WO2022204150A1 - Compounds and compositions for treating cns disorders - Google Patents

Compounds and compositions for treating cns disorders Download PDF

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Publication number
WO2022204150A1
WO2022204150A1 PCT/US2022/021351 US2022021351W WO2022204150A1 WO 2022204150 A1 WO2022204150 A1 WO 2022204150A1 US 2022021351 W US2022021351 W US 2022021351W WO 2022204150 A1 WO2022204150 A1 WO 2022204150A1
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Prior art keywords
compound
optionally substituted
mmol
alkyl
independently
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PCT/US2022/021351
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French (fr)
Inventor
Kerry L. Spear
Douglas Burdi
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Blue Oak Pharmaceuticals, Inc.
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Publication of WO2022204150A1 publication Critical patent/WO2022204150A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems

Definitions

  • TAAR1 agonists such as p-Octopamine, ⁇ -PEA, p-Tyramine, and T1AM
  • TAAR1 is an important target in neurology and/or psychiatry.
  • T1AM can also interact with other TAAR subtypes (particularly TAAR5), ⁇ 2A- and ⁇ -adrenergic receptors, serotonin 1A receptor (5HT1A), TRM8 calcium channels, and membrane amine transporters like dopamine transporter (DAT), norepinephrine transporter (NET), and vesicular monoamine transporter (VMAT).
  • DAT dopamine transporter
  • NET norepinephrine transporter
  • VMAT vesicular monoamine transporter
  • the compound may be encompassed by Formula (I): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently), X2 or X3 each is independently C(R1)(R2), O, N(R3), S, CO, SO, or SO 2 ; X4 is C(R4) or N; X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein optionally R5a or R5b is attached to any atom on ring A and form a cyclic group, and optionally R5a or R5b is attached to X1 to form a cyclic group; R1, R2, R3, R4, R5a, or R5b each is independently hydrogen, halo, cyano, (C1-C10)alkyl optionally substituted with one or more R7, (C2-C10)alkenyl optionally substituted with one or more R7, (C3-C10)cycloalky
  • the compounds may be anyone of Compounds 1-206.
  • the present disclosure also provides a method of activating TAAR1 in a subject in need thereof, comprising administering to said subject an effective amount of the compounds of the present disclosure or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition comprising the compounds of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure further provides a method of treating, preventing, or managing a CNS disorder in a subject in need thereof, comprising administering to said subject an effective amount of the compounds of the present disclosure or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition comprising the compounds of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the CNS disorder is a neurological or psychiatric disorder.
  • the CNS disorder is psychosis, geriatric psychosis, Alzheimer’s-related psychosis, Parkinson’s related psychosis, age-related psychosis or schizophrenia.
  • the CNS disorder is dementia-related agitation, Alzheimer’s agitation, paranoia and mania.
  • the CNS disorder is affective disorders.
  • the CNS disorder is depression or dysthymia.
  • the CNS disorder is bipolar depression, unipolar depression, major depressive disorder, treatment-resistant depression, suicidal behavior disorder, apathy or anhedonia.
  • CNS drug discovery differs from most other therapeutic areas because of the complex and multigenic nature of most psychiatric and neurological disorders.
  • therapies that (i) have a rapid onset of action to treat the CNS disorder, (ii) have efficacy in achieving and sustaining long term remission, (iii) have improved safety and a more tolerable side effect profile.
  • Applicant has used multiple and complementary assays to drive therapeutic drug discovery.
  • the compounds of the present disclosure are bicyclic or multicyclic small molecule compounds described below.
  • the molecular weight (MW) of the compound may not be more than 500 g/mol. In some embodiments, the molecular weight (MW) of the compound may not be more than 300 g/mol. In some embodiments, the compound has low lipophilicity. For example, the logP of the compound may not be more than 3. In some embodiments, the hydrogen bond donor (HBD) of the compound may not be more than 3. In some embodiments, the hydrogen bond acceptor (HBA) of the compound may not be more than 3. [0011] Unless otherwise stated, structures presented herein can include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center.
  • the compounds of the present disclosure have a general structure of Formula (I): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently), X2 or X3 each is independently C(R1)(R2), O, N(R3), S, CO, SO, or SO 2 ; X4 is C(R4) or N; X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein optionally R5a or R5b may be attached to any atom on ring A and form a cyclic group, and optionally R5a or R5b may be attached to X1 to form a cyclic group; R1, R2, R3, R4, R5a, or R5b each is independently hydrogen, halo, cyano, (C1-C10)alkyl optionally substituted with one or more R7, (C2-C10)
  • Ring A and the cyclic structure attached to Ring A is referred to as the bicyclic core or bicyclic core structure.
  • ring A is an aryl group.
  • ring A is an optionally substituted phenyl group.
  • ring A is an optionally substituted 5-7 membered heteroaryl group, comprising at least one heteroatom selected from the group consisting of S, N and O.
  • ring A is an optionally substituted thiophene group.
  • ring A is an optionally substituted pyridine group.
  • ring A is an optionally substituted furan group.
  • R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH 3), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3).
  • R5a or R5b is attached to any atom on ring A and form a 5-7 membered cyclic group.
  • R12 or R13 is attached to X1, X2, X3, X4, R1, R2, R3, R4, R11 or any atom on ring A and form a 5-7 membered heterocycle. In some embodiments, R12 or R13 is attached to X1 or X4 and form a 5-7 membered heterocycle. [0022] In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • X1 and X2 are independently C(R1)(R2), wherein R1 and R2 are independently optionally substituted alkyl or alkenyl, wherein two vicinal R1 or R2 substituents together with the atom(s) to which they are attached form an optionally substituted 6-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring;
  • X3 is independently C(R1’)(R2’), O, N(R3), S, CO, SO, or SO 2 , wherein each R1’, R2’ and R3 are independently optionally substituted H, alkyl, halogen, hydroxyl, ether, CN, amine, or CF3;
  • X4 is CH;
  • X5 is C(R5a)(R5b), wherein each R5a and R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino
  • Non-limiting examples of the compounds include Compounds 16, 91, 92, 93, or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of compounds encompassed by Formula (I) include Compounds 1-138, 140-206, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (II): a tautomer or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, Y3 or Y4 each is independently N or CR11, X1 (when n>1, each X1 independently), X2 or X3 each is independently C(R1)(R2), O, N(R3), S, CO, SO, or SO 2 , X4 is C(R4) or N, X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein optionally R5a or R5b may be attached to Y4 to form a cyclic group, R1, R2, R3, R4, R5a, or R5b each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroary
  • R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH 3 ), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3).
  • R5a or R5b is attached to Y4 and form a 5-6 membered cyclic group.
  • R12 or R13 is attached to X1, X2, X3, X4, R1, R2, R3, R4, R11, Y1, Y2, Y3 or Y4 and form a 5-7 membered heterocycle. In some embodiments, R12 or R13 is attached to Y4, X1, or X4 and form a 5-7 membered heterocycle.
  • each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3.
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • Y1, Y2, Y3, Y4, and X4 are carbons
  • R13 is CH2CH2 and is connected to Y4 to form a 7-membered heterocycle
  • X1, X2 and X3 are independently O or C(R1)(R2)
  • Non-limiting examples of compounds encompassed by Formula (II) include Compounds 1-15, 17-25, 27-88, 90, 94-123, 166-205, or a pharmaceutically acceptable salt thereof.
  • compounds encompassed by Formula (II) include Compounds 10-13, 22-25, 69-70, 72-75, 83-88, 114-115, 166, 168, 169, 171-173, 176-205, a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (II-1): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), O, or N(R3), X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein optionally R5a or R5b may be attached to any atom on the aryl ring and form a cyclic group, R1, R2, R3, R5a, R5b, R21 or R22 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine
  • R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH 3 ), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3).
  • each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3.
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • Non-limiting examples of compounds encompassed by Formula (II-1) include Compounds 1-11, 21-25, 47-64, 66, 68-78, 84-85, 110-115, 174, 175, 184, or a pharmaceutically acceptable salt thereof.
  • compounds encompassed by Formula (II-1) include Compounds 10-11, 21, 23-24, 69-70, 72-75, 84-85, 114-115, 184, or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3,
  • Non- limiting examples of the compounds include Compounds 11, 23, 84-85, or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2)
  • X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3
  • each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl,
  • Non- limiting examples of the compounds include Compound 11, or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl,
  • Non-limiting examples of the compounds include Compounds 23, 85 or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl
  • Non-limiting examples of the compounds include Compound 84, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (II-2): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), X5 (when m>1, each X5 independently) is C(R5a)(R5b), R1, R2, R5a, R5b, R21, or R22 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optional
  • R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH 3 ), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3).
  • each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3.
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • Non-limiting examples of compounds encompassed by Formula (II-2) include Compounds 12, 13, 15, 17, 18, 79-83, 86, 90, 116-119, 166-170, 173, 178, 179, 181, 183, 186, 187, 189, 191, 193, 197, 201, 203, 205, or a pharmaceutically acceptable salt thereof.
  • compounds encompassed by Formula (II-2) include Compounds 12, 13, 17, 18, 83, 86, 90, 166, 168, 169, 173, 178, 179, 181, 183, 186, 187, 191, 193, 197, 199, 201, 203, 205, or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3,
  • Non- limiting examples of the compounds include Compounds 12, 13, 15, 17, 18, 83, 166, 168, 169, 173, 178, 179, 181, 183, 186, 191, 193, 197, 199, 201, 203, 205, or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2);
  • X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3;
  • each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl;
  • Non- limiting examples of the compounds include Compounds 13, 166, 201, or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl),
  • Non-limiting examples of the compounds include Compounds 12, or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2);
  • X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3;
  • each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl,
  • Non- limiting examples of the compounds include Compounds 15, 17, 18, 83, 168, 169, 173, 178, 179, 181, 183, 186, 191, 193, 197, 199, 201, 203, 205, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (II-3): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X2 (when n>1, each X2 independently) is C(R1)(R2), X5 (when m>1, each X5 independently) is C(R5a)(R5b), R1, R2, R5a, R5b, R21, or R22 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optionally has an R11 substituent, wherein each R11 is H, optionally substituted alky
  • R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH 3 ), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3).
  • each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3.
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • Non-limiting examples of compounds encompassed by Formula (II-3) include Compounds 19, 20, 87, 88, 170, 171, 172, 176, 177, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof.
  • compounds encompassed by Formula (II-3) include Compounds 19, 20, 87, 88, 171, 172, 176, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof.
  • X2 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3,
  • Non-limiting examples of the compounds include Compounds 19, 20, 87, 88, 171, 172, 176, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof.
  • X2 is C(R1)(R2);
  • X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3;
  • each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl;
  • X2 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3,
  • X2 is C(R1)(R2);
  • X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3;
  • each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl;
  • Non- limiting examples of the compounds include Compounds 19, 20, 87, 171, 172, 176, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof.
  • X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3,
  • Non-limiting examples of the compounds include Compound 88 or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (II-4): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) each is independently C(R1)(R2), O, N(R3), S, CO, SO, or SO2, X2 is C(R1)(R2), CO, R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optionally has an R11 substituent
  • each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3.
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • Non-limiting examples of compounds encompassed by Formula (II-4) include Compounds 27-46, 94-109, or a pharmaceutically acceptable salt thereof.
  • X1 and X2 are both C(R1)(R2); wherein each R1, R2, and R3 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the
  • X1 and X2 are both C(R1)(R2); wherein each R1, R2, and R3 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the
  • X1 and X2 are both C(R1)(R2); wherein each R1, R2, and R3 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the
  • X1 and X2 are both C(R1)(R2); wherein each R1, R2, and R3 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the
  • the compounds of the present disclosure have a general structure of Formula (II-5): a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R21, R22, R23 or R24 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optionally has an R11 substituent, wherein each R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalky
  • R11 is halogen (such as F or Cl), alkoxy (such as OCH 3 ), a methyl group substituted with amine (such as CH2NH2), or a methyl group substituted with halogen(s) (such as CF3).
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • m 2.
  • Non-limiting examples of compounds encompassed by Formula (II-5) include Compound 14, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (III): a tautomer, or a pharmaceutically acceptable salt thereof, wherein Z1, Z2, or Z3 each independently is CR11, N, O, or S, Z4 or Z5 each independently is C or N, X1 (when n>1, each X1 independently), X2 or X3 each independently is C(R1)(R2), O, N(R3), S, CO, SO, or SO 2 , R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R11 is H, optionally substituted alkyl (including but not limited to lower alky
  • [0078] in Formula (III) is a heteroaromatic ring.
  • Z1, Z2 and Z3 can all be CR11.
  • Z4 and Z5 are both C, at least one of Z1, Z2 or Z3 is not CR11.
  • X2 is C(R1)(R2).
  • R12 or R13 is attached to Z3 or X1 and form a 5-7 membered heterocycle.
  • R12 or R13 is an alkyl and is attached to X1 and form a 5-7 membered heterocycle.
  • R12 or R13 is H or a lower alkyl.
  • both R12 and R13 are H.
  • Non-limiting examples of compounds encompassed by Formula (III) include Compounds 124-165, or a pharmaceutically acceptable salt thereof.
  • the compounds encompassed by Formula (III) include Compounds 124-138, or a pharmaceutically acceptable salt thereof.
  • the compounds encompassed by Formula (III) include Compounds 140-148 or 154-165, or a pharmaceutically acceptable salt thereof.
  • the compounds encompassed by Formula (III) include Compounds 149-150, or a pharmaceutically acceptable salt thereof.
  • the compounds encompassed by Formula (III) include Compounds 151-152, or a pharmaceutically acceptable salt thereof.
  • the compounds encompassed by Formula (III) include Compounds 153 or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (III-1): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), O, N(R3), S, CO, SO, or SO 2 , X2 or X3 each independently is C(R1)(R2), O, N(R3), CO, SO, or SO 2 , R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R12 or R13 each is independently H or optionally substituted alkyl (including but
  • R12 or R13 is an alkyl and is attached to X1 and form a 5-7 membered heterocycle.
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • Non-limiting examples of compounds encompassed by Formula (III-1) include Compounds 124-127, 130-134, 146-148, 154-159 or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (III-2): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), O, N(R3), S, CO, SO, or SO 2 , X2 or X3 each independently is C(R1)(R2), O, N(R3), CO, SO, or SO 2 , R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R12 or R13 each is independently H or optionally substituted alkyl (including but
  • R12 or R13 is an alkyl and is attached to X1 and form a 5-7 membered heterocycle.
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • Non-limiting examples of compounds encompassed by Formula (III-2) include Compounds 128-129, 135, 138, 143-145, 160-162, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (III-3): a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), O, N(R3), S, CO, SO, or SO 2 , X2 or X3 each independently is C(R1)(R2), O, N(R3), CO, SO, or SO 2 , R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R12 or R13 each is independently H or optionally substituted alkyl (including but
  • R12 or R13 is an alkyl and is attached to X1 and form a 5-7 membered heterocycle.
  • R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H.
  • Non-limiting examples of compounds encompassed by Formula (III-3) include Compounds 136-137, 140-142, 149-159, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure have a general structure of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein Z is C(R1)(R2), O, N(R3), S, CO, SO, or SO 2 , X5 (when m>1, each X5 independently) is C(R5a)(R5b), R1, R2, R3, R5a or R5b each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino al
  • R11 is halogen (such as F or Cl), alkoxy (such as OCH 3 ), a methyl group substituted with amine (such as CH2NH2), or a methyl group substituted with halogen(s) (such as CF3).
  • R12 is H or a lower alkyl
  • R13 is a lower alkyl
  • R13 is attached to any position on the aromatic rings and form a 5-7 membered heterocycle.
  • R12 or R13 is H or a lower alkyl.
  • both R12 and R13 are H.
  • Z is C(R1)(R2), O, N(R3), S, CO, SO, or SO 2
  • X5 is C(R5a)(R5b), wherein each R1, R2, R3, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3;
  • R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl,
  • Non-limiting examples of the compounds include Compounds 16, 91, 92, 93, or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of compounds encompassed by Formula (IV) include Compounds 16, 26, 89, 91, 92, 93, or a pharmaceutically acceptable salt thereof. II. FORMULATIONS [0109]
  • compositions are administered to humans, human patients or subjects.
  • the phrase “active ingredient” generally refers to the conjugate as described herein.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation.
  • compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • a pharmaceutical composition in accordance with the disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • compositions in accordance with the disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100%, e.g., between .5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.
  • the compounds of the present disclosure can be formulated using one or more excipients to: (1) increase stability; (2) permit the sustained or delayed release; (3) alter the biodistribution; (4) alter the release profile of the compounds in vivo.
  • Non-limiting examples of the excipients include any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, and preservatives.
  • Excipients of the present disclosure may also include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, hyaluronidase, nanoparticle mimics and combinations thereof. Accordingly, the formulations of the disclosure may include one or more excipients, each in an amount that together increases the stability of the compounds.
  • compositions may comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington s The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure.
  • an excipient is approved for use in humans and for veterinary use.
  • an excipient is approved by United States Food and Drug Administration.
  • an excipient is pharmaceutical grade.
  • an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia.
  • Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical compositions.
  • Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and/or combinations thereof.
  • Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, quaternary ammonium compounds, and/or combinations thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • crospovidone cross
  • Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and VEEGUM® [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • polyoxyethylene monostearate [MYRJ®45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Kolliphor® (SOLUTOL®)), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. CREMOPHOR®), polyoxyethylene ethers, (e.g.
  • polyoxyethylene lauryl ether [BRIJ®30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLUORINC®F 68, POLOXAMER®188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or combinations thereof.
  • Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g.
  • natural and synthetic gums e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghat
  • Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives.
  • Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and/or sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid monohydrate disodium edetate
  • dipotassium edetate dipotassium edetate
  • edetic acid fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate.
  • antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal.
  • Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid.
  • Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol.
  • Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid.
  • preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS®, PHENONIP®, methylparaben, GERMALL®115, GERMABEN®II, NEOLONETM, KATHONTM, and/or EUXYL®.
  • Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, is
  • Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof.
  • oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana,
  • oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof.
  • Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be present in the composition, according to the judgment of the formulator.
  • the compounds of the present disclosure are used to modulate such as activate TAAR1.
  • the compounds of the present disclosure can be used as a TAAR1 agonist.
  • the compounds of the present disclosure may also modulate the serotonin 1A receptor (5HT1A), the serotonin 2A receptor (5HT2A), the serotonin 2C receptor (5HT2C), the serotonin receptor 6 (5HT6), or the serotonin receptor 7 (5HT7).
  • the compounds may be a 5HT1A agonist, a 5HT2A antagonist, a 5HT2C agonist, a 5HT6 antagonist, or a 5HT7 antagonist.
  • the compounds may be used to activate 5HT1A.
  • the compounds may be used to inhibit 5HT2A. In some embodiments, the compounds may be used to inhibit 5HT2C. In some embodiments, the compound may be used to activate 5HT2C. [0128]
  • the present disclosure also provides methods of administering a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof, as described herein, to a subject.
  • the subject may have a CNS disorder, may be suspected of having a CNS disorder, or may have a predisposition to a CNS disorder.
  • the CNS disorder may be related to the trace amine associated receptors (TAAR), such as TAAR1.
  • TAAR trace amine associated receptors
  • the CNS disorder may also be related to the serotonin receptors (5HT), such as 5HT1A, 5HT2A, 5HT2C, 5HT6 or 5HT7.
  • 5HT serotonin receptors
  • the CNS disorder is not limited to the CNS disorders related to TAAR or 5HT.
  • the CNS disorder is not related to TAAR or 5HT.
  • the compounds or pharmaceutically acceptable salts thereof are administered to the subject as a treatment for a CNS disorder and maintenance in all patients (including both the acute phase of the CNS disorder and as a maintenance therapeutic for the CNS disorder).
  • CNS disorders affect a wide range of the population with differing severity.
  • Neurological and psychiatric disorders that can be treated with the compounds of the present disclosure include but not limited to psychosis (such as geriatric psychosis, Alzheimer’s- related psychosis, Parkinson’s related psychosis, age-related psychosis, or schizophrenia), agitation (such as dementia-related agitation, Alzheimer’s agitation, paranoia, or mania), depression (such as treatment-resistant depression (TRD), major depressive disorder (MDD), bipolar depression, unipolar depression, suicidal behavior disorder, apathy, anhedonia, or depression associated with another disease or disorder), dysthymia, anxiety, cognitive impairment, schizophrenia, bipolar disorder, obsessive compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), addiction, social disorder, attention deficit hyperactivity disorder (ADHD), neuropsychiatric symptoms such as apathy, aggression, agitation, poor impulse control, and sleep disruptions in neurological disorders such as Alzheimer's and Parkinson's diseases.
  • psychosis such as geria
  • the compounds of the present disclosure are used to treat one or more symptoms of CNS disorders, such as but not limited to depression (e.g., major depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive deficit; sleep related disorder (e.g., sleep apnea, insomnia, narcolepsy, cataplexy) including those sleep disorders which are produced by psychiatric conditions; chronic fatigue syndrome; anxieties (e.g., general anxiety disorder, social anxiety disorder, panic disorder); obsessive compulsive disorder; post-menopausal vasomotor symptoms (e.g., hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis); manic disorder; dysthymic disorder; obesity; acute suicidality or suicide ideation; suicidal
  • Depression or Major depressive disorder (MDD)
  • MDD Major depressive disorder
  • depression is a CNS disorder characterized by at least 2 weeks of low mood across most situations, often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause.
  • Depression may be unipolar or bipolar.
  • bipolar depression For patients who have been diagnosed with bipolar disorder and have an episode of mania or markedly elevated mood, the depression episode is called bipolar depression.
  • Depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state.
  • Symptoms of depression include anhedonia, depressed mood (sadness), poor concentration, hopelessness, poor self-esteem, insomnia, fatigue, appetite disturbances, generalized symptoms of pain, excessive guilt and thoughts of suicide.
  • Bipolar disorder is a severe, recurrent, lifelong psychiatric illness that affects a lot of adult Americans and imposes significant economic burden to patients, families, and society.
  • existing medications e.g. lithium
  • the treatment of bipolar depression (BPD) relies on repurposing older classes of antipsychotic and anticonvulsant drugs. These older drugs have limited efficacy in treating the symptoms of BPD and many are concomitant with adverse side effects and reduced tolerability. Consequently, nonadherence to medication is common and BPD is associated with high morbidity, substance abuse, and a high rate of patient suicide.
  • Older medications such as lithium similarly have variable and modest efficacy in the treatment of depression and relapse prevention.
  • Another limitation of existing mood stabilizing drugs is that they are associated with a considerable lag of onset. Only a fraction of patients meet response criteria by the end of the first week of treatment, and continued use is associated with many undesirable side effects. Slow therapeutic onset contributes to the life disruptions experienced by individuals, and the delay in treating suicidal behavior is an issue of particular concern for this already vulnerable population.
  • the present disclosure provides methods of treating depression (such as but not limited to bipolar depression, unipolar depression, major depressive disorder, or treatment- resistant depression) or maintenance therapy of depression (such as but not limited to bipolar depression, unipolar depression, major depressive disorder, or treatment-resistant depression), wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.
  • depression such as but not limited to bipolar depression, unipolar depression, major depressive disorder, or treatment-resistant depression
  • maintenance therapy of depression such as but not limited to bipolar depression, unipolar depression, major depressive disorder, or treatment-resistant depression
  • Psychosis is a group of disorders including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (e.g., phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychotic disorders, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post- traumatic stress syndrome), including both positive, negative, and cognitive symptoms of schizophrenia and other psychoses [0137] Schizophrenia is a psychopathic disorder marked by characteristics such as
  • Characteristic psychotic symptoms are disorders of thought content (e.g., multiple, fragmentary, incoherent, implausible or simply delusional contents, or ideas of doctrine) and of mentality (e.g., loss of association, flight of imagination, incoherence up to incomprehensibility), as well as disorders of perceptibility (e.g., hallucinations), emotions (e.g., superficial or inadequate emotions), self-perceptions, intentions, impulses, and/or inter-human relationships, and psychomotoric disorders (e.g., catatonia).
  • Schizophrenia is classified into subgroups: the paranoid type, the disorganized type, the catatonic type, and the undifferentiated type.
  • the paranoid subgroup is characterized by delusions and hallucinations and absence of thought disorder, disorganized behavior, and affective flattening. Thought disorder and flat affect are present together in the disorganized type, also named “hebephrenic schizophrenia.” Prominent psychomotor disturbances are evident in the catatonic type, wherein symptoms may include catatonic stupor and waxy flexibility. In the undifferentiated type, psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met. [0139] The symptoms of schizophrenia include three broad categories: positive, negative and cognitive symptoms. Positive symptoms are those which represent an “excess” of normal experiences, such as hallucinations and delusions.
  • Negative symptoms are those where the patient suffers from a lack of normal experiences, such as anhedonia and lack of social interaction.
  • the cognitive symptoms relate to cognitive impairment in schizophrenics, such as lack of sustained attention and deficits in decision making.
  • the present disclosure provides methods of treating psychosis (such as schizophrenia) or maintenance therapy of psychosis (such as schizophrenia), wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.
  • Cognitive disorders include dementia (semantic dementia, frontotemporal dementia, dementia with depressive features, persisting, subcortical dementia, dementia with Lewy Bodies, Parkinsonism-ALS Dementia Complex, and dementia associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems, stroke, HIV disease, Parkinson's disease, Huntington's disease, Down syndrome, Pick's disease, Creutzfeldt- Jacob disease, perinatal hypoxia, or substance abuse), delirium, amnestic disorders or age related cognitive decline.
  • Cognitive impairment includes a decline in cognitive functions or cognitive domains, e.g., working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving (e.g., executive function, speed of processing and/or social cognition).
  • cognitive impairment may indicate deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulties in expressing thoughts, and/or difficulties in integrating thoughts, feelings and behavior, or difficulties in extinction of irrelevant thoughts.
  • the present disclosure provides methods of treating cognitive disorders and/or cognitive impairment or maintenance therapy of cognitive disorders and/or cognitive impairment, wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.
  • Anxiety disorders are disorders characterized by fear, worry, and uneasiness, usually generalized and unfocused as an overreaction to a situation. Anxiety disorders differ in the situations or types of objects that induce fear, anxiety, or avoidance behavior, and the associated cognitive ideation. Anxiety differs from fear in that anxiety is an emotional response to a perceived future threat while fear is associated with a perceived or real immediate threat. They also differ in the content of the associated thoughts or beliefs.
  • Anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, paranoia, post- traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition.
  • the present disclosure provides methods of treating anxiety or maintenance therapy of anxiety, wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.
  • Administration [0147]
  • the compounds of the present disclosure may be administered by any route which results in a therapeutically effective outcome.
  • compositions may be administered in a way which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier.
  • the compounds are administered orally.
  • the oral formulations contain an effective amount of compounds in a pharmaceutical carrier appropriate for administration to an individual in need thereof.
  • Dosing [0149] The present disclosure provides methods comprising administering compounds as described herein to a subject in need thereof.
  • Compounds as described herein may be administered to a subject using any amount and any route of administration effective for preventing or treating or imaging a disease, disorder, and/or condition (e.g., a disease, disorder, and/or condition relating to working memory deficits).
  • compositions in accordance with the disclosure are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure may be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, from about 25 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 125 mg/kg, from about 125 mg/kg to about 150 mg/kg, from about 150 mg/ to about 175 mg/
  • the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • split dosing regimens such as those described herein may be used.
  • a “split dose” is the division of single unit dose or total daily dose into two or more doses, e.g, two or more administrations of the single unit dose.
  • a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event.
  • a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose.
  • Dosage Forms [0153] A pharmaceutical composition described herein can be formulated into a dosage form described herein, such as a topical, intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, and subcutaneous).
  • Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs.
  • liquid dosage forms may comprise inert diluents commonly used in the art including, but not limited to, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art including, but not limited to,
  • compositions may be mixed with solubilizing agents such as CREMOPHOR®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art and may include suitable dispersing agents, wetting agents, and/or suspending agents.
  • Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, a solution in 1,3-butanediol.
  • acceptable vehicles and solvents include, but are not limited to, water, Ringer's solution, U.S.P., and isotonic sodium chloride solution.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid can be used in the preparation of injectables.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include, but are not limited to, poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations may be prepared by entrapping the compounds in liposomes or microemulsions which are compatible with body tissues.
  • Pulmonary [0159] Formulations described herein as being useful for pulmonary delivery may also be used for intranasal delivery of a pharmaceutical composition.
  • Another formulation suitable for intranasal administration may be a coarse powder comprising the active ingredient and having an average particle from about 0.2 ⁇ m to 500 ⁇ m.
  • Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration.
  • formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, contain about 0.1% to 20% (w/w) active ingredient, where the balance may comprise an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations, when dispersed may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein.
  • the present invention provides a method of treating a neurological and/or psychiatric disease or disorder described herein, comprising administering a compound of the present disclosure in combination with one or more additional active agents or therapies.
  • Suitable pharmaceutical agents that may be used in combination with the compounds of the present disclosure include antidepressants, anti- psychotics, anti-Parkinson's drugs, anti-Alzheimer's drugs, anti-ischemics, CNS depressants, anti-cholinergics, nootropics, epilepsy medication, attention (e.g., ADD/ ADHD) medications, sleep-promoting medications, wakefulness-promoting medications, pain medications, or anxiolytics.
  • the compounds of the present disclosure and the additional active agent(s) may be administered simultaneously, sequentially, or at any order.
  • the compounds of the present disclosure and the additional active agent(s) may be administered at different dosages, with different dosing frequencies, or via different routes, whichever is suitable. IV.
  • kits and devices for conveniently and/or effectively carrying out methods of the present disclosure.
  • kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments.
  • the present disclosure provides kits for treating CNS disorders, comprising a compound of the present disclosure or a combination of compounds of the present disclosure, optionally in combination with any other active agents.
  • the kit may further comprise packaging and instructions and/or a delivery agent to form a formulation composition.
  • the delivery agent may comprise a saline, a buffered solution, or any delivery agent disclosed herein.
  • the amount of each component may be varied to enable consistent, reproducible higher concentration saline or simple buffer formulations.
  • the components may also be varied in order to increase the stability of the compound(s) in the buffer solution over a period of time and/or under a variety of conditions.
  • the present disclosure provides for devices which may incorporate compound(s) of the present disclosure. These devices contain in a stable formulation available to be immediately delivered to a subject in need thereof, such as a human patient. In some embodiments, the subject has BPD.
  • Non-limiting examples of the devices include a pump, a catheter, a needle, a transdermal patch, a pressurized olfactory delivery device, iontophoresis devices, multi- layered microfluidic devices.
  • the devices may be employed to deliver compound(s) of the present disclosure according to single, multi- or split-dosing regiments.
  • the devices may be employed to deliver compound(s) of the present disclosure across biological tissue, intradermal, subcutaneously, or intramuscularly.
  • V. DEFINITIONS [0169] The abbreviations used herein have their conventional meaning within the scientific arts. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in M. Loudon, Organic Chemistry, 5th Ed., Roberts and Company, Greenwood Village, Colo.: 2009; and M. B.
  • the term “compound”, as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Examples prototropic tautomers include ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. [0174]
  • the compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents which would result from writing the structure from right to left, e.g., —CH 2 O— is intended to also recite —OCH 2 —; —NHS(O) 2 — is also intended to represent —S(O) 2 HN—; etc.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical (also called cycloalkyl or cyclic alkyl group), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C 1 -C 10 means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n- octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • alkyl groups examples include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.”
  • Alkyl groups, which are limited to hydrocarbon groups are termed “homoalkyl”.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by —CH 2 CH 2 CH 2 CH 2 —, and further includes those groups described below as “heteroalkylene.”
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkoxy (or “alkoxyl”) “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • Examples include, but are not limited to, —CH 2 —CH 2 —O— CH 3 , —CH 2 —CH 2 —NH—CH 3 , —CH 2 —CH 2 —N(CH 3 )—CH 3 , —CH 2 —S—CH 2 —CH 3 , — CH 2 —CH 2 , —S(O)—CH 3 , —CH 2 —CH 2 —S(O) 2 —CH 3 , —CH ⁇ CH—O—CH 3 , —Si(CH 3 ) 3 , —CH 2 —CH ⁇ N—OCH 3 , and —CH ⁇ CH—N(CH 3 )—CH 3 .
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH 2 —CH 2 — S—CH 2 —CH 2 — and —CH 2 —S—CH 2 —CH 2 —NH—CH 2 —.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O) 2 R′— represents both —C(O) 2 R′— and —R′C(O) 2 —. [0180] In general, an “acyl substituent” is also selected from the group set forth above.
  • acyl substituent refers to groups attached to, and fulfilling the valence of a carbonyl carbon that is either directly or indirectly attached to the polycyclic nucleus of the compounds of the present invention.
  • cycloalkyl and heterocycloalkyl represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl examples include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
  • an alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like.
  • the terms “carbocycle” and “heterocycle” refers to non-aromatic (such as “cycloalkyl” and “heterocycloalkyl” as defined herein) or aromatic (such as “aryl” and “heteroaryl” as defined herein) rings.
  • the “carbocycle” and “heterocycle” groups may be saturated or non-saturated.
  • Each of the above terms e.g., “alkyl,” “heteroalkyl,” “aryl,” “heteroaryl,” “carbocycle,” and “heterocycle” include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • alkyl substituents are generally referred to as “alkyl substituents” and “heteroalkyl substituents,” respectively, and they can be one or more of a variety of groups selected from, but not limited to: —OR′, ⁇ O, ⁇ NR′, ⁇ N—OR′, —NR′R′′, —SR′, -halogen, —SiR′R′′R′′′, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R′′, — OC(O)NR′R′′, —NR′′C(O)R′, —NR′—C(O)NR′′
  • R′, R′′, R′′′ and R′′′′ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R′, R′′, R′′′ and R′′′′ groups when more than one of these groups is present.
  • R′ and R′′ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5- , 6-, or 7-membered ring.
  • —NR′R′′ is meant to include, but not be limited to, 1- pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF 3 and —CH 2 CF 3 ) and acyl (e.g., —C(O)CH 3 , —C(O)CF 3 , —C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., —CF 3 and —CH 2 CF 3
  • acyl e.g., —C(O)CH 3 , —C(O)CF 3 , —C(O)CH 2 OCH 3 , and the like.
  • aryl substituents and heteroaryl substituents are generally referred to as “aryl substituents” and “heteroaryl substituents,” respectively and are varied and selected from, for example: halogen, —OR′, ⁇ O, ⁇ NR′, ⁇ N—OR′, —NR′R′′, —SR′, -halogen, —SiR′R′′R′′′, —OC(O)R′, —C(O)R′, — CO 2 R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′—C(O)NR′′R′′′, —NR′′C(O) 2 R′, —NR—C(NR′R′′) ⁇ NR′′′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R′′, —NRSO
  • each of the R groups is independently selected as are each R′, R′′, R′′′ and R′′′′ groups when more than one of these groups is present.
  • Two of the aryl substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)—(CRR′) q —U—, wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r —B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O) 2 —, — S(O) 2 NR′— or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′) s —X—(CR′′R′′′) d —, where s and d are independently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O) 2 —, or — S(O) 2 NR′—.
  • the substituents R, R′, R′′ and R′′′ are preferably independently selected from hydrogen or substituted or unsubstituted (C 1 -C 6 )alkyl.
  • alkyl amide refers to carboxylic acid amides that are functionalized on the amide nitrogen by one or more alkyl groups as defined herein.
  • alkyl amine refers to amines in which the nitrogen atom is functionalized with one or more alkyl groups as defined herein.
  • heteroatom includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • the term “optionally substituted” means the functional group may be optionally substituted by any suitable substituents, such as but not limited to, alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroaryl
  • R is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl groups.
  • pharmaceutically acceptable salts includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • the terms "subject” or "patient”, as used herein, refer to any organism to which the particles may be administered, e.g., for experimental, therapeutic, diagnostic, and/or prophylactic purposes.
  • Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, guinea pigs, cattle, pigs, sheep, horses, dogs, cats, hamsters, lamas, non-human primates, and humans).
  • animals e.g., mammals such as mice, rats, rabbits, guinea pigs, cattle, pigs, sheep, horses, dogs, cats, hamsters, lamas, non-human primates, and humans.
  • the terms "treating” or “preventing”, as used herein, can include preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder or condition; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • the terms “managing” or “maintaining”, as used herein, can refer to reducing the symptom(s) of a disease, reducing the severity of symptom(s) of the disease, or preventing the symptom(s) of the disease from getting worse.
  • the term "therapeutic effect” is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, disorder or condition in the enhancement of desirable physical or mental development and conditions in an animal, e.g., a human.
  • the term “modulation” is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart. The modulation is generally compared to a baseline or reference that can be internal or external to the treated entity.
  • Parenteral administration means administration by any method other than through the digestive tract (enteral) or non-invasive topical routes.
  • parenteral administration may include administration to a patient intravenously, intradermally, intraperitoneally, intrapleurally, intratracheally, intraossiously, intracerebrally, intrathecally, intramuscularly, subcutaneously, subjunctivally, by injection, and by infusion.
  • Topical administration means the non-invasive administration to the skin, orifices, or mucosa. Topical administration can be delivered locally, i.e., the therapeutic can provide a local effect in the region of delivery without systemic exposure or with minimal systemic exposure.
  • Topical administration can include, but is not limited to, cutaneous and transdermal administration, buccal administration, intranasal administration, intravaginal administration, intravesical administration, ophthalmic administration, and rectal administration.
  • Enteral administration means administration via absorption through the gastrointestinal tract. Enteral administration can include oral and sublingual administration, gastric administration, or rectal administration.
  • Promonary administration means administration into the lungs by inhalation or endotracheal administration. As used herein, the term “inhalation” refers to intake of air to the alveoli.
  • the intake of air can occur through the mouth or nose.
  • a “therapeutically effective amount” is at least the minimum concentration required to affect a measurable improvement or prevention of at least one symptom or a particular condition or disorder, to affect a measurable enhancement of life expectancy, or to generally improve patient quality of life. The therapeutically effective amount is thus dependent upon the specific biologically active molecule and the specific condition or disorder to be treated. Therapeutically effective amounts of many active agents, such as antibodies, are known in the art.
  • bioactive agent and “active agent”, as used interchangeably herein, include, without limitation, physiologically or pharmacologically active substances that act locally or systemically in the body.
  • a bioactive agent is a substance used for the treatment (e.g., therapeutic agent), prevention (e.g., prophylactic agent), diagnosis (e.g., diagnostic agent), cure or mitigation of disease or illness, a substance which affects the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of agencies such as the U.S. Food and Drug Administration.
  • pharmaceutically acceptable carrier refers to all components of a pharmaceutical formulation that facilitate the delivery of the composition in vivo.
  • Pharmaceutically acceptable carriers include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i
  • Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • an addition salt particularly a pharmaceutically acceptable addition salt
  • a suitable organic solvent may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • a pharmaceutically acceptable salt can be derived from an acid selected from 1- hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10- sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,
  • protective group refers to a functional group that can be added to and/or substituted for another desired functional group to protect the desired functional group from certain reaction conditions and selectively removed and/or replaced to deprotect or expose the desired functional group.
  • Protective groups are known to the skilled artisan. Suitable protective groups may include those described in Greene and Wuts, Protective Groups in Organic Synthesis, (1991). Acid sensitive protective groups include dimethoxytrityl (DMT), tert- butylcarbamate (tBoc) and trifluoroacetyl (tFA).
  • Base sensitive protective groups include 9-fluorenylmethoxycarbonyl (Fmoc), isobutyrl (iBu), benzoyl (Bz) and phenoxyacetyl (pac).
  • Other protective groups include acetamidomethyl, acetyl, tert- amyloxycarbonyl, benzyl, benzyloxycarbonyl, 2-(4-biph ⁇ nylyl)-2-propy!oxycarbonyl, 2- bromobenzyloxycarbonyl, tert-butyl7 tert-butyloxycarbonyl, l-carbobenzoxamido-2,2.2- trifluoroethyl, 2,6-dichlorobenzyl, 2-(3,5-dimethoxyphenyl)-2-propyloxycarbonyl, 2,4- dinitrophenyl, dithiasuccinyl, formyl, 4-methoxybenzenesulfonyl, 4-methoxy
  • bioavailable is art-recognized and refers to a form of the subject disclosure that allows for it, or a portion of the amount administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered.
  • bioavailable is art-recognized and refers to a form of the subject disclosure that allows for it, or a portion of the amount administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered.
  • the present disclosure is further illustrated by the following non-limiting examples. EXAMPLES Example 1. Synthesis of the Compounds [0217]
  • the compounds of the disclosure may be prepared using any convenient methodology known to a person of the art. Non-limiting synthetic methods for the compounds of the present disclosure are provided below.
  • Chroman-4-ylmethanamine hydrochloride (47) Chroman-4-ylmethanamine (100 mg ,0.61 mmol) was dissolved in deionized water (3 ml) and acidified with 4N HCl/MeOH (1 ml). The mixture was removed under vacuum to give the title compound (120 mg, Y: 98.3%) as a white solid.
  • tert-Butyl (chroman-4-ylmethyl)carbamate (B-1) Chroman-4-ylmethanamine (500 mg, 3.06 mmol) was dissolved in DCM (15 mL). Triethylamine (620 mg,6.13 mmol) and di- tert-butyl decarbonate (802 mg,3.68 mmol) were added and the mixture was stirred at 25 o C overnight. The reaction was quenched with saturated ammonium chloride and extracted with DCM (15 mL ⁇ 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated.
  • N-(Chroman-4-ylmethyl)propan-2-amine hydrochloride (49) Chroman-4- ylmethanamine(100 mg ,0.61 mmol) was dissolved in DCM (6 mL). Acetone (64 mg,1.1 mmol) was added and the mixture was stirred at 25 o C for 4 h. Sodium triacetoxyborohydride (243 mg, 1.15 mmol) was added and the reaction continued stirring at 25 o C overnight. The mixture was quenched by water and extracted with DCM (8 mL ⁇ 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated.
  • N,N-Dimethyl-1-(2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methanamine hydrochloride (111): To a solution of (2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methanamine (100 mg, 0.6 mmol) and formaldehyde (0.5 mL) in methanol (5 mL) was added 10% Pd/C (10 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours.
  • N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methanaminium chloride (38) A solution of F-4 (380 mg, 1.2 mmol) and p-toluenesulfonic acid (105.1 mg, 0.6 mmol) in TFA (5 mL) was reacted in microwave reactor at 120 o C for 1.5 hours. After cooling to room temperature, the mixture was filtered and concentrated. The residue was purified by prep-HPLC (CH 3 CN/H 2 O, 0.1%HCl) to obtain the desired product (28.4 mg, 10.2% yield) as a colorless gel.
  • G-2 1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-carbonitrile (G-2): To a stirred solution of G-1 (2.0 g, 11.4 mmol), EtOH (0.6 g, 13.6 mmol) and TOSMIC (2.2 g, 11.4 mmol) in 1,2-dimethoxy ethane (20 mL) was added potassium tert-butoxide (1.5 g, 13.6 mmol) slowly at 0 o C under nitrogen. The mixture was stirred for 15 min at 0 o C and then for 1 hour at room temperature. After which period, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (200 mL).
  • N-((1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methyl)propan-2-aminium chloride (42) A solution of 39 (100 mg, 0.6 mmol), NaBH(OAc) 3 (0.05 g, 0.9 mmol) and acetone (1 mL) in MeOH (2 mL) was stirred at room temperature for 2 hours. After then, the mixture was diluted with saturated NH 4 Cl (5 mL), extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • N-Methyl-1-(2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methanamine hydrochloride (112) Lithium aluminum hydride (16.1 mg, 0.4 mmol) was added in portions to a solution of J-1 (100 mg, 0.4 mmol) in tetrahydrofuran (6 mL) at 0°C. The mixture was refluxed for 1 hour. Sodium sulfate decahydrate was added to quench the reaction at room temperature.
  • Ethyl 2-(isochroman-4-yl)acetate (L-2): To a solution of 1 (1.4 g, 6.4 mmol) in methanol (30 mL) was added 10% Pd/C (0.3 g) and stirred at room temperature under hydrogen atmosphere for 3 hours. The mixture was then filtered through a pad of celite, the filtrate was concentrated to obtain the desired compound (1.4 g, 99.4% yield) as a colorless oil.
  • 2-(Isochroman-4-yl)acetic acid (L-3): To a solution of L-2 (1.4 g, 6.4 mmol) in methanol (15 mL) was added aq.
  • tert-Butyl (isochroman-4-ylmethyl)carbamate (L-4) Diphenyl azidophosphate (2.6 g, 9.36 mmol) was added to the solution of L-3 (1.2 g, 6.2 mmol) and triethylamine (2.5 g, 24.9 mmol) in tert-butanol (20 mL) at 40 o C, and the reaction solution was stirred for 30 min followed by stirring for another 100 o C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated to remove tert-butanol and diluted with water (100 mL), extracted with ethyl acetate (50 mL*2).
  • N-2-oxo-1,2,3,4-tetrahydroquinolin-4- yl)methyl carbamate (N-2): To a solution of N-1 (1.1 g, 4.0 mmol) in DMF (10 mL) and was added sodium hydride (0.48 g, 20 mmol) at ice/water bath. After stirring for 30 min, iodomethane (2.8 g, 20 mmol) was added dropwise to above solution. The resulting reaction mixture was warmed to room temperature and stirred for another 2 hours and then quenched by addition of water (30 mL), which was extracted with ethyl acetate (50 mL).
  • N,N-Dimethyl-1-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methanaminium chloride (34) The title compound was prepared using the same procedure for 33.
  • N-Methyl-1-(1,2,3,4-tetrahydroquinolin-4-yl)methanamine (N-3) To a solution of tert-butyl ((2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methyl)carbamate (150 mg, 0.5 mmol) in THF(10 mL) was added lithium aluminum hydride (41.1 mg, 1.1 mmol) at 0 o C and the reaction mixture was stirred at 60 o C for 2 hours.
  • the reaction mixture was stirred at room temperature for 1 hour and then concentrated to dryness.
  • the residue was purified by Prep-HPLC (CH 3 CN/H 2 O, 0.1%HCl) to obtain the desired compound (50.0 mg, 44.3 % yield) as a yellow gel.
  • tert-Butyl 5-((dimethylamino)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1- carboxylate P-4): The mixture of tert-butyl 5-(aminomethyl)-2,3,4,5-tetrahydro-1H-1- benzazepine-1-carboxylate (160.0 mg, 0.6 mmol), formaldehyde (34.5 mg, 1.2 mmol) and Pd/C (16.0 mg, 0.2 mmol) in methanol (5 mL) was stirred at room temperature under hydrogen atmosphere for 12 hours.
  • N,N-Dimethyl-1-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5- yl)methanamine hydrochloride (101) A solution of 94 (90 mg, 0.5 mmol) and formaldehyde (76.5 mg, 2.6 mmol) in DCE/MeOH (20 mL, 1:1) was stirred at room temperature for 2 hours.
  • Dodecanoyl dodecaneperoxoate (1.0 g, 2.4 mmol) was added to the above solution, and the resulting mixture was continued to stir for 1 hour.
  • Dodecanoyl dodecaneperoxoate (1.0 g, 2.4 mmol) was added twice every 1 hour till compound Q-2 was consumed (assessed by TLC).
  • N-Methyl-1-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)methanaminium chloride (95): To the solution of Q-4 (150.0 mg, 0.5 mmol) in THF (5 mL) was added LAH (38.1 mg, 1.0 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour and then raised up to 60°C for 16 hours.
  • R-2 5-Methylene-1,3,4,5-tetrahydrobenzo[c]oxepine (R-2): A mixture of R-1 (9.0 g, 37.6 mmol), Pd(PPh 3 ) 4 (1.3 g, 1.1 mmol), cesium carbonate (30.8 g, 94.0 mmol), and ammonium formate (4.7 g, 75.2 mmol) in DMF (120 mL) was stirred at 90 o C under nitrogen for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (200 mL*2).
  • R-3 1,3,4,5-Tetrahydro-2-benzoxepin-5-one (R-3): To the solution of R-2 (5.0 g, 31.2 mmol) in DCM/MeOH (40 mL, 1:1) at -78 o C was gassed with ozone until starting material was consumed, and the mixture was then gassed with nitrogen for 15 min. Then, the reaction mixture was added triphenylphosphine (0.8 g, 3.1 mmol) at -78 o C and continued to stir at room temperature for 1 hour. The mixture was diluted with water (100 mL), extracted with dichloromethane (50 mL*2).
  • Ethyl (E/Z)-2-(3,4-dihydrobenzo[c]oxepin-5(1H)-ylidene)acetate (R-4) To a solution of sodium hydride (1.5 g, 36.9 mmol, 60%wt) in THF (50 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (10.3 g, 46.1 mmol) at 0°C. The mixture was stirred at room temperature for 30 min followed by addition of R-3 (1.5 g, 9.2 mmol) The reaction mixture was stirred at room temperature for 1 hour and quenched by adding water (200 mL), extracted with ethyl acetate (100 mL*2).
  • tert-Butyl N-[(1,3,4,5-tetrahydro-2-benzoxepin-5- yl)methyl]carbamate (R-7) To a solution of R-6 (1.1 g, 5.3 mmol) and triethylamine (2.2 g, 21.3 mmol) in tert-butanol (20 mL) was added diphenyl azidophosphate (2.2 g, 8.0 mmol) at 40 o C and stirred for 30 min. Then, the reaction mixture was heated to 100 o C and stirred for additional 16 hours. After cooling to room temperature, the mixture was concentrated and diluted with water (100 mL), extracted with ethyl acetate (50 mL*2).
  • T-3 4-(Thiophen-3-yloxy)butanoic acid (T-3): The solution of T-2 (50.0 g, 0.2 mol) in THF/MeOH/H 2 O (1000 mL, 7:1:2) was added NaOH (18.6 g, 0.5 mol) at 0°C. Then, the mixture was stirred at room temperature for 2.5 hours. Aqueous HCl (2 M) was added to the reaction to adjust the pH about 3. The resulting mixture was extracted with ethyl acetate (250 mL*3) and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated.
  • T-4 4-(Thiophen-3-yloxy)butanoyl chloride (T-4): To the solution of T-3 (10.0 g, 53.6 mmol) in DCM (150 mL ) was added oxalic dichloride (6.8 g, 53.6 mmol) at 0°C, and the mixture was stirred at room temperature for 3.5 hours. After which period, the reaction mixture was concentrated to have desired product (9 g, 81.9%) as a colorless oil, which was used directly to next step.
  • T-7 (5,6,7,8-Tetrahydrothieno[3,2-b]oxepin-8-yl)methanamine(T-7): To the solution of ammonium acetate (2.8 g, 36.1 mmol) in ethyl alcohol (2 mL) was added T-6 (330.0 mg, 1.8 mmol), sodium cyanoborohydride (343.0 mg, 5.5 mmol), and ammonium hydroxide (4.4 g, 125.0 mmol). The mixture was stirred at 80°C for 12 hours in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL).
  • T-7 tert-Butyl ((5,6,7,8-tetrahydrothieno[3,2-b]oxepin-8-yl)methyl)carbamate (T-8): The mixture of T-7 (220.0 mg, 1.2 mmol) and di-tert-butyl dicarbonate (390.0 mg, 1.8 mmol) in saturated sodium bicarbonate (5 mL, 65.5 mmol) and tetrahydrofuran (5 mL) was stirred at room temperature for 1 hour. Then, the mixture was diluted with H 2 O (10 mL), extracted with ethyl acetate (15 mL * 3).
  • N-Methyl-1-(5,6,7,8-tetrahydrothieno[3,2-b]oxepin-8-yl)methanamine hydrochloride (155): To the solution of methylamine in MeOH (2 N, 50 mL) was added 5,6,7,8-tetrahydrothieno[3,2-b]oxepine-8-carbaldehyde (0.3 g, 1.4 mmol) and 10% Pd/C (0.1 g). The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. Then, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness.
  • V-2 4-Methylchromane-4-carbonitrile: To a solution of V-1 (820 mg, 5.15 mmol) and iodomethane (4.4 g, 30.9 mmol) in dimethylformamide (50 mL) was added sodium hydride (1.2 g, 30.9 mmol, 60%wt) at 0 °C, and the mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. Then, the mixture was poured into water (500 mL), extracted with ethyl acetate (150 mL* 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to get crude product (820 mg) for the next step without further purification.
  • V-1 820 mg, 5.15 mmol
  • iodomethane 4.4 g, 30.9 mmol
  • dimethylformamide 50 mL
  • sodium hydride 1.2 g, 30.9 mmol, 60%wt
  • tert-Butyl (2-(chroman-4-yl)ethyl)carbamate (V-5) To a solution of 2-(chroman-4-yl)ethan-1-amine (0.8 g, 4.5 mmol) and (Boc) 2 O (1.5 g, 6.75 mmol) in THF (10 mL) was added saturated NaHCO 3 (5 mL), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • AA-7 2,2,2-Trifluoro-N-((7-oxido-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4- yl)methyl)acetamide (AA-7): To a solution of AA-6 (219.8 mg, 0.8 mmol) in DCM (20 mL ) was added m-CPBA (33.4 mg, 0.8 mmol) at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NaHSO 3 and extracted with DCM (20 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness.
  • Ethyl 2-(5-fluoro-3,4-dihydro-2H-1-benzopyran-4-ylidene)acetate (CC-4): To the solution of ethyl 2-(diethoxyphosphoryl)acetate (6.4 g, 27.0 mmol) in THF (35 mL) was added sodium hydride (0.6 g, 27.0 mmol, 60%wt) at 0°C and stirred for another 1.5 hours under nitrogen atmosphere. CC-3 (1.5 g, 9.0 mmol) was added slowly and continued to stir at room temperature for 2.5 hour.
  • Ethyl 2-(5-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)acetate (CC-5): To a solution of CC-4 (0.8 g, 3.4 mmol) in MeOH (10 mL ) was added 10% Pd/C (0.2 g), and the mixture was stirred at room temperature for 2.5 hour under hydrogen atmosphere. Then, the reaction mixture was filtered with celite, and the filtrate was concentrated to have desired product (0.7 g, 87.5%) as a pale solid.
  • Ethyl (E)-3-(2-(tert-butoxy)thiophen-3-yl)acrylate (DD-3) To a solution of sodium hydride (662 mg, 27.6 mmol, 60%wt) in THF (20 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (5.8 g, 27.6 mmol) at 0 o C; the mixture was stirred at 0 o C for 1 hour, followed by addition of solution of DD-2 (1.7 g, 9.2 mmol) in THF (10 mL). The resulting mixture was stirred for another 1 hour from 0 o C to room temperature.
  • Ethyl 3-(2-(tert-butoxy)thiophen-3-yl)-4-nitrobutanoate (DD-4) To a solution of DD-3 (2.3 g, 9.0 mmol) in nitromethane (60 mL) was added DBU (4.1 g, 27.1 mmol) at room temperature, and the mixture was stirred at 75 o C for 3 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and concentrated to dryness.
