24 (m, 2H), 3.1 1 -3.02 (m, 1 H), 2.21 (dt, J = 3.4, 13.2 Hz, 2H), 2.05- 1 .87 (m, 2H), 1 .69 (s, 6H); LCMS (ESI) [M+H]+: 503.2.
Figure imgf000300_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.83-7.78 (m, 2H), 7.67 (br t, J = 8.6 Hz, 1 H), 7.58-7.47 (m, 2H), 7.46-7.40 (m, 2H), 7.16 (br d, J = 6.6 Hz, 1 H), 6.97-6.90 (m, 1 H), 5.09-4.96 (m, 1 H), 4.59-4.38 (m, 1 H), 4.23-4.06 (m, 1 H), 3.99-3.91 (m, 6H), 3.49-3.25 (m, 2H), 3.21 -3.04 (m, 1 H), 2.34-2.13 (m, 2H), 2.10-1 .90 (m, 2H), 1 .25 (br d, J = 5.7 Hz, 1 H), 0.74-0.43 (m, 4H); LCMS (ESI) [M+H]+: 491 .0.
Figure imgf000300_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.08 (br d, J = 6.6 Hz, 1 H), 7.85-7.77 (m, 3H), 7.75-7.67 (m,
1 H), 7.53-7.46 (m, 1 H), 7.45-7.40 (m, 2H), 7.18 (br s, 1 H), 5.09-4.96 (m, 1 H), 4.59-4.43 (m, 1 H), 4.23- 4.10 (m, 1 H), 4.06 (br d, J = 5.3 Hz, 3H), 3.52-3.30 (m, 2H), 3.21 -3.05 (m, 1 H), 2.58 (d, J = 2.2 Hz, 3H), 2.37-2.19 (m, 2H), 2.13-1 .97 (m, 1 H), 2.13-1 .97 (m, 1 H), 1 .27 (br s, 1 H), 0.63-0.43 (m, 4H); LCMS (ESI) [M+H]+: 499.3.
Figure imgf000300_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.04 (d, J = 5.7 Hz, 2H), 7.88-7.78 (m, 4H), 7.55-7.40 (m, 3H), 7.33 (br s, 1 H), 4.51 (br d, J = 13.7 Hz, 1 H), 4.30 (d, J = 3.7 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.90 (br d, J = 14.1 Hz, 1 H), 3.39-3.28 (m, 2H), 3.12 (br t, J = 1 1 .1 Hz, 1 H), 2.32-2.17 (m, 2H), 1 .99 (s, 8H), 1 .15 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 545.2.
Figure imgf000301_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.53 (s, 1 H), 8.12 (s, 1 H), 7.76-7.71 (m, 2H), 7.58 (br d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1 H), 4.51 -4.37 (m, 1 H), 4.28 (q, J = 8.3 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2H), 4.01 -3.89 (m, 2H), 3.57 (quin, J = 8.4 Hz, 1 H), 3.45-3.28 (m, 2H), 3.23-3.09 (m, 1 H), 3.02-2.91 (m, 1 H), 2.86-2.76 (m, 1 H), 2.31 -2.1 6 (m, 2H), 2.00 (s, 8H), 1 .17 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 571 .2.
Figure imgf000301_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.55 (s, 1 H), 8.15 (s, 1 H), 7.86 (d, J = 7.1 Hz, 2H), 7.76 (s, 2H), 7.56-7.42 (m, 3H), 7.36 (br s, 1 H), 4.45 (br d, J = 13.7 Hz, 1 H), 4.32 (br s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.91 (br d, J = 14.1 Hz, 1 H), 3.42-3.29 (m, 2H), 3.22 (br t, J = 10.6 Hz, 1 H), 2.26 (br t, J = 10.8 Hz, 2H), 2.10-1 .94 (m, 8H),1 .20 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 545.2.
Figure imgf000301_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.44-8.31 (m, 2H), 8.1 1 (s, 1 H), 7.87-7.81 (m, 1 H), 7.78-7.66 (m, 2H), 7.06 (br s, 1 H), 4.64-4.52 (m, 1 H), 4.44 (dd, J = 9.0, 1 1 .0 Hz, 1 H), 4.25-4.17 (m, 1 H), 4.09 (s, 3H), 4.04 (br d, J = 13.0 Hz, 1 H), 3.58 (quin, J = 8.2 Hz, 1 H), 3.48-3.32 (m, 2H), 3.27 (dd, J = 7.7, 17.4 Hz, 1 H), 3.17-3.05 (m, 1 H), 2.88-2.78 (m, 1 H), 2.61 (s, 3H), 2.36-2.22 (m, 2H), 2.14-1 .94 (m, 2H); LCMS (ESI) [M+H]+: 486.3.
Figure imgf000302_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.08-8.02 (m, 2H), 7.88-7.79 (m, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.19-7.12 (m, 1 H), 4.60-4.47 (m, 1 H), 4.36-4.26 (m, 1 H), 4.20 (br dd, J = 3.4, 6.9 Hz, 2H), 3.94 (q, J = 9.3 Hz, 2H), 3.58 (quin, J = 8.4 Hz, 1 H), 3.43-3.27 (m, 2H), 3.16-2.89 (m, 2H), 2.88- 2.79 (m, 1 H), 2.25 (br t, J = 12.8 Hz, 2H), 1 .99 (s, 8H), 1 .18-1 .10 (m, 3H); LCMS (ESI) [M+H]+: 571 .2.
Figure imgf000302_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 9.09 (d, J = 1 .6 Hz, 1 H), 8.76 (dd, J = 1 .6, 4.9 Hz, 1 H), 8.16 (td, J = 2.0, 8.0 Hz, 1 H), 8.1 0 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.71 (m, 1 H), 7.46-7.37 (m, 2H), 4.58-4.48 (m,
1 H), 4.33 (d, J = 3.9 Hz, 2H), 4.08 (s, 3H), 3.93 (br d, J = 13.8 Hz, 1 H), 3.44-3.33 (m, 2H), 3.23-3.13 (m,
1 H), 2.60 (s, 3H), 2.36-2.24 (m, 2H), 2.13-1 .97 (m, 2H); LCMS (ESI) [M+H]+: 460.2.
Figure imgf000302_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.81 -8.76 (m, 2H), 8.09 (s, 1 H), 7.86-7.80 (m, 1 H), 7.77-7.67 (m, 3H), 7.48 (br s, 1 H), 4.58-4.48 (m, 1 H), 4.31 (d, J = 3.9 Hz, 2H), 4.08 (s, 3H), 3.92 (br d, J = 14.1 Hz, 1 H), 3.38 (ddd, J = 3.4, 1 0.6, 14.0 Hz, 2H), 3.23-3.13 (m, 1 H), 2.60 (s, 3H), 2.36-2.24 (m, 2H), 2.12-1 .96 (m, 2H); LCMS (ESI) [M+H]+: 460.3.
Figure imgf000302_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.89-7.83 (m, 2H), 7.67 (dd, J = 1 .9, 8.3 Hz, 1 H), 7.60-7.42 (m, 4H), 7.35 (br s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.55-4.46 (m, 1 H), 4.31 (d, J = 3.9 Hz, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.94 (s, 3H), 3.93-3.87 (m, 1 H), 3.40-3.27 (m, 2H), 3.20-3.09 (m, 1 H), 2.25 (dt, J = 3.9, 12.8 Hz, 2H), 2.08-1 .92 (m, 2H), 1 .51 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 465.3.
Figure imgf000303_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 9.16 (br d, J = 1 .8 Hz, 1 H), 8.33 (d, J = 1 .5 Hz, 1 H), 7.82 (br d, J = 7.5 Hz, 1 H), 7.55-7.48 (m, 1 H), 7.45-7.39 (m, 2H), 4.54 (s, 2H), 4.49-4.41 (m, 3H), 4.05 (s, 4H), 3.41 - 3.24 (m, 2H), 3.03 (br t, J = 1 1 .8 Hz, 1 H), 2.65 (s, 3H), 2.22 (br t, J = 15.8 Hz, 2H), 2.07-1 .86 (m, 4H); LCMS (ESI) [M+H]+: 472.1 .
Figure imgf000303_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.48 (s, 1 H), 8.08 (s, 1 H), 7.74 (s, 2H), 7.58 (d, J = 7.7 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.18-7.1 1 (m, 1 H), 4.53-4.40 (m, 1 H), 4.33-4.24 (m, 1 H), 4.00-3.89 (m, 4H), 3.57 (quin, J = 8.4 Hz, 1 H), 3.44-3.28 (m, 2H), 3.20-3.06 (m, 1 H), 3.03-2.90 (m, 1 H), 2.86-2.77 (m, 1 H), 2.30- 2.18 (m, 2H), 2.07-1 .88 (m, 3H), 1 .71 (s, 6H); LCMS (ESI) [M+H]+: 529.3.
Figure imgf000303_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.50 (d, J = 0.9 Hz, 1 H), 8.10 (d, J = 0.7 Hz, 1 H), 7.86 (d, J =
7.3 Hz, 2H), 7.77 (s, 2H), 7.56-7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.36 (br s, 1 H), 4.47 (br d, J = 13.5 Hz,
1 H), 4.31 (d, J = 2.6 Hz, 2H), 4.06 (br s, 1 H), 3.99-3.87 (m, 3H), 3.43-3.31 (m, 2H), 3.21 (br t, J = 10.7 Hz, 1 H), 2.33-2.21 (m, 2H), 2.1 1 -1 .94 (m, 2H), 1 .73 (s, 6H); LCMS (ESI) [M+H]+: 503.3.
Figure imgf000303_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.39 (s, 1 H), 7.99 (s, 1 H), 7.88-7.79 (m, 1 H), 7.88-7.79 (m, 1 H),
7.58 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.19-7.12 (m, 1 H), 4.64-4.49 (m, 1 H), 4.36-4.27 (m, 1 H), 4.07 (br s, 2H), 4.02-3.85 (m, 3H), 3.57 (quin, J = 8.5 Hz, 1 H), 3.43-3.29 (m, 2H), 3.16-2.89 (m, 2H), 2.88- 2.78 (m, 1 H), 2.34-2.19 (m, 2H), 2.05-1 .96 (m, 2H), 1 .74 (d, J = 2.0 Hz, 6H); LCMS (ESI) [M+H]+: 529.3.
Figure imgf000304_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 8.01 (s, 1 H), 7.87-7.78 (m, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.24 (s, 1 H), 4.64 (br s, 1 H), 4.14 (s, 3H), 4.09-3.71 (m, 1 H), 3.37-3.27 (m, 1 H), 3.20 (br s, 2H), 2.97- 2.87 (m, 1 H), 2.28-1 .96 (m, 4H), 1 .24 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 430.0.
Figure imgf000304_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 8.01 (d, J = 0.7 Hz, 1 H), 7.87-7.78 (m, 2H), 7.34- 7.26 (m, 3H), 7.21 (br d, J = 7.3 Hz, 1 H), 4.66 (br s, 1 H), 4.14 (s, 3H), 3.97-3.78 (m, 1 H), 3.36-3.12 (m, 3H), 2.96-2.87 (m, 1 H), 2.32-1 .90 (m, 4H), 1 .25 (d, J = 7.1 Hz, 6H); LCMS (ESI) [M+H]+: 430.0.
Figure imgf000304_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (br d, J = 4.9 Hz, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.72 (m,
1 H), 7.49 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.64-4.51 (m, 1 H), 4.30 (br s, 1 H), 4.09 (d, J = 3.5 Hz, 3H), 3.99 (br s, 1 H), 3.91 (br t, J = 8.8 Hz, 1 H), 3.81 (s, 3H), 3.59 (quin, J = 8.2 Hz, 1 H), 3.47-3.31 (m, 2H), 3.1 9-3.03 (m, 1 H), 3.00-2.79 (m, 2H), 2.61 (s, 3H), 2.34-2.23 (m, 2H), 2.01 (br d, J = 10.8 Hz, 2H); LCMS (ESI) [M+H]+: 515.3.
Figure imgf000304_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1 H), 7.84 (d, J = 7.1 Hz, 2H), 7.79-7.66 (m, 2H), 7.55- 7.41 (m, 3H), 7.22 (br s, 1 H), 4.29-4.13 (m, 2H), 4.06 (s, 3H), 4.04-3.96 (m, 2H), 3.96-3.84 (m, 2H), 3.69- 3.56 (m, 3H), 3.50 (dd, J = 5.1 , 10.8 Hz, 1 H), 3.31 -3.22 (m, 1 H), 3.20-3.1 1 (m, 1 H), 2.59 (s, 3H); LCMS (ESI) [M+H]+: 486.3.
Figure imgf000305_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.79 (d, J = 4.8 Hz, 1 H), 8.16 (s, 1 H), 8.05-7.99 (m, 3H), 7.87- 7.80 (m, 2H), 7.75 (s, 1 H), 7.52-7.44 (m, 3H), 7.25 (d, J = 4.8 Hz, 1 H), 4.67 (br d, J = 1 1 .4 Hz, 1 H), 4.16 (s, 3H), 3.83 (br d, J = 14.0 Hz, 1 H), 3.41 -3.21 (m, 3H), 2.34 (br s, 1 H), 2.22-1 .97 (m, 3H); LCMS (ESI) [M+H]+: 465.0.
Figure imgf000305_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12-8.08 (m, 1 H), 7.89-7.80 (m, 3H), 7.77-7.72 (m, 1 H), 7.56- 7.42 (m, 3H), 7.25 (br d, J = 3.1 Hz, 1 H), 4.33-4.24 (m, 2H), 4.17-3.99 (m, 5H), 3.97-3.68 (m, 3H), 2.68- 2.38 (m, 5H); LCMS (ESI) [M+H]+: 445.2.
Figure imgf000305_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1 H), 7.79-7.74 (m, 1 H), 7.73-7.67 (m, 1 H), 7.46-7.30 (m, 5H), 4.71 -4.51 (m, 1 H), 4.44 (br d, J = 10.4 Hz, 1 H), 4.39-4.25 (m, 2H), 4.15 (br d, J = 1 1 .7 Hz, 1 H), 4.07 (s, 3H), 3.90-3.65 (m, 2H), 3.51 -3.1 7 (m, 3H), 2.98-2.70 (m, 2H), 2.59 (s, 3H), 2.1 1 -1 .79 (m, 4H) ; LCMS (ESI) [M+H]+: 487.3.
Figure imgf000305_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1 H), 7.79-7.73 (m, 1 H), 7.72-7.65 (m, 1 H), 7.47-7.30 (m, 5H), 4.71 -4.51 (m, 1 H), 4.44 (br d, J = 10.4 Hz, 1 H), 4.39-4.25 (m, 2H), 4.15 (br d, J = 1 1 .7 Hz, 1 H), 4.06 (s, 3H), 3.90-3.66 (m, 2H), 3.51 -3.1 7 (m, 3H), 2.98-2.71 (m, 2H), 2.59 (s, 3H), 2.1 1 -1 .79 (m, 4H) ; LCMS (ESI) [M+H]+: 487.3.
Figure imgf000306_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.01 (t, J = 1 .0 Hz, 1 H), 7.89-7.80 (m, 2H), 7.72 (dq, J = 1 .0, 8.6 Hz, 2H), 7.60-7.50 (m, 1 H), 7.50-7.43 (m, 2H), 6.98 (br s, 1 H), 4.52 (s, 4H), 4.49 (s, 2H), 4.34 (s, 2H),
4.08 (d, J = 4.6 Hz, 2H), 4.07 (s, 3H), 2.59 (s, 3H); LCMS (ESI) [M+H]+: 472.3.
Figure imgf000306_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.00 (s, 1 H), 7.91 (d, J = 0.9 Hz, 1 H), 7.59 (dd, J = 8.5, 12.0 Hz, 3H), 7.43-7.32 (m, 2H), 7.22-7.13 (m, 1 H), 6.85 (td, J = 1 .5, 8.6 Hz, 1 H), 4.71 -4.53 (m, 1 H), 4.27 (ddd, J = 6.8, 9.6, 18.8 Hz, 1 H), 4.03 (s, 3H), 4.00-3.91 (m, 2H), 3.57 (quin, J = 8.3 Hz, 1 H), 3.25- 3.1 1 (m, 1 H), 3.04-2.90 (m, 1 H), 2.87-2.76 (m, 2H), 2.57 (dt, J = 4.1 , 1 0.9 Hz, 1 H), 2.08-1 .94 (m, 2H),
1 .89-1 .80 (m, 1 H), 1 .89-1 .79 (m, 1 H); LCMS (ESI) [M+H]+: 446.1 .
Figure imgf000306_0003
1 H NMR (400 MHz, METHANOL-d4) d 7.93-7.70 (m, 4H), 7.55-7.35 (m, 3H), 7.25-7.10 (m, 1 H), 5.23-5.19 (t, J = 6.0 Hz, 1 H), 4.60-4.40 (m, 1 H), 4.30-4.1 5 (m, 1 H), 3.90-3.75 (m, 2H), 3.55-3.35 (m, 8H), 3.20-2.95 (m, 1 H), 2.30-2.10 (m, 2H), 2.10-1 .95 (m, 1 H), 1 .95-1 .75 (m, 1 H); LCMS (ESI) [M+H]+: 505.2.
Figure imgf000306_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.47 (s, 1 H), 7.84 (d, J = 7.3 Hz, 2H), 7.54-7.41 (m, 4H), 7.38 (s, 1 H), 7.26-7.22 (t, 2H), 4.53 (br d, J = 13.9 Hz, 1 H), 4.30 (t, J = 3.7 Hz, 2H), 3.91 (br d, J = 13.7 Hz, 1 H), 3.38-3.27 (m, 2H), 3.1 1 (br t, J = 1 1 .1 Hz, 1 H), 2.73 (s, 3H), 2.31 -2.19 (t, 2H), 2.07-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 445.2.
Figure imgf000307_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.42 (br d, J = 4.4 Hz, 1 H), 7.53 (br d, J = 8.2 Hz, 2H), 7.43 (d, J = 9.5 Hz, 1 H), 7.36-7.28 (dd, 3H), 7.20 (m, 1 H), 7.14-7.07 (t, 1 H), 4.59-4.43 (dd, 1 H), 4.31 -4.23 (m, 1 H), 3.98-3.82 (m, 2H), 3.52 (quin, J = 8.4 Hz, 1 H), 3.39-3.21 (m, 2H), 3.15-2.73 (m, 3H), 2.68 (d, J = 5.7 Hz, 3H), 2.27-2.13 (t, 2H), 1 .99-1 .81 (m, 2H); LCMS (ESI) [M+H]+: 471 .3.
Figure imgf000307_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.57 (br d, J = 8.3 Hz, 1 H), 7.49 (s, 1 H), 7.43-7.31 (m, 5H), 6.90 (d, J = 8.3 Hz, 1 H), 4.65 (br d, J = 13.6 Hz, 1 H), 4.53 (br d, J = 12.7 Hz, 1 H), 4.42 (br d, J = 10.5 Hz, 1 H), 4.34-4.21 (m, 2H), 4.14 (q, J = 7.0 Hz, 3H), 3.93 (s, 3H), 3.86-3.64 (m, 2H), 3.43 (br t, J = 1 1 .4 Hz, 1 H), 3.27-3.16 (m, 2H), 2.91 (br t, J = 1 1 .4 Hz, 1 H), 2.81 -2.67 (m, 2H), 2.07-1 .77 (m, 4H), 1 .48 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 493.0.
Figure imgf000307_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.57 (br d, J = 8.3 Hz, 1 H), 7.49 (s, 1 H), 7.43-7.32 (m, 5H), 6.90 (d, J = 8.3 Hz, 1 H), 4.66 (br d, J = 13.6 Hz, 0.5H), 4.54 (br d, J = 13.6 Hz, 0.5H), 4.42 (br d, J = 10.1 Hz,
1 H), 4.34-4.22 (m, 2H), 4.1 5 (q, J = 7.0 Hz, 3H), 3.93 (s, 3H), 3.87-3.65 (m, 2H), 3.44 (br t, J = 1 1 .6 Hz, 0.5H), 3.27-3.17 (m, 2H), 2.91 (br t, J = 1 1 .8 Hz, 0.5H), 2.81 -2.69 (m, 2H), 2.06-1 .78 (m, 4H), 1 .48 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 493.0.
Figure imgf000308_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.01 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.78-7.67 (m, 2H), 7.61- 7.55 (m, 1 H), 7.52-7.46 (m, 2H), 4.59 (s, 2H), 4.52 (s, 2H), 4.06 (s, 3H), 3.83-3.73 (m, 8H), 2.59 (s, 3H); LCMS (ESI) [M+H]+: 472.0.
Figure imgf000308_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.00 (br d, J = 7.5 Hz, 1 H), 7.95 (br s, 1 H), 7.59 (d, J = 7.9 Hz, 2H), 7.41-7.33 (m, 3H), 7.19-7.14 (m, 1H), 5.16 (s, 4H), 4.58-4.47 (m, 1H), 4.31 (dd, J = 7.2, 9.4 Hz, 1H), 4.00-3.89 (m, 2H), 3.62-3.55 (m, 1H), 3.44-3.28 (m, 2H), 3.18-2.92 (m, 2H), 2.87-2.80 (m, 1H), 2.32-2.18 (m, 2H), 2.06-1.90 (m, 2H); LCMS (ESI) [M+H]+: 459.2.
Figure imgf000308_0003
1H NMR (400 MHz, DMSO-de) d 8.75 (d, J = 5.3 Hz, 1 H), 8.57 (br t, J = 5.7 Hz, 1 H), 8.06-8.00 (m, 1 H), 7.96 (s, 1 H), 7.89 (d, J = 7.0 Hz, 2H), 7.58-7.52 (m, 1H), 7.52-7.44 (m, 2H), 7.29 (d, J = 5.3 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1 H), 4.51 (brd, J = 12.3 Hz, 1H), 4.27-4.12 (m, 2H), 4.06 (brd, J = 13.6 Hz, 1H), 3.84 (d, J = 4.4 Hz, 6H), 3.23 (br t, J = 12.1 Hz, 1H), 3.04 (br t, J = 11.8 Hz, 1H), 2.79 (br t, J = 12.1 Hz, 1H), 2.00 (br t, J = 12.1 Hz, 2H), 1.86-1.73 (m, 1H), 1.70-1.56 (m, 1H); LCMS (ESI) [M+H]+: 461.3.
Figure imgf000308_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1H), 7.95 (dd, J = 1.2, 2.8 Hz, 1H), 7.86-7.80 (m, 1H), 7.78-7.72 (m, 1 H), 7.46 (dd, J = 1.1 , 5.1 Hz, 1 H), 7.36 (dd, J = 3.1 , 5.1 Hz, 1 H), 7.15 (br s, 1 H), 4.53 (br d, J = 13.7 Hz, 1 H), 4.29 (d, J = 4.0 Hz, 2H), 4.09 (s, 3H), 3.93 (brd, J = 14.3 Hz, 1H), 3.42-3.32 (m, 2H), 3.16 (br t, J = 10.8 Hz, 1 H), 2.60 (s, 3H), 2.29 (br t, J = 10.9 Hz, 2H), 2.1 1 -1 .95 (m, 2H); LCMS (ESI) [M+H]+: 465.2.
Figure imgf000309_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.99 (d, J = 7.9 Hz, 1 H), 7.94 (s, 1 H), 7.86 (d, J = 8.3 Hz, 1 H), 7.57-7.52 (m, 1 H), 7.49-7.43 (m, 2H), 7.34 (d, J = 7.9 Hz, 1 H), 5.16 (s, 4H), 4.60-4.39 (m, 5H), 4.07 (br d, J = 14.0 Hz, 1 H), 3.43-3.24 (m, 2H), 3.07 (br t, J = 1 1 .2 Hz, 1 H), 2.21 (br t, J = 13.8 Hz, 2H), 2.03-1 .88 (m, 2H); LCMS (ESI) [M+H]+: 445.2.
Figure imgf000309_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.99 (d, J = 7.9 Hz, 1 H), 7.94 (s, 1 H), 7.85 (d, J = 7.0 Hz, 2H), 7.54-7.48 (m, 1 H), 7.48-7.42 (m, 2H), 7.35 (br d, J = 7.9 Hz, 2H), 5.16 (s, 4H), 4.49 (br d, J = 14.0 Hz,
1 H), 4.30 (d, J = 3.9 Hz, 2H), 3.90 (br d, J = 14.0 Hz, 1 H), 3.40-3.26 (m, 2H), 3.21 -3.13 (m, 1 H), 2.32-2.18 (m, 2H), 2.07-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 433.2.
Figure imgf000309_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.87 (d, J = 7.5 Hz, 1 H), 7.59-7.54 (m, 2H), 7.51 -7.45 (m, 3H), 6.91 (d, J = 8.4 Hz, 1 H), 4.58 (s, 2H), 4.51 (s, 2H), 4.1 5 (q, J = 6.9 Hz, 2H), 3.94 (s, 3H), 3.79-3.68 (m, 8H), 1 .49 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 478.2.
Figure imgf000309_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.70 (d, J = 4.6 Hz, 1 H), 8.23 (br s, 1 H), 8.10 (s, 1 H), 7.89-7.80 (m, 2H), 7.77-7.70 (m, 1 H), 4.55 (br d, J = 14.1 Hz, 1 H), 4.32 (d, J = 4.4 Hz, 2H), 4.09 (s, 3H), 3.93 (br d, J = 13.5 Hz, 1 H), 3.41 -3.32 (m, 2H), 3.15 (br t, J = 1 1 .4 Hz, 1 H), 2.60 (s, 3H), 2.34-2.22 (m, 2H), 2.12- 1 .95 (m, 2H); LCMS (ESI) [M+H]+: 466.2.
Figure imgf000310_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.88-7.81 (m, 3H), 7.78-7.72 (m, 1 H), 7.55-7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.35 (br s, 1 H), 4.42-4.31 (m, 2H), 4.28-4.19 (m, 1 H), 4.10 (s, 3H), 3.76 (br d, J = 14.3 Hz, 1 H), 3.46-3.36 (m, 1 H), 3.21 -3.1 1 (m, 1 H), 2.61 (s, 3H), 2.58-2.45 (m, 2H), 1 .84-1 .74 (m, 2H), 1 .61 (s, 3H); LCMS (ESI) [M+H]+: 473.3.
Figure imgf000310_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.49 (s, 1 H), 8.1 1 -8.04 (m, 2H), 7.87-7.83 (m, 2H), 7.54-7.49 (m, 2H), 7.47-7.42 (m, 2H), 7.35 (br s, 1 H), 4.88 (td, J = 6.7, 13.3 Hz, 1 H), 4.53-4.46 (m, 1 H), 4.31 (d, J = 3.7 Hz, 2H), 3.96-3.88 (m, 1 H), 3.40-3.28 (m, 2H), 3.22-3.12 (m, 1 H), 2.26 (dt, J = 3.6, 13.0 Hz, 2H), 2.09- 1 .93 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 473.3.
Figure imgf000310_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.45 (s, 1 H), 8.06 (s, 1 H), 7.95 (dd, J = 1 .3, 9.0 Hz, 1 H), 7.85 (d, J = 7.3 Hz, 2H), 7.79 (d, J = 9.0 Hz, 1 H), 7.54-7.49 (m, 1 H), 7.47-7.42 (m, 2H), 7.35 (br s, 1 H), 4.82 (quin, J = 6.7 Hz, 1 H), 4.49 (td, J = 4.0, 13.7 Hz, 1 H), 4.30 (d, J = 4.0 Hz, 2H), 3.95-3.87 (m, 1 H), 3.38-3.27 (m, 2H), 3.21 -3.13 (m, 1 H), 2.25 (dt, J = 3.7, 12.9 Hz, 2H), 2.07-1 .95 (m, 2H), 1 .68 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 473.2.
Figure imgf000310_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.93 (br s, 1 H), 8.64 (br d, J = 4.3 Hz, 1 H), 8.20 (d, J = 7.9 Hz, 1 H), 7.94-7.84 (m, 2H), 7.70 (s, 1H), 7.49-7.41 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 4.56 (brd, J = 13.6 Hz, 1 H), 4.36 (br d, J = 4.4 Hz, 2H), 3.97 (br d, J = 14.3 Hz, 1 H), 3.50 (d, J = 8.3 Hz, 6H), 3.43-3.32 (m, 2H), 3.16 (brt, J = 11.2 Hz, 1H), 2.27 (br t, J = 12.1 Hz, 2H), 2.11-1.91 (m, 2H); LCMS (ESI) [M+H]+: 476.3.
Figure imgf000311_0001
1HNMR (400 MHz, CHLOROFORM-d) d 7.60-7.54 (m, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.19-7.10 (m, 1H), 4.81 (s, 4H), 4.52-4.39 (m, 1H), 4.27 (dd, J = 7.3, 9.7 Hz, 1H), 4.20 (s, 4H), 3.95-3.84 (m, 2H), 3.53 (quin, J = 8.4 Hz, 1 H), 3.34-3.23 (m, 1 H), 3.15-2.87 (m, 3H), 2.84-2.75 (m, 1 H), 2.16-2.04 (m, 2H), 1.90-1.75 (m, 2H); LCMS (ESI) [M+H]+: 438.2.
Figure imgf000311_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.94 (br s, 1 H), 8.63 (br s, 1 H), 8.36-8.27 (m, 1 H), 8.19 (br d, J = 7.3 Hz, 1 H), 8.08 (br d, J = 7.9 Hz, 1 H), 7.90-7.81 (m, 1 H), 7.73 (br d, J = 7.7 Hz, 1 H), 7.52-7.40 (m,
1 H), 4.75 (br d, J = 12.1 Hz, 1H), 4.36 (brs, 2H), 4.10 (brs, 3H), 4.02 (brd, J = 12.6 Hz, 1H), 3.51 (brs, 1 H), 3.36 (br t, J = 11.2 Hz, 1H), 3.08-2.94 (m, 1H), 2.61 (brs, 3H), 2.32 (brd, J = 14.8 Hz, 2H), 1.96 (br d, J = 10.8 Hz, 2H); LCMS (ESI) [M+H]+: 476.2.
Figure imgf000311_0003
1H NMR (400 MHz, CHLOROFORM-d) d 9.10 (dd, J = 0.7, 2.3 Hz, 1H), 8.77 (dd, J = 1.7, 4.9 Hz, 1H), 8.17 (td, J = 2.0, 7.9 Hz, 1H), 7.89 (dd, J = 1.5, 8.2 Hz, 1H), 7.69 (d, J = 1.3 Hz, 1H), 7.42 (ddd, J = 0.8, 4.9, 7.9 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H), 4.53 (td, J = 3.8, 13.8 Hz, 1H), 4.33 (d, J = 3.9 Hz, 2H), 3.96- 3.89 (m, 1 H), 3.49 (d, J = 7.6 Hz, 6H), 3.42-3.32 (m, 2H), 3.18 (ddd, J = 3.1, 10.9, 13.6 Hz, 1H), 2.29 (dt, J = 3.8, 13.8 Hz, 2H), 2.12-1.95 (m, 2H); LCMS (ESI) [M+H]+: 476.2.
Figure imgf000312_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.67-7.58 (m, 1 H), 7.55-7.46 (m, 3H), 7.42-7.32 (m, 3H), 6.91 (br d, J = 8.4 Hz, 1 H), 4.57-4.39 (m, 1 H), 4.13 (q, J = 7.1 Hz, 2H), 4.05-3.97 (m, 1 H), 3.96-3.91 (m, 3H), 3.90-3.61 (m, 3H), 3.58-3.42 (m, 1 H), 3.39-3.1 8 (m, 3H), 3.08-2.91 (m, 1 H), 2.34-1 .82 (m, 6H), 1 .47 (t, J =
6.9 Hz, 3H); LCMS (ESI) [M+H]+: 505.3.
Figure imgf000312_0002
Ή NMR (400 MHz, CHLOROFORM-d) d 7.63 (br s, 1 H), 7.54 (br s, 1 H), 7.45-7.39 (m, 2H), 7.38-7.34 (m, 2H), 7.32-7.27 (m, 1 H), 6.93 (br d, J = 8.4 Hz, 1 H), 4.67 (br s, 1 H), 4.45-4.39 (m, 1 H), 4.26 (br dd, J = 8.5, 12.7 Hz, 1 H), 4.15 (q, J = 6.6 Hz, 2H), 3.94 (br s, 3H), 3.77 (br d, J = 12.8 Hz, 1 H), 3.47 (br t, J = 1 1 .5 Hz, 0.5H), 3.35-3.15 (m, 2H), 2.97 (br t, J = 12.1 Hz, 0.5H), 2.23 (br s, 2H), 2.12-1 .87 (m, 2H), 1 .49 (br t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 507.3.
Figure imgf000312_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (br d, J = 8.6 Hz, 1 H), 7.82 (br s, 1 H), 7.77-7.70 (m, 1 H), 7.65 (d, J = 7.1 Hz, 2H), 7.51 -7.38 (m, 3H), 4.75 (br s, 1 H), 4.63-4.27 (m, 4H), 4.08 (br d, J = 4.6 Hz, 3H), 3.70-3.59 (m, 2H), 3.39-2.99 (m, 3H), 2.60 (s, 3H), 2.24 (br d, J = 1 1 .0 Hz, 2H), 2.05-1 .91 (m, 2H); LCMS
(ESI) [M+H]+: 485.3.
Figure imgf000312_0004
1H NMR (400 MHz, CHLOROFORM-d) d 7.65 (br d, J = 7.1 Hz, 3H), 7.56 (br s, 1 H), 7.51 -7.39 (m, 3H), 6.95 (br d, J = 8.2 Hz, 1 H), 4.74 (br t, J = 7.1 Hz, 1 H), 4.59-4.25 (m, 4H), 4.17 (q, J = 7.1 Hz, 2H), 3.97 (br s, 3H), 3.68-3.57 (m, 2H), 3.35-2.97 (m, 3H), 2.20 (br d, J = 12.1 Hz, 2H), 2.03-1.87 (m, 2H), 1.51 (t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 491.3.
Figure imgf000313_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.80-8.74 (m, 2H), 7.87 (dd, J = 1.5, 8.2 Hz, 1 H), 7.70-7.66 (m, 3H), 7.46 (brs, 1 H), 7.07-7.02 (m, 1H), 7.05 (d, J = 8.2 Hz, 1 H), 4.51 (td, J = 3.7, 13.7 Hz, 1H), 4.30 (d, J = 3.7 Hz, 2H), 3.93-3.86 (m, 1H), 3.47 (d, J = 7.1 Hz, 6H), 3.40-3.29 (m, 2H), 3.21-3.13 (m, 1H), 2.27 (dt, J = 3.5, 13.3 Hz, 2H), 2.09-1.94 (m, 2H); LCMS (ESI) [M+H]+: 476.2.
Figure imgf000313_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.11-8.04 (m, 1H), 7.84-7.76 (m, 1H), 7.74-7.70 (m, 1H), 7.56- 7.48 (m, 2H), 7.43-7.35 (m, 3H), 4.62-4.46 (m, 1H), 4.10-4.02 (m, 4H), 4.00-3.67 (m, 3H), 3.62-3.45 (m, 1 H), 3.41 -3.20 (m, 3H), 3.12-2.94 (m, 1 H), 2.58 (s, 3H), 2.38-1.86 (m, 6H); LCMS (ESI) [M+H]+: 499.3.
Figure imgf000313_0003
1H NMR (400 MHz, DMSO-de) d 8.22-8.17 (m, 1H), 7.91-7.86 (m, 1H), 7.76-7.64 (m, 3H), 7.41-7.34 (m, 2H), 7.18-7.11 (m, 1H), 4.99-4.34 (m, 1H), 4.13-3.86 (m, 6H), 3.77-3.64 (m, 1H), 3.49 (brs, 1H), 2.90- 2.62 (m, 3H), 2.52-2.52 (m, 3H), 2.38-2.03 (m, 4H), 1.42-0.87 (m, 3H); LCMS (ESI) [M+H]+: 499.3.
Figure imgf000314_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (br s, 1 H), 7.85 (br d, J = 8.4 Hz, 1 H), 7.80-7.71 (m, 1 H), 7.60 (br d, J = 7.0 Hz, 2H), 7.47-7.33 (m, 2H), 7.1 9 (br d, J = 5.1 Hz, 1 H), 4.76-4.1 6 (m, 3H), 4.09 (br s, 3H), 4.03-3.39 (m, 5H), 3.08-2.80 (m, 2H), 2.61 (s, 3H), 2.52-2.23 (m, 2H); LCMS (ESI) [M+H]+: 521 .2.
Figure imgf000314_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.59 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.21 -7.14 (m,
1 H), 4.56-4.42 (m, 1 H), 4.33-4.23 (m, 3H), 3.97-3.83 (m, 4H), 3.56 (quin, J = 8.5 Hz, 1 H), 3.37-3.27 (m,
1 H), 3.1 9-2.90 (m, 4H), 2.87-2.78 (m, 1 H), 2.75 (d, J = 7.1 Hz, 2H), 2.14 (br t, J = 12.5 Hz, 2H), 1 .93-1 .78 (m, 2H); LCMS (ESI) [M+H]+: 435.1 .
Figure imgf000314_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.59 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.32 (s, 1 H), 7.22-7.13 (m, 1 H), 4.55-4.41 (m, 3H), 4.31 (br t, J = 8.3 Hz, 1 H), 3.96-3.79 (m, 4H), 3.76 (s, 3H), 3.56 (quin, J = 8.5 Hz, 1 H), 3.38-3.27 (m, 1 H), 3.18-2.90 (m, 3H), 2.89-2.74 (m, 3H), 2.14 (br t, J = 13.0 Hz, 2H), 1 .94-1 .79 (m, 2H); LCMS (ESI) [M+H]+: 476.2.
Figure imgf000314_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.85 (t, J = 7.3 Hz, 3H), 7.78-7.73 (m, 1 H), 7.58- 7.51 (m, 1 H), 7.50-7.43 (m, 2H), 7.22 (br s, 1 H), 4.65-4.49 (m, 0.5H), 4.44-4.1 8 (m, 3H), 4.09 (s, 3H), 4.07-4.01 (m, 0.5H), 3.94-3.70 (m, 2H), 3.67-3.50 (m, 1 H), 2.61 (s, 3H), 2.47-2.31 (m, 2H); LCMS (ESI) [M+H]+: 495.3.
Figure imgf000315_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.88-7.80 (d, J = 2, 1 H), 7.60 (dd, J = 1 .1 , 8.4 Hz, 1 H), 7.52 (d,
J = 8.4 Hz, 1 H), 4.40-4.26 (m, 1 H), 3.88-3.84 (s, 3H), 3.80-3.64 (m, 2H), 3.40 (t, J = 9.2 Hz, 1 H), 3.25 (td, J = 8.4, 16.6 Hz, 1 H), 3.18-3.08 (m, 2H), 3.03-2.78 (m, 3H), 2.57-2.41 (m, 2H), 2.38 (s, 3H), 2.1 1 -1 .96 (m, 2H), 1 .85-1 .67 (m, 2H), 0.76-0.66 (m, 1 H), 0.36-0.29 (m, 2H), 0.02 (q, J = 4.8 Hz, 2H); LCMS (ESI)
[M+H]+: 463.2.
Figure imgf000315_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 9.13 (d, J = 1 .8 Hz, 1 H), 8.28 (d, J = 1 .8 Hz, 1 H), 7.61 -7.55 (m, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.19-7.14 (m, 1 H), 4.32 (dd, J = 7.2, 9.4 Hz, 1 H), 4.07 (s, 3H), 3.95 (t, J = 9.2 Hz, 1 H), 3.86-3.67 (m, 8H), 3.63-3.54 (m, 1 H), 2.97-2.81 (m, 2H), 2.68 (s, 3H) ; LCMS (ESI) [M+H]+: 487.2.
Figure imgf000315_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.75 (br s, 1 H), 7.64 (d, J = 3.7 Hz, 1 H), 7.58 (d, J = 7.9 Hz, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.20-7.13 (m, 1 H), 4.61 -4.46 (m, 1 H), 4.30 (br t, J = 8.4 Hz, 1 H), 4.01 -3.88 (m, 2H), 3.56 (quin, J = 8.4 Hz, 1 H), 3.43-3.25 (m, 2H), 3.12-2.88 (m, 2H), 2.87-2.79 (m, 1 H), 2.23 (br t, J = 12.8 Hz, 2H), 2.01 -1 .86 (m, 2H); LCMS (ESI) [M+H]+: 448.1 .
Figure imgf000315_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.54-7.43 (m, 3H), 7.34-7.26 (m, 2H), 7.12-7.03 (m, 2H), 4.44 (br t, J = 15.5 Hz, 1 H), 4.22 (br d, J = 2.3 Hz, 1 H), 3.94-3.83 (m, 2H), 3.55-3.45 (m, 1 H), 3.35-3.15 (m, 2H), 3.05-2.83 (m, 2H), 2.81 -2.71 (m, 1 H), 2.15 (br t, J = 13.6 Hz, 2H), 1 .95-1 .78 (m, 2H); LCMS (ESI) [M+H]+: 501 .1 .
Figure imgf000316_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.93-7.82 (m, 2H), 7.69 (dd, J = 1 .9, 8.4 Hz, 1 H), 7.61 -7.42 (m, 4H), 7.38-7.31 (m, 2H), 4.57-4.45 (m, 1 H), 4.31 (d, J = 3.8 Hz, 2H), 3.94 (s, 3H), 3.93-3.86 (m, 1 H), 3.85- 3.78 (m, 1 H), 3.41 -3.26 (m, 2H), 3.22-3.09 (m, 1 H), 2.34-2.18 (m, 2H), 2.10-1 .92 (m, 2H), 0.95-0.81 (m, 4H); LCMS (ESI) [M+H]+: 477.2.
Figure imgf000316_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 7.3 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1 H), 7.56-7.50 (m, 1 H), 7.49-7.44 (m, 2H), 7.36 (br s, 1 H), 4.72 (br d, J = 13.4 Hz,
1 H), 4.40-4.27 (m, 2H), 4.1 0 (s, 3H), 4.00 (br d, J = 13.9 Hz, 1 H), 3.52 (tt, J = 3.7, 1 1 .0 Hz, 1 H), 3.41 -3.31 (m, 1 H), 3.04 (br t, J = 1 1 .3 Hz, 1 H), 2.61 (s, 3H), 2.35 (br t, J = 15.7 Hz, 2H), 1 .95 (dquin, J = 3.9, 12.1 Hz, 2H); LCMS (ESI) [M+H]+: 475.2.
Figure imgf000316_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.22-7.15 (m, 1 H), 4.75 (br t, J = 14.6 Hz, 1 H), 4.35 (q, J = 8.1 Hz, 1 H), 4.10 (d, J = 2.2 Hz, 3H), 4.04 (br s, 1 H), 3.96 (dt, J = 3.1 , 9.0 Hz, 1 H), 3.60 (quin, J = 8.5 Hz, 1 H), 3.51 (dt, J = 4.0, 1 1 .0 Hz, 1 H), 3.46-3.33 (m, 1 H), 3.07-2.92 (m, 2H), 2.91 -2.82 (m, 1 H), 2.61 (s, 3H), 2.43-2.28 (m, 2H), 2.01 -1 .87 (m, 2H); LCMS (ESI) [M+H]+: 501 .2.
Figure imgf000317_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 9.24 (s, 1 H), 8.53 (br d, J = 8.1 Hz, 1 H), 8.35 (d, J = 8.1 Hz,
1 H), 8.07 (br s, 1 H), 7.62 (d, J = 8.1 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.22-7.1 7 (m, 1 H), 4.64-4.50 (m,
1 H), 4.37-4.30 (m, 1 H), 4.05-3.94 (m, 2H), 3.61 (quin, J = 8.4 Hz, 1 H), 3.47-3.33 (m, 2H), 3.09 (d, J = 5.1 Hz, 4H), 3.04-2.94 (m, 1 H), 2.91 -2.82 (m, 1 H), 2.35-2.22 (m, 2H), 2.07-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 475.2.
Figure imgf000317_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.89-7.83 (m, 2H), 7.73-7.67 (m, 2H), 7.57-7.50 (m, 1 H), 7.50- 7.43 (m, 2H), 7.38-7.31 (m, 2H), 4.53 (br d, J = 14.6 Hz, 1 H), 4.32 (d, J = 3.3 Hz, 2H), 3.98 (s, 3H), 3.92 (br d, J = 13.5 Hz, 1 H), 3.40-3.30 (m, 2H), 3.19-3.09 (m, 1 H), 2.32-2.20 (m, 2H), 2.08-1 .93 (m, 2H); LCMS (ESI) [M+H]+: 505.1 .
Figure imgf000317_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.60 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.21 -7.14 (m,
1 H), 4.49 (br t, J = 14.6 Hz, 1 H), 4.30 (dd, J = 7.3, 9.7 Hz, 1 H), 4.21 -4.13 (m, 2H), 4.05-3.98 (m, 2H), 3.93 (br t, J = 8.7 Hz, 2H), 3.57 (quin, J = 8.5 Hz, 1 H), 3.39-3.27 (m, 1 H), 3.18-2.92 (m, 3H), 2.88-2.79 (m, 2H), 2.20-2.08 (m, 2H), 1 .88 (br d, J = 12.1 Hz, 2H), 1 .35 (s, 6H); LCMS (ESI) [M+H]+: 463.2.
Figure imgf000317_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (d, J = 4.4 Hz, 1 H), 7.86-7.79 (m, 1 H), 7.77-7.71 (m, 1 H), 4.87-4.78 (m, 2H), 4.61 -4.45 (m, 3H), 4.09 (d, J = 2.6 Hz, 3H), 3.92 (br d, J = 8.4 Hz, 1 H), 3.87-3.79 (m, 1 H), 3.77-3.69 (m, 1 H), 3.63-3.56 (m, 1 H), 3.50-3.42 (m, 2H), 3.41 -3.23 (m, 3H), 3.15-3.00 (m, 1 H), 2.79- 2.63 (m, 2H), 2.61 (s, 3H), 2.26 (br s, 2H), 2.06-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 479.2.
Figure imgf000318_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.35-8.25 (m, 2H), 7.82 (br d, J = 8.2 Hz, 1 H), 7.66-7.59 (m,
2H), 7.02-6.95 (m, 2H), 4.52-4.42 (m, 1 H), 4.35 (dd, J = 8.9, 1 1 .0 Hz, 1 H), 4.18-4.08 (m, 1 H), 3.95 (br d, J = 13.6 Hz, 1 H), 3.54-3.47 (m, 1 H), 3.41 (d, J = 8.8 Hz, 6H), 3.36-3.23 (m, 2H), 3.18 (dd, J = 7.8, 1 7.2 Hz,
1 H), 3.1 0-2.97 (m, 1 H), 2.81 -2.69 (m, 1 H), 2.22-2.1 5 (m, 2H), 2.07-1 .84 (m, 2H); LCMS (ESI) [M+H]+: 502.3.
Figure imgf000318_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.71 (m, 1 H), 7.43-7.29 (m, 5H), 4.63 (s, 2H), 4.51 (br d, J = 13.0 Hz, 1 H), 4.23 (d, J = 2.8 Hz, 2H), 4.08 (s, 3H), 4.02 (br d, J = 13.6 Hz, 1 H), 3.36-3.23 (m, 2H), 3.04 (br t, J = 1 1 .8 Hz, 1 H), 2.61 (s, 3H), 2.21 (br s, 2H), 2.04-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 446.2.
Figure imgf000318_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.66 (m, 1 H), 4.43 (br d, J = 13.8 Hz, 2H), 4.08 (s, 3H), 3.36-3.26 (m, 1 H), 3.16 (br t, J = 1 1 .8 Hz, 2H), 2.60 (s, 3H), 2.26-2.1 8 (m, 2H), 2.03-1 .92 (m, 2H), 1 .33 (s, 9H); LCMS (ESI) [M+H]+: 382.2.
Figure imgf000318_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.00 (s, 1 H), 7.77-7.70 (m, 1 H), 7.67-7.62 (m, 1 H), 7.30-7.23 (m, 2H), 7.23-7.16 (m, 3H), 4.48 (brd, J = 13.4 Hz, 1H), 4.00 (s, 3H), 3.87 (brd, J = 13.7 Hz, 1H), 3.72 (s, 2H), 3.22-3.12 (m, 2H), 2.97 (br t, J = 11.1 Hz, 1H), 2.52 (s, 3H), 2.12 (brd, J = 10.8 Hz, 1H), 1.97 (brd, J = 10.8 Hz, 1 H), 1.91 -1.80 (m, 1 H), 1.71 -1.60 (m, 1 H); LCMS (ESI) [M+H]+: 416.2.
Figure imgf000319_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1H), 7.87-7.80 (m, 1H), 7.77-7.70 (m, 1H), 4.55 (br s,
1 H), 4.31 (br s, 1 H), 4.08 (s, 3H), 3.49-3.27 (m, 2H), 3.01 (br s, 1 H), 2.60 (s, 3H), 2.24 (br s, 2H), 2.01 (br s, 2H), 1.85-1.75 (m, 1 H), 1.02 (br s, 2H), 0.80 (br dd, J = 2.8, 7.6 Hz, 2H); LCMS (ESI) [M+H]+: 366.1.
Figure imgf000319_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.04 (s, 1 H), 7.80-7.70 (m, 2H), 7.53-7.45 (m, 5H), 4.08 (s, 3H), 3.96-3.65 (m, 8H), 2.61 (s, 3H); LCMS (ESI) [M+H]+: 403.1.
Figure imgf000319_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.03 (s, 1H), 7.81-7.67 (m, 2H), 7.52-7.32 (m, 4H), 4.19-4.06 (m, 4H), 3.94-3.70 (m, 5H), 3.55-3.35 (m, 2H), 2.61 (s, 3H); LCMS (ESI) [M+H]+: 437.0.
Figure imgf000319_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.78-7.70 (m, 1H), 4.62 (br d, J = 13.1 Hz, 1H), 4.08 (s, 3H), 4.05 (brd, J = 15.3 Hz, 1H), 3.36-3.25 (m, 2H), 2.97 (br t, J = 11.7 Hz, 1 H), 2.60 (s, 3H), 2.32 (s, 2H), 2.22 (br d, J = 12.2 Hz, 2H), 2.05-1.88 (m, 2H), 1.09 (s, 9H); LCMS (ESI) [M+H]+: 396.2.
Figure imgf000320_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.87-7.79 (m, 1 H), 7.77-7.69 (m, 1 H), 4.59 (br d, J = 13.1 Hz, 1 H), 4.08 (s, 3H), 4.02-3.90 (m, 1 H), 3.38-3.23 (m, 2H), 3.00 (br t, J = 1 1 .5 Hz, 1 H), 2.60 (s, 3H), 2.34 (d, J = 6.8 Hz, 2H), 2.23 (br d, J = 13.1 Hz, 2H), 2.06-1 .89 (m, 2H), 1 .15-1 .02 (m, 1 H), 0.66-0.53 (m, 2H), 0.25-0.18 (m, 2H); LCMS (ESI) [M+H]+: 380.2.
Figure imgf000320_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.06 (s, 1 H), 7.90-7.77 (m, 2H), 5.10-4.88 (m, 1 H), 4.30-4.01 (m, 2H), 3.32-3.15 (m, 1 H), 3.02 (t, J = 12.0 Hz, 2H), 2.29-2.06 (m, 2H), 2.04 -1 .87 (m, 2H),
1 .63 (d, J = 6.8 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 412.1 .
Figure imgf000320_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.69 (m, 1 H), 7.32 (t, J = 7.7 Hz, 2H), 7.05-6.94 (m, 3H), 4.74 (s, 2H), 4.49 (br d, J = 13.3 Hz, 1 H), 4.14 (br s, 1 H), 4.08 (s, 3H), 3.46-3.25 (m, 2H), 3.10 (br t, J = 1 1 .4 Hz, 1 H), 2.60 (s, 3H), 2.22 (br s, 2H), 2.1 0-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 432.2.
Figure imgf000320_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.98 (d, J = 8.2 Hz, 2H), 7.87-7.83 (m, 1 H), 7.81 - 7.74 (m, 3H), 7.42 (br s, 1 H), 4.54 (br d, J = 13.6 Hz, 1 H), 4.33 (d, J = 3.7 Hz, 2H), 4.10 (s, 3H), 3.93 (br d, J = 14.1 Hz, 1 H), 3.40 (br t, J = 1 0.7 Hz, 2H), 3.27-3.16 (m, 1 H), 2.62 (s, 3H), 2.37-2.25 (m, 2H), 2.14- 2.00 (m, 2H); LCMS (ESI) [M+H]+: 484.2.
Figure imgf000321_0004
/A
1 H NMR (400 MHz, CHLOROFORM-d) d 8.19 (s, 1 H), 8.12-8.06 (m, 2H), 7.86-7.81 (m, 2H), 7.74 (s, 1 H), 7.64-7.58 (m, 1 H), 7.43 (br s, 1 H), 4.58-4.50 (m, 1 H), 4.33 (d, J = 3.8 Hz, 2H), 4.1 0 (s, 3H), 3.98-3.89 (m, 1 H), 3.46-3.33 (m, 2H), 3.28-3.15 (m, 1 H), 2.62 (s, 3H), 2.31 (dt, J = 3.3, 13.3 Hz, 2H), 2.14-1 .98 (m, 2H); LCMS (ESI) [M+H]+: 484.2.
Figure imgf000321_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.88-7.79 (m, 3H), 7.78-7.74 (m, 1 H), 7.45 (d, J = 8.3 Hz, 2H), 7.33 (br s, 1 H), 4.54 (br d, J = 13.4 Hz, 1 H), 4.32 (d, J = 3.5 Hz, 2H), 4.10 (s, 3H), 3.94 (br d, J = 14.1 Hz, 1 H), 3.39 (br t, J = 10.6 Hz, 2H), 3.19 (br t, J = 10.8 Hz, 1 H), 2.62 (s, 3H), 2.35-2.23 (m, 2H), 2.13-1 .99 (m, 2H); LCMS (ESI) [M+H]+: 493.1 .
Figure imgf000321_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.94 (s, 1 H), 7.70-7.60 (m, 2H), 7.41 -7.32 (m, 1 H), 7.17-7.07 (m, 3H), 3.98 (s, 3H), 3.89-3.55 (m, 8H), 2.51 (s, 3H); LCMS (ESI) [M+H]+: 421 .2.
Figure imgf000321_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.81 -7.72 (m, 2H), 7.66- 7.55 (m, 3H), 7.03 (br s, 1 H), 4.52 (br d, J = 13.4 Hz, 1 H), 4.34 (d, J = 3.9 Hz, 2H), 4.13 (s, 3H), 3.92 (br d, J = 13.7 Hz, 1 H), 3.38 (br t, J = 1 0.6 Hz, 2H), 3.17 (br t, J = 1 1 .0 Hz, 1 H), 2.65 (s, 3H), 2.30 (br t, J = 13.9 Hz, 2H), 2.14-1 .99 (m, 2H); LCMS (ESI) [M+H]+: 527.1 .
Figure imgf000322_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1H), 7.85 (dd, J = 1.0, 8.4 Hz, 1H), 7.78-7.71 (m, 1H), 7.43-7.34 (m, 2H), 7.25-7.19 (m, 1H), 7.14 (d, J = 7.7 Hz, 2H), 4.43-4.25 (m, 2H), 4.09 (s, 3H), 3.32 (tt, J = 3.9, 10.7 Hz, 2H), 3.20 (brs, 1H), 2.61 (s, 3H), 2.28 (brdd, J = 3.3, 13.4 Hz, 2H), 2.09 (brd, J = 10.8 Hz, 2H); LCMS (ESI) [M+H]+: 418.1.
Figure imgf000322_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.78-7.69 (m, 1H), 4.20 (br s, 2H), 4.08 (s, 3H), 3.74 (s, 3H), 3.29-3.19 (m, 1 H), 3.10 (br t, J = 11.6 Hz, 2H), 2.60 (s, 3H), 2.18 (br d, J = 11.0 Hz, 2H), 2.03-1.90 (m, 2H); LCMS (ESI) [M+H]+: 356.2.
Figure imgf000322_0003
1H NMR (400 MHz, CHLOROFORM-d) d 7.86 (d, J = 7.2 Hz, 2H), 7.67 (dd, J = 1.8, 8.3 Hz, 1 H), 7.60 (d,
J = 1.8 Hz, 1 H), 7.56-7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.34 (br s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.66 (spt,
J = 6.1 Hz, 1 H), 4.55-4.45 (m, 1 H), 4.31 (d, J = 3.9 Hz, 2H), 3.92 (s, 3H), 3.90 (br d, J = 3.7 Hz, 1 H), 3.39- 3.27 (m, 2H), 3.21-3.10 (m, 1H), 2.24 (dt, J = 3.5, 12.9 Hz, 2H), 2.08-1.92 (m, 2H), 1.41 (d, J = 6.0 Hz, 6H); LCMS (ESI) [M+H]+: 479.2.
Figure imgf000322_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.45-8.39 (m, 1H), 8.18 (brs, 1H), 8.09 (s, 1H), 7.86-7.80 (m,
1 H), 7.76-7.72 (m, 1 H), 7.44 (br t, J = 8.3 Hz, 1 H), 4.61 -4.51 (m, 1 H), 4.41 -4.34 (m, 1 H), 4.20 (td, J = 5.9, 1 1 .3 Hz, 1 H), 4.08 (s, 3H), 4.02 (br d, J = 14.3 Hz, 1 H), 3.57 (quin, J = 8.0 Hz, 1 H), 3.47-3.31 (m, 2H), 3.22 (dd, J = 7.6, 17.3 Hz, 1 H), 3.1 6-3.04 (m, 1 H), 2.88-2.78 (m, 1 H), 2.60 (s, 3H), 2.37-2.21 (m, 2H), 2.12-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 504.2.
Figure imgf000323_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (dd, J = 4.9, 7.9 Hz, 1 H), 8.10 (s, 1 H), 7.85-7.80 (m, 1 H), 7.76-7.72 (m, 1 H), 7.57 (t, J = 7.9 Hz, 1 H), 6.89 (d, J = 7.5 Hz, 1 H), 4.64-4.49 (m, 1 H), 4.47-4.39 (m, 1 H), 4.20 (dd, J = 7.1 , 1 1 .2 Hz, 1 H), 4.08 (s, 3H), 4.03 (br s, 1 H), 3.55 (quin, J = 8.3 Hz, 1 H), 3.47-3.31 (m, 2H), 3.26-3.01 (m, 2H), 2.85-2.76 (m, 1 H), 2.60 (s, 3H), 2.46 (d, J = 2.2 Hz, 3H), 2.26 (br d, J = 14.1 Hz, 2H), 2.12-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 500.2.
Figure imgf000323_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.53 (s, 1 H), 8.00 (s, 1 H), 7.79-7.70 (m, 2H), 4.91 -4.77 (m, 1 H), 4.22-4.05 (m, 2H), 3.26-3.14 (m, 1 H), 3.03 (br t, J = 1 1 .2 Hz, 2H), 2.22-2.08 (m, 2H), 1 .98-1 .85 (m, 2H),
1 .69 (d, J = 6.8 Hz, 6H), 1 .94 (s, 9H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000323_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.94 (s, 1 H), 7.70-7.60 (m, 2H), 7.35 (dd, J = 4.8, 8.8 Hz, 1 H), 7.06-6.96 (m, 2H), 4.07-3.96 (m, 4H), 3.88-3.60 (m, 5H), 3.45-3.28 (m, 2H), 2.51 (s, 3H); LCMS (ESI) [M+H]+: 455.1 .
Figure imgf000323_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.78-7.69 (m, 1H), 4.09 (s, 3H), 3.89 (brd, J = 13.1 Hz, 2H), 3.28-3.14 (m, 4H), 2.60 (s, 3H), 2.26 (brdd, J = 2.9, 13.4 Hz, 2H), 2.17- 2.05 (m, 2H), 1.38 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 404.1.
Figure imgf000324_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1H), 7.90-7.81 (m, 1H), 7.78-7.70 (m, 1H), 7.44 (s, 5H), 4.82-4.37 (m, 1 H), 4.09 (s, 3H), 3.91 (br s, 1 H), 3.40-3.30 (m, 1 H), 3.30-3.17 (m, 2H), 2.61 (s, 3H), 2.37- 1.96 (m, 4H); LCMS (ESI) [M+H]+: 402.1.
Figure imgf000324_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1H), 7.89-7.84 (m, 2H), 7.83-7.78 (m, 1H), 7.75-7.70 (m, 1H), 7.55-7.49 (m, 1 H), 7.49-7.42 (m, 2H), 7.33 (brs, 1H), 4.88 (m, 1 H), 4.53 (m, J = 3.7, 13.5 Hz,
1 H), 4.32 (d, J = 3.9 Hz, 2H), 3.99-3.87 (m, 1H), 3.43-3.29 (m, 2H), 3.23-3.09 (m, 1H), 2.61 (s, 3H), 2.28 (m, 2H), 2.13-1.92 (m, 2H), 1.60 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 487.2.
Figure imgf000324_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77-7.70 (m, 1H), 4.35 (brs, 1 H), 4.08 (s, 3H), 3.96 (brd, J = 13.4 Hz, 2H), 3.26-3.16 (m, 1H), 3.08-2.99 (m, 2H), 2.60 (s, 3H), 2.19 (br d, J = 10.3 Hz, 2H), 2.04-1.92 (m, 2H), 1.38 (s, 9H); LCMS (ESI) [M+H]+: 397.2.
Figure imgf000324_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.88-7.80 (m, 1 H), 7.74 (br d, J = 7.9 Hz, 2H), 7.68-7.60 (m, 1H), 7.59-7.52 (m, 1H), 7.38 (dd, J = 7.5, 17.2 Hz, 1H), 4.78-4.63 (m, 1H), 4.09 (s, 3H), 3.58-3.46 (m, 1 H), 3.39-3.14 (m, 3H), 2.61 (s, 3H), 2.38-2.30 (m, 1 H), 2.16-1 .86 (m, 3H); LCMS (ESI) [M+H]+: 470.1 .