  • DBU 4.1 g, 27.1 mmol
  • Ethyl (E)-3-(2-(benzyloxy)-6-chlorophenyl)acrylate (EE-2) The mixture of EE-1 (5.3 g, crude) and potassium carbonate (6.4 g, 46.6 mmol) in acetone (50 mL) was stirred at room temperature for 30 min, followed by addition of benzyl bromide (8.0 g, 46.6 mmol) dropwise. The resulting mixture was stirred at 50 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL * 3).
  • Ethyl 3-(2-(benzyloxy)-6-chlorophenyl)-4-nitrobutanoate (EE-3) To a solution of EE-2 (5.3 g, 16.7 mmol) in nitromethane (50 mL, 933.0 mmol) was added 1,8- diazabicycloundec-7-ene (12.6 g, 83.4 mmol) at 0 °C, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetated (30 mL * 3).
  • GG-3 4-(Nitromethyl)-3,4-dihydroquinazolin-2(1H)-one (GG-3): The mixture of GG-2 (400.0 mg, 2.2 mmol), nitromethane (1.4 g, 22.3 mmol) and ammonium acetate (343.0 mg, 4.5 mmol) in acetic acid (3 mL) was stirred at 130 °C for 10 min under microwave. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • GG-4 4-(Aminomethyl)-3,4-dihydroquinazolin-2(1H)-one (GG-4): To a solution of GG- 3 (100.0 mg, 0.5 mmol) in methanol (5 mL) was added 10% Pd/C (33 mg), and the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. Then, the mixture was filtered through pad of celite; the filtrate was concentrated to obtain the desired compound (85.0 mg, crude) as a white solid for the next step without further purification. MS(ESI) calculated for C 9 H 11 N 3 O, 177.1; found 178.2.
  • GG-5 tert-Butyl ((2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methyl)carbamate (GG-5): The mixture of GG-4 (85.0 mg, crude) and di-tert-butyl dicarbonate (156.0 mg, 0.7 mmol) in saturated sodium bicarbonate (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 1 hour. Then, the reaction mixture was diluted with H 2 O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness.
  • GG-7 tert-Butyl methyl((2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methyl)carbamate (GG-7): The mixture of GG-6 (50 mg, crude) and di-tert-butyl dicarbonate (85.3 mg, 0.4 mmol) in saturated sodium bicarbonate (2.5 mL) and tetrahydrofuran (2.5 mL ) was stirred at room temperature for 1 hour. The mixture was poured into H 2 O (10 mL), and extracted with EA (10 mL*3).
  • N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methanamine hydrochloride (44) The solution of GG-7 (50.0 mg, 0.2 mmol) in HCl/dioxane (2 M, 1.5 mL) and methanol (1.5 mL) was stirred at room temperature for 2 hours.
  • Ethyl (E)-3-(3-methoxythiophen-2-yl)acrylate (HH-2): To a solution of ethyl 2- (diethoxyphosphoryl)acetate (12.6 g, 56.4 mmol) in THF (40 mL) was added sodium hydride (1.4 g, 56.4 mmol, 60%wt) at ice/water bath. The resulting mixture was stirred at 0°C for additional 30 min. HH-1 (4.0 g, 28.2 mmol) was added to above solution; the resulting solution was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (60 mL).
  • HH-3 Ethyl 3-(3-methoxythiophen-2-yl)-4-nitrobutanoate (HH-3): To a solution of HH- 2 (4.0 g, 18.9 mmol) in nitromethane (40 mL) was added DBU (8.6 g, 56.7 mmol), and the mixture was stirred at 75 o C for 2 hours. After cooling to room temperature, the mixture was diluted with water (40 mL), extracted with DCM (80 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • Ethyl (3S,4S)-1-benzyl-4-(2-methoxyphenyl)pyrrolidine-3-carboxylate (JJ-2): To a solution of JJ-1 (5.0 g, 19.1 mmol) and N-benzyl-1-methoxy- N((trimethylsilyl)methyl)methanamine (9.1 g, 38.1 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (217.0 mg, 1.9 mmol) at 0 o C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL*2).
  • JJ-3 Ethyl (3S,4S)-1-benzyl-4-(2-hydroxyphenyl)pyrrolidine-3-carboxylate (JJ-3): To a solution of JJ-2 (5.0 g, 14.7 mmol) in dichloromethane (150 mL) was added boron tribromide (35.1 mL, 1.0 M in DCM) at -78 o C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • boron tribromide 35.1 mL, 1.0 M in DCM
  • tert-Butyl (3aR,9bS)-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrole-2(3H)- carboxylate JJ-6: To a solution of JJ-5 (0.5 g, 1.9 mmol) in methanol (30 mL) was added 10% Pd(OH) 2 (0.5 g) and di-tert-butyl pyrocarbonate (0.8 g, 3.8 mmol). The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. After which period, the mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness.
  • KK-2 Methyl 4-bromo-3-(pent-4-en-1-yloxy)thiophene-2-carboxylate (KK-2): To a solution of KK-1 (9.0 g, 37.9 mmol), pent-4-en-1-ol (4.9 g, 56.8 mmol) and PPh 3 (14.8 g, 56.8 mmol) in THF (200 mL) was added DEAD (9.9 g, 56.8 mmol) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 hours.
  • KK-7 5-(Azidomethyl)-2,3,4,5-tetrahydrothieno[3,4-b]oxepine (KK-7): To a solution of KK-6 (1.2 g, 6.5 mmol), PPh 3 (5.1 g, 19.5 mmol) and DPPA (4.7 g, 19.5 mmol) in dry THF (20 mL) was added DEAD (3.4 g, 19.5 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. After which period, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL).
  • LL-2 tert-Butyl 4-(2-hydroxyethyl)-3,6-dihydropyridine-1(2H)-carboxylate
  • LL- 3 tert-Butyl 4-(2-(2-bromophenoxy)ethyl)-3,6-dihydropyridine-1(2H)-carboxylate (LL- 3): To the solution of LL-2 (1.0 g, 4.4 mmol), 2-bromophenol (758.8 mg, 4.4mmol), and triphenylphosphine (1.4 g, 5.3 mmol) in THF (50 mL ) was added DIAD (0.9 g, 5.3 mmol) at 0 o C, and the mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100mL*2).
  • tert-Butyl spiro[chromane-4,4'-piperidine]-1'-carboxylate (LL-4) and tert-Butyl 3,4,4a,5,6,11b-hexahydrobenzo[2,3]oxepino[4,5-c]pyridine-2(1H)-carboxylate (LL-5) The mixture of LL-3 (0.8 g, 2.1 mmol), tributylstannane (1.2 g, 4.2 mmol) and AIBN (34.3 mg, 0.3 mmol) in toluene (50 mL) was stirred at 110 o C under nitrogen atmosphere for 5 hours.
  • Spiro[chromane-4,4'-piperidin]-1'-ium chloride (71) The solution of LL-4 (0.1 g, 0.3 mmol) in HCl/dioxane (4 M, 3 mL) was stirred at room temperature for 1 hour. After then, the mixture was concentrated to obtain the desired product (70.0 mg, 85.8 % yield) as a white solid.
  • E Ethyl (E)-3-(3-((diphenylmethylene)amino)thiophen-2-yl)acrylate (MM-2): The solution of MM-1 (50 g, 191.5 mmol), diphenylmethanimine (69.0 g, 383.0 mmol), BINAP (9.0 g, 14.4 mmol), Pd 2 (dba) 3 (4.4 g, 4.8 mmol) and CS 2 CO 3 (124.8 g, 383.0 mmol) in toluene (200 mL) was stirred at 110°C under nitrogen atmosphere for 16 hours.
  • Ethyl (3S,4R)-1-benzyl-4-(3-((diphenylmethylene)amino)thiophen-2- yl)pyrrolidine-3-carboxylate (MM-3): To the solution of MM-2 (4.0 g, 11.1 mmol) and N- benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (5.2 g, 22.0 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (125.0 mg, 1.1 mmol) at 0 o C, and the resulting mixture was stirred at room temperature for 1 hour.
  • Ethyl (3S,4R)-4-(3-aminothiophen-2-yl)-1-benzylpyrrolidine-3-carboxylate (MM- 4): To a solution of MM-3 (2.6 g, 5.3 mmol) in dioxane (20 mL) was added HCl/dioxane (4 M, 20 mL), and the mixture was stirred at room temperature for 1 hour. After which period, the reaction mixture was adjusted to pH ⁇ 8 with basic anion exchange resin and filtered. The filtrate was concentrated to dryness.
  • E -3-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)acrylate (OO-2): The solution of OO-1 (12 g, 60.9 mmol) and di-tert-butyl dicarbonate (19.9 g, 91.3 mmol) in tetrahydrofuran (300 mL) and saturated sodium bicarbonate solution (300 mL) was stirred at room temperature for 48 hours.
  • Ethyl 3-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)-4-nitrobutanoate (OO-3) To a solution of OO-2 (12 g, 40.4 mmol) in nitromethane (60 mL) was added DBU (18.4 g, 121.2 mmol), and the resulting mixture was stirred at 75°C for 1 hour. After cooling to room temperature, the mixture was poured into H 2 O (100 mL) and extracted with CH 2 Cl 2 (100 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness.
  • tert-Butyl-7-(((tert-butoxycarbonyl)amino)methyl)-6,7-dihydrothieno[3,2- b]pyridine-4(5H)-carboxylate (OO-6) A solution of OO-5 (60 mg, 356 ⁇ mol) and di-tert- butyl dicarbonate (386 mg, 1.77 mmol) in tetrahydrofuran (20 mL) and saturated sodium bicarbonate solution (20 mL) was stirred at room temperature for 1 hour. The mixture was poured into H 2 O (100 mL) and extracted with ethyl acetate (100 mL* 3).
  • N-Methyl-1-(4,5,6,7-tetrahydrothieno[3,2-b]pyridin-7-yl)methanamine (OO-8): To the solution of OO-7 (220 mg, 0.8 mmol) in tetrahydrofuran (20 mL) was added LiAlH 4 (440.0 mg, 11.6 mmol) at 0 °C. Then reaction was stirred at 60°C for 16 hours. After cooling to room temperature, the reaction was quenched with sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product (100 mg, 67.1% yield) as colorless oil, which was used in next step directly.
  • tert-Butyl-7-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6,7- dihydrothieno[3,2-b]pyridine-4(5H)-carboxylate (OO-9) The mixture of OO-8 (100 mg, 548 ⁇ mol) and di-tert-butyl dicarbonate (595 mg, 2.73 mmol) in saturated sodium bicarbonate solution (20 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 1 hour. The mixture was poured into H 2 O (100 mL), and extracted with EA (100 mL* 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness.
  • tert-Butyl (2-formylthiophen-3-yl)carbamate (PP-2): To the solution of PP-1 (10 g, 50.1 mmol) in tetrahydrofuran (100 mL) was added n-BuLi (40 mL, 100.0 mmol) at - 78°C under nitrogen. The resulting solution was continued to stir at -78°C for 1 h. Then, N,N-dimethylformamide (5.8 mL, 75.1 mmol) was added dropwise to above solution, and the resulting solution was stirred for another 2 hours. Saturated NH 4 Cl was added to quench the reaction.
  • Ethyl (3s,4r)-4-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)pyrrolidine-3- carboxylate (TT-3) To a solution of TT-2 (3.8 g, 8.8 mmol) and potassium carbonate (6.1 g, 44.1 mmol) in 1,2-dichloroethane (150 mL) was added 1-chloroethyl chloroformate (6.3 g, 44.1 mmol), and the mixture was refluxed for 6 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in ethanol (100 mL) and refluxed for 2 hours.
  • TT-5 (5aR,8aR)-4,5a,6,7,8,8a-Hexahydro-5H-pyrrolo[3,4-d]thieno[3,2-b]pyridin-5-one (TT-5): To a solution of TT-4 (970.0 mg, 4.0 mmol) in toluene (30 mL) was added trimethylaluminium (12 mL, 1.0 M in toluene) at 0°C, and the resulting mixture was continued to stirred at 0 o C for 2 hours. The mixture was poured into a solution of silica gel in methanol (50 mL) and filtered. The filtrate was concentrated to dryness.
  • Trifluoromethanesulfonic anhydride (13.4 g, 47.8 mmol) in methylene chloride (10 mL) was added slowly to above solution. After addition, the mixture was stirred at -78°C for 30 min and slowly warmed to room temperature. Then, the reaction was cooled to 0°C and quenched by 10% Na 2 CO 3 (200 mL). The layers were separated and the aqueous layer was extracted with DCM (300 mL*2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness.
  • VV-2 1-(tert-Butyl)-3-ethyl4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1,3(2H)-dicarboxylate (VV-2): A mixture of VV-1 (10 g, 24.7 mmol), bis(pinacolato)diboron (7.5 g,26.9 mmol), potassium acetate (7.3 g, 74.1 mmol) and palladium bis((cyclopenta-1,3-dien-1-yl)diphenylphosphane) dichloromethane iron dichloride (2.0 g, 2.5 mmol) in dioxane (100 mL ) was stirred at 110°C under nitrogen atmosphere for 3 h.
  • VV-3 Di-tert-butyl-5-oxo-8,9-dihydrothieno[3,2-c][2,7]naphthyridine-4,7(5H,6H)- dicarboxylate (VV-3): A mixture of VV-2 (500 mg, 1.8 mmol), 4 (1.4 g, 3.6 mmol), palladium diacetate (40.1 mg, 0.2 mmo), S-Phos (147.0 mg, 0.3 mmol) and potassium carbonate (494.2 mg, 3.6 mmol) in dioxane/water (36 mL, 8:1) was stirred at 80°C for 3 hours and then at room temperature for 16 hours.
  • Ethyl 2-(chroman-4-yl)acetate (WW-2): A mixture of WW-1 (12.0 g, 54.9 mmol) and 10% Pd/C (500 mg) in MeOH (20 mL) was stirred at room temperature under hydrogen atmosphere for 3 hours. The reaction mixture was filtrated; the filtrate was concentrated to obtain the desired compound (12.0 g, 99.1% yield) as a yellow oil. MS(ESI) calculated for C 13 H 16 O 3 , 220.1; found 222.2.
  • N-(4-Bromothiophen-3-yl)-1,1-diphenylmethanimine (YY-1) The solution of 3,4- dibromothiophene (20.0 g, 83.3 mmol), diphenylmethanimine (16.6 g, 91.6 mmol), Pd(OAc) 2 (0.6 g, 2.5 mmol), BINAP (2.6 g, 4.2 mmol) and Cs 2 CO 3 (54.3 g, 166.6 mmol) in toluene (300 mL) was stirred at 110 o C under nitrogen atmosphere for 16 hours.
  • Ethyl (E)-3-(4-((diphenylmethylene)amino)thiophen-3-yl)acrylate (YY-2) The solution of YY-1 (10.0 g, 29.3 mmol), ethyl acrylate (8.8 g, 87.9 mmol), Pd(PPh 3 ) 4 (3.4 g, 2.9 mmol) and TEA (8.9 g, 87.9 mmol) in DMF (100 mL) was stirred at 110 o C under nitrogen for 16 hours. After cooling to room temperature, the mixture was diluted with water (300 mL), extracted with ethyl acetate (150 mL).
  • Ethyl (3S,4R)-1-benzyl-4-(4-((diphenylmethylene)amino)thiophen-3- yl)pyrrolidine-3-carboxylate (YY-3): To a solution of YY-2 (5.0 g, 13.9 mmol) and N- benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (6.6 g, 27.8 mmol) in DCM (50 mL) was added TFA (0.2 g, 1.4 mmol) at 0°C. The reaction mixture was stirred at 0°C for an additional 10 min, and then at room temperature for 2 hours.
  • Ethyl (3S,4R)-4-(4-aminothiophen-3-yl)-1-benzylpyrrolidine-3-carboxylate (YY- 4): A solution of YY-3 (4.0 g, 8.1 mmol), hydroxylamine hydrochloride (1.0 g, 14.6 mmol) and NaOAc (1.7 g, 20.3 mmol) in MeOH (40 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL), extracted with DCM (90 mL).
  • BBB-2 3-[(tert-Butyldimethylsilyl)oxy]propan-1-ol (BBB-2): To a solution of BBB-1 (25.0 g, 89.1 mmol) in MeOH (300 mL) was added 10%Pd/C (2.8 g) at room temperature. The mixture was stirred under hydrogen atmosphere for 19 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give the desired product (15.0 g, 88.3% yield) as a colorless oil.
  • BBB-2 (25.0 g, 131.0 mmol) was added slowly and the resulting mixture was continued to stir for 1 hour.
  • Et 3 N (58.2 g, 576.0 mmol) was added thereto and the reaction mixture was allowed to warm to 0°C.
  • the mixture was poured into HCl (0.1 M, 100 mL).
  • the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL*2).
  • the combined organic layers were washed with water (100 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • BBB-4 3-[(tert-Butyldimethylsilyl)oxy]-1-(2,4-dichloro-1,3-thiazol-5-yl)propan-1-ol (BBB-4): To a solution of 2,4-dichloro-1,3-thiazole (16.6 g, 108.4 mmol) in THF (150 mL ) was added LDA (1 N, 135 mL, 135 mmol) at -60°C under nitrogen. After stirring for 30 min, BBB-3 (17.0 g, 90.2 mmol) was added dropwise to above solution.
  • BBB-5 5- ⁇ 3-[(tert-Butyldimethylsilyl)oxy]-1-(oxan-2-yloxy)propyl ⁇ -2,4-dichloro-1,3- thiazole (BBB-5): To the solution of BBB-4 (12.0 g, 35.0 mmol) and DHP (29.4 g, 350.0 mmol) in DCM (150 mL ) was added TsOH . Py (879 mg, 3.5 mmol) at room temperature. The reaction mixture was heated at reflux for 3.5 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (eluted with petroleum ether) to give the desired product (10.0 g, 66.9% yield) as a colorless oil.
  • BBB-6 5- ⁇ 3-[(tert-Butyldimethylsilyl)oxy]-1-(oxan-2-yloxy)propyl ⁇ -4-chloro-1,3-thiazole (BBB-6): To the solution of BBB-5 (10.0 g, 23.4 mmol) in THF (300 mL ) was added n- BuLi (2.5 N, 11.2 mL, 28.0 mmol) at -70°C under nitrogen atmosphere. The mixture was stirred at -60°C for 30 min. After which period, the reaction was quenched with saturated NH 4 Cl, and the resulting mixture was extracted with ethyl acetate (100 mL*3).
  • BBB-10 5H,6H,7H-Pyrano[2,3-d][1,3]thiazole-7-carbonitrile (BBB-10): To a solution of BBB-9 (0.8 g, 5.08 mmol), 2-hydroxy-2-methylpropanenitrile (1.3 g, 15.2 mmol) and (n- Bu) 3 P (3.07 g, 15.2 mmol) in THF (50 mL ) was added ADDP (3.8 g, 15.2 mmol) portionwise at 0°C under nitrogen atmosphere. After stirring at 0°C for 1.5 hours, the reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL* 3).
  • BBB-12 Tert-butyl-((6,7-dihydro-5H-pyrano[2,3-d]thiazol-7- yl)methyl)(methyl)carbamate
  • E Ethyl (E)-3-(2-nitrothiophen-3-yl)acrylate (CCC-2): The mixture of CCC-1 (10.0 g, 47.7 mmol), ethyl prop-2-enoate (19.2 g, 192.1 mmol), Pd(OAc) 2 (1.6 g, 9.6 mmol) and triphenylphosphine (1.3 g, 4.8 mmol) in TEA (100 mL) was stirred at 100°C under nitrogen for 16 hours.
  • Ethyl (3S,4R)-1-benzyl-4-(2-nitrothiophen-3-yl)pyrrolidine-3-carboxylate (CCC- 3): To the solution of CCC-2 (5.2 g, 13.8 mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (6.6 g, 27.6 mmol) in DCM (30 mL) was added trifluoroacetic acid (156.6 mg, 1.4 mmol) at 0 o C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and extracted with DCM (20 mL*2).
  • Ethyl (3S,4R)-4-(2-aminothiophen-3-yl)-1-benzylpyrrolidine-3-carboxylate (CCC-4): To a solution of CCC-3 (2.0 g, 5.6 mmol) in EtOH (50 mL) and H 2 O (50 mL) was added ammonium chloride (1.5 g, 27.8 mmol) and iron powder (1.6 g, 27.8 mmol), and the mixture was stirred at 90 o C for 2 hours.
  • CCC-5 (3aS,8bR)-2-Benzyl-1,2,3,3a,5,8b-hexahydro-4H-pyrrolo[3,4-d]thieno[2,3- b]pyridin-4-one (CCC-5): To a solution of CCC-4 (1.0 g, 3.0 mmol) in toluene (50 mL) was added dropwise AlMe 3 (6.0 mL, 2 M in toluene) at 0°C. The reaction mixture was stirred at 0 o C for 10 min and then at room temperature for 1 hour. The reaction was quenched with MeOH and celite, the resulting mixture was continued to stir for 10 min, then filtered through a pad of celite.
  • the reaction was quenched with methanol (7 mL) and acetic acid (10 mL) at 0°C.
  • the mixture was diluted with brine (500 mL) and extracted with ethyl acetate (200 mL*2).
  • the combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • Ethyl (Z)-3-(2-nitrothiophen-3-yl)acrylate (DDD-3): To a solution of 18-crown-6 (10.9 g, 79.5 mmol), ethyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (6.3 g, 19.0 mmol) in THF (150 mL) was added NaHMDS (9.5 mL, 2.0 M) at -78 o C under nitrogen atmosphere. After stirring for 1 hour, DDD-2 (2.5 g, 15.9 mmol) was added to the above solution. The resulting mixture was continued to stir at -78 o C for 2 hours.
  • Ethyl (3S,4S)-1-benzyl-4-(2-nitrothiophen-3-yl)pyrrolidine-3-carboxylate (DDD- 4): To a solution of DDD-3 (2.2 g, 9.7 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (4.6 g, 19.3 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (110.0 mg, 1.0 mmol) at 0 o C. The mixture was stirred at 0°C for 30 min and then at room temperature for 1 hour.
  • Ethyl (3S,4S)-4-(2-aminothiophen-3-yl)-1-benzylpyrrolidine-3-carboxylate (DDD-5): To a solution of DDD-4 (2.5 g, 6.9 mmol) in ethanol (100 mL) was added 10% Pd/C (0.7 g), and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the desired compound (1.7 g, 74.6% yield). MS(ESI) calculated for C 18 H 22 N 2 O 2 S, 330.1; found 331.1.
  • FFF-2 4-Methyleneisochromane
  • the solution of FFF-1 (12.8 g, 46.6 mmol), palladium diacetate (0.5 g, 2.3 mmol), triethylamine (23.5 g, 233 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in acetonitrile (100 mL) was stirred at 80°C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • FFF-3 Isochroman-4-ylmethanol (FFF-3): To a solution of FFF-2 (3.1 g, 21.2 mmol) in dry THF (20 mL) was added BH 3-THF (1 M, 63.6 mL) dropwise at 0°C under nitrogen atmosphere. The reaction was stirred at 0°C for 1 hour and then allowed to stir for 2 hours at room temperature. Aqueous NaOH (3 N, 35.3 mL) was added thereto, followed by H 2 O 2 (13 mL,30% in water). The reaction was stirred for 2 hours at room temperature. The reaction was continued to stir at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (300 mL).
  • N-(2,2-Dimethoxyethyl)-1,1,1-trifluoro-N-(isochroman-4- ylmethyl)methanesulfonamide (FFF-4): The mixture of FFF-3 (1.7 g, 10.3 mmol), N-(2,2- dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (2.9 g, 12.3 mmol) and PPh 3 (5.4 g, 20.6 mmol) in dry THF (20 mL) was stirred at 0°C under nitrogen atmosphere. Diethyl azodicarboxylate (3.6 g, 20.6 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours.
  • tert-Butyl 3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)-carboxylate (FFF-8): To a solution of FFF-7 (0.1 g, 0.5 mmol) in THF (6 mL) and NaHCO 3 (6 mL) was added Boc 2 O (0.2 g, 1.0 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness.
  • Boc 2 O 0.2 g, 1.0 mmol
  • Ethyl (Z)-3-(4-bromothiophen-3-yl)acrylate (GGG-2): To a solution of ethyl 2- (bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (12.6 g, 37.9 mmol,) and 18-Crown-6 (30.0 g, 113.8 mmol) in THF (100 mL) was added NaHMDS (2 N, 19.0 mL, 37.9 mmol) at -78 o C under nitrogen atmosphere. The reaction mixture was stirred at -78°C for an additional 30 min, followed by addition of GGG-1 (6.0 g, 31.6 mmol). The reaction was continued to stir at -78 o C for 1 hour.
  • Ethyl (3r,4r)-1-benzyl-4-(4-bromothiophen-3-yl)pyrrolidine-3-carboxylate (GGG-3): To a solution of GGG-2 (3.0 g, 11.5 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (5.5 g, 23.0 mmol) in DCM (30 mL) was added TFA (136.8 mg, 1.2 mmol) at 0°C. The reaction mixture was stirred at 0 °C for 10 min, and then at room temperature for an additional 2 hours. The mixture was diluted with water (50 mL) and extracted with DCM (60 mL).
  • Ethyl (3r,4r)-4-(4-bromothiophen-3-yl)pyrrolidine-3-carboxylate (GGG-4): To the solution of GGG-3 (3.0 g, 7.6 mmol) and K 2 CO 3 (2.1 g, 15.2 mmol) in DCE (30 mL) was added ACE-Cl (2.2 g, 15.2 mmol), and the resulting mixture was stirred at 80 o C for 16 hours. After cooling to room temperature, the mixture was filtered and concentrated to dryness. The residue was dissolved in MeOH (20 mL) and stirred at room temperature for 2 hours.
  • GGG-7 1-(tert-Butyl) 3-ethyl (3r,4r)-4-(4-(((benzyloxy)carbonyl)amino)thiophen-3- yl)pyrrolidine-1,3-dicarboxylate (GGG-7): The solution of GGG-6 (1.8 g, 4.9 mmol), benzyl alcohol (1.6 g, 14.7 mmol), DPPA (2.0 g, 7.4 mmol) and TEA (2.0 g, 19.6 mmol) in toluene (20 mL) was stirred at 110 o C for 2 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (60 mL).
  • tert-Butyl (5aR,8aR)-5-oxo-4,5,5a,6,8,8a-hexahydro-7H-pyrrolo[3,4-d]thieno[3,4- b]pyridine-7-carboxylate (GGG-8): To a solution of GGG-7 (120.0 mg, 0.3 mmol) and 10% Pd/C (10.6 mg, 0.1 mmol) in MeOH (6 mL) was stirred at room temperature under hydrogen atmosphere for 16 hours.
  • HHH-2 3,3a,4,5-Tetrahydro-2H-chromeno[5,4-cd]azepine
  • Phosphorus oxychloride 1.5 g, 9.7 mmol
  • PPA 19.7 g, 58.4 mmol
  • a solution of HHH-1 1.0 g, 4.9 mmol
  • toluene 50 mL
  • the resulting mixture was continued to stir at 70°C for 30 min, and then at 120°C for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice-NaHCO 3 solution.
  • HHH-3 tert-Butyl 2,3,3a,4,5,7-hexahydro-6H-chromeno[5,4-cd]azepine-6-carboxylate (HHH-3): To a solution of HHH-2 (80.0 mg, 0.4 mmol) in methanol (20 mL) was added sodium borohydride (47.0 mg, 1.3 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove methanol. The residue was re- dissolved in THF (20 mL), and then sodium bicarbonate (107.0 mg, 1.3 mmol) and di-tert- butyl pyrocarbonate (186.0 mg, 0.9 mmol) were added.
  • III-2 Chroman-4-ylmethanol
  • JJJ-2 (2,3-Dihydrobenzofuran-3-yl)methanol
  • JJJ-3 N-((2,3-Dihydrobenzofuran-3-yl)methyl)-N-(2,2-dimethoxyethyl)-1,1,1- trifluoromethanesulfonamide (JJJ-3): To a solution of JJJ-2 (2.0 g, 13.3 mmol), N-(2,2- dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (3.8 g, 15.9 mmol) and triphenylphosphine (10.4 g, 40.0 mmol) in tetrahydrofuran (100 mL) was added DEAD (7.0 g, 40.0 mmol) dropwise at 0°C.
  • DEAD 7.0 g, 40.0 mmol
  • JJJ- 4 8-((Trifluoromethyl)sulfonyl)-1,8,9,9a-tetrahydrobenzofuro[3,4-cd]azepine (JJJ- 4): Phosphorus oxychloride (0.7 mL, 7.3 mmol) was added to a solution of PPA (1 mL) in toluene (40 mL) at 60°C under nitrogen atmosphere. After stirring for 15 min, a solution of JJJ-3 (1.2 g, 3.3 mmol) in toluene (5 mL) was added thereto and the resulting mixture was continued to stir at 120°C for 16 hours.
  • JJJ-5 8-((Trifluoromethyl)sulfonyl)-1,6,7,8,9,9a-hexahydrobenzofuro[3,4-cd]azepine (JJJ-5): The solution of JJJ-4 (160.0 mg, 0.5 mmol) and 10 % Pd/C (16.0 mg) in MeOH (10 mL) was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to get the crude compound (160.0 mg) without further purification. MS(ESI) calculated for C 12 H 10 F 3 NO 3 S, 305.0; found 306.0.
  • LLL-2 4-Methyleneisochromane (LLL-2): A mixture of LLL-1 (45.0 g, 164.2 mmol), palladium diacetate (1.84 g, 8.2 mmol), triethylamine (82.9 g, 821.1 mmol) and triphenylphosphine (4.3 g, 16.4 mmol) in acetonitrile (200 mL) was stirred at 80°C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL*3).
  • Isochroman-4-one (LLL-3): To a solution LLL-2 (11.5 g, 78.6 mmol) in dioxane (80 mL) and water (80 mL) was added sodium periodate (50.4 g, 235.8 mmol) at 0°C, and the mixture was stirred at 0°C for 30 min. Then, K 2 OsO 4 .2H 2 O (1.5 g, 3.9 mmol) was added to the above mixture, which was continued to stir at room temperature for 16 hours. The reaction was poured into water (1000 mL) and extracted with ethyl acetate (1000 mL*3).
  • LLL-7 1-(3,4-Dichlorophenyl)-N-(2-(isochroman-4-yl)ethyl)methanesulfonamide (LLL- 7): To the solution of LLL-6 (1 g, 5.6 mmol) and DIPEA (1.1 g, 8.5 mmol) in DCM (20 mL) was added (3,4-dichlorophenyl)methanesulfonyl chloride (2.2 g, 8.5 mmol) in DCM (10 mL) dropwise. The reaction was stirred at 0°C for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with DCM (100 mL*3).

Abstract

The present disclosure provides compounds and pharmaceutical compositions thereof. Methods of making and using the compounds are also provided. The compounds can be used to modulate such as activate TAAR1 and can be used for the treatment, prevention, diagnosis and/or management of various CNS disorders.

Description

COMPOUNDS AND COMPOSITIONS FOR TREATING CNS DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to US Prov. Application No. 63/164,057 filed March 22, 2021, entitled “COMPOUNDS AND COMPOSITIONS FOR MODULATING TAAR1,” the contents of each of which are incorporated herein by reference in their entirety. BACKGROUND [0002] Trace amine-associated receptor 1 (TAAR1) is widely expressed in the central nervous system (CNS) such as brain. It is involved in neuronal interactions and pathways and has profound effects on the modulation of the CNS function. The neural effects of the known TAAR1 agonists, such as p-Octopamine, β-PEA, p-Tyramine, and T1AM, include increasing neuronal responses to noradrenaline, norepinephrine, or dopamine, as discussed by Rutigliano et al. in Front Pharmacol, vol.8:987 (2018). Therefore, TAAR1 is an important target in neurology and/or psychiatry. [0003] However, it has been difficult to find a selective TAAR1 agonist. A lot of TAAR1 agonists have multiple targets. For example, in addition to TAAR1, T1AM can also interact with other TAAR subtypes (particularly TAAR5), α2A- and β-adrenergic receptors, serotonin 1A receptor (5HT1A), TRM8 calcium channels, and membrane amine transporters like dopamine transporter (DAT), norepinephrine transporter (NET), and vesicular monoamine transporter (VMAT). There remains a need to find therapeutic agents as TAAR1 agonists, methods and therapies for modulating such as activating TAAR1. SUMMARY OF THE DISCLOSURE [0004] The present disclosure provides compounds and compositions for activating TAAR1 and treating CNS disorders. The compound may be encompassed by Formula (I): a tautomer, or a pharmaceutically acceptable salt thereof,
Figure imgf000002_0001
wherein X1 (when n>1, each X1 independently), X2 or X3 each is independently C(R1)(R2), O, N(R3), S, CO, SO, or SO2; X4 is C(R4) or N; X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein optionally R5a or R5b is attached to any atom on ring A and form a cyclic group, and optionally R5a or R5b is attached to X1 to form a cyclic group; R1, R2, R3, R4, R5a, or R5b each is independently hydrogen, halo, cyano, (C1-C10)alkyl optionally substituted with one or more R7, (C2-C10)alkenyl optionally substituted with one or more R7, (C3-C10)cycloalkyl optionally substituted with one or more R7, (C1- C10)heteroalkyl optionally substituted with one or more R7, (3 to 10 membered)heterocyclyl optionally substituted with one or more R7, (C6-C12)aralkyl optionally substituted with one or more R7, (6 to 10 membered)aryl optionally substituted with one or more R7, (5 to 10 membered)heteroaryl optionally substituted with one or more R7, =O, -OR7, NR7R8, - N(R7)C(O)R8, -C(O)NR7R8, -C(O)R7, -C(O)OR7, -OC(O)R7, -OC(O)NR7R8, - NR7C(O)OR8, -SR7, -S(O)R7, -S(O)2R7, -S(O)2NR7R8, -NR7S(O)2R8, or - NR7C(O)NR8R9; optionally two geminal R1, R2, R3, R4, R5a, or R5b substituents together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl ring; optionally two vicinal R1, R2, R3, R4, R5a, or R5b substituents together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; R7, R8, and R9 are each independently hydrogen, halo, cyano, (C1-C6)alkyl, (C2- C6)alkenyl, (C3-C7)cycloalkyl, (C7-C10)aralkyl; (C1-C6)heteroalkyl, (3 to 8 membered)heterocyclyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl; optionally two geminal or vicinal R7 substituents together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered ring; optionally R7 and R8, or R8 and R9 together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered ring; ring A is an optionally substituted aryl or heteroaryl group, wherein optionally each atom on ring A is substituted with R11; each R11 is independently hydrogen, halo, cyano, (C1-C10)alkyl, (C2-C10)alkenyl, (C3- C10)cycloalkyl, (C1-C10)heteroalkyl, (3 to 10 membered)heterocyclyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, alkoxyl, aryloxyl, aminoalkyl, hydroxyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which may be optionally substituted with one or more R10; optionally two adjacent R11 substituents together with the atoms to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; each R10 is independently a bond, hydrogen, halo, cyano, (C1-C10)alkyl, (C2- C10)alkenyl, (C3-C10)cycloalkyl, (C1-C10)heteroalkyl, (3 to 10 membered)heterocyclyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, alkoxyl, aminoalkyl, hydroxyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which may be optionally substituted with one or more R1; optionally two geminal or vicinal R10 substituents together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered ring; R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to X1, X2, X3, X4, R1, R2, R3, R4, R11 or any atom on ring A and form a heterocycle which may be optionally substituted, optionally R12 and R13 together with the nitrogen to which they are attached can be joined together to form an optionally substituted 3 to 8 membered ring; n is 0, 1, or 2, and m is 1, 2, or 3. [0005] In some embodiments, the compounds may be anyone of Compounds 1-206. [0006] The present disclosure also provides a method of activating TAAR1 in a subject in need thereof, comprising administering to said subject an effective amount of the compounds of the present disclosure or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition comprising the compounds of the present disclosure or a pharmaceutically acceptable salt thereof. [0007] The present disclosure further provides a method of treating, preventing, or managing a CNS disorder in a subject in need thereof, comprising administering to said subject an effective amount of the compounds of the present disclosure or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition comprising the compounds of the present disclosure or a pharmaceutically acceptable salt thereof. In some cases, the CNS disorder is a neurological or psychiatric disorder. In some cases, the CNS disorder is psychosis, geriatric psychosis, Alzheimer’s-related psychosis, Parkinson’s related psychosis, age-related psychosis or schizophrenia. In some cases, the CNS disorder is dementia-related agitation, Alzheimer’s agitation, paranoia and mania. In some cases, the CNS disorder is affective disorders. In some cases, the CNS disorder is depression or dysthymia. In some cases, the CNS disorder is bipolar depression, unipolar depression, major depressive disorder, treatment-resistant depression, suicidal behavior disorder, apathy or anhedonia. DETAILED DESCRIPTION [0008] CNS drug discovery differs from most other therapeutic areas because of the complex and multigenic nature of most psychiatric and neurological disorders. Of particular interest are therapies that (i) have a rapid onset of action to treat the CNS disorder, (ii) have efficacy in achieving and sustaining long term remission, (iii) have improved safety and a more tolerable side effect profile. I. COMPOSITIONS OF THE DISCLOSURE [0009] Applicant has used multiple and complementary assays to drive therapeutic drug discovery. In general, the compounds of the present disclosure are bicyclic or multicyclic small molecule compounds described below. [0010] In some embodiments, the molecular weight (MW) of the compound may not be more than 500 g/mol. In some embodiments, the molecular weight (MW) of the compound may not be more than 300 g/mol. In some embodiments, the compound has low lipophilicity. For example, the logP of the compound may not be more than 3. In some embodiments, the hydrogen bond donor (HBD) of the compound may not be more than 3. In some embodiments, the hydrogen bond acceptor (HBA) of the compound may not be more than 3. [0011] Unless otherwise stated, structures presented herein can include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the present disclosure. Compounds of the present disclosure may exist in alternative tautomeric forms. A representation of one tautomer is meant to include the other. [0012] Unless otherwise stated, structures presented herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, replacements of a hydrogen atom by deuterium or tritium, or carbon atom by a 13C- or 14C-enriched carbon are within the scope of the present disclosure. [0013] In some embodiments, the compounds of the present disclosure are selected from the group consisting of any compounds in Table 1. Table 1. Structures of Non-limiting Examples of Compounds
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
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_0002
[0014] In some embodiments, the compounds of the present disclosure have a general structure of Formula (I): a tautomer, or a pharmaceutically
Figure imgf000049_0001
acceptable salt thereof, wherein X1 (when n>1, each X1 independently), X2 or X3 each is independently C(R1)(R2), O, N(R3), S, CO, SO, or SO2; X4 is C(R4) or N; X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein optionally R5a or R5b may be attached to any atom on ring A and form a cyclic group, and optionally R5a or R5b may be attached to X1 to form a cyclic group; R1, R2, R3, R4, R5a, or R5b each is independently hydrogen, halo, cyano, (C1-C10)alkyl optionally substituted with one or more R7, (C2-C10)alkenyl optionally substituted with one or more R7, (C3-C10)cycloalkyl optionally substituted with one or more R7, (C1- C10)heteroalkyl optionally substituted with one or more R7, (3 to 10 membered)heterocyclyl optionally substituted with one or more R7, (C6-C12)aralkyl optionally substituted with one or more R7, (6 to 10 membered)aryl optionally substituted with one or more R7, (5 to 10 membered)heteroaryl optionally substituted with one or more R7, =O, -OR7, NR7R8, - N(R7)C(O)R8, -C(O)NR7R8, -C(O)R7, -C(O)OR7, -OC(O)R7, -OC(O)NR7R8, - NR7C(O)OR8, -SR7, -S(O)R7, -S(O)2R7, -S(O)2NR7R8, -NR7S(O)2R8, or - NR7C(O)NR8R9; optionally two geminal R1, R2, R3, R4, R5a, or R5b substituents together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl ring; optionally two vicinal R1, R2, R3, R4, R5a, or R5b substituents together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; R7, R8, and R9 are each independently hydrogen, halo, cyano, (C1-C6)alkyl, (C2- C6)alkenyl, (C3-C7)cycloalkyl, (C7-C10)aralkyl; (C1-C6)heteroalkyl, (3 to 8 membered)heterocyclyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl; optionally two geminal or vicinal R7 substituents together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered ring; optionally R7 and R8, or R8 and R9 together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered ring; ring A is an optionally substituted aryl or heteroaryl group, wherein optionally each atom on ring A is substituted with R11; each R11 is independently hydrogen, halo, cyano, (C1-C10)alkyl, (C2-C10)alkenyl, (C3- C10)cycloalkyl, (C1-C10)heteroalkyl, (3 to 10 membered)heterocyclyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, alkoxyl, aryloxyl, aminoalkyl, hydroxyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which may be optionally substituted with one or more R10; optionally two adjacent R11 substituents together with the atoms to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; each occurrence of R10 is independently a bond, hydrogen, halo, cyano, (C1-C10)alkyl, (C2-C10)alkenyl, (C3-C10)cycloalkyl, (C1-C10)heteroalkyl, (3 to 10 membered)heterocyclyl, (6 to 10 membered)aryl, (5 to 10 membered)heteroaryl, alkoxyl, aminoalkyl, hydroxyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which may be optionally substituted with one or more R1; optionally two geminal or vicinal R10 substituents together with the atom(s) to which they are attached form an optionally substituted 3 to 10 membered ring; R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to X1, X2, X3, X4, R1, R2, R3, R4, R11 or any atom on ring A and form a heterocycle which may be optionally substituted, optionally R12 and R13 together with the nitrogen to which they are attached can be joined together to form an optionally substituted 3 to 8 membered ring; n is 0, 1, or 2, and m is 1, 2, or 3. [0015] Ring A and the cyclic structure attached to Ring A is referred to as the bicyclic core or bicyclic core structure. [0016] In some embodiments, ring A is an aryl group. In some embodiments, ring A is an optionally substituted phenyl group. [0017] In some embodiments, ring A is an optionally substituted 5-7 membered heteroaryl group, comprising at least one heteroatom selected from the group consisting of S, N and O. In some embodiments, ring A is an optionally substituted thiophene group. In some embodiments, ring A is an optionally substituted pyridine group. In some embodiments, ring A is an optionally substituted furan group. [0018] In some embodiments, R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH 3), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3). [0019] In some embodiments, m=1 and X5 is CH2. In some embodiments, m=2 and X5 is CH2. [0020] In some embodiments, R5a or R5b is attached to any atom on ring A and form a 5-7 membered cyclic group. [0021] In some embodiments, R12 or R13 is attached to X1, X2, X3, X4, R1, R2, R3, R4, R11 or any atom on ring A and form a 5-7 membered heterocycle. In some embodiments, R12 or R13 is attached to X1 or X4 and form a 5-7 membered heterocycle. [0022] In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0023] In some embodiments, X1 and X2 are independently C(R1)(R2), wherein R1 and R2 are independently optionally substituted alkyl or alkenyl, wherein two vicinal R1 or R2 substituents together with the atom(s) to which they are attached form an optionally substituted 6-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; X3 is independently C(R1’)(R2’), O, N(R3), S, CO, SO, or SO2, wherein each R1’, R2’ and R3 are independently optionally substituted H, alkyl, halogen, hydroxyl, ether, CN, amine, or CF3; X4 is CH; X5 is C(R5a)(R5b), wherein each R5a and R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl); R13 is connected to ring A to form a 6 or 7-membered heterocycle; ring A is aryl, 6-membered heteroaryl, or 5-membered heteroaryl; n=1; and m=1. Non-limiting examples of the compounds include Compounds 16, 91, 92, 93, or a pharmaceutically acceptable salt thereof. [0024] Non-limiting examples of compounds encompassed by Formula (I) include Compounds 1-138, 140-206, or a pharmaceutically acceptable salt thereof. Generic Structure (II): [0025] In some embodiments, the compounds of the present disclosure have a general structure of Formula (II): a tautomer or a pharmaceutically
Figure imgf000052_0001
acceptable salt thereof, wherein Y1, Y2, Y3 or Y4 each is independently N or CR11, X1 (when n>1, each X1 independently), X2 or X3 each is independently C(R1)(R2), O, N(R3), S, CO, SO, or SO2, X4 is C(R4) or N, X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein optionally R5a or R5b may be attached to Y4 to form a cyclic group, R1, R2, R3, R4, R5a, or R5b each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, amine, aryl, or heteroaryl, wherein optionally two adjacent R11 substituents together with the atoms to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to X1, X2, X3, X4, Y1, Y2, Y3, Y4, R1, R2, R3, R4, or R11 and form a heterocycle which may be optionally substituted, n is 0, 1, or 2, and m is 1, 2, or 3. [0026] In some embodiments, R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH3), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3). [0027] In some embodiments, m=1 and X5 is CH2. In some embodiments, m=2 and X5 is CH2. [0028] In some embodiments, R5a or R5b is attached to Y4 and form a 5-6 membered cyclic group. [0029] In some embodiments, R12 or R13 is attached to X1, X2, X3, X4, R1, R2, R3, R4, R11, Y1, Y2, Y3 or Y4 and form a 5-7 membered heterocycle. In some embodiments, R12 or R13 is attached to Y4, X1, or X4 and form a 5-7 membered heterocycle. [0030] In some embodiments, each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3. In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0031] In some embodiments, Y1, Y2, Y3, Y4, and X4 are carbons, R13 is CH2CH2 and is connected to Y4 to form a 7-membered heterocycle, X1, X2 and X3 are independently O or C(R1)(R2), X5 is CH2, n=0 or 1, and m=1. [0032] Non-limiting examples of compounds encompassed by Formula (II) include Compounds 1-15, 17-25, 27-88, 90, 94-123, 166-205, or a pharmaceutically acceptable salt thereof. [0033] When R12 is H or a lower alkyl, R13 is a lower alkyl, and R13 is attached to X1 or Y4 and form a 5-7 membered heterocycle, compounds encompassed by Formula (II) include Compounds 10-13, 22-25, 69-70, 72-75, 83-88, 114-115, 166, 168, 169, 171-173, 176-205, a pharmaceutically acceptable salt thereof. [0034] In some embodiments, the compounds of the present disclosure have a general structure of Formula (II-1): a tautomer, or a
Figure imgf000054_0001
pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), O, or N(R3), X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein optionally R5a or R5b may be attached to any atom on the aryl ring and form a cyclic group, R1, R2, R3, R5a, R5b, R21 or R22 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optionally has an R11 substituent, wherein each R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, amine, aryl, or heteroaryl, and wherein optionally two adjacent R11 substituents together with the carbons to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to R11 or any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, n is 0, 1, or 2, and m is 1, 2, or 3. [0035] In some embodiments, R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH3), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3). [0036] In some embodiments, m=1 and X5 is CH2. In some embodiments, m=2 and X5 is CH2. [0037] In some embodiments, each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3. In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0038] Non-limiting examples of compounds encompassed by Formula (II-1) include Compounds 1-11, 21-25, 47-64, 66, 68-78, 84-85, 110-115, 174, 175, 184, or a pharmaceutically acceptable salt thereof. [0039] When R12 is H or a lower alkyl, R13 is a lower alkyl, and R13 is attached to X1 or any position on the aromatic ring and form a 5-7 membered heterocycle, compounds encompassed by Formula (II-1) include Compounds 10-11, 21, 23-24, 69-70, 72-75, 84-85, 114-115, 184, or a pharmaceutically acceptable salt thereof. [0040] In some embodiments, X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and wherein when n is 1, m is 1 or 2 and when n is 0, m is 2. Non- limiting examples of the compounds include Compounds 11, 23, 84-85, or a pharmaceutically acceptable salt thereof. [0041] In some embodiments, X1 is C(R1)(R2); X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6- 7 membered heterocycle which may be optionally substituted; and n is 0 and m is 2. Non- limiting examples of the compounds include Compound 11, or a pharmaceutically acceptable salt thereof. [0042] In some embodiments, X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and n is 1 and m is 1. Non-limiting examples of the compounds include Compounds 23, 85 or a pharmaceutically acceptable salt thereof. [0043] In some embodiments, X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and n is 1 and m is 2. Non-limiting examples of the compounds include Compound 84, or a pharmaceutically acceptable salt thereof. [0044] In some embodiments, the compounds of the present disclosure have a general structure of Formula (II-2): a tautomer, or a
Figure imgf000057_0001
pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), X5 (when m>1, each X5 independently) is C(R5a)(R5b), R1, R2, R5a, R5b, R21, or R22 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optionally has an R11 substituent, wherein each R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, amine, aryl, or heteroaryl, wherein optionally two adjacent R11 substituents together with the carbons to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to R11 or any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, n is 0, 1, or 2, and m is 1, 2, or 3. [0045] In some embodiments, R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH3), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3). [0046] In some embodiments, m=1 and X5 is CH2. In some embodiments, m=2 and X5 is CH2. [0047] In some embodiments, each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3. In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0048] Non-limiting examples of compounds encompassed by Formula (II-2) include Compounds 12, 13, 15, 17, 18, 79-83, 86, 90, 116-119, 166-170, 173, 178, 179, 181, 183, 186, 187, 189, 191, 193, 197, 201, 203, 205, or a pharmaceutically acceptable salt thereof. [0049] When R12 is H or a lower alkyl, R13 is a lower alkyl, and R13 is attached to X1 or any position on the aromatic ring and form a 5-7 membered heterocycle, compounds encompassed by Formula (II-2) include Compounds 12, 13, 17, 18, 83, 86, 90, 166, 168, 169, 173, 178, 179, 181, 183, 186, 187, 191, 193, 197, 199, 201, 203, 205, or a pharmaceutically acceptable salt thereof. [0050] In some embodiments, X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and wherein when n is 0, m is 1 or 2 and when n is 1, m is 1. Non- limiting examples of the compounds include Compounds 12, 13, 15, 17, 18, 83, 166, 168, 169, 173, 178, 179, 181, 183, 186, 191, 193, 197, 199, 201, 203, 205, or a pharmaceutically acceptable salt thereof. [0051] In some embodiments, X1 is C(R1)(R2); X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6- 7 membered heterocycle which may be optionally substituted; and n is 0 and m is 1. Non- limiting examples of the compounds include Compounds 13, 166, 201, or a pharmaceutically acceptable salt thereof. [0052] In some embodiments, X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and n is 0 and m is 2. Non-limiting examples of the compounds include Compounds 12, or a pharmaceutically acceptable salt thereof. [0053] In some embodiments, X1 is C(R1)(R2); X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6- 7 membered heterocycle which may be optionally substituted; and n is 1 and m is 1. Non- limiting examples of the compounds include Compounds 15, 17, 18, 83, 168, 169, 173, 178, 179, 181, 183, 186, 191, 193, 197, 199, 201, 203, 205, or a pharmaceutically acceptable salt thereof. [0054] In some embodiments, the compounds of the present disclosure have a general structure of Formula (II-3):
Figure imgf000060_0001
a tautomer, or a pharmaceutically acceptable salt thereof, wherein X2 (when n>1, each X2 independently) is C(R1)(R2), X5 (when m>1, each X5 independently) is C(R5a)(R5b), R1, R2, R5a, R5b, R21, or R22 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optionally has an R11 substituent, wherein each R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, amine, aryl, or heteroaryl, wherein optionally two adjacent R11 substituents together with the carbons to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to R11 or any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, m is 1 or 2, and n is 0, 1, or 2. [0055] In some embodiments, R11 is halogen (such as F or Cl), CN, alkoxy (such as OCH3), a methyl group substituted with amine (such as CH2NH2), a methyl group substituted with halogen(s) (such as CF3). [0056] In some embodiments, m=1 and X5 is CH2. In some embodiments, m=2 and X5 is CH2. [0057] In some embodiments, each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3. In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0058] Non-limiting examples of compounds encompassed by Formula (II-3) include Compounds 19, 20, 87, 88, 170, 171, 172, 176, 177, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof. [0059] When R12 is H or a lower alkyl, R13 is a lower alkyl, and R13 is attached to any position on the aromatic ring and form a 5-7 membered heterocycle, compounds encompassed by Formula (II-3) include Compounds 19, 20, 87, 88, 171, 172, 176, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof. [0060] In some embodiments, X2 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and wherein n is 0 or 1 and m is 1 or 2. Non-limiting examples of the compounds include Compounds 19, 20, 87, 88, 171, 172, 176, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof. [0061] In some embodiments, X2 is C(R1)(R2); X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6- 7 membered heterocycle which may be optionally substituted; and n is 0 and m is 1. [0062] In some embodiments, X2 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and n is 0 and m is 2. [0063] In some embodiments, X2 is C(R1)(R2); X5 is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6- 7 membered heterocycle which may be optionally substituted; and n is 1 and m is 1. Non- limiting examples of the compounds include Compounds 19, 20, 87, 171, 172, 176, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof. [0064] In some embodiments, X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), wherein each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and n is 1 and m is 2. Non-limiting examples of the compounds include Compound 88 or a pharmaceutically acceptable salt thereof. [0065] In some embodiments, the compounds of the present disclosure have a general structure of Formula (II-4): a tautomer, or a
Figure imgf000063_0001
pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) each is independently C(R1)(R2), O, N(R3), S, CO, SO, or SO2, X2 is C(R1)(R2), CO, R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optionally has an R11 substituent, wherein each R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, amine, aryl, or heteroaryl, wherein optionally two adjacent R11 substituents together with the carbons to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to R11 or any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, n is 0, 1, or 2, and m is 1, 2, or 3. [0066] In some embodiments, each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3. In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0067] Non-limiting examples of compounds encompassed by Formula (II-4) include Compounds 27-46, 94-109, or a pharmaceutically acceptable salt thereof. [0068] In some embodiments, X1 and X2 are both C(R1)(R2); wherein each R1, R2, and R3 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; wherein when n is 1, m is 1 or 2 and when n is 0, m is 2. [0069] In some embodiments, X1 and X2 are both C(R1)(R2); wherein each R1, R2, and R3 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and n is 1 and m is 1. [0070] In some embodiments, X1 and X2 are both C(R1)(R2); wherein each R1, R2, and R3 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and n is 1 and m is 2. [0071] In some embodiments, X1 and X2 are both C(R1)(R2); wherein each R1, R2, and R3 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and n is 0 and m is 2. [0072] In some embodiments, the compounds of the present disclosure have a general structure of Formula (II-5):
Figure imgf000065_0001
a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R21, R22, R23 or R24 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, any carbon on the phenyl ring optionally has an R11 substituent, wherein each R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, amine, aryl, or heteroaryl, wherein optionally two adjacent R11 substituents together with the carbons to which they are attached form an optionally substituted 3 to 10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to R11 or any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, and m is 1, 2, or 3. [0073] In some embodiments, R11 is halogen (such as F or Cl), alkoxy (such as OCH3), a methyl group substituted with amine (such as CH2NH2), or a methyl group substituted with halogen(s) (such as CF3). [0074] In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0075] In some embodiments, m=2. [0076] Non-limiting examples of compounds encompassed by Formula (II-5) include Compound 14, or a pharmaceutically acceptable salt thereof. Generic Structure (III): [0077] In some embodiments, the compounds of the present disclosure have a general structure of Formula (III): a tautomer, or a pharmaceutically
Figure imgf000066_0001
acceptable salt thereof, wherein Z1, Z2, or Z3 each independently is CR11, N, O, or S, Z4 or Z5 each independently is C or N, X1 (when n>1, each X1 independently), X2 or X3 each independently is C(R1)(R2), O, N(R3), S, CO, SO, or SO2, R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, amine, aryl, or heteroaryl, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to R11 or any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, n is 0, 1, or 2, and m is 1, 2, or 3. [0078]
Figure imgf000067_0001
in Formula (III) is a heteroaromatic ring. [0079] When at least one of Z4 or Z5 is N, Z1, Z2 and Z3 can all be CR11. [0080] When Z4 and Z5 are both C, at least one of Z1, Z2 or Z3 is not CR11. [0081] In some embodiments, X2 is C(R1)(R2). [0082] In some embodiments, R12 or R13 is attached to Z3 or X1 and form a 5-7 membered heterocycle. In some embodiments, R12 or R13 is an alkyl and is attached to X1 and form a 5-7 membered heterocycle. [0083] In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0084] Non-limiting examples of compounds encompassed by Formula (III) include Compounds 124-165, or a pharmaceutically acceptable salt thereof. [0085] When X3 is N, the compounds encompassed by Formula (III) include Compounds 124-138, or a pharmaceutically acceptable salt thereof. [0086] When X3 is O, the compounds encompassed by Formula (III) include Compounds 140-148 or 154-165, or a pharmaceutically acceptable salt thereof. [0087] When X3 is S, the compounds encompassed by Formula (III) include Compounds 149-150, or a pharmaceutically acceptable salt thereof. [0088] When X3 is SO, the compounds encompassed by Formula (III) include Compounds 151-152, or a pharmaceutically acceptable salt thereof. [0089] When X3 is SO2, the compounds encompassed by Formula (III) include Compounds 153 or a pharmaceutically acceptable salt thereof. [0090] In some embodiments, the compounds of the present disclosure have a general structure of Formula (III-1): a tautomer, or a
Figure imgf000068_0001
pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), O, N(R3), S, CO, SO, or SO2, X2 or X3 each independently is C(R1)(R2), O, N(R3), CO, SO, or SO2, R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, n is 0, 1, or 2, and m is 1, 2, or 3. [0091] In some embodiments, R12 or R13 is an alkyl and is attached to X1 and form a 5-7 membered heterocycle. [0092] In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0093] Non-limiting examples of compounds encompassed by Formula (III-1) include Compounds 124-127, 130-134, 146-148, 154-159 or a pharmaceutically acceptable salt thereof. [0094] In some embodiments, the compounds of the present disclosure have a general structure of Formula (III-2):
Figure imgf000069_0001
a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), O, N(R3), S, CO, SO, or SO2, X2 or X3 each independently is C(R1)(R2), O, N(R3), CO, SO, or SO2, R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, n is 0, 1, or 2, and m is 1, 2, or 3. [0095] In some embodiments, R12 or R13 is an alkyl and is attached to X1 and form a 5-7 membered heterocycle. [0096] In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0097] Non-limiting examples of compounds encompassed by Formula (III-2) include Compounds 128-129, 135, 138, 143-145, 160-162, or a pharmaceutically acceptable salt thereof. [0098] In some embodiments, the compounds of the present disclosure have a general structure of Formula (III-3): a tautomer, or a