Figure imgf000325_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.84 (dd, J = 1 .0, 8.4 Hz, 1 H), 7.79-7.70 (m, 1 H), 7.48-7.37 (m, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 7.19-7.1 0 (m, 2H), 4.65 (br s, 1 H), 4.09 (s, 3H), 3.91 (br s,
1 H), 3.45-3.1 6 (m, 3H), 2.61 (s, 3H), 2.42-1 .91 (m, 4H); LCMS (ESI) [M+H]+: 420.1 .
Figure imgf000325_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.67 (s, 1 H), 8.10 (s, 1 H), 7.54 (s, 1 H), 7.38-7.33 (m, 2H), 7.29- 7.26 (m, 2H), 4.62 (br s, 1 H), 4.10 (s, 1 H), 3.93 (s, 3H), 3.34 (tt, J = 4.0, 10.8 Hz, 1 H), 3.19 (br s, 2H), 2.94 (spt, J = 6.9 Hz, 1 H), 2.18 (br d, J = 4.6 Hz, 2H), 1 .98 (br d, J = 9.5 Hz, 2H), 1 .27 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.
Figure imgf000325_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 7.89-7.82 (m, 3H), 7.72 (d, J = 8.6 Hz, 1 H), 7.56- 7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.35 (br s, 1 H), 4.59-4.49 (m, 1 H), 4.32 (d, J = 3.7 Hz, 2H), 3.94 (br d, J = 13.9 Hz, 1 H), 3.58 (tt, J = 3.6, 6.9 Hz, 1 H), 3.44-3.30 (m, 2H), 3.23-3.10 (m, 1 H), 2.58 (s, 3H), 2.29 (dt, J = 3.2, 13.1 Hz, 2H), 2.15-1 .95 (m, 2H), 1 .28-1 .1 7 (m, 4H); LCMS (ESI) [M+H]+: 485.2.
Figure imgf000325_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.52 (s, 1 H), 7.49 (d, J = 1 .8 Hz, 1 H), 7.38-7.34 (m, 2H), 7.28 (d, J = 7.7 Hz, 2H), 6.43 (d, J = 1 .8 Hz, 1 H), 4.84-4.39 (m, 1 H), 4.35-3.91 (m, 1 H), 3.85 (s, 3H), 3.37 (tt, J = 4.0, 1 0.9 Hz, 1 H), 3.28-3.10 (m, 2H), 2.95 (spt, J = 6.9 Hz, 1 H), 2.19 (br d, J = 9.9 Hz, 2H), 2.08-1 .87 (m, 2H), 1 .27 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.
Figure imgf000326_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (d, J = 2.6 Hz, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.70 (m, 1 H), 7.43 (br d, J = 5.4 Hz, 1 H), 7.40-7.28 (m, 3H), 4.80-4.63 (m, 1 H), 4.08 (s, 3H), 3.67-3.53 (m, 1 H), 3.41 - 3.12 (m, 3H), 2.60 (s, 3H), 2.34 (br d, J = 13.1 Hz, 1 H), 2.20-1 .87 (m, 3H); LCMS (ESI) [M+H]+: 436.1 .
Figure imgf000326_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.50 (s, 1 H), 7.85 (br d, J = 7.3 Hz, 2H), 7.66 (m, 2H), 7.55-7.41 (m, 3H), 7.35 (br s, 1 H), 4.78 (td, J = 6.7, 13.3 Hz, 1 H), 4.44 (br d, J = 13.2 Hz, 1 H), 4.30 (m, 2H), 3.90 (br d, J = 13.5 Hz, 1 H), 3.43-3.28 (m, 2H), 3.22 (br t, J = 1 1 .4 Hz, 1 H), 2.72-2.56 (s, 3H), 2.33-2.17 (m, 2H), 2.13-1 .91 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 487.2.
Figure imgf000326_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.79-7.67 (m, 1 H), 7.39 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 4.63 (br s, 1 H), 4.10 (s, 3H), 3.92 (br s, 1 H), 3.45-3.13 (m, 3H), 2.96 (quind, J = 6.8, 13.8 Hz, 1 H), 2.62 (s, 3H), 2.38-1 .94 (m, 4H), 1 .28 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 444.2.
Figure imgf000327_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.88-7.81 (m, 1 H), 7.78-7.71 (m, 1 H), 7.46-7.37 (m, 4H), 4.60 (br s, 1 H), 4.09 (s, 3H), 3.91 (br s, 1 H), 3.44-3.13 (m, 3H), 2.61 (s, 3H), 2.40-1 .88 (m, 4H); LCMS (ESI) [M+H]+: 436.1 .
Figure imgf000327_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.88-7.80 (m, 1 H), 7.78-7.69 (m, 2H), 7.27-7.20 (m, 1 H), 7.09 (br dd, J = 7.9, 16.6 Hz, 1 H), 4.78-4.55 (m, 1 H), 4.09 (s, 3H), 3.58-3.46 (m, 1 H), 3.41 -3.16 (m, 3H), 2.61 (s, 3H), 2.43-2.26 (m, 1 H), 2.19-1 .90 (m, 3H); LCMS (ESI) [M+H]+: 488.1 .
Figure imgf000327_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.93 (s, 1 H), 7.72-7.60 (m, 3H), 7.21 (br d, J = 2.3 Hz, 1 H), 7.17 (d, J = 2.2 Hz, 1 H), 7.02 (dd, J = 2.4, 7.9 Hz, 1 H), 4.05-3.96 (m, 4H), 3.86-3.69 (m, 3H), 3.65-3.55 (m, 2H), 3.30 (t, J = 5.2 Hz, 2H), 2.51 (s, 3H); LCMS (ESI) [M+H]+: 489.1 .
Figure imgf000327_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09-8.00 (m, 2H), 7.95 (d, J = 7.8 Hz, 1 H), 7.78-7.65 (m, 3H), 7.56-7.50 (m, 1 H), 7.32 (br s, 1 H), 4.49-4.41 (m, 1 H), 4.25 (d, J = 3.9 Hz, 2H), 4.01 (s, 3H), 3.89-3.81 (m, 1 H), 3.34-3.26 (m, 2H), 3.1 6-3.07 (m, 1 H), 2.52 (s, 3H), 2.22 (dt, J = 3.5, 13.5 Hz, 2H), 2.04-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 527.1 .
Figure imgf000328_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1 H), 7.82-7.69 (m, 3H), 7.69-7.57 (m, 2H), 7.39 (d, J = 7.5 Hz, 1 H), 4.15-4.06 (m, 4H), 3.96-3.79 (m, 3H), 3.71 -3.61 (m, 2H), 3.40-3.33 (m, 2H), 2.60 (s, 3H); LCMS (ESI) [M+H]+: 471 .1 .
Figure imgf000328_0002
1 H NMR (400 MHz, CHLOROFORM-d) 8.02-7.83 (m, 2H), 7.66 (br d, J = 8.4 Hz, 1 H), 7.58 (s, 1 H), 7.51 - 7.40 (m, 2H), 6.95 (d, J = 8.6 Hz, 1 H), 4.67-4.62 (m, 1 H), 4.58-4.44 (m, 1 H), 4.37-4.27 (m, 1 H), 4.01 -3.93 (m, 2H), 3.91 (s, 3H), 3.64-3.56 (m, 1 H), 3.45-3.24 (m, 2H), 3.19-3.02 (m, 1 H), 3.01 -2.83 (m, 2H), 2.24 (br t, J = 14.4 Hz, 2H), 2.09-1 .88 (m, 2H), 1 .40 (br d, J = 5.7 Hz, 6H); LCMS (ESI) [M+H]+: 530.2.
Figure imgf000328_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.41 (s, 1 H), 8.08 (d, J = 8.8 Hz, 1 H), 7.44-7.33 (m, 3H), 7.27 (d, J = 7.9 Hz, 2H), 4.63 (br s, 1 H), 4.03 (s, 4H), 3.32 (br t, J = 10.7 Hz, 1 H), 3.21 (br s, 2H), 2.97-2.90 (m, 1 H), 2.62 (s, 3H), 2.36-1 .87 (m, 4H), 1 .26 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 444.1 .
Figure imgf000328_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.86 (d, J = 7.1 Hz, 2H), 7.75 (dd, J = 1 .5, 8.4 Hz, 1 H), 7.65 (d, J = 1 .3 Hz, 1 H), 7.57-7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.35 (br s, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 4.52 (br d,
J = 13.7 Hz, 1 H), 4.31 (d, J = 3.7 Hz, 2H), 4.1 7-4.05 (m, 2H), 3.92 (br d, J = 14.1 Hz, 1 H), 3.85 (s, 2H), 3.42-3.28 (m, 2H), 3.19-3.07 (m, 1 H), 2.92 (s, 3H), 2.33-2.19 (m, 2H), 2.10-1 .91 (m, 2H), 1 .32 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 503.2.
Figure imgf000329_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.42 (s, 1 H), 8.07 (dd, J = 0.9, 8.8 Hz, 1 H), 7.87 (d, J = 7.3 Hz, 2H), 7.56-7.51 (m, 1 H), 7.45 (dd, J = 8.4, 17.2 Hz, 3H), 7.35 (br s, 1 H), 4.53 (br d, J = 13.7 Hz, 1 H), 4.43- 4.37 (m, 2H), 4.32 (d, J = 3.7 Hz, 2H), 3.94 (br d, J = 13.9 Hz, 1 H), 3.41 -3.32 (m, 1 H), 3.36 (dt, J = 4.1 ,
10.3 Hz, 1 H), 3.17 (br t, J = 10.9 Hz, 1 H), 2.63 (s, 3H), 2.35-2.22 (m, 2H), 2.12-1 .96 (m, 2H), 1 .52 (t, J =
7.3 Hz, 3H; LCMS (ESI) [M+H]+: 473.2.
Figure imgf000329_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 4.26 (br s, 2H), 4.09 (s, 3H), 3.41 -3.31 (m, 1 H), 2.98 (br t, J = 12.0 Hz, 2H), 2.60 (s, 3H), 2.23 (br d, J = 12.0 Hz, 2H), 1 .85 (dq, J = 4.0, 12.0 Hz, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 414.1 .
Figure imgf000329_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.34 (s, 1 H), 7.99 (dd, J = 1 .2, 8.7 Hz, 1 H), 7.34 (d, J = 8.8 Hz,
1 H), 4.31 (q, J = 7.3 Hz, 2H), 4.08 (br d, J = 10.1 Hz, 2H), 3.15-3.08 (m, 1 H), 2.94 (br t, J = 1 1 .7 Hz, 2H), 2.55 (s, 3H), 2.07 (br dd, J = 2.9, 13.2 Hz, 2H), 1 .93-1 .82 (m, 2H), 1 .46-1 .43 (m, 3H), 1 .41 (s, 9H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000329_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.28-8.24 (m, 1H), 8.14 (br s, 1H), 8.09 (d, J = 3.5 Hz, 1H), 7.85-7.80 (m, 1 H), 7.74-7.72 (m, 1 H), 7.51 (br d, J = 8.8 Hz, 1 H), 4.56 (br t, J = 13.4 Hz, 1 H), 4.40 (dd, J = 9.2, 11.0 Hz, 1 H), 4.21-4.12 (m, 1H), 4.08 (s, 3H), 4.03 (brd, J = 13.6 Hz, 1H), 3.62-3.51 (m, 1H), 3.46- 3.30 (m, 2H), 3.25 (dd, J = 7.9, 17.1 Hz, 1H), 3.15-3.01 (m, 1H), 2.86-2.74 (m, 1H), 2.59 (s, 3H), 2.35- 2.20 (m, 5H), 2.12-1.91 (m, 2H); LCMS (ESI) [M+H]+: 500.2.
Figure imgf000330_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.28-8.24 (m, 1H), 8.14 (br s, 1H), 8.09 (d, J = 3.5 Hz, 1H), 7.85-7.80 (m, 1H), 7.76-7.71 (m, 1H), 7.51 (br d, J = 8.3 Hz, 1H), 4.56 (br t, J = 12.7 Hz, 1H), 4.40-4.37 (m, 1 H), 4.21-4.13 (m, 1H), 4.08 (s, 3H), 4.03 (brd, J = 13.2 Hz, 1H), 3.62-3.51 (m, 1H), 3.46-3.30 (m, 2H), 3.25 (dd, J = 7.7, 17.3 Hz, 1H), 3.15-3.01 (m, 1H), 2.86-2.75 (m, 1H), 2.59 (s, 3H), 2.35-2.20 (m, 5H), 2.11 -1.91 (m, 2H); LCMS (ESI) [M+H]+: 500.2.
Figure imgf000330_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1 H), 7.75 (dd, J = 0.9, 8.4 Hz, 1 H), 7.69-7.62 (m, 2H), 7.22 (dd, J = 2.4, 8.1 Hz, 1 H), 7.19-7.14 (m, 1H), 6.97 (br s, 1 H), 4.46-4.36 (m, 1H), 4.23 (d, J = 4.0 Hz, 2H), 4.01 (s, 3H), 3.81 (brd, J = 13.9 Hz, 1H), 3.34-3.24 (m, 2H), 3.13-3.04 (m, 1H), 2.53 (s, 3H), 2.27 - 2.15 (m, 2H), 2.05-1.91 (m, 2H); LCMS (ESI) [M+H]+: 545.1.
Figure imgf000330_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.11 (d, J = 2.3 Hz, 1 H), 8.02-7.89 (m, 2H), 7.87-7.82 (m, 1 H), 7.79-7.73 (m, 1 H), 7.54-7.43 (m, 2H), 4.66-4.48 (m, 1 H), 4.35 (dd, J = 6.6, 9.4 Hz, 1 H), 4.10 (d, J = 2.1 Hz, 3H), 4.06-3.92 (m, 2H), 3.64 (m, 1H), 3.52-3.33 (m, 2H), 3.25-3.07 (m, 1H), 3.06-2.86 (m, 2H), 2.62 (s, 3H), 2.39-2.23 (m, 2H), 2.15-1.95 (m, 2H); LCMS (ESI) [M+H]+: 510.2.
Figure imgf000331_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (d, J = 2.3 Hz, 1 H), 8.00-7.87 (m, 2H), 7.86-7.80 (m, 1 H), 7.77-7.70 (m, 1 H), 7.53-7.40 (m, 2H), 4.62-4.47 (m, 1 H), 4.33 (dd, J = 6.7, 9.4 Hz, 1 H), 4.08 (d, J = 2.3 Hz, 3H), 4.03-3.90 (m, 2H), 3.61 (td, J = 8.3, 1 6.1 Hz, 1 H), 3.51 -3.31 (m, 2H), 3.13 (m, 1 H), 3.02-2.83 (m, 2H), 2.60 (s, 3H), 2.38-2.20 (m, 2H), 2.12-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 510.2.
Figure imgf000331_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.85-7.71 (m, 4H), 7.66 (d, J = 8.8 Hz, 2H), 4.62- 4.47 (m, 1 H), 4.35 (dd, J = 6.8, 9.6 Hz, 1 H), 4.08 (s, 3H), 4.03-3.91 (m, 2H), 3.61 (m, 1 H), 3.48-3.30 (m, 2H), 3.22-3.05 (m, 1 H), 3.03-2.84 (m, 2H), 2.60 (s, 3H), 2.29 (br t, J = 13.2 Hz, 2H), 2.12-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 510.2.
Figure imgf000331_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.85-7.72 (m, 4H), 7.66 (d, J = 8.8 Hz, 2H), 4.65- 4.47 (m, 1 H), 4.35 (dd, J = 6.8, 9.6 Hz, 1 H), 4.08 (s, 3H), 4.03-3.89 (m, 2H), 3.61 (m, 1 H), 3.48-3.31 (m, 2H), 3.22-3.05 (m, 1 H), 3.03-2.85 (m, 2H), 2.60 (s, 3H), 2.29 (br t, J = 13.3 Hz, 2H), 2.14-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 510.2.
Figure imgf000331_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.90-7.77 (m, 4H), 7.57-7.45 (m, 3H), 7.36 (br s,
1 H), 4.59-4.50 (m, 1 H), 4.33 (d, J = 3.8 Hz, 2H), 4.1 0 (s, 3H), 3.95 (br d, J = 14.1 Hz, 1 H), 3.38 (ddd, J = 3.3, 10.6, 14.0 Hz, 2H), 3.22-3.12 (m, 1 H), 3.07-3.00 (m, 1 H), 3.04 (q, J = 7.6 Hz, 1 H), 2.30 (dt, J = 3.3, 13.0 Hz, 2H), 2.1 1 -1 .97 (m, 2H), 1 .44 (t, J = 7.6 Hz, 3H); LCMS (ESI) [M+H]+: 473.2.
Figure imgf000332_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.86 (br d, J = 6.8 Hz, 2H), 7.60 (dd, J = 1 .6, 8.4 Hz, 1 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.38 (d, J = 1 .2 Hz, 1 H), 7.37-7.31 (m, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 4.52 (td, J = 3.6, 13.6 Hz, 1 H), 4.31 (d, J = 8.0 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.92 (d, J = 13.6 Hz, 1 H), 3.42-3.27 (m, 2H), 3.20-3.07 (m, 1 H), 2.93 (s, 3H), 2.34-2.17 (m, 2H), 2.08-1 .90 (m, 2H), 1 .31 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 503.3.
Figure imgf000332_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.87-7.79 (m, 1 H), 7.78-7.66 (m, 1 H), 4.08 (s, 3H), 3.79 (br d, J = 13.4 Hz, 2H), 3.74-3.64 (m, 4H), 3.37-3.28 (m, 4H), 3.28-3.18 (m, 1 H), 3.04 (br t, J = 1 1 .6 Hz, 2H), 2.60 (s, 3H), 2.20 (br d, J = 10.9 Hz, 2H), 2.09-1 .95 (m, 2H); LCMS (ESI) [M+H]+: 41 1 .2.
Figure imgf000332_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.70 (m, 1 H), 7.45-7.32 (m, 1 H), 7.16-6.98 (m, 2H), 4.76-4.60 (m, 1 H), 4.09 (s, 3H), 3.59 (br t, J = 12.8 Hz, 1 H), 3.41 -3.16 (m, 3H), 2.60 (s, 3H), 2.34 (br d, J = 1 1 .1 Hz, 1 H), 2.24-1 .87 (m, 3H); LCMS (ESI) [M+H]+: 454.1 .
Figure imgf000332_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.77-7.68 (m, 1 H), 4.08 (s, 3H), 3.75 (br d, J = 13.4 Hz, 2H), 3.30-3.15 (m, 5H), 2.99 (br t, J = 1 1 .8 Hz, 2H), 2.60 (s, 3H), 2.18 (br d, J = 1 0.9 Hz, 2H), 2.08-1 .95 (m, 2H), 1 .60 (br s, 6H); LCMS (ESI) [M+H]+: 409.2.
Figure imgf000333_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.79 (br s, 1 H), 8.55 (s, 1 H), 8.14-8.07 (m, 2H), 7.81 (br d, J = 8.4 Hz, 2H), 7.75-7.70 (m, 1 H), 4.54 (br d, J = 13.7 Hz, 1 H), 4.32 (br d, J = 4.2 Hz, 2H), 4.07 (s, 3H), 3.93 (br d, J = 13.7 Hz, 1 H), 3.41 -3.30 (m, 2H), 3.13 (br t, J = 1 1 .6 Hz, 1 H), 2.59 (s, 3H), 2.32-2.19 (m, 2H), 2.10-1 .93 (m, 2H); LCMS (ESI) [M+H]+: 494.1 .
Figure imgf000333_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.59 (br d, J = 7.7 Hz, 2H), 7.38 (br t, J = 7.4 Hz, 2H), 7.22-7.13 (m, 1 H), 4.83 (s, 4H), 4.49 (br t, J = 15.0 Hz, 1 H), 4.33-4.27 (m, 1 H), 4.22 (s, 4H), 3.97-3.87 (m, 2H),
3.61 -3.50 (m, 1 H), 3.31 (br d, J = 8.2 Hz, 1 H), 3.16-2.90 (m, 3H), 2.87-2.77 (m, 1 H), 2.19-2.07 (m, 2H),
1 .86 (br d, J = 10.4 Hz, 2H); LCMS (ESI) [M+H]+: 438.2.
Figure imgf000333_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.59 (br d, J = 7.5 Hz, 2H), 7.38 (br t, J = 7.2 Hz, 2H), 7.22-7.13 (m, 1 H), 4.83 (br s, 4H), 4.49 (br t, J = 15.0 Hz, 1 H), 4.30 (br t, J = 8.2 Hz, 1 H), 4.22 (br s, 4H), 3.97-3.87 (m, 2H), 3.61 -3.51 (m, 1 H), 3.31 (br d, J = 6.8 Hz, 1 H), 3.17-2.90 (m, 3H), 2.87-2.77 (m, 1 H), 2.19-2.07 (m, 2H), 1 .86 (br d, J = 10.6 Hz, 2H); LCMS (ESI) [M+H]+: 438.2.
Figure imgf000333_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.99 (d, J = 8.1 Hz, 2H), 7.84 (dd, J = 0.9, 8.4 Hz, 1 H), 7.75 (dd, J = 5.0, 8.1 Hz, 3H), 7.43 (br s, 1 H), 4.60-4.50 (m, 1 H), 4.34 (d, J = 3.8 Hz, 2H), 4.1 0 (s, 3H), 3.94 (br d, J = 14.1 Hz, 1 H), 3.45-3.33 (m, 2H), 3.25-3.14 (m, 1 H), 2.62 (s, 3H), 2.37-2.25 (m, 2H), 2.14-1 .99 (m, 2H); LCMS (ESI) [M+H]+: 527.1 .
Figure imgf000334_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.29 (s, 1 H), 7.86 (dd, J = 1 .5, 9.0 Hz, 1 H), 7.61 (d, J = 9.0 Hz,
1 H), 7.29 (d, J = 8.0, 2H), 7.20 (d, J = 7.6 Hz, 2H), 4.54 (br s, 1 H), 4.05 (s, 4H), 4.26-3.24 (m, 1 H), 3.15 (br t, J = 1 1 .4 Hz, 2H), 2.90-2.81 (m, 1 H), 2.60 (s, 3H), 2.22-1 .86 (m, 4H), 1 .19 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 444.2.
Figure imgf000334_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 7.86-7.83 (m, 1 H), 7.79-7.76 (m, 1 H), 4.16 (br s, 2H), 4.09 (s, 3H), 3.10-2.91 (m, 3H), 2.61 (s, 3H), 2.08 (br d, J = 10.6 Hz, 2H), 1 .94-1 .82 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 398.2.
Figure imgf000334_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.38 (s, 1 H), 7.95 (br d, J = 9.2 Hz, 1 H), 7.88 (br d, J = 7.6 Hz, 2H), 7.72 (d, J = 8.9 Hz, 1 H), 7.57-7.44 (m, 3H), 7.36 (br s, 1 H), 4.58-4.40 (m, 3H), 4.33 (br d, J = 3.5 Hz, 2H), 3.94 (br d, J = 13.6 Hz, 1 H), 3.43-3.32 (m, 2H), 3.19 (br t, J = 1 1 .1 Hz, 1 H), 2.70 (s, 3H), 2.33-2.23 (m, 2H), 2.13-1 .99 (m, 2H), 1 .60 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 473.2.
Figure imgf000334_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.43 (s, 1 H), 7.88 (br d, J = 7.7 Hz, 2H), 7.71 (s, 2H), 7.57-7.51 (m, 1 H), 7.51 -7.45 (m, 2H), 7.36 (br s, 1 H), 4.51 (br d, J = 13.8 Hz, 1 H), 4.33 (br d, J = 2.3 Hz, 2H), 4.18 (s, 3H), 3.94 (br d, J = 13.9 Hz, 1 H), 3.42-3.33 (m, 2H), 3.21 (br t, J = 10.7 Hz, 1 H), 3.13-3.07 (m, 2H), 2.34-2.24 (m, 2H), 2.12-2.00 (m, 2H), 1 .40 (t, J = 7.6 Hz, 3H); LCMS (ESI) [M+H]+: 473.2.
Figure imgf000335_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.18 (s, 1 H), 8.1 1 -8.00 (m, 2H), 7.81 (d, J = 7.6 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.42 (br s, 1 H), 4.90 (br d, J = 13.2 Hz, 1 H), 4.43-
4.22 (m, 2H), 4.10 (s, 3H), 3.97 (d, J = 14.0 Hz, 1 H), 3.60-3.46 (m, 1 H), 3.37 (t, J = 12.0 Hz, 1 H), 3.06 (t,
J = 1 1 .6 Hz, 1 H), 2.61 (s, 3H), 2.37 (t, J = 1 1 .6 Hz, 2H), 2.05-1 .86 (m, 2H); LCMS (ESI) [M+H]+: 500.2.
Figure imgf000335_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.67 (br s, 1 H), 7.53 (br t, J = 6.0 Hz, 1 H), 7.30 (t, J = 8.2 Hz,
1 H), 7.1 5 (br d, J = 7.9 Hz, 1 H), 4.56-4.38 (m, 1 H), 4.28 (dd, J = 7.1 , 9.5 Hz, 1 H), 4.01 -3.86 (m, 2H), 3.84- 3.76 (m, 4H), 3.60-3.52 (m, 1 H), 3.44 (br t, J = 4.3 Hz, 4H), 3.39-3.28 (m, 1 H), 3.20-2.90 (m, 3H), 2.89- 2.78 (m, 1 H), 2.23-2.08 (m, 2H), 1 .96-1 .77 (m, 2H); LCMS (ESI) [M+H]+: 460.2.
Figure imgf000335_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.67 (s, 1 H), 7.56-7.49 (m, 1 H), 7.30 (t, J = 8.2 Hz, 1 H), 7.1 5 (d, J = 8.2 Hz, 1 H), 4.56-4.41 (m, 1 H), 4.28 (dd, J = 7.1 , 9.5 Hz, 1 H), 4.19-4.03 (m, 2H), 3.91 (br t, J = 7.9 Hz, 2H), 3.63-3.46 (m, 3H), 3.40-3.27 (m, 1 H), 3.21 -2.90 (m, 5H), 2.89-2.76 (m, 1 H), 2.15 (br t, J = 13.2 Hz, 2H), 1 .96-1 .77 (m, 2H), 1 .27 (d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 488.1 .
Figure imgf000336_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.67 (br s, 1 H), 7.53 (br d, J = 6.0 Hz, 1 H), 7.30 (t, J = 8.2 Hz, 1 H), 7.1 5 (br d, J = 7.1 Hz, 1 H), 4.48 (s, 5H), 4.28 (dd, J = 7.1 , 9.5 Hz, 1 H), 3.91 (br t, J = 7.9 Hz, 2H), 3.56 (quin, J = 8.3 Hz, 1 H), 3.43-3.28 (m, 5H), 3.1 8-2.89 (m, 3H), 2.87-2.77 (m, 1 H), 2.20-2.07 (m, 2H), 1 .98-1 .92 (m, 4H), 1 .91 -1 .76 (m, 2H); LCMS (ESI) [M+H]+: 500.2.
Figure imgf000336_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 7.89-7.82 (m, 3H), 7.80-7.75 (m, 1 H), 7.55-7.49 (m, 1 H), 7.48-7.42 (m, 2H), 7.36 (br s, 1 H), 4.57 (br d, J = 13.8 Hz, 1 H), 4.31 (d, J = 3.8 Hz, 2H), 4.09 (s, 3H), 3.92 (br d, J = 13.9 Hz, 1 H), 3.37-3.28 (m, 1 H), 3.26-3.17 (m, 1 H), 3.13-3.04 (m, 1 H), 2.60 (s, 3H), 2.26-2.15 (m, 2H), 2.05-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 459.1 .
Figure imgf000336_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.89-7.84 (m, 1 H), 7.79-7.75 (m, 1 H), 4.20 (s, 3H), 3.81 -3.73 (m, 4H), 3.44-3.36 (m, 4H), 3.27 (br s, 4H), 2.71 (s, 3H); LCMS (ESI) [M+H]+: 410.2.
Figure imgf000336_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.70-7.65 (m, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.54-7.42 (m, 2H), 6.97 (br s, 1 H), 4.42 (br d, J = 13.6 Hz, 1 H), 4.23 (d, J = 3.9 Hz, 2H), 4.01 (s, 3H), 3.81 (br d, J = 14.2 Hz, 1 H), 3.34-3.23 (m, 2H), 3.09 (br t, J = 1 1 .1 Hz, 1 H), 2.53 (s, 3H), 2.21 (br t, J = 13.4 Hz, 2H), 2.05-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 561 .1 .
Figure imgf000337_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.17-7.97 (m, 1 H), 7.87-7.77 (m, 1 H), 7.75-7.66 (m, 1 H), 7.24 (br d, J = 6.6 Hz, 2H), 7.20-7.12 (m, 3H), 4.89 (s, 1 H), 4.06 (s, 3H), 3.99 (br d, J = 13.5 Hz, 2H), 3.21 (br t, J = 10.8 Hz, 1 H), 3.06 (br t, J = 1 1 .5 Hz, 2H), 2.85 (br s, 1 H), 2.58 (s, 3H), 2.18 (br d, J = 1 1 .5 Hz, 2H), 2.09-1 .87 (m, 3H), 1 .25-1 .20 (m, 1 H), 1 .17-1 .1 0 (m, 1 H); LCMS (ESI) [M+H]+: 457.2.
Figure imgf000337_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 4.26 (br s, 2H), 4.09 (s, 3H), 3.41 -3.31 (m, 1 H), 2.98 (br t, J = 12.0 Hz, 2H), 2.60 (s, 3H), 2.23 (br d, J = 12.0 Hz, 2H), 1 .85 (dq, J = 4.0, 12.0 Hz, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 414.1 .
Figure imgf000337_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.18 (d, J = 4.3 Hz, 1 H), 8.00 (br d, J = 4.6 Hz, 1 H), 7.94 (br t, J = 7.6 Hz, 1 H), 7.89-7.84 (d, 1 H), 7.83-7.77 (d, 1 H), 7.54-7.43 (m, 2H), 4.61 (m, 1 H), 4.35 (m, 1 H), 4.12 (d, J = 1 .7 Hz, 3H), 4.05-3.92 (m, 2H), 3.65 (m, 1 H), 3.47-3.34 (m, 1 H), 3.31 -3.1 9 (m, 1 H), 3.16-2.86 (m, 3H), 2.63 (s, 3H), 2.31 -2.16 (m, 2H), 2.09-1 .89 (m, 2H); LCMS (ESI) [M+H]+: 51 0.2.
Figure imgf000337_0004
1H NMR (400 MHz, CHLOROFORM-d) d 7.96 (brd, J = 10.6 Hz, 1H), 7.90 (br t, J = 9.0 Hz, 1H), 7.52- 7.41 (m, 2H), 4.83 (s, 4H), 4.47 (br t, J = 14.4 Hz, 1H), 4.35-4.27 (m, 1H), 4.22 (s, 4H), 3.99-3.84 (m, 2H), 3.58 (quin, J = 8.2 Hz, 1H), 3.40-3.26 (m, 1H), 3.19-2.82 (m, 4H), 2.14 (br t, J = 14.0 Hz, 2H), 1.96-1.72 (m, 2H); LCMS (ESI) [M+H]+: 463.2.
Figure imgf000338_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.25 (dd, J = 3.9, 8.3 Hz, 1 H), 8.13 (s, 1 H), 7.50 (dd, J = 1.8, 8.3 Hz, 1 H), 4.82 (s, 4H), 4.52-4.41 (m, 1 H), 4.36 (t, J = 9.9 Hz, 1 H), 4.21 (s, 4H), 4.13 (br t, J = 7.7 Hz, 1 H), 3.93 (brd, J = 13.2 Hz, 1H), 3.51 (quin, J = 8.1 Hz, 1H), 3.32 (br t, J = 11.2 Hz, 1H), 3.21 (brdd, J = 7.5, 17.1 Hz, 1 H), 3.14-2.93 (m, 2H), 2.77 (brdd, J = 9.2, 18.9 Hz, 1H), 2.29 (s, 3H), 2.18-2.05 (m, 2H), 1.94- 1.74 (m, 2H); LCMS (ESI) [M+H]+: 453.2.
Figure imgf000338_0002
1H NMR (400 MHz, CHLOROFORM-d) d 7.48-7.36 (m, 5H), 4.83 (s, 4H), 4.74-4.45 (m, 1H), 4.22 (s, 4H), 3.81 (br d, J = 15.4 Hz, 1 H), 3.27-3.00 (m, 3H), 2.30-1.94 (m, 2H), 1.87 (br s, 2H); LCMS (ESI) [M+H]+: 355.2.
Figure imgf000338_0003
1H NMR (400 MHz, CHLOROFORM-d) d 7.49-7.35 (m, 5H), 4.59 (br s, 1H), 4.13 (d, J = 8.6 Hz, 2H), 4.01 (d, J = 8.6 Hz, 2H), 3.87 (t, J = 6.8 Hz, 2H), 3.84-3.67 (m, 1 H), 3.26-3.02 (m, 3H), 2.25-2.11 (m, 3H), 2.02- 1.73 (m, 5H); LCMS (ESI) [M+H]+: 369.2.
Figure imgf000338_0004
1 H NMR (400 MHz, METHANOL-d4) d 7.39-7.29 (m, 4H), 4.52 (br s, 1 H), 4.08-3.97 (m, 4H), 3.86 (t, J = 6.8 Hz, 3H), 3.23 (tt, J = 4.0, 10.8 Hz, 3H), 2.96 (td, J = 6.9, 13.8 Hz, 1 H), 2.25-2.02 (m, 4H), 1 .95 (quin, J = 7.1 Hz, 2H), 1 .81 (br s, 2H), 1 .27 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 41 1 .2.
Figure imgf000339_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.38-7.31 (m, 2H), 7.27-7.24 (m, 2H), 4.83 (s, 4H), 4.71 -4.40 (m, 1 H), 4.22 (s, 4H), 4.09-3.68 (m, 1 H), 3.31 -3.03 (m, 3H), 2.94 (spt, J = 6.9 Hz, 1 H), 2.06 (br d, J = 7.1 Hz, 2H), 1 .88 (br s, 2H), 1 .26 (d, J = 7.1 Hz, 6H); LCMS (ESI) [M+H]+: 397.2.
Figure imgf000339_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.05-7.92 (m, 2H), 7.71 -7.60 (m, 1 H), 7.50 (br t, J = 7.4 Hz, 1 H), 7.28 (t, J = 8.2 Hz, 1 H), 7.13 (dd, J = 1 .0, 8.0 Hz, 1 H), 4.64-4.40 (m, 2H), 4.26 (dd, J = 7.1 , 9.3 Hz, 1 H), 4.00-3.85 (m, 2H), 3.60-3.51 (m, 1 H), 3.41 -3.20 (m, 2H), 3.15-2.99 (m, 1 H), 2.99-2.77 (m, 2H), 2.21 (br t,
J = 13.6 Hz, 2H), 2.02-1 .84 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 483.1 .
Figure imgf000339_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.68-7.64 (m, 1 H), 7.52 (br t, J = 6.2 Hz, 1 H), 7.30 (t, J = 8.2 Hz, 1 H), 7.1 5 (d, J = 7.9 Hz, 1 H), 4.84 (s, 4H), 4.56-4.39 (m, 1 H), 4.30-4.24 (m, 1 H), 4.22 (s, 4H), 3.90 (dt, J = 3.5, 8.9 Hz, 2H), 3.60-3.51 (m, 1 H), 3.40-3.25 (m, 1 H), 3.18-2.97 (m, 2H), 2.97-2.88 (m, 1 H), 2.87-2.78 (m, 1 H), 2.13 (t, J = 12 Hz, 2H), 1 .96-1 .72 (m, 2H) ; LCMS (ESI) [M+H]+: 472.2.
Figure imgf000339_0004
1 H NMR (400 MHz, DMSO-de) d 8.51 (d, J = 2.0 Hz, 1 H), 8.06 (s, 1 H), 7.86-7.80 (m, 1 H), 7.55 (br d, J = 8.2 Hz, 1 H), 7.37 (dt, J = 2.3, 8.1 Hz, 1 H), 7.17 (br d, J = 8.2 Hz, 1 H), 5.68-5.61 (m, 1 H), 4.96-4.83 (m, 4H), 4.31 (br d, J = 12.6 Hz, 1 H), 4.08-4.01 (m, 1 H), 3.97 (br d, J = 13.9 Hz, 1 H), 3.91 (dd, J = 5.7, 9.7 Hz, 1 H), 3.76-3.65 (m, 1 H), 3.44-3.34 (m, 1 H), 3.29-3.21 (m, 1 H), 2.90 (br t, J = 13.8 Hz, 1 H), 2.79-2.68 (m, 2H), 2.09 (br t, J = 14.0 Hz, 2H), 1 .87-1 .56 (m, 2H); LCMS (ESI) [M+H]+: 497.1 .
Figure imgf000340_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (t, 1 H), 7.79 (m, 2H), 4.38 (m, 2H), 4.09 (s, 3H), 3.59 (m, 1 H), 2.61 (s, 3H), 2.06 (m, 5H), 1 .81 (d, J = 8Hz, 2H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 424.
Figure imgf000340_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.29 (s, 1 H), 7.86 (dd, J = 1 .5, 9.0 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 4.35 (q, J = 7.3 Hz, 2H), 4.06 (br s, 2H), 3.1 1 (tt, J = 3.6, 1 0.8 Hz, 1 H), 2.93 (br t, J = 1 1 .7 Hz, 2H), 2.60 (s, 3H), 2.06 (br dd, J = 2.7, 13.1 Hz, 2H), 1 .90-1 .81 (m, 2H), 1 .50 (t, J = 7.3 Hz, 3H), 1 .41 (s, 9H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000340_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 7.84-7.78 (m, 1 H), 7.75-7.69 (m, 1 H), 4.88 (m, 1 H), 4.16 (br s, 2H), 3.25-3.15 (m, 1 H), 3.07-2.94 (m, 2H), 2.60 (s, 3H), 2.20-2.10 (m, 2H), 2.00-1 .87 (m, 2H),
1 .59 (d, J = 6.6 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 426.2.
Figure imgf000340_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.07 (s, 1 H), 7.95-7.78 (m, 2H), 7.49-7.36 (m, 1 H), 7.25-7.20 (m, 1 H), 7.19-7.10 (m, 2H), 5.06-4.89 (m, 1 H), 4.86-4.50 (m, 1 H), 4.05-3.72 (m, 1 H), 3.46-3.32 (m, 1 H), 3.30-3.15 (m, 2H), 2.46-1 .92 (m, 4H), 1 .64 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 434.2.
Figure imgf000341_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.90-7.74 (m, 2H), 7.49-7.27 (m, 4H), 5.09-4.98 (m, 1 H), 4.82-4.68 (m, 1 H), 3.70-3.52 (m, 1 H), 3.44-3.10 (m, 3H), 2.43-2.27 (m, 1 H), 2.22-1 .81 (m, 3H), 1 .64 (d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 450.2.
Figure imgf000341_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.07 (s, 1 H), 7.84 (q, J = 8.4 Hz, 2H), 7.45 (s, 5H), 5.06-4.90 (m, 1 H), 4.77-4.54 (m, 1 H), 4.10-3.77 (m, 1 H), 3.45-3.30 (m, 1 H), 3.30-3.07 (m, 2H), 2.45-1 .93 (m, 4H), 1 .64 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 416.2.
Figure imgf000341_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 1 1 .23-10.26 (m, 1 H), 8.16 (s, 2H), 7.72-7.63 (m, 1 H), 7.53 (br t, J = 7.3 Hz, 1 H), 7.31 (t, J = 8.1 Hz, 1 H), 7.15 (d, J = 7.9 Hz, 1 H), 4.66-4.44 (m, 1 H), 4.35-4.23 (m, 1 H), 4.02-3.89 (m, 2H), 3.63-3.54 (m, 1 H), 3.44-3.26 (m, 2H), 3.21 -2.77 (m, 3H), 2.24 (br t, J = 13.5 Hz, 2H), 2.06-1 .87 (m, 2H); LCMS (ESI) [M+H]+: 441 .1 .
Figure imgf000341_0004
1H NMR (400 MHz, CHLOROFORM-d) d 7.67 (br d, J = 10.1 Hz, 1H), 7.52 (br t, J = 8.7 Hz, 1H), 7.30 (t, J = 8.2 Hz, 1 H), 7.15 (brd, J = 7.9 Hz, 1H), 4.50 (brdd, J = 14.2, 18.4 Hz, 1H), 4.34-4.18 (m, 1H), 4.04- 3.85 (m, 2H), 3.60-3.52 (m, 1H), 3.44-3.22 (m, 2H), 3.16-3.00 (m, 1H), 3.00-2.77 (m, 2H), 2.31-2.13 (m, 2H), 2.03-1.79 (m, 2H); LCMS (ESI) [M+H]+: 409.0.
Figure imgf000342_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 8.03 (s, 1H), 7.77 (s, 2H), 4.94 (spt, J = 6.6 Hz,
1 H), 3.70 (br d, J = 5.1 Hz, 4H), , 3.62-3.55 (m, 4H), 1.61 (d, J = 6.8 Hz, 6H), 1.49 (s, 9H); LCMS (ESI) [M+H]+: 413.2.
Figure imgf000342_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.03-7.94 (m, 1H), 7.89 (br dd, J = 8.2, 19.2 Hz, 1H), 7.54-7.41 (m, 2H), 4.50 (br t, J = 14.3 Hz, 1H), 4.36-4.24 (m, 1H), 4.02-3.87 (m, 2H), 3.60 (s, J = 8.2 Hz, 1H), 3.46- 3.24 (m, 2H), 3.18-3.01 (m, 1H), 3.00-2.82 (m, 2H), 2.22 (br t, J = 14.0 Hz, 2H), 2.03-1.79 (m, 2H); LCMS (ESI) [M+H]+: 400.1.
Figure imgf000342_0003
1H NMR (400 MHz, CHLOROFORM-d) d 7.49-7.34 (m, 5H), 4.61 (br s, 1H), 3.86 (br s, 1H), 3.31-3.10 (m, 3H), 2.27 -1.92 (m, 4H); LCMS (ESI) [M+H]+: 292.1.
Figure imgf000342_0004
1H NMR (400 MHz, CHLOROFORM-d) d 7.38-7.32 (m, 2H), 7.29-7.25 (m, 2H), 4.60 (br s, 1 H), 3.94 (br s, 1 H), 3.35-3.08 (m, 3H), 2.94 (spt, J = 6.8 Hz, 1 H), 2.15 (br s, 2H), 1.93 (br s, 2H), 1.26 (d, J = 7.1 Hz, 6H); LCMS (ESI) [M+H]+: 334.2.
Figure imgf000343_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.26 (t, J = 8.6 Hz, 1 H), 8.14 (br s, 1 H), 7.51 (br d, J = 7.9 Hz, 1 H), 4.50 (br s, 1 H), 4.38 (br t, J = 1 0.1 Hz, 1 H), 4.13 (dd, J = 7.2, 1 1 .2 Hz, 1 H), 3.98 (br d, J = 13.6 Hz, 1 H), 3.57-3.48 (m, 1 H), 3.37 (br t, J = 1 1 .8 Hz, 1 H), 3.31 -3.1 7 (m, 2H), 3.09-2.98 (m, 1 H), 2.78 (dd, J = 9.2, 17.1 Hz, 1 H), 2.30 (s, 3H), 2.18 (br d, J = 14.0 Hz, 2H), 1 .99-1 .83 (m, 2H); LCMS (ESI) [M+H]+: 390.3.
Figure imgf000343_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 7.86-7.82 (d, J = 1 .2 Hz, 1 H), 7.78-7.74 (d, J = 8.4 Hz, 1 H), 7.34-7.27 (m, 5H), 4.86 (d, J = 14.7 Hz, 1 H), 4.52 (d, J = 14.7 Hz, 1 H), 4.10 (s, 3H), 3.63 (tdd, J = 3.6, 7.3, 13.5 Hz, 1 H), 3.40-3.34 (m, 2H), 3.05 (d, J = 7.5 Hz, 2H), 2.62 (s, 3H), 2.45-2.36 (m, 1 H), 2.29- 2.19 (m, 1 H); LCMS (ESI) [M+H]+: 402.2.
Figure imgf000343_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.05 (s, 1 H), 7.90-7.75 (m, 2H), 4.95 (spt, J = 6.6 Hz, 1 H), 4.18 (br s, 2H), 3.72 (s, 3H), 3.22 (tt, J = 3.9, 10.7 Hz, 1 H), 3.08 (br t, J = 1 1 .7 Hz, 2H), 2.16 (br d, J = 1 1 .0 Hz, 2H), 2.03-1 .86 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 370.2.
Figure imgf000343_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 8.03 (s, 1 H), 7.77 (s, 2H), 4.94 (spt, J = 6.6 Hz, 1 H), 3.76 (s, 3H), 3.72 (br s, 4H), 3.65 (br s, 4H), 1 .61 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 371 .2.
Figure imgf000343_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.06 (s, 1 H), 7.83 (q, J = 8.4 Hz, 2H), 5.07-4.87 (m, 2H), 4.20 (br s, 2H), 3.23 (tt, J = 4.0, 1 0.8 Hz, 1 H), 3.06 (br t, J = 1 1 .6 Hz, 2H), 2.25-2.09 (m, 2H), 2.05- 1 .87 (m, 2H), 1 .64 (d, J = 6.8 Hz, 6H), 1 .28 (d, J = 6.0 Hz, 6H); LCMS (ESI) [M+H]+: 398.2.
Figure imgf000344_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.93-7.77 (m, 2H), 7.32 (br t, J = 7.2 Hz, 2H), 7.09-6.92 (m, 3H), 5.09-4.90 (m, 1 H), 4.74 (s, 2H), 4.49 (br d, J = 13.6 Hz, 1 H), 4.13 (br d, J = 13.6 Hz, 1 H), 3.57-3.25 (m, 2H), 3.10 (br t, J = 1 1 .6 Hz, 1 H), 2.35-2.17 (m, 2H), 2.12-1 .87 (m, 2H), 1 .64 (d, J = 5.6 Hz, J = 6H); LCMS (ESI) [M+H]+: 446.2.
Figure imgf000344_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.18 (s, 1 H), 8.04 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 4.26-4.08 (m, 5H), 3.27-3.16 (m, 1 H), 3.03 (br t, J = 1 1 .6 Hz, 2H), 2.16 (br d, J = 10.0 Hz, 2H), 2.03-1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 384.2.
Figure imgf000344_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.34 (s, 1 H), 7.98 (s, 1 H), 7.92-7.84 (m, 1 H), 7.83-7.75 (m, 1 H), 4.24-4.07 (m, 2H), 3.72-3.62 (m, 1 H), 3.27-3.1 5 (m, 1 H), 3.09-2.93 (m, 2H), 2.16 (br d, J = 1 1 .0 Hz, 2H), 2.01 -1 .87 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 410.2.
Figure imgf000344_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.05 (s, 1 H), 7.82 (q, J = 8.5 Hz, 2H), 4.96 (spt, J = 6.7 Hz, 1 H), 4.16 (q, J = 7.2 Hz, 4H), 3.22 (tt, J = 3.9, 10.8 Hz, 1 H), 3.07 (br t, J = 1 1 .7 Hz, 2H), 2.22-2.1 1 (m, 2H), 2.02-1 .89 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H), 1 .28 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 384.2.
Figure imgf000345_0001
1 H NMR (400 MHz, DMSO-de) d 8.17 (s, 1 H), 8.12 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.67 (dd, J = 1 .0, 8.5 Hz, 1 H), 7.53-7.41 (m, 4H), 5.06 (quin, J = 6.5 Hz, 1 H), 3.78-3.62 (m, 8H), 1 .53 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 417.1 .
Figure imgf000345_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.09 (s, 1 H), 7.91 -7.81 (m, 2H), 7.47-7.39 (m, 4H), 5.07-4.92 (m, 1 H), 4.65 (br s, 1 H), 3.89 (br s, 1 H), 3.44-3.15 (m, 3H), 2.40-1 .94 (m, 4H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 450.2.
Figure imgf000345_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 8.04 (s, 1 H), 7.77 (s, 2H), 7.47-7.30 (m, 4H), 5.01 - 4.86 (m, 1 H), 4.16-4.07 (m, 1 H), 3.95-3.64 (m, 5H), 3.52-3.31 (m, 2H), 1 .61 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 451 .0.
Figure imgf000345_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 7.89-7.81 (d, J = 8.4 Hz, 1 H), 7.78-7.69 (d, J = 8.4 Hz, 1 H), 4.48-4.33 (m, 4H), 4.15-4.02 (m, 4H), 2.61 (s, 3H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 370.1 .
Figure imgf000345_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.19 (s, 1 H), 8.05 (s, 1 H), 7.87 (d, J = 7.2 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 4.52 (q, J = 7.2 Hz, 2H), 4.30-4.12 (m, 2H), 3.24-3.18 (m, 1 H), 3.01 (t, J = 5.6 Hz, 2H), 2.18- 2.14 (m, 2H), 1 .98-1 .92 (m, 2H), 1 .57 (t, J = 7.2 Hz, 3H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 398.1 .
Figure imgf000346_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.17 (s, 1 H), 8.04 (s, 1 H), 7.92-7.85 (d, J = 8.4 Hz, 1 H), 7.84- 7.78 (d, J = 8.4 Hz, 1 H), 5.36-5.26 (m, 1 H), 4.36-4.06 (m, 5H), 4.00-3.82 (m, 4H), 3.29-3.18 (m, 1 H), 3.16- 3.00 (m, 2H), 2.30-2.17 (m, 3H), 2.1 1 -1 .88 (m, 3H); LCMS (ESI) [M+H]+: 398.1 .
Figure imgf000346_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.86-7.80 (d, J = 8.4 Hz, 1 H), 7.78-7.72 (d, J = 8.4 Hz, 1 H), 4.08 (s, 3H), 3.98-3.46 (m, 5H), 2.60 (s, 3H), 2.50-2.35 (m, 2H), 1 .50 (s, 9H); LCMS (ESI)
[M+H]+: 384.2.
Figure imgf000346_0003
1 H NMR (400 MHz, DMSO-de) d 8.23 (s, 1 H), 8.1 1 (s, 1 H), 7.90 (d, J = 8.6 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 2H), 7.39 (s, 0.2H), 7.25-7.22 (d, J = 8.4 Hz, 2H), 7.22-7.20 (s, 0.6H), 7.03 (s, 0.2H), 4.14-3.93 (m, 5H), 3.54-3.43 (m, 1 H), 3.23 (br t, J = 1 1 .2 Hz, 2H), 2.17 (br dd, J = 2.5, 13.1 Hz, 2H), 1 .93-1 .82 (m, 2H); LCMS (ESI) [M+H]+: 454.2.
Figure imgf000346_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.50 (s, 1 H), 7.97 (s, 1 H), 7.79-7.71 (m, 2H), 4.51 (q, J = 7.6 Hz, 2H), 4.13 (br d, J = 8.8 Hz, 2H), 3.19 (tt, J = 4.0, 10.8 Hz, 1 H), 3.01 (br t, J = 1 1 .6 Hz, 2H), 2.14 (br dd, J = 2.8, 13.2 Hz, 2H), 2.00-1 .86 (m, 2H), 1 .66 (t, J = 7.6 Hz, 3H), 1 .48 (s, 9H); LCMS (ESI) [M+H-56]+: 342.2, LCMS (ESI) [M+23]+: 420.2.
Figure imgf000347_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.85-7.80 (d, J = 8.4 Hz, 1 H), 7.76-7.71 (d, J = 8.4 Hz, 1 H), 4.51 (brd, J = 13.0 Hz, 1H), 4.19 (d, J = 6.8 Hz, 2H), 4.08 (s, 4H), 3.64-3.56 (m, 2H), 3.37-3.25 (m, 2H), 3.03 (br t, J = 11.5 Hz, 1H), 2.60 (s, 3H), 2.24 (brd, J = 12.3 Hz, 2H), 2.07-1.91 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 384.2.
Figure imgf000347_0002
1H NMR (400 MHz, DMSO-de) d 8.10 (s, 1H), 7.85-7.81 (d, J = 8.4 Hz, 1H), 7.77-7.72 (d, J = 8.4 Hz, 1H), 4.55 (brd, J = 13.5 Hz, 1H), 4.09 (s, 3H), 3.91 (brd, J = 14.3 Hz, 1H), 3.46-3.25 (m, 4H), 3.20-3.07 (m,
1 H), 2.61 (s, 3H), 2.33-2.21 (m, 2H), 2.11-1.95 (m, 2H); LCMS (ESI) [M+H]+: 408.2.
Figure imgf000347_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 2H), 8.10 (s, 1H), 7.83 (dd, J = 1.1, 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1 H), 4.76 (td, J = 3.5, 13.5 Hz, 2H), 4.07 (s, 3H), 3.32 (tt, J = 4.0, 11.0 Hz, 1 H), 3.25-3.15 (m, 2H), 2.59 (s, 3H), 2.49 (q, J = 7.5 Hz, 2H), 2.25 (br dd, J = 3.0, 13.6 Hz, 2H), 2.07-1.95 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H); LCMS (ESI) [M+H]+: 404.2.
Figure imgf000347_0004
1H NMR (400 MHz, DMSO-de) d 8.18 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 1.3 Hz, 1 H), 6.59 (d, J = 1.3 Hz, 1 H), 4.04 (s, 3H), 3.45 (s, 3H), 3.38-3.32 (m, 1 H), 3.27-3.24 (m, 2H), 2.92 (br t, J = 10.7 Hz, 2H), 2.21-2.12 (m, 2H), 2.08-1.96 (m, 2H); LCMS (ESI) [M+H]+: 378.3.
Figure imgf000347_0005
1 H NMR (400 MHz, DMSO-de) d 8.18 (s, 1 H), 7.88-7.86 (d, J = 8 Hz, 1 H), 4.71 - 4.73 (d, J = 8 Hz, 1 H), 4.05 (s, 3H), 3.95-9.32 (m, 2H), 3.49-3.53 (m, 1 H), 3.32-3.48 (m, 1 H), 2.25-2.22 (m, 2H), 1 .99-1 .96 (m, 2H); LCMS (ESI) [M+H]+: 380.2.
Figure imgf000348_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.05 (s, 1 H), 7.82 (q, J = 8.5 Hz, 2H), 5.05-4.90 (m, 1 H), 4.62 (br d, J = 13.7 Hz, 1 H), 4.03 (br d, J = 13.2 Hz, 1 H), 3.36-3.22 (m, 2H), 2.95 (br t, J = 1 1 .1 Hz,
1 H), 2.31 (s, 2H), 2.21 (br d, J = 1 0.8 Hz, 2H), 2.07-1 .86 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 410.1 .
Figure imgf000348_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.06 (s, 1 H), 7.98 (s, 1 H), 7.70 (s, 2H), 4.88 (spt, J = 6.6 Hz,
1 H), 3.75 (br d, J = 4.8 Hz, 2H), 3.67 (br d, J = 4.9 Hz, 4H), 3.62 (br d, J = 5.3 Hz, 2H), 2.26 (s, 2H), 1 .55 (d, J = 6.7 Hz, 6H), 1 .02 (s, 9H); LCMS (ESI) [M+H]+: 41 1 .2.
Figure imgf000348_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 7.87-7.81 (d, J = 8.4 Hz, 1 H), 7.78-7.72 (d, J = 8.4 Hz, 1 H), 4.65-4.40 (m, 4H), 4.17-4.1 1 (m, 1 H), 4.09 (s, 3H), 2.61 (s, 3H), 2.06 (s, 2H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 368.2.
Figure imgf000348_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.19 (s, 1 H), 8.07 (s, 1 H), 7.83 (q, J = 8.4 Hz, 2H), 4.72-4.62 (m, 1 H), 4.1 6 (br s, 2H), 3.25-3.16 (m, 1 H), 3.01 (br t, J = 1 1 .7 Hz, 2H), 2.20-2.08 (m, 3H), 2.00-1 .87 (m, 3H),
1 .60 (d, J = 6.6 Hz, 3H), 1 .48 (s, 9H), 0.80 (t, J = 7.4 Hz, 3H); LCMS (ESI) [M+H]+: 426.2.
Figure imgf000349_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.53 (s, 1 H), 7.96 (s, 1 H), 7.77-7.70 (m, 2H), 4.54 (qd, J = 6.9, 14.0 Hz, 1 H), 4.10 (br s, 2H), 3.22-3.13 (m, 1 H), 3.02 (br t, J = 1 1 .4 Hz, 2H), 2.17-2.04 (m, 3H), 2.00-1 .85 (m, 3H), 1 .66 (d, J = 6.8 Hz, 3H), 1 .48 (s, 9H), 0.84 (t, J = 7.4 Hz, 3H); LCMS (ESI) [M+H]+: 426.2, LCMS (ESI) [M-55]+: 370.1 .
Figure imgf000349_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.51 (s, 1 H), 8.15 (s, 1 H), 8.04 (d, J = 8.6 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.66 (s, 0.2H), 7.51 (s, 0.5H), 7.36 (s, 0.3H), 4.15 (br s, 2H), 3.26-3.1 6 (m, 1 H), 3.01 (br t, J = 12.8 Hz, 2H), 2.15 (br d, J = 1 0.4 Hz, 2H), 1 .99-1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 420.2, LCMS (ESI) [M+23]+: 442.1 , LCMS (ESI) [M-100+23]+: 342.0.
Figure imgf000349_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.08 (s, 1 H), 7.82-7.80 (d, J = 8.4 Hz, 1 H), 7.76-7.69 (d, J = 8.4 Hz, 1 H), 4.57-4.37 (m, 1 H), 4.07 (s, 3H), 3.65-3.47 (m, 1 H), 3.04-2.87 (m, 1 H), 2.59 (s, 3H), 2.36-2.14 (m, 4H), 1 .82 (dq, J = 2.9, 12.9 Hz, 2H), 1 .46 (s, 9H), 1 .29 (dq, J = 3.0, 12.5 Hz, 2H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000349_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.53 (s, 1 H), 8.39 (s, 1 H), 7.87-7.78 (m, 2H), 7.65 (s, 0.2H), 7.49 (s, 0.5H), 7.34 (s, 0.3H), 4.13 (br s, 2H), 3.24-3.15 (m, 1 H), 3.07-2.96 (m, 2H), 2.15 (br d, J = 10.8 Hz, 2H), 1 .98-1 .86 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+23]+: 442.1 , LCMS (ESI) [M-100]+: 320.0, LCMS (ESI) [M-55]+: 364.0.
Figure imgf000350_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.42 (s, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 8.04 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.35-4.14 (m, 2H), 3.43-3.29 (m, 1 H), 2.97 (br t, J = 12.0 Hz, 2H), 2.22 (br d, J = 1 1 .7 Hz, 2H), 1 .85 (m, 2H), 1 .63 (d, J = 6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 428.2.
Figure imgf000350_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.85-7.79 (m, 1 H), 7.77-7.70 (m, 1 H), 4.08 (d, J = 1 .8 Hz, 3H), 4.06-3.92 (m, 2H), 3.88-3.73 (m, 2H), 3.71 -3.62 (m, 1 H), 2.60 (s, 3H), 2.56-2.35 (m, 2H), 2.30-2.20 (m, 2H), 1 .10 (d, J = 1 .8 Hz, 9H); LCMS (ESI) [M+H]+: 382.2.
Figure imgf000350_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12-8.08 (m, 1 H), 7.83 (dd, J = 1 .1 , 8.6 Hz, 1 H), 7.76-7.72 (m, 1 H), 4.09 (s, 3H), 3.99-3.49 (m, 5H), 2.60 (s, 3H), 2.50-2.34 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 384.1 .
Figure imgf000350_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.87-7.81 (m, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 4.64- 4.62 (m, 1 H), 4.09 (s, 3H), 3.77-3.74 (m, 1 H), 3.23-3.20 (m, 1 H), 2.61 (s, 3H), 2.15 (br s, 2H), 2.01 (dt, J = 4.2, 8.9 Hz, 2H), 1 .85 (br d, J = 4.4 Hz, 2H), 1 .73 (br s, 2H), 1 .46 (s, 9H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000350_0005
1 H NMR (400 MHz, METHANOL-d ) d 8.16 (s, 1 H), 7.85-7.74 (m, 2H), 4.04 (s, 3H), 3.27-3.06 (m, 2H), 2.56 (s, 3H), 2.44-2.30 (m, 2H), 2.21 (br d, J = 10.6 Hz, 2H), 1 .83 (m, 2H), 1 .70-1 .51 (m, 2H); LCMS (ESI) [M+H]+: 312.2.
Figure imgf000351_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.06 (s, 1 H), 7.94-7.78 (m, 2H), 4.97 (td, J = 6.7,
13.3 Hz, 1 H), 4.59 (br d, J = 13.7 Hz, 1 H), 3.95 (br d, J = 13.9 Hz, 1 H), 3.39-3.21 (m, 2H), 3.00 (br t, J =
1 1 .4 Hz, 1 H), 2.34 (d, J = 6.8 Hz, 2H), 2.28-2.13 (m, 2H), 2.07-1 .88 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H),
1 .14-1 .00 (m, 1 H), 0.67-0.52 (m, 2H), 0.21 (q, J = 4.9 Hz, 2H); LCMS (ESI) [M+H]+: 394.3.
Figure imgf000351_0002
1 H NMR (400 MHz, METHANOL-d4) d 8.24 (s, 1 H), 7.86 (s, 2H), 4.08 (s, 3H), 3.47 (br t, J = 4.3 Hz, 1 H), 3.36-3.32 (m, 1 H), 2.60 (s, 3H), 2.49-2.39 (m, 2H), 2.12-1 .98 (m, 4H), 1 .84-1 .68 (m, 2H); LCMS (ESI) [M+H]+: 312.2.
Figure imgf000351_0003
1 H NMR (400 MHz, METHANOL-d ) d 8.40 (br s, 1 H), 8.22 (s, 1 H), 7.83 (s, 2H), 4.63-4.45 (m, 5H), 4.05 (s, 3H), 2.57 (s, 3H); LCMS (ESI) [M+H]+: 270.1 .
Figure imgf000351_0004
1 H NMR (400 MHz, METHANOL-d4) d 8.25 (s, 1 H), 7.87 (s, 2H), 4.15 (quin, J = 7.2 Hz, 1 H), 4.09 (s, 3H), 3.91 -3.80 (m, 2H), 3.63-3.50 (m, 2H), 2.72-2.62 (m, 1 H), 2.61 (s, 3H), 2.50 (qd, J = 6.9, 13.8 Hz, 1 H); LCMS (ESI) [M+H]+: 284.2.
Figure imgf000352_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.06 (s, 1 H), 7.87-7.79 (m, 2H), 4.96 (quind, J = 6.7, 13.3 Hz, 1 H), 4.52 (dq, J = 2.0, 8.5 Hz, 2H), 4.19 (br t, J = 17.3 Hz, 2H), 3.33-3.08 (m, 3H), 2.21 (br d, J = 1 1 .5 Hz, 2H), 2.07-1 .92 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 438.1 .
Figure imgf000352_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.05 (s, 1 H), 7.90-7.75 (m, 2H), 4.95 (spt, J = 6.6 Hz, 1 H), 4.18 (br s, 2H), 3.72 (s, 3H), 3.22 (tt, J = 3.9, 10.7 Hz, 1 H), 3.08 (br t, J = 1 1 .7 Hz, 2H), 2.16 (br d, J = 1 1 .0 Hz, 2H), 2.03-1 .86 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 370.2.
Figure imgf000352_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.79 (m, 2H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.62 (br t, J = 12.5 Hz, 2H), 4.31 -4.08 (m, 2H), 3.36-3.09 (m, 4H), 2.23 (br s, 2H), 2.02 (br s, 2H), 1 .65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 488.0.
Figure imgf000352_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.80 (m, 2H), 5.81 (spt, J = 6.1 Hz, 1 H), 4.99 (spt, J = 6.6 Hz, 1 H), 4.34-4.07 (m, 2H), 3.42-3.14 (m, 3H), 2.26 (br d, J = 3.5 Hz, 2H), 2.13- 1 .94 (m, 2H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 506.0.
Figure imgf000352_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.72 (d, J = 6.0 Hz, 2H), 8.20 (s, 1 H), 8.06 (s, 1 H), 7.91 -7.77 (m, 2H), 7.32 (d, J = 6.0 Hz, 2H), 4.96 (spt, J = 6.6 Hz, 1 H), 4.64 (br d, J = 1 1 .2 Hz, 1 H), 3.76 (br d, J = 1 1 .9 Hz, 1 H), 3.44-3.32 (m, 1 H), 3.26 (br d, J = 1 0.8 Hz, 2H), 2.32 (br s, 1 H), 2.23-1 .88 (m, 3H), 1 .63 (d, J =
6.8 Hz, 6H); LCMS (ESI) [M+H]+: 417.1 .
Figure imgf000353_0001
1 H NMR (400 MHz, DMSO-de) d 8.27 (s, 1 H), 8.1 5 (s, 1 H), 7.91 (d, J = 8.6 Hz, 1 H), 7.75 (d, J = 8.6 Hz,
1 H), 5.1 1 (spt, J = 6.7 Hz, 1 H), 4.14-4.00 (m, 1 H), 3.94 (br d, J = 13.5 Hz, 2H), 3.49-3.36 (m, 1 H), 3.49- 3.36 (m, 1 H), 3.13-3.08 (m, 2H), 2.13 (br dd, J = 3.3, 13.2 Hz, 2H), 1 .86-1 .70 (m, 2H), 1 .53 (d, J = 6.4 Hz, 6H), 0.72-0.60 (m, 4H); LCMS (ESI) [M+H]+: 396.2.
Figure imgf000353_0002
1 H NMR (400 MHz, DMSO-de) d 8.68-8.63 (m, 2H), 8.28 (s, 1 H), 8.16 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 7.9 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.48 (dd, J = 4.9, 7.7 Hz, 1 H), 5.1 1 (spt, J = 6.6 Hz, 1 H), 4.06 (br s, 2H), 3.59-3.46 (m, 1 H), 3.29 (br t, J = 1 1 .2 Hz, 2H), 2.25-2.15 (m, 2H), 1 .98-1 .83 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 41 7.1 .
Figure imgf000353_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.60 (br d, J = 4.4 Hz, 1 H), 8.21 (s, 1 H), 8.05 (s, 1 H), 7.88-7.78 (m, 3H), 7.67 (br d, J = 7.7 Hz, 1 H), 7.40-7.33 (m, 1 H), 4.96 (td, J = 6.6, 13.2 Hz, 1 H), 4.68 (br d, J = 13.2 Hz, 1 H), 4.1 1 (br d, J = 13.2 Hz, 1 H), 3.36 (br t, J = 10.5 Hz, 2H), 3.24 (br t, J = 1 1 .5 Hz, 1 H), 2.32 (br d, J = 1 1 .7 Hz, 1 H), 2.24-2.01 (m, 3H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 417.1 .
Figure imgf000353_0004
1H NMR (400 MHz, DMSO-de) d 8.26 (s, 1H), 8.13 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz,
1 H), 7.32 (q, J = 8.2 Hz, 4H), 5.09 (spt, J = 6.5 Hz, 1 H), 4.06 (br s, 2H), 3.58-3.42 (m, 1 H), 3.27-3.11 (m, 2H), 2.94 (spt, J = 6.8 Hz, 1H), 2.16 (br dd, J = 2.9, 13.0 Hz, 2H), 1.93-1.77 (m, 2H), 1.52 (d, J = 6.6 Hz, 6H), 1.23 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 458.3.
Figure imgf000354_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.09-8.06 (m, 1 H), 7.90-7.76 (m, 2H), 5.52 (br s,
1 H), 4.96 (dq, J = 4.2, 6.5 Hz, 1H), 4.49 (brd, J = 13.2 Hz, 1H), 4.01 (brs, 2H), 3.82 (br d, J = 13.5 Hz,
1 H), 3.39-3.22 (m, 2H), 3.08 (br t, J = 12.0 Hz, 1H), 2.21 (brs, 2H), 2.06-1.89 (m, 2H), 1.63 (dd, J = 2.6, 6.6 Hz, 6H), 1.46 (d, J = 2.0 Hz, 9H); LCMS (ESI) [M+H]+: 349.2.
Figure imgf000354_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.49 (d, J = 1.7 Hz, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.91-7.82 (m, 2H), 7.70-7.62 (m, 2H), 4.71 (br d, J = 13.4 Hz, 1 H), 4.18 (s, 4H), 3.45-3.33 (m, 2H), 3.25 (br t, J = 11.1 Hz, 1 H), 3.02 (spt, J = 6.9 Hz, 1H), 2.34 (brd, J = 10.9 Hz, 1H), 2.23-2.11 (m, 3H), 1.33 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 431.1.
Figure imgf000354_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.06 (s, 1 H), 7.89-7.81 (m, 2H), 4.35 (d, J = 6.8 Hz, 2H), 4.25-4.11 (m, 2H), 3.25-3.18 (m, 1H), 3.09-2.97 (m, 2H), 2.21-2.12 (m, 2H), 2.01-1.89 (m, 2H), 1.50 (s, 9H), 1.41 (br d, J = 4.9 Hz, 1 H), 0.65-0.59 (m, 2H), 0.49-0.44 (m, 2H); LCMS (ESI) [M+H]+: 424.1.
Figure imgf000354_0004
1 H NMR (400 MHz, DMSO-de) d 8.30 (s, 1 H), 8.1 9 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.75 (dd, J = 1 .1 , 8.4 Hz, 1 H), 5.14 (quin, J = 6.6 Hz, 1 H), 3.93 (br d, J = 7.3 Hz, 1 H), 3.78 (br d, J = 8.2 Hz, 1 H), 3.68-3.60 (m,
1 H), 3.52-3.44 (m, 1 H), 3.40 (br d, J = 7.5 Hz, 1 H), 2.40 (br s, 1 H), 2.24 (br d, J = 6.8 Hz, 1 H), 1 .50 (d, J = 6.4 Hz, 6H), 1 .42 (s, 9H); LCMS (ESI) [M+H]+: 398.2.
Figure imgf000355_0001
1 H NMR (400 MHz, DMSO-de) d 9.05 (br s, 2H), 7.85 (d, J = 1 .3 Hz, 1 H), 7.80 (dd, J = 1 .5, 8.4 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 4.58 (spt, J = 6.9 Hz, 1 H), 3.52 (tt, J = 3.8, 10.9 Hz, 1 H), 3.38-3.33 (m, 2H), 3.07 (br t, J = 1 1 .2 Hz, 2H), 2.27 (br dd, J = 2.9, 14.1 Hz, 2H), 2.10-1 .98 (m, 2H), 1 .49 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 329.1 .
Figure imgf000355_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.08 (s, 1 H), 7.85-7.79 (d, J = 8.4 Hz 1 H), 7.75-7.68 (d, J = 8.4 Hz 1 H), 7.42-7.29 (m, 5H), 5.1 1 (s, 2H), 4.68 (br d, J = 5.5 Hz, 1 H), 4.07 (s, 3H), 3.73-3.55 (m, 1 H), 3.05- 2.90 (m, 1 H), 2.59 (s, 3H), 2.36-2.16 (m, 4H), 1 .94-1 .75 (m, 2H), 1 .43-1 .24 (m, 2H); LCMS (ESI) [M+H]+: 446.2.
Figure imgf000355_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.52 (s, 2H), 8.10 (s, 1 H), 7.86-7.81 (d, J = 8.4 Hz, 1 H), 7.76- 7.72 (d, J = 8.4 Hz, 1 H), 4.85 (td, J = 3.7, 13.6 Hz, 2H), 4.08 (s, 3H), 3.45-3.25 (m, 3H), 2.60 (s, 3H), 2.29 (br dd, J = 3.3, 13.6 Hz, 2H), 2.1 1 -1 .94 (m, 2H); LCMS (ESI) [M+H]+: 444.2.
Figure imgf000355_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.08 (s, 1 H), 7.82-7.80 (d,J = 8.0 Hz, 1 H) 7.73- 7.70 (d,J = 8.0 Hz, 1 H), 5.40-5.30 (m, 1 H), 4.07 (s, 3H), 3.89 (m, 1 H), 2.97 (tt, J = 3.5, 12.2 Hz, 1 H), 2.59 (s, 3H), 2.34- 2.15 (m, 4H), 1 .99 (s, 3H), 1 .86 (m, 2H), 1 .39-1 .20 (m, 2H); LCMS (ESI) [M+H]+: 354.2.
Figure imgf000356_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.78-7.70 (m, 1 H), 5.50- 5.47 (br s, 1 H), 4.09 (s, 3H), 4.08-3.99 (m, 1 H), 3.31 -3.23 (m, 1 H), 2.61 (s, 3H), 2.27-2.1 6 (m, 2H), 2.08- 2.00 (m, 2H), 1 .99 (s, 3H), 1 .95-1 .84 (m, 2H), 1 .73-1 .64 (m, 2H); LCMS (ESI) [M+H]+: 354.2.
Figure imgf000356_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.79-7.71 (m, 3H), 7.54- 7.40 (m, 3H), 6.10 (br d, J = 7.1 Hz, 1 H), 4.26 (tt, J = 4.1 , 7.9 Hz, 1 H), 4.09 (s, 3H), 3.32 (quin, J = 5.2 Hz, 1 H), 2.61 (s, 3H), 2.35-2.23 (m, 2H), 2.15-1 .98 (m, 4H), 1 .86-1 .73 (m, 2H); LCMS (ESI) [M+H]+: 416.3.
Figure imgf000356_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.07 (s, 1 H), 7.85 (q, J = 8.4 Hz, 2H), 4.98 (quin, J = 6.7 Hz, 1 H), 4.48-4.32 (m, 4H), 4.16-4.02 (m, 1 H), 1 .64 (d, J = 6.8 Hz, 6H), 1 .50-1 .45 (m, 9H); LCMS (ESI) [M+H]+: 384.2.
Figure imgf000356_0004
1 H NMR (400 MHz, DMSO-de) d 8.28 (s, 1 H), 8.14 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz,
1 H), 4.41 (d, J = 6.8 Hz, 2H), 3.93 (br d, J = 13.5 Hz, 2H), 3.45-3.32 (m, 1 H), 3.04-2.95 (m, 2H), 2.1 1 (br dd, J = 3.2, 13.8 Hz, 2H), 1 .84-1 .67 (m, 2H), 1 .51 (s, 3H), 1 .39-1 .26 (m, 1 H), 0.89-0.77 (m, 2H), 0.64-0.59 (m, 2H), 0.56-0.50 (m, 2H), 0.44-0.38 (m, 2H); LCMS (ESI) [M+H]+: 422.2.
Figure imgf000357_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.86-7.82 (m, 1 H), 7.80-7.71 (m, 3H), 7.55-7.42 (m, 3H), 5.99 (br d, J = 7.8 Hz, 1 H), 4.20-4.03 (m, 4H), 3.03 (tt, J = 3.2, 12.2 Hz, 1 H), 2.60 (s, 3H), 2.41 - 2.28 (m, 4H), 2.03-1 .84 (m, 2H), 1 .52-1 .36 (m, 2H); LCMS (ESI) [M+H]+: 41 6.3.
Figure imgf000357_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.70 (m, 1 H), 4.08 (s, 3H), 3.96-3.49 (m, 5H), 2.60 (s, 3H), 2.51 -2.32 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 384.2.
Figure imgf000357_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.83 (dd, J = 1 .0, 8.4 Hz, 1 H), 7.76-7.72 (d,J = 8.4 Hz, 1 H), 4.61 (t, J = 12.7 Hz, 2H), 4.27-4.1 0 (m, 2H), 4.08 (s, 3H), 3.32-3.10 (m, 3H), 2.60 (s, 3H), 2.24- 2.15 (m, 2H), 2.00 (br d, J = 4.9 Hz, 2H); LCMS (ESI) [M+H]+: 474.1 .
Figure imgf000357_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.71 (m, 1 H), 5.79 (spt, J = 6.2 Hz, 1 H), 4.25-4.15 (m, 2H), 4.09 (s, 3H), 3.37-3.20 (m, 3H), 2.61 (s, 3H), 2.32-2.21 (m, 2H), 2.12-1 .97 (m, 2H); LCMS (ESI) [M+H]+: 492.1 .
Figure imgf000357_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.07 (s, 1 H), 7.92-7.86 (m, 1 H), 7.85-7.80 (m, 1 H), 5.01 -4.91 (m, 1 H), 4.80 (s, 2H), 3.60 (s, 3H), 1 .63 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 273.1 .
Figure imgf000358_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.29 (s, 1 H), 8.06 (s, 1 H), 7.93-7.86 (m, 1 H), 7.83-7.77 (m, 1 H), 4.96 (spt, J = 6.8 Hz, 1 H), 4.83 (dd, J = 2.8, 10.7 Hz, 1 H), 4.24 (br d, J = 1 1 .7 Hz, 1 H), 3.84-3.62 (m, 1 H), 2.22-2.1 1 (m, 1 H), 2.09-1 .91 (m, 2H), 1 .86-1 .74 (m, 2H), 1 .73-1 .65 (m, 1 H), 1 .62 (dd, J = 1 .1 , 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 313.1 .
Figure imgf000358_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.06 (s, 1 H), 7.91 -7.85 (m, 1 H), 7.84-7.78 (m, 1 H), 5.29 (dd, J = 5.4, 7.8 Hz, 1 H), 4.97 (spt, J = 6.7 Hz, 1 H), 4.27-4.14 (m, 1 H), 4.1 1 -3.99 (m, 1 H), 2.55-2.42 (m, 1 H), 2.40-2.31 (m, 1 H), 2.28-2.04 (m, 2H), 1 .63 (dd, J = 1 .1 , 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 299.1 .
Figure imgf000358_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.16 (s, 1 H), 8.02 (s, 1 H), 7.88-7.79 (m, 2H), 4.80 (d, J = 7.0 Hz, 2H), 4.50 (d, J = 7.0 Hz, 2H),4.21 -4.08 (m, 5H), 3.29-3.20 (m, 1 H), 3.21 -3.09 (m, 2H), 2.18 (br d, J = 13.6 Hz, 2H), 2.02-1 .92 (m, 2H), 1 .75 (s, 3H); LCMS (ESI) [M+H]+: 398.1 .
Figure imgf000358_0004
1 H NMR (400 MHz, DMSO-de) d 8.28 (d, J = 0.9 Hz, 1 H), 8.17 (d, J = 0.9 Hz, 1 H), 7.94 (dd, J = 0.6, 8.4 Hz, 1 H), 7.77 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.69-7.64 (m, 2H), 7.60-7.56 (m, 2H), 7.24-6.96 (t, J = 55.6 Hz,
1 H), 4.55-4.45 (m, 1 H), 4.1 5 (s, 3H), 3.67-3.48 (m, 2H), 3.29-3.08 (m, 2H), 2.33-2.00 (m, 2H), 1 .91 -1 .75 (m, 2H); LCMS (ESI) [M+H]+: 438.2.
Figure imgf000359_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.16 (s, 1H), 8.02 (s, 1H), 7.87-7.78 (m, 2H), 4.31-3.96 (m, 5H), 3.26-3.16 (m, 1 H), 3.03 (br t, J = 11.1 Hz, 2H), 2.15 (br d, J = 11.5 Hz, 2H), 1.92 (br d, J = 9.3 Hz, 2H),
1.56 (s, 3H), 0.91 -0.84 (m, 2H), 0.67-0.55 (m, 2H); LCMS (ESI) [M+H]+: 382.1.
Figure imgf000359_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.76-7.69 (d, J = 8.4 Hz,
1 H), 7.42-7.32 (m, 2H), 7.25-7.08 (m, 3H), 4.96 (br d, J = 7.6 Hz, 1 H), 4.07 (s, 3H), 3.70 (br dd, J = 4.1 , 7.4 Hz, 1 H), 3.01 (br t, J = 12.2 Hz, 1H), 2.59 (s, 3H), 2.40-2.25 (m, 4H), 1.95-1.81 (m, 2H), 1.49-1.36 (m, 2H); LCMS (ESI) [M+H]+: 432.2.
Figure imgf000359_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.51 (s, 1 H), 8.15 (s, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.66- 7.36 (t,J = 59.2 Hz, 1H), 4.62 (brd, J = 13.6 Hz, 1H), 4.04 (br d, J = 13.9 Hz, 1H), 3.35- 3.24 (m, 2H), 3.01-2.90 (m, 1H), 2.31 (s, 2H), 2.22 (brd, J = 12.7 Hz, 2H), 2.04-1.86 (m, 2H), 1.08 (s,
9H); LCMS (ESI) [M+H]+: 418.
Figure imgf000359_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.51 (s, 1H), 8.15 (s, 1H), 8.07-8.01 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1 H), 7.67-7.37(t, J = 59.6 Hz,1 H), 7.45-7.40 (m, 1 H), 7.36-7.27(m, 3H), 4.78-4.63 (m, 1 H), 3.64-3.53 (m, 1H), 3.40-3.13 (m, 3H), 2.34 (br dd, J = 3.3, 13.6 Hz, 1H), 2.20-1.85 (m, 3H); LCMS (ESI) [M+H]+: 458.0.
Figure imgf000360_0001
1H NMR (400 MHz, CHLOROFORM-d) d 7.97 (br s, 1 H), 7.82 (br d, J = 6.4 Hz, 1 H), 7.66-7.50 (m, 2H), 4.78-4.64 (m, 1 H), 3.87-3.34 (m, 5H), 2.35-2.09 (m, 2H), 2.06-1.93 (m, 2H), 1.45-1.31 (m, 6H), 0.95-0.75 (m, 9H); LCMS (ESI) [M+H]+: 396.2.
Figure imgf000360_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.31-8.21 (m, 1H), 8.15-8.04 (m, 1H), 7.91-7.77 (m, 2H), 4.99 (quind, J = 6.6, 13.3 Hz, 1H), 4.69-4.39 (m, 4H), 4.14 (tt, J = 6.0, 8.9 Hz, 1H), 2.14-2.00 (m, 2H), 1.65 (d, J = 6.6 Hz, 6H), 1.15-1.03 (m, 9H); LCMS (ESI) [M+H]+: 382.1.
Figure imgf000360_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.80 (br s, 1H), 8.57 (s, 1H), 8.21 (s, 1 H), 8.14 (br d, J = 8.4 Hz, 1 H), 8.07 (s, 1 H), 7.90-7.76 (m, 3H), 4.97 (td, J = 6.6, 13.1 Hz, 1H), 4.56 (br d, J = 13.0 Hz, 1H), 4.33 (br s, 2H), 3.94 (br d, J = 14.1 Hz, 1H), 3.44-3.26 (m, 2H), 3.15 (br t, J = 11.5 Hz, 1H), 2.28 (br t, J = 12.5 Hz, 2H), 2.14-1.94 (m, 2H), 1.63 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 508.2.
Figure imgf000360_0004
1H NMR (400 MHz, DMSO-de) d 8.26 (s, 1H), 8.14 (s, 1H), 7.90 (d, J = 8.4 Hz, 1 H), 7.79-7.71 (m, 1H), 7.08 (d, J = 5.1 Hz, 1 H), 5.09 (spt, J = 6.7 Hz, 1 H), 4.03 (br d, J = 10.8 Hz, 2H), 3.56-3.45 (m, 1 H), 3.36- 3.22 (m, 2H), 2.21 (br dd, J = 3.1 , 13.2 Hz, 2H), 1.96-1.78 (m, 2H), 1.52 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 456.1.
Figure imgf000360_0005
1 H NMR (400 MHz, DMSO-de) d 8.30 (s, 1 H), 8.20 (br s, 2H), 8.14-8.08 (m, 1 H), 7.94 (br d, J = 8.3 Hz,
1 H), 7.75 (br d, J = 8.3 Hz, 1 H), 5.14 (td, J = 6.3, 12.8 Hz, 1 H), 4.36 (br d, J = 12.8 Hz, 1 H), 4.02-3.74 (m, 3H), 3.63-3.47 (m, 1 H), 3.30-3.21 (m, 1 H), 3.01 (br t, J = 1 1 .7 Hz, 1 H), 2.18 (br d, J = 12.1 Hz, 2H), 2.00- 1 .83 (m, 1 H), 1 .78-1 .61 (m, 1 H), 1 .51 (br d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 369.1 .
Figure imgf000361_0001
1 H NMR (300 MHz, CHLOROFORM-d) d 8.74 (s, 1 H), 8.46 (s, 2H), 8.12 (s, 1 H), 7.91 -7.80 (m, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 4.10 (s, 3H), 3.83 (d, J = 12.8 Hz, 2H), 3.12 (t, J = 10.3 Hz, 2H), 2.61 (s, 3H), 2.37 (d, J = 12.7 Hz, 2H), 2.29-2.16 (m, 2H); LCMS (ESI) [M+H]+: 376.1 .
Figure imgf000361_0002
1 H NMR (300 MHz, CHLOROFORM-d) d 8.21 (d, J = 14.0 Hz, 2H), 7.96-7.82 (m, 2H), 5.91 (t, J = 7.1 Hz, 1 H), 5.35 (t, J = 6.5 Hz, 2H), 5.17 (t, J = 7.2 Hz, 2H), 4.16 (s,2H), 3.02 (t, J = 12.0 Hz, 2H), 2.17 (d, J = 13.4 Hz, 2H), 2.07-1 .77 (m, 2H), 1 .50 (s, 8H); LCMS (ESI) [M+H]+: 426.
Figure imgf000361_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.16 (s, 1 H), 7.86 (dd, J = 1 .3, 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 4.80 (s, 2H), 4.08 (s, 3H), 3.60 (s, 3H), 2.60 (s, 3H); LCMS (ESI) [M+H]+: 259.1 .
Figure imgf000361_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.18 (s, 1 H), 7.87 (dd, J = 1 .1 , 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 4.83 (dd, J = 2.6, 10.5 Hz, 1 H), 4.24 (br d, J = 1 1 .8 Hz, 1 H), 4.07 (s, 3H), 3.75-3.67 (m, 1 H), 2.60 (s, 3H), 2.1 6 (br d, J = 15.8 Hz, 1 H), 2.08-1 .91 (m, 2H), 1 .84-1 .64 (m, 3H); LCMS (ESI) [M+H]+: 299.1 .
Figure imgf000362_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 7.85 (dd, J = 1 .3, 8.3 Hz, 1 H), 7.76-7.70 (m, 1 H), 5.29 (dd, J = 5.3, 7.9 Hz, 1 H), 4.24-4.15 (m, 1 H), 4.08 (s, 3H), 4.07-4.02 (m, 1 H), 2.60 (s, 3H), 2.54-2.43 (m, 1 H), 2.41 -2.32 (m, 1 H), 2.26-2.06 (m, 2H); LCMS (ESI) [M+H]+: 285.1 .
Figure imgf000362_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.40 (s, 1 H), 8.30 (dd, J = 1 .5, 8.8 Hz, 1 H), 7.69-7.61 (m, 1 H), 4.20-4.05 (m, 2H), 3.20 (tt, J = 3.9, 1 0.9 Hz, 1 H), 3.02 (br t, J = 1 1 .3 Hz, 2H), 2.66 (s, 3H), 2.15 (br d, J = 10.8 Hz, 2H), 1 .98-1 .88 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 385.1 .
Figure imgf000362_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.86-7.78 (m, 1 H), 7.71 (s, 1 H), 7.44-7.28 (m, 3H), 7.25-7.19 (m, 2H), 4.70-4.57 (m, 1 H), 4.52 (td, J = 7.0, 13.9 Hz, 1 H), 3.51 (br t, J = 13.9 Hz, 1 H), 3.28-3.19 (m, 2H), 3.16-3.05 (m, 1 H), 2.25 (br d, J = 13.4 Hz, 1 H), 2.08-1 .99 (m, 2H), 1 .90-1 .74 (m, 1 H), 1 .53 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 467.0.
Figure imgf000362_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.88 (d, J = 8.4 Hz, 1 H), 7.78 (s, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.59 (spt, J = 6.9 Hz, 1 H), 4.32-3.96 (m, 2H), 3.25-3.13 (m, 1 H), 3.05-3.00 (m, 2H), 2.18-2.10 (m, 2H),
1 .95-1 .89 (m, 2H), 1 .64-1 .56 (m, 9H), 0.92-0.86 (m, 2H), 0.69-0.61 (m, 2H); LCMS (ESI) [M+H]+: 427.1 .
Figure imgf000362_0005
1 H NMR (400 MHz, METHANOL-d4) d 8.32 (s, 1 H), 8.10 (s, 1 H), 7.96-7.78 (m, 2H), 4.39 (d, J = 6.8 Hz, 2H), 3.60-3.50 (m, 3H), 3.29-3.21 (m, 2H), 2.47 (br dd, J = 3.3, 14.5 Hz, 2H), 2.29-2.10 (m, 2H), 1 .44-1 .28 (m, 1 H), 0.64-0.53 (m, 2H), 0.46 (m, 2H); LCMS (ESI) [M+H]+: 324.1 .
Figure imgf000363_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.06 (s, 1 H), 7.92-7.78 (m, 2H), 4.61 (br d, J = 14.1 Hz, 1 H), 4.36 (d, J = 6.8 Hz, 2H), 3.98 (br d, J = 13.4 Hz, 1 H), 3.37-3.22 (m, 2H), 3.05-2.90 (m, 1 H), 2.40 (d, J = 4.0 Hz, 2H), 2.23 (br d, J = 13.3 Hz, 2H), 2.06-1 .86 (m, 2H), 1 .40 (br d, J = 7.2 Hz, 1 H), 1 .1 8 (s, 3H), 0.67-0.55 (m, 2H), 0.49-0.40 (m, 6H); LCMS (ESI) [M+H]+: 420.2.
Figure imgf000363_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.85 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.75 (s, 1 H), 7.36-7.30 (m, 2H), 7.24 (m, 3H), 4.60-4.50 (m, 2H), 3.98-3.94 (m, 1 H), 3.33-3.08 (m, 3H), 2.91 (td, J = 6.9, 13.8 Hz, 1 H), 2.30-1 .90 (m, 4H), 1 .56 (d, J = 7.0 Hz, 6H), 1 .23 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 475.1 .
Figure imgf000363_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.81 (dd, J = 1 .1 , 8.3 Hz, 1 H), 7.71 (s, 1 H), 7.22 (d, J = 8.3 Hz, 1 H), 4.59-4.48 (m, 2H), 3.96 (br d, J = 13.8 Hz, 1 H), 3.28-3.15 (m, 2H), 2.87 (br t, J = 1 1 .2 Hz, 1 H), 2.24 (d, J = 1 .7 Hz, 2H), 2.12 (br d, J = 13.2 Hz, 2H), 1 .94-1 .79 (m, 2H), 1 .52 (d, J = 7.0 Hz, 6H), 1 .00 (s, 9H); LCMS (ESI) [M+H]+: 427.1 .
Figure imgf000363_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.06 (s, 1 H), 7.87-7.80 (m, 2H), 4.96 (spt, J = 6.7 Hz, 1 H), 4.57 (br d, J = 13.6 Hz, 1 H), 3.93 (br d, J = 14.5 Hz, 1 H), 3.66-3.51 (m, 1 H), 3.30-3.22 (m, 1 H), 2.43-2.21 (m, 6H), 1 .62 (d, J = 7.0 Hz, 6H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 428.2.
Figure imgf000364_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.08 (s, 1 H), 7.90-7.82 (m, 2H), 5.02-4.95 (m, 1 H), 4.08-4.00 (m, 2H), 3.40 (br d, J = 9.8 Hz, 2H), 2.40-2.24 (m, 4H), 1 .65 (d, J = 6.7 Hz, 6H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 430.2.
Figure imgf000364_0002
1 H NMR (400 MHz, DMSO-de) d 8.47 (s, 1 H), 8.45 (s, 1 H), 8.36-8.07 (t, J = 58.8, 1 H), 8.09-8.05 (m, 1 H), 7.99-7.95 (m, 1 H), 7.36-7.28 (m, 4H), 4.05 (br d, J = 4.6 Hz, 2H), 3.54-3.41 (m, 1 H), 3.26-3.17 (m, 2H), 2.98-2.88 (m, 1 H), 2.17 (br dd, J = 3.2, 13.3 Hz, 2H), 1 .91 -1 .80 (m, 2H), 1 .23 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 466.0.
Figure imgf000364_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.16 (s, 1 H), 8.05 (s, 1 H), 7.84-7.77 (m, 2H), 4.94 (m, 1 H), 3.92- 3.72 (m, 2H), 3.61 -3.48 (m, 2H), 2.40 (m, 2H), 2.17 (t, J = 3.1 Hz, 1 H), 1 .62 (d, J = 7.0 Hz, 6H), 1 .47 (s, 9H); LCMS (ESI) [M+H]+: 410.2.
Figure imgf000364_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.44 (s, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 8.04 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 6.89 (br s, 1 H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.21 (m, 2H), 3.71 (br t, J = 5.5 Hz, 2H), 2.77 (br s, J = 1 .6 Hz, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 426.2.
Figure imgf000364_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.08 (s, 1 H), 7.86 (m, 2H), 4.97 (td, J = 6.6, 13.2 Hz, 1 H), 4.20-4.12 (m, 2H), 3.12-2.87 (m, 3H), 2.08 (br d, J = 1 1 .2 Hz, 2H), 1 .95-1 .79 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000365_0001
1 H NMR (400 MHz, METHANOL-d4) d 8.36 (s, 1 H), 8.13 (s, 1 H), 7.97-7.82 (m, 2H), 5.08 (td, J = 6.6, 13.2 Hz, 1 H), 4.25-4.12 (m, 1 H), 3.92-3.80 (m, 2H), 3.70-3.49 (m, 2H), 2.79-2.64 (m, 1 H), 2.52 (qd, J = 6.9, 13.6 Hz, 1 H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 298.1 .
Figure imgf000365_0002
1 H NMR (400 MHz, DMSO-de) d 9.33 (br s, 2H), 8.34 (s, 1 H), 8.21 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 5.14 (td, J = 6.6, 13.0 Hz, 1 H), 4.64-4.45 (m, 1 H), 4.41 -4.28 (m, 4H), 1 .51 (d, J = 6.5 Hz, 6H); LCMS (ESI) [M+H]+: 284.1 .
Figure imgf000365_0003
1 H NMR (400 MHz, DMSO-de) d 9.04 (br s, 2H), 8.56 (s, 1 H), 8.50-8.21 (t, J = 58 Hz, 1 H), 8.47 (s, 1 H), 8.1 1 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 3.60-3.51 (m, 1 H), 3.36 (br d, J = 12.8 Hz, 2H), 3.09 (br t, J = 1 1 .0 Hz, 2H), 2.30 (br d, J = 14.3 Hz, 2H), 2.14-2.01 (m, 2H); LCMS (ESI) [M+H]+: 320.1 .
Figure imgf000365_0004
1 H NMR (400 MHz, DMSO-de) d 9.31 -8.98 (m, 2H), 8.36 (s, 1 H), 7.94 (br d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 4.08 (s, 3H), 3.62-3.58 (m, 1 H), 3.39-3.24 (m, 3H), 3.15-3.01 (m, 2H), 2.52 (s, 3H), 2.25-2.1 5 (m, 2H), 2.09-1 .95 (m, 2H); LCMS (ESI) [M+H]+: 298.1 .
Figure imgf000366_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 7.86-7.82 (m, 1 H), 7.79-7.75 (m, 1 H), 4.66 (br d, J = 13.8 Hz, 1 H), 4.09 (s, 3H), 4.04 (br d, J = 15.0 Hz, 1 H), 3.26 (br t, J = 1 1 .7 Hz, 1 H), 3.18-3.08 (m, 1 H), 2.89 (br t, J = 1 1 .8 Hz, 1 H), 2.60 (s, 3H), 2.31 (s, 2H), 2.14 (br dd, J = 3.1 , 13.6 Hz, 2H), 1 .99-1 .80 (m, 2H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 396.2.
Figure imgf000366_0002
1 H NMR (400 MHz, DMSO-de) d 8.55 (s, 1 H), 8.49-8.21 (t, J = 58 Hz, 1 H), 8.48 (s, 1 H), 8.1 1 (d, J = 8.2 Hz, 1 H), 7.99 (dd, J = 1 .2, 8.4 Hz, 1 H), 4.05-3.80 (m, 2H), 3.41 (tt, J = 3.9, 1 1 .0 Hz, 1 H), 3.02 (br t, J =
10.8 Hz, 2H), 2.16-2.07 (m, 2H), 1 .79-1 .66 (m, 2H), 1 .49 (s, 3H), 0.83-0.78 (m, 2H), 0.67-0.57 (m, 2H); LCMS (ESI) [M+H]+: 418.1 .
Figure imgf000366_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28 (s, 1 H), 8.10 (s, 1 H), 7.87 (m, 2H), 4.98 (td, J = 6.7, 13.3 Hz, 1 H), 4.67 (br d, J = 13.5 Hz, 1 H), 4.06-4.00 (m, 1 H), 3.27 (br t, J = 1 1 .6 Hz, 1 H), 3.18-3.07 (m, 1 H), 2.90 (br t, J = 1 1 .4 Hz, 1 H), 2.33 (d, J = 1 .1 Hz, 2H), 2.16 (br dd, J = 3.1 , 13.2 Hz, 2H), 2.02-1 .78 (m, 2H), 1 .65 (d, J = 6.8 Hz, 6H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 410.2.
Figure imgf000366_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 7.85 (dd, J = 1 .2 ,8.4 Hz, 1 H), 7.78-7.72 (d,J = 8.4 Hz,1 H), 7.41 -7.32 (m, 2H), 7.24-7.17 (m, 1 H), 7.14 (d, J = 7.7 Hz, 2H), 5.1 1 (br d, J = 6.5 Hz, 1 H), 4.09 (s, 3H), 3.95-3.83 (m, 1 H), 3.31 -3.21 (m, 1 H), 2.61 (s, 3H), 2.29-2.18 (m, 2H), 2.1 1 -1 .92 (m, 4H), 1 .89-1 .78 (m, 2H); LCMS (ESI) [M+H]+: 432.2.
Figure imgf000367_0001
1H NMR (400 MHz, MATHANOL-d4) d 8.27 (s, 1 H), 7.98-7.83 (m, 2H), 4.42-4.25 (m, 1 H), 4.11 (s, 3H), 3.99 (td, J = 8.6, 13.6 Hz, 1H), 3.88-3.74 (m, 1H), 3.69 (brd, J = 13.6 Hz, 1H), 3.46-3.35 (m, 1H), 2.72- 2.56 (m, 5H); LCMS (ESI) [M+H]+: 334.1.
Figure imgf000367_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1H), 7.84 (dd, J = 1.2, 8.4 Hz, 1H), 7.73 (dd, J = 0.6, 8.4 Hz, 1 H), 7.42-7.30 (m, 5H), 5.11 (s, 2H), 4.86-4.82 (m, 1 H), 4.08 (s, 3H), 3.86-3.82 (m, 1 H), 3.27-3.18 (m, 1 H), 2.60 (s, 3H), 2.22-2.10 (m, 2H), 2.07-1.97 (m, 2H), 1.91 -1.87 (m, 2H), 1.81 -1.69 (m, 2H); LCMS (ESI) [M+H]+: 446.2.
Figure imgf000367_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.15 (d, J = 0.7 Hz, 1H), 7.99 (s, 1H), 7.82-7.77 (m, 1H), 7.76- 7.72 (m, 1 H), 4.89 (spt, J = 6.7 Hz, 1H), 4.40-3.98 (m, 2H), 3.75-3.58 (m, 1H), 3.51-3.36 (m, 1H), 3.31- 3.13 (m, 1 H), 2.39-2.12 (m, 2H), 1.56 (d, J = 6.6 Hz, 6H), 1.48-1.32 (m, 9H); LCMS (ESI) [M+H]+: 448.2.
Figure imgf000367_0004
1H NMR (300 MHz, CHLOROFORM-d) d 8.39 (s, 1 H), 8.12 (s, 2H), 7.85 (dd, J = 8.4, 1.3 Hz, 1 H), 7.75 (dd, J = 8.4, 0.9 Hz, 1H), 7.26-7.14 (m, 1H), 4.09 (s, 3H), 3.80 (d, J = 12.7 Hz, 2H), 3.25 (m, 1H), 3.07 (d, J = 14.2 Hz, 2H), 2.61 (s, 3H), 2.32 (s, 2H), 2.26-2.16 (m, 1H); LCMS (ESI) [M+H]+: 375.1.
Figure imgf000367_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.07 (s, 1 H), 7.88-7.80 (m, 2H), 4.98 (td, J = 6.6, 13.4 Hz, 1 H), 4.65-4.50 (m, 1 H), 3.80-3.70 (m, 1 H), 3.21 (br d, J = 4.0 Hz, 1 H), 2.1 6 (br d, J = 7.9 Hz, 2H), 2.05-1 .97 (m, 2H), 1 .85 (br d, J = 4.4 Hz, 2H), 1 .75-1 .70 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .46 (s, 9H); LCMS (ESI) [M+H]+: 426.2.
Figure imgf000368_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.04 (s, 1 H), 7.79-7.76 (m, 1 H), 7.73-7.70 (m, 1 H), 4.08 (s, 3H), 3.76-3.70 (m, 4H), 3.65-3.59 (m, 4H), 2.61 (s, 3H), 1 .52 (s, 9H); LCMS (ESI) [M+H]+: 399.1 .
Figure imgf000368_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.06 (s, 1 H), 7.88-7.78 (m, 2H), 5.50-5.35 (m, 1 H), 4.96 (spt, J = 6.7 Hz, 1 H), 4.04 (td, J = 3.9, 8.2 Hz, 1 H), 3.30-3.22 (m, 1 H), 2.25-2.16 (m, 2H), 2.03 (qd, J = 4.6, 9.2 Hz, 2H), 1 .98 (s, 3H), 1 .93-1 .84 (m, 2H), 1 .70-1 .60 (m, 8H); LCMS (ESI) [M+H]+: 368.2.
Figure imgf000368_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.18 (d, J = 8.4 Hz, 1 H), 8.09 (s, 1 H), 7.95 (d, J = 8.2 Hz, 1 H), 5.52 (spt, J = 6.7 Hz, 1 H), 4.20-4.1 0 (m, 2H), 3.26 (tt, J = 3.8, 1 1 .1 Hz, 1 H), 2.99 (br t, J = 12.0 Hz, 2H), 2.16 (br d, J = 10.4 Hz, 2H), 2.00-1 .89 (m, 2H), 1 .59 (d, J = 6.6 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI)
[M+H]+: 413.2.
Figure imgf000368_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 2H), 8.10 (s, 1 H), 7.83 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.73 (dd, J = 0.6, 8.4 Hz, 1 H), 4.74 (td, J = 3.5, 13.6 Hz, 2H), 4.07 (s, 3H), 3.32 (tt, J = 4.0, 1 1 .0 Hz, 1 H), 3.20 (ddd, J = 2.8, 1 1 .3, 13.7 Hz, 2H), 2.60 (s, 3H), 2.24 (br dd, J = 3.2, 13.5 Hz, 2H), 2.07-1 .92 (m, 2H), 1 .73 (tt, J = 5.1 , 8.5 Hz, 1 H), 0.97-0.86 (m, 2H), 0.63-0.57 (m, 2H); LCMS (ESI) [M+H]+: 416.1 .
Figure imgf000369_0001
1 H NMR (400 MHz, DMSO-de) d 8.29 (s, 1 H), 8.1 9 (s, 1 H), 7.92 (d, J = 8.3 Hz, 1 H), 7.75 (dd, J = 1 .0, 8.4 Hz, 1 H), 5.14 (spt, J = 6.5 Hz, 1 H), 3.93 (br d, J = 6.7 Hz, 1 H), 3.78 (br d, J = 7.2 Hz, 1 H), 3.68-3.61 (m,
1 H), 3.51 -3.44 (m, 1 H), 3.40 (br d, J = 6.6 Hz, 1 H), 2.46-2.33 (m, 1 H), 2.24 (br d, J = 7.1 Hz, 1 H), 1 .50 (d, J = 6.6 Hz, 6H), 1 .42 (s, 9H); LCMS (ESI) [M+H]+: 398.2.
Figure imgf000369_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.08 (s, 1 H), 7.92-7.81 (m, 2H), 4.98 (quind, J = 6.7, 13.3 Hz, 1 H), 4.83 (d, J = 7.1 Hz, 2H), 4.53 (d, J = 7.5 Hz, 2H), 4.1 7 (br s, 2H), 3.35-3.20 (m, 1 H), 3.13 (br s, 2H), 2.22 (br d, J = 1 1 .1 Hz, 2H), 2.06-1 .92 (m, 2H), 1 .78 (s, 3H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 426.1 .
Figure imgf000369_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.72 (m, 1 H), 4.53 (dq, J = 2.2, 8.4 Hz, 2H), 4.20 (br t, J = 16.1 Hz, 2H), 4.08 (s, 3H), 3.32-3.23 (m, 1 H), 3.22-3.10 (m, 2H), 2.60 (s, 3H), 2.22 (br d, J = 1 1 .9 Hz, 2H), 2.07-1 .94 (m, 2H); LCMS (ESI) [M+H]+: 424.1 .
Figure imgf000369_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.84 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.73 (dd, J = 0.7, 8.4 Hz, 1 H), 4.08 (s, 3H), 3.60 (t, J = 5.9 Hz, 2H), 3.54 (q, J = 7.0 Hz, 2H), 3.10-2.99 (m, 3H), 2.65 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H), 2.27 (dt, J = 2.3, 1 1 .3 Hz, 2H), 2.21 -2.03 (m, 4H), 1 .23 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 370.2.
Figure imgf000370_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.06 (s, 1 H), 7.89-7.78 (m, 2H), 4.97 (td, J = 6.6, 13.4 Hz, 1 H), 4.02-3.43 (m, 5H), 2.52-2.32 (m, 2H), 1.64 (d, J = 6.6 Hz, 6H), 1.50 (s, 9H); LCMS (ESI) [M+H]+: 398.2.
Figure imgf000370_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.28 (s, 1H), 8.10 (s, 1H), 7.91-7.81 (m, 2H), 7.47-7.40 (m, 1H), 7.39-7.28 (m, 3H), 4.98 (td, J = 6.6, 13.5 Hz, 1H), 4.76 (br t, J = 12.5 Hz, 1H), 3.65-3.52 (m, 1H), 3.36- 3.10 (m, 3H), 2.28 (br dd, J = 3.5, 13.6 Hz, 1 H), 2.15-1.95 (m, 2.5H), 1.94-1.79 (m, 0.5H), 1.65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 450.1.
Figure imgf000370_0003
1H NMR (400 MHz, DMSO-de) d 9.13 (s, 2H), 8.49 (s, 1H), 8.25 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.80 (dd, J = 1.1, 8.6 Hz, 1 H), 5.22 (spt, J = 6.4 Hz, 1H), 3.39-3.35 (m, 1H), 3.33-3.24 (m, 2H), 3.14-3.00 (m, 2H), 2.20 (br d, J = 11.8 Hz, 2H), 2.08-1.92 (m, 2H), 1.50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 312.1.
Figure imgf000370_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.16 (s, 1H), 8.12 (s, 1H), 7.94-7.89 (m, 1H), 7.87-7.82 (m, 1H), 5.46 (q, J = 7.2 Hz, 1 H), 4.20-4.05 (m 2H), 3.72 (s, 3H), 3.21 (tt, J = 3.9, 10.8 Hz, 1 H), 3.02 (br t, J = 11.9 Hz, 2H), 2.15 (br d, J = 10.5 Hz, 2H), 1.98 (d, J = 7.2 Hz, 3H), 1.97-1.87 (m, 2H), 1.49 (s, 9H); LCMS (ESI) [M+H]+: 456.2.
Figure imgf000370_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 8.04 (s, 1 H), 7.77 (m, 2H), 4.95 (m, 1 H), 3.99-3.87 (m, 2H), 3.74-3.56 (m, 4H), 3.47-3.24 (m, 2H), 3.07 (br s, 2H), 1 .61 (d, J = 7.0 Hz, 6H), 1 .47 (s, 9H) LCMS (ESI) [M+H]+: 439.2.
Figure imgf000371_0001
1 H NMR (400 MHz, METHANOL-d4) d 8.22 (s, 1 H), 8.09 (s, 1 H), 7.84 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.73 (dd, J = 0.7, 8.4 Hz, 1 H), 5.03 (m, 1 H), 3.93 (br dd, J = 7.4, 1 1 .2 Hz, 2H), 3.75 (dd, J = 3.1 , 1 1 .2 Hz, 2H), 3.65 (br dd, J = 6.8, 1 1 .6 Hz, 2H), 3.41 -3.32 (m, 3H), 3.29 (m, 1 H), 1 .59 (d, J = 6.6 Hz, 6H); LCMS (ESI)
[M+H]+: 339.1 .
Figure imgf000371_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.92-7.84 (m, 3H), 7.79 (d, J = 1 .1 Hz, 1 H), 7.56-7.51 (m, 1 H), 7.49-7.43 (m, 2H), 7.36-7.28 (m, 2H), 4.64-4.49 (m, 2H), 4.32 (t, J = 3.2 Hz, 2H), 3.93 (br d, J = 13.7 Hz,
1 H), 3.40-3.30 (m, 2H), 3.14 (br t, J = 1 1 .0 Hz, 1 H), 2.33-2.21 (m, 2H), 2.09-1 .94 (m, 2H), 1 .60 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 490.2.
Figure imgf000371_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.29 (s, 1 H), 8.04 (dd, J = 1 .2, 8.3 Hz, 1 H), 7.81 (dd, J = 0.6, 8.2 Hz, 1 H), 4.20-4.05 (m, 2H), 3.46 (spt, J = 7.0 Hz, 1 H), 3.21 (tt, J = 3.9, 10.9 Hz, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.15 (br dd, J = 3.0, 13.3 Hz, 2H), 1 .92 (dtd, J = 4.2, 1 1 .1 , 13.5 Hz, 2H), 1 .53 (d, J = 7.0 Hz, 6H),
1 .49 (s, 9H); LCMS (ESI) [M+H]+: 413.2.
Figure imgf000371_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28 (s, 1 H), 8.05 (dd, J = 1 .1 , 8.2 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 4.20-4.05 (m, 2H), 3.20 (tt, J = 3.9, 10.9 Hz, 1 H), 3.01 (br t, J = 1 1 .9 Hz, 2H), 2.63 (s, 3H), 2.14 (br dd, J = 3.0, 13.3 Hz, 2H), 1 .97-1 .85 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-55]+: 329.1 .
Figure imgf000372_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.87 (m, 1 H), 7.86-7.81 (m, 1 H), 4.95-4.83 (m, 1 H), 4.27-4.02 (m, 4H), 3.21 (tt, J = 3.9, 10.9 Hz, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.82-2.78 (m, 1 H), 2.16 (br dd, J = 2.6, 13.3 Hz, 2H), 2.00-1 .87 (m, 2H), 1 .60 (d, J = 6.7 Hz, 3H), 1 .49 (s, 9H) ;
LCMS (ESI) [M+H]+: 428.2.
Figure imgf000372_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.06 (s, 1 H), 7.88-7.78 (m, 2H), 5.01 -4.93 (m, 1 H), 3.19-2.99 (m, 4H), 2.37-2.24 (m, 4H), 1 .63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 330.1 .
Figure imgf000372_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.69 (s, 1 H), 7.45-7.41 (m, 1 H), 7.36-7.32 (m, 1 H), 4.20 (br d, J = 13.5 Hz, 1 H), 3.68 (s, 3H), 3.57 (br d, J = 14.1 Hz, 1 H), 2.92-2.84 (m, 2H), 2.58 (br t, J = 1 1 .8 Hz, 1 H), 2.20 (s, 3H), 2.00 (d, J = 3.1 Hz, 2H), 1 .83 (br d, J = 13.2 Hz, 2H), 1 .62-1 .50 (m, 2H), 0.78 (s, 3H), 0.08- 0.03 (m, 4H); LCMS (ESI) [M+H]+: 394.2.
Figure imgf000372_0004
1 H NMR (300 MHz, CHLOROFORM-d) d 8.1 1 (s, J = 1 .0 Hz, 1 H), 7.85 (dd, J = 8.4, 1 .3 Hz, 1 H), 7.75 (dd, J = 8.4, 0.8 Hz, 1 H), 7.22 (d, J = 3.6 Hz, 1 H), 6.62 (d, J = 3.6 Hz, 1 H), 4.14 (m, 2H), 4.09 (s, 3H), 3.32 (td, J = 12.9, 1 1 .9, 3.1 Hz, 2H), 2.61 (s, 3H), 2.38-2.25 (m, 2H), 2.25-2.10 (m, 2H); LCMS (ESI) [M+H]+: 381 .1 .
Figure imgf000373_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 8.05 (s, 1 H), 7.78 (s, 2H), 4.95 (td, J = 6.6, 13.3 Hz, 1 H), 3.93-3.57 (m, 8H), 2.41 (s, 2H), 1 .63 (d, J = 6.7 Hz, 6H), 1 .18 (s, 3H), 0.58-0.37 (m, 4H); LCMS (ESI) [M+H]+: 409.2.
Figure imgf000373_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 8.05 (s, 1 H), 7.78 (d, J = 0.9 Hz, 2H), 5.03-4.86 (m, 1 H), 3.84-3.49 (m, 8H), 1 .62 (d, J = 6.7 Hz, 6H), 1 .59 (s, 3H), 0.95-0.88 (m, 2H), 0.72-0.64 (m, 2H);
LCMS (ESI) [M+H]+: 41 1 .2.
Figure imgf000373_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 8.04 (s, 1 H), 7.79-7.75 (m, 2H), 5.01 -4.90 (m, 1 H), 3.96 (td, J = 7.9, 10.8 Hz, 2H), 3.88-3.77 (m, 2H), 3.68-3.50 (m, 3H), 3.45 (dd, J = 5.3, 10.7 Hz, 1 H), 3.23- 3.03 (m, 2H), 2.19 (s, 2H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .06 (s, 9H); LCMS (ESI) [M+H]+: 437.2.
Figure imgf000373_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.04 (s, 1 H), 7.86-7.74 (m, 2H), 5.02-4.89 (m, 1 H), 4.02 (d, J = 1 1 .5 Hz, 1 H), 3.81 (d, J = 1 1 .5 Hz, 1 H), 3.50 (dt, J = 2.8, 1 1 .9 Hz, 2H), 2.32-2.16 (m, 3H),
1 .61 (dd, J = 6.7, 1 1 .7 Hz, 6H), 1 .1 9 (s, 9H); LCMS (ESI) [M+H]+: 410.2.
Figure imgf000373_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.62 (d, J = 4.2 Hz, 1 H), 8.29 (d, J = 0.9 Hz, 1 H), 8.10 (s, 1 H), 7.87 (s, 2H), 7.82 (dt, J = 1 .8, 7.7 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 1 H), 7.36 (ddd, J = 1 .1 , 4.9, 7.7 Hz, 1 H), 4.99 (td, J = 6.6, 13.4 Hz, 1 H), 4.74 (br d, J = 13.9 Hz, 1 H), 4.08 (br d, J = 12.6 Hz, 1 H), 3.40-3.27 (m, 1 H), 3.26-3.1 0 (m, 2H), 2.26 (br d, J = 1 0.6 Hz, 1 H), 2.16-1 .95 (m, 3H), 1 .65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 417.1 .
Figure imgf000374_0001
1 H NMR (400 MHz, METHANOL-d4) d 8.27 (s, 1 H), 8.08 (s, 1 H), 7.90-7.83 (m, 2H), 4.14 (s, 3H), 3.59-3.50 (m, 3H), 3.28-3.21 (m, 2H), 2.46 (br dd, J = 3.6, 14.9 Hz, 2H), 2.24-2.13 (m, 2H); LCMS (ESI) [M+H]+: 284.1 .
Figure imgf000374_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.63 (d, J = 1 .8 Hz, 1 H), 8.10 (d, J = 0.6 Hz, 1 H), 7.96 (d, J =
0.7 Hz, 1 H), 7.81 -7.73 (m, 3H), 7.59 (d, J = 8.2 Hz, 1 H), 5.42 (s, 1 H), 5.19 (s, 1 H), 4.62 (br d, J = 13.4 Hz, 1 H), 4.09 (s, 4H), 3.36-3.27 (m, 2H), 3.22-3.1 1 (m, 1 H), 2.30-2.20 (m, 1 H), 2.14-2.03 (m, 6H); LCMS (ESI) [M+H]+: 429.2.
Figure imgf000374_0003
1 H NMR (400 MHz, METHANOL-d4) d 8.25-8.12 (m, 1 H), 7.83 (br s, 2H), 4.47 (br d, J = 13.4 Hz, 1 H), 4.14-4.01 (m, 6H), 3.63 (br s, 2H), 3.47-3.35 (m, 2H), 3.07-2.90 (m, 2H), 2.83 (br d, J = 5.7 Hz, 2H), 2.59 (s, 3H), 2.34-2.18 (m, 2H), 2.03-1 .83 (m, 2H), 1 .45 (s, 9H); LCMS (ESI) [M+H]+: 495.3.
Figure imgf000374_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.1 1 (s, 1 H), 7.92-7.86 (m, 1 H), 7.86-7.79 (m, 1 H), 5.17-5.02 (m, 1 H), 4.91 (dd, J = 8.0, 9.2 Hz, 0.5H), 4.84-4.74 (m, 1 H), 4.67 (dd, J = 4.9, 9.3 Hz, 0.5H),
4.16 (br s, 2H), 3.21 (tt, J = 3.9, 10.9 Hz, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.22-2.09 (m, 2H), 2.02-1 .87 (m, 2H), 1 .66 (dd, J = 1 .6, 6.8 Hz, 3H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 430.1 .
Figure imgf000375_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 7.89 (dd, J = 0.9, 8.4 Hz, 1 H), 7.77 (d, J = 8.4 Hz,
1 H), 4.31 (br s, 1 H), 4.22-4.14 (m, 1 H), 4.13 (s, 3H), 3.79-3.66 (m, 1 H), 3.48 (br d, J = 14.5 Hz, 1 H), 3.27 (br t, J = 10.6 Hz, 1 H), 2.65 (s, 3H), 2.42-2.30 (m, 1 H), 2.30-2.20 (m, 1 H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 434.2.
Figure imgf000375_0002
1 H NMR (400 MHz, DMSO-de) d 8.44 (s, 1 H), 8.21 (s, 1 H), 7.98 (m, J = 8.4 Hz, 1 H), 7.80 (dd, J = 0.9, 8.4 Hz, 1 H), 7.53-7.48 (m, 2H), 7.47-7.42 (m, 2H), 5.18 (spt, J = 6.7 Hz, 1 H), 4.00-4.2 (m, 2H), 3.35-3.16 (m, 3H), 2.1 0 (br d, J = 10.8 Hz, 2H), 1 .90-1 .71 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 450.1 .
Figure imgf000375_0003
1 H NMR (400 MHz, DMSO-de) d 8.44 (s, 1 H), 8.21 (s, 1 H), 7.98 (m, J = 8.6 Hz, 1 H), 7.81 (dd, J = 1 .0, 8.5 Hz, 1 H), 7.51 (dt, J = 5.7, 7.9 Hz, 1 H), 7.32-7.20 (m, 3H), 5.18 (spt, J = 6.6 Hz, 1 H), 4.00-4.20 (m, 2H), 3.36-3.16 (m, 3H), 2.1 1 (br d, J = 10.6 Hz, 2H), 1 .89-1 .75 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 434.1 .
Figure imgf000375_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.89 (dd, J = 1 .5, 8.4 Hz, 1 H), 7.79 (s, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.96 (spt, J = 6.2 Hz, 1 H), 4.64-4.53 (m, 1 H), 4.19 (br d, J = 1 1 .9 Hz, 2H), 3.20 (tt, J = 3.9, 10.9 Hz, 1 H), 3.1 1 -2.99 (m, 2H), 2.1 5 (br dd, J = 3.1 , 13.2 Hz, 2H), 1 .99-1 .87 (m, 2H), 1 .60 (d, J = 6.8 Hz, 6H),
1 .27 (d, J = 6.2 Hz, 6H); LCMS (ESI) [M+H]+: 41 5.2.
Figure imgf000375_0005
1 H NMR (400 MHz, METHANOL-d4) d 8.35 (s, 1 H), 8.12 (s, 1 H), 7.93-7.84 (m, 2H), 5.13-5.02 (m, 1 H), 4.36-4.21 (m, 1 H), 3.99 (td, J = 8.5, 13.4 Hz, 1 H), 3.86-3.63 (m, 2H), 3.43-3.34 (m, 1 H), 2.68-2.56 (m,
2H), 1 .60 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 348.1 .
Figure imgf000376_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 7.99 (s, 1 H), 7.80-7.72 (m, 2H), 7.03 (br d, J = 10.3 Hz, 1 H), 4.95-4.84 (m, 1 H), 4.1 1 (q, J = 5.0 Hz, 1 H), 3.98-3.78 (m, 1 H), 3.52-3.35 (m, 1 H), 2.35-2.14 (m, 2H), 1 .56 (d, J = 6.6 Hz, 6H), 1 .45 (s, 9H); LCMS (ESI) [M+H]+: 428.2.
Figure imgf000376_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.31 -8.23 (m, 1 H), 8.09 (s, 1 H), 7.94-7.89 (m, 1 H), 7.86-7.80 (m, 1 H), 5.08-4.93 (m, 1 H), 4.28 (br s, 2H), 3.69 (br d, J = 5.0 Hz, 2H), 2.85 (br s, 2H), 1 .65 (dd, J = 1 .3, 6.7 Hz, 6H), 1 .53 (d, J = 1 .3 Hz, 9H); LCMS (ESI) [M+H]+: 428.2.
Figure imgf000376_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.84 (s, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 6.40 (dd, J = 8.8, 2.0 Hz,
1 H), 6.22 (s, 1 H), 4.79-4.61 (m, 1 H), 3.71 (s, 4H), 3.43 (t, J = 5.6 Hz, 4H), 1 .81 (br t, J = 5.2 Hz, 4H), 1 .56 (d, J = 6.8 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 385.2.
Figure imgf000376_0004
1 H NMR (400 MHz, METHANOL-d4) d 8.29 (s, 1 H), 7.97-7.85 (m, 2H), 4.80 (td, J = 9.1 , 13.6 Hz, 0.7H), 4.63 (br d, J = 14.2 Hz, 0.4H), 4.34-4.16 (m, 2.4H), 4.13 (s, 3H), 4.10-3.98 (m, 1 .5H), 3.96-3.79 (m, 0.6H), 3.66-3.48 (m, 1 H), 3.33-3.25 (m, 0.4H), 2.64 (s, 3H), 2.56-2.26 (m, 2H); LCMS (ESI) [M+H]+: 391 .1 .