Figure imgf000070_0001
pharmaceutically acceptable salt thereof, wherein X1 (when n>1, each X1 independently) is C(R1)(R2), O, N(R3), S, CO, SO, or SO2, X2 or X3 each independently is C(R1)(R2), O, N(R3), CO, SO, or SO2, R1, R2, or R3 each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to any atom on the bicyclic core structure and form a heterocycle which may be optionally substituted, n is 0, 1, or 2, and m is 1, 2, or 3. [0099] In some embodiments, R12 or R13 is an alkyl and is attached to X1 and form a 5-7 membered heterocycle. [0100] In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0101] Non-limiting examples of compounds encompassed by Formula (III-3) include Compounds 136-137, 140-142, 149-159, or a pharmaceutically acceptable salt thereof. Generic Structure (IV): [0102] In some embodiments, the compounds of the present disclosure have a general structure of Formula (IV): or a pharmaceutically
Figure imgf000071_0001
acceptable salt thereof, wherein Z is C(R1)(R2), O, N(R3), S, CO, SO, or SO2, X5 (when m>1, each X5 independently) is C(R5a)(R5b), R1, R2, R3, R5a or R5b each is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, ether, CN, amine, aryl, or heteroaryl, R11 is H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, amine, aryl, or heteroaryl, R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), wherein optionally R12 or R13 may be attached to any position in the aromatic rings and form a heterocycle which may be optionally substituted, and m is 1, 2, or 3. [0103] In some embodiments, R11 is halogen (such as F or Cl), alkoxy (such as OCH3), a methyl group substituted with amine (such as CH2NH2), or a methyl group substituted with halogen(s) (such as CF3). [0104] In some embodiments, m=1 and X5 is CH2. In some embodiments, m=2 and X5 is CH2. [0105] In some embodiments, R12 is H or a lower alkyl, R13 is a lower alkyl, and R13 is attached to any position on the aromatic rings and form a 5-7 membered heterocycle. [0106] In some embodiments, R12 or R13 is H or a lower alkyl. In some embodiments, both R12 and R13 are H. [0107] In some embodiments, wherein Z is C(R1)(R2), O, N(R3), S, CO, SO, or SO2, X5 is C(R5a)(R5b), wherein each R1, R2, R3, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl;R13 is connected to one of the aromatic rings to form a 6-7-membered heterocycle; and m=1. Non-limiting examples of the compounds include Compounds 16, 91, 92, 93, or a pharmaceutically acceptable salt thereof. [0108] Non-limiting examples of compounds encompassed by Formula (IV) include Compounds 16, 26, 89, 91, 92, 93, or a pharmaceutically acceptable salt thereof. II. FORMULATIONS [0109] In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase “active ingredient” generally refers to the conjugate as described herein. [0110] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and/or turkeys. [0111] Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit. [0112] A pharmaceutical composition in accordance with the disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. [0113] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100%, e.g., between .5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient. [0114] The compounds of the present disclosure can be formulated using one or more excipients to: (1) increase stability; (2) permit the sustained or delayed release; (3) alter the biodistribution; (4) alter the release profile of the compounds in vivo. Non-limiting examples of the excipients include any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, and preservatives. Excipients of the present disclosure may also include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, hyaluronidase, nanoparticle mimics and combinations thereof. Accordingly, the formulations of the disclosure may include one or more excipients, each in an amount that together increases the stability of the compounds. Excipients [0115] Pharmaceutical formulations may comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. [0116] In some embodiments, a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient is approved for use in humans and for veterinary use. In some embodiments, an excipient is approved by United States Food and Drug Administration. In some embodiments, an excipient is pharmaceutical grade. In some embodiments, an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia. [0117] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical compositions. [0118] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and/or combinations thereof. [0119] Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, quaternary ammonium compounds, and/or combinations thereof. [0120] Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and VEEGUM® [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [TWEEN®20], polyoxyethylene sorbitan [TWEEN®60], polyoxyethylene sorbitan monooleate [TWEEN®80], sorbitan monopalmitate [SPAN®40], sorbitan monostearate [SPAN®60], sorbitan tristearate [SPAN®65], glyceryl monooleate, sorbitan monooleate [SPAN®80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [MYRJ®45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Kolliphor® (SOLUTOL®)), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. CREMOPHOR®), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [BRIJ®30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLUORINC®F 68, POLOXAMER®188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or combinations thereof. [0121] Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol,); natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl- pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol; and combinations thereof. [0122] Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and/or sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS®, PHENONIP®, methylparaben, GERMALL®115, GERMABEN®II, NEOLONE™, KATHON™, and/or EUXYL®. [0123] Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and/or combinations thereof. [0124] Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof. [0125] Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof. [0126] Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be present in the composition, according to the judgment of the formulator. III. METHODS OF USING THE COMPOUNDS [0127] In various embodiments, methods of using the compounds are provided. In some embodiments, the compounds of the present disclosure are used to modulate such as activate TAAR1. The compounds of the present disclosure can be used as a TAAR1 agonist. In some embodiments, the compounds of the present disclosure may also modulate the serotonin 1A receptor (5HT1A), the serotonin 2A receptor (5HT2A), the serotonin 2C receptor (5HT2C), the serotonin receptor 6 (5HT6), or the serotonin receptor 7 (5HT7). In some embodiments, the compounds may be a 5HT1A agonist, a 5HT2A antagonist, a 5HT2C agonist, a 5HT6 antagonist, or a 5HT7 antagonist. In embodiments, the compounds may be used to activate 5HT1A. In some embodiments, the compounds may be used to inhibit 5HT2A. In some embodiments, the compounds may be used to inhibit 5HT2C. In some embodiments, the compound may be used to activate 5HT2C. [0128] The present disclosure also provides methods of administering a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof, as described herein, to a subject. The subject may have a CNS disorder, may be suspected of having a CNS disorder, or may have a predisposition to a CNS disorder. The CNS disorder may be related to the trace amine associated receptors (TAAR), such as TAAR1. The CNS disorder may also be related to the serotonin receptors (5HT), such as 5HT1A, 5HT2A, 5HT2C, 5HT6 or 5HT7. However, the CNS disorder is not limited to the CNS disorders related to TAAR or 5HT. In some embodiments, the CNS disorder is not related to TAAR or 5HT. The compounds or pharmaceutically acceptable salts thereof are administered to the subject as a treatment for a CNS disorder and maintenance in all patients (including both the acute phase of the CNS disorder and as a maintenance therapeutic for the CNS disorder). [0129] CNS disorders affect a wide range of the population with differing severity. Neurological and psychiatric disorders that can be treated with the compounds of the present disclosure include but not limited to psychosis (such as geriatric psychosis, Alzheimer’s- related psychosis, Parkinson’s related psychosis, age-related psychosis, or schizophrenia), agitation (such as dementia-related agitation, Alzheimer’s agitation, paranoia, or mania), depression (such as treatment-resistant depression (TRD), major depressive disorder (MDD), bipolar depression, unipolar depression, suicidal behavior disorder, apathy, anhedonia, or depression associated with another disease or disorder), dysthymia, anxiety, cognitive impairment, schizophrenia, bipolar disorder, obsessive compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), addiction, social disorder, attention deficit hyperactivity disorder (ADHD), neuropsychiatric symptoms such as apathy, aggression, agitation, poor impulse control, and sleep disruptions in neurological disorders such as Alzheimer's and Parkinson's diseases. These disorders and symptoms affect a person's thoughts, mood, behavior and social interactions and can significantly impair daily functioning. [0130] In some embodiments, the compounds of the present disclosure are used to treat one or more symptoms of CNS disorders, such as but not limited to depression (e.g., major depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive deficit; sleep related disorder (e.g., sleep apnea, insomnia, narcolepsy, cataplexy) including those sleep disorders which are produced by psychiatric conditions; chronic fatigue syndrome; anxieties (e.g., general anxiety disorder, social anxiety disorder, panic disorder); obsessive compulsive disorder; post-menopausal vasomotor symptoms (e.g., hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis); manic disorder; dysthymic disorder; obesity; acute suicidality or suicide ideation; suicidal behavior disorder; senile dementia; Alzheimer's type dementia; cognition, memory loss; amnesia/amnestic syndrome; disturbances of consciousness; coma; lowering of attention; speech disorder; Lennox syndrome; hyperkinetic syndrome; neuropathic pain, including post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy/causalgia or nerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy arising from chronic alcohol use); migraine or migraine headache; sexual dysfunction, in men or women, including sexual dysfunction caused by psychological and/or physiological factors, erectile dysfunction, premature ejaculation, vaginal dryness, lack of sexual excitement, inability to obtain orgasm, and psycho-sexual dysfunction, including inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction; rapid eye movement (REM) during both sleep and daytime equivalent; cataplexy (sudden involuntary transient bouts of muscle weakness or paralysis while awake); nighttime sleep disturbance/sleep fragmentation associated with narcolepsy or other conditions; and sleep paralysis associated with narcolepsy or other conditions; hypnagogic and hypnapompic hallucinations associated with narcolepsy or other conditions; and excessive daytime sleepiness associated with narcolepsy, sleep apnea or shift work disorder and other medical conditions such as cancer, chronic fatigue syndrome and fibromyalgia. Depression [0131] Depression (or Major depressive disorder (MDD)), is a CNS disorder characterized by at least 2 weeks of low mood across most situations, often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause. Depression may be unipolar or bipolar. For patients who have been diagnosed with bipolar disorder and have an episode of mania or markedly elevated mood, the depression episode is called bipolar depression. Depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state. Symptoms of depression include anhedonia, depressed mood (sadness), poor concentration, hopelessness, poor self-esteem, insomnia, fatigue, appetite disturbances, generalized symptoms of pain, excessive guilt and thoughts of suicide. [0132] Bipolar disorder is a severe, recurrent, lifelong psychiatric illness that affects a lot of adult Americans and imposes significant economic burden to patients, families, and society. Although the bipolar mania phase can be reasonably well controlled with existing medications (e.g. lithium), the treatment of bipolar depression (BPD) relies on repurposing older classes of antipsychotic and anticonvulsant drugs. These older drugs have limited efficacy in treating the symptoms of BPD and many are concomitant with adverse side effects and reduced tolerability. Consequently, nonadherence to medication is common and BPD is associated with high morbidity, substance abuse, and a high rate of patient suicide. Thus, there remains a significant medical need for the focused discovery and development of new, safe, and effective drugs for the treatment of BPD. [0133] Medications that work well in the manic phase of bipolar disorder have been repurposed from other mental health disorders (e.g. schizophrenia, major depressive disorder), and frequently fail to treat the depressive phase of the illness. Although the broad consensus is that antispychotics (e.g. quetiapine, olanzapine, lurasidone) and/or antiepileptics (e.g. valproate, lamotrignine, carbamazapine) can help stabilize moods, many patients with bipolar depression do not respond adequately to these medications, despite adequate clinical trials. Older medications such as lithium similarly have variable and modest efficacy in the treatment of depression and relapse prevention. [0134] Another limitation of existing mood stabilizing drugs is that they are associated with a considerable lag of onset. Only a fraction of patients meet response criteria by the end of the first week of treatment, and continued use is associated with many undesirable side effects. Slow therapeutic onset contributes to the life disruptions experienced by individuals, and the delay in treating suicidal behavior is an issue of particular concern for this already vulnerable population. [0135] The present disclosure provides methods of treating depression (such as but not limited to bipolar depression, unipolar depression, major depressive disorder, or treatment- resistant depression) or maintenance therapy of depression (such as but not limited to bipolar depression, unipolar depression, major depressive disorder, or treatment-resistant depression), wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof. Psychosis [0136] Psychosis is a group of disorders including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (e.g., phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychotic disorders, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post- traumatic stress syndrome), including both positive, negative, and cognitive symptoms of schizophrenia and other psychoses [0137] Schizophrenia is a psychopathic disorder marked by characteristics such as psychotic symptoms, phasic progression and development, and/or deterioration in social behavior and professional capability. It usually appears for the first time in early adulthood. Characteristic psychotic symptoms are disorders of thought content (e.g., multiple, fragmentary, incoherent, implausible or simply delusional contents, or ideas of persecution) and of mentality (e.g., loss of association, flight of imagination, incoherence up to incomprehensibility), as well as disorders of perceptibility (e.g., hallucinations), emotions (e.g., superficial or inadequate emotions), self-perceptions, intentions, impulses, and/or inter-human relationships, and psychomotoric disorders (e.g., catatonia). [0138] Schizophrenia is classified into subgroups: the paranoid type, the disorganized type, the catatonic type, and the undifferentiated type. The paranoid subgroup is characterized by delusions and hallucinations and absence of thought disorder, disorganized behavior, and affective flattening. Thought disorder and flat affect are present together in the disorganized type, also named “hebephrenic schizophrenia.” Prominent psychomotor disturbances are evident in the catatonic type, wherein symptoms may include catatonic stupor and waxy flexibility. In the undifferentiated type, psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met. [0139] The symptoms of schizophrenia include three broad categories: positive, negative and cognitive symptoms. Positive symptoms are those which represent an “excess” of normal experiences, such as hallucinations and delusions. Negative symptoms are those where the patient suffers from a lack of normal experiences, such as anhedonia and lack of social interaction. The cognitive symptoms relate to cognitive impairment in schizophrenics, such as lack of sustained attention and deficits in decision making. [0140] The present disclosure provides methods of treating psychosis (such as schizophrenia) or maintenance therapy of psychosis (such as schizophrenia), wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof. Cognitive Disorders & Cognitive Impairment [0141] Cognitive disorders include dementia (semantic dementia, frontotemporal dementia, dementia with depressive features, persisting, subcortical dementia, dementia with Lewy Bodies, Parkinsonism-ALS Dementia Complex, and dementia associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems, stroke, HIV disease, Parkinson's disease, Huntington's disease, Down syndrome, Pick's disease, Creutzfeldt- Jacob disease, perinatal hypoxia, or substance abuse), delirium, amnestic disorders or age related cognitive decline. [0142] Cognitive impairment includes a decline in cognitive functions or cognitive domains, e.g., working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving (e.g., executive function, speed of processing and/or social cognition). In particular, cognitive impairment may indicate deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulties in expressing thoughts, and/or difficulties in integrating thoughts, feelings and behavior, or difficulties in extinction of irrelevant thoughts. [0143] The present disclosure provides methods of treating cognitive disorders and/or cognitive impairment or maintenance therapy of cognitive disorders and/or cognitive impairment, wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof. Anxiety [0144] Anxiety disorders are disorders characterized by fear, worry, and uneasiness, usually generalized and unfocused as an overreaction to a situation. Anxiety disorders differ in the situations or types of objects that induce fear, anxiety, or avoidance behavior, and the associated cognitive ideation. Anxiety differs from fear in that anxiety is an emotional response to a perceived future threat while fear is associated with a perceived or real immediate threat. They also differ in the content of the associated thoughts or beliefs. [0145] Anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, paranoia, post- traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition. [0146] The present disclosure provides methods of treating anxiety or maintenance therapy of anxiety, wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof. Administration [0147] The compounds of the present disclosure may be administered by any route which results in a therapeutically effective outcome. These include, but are not limited to enteral, gastroenteral, epidural, oral, transdermal, epidural (peridural), intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavernous injection, ( into the base of the penis), intravaginal administration, intrauterine, extra- amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), or in ear drops. In specific embodiments, compositions may be administered in a way which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier. [0148] In some embodiments, the compounds are administered orally. The oral formulations contain an effective amount of compounds in a pharmaceutical carrier appropriate for administration to an individual in need thereof. Dosing [0149] The present disclosure provides methods comprising administering compounds as described herein to a subject in need thereof. Compounds as described herein may be administered to a subject using any amount and any route of administration effective for preventing or treating or imaging a disease, disorder, and/or condition (e.g., a disease, disorder, and/or condition relating to working memory deficits). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like. [0150] Compositions in accordance with the disclosure are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. [0151] In some embodiments, compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, from about 25 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 125 mg/kg, from about 125 mg/kg to about 150 mg/kg, from about 150 mg/ to about 175 mg/kg, from about 175 mg/kg to about 200 mg/kg, from about 200 mg/kg to about 250 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic, prophylactic, or imaging effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In some embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). When multiple administrations are employed, split dosing regimens such as those described herein may be used. [0152] As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses, e.g, two or more administrations of the single unit dose. As used herein, a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event. As used herein, a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose. Dosage Forms [0153] A pharmaceutical composition described herein can be formulated into a dosage form described herein, such as a topical, intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, and subcutaneous). Coatings or Shells [0154] Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Liquid dosage forms [0155] Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art including, but not limited to, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments for parenteral administration, compositions may be mixed with solubilizing agents such as CREMOPHOR®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof. Injectable [0156] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art and may include suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables. [0157] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [0158] In order to prolong the effect of an active ingredient, it may be desirable to slow the absorption of the active ingredient from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compounds then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound may be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compounds to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include, but are not limited to, poly(orthoesters) and poly(anhydrides). Depot injectable formulations may be prepared by entrapping the compounds in liposomes or microemulsions which are compatible with body tissues. Pulmonary [0159] Formulations described herein as being useful for pulmonary delivery may also be used for intranasal delivery of a pharmaceutical composition. Another formulation suitable for intranasal administration may be a coarse powder comprising the active ingredient and having an average particle from about 0.2 μm to 500 μm. Such a formulation may be administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose. [0160] Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, contain about 0.1% to 20% (w/w) active ingredient, where the balance may comprise an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein. [0161] General considerations in the formulation and/or manufacture of pharmaceutical agents may be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference in its entirety). Combo Therapies [0162] In some embodiments, the present invention provides a method of treating a neurological and/or psychiatric disease or disorder described herein, comprising administering a compound of the present disclosure in combination with one or more additional active agents or therapies. Suitable pharmaceutical agents that may be used in combination with the compounds of the present disclosure include antidepressants, anti- psychotics, anti-Parkinson's drugs, anti-Alzheimer's drugs, anti-ischemics, CNS depressants, anti-cholinergics, nootropics, epilepsy medication, attention (e.g., ADD/ ADHD) medications, sleep-promoting medications, wakefulness-promoting medications, pain medications, or anxiolytics. [0163] The compounds of the present disclosure and the additional active agent(s) may be administered simultaneously, sequentially, or at any order. The compounds of the present disclosure and the additional active agent(s) may be administered at different dosages, with different dosing frequencies, or via different routes, whichever is suitable. IV. KITS AND DEVICES [0164] The disclosure provides a variety of kits and devices for conveniently and/or effectively carrying out methods of the present disclosure. Typically, kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments. [0165] In one embodiment, the present disclosure provides kits for treating CNS disorders, comprising a compound of the present disclosure or a combination of compounds of the present disclosure, optionally in combination with any other active agents. [0166] The kit may further comprise packaging and instructions and/or a delivery agent to form a formulation composition. The delivery agent may comprise a saline, a buffered solution, or any delivery agent disclosed herein. The amount of each component may be varied to enable consistent, reproducible higher concentration saline or simple buffer formulations. The components may also be varied in order to increase the stability of the compound(s) in the buffer solution over a period of time and/or under a variety of conditions. [0167] The present disclosure provides for devices which may incorporate compound(s) of the present disclosure. These devices contain in a stable formulation available to be immediately delivered to a subject in need thereof, such as a human patient. In some embodiments, the subject has BPD. [0168] Non-limiting examples of the devices include a pump, a catheter, a needle, a transdermal patch, a pressurized olfactory delivery device, iontophoresis devices, multi- layered microfluidic devices. The devices may be employed to deliver compound(s) of the present disclosure according to single, multi- or split-dosing regiments. The devices may be employed to deliver compound(s) of the present disclosure across biological tissue, intradermal, subcutaneously, or intramuscularly. V. DEFINITIONS [0169] The abbreviations used herein have their conventional meaning within the scientific arts. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in M. Loudon, Organic Chemistry, 5th Ed., Roberts and Company, Greenwood Village, Colo.: 2009; and M. B. Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 7th Ed., John Wiley & Sons, Hoboken: 2013, the entire contents of which are hereby incorporated by reference. [0170] The term “compound”, as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. [0171] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. [0172] Compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples prototropic tautomers include ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. [0173] Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. [0174] The compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods. [0175] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents which would result from writing the structure from right to left, e.g., —CH2O— is intended to also recite —OCH2—; —NHS(O)2— is also intended to represent —S(O)2HN—; etc. [0176] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical (also called cycloalkyl or cyclic alkyl group), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n- octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.” Alkyl groups, which are limited to hydrocarbon groups are termed “homoalkyl”. [0177] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by —CH2CH2CH2CH2—, and further includes those groups described below as “heteroalkylene.” Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. [0178] The terms “alkoxy,” (or “alkoxyl”) “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. [0179] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, —CH2—CH2—O— CH3, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)—CH3, —CH2—S—CH2—CH3, — CH2—CH2, —S(O)—CH3, —CH2—CH2—S(O)2—CH3, —CH═CH—O—CH3, —Si(CH3)3, —CH2—CH═N—OCH3, and —CH═CH—N(CH3)—CH3. Up to two heteroatoms may be consecutive, such as, for example, —CH2—NH—OCH3 and —CH2—O—Si(CH3)3. Similarly, the term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH2—CH2— S—CH2—CH2— and —CH2—S—CH2—CH2—NH—CH2—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)2R′— represents both —C(O)2R′— and —R′C(O)2—. [0180] In general, an “acyl substituent” is also selected from the group set forth above. As used herein, the term “acyl substituent” refers to groups attached to, and fulfilling the valence of a carbonyl carbon that is either directly or indirectly attached to the polycyclic nucleus of the compounds of the present invention. [0181] The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. [0182] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0183] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2- quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. [0184] For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like). [0185] The terms “carbocycle” and “heterocycle” refers to non-aromatic (such as “cycloalkyl” and “heterocycloalkyl” as defined herein) or aromatic (such as “aryl” and “heteroaryl” as defined herein) rings. The “carbocycle” and “heterocycle” groups may be saturated or non-saturated. [0186] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” “heteroaryl,” “carbocycle,” and “heterocycle”) include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. [0187] Substituents for the alkyl, and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generally referred to as “alkyl substituents” and “heteroalkyl substituents,” respectively, and they can be one or more of a variety of groups selected from, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO2R′, —CONR′R″, — OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)2R′, —NR— C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, — NRSO2R′, —CN and —NO2 in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R′, R″, R′″ and R″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5- , 6-, or 7-membered ring. For example, —NR′R″ is meant to include, but not be limited to, 1- pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF3 and —CH2CF3) and acyl (e.g., —C(O)CH3, —C(O)CF3, —C(O)CH2OCH3, and the like). [0188] Similar to the substituents described for the alkyl radical, the aryl substituents and heteroaryl substituents are generally referred to as “aryl substituents” and “heteroaryl substituents,” respectively and are varied and selected from, for example: halogen, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, — CO2R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)2R′, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NRSO2R′, —CN and — NO2, —R′, —N3, —CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″, R′″ and R″″ are preferably independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl, and (unsubstituted aryl)oxy-(C1-C4)alkyl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present. [0189] Two of the aryl substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)—(CRR′)q—U—, wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r—B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)2—, — S(O)2NR′— or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)s—X—(CR″R′″)d—, where s and d are independently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)2—, or — S(O)2NR′—. The substituents R, R′, R″ and R′″ are preferably independently selected from hydrogen or substituted or unsubstituted (C1-C6)alkyl. [0190] The term “alkyl amide” refers to carboxylic acid amides that are functionalized on the amide nitrogen by one or more alkyl groups as defined herein. [0191] The term “alkyl amine” refers to amines in which the nitrogen atom is functionalized with one or more alkyl groups as defined herein. [0192] As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). [0193] As used herein, the term “optionally substituted” means the functional group may be optionally substituted by any suitable substituents, such as but not limited to, alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R21—OR20, —R21—OC(O)—R20, —R21— N(R20)2, —R21—C(O)R20, —R21—C(O)OR20, —R21—C(O)N(R20)2, —R21—O—R22— C(O)N(R20)2, —R21—N(R20)C(O)OR20, —R21—N(R20)C(O)R20, —R21— N(R20)S(O)tR20 (where t is 1 or 2), —R21—S(O)tOR20 (where t is 1 or 2), —R21— S(O)pR20 (where p is 0, 1 or 2), and —R21—S(O)tN(R20)2 (where t is 1 or 2), where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, may optionally form an optionally substituted N-heterocyclyl or an optionally substituted N- heteroaryl, each R21 is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R22 is a straight or branched alkylene or alkenylene chain. [0194] The symbol “R” is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl groups. [0195] The term “pharmaceutically acceptable salts” includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0196] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. [0197] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. [0198] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. [0199] The terms "subject" or "patient", as used herein, refer to any organism to which the particles may be administered, e.g., for experimental, therapeutic, diagnostic, and/or prophylactic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, guinea pigs, cattle, pigs, sheep, horses, dogs, cats, hamsters, lamas, non-human primates, and humans). [0200] The terms "treating" or “preventing”, as used herein, can include preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder or condition; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. [0201] The terms “managing” or “maintaining”, as used herein, can refer to reducing the symptom(s) of a disease, reducing the severity of symptom(s) of the disease, or preventing the symptom(s) of the disease from getting worse. [0202] The term "therapeutic effect" is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, disorder or condition in the enhancement of desirable physical or mental development and conditions in an animal, e.g., a human. [0203] The term “modulation” is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart. The modulation is generally compared to a baseline or reference that can be internal or external to the treated entity. [0204] “Parenteral administration”, as used herein, means administration by any method other than through the digestive tract (enteral) or non-invasive topical routes. For example, parenteral administration may include administration to a patient intravenously, intradermally, intraperitoneally, intrapleurally, intratracheally, intraossiously, intracerebrally, intrathecally, intramuscularly, subcutaneously, subjunctivally, by injection, and by infusion. [0205] “Topical administration”, as used herein, means the non-invasive administration to the skin, orifices, or mucosa. Topical administration can be delivered locally, i.e., the therapeutic can provide a local effect in the region of delivery without systemic exposure or with minimal systemic exposure. Some topical formulations can provide a systemic effect, e.g., via adsorption into the blood stream of the individual. Topical administration can include, but is not limited to, cutaneous and transdermal administration, buccal administration, intranasal administration, intravaginal administration, intravesical administration, ophthalmic administration, and rectal administration. [0206] “Enteral administration”, as used herein, means administration via absorption through the gastrointestinal tract. Enteral administration can include oral and sublingual administration, gastric administration, or rectal administration. [0207] “Pulmonary administration”, as used herein, means administration into the lungs by inhalation or endotracheal administration. As used herein, the term “inhalation” refers to intake of air to the alveoli. The intake of air can occur through the mouth or nose. [0208] The terms “sufficient” and “effective”, as used interchangeably herein, refer to an amount (e.g., mass, volume, dosage, concentration, and/or time period) needed to achieve one or more desired result(s). A “therapeutically effective amount” is at least the minimum concentration required to affect a measurable improvement or prevention of at least one symptom or a particular condition or disorder, to affect a measurable enhancement of life expectancy, or to generally improve patient quality of life. The therapeutically effective amount is thus dependent upon the specific biologically active molecule and the specific condition or disorder to be treated. Therapeutically effective amounts of many active agents, such as antibodies, are known in the art. The therapeutically effective amounts of compounds and compositions described herein, e.g., for treating specific disorders may be determined by techniques that are well within the craft of a skilled artisan, such as a physician. [0209] The terms “bioactive agent” and “active agent”, as used interchangeably herein, include, without limitation, physiologically or pharmacologically active substances that act locally or systemically in the body. A bioactive agent is a substance used for the treatment (e.g., therapeutic agent), prevention (e.g., prophylactic agent), diagnosis (e.g., diagnostic agent), cure or mitigation of disease or illness, a substance which affects the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment. [0210] The term “pharmaceutically acceptable”, as used herein, refers to compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of agencies such as the U.S. Food and Drug Administration. A “pharmaceutically acceptable carrier”, as used herein, refers to all components of a pharmaceutical formulation that facilitate the delivery of the composition in vivo. Pharmaceutically acceptable carriers include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof. [0211] The term “pharmaceutically acceptable salt(s)” refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. [0212] If the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts. [0213] A pharmaceutically acceptable salt can be derived from an acid selected from 1- hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10- sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, trifluoroacetic, and undecylenic acid. [0214] The term “protective group”, as used herein, refers to a functional group that can be added to and/or substituted for another desired functional group to protect the desired functional group from certain reaction conditions and selectively removed and/or replaced to deprotect or expose the desired functional group. Protective groups are known to the skilled artisan. Suitable protective groups may include those described in Greene and Wuts, Protective Groups in Organic Synthesis, (1991). Acid sensitive protective groups include dimethoxytrityl (DMT), tert- butylcarbamate (tBoc) and trifluoroacetyl (tFA). Base sensitive protective groups include 9-fluorenylmethoxycarbonyl (Fmoc), isobutyrl (iBu), benzoyl (Bz) and phenoxyacetyl (pac). Other protective groups include acetamidomethyl, acetyl, tert- amyloxycarbonyl, benzyl, benzyloxycarbonyl, 2-(4-biphεnylyl)-2-propy!oxycarbonyl, 2- bromobenzyloxycarbonyl, tert-butyl7 tert-butyloxycarbonyl, l-carbobenzoxamido-2,2.2- trifluoroethyl, 2,6-dichlorobenzyl, 2-(3,5-dimethoxyphenyl)-2-propyloxycarbonyl, 2,4- dinitrophenyl, dithiasuccinyl, formyl, 4-methoxybenzenesulfonyl, 4-methoxybenzyl, 4- methylbenzyl, o-nitrophenylsulfenyl, 2-phenyl-2-propyloxycarbonyl, α-2,4,5- tetramethylbenzyloxycarbonyl, p-toluenesulfonyl, xanthenyl, benzyl ester, N- hydroxysuccinimide ester, p-nitrobenzyl ester, p-nitrophenyl ester, phenyl ester, p- nitrocarbonate, p-nitrobenzylcarbonate, trimethylsilyl and pentachlorophenyl ester. [0215] The term “bioavailable” is art-recognized and refers to a form of the subject disclosure that allows for it, or a portion of the amount administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered. [0216] The present disclosure is further illustrated by the following non-limiting examples. EXAMPLES Example 1. Synthesis of the Compounds [0217] The compounds of the disclosure may be prepared using any convenient methodology known to a person of the art. Non-limiting synthetic methods for the compounds of the present disclosure are provided below.
Figure imgf000101_0001
Scheme 2 [0218] Chroman-4-ylmethanamine hydrochloride (47): Chroman-4-ylmethanamine (100 mg ,0.61 mmol) was dissolved in deionized water (3 ml) and acidified with 4N HCl/MeOH (1 ml). The mixture was removed under vacuum to give the title compound (120 mg, Y: 98.3%) as a white solid. 1H NMR (400 MHz, D2O) δ 7.21 (t, J = 7.9 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 4.19 (dd, J = 6.8, 3.3 Hz, 2H), 3.40 – 3.14 (m, 4H), 2.19 – 2.10 (m, 1H), 1.96 – 1.89 (m, 1H). LCMS: (ESI) m/z=164.1(M+H)+, t=1.691 min (215 nm). [0219] tert-Butyl (chroman-4-ylmethyl)carbamate (B-1): Chroman-4-ylmethanamine (500 mg, 3.06 mmol) was dissolved in DCM (15 mL). Triethylamine (620 mg,6.13 mmol) and di- tert-butyl decarbonate (802 mg,3.68 mmol) were added and the mixture was stirred at 25 oC overnight. The reaction was quenched with saturated ammonium chloride and extracted with DCM (15 mL^3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE/EA=20:1) to get tert- butyl (chroman-4-ylmethyl)carbamate (800 mg, Y: 99%) as a white powder. LCMS: (ESI) m/z=164.0(M-(CH3)3)+, t=1.156 min (215 nm). [0220] tert-Butyl (chroman-4-ylmethyl)(methyl)carbamate (B-3): tert-Butyl (chroman-4- ylmethyl)carbamate(150 mg,0.57 mmol) was dissolved in DMF(6 mL ). 60% NaH (35 mg,0.85 mmol) was added at 0oC. The mixture was stirred at room temperature for 30 min. Methyl iodide (645 mg,4.56 mmol) was added, and the mixture continued stirring at room temperature for 8 h. The reaction was quenched with water (3 mL) and extracted with EtOAc (10 mL^3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE/EA=15:1) to get tert-butyl (chroman-4-ylmethyl)(methyl)carbamate (120 mg, Y: 75.9%) as a colorless oil. LCMS: (ESI) m/z=178.0(M-(CH3)3)+, t=2.268 min (215 nm). [0221] 1-(Chroman-4-yl)-N-methylmethanamine hydrochloride (48): tert-Butyl (chroman-4-ylmethyl)(methyl)carbamate (120 mg)was dissolved in 4N HCl/MeOH (4 ml) and the mixture was stirred at room temperature for 5 h. The reaction was concentrated under vacuum and the residue was washed with Et2O to obtain the title compound (65 mg, 84.7%) as white powder. 1H NMR (400 MHz, D2O) δ 7.20 (dd, J = 7.4, 4.4 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.88 – 6.83 (m, 1H), 4.23 – 4.13 (m, 2H), 3.39 – 3.23 (m, 3H), 2.73 (s, 3H), 2.16 (ddd, J = 19.3, 8.3, 5.1 Hz, 1H), 1.98 – 1.85 (m, 1H). LCMS: (ESI) m/z=177.9(M+H)+, t=0.635 min (215 nm). [0222] N-(Chroman-4-ylmethyl)propan-2-amine hydrochloride (49): Chroman-4- ylmethanamine(100 mg ,0.61 mmol) was dissolved in DCM (6 mL). Acetone (64 mg,1.1 mmol) was added and the mixture was stirred at 25 oC for 4 h. Sodium triacetoxyborohydride (243 mg, 1.15 mmol) was added and the reaction continued stirring at 25 oC overnight. The mixture was quenched by water and extracted with DCM (8 mL^3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC and acidified by HCl/MeOH to give the title compound (80 mg, Y: 54%) as a colorless solid. 1H NMR (400 MHz, D2O) δ 7.21 (s, 2H), 6.97 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.0 Hz, 1H), 4.19 (s, 2H), 3.53 – 3.21 (m, 4H), 2.14 (s, 1H), 1.94 (s, 1H), 1.30 (d, J = 6.5 Hz, 6H). LCMS: (ESI) m/z=205.9(M+H)+, t=2.520 min (215 nm). [0223] 1-(Chroman-4-yl)-N,N-dimethylmethanamine hydrochloride (50): Chroman-4- ylmethanamine (100 mg, 0.61 mmol) was dissolved in MeOH (3ml), was added formaldehyde (3 ml). The mixture was stirred at 40 oC for 1 h under N2 atmosphere. Sodium borohydride (2.4 g, 6.1 mmol) was added and the mixture was stirred at 40 oC overnight. The reaction was quenched with sat NH4Cl solution and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC and acidified with MeOH/HCl to give the title compound (100 mg,Y: 72%) as a light yellow powder. 1H NMR (400 MHz, D2O) δ 7.21 (t, J = 7.3 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 4.19 (t, J = 4.6 Hz, 2H), 3.42 (dd, J = 24.3, 13.1 Hz, 3H), 2.95 (s, 6H), 2.17 (s, 1H), 1.95 – 1.87 (m, 1H). LCMS: (ESI) m/z=192.2(M+H)+, t=2.265 min (215 nm). [0224] tert-Butyl (chroman-4-ylmethyl)(ethyl)carbamate (B-2): tert-Butyl (chroman-4- ylmethyl)carbamate(150 mg,0.57 mmol) was dissolved in THF (6 mL ). 60% sodium hydride (35 mg, 0.85 mmol) was added at 0 oC. The mixture was stirred at room temperature for 30 min. Iodoethane (710 mg,4.56 mmol) was added and the reaction was stirred at room temperature for 8 h. The mixture was quenched by water and extracted with EtOAc (10 mL^ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the title compound (110 mg, Y: 66.3%) as a colorless oil. LCMS: (ESI) m/z=192.2(M+H)+, t=1.742 min (215 nm). [0225] N-(Chroman-4-ylmethyl)ethanamine hydrochloride (51): tert-Butyl (chroman-4- ylmethyl)(methyl)carbamate (110 mg, 0.37 mmol) was dissolved in 4N HCl/MeOH (4 ml). The mixture was stirred at room temperature for 5 h. The mixture was concentrated under vacuum and the residue was washed by Et2O to give the title compound (70 mg, Y: 81.3%) as a white powder. 1H NMR (400 MHz, D2O) δ 7.20 (t, J = 7.3 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.18 (d, J = 5.1 Hz, 2H), 3.38 – 3.23 (m, 3H), 3.11 (dd, J = 7.3, 3.4 Hz, 2H), 2.15 (s, 1H), 1.93 (d, J = 10.9 Hz, 1H), 1.25 (t, J = 7.3 Hz, 3H). LCMS: (ESI) m/z=192.2(M+H)+, t=1.762 min (215 nm).
Figure imgf000103_0001
Scheme 4 [0226] 3,4-Dihydrobenzo[b]oxepin-5(2H)-one (D-1): A mixture of 4-phenoxybutanoic acid (15.0 g, 83.2 mmol) in polyphosphoric acid (150 mL) was stirred at 110°C for 1 hour. After cooling to room temperature, the mixture was diluted with 600 mL water, and extracted with ethyl acetate (300 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether : ethyl acetate=10:1) to obtain the desired compound (2.7 g, 20.0% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.8, 1.8 Hz, 1H), 7.45-7.41 (m, 1H), 7.12-7.06 (m, 2H), 4.25 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H), 2.25- 2.18 (m, 2H). [0227] 2,3,4,5-Tetrahydrobenzo[b]oxepine-5-carbonitrile (D-2): To a solution of 1 (2.4 g, 14.7mmol), TOSMIC (2.9 g, 14.7 mmol), and ethanol (1.0 mL, 17.6 mmol) in 1,2- dimethoxyethane (100 mL) was added potassium tert-butoxide (2.1 g, 19.1 mmol) by portions at 0°C. After addition, the reaction mixture was stirred at 0°C for an additional 30 min before stirring at room temperature for 3 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (1.5 g, 59.0%) as a yellow oil.1H NMR (400 MHz, CDCl 3) δ 7.42-7.40 (m, 1H), 7.29-7.25 (m, 1H), 7.17-7.02 (m, 2H), 4.18-4.03 (m, 2H), 3.99-3.93 (m, 1H), 2.37-1.95 (m, 4H). [0228] (2,3,4,5-Tetrahydrobenzo[b]oxepin-5-yl)methanamine hydrochloride (110): The solution of D-2 (1.0 g, 5.8 mmol) and Raney Ni (500.0 mg, 8.5 mmol) in NH3/methanol (2.0 M, 60 mL) was stirred at room temperature under hydrogen atmosphere for 4 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by chromatography (eluted with DCM: MeOH = 10:1) to obtain desired compound (500 mg, 48.6% yield) as a colorless gel. The compound (20 mg) was dissolved in HCl/MeOH (4 M, 0.2 mL) and deionized water (20 mL), and the solution was lyophilized to obtain title compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 3H), 7.23-7.19 (m, 2H), 7.07-7.03 (m, 1H), 6.99-6.96 (m, 1H), 4.24-4.19 (m, 1H), 3.64-3.58 (m, 1H), 3.26-3.12 (m, 2H), 3.12- 2.99 (m, 1H), 2.20- 2.01 (m, 1H), 2.01-1.88 (m, 1H), 1.75-1.69 (m, 2H). MS(ESI) calculated for C11H15NO, 177.1; found 178.2. [0229] N,N-Dimethyl-1-(2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methanamine hydrochloride (111): To a solution of (2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methanamine (100 mg, 0.6 mmol) and formaldehyde (0.5 mL) in methanol (5 mL) was added 10% Pd/C (10 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through a pad of celite and concentrated to purify by Prep- HPLC (CH3CN/H2O, 0.1%HCl) to obtain title compound (36.0 mg, 31.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.31 (brs, 1H), 7.35 (dd, J = 7.5, 1.6 Hz, 1H), 7.22 (td, J = 7.7, 1.7 Hz, 1H), 7.07 (td, J = 7.4, 1.3 Hz, 1H), 6.98 (dd, J = 7.9, 1.2 Hz, 1H), 4.37- 4.24 (m, 1H), 3.65-3.43 (m, 3H), 3.33-3.27 (m, 1H), 2.76 (s, 3H), 2.61 (s, 3H), 2.22-2.01 (m, 2H), 1.83-1.60 (m, 2H). MS(ESI) calculated for C13H19NO, 205.1; found 206.2. [0230] C12H18N2,190.2; found 191.2.
Figure imgf000105_0001
Scheme 6 [0231] Ethyl 3-cyano-3-(2-nitrophenyl)propanoate (F-1): To a solution of 2-(2- nitrophenyl)acetonitrile (10.0 g, 61.7 mmol) and K2CO3 (25.5 g, 185.1 mmol) in DMF (100 mL) was added ethyl 2-bromoacetate (12.3 g, 74.0 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 min, and then at room temperature for 3 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL). The combined organic layers were washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (10.0 g, 65.4%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 8.2, 1.3 Hz, 1H), 7.83 (dd, J = 7.9, 1.3 Hz, 1H), 7.74 (m, 1H), 7.61 – 7.55 (m, 1H), 5.09 (dd, J = 8.0, 6.2 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.03 (dd, J = 7.1, 3.2 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). [0232] 2-Oxo-1,2,3,4-tetrahydroquinoline-4-carbonitrile (F-2): A solution of F-1 (10.0 g, 40.3 mmol) and Sn (40.8 g, 342.8 mmol) in HCl/methanol (40 mL/40 mL) was stirred at room temperature under nitrogen atmosphere for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain title compound (4.1g, 59.4% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.41 (brs, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.25 (dd, J = 10.2, 6.2 Hz, 1H), 3.06 – 2.90 (m, 2H). [0233] (2-Oxo-1,2,3,4-tetrahydroquinolin-4-yl)methanamine hydrochloride (35): A solution of F-2 (100.0 mg, 0.6 mmol) and Raney Ni (50.0 mg, 0.9 mmol) in NH 3/methanol (2 N, 6 mL) was stirred at room temperature under hydrogen atmosphere for 4 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (36.2 mg, 29.4% yield) as a colorless gel. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.16 (brs, 3H), 7.28 (d, J = 7.2 Hz, 1H), 7.22 (m, 1H), 6.99 (m, 1H), 6.95 – 6.88 (m, 1H), 3.37 – 3.29 (m, 1H), 2.94 (d, J = 5.5 Hz, 2H), 2.76 (dd, J = 16.6, 6.3 Hz, 1H), 2.55 (dd, J = 16.6, 4.6 Hz, 1H). MS(ESI) calculated for C10H12N2O, 176.1; found 177.1. [0234] N-((2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methyl)propan-2-amine hydrochloride (36): To a solution of 4-(aminomethyl)-3,4-dihydroquinolin-2(1H)-one (150 mg, 0.9 mmol) in methanol (10 mL) was added acetone (1 mL) and acetic acid (102.0 mg, 1.7 mmol) at room temperature and the reaction mixture was stirred for 30 min. Sodium cyanoborohydride (106.0 mg, 1.7 mmol) was added to above solution and the reaction mixture was continued to stir for 2 hours. The mixture was quenched with water (1 mL) and filtered through a pad of celite. The filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (75.0 mg, 41.1 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.25 (brs, 1H), 8.76 (brs, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.23 (td, J = 7.7, 1.3 Hz, 1H), 7.00 (td, J = 7.5, 1.0 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 3.70 – 3.33 (m, 1H), 3.33 – 3.27 (m, 1H), 3.02 (dd, J = 13.2, 6.6 Hz, 2H), 2.79 (dd, J = 16.6, 6.2 Hz, 1H), 2.60 (dd, J = 16.6, 4.5 Hz, 1H), 1.25 (d, J = 5.5 Hz, 1H), 1.23 (d, J = 6.1 Hz, 1H). MS(ESI) calculated for C13H18N2O, 218.1; found, 219.1. [0235] 4‐[(Dimethylamino)methyl]‐1,2,3,4‐tetrahydroquinolin‐2‐one (37): The title compound was prepared using the same procedure for 36, substituting formaldehyde for acetone.1H NMR (400 MHz, DMSO-d6) δ 10.35 (brs, 1H), 10.27 (brs, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.23 (td, J = 7.7, 1.3 Hz, 1H), 7.00 (td, J = 7.5, 1.0 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 4.93 (s, 5H), 3.66 – 3.50 (m, 1H), 3.24 (dd, J = 7.8, 4.8 Hz, 2H), 2.81 (d, J = 4.7 Hz, 3H), 2.77 (d, J = 4.7 Hz, 3H), 2.65 (dd, J = 16.7, 4.4 Hz, 1H). MS(ESI) calculated for C12H16N2O, 204.1; found, 205.1. [0236] 4-(((4-Methoxybenzyl)amino)methyl)-3,4-dihydroquinolin-2(1H)-one (F-3): To the solution of 4-(aminomethyl)-3,4-dihydroquinolin-2(1H)-one (600 mg, 3.4 mmol) in methanol (50 mL) was added 4-methoxybenzaldehyde (695.3 mg, 5.1 mmol) and the reaction mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (428.1 mg, 6.8 mmol) was added into above solution, and the resulting mixture was continued to stir for 4 hours. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (440.3 mg, 44.1% yield) as a yellow oil. MS(ESI) calculated for C18H20N2O2, 296.2; found, 297.2. [0237] 4-(((4-Methoxybenzyl)(methyl)amino)methyl)-3,4-dihydroquinolin-2(1H)-one (F- 4): To a solution of F-3 (440 mg, 1.5 mmol) in methanol (50 mL) was added formaldehyde (89.8 mg, 3.0 mmol) at room temperature, and the reaction mixture was stirred for 30 min. Sodium cyanoborohydride (189.6 mg, 3.0 mmol) was added and the reaction was continued to stir for 2 hours. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography column (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (379.9 mg, 83.4% yield) as a yellow oil. MS(ESI) calculated for C18H20N2O2, 310.2; found, 311.2. [0238] N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methanaminium chloride (38): A solution of F-4 (380 mg, 1.2 mmol) and p-toluenesulfonic acid (105.1 mg, 0.6 mmol) in TFA (5 mL) was reacted in microwave reactor at 120oC for 1.5 hours. After cooling to room temperature, the mixture was filtered and concentrated. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired product (28.4 mg, 10.2% yield) as a colorless gel. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (brs, 1H), 8.50 (brs, 1H), 8.19 (brs, 1H), 7.24 (dd, J = 12.0, 4.4 Hz, 2H), 7.01 (dt, J = 7.6, 1.1 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 3.37 – 3.24 (m, 1H), 3.06 (dd, J = 13.3, 6.9 Hz, 2H), 2.78 (dd, J = 16.6, 6.3 Hz, 1H), 2.59 (t, J = 5.3 Hz, 3H). MS(ESI) calculated for C18H20N2O2, 190.1; found, 191.1.
Figure imgf000108_0001
Scheme 7 [0239] 1-Methyl-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (G-1): A mixture of 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (2.0 g, 12.4 mmol), paraformaldehyde (4.1 g, 45.8 mmol), NaBH(OAc)3 (9.7 g, 45.8 mmol) and acetic acid (744 mg, 12.4 mmol) in DCE (40 mL) was stirred at room temperature for 16 hours. Saturated NaHCO 3 (60 mL) was added to above reaction solution, the resulting mixture was stirred 30 min at 0 °C and then extracted with DCM (60 mL* 2). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10: 1) to obtain the desired product (2.0 g, 91.9% yield) as a yellow oil. MS(ESI) calculated for C11H13NO, 175.1; found 176.1. [0240] 1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-carbonitrile (G-2): To a stirred solution of G-1 (2.0 g, 11.4 mmol), EtOH (0.6 g, 13.6 mmol) and TOSMIC (2.2 g, 11.4 mmol) in 1,2-dimethoxy ethane (20 mL) was added potassium tert-butoxide (1.5 g, 13.6 mmol) slowly at 0oC under nitrogen. The mixture was stirred for 15 min at 0oC and then for 1 hour at room temperature. After which period, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to get the desired product (182.8 mg, 8.6% yield) as a yellow oil. MS(ESI) calculated for C12H14N2, 186.1; found 187.1. [0241] (1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)methanamine (G-3): To a solution of G-2 (182.8 mg, 1.0 mmol) in THF (4 mL) at 0 °C under atmosphere of nitrogen was added LiAlH4 (55.4 mg, 1.5 mmol). The reaction mixture was stirred at 50 °C for 3 hours. Then, the reaction mixture was quenched with sodium sulfate decahydrate at room temperature before filtration. The filtrate was concentrated to get the crude product (178.5 mg, 93.9% yield) as yellow oil, which was used to next step directly. MS(ESI) calculated for C12H18N2, 190.2; found 174.1, 191.1. [0242] N-((1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)methyl)propan-2- aminium chloride (99): The solution of G-3 (77 mg, 0.4 mmol) and NaBH3CN (38 mg, 0.6 mmol) in MeOH (2 mL) and acetone (1 mL) was stirred at room temperature for 3 hours. Then, the mixture was filtered, the filtrate was concentrated and purified by Prep-HPLC (CH 3CN/H2O, 0.1%HCl) to get desired product (30.0 mg, 32.3% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (brs, 1H), 8.42 (brs. 1H), 7.34 - 6.81 (m, 4H), 3.57 - 3.19 (m, 4H), 3.13 - 2.73 (m, 5H), 1.90 -1.50 (m, 4H), 1.30 -1.15 (m, 6H). MS(ESI) calculated for C15H24N2, 232.2; found 233.2.