Figure imgf000376_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (d, J = 0.9 Hz, 1 H), 8.03 (s, 1 H), 7.81 -7.74 (m, 2H), 5.03- 4.87 (m, 1 H), 4.03-3.90 (m, 2H), 3.84-3.67 (m, 2H), 3.43-3.32 (m, 2H), 3.13 (t, J = 10.3 Hz, 2H), 2.41 (m, 2H), 1 .61 (d, J = 6.7 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 439.2.
Figure imgf000377_0001
1 H NMR (300 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.85 (dd, J = 8.4, 1 .3 Hz, 1 H), 7.75 (dd, J = 8.5, 0.8 Hz, 1 H), 7.39 (s, 1 H), 7.21 (d, J = 1 .2 Hz, 1 H), 7.15-7.04 (m, 1 H), 4.45-4.32 (m, 2H), 4.09 (s, 3H), 3.53- 3.30 (m, 3H), 2.61 (s, 3H), 2.43-2.28 (m, 2H), 2.28-2.12 (m, 2H); LCMS (ESI) [M+H]+: 415.3.
Figure imgf000377_0002
1 H NMR (300 MHz, CHLOROFORM-d) d 7.98 (t, J = 0.7 Hz, 1 H), 7.88-7.77 (m, 1 H), 7.72 (d, J = 8.8 Hz 1 H), 7.20 (d, J = 8.8, 1 H), 4.90-4.76 (m, 1 H), 3.95 (ms, 2H), 3.88 (s, 2H), 3.38 (t, J = 12.4 Hz, 2H), 2.02 (m, 2H), 1 .84 (m, 2H), 1 .60 (d, J = 6.7 Hz, 6H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 415.3.
Figure imgf000377_0003
1 H NMR (300 MHz, DMSO-de) d 8.31 (s, 1 H), 8.1 9 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.75 (dd, J = 8.4, 1 .2 Hz, 1 H), 5.16 (p, J = 6.5 Hz, 1 H), 3.71 (dt, J = 13.2, 3.8 Hz, 2H), 3.39 (tt, J = 10.9, 3.8 Hz, 1 H), 3.13 (td, J = 12.4, 12.0, 2.7 Hz, 3H), 2.19 (dd, J = 13.7, 3.6 Hz, 2H), 2.01 (t, J = 1 1 .9 Hz, 2H), 1 .92-1 .72 (m, 4H), 1 .62 (d, J = 12.6 Hz, 1 H), 1 .50 (d, J = 6.5 Hz, 6H), 1 .45-1 .21 (m, 5H); LCMS (ESI) [M+H]+: 458.4.
Figure imgf000377_0004
1 H NMR (300 MHz, DMSO-de) d 8.31 (s, 1 H), 8.1 9 (d, J = 0.8 Hz, 1 H), 7.93 (dd, J = 8.4, 0.8 Hz, 1 H), 7.75 (dd, J = 8.5, 1 .3 Hz, 1 H), 5.15 (p, J = 6.5 Hz, 1 H), 3.71 (d, J = 12.7 Hz, 3H), 3.47-3.35 (m, 2H), 3.21 (s, 2H), 3.13 (t, J = 1 1 .4 Hz, 2H), 2.19 (dd, J = 13.9, 2.4 Hz, 3H), 1 .95 (d, J = 13.7 Hz, 2H), 1 .88-1 .60 (m,
7H), 1 .50 (d, J = 6.5 Hz, 6H), 1 .44 (d, J = 2.9 Hz, 1 H); LCMS (ESI) [M+H]+: 488.4..
Figure imgf000377_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.85-7.81 (m, 1 H), 7.76-7.72 (m, 1 H), 4.54 (br d, J = 13.9 Hz, 1 H), 4.08 (s, 3H), 3.99-3.89 (m, 1 H), 3.39-3.28 (m, 2H), 3.10-2.99 (m, 1 H), 2.66-2.61 (m, 2H), 2.60 (s, 3H), 2.59-2.50 (m, 2H), 2.31 -2.1 7 (m, 2H), 2.09-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 422.1 .
Figure imgf000378_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 8.00 (s, 1 H), 7.83-7.72 (m, 4H), 7.50-7.43 (m, 1 H), 7.42-7.34 (m, 2H), 7.14 (br s, 1 H), 4.90 (td, J = 6.6, 13.3 Hz, 1 H), 4.51 (dt, J = 6.7, 14.7 Hz, 0.5H), 4.38- 4.08 (m, 3H), 3.96 (br s, 0.5H), 3.86-3.63 (m, 2H), 3.61 -3.41 (m, 1 H), 2.40-2.1 8 (m, 2H), 1 .56 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 509.2.
Figure imgf000378_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.10 (s, 1 H), 7.94-7.83 (m, 4H), 7.31 -7.23 (m, 1 H), 7.15 (br t, J = 8.6 Hz, 2H), 5.07-4.93 (m, 1 H), 4.70-4.50 (m, 0.5H), 4.45-4.16 (m, 3H), 4.06 (br d, J = 13.4 Hz, 0.5H), 3.95-3.69 (m, 2H), 3.67-3.49 (m, 1 H), 2.51 -2.26 (m, 2H), 1 .66 (br d, J = 6.5 Hz, 6H); LCMS (ESI) [M+H]+: 527.2.
Figure imgf000378_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28-8.22 (m, 1 H), 8.13 (br s, 1 H), 7.95-7.79 (m, 4H), 7.49 (br d, J = 8.2 Hz, 2H), 7.35-7.1 8 (m, 1 H), 5.02 (br d, J = 6.7 Hz, 1 H), 4.62 (br s, 0.5H), 4.46-4.18 (m, 3H), 4.07 (br s, 0.5H), 3.99-3.50 (m, 3H), 2.56-2.28 (m, 2H), 1 .69 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 543.2.
Figure imgf000378_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 8.00 (s, 1 H), 7.86-7.71 (m, 3H), 7.64 (br d, J = 7.6 Hz, 1 H), 7.43 (br d, J = 7.7 Hz, 1 H), 7.37-7.28 (m, 1 H), 4.98-4.80 (m, 1 H), 4.50 (dt, J = 6.2, 14.5 Hz, 0.5H), 4.37-4.22 (m, 2.5H), 4.22-4.08 (m, 0.5H), 3.96 (br d, J = 13.6 Hz, 0.5H), 3.87-3.62 (m, 2H), 3.60- 3.38 (m, 1 H), 2.42-2.18 (m, 2H); LCMS (ESI) [M+H]+: 543.2.
Figure imgf000379_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 8.09 (br d, J = 4.6 Hz, 1 H), 8.02-7.95 (m, 2H), 7.83-7.68 (m, 3H), 7.52 (br t, J = 7.7 Hz, 1 H), 7.38-7.21 (m, 1 H), 4.90 (td, J = 6.6, 13.2 Hz, 1 H), 4.60-4.41 (m, 0.5H), 4.37-4.21 (m, 2.5H), 4.20-4.08 (m, 0.5H), 3.97 (br d, J = 13.4 Hz, 0.5H), 3.89-3.62 (m, 2H), 3.61 -3.42 (m, 1 H), 2.42-2.22 (m, 2H), 1 .56 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 534.2.
Figure imgf000379_0002
1 H NMR (400 MHz, DMSO-de) d 8.50 (s, 1 H), 8.25 (s, 1 H), 7.99 (m, J = 8.4 Hz, 1 H), 7.81 (dd, J = 1 .2, 8.5 Hz, 1 H), 5.23 (spt, J = 6.6 Hz, 1 H), 3.78-3.66 (m, 2H), 3.60-3.52 (m, 1 H), 3.52-3.43 (m, 1 H), 3.38 (br t, J = 8.4 Hz, 1 H), 2.33 (br s, 1 H), 2.25-2.07 (m, 1 H), 1 .50 (d, J = 6.6 Hz, 6H), 1 .42 (s, 9H); LCMS (ESI)
[M+H]+: 398.2.
Figure imgf000379_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.06 (s, 1 H), 7.88-7.79 (m, 2H), 5.51 -5.37 (m, 1 H), 4.97 (td, J = 6.6, 13.2 Hz, 1 H), 4.60-4.48 (m, 0.5H), 4.30 (m, 0.5H), 4.20-4.01 (m, 2.5H), 3.93 (m, 0.5H), 3.89-3.59 (m, 2H), 3.56-3.37 (m, 1 H), 2.46-2.21 (m, 2H), 1 .63 (d, J = 6.6 Hz, 6H), 1 .46 (s, 9H); LCMS (ESI) [M-55]+: 449.1 .
Figure imgf000379_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.02 (s, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.68-7.63 (m, 1 H), 4.00 (s, 3H), 3.69 (br t, J = 10.3 Hz, 1 H), 2.93 (tt, J = 3.7, 1 1 .8 Hz, 1 H), 2.52 (s, 3H), 2.26-2.18 (m, 2H), 2.1 0 (br dd, J = 3.3, 13.0 Hz, 2H), 1 .79-1 .69 (m, 2H), 1 .45-1 .34 (m, 2H); LCMS (ESI) [M+H]+: 313.1 .
Figure imgf000380_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.70 (m, 1 H), 5.55-5.39 (m, 1 H), 4.55 (dt, J = 6.6, 14.4 Hz, 0.5H), 4.35-4.26 (m, 0.5H), 4.22-4.1 0 (m, 1 H), 4.08 (s, 3H), 4.07-3.90 (m, 2H), 3.89-3.60 (m, 2H), 3.58-3.39 (m, 1 H), 2.60 (s, 3H), 2.43-2.25 (m, 2H), 1 .47 (s, 9H); LCMS (ESI) [M+H]+: 435.1 .
Figure imgf000380_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (br s, 1 H), 8.09 (s, 1 H), 8.02-7.82 (m, 4H), 7.54-7.44 (m, 2H), 5.05-4.92 (m, 1 H), 4.66-4.51 (m, 1 H), 4.36 (dd, J = 6.6, 9.5 Hz, 1 H), 4.06-3.93 (m, 2H), 3.69-3.60 (m, 1 H), 3.49-3.35 (m, 2H), 3.23-3.07 (m, 1 H), 3.02-2.90 (m, 2H), 2.31 (br t, J = 14.1 Hz, 2H), 2.13-1 .96 (m, 2H), 1 .65 (dd, J = 1 .2, 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 524.2.
Figure imgf000380_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (br s, 1 H), 7.99 (s, 1 H), 7.93-7.73 (m, 4H), 7.43-7.34 (m, 2H), 4.89 (qd, J = 6.6, 13.3 Hz, 1 H), 4.55-4.41 (m, 1 H), 4.26 (dd, J = 7.0, 8.9 Hz, 1 H), 3.96-3.84 (m, 2H), 3.55 (td, J = 8.3, 16.0 Hz, 1 H), 3.40-3.26 (m, 2H), 3.13-2.97 (m, 1 H), 2.94-2.81 (m, 2H), 2.22 (br t, J = 14.3 Hz, 2H), 2.03-1 .89 (m, 2H), 1 .56 (br d, J = 5.9 Hz, 6H); LCMS (ESI) [M+H]+: 524.2.
Figure imgf000380_0004
1 H NMR (400 MHz, METHANOL-d4) d 8.23 (s, 1 H), 8.1 1 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 5.12-4.98 (m, 1 H), 4.07-3.96 (m, 2H), 3.63 (br dd, J = 5.9, 1 0.5 Hz, 2H), 3.51 (br t, J = 9.7 Hz, 2H), 3.1 7 (br t, J = 10.8 Hz, 2H), 2.81 -2.65 (m, 2H), 1 .61 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 339.1 .
Figure imgf000381_0001
1 H NMR (400 MHz, DMSO-de) d 8.51 (s, 1 H), 8.25 (s, 1 H), 8.01 (m, J = 8.4 Hz, 1 H), 7.82 (dd, J = 1 .1 , 8.6 Hz, 1 H), 5.20 (spt, J = 6.5 Hz, 1 H), 3.86 (quin, J = 7.6 Hz, 1 H), 3.68 (dd, J = 8.2, 1 1 .7 Hz, 1 H), 3.46 (dd, J = 7.5, 1 1 .7 Hz, 1 H), 3.41 -3.26 (m, 2H), 2.47-2.37 (m, 1 H), 2.29-2.15 (m, 1 H), 1 .50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 298.1 .
Figure imgf000381_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.07 (s, 1 H), 7.88-7.79 (m, 2H), 7.47-7.39 (m, 2H), 7.26-7.22 (m, 1 H), 7.16-7.10 (m, 1 H), 4.98 (td, J = 6.7, 13.3 Hz, 1 H), 4.71 (br d, J = 12.8 Hz, 1 H), 3.72 (br d, J = 13.6 Hz, 1 H), 3.42-3.17 (m, 3H), 2.33 (br dd, J = 3.3, 13.6 Hz, 1 H), 2.23-2.03 (m, 3H), 1 .64 (d, J = 6.7 Hz, 5H), 1 .66-1 .62 (m, 1 H). ; LCMS (ESI) [M+H]+: 434.2.
Figure imgf000381_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.88-7.80 (m, 2H), 7.41 -7.36 (m, 1 H), 7.25 (dd, J = 1 .8, 8.3 Hz, 1 H), 7.18 (dd, J = 1 .9, 9.2 Hz, 1 H), 4.97 (spt, J = 6.7 Hz, 1 H), 4.67 (br d, J =
13.4 Hz, 1 H), 3.70 (br d, J = 13.8 Hz, 1 H), 3.42-3.18 (m, 3H), 2.33 (br dd, J = 3.4, 13.6 Hz, 1 H), 2.24-1 .95 (m, 3H), 1 .66-1 .62 (m, 1 H), 1 .64 (d, J = 6.7 Hz, 5H); LCMS (ESI) [M+H]+: 468.1 .
Figure imgf000381_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.85 (s, 1 H), 7.54 (d, J = 8.7 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.38- 7.28 (m, 3H), 6.40 (dd, J = 1 .6, 8.7 Hz, 1 H), 6.23 (s, 1 H), 4.70 (spt, J = 6.6 Hz, 1 H), 3.92-3.70 (m, 6H), 3.38-3.17 (m, 2H), 2.06-1 .87 (m, 3H), 1 .82-1 .73 (m, 1 H), 1 .56 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.
Figure imgf000382_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 7.98 (s, 1 H), 7.80-7.71 (m, 2H), 5.27 (br d, J = 7.9 Hz, 1 H), 4.94-4.84 (m, 1 H), 3.90-3.78 (m, 1 H), 2.91 (tt, J = 3.5, 12.2 Hz, 1 H), 2.25-2.1 1 (m, 4H), 1 .93 (s, 3H), 1 .79 (dq, J = 3.2, 13.0 Hz, 2H), 1 .56 (d, J = 6.7 Hz, 6H), 1 .24 (dq, J = 3.3, 12.5 Hz, 2H); LCMS (ESI) [M+H]+: 368.1 .
Figure imgf000382_0002
1 H NMR (400 MHz, DMSO-de) d 8.30 (s, 1 H), 8.1 9 (s, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.77 (dd, J = 1 .1 , 8.4 Hz, 1 H), 5.17-5.07 (m, 1 H), 3.43 (br t, J = 4.5 Hz, 1 H), 3.25-3.16 (m, 1 H), 2.25 (br dd, J = 4.6, 9.2 Hz, 2H), 1 .97-1 .88 (m, 4H), 1 .66-1 .57 (m, 2H), 1 .50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 326.2.
Figure imgf000382_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.07 (s, 1 H), 7.89-7.81 (m, 2H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.48 (br s, 1 H), 3.57 (br s, 1 H), 2.99 (tt, J = 3.4, 12.2 Hz, 1 H), 2.33-2.20 (m, 4H), 1 .85 (dq, J = 3.0, 13.0 Hz, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .48 (s, 9H), 1 .38-1 .26 (m, 2H); LCMS (ESI) [M+H]+: 426.2.
Figure imgf000382_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.84 (s, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 6.40 (dd, J = 8.8, 2.0 Hz,
1 H), 6.22 (s, 1 H), 4.79-4.61 (m, 1 H), 3.69 (s, 4H), 3.10-2.66 (m, 5H), 1 .83 (br t, J = 5.2 Hz, 4H), 1 .56 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 285.1 .
Figure imgf000382_0005
1 H NMR (300 MHz, DMSO-de) d 8.27 (d, J = 1 .2 Hz, 1 H), 8.19 (s, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 2.3 Hz, 1 H), 7.79 (dd, J = 8.7, 2.3 Hz, 1 H), 7.72 (dd, J = 8.5, 1 .3 Hz, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 5.14 (p, J = 6.6 Hz, 1 H), 3.96 (s, 3H), 3.69 (d, J = 1 1 .9 Hz, 3H), 2.22 (d, J = 12.9 Hz, 3H), 1 .87 (q, J = 10.5, 9.9 Hz, 2H), 1 .50 (d, J = 6.5 Hz, 6H); LCMS (ESI) [M+H]+: 560.2, 562.1 .
Figure imgf000383_0001
1 H NMR (300 MHz, DMSO-de) d 8.29 (d, J = 1 .1 Hz, 1 H), 8.19 (s, 1 H), 8.02 (dd, J = 7.7, 1 .6 Hz, 1 H), 7.92 (dd, J = 8.5, 0.8 Hz, 1 H), 7.76-7.66 (m, 3H), 7.59 (ddd, J = 7.9, 6.8, 1 .9 Hz, 1 H), 5.15 (p, J = 6.5 Hz, 1 H), 3.78 (d, J = 12.8 Hz, 2H), 3.39 (d, J = 15.0 Hz, 1 H), 3.09-2.93 (m, 2H), 2.21 (dd, J = 13.4, 3.5 Hz, 2H),
1 .93-1 .74 (m, 1 H), 1 .50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 486.3, 488.2.
Figure imgf000383_0002
1 H NMR (400 MHz, DMSO-de) d 8.28 (s, 1 H), 8.1 5 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz,
1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.48 (dd, J = 1 .9, 9.6 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 1 H), 5.10 (td, J = 6.6, 13.2 Hz, 1 H), 4.03 (br s, 1 H), 4.20-3.86 (m, 1 H), 3.58-3.43 (m, 1 H), 3.25 (br t, J = 1 1 .2 Hz, 2H), 2.19 (br d, J = 9.9 Hz, 2H), 1 .99-1 .81 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 468.1 .
Figure imgf000383_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.29 (s, 1 H), 8.1 1 (d, J = 3.4 Hz, 1 H), 7.88 (d, J = 5.4 Hz, 2H), 5.07-4.90 (m, 1 H), 4.09-3.95 (m, 1 H), 3.94-3.77 (m, 2H), 3.76-3.57 (m, 2H), 2.55-2.31 (m, 2H), 2.29-2.24 (m, 2H), 1 .66 (d, J = 6.6 Hz, 6H), 1 .1 1 (d, J = 1 .8 Hz, 9H); LCMS (ESI) [M+H]+: 396.2.
Figure imgf000383_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.08 (d, J = 2.9 Hz, 1 H), 7.82 (br dd, J = 2.6, 8.4 Hz, 1 H), 7.72 (dd, J = 3.4, 8.3 Hz, 1 H), 4.24-4.13 (m, 2H), 4.07 (d, J = 3.7 Hz, 3H), 3.44-3.25 (m, 3H), 2.59-2.57 (m, 3H), 2.29-2.27 (m, 2H), 2.23 (d, J = 4.0 Hz, 3H), 2.1 6-2.04 (m, 2H); LCMS (ESI) [M+H]+: 380.2.
Figure imgf000384_0001
1 H NMR (400 MHz, DMSO-de) d 8.28 (s, 1 H), 8.1 6 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.76 (dd, J = 1 .0, 8.5 Hz, 1 H), 7.55-7.47 (m, 2H), 7.30-7.22 (m, 2H), 5.1 1 (quin, J = 6.6 Hz, 1 H), 4.06 (br s, 2H), 3.57-3.45 (m,
1 H), 3.32-3.1 8 (m, 2H), 2.1 9 (br dd, J = 3.4, 13.1 Hz, 2H), 1 .97-1 .81 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 434.2.
Figure imgf000384_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (d, J = 0.9 Hz, 1 H), 8.01 (d, J = 0.9 Hz, 1 H), 7.79-7.77 (m, 2H), 4.14 (s, 3H), 3.74-3.68 (m, 4H), 3.62-3.56 (m, 4H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 385.2.
Figure imgf000384_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28 (s, J = 0.7 Hz, 1 H), 8.10 (s, 1 H), 7.91 -7.82 (m, 2H), 4.98 (spt, J = 6.6 Hz, 1 H), 4.64 (br d, J = 13.6 Hz, 1 H), 3.98 (br d, J = 13.6 Hz, 1 H), 3.32-3.20 (m, 1 H), 3.1 5 (tt, J = 3.9, 10.9 Hz, 1 H), 2.91 (br t, J = 1 1 .2 Hz, 1 H), 2.40 (d, J = 4.2 Hz, 2H), 2.16 (br d, J = 1 1 .1 Hz, 2H),
1 .99-1 .80 (m, 2H), 1 .65 (d, J = 6.7 Hz, 6H), 1 .18 (s, 3H), 0.55-0.31 (m, 4H); LCMS (ESI) [M+H]+: 408.2.
Figure imgf000384_0004
1 H NMR (400 MHz, DMSO-de) d 8.17 (d, J = 10.8 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1 H), 7.67 (dd, J = 1 .1 , 8.4 Hz, 1 H), 7.61 -7.49 (m, 1 H), 7.41 -7.24 (m, 3H), 5.10 (td, J = 6.6, 13.1 Hz, 1 H), 3.94-3.43 (m, 8H), 1 .50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 435.2.
Figure imgf000384_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.09 (s, 1 H), 7.84 (d, J = 0.7 Hz, 2H), 4.97 (quin, J = 6.7 Hz, 1 H), 3.57 (br d, J = 5.5 Hz, 8H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 413.2.
Figure imgf000385_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.06 (s, 1 H), 7.92 (d, J = 3.1 Hz, 1 H), 7.88-7.77 (m, 2H), 7.57 (d, J = 3.3 Hz, 1 H), 5.43 (br d, J = 13.7 Hz, 1 H), 4.97 (spt, J = 6.7 Hz, 1 H), 4.67 (br d, J = 12.6 Hz, 1 H), 3.80-3.60 (m, 1 H), 3.48-3.36 (m, 1 H), 3.34-3.18 (m, 1 H), 2.31 (br s, 2H), 2.15 (br s, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.1 .
Figure imgf000385_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.84 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.77-7.71 (m, 1 H), 4.76 (br s, 1 H), 4.09 (s, 3H), 3.81 (br s, 1 H), 3.68 (s, 3H), 3.28-3.16 (m, 1 H), 2.61 (s, 3H), 2.25-2.12 (m, 2H), 2.07-1 .97 (m, 2H), 1 .88 (dt, J = 4.0, 8.7 Hz, 2H), 1 .79-1 .69 (m, 2H); LCMS (ESI) [M+H]+: 370.1 .
Figure imgf000385_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (br s, 1 H), 8.06 (br s, 1 H), 7.91 -7.77 (m, 2H), 7.65-7.55 (m, 2H), 7.43 (br d, J = 5.7 Hz, 1 H), 7.33-7.15 (m, 2H), 5.04-4.91 (m, 0.8H), 4.57 (br s, 0.4H), 4.44-4.31 (m, 2H), 4.28-4.14 (m, 0.5H), 4.02 (br s, 0.5H), 3.93-3.68 (m, 2H), 3.68-3.46 (m, 1 H), 2.50-2.25 (m, 2H), 1 .63 (br d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 527.2.
Figure imgf000385_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.96-7.94 (d, J = 8.0 Hz, 2H), 7.87- 7.81 (m, 2H), 7.80-7.60 (d, J = 8.0 Hz, 2H), 7.33-7.25 (m, 1 H), 5.00-4.93 (m, 1 H), 4.65-4.50 (m, 0.5H), 4.45-4.25 (m, 2.6H, 4.25-4.15 (m, 0.5 h), 4.08-3.98 (m, 0.5H), 3.95-3.80 (m, 1 .5H), 3.80 -3.05 (m, 0.5H), 3.65-3.50 (m, 1 H), 2.50-2.33 (m, 2H), 1 .64-1 .62 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 534.2.
Figure imgf000386_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.73 (br d, J = 15.2 Hz, 1 H), 8.57 (d, J = 2.3 Hz, 1 H), 8.20-8.1 1 (m, 2H), 7.92 (d, J = 8.6 Hz, 1 H), 7.87-7.78 (m, 2H), 4.64 (dt, J = 6.8, 14.3 Hz, 0.5H), 4.39 (br t, J = 5.4 Hz, 2.4H), 4.30-4.22 (m, 0.6H), 4.18 (s, 3H), 4.06 (br d, J = 14.4 Hz, 0.6H), 3.93-3.70 (m, 2H), 3.62-3.49 (m, 1 H), 2.69 (s, 3H), 2.50-2.29 (m, 2H); LCMS (ESI) [M+H]+: 530.1 .
Figure imgf000386_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.17 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.79 (d, J = 8.3 Hz, 2H), 7.48-7.39 (m, 2H), 7.28-7.19 (m, 1 H), 4.64 (dt, J = 7.3, 14.2 Hz, 0.5H), 4.48-4.32 (m, 2.3H), 4.26 (br s, 0.6H), 4.22 (s, 3H), 4.06 (br d, J = 8.8 Hz, 0.7H), 3.95-3.69 (m, 2H), 3.61 -3.47 (m,
1 H), 2.73 (s, 3H), 2.50-2.30 (m, 2H); LCMS (ESI) [M+H]+: 529.1 .
Figure imgf000386_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (d, J = 0.8 Hz, 1 H), 8.04 (s, 1 H), 7.77 (d, J = 0.8 Hz, 2H), 5.05-4.85 (m, 1 H), 4.06 (s, 4H), 3.42 (t, J = 5.6 Hz, 4H), 1 .85 (t, J = 5.6 Hz, 4H), 1 .61 (d, J = 6.4 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 453.2.
Figure imgf000386_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.19 (s, 1 H),8.16 (s, 1 H), 8.08-8.04 (m, 2H), 7.87-7.78 (m, 3H), 7.59 (t, J = 7.8 Hz, 1 H), 7.41 -7.35 (m, 1 H), 4.96 (quin, J = 6.7 Hz, 1 H), 4.52 (br d, J = 13.7 Hz, 1 H), 4.31 (d, J = 3.7 Hz, 2H), 3.91 (br d, J = 13.9 Hz, 1 H), 3.37 (ddd, J = 3.3, 10.5, 13.9 Hz, 2H), 3.25-3.1 1 (m, 1 H), 2.37-2.21 (m, 2H), 2.13-1 .94 (m, 2H), 1 .63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 498.2.
Figure imgf000387_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.11 (s, 1H), 7.93-7.81 (m, 3H), 7.79-7.72 (m, 1H), 7.25-7.10 (m, 3H), 4.59 (dt, J = 6.7, 14.9 Hz, 0.5H), 4.43-4.30 (m, 2.5H), 4.24 (dt, J = 6.3, 14.6 Hz, 0.5H), 4.10 (s, 3H), 4.05 (brd, J = 13.9 Hz, 0.5H), 3.95-3.70 (m, 2H), 3.68-3.50 (m, 1H), 2.61 (s, 3H), 2.49-2.31 (m, 2H); LCMS (ESI) [M+H]+: 513.1.
Figure imgf000387_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.06-7.90 (m, 2H), 7.75-7.57 (m, 2H), 5.76-5.60 (m, 1H), 5.12 (t, J = 6.5 Hz, 2H), 4.95 (t, J = 7.3 Hz, 2H), 4.38 (m, 1H), 3.74 (m, 1H), 3.17-2.98 (m, 2H), 2.86-2.69 (m, 1H), 2.12 (d, J = 6.8 Hz, 2H), 2.07-1.95 (m, 2H), 1.84-1.66 (m, 2H), 0.93-0.80 (m, 1H), 0.44-0.33 (m, 2H), 0.05- -0.05 (m, 2H); LCMS (ESI) [M+H]+: 408.2.
Figure imgf000387_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.21 (d, J = 0.7 Hz, 1H), 8.17 (s, 1H), 7.93-7.81 (m, 2H), 5.96- 5.83 (m, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.16 (t, J = 7.3 Hz, 2H), 4.60 (brd, J = 13.4 Hz, 1H), 3.97 (brd, J = 13.9 Hz, 1 H), 3.36-3.20 (m, 2H), 2.96 (br t, J = 11.2 Hz, 1H), 2.39 (m, 2H), 2.22 (brd, J = 13.4 Hz, 2H), 2.05-1.85 (m, 2H), 1.17 (s, 3H), 0.55-0.32 (m, 4H); LCMS (ESI) [M+H]+: 422.2.
Figure imgf000387_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.85-7.80 (m, 1H), 7.73 (d, J = 8.3 Hz, 1 H), 4.32 (brd, J = 13.2 Hz, 2H), 4.08 (s, 3H), 3.36-3.27 (m, 1H), 3.23-3.11 (m, 2H), 2.72 (q, J = 7.7 Hz, 2H), 2.60 (s, 3H), 2.34-2.25 (m, 2H), 2.15-2.03 (m, 2H), 1.28 (t, J = 7.7 Hz, 3H); LCMS (ESI) [M+H]+: 404.1.
Figure imgf000388_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.51 (s, 1 H), 8.15 (d, J = 0.7 Hz, 1 H), 8.04 (dd, J = 1.1 , 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.68-7.35 (t, J = 59.2 Hz, 1 H), 4.19 (br s, 2H), 3.73 (s, 3H), 3.23 (tt, J = 3.9, 10.9 Hz, 1 H), 3.08 (br t, J = 11.6 Hz, 2H), 2.17 (br d, J = 10.9 Hz, 2H), 2.01 -1.89 (m, 2H); LCMS (ESI) [M+H]+: 378.1.
Figure imgf000388_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1H), 8.10 (s, 1H), 7.85-7.82 (m, 1H), 7.80-7.75 (m, 1H), 7.40-7.33 (m, 1H), 7.32-7.20 (m, 3H), 5.92-5.74 (m, 1H), 5.26 (t, J = 6.6 Hz, 2H), 5.09 (t, J = 7.0 Hz, 2H), 4.76-4.55 (m, 1 H), 3.61 -3.44 (m, 1 H), 3.36-3.01 (m, 3H), 2.27 (m, 1 H), 2.15-1.93 (m, 2H), 1.93-1.77 (m,
1 H); LCMS (ESI) [M+H]+: 464.1.
Figure imgf000388_0003
1H NMR (400 MHz, DMSO-de) d 8.25 (s, 1H), 8.14 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz,
1 H), 5.11-5.05 (m, 1H), 4.07-3.99 (m, 1H), 3.66-3.56 (m, 1H), 3.49 (br dd, J = 9.2, 13.3 Hz, 1H), 3.32-3.15 (m, 2H), 2.22-2.13 (m, 1H), 1.98-1.93 (m, 1H), 1.84-1.75 (m, 1H), 1.60-1.45 (m, 7H), 1.38 (s, 9H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000388_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.29-8.16 (m, 2H), 7.97-7.84 (m, 2H), 7.46 (m, 5H), 5.99-5.85 (m, 1 H), 5.36 (t, J = 6.7 Hz, 2H), 5.18 (t, J = 7.3 Hz, 2H), 4.86-4.54 (m, 1 H), 3.94 (m, 1 H), 3.46-3.31 (m, 1 H), 3.25 (br s, 2H), 2.39-1.82 (m, 4H); LCMS (ESI) [M+H]+: 430.1.
Figure imgf000388_0005
1H NMR (300 MHz, DMSO-de) d 8.31 (d, J = 1.1 Hz, 1H), 8.19 (s, OH), 7.93 (dd, J = 8.4, 0.8 Hz, 1H), 7.75 (dd, J = 8.5, 1.3 Hz, 1 H), 5.16 (h, J = 6.6 Hz, 1 H), 3.65 (dt, J = 11.7, 3.3 Hz, 3H), 3.43-3.27 (m, 1 H), 3.02 (td, J = 12.6, 2.7 Hz, 3H), 2.95 (d, J = 6.6 Hz, 2H), 2.23 (dd, J = 13.6, 3.7 Hz, 2H), 2.12 (dq, J = 13.3, 6.7 Hz, 1 H), 1.97-1.78 (m, 2H), 1.50 (d, J = 6.6 Hz, 6H), 1.05 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 432.3.
Figure imgf000389_0001
1H NMR (400 MHz, CHLOROFORM-d) d 7.77 (dd, J = 1.1 , 7.7 Hz, 1 H), 7.67 (s, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 4.68 (spt, J = 7.0 Hz, 1H), 4.14 (m, 2H), 3.56 (s, 2H), 3.19 (tt, J = 4.0, 10.9 Hz, 1H), 3.01 (br t, J = 11.6 Hz, 2H), 2.14 (br dd, J = 2.8, 13.3 Hz, 2H), 1.98-1.84 (m, 2H), 1.54 (d, J = 7.1 Hz, 6H), 1.49 (s, 9H); LCMS (ESI) [M+H]+: 427.2.
Figure imgf000389_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.86-7.81 (m, 1 H), 7.74 (d, J = 8.4 Hz, 1H),4.42 (dd, J = 7.2, 9.2 Hz, 1H), 4.16 (dd, J = 5.3, 9.3 Hz, 1H), 4.08 (s, 3H), 3.09-2.89 (m, 3H), 2.87-2.76 (m,
1 H), 2.68-2.61 (m, 1H), 2.60 (s, 3H), 2.45 (d, J = 7.9 Hz, 2H), 2.37 (dd, J = 5.7, 17.6 Hz, 1H), 2.31-2.13 (m, 4H), 2.11-1.98 (m, 2H)
Figure imgf000389_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.13 (d, J = 0.7 Hz, 1H), 8.04 (s, 1H), 7.77 (m, 2H), 4.95 (m,
1 H), 3.99 (m, 2H), 3.84 (dd, J = 6.3, 9.8 Hz, 1 H), 3.80-3.71 (m, 4H), 3.39 (m, 2H), 3.17 (q, J = 10.4 Hz, 2H), 2.53-2.34 (m, 2H), 1.61 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 397.1.
Figure imgf000389_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.13 (d, J = 0.9 Hz, 1H), 8.04 (s, 1H), 7.81-7.73 (m, 2H), 4.95 (m, 1 H), 4.07-3.93 (m, 3H), 3.84 (dd, J = 6.6, 8.9 Hz, 1H), 3.45-3.36 (m, 2H), 3.30 (dd, J = 9.2, 10.8 Hz, 1 H), 3.16 (t, J = 11.0 Hz, 1H), 2.57-2.32 (m, 2H), 2.26-2.15 (m, 2H), 1.61 (d, J = 6.6 Hz, 6H), 1.12-1.04 (m, 9H); LCMS (ESI) [M+H]+: 437.2.
Figure imgf000390_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 8.04 (s, 1 H), 7.77 (s, 2H), 5.00-4.88 (m, 1 H), 4.07 (s, 4H), 3.71 (s, 3H), 3.47 (t, J = 4.8 Hz, 4H), 1 .86 (t, J = 5.6 Hz, 4H), 1 .61 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 41 1 .1 .
Figure imgf000390_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s. 1 H), 8.05 (s, 1 H), 7.76 (s, 2H), 5.01 -4.90 (m, 1 H), 4.15- 4.04 (m, 4H), 3.61 (t, J = 5.2 Hz, 2H), 3.45 (t, J = 5.6 Hz, 2H), 2.13 (s, 3H), 1 .89 (dt, J = 16.6, 4.4 Hz, 4H), 1 .61 (d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 395.1 .
Figure imgf000390_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.83 (s, 1 H), 7.71 (dd, J = 1 .2, 7.6 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 4.73 (spt, J = 6.9 Hz, 1 H), 4.25-4.00 (m, 2H), 3.18 (tt, J = 3.9, 10.9 Hz, 1 H), 3.00 (br t, J = 1 1 .7 Hz, 2H), 2.91 -2.85 (m, 2H), 2.60 (dd, J = 5.8, 8.3 Hz, 2H), 2.13 (br dd, J = 2.8, 13.1 Hz, 2H), 1 .96-1 .85 (m, 2H), 1 .58 (d, J = 7.1 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 385.1 .
Figure imgf000390_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.82 (d, J = 2.2 Hz, 1 H), 8.22 (s, 1 H), 8.06 (s, 1 H), 8.03 (d, J = 2.2 Hz, 1 H), 7.92-7.77 (m, 2H), 4.97 (spt, J = 6.7 Hz, 1 H), 4.63 (br d, J = 7.3 Hz, 2H), 3.47 (br s, 1 H), 3.38 (tt, J = 4.2, 10.5 Hz, 1 H), 3.24 (br s, 1 H), 2.29 (br s, 2H), 2.19-2.07 (m, 2H), 1 .63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.1 .
Figure imgf000390_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.07 (s, 1 H), 7.90-7.79 (m, 2H), 7.48 (dd, J = 1 .0, 5.0 Hz, 1 H), 7.34 (dd, J = 1 .0, 3.6 Hz, 1 H), 7.08 (dd, J = 3.7, 4.9 Hz, 1 H), 4.98 (td, J = 6.6, 13.2 Hz, 1 H), 4.47 (br d, J = 12.8 Hz, 2H), 3.45-3.27 (m, 3H), 2.28 (br dd, J = 3.4, 13.6 Hz, 2H), 2.15-2.01 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 422.1 .
Figure imgf000391_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.89-7.79 (m, 2H), 7.18 (d, J = 5.7 Hz, 1 H), 6.99 (d, J = 5.7 Hz, 1 H), 4.97 (td, J = 6.6, 13.4 Hz, 1 H), 4.66 (br d, J = 12.8 Hz, 1 H), 3.80 (br d, J = 13.5 Hz, 1 H), 3.43-3.16 (m, 3H), 2.40-2.17 (m, 2H), 2.17-1 .93 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 456.1 .
Figure imgf000391_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (d, J = 0.6 Hz, 1 H), 8.16 (s, 1 H), 7.93-7.87 (m, 1 H), 7.86- 7.81 (m, 1 H), 5.89 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.15 (t, J = 7.3 Hz, 2H), 4.32-3.96 (m, 2H), 3.20 (m, 1 H), 3.08-2.96 (m, 2H), 2.15 (br d, J = 12.5 Hz, 2H), 1 .99-1 .83 (m, 2H), 1 .59 (br s, 1 H), 1 .57 (s, 3H), 0.93-0.83 (m, 2H), 0.72-0.59 (m, 2H); LCMS (ESI) [M+H]+: 424.2.
Figure imgf000391_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.92-7.81 (m, 3H), 7.79-7.72 (m, 1 H), 7.57-7.52 (m, 1 H), 7.51 -7.43 (m, 2H), 7.26-7.17 (m, 1 H), 4.65-4.50 (m, 0.5H), 4.44-4.32 (m, 2.5H), 4.25 (dt, J = 5.7, 14.8 Hz, 0.5H), 4.09 (s, 3H), 4.04 (br d, J = 4.9 Hz, 0.5H), 3.96-3.69 (m, 2H), 3.68-3.50 (m, 1 H), 2.61 (s, 3H), 2.50-2.23 (m, 2H); LCMS (ESI) [M+H]+: 495.1 .
Figure imgf000391_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.90-7.81 (m, 3H), 7.78-7.73 (m, 1 H), 7.58-7.51 (m, 1 H), 7.50-7.43 (m, 2H), 7.30-7.19 (m, 1 H), 4.65-4.49 (m, 0.5H), 4.45-4.31 (m, 2.5H), 4.25 (dt, J = 5.6, 14.8 Hz, 0.5H), 4.09 (s, 3H), 4.08-4.00 (m, 0.5H), 3.98-3.70 (m, 2H), 3.66-3.51 (m, 1 H), 2.61 (s, 3H), 2.50-2.31 (m, 2H); LCMS (ESI) [M+H]+: 495.1 .
Figure imgf000392_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.10 (s, 1 H), 7.91 -7.83 (m, 2H), 6.77-6.62 (m, 1 H), 5.00 (td, J = 6.6, 13.2 Hz, 1 H), 4.58 (dt, J = 6.8, 14.5 Hz, 0.5H), 4.34 (br d, J = 13.9 Hz, 0.5H), 4.28-4.14 (m, 2.5H), 4.00 (br d, J = 13.6 Hz, 0.5H), 3.94-3.45 (m, 3H), 2.36 (br d, J = 16.4 Hz, 2H), 1 .66 (d, J = 6.7 Hz, 6H), 1 .57-1 .49 (m, 1 H), 1 .06-0.99 (m, 2H), 0.82 (td, J = 3.6, 7.4 Hz, 2H); LCMS (ESI) [M+H]+: 473.2.
Figure imgf000392_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.09 (s, 1 H), 7.87-7.79 (m, 2H), 7.48-7.43 (m, 1 H), 7.42-7.30 (m, 3H), 4.97 (td, J = 6.8, 13.2 Hz, 1 H), 4.13-4.00 (m, 1 H), 3.97-3.84 (m, 1 H), 3.72 (br s, 2H), 3.66-3.57 (m, 1 H), 3.56-3.41 (m, 2H), 3.38 (br d, J = 7.1 Hz, 1 H), 1 .64 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 451 .1 .
Figure imgf000392_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.07 (s, 1 H), 7.83-7.78 (m, 1 H), 7.74-7.69 (m, 1 H), 4.19 (td, J = 3.8, 13.6 Hz, 2H), 4.06 (s, 3H), 3.40-3.23 (m, 3H), 2.94-2.84 (m, 1 H), 2.58 (s, 3H), 2.27 (br dd, J = 3.3, 13.7 Hz, 2H), 2.15-2.02 (m, 2H), 1 .28 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 408.2.
Figure imgf000392_0004
1 H NMR (400 MHz, DMSO-de) d 8.37 (s, 1 H), 8.1 9 (s, 1 H), 7.95 (m, J = 8.6 Hz, 1 H), 7.75 (d, J = 8.4 Hz,
1 H), 7.54-7.37 (m, 5H), 5.1 5 (spt, J = 6.6 Hz, 1 H), 3.66 (br s, 4H), 3.58-3.50 (m, 4H), 1 .53 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 417.2.
Figure imgf000392_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.1 1 (s, 1 H), 7.91 -7.86 (m, 1 H), 7.85-7.81 (m, 1 H), 5.16-5.03 (m, 1 H), 4.91 (dd, J = 7.9, 9.3 Hz, 0.5H), 4.82-4.76 (m, 1 H), 4.67 (dd, J = 4.9, 9.4 Hz, 0.5H), 4.61 (br s, 1 H), 4.04 (br d, J = 13.7 Hz, 1 H), 3.36-3.24 (m, 2H), 2.97 (br t, J = 12.1 Hz, 1 H), 2.32 (s, 2H), 2.27-2.17 (m, 2H), 2.05-1 .89 (m, 2H), 1 .66 (dd, J = 1 .6, 6.8 Hz, 3H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 428.2.
Figure imgf000393_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.07 (s, 1 H), 7.90-7.81 (m, 2H), 4.98 (spt, J = 6.6 Hz, 1 H), 4.48-3.98 (m, 2H), 3.81 -3.68 (m, 1 H), 3.61 -3.47 (m, 1 H), 3.32 (br t, J = 1 0.1 Hz, 1 H), 2.42-2.20 (m, 2H), 1 .64 (d, J = 6.7 Hz, 6H), 1 .59 (s, 3H), 0.96-0.90 (m, 2H), 0.72-0.65 (m, 2H); LCMS (ESI) [M+H]+: 446.1 .
Figure imgf000393_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.1 1 (s, 1 H), 7.92-7.86 (m, 1 H), 7.85-7.79 (m, 1 H), 5.16-5.03 (m, 1 H), 4.90 (dd, J = 8.0, 9.4 Hz, 0.5H), 4.82-4.76 (m, 1 H), 4.67 (dd, J = 4.9, 9.4 Hz, 0.5H), 4.60 (br d, J = 13.6 Hz, 1 H), 3.97 (br d, J = 13.4 Hz, 1 H), 3.34-3.24 (m, 2H), 2.98 (br t, J = 1 1 .9 Hz, 1 H), 2.40 (d, J = 3.2 Hz, 2H), 2.22 (br d, J = 13.1 Hz, 2H), 1 .96 (quin, J = 1 1 .9 Hz, 2H), 1 .66 (dd, J = 1 .5, 6.8 Hz, 3H), 1 .18 (s, 3H), 0.50-0.44 (m, 2H), 0.44-0.38 (m, 2H); LCMS (ESI) [M+H]+: 426.2.
Figure imgf000393_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.57 (d, J = 2.0 Hz, 1 H), 8.22 (s, 1 H), 8.07 (s, 1 H), 7.89-7.78 (m, 3H), 7.69 (d, J = 8.3 Hz, 1 H), 4.98 (td, J = 6.7, 13.4 Hz, 1 H), 4.67 (br d, J = 13.1 Hz, 1 H), 4.1 6 (br d, J = 13.4 Hz, 1 H), 3.45-3.33 (m, 2H), 3.26 (br t, J = 10.8 Hz, 1 H), 2.33 (br d, J = 10.9 Hz, 1 H), 2.24-2.07 (m, 3H), 1 .64 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 451 .2.
Figure imgf000393_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.56 (dd, J = 1 .2, 4.6 Hz, 1 H), 8.22 (s, 1 H), 8.07 (s, 1 H), 7.91 - 7.75 (m, 3H), 7.33 (dd, J = 4.6, 8.2 Hz, 1 H), 4.98 (td, J = 6.6, 13.3 Hz, 1 H), 4.78-4.63 (m, 1 H), 3.53 (td, J = 3.8, 13.6 Hz, 1 H), 3.42-3.19 (m, 3H), 2.35 (br dd, J = 3.9, 13.6 Hz, 1 H), 2.25-2.03 (m, 2H), 2.25-2.03 (m, 1 H), 1 .64 (d, J = 6.6 Hz, 6H); M+H]+: 451 .1 .
Figure imgf000394_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.71 (d, J = 4.6 Hz, 1 H), 8.22 (s, 1 H), 8.07 (s, 1 H), 7.89-7.79 (m, 2H), 7.68 (d, J = 4.9 Hz, 1 H), 4.98 (td, J = 6.6, 13.4 Hz, 1 H), 4.68 (br d, J = 13.5 Hz, 1 H), 4.57 (br d, J = 13.9 Hz, 1 H), 3.53-3.44 (m, 1 H), 3.44-3.35 (m, 1 H), 3.32-3.17 (m, 1 H), 2.38-2.21 (m, 2H), 2.21 -2.07 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.
Figure imgf000394_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.89-7.80 (m, 2H), 7.68 (s, 1 H), 5.41 (br d, J = 12.3 Hz, 1 H), 4.97 (td, J = 6.6, 13.4 Hz, 1 H), 4.60 (br d, J = 1 1 .5 Hz, 1 H), 3.75-3.62 (m, 1 H), 3.49-3.35 (m, 1 H), 3.33-3.19 (m, 1 H), 2.30 (br s, 2H), 2.14 (br s, 2H), 1 .64 (d, J = 6.6 Hz, 5H), 1 .66-1 .61 (m, 1 H); LCMS (ESI) [M+H]+: 457.1 .
Figure imgf000394_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.05 (dd, J = 1 .1 , 8.2 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 4.1 6 (br s, 2H), 3.20 (tt, J = 3.9, 1 0.8 Hz, 1 H), 3.09-2.97 (m, 2H), 2.62 (s, 3H), 2.14 (br d, J = 1 1 .4 Hz, 2H), 1 .98-1 .84 (m, 2H), 1 .56 (s, 3H), 0.91 -0.85 (m, 2H), 0.67-0.61 (m, 2H); LCMS (ESI) [M+H]+: 383.1 .
Figure imgf000394_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28 (s, 1 H), 8.05 (dd, J = 1 .1 , 8.2 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 4.58 (br d, J = 13.7 Hz, 1 H), 3.96 (br d, J = 13.5 Hz, 1 H), 3.34-3.22 (m, 2H), 2.97 (br t, J = 1 1 .2 Hz, 1 H), 2.63 (s, 3H), 2.39 (s, 2H), 2.21 (br d, J = 13.2 Hz, 2H), 2.03-1 .85 (m, 2H), 1 .16 (s, 3H), 0.48-0.38 (m, 4H); LCMS (ESI) [M+H]+: 381 .1 .
Figure imgf000395_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.88-7.81 (m, 1 H), 7.79-7.70 (m, 1 H), 4.94 (t, J = 7.0 Hz, 2H), 4.52 (br d, J = 13.7 Hz, 1 H), 4.43 (t, J = 5.6 Hz, 2H), 4.09 (s, 3H), 3.98 (br d, J = 13.6 Hz,
1 H), 3.50-3.39 (m, 1 H), 3.33 (br s, 2H), 3.00 (br s, 1 H), 2.83 (d, J = 7.7 Hz, 2H), 2.61 (s, 3H), 2.25 (br t, J = 14.4 Hz, 2H), 2.09-1 .89 (m, 2H); LCMS (ESI) [M+H]+: 396.2.
Figure imgf000395_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (d, J = 0.7 Hz, 1 H), 8.05 (s, 1 H), 7.78 (d, J = 0.9 Hz, 2H), 4.95 (spt, J = 6.6 Hz, 1 H), 4.56 (q, J = 8.4 Hz, 2H), 3.78 (br s, 4H), 3.74-3.68 (m, 4H), 1 .63 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 439.2.
Figure imgf000395_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.84 (s, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 8.39 (dd, J = 8.4, 1 .6 Hz, 1 H), 6.22 (s, 1 H), 4.75-4.64 (m, 1 H), 4.13-4.05 (m, 1 H), 3.71 (s, 4H), 3.55-3.30 (m, 4H), 1 .93-1 .72 (m, 4H), 1 .56 (d, J = 6.8 Hz, 6H), 0.75-0.62 (m, 4H); LCMS (ESI) [M+H]+: 369.2.
Figure imgf000395_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (d, J = 0.9 Hz, 1 H), 8.05 (s, 1 H), 7.78 (d, J = 1 .0 Hz, 2H), 4.95 (td, J = 6.7, 13.3 Hz, 1 H), 4.17 (s, 2H), 3.84-3.68 (m, 8H), 3.51 -3.42 (m, 1 H), 3.46 (s, 2H), 1 .63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 485.1 .
Figure imgf000395_0005
1 H NMR (400 MHz, DMSO-de) d 8.26 (s, 1 H), 8.1 8 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.73 (dd, J = 1 .1 , 8.4 Hz, 1 H), 5.09 (spt, J = 6.6 Hz, 1 H), 3.16-3.05 (m, 2H), 2.24 (br d, J = 1 1 .4 Hz, 2H), 2.10 (br d, J = 10.0 Hz, 2H), 1 .76-1 .65 (m, 2H), 1 .54 (br dd, J = 2.8, 12.6 Hz, 2H), 1 .49 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 326.1 .
Figure imgf000396_0001
1 H NMR (300 MHz, CHLOROFORM-d) d 8.19 (dd, J = 14.6, 1 .0 Hz, 2H), 7.95-7.80 (m, 2H), 5.89 (p, J = 7.1 Hz, 1 H), 5.33 (t, J = 6.9, 6.2 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.51 (q, J = 6.7 Hz, 2H), 3.83 (s, 1 H), 3.37 (d, J = 10.6 Hz, 1 H), 3.32 (s, 1 H), 3.1 9-3.05 (m, 1 H), 2.80 (s, 1 H), 2.25 (s, 1 H), 1 .64 (d, J = 7.0 Hz, 1 H), 1 .57-1 .42 (m, 1 H), 1 .38 (dd, J = 8.8, 6.1 Hz, 3H), 1 .25 (s, 1 H), 1 .06 (s, 1 H); LCMS (ESI) [M+H]+: 398.3.
Figure imgf000396_0002
1 H NMR (300 MHz, CHLOROFORM-d) d 8.26-8.14 (m, 2H), 7.96-7.80 (m, 4H), 7.59-7.40 (m, 3H), 7.33 (s, 1 H), 5.88 (q, J = 6.8 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.3 Hz, 2H), 4.54 (d, J = 14.0 Hz,
1 H), 4.32 (d, J = 4.0 Hz, 2H), 3.93 (d, J = 13.8 Hz, 1 H), 3.43-3.28 (m, 2H), 3.1 5 (t, J = 12.1 Hz, 1 H), 2.02 (dd, J = 14.6, 1 0.7 Hz, 2H), 1 .47 (s, 1 H), 1 .25 (s, 2H); LCMS (ESI) [M+H]+: 487.3.
Figure imgf000396_0003
1 H NMR (300 MHz, CHLOROFORM-d) d 8.27-8.14 (m, 2H), 8.01 -7.81 (m, 4H), 7.55-7.40 (m, 2H), 5.90 (s, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.57 (t, J = 15.7 Hz, 1 H), 4.34 (dd, J = 9.5, 6.6 Hz, 1 H), 3.95 (t, J = 8.1 Hz, 2H), 3.62 (p, J = 8.2 Hz, 1 H), 3.40 (d, J = 8.2 Hz, 1 H), 3.37 (s, 1 H), 3.21 -2.87 (m, 3H), 2.28 (d, J = 13.1 Hz, 2H), 2.06 (s, 1 H), 1 .25 (s, 1 H); LCMS (ESI) [M+H]+: 538.3.
Figure imgf000396_0004
1 H NMR (300 MHz, CHLOROFORM-d) d 8.27-8.14 (m, 2H), 8.01 -7.81 (m, 4H), 7.55-7.40 (m, 2H), 5.89 (s, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.17 (t, J = 7.1 Hz, 2H), 4.57 (s, 1 H), 4.34 (dd, J = 9.5, 6.6 Hz, 1 H), 3.96 (t, J = 8.5 Hz, 2H), 3.68-3.56 (m, 1 H), 3.39 (s, 1 H), 3.12 (s, 1 H), 3.06-2.89 (m, 2H), 2.29 (s, 1 H), 2.06 (s, 1 H), 1 .25 (s, 1 H); LCMS (ESI) [M+H]+: 538.3.
Figure imgf000397_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.09 (s, 1 H), 7.95 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 0.7, 8.4 Hz,
1 H), 7.79-7.71 (m, 3H), 7.42-7.29 (m, 1 H), 4.58 (dt, J = 6.5, 14.7 Hz, 0.5H), 4.44-4.30 (m, 2.5H), 4.29- 4.16 (m, 0.5H), 4.08 (s, 3H), 4.06-3.99 (m, 0.5H), 3.96-3.69 (m, 2H), 3.67-3.50 (m, 1 H), 2.60 (s, 3H), 2.49- 2.29 (m, 2H); LCMS (ESI) [M+H]+: 520.1 .
Figure imgf000397_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.03 (s, 1 H), 7.76 (dd, J = 1 .1 , 8.4 Hz, 1 H), 7.70-7.64 (m, 1 H), 7.57-7.46 (m, 2H), 7.36 (dt, J = 5.6, 7.9 Hz, 1 H), 7.21 -7.1 1 (m, 2H), 4.57-4.42 (m, 0.5H), 4.34-4.22 (m, 2.6H), 4.21 -4.10 (m, 0.6H), 4.01 (s, 3H), 3.99-3.90 (m, 0.5H), 3.87-3.62 (m, 2H), 3.60-3.42 (m, 1 H), 2.53 (s, 3H), 2.41 -2.22 (m, 2H); LCMS (ESI) [M+H]+: 513.2.
Figure imgf000397_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 7.91 -7.85 (m, 2H), 7.81 -7.76 (m, 1 H), 7.74 (d, J =
7.7 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.23 (br d, J = 19.8 Hz, 1 H), 4.60 (dt, J = 6.4,
14.7 Hz, 0.5H), 4.44-4.32 (m, 2.5H), 4.25 (dt, J = 5.3, 14.7 Hz, 0.5H), 4.13 (s, 3H), 4.06 (br d, J = 13.4 Hz, 0.5H), 3.97-3.71 (m, 2H), 3.69-3.52 (m, 1 H), 2.65 (s, 3H), 2.48-2.33 (m, 2H); LCMS (ESI) [M+H]+: 529.1 .
Figure imgf000397_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.17 (br d, J = 5.3 Hz, 1H), 8.11 (s, 1H), 8.07 (brd, J = 7.9 Hz, 1 H), 7.87-7.80 (m, 2H), 7.76 (dd, J = 0.7, 8.4 Hz, 1 H), 7.64-7.59 (m, 1 H), 7.35-7.26 (m, 1 H), 4.58 (dt, J = 6.3, 14.9 Hz, 0.5H), 4.44-4.30 (m, 2.5H), 4.24 (dt, J = 5.6, 15.1 Hz, 0.5H), 4.09 (s, 3H), 4.04 (brd, J = 14.5 Hz, 0.5H), 3.96-3.84 (m, 1.5H), 3.82-3.70 (m, 0.5H), 3.70-3.49 (m, 1H), 2.61 (s, 3H), 2.47-2.31 (m, 2H); LCMS (ESI) [M+H]+: 520.2.
Figure imgf000398_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.32 (s, 1 H), 8.11 (s, 1 H), 7.95-7.79 (m, 2H), 5.00 (spt, J = 6.6 Hz, 1 H), 4.42-4.24 (m, 4H), 4.01 (tt, J = 6.1 , 8.8 Hz, 1 H), 1.66 (d, J = 6.6 Hz, 6H), 1.49 (s, 9H); LCMS (ESI) [M-55]+: 328.1.
Figure imgf000398_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.11 (s, 1 H), 7.88 (m, 2H), 4.99 (spt, J = 6.7 Hz,
1 H), 4.59-4.49 (m, 2H), 4.48-4.41 (m, 1H), 4.39-4.32 (m, 1H), 4.04 (tt, J = 6.0, 8.8 Hz, 1H), 2.14-2.02 (m, 2H), 1.66 (d, J = 6.6 Hz, 6H), 1.10 (s, 9H); LCMS (ESI) [M+H]+: 382.2.
Figure imgf000398_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1H), 8.11 (s, 1 H), 7.91 -7.86 (m, 1 H), 7.85-7.80 (m, 1H), 5.16-5.03 (m, 1H), 4.90 (t, J = 8.6 Hz, 0.5H), 4.82-4.74 (m, 1H), 4.67 (dd, J = 5.0, 9.4 Hz, 0.5H), 4.34-3.93 (brs, 2H), 3.21 (tt, J = 3.9, 10.8 Hz, 1H), 3.11-2.97 (m, 2H), 2.16 (brd, J = 12.0 Hz, 2H), 1.94 (brd, J =
9.7 Hz, 2H), 1.66 (dd, J = 1.5, 6.9 Hz, 3H), 1.58 (s, 3H), 0.95-0.84 (m, 2H), 0.69-0.60 (m, 2H); LCMS (ESI) [M+H]+: 428.1.
Figure imgf000398_0004
1H NMR (400 MHz, DMSO-de) d 8.29 (s, 1 H), 8.19 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz,
1 H), 6.95 (brd, J = 4.5 Hz, 1H), 5.14 (spt, J = 6.5 Hz, 1H), 4.65-4.43 (m, 1H), 3.20-3.12 (m, 1H), 2.58 (d, J = 4.5 Hz, 3H), 2.21 (br d, J = 11.4 Hz, 2H), 2.04 (br dd, J = 3.1 , 12.5 Hz, 2H), 1.82-1.71 (m, 2H), 1.57- 1.44 (m, 8H); LCMS (ESI) [M+H]+: 384.2.
Figure imgf000399_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.83 (dd, J = 1 .0, 8.4 Hz, 1 H), 7.76-7.70 (m, 1 H), 4.80-4.54 (m, 2H), 4.08 (s, 3H), 3.06-2.96 (m, 1 H), 2.82 (d, J = 4.8 Hz, 3H), 2.60 (s, 3H), 2.34-2.16 (m, 4H), 1 .94-1 .82 (m, 2H), 1 .60-1 .46 (m, 2H); LCMS (ESI) [M+H]+: 370.1 .
Figure imgf000399_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 7.77 (d, J = 7.7 Hz, 1 H), 7.66 (s, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 4.72-4.65 (m, 1 H), 4.25-4.00 (m, 2H), 3.56 (s, 2H), 3.24-3.15 (m, 1 H), 3.03 (br t, J = 1 1 .1 Hz, 2H), 2.14 (br d, J = 1 1 .9 Hz, 2H), 1 .92 (br d, J = 9.5 Hz, 2H), 1 .57 (s, 3H), 1 .54 (d, J = 7.0 Hz, 6H), 0.92-0.87 (m, 2H), 0.68-0.63 (m, 2H); LCMS (ESI) [M+H]+: 425.2.
Figure imgf000399_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.77 (d, J = 7.7 Hz, 1 H), 7.66 (s, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 4.72-4.65 (m, 1 H), 4.62 (br d, J = 14.1 Hz, 1 H),4.03 (br d, J = 14.1 Hz, 1 H), 3.56 (s, 2H), 3.34-3.22 (m, 2H), 2.95 (br t, J = 1 1 .5 Hz, 1 H), 2.32 (s, 2H), 2.20 (br d, J = 1 1 .5 Hz, 2H), 2.03-1 .84 (m, 2H), 1 .54 (d, J = 6.8 Hz, 6H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 425.2.
Figure imgf000399_0004
1 H NMR (400 MHz, METHANOL-d4) d 7.80 (d, J = 7.7 Hz, 1 H), 7.75 (s, 1 H), 7.54 (d, J = 7.7 Hz, 1 H), 7.49-7.35 (m, 4H), 4.70-4.63 (m, 2H), 3.60-3.53 (m, 1 H), 3.44-3.39 (m, 1 H), 3.52-3.37 (m, 1 H), 3.32-3.22 (m, 2H), 2.35 (br d, J = 1 1 .9 Hz, 1 H), 2.17 (br d, J = 13.0 Hz, 1 H), 2.10-1 .96 (m, 2H), 1 .95-1 .81 (m, 1 H),
1 .55 (d, J = 7.1 Hz, 6H). LCMS (ESI) [M+H]+: 465.1 .