Figure imgf000109_0001
Scheme 8 [0243] 4-Cyano-4-(2-nitrophenyl)butanoate (H-1): The mixture of 2-(2- nitrophenyl)acetonitrile (15.0 g, 92.5 mmol) and methyl prop-2-enoate (8.3 g, 97.1 mmol) in tetrahydrofuran (150.0 mL) was added t-BuOK (1.0 g, 9.05 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and then quenched by addition of sat. aqueous NH4Cl (150 mL). The resulting mixture was extracted with dichloromethane (100 mL*3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (eluted with Petroleum ether /ethyl acetate=10:1) to obtain target product (14.8 g, 65.0% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 8.2, 1.1 Hz, 1H), 7.74 (m, J = 8.8, 7.8, 1.3 Hz, 2H), 7.59 – 7.51 (m, 1H), 4.83 (dd, J = 9.2, 5.3 Hz, 1H), 3.70 (s, 3H), 2.61 (t, J = 7.5 Hz, 2H), 2.37 – 2.20 (m, 2H). [0244] Methyl 4-(2-aminophenyl)-4-cyanobutanoate (H-2): To a solution of H-1 (14.8 g, 59.6 mmol) in methanol (100 mL), 10% Pd/C (5.2 g) was added, the reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with Petroleum ether/ethyl acetate =1:5) to obtain the title product (10.0 g, 77.0% yield) as a white solid. MS(ESI) calculated for C12H14N2O2, 218.1; found 219.1. [0245] 2-Oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-carbonitrile (H-3): To a solution of H-2 (10.0 g, 45.8 mmol) in toluene (150 mL) at 0 °C was added AlMe3 (2 M in hexane, 69.0 mL, 137.4 mmol) cautiously under nitrogen atmosphere. After addition, the reaction mixture was stirred at 80 °C for 3 hours. After which period, the mixture was cooled down to room temperature and carefully poured into 1 M HCl (200 mL). The resulting mixture was extracted with CH2Cl2 (200 mL*3). The combined organic layers were washed with H2O (100 mL), dried over sodium sulfate and filtered. The filtrate was evaporated to dryness, and the residue was purified by column chromatography (elute with Petroleum ether: ethyl acetate = 8: 92) to obtain target product (4.0 g, 47.0% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.46 (dd, J = 7.6, 1.0 Hz, 1H), 7.38 (m, 1H), 7.25 (m, 1H), 7.06 (dd, J = 7.9, 1.0 Hz, 1H), 4.48 (dd, J = 9.1, 7.5 Hz, 1H), 2.64 – 2.53 (m, 1H), 2.29 (m, 1H), 2.22 – 2.12 (m, 2H). [0246] 5-(Aminomethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one hydrochloride (102): To a solution of H-3 (200 mg, 1.0 mmol) in methanol (20 mL) was added catalytic amount of Raney Ni, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl system) to obtain the title product (48.7 mg, 23.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.65 (brs, 1H), 8.16 (brs, 3H), 7.34 – 7.22 (m, 2H), 7.18 (m, 1H), 7.02 (dd, J = 7.7, 1.0 Hz, 1H), 3.30 – 3.14 (m, 3H), 2.43 (dd, J = 17.2, 11.5 Hz, 1H), 2.18 – 2.03 (m, 2H), 1.80 – 1.69 (m, 1H). MS(ESI) calculated for C11H14N2O, 190.1; found 191.2. [0247] 5‐{[(Propan‐2‐yl)amino]methyl}‐2,3,4,5‐tetrahydro‐1H‐1‐benzazepin‐2‐one (103): The title compound was prepared in a similar manner to 99.1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.28 (t, J = 7.8 Hz, 2H), 7.21 – 7.16 (m, 1H), 7.02 (d, J = 7.8 Hz, 1H), 3.22 – 3.16 (m, 4H), 2.45 (s, 1H), 2.16 – 2.06 (m, 2H), 1.74 (m, 1H), 1.21 (d, J = 2.7 Hz, 3H). 1.20 (d, J=2.7 Hz, 3H). MS(ESI) calculated for C14H20N2O, 232.1; found 233.3. [0248] 5‐[(Dimethylamino)methyl]‐2,3,4,5‐tetrahydro‐1H‐1‐benzazepin‐2‐one (104): The title compound was prepared in a manner similar to 29.1H NMR (400 MHz, DMSO-d6) δ 10.21 (brs, 1H), 9.65 (brs, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.30 (dd, J = 7.5, 0.8 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 3.62 – 3.49 (m, 3H), 2.79 (d, J=4.6, 3H), 2.70 (d, J=4.6, 3H), 2.48-2.46 (m, 1H), 2.11 (dd, J = 9.7, 7.0 Hz, 2H), 1.89-1.80 (m, 1H). MS(ESI) calculated for C13H18N2O, 218.2; found 219.1.
Figure imgf000111_0001
Scheme 9 [0249] 1-Methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carbonitrile (I-1): To a solution of 2-oxo-1,2,3,4-tetrahydroquinoline-4-carbonitrile (200 mg, 1.2 mmol) in DMF (3 mL) was added sodium hydride (46.2 mg, 60% in mineral oil) at 0oC, and the solution was stirred at room temperature for 1 hour. Iodomethane (170.0 mg, 1.2 mmol) was added dropwise to above solution, and the resulting reaction mixture was stirred for another 1 hour. The reaction solution was quenched with addition of water (10 mL) and then extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with water (20mL*2) and brine (20mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by Prep-TLC (Petroleum ether: ethyl acetate=3:1) to obtain the desired product (134.8 mg, 61.1% yield) as a yellow solid. MS(ESI) calculated for C11H14N2O, 186.1; found, 187.1. [0250] (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methanamine hydrochloride (39): The solution of compound I-1 (134.8 mg, 0.7 mmol) and Raney Ni (211.0 mg, 3.6 mmol) in NH3/methanol (2.0 N, 2 mL) was stirred at room temperature under hydrogen atmosphere for 4 hours. The mixture was then filtered through a pad of celite, and the filtrate was concentrated purify by Pre-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the compound (30.0 mg, 25.1 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 3H), 7.45 – 7.21 (m, 2H), 7.11 (m, 2H), 3.31 (dd, J = 11.9, 5.8 Hz, 1H), 3.26 (s, 3H), 3.02 – 2.89 (m, 2H), 2.84 (dd, J = 16.4, 5.9 Hz, 1H), 2.67 (dd, J = 16.4, 4.5 Hz, 1H). MS(ESI) calculated for C11H14N2O, 190.1; found, 191.1. [0251] (1-Methyl-1,2,3,4-tetrahydroquinolin-4-yl)methanamine hydrochloride (31): The solution of 4-(aminomethyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.5 mmol) and borane tetrahydrofuran complex (1 M, 2 mL) in THF (2 mL) was refluxed for 3 hours. After cooling to 0°C, methanol (1 mL) was added thereto and the reaction mixture was continued to stir at room temperature for 1 hour. Then, the mixture was concentrated and purified by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (56.8 mg, 61.1 % yield) as a colorless gel.1H NMR (400 MHz, DMSO-d6) δ 8.25 (brs, 3H), 7.90 – 7.00 (m, 4H), 6.89-6.74 (m, 2H), 3.32-3.14 (m, 3H), 3.06-2.92 (m, 2H), 2.91 (s, 3H), 2.14 – 1.93 (m, 2H). MS(ESI) calculated for C11H16N2, 176.1; found, 177.1. [0252] N-((1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methyl)propan-2-aminium chloride (42): A solution of 39 (100 mg, 0.6 mmol), NaBH(OAc)3 (0.05 g, 0.9 mmol) and acetone (1 mL) in MeOH (2 mL) was stirred at room temperature for 2 hours. After then, the mixture was diluted with saturated NH4Cl (5 mL), extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (43.3 mg, 30.7%) as a colorless gel.1H NMR (400 MHz, DMSO-d6) δ 9.02 (brs, 2H), 7.45 (dd, J = 7.5, 1.2 Hz, 1H), 7.39 – 7.31 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.12-7.08 (m, 1H), 3.55 (dd, J = 11.7, 6.1 Hz, 1H), 3.35 – 3.28 (m, 1H), 3.27 (s, 3H), 3.02 (dd, J = 12.6, 7.3 Hz, 2H), 2.88 (dd, J = 16.4, 5.9 Hz, 1H), 2.75 (dd, J = 16.5, 4.6 Hz, 1H), 1.25 (d, J = 5.2 Hz, 3H), 1.24 (d, J = 5.2 Hz, 3H). MS(ESI) calculated for C14H20N2O, 232.2; found 233.2. [0253] (1‐Methyl‐1,2,3,4‐tetrahydroquinolin‐4‐yl)methyl](propan‐2‐yl)amine hydrochloride (33): The title compound was prepared from 42 using the same general procedures used for 99 and 31.1H NMR (400 MHz, DMSO-d6) δ 9.24 (brs, 1H), 9.03 (brs, 1H), 7.31 (d, J = 7.0 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.96-6.91 (m, 2H), 3.37-3.31 (m, 3H), 3.25 (d, J = 12.3 Hz, 1H), 3.17 – 3.01 (m, 2H), 2.96 (s, 3H), 2.25 (d, J = 11.3 Hz, 1H), 2.06 (s, 1H), 1.32 (d, J = 6.5 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H). MS(ESI) calculated for C14H22N2, 218.2; found 219.2.
Figure imgf000113_0001
Scheme 10 [0254] Methyl ((2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methyl)carbamate (J-1): To a solution of (2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methanamine (120 mg, 0.7 mmol) and triethylamine (0.2 mL, 1.4 mmol ) in dichloromethane (5 mL) at 0°C was added methyl chloroformate (95.4 mg, 1.0 mmol) dropwise. After addition, the mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (20 mL), washed with water (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with Petroleum ether: ethyl acetate = 2:1) to obtain title compound (130 mg, 81.5% yield) as a colorless gel. MS(ESI) calculated for C13H17NO3, 235.1; found 236.2. [0255] N-Methyl-1-(2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methanamine hydrochloride (112): Lithium aluminum hydride (16.1 mg, 0.4 mmol) was added in portions to a solution of J-1 (100 mg, 0.4 mmol) in tetrahydrofuran (6 mL) at 0°C. The mixture was refluxed for 1 hour. Sodium sulfate decahydrate was added to quench the reaction at room temperature. The resulting mixture was filtered, and the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (32.0 mg, 35.1% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ 7.35 – 7.17 (m, 2H), 7.15 – 6.90 (m, 2H), 4.48 – 4.29 (m, 1H), 3.71 – 3.51 (m, 2H), 3.39 – 3.32 (m, 1H), 3.26 – 3.18 (m, 1H), 2.66 (s, 3H), 2.25 – 2.02 (m, 2H), 1.88 – 1.76 (m, 2H). MS(ESI) calculated for C12H17NO, 191.1; found 192.2. [0256] (Propan‐2‐yl)[(2,3,4,5‐tetrahydro‐1‐benzoxepin‐5‐yl)methyl]amine (113): The title compound was prepared in a similar manner to 99.1H NMR (400 MHz, DMSO-d6) δ 8.68 (brs, 1H), 8.42 (s, 1H), 7.31 – 7.16 (m, 2H), 7.07 (td, J = 7.4, 1.3 Hz, 1H), 6.98 (dd, J = 7.9, 1.2 Hz, 1H), 4.25 – 4.20 (m, 1H), 3.65 – 3.59 (m, 1H), 3.42 – 3.10 (m, 4H), 2.19 – 2.04 (m, 1H), 2.00 – 1.96 (m, 1H), 1.84 – 1.67 (m, 2H), 1.24 – 1.21 (m, 6H). MS(ESI) calculated for C14H21NO, 219.2; found 220.1.
Figure imgf000114_0001
Scheme 11 [0257] 1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-carbonitrile (K-1): A solution of 2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-carbonitrile (2.0 g, 10.7 mmol) in dry THF (20 mL) under nitrogen atmosphere was cooled to 0 °C. Sodium hydride (1.1 g, 16.0 mmol) was added by portions to above solution, and the resulting mixture was stirred at room temperature for 30 min. Iodomethane (2.3 g, 16.0 mmol) in dry THF (3 mL) was added dropwise, and the reaction mixture was stirred for 1 hour. The reaction was quenched with addition of water (50 mL), the resulting mixture was extracted with ethyl acetate (50 mL*2), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to get the desired product (1.0 g, 46.7% yield) as a yellow solid. MS(ESI) calculated for C12H12N2O, 200.1; found 201.1. [0258] (1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)methanamine hydrochloride (106): To a solution of 1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine- 5-carbonitrile (0.3 g, 1.5 mmol) in NH3/MeOH (2 N, 15 mL) was added Raney Ni (8.7 mg, 0.1 mmol). The mixture was stirred at room temperature for 3.5 hours under hydrogen atmosphere. After which period, the catalyst in the reaction mixture was removed by filtration and the filtrate was concentrated. The residue was dissolved in MeOH (1 mL), and HCl (1 M, 2 mL) was added thereto. The solvent was removed by lyophilization to obtain the desired product (200 mg, 51.7%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.20 (br s, 3H), 7.42-7.37 (m, 2H), 7.35 – 7.20 (m, 2H), 3.37 – 3.09 (m, 6H), 2.43-2.37 (m, 1H), 2.21 – 1.95 (m, 2H), 1.70-1.60 (m, 1H). MS(ESI) calculated for C15H22N2O, 204.1; found 205.1. [0259] 1‐Methyl‐5‐{[(propan‐2‐yl)amino]methyl}‐2,3,4,5‐tetrahydro‐1H‐1‐benzazepin‐2‐ one (107): The title compound was prepared in a similar manner to 99. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (brs, 1H), 8.63 (brs, 1H), 7.46 – 7.15 (m, 4H), 3.43-3.32 (m, 4H), 3.24 (s, 3H), 2.49-2.46 (m, 1H), 2.21 – 1.97 (m, 2H), 1.67 (m, 1H), 1.29 (d, J = 6.5 Hz, 6H). MS(ESI) calculated for C15H22N2O, 246.2; found 247.1. [0260] (1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)methanamine hydrochloride (98): BH3-THF (1 M, 1.0 mL) was added dropwise to the solution of 106 (0.1 g, 0.5 mmol) in THF (10 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 60oC for another 1 hour. After cooling to room temperature, the reaction mixture was quenched with methanol (10 mL) and concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (30.0 mg, 29.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.17 (brs, 3H), 7.40 - 7.00 (m, 4H), 3.52 - 2.80 (m, 8H), 2.10 - 1.39 (m, 4H). MS(ESI) calculated for C12H18N2, 190.1; found 191.1. [0261] 1-Methyl-5-((methylamino)methyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one hydrochloride (109): A mixture of 106 (150 mg, 0.7 mmol), formaldehyde (4 mL, 37% aqueous solution), and 10% Pd/C (60 mg) in methanol (10 mL) was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through a pad of celite; the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl system) to obtain the desired product (11 mg, 6.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (brs, 1H), 7.43-7.40 (m, 3H), 7.29 (t, J = 6.5 Hz, 1H), 3.57-3.33 (m, 3H), 3.25 (d, J = 7.8 Hz, 3H), 2.79 (d, J = 4.4 Hz, 3H), 2.71 (d, J = 4.0 Hz, 3H), 2.47 – 2.35 (m, 1H), 2.22 – 2.10 (m, 1H), 2.04 (dd, J = 19.8, 10.1 Hz, 1H), 1.86 – 1.65 (m, 1H). MS(ESI) calculated for C 14H20N2O, 232.1; found 233.2.
Figure imgf000116_0001
Scheme 12 [0262] Ethyl (Z)-2-(isochroman-4-ylidene)acetate (L-1): To a solution of sodium hydride (1.1 g, 26.9 mmol, 60%wt) in THF (40 mL) at 0oC was added ethyl 2- (diethoxyphosphoryl)acetate (7.5 g, 33.7 mmol), followed by stirring at room temperature for 30 min. Then, 3,4- dihydro-1H-2-benzopyran-4-one (1.0 g, 6.7 mmol) was added to above solution, and the resulting reaction mixture was continued to stir at room temperature for 1 hour. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (1.4 g, 95.9% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.6 Hz, 1H), 7.37-7.25 (m, 2H), 7.11 (d, J = 7.6 Hz, 1H), 6.38 (t, J = 2.0 Hz, 1H), 5.13(d, J = 2.4 Hz, 2H), 4.70 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). [0263] Ethyl 2-(isochroman-4-yl)acetate (L-2): To a solution of 1 (1.4 g, 6.4 mmol) in methanol (30 mL) was added 10% Pd/C (0.3 g) and stirred at room temperature under hydrogen atmosphere for 3 hours. The mixture was then filtered through a pad of celite, the filtrate was concentrated to obtain the desired compound (1.4 g, 99.4% yield) as a colorless oil. [0264] 2-(Isochroman-4-yl)acetic acid (L-3): To a solution of L-2 (1.4 g, 6.4 mmol) in methanol (15 mL) was added aq. NaOH (2 N, 12.7 mL), and the reaction mixture was stirred at room temperature for 1 hour. Then, the mixture was concentrated to remove methanol, the water phase was adjusted with HCl (2 M) to pH = 1. The mixture was extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (1.2 g, 97.7% yield) as a colorless oil. MS(ESI, negative) calculated for C11H12O3, 192.1; found 191.1. [0265] tert-Butyl (isochroman-4-ylmethyl)carbamate (L-4): Diphenyl azidophosphate (2.6 g, 9.36 mmol) was added to the solution of L-3 (1.2 g, 6.2 mmol) and triethylamine (2.5 g, 24.9 mmol) in tert-butanol (20 mL) at 40oC, and the reaction solution was stirred for 30 min followed by stirring for another 100oC for 2 hours. After cooling to room temperature, the reaction mixture was concentrated to remove tert-butanol and diluted with water (100 mL), extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (450.0 mg, 27.6% yield) as a white solid. MS(ESI) calculated for C15H21NO3, 263.1; found 264.1. [0266] Isochroman-4-ylmethanaminium chloride (79): The solution of L-4 (50 mg, 0.2 mmol) in HCl/dioxane (4 M, 1 mL) was stirred at room temperature for 1 hour. Then the mixture was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (23.0 mg, 61.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (brs, 3H), 7.32-7.29 (m, 1H), 7.27-7.22 (m, 2H), 7.09-7.07 (m, 1H), 4.71 (q, J = 4.0 Hz, 2H), 4.14 (d, J = 1.2 Hz, 1H), 3.74 (d, J = 1.2 Hz, 1H), 3.07-2.97(m, 3H). MS(ESI) calculated for C10H13NO, 163.1; found 164.1. [0267] (3,4‐dihydro‐1H‐2‐benzopyran‐4‐yl)methyl]dimethylamine hydrochloride (80): The title compound was prepared in a similar manner to 99, substituting formaldehyde for acetone. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (brs, 1H), 7.35 (s, 1H), 7.28-7.22 (m, 2H), 7.08 (s, 1H), 4.77-4.65 (m, 1H), 4.29 (s, 1H), 3.75 (d, J = 12 Hz, 1H), 3.44-3.37 (m, 1H), 3.26-3.23 (m, 1H), 3.19-3.14 (m, 1H), 2.90 (s, 3H), 2.82 (s, 3H). MS(ESI) calculated for C12H17NO, 191.1; found 192.2. [0268] [(3,4‐dihydro‐1H‐2‐benzopyran‐4‐yl)methyl](methyl)amine hydrochloride (81): The title compound was synthesized via a procedure similar to that used for 48. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (brs, 2H), 7.36-7.34 (m, 1H), 7.26-7.24 (m, 2H), 7.09-7.07 (m, 1H), 4.77-4.64 (m, 2H), 4.22 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 12.0 Hz, 1H), 3.21-3.12 (m, 2H), 3.08-3.05 (m, 1H), 2.59 (s, 3H). MS(ESI) calculated for C11H15NO, 177.1; found 178.2. [0269] [(3,4‐Dihydro‐1H‐2‐benzopyran‐4‐yl)methyl](propan‐2‐yl)amine hydrochloride (82): The title compound was prepared in a manner similar to 107. 1H NMR (400 MHz, DMSO- d6) δ 8.96 (brs, 1H), 8.66 (brs, 1H), 7.39-7.36 (m, 1H), 7.26-7.24 (m, 2H), 7.09-7.07 (m, 1H), 4.71 (q, J = 15.2 Hz, 2H), 4.22 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 12.0 Hz, 1H), 3.41-3.31(m, 2H), 3.22-3.19 (m, 1H), 3.03-2.99 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H). MS(ESI) calculated for C13H19NO, 205.1; found 206.2.
Figure imgf000119_0001
Scheme 13 [0270] tert-Butyl N-methyl-N-[(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5- yl)methyl]carbamate (M-1): Sodium hydride (0.1 g, 5.4 mmol) was added to the solution of tert-butyl N-[(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)methyl]carbamate (0.4 g, 1.3 mmol) in DMF (5 mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30 min, iodomethane (0.6 g, 4.0 mmol) was added dropwise was added to above solution. The resulting reaction mixture was continued to stir at room temperature for 2.5 hours before pouring into water (25 mL), which was then extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with Petroleum ether: ethyl acetate=1:1) to obtain the desired product (250 mg, 58.6%) as a pale solid. MS(ESI) calculated for C18H26N2O3, 318.2; found 219.2. [0271] N-Methyl-1-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5- yl)methanamine hydrochloride (108): To the solution of M-1 (0.25 g, 0.8 mmol) in MeOH (5 mL) was added HCl/dioxane (4 M, 5 mL) at room temperature. The mixture was stirred at room temperature for 4.5 hours under nitrogen atmosphere and then concentrated to dryness. The residue was slurried with ethyl acetate to get the desired product (150 mg, 87.7%) as a pale solid. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (brs, 1H), 8.48 (brs, 1H), 7.40 (m, 2H), 7.29 (m, 2H), 3.50 – 3.39 (m, 1H), 3.28-3.24 (m, 5H), 2.59 (m, 3H), 2.45-2.34 (m, 1H), 2.22 – 2.11 (m, 1H), 2.11 – 1.98 (m, 1H), 1.69 (brs, 1H). MS(ESI) calculated for C13H18N2O, 218.1; found 219.2.
Figure imgf000120_0001
Scheme 14 [0272] tert-Butyl ((2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methyl)carbamate (N-1): To a solution of 4-(aminomethyl)-3,4-dihydroquinolin-2(1H)-one (3.7 g, 21.0 mmol) and (Boc)2O (6.9 g, 31.5 mmol) in THF (40 mL) was added saturated NaHCO3 (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (1.6 g, 27.6%) as a yellow oil. MS(ESI) calculated for C15H20N2O3, 276.2; found 277.2. [0273] tert-Butyl methyl((1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-4- yl)methyl)carbamate (N-2): To a solution of N-1 (1.1 g, 4.0 mmol) in DMF (10 mL) and was added sodium hydride (0.48 g, 20 mmol) at ice/water bath. After stirring for 30 min, iodomethane (2.8 g, 20 mmol) was added dropwise to above solution. The resulting reaction mixture was warmed to room temperature and stirred for another 2 hours and then quenched by addition of water (30 mL), which was extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 2:1) to obtain the desired compound (0.5 g, 41.7%) as a yellow oil. MS(ESI) calculated for C17H24N2O3, 304.2; found 305.2. [0274] N-methyl-1-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methanaminium chloride (40): To a solution of N-2 (0.1 g, 0.3 mmol) in DCM (1 mL) was added HCl /dioxane (4 M, 1 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed by vacuum, and the residue was purified by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (34.3 mg, 43.5%) as a colorless gel. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (brs, 1H), 8.69 (brs, 1H), 7.37 (dd, J = 11.1, 4.4 Hz, 2H), 7.19 – 7.14 (m, 1H), 7.13 – 7.05 (m, 1H), 3.50 – 3.39 (m, 1H), 3.26 (s, 3H), 3.05 (dd, J = 13.7, 6.8 Hz, 2H), 2.87 (dd, J = 16.4, 6.0 Hz, 1H), 2.67 (dd, J = 16.5, 4.2 Hz, 1H), 2.53 (t, J = 5.4 Hz, 3H). MS(ESI) calculated for C12H16N2O, 204.1; found 304.1. [0275] 4‐[(Dimethylamino)methyl]‐1‐methyl‐1,2,3,4‐tetrahydroquinolin‐2‐one (41): The title compound was synthesized from 40 following the same procedure used for 80. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (brs, 1H), 7.51 – 7.22 (m, 2H), 7.22 – 6.95 (m, 2H), 3.56 (dd, J = 12.2, 5.9 Hz, 3H), 3.31 – 3.19 (m, 5H), 2.92 – 2.64 (m, 8H). MS(ESI) calculated for C13H18N2O, 218.1; found, 219.1. [0276] Methyl[(1‐methyl‐1,2,3,4‐tetrahydroquinolin‐4‐yl)methyl]amine hydrochloride (32): The title compound was synthesized in a manner similar to 31. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (brs, 1H), 8.83 (brs, 1H), 7.09 (t, J = 7.5 Hz, 2H), 6.65 (dd, J = 18.1, 7.8 Hz, 2H), 3.29 – 3.00 (m, 5H), 2.86 (s, 3H), 2.57 (t, J = 5.4 Hz, 3H), 2.07 (dd, J = 13.9, 3.6 Hz, 1H), 1.93 (dd, J = 15.1, 9.6 Hz, 1H). MS(ESI) calculated for C12H18N2, 190.2; found, 191.2. [0277] N,N-Dimethyl-1-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methanaminium chloride (34): The title compound was prepared using the same procedure for 33. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (brs, 1H), 7.26 – 7.03 (m, 2H), 6.91 – 6.60 (m, 2H), 3.40 – 3.24 (m, 3H), 3.23 – 3.09 (m, 2H), 2.90 (s, 3H), 2.84 (d, J = 4.9 Hz, 3H), 2.78 (d, J = 4.8 Hz, 3H), 2.31 – 2.20 (m, 1H), 2.00 (d, J = 11.6 Hz, 1H). MS(ESI) calculated for C13H20N2, 204.2; found, 205.2. [0278] N-Methyl-1-(1,2,3,4-tetrahydroquinolin-4-yl)methanamine (N-3): To a solution of tert-butyl ((2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methyl)carbamate (150 mg, 0.5 mmol) in THF(10 mL) was added lithium aluminum hydride (41.1 mg, 1.1 mmol) at 0oC and the reaction mixture was stirred at 60oC for 2 hours. After cooling to 0oC, the reaction solution was quenched by adding Na2SO4.10H2O (425.0 mg, 1.3 mmol) and stirred at room temperature for additional 30 min. Then, the mixture was filtrated, and the filtrate was concentrated to obtain the desired product (110.1 mg, crude) as a yellow solid. MS(ESI) calculated for C11H16N2, 176.1; found, 177.1. [0279] tert-butyl 4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-3,4- dihydroquinoline-1(2H)-carboxylate (N-4): To a solution of 1(110.1 mg, crude) in THF (5 mL) and saturated NaHCO3(5 mL) was added di-tert-butyl decarbonate (212.2 mg, 1.0 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 8 hours. Then, the mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL) and brine (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to give the desired product (200.3 mg, 98.3% yield by two steps) as a white solid. MS(ESI) calculated for C11H16N2, 376.2; found, 377.2. [0280] N-Methyl-1-(1,2,3,4-tetrahydroquinolin-4-yl)methanamine hydrochloride (30): To the solution of N-4 (200 mg, 0.5 mmol) in dichloromethane (5 mL) was added HCl/dioxane (4 M, 1 mL) at 0oC. The reaction mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (50.0 mg, 44.3 % yield) as a yellow gel. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (brs, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 3.38 – 3.24 (m, 3H), 3.25 – 3.02 (m, 2H), 2.58 (t, J = 5.3 Hz, 3H), 2.23 (dd, J = 10.1, 4.3 Hz, 1H), 2.15 – 2.02 (m, 1H). MS(ESI) calculated for C11H16N2,176.1; found 177.1.
Figure imgf000122_0001
Scheme 15 [0281] 5-((Methyleneamino)methyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (O-1): Formaldehyde (234.2 mg, 7.8 mmol) was added to a solution of 5-(aminomethyl)-2,3,4,5- tetrahydro-1H-1-benzazepin-2-one (500 mg, 2.6 mmol) in methanol (10 mL). The mixture was stirred at room temperature under nitrogen atmosphere for 4 hours and concentrated to dryness. The residue was purified by column chromatography (eluted with ethyl acetate: methanol=70:30) to obtain the title product (100 mg, 18.8% yield) as a white solid. MS(ESI) calculated for C12H14N2O, 202.1; found 203.2 [0282] 5-((Methylamino)methyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one hydrochloride (105): To a solution of O-1 (73 mg, 0.4 mmol) in methanol (20 mL), NaBH3CN (31.4 mg, 0.5 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen atmosphere overnight and then concentrated to dryness. The residue was purified by chromatography column (eluted with dichloromethane: methanol = 4:1) to obtain the title product (10.3 mg, 13.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.42 – 7.24 (m, 3H), 3.32 (s, 1H), 3.30 – 3.23 (m, 2H), 2.88 (s, 3H), 2.42 (m, 1H), 2.32 – 2.23 (m, 1H), 2.01 (m, 1H), 1.92 – 1.80 (m, 1H). MS(ESI) calculated for C12H16N2O, 204.1; found 205.2.
Figure imgf000123_0001
Scheme 16 [0283] tert-Butyl 5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate (P-1): To a solution of 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (15.0 g, 93.0 mmol) and di-tert-butyl dicarbonate (22.2 g, 102.0 mmol) in tetrahydrofuran (200 mL) was added 4- dimethylaminopyridine (11.3 g, 93.0 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 12 hours and then diluted with water (100 mL), which was extracted with ethyl acetate (30 mL * 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to obtain the desired compound (2.9 g, 11.9% yield) as a white solid. MS(ESI) calculated for C15H19NO3, 261.1; found 262.2. [0284] tert-Butyl 5-cyano-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate (P-2): To a solution of P-1 (2.8 g, 10.7 mmol), TosMIC (2.1 g, 10.7 mmol) and ethanol(0.6 g, 12.8 mmol) in 1,2-dimethoxyethane (100 mL) was added potassium tert-butoxide (1.4 g, 12.8 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, and then quenched with water (50 mL). The resulting mixture was extracted with DCM (10 mL * 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:4) to obtain the desired compound (580.0 mg, 19.9 % yield) as a white solid. [0285] tert-Butyl 5-(aminomethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate (P-3): To a solution of P-2 (200 mg, 0.7 mmol) in NH3/MeOH(2 N, 5 mL) was added Raney Ni (171.0 mg, 2.9 mmol), and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (elute with MeOH: DCM=1:9) to obtain the desired compound (175 mg, 86.2% yield) as a colorless oil. MS(ESI) calculated for C15H19N2O2, 276.2; found 277.2. [0286] (2,3,4,5-Tetrahydro-1H-benzo[b]azepin-5-yl)methanamine hydrochloride (94): To a solution of P-3 (75.0 mg, 0.3 mmol) in DCM (2 mL) was added HCl/dioxane (4 M, 2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain the title compound (100.7 mg, 65% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.39 (brs, 1H), 8.18 (brs, 3H), 7.70 – 7.45 (m, 1H), 7.44 – 7.21 (m, 3H), 3.49 – 3.20 (m, 5H), 2.13 – 1.67 (m, 4H). MS(ESI) calculated for C11H16N2, 176.1; found 177.3. [0287] tert-Butyl 5-((dimethylamino)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1- carboxylate (P-4): The mixture of tert-butyl 5-(aminomethyl)-2,3,4,5-tetrahydro-1H-1- benzazepine-1-carboxylate (160.0 mg, 0.6 mmol), formaldehyde (34.5 mg, 1.2 mmol) and Pd/C (16.0 mg, 0.2 mmol) in methanol (5 mL) was stirred at room temperature under hydrogen atmosphere for 12 hours. Then, the mixture was filtered through a pad of celite; the filtrate was concentrated and purified by column chromatography (eluted with DCM: MeOH=15:1) to obtain the desired compound (70.0 mg, 39.7% yield) as a colorless oil. MS(ESI) calculated for C18H28N2O2, 304.2; found 305.2. [0288] N,N-Dimethyl-1-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)methanamine hydrochloride (96): To a solution of P-4 (70.0 mg, 0.2 mmol) in MeOH (2 mL) was added HCl/dioxane (4 M, 2 mL), and the mixture was stirred at room temperature for 2 hours. After then, the reaction mixture was concentrated to obtain title compound (43.0 mg, 91.5% yield) as a white solid. MS(ESI) calculated for C13H20N2, 204.2; found 205.4. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (brs, 1H), 7.60 – 7.16 (m, 4H), 4.09 – 2.99 (m, 5H), 2.92 – 2.70 (m, 6H), 2.17 – 1.52 (m, 4H). [0289] N,N-Dimethyl-1-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5- yl)methanamine hydrochloride (101): A solution of 94 (90 mg, 0.5 mmol) and formaldehyde (76.5 mg, 2.6 mmol) in DCE/MeOH (20 mL, 1:1) was stirred at room temperature for 2 hours. Then, AcOH (0.3 g, 0.5 mmol) and NaBH3CN (0.2 g, 3.2 mmol) were added to above solution; and resulting reaction solution was continued to stir at room temperature for 16 hours. Saturated NaHCO3 (20 mL) was added to the reaction; the mixture was extracted with EA (30 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the desired compound (20 mg, 18.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (brs, 1H), 7.43 - 6.99 (m, 4H), 3.560 - 3.46 (m, 2H), 3.19 - 2.91 (m, 5H), 2.82 - 2.77 (P, 3H), 2.69 (s, 3H), 2.51 (s, 1H), 2.06 - 1.46 (m, 4H). MS(ESI) calculated for C14H22N2, 218.2; found 219.3. [0290] (Propan‐2‐yl)[(2,3,4,5‐tetrahydro‐1H‐1‐benzazepin‐5‐yl)methyl]amine hydrochloride (97): The title compound was synthesized in a manner similar to the procedure used for 99. 1H NMR (400 MHz, DMSO-d6) δ 11.54 (brs, 1H), 9.07 – 8.68 (m, 2H), 7.64 (s, 1H), 7.53 – 7.29 (m, 3H), 3.68 (s, 1H), 3.55 – 3.25 (m, 4H), 3.20 – 3.02 (m, 1H), 2.18 – 1.76 (m, 4H), 1.29 (d, J = 6.9 Hz, 3H), 1.27 (d, J = 6.8 Hz, 3H). MS(ESI) calculated for C14H22N2, 218.2; found 219.4.
Figure imgf000126_0001
Scheme 17 [0291] 2-Chloro-N-methanesulfonyl-N-phenylacetamide (Q-1): To the solution of N- phenylmethanesulfonamide (20.0 g, 0.1 mol) in DMF (100 mL) was added sodium hydride (4.6 g, 0.1 mol, 60% in mineral oil) at 0°C, and the mixture was stirred for 30 min under nitrogen atmosphere. Then, 2-chloroacetyl chloride (13.1 g, 0.1 mol) was added dropwise thereto and continued to stir for 3 hours at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (elute with petroleum ether: ethyl acetate =1:1) to have desired product (15.0 g, 52.2%) as a light brown solid. [0292] 2-[(Ethoxymethanethioyl)sulfanyl]-N-methanesulfonyl-N-phenylacetamide (Q- 2): To the solution of Q-1 (15.0 g, 60.5 mmol) in acetone (150 mL ) was added ethoxy(potassiosulfanyl)methanethione (10.6 g, 66.5 mmol), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: methanol= 20:1) to have desired product (16 g, 79.6 %) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.66 – 7.45 (m, 5H), 4.58 (q, J = 7.1 Hz, 2H), 3.88 (s, 2H), 3.56 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). [0293] 5-{[(tert-butoxy)carbonyl]amino}-4-[(ethoxymethanethioyl)sulfanyl]-N- methanesulfonyl-N-phenylpentanamide (Q-3): A solution of Q-2 (16.0 g, 47.9 mmol) and tert-butyl N-(prop-2-en-1-yl)carbamate (7.5 g, 47.9 mmol) in ethyl acetate (300 mL ) was stirred at 80°C for 30 min. Dodecanoyl dodecaneperoxoate (1.0 g, 2.4 mmol) was added to the above solution, and the resulting mixture was continued to stir for 1 hour. Dodecanoyl dodecaneperoxoate (1.0 g, 2.4 mmol) was added twice every 1 hour till compound Q-2 was consumed (assessed by TLC). The reaction mixture was concentrated and purified with column chromatography (eluted with DCM: ethyl acetate = 5:95) to have desired product (18.0 g, 76.5%) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.50-7.44 (m, 5H), 7.07 (t, J = 5.9 Hz, 1H), 4.58-4.45 (m, 2H), 3.70-3.65 (m, 1H), 3.53 (s, 1H), 3.15- 3.07 (m, 1H), 2.22-2.17 (m, 1H), 1.97-1.95 (m, 1H), 1.76 – 1.58 (m, 1H), 1.36 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H). [0294] tert-Butyl N-[(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)methyl]carbamate (Q-4): The solution of Q-3 (18.0 g, 36.6 mmol) and 2,6-dimethylpyridine (3.9 g, 36.6 mmol) in chlorobenzene (200 mL ) was stirred at reflux for 30 min. 2-(tert-Butylperoxy)-2- methylpropane (10.7 g, 73.2 mmol) was added to above solution. The resulting mixture was refluxed for another 2 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated and purified with column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to give the desired product (4.2 g, 39.6%) as a light yellow solid. [0295] N-Methyl-1-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)methanaminium chloride (95): To the solution of Q-4 (150.0 mg, 0.5 mmol) in THF (5 mL) was added LAH (38.1 mg, 1.0 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour and then raised up to 60°C for 16 hours. After cooling to room temperature, sodium sulfate decahydrate was added to quench the reaction. The resulting mixture was filtered and concentrated to purify with reverse column (CH3CN/H2O, 0.1%HCl) to have desired product (15.0 mg, 12.8%) as a pale solid. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (brs, 1H), 9.35 (brs, 1H), 8.81 (brs, 1H), 7.75-7.73 (m, 1H), 7.43 – 7.39 (m, 3H), 3.75-3.61 (m, 2H), 3.51 – 3.10 (m, 3H), 2.55 (t, J = 5.1 Hz, 3H), 2.04-1.74 (m, 4H). MS(ESI) calculated for C11H15NO, 190.1; found 191.2.
Figure imgf000128_0001
Scheme 18 [0296] N-Methyl-1-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)methanamine hydrochloride (100): To a solution of 1-methyl-5-[(methylamino)methyl]-2,3,4,5- tetrahydro-1H-1-benzazepin-2-one (0.1 g, 0.5 mmol) in THF (8 mL) was added LiAlH4 (34.7 mg, 0.9 mmol) at 0 °C under nitrogen atmosphere. After addition, the reaction mixture was stirred at room temperature for 1 hour and then quenched with sodium sulfate decahydrate. The resulting mixture was filtered and concentrated to purify by Pre-HPLC (CH3CN/H2O, 0.1%HCl) to get the desired compound (30.0 mg, 29.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (brs, 1H), 8.57 (brs, 1H), 7.26 - 7.02 (m, 4H), 3.49 (brs, 1H), 3.31-3.32 (m, 2H), 3.05- 2.84 (m, 5H), 2.54- 2.53 (m, 4H), 1.87-1.57 (m, 4H). MS(ESI) calculated for C13H20N2, 204.1; found 205.2.
Figure imgf000128_0002
Scheme 19 [0297] 1-Bromo-2-((but-3-yn-1-yloxy)methyl)benzene (R-1): To a solution of but-3-yn-1- ol (7.0 g, 100 mmol) in THF (300 mL) was added NaH (6.0 g, 150 mmol, 60%wt) at 0oC, and the mixture was stirred at room temperature for 1 hour. Then, the mixture was added 1- bromo-2- (bromomethyl)benzene (25.0 g, 100 mmol) dropwise. After addition, the resulting mixture was continued to stir at room temperature for 16 hours. After which period, the reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (18 g, 75.3% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 4.63 (s, 2H), 3.69 (t, J = 6.8 Hz, 2H), 2.55 (td, J = 6.8 Hz, J = 2.8 Hz, 2H), 2.01 (t, J = 2.8 Hz, 1H). [0298] 5-Methylene-1,3,4,5-tetrahydrobenzo[c]oxepine (R-2): A mixture of R-1 (9.0 g, 37.6 mmol), Pd(PPh3)4 (1.3 g, 1.1 mmol), cesium carbonate (30.8 g, 94.0 mmol), and ammonium formate (4.7 g, 75.2 mmol) in DMF (120 mL) was stirred at 90oC under nitrogen for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the title compound (2.6 g, 43.3% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 5.17-5.13 (m, 2H), 4.64 (s, 2H), 4.01 (t, J = 5.2 Hz, 2H), 2.60 (t, J = 5.2 Hz, 2H). [0299] 1,3,4,5-Tetrahydro-2-benzoxepin-5-one (R-3): To the solution of R-2 (5.0 g, 31.2 mmol) in DCM/MeOH (40 mL, 1:1) at -78oC was gassed with ozone until starting material was consumed, and the mixture was then gassed with nitrogen for 15 min. Then, the reaction mixture was added triphenylphosphine (0.8 g, 3.1 mmol) at -78oC and continued to stir at room temperature for 1 hour. The mixture was diluted with water (100 mL), extracted with dichloromethane (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (3.8 g, 75.2% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.92 (s, 2H), 3.07 (t, J = 6.4 Hz, 2H), 4.07 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 6.4 Hz, 2H). [0300] Ethyl (E/Z)-2-(3,4-dihydrobenzo[c]oxepin-5(1H)-ylidene)acetate (R-4): To a solution of sodium hydride (1.5 g, 36.9 mmol, 60%wt) in THF (50 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (10.3 g, 46.1 mmol) at 0°C. The mixture was stirred at room temperature for 30 min followed by addition of R-3 (1.5 g, 9.2 mmol) The reaction mixture was stirred at room temperature for 1 hour and quenched by adding water (200 mL), extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (1.6 g, 75.1% yield) as white solid. 1H NMR (400 MHz, CDCl 3) δ 7.35-7.32 (m, 1H), 7.30-7.26 (m, 2H), 7.18-7.14 (m, 1H), 6.06 (s, 1H), 4.72 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.30 (t, J = 5.6 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).and δ 7.25-7.18 (m, 4H), 5.99 (s, 1H), 4.62 (s, 2H), 4.10 (t, J = 5.2 Hz, 2H), 4.03 (q, J = 7.6 Hz, 2H), 2.58 (t, J = 5.2 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H). [0301] Ethyl 2-(1,3,4,5-tetrahydro-2-benzoxepin-5-yl)acetate (R-5): To a solution of R-4 (1.5 g, 6.4 mmol) in methanol (40 mL) was added 10% Pd/C (0.3 g), and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. Then, the mixture was filtered through a pad of celite. The filtrate was concentrated to obtain the desired compound (1.5 g, 99.1% yield), which was used in the next run directly. [0302] 2-(1,3,4,5-Tetrahydro-2-benzoxepin-5-yl)acetic acid (R-6): To a solution of R-5 (1.5 g, 6.4 mmol) in methanol (15 mL) was added aqueous NaOH (2 N, 12.7 mL), and the mixture was stirred at room temperature for 1 hour. Then, the solvent was removed by vacuum, and the residue was added HCl (2 M) until pH = 1. The mixture was extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (1.3 g, 98.5% yield) as a colorless oil. MS(ESI, negative) calculated for C12H14O3, 206.1; found 205.1. [0303] tert-Butyl N-[(1,3,4,5-tetrahydro-2-benzoxepin-5- yl)methyl]carbamate (R-7): To a solution of R-6 (1.1 g, 5.3 mmol) and triethylamine (2.2 g, 21.3 mmol) in tert-butanol (20 mL) was added diphenyl azidophosphate (2.2 g, 8.0 mmol) at 40oC and stirred for 30 min. Then, the reaction mixture was heated to 100oC and stirred for additional 16 hours. After cooling to room temperature, the mixture was concentrated and diluted with water (100 mL), extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (0.4 g, 27.2% yield) as a colorless oil. MS(ESI) calculated for C16H23NO3, 277.2; found 278.2 [0304] (1,3,4,5-Tetrahydrobenzo[c]oxepin-5-yl)methanamine hydrochloride (116): The solution of R-7 (0.1 g, 0.4 mmol) in HCl/dioxane (4 M, 3 mL) was stirred at room temperature for 1 hour. Then, the mixture was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (54.0 mg, 70.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (brs, 2H), 7.26-7.19 (m, 4H), 4.70 (d, J = 14.4 Hz, 1H), 4.62 (d, J = 14.4 Hz, 1H), 4.05-3.99 (m, 1H), 4.90-3.84 (m, 1H), 3.47-3.41 (m, 1H), 3.29-3.22 (m, 1H), 3.19-3.14 (m, 1H), 2.07-1.99 (m, 1H), 1.87-1.80 (m, 1H). MS(ESI) calculated for C11H15NO, 177.1; found 178.2. [0305] Methyl[(1,3,4,5‐tetrahydro‐2‐benzoxepin‐5‐yl)methyl]amine hydrochloride (117): The title compound was synthesized in a manner similar to 40. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (brs, 1H), 8.78 (brs, 1H), 7.29-7.19 (m, 4H), 4.67 (d, J = 14.4 Hz, 1H), 4.62 (d, J = 14.4 Hz, 1H), 4.06-4.00 (m, 1H), 3.91-3.85 (m, 1H), 3.57-3.49 (m, 1H), 3.43- 3.35 (m, 1H), 3.29-3.21 (m, 1H), 2.57 (t, J = 5.2 Hz, 3H), 2.09-2.01 (m, 1H), 1.94-1.83 (m, 1H). MS(ESI) calculated for C12H17NO, 191.1; found 192.2. [0306] (Propan‐2‐yl)[(1,3,4,5‐tetrahydro‐2‐benzoxepin‐5‐yl)methyl]amine hydrochloride (118): The title compound was synthesized in a manner similar to 97. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (brs, 1H), 8.78 (brs, 1H), 7.33-7.27 (m, 1H), 7.26-7.25 (m, 1H), 7.25-7.20 (m, 2H), 4.70 (d, J = 14.4 Hz, 1H), 4.62 (d, J = 14.4 Hz, 1H) , 4.05-4.03 (m, 1H), 3.91-3.88 (m, 1H), 3.62-3.60 (m, 2H), 3.40-3.33 (m, 2H), 3.23-3.19 (m, 1H), 2.08-2.03 (m, 1H), 1.93- 1.85 (m, 1H), 1.29 (d, J = 4.0 Hz, 3H) 1.28 (d, J = 4.0 Hz, 3H). MS(ESI) calculated for C14H21NO, 219.1; found 220.2. [0307] Dimethyl[(1,3,4,5‐tetrahydro‐2‐benzoxepin‐5‐yl)methyl]amine hydrochloride (119): The title compound was synthesized in a manner similar to 101. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.34-7.27 (m, 1H), 7.26-7.22 (m, 1H), 7.22-7.19 (m, 2H), 4.73 (d, J = 14.4 Hz, 1H), 4.67 (d, J = 14.4 Hz, 1H), 4.04-4.02 (m, 1H), 3.93-3.90 (m, 1H), 3.64-3.60 (m, 2H), 3.39-3.36 (m, 1H), 2.83 (s, 3H), 2.77 (s, 3H), 2.09-2.05 (m, 1H), 1.98-1.93 (m, 1H). MS(ESI) calculated for C13H19NO, 205.2; found 206.2.
Figure imgf000132_0001
Scheme 21 [0308] Thiophen-3-ol (T-1): A solution of (thiophen-3-yl)boronic acid (50.0 g, 0.4 mol) in Et2O (500 mL ) was added H2O2 ( 265.0 g, 0.8 mol, 10% H2O2), and the mixture was stirred at 40°C for 3.5 hours. After cooling to room temperature, the mixture was diluted with water (250 mL), extracted with Et2O (150 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to have crude desired product (40 g) as colorless oil which was used for the next step without further purification. MS(ESI) calculated for C4H4OS, 100.0; found 101.1. [0309] Ethyl 4-(thiophen-3-yloxy)butanoate (T-2): To a solution of T-1 (40.0 g, 0.4 mol) and ethyl 4-bromobutanoate (155.0 g, 0.8 mol) in DMF (500 mL ) was added K2CO3 (55.3 g, 0.4 mol) at room temperature. The mixture was stirred at 120°C for 19 hours. After cooling to room temperature, the reaction mixture was poured into ice water (1500 mL), extracted with ethyl acetate (100 mL*4). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to have desired product (50 g, 58.8%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J =5.2, 3.1 Hz, 1H), 6.74 (dd, J =5.2, 3.1 Hz, 1H), 6.24 (dd, J =3.1, 1.5 Hz, 1H), 4.14 (q, J =7.1 Hz, 2H), 3.99 (t, J =6.1 Hz, 2H), 2.50 (t, J =7.3 Hz, 2H), 2.10 (dt, J =13.3, 3.6 Hz, 2H), 1.26 (dt, J =7.1 Hz, 3H). [0310] 4-(Thiophen-3-yloxy)butanoic acid (T-3): The solution of T-2 (50.0 g, 0.2 mol) in THF/MeOH/H2O (1000 mL, 7:1:2) was added NaOH (18.6 g, 0.5 mol) at 0°C. Then, the mixture was stirred at room temperature for 2.5 hours. Aqueous HCl (2 M) was added to the reaction to adjust the pH about 3. The resulting mixture was extracted with ethyl acetate (250 mL*3) and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was slurried with ethyl acetate/hexane (1:10) to obtain desired product (38 g, 87.8%) as a pale solid. 1H NMR (400 MHz, CDCl3) δ 12.13 (brs, 1H), 7.41 (dd, J = 5.2, 3.1 Hz, 1H), 6.77 (dd, J = 5.2, 1.6 Hz, 1H), 6.56 (dd, J = 3.1, 1.6 Hz, 1H), 3.94 (t, J = 6.4 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H), 1.96-1.86 (m, 2H). [0311] 4-(Thiophen-3-yloxy)butanoyl chloride (T-4): To the solution of T-3 (10.0 g, 53.6 mmol) in DCM (150 mL ) was added oxalic dichloride (6.8 g, 53.6 mmol) at 0°C, and the mixture was stirred at room temperature for 3.5 hours. After which period, the reaction mixture was concentrated to have desired product (9 g, 81.9%) as a colorless oil, which was used directly to next step. [0312] 6,7-Dihydrothieno[3,2-b]oxepin-8(5H)-one (T-5): The solution of T-4 (9.0 g, 43.9 mmol) in HFIPA (250 mL ) was stirred at room temperature for 1.5 hours under nitrogen atmosphere and then concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 8:1) to obtain desired product (2.70 g, 36.4%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 5.4 Hz, 1H), 6.74 (d, J = 5.4 Hz, 1H), 4.43 (dd, J = 5.7, 3.5 Hz, 2H), 2.77 (dd, J = 7.0, 5.4 Hz, 2H), 2.20 – 1.97 (m, 2H). [0313] 5,6,7,8-Tetrahydrothieno[3,2-b]oxepine-8-carbaldehyde (T-6): To the solution of trimethylsulfonium iodide (3.0 g, 14.8 mmol) in DMSO (25 mL ) was added sodium hydride (0.9 g, 22.2 mmol, 60%wt) at 0°C under nitrogen; the mixture was stirred for 30 min, followed by addition of T-5 (1.3 g, 7.4 mmol). The resulting mixture was continued to stir at room temperature for 2.5 hours and diluted with water (50 mL), extracted with ethyl acetate (25 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 8:1) to have desired product (0.6 g, 22.2%) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 7.03 (d, J = 5.4 Hz, 1H), 6.73 (d, J = 5.4 Hz, 1H), 4.19 – 4.11 (m, 1H), 3.88 – 3.80 (m, 1H), 3.67 – 3.65 (m, 1H), 2.41 – 2.30 (m, 1H), 2.14 – 2.04 (m, 1H), 2.02 – 1.89 (m, 2H). [0314] (5,6,7,8-Tetrahydrothieno[3,2-b]oxepin-8-yl)methanamine(T-7): To the solution of ammonium acetate (2.8 g, 36.1 mmol) in ethyl alcohol (2 mL) was added T-6 (330.0 mg, 1.8 mmol), sodium cyanoborohydride (343.0 mg, 5.5 mmol), and ammonium hydroxide (4.4 g, 125.0 mmol). The mixture was stirred at 80°C for 12 hours in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL). The organic solution was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: MeOH= 4:1)to obtain the desired compound (220.0 mg, 66.3% yield). MS(ESI) calculated for C9H13NOS, 183.1; found 184.2 [0315] tert-Butyl ((5,6,7,8-tetrahydrothieno[3,2-b]oxepin-8-yl)methyl)carbamate (T-8): The mixture of T-7 (220.0 mg, 1.2 mmol) and di-tert-butyl dicarbonate (390.0 mg, 1.8 mmol) in saturated sodium bicarbonate (5 mL, 65.5 mmol) and tetrahydrofuran (5 mL) was stirred at room temperature for 1 hour. Then, the mixture was diluted with H2O (10 mL), extracted with ethyl acetate (15 mL * 3). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 9:1) to obtain the desired compound (185.0 mg, 54.4 % yield) as a white solid. MS(ESI) calculated for C14H21NO3S, 283.1; found 284.2. [0316] (5,6,7,8-Tetrahydrothieno[3,2-b]oxepin-8-yl)methanamine hydrochloride (154): To a solution of T-8 (110 mg, 0.3 mmol) in MeOH (2 mL) was added HCl/ dioxane (4 M, 2 mL), and the mixture was stirred at room temperature for 2 hours. After which period, the reaction mixture was concentrated to obtain the title compound (20.0 mg, 28.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (brs, 3H), 7.21 (d, J = 5.4 Hz, 1H), 6.70 (d, J = 5.4 Hz, 1H), 4.16 – 4.08 (m, 1H), 3.76 – 3.67 (m, 1H), 3.28 – 3.20 (m, 1H), 3.08 – 2.93 (m, 2H), 2.15 – 2.01 (m, 1H), 1.98 – 1.73 (m, 3H). MS(ESI) calculated for C9H13NOS, 183.1; found 184.2. [0317] N-Methyl-1-(5,6,7,8-tetrahydrothieno[3,2-b]oxepin-8-yl)methanamine hydrochloride (155): To the solution of methylamine in MeOH (2 N, 50 mL) was added 5,6,7,8-tetrahydrothieno[3,2-b]oxepine-8-carbaldehyde (0.3 g, 1.4 mmol) and 10% Pd/C (0.1 g). The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. Then, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by Prep-HPLC to obtain title compound (60.0 mg, 18.8%) as a pale solid. 1H NMR (400 MHz, DMSO-d6) δ 9.22 – 8.59 (m, 2H), 7.21 (d, J = 5.4 Hz, 1H), 6.70 (d, J = 5.4 Hz, 1H), 4.23 – 4.07 (m, 1H), 3.78 – 3.60 (m, 1H), 3.51 – 3.36 (m, 1H), 3.24 – 3.09 (m, 1H), 3.09 – 2.92 (m, 1H), 2.55 (s, 3H), 2.12 (m, 1H), 1.97 (m, 1H), 1.91 – 1.66 (m, 2H). MS(ESI) calculated for C11H15NO, 197.1; found 198.2. [0318] Dimethyl({5H,6H,7H,8H‐thieno[3,2‐b]oxepin‐8‐yl}methyl)amine hydrochloride (156): The title compound was prepared using the same procedure as 155, substituting dimethylamine for methylamine. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.23 (d, J = 5.4 Hz, 1H), 6.74 – 6.67 (m, 1H), 4.23 – 4.12 (m, 1H), 3.73 – 3.63 (m, 1H), 3.57 – 3.47 (m, 1H), 3.44 – 3.27 (m, 1H), 3.25 – 3.11 (m, 1H), 2.81 (d, J = 4.1 Hz, 3H), 2.74 (d, J = 4.1 Hz, 3H), 2.21 – 1.98 (m, 2H), 1.93 – 1.72 (m, 2H). MS(ESI) calculated for C11H17NOS, 247.1; found 248.2.