Figure imgf000399_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 7.94 (s, 1 H), 7.70-7.61 (m, 2H), 3.99 (s, 3H), 3.67-3.49 (m, 8H), 2.51 (s, 3H), 1 .51 (s, 3H), 0.88-0.79 (m, 2H), 0.64-0.56 (m, 2H); LCMS (ESI) [M+H]+: 397.1 .
Figure imgf000400_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 8.03 (s, 1 H), 7.81 -7.73 (m, 2H), 4.95 (m, 1 H), 4.30 (m, 2H), 3.49 (q, J = 7.1 Hz, 2H), 3.32 (d, J = 6.0 Hz, 2H), 3.15 (dt, J = 2.3, 12.8 Hz, 2H), 1 .96-1 .80 (m, 3H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .46-1 .29 (m, 2H), 1 .21 (t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 370.2.
Figure imgf000400_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.07 (s, 1 H), 7.90-7.78 (m, 3H), 7.28 (s, 1 H), 5.09- 4.91 (m, 2H), 4.65 (br d, J = 13.2 Hz, 1 H), 3.70-3.58 (m, 1 H), 3.47-3.36 (m, 1 H), 3.34-3.23 (m, 1 H), 2.30 (br d, J = 3.5 Hz, 2H), 2.23-2.05 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 407.1 .
Figure imgf000400_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.79 (m, 2H), 4.98 (td, J = 6.6, 13.3 Hz, 1 H), 4.74-4.49 (m, 1 H), 4.25-4.03 (m, 1 H), 3.53-3.29 (m, 3H), 3.23-2.97 (m, 2H), 2.77 (s, 3H), 2.48 (br dd, J = 7.6, 17.0 Hz, 1 H), 2.38-2.21 (m, 2H), 2.1 1 -1 .92 (m, 2H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .43 (s, 3H), 1 .1 7 (d, J = 5.0 Hz, 3H); LCMS (ESI) [M+H]+: 465.2.
Figure imgf000400_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.17 (s, 1 H), 7.94-7.89 (m, 1 H), 7.88-7.83 (m, 1 H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.34 (t, J = 6.6 Hz, 2H), 5.1 6 (t, J = 7.3 Hz, 2H), 4.63 (br d, J = 13.4 Hz, 1 H), 4.05 (br d, J = 13.4 Hz, 1 H), 3.37-3.23 (m, 2H), 2.96 (br t, J = 1 1 .2 Hz, 1 H), 2.32 (s, 2H), 2.22 (br d, J = 12.8 Hz, 2H), 2.03-1 .88 (m, 2H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 424.2.
Figure imgf000401_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.17 (s, 1 H), 7.94-7.88 (m, 1 H), 7.88-7.82 (m, 1 H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.34 (t, J = 6.5 Hz, 2H), 5.1 6 (t, J = 7.3 Hz, 2H), 4.39-3.91 (m, 3H), 3.23 (tt, J = 3.9, 1 0.9 Hz, 1 H), 3.07 (ddd, J = 2.9, 1 1 .2, 13.8 Hz, 2H), 2.25-2.08 (m, 2H), 2.03-1 .85 (m, 2H), 0.76- 0.66 (m, 4H); LCMS (ESI) [M+H]+: 410.1 .
Figure imgf000401_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (br d, J = 2.9 Hz, 2H), 7.86-7.78 (m, 2H), 5.93-5.84 (m,
1 H), 5.33 (m, 2H), 5.19-5.1 1 (m, 2H), 3.85-3.67 (m, 8H), 2.33 (d, J = 2.4 Hz, 2H), 1 .09 (d, J = 2.4 Hz, 9H); LCMS (ESI) [M+H]+: 425.2.
Figure imgf000401_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (d, J = 7.1 Hz, 2H), 7.84-7.78 (m, 2H), 5.88 (quin, J = 7.1 Hz, 1 H), 5.32 (t, J = 6.6 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.74-3.56 (m, 8H), 1 .58 (s, 3H), 0.93-0.88 (t, J = 6.4 Hz, 2H), 0.70-0.65 (t, J = 6.4 Hz, 2H); LCMS (ESI) [M+H]+: 425.2.
Figure imgf000401_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.46 (s, 1 H), 8.21 -8.14 (m, 2H), 7.85 (d, J = 8.4 Hz, 1 H), 5.94 (m, 1 H), 5.37 (t, J = 6.6 Hz, 2H), 5.18 (t, J = 7.3 Hz, 2H), 4.26 (m, 2H), 3.38 (m, 1 H), 3.00 (m, 2H), 2.25 (m, 2H), 1 .87 (m, 2H), 1 .52 (s, 9H); LCMS (ESI) [M+H]+: 442.1 .
Figure imgf000401_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.07 (s, 1 H), 7.89-7.80 (m, 2H), 5.02-4.93 (m, 1 H), 4.10 (br s, 2H), 3.75 (s, 3H), 3.42 (br t, J = 10.6 Hz, 2H), 2.41 -2.23 (m, 4H), 1 .63 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 388.1 .
Figure imgf000402_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.09 (s, 1 H), 7.90-7.83 (m, 2H), 5.03-4.96 (m, 1 H), 4.56 (br d, J = 13.4 Hz, 1 H), 3.89 (br d, J = 13.9 Hz, 1 H), 3.62 (br t, J = 1 1 .4 Hz, 1 H), 3.29 (br t, J = 1 1 .2 Hz, 1 H), 2.48-2.24 (m, 6H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .20 (s, 3H), 0.52-0.40 (m, 4H); LCMS (ESI) [M+H]+: 426.2.
Figure imgf000402_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 7.99 (s, 1 H), 7.80-7.73 (m, 2H), 4.95-4.84 (m, 1 H), 4.19-3.78 (m, 3H), 3.39-3.24 (m, 2H), 2.34-2.1 1 (m, 4H), 1 .55 (d, J = 6.7 Hz, 6H), 0.67-0.61 (m, 4H); LCMS (ESI) [M+H]+: 414.1 .
Figure imgf000402_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.08 (s, 1 H), 7.89-7.82 (m, 2H), 4.98 (spt, J = 6.6 Hz, 1 H), 4.22-3.89 (m, 2H), 3.46-3.32 (m, 2H), 2.40-2.23 (m, 4H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .59 (s, 3H),
1 .05-0.86 (m, 2H), 0.71 -0.65 (m, 2H); LCMS (ESI) [M+H]+: 428.1 .
Figure imgf000402_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.77 (d, J = 7.7 Hz, 1 H), 7.66 (s, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 4.72-4.65 (m, 1 H), 4.59 (br d, J = 13.5 Hz, 1 H), 3.96 (br d, J = 13.7 Hz, 1 H), 3.56 (s, 2H), 3.33-3.23 (m, 2H), 2.97 (br t, J = 1 1 .4 Hz, 1 H), 2.39 (d, J = 4.4 Hz, 2H), 2.21 (br d, J = 13.2 Hz, 2H), 2.01 -1 .87 (m, 2H), 1 .54 (d, J = 7.1 Hz, 6H), 1 .17 (s, 3H), 0.48-0.38 (m, 4H); LCMS (ESI) [M+H]+: 423.2.
Figure imgf000402_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 7.77 (dd, J = 1 .0, 7.6 Hz, 1 H), 7.66 (s, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 4.68 (spt, J = 7.0 Hz, 1 H), 4.30-4.00 (m, 2H), 3.73 (s, 3H), 3.55 (s, 2H), 3.22 (tt, J = 4.0, 10.8 Hz,
1 H), 3.08 (br t, J = 1 1 .7 Hz, 2H), 2.16 (br d, J = 10.8 Hz, 2H), 2.03-1 .84 (m, 2H), 1 .54 (d, J = 7.1 Hz, 6H); LCMS (ESI) [M+H]+: 385.2.
Figure imgf000403_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.10 (s, 1 H), 7.87 (m, 2H), 5.06-4.92 (m, 1 H), 4.37- 3.97 (m, 2H), 3.14-2.90 (m, 3H), 2.09 (br d, J = 10.8 Hz, 2H), 1 .88 (br d, J = 9.9 Hz, 2H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .58 (s, 3H), 0.97-0.83 (m, 2H), 0.70-0.59 (m, 2H); LCMS (ESI) [M+H]+: 410.2.
Figure imgf000403_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28 (s, J = 0.6 Hz, 1 H), 8.10 (s, 1 H), 7.92-7.82 (m, 2H), 4.98 (spt, J = 6.7 Hz, 1 H), 4.22 (br s, 2H), 3.74 (s, 3H), 3.1 6-2.97 (m, 3H), 2.1 1 (m, J = 1 1 .7 Hz, 2H), 1 .99-1 .82 (m, 2H), 1 .65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 370.1 .
Figure imgf000403_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.09 (s, 1 H), 7.84 (m, 2H), 4.97 (spt, J = 6.6 Hz, 1 H), 3.76 (s, 3H), 3.69-3.44 (m, 8H), 1 .64 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 371 .1 .
Figure imgf000403_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 8.03-7.82 (m, 3H), 7.78-7.73 (m, 1 H), 7.53-7.43 (m, 2H), 4.65 (m 0.4H), 4.48 (m, 0.5H), 4.41 -4.24 (m, 2H), 4.1 0 (br d, J = 2.4 Hz, 3H), 4.00 (t, J = 9.0 Hz, 1 H), 3.95-3.75 (m, 2H), 3.73-3.45 (m, 2H), 3.07-2.89 (m, 2H), 2.62 (s, 3H), 2.49-2.32 (m, 2H); LCMS (ESI) [M+H]+: 546.2.
Figure imgf000404_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.85 (s, 1 H), 7.54 (d, J = 8.7 Hz, 1 H), 6.40 (dd, J = 1 .6, 8.7 Hz,
1 H), 6.23 (s, 1 H), 4.83-4.60 (m, 1 H), 3.73 (s, 4H), 3.69-3.44 (m, 4H), 2.30 (s, 2H), 1 .85 (br dd, J = 5.4, 8.8 Hz, 4H), 1 .57 (d, J = 6.6 Hz, 6H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 383.2.
Figure imgf000404_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.38 (s, 1 H), 8.14-8.04 (m, 2H), 7.76 (d, J = 8.4 Hz, 1 H), 6.83 (br s, 1 H), 5.85 (t, J = 6.9 Hz, 1 H), 5.28 (t, J = 6.5 Hz, 2H), 5.09 (t, J = 7.3 Hz, 2H), 4.15 (d, J = 2.4 Hz, 2H), 3.64 (t, J = 5.4 Hz, 2H), 2.70 (m, 2H), 1 .44 (s, 9H) LCMS (ESI) [M+H]+: 440.1 .
Figure imgf000404_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.08 (s, 1 H), 7.89-7.81 (m, 2H), 5.04-4.93 (m, 1 H), 3.84-3.73 (m, 1 H), 3.03 (tt, J = 3.7, 1 1 .9 Hz, 1 H), 2.33-2.26 (m, 2H), 2.24-2.15 (m, 2H), 1 .88-1 .77 (m, 2H), 1 .64 (d, J = 6.7 Hz, 6H), 1 .55-1 .44 (m, 2H); LCMS (ESI) [M+H]+: 327.1 .
Figure imgf000404_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.17 (s, 1 H), 7.94-7.88 (m, 1 H), 7.87-7.81 (m, 1 H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.34 (t, J = 6.5 Hz, 2H), 5.1 6 (t, J = 7.3 Hz, 2H), 4.31 -4.08 (m, 2H), 3.74 (s, 3H), 3.23 (tt, J = 3.9, 10.9 Hz, 1 H), 3.09 (br t, J = 1 1 .5 Hz, 2H), 2.18 (br dd, J = 2.8, 13.3 Hz, 2H), 2.02- 1 .89 (m, 2H); LCMS (ESI) [M+H]+: 384.1 .
Figure imgf000404_0005
1 HNMR (400 MHz, CHLOROFORM-d) d 8.14 (d, J = 4.5 Hz, 2H), 7.81 -7.81 (m, 2H), 5.87 (quin, J = 7.0 Hz, 1 H), 5.32 (t, J = 6.5 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H), 3.72 (m, 4H), 3.65 (m, 4H); LCMS (ESI) [M+H]+: 385.1 .
Figure imgf000405_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.12 (s, 1 H), 8.03 (s, 1 H), 7.81 -7.73 (m, 2H), 4.95 (m, 1 H), 4.33 (m, 2H), 3.57 (d, J = 6.2 Hz, 2H), 3.16 (dt, J = 2.8, 13.0 Hz, 2H), 1 .90 (br d, J = 12.6 Hz, 2H), 1 .84-1 .73 (m, 1 H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .45-1 .33 (m, 2H); LCMS (ESI) [M+H]+: 342.1 .
Figure imgf000405_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.08 (s, 1 H), 7.84-7.79 (m, 1 H), 7.75-7.71 (m, 1 H), 4.50 (br dd,
J = 10.0, 13.3 Hz, 1 H), 4.37 (t, J = 8.5 Hz, 1 H), 4.19 (t, J = 9.3 Hz, 1 H), 4.07 (s, 3H), 3.92 (br d, J = 13.5 Hz, 1 H), 3.79 (dd, J = 5.6, 8.5 Hz, 1 H), 3.67 (br dd, J = 5.7, 9.5 Hz, 1 H), 3.31 (br t, J = 1 0.9 Hz, 2H), 3.06- 2.96 (m, 2H), 2.80-2.62 (m, 2H), 2.59 (s, 3H), 2.29-2.1 8 (m, 2H), 2.05-1 .91 (m, 2H), 1 .85 (s, 3H); LCMS (ESI) [M+H]+: 437.5.
Figure imgf000405_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.45 (s, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.65 (d, J = 8.8 Hz, 1 H), 4.16 (br s, 2H), 3.48 (td, J = 7.0, 14.0 Hz, 1 H), 3.28-3.13 (m, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.1 5 (br d, J = 1 0.4 Hz, 2H), 2.03-1 .86 (m, 2H), 1 .54 (d, J = 7.0 Hz, 6H), 1 .49 (s, 9H).; LCMS (ESI) [M+H]+: 413.1 .
Figure imgf000405_0004
1 H NMR (400 MHz, DMSO-de) d 8.29 (s, 1 H), 8.20 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.74 (dd, J = 1 .2, 8.5 Hz, 1 H), 4.46-4.29 (m, 1 H), 3.98 (br d, J = 13.2 Hz, 2H), 3.48-3.35 (m, 1 H), 2.99 (br s, 2H), 2.10 (br dd, J = 3.1 , 13.2 Hz, 2H), 1 .80-1 .64 (m, 2H), 1 .59 (d, J = 6.6 Hz, 3H), 1 .47-1 .36 (m, 10H), 0.64-0.55 (m, 1 H), 0.44 (qd, J = 4.8, 9.5 Hz, 1 H), 0.38-0.30 (m, 1 H), 0.25 (qd, J = 4.9, 9.6 Hz, 1 H); LCMS (ESI) [M+H]+: 438.2.
Figure imgf000406_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.07 (s, 1 H), 7.88-7.84 (d, J = 12 Hz, 1 H), 7.83- 7.79 (d, J = 12 Hz, 1 H), 5.15-5.01 (m, 1 H), 4.1 6 -4.13 (m, 2H), 3.64-3.62 (m, 1 H), 3.45-3.34 (m, 1 H), 3.21 -3. 18 (m, 1 H), 2.98-3.02 (m, 2H), 2.39- 2.36 (m, 1 H), 2.24-2.09 (m, 3H), 1 .99-1 .86 (m, 3H), 1 .63 (d, J = 6.6 Hz, 3H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 442.2.
Figure imgf000406_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (d, J = 6.1 Hz, 2H), 7.84-7.78 (m, 2H), 5.88 (quin, J = 7.1 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 4.16-4.10 (m, 1 H), 3.79-3.56 (m, 8H), 0.78-0.67 (m, 4H); LCMS (ESI) [M+H]+: 41 1 .1 .
Figure imgf000406_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.98-7.83 (m, 2H), 5.91 (m, J = 7.0 Hz, 1 H), 5.40-5.30 (m, 2H), 5.24-5.1 1 (m, 2H), 4.29-4.06 (m, 2H), 3.06 (tt, J = 3.7, 1 1 .2 Hz, 1 H), 2.97 (br t, J = 1 1 .9 Hz, 2H), 2.16-2.01 (m, 2H), 1 .97-1 .79 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 370.1 .
Figure imgf000406_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (d, J = 8.4 Hz, 2H), 8.00-7.94 (m, 1 H), 7.92-7.83 (m, 1 H), 5.90-5.75 (m, 1 H), 5.16 (s, 2H), 4.25-4.1 0 (m, 2H), 3.29-2.96 (m, 3H), 2.80 (d, J = 4.8 Hz, 3H), 2.18 (br d, J = 1 1 .1 Hz, 2H), 2.05-1 .85 (m, 2H), 1 .51 (s, 9H); LCMS (ESI) [M-1 00+H]+: 341 .1 .
Figure imgf000406_0005
1H NMR (400 MHz, CHLOROFORM-d) d 8.32 (s, 1H), 8.08 (s, 1 H), 7.91 -7.88 (m, 1 H), 7.85-7.81 (m, 1H), 5.61 (brs, 1 H), 4.92 (dd, J = 4.3, 14.4 Hz, 1H), 4.63 (dd, J = 8.5, 14.4 Hz, 1H), 4.17 (m, 2H), 3.39-3.16 (m, 3H), 3.14-2.95 (m, 3H), 2.31-2.07 (m, 4H), 2.02-1.89 (m, 2H); LCMS (ESI) [M+H]+: 367.1.
Figure imgf000407_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.45 (s, 1 H), 8.28 (dd, J = 1.6, 8.8 Hz, 1 H), 7.65 (d, J = 8.9 Hz,
1 H), 4.19 (brs, 2H), 3.74 (s, 3H), 3.48 (td, J = 6.9, 14.0 Hz, 1H), 3.29-3.18 (m, 1H), 3.09 (br t, J = 12.5 Hz, 2H), 2.17 (br d, J = 13.6 Hz, 2H), 2.02-1.88 (m, 2H), 1.55 (s, 3H), 1.54 (s, 3H); LCMS (ESI) [M+H]+: 371.1.
Figure imgf000407_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.06 (s, 1 H), 7.89-7.80 (m, 2H), 5.04-4.93 (m, 2H), 4.65 (br s, 1 H), 3.18-3.09 (m, 1 H), 2.82 (d, J = 4.9 Hz, 3H), 2.23-1.97 (m, 6H), 1.77 (br d, J = 11.1 Hz, 2H), 1.63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 384.1.
Figure imgf000407_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.11 (s, 1H), 8.01-7.83 (m, 3H), 7.79-7.73 (m, 1H), 7.52-7.43 (m, 2H), 4.64 (dt, J = 6.5, 14.2 Hz, 1H), 4.47 (br d, J = 13.3 Hz, 1H), 4.41-4.25 (m, 2H), 4.10 (br d, J = 2.8 Hz, 3H), 3.99 (t, J = 9.0 Hz, 1H), 3.94-3.75 (m, 2H), 3.71-3.43 (m, 2H), 3.05-2.87 (m, 2H), 2.61 (s, 3H), 2.48-2.30 (m, 2H); LCMS (ESI) [M+H]+: 546.2.
Figure imgf000407_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 5.55-5.48 (m, 1 H), 5.24-5.21 (m, 2H), 5.15-5.11 (m, 2H), 4.22-4.05 (m, 2H), 3.19 (tt, J = 3.8, 11.0 Hz, 1 H), 3.00 (br t, J = 11.8 Hz, 2H), 2.14 (br d, J = 10.6 Hz, 2H), 1.98-1.85 (m, 2H), 1.49 (s, 9H); LCMS (ESI) [M- 55]+: 387.1.
Figure imgf000408_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.08 (s, 1 H), 7.93-7.87 (m, 1 H), 7.86-7.79 (m, 1 H), 5.43-5.33 (m, 1 H), 4.34-4.12 (m, 5H), 4.05 (q, J = 7.3 Hz, 1 H), 3.21 (br t, J = 10.9 Hz, 1 H), 3.02 (br t, J =
1 1 .7 Hz, 2H), 2.55 (q, J = 6.7 Hz, 2H), 2.1 6 (br d, J = 13.0 Hz, 2H), 2.01 -1 .86 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 440.5.
Figure imgf000408_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28 (s, 1 H), 8.07 (s, 1 H), 7.88-7.84 (d, J = 8.4 Hz, 1 H), 7.82- 7.77 (d, J = 8.4 Hz, 1 H), 5.35-5.23 (m, 1 H), 4.18 -4.16 (m, 2H), 4.05-3.96 (m, 2H), 3.25-3.14 (m, 2H), 3.03 (br t, J = 1 1 .9 Hz, 2H), 2.93 (dd, J = 6.1 , 16.0 Hz, 1 H), 2.16 (br d, J = 10.8 Hz, 2H), 2.01 -1 .89 (m, 2H), 1 .64 (d, J = 6.6 Hz, 3H), 1 .50 (s, 9H), 1 .10 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 484.2.
Figure imgf000408_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.17 (s, 1 H), 8.14 (s, 1 H), 7.93-7.87 (m, 1 H), 7.86-7.80 (m, 1 H), 5.54-5.42 (m, 1 H), 4.60-4.52 (m, 2H), 4.51 -4.43 (m, 2H), 4.22-4.07 (m, 2H), 3.20 (tt, J = 3.9, 10.9 Hz, 1 H), 3.01 (br t, J = 12.0 Hz, 2H), 2.15 (br dd, J = 2.6, 13.2 Hz, 2H), 2.00-1 .83 (m, 2H), 1 .49 (d, J = 2.6 Hz,
18H); LCMS (ESI) [M-100+HJ+: 425.2.
Figure imgf000408_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.18 (s, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.93-7.85 (m, 1 H), 7.07 (dd, J = 1 1 .5, 1 8.0 Hz, 1 H), 6.09 (d, J = 18.1 Hz, 1 H), 5.63-5.46 (m, 1 H), 5.05-4.85 (m, 1 H), 4.16 (br s, 2H), 3.21 (ddd, J = 4.2, 6.9, 10.8 Hz, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.16 (br d, J = 1 1 .1 Hz, 2H), 2.00- 1 .88 (m, 2H), 1 .63 (d, J = 6.7 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 438.5.
Figure imgf000409_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.06 (s, 1 H), 7.90-7.80 (m, 2H), 4.98 (spt, J = 6.6 Hz, 1 H), 4.05 (br d, J = 2.9 Hz, 1 H), 3.19-3.03 (m, 1 H), 2.32-2.21 (m, 2H), 1 .98 (qd, J = 4.5, 13.7 Hz, 2H), 1 .91 -1 .77 (m, 4H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .43 (d, J = 3.4 Hz, 1 H); LCMS (ESI) [M+H]+: 327.1
Figure imgf000409_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.51 (s, 1 H), 8.07 (s, 1 H), 7.80-7.76 (m, 1 H), 7.75-7.72 (m, 1 H), 5.36-5.26 (m, 1 H), 4.32-4.08 (m, 5H), 4.06-3.99 (m, 1 H), 3.24-3.14 (m, 1 H), 3.03 (br t, J = 1 1 .8 Hz, 2H), 2.69-2.58 (m, 1 H), 2.54-2.44 (m, 1 H), 2.15 (br d, J = 1 1 .4 Hz, 2H), 1 .99-1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 440.5.
Figure imgf000409_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.53 (d, J = 0.7 Hz, 1 H), 8.10 (s, 1 H), 7.82-7.77 (m, 1 H), 7.76- 7.71 (m, 1 H), 5.35 (m, 1 H), 4.55-4.45 (m, 4H), 4.21 -4.04 (m, 2H), 3.25-3.12 (m, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.14 (br dd, J = 2.9, 13.2 Hz, 2H), 2.00-1 .83 (m, 2H), 1 .48 (d, J = 1 .5 Hz, 18H); LCMS (ESI) [M+23]+: 547.2, LCMS (ESI) [M-100+H]+: 425.2, LCMS (ESI) [M-100-55+H]+: 369.1 .
Figure imgf000409_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 8.07 (s, 1 H), 7.79 (m, 2H), 5.04-4.88 (m, 1 H), 3.85 (m, 8H), 2.28 (s, 3H), 1 .64 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 395.1 .
Figure imgf000409_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 7.98-7.90 (m, 2H), 7.46-7.36 (m, 2H), 4.22-4.05 (m, 4H), 3.94 (q, J = 7.9 Hz, 1 H), 3.80-3.73 (m, 1 H), 3.48 (quin, J = 7.8 Hz, 1 H), 3.17 (m, 1 H), 2.99 (br t, J = 1 1 .4 Hz, 2H), 2.41 (m, 1 H), 2.18-1 .99 (m, 3H), 1 .97-1 .83 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-100+H]+: 300.1 .
Figure imgf000410_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (d, J = 3.4 Hz, 2H), 7.85-7.78 (m, 2H), 5.88 (quin, J = 7.1 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.83-3.62 (m, 8H), 2.35 (d, J = 6.7 Hz, 2H), 1 .12-1 .02 (m, 1 H), 0.65-0.58 (m, 2H), 0.25-0.18 (m, 2H); LCMS (ESI) [M+H]+: 409.2.
Figure imgf000410_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.43 (s, 1 H), 8.13 (s, 1 H), 7.96 (d, J = 8.3 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.68-7.34 (t,J = 59.6 Hz, 1 H), 3.70 (m, 4H), 3.62-3.57 (m, 4H),1 .50 (s, 9H); LCMS (ESI) [M- 55]+: 365.1 .
Figure imgf000410_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.04 (d, J = 0.7 Hz, 1 H), 7.91 -7.86 (m, 1 H), 7.84- 7.80 (m, 1 H), 4.85 (dd, J = 6.5, 7.5 Hz, 2H), 4.76 (d, J = 7.5 Hz, 2H), 4.62 (t, J = 6.1 Hz, 2H), 4.26-4.05 (m, 2H), 3.72-3.60 (m, 1 H), 3.21 (tt, J = 3.9, 1 1 .0 Hz, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 1 H), 3.08-2.96 (m, 1 H), 2.16 (br dd, J = 2.4, 13.6 Hz, 2H), 2.01 -1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 440.2.
Figure imgf000410_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 7.76 (d, J = 7.7 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.05 (s, 1 H), 5.22-5.09 (m, 1 H), 5.02 (t, J = 7.1 Hz, 2H), 4.70 (t, J = 7.3 Hz, 2H), 4.21 -4.08 (m, 2H), 3.1 7 (tt, J = 3.8, 10.9 Hz, 1 H), 3.06-2.94 (m, 4H), 2.62 (t, J = 7.2 Hz, 2H), 2.12 (br d, J = 1 1 .0 Hz, 2H), 1 .97-1 .83 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 455.2.
Figure imgf000411_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.34 (s, 1 H), 8.24 (s, 1 H), 8.00-7.89 (m, 2H), 5.93 (quin, J = 6.9 Hz, 1 H), 5.35 (t, J = 6.5 Hz, 2H), 5.20 (t, J = 7.2 Hz, 2H), 4.53-4.04 (m, 2H), 3.69-3.38 (m, 2H), 3.35-3.22 (m, 1 H), 2.41 -2.14 (m, 2H), 1 .53 (s, 9H); LCMS (ESI) [M+H]+: 462.1 .
Figure imgf000411_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (d, J = 4.4 Hz, 2H), 7.85-7.78 (m, 2H), 5.88(quin, J = 7.1 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.75-3.67 (m, 4H), 3.63-3.57(m, 4H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 427.1 .
Figure imgf000411_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.02 (d, J = 7.7 Hz, 1 H), 7.64 (br d, J = 8.1 Hz,
1 H), 7.40-7.33 (m, 1 H), 4.14 (br s, 2H), 3.18 (tt, J = 3.8, 10.9 Hz, 1 H), 3.01 (br t, J = 1 1 .6 Hz, 2H), 2.13 (br d, J = 10.9 Hz, 2H), 1 .98-1 .82 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 352.0.
Figure imgf000411_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.07 (s, 1 H), 7.84 (q, J = 8.4 Hz, 1 H), 7.90-7.80 (m, 1 H), 4.98 (td, J = 6.7, 13.4 Hz, 1 H), 4.86 (t, J = 6.8 Hz, 1 H), 3.93 (br t, J = 12.8 Hz, 2H), 3.59-3.41 (m,
2H), 3.34-3.22 (m, 1 H), 3.20-3.03 (m, 2H), 2.38-2.28 (m, 1 H), 2.36-1 .92 (m, 7H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 434.2.
Figure imgf000411_0005
1H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.07 (s, 1 H), 7.90-7.79 (m, 2H), 4.98 (td, J = 6.7,
13.3 Hz, 1 H), 3.68 (br d, J = 13.4 Hz, 2H), 3.50 (t, J = 6.6 Hz, 2H), 3.19 (tt, J = 4.0, 11.1 Hz, 1 H), 2.99- 2.82 (m, 2H), 2.26-2.13 (m, 2H), 2.06-1.94 (m, 2H), 1.91-1.82 (m, 2H), 1.80-1.74 (m, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.46 (s, 6H); LCMS (ESI) [M+H]+: 437.2.
Figure imgf000412_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1H), 8.05 (s, 1H), 7.78 (s, 2H), 4.96 (td, J = 6.6, 13.3 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2H), 3.79-3.61 (m, 8H), 1.63 (d, J = 6.7 Hz, 6H), 1.31 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 385.1.
Figure imgf000412_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1H), 8.05 (s, 1H), 7.78 (s, 2H), 4.95 (td, J = 6.6, 13.3 Hz, 1 H), 3.92-3.68 (m, 8H), 3.18 (s, 2H), 2.31 (s, 6H), 1.63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 398.2.
Figure imgf000412_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.45 (s, 1 H), 8.28 (dd, J = 1.4, 8.7 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 4.60 (brd, J = 13.3 Hz, 1H), 3.97 (br d, J = 13.6 Hz, 1H), 3.48 (td, J = 6.9, 14.0 Hz, 1H), 3.37-3.22 (m, 2H), 2.97 (br t, J = 11.1 Hz, 1H), 2.40 (d, J = 4.0 Hz, 2H), 2.22 (brd, J = 12.6 Hz, 2H), 2.04-1.86 (m, 2H), 1.55 (s, 6H), 1.18 (s, 3H), 0.49-0.40 (m, 4H); LCMS (ESI) [M+H]+: 409.2.
Figure imgf000412_0004
1H NMR (400 MHz, CHLOROFORM-d) d 9.20 (s, 1 H), 8.24 (s, 1 H), 8.09 (m, J = 8.2 Hz, 1 H), 7.85 (br d, J = 8.2 Hz, 1 H), 4.58 (brd, J = 14.1 Hz, 1H), 4.03 (brd, J = 13.7 Hz, 1H), 3.28 (brd, J = 11.7 Hz, 3H), 2.98 (br t, J = 11.8 Hz, 1H), 2.32 (s, 2H), 2.21 (brd, J = 12.6 Hz, 2H), 2.05-1.80 (m, 2H), 1.37 (m, 2H), 1.18 (m, J = 4.0 Hz, 2H), 1.09 (s, 9H); LCMS (ESI) [M+H]+: 436.20.
Figure imgf000413_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 7.71 (d, J = 7.7 Hz, 1 H), 7.43-7.35 (m, 2H), 6.89 (dd, J = 2.5, 8.3 Hz, 1 H), 5.32-5.26 (m, 1 H), 5.02 (t, J = 6.8 Hz, 2H), 4.79 (dd, J = 5.3, 7.2 Hz, 2H), 4.13 (br d, J = 9.9 Hz, 2H), 3.17 (tt, J = 3.9, 1 0.9 Hz, 1 H), 3.00 (br t, J = 1 1 .8 Hz, 2H), 2.12 (br dd, J = 2.8, 13.3 Hz, 2H),
1 .94-1 .83 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 346.1 .
Figure imgf000413_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.18 (s, 1 H), 8.04 (s, 1 H), 7.79 (s, 2H), 5.01 -4.90 (m, 1 H), 4.24 (br s, 2H),3.12-3.04 (m, 1 H), 2.99-2.88 (m, 2H), 2.15-2.06 (m, 2H), 1 .89-1 .80 (m, 2H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 41 1 .2.
Figure imgf000413_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.79 (s, 1 H), 8.54 (s, 1 H), 7.79 (m, 2H), 4.60 (m, J = 13.0 Hz, 1 H), 4.04 (m, J = 13.5 Hz, 1 H), 3.47 (s, 1 H), 3.39-3.22 (m, 2H), 3.00 (t, J = 1 1 .7 Hz, 1 H), 2.33 (m, 2H), 2.22 (m, J = 13.5 Hz, 2H), 2.07-1 .82 (m, 2H), 1 .44 (m, 2H), 1 .32 (m, 2H), 1 .09 (s, 9H); LCMS (ESI)
[M+H]+: 436.2.
Figure imgf000413_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 8.01 -7.82 (m, 2H), 5.91 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.19 (t, J = 7.2 Hz, 2H), 4.27 (m, 1 H), 4.1 6-3.98 (m, 2H), 3.18-2.93 (m, 3H), 2.08 (m, 2H), 1 .90 (m, 2H), 0.78-0.65 (m, 4H); LCMS (ESI) [M+H]+: 410.1 .
Figure imgf000413_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.98-7.86 (m, 2H), 5.97-5.81 (m, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.18 (t, J = 7.2 Hz, 2H), 4.21 (m, 2H), 3.74 (s, 3H), 3.20-2.92 (m, 3H), 2.1 1 (m, J = 1 1 .8 Hz, 2H), 1 .96-1 .79 (m, 2H); LCMS (ESI) [M+H]+: 384.1 .
Figure imgf000414_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 7.97 (s, 1 H), 7.73-7.66 (m, 2H), 4.94-4.78 (m, 1 H), 4.19 (br s, 2H), 3.66 (s, 3H), 3.09-2.86 (m, 3H), 2.06 (br d, J = 10.9 Hz, 2H), 1 .87-1 .71 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 369.1 .
Figure imgf000414_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.54 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.71 (m, 2H), 6.65 (br s, 1 H), 5.15 (s, 2H), 4.25-4.07 (m, 2H), 3.22 (br t, J = 10.8 Hz, 1 H), 3.12-2.97 (m, 2H), 2.83 (d, J = 4.9 Hz, 3H), 2.17 (br d, J = 1 1 .1 Hz, 2H), 2.04-1 .87 (m, 2H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 441 .2.
Figure imgf000414_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 7.94 (s, 1 H), 7.73-7.62 (m, 2H), 7.37-7.25 (m, 5H), 4.84-4.64 (m, 2H), 3.87-3.67 (m, 1 H), 3.16-2.88 (m, 3H), 2.12-1 .74 (m, 4H), 1 .47 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 415.2.
Figure imgf000414_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.56 (br s, 1 H), 8.02 (s, 1 H), 7.77-7.72 (m, 1 H), 7.68-7.63 (m,
1 H), 4.38 (br d, J = 13.4 Hz, 1 H), 4.20-4.07 (m, 2H), 4.01 (s, 3H), 3.85 (br d, J = 14.4 Hz, 1 H), 3.66 (br s, 2H), 3.30-3.1 0 (m, 3H), 2.93 (br t, J = 10.5 Hz, 1 H), 2.84-2.73 (m, 2H), 2.52 (s, 3H), 2.21 -2.08 (m, 2H),
1 .96-1 .81 (m, 2H); LCMS (ESI) [M+H]+: 395.2.
Figure imgf000414_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.35 (s, 1 H), 8.21 (s, 1 H), 7.98-7.90 (m, 1 H), 7.89-7.81 (m, 1 H), 5.99-5.86 (m, 1 H), 5.35 (t, J = 6.6 Hz, 2H), 5.24-5.12 (m, 2H); LCMS (ESI) [M+H]+: 219.0.
Figure imgf000415_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.08 (s, 1 H), 7.82 (m, 2H), 5.08-4.88 (m, 1 H), 3.55 (m, 8H), 1 .63 (d, J = 6.6 Hz, 6H), 1 .57 (s, 3H), 0.96-0.85 (m, 2H), 0.68-0.60 (m, 2H); LCMS (ESI) [M+H]+: 41 1 .1 .
Figure imgf000415_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (d, J = 0.9 Hz, 1 H), 8.18 (s, 1 H), 7.94-7.90 (m, 1 H), 7.87- 7.84 (m, 1 H), 5.92 (quin, J = 7.1 Hz, 1 H), 5.35 (t, J = 6.7 Hz, 2H), 5.17 (t, J = 7.4 Hz, 2H), 4.61 (br s, 1 H), 3.76 (br s, 1 H), 3.26-3.16 (m, 1 H), 2.21 -2.10 (m, 2H), 2.06-1 .96 (m, 2H), 1 .92-1 .81 (m, 2H), 1 .77-1 .66 (m, 2H), 1 .46 (s, 9H); LCMS (ESI) [M+H]+: 440.2.
Figure imgf000415_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.06 (s, 1 H), 7.88-7.80 (m, 2H), 4.97 (quin, J = 6.6 Hz, 1 H), 3.99-3.90 (m, 4H), 3.22 (tt, J = 3.9, 10.9 Hz, 1 H), 3.01 -2.92 (m, 2H), 2.16 (br dd, J = 3.2, 13.4 Hz, 2H), 2.05-1 .95 (m, 4H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .53 (s, 6H); LCMS (ESI) [M+H]+: 423.2.
Figure imgf000415_0004
1 H NMR (400 MHz, DMSO-de) d 8.49 (s, 1 H), 8.37 (s, 1 H), 8.03 (d, J = 8.6 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.50-7.39 (m, 5H), 6.28-6.15 (m, 1 H), 5.08 (d, J = 6.8 Hz, 4H), 4.07 (br s, 2H), 3.32-3.15 (m, 3H), 2.1 1 (br d, J = 1 1 .5 Hz, 2H), 1 .89-1 .74 (m, 2H); LCMS (ESI) [M+H]+: 430.1 .
Figure imgf000415_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.84 (q, J = 8.4 Hz, 2H), 4.97 (td, J = 6.5, 13.4 Hz, 1 H), 4.54 (br d, J = 12.7 Hz, 1 H), 4.22 (br d, J = 13.8 Hz, 1 H), 3.31 (br t, J = 10.5 Hz, 2H), 3.25-3.10 (m, 2H), 3.01 (br t, J = 1 1 .0 Hz, 1 H), 2.33 (s, 6H), 2.23 (br d, J = 13.6 Hz, 2H), 2.07-1 .89 (m, 2H), 1 .64 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 397.1 .
Figure imgf000416_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.06 (s, 1 H), 7.89-7.78 (m, 2H), 5.66 (dd, J = 1 .7,
9.5 Hz, 1 H), 4.97 (td, J = 6.6, 13.3 Hz, 1 H), 3.80-3.67 (m, 3H), 3.63-3.45 (m, 3H), 3.23 (tt, J = 4.1 , 10.9 Hz, 1 H), 3.07-2.90 (m, 2H), 2.22 (br t, J = 10.7 Hz, 2H), 2.13-1 .91 (m, 2H), 1 .90-1 .73 (m, 4H), 1 .63 (d, J =
6.6 Hz, 6H), 1 .43 (s, 3H); LCMS (ESI) [M+H]+: 453.2.
Figure imgf000416_0002
1 H NMR (400 MHz, DMSO-de) d 8.28 (s, 1 H), 8.1 5 (s, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz,
1 H), 5.1 1 (td, J = 6.7, 13.1 Hz, 1 H), 4.26 (br d, J = 13.9 Hz, 2H), 3.62-3.47 (m, 1 H), 3.39-3.26 (m, 2H), 2.29-2.20 (m, 2H), 1 .89 (q, J = 10.4 Hz, 2H), 1 .62-1 .56 (m, 2H), 1 .53 (m, 8H); LCMS (ESI) [M+H]+: 405.1 .
Figure imgf000416_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 8.05 (s, 1 H), 7.78 (d, J = 0.7 Hz, 2H), 4.95 (td, J = 6.7, 13.3 Hz, 1 H), 4.21 -4.05 (m, 1 H), 3.80-3.52 (m, 8H), 1 .62 (d, J = 6.6 Hz, 6H), 0.79-0.67 (m, 4H); LCMS (ESI) [M+H]+: 397.1 .
Figure imgf000416_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (d, J = 4.5 Hz, 2H), 7.91 -7.85 (m, 1 H), 7.81 -7.77 (m, 1 H), 5.53-5.42 (m, 1 H), 4.93-4.83 (m, 2H), 4.66-4.56 (m, 2H), 4.08 (br s, 2H), 3.14 (tt, J = 3.8, 10.9 Hz, 1 H), 2.95 (br t, J = 1 1 .6 Hz, 2H), 2.14-2.03 (m, 2H), 1 .93-1 .80 (m, 2H), 1 .42 (s, 9H); LCMS (ESI) [M+H]+: 418.1 .
Figure imgf000417_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.05 (s, 1 H), 7.87-7.76 (m, 2H), 4.96 (td, J = 6.6, 13.2 Hz, 1 H), 4.76 (br d, J = 13.3 Hz, 1 H), 4.03 (br d, J = 13.6 Hz, 1 H), 3.30-3.13 (m, 2H), 2.85 (br t, J = 1 1 .7 Hz, 1 H), 2.51 -2.35 (m, 2H), 2.28-2.10 (m, 2H), 2.02-1 .84 (m, 2H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .19 (s, 2H), 1 .20-1 .1 7 (m, 1 H), 0.50-0.38 (m, 4H); LCMS (ESI) [M+H]+: 407.2.
Figure imgf000417_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.55 (dd, J = 1 .0, 4.7 Hz, 1 H), 8.29 (s, 1 H), 8.09 (s, 1 H), 7.86 (s, 2H), 7.78 (dd, J = 1 .0, 8.2 Hz, 1 H), 7.32 (dd, J = 4.6, 8.2 Hz, 1 H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.78- 4.71 (m, 1 H), 3.55-3.46 (m, 1 H), 3.30-3.14 (m, 3H), 2.28 (br dd, J = 3.5, 13.6 Hz, 1 H), 2.14-2.02 (m, 3H),
1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 451 .1 .
Figure imgf000417_0003
1 H NMR (400 MHz, DMSO-de) d 8.53 (s, 1 H), 8.41 (s, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.84 (dd, J = 1 .2, 8.5 Hz, 1 H), 7.55-7.47 (m, 1 H), 7.44 (br t, J = 6.7 Hz, 1 H), 7.35-7.27 (m, 2H), 6.29 (quin, J = 6.9 Hz, 1 H), 5.04 (d, J = 7.1 Hz, 4H), 4.53 (br d, J = 13.2 Hz, 1 H), 3.49 (br d, J = 13.7 Hz, 1 H), 3.31 -3.23 (m, 2H), 3.15-3.06 (m, 1 H), 2.16 (br d, J = 1 1 .5 Hz, 1 H), 2.02 (br d, J = 12.1 Hz, 1 H), 1 .82-1 .65 (m, 2H); LCMS (ESI) [M+H]+: 448.1 .
Figure imgf000417_0004
1 H NMR (400 MHz, DMSO-de) d 8.53 (s, 1 H), 8.42 (s, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4 Hz,
1 H), 7.55 (br d, J = 6.8 Hz, 1 H), 7.49-7.36 (m, 3H), 6.34-6.23 (m, 1 H), 5.04 (d, J = 6.8 Hz, 4H), 4.54 (br d, J = 12.1 Hz, 1 H), 3.37 (br d, J = 2.4 Hz, 1 H), 3.32-3.16 (m, 2H), 3.16-3.05 (m, 1 H), 2.20-2.09 (m, 1 H), 2.07-1 .95 (m, 1 H), 1 .85-1 .72 (m, 2H), 1 .72-1 .61 (m, 1 H); LCMS (ESI) [M+H]+: 464.1 .
Figure imgf000418_0001
1 H NMR (400 MHz, DMSO-de) d 8.48 (s, 1 H), 8.37 (s, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 5.3 Hz, 1 H), 7.10 (d, J = 5.3 Hz, 1 H), 6.21 (m, 1 H), 5.08 (d, J = 6.8 Hz, 4H), 4.15-3.95 (m, 2H), 3.35-3.23 (m, 3H), 2.14 (br dd, J = 3.2, 13.3 Hz, 2H), 1 .89-1 .75 (m, 2H); LCMS (ESI) [M+H]+: 470.0.
Figure imgf000418_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.17 (s, 1 H), 7.90-7.81 (m, 1 H), 7.79-7.67 (m, 1 H), 4.91 (td, J = 6.6, 13.3 Hz, 1 H), 4.16 (br s, 2H), 4.09 (q, J = 5.9 Hz, 2H), 3.28-3.18 (m, 3H), 3.1 1 (t, J = 6.3 Hz, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.16 (br d, J = 1 1 .5 Hz, 2H), 2.02-1 .87 (m, 2H), 1 .60 (d, J = 6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 456.2.
Figure imgf000418_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.17 (s, 1 H), 7.94-7.89 (m, 1 H), 7.88-7.82 (m, 1 H), 5.96-5.85 (m, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.1 7 (t, J = 7.3 Hz, 2H), 4.47-4.32 (m, 4H), 4.14-4.04 (m, 1 H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 398.1 .
Figure imgf000418_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.46 (d, J = 0.9 Hz, 1 H), 8.18-8.1 1 (m, 1 H), 7.72 (m, 2H), 5.79- 5.71 (m, 1 H), 5.25-5.16 (m, 4H), 3.72-3.67 (m, 4H), 3.62-3.56 (m, 4H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 427.1 .
Figure imgf000418_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 7.81 (s, 2H), 4.90 (quin, J = 6.7 Hz, 1 H), 4.15 (br s, 2H), 3.88-3.75 (m, 2H), 3.40 (s, 3H), 3.29 (t, J = 7.1 Hz, 2H), 3.24-3.14 (m, 1 H), 3.02 (br t, J = 1 1 .1 Hz, 2H), 2.1 5 (br d, J = 13.3 Hz, 2H), 2.01 -1 .88 (m, 2H), 1 .63-1 .57 (m, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 470.2.
Figure imgf000419_0001
1 H NMR (400 MHz, DMSO-de) d 8.27 (s, 1 H), 8.1 5 (s, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 5.1 1 (td, J = 6.6, 13.2 Hz, 1 H), 4.56-4.37 (m, 2H), 3.97-3.85 (m, 1 H), 3.75 (q, J = 7.4 Hz, 1 H), 3.53- 3.41 (m, 1 H), 3.24-3.1 1 (m, 2H), 2.72-2.63 (m, 1 H), 2.1 6 (br s, 2H), 1 .91 -1 .71 (m, 4H), 1 .64-1 .56 (m, 1 H), 1 .53 (d, J = 6.6 Hz, 6H), 1 .42 (s, 3H); LCMS (ESI) [M+H]+: 424.2.
Figure imgf000419_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.06 (s, 1 H), 7.90-7.78 (m, 2H), 4.97 (td, J = 6.7, 13.3 Hz, 1 H), 4.06 (td, J = 3.8, 13.4 Hz, 2H), 3.36-3.22 (m, 3H), 2.42 (s, 3H), 2.29 (br dd, J = 3.4, 13.7 Hz, 2H), 2.20-2.05 (m, 2H), 1 .65-1 .62 (m, 6H); LCMS (ESI) [M+H]+: 394.1 .
Figure imgf000419_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.89-7.78 (m, 2H), 5.03-4.90 (m, 1 H), 4.51 (br d, J = 13.2 Hz, 1 H), 4.27 (br d, J = 13.4 Hz, 1 H), 3.40-3.24 (m, 2H), 3.03-2.90 (m, 1 H), 2.53 (s,
1 H), 2.27-2.1 5 (m, 8H), 2.03-1 .89 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 406.1 .
Figure imgf000419_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.07 (s, 1 H), 7.92-7.77 (m, 2H), 4.97 (td, J = 6.6, 13.2 Hz, 1 H), 4.74-4.49 (m, 1 H), 4.40-4.16 (m, 1 H), 3.31 (br s, 2H), 3.23-2.91 (m, 3H), 2.38 (s, 3H), 2.30- 2.13 (m, 4H), 2.04-1 .76 (m, 5H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.
Figure imgf000420_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.24 (d, J = 0.7 Hz, 1H), 8.17 (s, 1H), 7.94-7.82 (m, 2H), 5.95- 5.83 (m, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.17 (t, J = 7.3 Hz, 2H), 4.66-4.36 (m, 4H), 4.18-4.07 (m, 1H), 2.05 (s, 2H), 1.09 (s, 9H); LCMS (ESI) [M+H]+: 369.2.
Figure imgf000420_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.56 (s, 1H), 8.17 (s, 1H), 7.84-7.73 (m, 2H), 5.76 (m, 1H), 5.28- 5.14 (m, 4H), 4.45-4.30 (m, 4H), 4.14-4.03 (m, 1H), 1.48 (s, 9H); LCMS (ESI) [M+H]+: 398.1.
Figure imgf000420_0003
1H NMR (400 MHz, CHLOROFORM-d) d 8.24 (d, J = 0.7 Hz, 1H), 8.17 (s, 1H), 7.94-7.90 (m, 1H), 7.88- 7.83 (m, 1 H), 5.96-5.85 (m, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.21 -5.11 (t, J = 7.3 Hz, 2H), 4.53-4.40 (m, 4H), 4.15 (m, 1 H), 3.80 (s, 2H), 0.96 (s, 9H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000420_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.53 (s, 1 H), 8.07 (s, 1 H), 7.82-7.77 (m, 1 H), 7.77-7.71 (m, 1 H), 5.40 (m, 1 H), 4.79 (dd, J = 5.3, 8.8 Hz, 1H), 4.73-4.65 (m, 1H), 4.63-4.55 (m, 2H), 4.13 (br d, J = 8.2 Hz, 2H), 3.25-3.13 (m, 1H), 3.02 (br t, J = 11.5 Hz, 2H), 2.14 (br d, J = 11.2 Hz, 2H), 1.99 (s, 3H), 1.97-1.85 (m, 2H), 1.48 (s, 9H); LCMS (ESI) [M-100+H]+: 367.1.
Figure imgf000420_0005
1H NMR (400 MHz, CHLOROFORM-d) d 8.16 (s, 2H), 7.95-7.89 (m, 1H), 7.87-7.82 (m, 1H), 5.54 (m, 1H), 4.80 (dd, J = 5.4, 8.7 Hz, 1H), 4.72-4.63 (m, 1H), 4.62-4.51 (m, 2H), 4.23-4.07 (m, 2H), 3.26-3.14 (m, 1H), 3.02 (br t, J = 1 1 .5 Hz, 2H), 2.15 (m, 2H), 1 .99 (s, 3H), 1 .98-1 .86 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M- 100+H]+: 367.1 .
Figure imgf000421_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.20 (s, 1 H), 7.88 (m, 2H), 7.46 (s, 5H), 5.90 (quin, J = 6.9 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.18 (t, J = 7.3 Hz, 2H), 3.61 (m, 8H); LCMS (ESI) [M+H]+:
431 .1 .
Figure imgf000421_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.19 (s, 1 H), 7.94-7.82 (m, 2H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.18 (t, J = 7.2 Hz, 2H), 3.76 (s, 3H), 3.69-3.41 (m, 8H); LCMS (ESI) [M+H]+: 385.1 .
Figure imgf000421_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.49 (d, J = 4.6 Hz, 1 H), 8.29 (s, 1 H), 8.10 (s, 1 H), 7.87 (s, 2H), 7.55-7.49 (m, 1 H), 7.40 (td, J = 4.4, 8.6 Hz, 1 H), 4.99 (spt, J = 6.7 Hz, 1 H), 4.78-4.68 (m, 1 H), 3.67 (br d, J = 13.8 Hz, 1 H), 3.32-3.17 (m, 3H), 2.27 (br dd, J = 3.5, 13.6 Hz, 1 H), 2.15-2.01 (m, 3H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 435.2.
Figure imgf000421_0004
1 H NMR (400 MHz, DMSO-de) d 8.43 (s, 1 H), 8.1 9 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.81 -7.75 (m, 2H), 7.08 (d, J = 5.3 Hz, 1 H), 5.22-5.1 0 (m, 1 H), 4.02 (br s, 2H), 3.33-3.20 (m, 3H), 2.13 (m, 2H), 1 .86-1 .75 (m, 2H), 1 .52 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 456.1 .
Figure imgf000422_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.85 (d, J = 5.0 Hz, 2H), 8.30 (s, 1 H), 8.09 (s, 1 H), 7.86 (d, J = 0.9 Hz, 2H), 7.37 (t, J = 5.0 Hz, 1 H), 4.99 (spt, J = 6.6 Hz, 1 H), 4.78-4.68 (m, 1 H), 3.73-3.65 (m, 1 H), 3.33-3.17 (m, 3H), 2.29-2.21 (m, 1 H), 2.16-2.04 (m, 3H), 1 .65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 418.2.
Figure imgf000422_0002
1 H NMR (400 MHz, DMSO-de) d 8.28 (s, 1 H), 8.1 6 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.6 Hz, 1 H), 5.12 (quin, J = 6.6 Hz, 1 H), 4.31 (br d, J = 14.1 Hz, 2H), 3.62-3.49 (m, 1 H), 3.33 (br t, J = 12.1 Hz, 2H), 2.25 (br d, J = 10.4 Hz, 2H), 1 .98-1 .82 (m, 2H), 1 .59 (s, 6H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 407.1 .
Figure imgf000422_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.18 (s, 1 H), 7.94-7.89 (m, 1 H), 7.88-7.83 (m, 1 H), 7.41 (d, J = 5.3 Hz, 1 H), 6.95 (d, J = 5.3 Hz, 1 H), 5.90 (quin, J = 7.1 Hz, 1 H), 5.34 (t, J = 6.5 Hz, 2H), 5.20-5.14 (m, 2H), 4.77-3.73 (m, 2H), 3.50-3.1 6 (m, 3H), 2.28 (br d, J = 1 1 .6 Hz, 2H), 2.18-2.03 (m, 2H); LCMS (ESI) [M+H]+: 470.1 .
Figure imgf000422_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.51 (s, 1 H), 8.14 (s, 1 H), 7.79-7.73 (m, 2H), 4.69-4.61 (m, 1 H), 4.23 (dd, J = 4.0, 1 1 .4 Hz, 1 H), 4.14 (br d, J = 6.2 Hz, 2H), 4.03-3.91 (m, 2H), 3.72-3.63 (m, 1 H), 3.19 (tt, J = 3.9, 10.8 Hz, 1 H), 3.03 (br t, J = 1 1 .4 Hz, 2H), 2.41 -2.32 (m, 2H), 2.15 (br d, J = 1 0.3 Hz, 2H), 1 .98- 1 .79 (m, 4H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 454.2.
Figure imgf000422_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.06 (s, 1 H), 7.91 -7.86 (m, 1 H), 7.84-7.79 (m, 1 H), 4.79-4.68 (m, 1 H), 4.24-4.02 (m, 4H), 3.85 (t, J = 10.7 Hz, 1 H), 3.60-3.50 (m, 1 H), 3.22 (tt, J = 3.9, 10.9 Hz, 1 H), 3.03 (br t, J = 1 1 .6 Hz, 2H), 2.48-2.35 (m, 1 H), 2.27 (br d, J = 12.5 Hz, 1 H), 2.17 (br d, J = 1 0.6 Hz, 2H), 2.02-1 .89 (m, 4H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 454.2.
Figure imgf000423_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.1 1 (d, J = 0.9 Hz, 1 H), 8.06 (s, 1 H), 7.79-7.74 (m, 2H), 5.16 (quin, J = 8.3 Hz, 1 H), 3.77-3.65 (m, 4H), 3.63-3.53 (m, 4H), 2.89-2.75 (m, 2H), 2.61 -2.50 (m, 2H), 2.06- 1 .86 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 425.2.
Figure imgf000423_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28 (br d, J = 2.6 Hz, 1 H), 8.10 (br d, J = 3.4 Hz, 1 H), 7.86 (br d, J = 4.2 Hz, 2H), 5.06-4.91 (m, 1 H), 4.60 (br d, J = 12.2 Hz, 2H), 3.36-3.03 (m, 3H), 2.27-2.13 (m, 2H), 2.05-1 .90 (m, 2H), 1 .70-1 .62 (m, 6H), 1 .17-1 .08 (m, 2H), 0.99 (br s, 2H); LCMS (ESI) [M+H]+: 396.2.
Figure imgf000423_0003
1 H NMR (400 MHz, METHANOL-d4) d 8.53 (s, 1 H), 8.35-8.27 (m, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 3.60-3.45 (m, 4H), 3.30-3.21 (m, 2H), 2.47 (br dd, J = 3.2, 14.4 Hz, 2H), 2.25-2.1 1 (m, 2H), 1 .51 (d, J = 7.1 Hz, 6H; LCMS (ESI) [M+H]+: 313.1 .
Figure imgf000423_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.17 (s, 1 H), 7.94-7.89 (m, 1 H), 7.88-7.83 (m, 1 H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.1 7 (t, J = 7.3 Hz, 2H), 4.50-4.31 (m, 4H), 4.18-4.03 (m, 1 H), 1 .57 (s, 3H), 0.96-0.85 (m, 2H), 0.68-0.61 (m, 2H); LCMS (ESI) [M+H]+: 396.1 .
Figure imgf000424_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, J = 0.9 Hz, 1 H), 8.20 (s, 1 H), 7.88 (m, J = 0.9 Hz, 2H), 7.50-7.40 (m, 2H), 7.28 (d, J = 0.9 Hz, 0.3H), 7.26-7.22 (m, 0.7H), 7.14 (t, J = 9.2 Hz, 1 H), 5.96-5.81 (m,
1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.18 (t, J = 7.5 Hz, 2H), 3.98 (br s, 2H), 3.71 (br t, J = 4.8 Hz, 2H), 3.62-3.41 (m, 4H); LCMS (ESI) [M+H]+: 449.1 .
Figure imgf000424_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.20 (s, 1 H), 7.88 (m, 2H), 7.48-7.42 (m, 1 H), 7.41 - 7.31 (m, 3H), 5.89 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.23-5.14 (m, 2H), 4.13-4.02 (m, 1 H), 3.98-3.85 (m, 1 H), 3.78-3.69 (m, 2H), 3.68-3.57 (m, 1 H), 3.57-3.41 (m, 2H), 3.40-3.32 (m, 1 H); LCMS (ESI) [M+H]+: 465.1 .
Figure imgf000424_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 9.23 (s, 1 H), 8.19 (d, J = 0.9 Hz, 1 H), 8.13 (dd, J = 1 .3, 8.3 Hz, 1 H), 7.86 (dd, J = 0.7, 8.3 Hz, 1 H), 6.22 (dd, J = 6.8, 9.0 Hz, 1 H), 4.93-4.76 (m, 2H), 4.57 (br d, J = 13.2 Hz, 1 H), 4.05 (br d, J = 12.2 Hz, 1 H), 3.41 -3.19 (m, 3H), 3.10-2.87 (m, 2H), 2.35 (s, 2H), 2.24 (br dd, J = 3.5, 13.4 Hz, 2H), 2.03 (m, 2H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 452.2.
Figure imgf000424_0004
1 H NMR (400 MHz, METHANOL-d4) d 8.54 (br d, J = 4.3 Hz, 1 H), 8.36 (s, 1 H), 8.33 (s, 1 H), 7.97-7.89 (m, 2H), 5.98 (quin, J = 7.2 Hz, 1 H), 4.72-4.57 (m, 4H), 4.14 (m, 2H), 3.42-3.34 (m, 1 H), 3.20-3.01 (m, 2H),
2.19 (m, 2H), 1 .94-1 .79 (m, 2H), 1 .56-1 .46 (s, 9H); LCMS (ESI) [M+H]+: 425.2.
Figure imgf000424_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.43 (d, J = 1 .0 Hz, 1 H), 7.98 (s, 1 H), 7.68 (d, J = 0.9 Hz, 2H), 5.07 (quin, J = 8.4 Hz, 1 H), 3.71 -3.64 (m, 4H), 3.62-3.54 (m, 4H), 2.83-2.67 (m, 2H), 2.66-2.51 (m, 2H), 2.06-1 .89 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 425.2.
Figure imgf000425_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.19 (s, 1 H), 8.07 (s, 1 H), 7.88-7.74 (m, 2H), 5.17 (quin, J = 8.3 Hz, 1 H), 4.15 (br s, 2H), 3.20 (tt, J = 3.9, 1 1 .0 Hz, 1 H), 3.01 (br t, J = 12.0 Hz, 2H), 2.91 -2.76 (m, 2H), 2.63-2.50 (m, 2H), 2.15 (br d, J = 10.8 Hz, 2H), 2.06-1 .84 (m, 4H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 424.2.
Figure imgf000425_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.52 (d, J = 1 .1 Hz, 1 H), 8.00 (s, 1 H), 7.77-7.70 (m, 2H), 5.08 (quin, J = 8.3 Hz, 1 H), 4.20-4.07 (m, 2H), 3.21 -3.12 (m, 1 H), 3.02 (br t, J = 1 1 .5 Hz, 2H), 2.82-2.58 (m, 4H), 2.14 (br d, J = 9.9 Hz, 2H), 2.06-1 .85 (m, 4H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 424.2.
Figure imgf000425_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 10.59 (br s, 1 H), 8.29 (s, J = 0.9 Hz, 1 H), 8.15 (s, J = 0.9 Hz,
1 H), 7.89 (m, J = 1 .0, 8.5 Hz, 2H), 4.62 (br d, J = 13.7 Hz, 1 H), 4.04 (br d, J = 13.9 Hz, 1 H), 3.45-3.20 (m, 2H), 2.99 (br t, J = 1 1 .0 Hz, 1 H), 2.33 (m, 2H), 2.22 (m, J = 13.5 Hz, 2H), 2.00-1 .85 (m, 2H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 368.1 .
Figure imgf000425_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.41 (br s, 1 H), 8.07 (s, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.86 (d, J = 8.3 Hz, 1 H), 7.71 (dd, J = 1 .1 , 8.6 Hz, 1 H), 7.47 (br d, J = 8.8 Hz, 1 H), 4.99 (spt, J = 6.7 Hz, 1 H), 4.05- 3.90 (m, 1 H), 3.86-3.60 (m, 3H), 3.58-3.45 (m, 1 H), 2.51 -2.22 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 408.2.
Figure imgf000426_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.55 (d, J = 5.1 Hz, 1 H), 8.00 (s, 1 H), 7.88 (dd, J = 1.3, 5.1 Hz,
1 H), 4.18 (brs, 2H), 3.73 (s, 3H), 3.23 (tt, J = 3.9, 10.9 Hz, 1H), 3.08 (br t, J = 11.7 Hz, 2H), 2.20-2.12 (m, 2H), 1.99-1.86 (m, 2H); LCMS (ESI) [M+H]+: 323.0.
Figure imgf000426_0002
1H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, J = 0.7 Hz, 1H), 8.20 (s, 1H), 7.88 (m, 2H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.22-5.11 (m, 2H), 3.56 (br s, 8H), 1.58 (s, 3H), 0.95-0.85 (m, 2H), 0.72-0.61 (m, 2H); LCMS (ESI) [M+H]+: 425.1.
Figure imgf000426_0003
1H NMR (400 MHz, DMSO-de) d 8.46 (d, J = 0.9 Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H), 7.97-7.88 (m, 1H), 7.73 (dd, J = 1.2, 8.4 Hz, 1H), 5.07 (t, J = 5.7 Hz, 1H), 3.98 (brd, J = 13.0 Hz, 2H), 3.81 (d, J = 5.7 Hz, 2H), 3.43-3.36 (m, 1H), 2.98 (br s, 2H), 2.11 (br dd, J = 2.9, 13.3 Hz, 2H), 1.79-1.63 (m, 8H), 1.42 (s, 9H); LCMS (ESI) [M+H]+: 442.1.
Figure imgf000426_0004
1H NMR (400 MHz, CHLOROFORM-d) d 8.16-8.12 (m, 2H), 7.85-7.78 (m, 2H), 5.92-5.84 (m, 1H), 5.33 (t, J = 6.7 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.84-3.71 (m, 8H), 3.17 (s, 2H), 2.30 (s, 6H); LCMS (ESI)
[M+H]+: 412.2.
Figure imgf000426_0005
1H NMR (400 MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.20 (s, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 13.7 Hz, 1H), 6.85-6.73 (m, 1H), 4.78 (dd, J = 2.9, 17.0 Hz, 1H), 4.67-4.52 (m, 1 H), 4.1 6 (br s, 2H), 3.21 (tt, J = 3.8, 1 0.9 Hz, 1 H), 3.01 (br t, J = 1 1 .4 Hz, 2H), 2.1 6 (br d, J = 1 1 .2 Hz, 2H), 2.00-1 .86 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 440.2.
Figure imgf000427_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.48 (s, 1 H), 8.07 (s, 1 H), 7.79-7.70 (m, 2H), 7.51 (d, J = 13.7 Hz, 1 H), 7.14-7.02 (m, 1 H), 4.92 (dd, J = 2.9, 16.3 Hz, 1 H), 4.81 -4.66 (d, J = 48 Hz, 1 H), 4.13 (br s, 2H), 3.25-3.14 (m, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.14 (br d, J = 1 1 .0 Hz, 2H), 1 .98-1 .85 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-55]+: 384.1 .
Figure imgf000427_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.15 (s, 2H), 7.93 (d, J = 3.2 Hz, 1 H), 7.86-7.79 (m, 2H), 7.60 (d, J = 3.2 Hz, 1 H), 5.93-5.84 (m, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.15 (t, J = 7.3 Hz, 2H), 4.66 (m, 2H), 3.98 (m, 2H), 3.87 (br t, J = 4.9 Hz, 4H); LCMS (ESI) [M+H]+: 438.1 .
Figure imgf000427_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (t, J = 1 .5 Hz, 1 H), 8.09 (td, J = 1 .4, 7.8 Hz, 1 H), 7.73 (td, J = 1 .4, 7.8 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 4.34-4.14 (m, 4H), 4.05 (br d, J = 9.0 Hz, 2H), 3.14-3.06 (m,
1 H), 2.94 (br t, J = 1 1 .7 Hz, 2H), 2.35-2.23 (m, 2H), 2.05 (br dd, J = 3.2, 13.3 Hz, 2H), 1 .88-1 .74 (m, 2H),
1 .41 (s, 9H); LCMS (ESI) [M-100+1 J+: 313.1 , LCMS (ESI) [M+23]+: 435.1 .
Figure imgf000427_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.17 (s, 1 H), 8.1 1 (s, 1 H), 7.92-7.88 (dd, J = 8.8, 1 H), 7.85-7.81 (d, J = 8.8, 1 H), 5.19-5.05 (m, 1 H), 4.14 (m, 2H), 3.51 -3.35 (m, 2H), 3.28-3.1 5 (m, 3H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.15 (br dd, J = 2.6, 13.4 Hz, 2H), 2.00-1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 404.1 .
Figure imgf000428_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 8.04 (s, 1 H), 7.81 -7.74 (m, 2H), 4.95 (td, J = 6.6, 13.4 Hz, 1 H), 4.81 (dd, J = 6.2, 7.7 Hz, 2H), 4.51 (t, J = 6.3 Hz, 2H), 4.33 (br d, J = 13.2 Hz, 2H), 3.17 (dt, J = 2.6, 12.9 Hz, 2H), 2.86-2.74 (m, 1 H), 2.03-1 .91 (m, 1 H), 1 .77 (br d, J = 1 1 .9 Hz, 2H), 1 .62 (d, J = 6.6 Hz, 6H), 1 .25 (dq, J = 4.4, 12.5 Hz, 2H); LCMS (ESI) [M+H]+: 368.2.
Figure imgf000428_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.13 (s, 1 H), 8.04 (s, 1 H), 7.80-7.75 (m, 2H), 4.95 (quin, J = 6.7 Hz, 1 H), 4.60 (t, J = 7.7 Hz, 2H), 3.85 (td, J = 4.9, 13.6 Hz, 2H), 3.68 (ddd, J = 3.3, 9.8, 13.3 Hz, 2H), 2.47 (t, J = 7.8 Hz, 2H), 2.13 (td, J = 4.2, 13.3 Hz, 2H), 1 .92 (ddd, J = 4.4, 9.6, 13.6 Hz, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 354.2.
Figure imgf000428_0003
1 H NMR (400 MHz, DMSO-de) d 9.44 (br s, 1 H), 8.25 (s, 1 H), 7.92 (br d, J = 8.3 Hz, 1 H), 7.76 (br d, J = 8.3 Hz, 1 H), 4.05 (s, 3H), 2.85 (br d, J = 3.5 Hz, 3H), 2.52 (br s, 3H); LCMS (ESI) [M+H]+: 272.1 .
Figure imgf000428_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.06 (s, 1 H), 7.90-7.78 (m, 2H), 7.19 (br s, 1 H), 5.03-4.87 (m, 1 H), 3.21 -3.06 (m, 3H), 1 .63 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 286.1 .
Figure imgf000428_0005
1 H NMR (300 MHz, Chloroform-d) d 8.10 (d, J = 0.9 Hz, 1 H), 7.80 (dd, J = 8.4, 0.8 Hz, 1 H), 7.70 - 7.56 (m, 3H), 7.43 (dd, J = 8.4, 1 .4 Hz, 1 H), 7.38 - 7.28 (m, 2H), 5.93 - 5.77 (m, 1 H), 5.35 (dd, J = 6.9, 6.2 Hz, 2H), 5.1 5 (t, J = 7.4 Hz, 2H), 4.27 (s, 2H), 2.91 - 2.66 (m, 3H), 1 .88 (d, J = 13.0 Hz, 2H), 1 .70 (td, J = 12.5, 4.3 Hz, 2H), 1 .52 - 1 .42 (m, 9H); LCMS (ESI) [M+H]+: 433.4.
Figure imgf000429_0001
1 H NMR (300 MHz, Chloroform-d) d 8.43 (dd, J = 1 .6, 0.8 Hz, 1 H), 8.26 (dd, J = 8.8, 1 .6 Hz, 1 H), 7.64 (dd, J = 8.8, 0.8 Hz, 1 H), 4.55 (d, J = 13.9 Hz, 1 H), 3.81 (d, J = 14.1 Hz, 1 H), 3.47 (hept, J = 7.0 Hz, 1 H), 3.38 - 3.10 (m, 3H), 3.03 - 2.87 (m, 1 H), 2.48 - 2.29 (m, 2H), 2.19 (dd, J = 10.7, 7.2 Hz, 4H), 2.09 - 1 .80 (m, 4H), 1 .53 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 395.6.
Figure imgf000429_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.31 (d, J=0.9 Hz, 1 H), 8.21 (s, 1 H), 7.95 - 7.87 (m, 2H), 5.96 - 5.86 (m, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.15 (m, 2H), 3.90 - 3.77 (m, 3H), 3.09 - 2.97 (m, 3H), 2.66 - 2.53 (m, 2H), 2.37 - 2.26 (m, 2H), 2.19 (br dd, J=3.6, 13.5 Hz, 2H), 2.10 - 1 .96 (m, 4H); LCMS (ESI) [M+H]+: 444.1 .
Figure imgf000429_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.25 (d, J=0.8 Hz, 1 H), 8.19 (br s, 1 H), 7.91 - 7.85 (m, 2H),
5.92 -5.84 (m, 1 H), 5.32 (t, J=6.4 Hz, 2H), 5.17 (t, J=7.2 Hz, 2H), 3.85 (br s, 4H), 3.67 - 3.60 (m, 4H), 1 .40 - 1 .22 (m, 4H); LCMS (ESI) [M+H]+: 413.2.
Figure imgf000429_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 8.09 (s, 1 H), 7.89 - 7.79 (m, 2H), 5.37 (quin, J=5.9 Hz, 1 H), 4.33 - 4.10 (m, 5H), 4.09 - 4.00 (m, 1 H), 3.20 (tt, J=3.8, 1 1 .0 Hz, 1 H), 3.01 (br t, J=1 1 .6 Hz, 2H), 2.61 - 2.48 (m, 2H), 2.15 (br dd, J=2.8, 13.2 Hz, 2H), 2.00 - 1 .86 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M- 56+H]+: 384.1 .
Figure imgf000430_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.48 (td, J=1 .2, 4.8 Hz, 1 H), 8.24 (d, J=0.8 Hz, 1 H), 8.1 8 (s,
1 H), 7.87 (d, J=0.8 Hz, 2H), 7.54 (dt, J=1 .2, 8.8 Hz, 1 H), 7.75 -7.40 (m, 1 H), 5.92 -5.84 (m, 1 H), 5.31 (t, J=6.4 Hz, 2H), 5.20 - 5.13 (t, J=6.8 Hz, 2H), 4.00 -3.98 (m, 2H), 3.77 - 3.70 (m, 2H), 3.63 - 3.57 (m, 2H), 3.52 - 3.46 (m, 2H); LCMS (ESI) [M+H]+: 450.2.
Figure imgf000430_0002
1 H NMR (400MHz, METHANOL-d4) d 8.74 (d, J=5.1 Hz, 1 H), 8.13 (s, 1 H), 7.93 (d, J=5.0 Hz, 1 H), 5.05 (t, J=6.9 Hz, 1 H), 4.20 - 4.09 (m, 3H), 4.00 (q, J=7.4 Hz, 1 H), 3.70 (s, 3H), 3.21 - 3.01 (m, 3H), 2.54 - 2.43 (m, 1 H), 2.13 - 1 .89 (m, 5H), 1 .86 - 1 .73 (m, 2H); LCMS (ESI) [M+H]+: 359.2.
Figure imgf000430_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.1 1 (s, 1 H), 7.95 - 7.83 (m, 2H), 5.40 (quin, J=5.8 Hz, 1 H), 4.63 (br d, J=13.5 Hz, 1 H), 4.34 - 4.18 (m, 3H), 4.09 - 4.01 (m, 1 H), 3.96 (br d, J=13.2 Hz, 1 H), 3.26 (br t, J=1 1 .5 Hz, 1 H), 3.20 - 3.1 1 (m, 1 H), 2.92 (br t, J=1 1 .7 Hz, 1 H), 2.62 - 2.50 (m, 2H), 2.33 (d, J=6.8 Hz, 2H), 2.15 (br d, J=13.0 Hz, 2H), 1 .99 - 1 .83 (m, 2H), 1 .14 - 1 .02 (m, 1 H), 0.63 - 0.55 (m, 2H), 0.24 - 0.18 (m, 2H); LCMS (ESI) [M+H]+: 422.2.
Figure imgf000430_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.32 (s, 1 H), 8.12 (s, 1 H), 7.94 - 7.85 (m, 2H), 5.45 - 5.35 (m,
1 H), 4.63 (br d, J=13.7 Hz, 1 H), 4.35 - 4.18 (m, 3H), 4.09 - 4.02 (m, 1 H), 3.98 (br d, J=13.2 Hz, 1 H), 3.25 (br t, J=1 1 .6 Hz, 1 H), 3.21 - 3.1 1 (m, 1 H), 2.91 (br t, J=1 1 .1 Hz, 1 H), 2.63 - 2.51 (m, 2H), 2.41 (q, J=7.5 Hz, 2H), 2.15 (br s, 2H), 2.00 - 1 .81 (m, 2H), 1 .19 (t, J=7.4 Hz, 3H); LCMS (ESI) [M+H]+: 396.1 .
Figure imgf000430_0005
1 H NMR (400MHz, CHLOROFORM-d) d = 8.15 (s, 1 H), 8.03 (s, 1 H), 7.86 - 7.81 (m, 1 H), 7.78 - 7.72 (m, 1 H), 5.86 (m, 1 H), 5.32 (t, J=6.5 Hz, 2H), 5.1 6 (t, J=7.3 Hz, 2H), 3.61 (s, 8H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 427.1 .
Figure imgf000431_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (dd, J=0.8, 4.8 Hz, 1 H), 7.49 (dd, J=1 .2, 4.0 Hz, 1 H), 7.44 -7.40 (m, 1 H), 5.69 - 5.62 (m, 1 H), 5.00 (t, J=6.4 Hz, 2H), 4.75 (t, J=7.2 Hz, 2H), 3.58 - 3.48 (m, 8H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 404.1 .
Figure imgf000431_0002
1 H NMR (400MHz, CHLOROFORM-d-d) d 8.25 (d, J=5.1 Hz, 1 H), 7.22 (br d, J=5.1 Hz, 1 H), 6.98 (s, 1 H), 5.18 (br s, 1 H), 5.05 (br s, 3H), 4.58 (br s, 2H), 3.77 (br s, 2H), 3.65 - 3.44 (m, 6H), 2.41 (q, J=7.4 Hz,
2H), 1 .1 9 (t, J=7.3 Hz, 3H); LCMS (ESI) [M+H]+: 359.1 .
Figure imgf000431_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 7.65 - 7.59 (m, 2H), 7.41 (t, J=8.0 Hz, 1 H), 7.12 (br d, J=8.0 Hz, 1 H), 4.28 - 4.05 (m, 2H), 3.93 - 3.86 (m, 4 H), 3.29 - 3.22 (m, 4H), 3.07 - 2.89 (m, 3H), 2.06 (br d, J=12.4 Hz, 2H), 1 .92 - 1 .78 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H-Boc]+: 31 5.2.
Figure imgf000431_0004
1 H NMR (400MHz, METHANOL-d4) d = 8.33 (s, 1 H), 8.27 (s, 1 H), 7.96 (d, J=7.8 Hz, 1 H), 7.85 (dd, J=1 .2, 8.3 Hz, 1 H), 6.14 (quin, J=6.8 Hz, 1 H), 5.28 - 5.15 (m, 4H), 4.1 0 (br s, 2H), 3.38 - 3.33 (m, 1 H), 3.1 0 (br s, 2H), 2.1 8 (br s, 2H), 1 .93 - 1 .77 (m, 2H), 1 .55 (s, 3H), 0.92 - 0.84 (m, 2H), 0.70 - 0.63 (m, 2H); LCMS (ESI) [M+H]+: 424.2.
Figure imgf000431_0005
1 H NMR (400MHz, CHLOROFORM-d) d = 8.19 (s, 2H), 7.92 - 7.83 (m, 2H), 5.89 (br t, J=6.8 Hz, 1 H),
5.33 (t, J=6.4 Hz, 2H), 5.23 - 5.15 (m, 2H), 4.1 7 (br s, 2H), 3.21 (br t, J=10.8 Hz, 1 H), 3.03 (br s, 2H), 2.41 - 2.28 (m, 2H), 2.23 - 2.1 0 (m, 4H), 1 .94 (q, J=10.6 Hz, 2H), 1 .82 (br d, J=1 0.8 Hz, 1 H), 1 .76 - 1 .62 (m,
1 H), 1 .59 (br s, 3H); LCMS (ESI) [M+H]+: 438.2.
Figure imgf000432_0001
1 H NMR (400 MHz, DMSO-d6) d 8.39 (d, J=4.8 Hz, 1 H), 7.62 (dd, J=5.6, 1 .2 Hz, 1 H), 7.47 (s, 1 H) 5.67 - 5.59 (m, 1 H), 4.91 (t, J=7.2 Hz, 2H), 4.59 (dd, J=7.6, 5.4 Hz, 2H), 3.96 (br d, J=12.0 Hz, 2H), 3.14 (tt,
J=1 1 .2, 3.6 Hz, 1 H), 3.05 - 2.85 (m, 2H), 2.00 (br dd, J=13.2, 2.4 Hz, 2H), 1 .68 - 1 .54 (m, 2H), 1 .41 (s, 9H); LCMS (ESI) [M+H]+: 403.1 .
Figure imgf000432_0002
1 H NMR (400 MHz, DMS0-d6) d 7.54 - 7.42 (m, 3H), 7.27 (dd, J=8.0, 1 .2 Hz, 1 H), 3.99 (br d, J=10.8 Hz, 2H), 3.79 - 3.72 (m, 4H), 3.60 (s, 3H), 3.24 - 3.16 (m, 4H), 3.1 5 - 2.94 (m, 3H), 2.04 - 1 .94 (m, 2H), 1 .69 - 1 .56 (m, 2H); LCMS (ESI) [M+H]+: 373.1 .
Figure imgf000432_0003
1 H NMR (300 MHz, Chloroform-d) d 8.84 (d, J = 0.9 Hz, 2H), 8.61 (q, J = 1 .1 Hz, 1 H), 8.30 (dd, J = 8.6,
1 .2 Hz, 1 H), 8.15 (d, J = 1 .0 Hz, 1 H), 7.84 (dd, J = 8.5, 0.9 Hz, 1 H), 6.25 (s, 1 H), 5.95 (p, J = 7.1 Hz, 1 H), 5.36 (t, J = 6.5 Hz, 2H), 5.22 - 5.05 (m, 2H), 4.16 (d, J = 3.2 Hz, 2H), 3.71 (t, J = 5.6 Hz, 2H), 2.58 (s, 2H), 1 .44 (s, 9H); LCMS (ESI) [M+H]+: 434.6.
Figure imgf000432_0004
1 H NMR (300 MHz, Chloroform-d) d 8.70 (s, 2H), 8.59 (s, 1 H), 8.28 (dd, J = 8.5, 1 .3 Hz, 1 H), 7.84 (dd, J = 8.6, 0.8 Hz, 1 H), 5.95 (p, J = 7.0 Hz, 1 H), 5.36 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.31 (s, 2H), 2.83 (dd, J = 29.2, 14.6 Hz, 3H), 1 .91 (d, J = 13.2 Hz, 2H), 1 .80 - 1 .62 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 436.6.
Figure imgf000433_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.10 (s, 1 H), 7.89 - 7.80 (m, 2H), 5.38 (quin, J=5.8 Hz, 1 H), 4.38 - 3.97 (m, 6H), 3.21 (tt, J=3.6, 10.9 Hz, 1 H), 3.03 (br t, J=1 1 .0 Hz, 2H), 2.59 - 2.52 (m, 2H), 2.16 (br d, J=12.3 Hz, 2H), 1 .98 - 1 .86 (m, 2H), 1 .58 (s, 3H), 0.93 - 0.87 (m, 2H), 0.69 - 0.63 (m, 2H); LCMS (ESI) [M+H]+: 438.2.
Figure imgf000433_0002
1 H NMR (400MHz, CHLOROFORM-d) 6 8.15 (s, 1 H), 8.05 (d, J=0.9 Hz, 1 H), 7.87 - 7.81 (m, 1 H), 7.79 - 7.72 (m, 1 H), 5.94 - 5.79 (m, 1 H), 5.32 (t, J=6.7 Hz, 2H), 5.16 (t, J=7.4 Hz, 2H), 3.85 (m, 4H), 3.76 - 3.58 (m, 4H), 1 .78 (m, 1 H), 1 .08 - 1 .00 (m, 2H), 0.88 - 0.81 (m, 2H); LCMS (ESI) [M+H]+: 395.1 .
Figure imgf000433_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.21 (d, J=2.2 Hz, 1 H), 7.82 (dd, J=5.6, 8.4 Hz, 1 H), 7.64 (d, J=8.6 Hz, 1 H), 6.17 - 6.07 (m, 1 H), 5.33 (t, J=6.4 Hz, 2H), 5.15 (t, J=7.0 Hz, 2H), 4.18 (br s, 2H), 3.09 (tt, J=3.8, 1 1 .2 Hz, 1 H), 2.97 (br t, J=1 1 .8 Hz, 2H), 2.10 (br d, J=10.8 Hz, 2H), 1 .95 - 1 .81 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H-56J+: 388.1 .
Figure imgf000433_0004
1 H NMR (400MHz, METHANOL-d4) d = 8.32 (d, J=2.2 Hz, 1 H), 7.86 - 7.78 (m, 1 H), 7.77 - 7.73 (m, 1 H), 6.23 - 6.13 (m, 1 H), 5.30 - 5.23 (m, 2H), 5.19 - 5.1 1 (m, 2H), 3.51 (td, J=3.8, 13.2 Hz, 2H), 3.40 - 3.32 (m, 1 H), 3.28 - 3.19 (m, 2H), 2.38 (br dd, J=3.4, 14.8 Hz, 2H), 2.19 - 2.06 (m, 2H); LCMS (ESI) [M+H]+: 344.1 .
Figure imgf000434_0001
1 H NMR (400MHz, CHLOROFORM-d) 8.24 (d, J=3.3 Hz, 2H), 8.00 - 7.96 (m, 1 H), 7.94 - 7.90 (m, 1 H), 5.62 - 5.53 (m, 1 H), 5.03 - 4.95 (m, 2H), 4.77 - 4.68 (m, 2H), 4.18 (br s, 2H), 3.1 1 - 2.91 (m, 3H), 2.09 (br d, J=1 1 .2 Hz, 2H), 1 .94 - 1 .82 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M-56+HJ+: 418.1 .
Figure imgf000434_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.18 (s, 1 H), 8.07 (s, 1 H), 7.88 - 7.83 (m, 1 H), 7.80 - 7.75 (m,
1 H), 5.95 - 5.82 (m, 1 H), 5.34 (m, 2H), 5.24 - 5.13 (m, 2H), 3.90 - 3.58 (m, 8H), 2.18 (dd, J=4.3, 7.4 Hz, 1 H), 1 .67 (m, 1 H), 1 .36 (dd, J=3.7, 7.4 Hz, 1 H), 1 .04 - 0.90 (m, 3H), 0.89 - 0.82 (m, 1 H); LCMS (ESI) [M+H]+: 421 .2.
Figure imgf000434_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.71 (d, J=5.1 Hz, 1 H), 7.85 (s, 1 H), 7.78 (dd, J=1 .5, 5.0 Hz,
1 H), 4.27 - 4.08 (m, 4H), 4.02 - 3.92 (m, 2H), 3.68 (quin, J=7.7 Hz, 1 H), 3.20 (tt, J=3.8, 1 1 .0 Hz, 1 H), 3.07 - 2.92 (m, 2H), 2.50 - 2.36 (m, 1 H), 2.28 (qd, J=7.8, 12.3 Hz, 1 H), 2.13 (br dd, J=2.5, 13.1 Hz, 2H), 1 .96 - 1 .83 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 401 .1 .
Figure imgf000434_0004
1 H NMR (400MHz, CHLOROFORM-d) 6 8.15 (s, 1 H), 8.04 (s, 1 H), 7.87 - 7.80 (m, 1 H), 7.78 - 7.71 (m,
1 H), 5.86 (m, 1 H), 5.31 (m, 2H), 5.22 - 5.10 (m, 2H), 3.91 - 3.77 (m, 2H), 3.67 - 3.52 (m, 6H), 3.51 - 3.40 (m, 1 H), 2.70 - 2.54 (m, 2H), 2.27 - 2.17 (m, 2H), 0.56 - 0.37 (m, 4H); LCMS (ESI) [M+H]+: 435.2.
Figure imgf000434_0005
1 H NMR (400MHz, CHLOROFORM-d) 6 8.15 (s, 1 H), 8.04 (s, 1 H), 7.86 - 7.81 (m, 1 H), 7.78 - 7.72 (m,
1 H), 5.86 (m, 1 H), 5.32 (m, 2H), 5.20 - 5.12 (m, 2H), 3.88 - 3.73 (m, 4H), 3.70 - 3.57 (m, 4H), 2.55 (s, 1 H), 2.21 (s, 6H); LCMS (ESI) [M+H]+: 421 .1 .
Figure imgf000435_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 8.05 (s, 1 H), 7.86 - 7.81 (m, 1 H), 7.78 - 7.72 (m, 1 H), 5.86 (m, 1 H), 5.32 (t, J=6.5 Hz, 2H), 5.1 6 (t, J=7.3 Hz, 2H), 3.82 (m, 2H), 3.66 (br s, 6H), 2.40 (s, 2H), 1 .1 7 (s, 3H), 0.51 - 0.37 (m, 4H); LCMS (ESI) [M+H]+: 423.2.
Figure imgf000435_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 8.04 (s, 1 H), 7.86 - 7.80 (m, 1 H), 7.78 - 7.72 (m,
1 H), 5.92 - 5.79 (m, 1 H), 5.32 (m, 2H), 5.22 - 5.10 (m, 2H), 3.86 - 3.75 (m, 2H), 3.67 - 3.49 (m, 6H), 3.31 (m, 1 H), 2.46 - 2.32 (m, 2H), 2.26 - 2.14 (m, 2H), 2.09 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 409.1 .
Figure imgf000435_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.18 (s, 1 H), 7.96 - 7.87 (m, 2H), 5.62 - 5.52 (m, 1 H), 5.02 - 4.94 (m, 2H), 4.76 - 4.68 (m, 2H), 3.60 - 3.54 (m, 8H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 419.0.
Figure imgf000435_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.18 (s, 1 H), 7.95 - 7.86 (m, 2H), 5.61 - 5.52 (m,
1 H), 5.02 - 4.94 (m, 2H), 4.74 - 4.68 (m, 2H), 3.75 (s, 3H), 3.63 -3.62 (m, 4H), 3.59 -3.53 (m, 4H); LCMS (ESI) [M+H]+: 433.1 .
Figure imgf000436_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.83 - 7.78 (m, 1 H), 4.27 - 4.08 (m, 4H), 4.03 - 3.91 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.1 1 - 3.01 (m, 1 H), 2.96 (br t, J=1 1 .4 Hz, 2H), 2.49 - 2.38 (m, 1 H), 2.34 - 2.22 (m, 1 H), 2.06 (br d, J=12.1 Hz, 2H), 1 .91 - 1 .78 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 401 .2.
Figure imgf000436_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.24 (d, J=4.2 Hz, 2H), 8.00 - 7.95 (m, 1 H), 7.94 - 7.90 (m, 1 H), 5.62 - 5.53 (m, 1 H), 4.99 (br dd, J=6.6, 14.6 Hz, 2H), 4.73 (br dd, J=9.0, 14.6 Hz, 2H), 4.21 (br s, 2H), 3.74 (s, 3H), 3.14 - 2.99 (m, 3H), 2.1 1 (br d, J=12.6 Hz, 2H), 1 .97 - 1 .83 (m, 2H); LCMS (ESI) [M+H]+: 432.1 .
Figure imgf000436_0003
1 H NMR (400MHz, CHLOROFORM-d-d) d 8.26 (d, J=5.1 Hz, 1 H), 7.22 (dd, J=1 .3, 5.3 Hz, 1 H), 6.97 (s, 1 H), 5.1 5 (br d, J=5.3 Hz, 1 H), 5.10 - 4.98 (m, 3H), 4.65 - 4.50 (m, 2H), 3.84 - 3.70 (m, 2H), 3.58 - 3.44 (m, 6H), 3.31 (quin, J=8.7 Hz, 1 H), 2.48 - 2.30 (m, 2H), 2.30 - 2.1 0 (m, 2H), 2.08 - 1 .80 (m, 2H); LCMS (ESI) [M+H]+: 385.1 .
Figure imgf000436_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.24 (d, J=5.2 Hz, 1 H), 7.49 (dd, J=1 .2, 5.2 Hz, 1 H), 7.42 (br s, 1 H), 5.66 (quin, J=5.6 Hz, 1 H), 5.00 (t, J=7.2 Hz, 2H), 4.75 (t, J=5.6 Hz, 2H), 3.75 (s, 3H), 3.65 - 3.58 (m, 4H), 3.53 -3.52 (m, 4H); LCMS (ESI) [M+H]+: 362.1 .
Figure imgf000436_0005
1 H NMR (400MHz, CHLOROFORM-d) d 8.76 (d, J=5.0 Hz, 1 H), 8.12 (s, 1 H), 7.82 (d, J=5.0 Hz, 1 H), 5.15 - 5.07 (m, 1 H), 4.26 - 4.1 1 (m, 3H), 4.07 - 3.97 (m, 1 H), 3.12 - 3.01 (m, 1 H), 3.01 - 2.88 (m, 2H), 2.55 - 2.42 (m, 1 H), 2.10 - 1 .96 (m, 5H), 1 .92 - 1 .78 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 401 .1 .
Figure imgf000437_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.21 (d, J=2.4 Hz, 1 H), 7.81 (dd, J=5.6, 8.3 Hz, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 6.1 1 (q, J=7.0 Hz, 1 H), 5.33 (t, J=6.4 Hz, 2H), 5.15 (t, J=7.6 Hz, 2H), 4.22 (br d, 2H), 3.73 (s, 3H), 3.1 8 - 3.09 (m, 1 H), 3.09 - 2.96 (m, 2H), 2.1 1 (br d, J=12.8 Hz, 2H), 1 .97 - 1 .82 (m, 2H); LCMS (ESI) [M+H]+: 402.1 .
Figure imgf000437_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 8.29 (d, J=1 .2 Hz, 1 H), 8.03 (dd, J=2.0, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 5.59 - 5.45 (m, 1 H), 5.25 - 5.10 (m, 4H), 4.27 - 4.04 (m, 2H), 3.17 - 2.83 (m, 3H), 2.07 (br d, J=1 1 .2 Hz, 2H), 1 .94 - 1 .76 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H-56J+: 387.1 .
Figure imgf000437_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 7.46 (dd, J=2.0, 8.4 Hz, 1 H), 7.02 (d, J=2.0 Hz, 1 H), 6.41 (d, J=8.4 Hz, 1 H), 5.33 (quin, J=5.6 Hz, 1 H), 5.08 (td, J=6.8, 18.0 Hz, 4H), 4.89 - 4.81 (m, 3H), 4.80 - 4.70 (m, 1 H), 4.61 (t, J=6.0 Hz, 2H), 4.14 (br s, 2H), 3.06 - 2.87 (m, 3H), 2.05 (br d, J=10.8 Hz, 2H), 1 .90 - 1 .78 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H-56J+: 41 7.2.
Figure imgf000437_0004
1 H NMR (400MHz, CHLOROFORM-d) d 7.52 (d, J=6.8 Hz, 1 H), 7.30 (br s, 1 H), 6.82 (br d, J=6.8 Hz,
1 H), 4.1 9 (br d, J=5.2 Hz, 2H), 4.06 (br t, J=4.4 Hz, 1 H), 3.74 (s, 3H), 3.64 - 3.55 (m, 6H), 3.51 (br s, 4H), 3.30 -3.10 (m, 1 H); LCMS (ESI) [M+H]+: 380.1 .
Figure imgf000437_0005
1 H NMR (400MHz, DMSO-d6) d 8.18 (d, J=5.3 Hz, 1 H), 7.77 (d, J=6.0 Hz, 1 H), 7.10 (s, 1 H), 7.03 (dd, J=1 .3, 5.3 Hz, 1 H), 4.98 - 4.88 (m, 1 H), 4.82 (t, J=6.6 Hz, 2H), 4.44 (t, J=6.3 Hz, 2H), 3.42 (br d, J=13.5 Hz, 8H), 1 .49 (s, 3H), 0.86 - 0.76 (m, 2H), 0.67 - 0.56 (m, 2H); LCMS (ESI) [M+H]+: 401 .1 .
Figure imgf000438_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 9.48 (br s, 1 H), 7.96 (dd, J=1 .6, 8.4 Hz, 1 H), 7.86 (d, J=1 .2 Hz, 1 H), 7.35 (d, J=8.4 Hz, 1 H), 4.30 - 4.06 (m, 2H), 3.10 - 2.90 (m, 3H), 2.13 - 1 .99 (m, 2H), 1 .92 - 1 .80 (m, 1 H), 1 .92 - 1 .80 (m, 2H), 1 .60 - 1 .40 (m, 9H); LCMS (ESI) [M+H-56]+: 331 .0.
Figure imgf000438_0002
1 H NMR (300 MHz, Chloroform-d) d 8.76 (dd, J = 2.3, 1 .0 Hz, 1 H), 8.21 (q, J = 1 .0 Hz, 1 H), 8.14 (d, J = 0.9 Hz, 1 H), 7.88 - 7.71 (m, 4H), 6.19 (s, 1 H), 6.00 - 5.84 (m, 1 H), 5.35 (dd, J = 6.9, 6.2 Hz, 2H), 5.21 -
5.09 (m, 2H), 4.14 (d, J = 3.2 Hz, 2H), 3.69 (t, J = 5.7 Hz, 2H), 2.58 (s, 2H), 1 .51 (d, J = 39.9 Hz, 9H),
1 .27 (d, J = 13.0 Hz, 1 H); LCMS (ESI) [M+H]+: 433.6.
Figure imgf000438_0003
1 H NMR (300 MHz, Chloroform-d) d 8.59 (d, J = 2.3 Hz, 1 H), 8.21 - 8.09 (m, 2H), 7.89 - 7.67 (m, 3H), 7.62 (dd, J = 8.2, 2.4 Hz, 1 H), 5.91 (ddd, J = 14.2, 7.7, 6.3 Hz, 1 H), 5.34 (dd, J = 6.9, 6.1 Hz, 2H), 5.14 (dd, J = 7.7, 6.8 Hz, 2H), 4.30 (d, J = 13.0 Hz, 2H), 2.93 - 2.68 (m, 3H), 1 .89 (d, J = 13.0 Hz, 2H), 1 .69 (tt, J = 13.2, 6.6 Hz, 2H), 1 .46 (d, J = 17.7 Hz, 9H); LCMS (ESI) [M+H]+: 435.6.
Figure imgf000438_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.20 (s, 1 H), 7.92 - 7.83 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.18 (t, J=7.3 Hz, 2H), 4.08 (br t, J=1 1 .9 Hz, 2H), 3.96 - 3.68 (m, 6H), 1 .50 (s, 9H); LCMS (ESI) [M-56+HJ+: 421 .1 .
Figure imgf000439_0001
1 H NMR (400MHz, CHLOROFORM-d) d 7.70 (br d, J=7.6 Hz, 1 H), 7.44 - 7.39 (m, 1 H), 7.34 -7.31 (m,
1 H), 6.94 -6.92(m, 1 H), 5.29 (quin, J=5.6 Hz, 1 H), 5.01 (t J = 8.0, 2H), 4.77 (t J = 8.0, 12.0, 2H), 3.74 (s, 3H), 3.65 -3.60 (m, 4H), 3.55 3.50 (m, 4H); LCMS (ESI) [M+H]+:361 .1 .
Figure imgf000439_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.18 (d, J=5.7 Hz, 2H), 7.99 - 7.94 (m, 1 H), 7.89 - 7.85 (m, 1 H), 5.61 - 5.52 (m, 1 H), 5.02 - 4.95 (m, 2H), 4.74 - 4.66 (m, 2H), 4.19 (br s, 2H), 3.74 (s, 3H), 3.29 - 3.19 (m, 1 H), 3.1 0 (br t, J=12.1 Hz, 2H), 2.1 9 (br d, J=1 1 .0 Hz, 2H), 2.03 - 1 .89 (m, 2H); LCMS (ESI) [M+H]+: 432.1 .
Figure imgf000439_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .1 , 5.0 Hz,
1 H), 4.31 - 4.08 (m, 4H), 4.03 - 3.93 (m, 2H), 3.76 - 3.66 (m, 4H), 3.14 - 2.97 (m, 3H), 2.49 - 2.38 (m, 1 H), 2.33 - 2.22 (m, 1 H), 2.08 (br d, J=12.2 Hz, 2H), 1 .94 - 1 .81 (m, 2H); LCMS (ESI) [M+H]+: 359.0.
Figure imgf000439_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.78 (d, J=5.0 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.0 Hz,
1 H), 4.29 - 4.03 (m, 4H), 4.02 - 3.92 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.12 - 2.90 (m, 3H), 2.49 - 2.38 (m, 1 H), 2.28 (qd, J=7.6, 12.4 Hz, 1 H), 2.06 (br d, J=1 1 .0 Hz, 2H), 1 .91 - 1 .77 (m, 2H), 1 .57 (s, 3H), 0.93 - 0.86 (m, 2H), 0.69 - 0.61 (m, 2H); LCMS (ESI) [M+H]+: 399.1 .
Figure imgf000439_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.99 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.34 (dt, J=3.1 , 6.5 Hz, 2H), 5.18 (t, J=7.3 Hz, 2H), 4.22 (sxt, J=6.6 Hz, 1 H), 4.01 - 3.91 (m, 1 H), 3.31 (ddd, J=5.5, 10.7, 14.0 Hz, 1 H), 3.22 - 3.12 (m, 1 H), 2.23 - 2.00 (m, 4H), 1 .49 (s, 9H), 1 .09 (d, J=6.6 Hz, 3H); LCMS (ESI) [M-56+HJ+: 384.1 .
Figure imgf000440_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.97 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.18 (t, J=7.3 Hz, 2H), 4.61 (br s, 1 H), 4.16 (br s, 1 H), 3.26 (tt, J=3.6, 12.4 Hz, 1 H), 3.03 (br t, J=13.2 Hz, 1 H), 2.16 - 1 .91 (m, 3H), 1 .80 (dq, J=4.7, 12.9 Hz, 1 H), 1 .49 (s, 9H), 1 .27 (d, J=7.1 Hz, 3H); LCMS (ESI) [M-56+HJ+: 384.2.
Figure imgf000440_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.96 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.24 - 5.14 (m, 2H), 4.60 (br s, 1 H), 4.1 5 (br s, 1 H), 3.26 (tt, J=3.6, 12.3 Hz, 1 H), 3.03 (br t, J=12.8 Hz, 1 H), 2.15 - 1 .93 (m, 3H), 1 .80 (dq, J=4.7, 12.9 Hz, 1 H), 1 .49 (s, 9H), 1 .27 (d, J=6.8 Hz, 3H); LCMS (ESI) [M-56+HJ+: 384.1 .
Figure imgf000440_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.13 (s, 1 H), 7.84 (q, J=8.4 Hz, 2H), 5.83 (quin, J=7.0 Hz, 1 H), 5.26 (t, J=6.5 Hz, 2H), 5.10 (t, J=7.2 Hz, 2H), 3.98 (s, 2H), 3.93 (s, 2H), 3.54 (quin, J=8.2 Hz, 1 H), 2.65 - 2.51 (m, 4H), 1 .38 (s, 9H); LCMS (ESI) [M+H]+: 438.2.
Figure imgf000440_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 8.28 (d, J=1 .2 Hz, 1 H), 8.03 (dd, J=1 .6, 8.4 Hz, 1 H), 7.40 (d, J=8.4 Hz, 1 H), 5.60 - 5.44 (m, 1 H), 5.25 - 5.09 (m, 4H), 4.61 (br d, J=13.2 Hz, 1 H), 3.83 (br d, J=13.6 Hz, 1 H), 3.45 (quin, J=8.4 Hz, 1 H), 3.22 - 3.06 (m, 2H), 2.99 - 2.83 (m, 1 H), 2.62 (td, J=7.6, 1 1 .6 Hz, 2H), 2.25 - 2.16 (m, 2H), 2.16 - 2.04 (m, 2H), 1 .93 - 1 .78 (m, 2H), 0.52 - 0.45 (m, 2H), 0.45 - 0.37 (m, 2H); LCMS (ESI) [M+H]+: 451 .9.
Figure imgf000441_0001
1 H NMR (400MHz, CHLOROFORM-d-d) d 8.28 (d, J=4.8 Hz, 1 H), 7.20 (dd, J=0.9, 5.3 Hz, 1 H), 7.12 (s,
1 H), 5.51 (quin, J=7.1 Hz, 1 H), 4.94 (t, J=7.2 Hz, 2H), 4.80 (t, J=6.8 Hz, 2H), 3.64 - 3.41 (m, 8H), 3.16 (s, 3H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+:417.1 .
Figure imgf000441_0002
1 H NMR (300 MHz, Chloroform-d) d 8.28 - 8.12 (m, 2H), 7.96 - 7.79 (m, 2H), 5.89 (tt, J = 7.6, 6.3 Hz,
1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.60 (d, J = 13.6 Hz, 1 H), 4.04 (d, J = 14.0 Hz, 1 H), 3.30 (tt, J = 10.6, 3.6 Hz, 2H), 2.96 (t, J = 12.7 Hz, 1 H), 2.84 (h, J = 6.7 Hz, 1 H), 2.22 (s, 2H), 1 .97 (d, J = 14.9 Hz, 2H), 1 .27 - 1 .05 (m, 7H); LCMS (ESI) [M+H]+ 396.6.
Figure imgf000441_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.31 (d, J=1 .0 Hz, 1 H), 8.10 (s, 1 H), 7.93 - 7.84 (m, 2H), 5.44 -
5.35 (m, 1 H), 4.63 (br d, J=1 1 .1 Hz, 1 H), 4.34 - 4.25 (m, 1 H), 4.25 - 4.1 7 (m, 2H), 4.10 - 4.00 (m, 2H),
3.36 - 3.08 (m, 2H), 2.98 - 2.78 (m, 2H), 2.62 - 2.49 (m, 2H), 2.14 (m, 2H), 2.01 - 1 .79 (m, 2H), 1 .16 (br d, J=6.7 Hz, 6H); LCMS (ESI) [M+H]+: 41 0.2.
Figure imgf000441_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 8.28 (d, J=1 .2 Hz, 1 H), 8.03 (dd, J=1 .6, 8.4 Hz, 1 H), 7.40 (d, J=8.4 Hz, 1 H), 5.60 - 5.44 (m, 1 H), 5.25 - 5.09 (m, 4H), 4.61 (br d, J=13.2 Hz, 1 H), 3.83 (br d, J=13.6 Hz, 1 H), 3.45 (quin, J=8.4 Hz, 1 H), 3.22 - 3.06 (m, 2H), 2.99 - 2.83 (m, 1 H), 2.62 (td, J=7.6, 1 1 .6 Hz, 2H), 2.25 - 2.16 (m, 2H), 2.16 - 2.04 (m, 2H), 1 .93 - 1 .78 (m, 2H), 0.52 - 0.45 (m, 2H), 0.45 - 0.37 (m, 2H); LCMS (ESI) [M+H]+: 451 .9.
Figure imgf000442_0001
1 H NMR (400MHz, CHLOROFORM-d-d) d 8.28 (d, J=4.8 Hz, 1 H), 7.20 (dd, J=0.9, 5.3 Hz, 1 H), 7.12 (s,
1 H), 5.51 (quin, J=7.1 Hz, 1 H), 4.94 (t, J=7.2 Hz, 2H), 4.80 (t, J=6.8 Hz, 2H), 3.64 - 3.41 (m, 8H), 3.16 (s, 3H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+:417.1 .
Figure imgf000442_0002
1 H NMR (300 MHz, Chloroform-d) d 8.28 - 8.12 (m, 2H), 7.96 - 7.79 (m, 2H), 5.89 (tt, J = 7.6, 6.3 Hz,
1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.60 (d, J = 13.6 Hz, 1 H), 4.04 (d, J = 14.0 Hz, 1 H), 3.30 (tt, J = 10.6, 3.6 Hz, 2H), 2.96 (t, J = 12.7 Hz, 1 H), 2.84 (h, J = 6.7 Hz, 1 H), 2.22 (s, 2H), 1 .97 (d, J = 14.9 Hz, 2H), 1 .27 - 1 .05 (m, 7H); LCMS (ESI) [M+H]+ 396.6.
Figure imgf000442_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.31 (d, J=1 .0 Hz, 1 H), 8.10 (s, 1 H), 7.93 - 7.84 (m, 2H), 5.44 -
5.35 (m, 1 H), 4.63 (br d, J=1 1 .1 Hz, 1 H), 4.34 - 4.25 (m, 1 H), 4.25 - 4.1 7 (m, 2H), 4.10 - 4.00 (m, 2H),
3.36 - 3.08 (m, 2H), 2.98 - 2.78 (m, 2H), 2.62 - 2.49 (m, 2H), 2.14 (m, 2H), 2.01 - 1 .79 (m, 2H), 1 .16 (br d, J=6.7 Hz, 6H); LCMS (ESI) [M+H]+: 41 0.2.
Figure imgf000442_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.21 (s, 1 H), 7.97 - 7.87 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.34 (dt, J=3.0, 6.4 Hz, 2H), 5.23 - 5.14 (m, 2H), 4.22 (sxt, J=6.7 Hz, 1 H), 4.01 - 3.90 (m, 1 H), 3.31 (ddd, J=5.6, 10.6, 14.0 Hz, 1 H), 3.23 - 3.13 (m, 1 H), 2.24 - 2.00 (m, 4H), 1 .49 (s, 9H), 1 .09 (d, J=6.6 Hz, 3H); LCMS (ESI) [M-100+HJ+: 340.2.
Figure imgf000442_0005
1H NMR (400MHz, CHLOROFORM-d) d 8.06 (s, 1 H), 7.88 (s, 1 H), 7.75 (d, J=8.4 Hz, 1 H), 7.46 (d, J=8.4 Hz, 1 H), 6.42 (s, 1 H), 5.78 (quin, J=7.0 Hz, 1H), 5.25 (t, J=6.5 Hz, 2H), 5.10 (t, J=7.2 Hz, 2H), 4.12 (br s, 2H), 2.97-2.89 (m, 1H), 2.89 - 2.77 (m, 2H), 1.97 - 1.90 (m, 2H), 1.65 (dq, J=4.3, 12.3 Hz, 2H), 1.42 (s, 9H); LCMS (ESI) [M-56+HJ+: 369.1.
Figure imgf000443_0001
H NMR (400MHz, CHLOROFORM-d) d 8.07 (s, 1H), 7.88 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1 H), 6.42 (s, 1 H), 5.78 (quin, J=7.0 Hz, 1 H), 5.25 (t, J=6.5 Hz, 2H), 5.14 - 5.06 (m, 2H), 4.16 (br s, 2H), 3.66 (s, 3H), 3.00 - 2.86 (m, 3H), 1.96 (brd, J=10.9 Hz, 2H), 1.68 (dq, J=4.2, 12.4 Hz, 2H); LCMS (ESI) [M+H]+: 383.1.
Figure imgf000443_0002
1H NMR (400MHz, CHLOROFORM-d) d 8.31 (d, J=0.7 Hz, 1H), 8.10 (s, 1H), 7.94 - 7.82 (m, 2H), 5.46 - 5.32 (m, 1 H), 4.54 (brd, J=13.2 Hz, 1H), 4.36 - 4.14 (m, 3H), 4.11 - 3.95 (m, 2H), 3.32 - 3.11 (m, 2H), 3.01 (br t, J=12.2 Hz, 1 H), 2.90 - 2.65 (m, 2H), 2.61 - 2.32 (m, 4H), 2.24 - 2.06 (m, 2H), 2.03 - 1.85 (m, 3H), 1.79 - 1.61 (m, 1 H); LCMS (ESI) [M+H]+: 440.3.
Figure imgf000443_0003
1H NMR (400MHz, CHLOROFORM-d) d 8.29 (s, 1 H), 8.20 (s, 1 H), 7.95 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.4 Hz, 2H), 5.22-5.14 (m, 2H), 4.55 (brd, J=13.5 Hz, 1H), 4.02 (br d, J=13.7 Hz,
1 H), 3.33 - 3.12 (m, 2H), 3.01 (br t, J=12.2 Hz, 1 H), 2.87 - 2.67 (m, 2H), 2.54 - 2.35 (m, 2H), 2.22 - 2.09 (m, 2H), 2.03 - 1.87 (m, 3H), 1.76- 1.62 (m, 1 H); LCMS (ESI) [M+H]+: 426.2.
Figure imgf000443_0004
1H NMR (300 MHz, Chloroform-d) d 8.38 (t, J = 1.1 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.96-7.82 (m, 2H), 7.77 (dd, J = 8.5, 1.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 5.90 (ddd, J = 14.1, 7.7, 6.3 Hz, 1H), 5.34 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.30 (s, 2H), 3.1 8 (tt, J = 1 1 .9, 3.7 Hz, 1 H), 2.93 (t, J = 12.7 Hz, 2H), 2.04 (d, J = 12.1 Hz, 2H), 1 .85 (qd, J = 12.5, 4.3 Hz, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+ 436.6.
Figure imgf000444_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 8.29 (d, J=1 .2 Hz, 1 H), 8.03 (dd, J=1 .2, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 5.60 - 5.44 (m, 1 H), 5.25 - 5.10 (m, 4H), 4.36 - 4.05 (m, 2H), 3.73 (s, 3H), 3.15 - 2.92 (m, 3H), 2.08 (br d, J=12.3 Hz, 2H), 1 .96 - 1 .80 (m, 2H); LCMS (ESI) [M+H]+: 401 .1 .
Figure imgf000444_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.13 (s, 1 H), 7.88 - 7.77 (m, 2H), 5.83 (quin, J 7.0 Hz, 1 H), 5.25 (t, J 6.5 Hz, 2H), 5.10 (t, J 7.2 Hz, 2H), 4.04 (s, 2H), 3.99 (s, 2H), 3.61 (s, 3H), 3.58 - 3.50 (m, 1 H), 2.66 - 2.53 (m, 4H); LCMS (ESI) [M+H]+: 396.1 .
Figure imgf000444_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.32 (s, 1 H), 8.22 (s, 1 H), 8.00 - 7.89 (m, 2H), 5.92 (quin, J 7.0 Hz, 1 H), 5.35 (t, J 6.5 Hz, 2H), 5.20 (t, J 7.3 Hz, 2H), 4.42 (br s, 2H), 4.14 (br s, 2H), 3.66 (br t, J 7.9 Hz, 1 H), 2.76 - 2.65 (m, 4H), 1 .23 (s, 9H); LCMS (ESI) [M+H]+:422.2.
Figure imgf000444_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.20 (s, 1 H), 7.91 - 7.83 (m, 2H), 5.91 (quin, J=7.1 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.19 (t, J=7.3 Hz, 2H), 4.12 (q, J=1 1 .2 Hz, 2H), 4.01 - 3.79 (m, 6H), 3.78 (s, 3H); LCMS (ESI) [M+H]+: 435.2.
Figure imgf000444_0005
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.21 (s, 1 H), 7.91 - 7.83 (m, 2H), 5.91 (quin, J=7.1 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.22 - 5.16 (m, 2H), 4.15 - 4.08 (m, 2H), 3.95 - 3.76 (m, 6H), 2.46 - 2.34 (m, 2H), 1 .20 - 1 .04 (m, 1 H), 0.68 - 0.53 (m, 2H), 0.22 - 0.16 (m, 2H); LCMS (ESI) [M+H]+: 459.3.
Figure imgf000445_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 7.89 (dd, J=1 .3, 8.4 Hz, 1 H), 7.76 (d, J=8.2 Hz,
1 H), 7.72 (d, J=3.3 Hz, 1 H), 6.72 (d, J=3.1 Hz, 1 H), 5.73 (quin, J=6.8 Hz, 1 H), 5.25 (t, J=7.4 Hz, 2H), 5.06 (t, J=6.6 Hz, 2H), 4.20 (br s, 2H), 3.73 (s, 3H), 3.12 - 2.97 (m, 3H), 2.1 1 (br d, J=12.1 Hz, 2H), 1 .97 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 383.1 .
Figure imgf000445_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.19 (s, 1 H), 7.84 (dd, J=1 .3, 8.2 Hz, 1 H), 7.72 (d, J=8.4 Hz,
1 H), 7.42 (d, J=3.1 Hz, 1 H), 6.60 (d, J=3.1 Hz, 1 H), 4.82 (td, J=6.6, 13.4 Hz, 1 H), 4.23 (br s, 2H), 3.73 (s, 3H), 3.1 1 - 2.97 (m, 3H), 2.1 1 (br d, J=12.3 Hz, 2H), 1 .97 - 1 .84 (m, 2H), 1 .58 (d, J=6.6 Hz, 6H); LCMS (ESI) [M+H]+: 369.2.
Figure imgf000445_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.20 (s, 1 H), 7.91 - 7.84 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.22 - 5.15 (m, 2H), 4.15 - 4.05 (m, 2H), 3.96 - 3.75 (m, 6H), 2.53 - 2.40 (m, 2H), 1 .23 - 1 .14 (m, 3H); LCMS (ESI) [M+H]+: 433.1 .
Figure imgf000445_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.20 (s, 1 H), 7.89 (dd, J=1 .2, 8.3 Hz, 1 H), 7.78 - 7.69 (m, 2H), 6.72 (d, J=3.3 Hz, 1 H), 5.73 (quin, J=6.8 Hz, 1 H), 5.24 (t, J=7.4 Hz, 2H), 5.06 (t, J=6.6 Hz, 2H), 4.1 8 (br d, J=6.2 Hz, 2H), 3.09 - 2.90 (m, 3H), 2.14 - 2.02 (m, 2H), 1 .94 - 1 .82 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M- 56+H]+: 369.1 .
Figure imgf000446_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.07 (s, 1 H), 7.83 (dd, J=0.7, 7.5 Hz, 1 H), 7.05 (dd, J=1 .5, 7.4 Hz, 1 H), 4.09 ( m, 2H), 3.34 (td, J=6.9, 13.8 Hz, 1 H), 3.03 - 2.78 (m, 3H), 1 .99 (br d, J=1 1 .0 Hz, 2H), 1 .86 - 1 .69 (m, 2H), 1 .41 (s, 9H), 1 .36 (d, J=7.0 Hz, 6H); LCMS (ESI) [M+H]+: 412.2.
Figure imgf000446_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.22 (s, 1 H), 8.20 (s, 1 H), 8.09 (d, J=0.8 Hz, 1 H), 5.92 - 5.82 (m, 1 H), 5.30 (t, J=6.4 Hz, 2H), 5.17 (t, J=7.2 Hz, 2H), 4.17 (br s, 2H), 3.10 - 3.00 (m, 1 H), 2.98 -2.93 (m, 2H), 2.08 -2.05 (m, 2H), 1 .93 - 1 .79 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-56+H]+: 448.0.
Figure imgf000446_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.28 (d, J=0.8 Hz, 1 H), 8.06 (br s, 1 H), 7.86 -7.82 (m, 2H), 5.10 -5.06 (m, 1 H), 4.30 - 4.14 (m, 2H), 3.72 (s, 3H), 3.16 - 2.94 (m, 3H), 2.26 - 2.16 (m, 4H), 2.14 - 2.06 (m, 2H), 2.04 - 1 .97 (m, 2H), 1 .96 - 1 .84 (m, 2H), 1 .83 - 1 .72 (m, 2H); LCMS (ESI) [M+H]+: 396.2.
Figure imgf000446_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.22 (m, 1 H), 8.10 - 8.09 (m, 1 H), 8.08 (m, 1 H), 5.59 -5.82 (m,
1 H), 5.30 (t, J=6.8 Hz, 2H), 5.30 (t, J=7.6 Hz, 2H), 4.20 (br s, 2H), 3.72 (s, 3H), 3.1 0 - 3.00 (m, 3H), 2.1 0 - 2.03 (m, 2H), 1 .92 - 1 .86 (m, 2H); LCMS (ESI) [M+H]+: 462.0.
Figure imgf000446_0005
1 H NMR (300 MHz, Chloroform-d) d 8.19 (d, J = 12.9 Hz, 2H), 7.87 (qd, J = 8.5, 1 .1 Hz, 2H), 5.97 - 5.81 (m, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.56 (d, J = 13.5 Hz, 1 H), 3.82 (d, J = 14.0 Hz, 1 H), 3.39 - 3.12 (m, 3H), 3.04 - 2.89 (m, 1 H), 2.39 (p, J = 9.2 Hz, 2H), 2.26 - 2.14 (m, 4H), 2.09 - 1 .82 (m, 4H); LCMS (ESI) [M+H] 408.5+.
Figure imgf000447_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.25 (s, 1 H), 8.07 (s, 1 H), 7.83 (dd, J=0.7, 7.3 Hz, 1 H), 7.05 (dd, J=1 .5, 7.3 Hz, 1 H), 4.24 - 4.00 (m, 2H), 3.65 (s, 3H), 3.34 (td, J=6.9, 13.8 Hz, 1 H), 3.05 - 2.88 (m, 3H), 2.00 (br d, J=1 1 .4 Hz, 2H), 1 .88 - 1 .72 (m, 2H), 1 .36 (d, J=7.0 Hz, 6H); LCMS (ESI) [M+H]+: 370.1 .
Figure imgf000447_0002
1 H NMR (400 MHz, DMSO) d 8.45 (s, 1 H), 8.41 (s, 1 H), 8.00 (dd, J=1 .4, 8.5 Hz, 1 H), 7.79 (d, J=8.4 Hz, 1 H), 6.33 - 6.22 (m, 1 H), 5.03 (d, J=6.8 Hz, 4H), 4.22 - 3.87 (m, 4H), 3.83 - 3.73 (m, 2H), 3.68 (q, J=5.1 Hz, 2H), 3.46 - 3.40 (m, 1 H), 2.20 - 2.04 (m, 4H), 1 .96 - 1 .82 (m, 1 H), 1 .79 - 1 .65 (m, 1 H); LCMS (ESI) [M+H]+: 459.1 .
Figure imgf000447_0003
1 H NMR (400MHz, CHLOROFORM-d) d 9.34 (d, J=1 .5 Hz, 1 H), 8.63 (s, 1 H), 8.46 (s, 1 H), 5.88 (quin, J=6.9 Hz, 1 H), 5.35 - 5.28 (m, 2H), 5.24 - 5.15 (m, 2H), 4.20 (br d, J=9.7 Hz, 2H), 3.08 (tt, J=3.7, 1 1 .2 Hz, 1 H), 2.97 (br s, 2H), 2.09 (br d, J=1 1 .0 Hz, 2H), 1 .95 - 1 .81 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-56+HJ+: 371 .1 .
Figure imgf000447_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.19 (s, 1 H), 7.85 (dd, J=1 .3, 8.4 Hz, 1 H), 7.72 (d, J=8.4 Hz,
1 H), 7.42 (d, J=3.1 Hz, 1 H), 6.60 (d, J=3.1 Hz, 1 H), 4.87 - 4.76 (m, 1 H), 4.18 (br d, J=5.7 Hz, 2H), 3.09 - 2.88 (m, 3H), 2.15 - 2.04 (m, 2H), 1 .95 - 1 .82 (m, 2H), 1 .58 (d, J=6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M-56+H]+: 355.1 .
Figure imgf000447_0005
1 H NMR (400MHz, CHLOROFORM-d-d) d 8.31 (d, J=0.9 Hz, 1 H), 8.1 1 (s, 1 H), 7.96 - 7.84 (m, 2H), 5.50 - 5.33 (m, 1 H), 4.63 (br d, J=13.4 Hz, 1 H), 4.36 - 4.17 (m, 3H), 4.09 - 4.02 (m, 1 H), 3.97 (br d, J=13.6 Hz,
1 H), 3.31 - 3.21 (m, 1 H), 3.16 (tt, J=3.9, 10.9 Hz, 1 H), 2.97 - 2.84 (m, 1 H), 2.60 - 2.51 (m, 2H), 2.41 (q, J=7.5 Hz, 2H), 2.21 - 2.09 (m, 2H), 1 .98 - 1 .79 (m, 2H), 1 .19 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:396.2.