Figure imgf000135_0001
Scheme 23 [0319] Chromane-4-carbonitrile (V-1): A mixture of 3,4-dihydro-2H-1-benzopyran-4-one (4.0 g, 26.9 mmol), 1-isocyanomethanesulfonyl-4-methylbenzene (15.7 g, 80.6 mmol) and ethanol (16 mL) in 1,2-dimethoxyethane (160 mL) was added potassium 2-methylpropan-2- olate (9.0 g, 80.6 mmol) at 0 °C. After addition, the reaction mixture was stirred at room temperature for 16 hours. Then, the mixture was poured into water (100 mL), extracted with DCM (100 mL* 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with Petroleum ether: ethyl acetate = 4:1) to obtain the title product (820 mg, 19.0% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 (m, , 1H), 7.31 – 7.25 (m, 1H), 7.22 (m, 1H), 7.06 – 6.99 (m, 1H), 6.99 – 6.92 (m, 2H), 6.85 (dd, J = 8.3, 1.1 Hz, 1H), 4.58 – 4.48 (m, 2H), 4.33 (m, 1H), 4.28 – 4.19 (m, 1H), 4.03 (t, J = 6.0 Hz, 1H), 2.86 – 2.76 (m, 2H), 2.33 (m, 1H). [0320] 4-Methylchromane-4-carbonitrile (V-2): To a solution of V-1 (820 mg, 5.15 mmol) and iodomethane (4.4 g, 30.9 mmol) in dimethylformamide (50 mL) was added sodium hydride (1.2 g, 30.9 mmol, 60%wt) at 0 °C, and the mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. Then, the mixture was poured into water (500 mL), extracted with ethyl acetate (150 mL* 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to get crude product (820 mg) for the next step without further purification. [0321] (4-Methylchroman-4-yl)methanamine hydrochloride (65): To a solution of V-2 (820 mg, crude) in NH3/MeOH (7 M, 30 mL) was added Raney Ni (100mg), the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by chromatography column (eluted with dichloromethane: methanol = 94:6) to obtain the title product (120.0 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (brs, 3H), 7.34 (dd, J = 7.8, 1.5 Hz, 1H), 7.17 – 7.07 (m, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 4.28 – 4.02 (m, 2H), 3.15 – 3.01 (m, 2H), 2.18 – 2.07 (m, 1H), 1.73 (m, 1H), 1.35 (s, 3H). MS(ESI) calculated for C11H15NO, 177.1; found 178.2. [0322] 2-(Chroman-4-ylidene)acetonitrile (V-3): To a solution of Diethyl (cyanomethyl)phosphonate (4.8 g, 27.0 mmol) in THF (20 mL) was added sodium hydride (129.6 mg, 5.4 mmol) at 0°C and the mixture was stirred at 0°C for 10 min. Chroman-4-one (2.0 g, 13.5 mmol) was added thereto and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated NH4Cl (20 mL), and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (2.0 g, 87.0%) as a yellow oil. [0323] 2-(Chroman-4-yl)acetonitrile (V-4): To a solution of V-3 (1.5 g, 8.8 mmol) in MeOH (15 mL) was added 10% Pd/C (0.4 g), and the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. Then, the mixture was filtered with celite; the filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (1.5 g, 98.7% yield) as a yellow oil. [0324] 2-(Chroman-4-yl)ethan-1-aminium chloride (76): The solution of V-4 (0.1g, 0.6 mmol) and Raney Ni (0.05 g, 0.9 mmol) in NH3/methanol (2 N ^6 mL) was stirred at room temperature under hydrogen atmosphere for 4 hours. After which period, the mixture was filtered with celite; the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (45.3 mg, 36.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (brs, 3H), 7.17 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 4.11 (dd, J = 7.3, 3.4 Hz, 2H), 2.94-2.90 (m, 3H), 2.12 – 1.91 (m, 2H), 1.87 – 1.69 (m, 2H). MS(ESI) calculated for C11H15NO, 177.1; found 178.1. [0325] [2‐(3,4‐Dihydro‐2H‐1‐benzopyran‐4‐yl)ethyl]dimethylamine hydrochloride (77): The title compound was prepared in a manner similar to 119. 1H NMR (400 MHz, DMSO- d6) δ 10.49 (brs, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.13 – 7.04 (m, 1H), 6.85 (dd, J = 10.7, 4.1 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 4.23 – 4.07 (m, 2H), 3.21 – 3.06 (m, 2H), 2.89 (dd, J = 9.6, 4.6 Hz, 1H), 2.75 (d, J = 4.5 Hz, 6H), 2.17-2.01 (m, 1H), 1.99-1.92 (m, 2H), 1.91-1.75 (m, 1H). MS(ESI) calculated for C13H19NO, 205.2; found 206.2. [0326] 2-(2,3-Dihydrobenzofuran-3-yl)ethan-1-amine hydrochloride (6): The title compound was prepared in a manner similar to 76, substituting benzofuran-3(2H)-one for chromane-4-one. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (brs, 3H), 7.23 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 4.59 (d, J = 8.8 Hz, 1H), 4.24-4.20 (m, 1H), 3.57-3.48 (m, 1H), 2.95-2.73 (m, 2H), 2.03-1.89 (m, 1H), 1.84-1.70 (m, 1H). MS(ESI) calculated for C10H13NO, 163.1; found 164.2. [0327] tert-Butyl (2-(chroman-4-yl)ethyl)carbamate (V-5): To a solution of 2-(chroman-4- yl)ethan-1-amine (0.8 g, 4.5 mmol) and (Boc)2O (1.5 g, 6.75 mmol) in THF (10 mL) was added saturated NaHCO3 (5 mL), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (1.0 g, 80.0%) as a yellow oil. MS(ESI) calculated for C16H23NO3, 277.2; found 278.2 [0328] tert-Butyl (2-(chroman-4-yl)ethyl)(methyl)carbamate (V-6): To the solution of V-5 (0.5 g, 1.8 mmol) in DMF (5 mL) was added sodium hydride (90 mg, 3.6mmol, 60%wt) at 0°C under nitrogen atmosphere, and the mixture was stirred at 0°C for 30 min. Iodomethane (0.4 g, 2.7 mmol) was added; the resulting solution was continued to stir at room temperature for 2 hours. The mixture was quenched with water (60 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (0.4 g, 75.5%) as a yellow oil. MS(ESI) calculated for C17H25NO3, 291.2; found 292.2. [0329] 2-(Chroman-4-yl)-N-methylethan-1-amine hydrochloride (78): To the solution of V-6 (0.2 g, 0.7 mmol) in DCM (2 mL) was added HCl /dioxane (4 M, 2 mL), and the mixture was stirred at room temperature for 2 hours. After then, the reaction mixture was concentrated and purified by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (100.7 mg, 64.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (brs, 1 H), 7.17 (d, J = 7.6 Hz, 1H), 7.12 – 7.03 (m, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 7.4 Hz, 1H), 4.18 – 4.06 (m, 2H), 2.98-2.89 (m, 3H), 2.55 (s, 3H), 2.17 – 1.93 (m, 2H), 1.91 – 1.69 (m, 2H). MS(ESI) calculated for C12H17NO, 191.1; found 192.1 [0330] [2‐(2,3‐Dihydro‐1‐benzofuran‐3‐yl)ethyl]dimethylamine hydrochloride (7): The title compound was prepared from 6 using the method utilized for synthesizing 77. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (brs, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 4.59 (d, J = 8.8 Hz, 1H), 4.27-4.23 (m, 1H), 3.56-3.48 (m, 1H), 3.18-3.09 (m, 1H), 3.08-1.00 (m, 1H), 2.73 (d, J = 4.4 Hz, 6H), 2.15-2.06 (m, 1H), 1.96-1.86 (m, 1H). MS(ESI) calculated for C12H17NO, 191.1; found 192.2. [0331] [2‐(2,3‐Dihydro‐1‐benzofuran‐3‐yl)ethyl](methyl)amine hydrochloride (8): The title compound was prepared from 6 using the method utilized for synthesizing 78. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (brs, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 4.59 (d, J = 8.8 Hz, 1H), 4.24-4.20 (m, 1H), 3.59-3.50 (m, 1H), 3.02-2.95 (m, 1H), 2.81-2.84 (m, 1H), 2.55 (s, 3H), 2.05-1.96 (m, 1H), 1.88-1.79 (m, 1H). MS(ESI) calculated for C11H15NO, 177.1; found 178.2.
Figure imgf000139_0001
Scheme 27 [0332] 5-Methoxy-4H-chromen-4-one (Z-1): To a solution of 1-(2-hydroxy-6- methoxyphenyl)ethan-1-one (5.0 g, 30.1 mmol) in ethyl formate (50 mL) was added sodium hydride (3.6 g, 150.5 mmol, 60%wt) at ice/water bath temperature. The reaction mixture was stirred at 0°C for 30 min, and then at room temperature for 16 hours. The mixture was diluted with saturated NH4Cl (50 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (4.5 g, 84.9%) as a yellow oil. MS(ESI) calculated for C10H8O3, 176.1; found 177.1. [0333] 5-Methoxychroman-4-ol (Z-2): To a solution of Z-1 (4.5 g, 25.6 mmol) in ethyl acetate (30 mL) was added 10% Pd/C (1.0 g), and the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. Then, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (3.2 g, 69.6% yield) as a yellow oil. MS(ESI) calculated for C10H12O3, 180.1; found 181.1. [0334] 4-Chloro-5-methoxychromane (Z-3): To a solution of Z-2 (0.2 g, 1.1 mmol) in DCM (4 mL) was added thionyl chloride (0.2 g, 1.65 mmol) dropwise at 0°C under nitrogen atmosphere. After addition, the reaction mixture was continued to stir at 0°C for 30 min, and then at room temperature for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (0.1 g, 45.5%) as a yellow oil. MS(ESI) calculated for C10H11ClO2, 198.0; found 199.0. [0335] 5-Methoxychromane-4-carbonitrile (Z-4): To a solution of Z-3 (0.1 g, 0.5 mmol) in DCM (4 mL) was added SnCl4 (0.1 mL, 0.05 mmol) and TMSCN (0.06 g, 0.6 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 min, and then at room temperature for 2 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (0.05 g, 52.4%) as a yellow oil. [0336] (5-Methoxychroman-4-yl)methanamine hydrochloride (61): The solution of Z-4 (50 mg, 0.3 mmol) and Raney Ni (50 mg) in NH3/methanol (2 M, 6 mL) was stirred at room temperature under hydrogen atmosphere for 4 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (17.7 mg, 29.2% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.03 (brs, 3H), 7.11 (t, J = 8.2 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 4.20 (d, J = 11.4 Hz, 1H), 4.04 (dd, J = 17.5, 6.5 Hz, 1H), 3.25 – 3.12 (m, 1H), 3.07 (d, J = 5.0 Hz, 1H), 2.91 (d, J = 5.6 Hz, 1H), 2.10 (d, J = 14.3 Hz, 1H), 1.82 (dd, J = 18.2, 9.0 Hz, 1H). MS(ESI) calculated for C11H15NO2, 193.1; found 194.1.
Figure imgf000140_0001
Scheme 28 [0337] 3-(Thiophen-2-ylthio)propanoic acid (AA-1): To the solution of thiophene-2-thiol (5 g, 43.0 mmol) and Et3N (8.7 g, 86.0 mmol) in THF (100 mL) was added acrylic acid (3.7 mL, 51.6 mmol), and the mixture was refluxed under nitrogen atmosphere for 12 hours. After cooling to room temperature, the reaction mixture was poured into a diluted aqueous hydrochloride solution and extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was crystallized from petroleum ether to give the desired product (6.5 g, 80.0 % yield) as a white solid. MS(ESI) calculated for C7H8O2S2, 188.0; found, 189.0. [0338] 5,6-Dihydro-4H-thieno[2,3-b]thiopyran-4-one(AA-2): To a solution of AA-1 (6.5 g, 34.5 mmol) in DCM (100 mL) was added 2 drops of DMF under nitrogen atmosphere. A solution of oxalyl chloride (3.2 g, 51.8 mmol) in DCM (50 mL) was added dropwise into above solution. The resulting solution was continued to stir at room temperature for 2 hours. The reaction mixture was cooled to -10°C with an ice/salt bath, and tin tetrachloride (1.7 mL, 14.5 mmol) in DCM(20 mL) was added dropwise. After addition, the mixture was stirred at 0°C for another 2 hours. The reaction was quenched with water (30 mL) and separated. The organic layer was washed with sodium carbonate solution, dried over sodium sulfate, filtered and concentrated. The residue was recrystallized from petroleum ether to obtain the desired product (5.2 g, 89.2 % yield) as a gray solid. MS(ESI) calculated for C7H6OS2, 170.0; found, 171.0. [0339] 5,6-Dihydro-4H-thieno[2,3-b]thiopyran-4-carbonitrile (AA-3): To the solution of AA-2 (500 mg, 2.9 mmol), TOSMIC (1.7 g, 8.8 mmol) and ethanol (3.5 mL) in 1,2- dimethoxyethane (50 mL) was added potassium tert-butoxide (987.0 mg, 8.8 mmol) by portions at ice/water bath. The reaction mixture was stirred at 0°C for 30 min, and then at room temperature for 3 hours. After that, the mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL *3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (85.4 mg, 17.2% yield) as a yellow solid. MS(ESI) calculated for C8H7NS2, 181.0; found, 182.0. [0340] (5,6-Dihydro-4H-thieno[2,3-b]thiopyran-4-yl)methanamine hydrochloride (149): The solution of AA-3 (85.4 mg, 0.5 mmol) and borane tetrahydrofuran complex (1 M, 2 mL) in THF (3 mL) was refluxed for 3 hours. After then, MeOH (1 mL) was added into the solution at 0oC, and the reaction mixture was stirred at room temperature for 1 hour. After which period, the mixture was concentrated and purified by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (10.3 mg, 9.9 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.11 (brs, 3H), 7.32 (d, J = 5.3 Hz, 1H), 7.05 (d, J = 5.3 Hz, 1H), 3.25 – 3.08 (m, 3H), 3.04 (m, 1H), 2.90 (t, J = 11.2 Hz, 1H), 2.19 (m, 1H), 2.12 – 1.97 (m, 1H). MS(ESI) calculated for C11H16N2, 185.0; found, 186.0. [0341] tert-Butyl ((5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)methyl)carbamate (AA- 4): To a solution of (5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)methanamine (440 mg, 2.4 mmol) in THF(10 mL) and sat. NaHCO3(10 mL) was added di-tert-butyl decarbonate (615.2 mg, 2.9 mmol) at room temperature, and the mixture was stirred for 8 hours. Then, the reaction mixture was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to give the desired product (519.9 mg, 76.8% yield) as a white solid. MS(ESI) calculated for C13H19NO2S2, 285.1; found, 286.1. [0342] tert-Butyl ((7,7-dioxido-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4- yl)methyl)carbamate (AA-5): To a solution of AA-4 (519.9 mg, 1.8 mmol) in dichloromethane (20 mL) was added m-CPBA (929.7 mg, 22.3 mmol), and the mixture was stirred at room temperature for 16 hours. Then, the reaction was quenched with saturated aqueous Na2S2O3 and extracted with DCM (20 mL*3). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to purify by prep-TLC to afford the desired product (270.0 mg, 47.2% yield) as a yellow solid. MS(ESI) calculated for C13H19NO4S2, 317.1; found, 318.1. [0343] (7,7-Dioxido-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)methanamine hydrochloride (153): To the solution of AA-5 (270.0 mg, 0.9 mmol) in dichloromethane (2 mL) was added HCl/dioxane (4 M, 2 mL) at 0oC, and the mixture was stirred at room temperature for 1 hour. Then, the mixture was concentrated and purified by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (50.0 mg, 22.1 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (brs, 3H), 8.01 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 3.72 (m, 1H), 3.55 (dd, J = 12.7, 8.2 Hz, 1H), 3.44-3.27 (m, 2H), 3.15-3.03 (m, 1H), 2.62-2.49 (m, 1H), 2.47-2.36 (m, 1H). MS(ESI) calculated for C8H11NO2S2,217.0; found 218.0. [0344] N-((5,6-Dihydro-4H-thieno[2,3-b]thiopyran-4-yl)methyl)-2,2,2-trifluoroacetamide (AA-6): To a solution of (5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)methanamine (200 mg, 1.1 mmol) in DCM (30 mL ) was added trifluoroacetic anhydride (336.1 mg, 1.6 mmol) and triethylamine (324.3 mg, 3.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. After which period, the mixture was diluted with water (30 mL) and extracted with DCM (20 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: MeOH = 20:1) to obtain the desired compound (219.8 mg, 65.9% yield) as a white solid. MS(ESI) calculated for C10H10F3NOS2, 281.0; found, 282.0. [0345] 2,2,2-Trifluoro-N-((7-oxido-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4- yl)methyl)acetamide (AA-7): To a solution of AA-6 (219.8 mg, 0.8 mmol) in DCM (20 mL ) was added m-CPBA (33.4 mg, 0.8 mmol) at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NaHSO3 and extracted with DCM (20 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: MeOH = 20:1) to obtain the desired compound (139.9 mg, 58.8% yield) as a brown oil. MS(ESI) calculated for C10H10F3NO2S2, 297.0; found, 298.0. [0346] ((4s,7s)-7-Oxido-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl)methanamine hydrochloride (151) and ((4r,7s)-7-Oxido-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4- yl)methanaminium chloride (152): To a solution of AA-7 (139.9 mg, 0.5 mmol) in MeOH (10 mL) was added potassium hydroxide (84.2 mg, 1.5 mmol) in water (2 mL), and the mixture was stirred at room temperature for 1 hour. Then, reaction mixture was concentrated and purified by Prep-TLC (DCM:MeOH=6:1) to obtain the 151 ( 35.2 mg, 29.7% yield) and 152 ( 8.5 mg, 6.6 % yield) as white solids. 1H NMR for 151 (400 MHz, DMSO-d6) δ 8.25 (brs, 2H), 7.99 (d, J = 5.1 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 3.50 (dd, J = 12.7, 3.8 Hz, 1H), 3.24 (m, 2H), 3.14 – 3.00 (m, 1H), 2.91 (dd, J = 12.7, 10.0 Hz, 1H), 2.38 – 2.13 (m, 2H). MS(ESI) for 151: calculated for C8H11NOS2,201.0; found 202.0. 1H NMR for 152 (400 MHz, DMSO-d6) δ 8.09 (brs, 2H), 7.97 (d, J = 5.1 Hz, 1H), 7.28 (d, J = 5.1 Hz, 1H), 3.36 (m, 2H), 3.04 (dt, J = 14.1, 5.0 Hz, 2H), 2.91 (dd, J = 12.8, 10.5 Hz, 1H), 2.47 – 2.39 (m, 1H), 2.22 (dd, J = 15.4, 2.9 Hz, 1H). MS(ESI) for 152 calculated for C8H11NOS2,201.0; found 202.0.
Figure imgf000144_0001
Scheme 30 [0347] 3-(Dimethylamino)-1-(2-fluoro-6-hydroxyphenyl)prop-2-en-1-one (CC-1): To a solution of 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one (11.0 g, 48.7 mmol) in toluene (250 mL) was added DMF-DMA (8.7 g, 73.1 mmol). Then, the mixture was stirred at 110 °C for 5 h. After cooling to room temperature, the mixture was concentrated to have desired product (10.0 g, 67.1% yield) as a yellow solid for the next step without further purification. [0348] 5-Fluoro-4H-chromen-4-one (CC-2): The solution of CC-1 (10.0 g, 47.8 mmol) in ethyl acetate (250 mL ) was added T3P (30.0 g, 95.6 mmol) at room temperature and stirred at 100°C for 1 hour. After cooling to room temperature, the mixture was poured into ice water (500 mL) and extracted with ethyl acetate (50 mL*4). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to purify with column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to have desired product (5.0 g, 63.8%) as a colorless oil. [0349] 5-Fluoro-3,4-dihydro-2H-1-benzopyran-4-one (CC-3): The mixture of CC-2 (1.5 g, 9.1 mmol) and 10% Pd/C (0.3 g ) in ethyl acetate (15 mL ) was stirred at room temperature for 19 hours under hydrogen atmosphere. Then, the mixture was filtered with celite, and the filtrate was concentrated to obtain the desired product (1.2 g, 80.0%) as a colorless oil. [0350] Ethyl 2-(5-fluoro-3,4-dihydro-2H-1-benzopyran-4-ylidene)acetate (CC-4): To the solution of ethyl 2-(diethoxyphosphoryl)acetate (6.4 g, 27.0 mmol) in THF (35 mL) was added sodium hydride (0.6 g, 27.0 mmol, 60%wt) at 0°C and stirred for another 1.5 hours under nitrogen atmosphere. CC-3 (1.5 g, 9.0 mmol) was added slowly and continued to stir at room temperature for 2.5 hour. The reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (25 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to have desired product (800 mg, 37.6%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.19-7.14 (m, 1H), 6.75 – 6.57 (m, 3H), 4.25-4.18 (m, 4H), 3.39 (t, J = 6.0 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). [0351] Ethyl 2-(5-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)acetate (CC-5): To a solution of CC-4 (0.8 g, 3.4 mmol) in MeOH (10 mL ) was added 10% Pd/C (0.2 g), and the mixture was stirred at room temperature for 2.5 hour under hydrogen atmosphere. Then, the reaction mixture was filtered with celite, and the filtrate was concentrated to have desired product (0.7 g, 87.5%) as a pale solid. [0352] 2-(5-Fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)acetic acid (CC-6): To the solution of CC-5 (0.7 g, 3.3 mmol) in THF/MeOH/H2O (11 mL, 7:1:3 ) was added NaOH (0.4 g, 10.0 mmol), and the mixture was stirred at room temperature for 2.5 hours. After which period, the mixture was acidified with aqueous HCl (3 N) to pH~ 4, and extracted with ethyl acetate (15 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to have desired product (0.6 g, 85.1%) as a colorless oil. [0353] tert-Butyl N-[(5-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]carbamate (CC-7): The solution of CC-6 (0.9 g, 8.6 mmol), Et3N (1.7 g, 17.2 mmol) and DPPA (1.2 g, 4.3 mmol) in t-BuOH (10.5 g, 0.1 mol) was stirred at 40°C for 1.5 hours and then at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to give the desired product (0.3 g, 11.6 %) as a white solid. MS(ESI) calculated for C11H15NO, 281.1; found 182.2. [0354] (5-Fluorochroman-4-yl)methanamine hydrochloride (62): To a solution of CC- 7 (0.1 g, 0.4 mmol) in MeOH (5 mL ) was added HCl/dioxane (4 M, 2.7 mL) at 0°C, and the mixture was stirred at room temperature for 6.5 hours and then concentrated to dryness. The residue was slurried with ethyl acetate/methanol (5 mL, 20:1) to have desired product (35.0 mg, 54.7%) as a white solid. [0355] 1H NMR (400 MHz, DMSO-d6) δ 8.36 (brs, 3H), 7.19 (dd, J = 15.2, 8.2 Hz, 1H), 6.82 – 6.70 (m, 1H), 6.66 (d, J = 8.3 Hz, 1H), 4.27-4.24 (m, 1H), 4.18 – 3.95 (m, 1H), 3.33- 3.31 (m, 1H), 3.10 – 2.93 (m, 2H), 2.23-2.21 (m, 1H), 2.00 – 1.76 (m, 1H). MS(ESI) calculated for C11H15NO, 181.1; found 182.2.
Figure imgf000146_0001
Scheme 31 [0356] 3-Bromo-2-(tert-butoxy)thiophene (DD-1): A solution of 2,3-dibromothiophene (10.0 g, 41.3 mmol) in diethyl ether (150 mL) was treated with n-BuLi (2.5 N, 16.5 mL) over 20 min at -78°C, and the mixture was stirred 1 hour at -78°C. Magnesium bromide ethyl etherate (12.8 g, 49.6 mmol) was added above solution in two portions. The mixture was continued to stir at -78°C for 1 hour and at room temperature for additional 2 hours. Tert- butyl peroxybenzoate (8.4 g, 43.4 mmol) was then added at 0°C, and the reaction was allowed to stir at room temperature for 16 hours. The mixture was then quenched with ice water (50 mL) and HCl (2 M, 25 mL). The organic layer was separated and washed with ice- cold NaOH (1 N, 30 mL), water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (5.0 g, 51.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.76 (s, 2H), 1.43 (s, 9H). MS(ESI) calculated for C8H11BrOS, 234.0; found, 235.0. [0357] 2-(tert-Butoxy)thiophene-3-carbaldehyde (DD-2): To the solution of DD-1 (5.0 g, 21.2 mmol) in THF (200 mL) was added n-BuLi (2.5 N, 10 mL) slowly at -78°C. The solution was stirred for 1 hour at this temperature, followed by addition of DMF (2.3 g, 31.8 mmol). The resulting solution was slowly warmed to 0oC and continued to stir for additional 2 hours. The reaction was then quenched by ice HCl (1M, 50 mL), and the mixture was extracted with ethyl acetate (200mL*2). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (1.7 g, 43.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.16 (d, J = 6.1 Hz, 1H), 6.66 (dd, J = 6.1, 0.5 Hz, 1H), 1.49 (s, 9H). [0358] Ethyl (E)-3-(2-(tert-butoxy)thiophen-3-yl)acrylate (DD-3): To a solution of sodium hydride (662 mg, 27.6 mmol, 60%wt) in THF (20 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (5.8 g, 27.6 mmol) at 0oC; the mixture was stirred at 0oC for 1 hour, followed by addition of solution of DD-2 (1.7 g, 9.2 mmol) in THF (10 mL). The resulting mixture was stirred for another 1 hour from 0oC to room temperature. After which period, the reaction was quenched with ice-water (100 mL) and extracted with ethyl acetate (50mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (2.3 g, 32.9% yield) as a yellow oil. MS(ESI) calculated for C13H18O3S, 254.1; found, 255.1. [0359] Ethyl 3-(2-(tert-butoxy)thiophen-3-yl)-4-nitrobutanoate (DD-4): To a solution of DD-3 (2.3 g, 9.0 mmol) in nitromethane (60 mL) was added DBU (4.1 g, 27.1 mmol) at room temperature, and the mixture was stirred at 75oC for 3 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (1.1 g, 39.6% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.65 (s, 2H), 4.72 – 4.61 (m, 2H), 4.09 (m, 3H), 2.71 (dd, J = 7.3, 2.1 Hz, 2H), 1.45 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H). MS(ESI) calculated for C14H21NO5S, 315.1; found, 316.1. [0360] 3-(2-(tert-Butoxy)thiophen-3-yl)-4-nitrobutan-1-ol (DD-5): To the solution of DD- 4 (1.1 g, 3.5 mmol) in THF (50 mL) was added BH3-THF (1 M, 4 mL) at 0°C, and the mixture was stirred at 40oC for 1 hour. After cooling to 0oC, the reaction was quenched by adding MeOH (2 mL) slowly, the resulting solution was continued to stir at room temperature for another 1 hour. After which period, the reaction mixture was concentrated to obtain the desired product (950.0 mg, quantitative) for the next step without further purification.1H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 6.0 Hz, 1H), 6.69 – 6.62 (m, 1H), 4.66 – 4.54 (m, 2H), 4.12 (q, J = 7.1 Hz, 1H), 3.96 – 3.81 (m, 1H), 3.58 (dd, J = 10.2, 5.4 Hz, 1H), 3.43 – 3.29 (m, 1H), 2.23 (s, 1H), 1.94 (m, 1H), 1.65 – 1.53 (m, 1H), 1.44 (s, 9H). [0361] 3-(4-Hydroxy-1-nitrobutan-2-yl)thiophen-2-ol (DD-6): To the solution of DD- 5 (1.1 g, 4.0 mmol) in DCM (20 mL ) was added HCl/dioxane (4 M, 1 mL) at room temperature and the mixture was stirred for 30 min. Then, the mixture was concentrated and purified by chromatography column (eluted with DCM: MeOH = 5:1) to obtain the desired compound (219.7 mg, 25.3% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J = 2.7 Hz, 1H), 4.79 (dd, J = 12.7, 8.6 Hz, 1H), 4.65 (dd, J = 12.7, 5.4 Hz, 1H), 4.02 (d, J = 2.6 Hz, 2H), 3.80 – 3.52 (m, 3H), 1.92 (m, 2H), 1.64 (s, 2H). [0362] 4-(Nitromethyl)-3,4-dihydro-2H-thieno[2,3-b]pyran (DD-7): To the solution of diethyl azodiformate (480.0 mg, 2.8 mmol) in THF (10 mL) was added triphenylphosphine (723.2 mg, 2.8 mmol) at 0°; and the mixture was stirred under nitrogen atmosphere for 1 hour followed by addition of a solution of DD-6 (219.7 mg, 1.0 mmol) in THF(10 mL) at 0oC. The resulting reaction mixture was continued to stir from 0oC to room temperature for 1 hour. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (30 mL*2). The organic layers were washed with brine, dried over sodium sulfate, filtrated and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (129.9 mg, 23.3% yield) as a pink oil. MS(ESI) calculated for C8H9NO3S, 199.0; found, 200.0. [0363] (3,4-Dihydro-2H-thieno[2,3-b]pyran-4-yl)methanamine hydrochloride (140): The mixture of DD-7 (129.9 mg, 0.7 mmol), iron (366.0 mg, 6.5 mmol) and NH4Cl (345.1 mg, 6.5 mmol) in EtOH/ H2O (150 mL, 2:1 ) was stirred at 80oC for 1 hour. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to purify by column chromatography (DCM: MeOH = 20:1) to obtain the desired product (60.0 mg, 45.2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (brs, 3H), 6.79 (d, J = 5.8 Hz, 1H), 6.66 (d, J = 5.8 Hz, 1H), 4.31 – 4.11 (m, 2H), 3.16 (dd, J = 12.6, 4.1 Hz, 1H), 3.05 (td, J = 9.8, 5.4 Hz, 1H), 2.83 (dd, J = 12.5, 10.1 Hz, 1H), 2.11 – 1.98 (m, 1H), 1.92 (m, 1H). MS(ESI) calculated for C8H11NOS, 169.1; found, 170.1. [0364] tert-Butyl ((3,4-dihydro-2H-thieno[2,3-b]pyran-4-yl)methyl)carbamate (DD-8): To the solution of (3,4-dihydro-2H-thieno[2,3-b]pyran-4-yl)methanamine (100 mg, 0.6 mmol) in THF(5 mL)and saturated NaHCO3 (5 mL)was added di-tert-butyl decarbonate (212.1 mg, 1.0 mmol) at room temperature, and the mixture was stirred for 8 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to purify by column chromatography(eluted with petroleum ether: ethyl acetate =5:1) to give the desired product(140.0 mg, 88.4% yield) as a white solid. MS(ESI) calculated for C13H19NO3S, 269.1; found, 270.1. [0365] 1-(3,4-Dihydro-2H-thieno[2,3-b]pyran-4-yl)-N-methylmethanaminium chloride (141): To the solution of DD-8 (140.0 mg, 0.5 mmol) in THF (10 mL) was added lithium aluminum hydride (41.2 mg, 1.1 mmol) at 0o C, and the mixture was stirred at 80 o C for 3 hours. After cooling to 0°C, sodium sulfate decahydrate (424.6 mg, 1.3 mmol) was added to above solution. The resulting mixture was stirred at room temperature for 30 min and filtrated. The filtrate was concentrated and purified by column chromatography (eluted with DCM: MeOH=10:1) to give the desired product (29.9 mg, 26.3% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 6.71 (d, J = 5.9 Hz, 1H), 6.56 (d, J = 5.9 Hz, 1H), 4.33 – 4.17 (m, 2H), 3.34 (d, J = 4.2 Hz, 1H), 3.21 – 3.01 (m, 2H), 2.75 (s, 3H), 2.15 (dd, J = 5.9, 4.1 Hz, 1H), 1.96 – 1.77 (m, 1H). MS(ESI) calculated for C9H13NOS, 183.1; found, 184.1. [0366] Dimethyl({2H,3H,4H‐thieno[2,3‐b]pyran‐4‐yl}methyl)amine (142): The title compound was synthesized using the same procedure used to synthesize 77. 1H NMR (400 MHz, CD3OD) δ 6.72 (dd, J = 5.9, 2.4 Hz, 1H), 6.56 (dd, J = 5.9, 1.7 Hz, 1H), 4.37 – 4.17 (m, 2H), 3.52 – 3.41 (m, 1H), 3.36 – 3.31 (m, 1H), 3.27 – 3.20 (m, 1H), 2.98 (d, J = 9.4 Hz, 6H), 2.27 – 2.12 (m, 1H), 2.00 – 1.80 (m, 1H). MS(ESI) calculated for C10H15NOS, 197.1; found, 198.1. [0367] 2‐{5H,6H,7H,8H‐Thieno[3,2‐b]oxepin‐8‐yl}ethan‐1‐amine hydrochloride (157): The title compound was prepared using the same procedure used for 76, substituting 6,7- dihydrothieno[3,2-b]oxepin-8(5H)-one for chromane-4-one. 1H NMR (400 MHz, DMSO-d6) δ 7.06 (d, J = 5.3 Hz, 1H), 6.64 (d, J = 5.3 Hz, 1H), 3.99 (m, 1H), 3.82 – 3.74 (m, 1H), 2.98 (m, 1H), 2.56 (d, J = 7.2 Hz, 1H), 2.04 (m, 1H), 1.86 – 1.54 (m, 6H). MS(ESI) calculated for C10H15NOS, 197.0; found 198.0. [0368] Following the same procedure describe in General procedure A, 158 was synthesized as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (brs, 1H), 7.15 (d, J = 5.3 Hz, 1H), 6.69 (d, J = 5.3 Hz, 1H), 4.10 (m, 1H), 3.74 (m, 1H), 3.13 m, 1H), 3.01 – 2.92 (m, 2H), 2.76 (s, 6H), 2.13 – 2.03 (m, 1H), 2.02 – 1.84 (m, 3H), 1.76 (dd, J = 8.7, 3.8 Hz, 2H). MS(ESI) calculated for C12H19NOS, 225.1; found 226.2. [0369] Dimethyl(2‐{5H,6H,7H,8H‐thieno[3,2‐b]oxepin‐8‐yl}ethyl)amine hydrochloride (158): The title compound was prepared from 5,6,7,8-tetrahydrothieno[3,2-b]oxepine-8- carbaldehyde using a procedure similar to the synthesis of 77. 1H NMR (400 MHz, DMSO- d6) δ 9.46 (brs, 1H), 7.15 (d, J = 5.3 Hz, 1H), 6.69 (d, J = 5.3 Hz, 1H), 4.10 (m, 1H), 3.74 (m, 1H), 3.13 m, 1H), 3.01 – 2.92 (m, 2H), 2.76 (s, 6H), 2.13 – 2.03 (m, 1H), 2.02 – 1.84 (m, 3H), 1.76 (dd, J = 8.7, 3.8 Hz, 2H). MS(ESI) calculated for C12H19NOS, 225.1; found 226.2. [0370] Methyl(2‐{5H,6H,7H,8H‐thieno[3,2‐b]oxepin‐8‐yl}ethyl)amine hydrochloride (159): The title compound was prepared from 5,6,7,8-tetrahydrothieno[3,2-b]oxepine-8- carbaldehyde using a procedure similar to the synthesis of 78. 1 H NMR (400 MHz, DMSO- d6) δ 8.64 (brs, 2H), 7.14 (d, J = 5.3 Hz, 1H), 6.68 (d, J = 5.3 Hz, 1H), 4.07 (m, 1H), 3.75 (m, 1H), 3.09 – 2.88 (m, 2H), 2.82 (dd, J = 11.1, 6.2 Hz, 1H), 2.54 (d, J = 5.3 Hz, 3H), 2.10 – 1.99 (m, 1H), 2.00 – 1.81 (m, 3H), 1.78 – 1.71 (m, 2H). MS(ESI) calculated for C11H17NOS, 211.1; found 212.2.
Figure imgf000150_0001
Scheme 32 [0371] Ethyl (E)-3-(2-chloro-6-hydroxyphenyl)acrylate (EE-1): To a solution of 2-chloro- 6-hydroxybenzaldehyde (5.0 g, 31.9 mmol) and ethyl 2-(diethoxyphosphoryl)acetate (14.3 g, 63.8 mmol) in dimethylformamide (30 mL) was added sodium hydride (1.5 g, 63.8 mmol, 60%wt) at 0 °C, and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (10.3 g, crude) as a yellow oil. MS(ESI, negative) calculated for C11H11ClO3, 226.0; found 225.3. [0372] Ethyl (E)-3-(2-(benzyloxy)-6-chlorophenyl)acrylate (EE-2): The mixture of EE-1 (5.3 g, crude) and potassium carbonate (6.4 g, 46.6 mmol) in acetone (50 mL) was stirred at room temperature for 30 min, followed by addition of benzyl bromide (8.0 g, 46.6 mmol) dropwise. The resulting mixture was stirred at 50 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to obtain the desired compound (5.6 g, 55.4% yield, two steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 16.2 Hz, 1H), 7.49 – 7.33 (m, 6H), 7.25 – 7.15 (m, 2H), 6.83 (d, J = 16.2 Hz, 1H), 5.29 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). MS(ESI) calculated for C18H17ClO3, 316.1; found 362.3. [0373] Ethyl 3-(2-(benzyloxy)-6-chlorophenyl)-4-nitrobutanoate (EE-3): To a solution of EE-2 (5.3 g, 16.7 mmol) in nitromethane (50 mL, 933.0 mmol) was added 1,8- diazabicycloundec-7-ene (12.6 g, 83.4 mmol) at 0 °C, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetated (30 mL * 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to obtain the desired compound (4.0 g, 63.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.53 – 7.47 (m, 2H), 7.47 – 7.41 (m, 2H), 7.41 – 7.34 (m, 1H), 7.25 (t, J = 8.2 Hz, 1H), 7.12 – 7.07 (m, 1H), 7.06 – 7.02 (m, 1H), 5.20 (s, 2H), 5.03 – 4.83 (m, 2H), 4.75 – 4.50 (m, 1H), 4.01 – 3.87 (m, 2H), 2.92 – 2.71 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H). [0374] 3-(2-(Benzyloxy)-6-chlorophenyl)-4-nitrobutan-1-ol (EE-4): To a solution of EE-3 (4.0 g, 10.5 mmol) in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran complex (1 M, 31 mL), and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (30 mL* 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography column (eluted with petroleum ether: ethyl acetate =3:1) to obtain the desired compound (3.4 g, 95.7% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.54 – 7.32 (m, 5H), 7.24 (t, J = 8.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.24 – 5.10 (m, 2H), 5.07 – 4.96 (m, 1H), 4.94 – 4.83 (m, 1H), 4.71 – 4.40 (m, 1H), 4.36 – 4.22 (m, 1H), 3.33 – 3.23 (m, 2H), 2.01 – 1.88 (m, 1H), 1.86 – 1.73 (m, 1H). [0375] 3-Chloro-2-(4-hydroxy-1-nitrobutan-2-yl)phenol (EE-5): The solution of EE-4 (600 mg, 1.78 mmol) and 10% Pd/C (100.0 mg) in ethyl acetate (10 mL) was stirred at room temperature for 1 hour under hydrogen atmosphere. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the title compound (420.0 mg, 95.7% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.10 – 7.01 (m, 1H), 7.01 – 6.94 (m, 1H), 6.70 – 6.57 (m, 1H), 5.13 – 4.80 (m, 3H), 4.58 – 4.40 (m, 1H), 3.72 – 3.54 (m, 2H), 2.40 – 2.23 (m, 2H), 2.04 – 1.91 (m, 1H). [0376] 5-Chloro-4-(nitromethyl)chromane (EE-6): Diethyl azodicarboxylate (0.8 mL, 4.9 mmol) was added dropwise to the solution of 5 (400 mg, 1.6 mmol) and triphenylphosphine (1.3 g, 4.9 mmol) in tetrahydrofuran (10 mL) at 0°C under nitrogen. The mixture was slowly warmed to room temperature and stirred for 1 hour. The solvent was removed by vacuum and the residue was purified by column chromatography to obtain the desired compound (130.0 mg, 35.1% yield) as a pink oil. 1H NMR (400 MHz, CDCl3) δ 7.13 (t, J = 8.1 Hz, 1H), 6.98 (dd, J = 7.9, 1.1 Hz, 1H), 6.79 (dd, J = 8.3, 0.9 Hz, 1H), 4.94 – 4.86 (m, 1H), 4.51 – 4.42 (m, 1H), 4.41 – 4.34 (m, 1H), 4.17 – 4.08 (m, 1H), 4.01 – 3.92 (m, 1H), 2.19 – 2.08 (m, 1H), 2.04 – 1.96 (m, 1H). [0377] (5-Chlorochroman-4-yl)methanamine hydrochloride (63): To a solution of EE-6 (130 mg, 0.6 mmol) in EtOH (4 mL) and water (2 mL) was added iron (159.0 mg, 2.9 mmol) and ammonium chloride (152.0 mg, 2.9 mmol). The resulting mixture was stirred at 60°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered; the filtrate was diluted with water (10 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the desired compound (35.0 mg, 31.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (brs, 3H), 7.19 (t, J = 8.1 Hz, 1H), 7.04 – 6.98 (m, 1H), 6.83 – 6.77 (m, 1H), 4.33 – 4.24 (m, 1H), 4.21 – 4.10 (m, 1H), 3.31 (s, 1H), 3.12 – 2.96 (m, 2H), 2.32 – 2.22 (m, 1H), 1.95 – 1.83 (m, 1H). MS(ESI) calculated for C10H12ClNO, 197.1; found 198.3.
Figure imgf000153_0001
Scheme 33 [0378] 3-Bromo-4-(tert-butoxy)thiophene (FF-1): A solution of 3,4-dibromothiophene (20.0 g, 82.6 mmol) in diethyl ether (200 mL) was treated with n-butyl lithium hydride (40.0 mL, 99.1 mmol) over a period of 20 minute at -78°C, and the mixture was stirred at -78 °C for 1 hour. Magnesium diethyl ether dibromide (26.0 g, 100.0 mmol) was added as a solid in two portions 15 minutes apart. The mixture was continued to stir at -78°C for 1 hour and then room temperature for 2 hours. Tert-butyl benzenecarboperoxoate (17.7 g, 91.1 mmol) was added at 0°C to above solution, and the reaction temperature was maintained between 0-5 °C. Then, the mixture was stirred at room temperature for 16 hours and quenched with ice water (100 mL) and hydrochloric acid (2 M, 50 mL). The organic layer was separated and washed with ice cold NaOH (1 N, 60 mL), water, and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (10.0 g, 51.7% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 3.5 Hz, 1H), 6.59 (d, J = 3.5 Hz, 1H), 1.41 (s, 9H). [0379] Methyl (E)-3-(4-(tert-butoxy)thiophen-3-yl)acrylate (FF-2): The mixture of FF-1 (6.0 g, 25.5 mmol), methyl prop-2-enoate (4.4 g, 51.0 mmol), Pd(PPh3)4 (5.9 g, 5.1 mmol) and triethylamine (7.7 g, 76.5 mmol) in DMF (100 mL) was stirred at 130 °C under nitrogen atmosphere for 12 hours. After cooling to room temperature, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:4) to afford the desired compound (2.3 g, 37.6% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 16.1 Hz, 1H), 7.41 (d, J = 3.3 Hz, 1H), 6.55 (d, J = 16.1 Hz, 1H), 6.52 (d, J = 3.3 Hz, 1H), 3.78 (s, 3H), 1.42 (s, 9H). [0380] Methyl 3-(4-(tert-butoxy)thiophen-3-yl)-4-nitrobutanoate (FF-3): The mixture of FF-2 (2.3 g, 9.6 mmol) and DBU (4.4 g, 28.7 mmol) in nitromethane (50 mL) was stirred at 75 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 96:4) to obtain the desired compound (2.3 g, 79.6% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J = 3.1 Hz, 1H), 6.41 (d, J = 3.1 Hz, 1H), 4.80 – 4.73 (m, 1H), 4.69 – 4.63 (m, 1H), 4.05 – 3.95 (m, 1H), 3.66 (s, 3H), 2.81 (d, J = 7.2 Hz, 2H), 1.47 (s, 9H). [0381] 3-(4-(tert-Butoxy)thiophen-3-yl)-4-nitrobutan-1-ol (FF-4): To a solution of FF-3 (2.3 g, 7.6 mmol) in anhydrous THF (10 mL) was added BH3-THF (22.8 mL, 22.9 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 40 °C for 1 hour and then quenched carefully with MeOH (20 mL) at room temperature. The resulting mixture was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 4:1) to obtain the desired compound (1.4 g, 67.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J = 3.4 Hz, 1H), 6.51 (d, J = 3.4 Hz, 1H), 4.76 – 4.68 (m, 1H), 4.65 – 4.55 (m, 1H), 3.89 – 3.76 (m, 1H), 3.68 – 3.57 (m, 1H), 3.50 – 3.39 (m, 1H), 2.01 – 1.91 (m, 2H), 1.82 – 1.70 (m, 1H), 1.46 (s, 9H). [0382] 4-(Nitromethyl)-3,4-dihydro-2H-thieno[3,4-b]pyran (FF-5): To a solution of FF-4 (1.4 g, 5.1 mmol) in DCM (15 mL) was added HCl/dioxane (4 M, 15 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 4 hours. Then, the mixture was concentrated and purified by column chromatography (eluted with petroleum ether: ethyl acetate = 96:4) to obtain the desired compound (0.9 g, 88.7% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J = 3.4 Hz, 1H), 6.39 (d, J = 3.4 Hz, 1H), 4.80 – 4.68 (m, 1H), 4.59 – 4.39 (m, 1H), 4.30 – 4.20 (m, 1H), 4.18 – 4.09 (m, 1H), 3.86 – 3.69 (m, 1H), 2.20 – 2.07 (m, 1H), 1.91 – 1.73 (m, 1H). [0383] (3,4-Dihydro-2H-thieno[3,4-b]pyran-4-yl)methanamine hydrochloride (143): The mixture of FF-5 (70.0 mg, 0.4 mmol), iron (97.7 mg, 1.8 mmol) and ammonium chloride (93.6 mg, 1.8 mmol) in EtOH/ H2O (12 mL, 1:1) was stirred at 80 °C for 1 hour. After cooling to room temperature, the mixture was filtered through a pad of celite; the filtrate was concentrated to purify by column chromatography (eluted with DCM: MeOH = 10:1) to obtain the title compound (30.0 mg, 50.5% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (brs, 3H), 7.39 (d, J = 3.4 Hz, 1H), 6.49 (d, J = 3.4 Hz, 1H), 4.26 – 4.15 (m, 1H), 4.06 – 3.93 (m, 1H), 3.33 – 3.24 (m, 1H), 3.24 – 3.14 (m, 1H), 2.99 – 2.79 (m, 1H), 2.13 – 2.01 (m, 1H), 1.79 – 1.68 (m, 1H). MS(ESI) calculated for C8H11NOS, 169.1; found 170.2. [0384] Methyl({2H,3H,4H‐thieno[3,4‐b]pyran‐4‐yl}methyl)amine hydrochloride (144): The title compound was synthesized in a manner analogous to 78. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 2H), 7.38 – 7.34 (m, 1H), 6.52 – 6.48 (m, 1H), 4.27 – 4.18 (m, 1H), 4.08 – 3.94 (m, 1H), 3.41 – 3.35 (m, 1H), 3.32 – 3.24 (m, 1H), 3.10 – 3.00 (m, 1H), 2.59 (s, 3H), 2.18 – 2.05 (m, 1H), 1.87 – 1.64 (m, 1H). MS(ESI) calculated for C9H13NOS, 183.1; found 184.2. [0385] Dimethyl({2H,3H,4H‐thieno[3,4‐b]pyran‐4‐yl}methyl)amine hydrochloride (145): The title compound was synthesized in a manner analogous to 142. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (brs, 1H), 7.36 – 7.32 (m, 1H), 6.53 – 6.49 (m, 1H), 4.26 – 4.17 (m, 1H), 4.06 – 3.96 (m, 1H), 3.59 – 3.47 (m, 1H), 3.41 – 3.38 (m, 1H), 3.31 – 3.22 (m, 1H), 2.87 – 2.77 (m, 6H), 2.29 – 2.16 (m, 1H), 1.90 – 1.75 (m, 1H). MS(ESI) calculated for C10H15NOS, 197.1; found 198.2.
Figure imgf000155_0001
Scheme 34 [0386] Methyl (2-(hydroxymethyl)phenyl)carbamate (GG-1): To a stirred solution of (2- aminophenyl)methanol (10.0 g, 81.1 mmol) in dioxane (50 mL), saturated NaHCO3 (50 mL) and water(20 mL) was added methyl carbonochloridate (9.2 g, 97.3 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 15 hours. After then, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (14.0 g, 96.0% yield) as a colorless oil. [0387] 1H NMR (400 MHz, CDCl3) δ 8.02 – 7.82 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 4.72 – 4.61 (m, 2H), 3.75 (s, 3H), 2.62 – 2.31 (m, 1H). [0388] Methyl (2-formylphenyl)carbamate (GG-2): The mixture of GG-1 (1.0 g, 5.5 mmol) and manganese dioxide (2.5 g, 27.5 mmol) in dichloromethane (20 mL) was stirred at room temperature for 48 hours. Then, the mixture was filtered through a pad of celite, and the filtrate was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (450.0 mg, 45.5% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 9.91 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 7.71 – 7.53 (m, 2H), 7.23 – 7.12 (m, 1H), 3.81 (s, 3H). [0389] 4-(Nitromethyl)-3,4-dihydroquinazolin-2(1H)-one (GG-3): The mixture of GG-2 (400.0 mg, 2.2 mmol), nitromethane (1.4 g, 22.3 mmol) and ammonium acetate (343.0 mg, 4.5 mmol) in acetic acid (3 mL) was stirred at 130 °C for 10 min under microwave. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography column (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (430.0 mg, 93.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (brs, 1H), 7.30 (brs, 1H), 7.22 – 7.15 (m, 2H), 6.93 – 6.87 (m, 1H), 6.82 (d, J = 7.7 Hz, 1H), 5.14 – 5.04 (m, 1H), 4.70 – 4.64 (m, 2H). [0390] 4-(Aminomethyl)-3,4-dihydroquinazolin-2(1H)-one (GG-4): To a solution of GG- 3 (100.0 mg, 0.5 mmol) in methanol (5 mL) was added 10% Pd/C (33 mg), and the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. Then, the mixture was filtered through pad of celite; the filtrate was concentrated to obtain the desired compound (85.0 mg, crude) as a white solid for the next step without further purification. MS(ESI) calculated for C9H11N3O, 177.1; found 178.2. [0391] tert-Butyl ((2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methyl)carbamate (GG-5): The mixture of GG-4 (85.0 mg, crude) and di-tert-butyl dicarbonate (156.0 mg, 0.7 mmol) in saturated sodium bicarbonate (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 1 hour. Then, the reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =90:10) to obtain the desired compound (58.0 mg, 43.3% yield, two steps) as a white solid. MS(ESI) calculated for C14H19N3O3, 277.1; found 222.3. [0392] (2-Oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methanamine hydrochloride (43): The mixture of GG-5 (58 mg, 0.2 mmol) in HCl/dioxane (2 M, 1.5 mL) and methanol (1.5 mL) was stirred at room temperature for 2 hours. Then, the mixture was concentrated to obtain the desired compound (39.8 mg, 89.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (brs, 1H), 8.05 (brs, 3H), 7.25 – 7.16 (m, 2H), 7.03 (s, 1H), 6.98 – 6.90 (m, 1H), 6.88 – 6.80 (m, 1H), 4.81 – 4.69 (m, 1H), 3.06 – 2.87 (m, 2H). MS(ESI) calculated for C9H1N3O, 177.1; found 178.3. [0393] 4-((Methylamino)methyl)-3,4-dihydroquinazolin-2(1H)-one (GG-6): To a solution of tert-butyl N-[(2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methyl]carbamate (100.0 mg, 0.4 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (136.0 mg, 3.6 mmol) at 0°C, and the mixture was stirred at 75°C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with sodium sulfate decahydrate and filtered. The filtrate was concentrated to afford crude compound, which was used for the next step without further purification. MS(ESI) calculated for C10H13N3O, 191.1; found 192.2. [0394] tert-Butyl methyl((2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methyl)carbamate (GG-7): The mixture of GG-6 (50 mg, crude) and di-tert-butyl dicarbonate (85.3 mg, 0.4 mmol) in saturated sodium bicarbonate (2.5 mL) and tetrahydrofuran (2.5 mL ) was stirred at room temperature for 1 hour. The mixture was poured into H2O (10 mL), and extracted with EA (10 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with DCM: MeOH =9:1) to obtain the title product (58.0 mg, 55.2% yield) as a colorless oil. MS(ESI) calculated for C15H21N3O3, 291.2; found 236.3. [0395] N-Methyl-1-(2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methanamine hydrochloride (44): The solution of GG-7 (50.0 mg, 0.2 mmol) in HCl/dioxane (2 M, 1.5 mL) and methanol (1.5 mL) was stirred at room temperature for 2 hours. Then, the mixture was concentrated to obtain the desired compound (13.7 mg, 30.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (brs, 1H), 9.05 (brs, 1H), 8.86 (s, 1H), 7.29 – 7.18 (m, 2H), 7.17 – 7.09 (m, 1H), 6.94 (t, J = 7.1 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 4.92 – 4.82 (m, 1H), 3.19 – 2.93 (m, 2H), 2.58 (t, J = 5.3 Hz, 3H). MS(ESI) calculated for C10H13N3O, 191.1; found 192.2.
Figure imgf000158_0001
Scheme 35 [0396] 3-Methoxythiophene-2-carbaldehyde (HH-1): To a solution of 3-methoxythiophene (10.0 g, 87.7 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 38.6 mL) dropwise at - 78oC. After stirring at -78 °C for additional 30 min, DMF (8.3 g, 114.0 mmol) was added dropwise to above solution. The resulting reaction solution was continued to stir at -78oC for 1 hour and diluted with water (50 mL), extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (4.0 g, 32.0%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.99 (d, J = 1.2 Hz, 1H), 7.64 (dd, J = 5.4, 1.2 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 3.99 (s, 3H). [0397] Ethyl (E)-3-(3-methoxythiophen-2-yl)acrylate (HH-2): To a solution of ethyl 2- (diethoxyphosphoryl)acetate (12.6 g, 56.4 mmol) in THF (40 mL) was added sodium hydride (1.4 g, 56.4 mmol, 60%wt) at ice/water bath. The resulting mixture was stirred at 0°C for additional 30 min. HH-1 (4.0 g, 28.2 mmol) was added to above solution; the resulting solution was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (4.0 g, 66.6%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 15.8 Hz, 1H), 7.27 (d, J = 5.5 Hz, 1H), 6.83 (d, J = 5.5 Hz, 1H), 6.16 (d, J = 15.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). [0398] Ethyl 3-(3-methoxythiophen-2-yl)-4-nitrobutanoate (HH-3): To a solution of HH- 2 (4.0 g, 18.9 mmol) in nitromethane (40 mL) was added DBU (8.6 g, 56.7 mmol), and the mixture was stirred at 75oC for 2 hours. After cooling to room temperature, the mixture was diluted with water (40 mL), extracted with DCM (80 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (4.0 g, 76.9%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 5.5 Hz, 1H), 6.80 (d, J = 5.5 Hz, 1H), 4.73 (dd, J = 7.2, 0.7 Hz, 2H), 4.25-4.19 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.81 (dd, J = 7.3, 2.5 Hz, 2H), 1.27 – 1.16 (m, 3H). [0399] 3-(3-Methoxythiophen-2-yl)-4-nitrobutan-1-ol (HH-4): To a solution of HH-3 (4 g, 14.7 mmol) in THF (20 mL) was added borane tetrahydrofuran complex (1 M, 44 mL), and the mixture was stirred at 66oC for 16 hours. After cooling to room temperature, the reaction was quenched with MeOH (10 mL); and the resulting mixture was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (2.5 g, 74.0%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 5.5 Hz, 1H), 6.84 (d, J = 5.5 Hz, 1H), 4.71-4.60 (m, 2H), 4.14 – 4.00 (m, 1H), 3.85 (s, 3H), 3.72 – 3.63 (m, 1H), 3.58 – 3.46 (m, 1H), 2.03 – 1.92 (m, 1H), 1.89-1.84 (m, 1H). [0400] 7-(Nitromethyl)-6,7-dihydro-5H-thieno[3,2-b]pyran (HH-5): To a solution of HH- 4 (1.0 g, 4.3 mmol) in toluene (10 mL) was added NaHSO4 (0.1 g, 0.9 mmol), and the mixture was stirred at 110oC for 4 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (0.6 g, 69.7%) as a yellow oil. [0401] (6,7-Dihydro-5H-thieno[3,2-b]pyran-7-yl)methanamine hydrochloride (146): To a solution of HH-5 (0.05 g, 0.3 mmol) in EtOH/H2O (4 mL, V:V=3:1) was added NH4Cl (0.08 g, 1.5 mmol) and Fe (0.08 g, 1.5 mmol). The resulting mixture was stirred at 90 o C for 1 hour. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (16.5 mg, 32.0% yield) as a colorless gel. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (brs, 3H), 7.33 (d, J = 5.4 Hz, 1H), 6.65 (d, J = 5.4 Hz, 1H), 4.32 – 3.98 (m, 2H), 3.24 (dd, J = 9.6, 3.8 Hz, 1H), 3.08 (d, J = 11.3 Hz, 1H), 2.91 (t, J = 10.8 Hz, 1H), 2.10-2.08 (m, 1H), 1.99-1.97 (m, 1H). MS(ESI) calculated for C8H11NOS, 169.1; found 170.1. [0402] Dimethyl({5H,6H,7H‐thieno[3,2‐b]pyran‐7‐yl}methyl)amine hydrochloride (147): The title compound was prepared using a similar procedure used in the preparation of 145. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (brs, 1H), 7.42 – 7.28 (m, 1H), 6.66 (d, J = 5.4 Hz, 1H), 4.26 – 4.05 (m, 2H), 3.45-3.39 (m, 1H), 3.36 – 3.23 (m, 2H), 2.83 (d, J = 4.8 Hz, 3H), 2.80 (d, J = 4.8 Hz, 3H), 2.26 – 2.04 (m, 2H). MS(ESI) calculated for C10H15NOS, 197.1; found 198.1. [0403] tert-Butyl ((6,7-dihydro-5H-thieno[3,2-b]pyran-7-yl)methyl)carbamate (HH-6): To a solution of (6,7-dihydro-5H-thieno[3,2-b]pyran-7-yl)methanamine (0.1 g, 0.6 mmol) and (Boc)2O (0.2 g, 0.9 mmol) in THF (4 mL) was added saturated NaHCO3 (2 mL), and the mixture was stirred at room temperature for 1 hour. After then, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (0.1g, 62.9%) as a yellow oil. MS(ESI) calculated for C13H19NO3S, 269.1; found 270.1. [0404] 1-(6,7-Dihydro-5H-thieno[3,2-b]pyran-7-yl)-N-methylmethanamine hydrochloride (148): To a solution of HH-6 (100 mg, 0.4 mmol) in THF (5 mL) was added LiAlH4 (30 mg, 0.6 mmol) at 0°C and the mixture was stirred at 66oC for 3 hours. After cooling to room temperature, the mixture was quenched with sodium sulfate decahydrate and filtered. The filtrate was concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (44.0 mg, 54.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (brs, 2H), 7.34 (dd, J = 5.4, 0.4 Hz, 1H), 6.65 (d, J = 5.4 Hz, 1H), 4.31 – 4.01 (m, 2H), 3.33 – 3.28 (m, 1H), 3.20 – 2.95 (m, 2H), 2.58 (s, 3H), 2.28 – 1.89 (m, 2H). MS(ESI) calculated for C9H13NOS, 183.1; found 184.1.
Figure imgf000161_0001
Scheme 36 [0405] (3aS,9bS)-2-Benzyl-2,3,3a,9b-tetrahydrochromeno[3,4-c]pyrrol-4(1H)-one (II-1): To a solution of 2H-chromen-2-one (10.0 g, 68.4 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (32.2 g, 136 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (779.0 mg, 6.8 mmol) at 0oC, and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (10.0 g, 52.4% yield) as white solid. MS(ESI) calculated for C18H17NO2, 279.2; found 280.2. [0406] 2-((3S,4S)-1-Benzyl-4-(hydroxymethyl)pyrrolidin-3-yl)phenol (II-2): To a solution of II-1 (2.0 g, 7.1 mmol) in THF (30 mL) was added lithium aluminum hydride (0.5 g, 14.3 mmol) at 0oC, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with aqueous NaOH (0.5 mL, 15%wt) and water (1.5 mL), and the mixture was continued to stir at room temperature for 30 min. After which period, the resulting mixture was dried over sodium sulfate, filtered and concentrated to obtain the desired compound (2.0 g, 98.5% yield) as crude. MS(ESI) calculated for C18H21NO2, 283.2; found 284.2. [0407] (3aS,9bS)-2-Benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole (II-3): To a solution of diethyl azodiformate (1.8 g, 10.5 mmol) in THF (15 mL) was added triphenylphosphine (2.7 g, 10.5 mmol) at 0oC under nitrogen atmosphere, and the mixture was stirred for 1 hour, followed by addition of II-2 (1.0 g, 3.5 mmol) at 0oC. The resulting solution was continued to stir at room temperature for 1 hour and then diluted with water (100 mL), extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (0.5 g, 54.3% yield) as a white solid.MS(ESI) calculated for C18H19NO, 265.2; found 266.2. [0408] (3aS,9bS)-1,2,3,3a,4,9b-Hexahydrochromeno[3,4-c]pyrrole (II-4): To a solution of II-3 (0.5 g, 1.9 mmol) in methanol (20 mL) was added 10% Pd(OH)2 (0.5 g), and the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. Then, the mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the desired compound (0.3 g, 90.4% yield) as crude. MS(ESI) calculated for C11H13O, 175.1; found 176.2. [0409] tert-Butyl (3aS,9bS)-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrole-2(3H)- carboxylate (II-5): To a solution of II-4 (300.0 mg, 1.7 mmol) in ethyl acetate (20 mL) was added Boc2O (558.0 mg, 2.6 mmol) and sodium carbonate (725.0 mg, 6.8 mmol). The mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (250.0 mg, 53.5% yield) as a white solid. MS(ESI) calculated for C16H21O3, 275.2; found 176.2. [0410] (3aS,9bS)-1,2,3,3a,4,9b-Hexahydrochromeno[3,4-c]pyrrol-2-ium chloride (70): A mixture of II-5 (250.0 mg, 0.9 mmol) in HCl/dioxane (4M, 5 mL) was stirred at room temperature for 1 hour. Then, the mixture was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (118.0 mg, 62.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (brs, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 4.19-4.13 (m, 1H), 3.89-3.84 (m, 1H), 3.78-3.73 (m, 1H), 3.56-3.47 (m, 2H), 3.15-3.08 (m, 1H), 3.04-2.99 (m, 1H), 2.83- 2.75 (m, 1H). MS(ESI) calculated for C11H13NO, 175.2; found 176.2.
Figure imgf000163_0001
Scheme 37 [0411] Ethyl (E)-3-(2-methoxyphenyl)acrylate (JJ-1): To a solution of sodium hydride (11.7 g, 293.0 mmol, 60%wt) in THF (150 mL) at 0oC was added ethyl 2- (diethoxyphosphoryl)acetate (82.2 g, 367.0 mmol), and the mixture was stirred at room temperature for 30 min. Then, 2-methoxybenzaldehyde (10.0 g, 73.4 mmol) was added to above solution, the resulting mixture was continued to stir at room temperature for 1 hour. After which period, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (15.0 g, 99.1% yield) as a white solid. [0412] Ethyl (3S,4S)-1-benzyl-4-(2-methoxyphenyl)pyrrolidine-3-carboxylate (JJ-2): To a solution of JJ-1 (5.0 g, 19.1 mmol) and N-benzyl-1-methoxy- N((trimethylsilyl)methyl)methanamine (9.1 g, 38.1 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (217.0 mg, 1.9 mmol) at 0oC. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (5.0 g, 77.3% yield) as a white solid. MS(ESI) calculated for C21H25NO3, 339.2; found 340.2. [0413] Ethyl (3S,4S)-1-benzyl-4-(2-hydroxyphenyl)pyrrolidine-3-carboxylate (JJ-3): To a solution of JJ-2 (5.0 g, 14.7 mmol) in dichloromethane (150 mL) was added boron tribromide (35.1 mL, 1.0 M in DCM) at -78oC, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (2.5 g, 52.3% yield) as a white solid. MS(ESI) calculated for C20H23NO3, 325.2; found 326.2. [0414] 2-((3S,4R)-1-Benzyl-4-(hydroxymethyl)pyrrolidin-3-yl)phenol (JJ-4): To a solution of JJ-3 (2.5 g, 7.7 mmol) in THF (50 mL) at 0oC was added lithium aluminum hydride (535.0 mg, 15.3 mmol), and the mixture was stirred at room temperature for 2 hours. Then, the reaction was quenched with aqueous NaOH (0.5 mL, 15%wt) and water (1.5 mL). The mixture was continued to stir at room temperature for 30 min. Then, the mixture was dried over sodium sulfate, filtered and concentrated to obtain the desired compound (2.0 g, 91.7% yield) as crude. MS(ESI) calculated for C18H21NO2, 283.2; found 284.2. [0415] (3aR,9bS)-2-Benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole (JJ-5): To a solution of diethyl azodiformate (1.8 g, 10.5 mmol) in THF (30 mL) was added triphenylphosphine (2.7 g, 10.5 mmol) at 0oC; the resulting solution was stirred for 1 hour under nitrogen atmosphere followed by addition of JJ-4 (1.0 g, 3.5 mmol) at 0oC. The reaction mixture was continued to stir at room temperature for 1 hour, diluted with water (100 mL) and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (0.9 g, 97.1% yield) as a white solid. MS(ESI) calculated for C18H19NO, 265.2; found 266.2. [0416] tert-Butyl (3aR,9bS)-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrole-2(3H)- carboxylate (JJ-6): To a solution of JJ-5 (0.5 g, 1.9 mmol) in methanol (30 mL) was added 10% Pd(OH)2 (0.5 g) and di-tert-butyl pyrocarbonate (0.8 g, 3.8 mmol). The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. After which period, the mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (350.0 mg, 67.0% yield) as a white solid. MS(ESI) calculated for C16H21O3, 275.2; found 176.2. [0417] (3aR,9bS)-1,2,3,3a,4,9b-Hexahydrochromeno[3,4-c]pyrrol-2-ium chloride (69): A mixture of JJ-6 (350.0 mg, 1.3 mmol) in HCl/dioxane (4 M, 8 mL) was stirred at room temperature for 1 hour. Then, the mixture was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (95.0 mg, 34.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (brs, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 4.54 (dd, J = 10.0 Hz, J = 4.0 Hz, 1H), 4.20 (t, J = 10.8 Hz, 1H),3.95-3.91 (m, 1H), 3.53-3.49 (m, 1H), 3.06-3.02 (m, 1H), 3.01-2.92 (m, 2H), 2.27-2.16 (m, 1H). MS(ESI) calculated for C11H13NO, 175.2; found 176.2.
Figure imgf000165_0001
Scheme 38 [0418] Methyl 4-bromo-3-hydroxythiophene-2-carboxylate (KK-1): To a solution of methyl 3-hydroxythiophene-2-carboxylate (9.0 g, 56.9 mmol) in AcOH (150 mL ) was added bromine (9.5 g, 59.7 mmol), and the mixture was stirred at room temperature for 6.5 hours. After then, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =3:1) to obtain the desired product (9.0 g, 67.1% yield) as a white solid. [0419] Methyl 4-bromo-3-(pent-4-en-1-yloxy)thiophene-2-carboxylate (KK-2): To a solution of KK-1 (9.0 g, 37.9 mmol), pent-4-en-1-ol (4.9 g, 56.8 mmol) and PPh3 (14.8 g, 56.8 mmol) in THF (200 mL) was added DEAD (9.9 g, 56.8 mmol) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was concentrated and purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired product (9.0 g, 78.2% yield) as a pale solid. [0420] Methyl 5-methylidene-2H,3H,4H,5H-thieno[3,4-b]oxepine-8-carboxylate (KK-3): A solution of KK-2 (9.0 g, 29.4 mmol), Et3N (8.9 g, 88.2 mmol) and Pd(PPh3)4 (1.0 g, 0.9 mmol) in DMF (100 mL) was stirred at 110°C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =15:1) to obtain the desired product (2.1 g, 31.8% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 5.22 (d, J = 1.5 Hz, 1H), 5.00 (d, J = 1.3 Hz, 1H), 4.31 (dd, J = 7.2, 4.4 Hz, 2H), 3.84 (s, 3H), 2.56 (td, J = 6.8, 0.7 Hz, 2H), 2.16 – 1.99 (m, 2H). [0421] 5-Methylene-2,3,4,5-tetrahydrothieno[3,4-b]oxepine-8-carboxylic acid (KK-4): To the solution of KK-3 (2.1 g, 9.4 mmol) in THF/MeOH/H2O (44 mL, 7:1:3) was added NaOH (0.7 g, 18.7 mmol), and the mixture was stirred at the room temperature for 16 hours. Then, the reaction mixture was acidified to pH~4 by hydrochloric acid (2 M) and extracted with ethyl acetate (30 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was used directly for the next step without further purification. [0422] 5-Methylene-2,3,4,5-tetrahydrothieno[3,4-b]oxepine (KK-5): The mixture of the KK-4 (1.8 g, 8.6 mmol) and Cu2O (2.4 g, 17.1 mmol) in pyridine (20 mL) was stirred at 115°C for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was purified by column chromatography (eluted with Petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (1.3 g, 91.1% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 3.6 Hz, 1H), 6.51 (d, J = 3.6 Hz, 1H), 5.18 – 5.16 (m, 1H), 4.97 – 4.94 (m, 1H), 4.10 – 4.05 (m, 2H), 2.55 – 2.51 (m, 2H), 2.03 – 1.94 (m, 2H). [0423] (2,3,4,5-Tetrahydrothieno[3,4-b]oxepin-5-yl)methanol (KK-6): A solution of KK- 5 (1.3 g, 7.8 mmol) in THF (20 mL) was added BH3-THF (1 M, 23.4 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 1 hour and then at room temperature for 2 hours. Aqueous NaOH (3 N, 13 mL) was added thereto, followed by H 2O2 (30%, 5.6 mL). The resulting mixture was continued to stir at room temperature for 2 hours. After which period, the reaction mixture was diluted with water (50 mL) and extracted with DCM (200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 4:1) to obtain the desired compound (1.2 g, 83.6% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.90 (d, J = 3.6 Hz, 1H), 6.65 (d, J = 3.6 Hz, 1H), 4.05 – 3.87 (m, 3H), 3.86 – 3.80 (m, 1H), 3.04 – 2.95 (m, 1H), 2.13 – 2.02 (m, 1H), 1.97 – 1.74 (m, 3H). [0424] 5-(Azidomethyl)-2,3,4,5-tetrahydrothieno[3,4-b]oxepine (KK-7): To a solution of KK-6 (1.2 g, 6.5 mmol), PPh3 (5.1 g, 19.5 mmol) and DPPA (4.7 g, 19.5 mmol) in dry THF (20 mL) was added DEAD (3.4 g, 19.5 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. After which period, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether) to obtain the desired compound (450.0 mg, 33.1% yield) as a yellow oil. [0425] (2,3,4,5-Tetrahydrothieno[3,4-b]oxepin-5-yl)methanamine hydrochloride (160): To the solution of KK-7 (50.0 mg, 0.2 mmol) in methanol (5 mL) was added 10% Pd/C (10 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. Then, the mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (10.7 mg, 24.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (brs, 3H), 7.20 (d, J = 3.6 Hz, 1H), 6.87 (d, J = 3.2 Hz, 1H), 3.98 – 3.89 (m, 1H), 3.85 – 3.77 (m, 1H), 3.24 – 2.94 (m, 3H), 2.09 – 1.92 (m, 1H), 1.89 – 1.61 (m, 3H). MS(ESI) calculated for C9H13NOS, 183.1; found 184.2. [0426] Methyl({2H,3H,4H,5H‐thieno[3,4‐b]oxepin‐5‐yl}methyl)amine (161): The title compound was prepared in a manner similar to the procedure used synthesize 144. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (brs, 1H), 8.66 (brs, 1H), 7.27 – 7.19 (m, 1H), 6.95 – 6.83 (m, 1H), 4.04 – 3.94 (m, 1H), 3.82 – 3.72 (m, 1H), 3.35 – 3.28 (m, 1H), 3.23 – 3.12 (m, 2H), 2.54 (t, J = 5.4 Hz, 3H), 2.09 – 1.95 (m, 1H), 1.88 – 1.63 (m, 3H). MS(ESI) calculated for C10H15NOS, 197.1; found 198.2. [0427] N,N-Dimethyl-1-(2,3,4,5-tetrahydrothieno[3,4-b]oxepin-5-yl)methanamine hydrochloride (162): To a solution of tert-butyl methyl((2,3,4,5-tetrahydrothieno[3,4- b]oxepin-5-yl)methyl)carbamate (130.0 mg, 0.4 mmol) in dry THF (10 mL) was added LiAlH4 (82.7 mg, 2.2 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at 70°C for 5 hours. After cooling to room temperature, the reaction was quenched with sodium sulfate decahydrate and filtered through a pad of celite. The filtrate was concentrated to purify with Prep-HPLC (CH3CN/H2O, 0.1%HCl) to afford the desired compound (20.0 mg, 23.7% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (brs, 1H), 7.34 – 7.29 (m, 1H), 6.93 – 6.86 (m, 1H), 4.09 – 3.99 (m, 1H), 3.78 – 3.67 (m, 1H), 3.49 – 3.36 (m, 3H), 2.79 (d, J = 4.8 Hz, 3H), 2.68 (d, J = 4.8 Hz, 3H), 2.12 – 1.94 (m, 1H), 1.89 – 1.75 (m, 3H). MS(ESI) calculated for C11H17NOS, 211.1; found 212.0.
Figure imgf000168_0001
Scheme 39 [0428] tert-Butyl 4-(2-ethoxy-2-oxoethyl)-3,6-dihydropyridine-1(2H)-carboxylate (LL- 1): To the solution of sodium hydride (3.6 g, 150.0 mmol, 60%wt) in THF (100 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (33.6 g, 150.0 mmol) at 0°C; the mixture was stirred for 1 hour followed by addition of solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.1 mmol) in THF (50 mL) slowly. The resulting solution was warmed to room temperature and stirred for additional 1 hour. The mixture was poured into ice water and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired product (7.6 g, 56.3 % yield) as a colorless oil. MS(ESI) calculated for C14H23NO4, 296.2; found, 297.2. [0429] tert-Butyl 4-(2-hydroxyethyl)-3,6-dihydropyridine-1(2H)-carboxylate (LL-2): To the solution of LL-1 (2.0 g, 7.4 mmol) in dry THF (30 mL) was added lithium aluminum hydride (0.3 g, 8.2 mmol) at 0°C, and the mixture was stirred at room temperature for 1 hour. Then, the reaction was quenched with water (1 mL), aqueous NaOH (2.5 N, 2 mL) and water (1mL). The mixture was filtrated, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired product (1.5 g, 89.3% yield) as a yellow oil. MS(ESI) calculated for C12H21NO3, 227.2; found, 228.2. [0430] tert-Butyl 4-(2-(2-bromophenoxy)ethyl)-3,6-dihydropyridine-1(2H)-carboxylate (LL- 3): To the solution of LL-2 (1.0 g, 4.4 mmol), 2-bromophenol (758.8 mg, 4.4mmol), and triphenylphosphine (1.4 g, 5.3 mmol) in THF (50 mL ) was added DIAD (0.9 g, 5.3 mmol) at 0oC, and the mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100mL*2). The combined organic layers were washed with brine (100mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to give the desired product (1.4 g, 83.3 % yield) as a brown oil. MS(ESI) calculated for C18H24BrNO3, 381.1; found, 382.1, 384.1. [0431] tert-Butyl spiro[chromane-4,4'-piperidine]-1'-carboxylate (LL-4) and tert-Butyl 3,4,4a,5,6,11b-hexahydrobenzo[2,3]oxepino[4,5-c]pyridine-2(1H)-carboxylate (LL-5): The mixture of LL-3 (0.8 g, 2.1 mmol), tributylstannane (1.2 g, 4.2 mmol) and AIBN (34.3 mg, 0.3 mmol) in toluene (50 mL) was stirred at 110oC under nitrogen atmosphere for 5 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) and then continued to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to get compound LL-4 (200.0 mg, 34.3%yield) and compound LL- 5 (200.0 mg, 34.2% yield) as white solids. MS(ESI) for LL-4 and LL-5 calculated for C18H25NO3, 303.2; found, 304.2. [0432] Spiro[chromane-4,4'-piperidin]-1'-ium chloride (71): The solution of LL-4 (0.1 g, 0.3 mmol) in HCl/dioxane (4 M, 3 mL) was stirred at room temperature for 1 hour. After then, the mixture was concentrated to obtain the desired product (70.0 mg, 85.8 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (brs, 1H), 8.86 (brs, 1H), 7.33 (dd, J = 7.9, 1.5 Hz, 1H), 7.20 – 7.00 (m, 1H), 6.93 (td, J = 7.9, 1.3 Hz, 1H), 6.76 (dd, J = 8.1, 1.2 Hz, 1H), 4.21 – 3.98 (m, 2H), 3.12 (m, 4H), 2.26 (td, J = 14.1, 4.6 Hz, 2H), 2.11 – 1.92 (m, 2H), 1.70 (d, J = 14.4 Hz, 2H). MS(ESI) calculated for C13H17NO, 203.1; found, 204.1. [0433] 1,2,3,4,4a,5,6,11b-Octahydrobenzo[2,3]oxepino[4,5-c]pyridin-2-ium chloride (114): A solution of LL-5 (0.1 mg, 0.3 mmol) in HCl/dioxane (4 M, 3 mL) was stirred at room temperature for 1 hour. After then, the mixture was concentrated to obtain the desired product (44.0 mg, 53.8 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (brs, 2H), 7.24 – 7.16 (m, 2H), 7.06 (td, J = 7.5, 1.3 Hz, 1H), 6.93 (dd, J = 7.9, 1.2 Hz, 1H), 4.37 (dt, J = 12.1, 3.3 Hz, 1H), 3.55 (t, J = 11.5 Hz, 1H), 3.31 (s, 2H), 3.15 (m, 2H), 2.90 (d, J = 7.0 Hz, 1H), 2.55 (m, 1H), 2.21 (d, J = 12.6 Hz, 1H), 2.06 (m, 1H), 1.74 – 1.63 (m, 2H). MS(ESI) calculated for C13H17NO, 203.1; found, 204.1.
Figure imgf000170_0001
Scheme 40 [0434] Ethyl (E)-3-(3-bromothiophen-2-yl)acrylate (MM-1): Ethyl 2- (diethoxyphosphoryl)acetate (117.4 g, 523.6 mmol) in THF(100 mL) was added drop wise to a suspension of sodium hydride (21.9 g, 523.6 mmol, 60%wt) in THF (200 mL) at 0°C and the reaction mixture was stirred at 0°C for 1 hour. Then, 3-bromothiophene-2-carbaldehyde (50 g, 261.8 mmol) in THF (300 mL) was added to the above solution. The mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. Then, the mixture was poured into H2O (300 mL), extracted with EA (300 mL* 2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with Petroleum ether: ethyl acetate= 90:10) to obtain the product (50.0 g, 73.5% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 15.8, 0.8 Hz, 1H), 7.33 (dd, J = 5.3, 0.7 Hz, 1H), 7.03 (d, J = 5.3 Hz, 1H), 6.30 (d, J = 15.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). [0435] Ethyl (E)-3-(3-((diphenylmethylene)amino)thiophen-2-yl)acrylate (MM-2): The solution of MM-1 (50 g, 191.5 mmol), diphenylmethanimine (69.0 g, 383.0 mmol), BINAP (9.0 g, 14.4 mmol), Pd2(dba)3 (4.4 g, 4.8 mmol) and CS2CO3 (124.8 g, 383.0 mmol) in toluene (200 mL) was stirred at 110°C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with Petroleum ether: ethyl acetate=95:5) to obtain the title product (25 g, 36.2% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.79 (m, 3H), 7.53-7.51 (m, 1H), 7.45-7.43 (m, 2H), 7.38 – 7.30 (m, 3H), 7.16-7.14 (m, 2H), 7.04 (d, J = 5.2 Hz, 1H), 6.20 (d, J = 5.3 Hz, 1H), 6.07 (d, J = 15.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.31 – 1.28 (m, 3H). [0436] Ethyl (3S,4R)-1-benzyl-4-(3-((diphenylmethylene)amino)thiophen-2- yl)pyrrolidine-3-carboxylate (MM-3): To the solution of MM-2 (4.0 g, 11.1 mmol) and N- benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (5.2 g, 22.0 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (125.0 mg, 1.1 mmol) at 0oC, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL), extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (2.6 g, 47.4% yield) as a brown solid. MS(ESI) calculated for C31H30N2O2S, 494.2; found 495.2. [0437] Ethyl (3S,4R)-4-(3-aminothiophen-2-yl)-1-benzylpyrrolidine-3-carboxylate (MM- 4): To a solution of MM-3 (2.6 g, 5.3 mmol) in dioxane (20 mL) was added HCl/dioxane (4 M, 20 mL), and the mixture was stirred at room temperature for 1 hour. After which period, the reaction mixture was adjusted to pH~8 with basic anion exchange resin and filtered. The filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:10) to obtain the desired compound (1.0 g, 57.1% yield) as a brown solid. MS(ESI) calculated for C18H22N2O2S, 330.1; found 331.2. [0438] (5aR,8aR)-7-Benzyl-4,5a,6,7,8,8a-hexahydro-5H-pyrrolo[3,4-d]thieno[3,2- b]pyridin-5-one (MM-5): To a solution of MM-4 (0.8 g, 2.4 mmol) in toluene (50 mL) was added trimethylaluminium (7.3 mL, 1.0 M in toluene) at 0o C, and the resulting mixture was stirred at 0oC for 2 hours. The reaction mixture was poured into a solution of silica gel in methanol (50 mL) and filtered. The filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (550.0 mg, 80.7% yield) as a brown solid. MS(ESI) calculated for C16H16N2OS, 284.1; found 285.2. [0439] (5aR,8aR)-5-Oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-d]thieno[3,2- b]pyridin-7-ium chloride (133): To a solution of MM-5 (450.0 mg, 1.6 mmol) and cesium carbonate (2.6 g, 7.9 mmol) in 1,2-dichloroethane (30 mL) was added 1-chloroethyl chloroformate (1.1 g, 7.9 mmol). The resulting mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in methanol (30 mL) and refluxed for 3 hours. The reaction mixture was cooled to room temperature and concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (80.0 mg, 21.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.60 (brs, 1H), 9.47 (brs, 2H),7.46 (d, J = 5.2 Hz, 1H), 6.71 (d, J = 5.2 Hz, 1H), 3.81 (q, J = 8.8 Hz, 1H), 3.67-3.60 (m, 2H), 3.58-3.50 (m, 1H), 3.47-3.42 (m, 1H), 2.92-2.83 (m, 1H). MS(ESI) calculated for C9H10N2OS, 194.1; found 195.0.
Figure imgf000173_0001
Scheme 41 [0440] Ethyl 3-(2-bromophenyl)acrylate (NN-1): The solution of 2-bromobenzaldehyde (10.0 g, 54.0 mmol) and ethyl 2-(triphenyl-λ^-phosphanylidene)acetate (20.6 g, 59.4 mmol) in THF (100 mL) was stirred at 60°C for 16 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (elute with petroleum ether: ethyl acetate = 3:1) to obtain the title compound (11.0 g, 79.7% yield) as a pale solid. [0441] Ethyl 3-(2-(methylsulfonamido)phenyl)acrylate (NN-2): To the solution of NN-1 (10.0 g, 39.1 mmol), methane sulfonamide (5.6 g, 58.6 mmol), CuI (1.5 g, 7.8 mmol) and 2- (dimethylamino)acetic acid (1.6 g, 15.6 mmol) in DMF (80 mL) was added K3PO4 (16.5 g, 78.2 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 110 °C for 16 hours. After cooling to room temperature, the mixture was diluted with water (600 mL), extracted with ethyl acetate (300 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (elute with petroleum ether: ethyl acetate = 3:1) to obtain the title compound (6.0 g, 56.7% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 16.1 Hz, 1H), 7.60 (dd, J = 7.3, 2.1 Hz, 1H), 7.44 – 7.28 (m, 2H), 7.28 – 7.10 (m, 6H), 6.27 (d, J = 16.1 Hz, 1H), 4.76 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.99 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). [0442] Ethyl 3-(2-(N-benzylmethylsulfonamido)phenyl)acrylate (NN-3): The solution of NN-2 (6.0 g, 22.2 mmol), (bromomethyl)benzene (4.5 g, 26.6 mmol) and K2CO3 (7.8 g, 55.5 mmol) in DMF (80 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was diluted with water (400 mL), extracted with ethyl acetate (100 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (elute with petroleum ether: ethyl acetate = 3:1) to obtain the title compound (5.7 g, 71.2% yield) as a colorless oil. [0443] Ethyl 2-(1-benzyl-2,2-dioxido-3,4-dihydro-1H-benzo[c][1,2]thiazin-4-yl)acetate (NN-4): The solution of NN-3 (5.0 g, 13.9 mmol) and Cs2CO3 (9.1 g, 27.8 mmol) in MeCN (80 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the solvent was removed by vacuum. The residue was diluted with water (100 mL), and extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (elute with petroleum ether: ethyl acetate = 3:1) to obtain the title compound (3.8 g, 76.3% yield) as a colorless oil. [0444] 2-(1-Benzyl-2,2-dioxido-3,4-dihydro-1H-benzo[c][1,2]thiazin-4-yl)acetic acid (NN-5): The solution of NN-4 (3.8 g, 10.5 mmol) and NaOH (1.3 g, 31.5 mmol) in THF/MeOH/H2O (115 mL, 70:30:15) (70 mL) was stirred at room temperature for 2.5 hours. The mixture was acidified with HCl (2 M) till pH ~ 4, and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1 to 2:1) to obtain the title compound (3.3 g, 94.8% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.25 (m, 5H), 7.22-7.17 (m, 2H), 7.08 (td, J = 7.5, 1.2 Hz, 1H), 6.96 (dd, J = 8.1, 0.9 Hz, 1H), 4.99 (q, J = 16.5 Hz, 2H), 3.98 – 3.86 (m, 1H), 3.47 (qd, J = 13.8, 6.5 Hz, 2H), 3.16 (dd, J = 17.5, 9.7 Hz, 1H), 2.89 (dd, J = 17.5, 4.1 Hz, 1H). [0445] Benzyl ((1-benzyl-2,2-dioxido-3,4-dihydro-1H-benzo[c][1,2]thiazin-4-yl)methyl) carbamate (NN-6): To the solution of NN-5 (1.0 g, 3.0 mmol), triethylamine (0.5 g, 4.5 mmol) and DPPA (0.8 g, 3.0 mmol) in toluene (25 mL) was stirred at 108°C under nitrogen atmosphere for 1 hour. Benzyl alcohol (1.6 g, 15.0 mmol) was added to above solution, and the reaction mixture was continued to stir at 110°C for another 3 hours. After cooling to room temperature, the mixture was diluted with water (50 mL), and extracted with ethyl acetate (25 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (elute with petroleum ether: ethyl acetate=3:1 to 1:1) to obtain the title compound (0.6 g, 45.9% yield) as a pale solid. [0446] (2,2-Dioxido-3,4-dihydro-1H-benzo[c][1,2]thiazin-4-yl)methanamine hydrochloride (45): The solution of NN-6 (160.0 mg, 0.4 mmol) and 10% Pd/C (0.8 g) in MeOH (6 mL) was stirred at room temperature under hydrogen atmosphere for 3 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography to get crude product. The compound was dissolved in HCl/dioxane (4 M, 1 mL), stirred for 30 min and then concentrated to dryness. The residue was slurried with EA/MeOH (3:1) to obtain the title compound (20.0 mg, 23.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (brs, 1H), 8.24 (brs, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 3.89 – 3.78 (m, 1H), 3.76 – 3.57 (m, 2H), 3.49 – 3.40 (m, 1H), 3.31 – 3.26 (m, 1H). MS(ESI) calculated for C9H12N2O2S, 212.1; found 213.0. [0447] Benzyl ((1-benzyl-2,2-dioxido-3,4-dihydro-1H-benzo[c][1,2]thiazin-4- yl)methyl)(methyl)carbamate (NN-7): To a solution of benzyl ((1-benzyl-2,2-dioxido-3,4- dihydro-1H-benzo[c][1,2]thiazin-4-yl)methyl)carbamate (0.3 g, 0.7 mmol) in DMF (10 mL) was added sodium hydride (0.1 g, 2.5 mmol, 60%wt) at 0 °C. The mixture was stirred for 30 min at 0 °C. Methyl iodide (0.4 g, 2.7 mmol) was added dropwise at 0 °C. The resulting mixture was slowly warmed to room temperature and continued to stir for 3 hours. The mixture was diluted with water (60 mL), extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (250.0 mg, 79.4% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.46 – 6.94 (m, 14H), 5.16 – 4.81 (m, 4H), 3.89 – 3.58 (m, 4H), 3.17 (d, J = 5.3 Hz, 1H), 2.87 (s, 3H). [0448] 4-((Chloro(methyl)- λ^-azanyl)methyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2- dioxide (46): The solution of NN-7 (250.0 mg, 0.6 mmol) and 10% Pd/C (50 mg) in MeOH (6 mL) was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (30.0 mg, 22.1% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (brs, 1H), 9.09 (brs, 2H), 7.49 – 7.42 (m, 1H), 7.29 – 7.22 (m, 1H), 7.10 – 7.03 (m, 1H), 6.86 – 6.80 (m, 1H), 3.98 – 3.87 (m, 1H), 3.78 – 3.71 (m, 1H), 3.68 – 3.55 (m, 2H), 3.39 – 3.31 (m, 1H), 2.62 (t, J = 5.3 Hz, 3H). MS(ESI) calculated for C10H14N2O2S, 226.1; found 227.0.
Figure imgf000176_0001
Scheme 42 [0449] Ethyl (E)-3-(3-aminothiophen-2-yl)acrylate (OO-1): A solution of ethyl (E)-3-(3- ((diphenylmethylene)amino)thiophen-2-yl)acrylate (25 g, 69.2 mmol) in HCl/dioxane (4 M, 50 mL) was stirred at room temperature for 30 min. The residue was diluted with ethyl acetate (500 mL), and washed with^saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with Petroleum ether: ethyl acetate = 78:22) to obtain the title compound (12 g, 88.2% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J = 15.1, 0.9 Hz, 1H), 7.40 (d, J = 5.4 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 6.21 (s, 2H), 5.59 (d, J = 15.1 Hz, 1H), 4.15 – 4.07 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). [0450] Ethyl (E)-3-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)acrylate (OO-2): The solution of OO-1 (12 g, 60.9 mmol) and di-tert-butyl dicarbonate (19.9 g, 91.3 mmol) in tetrahydrofuran (300 mL) and saturated sodium bicarbonate solution (300 mL) was stirred at room temperature for 48 hours. The mixture was extracted with EA (300 mL* 2), and the combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether : ethyl acetate= 4:1) to obtain the title compound (12 g, 66.6% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 15.3 Hz, 1H), 7.52 (s, 1H), 7.27 (d, J = 5.5 Hz, 1H), 7.10 (s, 1H), 6.12 (d, J = 15.3 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.52 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H). [0451] Ethyl 3-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)-4-nitrobutanoate (OO-3): To a solution of OO-2 (12 g, 40.4 mmol) in nitromethane (60 mL) was added DBU (18.4 g, 121.2 mmol), and the resulting mixture was stirred at 75°C for 1 hour. After cooling to room temperature, the mixture was poured into H2O (100 mL) and extracted with CH2Cl2 (100 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate= 9:1) to give the desired product (7 g, 48.6% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 5.4 Hz, 1H), 7.04 (s, 1H), 4.74 – 4.56 (m, 2H), 4.32 (t, J = 12.9 Hz, 1H), 4.19 – 4.05 (m, 2H), 2.75 (m, 2H), 1.53 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H). [0452] 7-(Nitromethyl)-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one (OO-4): The solution of OO-3 (7 g, 19.5 mmol) in HCl/dioxane (4 M, 50 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness. The residue was diluted with ethyl acetate (300 mL) and washed with^saturated sodium bicarbonate solution. The organic solution was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=1:1) to obtain the title compound (2.3 g, 56.0% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (brs, 1H), 7.40 (d, J = 5.2 Hz, 1H), 6.66 (d, J = 5.3 Hz, 1H), 4.77 – 4.66 (m, 2H), 3.95 – 3.83 (m, 1H), 2.87 (dd, J = 16.6, 7.5 Hz, 1H), 2.49 – 2.45 (m, 1H). [0453] (5-Oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-7-yl)methanamine hydrochloride (130): To a solution of OO-4 (2.3 g, 10.8 mmol) in methanol (100 mL) was added 10% Pd/C (800 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with DCM: MeOH=85:15) to obtain the title compound (1.2 g, 63.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 10.26 (brs, 1H), 8.17 (brs, 3H), 7.42 (d, J = 5.2 Hz, 1H), 6.69 (d, J = 5.2 Hz, 1H), 3.51 – 3.41 (m, 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.92 (d, J = 9.8 Hz, 1H), 2.83 (dd, J = 16.5, 6.7 Hz, 1H), 2.58 (dd, J = 16.5, 6.9 Hz, 1H). MS(ESI) calculated for C8H10N2OS, 182.0; found 183.2. [0454] 1‐{4H,5H,6H,7H‐Thieno[3,2‐b]pyridin‐7‐yl}methanamine (OO-5): To a solution of 7-(aminomethyl)-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one (150 mg, 0.82 mmol) in tetrahydrofuran (10 mL ) was added BH3-THF (1 M, 3.5 mL) at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with methanol (30 mL), and the solvent was removed under reduced pressure. The residue was dissolved in methanol (10 mL) and HCl/methanol (10 mL, 4 M), and the resulting mixture was stirred at 60°C for 16 hours. After cooling to room temperature, the mixture was concentrated to purity by column chromatography (eluted with DCM: MeOH=85:15) to obtain the title compound (60 mg, 64.5% yield) as a colorless oil. MS(ESI) calculated for C8H12N2S, 168.0; found 169.0. [0455] tert-Butyl-7-(((tert-butoxycarbonyl)amino)methyl)-6,7-dihydrothieno[3,2- b]pyridine-4(5H)-carboxylate (OO-6): A solution of OO-5 (60 mg, 356 μmol) and di-tert- butyl dicarbonate (386 mg, 1.77 mmol) in tetrahydrofuran (20 mL) and saturated sodium bicarbonate solution (20 mL) was stirred at room temperature for 1 hour. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL* 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate= 4:1) to obtain the title compound (80 mg, 61.0% yield) as a white solid. [0456] 1‐{4H,5H,6H,7H‐Thieno[3,2‐b]pyridin‐7‐yl}methanamine hydrochloride (124): To a solution of OO-6 (80 mg, 0.2 mmol) in methylene chloride (3 mL) was added HCl/dioxane (4 M, 3 mL), and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated to obtain the title compound (43 mg 82.6% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.65 (dd, J = 5.5, 0.7 Hz, 1H), 7.10 (d, J = 5.5 Hz, 1H), 3.73 (m,1H), 3.60 – 3.49 (m, 2H), 3.43 (dd, J = 13.0, 3.9 Hz, 1H), 3.16 (dd, J = 12.9, 10.4 Hz, 1H), 2.52 – 2.42 (m, 1H), 2.13 (m, 1H). MS(ESI) calculated for C8H12N2S, 168.0; found 169.0. [0457] tert-Butyl ((5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-7-yl)methyl)carbamat (OO-7): A solution of 7-(aminomethyl)-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one (220 mg, 1.2 mmol), saturated sodium bicarbonate solution (40 mL) and di-tert-butyl dicarbonate (595 mg, 2.4 mmol) in tetrahydrofuran (40 mL ) was stirred at room temperature for 1 hour. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate= 53: 47) to obtain the desired product (220 mg, 65.0% yield) as white solid. MS(ESI) calculated for C13H18N2O3S, 282.1; found 183.1. [0458] N-Methyl-1-(4,5,6,7-tetrahydrothieno[3,2-b]pyridin-7-yl)methanamine (OO-8): To the solution of OO-7 (220 mg, 0.8 mmol) in tetrahydrofuran (20 mL) was added LiAlH4 (440.0 mg, 11.6 mmol) at 0 °C. Then reaction was stirred at 60°C for 16 hours. After cooling to room temperature, the reaction was quenched with sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product (100 mg, 67.1% yield) as colorless oil, which was used in next step directly. [0459] tert-Butyl-7-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6,7- dihydrothieno[3,2-b]pyridine-4(5H)-carboxylate (OO-9): The mixture of OO-8 (100 mg, 548 μmol) and di-tert-butyl dicarbonate (595 mg, 2.73 mmol) in saturated sodium bicarbonate solution (20 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 1 hour. The mixture was poured into H2O (100 mL), and extracted with EA (100 mL* 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate= 9:1) to obtain the title product (55 mg, 26.0% yield) as a colorless oil. MS(ESI) calculated for C19H30N2O4S, 382.1; found 283.1. [0460] 7-((Methylammonio)methyl)-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-4-ium chloride (125): To the solution of OO-9 (55 mg, 0.1 mmol) in methylene chloride (2 mL) was added HCl/dioxane (4 M, 2 mL), and the resulting mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated to obtain the title compound (13.4 mg, 51.5% yield) as a yellow gel. 1H NMR (400 MHz, CD3OD) δ 7.11 (d, J = 5.3 Hz, 1H), 6.55 (d, J = 5.3 Hz, 1H), 3.21 (m, 3H), 3.10 (dd, J = 12.3, 4.8 Hz, 1H), 2.94 (dd, J = 12.3, 9.3 Hz, 1H), 2.63 (s, 3H), 2.14 – 2.04 (m, 1H), 1.84 (m, 1H). MS(ESI) calculated for C9H14N2S, 182.0; found 183.2. [0461] 7‐(Aminomethyl)‐4‐methyl‐4H,5H,6H,7H‐thieno[3,2‐b]pyridin‐5‐one hydrochloride (132): A slurry of activated sieves 4A (100 mg) in anhydrous DMF (4 mL) was added CsOH. H2O (18.5 mg, 0.11 mmol), and the mixture was stirred for 10 minutes. 7- (Aminomethyl)-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one (130) (20 mg, 109 μmol) in anhydrous DMF (2 mL) was added to the reaction. After stirring at room temperature for 30 min, a solution of iodomethane (15.4 mg, 109 μmol) in anhydrous DMF (0.5 mL) was added thereto. The resulting mixture was stirred for 16 hours and poured into H2O (100 mL), and extracted with CH2Cl2 (100 mL* 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate= 50:50) to obtain the product (10 mg,47.6% yield) as colorless oil. 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 5.4 Hz, 1H), 7.04 (d, J = 5.4 Hz, 1H), 3.48 (m, 1H), 3.34 (s, 3H), 3.16 – 2.98 (m, 3H), 2.71 (dd, J = 16.4, 5.7 Hz, 1H). MS(ESI) calculated for C9H12N2OS, 196.0; found 197.0. [0462] N-((5-Oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-7-yl)methyl)formamide (OO- 10): To a solution of 7-(aminomethyl)-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one (210 mg, 1.15 mmol) in methylene chloride (50 mL) was added ethyl formate (2.55 g, 34.5 mmol), and the mixture was stirred at 50°C for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by column chromatography (elute with DCM: MeOH=90:10) to obtain the title product (200 mg, 82.9% yield) as a colorless oil. MS(ESI) calculated for C9H10N2O2S, 210.0; found 211.0. [0463] N-Methyl-1-(5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-7-yl)methanamine hydrochloride (131): To a solution of OO-10 (200 mg, 1.0 mmol) in tetrahydrofuran (20 mL) was added BH3/THF (1 M, 1 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with methanol (30 mL) and the solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (CH3CN/H2O, 0.1%HCl system) to obtain the title product (4.8 mg, 2.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ10.29 (brs, 1H), 8.81 (brs, 2H), 7.43 (d, J = 5.2 Hz, 1H), 6.70 (d, J = 5.2 Hz, 1H), 3.14 – 3.00 (m, 3H), 2.86 (dd, J = 16.5, 6.7 Hz, 1H), 2.59 (dd, J = 10.7, 5.8 Hz, 4H). MS(ESI) calculated for C9H12N2OS, 196.0; found 197.2.
Figure imgf000180_0001
Scheme 43 [0464] tert-Butyl thiophen-3-ylcarbamate (PP-1): To the solution of thiophene-3- carboxylic acid (25 g, 195 mmol) in 2-methylpropan-2-ol (300 mL) was added diphenylphosphinoyl azide (71.0 g, 292 mmol) and triethylamine (108.5 mL, 780 mmol). Then, the mixture was refluxed for 16 hours. After cooling to room, the reaction was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (25 g, 64.4%) as a white solid. [0465] 1H NMR (400 MHz, DMSO-d6) δ 9.62 (brs, 1H), 7.38 (dd, J = 5.1, 3.2 Hz, 1H), 7.17 (brs, 1H), 6.98 (d, J = 5.1 Hz, 1H), 1.46 (s, 9H). [0466] tert-Butyl (2-formylthiophen-3-yl)carbamate (PP-2): To the solution of PP-1 (10 g, 50.1 mmol) in tetrahydrofuran (100 mL) was added n-BuLi (40 mL, 100.0 mmol) at - 78°C under nitrogen. The resulting solution was continued to stir at -78°C for 1 h. Then, N,N-dimethylformamide (5.8 mL, 75.1 mmol) was added dropwise to above solution, and the resulting solution was stirred for another 2 hours. Saturated NH4Cl was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain title compound (10.0 g, 87.6% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 9.81 (brs, 1H), 9.67 (s, 1H), 7.94 (d, J = 5.3 Hz, 1H), 7.66 (d, J = 5.3 Hz, 1H), 1.53 (s, 9H). MS(ESI) calculated for C10H13NO3S, 227.1; found 128.2, 172.2. [0467] Ethyl (Z)-3-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)acrylate (PP-3): To the solution of ethyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (12.8 g, 38.5 mmol) and 18- crown-6 ether (35.6 g, 132.4 mmol) in tetrahydrofuran (20 mL) was added sodium bis(trimethylsilyl)azanide (14 mL, 28.0 mmol) dropwise at -78°C, and the reaction mixture was stirred for 30 min, followed by the addition of tert-butyl N-(2-formylthiophen-3- yl)carbamate (6.2 g, 27.2 mmol) dissolved in tetrahydrofuran (5 mL) was added dropwise, and the mixture was continued to stir at -78°C for 1h. The reaction was quenched with saturated NH4Cl, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography to obtain desired product (5.7 g, Z/E=1:1, 70.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 5.2 Hz, 1H), 7.42 (s, 1H), 7.28 (d, J = 5.5 Hz, 1H), 6.93 (d, J = 12.5 Hz, 1H), 5.77 (d, J = 12.5 Hz, 1H), 4.29 – 4.21 (m, 2H), 1.53 (d, J = 6.4 Hz, 9H), 1.32 (td, J = 7.1, 1.6 Hz, 3H). MS(ESI) calculated for C14H19NO4S, 297.1; found 198.0,242.0,298.0. [0468] Ethyl (3S,4R)-1-benzyl-4-(3-((tert-butoxycarbonyl)amino)thiophen-2- yl)pyrrolidine-3-carboxylate (PP-4): A solution of PP-3 (5.6 g, 18.8 mmol, Z/E=1:1), benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (9.6 mL, 37.6 mmol) and lithium fluoride (1.95 g, 75.2 mmol) in dimethylformamide (50 mL ) was stirred at 110°C under nitrogen for 1 hour. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography to obtain desired compound (2.80 g, 69.1% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 7.51 – 7.44 (m, 3H), 7.36 – 7.30 (m, 2H), 7.30 – 7.23 (m, 1H), 6.99 (d, J = 5.5 Hz, 1H), 3.93 – 3.63 (m, 5H), 3.53 – 3.49 (m, 1H), 3.42 – 3.36 (m, 1H), 3.11 – 3.09 (m, 1H), 2.73 – 2.68 (m, 1H), 2.45 (t, J = 9.3 Hz, 1H), 1.50 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H). MS(ESI) calculated for C 23H30N2O4S, 430.2; found 431.2. [0469] (5aS,8aR)-5-Oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-d]thieno[3,2-b]pyridin- 7-ium chloride (134): The solution of PP-4 (1.7 g, 3.9 mmol) in ethylene dichloride (50 mL ) was cooled to 0°C. 1-chloroethyl carbonochloridate (2 mL, 18.5 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 1 h, then continued to stir at 50°C for 30 min. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was dissolved in ethanol (30 mL) and stirred at 90°C for 1 hour. The reaction mixture was concentrated to purify by column chromatography (eluted with DCM: MeOH=5:1) to obtain 600 mg gray solid. The solid was slurried with methanol (10 mL), filtered and washed with methanol (2 mL) to obtain title compound (400 mg, 52.6% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.71 (brs, 1H), 9.46 (brs, 1H), 7.45 (d, J = 5.3 Hz, 1H), 6.72 (d, J = 5.3 Hz, 1H), 3.87 – 3.75 (m, 1H), 3.70 – 3.50 (m, 3H), 3.48 – 3.42 (m, 1H), 2.96 – 2.77 (m, 1H). MS(ESI) calculated for C9H10N2OS, 194.1; found 195.0. [0470] (1R,9S)‐3‐Thia‐7,11‐diazatricyclo[7.3.0.02,6]dodeca‐2(6),4‐diene hydrochloride (126): The title compound was prepared using a procedure similar to the method used for the synthesis of intermediate OO-8. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (brs, 1H), 9.55 (brs, 1H), 7.54 (d, J = 5.4 Hz, 1H), 6.91 (d, J = 5.4 Hz, 1H), 3.73 – 3.61 (m, 2H), 3.53 – 3.34 (m, 2H), 3.31 – 3.14 (m, 2H), 3.14 – 2.88 (m, 2H). MS(ESI) calculated for C9H12N2S, 180.1; found 181.0.
Figure imgf000183_0001
Scheme 44 [0471] Ethyl 2-(chroman-4-ylidene)acetate (QQ-1): To the solution of ethyl 2- (diethoxyphosphoryl)acetate (32.2 g, 0.1 mol) in THF (250 mL ) was added sodium hydride (3.3 g, 0.1 mol, 60%wt) at 0°C, and the resulting mixture was stirred under nitrogen atmosphere for 1.5 hours. Chroman-4-one (13 g, 90 mmol) was added slowly to above solution; the reaction mixture was continued to stirred at room temperature for 2.5 hours. After which period, the reaction mixture was poured into ice water (500 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with Petroleum ether: ethyl acetate = 10: 1) to have desired product (7.4g, 50.1%) as a colorless oil. [0472] Ethyl 2-(chroman-4-yl)acetate (QQ-2): To the solution of QQ-1 (7.4 g, 33.9 mmol) in EtOH (100 mL) was added 10% Pd/C (2.5 g), and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 2.5 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to have desired product (7.0 g, 94.5%) as a pale solid. [0473] 4-tert-Butyl 1-ethyl 2-(3,4-dihydro-2H-1-benzopyran-4-yl)butanedioate (QQ-3): To the solution of QQ-2 (4.4 g, 19.9 mmol) in THF (50 mL ) was added LDA (19.9 mL, 19.9 mmol, 1M in THF) at -70°C under nitrogen atmosphere. The mixture was stirred at -70°C for another 30 min, followed by addition of tert-butyl 2-bromoacetate (3.9 g, 19.9 mmol) dropwise. The reaction mixture was stirred for additional 1 hour and quenched by water (200 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20: 1) to have desired product (3.0 g, 45.0%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.19 – 7.03 (m, 2H), 6.88 (td, J = 7.5, 1.2 Hz, 1H), 6.80 (dd, J = 8.2, 1.2 Hz, 1H), 4.36 – 3.96 (m, 4H), 3.48 (dd, J = 11.1, 8.2 Hz, 2H), 2.64 (dd, J = 16.8, 11.2 Hz, 1H), 2.09 (dd, J = 16.8, 2.9 Hz, 1H), 1.92 – 1.80 (m, 2H), 1.40 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H). [0474] 3-(3,4-Dihydro-2H-1-benzopyran-4-yl)-4-ethoxy-4-oxobutanoic acid (QQ-4): To the solution of QQ-3 (3.0 g, 9.0 mmol) in DCM (40 mL) was added TFA (10 mL). After stirring at room temperature for 16 hours, the mixture was concentrated to have desired product (2.5 g, 99.1%) as a colorless oil. [0475] Ethyl 6-oxo-2,3,3a,4,5,6-hexahydrobenzo[de]chromene-4-carboxylate (QQ-5): To the solution of QQ-4 (2.5 g, 9.0 mmol) in DCM (50 mL) was added oxalic dichloride (1.2 g, 9.4 mmol) dropwise at 0°C under nitrogen atmosphere. After stirring at room temperature for 2.5 hours, the mixture was concentrated to crude desired product (2.5 g, 93.8%) as a light- yellow oil. To a solution of the above crude compound (2.0 g, 6.7 mmol) in DCE (50 mL) was added AlCl3 (1.1 g, 8.0 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 2.5 hours. After which period, the reaction was quenched by water (200 mL), and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10: 1) to have desired product (0.7 g, 39.8%) as a pale solid. 1H NMR (400 MHz, CDCl3) δ 7.00-6.97 (m, 1H), 6.62 – 6.58 (m, 2H), 4.39-4.36 (m, 1H), 4.15 (td, J = 10.8, 2.2 Hz, 1H), 4.10 – 3.97 (m, 2H), 3.22 – 2.70 (m, 4H), 2.40 – 1.80 (m, 4H), 1.19 – 1.08 (m, 3H). [0476] Ethyl 2,3,3a,4,5,6-hexahydrobenzo[de]chromene-4-carboxylate (QQ-6): The solution of QQ-5 (0.5 g, 1.9 mmol) and 10% Pd/C (0.4 g) in EtOH (20 mL) was stirred at room temperature for 30 min under hydrogen atmosphere. Then, the reaction mixture was filtered through a pad of celite, the filtrate was concentrated to have desired product (0.4 g, 84.4%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.06 – 6.94 (m, 1H), 6.67 – 6.54 (m, 2H), 4.38 (ddd, J = 10.8, 4.1, 2.4 Hz, 1H), 4.15 (ddd, J = 12.4, 10.8, 2.4 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.18 – 2.71 (m, 4H), 2.32 – 1.80 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H). [0477] 2,3,3a,4,5,6-Hexahydrobenzo[de]chromene-4-carboxylic acid (QQ-7): To the solution of QQ-6 (0.4 g, 1.6 mmol) in THF/MeOH/H2O (11 mL, 7:3:1) was added NaOH (0.1 g, 3.2 mmol), and the resulting mixture was stirred at room temperature for 2.5 hours. Then, the reaction mixture was acidified with HCl (3 M) to pH~4, and extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to have crude desired product (0.3 g, 98.8%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.13 – 6.91 (m, 1H), 6.65-6.58 (m, 2H), 4.54 – 4.29 (m, 1H), 4.25 – 4.04 (m, 1H), 3.20 – 2.72 (m, 4H), 2.36 – 1.86 (m, 4H). [0478] Benzyl (2,3,3a,4,5,6-hexahydrobenzo[de]chromen-4-yl)carbamate (QQ-8): To the solution of QQ-7 (0.3 g, 1.1 mmol) and Et3N (0.2 g, 2.3 mmol) in toluene (50 mL) was added DPPA (0.8 g, 3.4 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 hours, followed by addition of benzyl alcohol (0.4 g, 3.4 mmol). The reaction mixture was continued to stir 2.5 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10: 1) to have desired product (0.1 g, 32.5%) as a pale solid. [0479] (3aS,4R)-2,3,3a,4,5,6-Hexahydrobenzo[de]chromen-4-amine hydrochloride (22): To the solution of QQ-8 (0.1 g, 0.4 mmol) in MeOH (15 mL) was added 10% Pd/C (78.8 mg) and the mixture was stirred at room temperature under hydrogen atmosphere for 2.5 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to have desired product as colorless oil. The compound was then dissolved in HCl/MeOH (4 M, 0.2 mL) and deionized water (20 mL), the solution was lyophilized to obtain title compound (50.0 mg, 71.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.56 (brs, 3H), 7.02 (t, J = 7.8 Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H), 4.40-4.36 (m, 1H), 4.19 – 4.01 (m, 1H), 3.64-3.62 (m, 1H), 3.18-3.14 (m, 1H), 2.89 – 2.71 (m, 2H), 2.21 – 1.71 (m, 4H). MS(ESI) calculated for C11H15NO, 189.1; found 190.2.