Figure imgf000448_0001
1 H NMR (400MHz, CHLOROFORM-d -d) d 8.32 (d, J=0.7 Hz, 1 H), 8.1 1 (s, 1 H), 7.94 - 7.84 (m, 2H), 5.44 - 5.34 (m, 1 H), 4.63 (br d, J=13.7 Hz, 1 H), 4.35 - 4.17 (m, 3H), 4.10 - 4.02 (m, 1 H), 3.97 (br d, J=13.2 Hz, 1 H), 3.32 - 3.21 (m, 1 H), 3.16 (tt, J=3.9, 10.9 Hz, 1 H), 2.91 (br t, J=1 1 .4 Hz, 1 H), 2.62 - 2.50 (m, 2H), 2.41 (q, J=7.5 Hz, 2H), 2.23 - 2.08 (m, 2H), 2.01 - 1 .78 (m, 2H), 1 .19 (t, J=7.5 Hz, 3H); LCMS (ESI)
[M+H]+:396.2.
Figure imgf000448_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.08 (s, 1 H), 7.91 - 7.79 (m, 2H), 4.99 (td, J=6.6, 13.3 Hz, 1 H), 3.32 - 3.1 7 (m, 1 H), 3.15 - 2.99 (m, 3H), 2.80 (br t, J=1 1 .1 Hz, 1 H), 2.62 (br t, J=1 1 .0 Hz,
1 H), 2.24 - 2.12 (m, 2H), 2.09 - 1 .94 (m, 2H), 1 .65 (d, J=6.7 Hz, 6H), 1 .30 (d, J=7.1 Hz, 3H); LCMS (ESI) [M+H]+:408.2.
Figure imgf000448_0003
1 H NMR (400MHz, CHLOROFORM-d) d 9.33 (d, J=1 .5 Hz, 1 H), 8.63 (s, 1 H), 8.45 (s, 1 H), 5.92 - 5.84 (m, 1 H), 5.31 (t, J=6.5 Hz, 2H), 5.24 - 5.17 (m, 2H), 4.21 (br s, 2H), 3.74 (s, 3H), 3.17 - 2.99 (m, 3H), 2.1 1 (br d, J=1 1 .2 Hz, 2H), 1 .97 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 385.1 .
Figure imgf000448_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.96 - 7.86 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.18 (t, J=7.4 Hz, 2H), 5.06 - 4.78 (m, 1 H), 4.63 - 4.30 (m, 1 H), 3.42 (br s, 1 5H), 3.04 (br s, 0.5H), 2.25 - 1 .78 (m, 4H), 1 .50 - 1 .1 8 (m, 7H); LCMS (ESI) [M+H]+: 426.1 .
Figure imgf000449_0001
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.97 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.13 (m, 2H), 4.66 (br s, 1 H), 4.20 (br s, 1 H), 3.74 (s, 3H), 3.28 (tt, J=3.9, 12.2 Hz, 1 H), 3.1 0 (br t, J=12.9 Hz, 1 H), 2.17 - 1 .95 (m, 3H), 1 .81 (dq, J=4.6, 12.9 Hz, 1 H), 1 .30 (d, J=7.1 Hz, 3H); LCMS (ESI) [M+H]+: 398.1 .
Figure imgf000449_0002
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.96 - 7.87 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.22 - 5.12 (m, 2.6H), 4.76 (br d, J=12.6 Hz, 0.4H), 4.45 (br s, 0.4H), 3.94 (br d, J=13.2 Hz, 0.6H), 3.44 - 3.28 (m, 1 6H), 2.92 - 2.76 (m, 1 4H), 2.23 - 1 .69 (m, 4H), 1 .44 - 1 .24 (m, 3H), 1 .22 - 1 .08 (m, 6H); LCMS (ESI) [M+H]+: 410.2.
Figure imgf000449_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.28 (s, 1 H), 8.19 (s, 1 H), 7.94 - 7.84 (m, 2H), 5.89 (quin, J=6.9 Hz, 1 H), 5.32 (t, J=6.5 Hz, 2H), 5.17 (t, J=7.3 Hz, 2H), 5.13 - 5.06 (m, 0.5H), 4.69 (br d, J=14.3 Hz, 0.5H), 4.19 (br s, 0.5H), 3.67 (br d, J=13.9 Hz, 0.5H), 3.41 - 3.15 (m, 2.5H), 2.93 - 2.78 (m, 0.5H), 2.50 - 2.28 (m, 2H), 2.26 - 2.07 (m, 3H), 2.05 - 1 .68 (m, 5H), 1 .37 - 1 .23 (m, 3H); LCMS (ESI) [M+H]+: 422.2.
Figure imgf000449_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.24 (s, 1 H), 8.21 (s, 1 H), 7.92 - 7.86 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.19 (t, J=7.3 Hz, 2H), 4.30 - 3.86 (m, 8H), 1 .44 - 1 .25 (m, 4H); LCMS (ESI) [M+H]+: 463.1 .
Figure imgf000449_0005
1H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.96 - 7.86 (m, 2H), 5.95 - 5.87 (m,
1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23-5.12 (m, 2.6H), 4.76 (brd, J=15.4 Hz, 0.4H), 4.45 (brs, 0.4H), 3.94 (br d, J=13.7 Hz, 0.6H), 3.43 - 3.28 (m, 16H), 2.93 - 2.77 (m, 14H), 2.22 - 1.69 (m, 4H), 1.43 - 1.25 (m, 3H), 1.22 - 1.10 (m, 6H); LCMS (ESI) [M+H]+: 410.2.
Figure imgf000450_0001
1H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.97 - 7.87 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.25 - 5.12 (m, 2H), 4.67 (br s, 1 H), 4.19 (br s, 1 H), 3.74 (s, 3H), 3.28 (tt, J=3.9, 12.1 Hz, 1 H), 3.15 - 3.02 (m, 1H), 2.19 - 1.94 (m, 3H), 1.82 (dq, J=4.6, 12.9 Hz, 1H), 1.30 (d, J=7.1 Hz, 3H); LCMS (ESI) [M+H]+: 398.1.
Figure imgf000450_0002
1H NMR (400MHz, DMSO-d6) d 8.62 (s, 1 H), 8.43 (s, 1 H), 8.04 (d, J=8.4 Hz, 1 H), 7.87 (dd, J=1.1 , 8.4 Hz, 1H), 6.16 - 6.01 (m, 1 H), 4.93 - 4.84 (m, 2H), 4.81 -4.73 (m,2H), 4.11 -3.83 (m, 2H), 3.20 - 3.10 (m, 1H), 3.00 (br s, 2H), 2.02 (br d, J=11.5 Hz, 2H), 1.72 - 1.58 (m, 2H), 1.49 (s, 3H), 0.83 - 0.75 (m, 2H), 0.65 - 0.58 (m, 2H); LCMS (ESI) [M+H]+: 472.1.
Figure imgf000450_0003
1H NMR (400MHz, CHLOROFORM-d) d 8.27 (s, 1H), 8.10 (s, 1H), 7.57 (d, J=9.9 Hz, 1H), 5.89 (quin, J=7.0 Hz, 1 H), 5.31 (t, J=6.5 Hz, 2H), 5.24 - 5.10 (m, 2H), 4.60 (brd, J=13.7 Hz, 1H), 3.82 (br d, J=13.5 Hz, 1 H), 3.31 (quin, J=8.6 Hz, 1 H), 3.22 - 3.04 (m, 2H), 2.96 - 2.83 (m, 1 H), 2.46 - 2.31 (m, 2H), 2.24 - 1.78 (m, 8H); LCMS (ESI) [M+H]+: 426.1.
Figure imgf000450_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.1 1 (s, 1 H), 7.58 (dd, J=0.7, 9.9 Hz, 1 H), 5.94 - 5.84 (m, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.23 - 5.14 (m, 2H), 4.45 (br s, 2H), 3.43 - 3.00 (m, 3H), 2.18 (br dd, J=3.1 , 13.5 Hz, 2H), 2.08 - 1 .89 (m, 2H), 1 .37 - 1 .19 (m, 4H); LCMS (ESI) [M+H]+: 430.1 .
Figure imgf000451_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.23 (d, J=1 .0 Hz, 1 H), 8.20 (s, 1 H), 7.87 (d, J=1 .0 Hz, 2H), 5.94 - 5.86 (m, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.17 (t, J=7.4 Hz, 2H), 4.29 (s, 4H), 4.21 (s, 4H), 3.70 (s, 3H); LCMS (ESI) [M+H]+: 397.1 .
Figure imgf000451_0002
1 H NMR (400MHz, DMSO-d6) d 8.43 - 8.36 (m, 1 H), 7.62 (dd, J=1 .2, 5.3 Hz, 1 H), 7.47 (s, 1 H), 5.64 (q, J=5.6 Hz, 1 H), 4.92 (t, J=7.2 Hz, 2H), 4.60 (dd, J=5.2, 7.6 Hz, 2H), 3.99 (br d, J=12.2 Hz, 2H), 3.61 (s, 3H), 3.1 7 (tt, J=3.6, 1 1 .2 Hz, 1 H), 3.12 - 2.93 (m, 2H), 2.02 (br d, J=10.8 Hz, 2H), 1 .73 - 1 .57 (m, 2H); LCMS (ESI) [M+H]+: 361 .2.
Figure imgf000451_0003
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (d, J=0.7 Hz, 1 H), 8.21 (s, 1 H), 7.98 - 7.86 (m, 2H), 5.95 - 5.87 (m, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.14 (m, 2H), 5.08 - 4.80 (m, 1 H), 4.64 - 4.31 (m, 1 H), 3.41 (br s, 1 5H), 3.04 (br s, 0.5H), 2.25 - 1 .76 (m, 4H), 1 .50 - 1 .19 (m, 7H); LCMS (ESI) [M+H]+: 426.1 .
Figure imgf000451_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.95 - 7.82 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.18 (t, J=7.3 Hz, 2H), 5.15 - 5.07 (m, 0.5H), 4.76 - 4.66 (m, 0.5H), 4.27 - 4.13 (m, 0.5H), 3.68 (br d, J=12.3 Hz, 0.5H), 3.41 - 3.20 (m, 2.5H), 2.88 (dt, J=2.9, 13.6 Hz, 0.5H), 2.51 - 2.31 (m, 2H), 2.26 - 2.09 (m, 3H), 2.06 - 1 .69 (m, 5H), 1 .37 - 1 .25 (m, 3H); LCMS (ESI) [M+H]+: 422.2.
Figure imgf000452_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.28 (s, 1 H), 8.1 1 (s, 1 H), 7.58 (d, J=9.9 Hz, 1 H), 5.89 (quin, J=7.0 Hz, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.22 - 5.15 (m, 2H), 4.59 (br s, 1 H), 4.33 (br s, 1 H), 3.36 (br s, 1 H), 3.18 (tt, J=3.9, 10.9 Hz, 1 H), 2.94 (br s, 1 H), 2.16 (br s, 2H), 2.06 - 1 .84 (m, 2H), 1 .84 - 1 .76 (m, 1 H), 1 .02 (br s, 2H), 0.80 (dd, J=3.0, 8.0 Hz, 2H); LCMS (ESI) [M+H]+: 412.1 .
Figure imgf000452_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.10 (s, 1 H), 7.58 (d, J=9.8 Hz, 1 H), 5.89 (quin, J=7.0 Hz, 1 H), 5.32 (t, J=6.5 Hz, 2H), 5.22 - 5.16 (m, 2H), 4.64 (br d, J=13.2 Hz, 1 H), 4.05 (br d, J=13.0 Hz, 1 H), 3.28 (br t, J=12.0 Hz, 1 H), 3.16 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.95 - 2.80 (m, 2H), 2.16 (br s, 2H), 1 .99 - 1 .79 (m, 2H), 1 .1 7 (br s, 6H); LCMS (ESI) [M+H]+: 414.2.
Figure imgf000452_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.10 (s, 1 H), 7.62 - 7.54 (m, 1 H), 5.94 - 5.83 (m, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.22 - 5.14 (m, 2H), 4.35 - 3.99 (m, 2H), 3.12 - 2.91 (m, 3H), 2.08 (br d,
J=1 1 .5 Hz, 2H), 1 .94 - 1 .79 (m, 2H), 1 .58 (s, 3H), 0.93 - 0.86 (m, 2H), 0.69 - 0.62 (m, 2H); LCMS (ESI) [M+H]+: 442.1 .
Figure imgf000452_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.19 (s, 1 H), 8.10 (s, 1 H), 7.70 (s, 1 H), 5.87 (quin, J=6.8 Hz,
1 H), 5.32 (t, J=6.4 Hz, 2H), 5.16 (t, J=7.2 Hz, 2H), 4.21 (br s, 2H), 3.73 (s, 3H), 3.13 - 2.93 (m, 3H), 2.69 (s, 3H), 2.09 (br d, J=12.8 Hz, 2H), 1 .98 - 1 .79 (m, 2H); LCMS (ESI) [M+H]+: 398.1 .
Figure imgf000453_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.10 (s, 1 H), 7.57 (d, J=9.9 Hz, 1 H), 5.88 (quin, J=6.9 Hz, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.22 - 5.15 (m, 2H), 4.34 - 4.04 (m, 3H), 3.13 - 2.96 (m, 3H), 2.15 - 2.01 (m, 2H), 1 .88 (br d, J=9.5 Hz, 2H), 0.76 - 0.65 (m, 4H); LCMS (ESI) [M+H]+: 428.2.
Figure imgf000453_0002
1 H NMR (400MHz, CHLOROFORM-d-d) d 8.27 (s, 1 H), 8.10 (s, 1 H), 7.58 (dd, J=0.8, 9.8 Hz, 1 H), 6.01 - 5.80 (m, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.23 - 5.13 (m, 2H), 4.63 (br d, J=13.3 Hz, 1 H), 3.97 (br d, J=13.8 Hz, 1 H), 3.36 - 3.09 (m, 2H), 2.98 - 2.81 (m, 1 H), 2.41 (q, J=7.5 Hz, 2H), 2.23 - 2.05 (m, 2H), 1 .98 - 1 .76 (m, 2H), 1 .19 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:400.1 .
Figure imgf000453_0003
1 H NMR (400MHz, DMSO-d6) d 8.09 (s, 1 H), 8.04 (s, 1 H), 7.47 (d, J=9.9 Hz, 1 H), 5.33 - 5.26 (m, 1 H), 4.25 - 4.16 (m, 2H), 4.14 (d, J=5.1 Hz, 2H), 4.12 - 3.94 (m, 2H), 3.66 (s, 3H), 3.05 - 2.99 (m, 1 H), 2.99 - 2.89 (m, 2H), 2.55 - 2.42 (m, 2H), 2.02 (br d, J=1 1 .4 Hz, 2H), 1 .88 - 1 .76 (m, 2H); LCMS (ESI) [M+H]+: 416.2.
Figure imgf000453_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.15 (s, 1 H), 8.12 (s, 1 H), 7.79 (d, J=0.9 Hz, 2H), 5.82 (quin, J=7.0 Hz, 1 H), 5.25 (t, J=6.6 Hz, 2H), 5.09 (t, J=7.3 Hz, 2H), 4.20 (s, 4H), 4.06 (s, 4H), 1 .38 (s, 9H); LCMS (ESI) [M+H]+: 439.1 .
Figure imgf000453_0005
1 H NMR (400MHz, CHLOROFORM-d) d 8.10 (s, 1 H), 8.04 (s, 1 H), 7.48 (d, J=9.9 Hz, 1 H), 5.34 - 5.26 (m, 1 H), 4.26 - 4.16 (m, 2H), 4.15 - 4.12 (m, 2H), 3.98 (dt, J=6.1 , 8.2 Hz, 2H), 3.03 - 2.95 (m, 1 H), 2.89 (br s, 2H), 2.55 - 2.41 (m, 2H), 2.01 (br d, J=1 1 .7 Hz, 2H), 1 .85 - 1 .74 (m, 2H), 1 .42 (s, 9H); LCMS (ESI)
[M+23]+: 480.2, [M-56+H]: 402.1 .
Figure imgf000454_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.16 (s, 1 H), 7.80 (s, 1 H), 7.14 (s, 1 H), 5.77 (quin, J=7.0 Hz,
1 H), 5.24 (t, J=6.5 Hz, 2H), 5.08 (t, J=7.2 Hz, 2H), 4.20 - 4.04 (m, 2H), 4.00 (s, 3H), 3.02 - 2.94 (m, 1 H), 2.89 (br t, J=1 1 .9 Hz, 2H), 2.01 (br d, J=1 1 .2 Hz, 2H), 1 .87 - 1 .73 (m, 2H), 1 .42 (s, 9H); LCMS (ESI) [M- 56+H]+: 400.1 .
Figure imgf000454_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.26 (s, 1 H), 8.12 (s, 1 H), 7.94 - 7.85 (m, 2H), 5.27 (quin, J=7.6 Hz, 1 H), 4.21 (br s, 2H), 3.73 (s, 3H), 3.10 - 3.00 (m, 3H), 2.97 - 2.69 (m, 2H), 2.66 - 2.51 (m, 1 H), 2.44 (q, J=7.5 Hz, 2H), 2.37 - 2.20 (m, 1 H), 2.10 -2.04 (m, 2H), 1 .97 - 1 .83 (m, 2H); LCMS (ESI) [M+H]+: 446.1 .
Figure imgf000454_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.26 (s, 1 H), 8.16 (s, 1 H), 7.97 - 7.74 (m, 2H), 5.56 (quin, J=7.2 Hz, 1 H), 4.20 (br s, 2H), 3.72 - 3.60 (m, 6H),3.30 - 3.1 1 (m, 1 H), 3.08 - 3.00 (m, 3H), 2.95 - 2.7(m, 2H), 2.20 - 1 .99 (m, 2H), 1 .97 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 432.1 .
Figure imgf000454_0004
1 H NMR (400MHz, CHLOROFORM-d) d 7.67 - 7.57 (m, 2H), 7.42 (t, J=7.9 Hz, 1 H), 7.13 (dd, J=2.1 , 8.3 Hz, 1 H), 4.58 (br d, J=13.3 Hz, 1 H), 3.97 - 3.86 (m, 4H), 3.81 (br d, J=13.7 Hz, 1 H), 3.36 - 3.24 (m, 5H), 3.20 - 3.07 (m, 2H), 2.94 - 2.83 (m, 1 H), 2.40 (quin, J=9.0 Hz, 2H), 2.25 - 2.15 (m, 2H), 2.15 - 2.07 (m, 2H), 2.05 - 1 .89 (m, 2H), 1 .89 - 1 .80 (m, 2H); LCMS (ESI) [M+H]+: 397.2.
Figure imgf000455_0001
1 H NMR (400MHz, CHLOROFORM-d) d 7.69 - 7.58 (m, 2H), 7.43 (t, J=7.9 Hz, 1 H), 7.14 (dd, J=2.0, 8.3 Hz, 1 H), 4.45 (br d, J=9.5 Hz, 2H), 3.96 - 3.87 (m, 4H), 3.39 - 3.04 (m, 7H), 2.18 (br d, J=1 0.8 Hz, 2H), 2.09 - 1 .89 (m, 2H), 1 .37 - 1 .21 (m, 4H); LCMS (ESI) [M+H]+: 401 .2.
Figure imgf000455_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 8.77 (d, J=5.0 Hz, 1 H), 7.96 (s, 1 H), 7.80 (d, J=4.9 Hz, 1 H), 4.22 (br s, 2H), 3.75 (s, 3H), 3.1 7 - 2.97 (m, 3H), 2.86 (d, J=7.0 Hz, 2H), 2.10 (br d, J=12.8 Hz, 2H), 1 .99 - 1 .81 (m, 2H), 1 .26 - 1 .13 (m, 1 H), 0.71 - 0.58 (m, 2H), 0.38 - 0.27 (m, 2H); LCMS (ESI) [M+H]+:343.1 .
Figure imgf000455_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.77 (d, J=5.1 Hz, 1 H), 7.96 (s, 1 H), 7.81 (d, J=4.8 Hz, 1 H), 4.20 (br s, 2H), 3.16 - 2.92 (m, 3H), 2.86 (d, J=7.1 Hz, 2H), 2.08 (br d, J=1 1 .2 Hz, 2H), 1 .97 - 1 .78 (m, 2H), 1 .50 (s, 9H), 1 .25 - 1 .13 (m, 1 H), 0.67 - 0.58 (m, 2H), 0.32 (q, J=4.8 Hz, 2H); LCMS (ESI)
[M+H]+:385.2.
Figure imgf000455_0004
1 H NMR (400 MHz, CHLOROFORM-d) d 8.23 (s, 1 H), 8.20 (s, 1 H), 7.91 - 7.85 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.15 (m, 2H), 4.21 - 4.04 (m, 3H), 4.02 - 3.66 (m, 6H), 0.74 (d, J=3.5 Hz, 4H); LCMS (ESI) [M+H]+: 461 .1 .
Figure imgf000455_0005
1 H NMR (400MHz, CHLOROFORM-d) d 8.21 (s, 1 H), 8.10 (s, 1 H), 7.90 - 7.80 (m, 2H), 5.43 - 5.34 (m,
1 H), 4.97 (q, J=7.4 Hz, 1 H), 4.34 - 4.26 (m, 1 H), 4.25 - 4.15 (m, 4H), 4.1 1 - 4.00 (m, 1 H), 3.23 (tt, J=3.8, 1 1 .0 Hz, 1 H), 3.06 (br s, 2H), 2.59 - 2.51 (m, 2H), 2.42 - 2.31 (m, 2H), 2.1 7 (br dd, J=2.8, 13.4 Hz, 2H), 2.13 - 2.02 (m, 2H), 2.01 - 1 .88 (m, 2H), 1 .79 (q, J=10.4 Hz, 1 H), 1 .69 - 1 .56 (m, 1 H); LCMS (ESI)
[M+H]+: 438.2.
Figure imgf000456_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.53 (s, 1 H), 8.40 (s, 1 H), 8.30 (s, 1 H), 5.96 -5.89 (m, 1 H), 5.30 (t, J=7.2 Hz, 2H), 5.20 (t, J=7.2 Hz, 2H), 4.21 (br s, 2H), 3.73 (s, 3H), 3.10 - 3.00 (m, 3H), 2.10 -1 .93 (m, 2H), 1 .92 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 409.1 .
Figure imgf000456_0002
1 H NMR (400MHz, CHLOROFORM-d) d 7.34 (s, 1 H), 7.20 (s, 1 H), 6.69 (br d, J=1 1 .6 Hz, 1 H), 4.09 (br s, 2H), 3.84 - 3.78 (m, 4H), 3.20 - 3.15 (m, 4H), 2.99 - 2.93 (m, 1 H), 2.89 (br d, J=1 5.3 Hz, 2H), 1 .98 (br d, J=12.2 Hz, 2H), 1 .82 - 1 .74 (m, 2H), 1 .41 (s, 9H); LCMS (ESI) [M-1 00+H]+: 333.1 .
Figure imgf000456_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.89 (s, 1 H), 7.81 (dd, J=1 .3, 5.1 Hz,
1 H), 4.45 (br s, 2H), 4.23 (t, J=8.2 Hz, 1 H), 4.13 (dt, J=5.2, 8.3 Hz, 1 H), 4.04 - 3.93 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.50 - 2.86 (m, 3H), 2.50 - 2.39 (m, 1 H), 2.28 (qd, J=7.6, 12.3 Hz, 1 H), 2.21 - 2.14 (m, 2H), 1 .96 (br d, J=10.8 Hz, 2H), 1 .39 - 1 .12 (m, 4H); LCMS (ESI) [M+H]+:387.1 .
Figure imgf000456_0004
1 H NMR (400MHz, CHLOROFORM-d) d 9.12 (s, 1 H), 8.19 (s, 1 H), 8.15 (s, 1 H), 6.74 (s, 1 H), 4.92 (quin, J=6.7 Hz, 1 H), 4.22 (br s, 2H), 3.73 (s, 3H), 3.1 1 - 2.94 (m, 3H), 2.13 (br d, J=1 1 .2 Hz, 2H), 1 .81 - 1 .66 (m, 2H), 1 .63 (d, J=6.6 Hz, 6H); LCMS (ESI) [M+H]+:370.1 .
Figure imgf000457_0001
1 H NMR (400MHz, CHLOROFORM-d) d 9.12 (d, J=0.9 Hz, 1 H), 8.19 (s, 1 H), 8.15 (s, 1 HJ. 6.74 (s, 1 H), 4.92 (td, J=6.6, 13.4 Hz, 1 H), 4.67 (br d, J=13.9 Hz, 1 H), 3.96 (br d, J=14.1 Hz, 1 H), 3.23 (br t, J=1 1 .7 Hz, 1 H), 3.1 8 - 3.08 (m, 1 H), 2.85 (br t, J=1 1 .7 Hz, 1 H), 2.40 (q, J=7.4 Hz, 2H), 2.1 8 (br t, J=13.7 Hz, 2H),
1 .82 - 1 .69 (m, 2H), 1 .63 (d, J=6.6 Hz, 6H), 1 .18 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:368.2.
Figure imgf000457_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz, 1 H), 4.64 (br d, J=13.7 Hz, 1 H), 4.23 (t, J=8.0 Hz, 1 H), 4.13 (dt, J=5.2, 8.4 Hz, 1 H), 4.09 - 3.94 (m, 3H), 3.71 (quin, J=7.6 Hz, 1 H), 3.32 - 3.12 (m, 2H), 2.93 - 2.80 (m, 2H), 2.49 - 2.39 (m, 1 H), 2.33 - 2.23 (m,
1 H), 2.1 9 - 2.09 (m, 2H), 1 .97 - 1 .77 (m, 2H), 1 .16 (br d, J=5.1 Hz, 6H); LCMS (ESI) [M+H]+:371 .2.
Figure imgf000457_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.14 (s, 1 H), 8.09 (s, 1 H), 7.85 - 7.81 (d,J=8.4 1 H), 7.79 - 7.74 (d,J=8.4 1 H), 5.87 - 5.76 (m, 1 H), 5.26 (t, J=6.7 Hz, 2H), 5.08 (t, J=7.3 Hz, 2H), 3.21 - 3.08 (m, 1 H), 3.05 - 2.91 (m, 3H), 2.71 (br t, J=10.8 Hz, 1 H), 2.53 (br t, J=1 1 .1 Hz, 1 H), 2.15 - 2.01 (m, 2H), 1 .99 - 1 .83 (m, 2H), 1 .21 (d, J=7.1 Hz, 3H); LCMS (ESI) [M+H]+:422.2.
Figure imgf000457_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 8.31 (s, 1 H), 8.1 1 (s, 1 H), 7.95 - 7.85 (m, 2H), 5.46 - 5.36 (m, 1 H), 4.38 - 4.1 1 (m, 5H), 4.09 - 3.98 (m, 1 H), 3.15 - 2.89 (m, 3H), 2.63 - 2.49 (m, 2H), 2.09 (br d, J=1 1 .9 Hz, 2H), 1 .98 - 1 .81 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-56+H]+:384.1 .
Figure imgf000457_0005
1 H NMR (400MHz, CHLOROFORM-d) d = 8.31 (s, 1 H), 8.1 1 (s, 1 H), 7.94 - 7.83 (m, 2H), 5.45 - 5.34 (m, 1 H), 4.60 (br d, J=13.2 Hz, 1 H), 4.36 - 4.25 (m, 1 H), 4.25 - 4.17 (m, 2H), 4.10 - 4.01 (m, 1 H), 3.82 (br d, J=13.7 Hz, 1 H), 3.31 (quin, J=8.6 Hz, 1 H), 3.21 - 3.08 (m, 2H), 2.95 - 2.84 (m, 1 H), 2.59 - 2.51 (m, 2H), 2.46 - 2.32 (m, 2H), 2.24 - 2.08 (m, 4H), 2.05 - 1 .94 (m, 1 H), 1 .93 - 1 .80 (m, 3H); LCMS (ESI)
[M+H]+:422.2.
Figure imgf000458_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.31 (s, 1 H), 8.10 (s, 1 H), 7.93 - 7.83 (m, 2H), 5.43 (quin, J=7.2 Hz, 1 H), 4.40 - 4.09 (m, 4H), 3.73 (s, 3H), 3.19 - 2.91 (m, 3H), 2.54 - 2.35 (m, 2H), 2.10 (br d, J=1 1 .2 Hz, 2H),1 .96 - 1 .84 (m, 2H), 1 .52 (s, 3H), 1 .40 (s, 3H) ; LCMS (ESI) [M+H]+:426.2.
Figure imgf000458_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.55 (s, 1 H), 8.15 (s, 1 H), 7.77 (s, 2H), 5.37 - 5.26 (m, 1 H), 4.41 - 4.29 (m, 2H), 4.1 8 (br s, 2H), 3.72 (s, 3H), 3.13 - 2.94 (m, 3H), 2.59 - 2.46 (m, 1 H), 2.39 (br dd, J=5.2, 13.2 Hz, 1 H), 2.09 (br d, J=12.0 Hz, 2H), 1 .97 - 1 .77 (m, 2H), 1 .46 (s, 3H), 1 .37 (s, 3H); LCMS (ESI) [M+H]+:426.2.
Figure imgf000458_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.32 (d, J=0.6 Hz, 1 H), 8.1 1 (s, 1 H), 7.94 - 7.84 (m, 2H), 5.45 - 5.35 (m, 1 H), 4.46 (br d, J=8.8 Hz, 2H), 4.34 - 4.17 (m, 3H), 4.1 1 - 4.00 (m, 1 H), 3.51 - 2.91 (m, 3H), 2.63 - 2.49 (m, 2H), 2.1 9 (br dd, J=3.0, 13.5 Hz, 2H), 2.00 (br d, J=10.1 Hz, 2H), 1 .39 - 1 .17 (m, 4H); LCMS (ESI) [M+H]+:426.2.
Figure imgf000458_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .4, 5.0 Hz,
1 H), 4.54 (br d, J=12.6 Hz, 1 H), 4.23 (t, J=8.0 Hz, 1 H), 4.13 (dt, J=5.1 , 8.3 Hz, 1 H), 4.06 - 3.94 (m, 3H), 3.71 (quin, J=7.6 Hz, 1 H), 3.29 - 3.13 (m, 2H), 3.00 (br t, J=12.5 Hz, 1 H), 2.87 - 2.66 (m, 2H), 2.55 - 2.36 (m, 3H), 2.28 (qd, J=7.6, 12.4 Hz, 1 H), 2.20 - 2.06 (m, 2H), 2.00 - 1 .84 (m, 3H), 1 .69 (qd, J=8.9, 17.9 Hz, 1 H); LCMS (ESI) [M+H]+:401 .1 .
Figure imgf000459_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz,
1 H), 4.23 (t, J=8.0 Hz, 2H), 4.17 - 4.03 (m, 3H), 4.02 - 3.94 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.16 - 2.93 (m, 3H), 2.50 - 2.38 (m, 1 H), 2.34 - 2.22 (m, 1 H), 2.07 (br d, J=1 1 .2 Hz, 2H), 1 .86 (br d, J=1 1 .5 Hz, 2H), 0.75 - 0.67 (m, 4H); LCMS (ESI) [M+H]+:385.1 .
Figure imgf000459_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.81 (dd, J=1 .2, 5.0 Hz,
1 H), 7.47 - 7.36 (m, 2H), 7.26 - 7.19 (m, 1 H), 7.12 (t, J=9.0 Hz, 1 H), 4.74 (br d, J=13.2 Hz, 1 H), 4.23 (t, J=8.0 Hz, 1 H), 4.13 (dt, J=5.1 , 8.3 Hz, 1 H), 4.03 - 3.93 (m, 2H), 3.78 - 3.64 (m, 2H), 3.38 - 3.05 (m, 3H), 2.51 - 2.38 (m, 1 H), 2.35 - 2.18 (m, 2H), 2.12 - 1 .80 (m, 3H); LCMS (ESI) [M+H]+:423.1 .
Figure imgf000459_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=4.9 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .2, 5.2 Hz,
1 H), 4.63 (br d, J=13.2 Hz, 1 H), 4.23 (t, J=8.0 Hz, 1 H), 4.13 (dt, J=5.1 , 8.3 Hz, 1 H), 3.97 (quin, J=7.6 Hz, 3H), 3.71 (quin, J=7.6 Hz, 1 H), 3.31 - 3.10 (m, 2H), 2.91 (br t, J=12.1 Hz, 1 H), 2.50 - 2.39 (m, 1 H), 2.33 (d, J=6.6 Hz, 2H), 2.31 - 2.22 (m, 1 H), 2.20 - 2.07 (m, 2H), 1 .97 - 1 .79 (m, 2H), 1 .14 - 1 .02 (m, 1 H), 0.63 - 0.55 (m, 2H), 0.25 - 0.18 (m, 2H); LCMS (ESI) [M+H]+:383.1 .
Figure imgf000459_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.30 (s, 1 H), 8.13 (s, 1 H), 7.92 - 7.83 (m, 2H), 5.41 (t, J=8.4 Hz,
1 H), 4.20 (br s, 2H), 3.78 - 3.66 (m, 4H), 3.59 -3.53 (m, 1 H), 3.12 - 2.97 (m, 6H), 2.82 - 2.63 (m, 2H), 2.09 (br d, J=1 1 .2 Hz, 2H), 1 .96 - 1 .82 (m, 2H); LCMS (ESI) [M+H]+:425.2.
Figure imgf000459_0005
1 H NMR (400MHz, CHLOROFORM-d) d 8.54 (d, J=0.9 Hz, 1 H), 8.22 (br s, 1 H), 7.82 - 7.73 (m, 2H), 5.27 - 5.18 (m, 1 H), 4.1 8 (br s, 2H), 3.78 - 3.73 (m, 1 H), 3.72 (s, 3H), 3.61 - 3.49 (m, 1 H), 3.1 1 - 3.01 (m, 3H), 3.00 (s, 3H), 2.97 - 2.85 (m, 1 H), 2.85 - 2.71 (m, 1 H), 2.09 (br d, J=1 1 .2 Hz, 2H), 1 .96 - 1 .81 (m, 2H); LCMS (ESI) [M+H]+:425.2.
Figure imgf000460_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 7.70 - 7.65 (m, 1 H), 7.55 (d, J=7.3 Hz, 1 H), 6.84 (d, J=8.6 Hz, 1 H), 4.57 (br d, J=13.0 Hz, 1 H), 3.89 - 3.85 (m, 4H), 3.81 (br d, J=13.3 Hz, 1 H), 3.68 - 3.63 (m, 4H), 3.31 (quin, J=8.6 Hz, 1 H), 3.19 - 3.09 (m, 2H), 2.96 - 2.86 (m, 1 H), 2.45 - 2.33 (m, 2H), 2.24 - 2.07 (m, 4H), 2.04 - 1 .94 (m, 1 H), 1 .93 - 1 .80 (m, 3H); LCMS (ESI) [M+H]+:398.2.
Figure imgf000460_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 8.31 (s, 1 H), 8.1 1 (s, 1 H), 7.94 - 7.84 (m, 2H), 5.45 - 5.35 (m, 1 H), 4.64 (br d, J=13.2 Hz, 1 H), 4.36 - 4.26 (m, 1 H), 4.25 - 4.17 (m, 2H), 4.1 1 - 4.01 (m, 1 H), 3.96 (br d, J=13.8Hz, 1 H), 3.26 (br t, J=1 1 .4 Hz, 1 H), 3.16 (tt, J=4.0, 1 0.9 Hz, 1 H), 2.92 (br t, J=1 1 .2 Hz, 1 H), 2.60 - 2.51 (m, 2H), 2.34 (d, J=6.8 Hz, 2H), 2.16 (br d, J=14.6 Hz, 2H), 2.00 - 1 .85 (m, 2H), 1 .14 - 1 .02 (m, 1 H), 0.65 - 0.55 (m, 2H), 0.26 - 0.17 (m, 2H); LCMS (ESI) [M+H]+:422.2.
Figure imgf000460_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.37 (d, J=5.1 Hz, 1 H), 7.29 (s, 1 H), 7.26 (br s, 1 H), 4.59 (br d, J=13.0 Hz, 1 H), 3.89 - 3.75 (m, 5H), 3.65 - 3.57 (m, 4H), 3.30 (quin, J=8.7 Hz, 1 H), 3.20 - 3.06 (m, 2H), 2.92 - 2.80 (m, 1 H), 2.46 - 2.30 (m, 2H), 2.22 - 1 .77 (m, 8H); LCMS (ESI) [M+H]+: 398.2.
Figure imgf000460_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.37 (d, J=5.1 Hz, 1 H), 7.29 (s, 1 H), 7.27 - 7.25 (m, 1 H), 4.20 (br s, 2H), 3.89 - 3.82 (m, 4H), 3.73 (s, 3H), 3.65 - 3.58 (m, 4H), 3.12 - 2.97 (m, 3H), 2.07 (br d, J=12.3 Hz, 2H), 1 .92 - 1 .81 (m, 2H); LCMS (ESI) [M+H]+: 374.1 .
Figure imgf000461_0001
1 H NMR (400MHz, CHLOROFORM-d) d 9.06 (s, 1 H), 8.22 (s, 1 H), 7.92 (s, 1 H), 6.80 (s, 1 H), 5.80 - 5.72 (m, 1 H), 5.23 (t, J=6.5 Hz, 2H), 5.1 5 - 5.04 (m, 2H), 4.15-4.01 (m, 2H), 2.97 - 2.71 (m, 3H), 1 .94 (br d, J=12.3 Hz, 2H), 1 .75 - 1 .57 (m, 2H), 1 .41 (s, 9H); LCMS (ESI) [M+H]+:426.2.
Figure imgf000461_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.1 1 (s, 1 H), 8.04 (s, 1 H), 7.80 - 7.73 (m, 2H), 5.01 - 4.86 (m, 1 H), 4.35 - 4.17 (m, 2H), 4.00 (dd, J=2.8, 13.2 Hz, 1 H), 3.86 - 3.74 (m, 1 H), 3.51 (t, J=8.8 Hz, 1 H), 3.26 - 3.16 (m, 1 H), 3.15 - 3.03 (m, 3H), 2.85 (s, 3H), 1 .62 (d, J=6.8 Hz, 6H); LCMS (ESI) [M+H]+:382.1 .
Figure imgf000461_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 9.06 (d, J=1 .0 Hz, 1 H), 8.23 (s, 1 H), 7.92 (s, 1 H), 6.79 (s, 1 H), 5.79 (quin, J=6.9 Hz, 1 H), 5.27 - 5.17 (m, 2H), 5.1 1 (t, J=7.3 Hz, 2H), 4.57 (br d, J=13.3 Hz, 1 H), 3.75 (br d, J=13.4 Hz, 1 H), 3.29 - 3.16 (m, 1 H), 3.12 - 2.95 (m, 2H), 2.79 - 2.68 (m, 1 H), 2.39 - 2.25 (m, 2H), 2.16 - 2.05 (m, 2H), 1 .99 (br d, J=13.1 Hz, 2H), 1 .95 - 1 .76 (m, 2H), 1 .70 - 1 .58 (m, 3H); LCMS (ESI)
[M+H]+:408.2.
Figure imgf000461_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 9.06 (d, J=1 .1 Hz, 1 H), 8.23 (s, 1 H), 7.93 (s, 1 H), 6.82 (s, 1 H), 5.86 - 5.72 (m, 1 H), 5.24 (t, J=6.6 Hz, 2H), 5.15 - 5.09 (m, 2H), 4.42 (br s, 2H), 3.36 - 2.75 (m, 3H), 2.06 (br d, J=1 1 .1 Hz, 2H), 1 .77 (br d, J=8.8 Hz, 2H), 1 .36 - 1 .06 (m, 4H); LCMS (ESI) [M+H]+:412.1 .
Figure imgf000461_0005
1H NMR (400MHz, CHLOROFORM-d) d = 9.13 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 6.86 (s, 1H), 5.85 (quin, J=6.9 Hz, 1 H), 5.30 (t, J=6.6 Hz, 2H), 5.21 - 5.14 (m, 2H), 4.22 (m, 2H), 3.72 (s, 3H), 3.10 - 2.86 (m, 3H), 2.03 (br d, J=12.6 Hz, 2H), 1.75 (dq, J=4.2, 12.3 Hz, 2H); LCMS (ESI) [M+H]+:384.1.
Figure imgf000462_0001
1H NMR (400MHz, CHLOROFORM-d) d = 8.21 (d, J=2.2 Hz, 1H), 7.82 (dd, J=5.6, 8.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1 H), 6.12 (quin, J=7.0 Hz, 1H), 5.33 (t, J=6.4 Hz, 2H), 5.15 (t, J=7.1 Hz, 2H), 4.64 (br d, J=13.7 Hz, 1 H), 4.05 (br d, J=12.8 Hz, 1 H), 3.36 - 3.13 (m, 2H), 2.98 - 2.78 (m, 2H), 2.17 (br s, 2H), 2.03 - 1.78 (m, 2H), 1.17 (br s, 6H); LCMS (ESI) [M+H]+:414.1.
Figure imgf000462_0002
1H NMR (400MHz, CHLOROFORM-d) d = 8.52 (d, J=2.4 Hz, 1H), 8.00 - 7.95 (m, 1H), 6.71 - 6.64 (m,
1 H), 5.86 - 5.76 (m, 1 H), 5.16 (t, J=7.6 Hz, 2H), 4.88 - 4.79 (m, 2H), 4.16 (br s, 2H), 3.08 - 2.85 (m, 3H), 2.11 - 1.94 (m, 2H), 1.90 - 1.74 (m, 2H), 1.48 (s, 9H); LCMS (ESI) [M-55+H]+:347.1.
Figure imgf000462_0003
1H NMR (400MHz, CHLOROFORM-d) d = 8.40 (d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4, 9.5 Hz, 1H), 6.65 (d, J=9.6 Hz, 1 H), 5.71 - 5.62 (m, 1 H), 4.25 (dt, J=5.6, 8.7 Hz, 1 H), 4.20 - 4.03 (m, 3H), 3.99 - 3.84 (m, 2H), 3.04 - 2.86 (m, 3H), 2.65 (dtd, J=5.6, 8.4, 14.2 Hz, 1H), 2.11 - 1.95 (m, 3H), 1.88 - 1.74 (m, 2H), 1.53 - 1.42 (m, 1 H), 1.48 (s, 9H); LCMS (ESI) [M+H]+:417.2.
Figure imgf000462_0004
1H NMR (400MHz, CHLOROFORM-d) d 8.28 (d, J=5.3 Hz, 1 H), 7.26 (d, J=1.3 Hz, 1 H), 7.03 (s, 1 H), 5.21 (br d, J=4.4 Hz, 1H), 5.10 - 5.02 (m, 3H), 4.63-4.55 (m, 3H), 4.30 (brd, J=12.8 Hz, 1H), 3.35 (br s, 1H), 3.17 (tt, J=3.9, 10.9 Hz, 1H), 2.92 (br s, 1H), 2.14 (br s, 2H), 2.01 - 1.75 (m, 3H), 1.01 (brs, 2H), 0.79 (dd, J=3.0, 8.0 Hz, 2H); 1 H NMR (400MHz, METHANOL-d4) d 8.17 (dd, J=0.6, 5.4 Hz, 1 H), 7.22 (s, 1 H), 7.1 9 (dd, J=1 .5, 5.4 Hz, 1 H), 5.08 - 5.01 (m, 1 H), 5.01 - 4.96 (m, 2H), 4.60 (t, J=6.0 Hz, 2H), 4.52 - 4.34 (m, 2H), 3.50 - 3.38 (m, 1 H), 3.28 - 3.21 (m, 1 H), 2.99 (br t, J=12.5 Hz, 1 H), 2.23 - 2.05 (m, 2H), 2.05 - 1 .97 (m, 1 H), 1 .88 (br d, J=10.1 Hz, 1 H), 1 .76 (br d, J=10.5 Hz, 1 H), 0.93 - 0.87 (m, 2H), 0.86 - 0.79 (m, 2H); LCMS (ESI) [M+H]+:370.1 .
Figure imgf000463_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.28 (d, J=5.1 Hz, 1 H), 7.26 (br s, 1 H), 7.03 (s, 1 H), 5.19 (br d, J=5.1 Hz, 1 H), 5.10 - 5.02 (m, 3H), 4.62 - 4.55 (m, 2H), 4.46 (br s, 2H), 3.33 (br s, 1 H), 3.24 - 3.15 (m,
1 H), 3.05 (br s, 1 H), 2.20 - 2.12 (m, 2H), 1 .95 (br d, J=9.7 Hz, 2H), 1 .35 - 1 .21 (m, 4H); LCMS (ESI) [M+H]+: 388.1 .
Figure imgf000463_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 8.30 - 8.21 (m, 1 H), 7.22 (dd, J=1 .1 , 5.3 Hz, 1 H), 6.98 (s, 1 H), 5.17 (br d, J=4.0 Hz, 1 H), 5.09 - 5.00 (m, 3H), 4.61 - 4.55 (m, 2H), 3.80 (br s, 4H), 3.57 (br s, 4H), 1 .83 - 1 .73 (m, 1 H), 1 .07 - 1 .01 (m, 2H), 0.86 - 0.78 (m, 2H); LCMS (ESI) [M+H]+: 371 .1 .
Figure imgf000463_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.61 (d, J=5.1 Hz, 1 H), 7.98 (s, 1 H), 7.85 (dd, J=1 .3, 5.1 Hz, 1 H), 3.81 (br s, 4H), 3.59 (br d, J=10.8 Hz, 4H), 1 .83 - 1 .73 (m, 1 H), 1 .08 - 1 .02 (m, 2H), 0.87 - 0.79 (m, 2H); LCMS (ESI) [M+H]+: 334.1 .
Figure imgf000463_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 8.61 (d, J=5.1 Hz, 1 H), 7.97 (s, 1 H), 7.84 (dd, J=1 .2, 5.2 Hz, 1 H), 3.85 - 3.62 (m, 4H), 3.57 (br s, 4H), 2.84 (td, J=6.7, 13.5 Hz, 1 H), 1 .18 (d, J=6.8 Hz, 6H); [M+H]+: 336.1 .
Figure imgf000464_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 8.61 (d, J=5.1 Hz, 1 H), 7.98 (s, 1 H), 7.85 (dd, J=1 .3, 5.1 Hz, 1 H), 3.85 (br s, 4H), 3.66 - 3.58 (m, 4H), 1 .38 - 1 .23 (m, 4H); LCMS (ESI) [M+H]+: 352.1 .
Figure imgf000464_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 7.80 (d, J=7.3 Hz, 1 H), 7.31 (d, J=1 .1 Hz, 1 H), 6.95 (dd, J=1 .8, 7.3 Hz, 1 H), 5.86 (quin, J=6.8 Hz, 1 H), 5.1 6 (t, J=7.5 Hz, 2H), 4.78 (t, J=6.7 Hz, 2H), 4.27 - 4.03 (m, 2H), 3.10 - 2.86 (m, 3H), 2.1 1 - 2.00 (m, 2H), 1 .89 - 1 .76 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-Boc+H]+:303.1 .
Figure imgf000464_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.64 (d, J=5.0 Hz, 1 H), 8.03 (s, 1 H), 7.90 (dd, J=1 .3, 5.0 Hz,
1 H), 4.45 (br d, J=1 1 .5 Hz, 2H), 3.45 - 2.92 (m, 3H), 2.17 (br dd, J=3.3, 13.3 Hz, 2H), 1 .95 (br d, J=1 1 .0 Hz, 2H), 1 .37 - 1 .26 (m, 3H), 1 .24 (br d, J=3.1 Hz, 1 H); LCMS (ESI) [M+H]+:351 .0.
Figure imgf000464_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.63 (d, J=5.0 Hz, 1 H), 8.03 (s, 1 H), 7.90 (dd, J=1 .3, 5.1 Hz,
1 H), 4.58 (br s, 1 H), 4.31 (br d, J=7.3 Hz, 1 H), 3.35 (br s, 1 H), 3.19 (tt, J=4.0, 1 1 .0 Hz, 1 H), 2.93 (br s,
1 H), 2.14 (br s, 2H), 2.02 - 1 .84 (m, 2H), 1 .83 - 1 .74 (m, 1 H), 1 .07 - 0.94 (m, 2H), 0.79 (dd, J=3.0, 8.0 Hz, 2H); LCMS (ESI) [M+H]+:333.0.
Figure imgf000464_0005
1 H NMR (400MHz, CHLOROFORM-d) d = 8.40 (d, J=5.3 Hz, 1 H), 7.86 (d, J=5.1 Hz, 1 H), 7.61 (s, 1 H), 4.59 (br d, J=12.5 Hz, 1 H), 4.05 (br d, J=13.0 Hz, 1 H), 3.41 - 3.23 (m, 2H), 2.97 (br t, J=1 1 .9 Hz, 1 H), 2.85 (td, J=6.7, 13.5 Hz, 1 H), 2.23 (br s, 2H), 2.03 - 1 .82 (m, 2H), 1 .17 (d, J=6.7 Hz, 6H); LCMS (ESI) [M+H]+:319.1 .
Figure imgf000465_0001
1 H NMR (400MHz, CHLOROFORM-d-d) d 8.32 (d, J=5.1 Hz, 1 H), 7.26 (dd, J=1 .3, 5.1 Hz, 1 H), 7.20 (s,
1 H), 5.53 (quin, J=7.2 Hz, 1 H), 4.96 (t, J=7.2 Hz, 2H), 4.84 (t, J=6.8 Hz, 2H), 4.69 - 4.51 (m, 1 H), 4.31 (br s, 1 H), 3.36 (br s, 1 H), 3.19 (s, 4H), 2.94 (br s, 1 H), 2.1 6 (br s, 2H), 2.05 - 1 .84 (m, 2H), 1 .83 - 1 .74 (m,
1 H), 1 .03 (br s, 2H), 0.80 (dd, J=3.1 , 7.9 Hz, 2H); LCMS (ESI) [MS+H]+:384.2.
Figure imgf000465_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 8.28 (d, J=1 .5 Hz, 1 H), 8.03 (dd, J=1 .6, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 5.58 - 5.48 (m, 1 H), 5.23 - 5.12 (m, 4H), 4.63 (br d, J=12.7 Hz, 1 H), 4.04 (br d, J=13.3 Hz, 1 H), 3.26 (br t, J=1 1 .9 Hz, 1 H), 3.14 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.96 - 2.79 (m, 2H), 2.16 (br d, J=13.1 Hz, 2H), 2.00 - 1 .76 (m, 2H), 1 .16 (br s, 6H); LCMS (ESI) [M+H]+:413.1 .
Figure imgf000465_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.29 (d, J=1 .3 Hz, 1 H), 8.04 (dd, J=1 .6, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 5.58 - 5.48 (m, 1 H), 5.23 - 5.12 (m, 4H), 4.63 (br d, J=13.0 Hz, 1 H), 4.04 (br d, J=13.2 Hz, 1 H), 3.26 (br t, J=12.0 Hz, 1 H), 3.14 (tt, J=3.8, 1 1 .0 Hz, 2H), 2.95 - 2.79 (m, 1 H), 2.50 - 2.31 (m, 1 H), 2.22 - 2.07 (m, 4H), 2.05 - 1 .93 (m, 1 H), 1 .92 - 1 .76 (m, 3H); LCMS (ESI) [M+H]+:425.1 .
Figure imgf000465_0004
1H NMR (400MHz, CHLOROFORM-d) d = 8.31 (d, J=5.1 Hz, 1 H), 7.78 (d, J=5.1 Hz, 1 H), 7.53 (s, 1 H), 4.54 - 4.13 (m, 2H), 3.39 - 3.17 (m, 2H), 2.93 (br s, 1H), 2.15 (br s, 2H), 1.98 - 1.77 (m, 2H), 1.75 - 1.66 (m, 1 H), 0.99 - 0.89 (m, 2H), 0.76 - 0.66 (m, 2H); LCMS (ESI) [M+H]+:317.1.
Figure imgf000466_0001
1H NMR (400MHz, CHLOROFORM-d) d 8.63 (d, J=5.0 Hz, 1 H), 8.03 (s, 1 H), 7.90 (d, J=4.8 Hz, 1 H), 4.64 (br d, J=12.8 Hz, 1H), 4.04 (br d, J=13.8 Hz, 1H), 3.26 (br t, J=11.9Hz, 1 H), 3.17 (tt, J=3.9, 11.0 Hz, 1H), 2.94 - 2.80 (m, 2H), 2.14 (br s, 2H), 1.96 - 1.76 (m, 2H), 1.16 (brd, J=4.2 Hz, 6H); LCMS (ESI)
[M+H]+:335.1.
Figure imgf000466_0002
1H NMR (400MHz, CHLOROFORM-d) d 8.63 (d, J=5.1 Hz, 1 H), 8.03 (s, 1 H), 7.89 (dd, J=1.2, 5.2 Hz,
1 H), 4.31 - 3.99 (m, 2H), 3.07 (tt, J=3.8, 11.2 Hz, 1 H), 2.97 (br t, J=12.1 Hz, 2H), 2.06 (br d, J=11.0 Hz, 2H), 1.83 (br d, J=10.4 Hz, 2H), 1.57 (s, 3H), 0.92 - 0.86 (m, 2H), 0.68 - 0.62 (m, 2H); LCMS (ESI)
[M+H]+:363.0.
Figure imgf000466_0003
1H NMR (400MHz, CHLOROFORM-d) d = 8.29 (d, J=1.5 Hz, 1 H), 8.04 (dd, J=1.6, 8.4 Hz, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 5.57 - 5.48 (m, 1H), 5.23 - 5.13 (m, 4H), 4.45 (brd, J=11.1 Hz, 2H), 3.48 - 2.95 (m, 3H), 2.23 - 2.10 (m, 2H), 1.97 (br d, J=10.9 Hz, 2H), 1.40 - 1.16 (m, 4H); LCMS (ESI) [M+H]+:429.1.
Figure imgf000466_0004
1H NMR (400MHz, CHLOROFORM-d) d 8.64 (d, J=4.9 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.90 (d, J=4.9 Hz,
1 H), 7.46 - 7.38 (m, 2H), 7.27 - 7.21 (m, 1 H), 7.17 - 7.08 (m, 1 H), 4.74 (br d, J=13.2 Hz, 1 H), 3.70 (br d, J=13.3 Hz, 1 H), 3.33 - 3.08 (m, 3H), 2.23 (brd, J=13.3 Hz, 1H), 2.11 - 1.83 (m, 3H); LCMS (ESI)
[M+H]+:387.1.
Figure imgf000467_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 8.29 - 8.22 (m, 1 H), 7.22 (dd, J=1 .3, 5.3 Hz, 1 H), 6.98 (s, 1 H), 5.17 (br d, J=4.0 Hz, 1 H), 5.12 - 4.98 (m, 3H), 4.64 - 4.52 (m, 2H), 3.82 - 3.61 (m, 4H), 3.55 (br s, 4H), 2.89 - 2.77 (m, 1 H), 1 .17 (d, J=6.8 Hz, 6H); LCMS (ESI) [M+H]+:373.2.
Figure imgf000467_0002
1 H NMR (400MHz, DMSO-d6) d 8.50 (s, 1 H), 8.37 (s, 1 H), 7.94 - 7.79 (m, 2H), 6.58 (br s, 2H), 6.29 (quin, J=7.1 Hz, 1 H), 5.15 - 4.95 (m, 4H), 4.13 - 3.95 (m, 2H), 2.95 - 2.70 (m, 2H), 2.43 - 2.29 (m, 1 H), 1 .85 - 1 .55 (m, 4H), 1 .42 (s, 9H); LCMS (ESI) [M-56+H]+:388.2.
Figure imgf000467_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.29 (d, J=1 .5 Hz, 1 H), 8.04 (dd, J=1 .6, 8.3 Hz, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 5.59 - 5.46 (m, 1 H), 5.25 - 5.10 (m, 4H), 4.58 (br s, 1 H), 4.30 (br s, 1 H), 3.35 (br s, 1 H),
3.16 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.93 (br s, 1 H), 2.15 (br s, 2H), 2.04 - 1 .86 (m, 2H), 1 .83 - 1 .76 (m, 1 H), 1 .02 (br s, 2H), 0.79 (dd, J=2.9, 7.9 Hz, 2H); LCMS (ESI) [M+H]+:41 1 .1 .
Figure imgf000467_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 8.78 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz,
1 H), 4.29 - 4.02 (m, 4H), 4.01 - 3.93 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.1 1 - 2.91 (m, 3H), 2.49 - 2.39 (m, 1 H), 2.28 (qd, J=7.6, 12.3 Hz, 1 H), 2.1 1 - 2.01 (m, 2H), 1 .84 (br d, J=1 0.4 Hz, 2H), 1 .57 (s, 3H), 0.94 - 0.86 (m, 2H), 0.69 - 0.61 (m, 2H); LCMS (ESI) [M+H]+:399.2.
Figure imgf000467_0005
1 H NMR (400MHz, CHLOROFORM-d) d = 8.78 (d, J=4.9 Hz, 1 H), 7.87 (s, 1 H), 7.80 (dd, J=1 .5, 5.1 Hz, 1 H), 4.32 - 4.02 (m, 4H), 4.02 - 3.91 (m, 2H), 3.70 (quin, J=7.6 Hz, 1 H), 3.10 - 2.88 (m, 3H), 2.50 - 2.38 (m, 1 H), 2.28 (qd, J=7.6, 12.3 Hz, 1 H), 2.1 0 - 2.01 (m, 2H), 1 .84 (br d, J=1 0.1 Hz, 2H), 1 .57 (s, 3H), 0.94 - 0.81 (m, 2H), 0.67 - 0.62 (m, 2H); LCMS (ESI) [M+H]+:399.2.
Figure imgf000468_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 9.34 (d, J=1 .6 Hz, 1 H), 8.64 (s, 1 H), 8.46 (s, 1 H), 5.88 (quin, J=6.9 Hz, 1 H), 5.35 - 5.28 (m, 2H), 5.25 - 5.16 (m, 2H), 4.66 (br d, J=13.2 Hz, 1 H), 4.06 (br d, J=13.2 Hz,
1 H), 3.28 (br t, J=12.7 Hz, 1 H), 3.1 9 (tt, J=4.0, 1 1 .0 Hz, 1 H), 2.96 - 2.78 (m, 2H), 2.25 - 2.09 (m, 2H), 2.02 - 1 .79 (m, 2H), 1 .1 7 (br t, J=5.9 Hz, 6H); LCMS (ESI) [M+H]+:397.2.
Figure imgf000468_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 9.35 (d, J=1 .6 Hz, 1 H), 8.65 (s, 1 H), 8.47 (s, 1 H), 5.90 (quin, J=6.9 Hz, 1 H), 5.38 - 5.29 (m, 2H), 5.27 - 5.18 (m, 2H), 4.43 - 3.98 (m, 3H), 3.18 - 3.08 (m, 1 H), 3.08 - 2.98 (m, 2H), 2.1 1 (br s, 2H), 1 .91 (br d, J=9.9 Hz, 2H), 0.78 - 0.69 (m, 4H); LCMS (ESI) [M+H]+:41 1 .1 .
Figure imgf000468_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 9.34 (d, J=1 .7 Hz, 1 H), 8.64 (s, 1 H), 8.46 (s, 1 H), 5.96 - 5.82 (m, 1 H), 5.31 (t, J=6.6 Hz, 2H), 5.26 - 5.17 (m, 2H), 4.49 (br s, 2H), 3.57 - 2.87 (m, 3H), 2.20 (br dd, J=2.8, 13.4 Hz, 2H), 2.1 0 - 1 .89 (m, 2H), 1 .42 - 1 .18 (m, 4H); LCMS (ESI) [M+H]+:413.1 .
Figure imgf000468_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.30 (d, J=0.9 Hz, 1 H), 8.20 (s, 1 H), 7.95 - 7.87 (m, 2H), 5.97 - 5.84 (m, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.23 - 5.1 1 (m, 2H), 3.60 - 3.53 (m, 2H), 3.51 - 3.36 (m, 2H), 3.34 - 3.27 (m, 1 H), 2.94 - 2.80 (m, 2H), 2.42 - 2.31 (m, 1 H), 2.29 - 2.15 (m, 1 H), 1 .09 - 0.96 (m, 1 H), 0.58 - 0.48 (m, 2H), 0.28 (q, J=5.0 Hz, 2H); LCMS (ESI) [M+H]+:394.1 .
Figure imgf000469_0001
1H NMR (400MHz, METHANOL-d4) d 8.25 (s, 1H), 8.21 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.79 - 7.75 (m,
1 H), 6.13 - 6.01 (m, 1H), 5.26 - 5.21 (m, 2H), 5.19 - 5.14 (m, 2H), 4.29 (dd, J=3.2, 12.8 Hz, 1H), 4.19 (br d, J=13.2 Hz, 1 H), 3.92 - 3.81 (m, 2H), 3.55 (t, J=8.8 Hz, 1 H), 3.25 - 3.10 (m, 4H), 2.82 (s, 3H); LCMS (ESI) [M+H]+:396.1.
Figure imgf000469_0002
1H NMR (400MHz, CHLOROFORM-d) d 8.45 (s, 1H), 8.14 (s, 1 H), 7.72 (s, 2H), 5.75 (quin, J=6.8 Hz,
1 H), 5.26 - 5.15 (m, 4H), 4.31 - 4.24 (m, 1 H), 4.18 (br d, J=13.2 Hz, 1 H), 4.03 - 3.95 (m, 1 H), 3.84 - 3.74 (m, 1 H), 3.51 (t, J=8.6Hz, 1 H), 3.25 - 3.15 (m, 1 H), 3.14 - 3.11 (m, 1 H), 3.10 - 3.03 (m, 2H), 2.85 (s, 3H); LCMS (ESI) [M+H]+:396.1.
Figure imgf000469_0003
1H NMR (400MHz, CHLOROFORM-d) d 9.16 (d, J=1.1 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 1HJ.6.73 (s, 1H), 5.85 (quin, J=6.9 Hz, 1H), 5.31 (t, J=6.6 Hz, 2H), 5.20 - 5.13 (m, 2H), 4.19 (brs, 2H), 3.09 -3.00 (m, 1H), 2.99 - 2.87 (m, 2H), 2.11 (br d, J=11.0 Hz, 2H), 1.80 - 1.67 (m, 2H), 1.49 (s, 9H); LCMS (ESI)
[M+H]+:426.2.