Figure imgf000185_0001
Scheme 45 [0480] 4-((Trimethylsilyl)oxy)chromane-4-carbonitrile (RR-1): To a solution of chroman- 4-one (5.0 g, 33.8 mmol) and ZnI2 (4.3 g, 1.4 mmol) in DCM (50 mL) was added TMSCN (10.0 g, 101.4 mmol) at ice/water bath. The reaction mixture was stirred for an additional 30 min at 0°C, and then at room temperature for 3 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (6.0 g, 71.9%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.8, 1.6 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.00-6.96 (m, 1H), 6.84 (dd, J = 8.3, 1.0 Hz, 1H), 4.40 – 4.28 (m, 2H), 2.44-2.37 (m, 2H), 0.17 (s, 9H). [0481] 2H-Chromene-4-carbonitrile (RR-2): A solution of RR-1 (6.0 g, 24.3 mmol) and p- toluenesulfonic acid (5.0 g, 29.2 mmol) in toluene (30 mL) was stirred at 110oC for 1 hour. After cooling to room temperature, the mixture was diluted with water (30 mL), extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (2.2 g, 57.7%) as a yellow oil. [0482] Chromane-4-carbonitrile (RR-3): The solution of RR-2 (2.2 g, 14.0 mmol) and NaBH4 (1.1 g, 28.0 mmol) in EtOH (20 mL) was stirred at 78oC for 1 hour. After cooling to room temperature, the mixture was diluted with saturated NH4Cl (10 mL), extracted with ethyl acetate (90 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (2.0 g, 89.7%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.26 (m, 1H), 7.25 – 7.19 (m, 1H), 6.97-6.93 (m, 1H), 6.85 (dd, J = 8.3, 1.2 Hz, 1H), 4.39 – 4.29 (m, 1H), 4.28 – 4.18 (m, 1H), 4.03 (t, J = 6.0 Hz, 1H), 2.40 – 2.24 (m, 2H). [0483] Chroman-4-ylmethanamine (RR-4): The solution of RR-3 (2.0 g, 12.6 mmol) and Raney Ni (1.1 g, 18.9 mmol) in NH3/methanol (2 M, 20 mL) was stirred at room temperature under hydrogen atmosphere for 4 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with DCM: MeOH = 10:1) to obtain the desired compound (1.6 g, 78.0% yield) as a yellow oil. MS(ESI) calculated for C10H13NO, 163.1; found 164.1. [0484] Methyl (chroman-4-ylmethyl)carbamate (RR-5): To a solution of RR-4 (1.6 g, 9.8 mmol) and TEA (2.0 g, 19.6 mmol) in DCM (20 mL) was added methyl chloroformate (1.4 g, 14.7 mmol) at ice/water bath temperature. The reaction mixture was stirred for an additional 10 min at 0°C, and then at room temperature for 2 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (80 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (1.5 g, 69.1%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.16-7.11 (m, 2H), 6.90-6.86 (m, 1H), 6.83 (dd, J = 8.2, 1.1 Hz, 1H), 4.80 (s, 1H), 4.25 – 4.13 (m, 2H), 3.69 (s, 3H), 3.62 – 3.38 (m, 2H), 3.08 – 2.93 (m, 1H), 2.14 – 2.01 (m, 1H), 1.95-1.89 (m, 1H). MS(ESI) calculated for C12H15NO3, 221.1; found 222.1. [0485] 3,3a,4,5-Tetrahydropyrano[4,3,2-de]isoquinolin-6(2H)-one (RR-6): A solution of RR-5 (1.5 g, 6.8 mmol) in CF3SO3H (10 mL) was stirred at 70oC for 16 hours. After cooling to room temperature, the mixture was diluted with water (30 mL), extracted with ethyl acetate (60 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography column (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (0.25 g, 19.5%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 7.6, 1.1 Hz, 1H), 7.28 – 7.22 (m, 2H), 6.98 (dd, J = 8.2, 1.1 Hz, 1H), 6.39 (s, 1H), 4.49-4.45 (m, 1H), 4.18-4.11 (m, 1H), 3.57 – 3.49 (m, 1H), 3.26 (dd, J = 6.2, 3.7 Hz, 2H), 2.08-2.03 (m, 1H), 1.82-1.78 (m, 1H). MS(ESI) calculated for C11H11NO2, 189.1; found 190.1. [0486] 2,3,3a,4,5,6-Hexahydropyrano[4,3,2-de]isoquinolin-5-ium chloride (23): To a solution of RR-6 (0.1 g, 0.5 mmol) in THF (5 mL) was added lithium aluminum hydride (0.06 g, 1.5 mmol) at 0°C, and the resulting mixture was stirred at 66oC for 3 hours. After cooling to room temperature, the mixture was quenched with sodium sulfate and filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (39.4 mg, 35.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (brs, 2H), 7.13 (t, J = 7.9 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 4.41-4.38 (m, 1H), 4.27 (d, J = 16.1 Hz, 1H), 4.23 – 4.10 (m, 2H), 3.56 (dd, J = 11.8, 4.8 Hz, 1H), 3.29 – 3.16 (m, 1H), 2.79 (d, J = 10.6 Hz, 1H), 2.05-2.03 (m, 1H), 1.63- 1.53 (m, 1H). MS(ESI) calculated for C11H13NO, 175.1; found 176.1.
Figure imgf000188_0001
Scheme 46 [0487] Methyl 3-(allyloxy)benzoate (SS-1): To a stirred suspension of methyl 3- hydroxybenzoate (9.5 g, 62.4 mmol) and K2CO3 (12.9 g, 93.5 mmol) in DMF (100 mL) was added allyl bromide (9.0 g, 74.8 mmol) slowly. The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the mixture was diluted with water (500 mL), extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with brine (600 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to give the title compound (11.0 g, 92.4% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.62 (m, 1H), 7.59 – 7.54 (m, 1H), 7.37 – 7.29 (m, 1H), 7.16 – 7.07 (m, 1H), 6.13 – 5.98 (m, 1H), 5.50 – 5.40 (m, 1H), 5.34 – 5.27 (m, 1H), 4.62 – 4.55 (m, 2H), 3.91 (s, 3H). [0488] 3-(Allyloxy)benzoic acid (SS-2): To the solution of SS-1 (11.0 g, 57.3 mmol) in THF/ MeOH/ H2O (44 mL, 7:1:3) was added NaOH (4.6 g, 114.6 mmol). The mixture was stirred at room temperature for 16 hours and acidified by adding HCl (4 M, 80 mL). The resulting mixture was extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 85: 15) to obtain the desired compound (9.0 g, 88.2% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.62 (m, 1H), 7.59 – 7.54 (m, 1H), 7.37 – 7.31 (m, 1H), 7.15 – 7.09 (m, 1H), 6.15 – 6.00 (m, 1H), 5.48 – 5.39 (m, 1H), 5.35 – 5.26 (m, 1H), 4.62 – 4.54 (m, 2H), 3.91 (s, 3H). [0489] [3‐(Prop‐2‐en‐1‐yloxy)phenyl]formamido 2,2‐dimethylpropanoate (SS-3): To a solution of SS-2 (1.0 g, 5.6 mmol) in dry DCM (20 mL) was added oxalylchloride (0.6 mL, 6.7 mmol) at 0 °C under nitrogen atmosphere followed by the addition of a catalytic amount of DMF (2 drops). The reaction was stirred for 4 hours at room temperature. Then, the solvent was removed under reduced pressure to afford the crude acid chloride. To a solution of above crude product (0.8 g, 6.7 mmol) in EtOAc (20 mL) and H2O (12 mL) was added K2CO3 (1.0 g, 7.1 mmol). The mixture was cooled to 0 °C, and the solution of O- pivaloylhydroxylamine (1.1 g, 5.6 mmol) in EtOAc (5 mL) was added drop wise. After addition, the mixture was allowed to warm to room temperature and stirred for 16 hours. After the separation of the organic layer, the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography column (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (0.7 g, 45.1% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.36 (brs, 1H), 7.39 – 7.33 (m, 3H), 7.14 – 7.08 (m, 1H), 6.13 – 5.97 (m, 1H), 5.46 – 5.39 (m, 1H), 5.35 – 5.27 (m, 1H), 4.61 – 4.54 (m, 2H), 1.36 (s, 9H). [0490] 2,2a,3,4-tetrahydro-5H-furo[4,3,2-de]isoquinolin-5-one (SS-4): A solution of SS-3 (0.5 g, 1.8 mmol), bis[(pentamethylcyclopentadienyl)dichloro-rhodium] (27.8 mg, 2.5 mol%) and CsOPiv (0.8 g, 3.6 mmol) in CH3CN (36 mL) was stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction mixture was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 2:1) to obtain the desired compound (0.2 g, 63.5% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.37 (m, 1H), 7.29 – 7.24 (m, 2H), 6.97 – 6.91 (m, 1H), 6.17 (brs, 1H), 4.89 (t, J = 8.8 Hz, 1H), 4.29 – 4.18 (m, 1H), 4.03 – 3.88 (m, 1H), 3.81 – 3.68 (m, 1H), 3.60 – 3.51 (m, 1H). [0491] 2a,3,4,5-tetrahydro-2H-furo[4,3,2-de]isoquinolin-4-ium chloride (24): To a solution of SS-4 (170.0 mg, 1.0 mmol) in THF (6 mL) was added lithium aluminum hydride (0.1 g, 2.9 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 hours. The reaction was quenched with sodium sulfate and filtered through a pad of celite. The filtrate was concentrated to purify by column chromatography (eluted with DCM: MeOH = 94:6) to obtain the title compound column (66.0 mg, 41.0% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (brs, 2H), 7.18 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 4.87 (t, J = 8.5 Hz, 1H), 4.37 – 4.25 (m, 1H), 4.16 – 4.05 (m, 2H), 3.84 – 3.71 (m, 2H), 3.02 – 2.89 (m, 1H). LCMS(ESI) calculated for C10H11NO, 161.1; found 162.2.
Figure imgf000190_0001
Scheme 47 [0492] Ethyl (E)-3-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)acrylate (TT-1): To a solution of sodium hydride (7.0 g, 175.0 mmol, 60%wt) in THF (200 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (49.0 g, 219.0 mmol) at 0oC, and the mixture was stirred at room temperature for 30 min. tert-Butyl (2-formylthiophen-3-yl) carbamate (10.0 g, 43.9 mmol) was added to above solution, and the resulting reaction mixture was a continued to stir at room temperature for 1 hour. The reaction was diluted with water (400 mL), and extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (8.8 g, 67.7% yield) as a white solid. MS(ESI) calculated for C14H19NO2S, 297.1; found 298.2. [0493] Ethyl (3s,4r)-1-benzyl-4-(3-((tert-butoxycarbonyl)amino)thiophen-2- yl)pyrrolidine-3-carboxylate (TT-2): To a solution of TT-1 (3.0 g, 15.2 mmol) and N- benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (7.2 g, 30.4 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (171.0 mg, 1.5 mmol) at 0oC, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL), extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (4.0 g, 61.2% yield) as a white solid. MS(ESI) calculated for C23H30N2O4S, 430.1; found 431.1. [0494] Ethyl (3s,4r)-4-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)pyrrolidine-3- carboxylate (TT-3): To a solution of TT-2 (3.8 g, 8.8 mmol) and potassium carbonate (6.1 g, 44.1 mmol) in 1,2-dichloroethane (150 mL) was added 1-chloroethyl chloroformate (6.3 g, 44.1 mmol), and the mixture was refluxed for 6 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in ethanol (100 mL) and refluxed for 2 hours. Then, the reaction mixture was concentrated to obtain the desired compound (2.0 g, 66.9% yield) as a crude. MS(ESI) calculated for C 16H24N2O4S, 340.2; found 341.2. [0495] Ethyl (3s,4r)-4-(3-aminothiophen-2-yl)pyrrolidine-3-carboxylate (TT-4): To a solution of TT-3 (2.0 g, 5.9 mmol) in dioxane (10 mL) was added HCl/dioxane (4 M, 10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness. The residue was dissolved in methanol (50 mL), and adjusted pH~8 with basic anion exchange resin. The mixture was filtered; the filtrate was concentrated to obtain the desired compound (1.0 g, 70.4% yield) as a crude. MS(ESI) calculated for C11H16N2O2S, 240.1; found 241.2. [0496] (5aR,8aR)-4,5a,6,7,8,8a-Hexahydro-5H-pyrrolo[3,4-d]thieno[3,2-b]pyridin-5-one (TT-5): To a solution of TT-4 (970.0 mg, 4.0 mmol) in toluene (30 mL) was added trimethylaluminium (12 mL, 1.0 M in toluene) at 0°C, and the resulting mixture was continued to stirred at 0oC for 2 hours. The mixture was poured into a solution of silica gel in methanol (50 mL) and filtered. The filtrate was concentrated to dryness. The residue was purified by reverse-phase chromatography (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (250.0 mg, 32.2% yield) as a white solid. MS(ESI) calculated for C9H10N2OS, 194.1; found 195.1. [0497] (5aS,8aR)-5,5a,6,7,8,8a-Hexahydro-4H-pyrrolo[3,4-d]thieno[3,2-b]pyridin-7-ium chloride (127): To a solution of TT-5 (200.0 mg, 1.0 mmol) in THF (20 mL) was added borane ( 5 mL, 1.0 M in THF) at 0oC, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with methanol and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN/H2O, 0.1%NH4OH) to obtain the desired compound (12.7 mg, 5.9% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.56 (d, J = 5.2 Hz, 1H), 6.99 (d, J = 5.2 Hz, 1H), 3.90-3.79 (m, 2H), 3.73-3.63 (m, 2H), 3.47-3.42 (m, 1H), 3.39-3.34 (m, 1H), 3.23-3.15 (m, 1H). MS(ESI) calculated for C9H12N2S, 180.1; found 181.2.
Figure imgf000192_0001
Scheme 48 [0498] 2-Bromo-3-(but-3-en-1-yloxy)pyridine (UU-1): To the solution of 2-bromo-3- hydroxypyridine (8.0 g, 45.9 mmol), but-3-en-1-ol (3.6 g, 50.4 mol), and PPh3 (14.4 g, 55.1mol) in THF (50 mL) was added diethyl azodicarboxylate (8.0 mL, 50.4 mol) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 50°C for 16 hours. After cooling to room temperature, the mixture was diluted with saturated NaHCO3 (150 mL) and extracted with ethyl acetate (100 mL*3). The organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (8.0 g, 76.9% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 5.2, 1.6 Hz, 1H), 7.24 – 7.17 (m, 1H), 7.16 – 7.09 (m, 1H), 6.05 – 5.75 (m, 1H), 5.31 – 5.06 (m, 2H), 4.09 (t, J = 8.5, 4.8 Hz, 2H), 2.67 – 2.57 (m, 2H). [0499] 4-Methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine (UU-2): To a solution of UU- 1 (7.5 g, 32.8 mmol), PPh3 (2.6 g, 9.8 mmol), KOAc (16.1 g, 164.0 mmol) and tetraethylammonium chloride (9.8 g, 59.0 mmol) in DMF (60 mL) was added Pd(OAc)2 (0.7 g, 3.3 mmol) under nitrogen atmosphere. The resulting reaction mixture was stirred at 105°C for 16 hours. After cooling to room temperature, the mixture was diluted with water (300 mL), extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with brine (80 mL*3), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 96:4) to obtain the desired compound (3.5 g, 72.3% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.23 – 8.16 (m, 1H), 7.17 – 7.07 (m, 2H), 6.24 – 6.17 (m, 1H), 5.13 – 5.03 (m, 1H), 4.30 – 4.19 (m, 2H), 2.88 – 2.78 (m, 2H). [0500] (3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-yl)methanol (UU-3): To the solution of UU-2 (1.8 g, 12.2 mmol) in THF (10 mL) was added BH3-THF (1 M, 36.5 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0°C for 1 h and then allowed to stir at room temperature for 2 hours. A solution of NaOH (3 N, 20.3 mL) was then added, followed by H2O2 (8.7 mL, 30% in water). The reaction was continued to stir at room temperature for 2 hours. The layers were then separated and the aqueous layer was extracted with EA (30 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 66:34) to obtain the desired compound (0.4 g, 19.9% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 4.4, 1.7 Hz, 1H), 7.16 – 7.08 (m, 2H), 4.37 – 4.28 (m, 1H), 4.14 (td, J = 10.9, 2.5 Hz, 1H), 3.90 – 3.77 (m, 2H), 3.24 – 3.14 (m, 1H), 2.09 – 1.99 (m, 1H), 1.88 – 1.75 (m, 1H). MS(ESI) calculated for C9H11NO2, 165.1; found 166.1. [0501] 4-(Azidomethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine (UU-4): The solution of UU-3 (330.0 mg, 2.0 mmol) and PPh3 (1.6 g, 6.0 mmol) in dry THF (10 mL) was cooled to 0 °C under nitrogen atmosphere. DEAD (1.0 g, 6.0 mmol) and DPPA (1.5 g, 6.0 mmol) were added dropwise. After addition, the reaction mixture was continued to stir at room temperature for 4 hours and then concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 97:3) to obtain the desired compound (230 mg, 60.8% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.19 – 8.12 (m, 1H), 7.15 – 7.04 (m, 2H), 4.34 – 4.15 (m, 2H), 4.01 – 3.95 (m, 1H), 3.73 – 3.61 (m, 1H), 3.26 – 3.15 (m, 1H), 2.30 – 2.17 (m, 1H), 2.15 – 2.06 (m, 1H). MS(ESI) calculated for C9H10N4O, 190.1; found 191.1. [0502] (3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-yl)methanamine hydrochloride (120): To the solution of UU-4 (230.0 mg, 1.2 mmol) in methanol (4 mL) was added 10% Pd/C (23 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. Then, the mixture was filtered through a pad of celite; the filtrate was concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (50.0 mg, 25.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (brs, 3H), 8.28 – 8.22 (m, 1H), 7.60 – 7.45 (m, 2H), 4.30 – 4.27 (m, 2H), 3.50 – 3.38 (m, 2H), 3.22 – 3.12 (m, 1H), 2.23 – 2.01 (m, 2H). MS(ESI) calculated for C9H12N2O, 164.1; found 165.2.
Figure imgf000194_0001
Scheme 49 [0503] 1-(tert-Butyl)3-ethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine- 1,3(2H)-dicarboxylate (VV-1): A solution of 1-(tert-butyl) 3-ethyl 4-oxopiperidine-1,3- dicarboxylate (10 g, 36.8 mmol) was dissolved in methylene chloride (100 mL) and DIPEA (11.8 g, 92.0 mmol) and cooled to -78°C. Trifluoromethanesulfonic anhydride (13.4 g, 47.8 mmol) in methylene chloride (10 mL) was added slowly to above solution. After addition, the mixture was stirred at -78°C for 30 min and slowly warmed to room temperature. Then, the reaction was cooled to 0°C and quenched by 10% Na2CO3 (200 mL). The layers were separated and the aqueous layer was extracted with DCM (300 mL*2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluted with Petroleum ether ethyl acetate = 9:1) to obtain the title product (10 g, 67.5% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.37 – 4.23 (m, 4H), 3.62 (t, J = 5.7 Hz, 2H), 2.57 – 2.48 (m, 2H), 1.48 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H). [0504] 1-(tert-Butyl)-3-ethyl4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1,3(2H)-dicarboxylate (VV-2): A mixture of VV-1 (10 g, 24.7 mmol), bis(pinacolato)diboron (7.5 g,26.9 mmol), potassium acetate (7.3 g, 74.1 mmol) and palladium bis((cyclopenta-1,3-dien-1-yl)diphenylphosphane) dichloromethane iron dichloride (2.0 g, 2.5 mmol) in dioxane (100 mL ) was stirred at 110°C under nitrogen atmosphere for 3 h. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate=9:1) to obtain the title product (6.9 g, 73.4% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.23 (d, J = 6.4 Hz, 2H), 4.09 (s, 2H), 3.44 (t, J = 5.2 Hz, 2H), 2.32 (s, 2H), 1.46 (s, 9H), 1.34 (s, 12H), 1.27 (d, J = 6.6 Hz, 4H). [0505] Di-tert-butyl-5-oxo-8,9-dihydrothieno[3,2-c][2,7]naphthyridine-4,7(5H,6H)- dicarboxylate (VV-3): A mixture of VV-2 (500 mg, 1.8 mmol), 4 (1.4 g, 3.6 mmol), palladium diacetate (40.1 mg, 0.2 mmo), S-Phos (147.0 mg, 0.3 mmol) and potassium carbonate (494.2 mg, 3.6 mmol) in dioxane/water (36 mL, 8:1) was stirred at 80°C for 3 hours and then at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was concentrated to dryness. The residue was purified by column chromatography (elute with petroleum ether: ethyl acetate = 88:12) to obtain the product (200 mg, 27.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 5.5 Hz, 1H), 7.07 (d, J = 5.4 Hz, 1H), 4.24 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 2.78 (t, J = 5.6 Hz, 2H), 1.60 (s, 9H), 1.44 (s, 9H). [0506] 5-Hydroxy-4,5,6,7,8,9-hexahydrothieno[3,2-c][2,7]naphthyridin-7-ium chloride (139): To a solution of VV-3 (150 mg, 0.4 mmol) in methylene chloride (5 mL) was added HCl/dioxane (4 M, 15 mL), and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated to obtain the title product (44.8 mg, 58.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.41 (brs, 1H), 9.41 (brs, 2H), 7.91 (d, J = 5.3 Hz, 1H), 7.08 (d, J = 5.3 Hz, 1H), 3.95 (brs, 2H), 3.40 (t, J = 5.9 Hz, 2H), 2.98 (t, J = 5.9 Hz, 2H). MS(ESI) calculated for: C10H10N2OS, 206.0; found 207.2. [0507] 1‐{2H,3H,4H‐Pyrano[2,3‐c]pyridin‐4‐yl}methanamine hydrochloride (121): The title compound was synthesized using the procedure utilized for 120, substituting 4- bromopyridin-3-ol for 2-bromopyridin-3-ol. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.40 (brs, 3H), 8.35 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 5.6 Hz, 1H), 4.38 – 4.33 (m, 2H), 3.44 (dd, J = 9.7, 4.8 Hz, 1H), 3.33 – 3.25 (m, 1H), 3.17 – 3.08 (m, 1H), 2.20 – 2.05 (m, 2H). MS(ESI) calculated for C9H12N2O, 164.1; found 165.1.
Figure imgf000196_0001
Scheme 50 [0508] Ethyl 2-(chroman-4-ylidene)acetate (WW-1): To a solution of sodium hydride (13.0 g, 324.3 mmol, 60%wt) in THF (300 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (72.7 g, 324.3 mmol), and the mixture was stirred at 0 °C to room temperature for 1 hour until no more bubbling was observed. A solution of 3,4-dihydro- 2H-1-benzopyran-4-one (16.0 g, 107.1 mmol) in THF (200 mL) was added to above solution at 0°C and stirred at room temperature for an additional 16 hours. The reaction mixture was poured into ice-water and extracted with EA (1000mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether : ethyl acetate=5:1) to obtain the desired compound (12.0 g, 50.9% yield) as a white solid. MS(ESI) calculated for C13H14O3, 218.1; found 219.2. [0509] Ethyl 2-(chroman-4-yl)acetate (WW-2): A mixture of WW-1 (12.0 g, 54.9 mmol) and 10% Pd/C (500 mg) in MeOH (20 mL) was stirred at room temperature under hydrogen atmosphere for 3 hours. The reaction mixture was filtrated; the filtrate was concentrated to obtain the desired compound (12.0 g, 99.1% yield) as a yellow oil. MS(ESI) calculated for C13H16O3, 220.1; found 222.2. [0510] 2-(Chroman-4-yl)acetic acid (WW-3): To a solution of WW-2 (9.0 g, 40.9 mmol) in THF/H2O (100 mL, 1:1) was added sodium hydroxide (4.9 g, 122.7 mmol) at room temperature, and the mixture was stirred at room temperature for 8 hours. Then, EA (100mL) was added into the mixture, and the organic layer was removed. The aqueous layer was adjusted to pH~2 with HCl (1 M) and extracted with EA (100mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to obtain the desired compound (7.7 g, 98.0% yield) as a white solid. MS(ESI) calculated for C11H12O3, 192.1; found 191.2. [0511] 2-(Chroman-4-yl)ethan-1-ol (WW-4): To a solution of WW-3 (7.7 g, 40.0 mmol) in tetrahydrofuran (60 mL) was added borane-tetrahydrofuran complex (1M, 60 mL) dropwise at 0 °C under nitrogen atmosphere, and the mixture was stirred at room temperature for 48 hours. The reaction was quenched by MeOH, and the mixture was concentrated to obtain the desired compound (7.1 g, 99.5% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.03 (m, 2H), 6.93 – 6.72 (m, 2H), 4.35 – 3.69 (m, 5H), 3.12 – 2.88 (m, 1H), 2.24 – 1.98 (m, 2H), 1.95 – 1.73 (m, 2H). [0512] 2-(Chroman-4-yl)ethyl methanesulfonate (WW-5): To a solution of WW-4 (7.1 g, 39.8 mmol) and triethylamine (8.1 g, 79.6 mmol) in DCM (70 mL) was added methanesulfonyl chloride (5.0 g, 43.7 mmol) at 0°C dropwise, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (150 mL), extracted with DCM (100 mL* 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (9.5 g, 92.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.15 – 7.08 (m, 2H), 6.91 – 6.85 (m, 1H), 6.83 – 6.79 (m, 1H), 4.37 (t, J = 6.4 Hz, 2H), 4.22 – 4.17 (m, 2H), 3.09 – 3.00 (m, 4H), 2.31 – 2.10 (m, 2H), 2.03 – 1.92 (m, 1H), 1.87 – 1.78 (m, 1H). MS(ESI) calculated for C12H12O4S, 256.1; found 257.2. [0513] 3-(Chroman-4-yl)propanenitrile (WW-6): To a solution of WW-5 (10.0 g, 39.0 mmol) in MeCN (100 mL) was added TMSCN (5.7 g, 58.4 mmol) and tetra-n- butylammonium fluoride (58.2 mL, 58.4 mmol, 1 M in THF) at 0°C. After addition, the mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was concentrated. The residue was diluted with water (100 mL), and extracted with EA (150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to obtain the desired compound (6.2 g, 84.9% yield). 1H NMR (400 MHz, CDCl3) δ 7.17 – 7.06 (m, 2H), 6.93 – 6.85 (m, 1H), 6.85 – 6.79 (m, 1H), 4.26 – 4.12 (m, 2H), 3.04 – 2.94 (m, 1H), 2.53 – 2.37 (m, 2H), 2.23 – 2.07 (m, 2H), 2.00 – 1.86 (m, 1H), 1.85 – 1.74 (m, 1H). [0514] 3-(Chroman-4-yl)propanoic acid (WW-7): To a solution of WW-6 (4.2 g, 22.4 mmol) in ethyl alcohol (40 mL) and water (25 mL) was added potassium hydroxide (2.5 g, 44.8 mmol), the resulting mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction was concentrated to dryness. The residue was diluted with water (50 mL), and washed with EA (50 mL). The aqueous layer was adjusted with HCl (6 M) to pH ~3, then extracted with EA (30mL *3). The combined organic layer was dried over sodium sulfate, filtered and concentrated to obtain the desired compound (4.6 g, 99.4% yield) as a white solid. MS(ESI) calculated for C12H12O3, 206.1; found 205.2. [0515] 3,3a,4,5-Tetrahydrobenzo[de]chromen-6(2H)-one (WW-8): A solution of WW-7 (4.5 g, 21.8 mmol) in toluene (25 mL) was added dropwise to polyphosphoric acid (50 g) at 90°C, and the resulting mixture was stirred for 10 mins. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EA. The organic layer was concentrated and purified by column chromatography to obtain the desired compound (2.3 g, 56.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 7.7, 1.2 Hz, 1H), 7.25 – 7.18 (m, 1H), 7.00 (dd, J = 8.1, 1.2 Hz, 1H), 4.52 – 4.41 (m, 1H), 4.27 – 4.15 (m, 1H), 3.08 – 2.95 (m, 1H), 2.85 – 2.75 (m, 1H), 2.67 – 2.54 (m, 1H), 2.30 – 2.18 (m, 1H), 2.13 – 2.02 (m, 1H), 1.86 – 1.71 (m, 2H). [0516] (E)-5-(Hydroxyimino)-3,3a,4,5-tetrahydrobenzo[de]chromen-6(2H)-one (WW-9): To a solution of 3-methylbutyl nitrite (372.0 mg, 3.2 mmol) in Et2O (5 mL) and t-BuOH (5 mL) was added t-BuOK (325.0 mg, 2.9 mmol). WW-8 (500.0 mg, 2.7 mmol) was added slowly to above solution, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed with MTBE, dissolved in aqueous HCl (1 M), extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated to purify by column chromatography to obtain the desired compound (190.0 mg, 32.9% yield) as a yellow oil. MS(ESI) calculated for C12H11NO3, 217.1; found 218.2. [0517] tert-Butyl (2,3,3a,4,5,6-hexahydrobenzo[de]chromen-5-yl)carbamate (WW-10): To a solution of WW-9 (190 mg, 0.9 mmol) in HCl/MeOH (4M, 10 mL) was added 10% Pd/C (20.0 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the desired compound (70 mg, crude) as a yellow oil. MS(ESI) calculated for C12H15NO, 189.1; found 190.2 A solution of above crude material (70.0 mg, crude), triethylamine (74.6 mg, 0.7 mmol) and di-tert-butyl dicarbonate (161.0 mg, 0.7 mmol) in DCM (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (50.0 mg, 19.8% yield, over two steps) as a white solid. MS(ESI) calculated for C17H23NO3, 289.1; found 234.2. [0518] 2,3,3a,4,5,6-hexahydrobenzo[de]chromen-5-aminium chloride (25): A mixture of WW-10 (50.0 mg, 0.2 mmol) in HCl/dioxane (4M, 1.5 mL) and methanol (1.5 mL) was stirred for 2 hours at room temperature. The mixture was concentrated to obtain the desired compound (20.0 mg, 51.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (brs, 3H), 7.06 – 6.96 (m, 1H), 6.63 (d, J = 7.5 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 4.38 – 4.29 (m, 1H), 4.19 – 4.06 (m, 1H), 3.62 – 3.48 (m, 1H), 3.23 – 3.12 (m, 1H), 2.95 – 2.83 (m, 1H), 2.81 – 2.70 (m, 1H), 2.26 – 2.15 (m, 1H), 2.06 – 1.95 (m, 1H), 1.67 – 1.53 (m, 1H), 1.41 (q, J = 12.1 Hz, 1H). MS(ESI) calculated for C12H15NO, 189.1; found 190.2.
Figure imgf000199_0001
Scheme 51 [0519] 3-Bromo-2-(but-3-en-1-yloxy)pyridine (XX-1): To a solution of 3-bromo-2- fluoropyridine (10.0 g, 56.8 mmol) and but-3-en-1-ol (8.1 g, 113 mmol) in DMF (80 mL) was added cesium carbonate (36.8 g, 113 mmol), and the reaction mixture was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was diluted with water (400 mL), extracted with ethyl acetate (100 mL*4). The combined organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 80:20) to obtain the desired compound (12.0 g, 92.6% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.11 – 8.04 (m, 1H), 7.84 – 7.76 (m, 1H), 6.80 – 6.71 (m, 1H), 6.03 – 5.86 (m, 1H), 5.24 – 5.06 (m, 2H), 4.42 (t, J = 6.8 Hz, 2H), 2.64 – 2.52 (m, 2H). [0520] 4-Methylene-3,4-dihydro-2H-pyrano[2,3-b]pyridine (XX-2): To a solution of XX- 1 (12.0 g, 52.6 mmol), PPh3 (4.1 g, 15.7 mmol), KOAc (25.8 g, 263.0 mmol) and tetraethylammonium chloride (15.6 g, 94.6 mmol) in DMF (60 mL) was added Pd(OAc)2 (0.9 g, 5.3 mmol) under nitrogen atmosphere. The resulting reaction mixture was stirred at 105°C for 16 hours. After cooling to room temperature, the mixture was diluted with water (300 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 77:13) to obtain the crude compound (5.0 g, 64.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 4.8, 1.9 Hz, 1H), 7.89 (dd, J = 7.6, 1.9 Hz, 1H), 6.92 (dd, J = 7.6, 4.8 Hz, 1H), 5.56 – 5.54 (m, 1H), 5.04 – 5.03 (m, 1H), 4.40 – 4.35 (m, 2H), 2.74 – 2.65 (m, 2H). MS(ESI) calculated for C9H9NO, 147.1; found 148.1. [0521] (3,4-Dihydro-2H-pyrano[2,3-b]pyridin-4-yl)methanol (XX-3): To the solution of XX-2 (5.0 g, 33.9 mmol) in THF (20 mL) was added BH3-THF (1 M, 101 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0°C for 1 hour and then allowed to stir at room temperature for 2 hours. After which period, a solution of NaOH (3 M, 56.3 mL) was then added, followed by H2O2 (24.2 mL, 30% in water). The reaction mixture was continued to stir at room temperature for 2 hours. The layers were separated and the aqueous layer was extracted with EA (40 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate).
Figure imgf000200_0001
NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 1.6, 2.0 Hz, 1H), 7.58 (ddd, J = 7.4, 1.9, 0.8 Hz, 1H), 6.90 – 6.85 (m, 1H), 4.41 – 4.30 (m, 2H), 3.94 – 3.85 (m, 1H), 3.86 – 3.76 (m, 1H), 3.11 – 3.00 (m, 1H), 2.15 – 2.05 (m, 2H). [0522] 4-(Azidomethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine (WW-4): A solution of WW-3 (0.7 g, 4.2 mmol) and PPh3 (3.3 g, 12.6 mmol) in dry THF (14 mL) was cooled to 0 °C under nitrogen atmosphere. DEAD (2.2 g, 12.6 mmol) was added dropwise, followed by DPPA (3.1 g, 12.6 mmol). The resulting mixture was stirred at room temperature for 16 hours and diluted with water (50 mL), extracted with EA (50 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 83:17) to obtain the crude compound as a yellow oil. MS(ESI) calculated for C9H10N4O, 190.1; found 191.1. [0523] (3,4-Dihydro-2H-pyrano[2,3-b]pyridin-4-yl)methanamine hydrochloride (122): To a solution of WW-4 (2.0 g, crude) in methanol (4 mL) was added 10% Pd/C (0.2 g) at room temperature. The resulting mixture was stirred under hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (30.0 mg, two step 4.4% yield) as a white gel. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (brs, 3H), 8.33 (d, J = 6.8 Hz, 1H), 8.25 (dd, J = 5.7, 1.6 Hz, 1H), 7.39 – 7.33 (m, 1H), 4.63 – 4.52 (m, 2H), 3.52 – 3.40 (m, 1H), 3.32 – 3.01 (m, 2H), 2.29 – 2.07 (m, 2H). MS(ESI) calculated for C 9H12N2O, 164.1; found 165.2.
Figure imgf000201_0001
Scheme 52 [0524] N-(4-Bromothiophen-3-yl)-1,1-diphenylmethanimine (YY-1): The solution of 3,4- dibromothiophene (20.0 g, 83.3 mmol), diphenylmethanimine (16.6 g, 91.6 mmol), Pd(OAc)2 (0.6 g, 2.5 mmol), BINAP (2.6 g, 4.2 mmol) and Cs2CO3 (54.3 g, 166.6 mmol) in toluene (300 mL) was stirred at 110oC under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was diluted with water (200 mL), extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 30:1) to obtain the desired compound (10.0 g, 35.2% yield) as a yellow oil. MS(ESI) calculated for C17H12BrNS, 341.0; found 342.0. [0525] Ethyl (E)-3-(4-((diphenylmethylene)amino)thiophen-3-yl)acrylate (YY-2): The solution of YY-1 (10.0 g, 29.3 mmol), ethyl acrylate (8.8 g, 87.9 mmol), Pd(PPh3)4 (3.4 g, 2.9 mmol) and TEA (8.9 g, 87.9 mmol) in DMF (100 mL) was stirred at 110oC under nitrogen for 16 hours. After cooling to room temperature, the mixture was diluted with water (300 mL), extracted with ethyl acetate (150 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 30:1) to obtain the desired compound (8.0 g, 75.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl 3) δ 7.83 (m, 1H), 7.81 (m, 1H), 7.70 (d, J = 16.0 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.46 – 7.39 (m, 3H), 7.37 – 7.29 (m, 3H), 7.15 – 7.09 (m, 2H), 6.40 (d, J = 16.0 Hz, 1H), 5.99 (d, J = 3.3 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). MS(ESI) calculated for C22H19NO2S, 361.1; found 362.1. [0526] Ethyl (3S,4R)-1-benzyl-4-(4-((diphenylmethylene)amino)thiophen-3- yl)pyrrolidine-3-carboxylate (YY-3): To a solution of YY-2 (5.0 g, 13.9 mmol) and N- benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (6.6 g, 27.8 mmol) in DCM (50 mL) was added TFA (0.2 g, 1.4 mmol) at 0°C. The reaction mixture was stirred at 0°C for an additional 10 min, and then at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with DCM (90 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (6.0 g, 87.7% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.37 – 7.33 (m, 4H), 7.31 (d, J = 5.9 Hz, 2H), 7.28 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.16 (dd, J = 6.4, 3.2 Hz, 2H), 7.00 (d, J = 3.1 Hz, 1H), 5.84 (d, J = 3.2 Hz, 1H), 3.98-3.92 (m, 2H), 3.85 (dd, J = 10.8, 7.1 Hz, 1H), 3.71 (d, J = 12.9 Hz, 1H), 3.62 (t, J = 9.9 Hz, 1H), 3.24 (d, J = 8.3 Hz, 1H), 2.89 – 2.76 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H). MS(ESI) calculated for C31H30N2O2S, 494.2; found 495.2. [0527] Ethyl (3S,4R)-4-(4-aminothiophen-3-yl)-1-benzylpyrrolidine-3-carboxylate (YY- 4): A solution of YY-3 (4.0 g, 8.1 mmol), hydroxylamine hydrochloride (1.0 g, 14.6 mmol) and NaOAc (1.7 g, 20.3 mmol) in MeOH (40 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL), extracted with DCM (90 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (1.2 g, 44.9% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.27 (m, 5H), 6.87 (d, J = 3.3 Hz, 1H), 6.05 (d, J = 3.4 Hz, 1H), 4.71 (s, 2H), 4.19 – 4.06 (m, 2H), 3.79 – 3.71 (m, 1H), 3.67 (s, 2H), 3.31 (t, J = 8.6 Hz, 1H), 3.24 – 3.15 (m, 1H), 3.05 – 2.95 (m, 1H), 2.76 (t, J = 9.2 Hz, 1H), 2.54 (t, J = 9.0 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). MS(ESI) calculated for C18H22N2O2S, 330.1; found 331.1. [0528] (5aS,8aR)-7-Benzyl-6,7,8,8a-tetrahydro-4H-pyrrolo[3,4-d]thieno[3,4-b]pyridin- 5(5aH)-one (YY-5): To a solution of YY-4 (0.6 g, 1.8 mmol) in toluene (6 mL) was added trimethylaluminum (1 M in toluene, 5.4 mL) at 0°C. The reaction mixture was stirred at 0 °C for 10 min, and then at room temperature for additional 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (0.3 g, 57.7% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.41 – 7.26 (m, 5H), 6.84 – 6.77 (m, 1H), 6.51 (d, J = 2.9 Hz, 1H), 3.94-3.83 (m, 2H), 3.35 (s, 1H), 3.27 – 3.05 (m, 3H), 2.96-2.84 (m, 1H), 2.78-2.70 (m, 1H). MS(ESI) calculated for C16H16N2OS, 284.1; found 285.1. [0529] (5aS,8aR)-5-Oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-d]thieno[3,4-b]pyridin- 7-ium chloride (135): To the solution of YY-5 (0.2 g, 0.7 mmol) and K2CO3 (0.2 g, 1.4 mmol) in DCE (6 mL) was added ACECl (0.2 g, 1.4 mmol) dropwise, and the resulting mixture was stirred at 80oC for 16 hours. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was dissolved in MeOH (6 mL) and stirred at room temperature for 2 hours. After cooling to room temperature, the mixture was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (51.0 mg, 31.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.47 (brs, 1H), 9.42 (brs, 1H), 7.32 (dd, J = 2.6, 1.6 Hz, 1H), 6.70 (d, J = 2.9 Hz, 1H), 3.88-3.79 (m, 1H), 3.51-3.42 (m, 1H), 3.29 – 3.09 (m, 3H), 2.91-2.83 (m, 1H). MS(ESI) calculated for C9H10N2OS, 194.1; found 195.1. [0530] (1S,9R)‐4‐Thia‐7,11‐diazatricyclo[7.3.0.02,6]dodeca‐2,5‐diene hydrochloride (129): The title compound was prepared utilizing the same procedure used for the synthesis of 126. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (brs, 2H), 7.27 (s, 1H), 6.66 (brs, 1H), 3.87 – 3.82 (m, 1H), 3.59 (dd, J = 11.3, 3.6 Hz, 1H), 3.52 – 3.45 (m, 1H), 3.21 (t, J = 11.4 Hz, 1H), 2.95-2.86 (m, 3H), 2.08 – 1.94 (m, 1H). MS(ESI) calculated for C9H12N2S, 180.1; found 181.1.
Figure imgf000204_0001
Scheme 53 [0531] 3-(2-(2-Iodophenoxy)ethyl)pyridine (ZZ-1): To the solution of 2-iodophenol (1.9 g, 8.5 mmol), 2-(pyridin-3-yl)ethan-1-ol (876.6 mg, 7.1 mmol) and triphenylphosphine (3.7 g, 14.2 mmol) in THF ( 100 mL) was added DEAD (2.5 g, 14.2 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (100mL) and extracted with EA (100mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired product (2.2 g, 72.3% yield yield) as a yellow solid. MS(ESI) calculated for C13H12INO, 325.0; found, 326.0. [0532] 1-Benzyl-3-(2-(2-iodophenoxy)ethyl)pyridin-1-ium (ZZ-2): The solution of ZZ-1 (2.2 g, 6.2 mmol) and (bromomethyl)benzene (1.5 g, 8.6 mmol) in dry acetonitrile (20 mL) was reflux for 3 hours. After cooling to room temperature, the precipitate collected by filtration and washed with dry acetonitrile (5 mL) to give pure desired compound (2.3 g, 88.7% yield) as a white solid. [0533] 1-Benzyl-5-(2-(2-iodophenoxy)ethyl)-1,2,3,6-tetrahydropyridine (ZZ-3): To a solution of ZZ-2 (2.3 g, 5.5 mmol) in EtOH (100 mL) was added NaBH4 (416.0 mg, 11.0 mmol), and the resulting mixture was stirred at room temperature for 12 hours. The solution was quenched by saturated NH4Cl, and extracted with EA (100 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate) to give the desired product (1.9 g, 81.8 % yield yield) as a yellow oil. MS(ESI) calculated for C20H22INO, 419.1; found, 420.1. [0534] 1'-Benzylspiro[chromane-4,3'-piperidine](ZZ-4) and 3-Benzyl-1,2,3,4,4a,5,6,11b- octahydrobenzo[6,7]oxepino[4,5-c]pyridine(5): A mixture of ZZ-3 (500 mg, 1.2 mmol), tributylstannane (527.6 mg, 1.8 mmol) and AIBN (10.0 mg, 0.6 mmol) in toluene (20 mL) was stirred at 110oC for 5 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with EA (50 mL*3). The combine organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum: ethyl acetate =5:1) and then continued to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to get compound ZZ-4 (100.0 mg, 28.5% yield) as a white solid and compound ZZ-5 (50.0 mg, 14.2% yield) as a white solid. MS(ESI) calculated for C20H23NO, 293.2; found, 294.2. [0535] Spiro[chromane-4,3'-piperidin]-1'-ium chloride (64): To a solution of ZZ-4 (100.0 mg, 0.3 mmol) in MeOH (20 mL) was added 10 % Pd(OH)2 (10.0 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated and purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired product (28.0 mg, 38.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (brs, 1H), 8.69 (brs, 1H), 7.52 (dd, J = 7.9, 1.4 Hz, 1H), 7.22 – 7.04 (m, 1H), 7.02 – 6.85 (m, 1H), 6.77 (dd, J = 8.2, 1.2 Hz, 1H), 4.21 – 3.97 (m, 2H), 3.21 (dd, J = 31.9, 16.0 Hz, 3H), 2.99 (t, J = 11.3 Hz, 1H), 2.34 (dt, J = 8.7, 4.2 Hz, 1H), 2.06 (td, J = 13.1, 4.2 Hz, 1H), 1.97 – 1.68 (m, 3H), 1.64 (d, J = 13.0 Hz, 1H). MS(ESI) calculated for C13H17NO, 203.1; found, 204.1. [0536] (4aR,11bS)-1,2,3,4,4a,5,6,11b-Octahydrobenzo[6,7]oxepino[4,5-c]pyridin-3-ium chloride (115): To the solution of ZZ-5 (50.0 mg, 0.2 mmol) in MeOH (10 mL) was added 10 % Pd(OH)2 (5 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated and purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired trans product (12.2 mg, 16.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (brs, 1H), 8.64 (brs, 1H), 7.26 – 7.10 (m, 2H), 7.02 (td, J = 7.4, 1.2 Hz, 1H), 6.90 (dd, J = 7.9, 1.1 Hz, 1H), 4.36 (dt, J = 12.1, 3.3 Hz, 1H), 3.55 (t, J = 11.6 Hz, 1H), 3.27 – 3.10 (m, 4H), 2.99 (m, 1H), 2.64 (td, J = 14.9, 3.1 Hz, 1H), 2.28 – 2.11 (m, 2H), 1.70 (d, J = 14.6 Hz, 1H), 1.49 (d, J = 11.7 Hz, 1H). MS(ESI) calculated for C13H17NO, 203.1; found, 204.1.
Figure imgf000206_0001
Scheme 54 [0537] 2‐Oxatricyclo[6.3.1.04,12]dodeca‐1(12),8,10‐trien‐6‐amine hydrochloride (9): The title compound was synthesized using the procedure utilized for synthesizing 25, substituting 2,3‐dihydro‐1‐benzofuran‐3‐one for chroman-4-one. 1H NMR (400 MHz, CD3OD) δ 7.07 (td, J = 7.8, 0.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 4.81 (t, J = 8.4 Hz, 1H), 4.00 (dd, J = 12.2, 8.4 Hz, 1H), 3.70 (m, 1H), 3.52 (d, J = 12.1 Hz, 1H), 3.27 (d, J = 6.7 Hz, 1H), 2.66 (dd, J = 16.6, 10.4 Hz, 1H), 2.50 – 2.36 (m, 1H), 1.55 (q, J = 11.7 Hz, 1H). MS(ESI) calculated for C11H9NO3, 175.1; found, 176.1. [0538] 1‐{2H,3H,4H‐Pyrano[3,2‐c]pyridin‐4‐yl}methanamine hydrochloride (123): The title compound was synthesized utilizing the procedure used for synthesizing 120, substituting 3‐bromopyridin‐4‐ol for 2-bromopyridin-3-ol. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (brs, 1H), 8.69 – 8.41 (m, 4H), 7.37 (d, J = 6.7 Hz, 1H), 4.60 – 4.44 (m, 2H), 3.50 – 3.46 (m, 1H), 3.32 – 3.24 (m, 1H), 3.21 – 3.11 (m, 1H), 2.29 – 2.17 (m, 1H), 2.16 – 2.02 (m, 1H). MS(ESI) calculated for C9H12N2O, 164.1; found 165.2.