Figure imgf000469_0004
1H NMR (400MHz, CHLOROFORM-d) d = 8.02 (dd, J=1.2, 7.7 Hz, 1H), 7.58 - 7.45 (m, 1H), 7.20 - 7.12 (m, 2H), 4.26 - 4.07 (m, 2H), 3.93 - 3.84 (m, 4H), 3.07 - 2.90 (m, 7H), 2.09 (br d, J=11.2 Hz, 2H), 1.92 - 1.80 (m, 2H), 1.49 (s, 9H); LCMS (ESI) [M+H]+:415.2.
Figure imgf000470_0001
1H NMR (400MHz, CHLOROFORM-d) d 8.27 (s, 1 H), 8.09 (s, 1 H), 7.89 - 7.83 (m, 2H), 4.97 (td, J=6.7, 13.3 Hz, 1 H), 3.59 - 3.52 (m, 2H), 3.50-3.26 (m, 3H), 2.97-2.79 (m, 2H), 2.36 (td, J=4.4, 9.0 Hz, 1H), 2.29 - 2.14 (m, 1H), 1.64 (d, J=6.7 Hz, 6H), 1.09 - 0.96 (m, 1H), 0.59 - 0.45 (m, 2H), 0.27 (q, J=4.9 Hz, 2H); LCMS (ESI) [M+H]+:380.2.
Figure imgf000470_0002
1H NMR (400MHz, CHLOROFORM-d) 69.17 (d, J=0.7 Hz, 1H), 8.32 (s, 1H), 8.17 (s, 1H),6.75 (s, 1H), 5.86 (quin, J=7.0 Hz, 1H), 5.32 (t, J=6.6 Hz, 2H), 5.23 - 5.12 (m, 2H), 4.68 (br d, J=13.3 Hz, 1H), 3.97 (br d, J=13.3 Hz, 1 H), 3.30 -3.19 (t, 1H), 3.19- 3.09 (m, 1H), 2.86 (br t, J=11.4 Hz, 1H), 2.41 (q, J=7.5 Hz, 2H), 2.19 (brt, J=14.2 Hz, 2H), 1.76 (q, J=12.0 Hz, 2H), 1.21 - 1.17 (t, 3 H); LCMS (ESI) [M+H]+:382.2.
Figure imgf000470_0003
1H NMR (400MHz, CHLOROFORM-d) d = 8.26 (d, J=5.3 Hz, 1 H), 7.22 (dd, J=1.1 , 5.3 Hz, 1 H), 6.98 (s, 1 H), 5.18 (br d, J=4.4 Hz, 1 H), 5.11 - 4.98 (m, 3H), 4.64 - 4.53 (m, 2H), 3.98 - 3.69 (m, 4H), 3.65 - 3.50 (m, 4H), 1.39 - 1.21 (m, 4H); LCMS (ESI) [M+H]+:389.1.
Figure imgf000470_0004
1H NMR (400MHz, CHLOROFORM-d) d 7.74 (ddd, J=2.1 , 4.4, 8.3 Hz, 1 H), 7.68 (dd, J=2.1 , 8.3 Hz, 1 H), 7.17 (dd, J=8.4, 12.1 Hz, 1 H), 4.15 (br s, 2H), 3.93 - 3.88 (m, 4H), 3.20 - 3.15 (m, 4H), 3.06 - 2.89 (m, 3H), 2.05 (br d, J=12.1 Hz, 2H), 1.91 -1.78 (m, 2H), 1.49 (s, 9H); LCMS (ESI) [M-100+H]+:333.1.
Figure imgf000470_0005
1 H NMR (400MHz, CHLOROFORM-d) d 8.00 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.15 (br d, J=6.8 Hz, 2H), 3.91 - 3.86 (m, 4H), 3.35 - 3.30 (m, 4H), 3.04 - 2.89 (m, 3H), 2.09 - 2.01 (m, 2H), 1 .90 - 1 .78 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-56+H]+:359.1 .
Figure imgf000471_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.27 (d, J=5.3 Hz, 1 H), 7.25 (br d, J=1 .2 Hz, 1 H), 7.03 (s, 1 H), 5.19 (br d, J=4.9 Hz, 1 H), 5.09 - 5.02 (m, 3H), 4.62 - 4.55 (m, 2H), 4.33 - 3.98 (m, 2H), 3.1 1 - 2.91 (m, 3H), 2.05 (br d, J=1 1 .7 Hz, 2H), 1 .83 (br d, J=10.6 Hz, 2H), 1 .57 (s, 3H), 0.92 - 0.86 (m, 2H), 0.68 - 0.62 (m, 2H); LCMS (ESI) [M+H]+:400.2.
Figure imgf000471_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.19 (s, 1 H), 8.07 (d, J=7.8 Hz, 1 H), 7.70 (d, J=7.7 Hz, 1 H), 7.62 - 7.54 (m, 1 H), 5.91 (t, J=7.5 Hz, 1 H), 4.95 - 4.85 (m, 1 H), 4.73 (td, J=5.8, 9.2 Hz, 1 H), 4.1 7-4.07 (m, 2H), 3.17 - 2.92 (m, 4H), 2.77 - 2.62 (m, 1 H), 2.08 (br d, J=1 1 .0 Hz, 2H), 1 .96 - 1 .83 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+Na]+:408.1 .
Figure imgf000471_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.28 (d, J=5.3 Hz, 1 H), 7.26 (s, 1 H), 7.03 (s, 1 H), 5.20 (br s, 1 H), 5.10 - 5.02 (m, 3H), 4.67 - 4.55 (m, 3H), 4.04 (br d, J=13.7 Hz, 1 H), 3.26 (br t, J=1 1 .7 Hz, 1 H), 3.20 - 3.10 (m, 1 H), 2.93 - 2.79 (m, 2H), 2.20 - 2.07 (m, 2H), 1 .96 - 1 .76 (m, 2H), 1 .17 (br s, 6H); LCMS (ESI) [M- Boc+H]+:333.1 .
Figure imgf000471_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 7.71 - 7.65 (m, 1 H), 7.25 - 7.20 (m, 1 H), 7.1 9 - 7.1 1 (m, 1 H), 4.16 (br s, 2H), 3.93 - 3.87 (m, 4H), 3.18 - 3.12 (m, 4H), 3.06 (tt, J=3.8, 1 1 .2 Hz, 1 H), 2.95 (br t, J=1 1 .5 Hz, 2H), 2.07 (br d, J=12.1 Hz, 2H), 1 .94 - 1 .77 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-Boc+H]+:333.1 .
Figure imgf000472_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.31 (dd, J=0.7, 5.1 Hz, 1 H), 7.25 (dd, J=1 .2, 5.1 Hz, 1 H), 7.18 (s, 1 H), 5.52 (quin, J=7.1 Hz, 1 H), 4.95 (t, J=7.3 Hz, 2H), 4.81 (t, J=6.9 Hz, 2H), 4.63 (br d, J=12.3 Hz,
1 H), 4.04 (br d, J=13.1 Hz, 1 H), 3.26 (br t, J=13.0 Hz, 1 H), 3.18 (s, 3H), 3.16 - 3.10 (m, 1 H), 2.94 - 2.80 (m, 2H), 2.22 - 2.07 (m, 2H), 1 .97 - 1 .73 (m, 2H), 1 .19 - 1 .15 (m, 6H); LCMS (ESI) [M+H]+:386.2.
Figure imgf000472_0002
1 H NMR (400MHz, CHLOROFORM-d) d 7.54 (dd, J=3.2, 5.6 Hz, 1 H), 7.20 - 7.14 (m, 1 H), 7.13 - 7.07 (m, 1 H), 4.1 5 (br s, 2H), 3.90 - 3.86 (m, 4H), 3.20 - 3.15 (m, 4H), 3.05 - 3.01 (m, 1 H), 2.97- 2.91 (m, 2H), 2.06 (br d, J=1 0.8 Hz, 2H), 1 .91 - 1 .79 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+23]+:455.1 , [M+H-1 00]+:333.1 .
Figure imgf000472_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.28 (d, J=5.3 Hz, 1 H), 7.45 - 7.38 (m, 2H), 7.26 - 7.20 (m, 2H), 7.15 - 7.08 (m, 1 H), 7.04 (s, 1 H), 5.22 (br d, J=5.1 Hz, 1 H), 5.08 - 5.02 (m, 3H), 4.73 (br d, J=13.2 Hz,
1 H), 4.63 - 4.53 (m, 2H), 3.70 (br d, J=13.7 Hz, 1 H), 3.30 - 3.08 (m, 3H), 2.28 - 2.16 (m, 1 H), 2.1 1 - 1 .85 (m, 3H); LCMS (ESI) [M+H]+:424.2.
Figure imgf000472_0004
1 H NMR (400MHz, CHLOROFORM-d) d 8.30 (dd, J=0.7, 5.1 Hz, 1 H), 7.24 (dd, J=1 .3, 5.1 Hz, 1 H), 7.17 (t, J=1 .0 Hz, 1 H), 5.52 (quin, J=7.2 Hz, 1 H), 4.94 (t, J=7.3 Hz, 2H), 4.80 (t, J=6.9 Hz, 2H), 4.37 - 3.90 (m, 2H), 3.1 7 (s, 3H), 3.10 - 2.87 (m, 3H), 2.13 - 1 .99 (m, 2H), 1 .84 (br d, J=9.9 Hz, 2H), 1 .57 (s, 3H), 0.92 - 0.85 (m, 2H), 0.68 - 0.61 (m, 2H); LCMS (ESI) [M+H]+:414.2.
Figure imgf000473_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 7.67 (t, J=6.3 Hz, 1 H), 7.25 - 7.1 9 (m, 1 H), 7.1 8 - 7.1 1 (m, 1 H), 4.59 (br d, J=13.0 Hz, 1 H), 4.00 - 3.84 (m, 5H), 3.27 - 3.09 (m, 6H), 2.88 (br t, J=1 1 .2 Hz, 1 H), 2.38 (q, J=7.5 Hz, 2H), 2.19 - 2.06 (m, 2H), 1 .96 - 1 .76 (m, 2H), 1 .17 (t, J=7.4 Hz, 3H); LCMS (ESI) [M+H]+:389.2.
Figure imgf000473_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 7.72 - 7.66 (m, 1 H), 7.26 - 7.20 (m, 1 H), 7.1 9 - 7.13 (m, 1 H), 4.62 (br d, J=13.0 Hz, 1 H), 4.03 (br d, J=13.5 Hz, 1 H), 3.94 - 3.85 (m, 4H), 3.32 - 3.12 (m, 6H), 2.96 - 2.79 (m, 2H), 2.22 - 2.07 (m, 2H), 1 .99 - 1 .78 (m, 2H), 1 .19 - 1 .12 (m, 6H); LCMS (ESI) [M+H]+:403.2.
Figure imgf000473_0003
1 H NMR (400MHz, CHLOROFORM-d) d 7.73 (ddd, J=2.1 , 4.3, 8.4 Hz, 1 H), 7.68 (dd, J=2.0, 8.1 Hz, 1 H), 7.17 (dd, J=8.4, 12.1 Hz, 1 H), 4.20 (br s, 2H), 3.94 - 3.87 (m, 4H), 3.73 (s, 3H), 3.20 - 3.16 (m, 4H), 3.09 - 2.97 (m, 3H), 2.07 (br d, J=12.7 Hz, 2H), 1 .93 - 1 .81 (m, 2H); LCMS (ESI) [M+H]+:391 .1 .
Figure imgf000473_0004
1 H NMR (400MHz, CHLOROFORM-d) d 7.74 (ddd, J=2.1 , 4.4, 8.4 Hz, 1 H), 7.68 (dd, J=2.1 , 8.2 Hz, 1 H), 7.18 (dd, J=8.4, 12.2 Hz, 1 H), 4.63 (br d, J=13.6 Hz, 1 H), 4.03 (br d, J=13.6 Hz, 1 H), 3.94 - 3.88 (m, 4H), 3.25 (br t, J=1 1 .6 Hz, 1 H), 3.21 - 3.16 (m, 4H), 3.15 - 3.08 (m, 1 H), 2.92 - 2.80 (m, 2H), 2.18 - 2.07 (m, 2H), 1 .97 - 1 .77 (m, 2H), 1 .16 (br t, J=5.7 Hz, 6H) ; LCMS (ESI) [M+H]+:403.2.
Figure imgf000473_0005
1 H NMR (400MHz, CHLOROFORM-d) d 8.00 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.18 (br s, 2H), 3.92 - 3.85 (m, 4H), 3.72 (s, 3H), 3.35 - 3.29 (m, 4H), 3.01 (tdd, J=3.7, 7.4, 1 1 .0 Hz, 3H), 2.07 (br d,
J=1 1 .9 Hz, 2H), 1 .93 - 1 .80 (m, 2H); LCMS (ESI) [M+H]+:373.2.
Figure imgf000474_0001
1 H NMR (400MHz, CHLOROFORM-d) d 7.73 (ddd, J=2.1 , 4.3, 8.4 Hz, 1 H), 7.68 (dd, J=2.1 , 8.2 Hz, 1 H), 7.17 (dd, J=8.4, 12.2 Hz, 1 H), 4.61 (br d, J=13.2 Hz, 1 H), 3.95 (br d, J=14.4 Hz, 1 H), 3.93 - 3.89 (m, 4H), 3.27 - 3.22 (m, 1 H), 3.21 - 3.16 (m, 4H), 3.1 1 (tt, J=4.0, 1 1 .0 Hz, 1 H), 2.93 - 2.83 (m, 1 H), 2.40 (q, J=7.5 Hz, 2H), 2.16 - 2.06 (m, 2H), 1 .95 - 1 .79 (m, 2H), 1 .18 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:389.2.
Figure imgf000474_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.03 - 7.97 (m, 2H), 6.98 - 6.92 (m, 2H), 4.61 (br d, J=13.1 Hz,
1 H), 4.02 (br d, J=14.2 Hz, 1 H), 3.91 - 3.85 (m, 4H), 3.35 - 3.30 (m, 4H), 3.24 (br t, J=1 1 .6 Hz, 1 H), 3.10 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.92 - 2.80 (m, 2H), 2.12 (br t, J=10.3 Hz, 2H), 1 .96 - 1 .77 (m, 2H), 1 .16 (br t, J=5.7 Hz, 6H); LCMS (ESI) [M+H]+:385.2.
Figure imgf000474_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.00 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.60 (br d, J=12.8 Hz, 1 H), 3.95 (br d, J=13.0 Hz, 1 H), 3.91 - 3.86 (m, 4H), 3.35 - 3.30 (m, 4H), 3.27 - 3.18 (m, 1 H), 3.09 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.93 - 2.84 (m, 1 H), 2.40 (q, J=7.4 Hz, 2H), 2.10 (br d, J=3.9 Hz, 2H), 1 .95 - 1 .78 (m, 2H), 1 .1 8 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:371 .2.
Figure imgf000474_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 7.94 (dd, J=1 .4, 7.8 Hz, 1 H), 7.50 - 7.40 (m, 1 H), 7.12 - 7.03 (m, 2H), 4.56 (br d, J=13.4 Hz, 1 H), 3.96 (br d, J=13.4 Hz, 1 H), 3.85 - 3.74 (m, 4H), 3.19 (br t, J=1 1 .8 Hz,
1 H), 3.07 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.98 - 2.89 (m, 4H), 2.86 - 2.73 (m, 2H), 2.08 (br t, J=1 1 .0 Hz, 2H), 1 .90 - 1 .70 (m, 2H), 1 .08 (br d, J=5.4 Hz, 6H); LCMS (ESI) [M+H]+:385.1 .
Figure imgf000475_0001
1 H NMR (400MHz, CHLOROFORM-d) d = 7.94 (dd, J=1 .4, 7.9 Hz, 1 H), 7.50 - 7.40 (m, 1 H), 7.12 - 7.04 (m, 2H), 4.54 (br d, J=13.2 Hz, 1 H), 3.88 (br d, J=13.6 Hz, 1 H), 3.84 - 3.77 (m, 4H), 3.21 - 3.13 (m, 1 H), 3.1 1 - 3.03 (m, 1 H), 2.99 - 2.91 (m, 4H), 2.88 - 2.77 (m, 1 H), 2.33 (q, J=7.5 Hz, 2H), 2.13 - 2.01 (m, 2H), 1 .88 - 1 .71 (m, 2H), 1 .1 1 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:371 .1 .
Figure imgf000475_0002
1 H NMR (400MHz, CHLOROFORM-d) d = 7.94 (dd, J=1 .4, 7.9 Hz, 1 H), 7.48 - 7.41 (m, 1 H), 7.1 1 - 7.05 (m, 2H), 4.27 - 3.95 (m, 2H), 3.86 - 3.77 (m, 4H), 3.65 (s, 3H), 3.02 - 2.91 (m, 7H), 2.03 (br d, J=1 1 .2 Hz, 2H), 1 .86 - 1 .74 (m, 2H); LCMS (ESI) [M+H]+:373.1 .
Figure imgf000475_0003
1 H NMR (400MHz, METHANOL-d4) d = 8.32 (d, J=5.3 Hz, 1 H), 7.31 (d, J=5.3 Hz, 1 H), 7.19 (s, 1 H), 4.54 (br d, J=13.4 Hz, 1 H), 4.16 (br d, J=13.8 Hz, 1 H), 3.93 (t, J=13.0 Hz, 2H), 3.78 (t, J=7.3 Hz, 2H), 3.43 - 3.35 (m, 1 H), 3.30 - 3.20 (m, 1 H), 3.07 - 2.90 (m, 2H), 2.59 (tt, J=7.1 , 13.9 Hz, 2H), 2.24 - 2.08 (m, 2H),
1 .92 - 1 .70 (m, 2H), 1 .14 (t, J=6.5 Hz, 6H); LCMS (ESI) [M+H]+:406.1 .
Figure imgf000475_0004
1 H NMR (400MHz, METHANOL-d4) d = 8.31 (dd, J=0.7, 5.3 Hz, 1 H), 7.28 (dd, J=1 .3, 5.3 Hz, 1 H), 7.16 (s, 1 H), 4.09 (br s, 2H), 3.91 (t, J=13.0 Hz, 2H), 3.76 (t, J=7.3 Hz, 2H), 3.20 - 2.97 (m, 3H), 2.64 - 2.51 (m, 2H), 2.12 - 2.00 (m, 2H), 1 .84 - 1 .69 (m, 2H), 1 .54 (s, 3H), 0.91 - 0.84 (m, 2H), 0.69 - 0.61 (m, 2H); LCMS (ESI) [M+H]+:434.2.
Figure imgf000475_0005
1 H NMR (400MHz, CHLOROFORM-d) d 7.40 (s, 1 H), 5.39 (quin, J=6.8 Hz, 1 H), 5.03 (d, J=7.2 Hz, 4H), 4.67 (s, 2H), 4.1 1 (br s, 2H), 3.92 (t, J=6.0 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.89 - 2.82 (m, 2H), 2.79 - 2.72 (m, 1 H), 1 .93 (br d, J=1 1 .2 Hz, 2H), 1 .78 - 1 .67 (m, 2H), 1 .46 (s, 9H); LCMS (ESI) [M+H]+:431 .2.
Figure imgf000476_0001
1 H NMR (400MHz, CHLOROFORM-d) d 7.48 (s, 1 H), 5.41 - 5.28 (m, 1 H), 5.23 - 5.14 (m, 2H), 5.04 - 4.95 (m, 2H), 4.63 (br s, 2H), 4.12 (br s, 2H), 4.01 - 3.86 (m, 2H), 2.86 (br s, 1 H), 2.85 - 2.78 (m, 3H), 2.77 - 2.71 (m, 1 H), 1 .92 (br d, J=10.2 Hz, 2H), 1 .77 - 1 .60 (m, 2H), 1 .48 - 1 .41 (m, 9H); LCMS (ESI)
[M+1 ]+:431 .2, [M+H-100]+:331 .1 .
Figure imgf000476_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.75 (br s, 1 H), 8.18 (br s, 1 H), 7.96 (br s, 1 H), 4.36 (br s, 2H), 4.02 - 3.71 (m, 4H), 3.30 - 2.92 (m, 3H), 2.86 (td, J=6.7, 13.5 Hz, 1 H), 2.70 (br s, 2H), 2.14 (br d, J=10.8 Hz, 2H), 1 .85 (br d, J=12.8 Hz, 2H), 1 .17 (d, J=6.8 Hz, 6H); LCMS (ESI) [M+H]+:406.2.
Figure imgf000476_0003
1 H NMR (400MHz, CHLOROFORM-d) d = 8.82 - 8.76 (m, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz, 1 H), 4.41 (br d, J=13.7 Hz, 2H), 4.23 (t, J=8.2 Hz, 1 H), 4.13 (dt, J=5.1 , 8.3 Hz, 1 H), 4.04 - 3.93 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.24 - 3.10 (m, 3H), 2.50 - 2.37 (m, 1 H), 2.28 (qd, J=7.6, 12.4 Hz, 1 H), 2.15 (br dd, J=3.3, 13.7 Hz, 2H), 1 .98 - 1 .86 (m, 2H), 1 .57 (s, 6H); LCMS (ESI) [M+H]+:439.2.
Figure imgf000476_0004
1 H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz, 1 H), 4.59 (br d, J=12.6 Hz, 1 H), 4.23 (t, J=8.0 Hz, 1 H), 4.13 (dt, J=5.2, 8.2 Hz, 1 H), 4.02 - 3.92 (m, 2H), 3.80 - 3.65 (m, 2H), 3.24 - 3.11 (m, 2H), 2.99 (br t, J=11.9 Hz, 1 H), 2.79 - 2.66 (m, 2H), 2.56 (br s, 2H), 2.50 - 2.38 (m, 1H), 2.28 (qd, J=7.6, 12.3 Hz, 1H), 2.20 - 2.06 (m, 3H), 1.97 - 1.81 (m, 3H); LCMS (ESI) [M+H]+:451.2.
Figure imgf000477_0001
1H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.3, 5.1 Hz,
1 H), 4.44 (br s, 2H), 4.22 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.3, 8.3 Hz, 1H), 4.05 - 3.92 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.41 -2.92 (m, 3H), 2.49 - 2.38 (m, 1H), 2.28 (qd, J=7.6, 12.3 Hz, 1 H), 2.16 (br dd, J=3.0, 13.6 Hz, 2H), 1.98 - 1.82 (m, 2H), 1.40 - 1.33 (m, 2H), 1.24 - 1.15 (m, 2H); LCMS (ESI) [M+H]+:437.2.
Figure imgf000477_0002
1H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.3, 5.1 Hz,
1 H), 4.48 (br d, J=13.5 Hz, 2H), 4.23 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.2, 8.3 Hz, 1H), 4.03-3.93 (m, 2H), 3.71 (quin, J=7.6 Hz, 1H), 3.25 - 2.95 (m, 3H), 2.51 - 2.38 (m, 1H), 2.28 (qd, J=7.6, 12.4 Hz, 1H), 2.14 (br dd, J=2.6, 13.5 Hz, 2H), 1.95 - 1.80 (m, 2H), 1.35 (s, 3H), 1.01 - 0.93 (m, 2H), 0.66 - 0.57 (m, 2H); LCMS (ESI) [M+H]+:383.2.
Figure imgf000477_0003
1H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.3, 5.1 Hz,
1 H), 4.58 (br d, J=11.0 Hz, 1H), 4.22 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.1, 8.3 Hz, 1H), 4.03-3.92 (m, 2H), 3.81 -3.65 (m, 2H), 3.14 (tdd, J=3.9, 7.3, 14.7 Hz, 2H), 2.87 (br t, J=11.1 Hz, 1 H), 2.63 - 2.51 (m, 2H), 2.49 - 2.38 (m, 1H), 2.28 (qd, J=7.6, 12.4 Hz, 1H), 2.17 - 2.05 (m, 2H), 2.04 - 1.81 (m, 5H), 1.80 - 1.70 (m, 1 H), 1.47 (s, 3H); LCMS (ESI) [M+H]+:397.2.
Figure imgf000477_0004
1H NMR (400MHz, CHLOROFORM-d) d = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.5, 5.1 Hz, 1 H), 4.59 (br d, J=13.0 Hz, 1H), 4.23 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.1, 8.3 Hz, 1H), 4.03-3.93 (m, 2H), 3.81 (br d, J=13.5 Hz, 1 H), 3.71 (quin, J=7.6 Hz, 1 H), 3.30 (quin, J=8.6 Hz, 1 H), 3.20 - 3.09 (m, 2H), 2.94 - 2.82 (m, 1 H), 2.49 - 2.33 (m, 3H), 2.33 - 2.24 (m, 1 H), 2.24 - 2.06 (m, 4H), 2.05 - 1 .76 (m, 4H); 1 H NMR (400MHz, METHANOL-d4) d = 8.97 (d, J=6.4 Hz, 1 H), 8.58 (s, 1 H), 8.54 (dd, J=1 .5, 6.2 Hz, 1 H), 4.49 (br d, J=13.0 Hz, 1 H), 4.21 (dt, J=4.9, 8.5 Hz, 1 H), 4.17 - 4.08 (m, 2H), 4.03 - 3.87 (m, 3H), 3.47 (quin, J=8.5 Hz, 1 H), 3.36 - 3.33 (m, 1 H), 3.29 - 3.22 (m, 1 H), 2.96 (br t, J=1 1 .5 Hz, 1 H), 2.73 - 2.61 (m, 1 H), 2.37 - 2.1 1 (m, 7H), 2.09 - 1 .98 (m, 1 H), 1 .90 - 1 .71 (m, 3H); LCMS (ESI) [M+H]+:383.2.
Figure imgf000478_0001
1 H NMR (400MHz, CHLOROFORM-d) d 8.76 (d, J=1 .6 Hz, 1 H), 8.17 (d, J=2.9 Hz, 1 H), 7.46 (dd, J=1 .8, 2.8 Hz, 1 H), 4.17 (br s, 2H), 3.80 (t, J=12.8 Hz, 2H), 3.67 (t, J=7.2 Hz, 2H), 3.13 - 2.87 (m, 3H), 2.58 (tt, J=7.0, 13.7 Hz, 2H), 2.07 (br d, J=1 1 .7 Hz, 2H), 1 .92 - 1 .78 (m, 2H), 1 .49 (s, 9H); LCMS (ESI)
[M+H]+:436.1 .
Figure imgf000478_0002
1 H NMR (400MHz, CHLOROFORM-d) d 8.74 (dd, J=0.8, 5.2 Hz, 1 H), 8.08 (s, 1 H), 8.06 (s, 1 H), 8.01 (s,
1 H), 7.75 - 7.70 (m, 1 H), 4.25 -4.10 (br s, 2H), 3.99 (s, 3H), 3.06 -3.02 (m, 1 H), 2.96 -2.90 (m, 2H), 2.08 - 2.05 (m, 2H), 1 .92 - 1 .80 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+:41 1 .2.
Figure imgf000478_0003
1 H NMR (400MHz, CHLOROFORM-d) d 8.82 (d, J=5.2 Hz, 1 H), 8.57 (s, 1 H), 7.83 (dd, J=1 .6, 5.2 Hz,
1 H), 7.46 (d, J=2.4 Hz, 1 H), 6.93 (d, J=2.0 Hz, 1 H), 4.1 8 (br d, J=8.4 Hz, 2H), 4.02 (s, 3H), 3.06 -3.02 (m,
1 H), 3.00 - 2.87 (m, 2H), 2.1 1 - 2.01 (m, 2H), 1 .91 - 1 .79 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+:41 1 .2.
Figure imgf000478_0004
1H NMR (400MHz, METHAN0L-d4) d 9.00 (d, J=0.9 Hz, 1 H), 8.90 (d, J=6.4 Hz, 1 H), 8.48 (dd, J=1.6, 6.4 Hz, 1 H), 7.93 (d, J=2.2 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 4.55 (br d, J=13.5 Hz, 1H), 4.17 (brd, J=13.7 Hz, 1 H), 4.11 (s, 3H), 3.44 - 3.32 (m, 2H), 3.06 - 2.92 (m, 2H), 2.29 - 2.11 (m, 2H), 1.97 - 1.72 (m, 2H), 1.13 (t, J=6.0 Hz, 6H); LCMS (ESI) [M+H]+:381.2.
Figure imgf000479_0001
1H NMR (400MHz, METHAN0L-d4) d 8.78 (d, J=5.2 Hz, 1 H), 8.60 (s, 1 H), 7.94 (dd, J=1.2, 5.2 Hz, 1 H), 7.69 (d, J=2.0 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 4.21 - 4.04 (m, 2H), 4.01 (s, 3H), 3.18-3.14 (m, 1H), 3.06 (br s, 2H), 2.17 - 2.00 (m, 2H), 1.79 (br d, J=11.0 Hz, 2H), 1.54 (s, 3H), 0.92 - 0.85 (m, 2H), 0.69 - 0.62 (m, 2H); LCMS (ESI) [M+H]+:409.2.
Figure imgf000479_0002
1H NMR (400MHz, METHAN0L-d4) d 8.71 (d, J=5.2 Hz, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.81 (dd, J=1.6, 5.2 Hz, 1H), 4.12 (brd, J=14.8 Hz, 2H), 3.97 (s, 3H), 3.17 (tt, J=3.6, 11.2 Hz, 1H), 3.05 (br s, 2H), 2.13 - 2.03 (m, 2H), 1.88 - 1.71 (m, 2H), 1.54 (s, 3H), 0.91 - 0.85 (m, 2H), 0.68 - 0.63 (m, 2H); LCMS (ESI) [M+H]+:409.1.
Figure imgf000479_0003
1H NMR (400MHz, METHANOL-d4) d 8.72 (d, J=5.2 Hz, 1 H), 8.28 (s, 1 H), 8.26 (s, 1 H), 8.11 (s, 1 H), 7.83 (dd, J=1.6, 5.2 Hz, 1H), 4.53 (brd, J=13.2 Hz, 1H), 4.15 (brd, J=13.6 Hz, 1H), 3.97 (s, 3H), 3.41 - 3.33 (m, 1 H), 3.29 - 3.23 (m, 1H), 3.10-2.88 (m, 2H), 2.29 - 2.04 (m, 2H), 1.95 - 1.69 (m, 2H), 1.13 (t, J=6.8 Hz, 6H); LCMS (ESI) [M+H]+:381.2.
Figure imgf000479_0004
1H NMR (400MHz, DMS0-d6) d = 8.10 - 7.99 (m, 2H), 7.65 (dd, J=1.0, 7.7 Hz, 1H), 4.39 (brd, J=12.8 Hz, 1 H), 4.11 (t, J=7.9 Hz, 1 H), 4.06 - 3.92 (m, 2H), 3.87 - 3.74 (m, 2H), 3.74 - 3.65 (m, 1 H), 3.27 - 3.18 (m, 2H), 2.96 - 2.79 (m, 2H), 2.40 - 2.29 (m, 1H), 2.18 (qd, J=7.7, 12.1 Hz, 1H), 2.12 - 1.96 (m, 2H), 1.78 - 1.50 (m, 2H), 1.02 (br d, J=6.4 Hz, 6H); LCMS (ESI) [M+H]+:371.1.
Figure imgf000480_0001
1H NMR (400MHz, CHLOROFORM-d) d = 7.98 (dd, J=0.7, 7.7 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.39 (dd, J=0.6, 7.8 Hz, 1 H), 4.18 - 4.01 (m, 4H), 3.93 - 3.85 (m, 1 H), 3.93 - 3.85 (m, 1 H), 3.70 (quin, J=7.3 Hz,
1 H), 3.00 (tt, J=3.8, 11.2 Hz, 1H), 2.88 (br t, J=11.6 Hz, 2H), 2.44 - 2.31 (m, 1 H), 2.18 (qd, J=7.4, 12.5 Hz, 1 H), 2.00 (br d, J=10.9 Hz, 2H), 1.85 - 1.72 (m, 2H), 1.41 (s, 9H); LCMS (ESI) [M+H]+:401.1.
Figure imgf000480_0002
1H NMR (400MHz, CHLOROFORM-d) d = 9.20 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.2 Hz, 1H), 8.26 (t, J=2.0 Hz, 1 H), 4.22 - 4.10 (m, 4H), 4.01 - 3.92 (m, 1H), 3.82 (dd, J=6.5, 8.7 Hz, 1H), 3.58 - 3.48 (m, 1H), 3.12 - 2.87 (m, 3H), 2.54 - 2.44 (m, 1 H), 2.12-1.98 (m, 3H), 1.92 - 1.78 (m, 2H), 1.48 (s, 9H); LCMS (ESI) [M+H]+:401.1.
Figure imgf000480_0003
1H NMR (400MHz, CHLOROFORM-d) d 8.19 (s, 1H), 8.10 - 8.05 (m, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.61 - 7.54 (m, 1 H), 5.91 (t, J=7.5 Hz, 1H), 4.90 (dt, J=6.0, 7.9 Hz, 1H), 4.74 (td, J=5.8, 9.2 Hz, 1H), 4.32-4.10 (m, 2H), 3.75 (s, 3H), 3.19 - 3.00 (m, 4H), 2.70 (tdd, J=7.5, 9.1 , 11.0 Hz, 1 H), 2.10 (br d, J=11.2 Hz, 2H), 1.98 - 1.82 (m, 2H); LCMS (ESI) [M+Na]+:366.1.
Figure imgf000480_0004
1H NMR (400MHz, CHLOROFORM-d) d 8.74 (d, J=5.1 Hz, 1H), 8.08 (s, 1H), 7.41 - 7.38 (m, 1H), 4.25 - 4.09 (m, 4H), 3.99-3.92 (m, 1H), 3.85 (dd, J=6.2, 8.8 Hz, 1H), 3.52 (quin, J=7.1 Hz, 1H), 3.13 - 3.03 (m, 1 H), 3.01 - 2.88 (m, 2H), 2.54 - 2.44 (m, 1 H), 2.1 1 - 2.00 (m, 3H), 1 .96 - 1 .83 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+:401 .2.
Figure imgf000481_0001
1 H NMR (400MHz, CHLOROFORM-d) d 7.46 (s, 1 H), 5.37 - 5.26 (m, 1 H), 5.16 (t, J=6.4 Hz, 2H), 4.96 (t, J=7.2 Hz, 2H), 4.61 (s, 2H), 4.23 - 3.95 (m, 2H), 3.90 (t, J=5.6 Hz, 2H), 2.87 (br t, J=1 1 .2 Hz, 2H), 2.79 (br t, J=5.6 Hz, 2H), 2.76 - 2.70 (m, 1 H), 1 .91 (br d, J=1 1 .2 Hz, 2H), 1 .80 - 1 .61 (m, 2H), 1 .53 (s, 3H), 0.94 - 0.80 (m, 2H), 0.65 - 0.55 (m, 2H); LCMS (ESI) [M+H]+:429.1 .
Figure imgf000481_0002
1 H NMR (400MHz, CHLOROFORM-d) d 7.48 (s, 1 H), 5.33 (quin, J=7.2 Hz, 1 H), 5.17 (t, J=6.4 Hz, 2H), 4.97 (t, J=7.2 Hz, 2H), 4.63 (s, 2H), 4.55 (br d, J=12.8 Hz, 1 H), 4.05 - 3.81 (m, 3H), 3.17 (br t, J=1 1 .6 Hz, 1 H), 2.95 - 2.69 (m, 5H), 1 .99 (br s, 2H), 1 .84 - 1 .68 (m, 2H), 1 .17 - 1 .08 (m, 6H); LCMS (ESI)
[M+H]+:401 .1 .
Figure imgf000481_0003
1 H NMR (400MHz, CHLOROFORM-d) d 7.39 (s, 1 H), 5.38 (quin, J=6.8 Hz, 1 H), 5.04 -4.99 (m, 4H), 4.67 (s, 2H), 4.61 - 4.45 (m, 1 H), 4.01 - 3.83 (m, 3H), 3.17 (br t, J=12.0 Hz, 1 H), 2.92 (t, J=6.0 Hz, 2H), 2.89 - 2.75 (m, 3H), 2.01 -1 .96 (m, 2H), 1 .80 - 1 .67 (m, 2H), 1 .16 -1 .07 (m, 6H); LCMS (ESI) [M+H]+:401 .1 .
Example 157. Description of yeast models
a-synuclein and ApoE4 yeast strains were previously engineered to express the human a- synuclein or ApoE4 genes under control of the yeast galactose-regulated promoter, GAL 1, as described in International Patent Publication No. WO2016/040794 and U.S. Patent Nos. 7,452,670 and 7,045,290, the procedures for the production of such strains of which are herein incorporated by reference. The induced expression of a-synuclein and ApoE4 confers cytotoxicity, thus enabling the identification of compounds that can restore cell viability. This instantaneous/synchronous induction of a-synuclein and ApoE4 can be achieved due to the following expression control. In glucose-containing media, gene expression from the GAL 1 promoter is‘off and actively repressed by additional epigenetic factors. In raffinose, expression is‘off, but the promoter not actively repressed. Upon transition to galactose- containing media, the promoter is instantaneously turned‘on’ to achieve robust and synchronous induction of a-synuclein or ApoE4 expression. This highly regulated induction provides a robust window for the determination of both efficacy (amplitude of protective effect) and potency (concentration of protective effect) of cytoprotective compounds.
Compound Profiling
Fresh powders (~5 mg) of newly synthesized compounds were dissolved to 10 mM in 100% DMSO using a Janus (Perkin Elmer) robotic workstation. Re-suspended compound stocks were subsequently arrayed into 384 well compound plates using automated pipetting. All other wells not receiving stock compound were filled with 10 pL of 100% DMSO using an automated plate filler (Multidrop Combi). An 1 1 point, 2-fold serial dilution was then performed using the robotic platform. Compound assay plates were covered with foil and stored at -20°C until use.
Each strain was handled according to standard protocols and cultured in media composed of CSM (complete synthetic media), YNB (yeast nitrogenous base), and a 2% (w/v) carbon source (either glucose, raffinose, or galactose). Single use frozen aliquots of each strain were generated by growing cells in CSM/glucose media to an Oϋboo of 0.6-0.8, concentrating the yeast to 12.5 Oϋboo units per 30 pl¬ ot CSM/glucose media supplemented with 20% glycerol, and freezing 30 pL aliquots at -80°C.
In a standard yeast assay, a single-use aliquot of cells was thawed on ice and diluted into CSM/glucose (5 ml_). Cultures were grown for 8 hours at 30°C. This pre-growth enables the yeast to exit the thaw and begin to grow without expressing aSyn or ApoE4. After 8 hours, cell density (Oϋboo) was determined and cultures diluted to an Oϋboo of 0.01 in CSM/raffinose for an overnight culture phase at 30°C. During this period, the active glucose repression of the GAL1 promoter was relieved; however, expression of the a-Syn/ApoE4 genes were not yet induced. After ~16 hours of growth, cultures attain an Oϋboo of 0.4-0.8 and were ready to apply to assay plates containing compound.
Compound profiling assays were executed in clear-bottom 384 well plates. First, compound plates were thawed at room temperature for 45’, centrifuged at 1 ,000xg for 1 minute, and the foil removed. Clear 384 well assay plates were then filled with 15 pL of CSM/galactose. Both compound and media-containing plates were arranged on the Janus workstation and a compound pin tool (384 x 100 nl_ slotted pins) used to deliver 100 nl_ of compounds to each well according to the well map of the compound plate. Based on the previous serial dilution, the final concentration of compound ranged from 33.3 pL to 12.5 nM. The pin tool was washed iteratively with both 50% DMSO and 100% ethanol between each assay plate. After delivering compound to each assay plate, the overnight CSM/raffinose aSyn or ApoE4 cultures were added at a 2X cell density (0.04 for aSyn and 0.08 for ApoE4) in CSM/galactose to achieve a final assay Oϋboo of 0.02 and 0.04 for aSyn and ApoE, respectively. The cultures (15 pL per well) were then dispensed to the compound-containing 384 well assay plates using an automated plate filler. Plates were incubated in a humidified 30°C incubator for 40 or 24 hours for aSyn and ApoE4, respectively. The Oϋboo oί each assay plate was then read with a microplate reader (e.g., Perkin Elmer Envision).
The efficacy and potency of compounds were calculated according to the following. Raw data (Oϋboo values) were first background corrected to account for Oϋboo contributed by the plate and media itself. The efficacy (percent above DMSO, herein referred to as“Emax”) was calculated according to the equation: (Experimental well - DMSO control well)/(DMSO control well)*100. For each individual compound with positive activity (>30% above DMSO - or 3 standard deviations from the DMSO negative control wells), the dose-response data were normalized to a scale of 0 - 1 00% to enable potency (herein referred to as“EC50”) determination. Normalized dose-response data was fit with a logistic regression curve using Spotfire (TIBCO), or similar curve-fitting software package. EC50 values were then reported along with EMax to provide both efficacy and potency measures for each analog and enable further compound design. As shown in Table 3, compounds of the invention are able to reduce the toxicity of the expressed alpha-synuclein and/or ApoE4 proteins.
Table 3: Yeast rescue data for examples 1 -155 showing that compounds of the invention were able to reduce toxicity in yeast strains expressing the human proteins a-synuclein and/or ApoE4.
Figure imgf000483_0001
Figure imgf000484_0001
Figure imgf000485_0001
Figure imgf000486_0001
Figure imgf000487_0002
Example 158: U20S transient overexpression induced cytotoxicity assay
U20S (Sigma-Aldrich), a human bone osteosarcoma epithelial cell line, is regularly maintained in McCoy’s 5A medium (ATCC) supplemented with 10% FBS (ThermoFisher) between passage 1 1 -21 and sub-cultured twice a week for the assay.
On the day of experiment, cells are about 80% confluence and trypsinized using 0.25% trypsin-EDTA (ThermoFisher Inc.) for 5 minutes at 37c. Based on a ratio of 2ug DNA/2e5 cells, required cells are spun down at 800 rpm for 5 minutes at room temperature. Cells are then re-suspended in SE solution (Lonza Inc.) at a density of 2e4 cells/mI. Nucleofection is performed using 4D-Nucleofector™ System (Lonza Inc.) under program code CM130. Cells are allowed to recover in the cuvette at room temperature for 10-15 minutes before further handling. Pre-warmed medium is added and cells suspension is thoroughly but gently mixed before plating. Cells are seeded at 2e4 cells/1 OOmI/well into 96 well PLD-coated white plate (Corning) using customized Viaflow program (Integra Biosciences). Serial dilution of drugs is carried out in DMSO. Drug solution is prepared at 6x fold, 20ul of which is added to cells 4 hours after
transfection. The final DMSO concentration is 0.3%. Microclimate lid (Labcyte) is strongly recommended to reduce evaporation and variation. Seventy-two hours post transfection, cells are lysed using CellTiter- Glow (Promega) and ATP content is determined using a luminescence plate reader (Perkin Elmer). %Maximum fold rescue at each concentration is calculated as follows:
Figure imgf000487_0001
FK506 (tacrolimus), a macrolide calcineurin inhibitor, is used as reference compound in the assay. FK506 has been shown to rescue aSyn toxicity in yeast models, and this activity has translated to rodent in vivo models of neurodegeneration.
% Rescue (normalized by max fold rescue of FK506) =(%Fold aSyn drug-100)*100/(%Max foldaSxn FK506- 100).
As shown in Table 4, the compounds of the invention were able to rescue human bone osteosarcoma epithelial U20S cells that were transiently overexpressing the toxic alpha-synuclein protein, reducing the level of induced cytotoxicity: Table 4.
% Rescue (normalized by FK506 max rescue)
Figure imgf000488_0001
Example 159: Stearoyl-CoA desaturase (SCD) is the target of 1 ,2,4-oxadiazoles
A. Materials and Methods
Strain Construction and OLE 1 Replacement with SCD 1 or SCD5
Strain GMYF was constructed from the ABC1 6/Green monster strain described in Suzuki et al. Nat. Methods 8(2):159-164, 201 1 . In this strain, YAP1 was deleted using a HIS3-MX6 cassette, and FLR1 was deleted using a NAT-MX6 cassette using standard methods. The knockout cassettes were PCR-amplified from plasmid templates (see, e.g., Bahler et al. Yeast 14(1 0):943-951 , 1 998; Longtine et al. Yeast 14(1 0):953-961 , 1 998) and transformed into yeast using lithium acetate-based transformation (Gietz et al. Methods Mol. Biol. 1205:1 -12, 2014). The yap1::his3 deletion strain was selected on media lacking histidine and flr1::NAT on plates containing 100 pg/mL nourseothricin. All strains were confirmed by diagnostic PCR. Strain W303 pdr1A pdr3A was constructed from W303-1 A (American Type Culture Collection (ATCC) 208352) by deleting PDR1 and PDR3 with kan-MX6 cassettes separately in MATa and MATa W303a isolates, mating, sporulating, and identifying double deletion haploids by tetrad dissection and identification of non-parental ditype tetrads. Strain W-erg3 was derived from W303 pdr1A pdr3A by deleting SA/Q2 with NAT-MX6, YAP1 with HIS3-MX6, and ERG3 with BleMX.
Strain ApoE-mga2A was generated by amplifying 1000 base pairs (bp) upstream and downstream of the MGA2 ORF in a strain in which MGA2 was deleted using a G418 (GENETICIN®) resistance cassette (kanMX) (Piotrowski et al. Proc. Natl. Acad. Sci. USA 1 12(12):E1490-1497, 2015) and transforming the resulting deletion cassette into the ApoE4 strain in the BY4741 (ATCC 201388) genetic background. The ApoE strain is described, for example, in International Patent Application Publication No. WO 2016/040794, which is incorporated herein by reference in its entirety.
The alpha-synuclein expression strain was made in the same manner as described in Su et al. Dis. Model Mech. 3(3-4):194-208, 2010, except that the alpha-synuclein construct lacked the green fluorescent protein (GFP) tag.
Strain ole1 (yeast ole1 deletion mutant) was constructed by deleting OLE1 with NAT-MX6 in BY4741 , amplifying the deletion cassette from the genomic DNA of the resulting strain with primers flanking the ORF by 1000 bp upstream and downstream, transforming the resulting deletion cassette into W303 pdr1A pdr3A , and plating transformants on YPD media containing G418 (200 pg/mL) and nourseothricin (100 pg/mL) with 0.01 % TWEEN®-20 and 0.5 mM oleic and palmitoleic acids.
To generate yeast strains expressing SCD1 or SCD5 as the sole desaturase, the human SCD1 and SCD5 genes were cloned from cDNAs (Harvard PlasmID database Clone ID HsCD00340237 for SCD1 and HsCD00342695 for SCD5) into yeast plasmid pRS316 (ATCC 77145) between the yeast TDH3 promoter and the CYC1 terminator. The coding sequence of yeast OLE1 was also cloned into this plasmid). These clones were then transformed into the ole1A strain and plated on CSM-Ura media (CSM lacking uracil) with 2% glucose (w/v) and independent colonies were isolated and amplified.
Compound Profiling Methods
All compound profiling experiments were performed using the same basic protocol. Different genetic backgrounds (e.g., gene deletions) or conditions (e.g., addition of oleic and palmitoleic acid) were replaced as indicated below.
Yeast were cultured using standard techniques in complete synthetic media (CSM) and yeast nitrogen base supplemented with 2% (w/v) carbon source (glucose, raffinose, or galactose) to regulate the expression of the toxic disease protein. An initial starter culture was inoculated in 3 ml_ CSM-Glucose media and incubated overnight in a 30°C shaker incubator (225 rpm). Saturated morning cultures were then diluted 1 :20 in fresh CSM-Raffinose media and grown for 6 h to an Oϋboo (optical density) of ~0.4- 0.8 at 30°C with shaking.
Compound stocks (10 mM in 100% DMSO) were arrayed into 384 round well, v-bottom polypropylene plates and diluted according to indicated dilution factors. Compound administration was performed in two separate steps. First, 15 mI_ of CSM-Galactose (induces expression of toxic protein) was dispensed into clear 384 well assay plates using a MULTIDROP™ Combi reagent dispenser. The diluted compound stock plates were then applied to the assay plates using an automated workstation (Perkin Elmer JANUS™) outfitted with a 384 pin tool containing slotted pins that deliver 100 nL of compound. The cultures described above were then diluted to a 2x concentration (0.03 and 0.08 for alpha-synuclein and ApoE, final Oϋboo of 0.015 and 0.04) in CSM-Galactose. For wild-type and
Ole1/SCD1/SCD5 plasmid-containing strains, the 2x cell density was 0.02. In all experiments, 15 pL culture was then dispensed into the pinned assay plate to achieve 30 pL of the 1 x Oϋboo culture and a top drug concentration of 33.3 pM. For 96-well assays (Figs. 1 A and 1 B), compound dilutions in DMSO were generated in 96 well plates and 1 pL was manually pipetted into 96 well clear bottom assay plates.
For experiments with oleic and palmitoleic acid supplementation (Figs. 2A, 2B, 4, and 5), TWEEN®-20 was first added to culture media at a concentration of 0.01 %. Oleic and palmitoleic acid were both then added at the indicated concentrations (0.08 to 0.5 mM) and mixed thoroughly prior to compound pinning or the addition of yeast.
For experiments using a plasmid-borne copy of Ole1 , SCD1 , or SCD5 (Figs. 3B, 6, and 7), media lacking uracil (SX-Ura, where X is glucose, raffinose, or galactose), was used for all steps of the compound profiling protocol to ensure its maintenance throughout the assay.
After yeast delivery, assay plates were incubated under humidified conditions at 30°C for 24 to 40 h. ApoE4 rescue experiments were stopped at 24 h, aSyn experiments at 40 h, Ole1 at 24 h, and SCD1/SCD5 at 40 h. The growth of yeast was monitored by reading the Oϋboo of each well using a microplate reader (Perkin Elmer EnVision™). Data were analyzed as follows. For model rescue experiments, raw data were processed by background subtracting and calculating a fold-change relative to DMSO control [(EXP-0.035)/(DMSO-0.035) - where 0.035 is the Oϋboo contributed by an empty well containing 30 pL of media alone]. For growth inhibition of wild-type cells, raw data were processed by background subtracting and converting values to a percent of the nontreated condition for that strain [(EXP-0.035)/(DMSO-0.035) x 100%]. Compound Sources
Compounds were sourced as follows: cycloheximide (Sigma Aldrich), A939572 (Abeam), CAY10566 (Abeam), MF-438 (Calbiochem), MK-8245 (Selleckchem), oleic acid (Sigma Aldrich), palmitoleic acid (Acros organics), mycophenolic acid (Sigma Aldrich), and tunicamycin (Cayman
Chemical).
Drug Resistant Mutant Selection
Strains GMYF and W-erg3 were grown to saturation in CSM-glucose, centrifuged, resuspended in phosphate-buffered Saline (PBS), and plated at a density of 107 cells/plate on solid 15cm petri dishes containing CSM with 2% galactose (w/v), 2% (w/v) agar, and 10 pM Compound 155, and incubated at 30°C. Resistant colonies were isolated after 5-7 days, re-streaked on the same media, and resistance reconfirmed. Cultures of validated strains were then inoculated for genomic DNA isolation using a YeaStar™ yeast genomic DNA kit (Zymo Research).
Libraries were prepared for sequencing using the ii!urnina NEXTERA™ library prep kit and sequenced via !i!umina HiSeq™ 2500 1 X50 bp (single end reads). Sequences were aligned to the S. cerevisiae reference genome (S288CCR64-1 -1 , Saccharomyces Genome Database (SGD)) using Burrows-Wheeler Aligner (BWA, see, e.g., Li et al. Bioinformatics 25:1754-1760, 2009; Li et al.
Bioinformatics 2010, Epub (PMID 20080505)). The BWA output SAI files were converted to SAM files using BWA. The SAM files were sorted using SAMtoo!s 1 .3.1 (Li et a!. Bioinformatics 25:2079-2079, 2009). Variants (single-nucleotide polymorphisms (SNPs), indeis) were identified using Freebayes (see, e.g., arXiv:1207.3907). Variant locations were summarized using snpEFF (Cingolani et a!. F/y (Austin) 6(2):80-92, 2012).
Quantitative Lipid Profiling
Overnight cultures of yeast strain W303 pdr1 pdr3A were diluted into CSM media with 2% (w/v) raffinose, Oϋboo 0.25, and grown for 4 h before resuspending at an Oϋboo of 0.2 in CSM media with 2% (w/v) galactose and adding Compound 95 or DMSO at the indicated concentrations. Cells were grown for the indicated timepoints before centrifugation, washing once in PBS, and freezing pellets. Lipids were extracted from pellets by resuspending the pellets in 600 pL methanol, 300 pL water, and 400 pL chloroform, followed by cell lysis by vortexing with glass beads for 1 min. Samples were then centrifuged at 10,000 x g for 10 min, and the bottom layer that formed (organic/lipids) was moved into a new tube and evaporated. Samples were then analyzed by LC/MS/MS using a Thermo Scientific Q Exactive™
Orbitrap™ coupled to a Dionex UltiMate® 3000 ultra-high performance liquid chromatography system, following the method described in Tafesse et al. PLoS Pathog. 11 (10): e1005188, 2015.
B. Results
The effect of 1 ,2,4-oxiadiazoles on cell growth was assessed in a control condition and in a yeast model for ApoE4 toxicity (see International Patent Application Publication No. WO 2016/040794). The control condition was growth of the ApoE4 strain under non-inducing conditions using raffinose as the carbon source. The 1 ,2,4-oxadiazoles exhibited a bell-shaped rescue curve in the ApoE4 model (Fig. 1 A, top panel). At higher concentrations, these compounds inhibited the growth in the control condition (Fig.
1 B, bottom panel). The potency of model rescue correlated well with the potency of growth inhibition across the entire series of 1 ,2,4-oxadiazoles tested (Fig. 1 B). These relationships indicate that the growth inhibition arises from an“on-target” activity, i.e., over activation or inhibition of a target that results in slowed growth.
Drug-resistant mutants can be used to identify the target of the compounds, for example, by preventing or reducing drug binding, and therefore allowing growth under inhibitory doses of 1 ,2,4- oxadiazole concentrations. Twenty drug-resistant mutants were isolated, and the mutants were subjected to whole-genome sequencing in order to identify genetic lesions associated with the drug resistance. Surprisingly, all mutations identified in the drug resistant mutants localized to OLE1 (YGL055W), the sole stearoyl-CoA desaturase (SCD; also referred to as A9-desaturase) in yeast (Fig. 9). The drug resistant mutants specifically conferred resistance to 1 ,2,4-oxadiazoles, but were not cross-resistant to other toxic compounds. The ole1 mutations identified included indels and substitution mutations, including A305V,
L1 18D, S190T, A305T, 1301 N, A91 T, S190T, P123T, and E1 18Q. These mutations are relative to the wild-type OLE1 sequence provided below.
MPTSGTTIELIDDQFPKDDSASSGIVDEVDLTEANILATGLNKKAPRIVNGFGSLMGSKE
MVSVEFDKKGNEKKSNLDRLLEKDNQEKEEAKTKIHISEQPWTLNNWHQHLNWLNMVLVC
GMPMIGWYFALSGKVPLHLNVFLFSVFYYAVGGVSITAGYHRLWSHRSYSAHWPLRLFYA
IFGCASVEGSAKWWGHSHRIHHRYTDTLRDPYDARRGLWYSHMGWMLLKPNPKYKARADI
TDMTDDWTIRFQHRHYILLMLLTAFVIPTLICGYFFNDYMGGLIYAGFIRVFVIQQATFC
INSLAHYIGTQPFDDRRTPRDNWITAIVTFGEGYHNFHHEFPTDYRNAIKWYQYDPTKVI
IYLTSLVGLAYDLKKFSQNAIEEALIQQEQKKINKKKAKINWGPVLTDLPMWDKQTFLAK
SKENKGLVIISGIVHDVSGYISEHPGGETLIKTALGKDATKAFSGGVYRHSNAAQNVLAD
MRVAVIKESKNSAIRMASKRGEIYETGKFF (SEQ ID NO: 1 )
These data strongly suggest that Ole1 is the target of 1 ,2,4-oxadiazoles. Additionally, addition of exogenous oleic acid reversed both growth inhibition of wild-type cells and rescue of toxicity in a yeast disease model of alpha-synuclein toxicity (Figs. 2A and 2B, respectively). Likewise, these effects were specific for 1 ,2,4-oxadiazoles, but not other toxic compounds.
Drug-resistant Ole1 mutations reduced 1 ,2,4-oxadiazole-induced growth inhibition in control conditions (Fig. 3A). The same mutations also increased the EC50 (concentration that gives half-maximal response) in the context of the alpha-synuclein model, which is consistent with reduced binding to the target. These shifts in does response were specific for 1 ,2,4-oxadiazoles. These data further support that Ole1/SCD is the target for both growth inhibition and rescue of toxicity in disease models.
The OLE1 gene is essential in Saccharomyces cerevisiae. However, strains deleted for OLE1 (ole1A) are viable if their growth media is supplemented with oleic/palmitoleic acid. The ole1A strain supplemented with exogenous fatty acids was fully resistant to 1 ,2,4-oxadiazoles (Fig. 4). In other words, in the absence of the target, Ole1 , the 1 ,2,4-oxadiazoles do not have growth inhibition activity.
Independently, a chemical genetics approach identified MGA2, the transcription factor that regulates Ole1 . Genetic deletion of MGA2 (mga2A) phenocopied the effects of 1 ,2,4-oxadiazoles (Fig. 5). mga2A cells have reduced Ole1 levels, which itself rescues toxicity in the yeast disease models (e.g., the ApoE4 model). Supplementation of the growth media with oleic acid reversed this effect, similar to the results described above. Consistent with these data, treatment of yeast cells with the 1 ,2,4-oxadiazole
Compound 95 inhibited lipid desaturation (Figs. 8A-8D). Overall, these data provide still further evidence that Ole1/SCD is the target of 1 ,2,4-oxadiazoles.
Humanized yeast strains expressing the human SCD proteins SCD1 or SCD5 were generated by genetic deletion of OLE1 and expressing human SCD1 or SCD5 on a plasmid. Yeast expressing OLE1 were resistant to known SCD1/SCD5 inhibitors such as A939572, CAY10566, MF-438, and MK-8245 (Fig. 6), suggesting that they do not target the yeast enzyme. In marked contrast, in the SCD1 and SCD5 humanized strains, the known SCD1/SCD5 inhibitors were extremely potent, with low nanomolar half- maximal inhibitory concentration (IC50) values (Fig. 6).
The effect of 1 ,2,4-oxadiazoles was also evaluated in both of the humanized SCD1 and SCD5 models. 1 ,2,4-oxadiazoles inhibited the growth of the SCD1 and/or SCD1 yeast strains, and differences in the structure-activity relationship (SAR) between the three SCD proteins was observed (Fig. 7). Some compounds inhibited the growth of both the SCD1 and the SCD5 strains. Other compounds appeared to target only the yeast enzyme. Out of a total of 250 1 ,2,4-oxadiazoles tested, approximately 50% exhibited activity against the human enzymes. The divergent SAR provides additional strong evidence for SCD being the target of 1 ,2,4-oxadiazoles.
Finally, treatment of yeast cells with the 1 ,2,4-oxadiazole Compound 95 inhibited lipid desaturation (Figs. 8A-8D), providing additional confimatory evidence that SCD is the target of 1 ,2,4- oxadiazoles.
Taken together, these data demonstrate that Ole1/SCD is the target of 1 ,2,4-oxadiazoles, and that these compounds inhibit Ole1/SCD.
Example 160. Inhibition of Ole1, SDC1, and SCD5 by Compounds of the Invention
Using the methods described above, the inhibition of Ole1 , SCD1 , and SCD5 was tested for compounds of the invention. The results are shown in Table 5.
Table 5. Inhibition of Ole1 , SCD1 , and SCD5 by Compounds of the Invention
Figure imgf000492_0001
Figure imgf000493_0001
Figure imgf000494_0001
Figure imgf000495_0001
Figure imgf000496_0001
Figure imgf000497_0001
Figure imgf000498_0001
Figure imgf000499_0001
Figure imgf000500_0001
Figure imgf000501_0001
Figure imgf000502_0001
Figure imgf000503_0001
Figure imgf000504_0001
Figure imgf000505_0001
Figure imgf000506_0001
Figure imgf000507_0001
Table 6. Inhibition of SCD1 and SCD5 by Compounds of the Invention
Figure imgf000507_0002
Figure imgf000508_0001
Figure imgf000509_0001
Figure imgf000510_0001
Table 7. Inhibition of SCD1 and SCD5 by Compounds of the Invention
Figure imgf000510_0002
Figure imgf000511_0001
Figure imgf000512_0001
Figure imgf000513_0001
Other Embodiments
While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.
Other embodiments are in the claims.

Claims

What is claimed is: CLAIMS
1 . A compound, or pharmaceutically acceptable salt thereof, having the structure of any one of compounds 967-1 195 in Table 2B.
2. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable excipient.
3. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 or a pharmaceutical composition of claim 2.
4. A method of inhibiting toxicity in a cell related to a protein, the method comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 or a pharmaceutical composition of claim 2.
5. The method of claim 4, wherein the toxicity is a-synuclein-related toxicity.
6. The method of claim 4, wherein the toxicity is ApoE4-related toxicity.
7. The method of any one of claims 4 to 6, wherein the cell is a mammalian neural cell.
8. A method of treating a stearoyl-CoA desaturase (SCD)-associated disorder in a subject in need thereof, the method comprising administering an effective amount of a compound, or
pharmaceutically acceptable salt thereof, of claim 1 or a pharmaceutical composition of claim 2.
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