Figure imgf000207_0001
Scheme 55 [0539] [3-(Benzyloxy)propoxy](tert-butyl)dimethylsilane (BBB-1): To a solution of 3- (benzyloxy)propan-1-ol (20.0 g, 120.4 mmol), Et3N (14.5 g, 144.0 mmol) and DMAP (293 mg, 2.4 mmol) in DCM (300 mL ) was added TBDMSCl (18.0 g, 120.0 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at room temperature for 17 hours. The reaction mixture was poured into water (500 mL), extracted with DCM (500 mL* 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 50:1) to have desired product (25.0 g, 74.3%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.29-7.28 (m, 5H), 4.45 (s, 2H), 3.68 (t, J = 6.2 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 1.83 – 1.71 (m, 2H), 0.91 – 0.79 (m, 9H), 0.01-0.00 (m, 6H). [0540] 3-[(tert-Butyldimethylsilyl)oxy]propan-1-ol (BBB-2): To a solution of BBB-1 (25.0 g, 89.1 mmol) in MeOH (300 mL) was added 10%Pd/C (2.8 g) at room temperature. The mixture was stirred under hydrogen atmosphere for 19 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give the desired product (15.0 g, 88.3% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.85 – 3.65 (m, 4H), 2.17 (s, 1H), 1.80 – 1.61 (m, 2H), 0.87 – 0.78 (m, 9H), 0.07 – -0.10 (m, 6H). [0541] 3-[(tert-Butyldimethylsilyl)oxy]propanal (BBB-3): To a solution of oxalic dichloride (18.2 g, 144.4 mmol) in DCM (500 mL ) was added DMSO (20.4 g, 262.0 mmol) dropwise at -78°C under nitrogen atmosphere, and the mixture was stirred for 15 minutes. BBB-2 (25.0 g, 131.0 mmol) was added slowly and the resulting mixture was continued to stir for 1 hour. Et3N (58.2 g, 576.0 mmol) was added thereto and the reaction mixture was allowed to warm to 0°C. The mixture was poured into HCl (0.1 M, 100 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with water (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 50:1) to give the desired product (17.0 g, 68.9% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 9.74 (t, J = 2.1 Hz, 1H), 3.92 (t, J = 6.0 Hz, 2H), 2.53 (m, 2H), 0.86 – 0.74 (m, 9H), 0.07 – -0.07 (m, 6H). [0542] 3-[(tert-Butyldimethylsilyl)oxy]-1-(2,4-dichloro-1,3-thiazol-5-yl)propan-1-ol (BBB-4): To a solution of 2,4-dichloro-1,3-thiazole (16.6 g, 108.4 mmol) in THF (150 mL ) was added LDA (1 N, 135 mL, 135 mmol) at -60°C under nitrogen. After stirring for 30 min, BBB-3 (17.0 g, 90.2 mmol) was added dropwise to above solution. The mixture was stirred for another 1.5 hours, then quenched with H2O (200 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:50) to have desired product (11.5 g, 37.1% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.13 – 5.03 (m, 1H), 4.47 (d, J = 2.5 Hz, 1H), 3.82 (dd, J = 6.2, 4.4 Hz, 2H), 2.01 – 1.74 (m, 2H), 0.81 (s, 9H), 0.00 (d, J = 2.5 Hz, 6H). [0543] 5-{3-[(tert-Butyldimethylsilyl)oxy]-1-(oxan-2-yloxy)propyl}-2,4-dichloro-1,3- thiazole (BBB-5): To the solution of BBB-4 (12.0 g, 35.0 mmol) and DHP (29.4 g, 350.0 mmol) in DCM (150 mL ) was added TsOH.Py (879 mg, 3.5 mmol) at room temperature. The reaction mixture was heated at reflux for 3.5 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (eluted with petroleum ether) to give the desired product (10.0 g, 66.9% yield) as a colorless oil. [0544] 5-{3-[(tert-Butyldimethylsilyl)oxy]-1-(oxan-2-yloxy)propyl}-4-chloro-1,3-thiazole (BBB-6): To the solution of BBB-5 (10.0 g, 23.4 mmol) in THF (300 mL ) was added n- BuLi (2.5 N, 11.2 mL, 28.0 mmol) at -70°C under nitrogen atmosphere. The mixture was stirred at -60°C for 30 min. After which period, the reaction was quenched with saturated NH4Cl, and the resulting mixture was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrate to purify by column chromatography (eluted with petroleum ether :ethyl acetate=15:1) to have desired product (8.0 g, 87.1% yield) as a colorless oil. [0545] 3-(4-Chloro-1,3-thiazol-5-yl)-3-(oxan-2-yloxy)propan-1-ol (BBB-7): To a solution of BBB-6 (8.0 g, 20.4 mmol) in THF (300 mL) was added TBAF/THF (1 M, 61.1 mL, 61.1 mmol) at room temperature. The reaction was stirred at 40°C for 2.5 hours. After cooling to room temperature, the mixture was poured into water (500 mL), extracted with ethyl acetate (200 mL* 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to have desired product (4.5 g, 79.4%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 0.5H), 8.67 (s, 0.5H), 5.48 – 5.16 (m, 1H), 4.67 (m, 1H), 4.05 – 3.32 (m, 4H), 2.18 – 1.40 (m, 8H). [0546] 7-(Oxan-2-yloxy)-5H,6H,7H-pyrano[2,3-d][1,3]thiazole (BBB-8): A solution of BBB-7 (4.0 g, 14.4 mmol), Pd(OAc)2 (483 mg, 2.2 mmol), TrixiePhos (1.1 g, 2.8 mmol) and Cs2CO3 (10.2 g, 31.6 mmol) in toluene (100 mL ) was stirred at 110°C for 16 hours. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate =1: 10) to give the desired product (2.0 g, 57.5%) as a light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 0.5H), 8.54 (s, 0.5 H), 4.94 – 4.77 (m, 2H), 4.50 – 4.26 (m, 2H), 3.94 – 3.85 (m, 1H), 3.60-3.56 (dd, J = 10.5, 5.3 Hz, 1H), 2.26 – 2.03 (m, 2H), 1.91 – 1.45 (m, 6H). [0547] 5H,6H,7H-Pyrano[2,3-d][1,3]thiazol-7-ol (BBB-9): To a solution of BBB-8 (2 g, 8.3 mmol) in H2O (15 mL ) and THF (15 mL ) was added TsOH (142.0 mg, 0.8 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL* 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to give the desired product (1.2 g, 92.1%) as a light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 4.97 (t, J = 3.7 Hz, 1H), 4.52 – 4.25 (m, 2H), 2.26 – 1.97 (m, 2H). [0548] 5H,6H,7H-Pyrano[2,3-d][1,3]thiazole-7-carbonitrile (BBB-10): To a solution of BBB-9 (0.8 g, 5.08 mmol), 2-hydroxy-2-methylpropanenitrile (1.3 g, 15.2 mmol) and (n- Bu)3P (3.07 g, 15.2 mmol) in THF (50 mL ) was added ADDP (3.8 g, 15.2 mmol) portionwise at 0°C under nitrogen atmosphere. After stirring at 0°C for 1.5 hours, the reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL* 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether :ethyl acetate= 1:1) to have desired product (500 mg, 59.1%) as a light brown oil. MS(ESI) calculated for C11H13NO, 166.0; found 167.0. [0549] (6,7-Dihydro-5H-pyrano[2,3-d]thiazol-7-yl)methanamine hydrochloride (163): To the solution of BBB-10 (200 mg, 1.2 mmol) in NH3/methanol (7 N, 15 mL) was added catalytic amount of Raney Ni, and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify with Prep-HPLC (CH3CN/H2O 0.1%HCl) to obtain the title product (15 mg, 14.7% yield) as a pale solid. 1H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 4.48-4.38 (m, 2H), 3.50-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.15-3.09 (m, 1H), 2.32-2.04 (m, 1H), 2.09-2.01 (m, 1H). MS(ESI) calculated for C7H10N2OS, 170.0; found 171.0. [0550] tert-Butyl ((6,7-dihydro-5H-pyrano[2,3-d]thiazol-7-yl)methyl)carbamate (BBB- 11): To a solution of 5H,6H,7H-pyrano[2,3-d][1,3]thiazole-7-carbonitrile (300 mg, 1.8 mmol), CoCl2.6H2O (215 mg, 0.9 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.4 mmol) in methanol (30 mL ) was added NaBH4 (205 mg, 5.4 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with H2O, and the mixture was extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether :ethyl acetate = 75:25) to obtain the desired product (190 mg, 66.4% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 4.37 – 4.19 (m, 2H), 3.26 – 3.09 (m, 3H), 2.15 – 2.06 (m, 1H), 1.86 – 1.78 (m, 1H), 1.45 (s, 9H). [0551] Tert-butyl-((6,7-dihydro-5H-pyrano[2,3-d]thiazol-7- yl)methyl)(methyl)carbamate (BBB-12): To a solution of BBB-11 (150 mg, 0.5 mmol) in dimethylformamide (6 mL) was added sodium hydride (64 mg, 1.6 mmol, 60%wt) at 0°C, and the resulting mixture was stirred at 0°C for 30 min. Iodomethane (156 mg, 1.1 mmol) in DMF (2 mL) was added dropwise, and the mixture was continued to stir at room temperature for 1 hour. After which period, the reaction was quenched with H2O and extracted with ethyl acetate (30 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate= 75:25) to obtain the title product (115 mg, 73.7% yield) as a colorless oil. MS(ESI) calculated for C13H20N2O3S, 284.1; found 285.1. [0552] 1-(6,7-dihydro-5H-pyrano[2,3-d]thiazol-7-yl)-N-methylmethanamine hydrochloride (164): To a solution of BBB-12 (115 mg, 0.4 mmol) in methylene chloride (2 mL) was added HCl/dioxane (4 M, 4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness. The residue was crystallized with ethyl acetate to get the title product (50 mg, 67.9% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H), 4.45 – 4.33 (m, 2H), 3.47 (m, 1H), 3.36 (dd, J = 12.6, 4.2 Hz, 1H), 3.24 – 3.16 (m, 1H), 2.79 (s, 3H), 2.27 (m, 1H), 2.06 – 1.96 (m, 1H). MS(ESI) calculated for C8H12N2OS, 184.0; found 185.2.
Figure imgf000211_0001
Scheme 56 [0553] 3-Bromo-2-nitrothiophene (CCC-1): Fuming nitric acid (7.4 ml) was slowly added to acetic acid (92.1 mL) under ice-cooling. Followed by stirring for 10 minute, a solution of acetic anhydride (52.1 mL) containing 3-bromothiophene (25.0 g, 153.3 mmol) was slowly added to the above reaction mixture (maintaining the temperature below 10°C). After stirring at room temperature for 2 hours, ice was added to the reaction solution. The resulting crystals were collected by filtration, and washed with water and diethyl ether/n-hexane (1/5) to give the title product (17.4 g, 54.5% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.58- 7.45 (d, J = 5.9 Hz, 1H), 7.18-7.05 (d, J =5.9 Hz, 1H). [0554] Ethyl (E)-3-(2-nitrothiophen-3-yl)acrylate (CCC-2): The mixture of CCC-1 (10.0 g, 47.7 mmol), ethyl prop-2-enoate (19.2 g, 192.1 mmol), Pd(OAc)2 (1.6 g, 9.6 mmol) and triphenylphosphine (1.3 g, 4.8 mmol) in TEA (100 mL) was stirred at 100°C under nitrogen for 16 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated by vacuum. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired product (5.2 g, 47.5 % yield) as a yellow oil. MS(ESI) calculated for C9H9NO4S, 227.0; found 228.0. [0555] Ethyl (3S,4R)-1-benzyl-4-(2-nitrothiophen-3-yl)pyrrolidine-3-carboxylate (CCC- 3): To the solution of CCC-2 (5.2 g, 13.8 mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (6.6 g, 27.6 mmol) in DCM (30 mL) was added trifluoroacetic acid (156.6 mg, 1.4 mmol) at 0oC. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and extracted with DCM (20 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether :ethyl acetate=10:1) to give the desired product(6.0 g, 87.7 % yield) as a yellow oil. MS(ESI) calculated for C18H20N2O4S, 360.1; found 361.1. [0556] Ethyl (3S,4R)-4-(2-aminothiophen-3-yl)-1-benzylpyrrolidine-3-carboxylate (CCC-4): To a solution of CCC-3 (2.0 g, 5.6 mmol) in EtOH (50 mL) and H2O (50 mL) was added ammonium chloride (1.5 g, 27.8 mmol) and iron powder (1.6 g, 27.8 mmol), and the mixture was stirred at 90oC for 2 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to purify with column chromatography (eluted with DCM :MeOH=20:1) to give the desired product(1.0 g, 54.6 % yield) as a yellow solid. MS(ESI) calculated for C18H22N2O2S, 330.1; found, 331.1. [0557] (3aS,8bR)-2-Benzyl-1,2,3,3a,5,8b-hexahydro-4H-pyrrolo[3,4-d]thieno[2,3- b]pyridin-4-one (CCC-5): To a solution of CCC-4 (1.0 g, 3.0 mmol) in toluene (50 mL) was added dropwise AlMe3 (6.0 mL, 2 M in toluene) at 0°C. The reaction mixture was stirred at 0oC for 10 min and then at room temperature for 1 hour. The reaction was quenched with MeOH and celite, the resulting mixture was continued to stir for 10 min, then filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography (eluted with DCM: MeOH=20:1) to give the desired product (369.9 mg, 43.3% yield) as a yellow solid. MS(ESI) calculated for C16H16N2OS, 284.1; found, 285.1. [0558] (3aS,8bR)-4-Oxo-2,3,3a,4,5,8b-hexahydro-1H-pyrrolo[3,4-d]thieno[2,3- b]pyridin-2-ium chloride (136): To a solution of CCC-5 (369.9 mg, 1.3 mmol) in DCE (50 mL )was added 1-chloroethyl carbonochloridate (743.3 mg, 5.2 mmol) and potassium carbonate (718.1 mg, 5.2 mmol) and the mixture was stirred at 80oC for 2 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated to get a yellow solid. This solid was dissolved in MeOH (20 mL) and the mixture was refluxed for 1 hour. Then, the reaction mixture was concentrated and purified by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to give the title compound (229.8 mg, 76.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.48 (s, 2H), 6.99 (d, J = 5.4 Hz, 1H), 6.88 (d, J = 5.4 Hz, 1H), 3.95 – 3.71 (m, 1H), 3.46 (s, 1H), 3.30 – 3.04 (m, 3H), 3.01 – 2.86 (m, 1H). MS(ESI) calculated for C9H10N2OS, 194.1; found, 195.1.
Figure imgf000213_0001
Scheme 57 [0559] 3-(Dichloromethyl)-2-nitrothiophene (DDD-1): 2-Nitro-thiophene (5.0 g, 38.7 mmol) and chloroform (5.1 g, 42.5 mmol) in N,N-dimethylformamide (12 mL) was added dropwise to a solution of potassium tert-butoxide in tetrahydrofuran (116 mL, 1.0 M) in N,N- dimethyl formamide (120 mL) at -78°C. After addition, the mixture was stirred at -78oC for 5 min. The reaction was quenched with methanol (7 mL) and acetic acid (10 mL) at 0°C. The mixture was diluted with brine (500 mL) and extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (6.0 g, 73.2% yield) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.57 (d, J = 5.7 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H). [0560] 2-Nitrothiophene-3-carbaldehyde (DDD-2): The solution of DDD-1 (11.0 g, 52 mmol) in formic acid (100 mL) was refluxed for 2 days under nitrogen atmosphere. After cooling to 0°C, the reaction mixture was neutralized with aqueous NaOH (5 N) till pH=8. The mixture was extracted with ethyl acetate (300 mL*2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (4.0 g, 49.6% yield) as a light brown solid. 1H NMR (400 MHz, CDCl 3) δ 10.62 (s, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.49 (d, J = 5.5 Hz, 1H). [0561] Ethyl (Z)-3-(2-nitrothiophen-3-yl)acrylate (DDD-3): To a solution of 18-crown-6 (10.9 g, 79.5 mmol), ethyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (6.3 g, 19.0 mmol) in THF (150 mL) was added NaHMDS (9.5 mL, 2.0 M) at -78oC under nitrogen atmosphere. After stirring for 1 hour, DDD-2 (2.5 g, 15.9 mmol) was added to the above solution. The resulting mixture was continued to stir at -78oC for 2 hours. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (2.0 g, 55.4% yield) as a white solid. MS(ESI) calculated for C9H9NO4S, 227.1; found 228.1. [0562] Ethyl (3S,4S)-1-benzyl-4-(2-nitrothiophen-3-yl)pyrrolidine-3-carboxylate (DDD- 4): To a solution of DDD-3 (2.2 g, 9.7 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (4.6 g, 19.3 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (110.0 mg, 1.0 mmol) at 0oC. The mixture was stirred at 0°C for 30 min and then at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (2.6 g, 74.5% yield) as white solid. MS(ESI) calculated for C18H20N2O4S, 360.1; found 361.1. [0563] Ethyl (3S,4S)-4-(2-aminothiophen-3-yl)-1-benzylpyrrolidine-3-carboxylate (DDD-5): To a solution of DDD-4 (2.5 g, 6.9 mmol) in ethanol (100 mL) was added 10% Pd/C (0.7 g), and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the desired compound (1.7 g, 74.6% yield). MS(ESI) calculated for C18H22N2O2S, 330.1; found 331.1. [0564] (3aS,8bS)-2-Benzyl-1,2,3,3a,5,8b-hexahydro-4H-pyrrolo[3,4-d]thieno[2,3- b]pyridin-4-one (DDD-6): To a solution of DDD-5 (1.7 g, 5.1 mmol) in dioxane (10 mL) was added HCl/dioxane (6.4 mL, 4 M), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted with aqueousNaHCO3 to pH~8 and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (600.0 mg, 41.4% yield) as a white solid. MS(ESI) calculated for C16H16N2O2S, 284.1; found 285.2. [0565] (3aS,8bS)-4-Oxo-2,3,3a,4,5,8b-hexahydro-1H-pyrrolo[3,4-d]thieno[2,3-b]pyridin- 2-ium chloride (137): To a solution of DDD-6 (100.0 mg, 0.4 mmol) and potassium carbonate (193.0 mg, 1.4 mmol) in 1,2-dichloroethane (10 mL) was added 1-chloroethyl chloroformate (198.0 mg, 1.4 mmol), and the resulting mixture was refluxed for 6 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in methanol (10 mL) and refluxed for 2 hours. Then, the mixture was concentrated to purify with Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (22.0 mg, 27.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (brs, 1H), 9.70 (brs, 1H), 9.29 (brs, 1H), 6.95 (d, J = 5.2 Hz, 1H), 6.88 (d, J = 5.2 Hz, 1H), 3.68-3.63 (m, 1H), 3.62-3.49 (m, 3H), 3.40-3.37 (m, 1H), 2.89- 2.82 (m, 1H). MS(ESI) calculated for C9H10N2OS, 194.1; found 195.1.
Figure imgf000216_0001
Scheme 58 [0566] 3-Bromofuran-2-carbaldehyde (EEE-1): 3-Bromofuran (20.0 g, 136.1 mmol) in THF (50 ml) was slowly added to a solution of LDA (64.6 mL 2.5 M) in THF (100 ml) at - 78°C under nitrogen atmosphere. After stirring for 15 min, a solution of DMF (11 ml, 144.0 mmol) in THF (50 ml) was added dropwise to the above mixture. The reaction was stirred at - 78°C for 1 hour and then allowed to warm to room temperature. The reaction was then quenched with water and extracted with EA (150 ml*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain the desired compound (8.8 g, 37.0% yield) as oil. 1H NMR (400 MHz, CDCl3) δ 9.74 (d, J = 0.7 Hz, 1H), 7.64 (dd, J = 1.8, 0.7 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H). MS(ESI) calculated for C5H3BrO2, 173.9; found 175.0, 177.1. [0567] 3-Methoxyfuran-2-carbaldehyde (EEE-2): To a solution of MeONa (3.8 g, 69.7 mmol, 30 w/w%) in MeOH (100 mL) was added EEE-1 (6.0 g, 34.3 mmol).The reaction was stirred at 65°C for 13 hours. After the reaction was complete, the mixture was cooled to 20°C and stirred at this temperature for 3 hours. The temperature was then lowered to -30°C, and AcOH (10 mL) was added. Most of the MeOH was removed under reduced pressure at 35 °C, and the remaining mixture was diluted with water (100 mL) and extracted with DCM (30 mL * 2). The combined organic layers were washed with half-saturated NaHCO3 (30 mL). Then, the organic layer was concentrated at 25 °C. The residue was purified by column chromatography to obtain the desired compound (2.1 g, 48.3% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 7.55 – 7.50 (m, 1H), 6.40 (d, J = 2.0 Hz, 1H), 3.96 (s, 3H). [0568] Ethyl (E)-3-(3-methoxyfuran-2-yl)acrylate (EEE-3): To a solution of EEE-2 (2.1 g, 16.6 mmol) in ethyl alcohol (25 mL) was added ethyl 2-(triphenyl-λ⁵- phosphanylidene)acetate (8.7 g, 24.9 mmol). The reaction mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to obtain the desired compound (2.1 g, 64.3% yield) as an oil.1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 15.7 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 6.13 (d, J = 15.8 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). [0569] Ethyl 3-(3-methoxyfuran-2-yl)-4-nitrobutanoate (EEE-4): To a solution of EEE-3 (2.1 g, 10.7 mmol) in nitromethane (25 mL, 466.0 mmol) was added DBU (4.9 g, 32.0 mmol), and the reaction was stirred at 75°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered with EA, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=1:1) to obtain the desired compound (1.2 g, 43.6% yield). 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 2.1 Hz, 1H), 6.27 (d, J = 2.1 Hz, 1H), 4.77 – 4.65 (m, 2H), 4.19 – 4.08 (m, 3H), 3.73 (s, 3H), 2.86 – 2.67 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). [0570] 3-(3-Methoxyfuran-2-yl)-4-nitrobutan-1-ol (EEE-5): To a solution of EEE-4 (1.2 g, 4.5 mmol) in tetrahydrofuran (10 mL) was added borane tetrahydrofuran complex (1 M, 22.4 mL), and the resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with MeOH and concentrated to obtain the desired compound (780.0 mg, 77.7% yield) as a crude product. 1H NMR (400 MHz, CDCl3) δ 7.16 – 7.11 (m, 1H), 6.17 (d, J = 2.1 Hz, 1H), 4.78 (dd, J = 12.6, 4.9 Hz, 1H), 4.43 – 4.32 (m, 1H), 4.18 – 4.07 (m, 2H), 3.80 – 3.72 (m, 1H), 3.49 (s, 3H), 2.27 – 2.15 (m, 1H), 1.93 – 1.85 (m, 1H). [0571] 7-(Nitromethyl)-6,7-dihydro-5H-furo[3,2-b]pyran (EEE-6): To a solution of EEE- 5 (780.0 mg, 3.6 mmol) in toluene (10 mL) was added sodium bisulfate (4.3 mg, 36.2 μmol), the resulting mixture was stirred at 110°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate=3:1) to obtain the desired compound (390.0 mg, 58.7% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.15 – 7.12 (m, 1H), 6.17 (d, J = 2.1 Hz, 1H), 4.82 – 4.74 (m, 1H), 4.42 – 4.32 (m, 1H), 4.18 – 4.07 (m, 2H), 3.81 – 3.71 (m, 1H), 2.26 – 2.16 (m, 1H), 1.95 – 1.85 (m, 1H). [0572] (6,7-Dihydro-5H-furo[3,2-b]pyran-7-yl)methanamine hydrochloride (165): To a solution of EEE-6 (230.0 mg, 1.3 mmol) in ethyl alcohol (5 mL) and water (5 mL) was added iron (139.0 mg, 2.5 mmol) and ammonium chloride (133.0 mg, 2.5 mmol). The mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of celite; the filtrate was concentrated to purify with prep-TLC to get crude product (75 mg). The compound was further slurried with EA to obtain the desired compound (45.0 mg, 18.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (brs, 3H), 7.44 – 7.40 (m, 1H), 6.30 (d, J = 2.1 Hz, 1H), 4.11 – 4.00 (m, 2H), 3.22 – 3.13 (m, 1H), 3.12 – 3.05 (m, 1H), 2.94 – 2.85 (m, 1H), 2.09 – 1.98 (m, 1H), 1.95 – 1.85 (m, 1H). MS(ESI) calculated for C8H11NO2, 153.1; found 154.2.
Figure imgf000218_0001
Scheme 59 [0573] 1-((Allyloxy)methyl)-2-iodobenzene (FFF-1): To a solution of (2- iodophenyl)methanol (12.0 g, 51.2 mmol) in THF (150 mL) was added sodium hydride (2.5 g, 61.4 mmol, 60%wt) at 0°C under nitrogen atmosphere, the mixture was stirred at 0°C for 30 min. 3-Bromoprop-1-ene (7.4 g, 61.4 mmol) was added dropwise to the above mixture, which was stirred at room temperature for 16 hours. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to obtain the title product (13.8 g, 98.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.9, 1.1 Hz, 1H), 7.46 (dd, J = 7.7, 1.5 Hz, 1H), 7.37-7.33 (m, 1H), 7.01-6.96 (m, 1H), 6.03-5.95 (m, 1H), 5.39-5.33 (m, 1H), 5.26-5.22 (m, 1H), 4.51 (s, 2H), 4.13-4.11 (m, 2H). [0574] 4-Methyleneisochromane (FFF-2): The solution of FFF-1 (12.8 g, 46.6 mmol), palladium diacetate (0.5 g, 2.3 mmol), triethylamine (23.5 g, 233 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in acetonitrile (100 mL) was stirred at 80°C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 80:20) to obtain the title product (3.1 g, 45.5% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.65 (m, 1H), 7.26 – 7.22 (m, 2H), 7.07 – 7.00 (m, 1H), 5.61 (s, 1H), 5.02 (t, J = 1.3 Hz, 1H), 4.82 (s, 2H), 4.45 (t, J = 1.2 Hz, 2H). [0575] Isochroman-4-ylmethanol (FFF-3): To a solution of FFF-2 (3.1 g, 21.2 mmol) in dry THF (20 mL) was added BH 3-THF (1 M, 63.6 mL) dropwise at 0°C under nitrogen atmosphere. The reaction was stirred at 0°C for 1 hour and then allowed to stir for 2 hours at room temperature. Aqueous NaOH (3 N, 35.3 mL) was added thereto, followed by H2O2 (13 mL,30% in water). The reaction was stirred for 2 hours at room temperature. The reaction was continued to stir at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (300 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography column (eluted with petroleum ether: ethyl acetate = 77:23) to obtain the desired compound (2.1 g, 60.3% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.18 (m, 3H), 7.05 – 6.98 (m, 1H), 4.87 – 4.71 (m, 2H), 4.31 – 4.24 (m, 1H), 3.96 – 3.83 (m, 3H), 2.88 – 2.79 (m, 1H). [0576] N-(2,2-Dimethoxyethyl)-1,1,1-trifluoro-N-(isochroman-4- ylmethyl)methanesulfonamide (FFF-4): The mixture of FFF-3 (1.7 g, 10.3 mmol), N-(2,2- dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (2.9 g, 12.3 mmol) and PPh3 (5.4 g, 20.6 mmol) in dry THF (20 mL) was stirred at 0°C under nitrogen atmosphere. Diethyl azodicarboxylate (3.6 g, 20.6 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 6:1) to obtain the desired compound (2.0 g, 50.7% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.18 (m, 2H), 7.18 – 7.13 (m, 1H), 7.03 – 6.98 (m, 1H), 4.89 – 4.72 (m, 2H), 4.54 (t, J = 5.3 Hz, 1H), 4.21 – 4.09 (m, 1H), 3.93 – 3.79 (m, 1H), 3.79 – 3.73 (m, 1H), 3.65 – 3.54 (m, 1H), 3.50 – 3.44 (m, 2H), 3.44 (s, 3H), 3.42 (s, 3H), 3.18 – 3.05 (m, 1H). [0577] 5-((Trifluoromethyl)sulfonyl)-3,3a,4,5-tetrahydro-1H-isochromeno[4,5- cd]azepine (FFF-5): To a solution of FFF-4 (1.8 g, 4.7 mmol) in DCM (30 mL) was added AlCl3 (5.0 g, 37.5 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched with NaOH (1 M, 100 mL), extracted with DCM (30*3 mL). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 88:12) to obtain the desired compound (1.0 g, 67.1 % yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.23 – 7.16 (m, 1H), 7.15 – 7.07 (m, 1H), 6.96 – 6.86 (m, 1H), 6.62 (d, J = 10.4 Hz, 1H), 5.86 (d, J = 10.5 Hz, 1H), 4.83 – 4.69 (m, 2H), 4.33 – 4.22 (m, 1H), 4.21 – 4.10 (m, 1H), 3.66 – 3.52 (m, 1H), 3.36 – 3.24 (m, 1H), 3.22 – 3.10 (m, 1H). [0578] 5-((Trifluoromethyl)sulfonyl)-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5- cd]azepine (FFF-6): The solution of FFF-5 (1.0 g, 3.1 mmol) and 10% Pd/C (0.1 g) in methanol (14 mL) was stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (0.5 g, 50.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.11 (m, 1H), 7.08 – 7.00 (m, 1H), 6.98 – 6.86 (m, 1H), 4.73 (s, 2H), 4.23 – 4.15 (m, 1H), 4.09 – 4.02 (m, 1H), 4.00 – 3.94 (m, 1H), 3.91 – 3.82 (m, 1H), 3.26 – 3.02 (m, 4H), 3.00 – 2.83 (m, 1H). [0579] 3,3a,4,5,6,7-Hexahydro-1H-isochromeno[4,5-cd]azepine (FFF-7): To the solution of FFF-6 (250.0 mg, 0.8 mmol) in dry THF (10 mL) was added Red-Al solution (2.0 mL, 3.9 mmol, 70% in toluene) at room temperature under nitrogen atmosphere. The reaction was stirred at 100 °C for 1 hour. After cooling to room temperature, the reaction was quenched with saturated NH4Cl (10 mL), and the solvent was removed in vacuum. The residue was dissolved in DCM and washed with water, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: MeOH = 10:1) to obtain the desired compound (0.1 g, 68.0% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.13 – 7.05 (m, 1H), 7.04 – 6.94 (m, 1H), 6.92 – 6.77 (m, 1H), 4.68 (s, 2H), 4.09 – 3.93 (m, 1H), 3.71 – 3.57 (m, 1H), 3.28 – 3.20 (m, 1H), 3.18 – 2.94 (m, 3H), 2.86 – 2.61 (m, 3H). [0580] tert-Butyl 3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)-carboxylate (FFF-8): To a solution of FFF-7 (0.1 g, 0.5 mmol) in THF (6 mL) and NaHCO3 (6 mL) was added Boc2O (0.2 g, 1.0 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography column (eluted with petroleum ether: ethyl acetate = 90:10) to afford the title product (150.0 mg, 98.6% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.14 – 7.07 (m, 1H), 7.05 – 6.97 (m, 1H), 6.93 – 6.83 (m, 1H), 4.72 (s, 2H), 4.24 – 4.05 (m, 2H), 3.93 – 3.67 (m, 1H), 3.13 – 2.74 (m, 5H), 1.69 – 1.51 (m, 1H), 1.44 (s, 9H). [0581] 3,3a,4,5,6,7-Hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (83): To a solution of FFF-8 (0.1 g, 0.3 mmol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and purified by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title product (40.0 mg, 61.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ9.55 (brs, 1H), 9.27 (brs, 1H), 7.20 – 7.08 (m, 2H), 7.03 – 6.97 (m, 1H), 4.65 (s, 2H), 4.01 – 3.93 (m, 1H), 3.83 – 3.74 (m, 1H), 3.58 – 3.46 (m, 1H), 3.43 – 3.36 (m, 2H), 3.32 – 3.24 (m, 1H), 2.98 – 2.67 (m, 3H). MS(ESI) calculated for C12H15NO, 189.1; found 190.2.
Figure imgf000221_0001
Scheme 60 [0582] 4-Bromothiophene-3-carbaldehyde (GGG-1): To a solution of 3,4- dibromothiophene (10.0 g, 41.7 mmol) in Et2O (100 mL) was added n-BuLi (2.5 M, 18.4 mL, 45.9 mmol) at -78oC under nitrogen atmosphere. The reaction mixture was stirred at -78°C for an additional 30 min, followed by addition of DMF (3.7 g, 50.0 mmol). The reaction was continued to stir at –78oC for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography column (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (6.0 g, 75.8%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.16 (d, J = 3.4 Hz, 1H), 7.37 (d, J = 3.4 Hz, 1H). MS(ESI) calculated for C5H3BrOS, 189.9; found 190.9, 192.9. [0583] Ethyl (Z)-3-(4-bromothiophen-3-yl)acrylate (GGG-2): To a solution of ethyl 2- (bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (12.6 g, 37.9 mmol,) and 18-Crown-6 (30.0 g, 113.8 mmol) in THF (100 mL) was added NaHMDS (2 N, 19.0 mL, 37.9 mmol) at -78oC under nitrogen atmosphere. The reaction mixture was stirred at -78°C for an additional 30 min, followed by addition of GGG-1 (6.0 g, 31.6 mmol). The reaction was continued to stir at -78oC for 1 hour. The mixture was diluted with saturated NH4Cl (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (3.0 g, 36.5%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 3.4 Hz, 1H), 7.25 (d, J = 3.4 Hz, 1H), 6.92 (d, J = 12.8 Hz, 1H), 5.99 (d, J = 12.8 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). MS(ESI) calculated for C9H9BrO2S, 260.0; found 261.0, 263.0. [0584] Ethyl (3r,4r)-1-benzyl-4-(4-bromothiophen-3-yl)pyrrolidine-3-carboxylate (GGG-3): To a solution of GGG-2 (3.0 g, 11.5 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (5.5 g, 23.0 mmol) in DCM (30 mL) was added TFA (136.8 mg, 1.2 mmol) at 0°C. The reaction mixture was stirred at 0 °C for 10 min, and then at room temperature for an additional 2 hours. The mixture was diluted with water (50 mL) and extracted with DCM (60 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (3.0 g, 66.2%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.28 (m, 4H), 7.27 – 7.21 (m, 1H), 7.18 (d, J = 3.4 Hz, 1H), 7.15 (d, J = 3.4 Hz, 1H), 3.92-3.86 (m, 1H), 3.80 – 3.68 (m, 3H), 3.60 (dd, J = 10.7, 7.1 Hz, 1H), 3.48 (dd, J = 10.1, 1.1 Hz, 1H), 3.12 – 3.00 (m, 3H), 2.74 (t, J = 8.9 Hz, 1H), 0.90 (t, J = 7.1 Hz, 3H). MS(ESI) calculated for C18H20BrNO2S, 393.0; found 394.0, 396.0. [0585] Ethyl (3r,4r)-4-(4-bromothiophen-3-yl)pyrrolidine-3-carboxylate (GGG-4): To the solution of GGG-3 (3.0 g, 7.6 mmol) and K2CO3 (2.1 g, 15.2 mmol) in DCE (30 mL) was added ACE-Cl (2.2 g, 15.2 mmol), and the resulting mixture was stirred at 80oC for 16 hours. After cooling to room temperature, the mixture was filtered and concentrated to dryness. The residue was dissolved in MeOH (20 mL) and stirred at room temperature for 2 hours. After then, the reaction mixture was concentrated to purify with column chromatography (eluted with DCM: MeOH = 10:1) to obtain the desired compound (2.0 g, 86.6% yield) as a colorless gel. MS(ESI) calculated for C11H14BrNO2S, 303.1; found 304.1, 306.1. [0586] 1-(tert-Butyl) 3-ethyl (3r,4r)-4-(4-bromothiophen-3-yl)pyrrolidine-1,3- dicarboxylate (GGG-5): To a solution of GGG-4 (2.0 g, 6.6 mmol) and (Boc)2O (2.2 g, 9.9 mmol) in THF (20 mL) was added saturated NaHCO3 (5 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (2.4 g, 90.2%) as a yellow oil. MS(ESI) calculated for C16H22BrNO4S, 403.1; found 404.1, 406.1. [0587] 4-((3r,4r)-1-(tert-Butoxycarbonyl)-4-(ethoxycarbonyl)pyrrolidin-3-yl)thiophene- 3-carboxylic acid (GGG-6): A solution of GGG-5 (2.4 g, 6.0 mmol), Pd(dppf)Cl2 (439.2 mg, 0.6 mmol) and HCOONa (4.1 g, 60.0 mmol) in DMF (30 mL) was stirred at 120oC under CO atmosphere for 24 hours. After cooling to room temperature, the mixture was diluted with water (90 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: MeOH = 10:1) to obtain the desired compound (1.8 g, 81.8%) as a yellow oil. MS(ESI) calculated for C17H23NO6S, 369.1; found 370.1. [0588] 1-(tert-Butyl) 3-ethyl (3r,4r)-4-(4-(((benzyloxy)carbonyl)amino)thiophen-3- yl)pyrrolidine-1,3-dicarboxylate (GGG-7): The solution of GGG-6 (1.8 g, 4.9 mmol), benzyl alcohol (1.6 g, 14.7 mmol), DPPA (2.0 g, 7.4 mmol) and TEA (2.0 g, 19.6 mmol) in toluene (20 mL) was stirred at 110oC for 2 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (1.0 g, 43.3%) as a yellow oil. MS(ESI) calculated for C24H30N2O6S, 474.2; found 475.2. [0589] tert-Butyl (5aR,8aR)-5-oxo-4,5,5a,6,8,8a-hexahydro-7H-pyrrolo[3,4-d]thieno[3,4- b]pyridine-7-carboxylate (GGG-8): To a solution of GGG-7 (120.0 mg, 0.3 mmol) and 10% Pd/C (10.6 mg, 0.1 mmol) in MeOH (6 mL) was stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to purify with column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (50.0 mg, 67.2%) as a yellow oil. MS(ESI) calculated for C14H18N2O3S, 294.1; found 295.1. [0590] (5aR,8aR)-5-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-d]thieno[3,4-b]pyridin- 7-ium chloride (138): To a solution of GGG-8 (50.0 mg, 0.2 mmol) in DCM (2 mL) was added HCl /dioxane (4 M, 2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to purify with prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (9.6 mg, 24.6% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 9.52 (brs, 2H), 7.48 (d, J = 3.1 Hz, 1H), 6.64 (d, J = 3.1 Hz, 1H), 3.74 (dd, J = 17.7, 7.8 Hz, 1H), 3.63 (dd, J = 11.8, 4.0 Hz, 1H), 3.57-3.46 (m, 2H), 2.89-2.81 (m, 1H). MS(ESI) calculated for C9H10N2OS, 194.1; found 195.1. [0591] (1R,9R)‐4‐Thia‐7,11‐diazatricyclo[7.3.0.02,6]dodeca‐2,5‐diene hydrochloride (128): The title compound was synthesized using the same procedure utilized for the synthesis of 128. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (brs, 1H), 9.34 (brs, 1H), 7.49 (s, 1H), 6.93 (brs, 1H), 3.72 – 3.63 (m, 1H), 3.56 (dd, J = 15.6, 7.8 Hz, 1H), 3.49 – 3.29 (m, 2H), 3.17 – 3.01 (m, 3H), 2.84 (s, 1H). MS(ESI) calculated for C9H12N2S, 180.1; found 181.1.
Figure imgf000225_0001
Scheme 61 [0592] N-(2-(Chroman-4-yl)ethyl)formamide (HHH-1): A mixture of formic acid (12.4 g, 270.0 mmol) and acetic anhydride (13.7 g, 135.0 mmol) was stirred at 50oC for 1 hour. After cooling to room temperature, a solution of 2-(chroman-4-yl)ethan-1-amine (6.0 g, 33.8 mmol) in dichloromethane (100 mL) was added to above solution, which was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (500 mL), extracted with dichloromethane (200 mL*2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (3.0 g, 43.3% yield) as a white solid. MS(ESI) calculated for C12H15NO2,205.1; found 206.1. [0593] 3,3a,4,5-Tetrahydro-2H-chromeno[5,4-cd]azepine (HHH-2): Phosphorus oxychloride (1.5 g, 9.7 mmol) was added to PPA (19.7 g, 58.4 mmol) at 60°C under nitrogen atmosphere. After stirring for 1 hour, a solution of HHH-1 (1.0 g, 4.9 mmol) in toluene (50 mL) was added thereto, and the resulting mixture was continued to stir at 70°C for 30 min, and then at 120°C for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice-NaHCO3 solution. The aqueous layer was extracted with EA (200 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to obtain the title compound (80.0 mg, 8.7% yield) as a crude. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.91 (d, J =8.0 Hz, 2H), 4.29-4.24 (m, 1H), 4.05 (td, J = 11.2 Hz, J = 2.0 Hz, 1H), 3.89-3.83 (m, 1H), 3.37-3.30(m, 1H), 2.84-2.76 (m, 1H), 2.56-2.47 (m, 1H), 2.14-2.07 (m, 1H), 2.04-1.96(m, 1H), 1.73-1.69 (m, 1H). MS(ESI) calculated for C12H13NO2, 187.1; found 188.1. [0594] tert-Butyl 2,3,3a,4,5,7-hexahydro-6H-chromeno[5,4-cd]azepine-6-carboxylate (HHH-3): To a solution of HHH-2 (80.0 mg, 0.4 mmol) in methanol (20 mL) was added sodium borohydride (47.0 mg, 1.3 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove methanol. The residue was re- dissolved in THF (20 mL), and then sodium bicarbonate (107.0 mg, 1.3 mmol) and di-tert- butyl pyrocarbonate (186.0 mg, 0.9 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 2:1) to obtain the desired compound (50.0 mg, 43.5% yield) as a white solid. MS(ESI) calculated for C17H23NO3, 289.2; found 290.2. [0595] 3,3a,4,5,6,7-Hexahydro-2H-chromeno[5,4-cd]azepin-6-ium chloride (84): A mixture of HHH-3 (50.0 mg, 0.2 mmol) in HCl/dioxane (4 M, 2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to purify with prep-HPLC to obtain the desired compound (12.6 mg, 32.3% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.13 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 4.26 (d, J = 7.2 Hz, 1H), 4.12-4.04 (m, 2H), 3.56-3.51 (m, 1H),3.45-3.38 (m, 1H), 3.28-3.24 (m, 1H), 2.30-2.22 (m, 1H), 2.05-2.01 (m, 1H), 1.95-1.85 (m, 2H). MS(ESI) calculated for C12H15NO, 189.1; found 190.2.
Figure imgf000226_0001
Scheme 62 [0596] 4-Methylenechromane (III-1): To a solution of LiHMDS (40.4 mL, 40.4 mmol, 1.0 M) was added methyltriphenylphosphanium bromide (14.4 g, 40.4 mmol) at 0°C under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. A solution of chroman-4-one (5.0 g, 33.7 mmol) in THF (10 mL) was slowly added thereto at -5°C. The resulting mixture was continued to stir at room temperature for 1 hour. The reaction was then quenched with saturated NH4Cl at 0°C and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (2.5 g, 50.8% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.9, 1.6 Hz, 1H), 7.20 – 7.11 (m, 1H), 6.93 – 6.79 (m, 2H), 5.51 (s, 1H), 4.93 – 4.82 (m, 1H), 4.29 – 4.18 (m, 2H), 2.76 – 2.59 (m, 2H). [0597] Chroman-4-ylmethanol (III-2): To a solution of III-1 (2.5 g, 17.1 mmol) in dry THF (20 mL) was added BH3-THF (1 M, 51.3 mL) dropwise at 0°C under nitrogen atmosphere. The reaction was stirred at 0°C for 1 hour and then at room temperature for 2 hours. Aqueous NaOH (3 N, 28.5 mL) was added thereto, followed by H2O2 (10.5 mL,30% in water). The mixture was continued to stir at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 80:20) to obtain the desired compound (2.1 g, 75.0% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.21 – 7.05 (m, 2H), 6.94 – 6.77 (m, 2H), 4.23 – 4.16 (m, 2H), 3.94 – 3.84 (m, 1H), 3.84 – 3.73 (m, 1H), 3.07 – 2.91 (m, 1H), 2.18 – 2.06 (m, 2H). [0598] N-(Chroman-4-ylmethyl)-N-(2,2-dimethoxyethyl)-1,1,1- trifluoromethanesulfonamide (III-3): To the solution of III-2 (0.9 g, 5.5 mmol), N-(2,2- dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (1.6 g, 6.6 mmol) and PPh3 (2.9 g, 10.9 mmol) in dry THF (20 mL) was added DEAD (1.8 g, 10.9 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 88:12) to obtain the desired compound (1.4 g, 66.6% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.19 – 7.10 (m, 1H), 7.09 – 7.00 (m, 1H), 6.93 – 6.78 (m, 2H), 4.59 – 4.43 (m, 2H), 4.31 – 4.18 (m, 1H), 4.17 – 4.06 (m, 1H), 3.82 – 3.68 (m, 1H), 3.66 – 3.56 (m, 1H), 3.56 – 3.51 (m, 2H), 3.48 (s, 3H), 3.46 (s, 3H), 3.34 – 3.22 (m, 1H), 2.09 – 1.98 (m, 2H). [0599] 5-((Trifluoromethyl)sulfonyl)-3,3a,4,5-tetrahydro-2H-chromeno[4,5-cd]azepine (III-4): Phosphorus oxychloride (0.7 mL, 7.3 mmol) was added to a solution of PPA (1 mL) in toluene (40 mL) at 60°C under nitrogen atmosphere. After stirring for 15 min, a solution of III-3 (1.4 g, 3.7 mmol) in toluene (5 mL) was added thereto, and the resulting mixture was continued to stir at 120°C for 16 hours. The reaction mixture was cooled to room temperature and poured into ice-NaHCO3 solution; the aqueous layer was extracted with EA (50 mL*2). The combined organic layers were washed with water (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 97:3) to obtain the title compound (150.0 mg, 12.9% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.15 – 7.07 (m, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 10.4 Hz, 1H), 5.84 (d, J = 10.4 Hz, 1H), 4.40 – 4.26 (m, 2H), 4.14 – 4.05 (m, 1H), 3.37 – 3.30 (m, 1H), 3.17 – 3.05 (m, 1H), 2.28 – 2.19 (m, 1H), 1.99 – 1.88 (m, 1H). [0600] 5-((Trifluoromethyl)sulfonyl)-3,3a,4,5,6,7-hexahydro-2H-chromeno[4,5- cd]azepine (III-5): A solution of III-4 (0.1 g, 0.3 mmol) and 10% Pd/C (16.6 mg) in methanol (14 mL) was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to get the crude compound (100 mg) without further purification. [0601] 3,3a,4,5,6,7-Hexahydro-2H-chromeno[4,5-cd]azepin-5-ium chloride (85): To a solution of III-5 (0.1 g, 0.3 mmol) in dry THF (6 mL) was added LiAlH4 (47.0 mg, 1.2 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture reaction was refluxed for 1 hour. After cooling to room temperature, the reaction was quenched with sodium sulfate. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify with prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (25.0 mg, 42.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (brs, 1H), 9.36 (brs, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.85 – 6.64 (m, 2H), 4.08 – 4.00 (m, 2H), 3.59 – 3.39 (m, 2H), 3.35 – 3.18 (m, 2H), 3.03 – 2.85 (m, 2H), 2.82 – 2.69 (m, 1H), 2.23 – 2.02 (m, 1H), 1.93 – 1.74 (m, 1H). MS(ESI) calculated for C12H15NO, 189.1; found 190.1.
Figure imgf000229_0001
Scheme 63 [0602] 2-((2-Iodophenoxy)methyl)oxirane (JJJ-1): To a solution of 2-iodophenol (20.0 g, 90.9 mmol) and NaOH (5.1 g, 126.6 mmol) in H2O (70 mL) was added 2- (chloromethyl)oxirane (25.1 g, 272.4 mmol). The reaction mixture was stirred at 50°C for 1.5 hours. The reaction was quenched with H2O (100 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether :ethyl acetate = 78:22) to obtain the title product (9.6 g, 38.4 % yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 7.8, 1.6 Hz, 1H), 7.29 (m, J = 8.3, 7.5, 1.6 Hz, 1H), 6.84 (dd, J = 8.2, 1.2 Hz, 1H), 6.73 (m, J = 7.6, 1.3 Hz, 1H), 4.29 (dd, J = 11.2, 3.0 Hz, 1H), 4.06 (dd, J = 11.2, 5.0 Hz, 1H), 3.43 – 3.36 (m, 1H), 2.96 – 2.86 (m, 2H). [0603] (2,3-Dihydrobenzofuran-3-yl)methanol (JJJ-2): To a solution of JJJ-1 (8.8 g, 31.8 mmol) in tetrahydrofuran (100 mL ) was added n-BuLi (2.5 M in hexane, 15.3 mL) at -78°C. The mixture was stirred at -78°C for 2 hours. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify with column chromatography (eluted with Petroleum ether: ethyl acetate = 78:22) to obtain the title product (3.1 g, 63.8% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 7.4 Hz, 1H), 7.16 (m, J = 8.0, 1.9, 1.3 Hz, 1H), 6.87 (m ^J = 7.4, 0.9 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.64 (t, J = 9.1 Hz, 1H), 4.48 (dd, J = 9.1, 5.4 Hz, 1H), 3.87 – 3.77 (m, 2H), 3.68 – 3.61 (m, 1H). [0604] N-((2,3-Dihydrobenzofuran-3-yl)methyl)-N-(2,2-dimethoxyethyl)-1,1,1- trifluoromethanesulfonamide (JJJ-3): To a solution of JJJ-2 (2.0 g, 13.3 mmol), N-(2,2- dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (3.8 g, 15.9 mmol) and triphenylphosphine (10.4 g, 40.0 mmol) in tetrahydrofuran (100 mL) was added DEAD (7.0 g, 40.0 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to purify with column chromatography (eluted with petroleum ether: ethyl acetate = 90:10) to obtain the title product (1.7 g, 34.6% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.20-7.14 (m, 2H), 6.88 (td, J = 7.5, 0.8 Hz, 1H), 6.83 (m, 1H), 4.54 (m, 3H), 3.93 – 3.81 (m, 1H), 3.70 – 3.50 (m, 3H), 3.45 (s, 3H), 3.44 (s, 3H), 3.42-3.37 (m, 1H). [0605] 8-((Trifluoromethyl)sulfonyl)-1,8,9,9a-tetrahydrobenzofuro[3,4-cd]azepine (JJJ- 4): Phosphorus oxychloride (0.7 mL, 7.3 mmol) was added to a solution of PPA (1 mL) in toluene (40 mL) at 60°C under nitrogen atmosphere. After stirring for 15 min, a solution of JJJ-3 (1.2 g, 3.3 mmol) in toluene (5 mL) was added thereto and the resulting mixture was continued to stir at 120°C for 16 hours. The reaction mixture was cooled to room and poured into ice-NaHCO3 solution, and the aqueous layer was extracted with EA (50 mL*2). The combined organic layers were washed with water (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 30:1) to obtain the title compound (160.0 mg, 16.1% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.15 (t, J = 7.6 Hz, 1H), 6.78-6.71 (m, 2H), 6.62 (d, J = 10.3 Hz, 1H), 5.88 (d, J = 10.3 Hz, 1H), 4.88 (t, J = 9.4 Hz, 1H), 4.51 (d, J = 13.2 Hz, 1H), 4.07 (dd, J = 11.0, 9.2 Hz, 1H), 3.79 (dd, J = 19.1, 9.5 Hz, 1H), 3.30 (dd, J = 13.2, 9.8 Hz, 1H). [0606] 8-((Trifluoromethyl)sulfonyl)-1,6,7,8,9,9a-hexahydrobenzofuro[3,4-cd]azepine (JJJ-5): The solution of JJJ-4 (160.0 mg, 0.5 mmol) and 10 % Pd/C (16.0 mg) in MeOH (10 mL) was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to get the crude compound (160.0 mg) without further purification. MS(ESI) calculated for C12H10F3NO3S, 305.0; found 306.0. [0607] 1,6,7,8,9,9a-Hexahydrobenzofuro[3,4-cd]azepin-8-ium chloride (10): To the solution JJJ-5 (160.0 mg, 0.5 mmol) in dry THF (6 mL) was added LiAlH4 (47.0 mg, 1.2 mmol) at 0°C under nitrogen atmosphere. The reaction was refluxed for 1 hour. After cooling to 0°C, the reaction was quenched with sodium sulfate. The resulting mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (30.0 mg, 27.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (brs, 2H), 7.06 (t, J = 7.8 Hz, 1H), 6.72-6.65 (m, 2H), 4.77 (t, J = 8.8 Hz, 1H), 4.21 – 3.96 (m, 2H), 3.59 (dd, J = 13.7, 3.5 Hz, 1H), 3.50 (dd, J = 12.7, 3.3 Hz, 1H), 3.37 (s, 1H), 3.30 (s, 1H), 3.04 – 2.78 (m, 3H). MS(ESI) calculated for C12H15NO, 175.1; found 176.1.
Figure imgf000231_0001
Scheme 64 [0608] Methyl (E)-3-((4-bromobut-2-en-1-yl)oxy)benzoate (KKK-1): The solution of methyl 3-hydroxybenzoate (10.0 g, 65.8 mmol), (E)-1,4-dibromobut-2-ene (27.9 g, 131.6 mmol) and K2CO3 (20.0 g, 144.8 mmol) in acetone (300 mL) was stirred at 55oC for 16 hours. After cooling to room temperature, the mixture was diluted with water (100 mL), extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (10.0 g, 53.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.63 (m, 1H), 7.55 (dd, J = 2.5, 1.5 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.12-7.09 (m, 1H), 6.14 – 6.06 (m, 1H), 6.03 – 5.96 (m, 1H), 4.63 – 4.58 (m, 2H), 4.00 (dd, J = 7.2, 0.7 Hz, 2H), 3.92 (s, 3H). MS(ESI) calculated for C12H13BrO3, 284.0; found 285.0. [0609] (E)-3-((4-Hydroxybut-2-en-1-yl)oxy)benzoic acid (KKK-2): The solution of KKK- 1 (5.0 g, 17.6 mmol) and NaOH (3 N, 12 mL, 35.2 mmol) in THF (50 mL) was stirred at 70oC for 16 hours. After cooling to room temperature, the mixture was adjusted to pH~2 with HCl (2 M), and continued to stir at room temperature for 1 hour. The resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: MeOH = 10:1) to obtain the desired compound (3.2 g, 86.5% yield) as a yellow oil. MS(ESI) calculated for C11H12O4, 208.1; found 209.1. [0610] (E)-3-((4-Hydroxybut-2-en-1-yl)oxy)-N-methoxybenzamide (KKK-3): The solution of KKK-2 (3.2 g, 15.4 mmol), methoxyammonium chloride (1.9 g, 23.1 mmol), DIPEA (8.0 g, 61.6 mmol) and HATU (7.0 g, 18.5 mmol) in DCM (30 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (3.0 g, 82.2% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 12.96 (brs, 1H), 7.53 (dd, J = 7.6, 1.1 Hz, 1H), 7.45 (dd, J = 2.3, 1.5 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.23 – 7.17 (m, 1H), 6.01 – 5.78 (m, 2H), 4.81 (s, 1H), 4.61 (dd, J = 5.5, 1.0 Hz, 2H), 4.01 – 3.95 (m, 2H). MS(ESI) calculated for C12H15NO4, 237.1; found 238.1. [0611] 3-Hydroxy-3,4,4a,5-tetrahydrobenzofuro[4,3-cd]azepin-1(2H)-one (KKK-4): To a solution of KKK-3 (0.7 g, 3.0 mmol), [Cp*RhCl2]2 (61.8 mg, 0.1 mmol) and CsOAc (1.2 g, 6.0 mmol) in t-AmOH (10 mL) was stirred at room temperature under nitrogen for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify with column chromatography (eluted with petroleum ether: ethyl acetate = 1:3) to obtain the desired compound (0.4 g, 65.6% yield) as a yellow oil. MS(ESI) calculated for C11H11NO3, 205.1; found 206.1. [0612] 4a,5-Dihydrobenzofuro[4,3-cd]azepin-1(2H)-one (KKK-5): To a solution of KKK- 4 (0.4 g, 2.0 mmol) in DCM (4 mL) was added TFA (0.9 mL, 12.0 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (10 mL) and extracted with DCM (30 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (196.0 mg, 53.7% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 7.9, 0.8 Hz, 1H), 7.24 (dd, J = 7.9, 0.7 Hz, 1H), 7.05 (s, 1H), 6.99 (dd, J = 7.9, 0.6 Hz, 1H), 6.00-5.97 (m, 1H), 5.09 (dd, J = 8.3, 1.9 Hz, 1H), 4.92 (dd, J = 10.1, 8.6 Hz, 1H), 4.58-4.51 (m, 1H), 4.42 – 4.34 (m, 1H). MS(ESI) calculated for C11H9NO2, 187.1; found 188.1. [0613] 3,4,4a,5-Tetrahydrobenzofuro[4,3-cd]azepin-1(2H)-one (KKK-6): A solution of KKK-5 (196.0 mg, 1.0 mmol) and 10% Pd/C (53.0 mg, 0.5 mmol) in MeOH (6 mL) was stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify with column chromatography (eluted with petroleum ether: ethyl acetate = 1:3) to obtain the desired compound (200.0 mg, 99.0% yield) as a yellow oil. MS(ESI) calculated for C11H11NO2, 189.1; found 190.1. [0614] 1,2,3,4,4a,5-Hexahydrobenzofuro[4,3-cd]azepin-2-ium chloride (11): To a solution of KKK-6 (100.0 mg, 0.5 mmol) in THF (5 mL) was added LiAlH4 (57.0 mg, 1.5 mmol) at 0°C, and the resulting mixture was stirred at 66o C for 3 hours. After cooling to room temperature, the reaction was quenched by sodium sulfate. The resulting mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (32.4 mg, 29.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (brs, 1H), 8.79 (brs, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.82 (t, J = 9.4 Hz, 1H), 4.39 – 4.20 (m, 2H), 4.08 (t, J = 9.2 Hz, 1H), 3.94 – 3.75 (m, 1H), 3.57 (d, J = 12.9 Hz, 1H), 3.27 (dd, J = 23.9, 12.2 Hz, 1H), 2.09 (d, J = 13.8 Hz, 1H), 1.83-1.73 (m, 1H). MS(ESI) calculated for C11H13NO, 175.1; found 176.1.
Figure imgf000233_0001
Scheme 65 [0615] 3,4-Dichlorobenzyl carbamimidothioate hydrochloride: A mixture of 1,2-dichloro- 4-(chloromethyl)benzene (4 g, 20.4 mmol) and thiourea (1.6 g, 20.4 mmol) in ethyl alcohol (30 mL ) was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated to obtain the title compound (5.4 g, 68.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (brs, 4H), 7.76 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 8.3, 2.1 Hz, 1H), 4.56 (s, 2H). [0616] (3,4-Dichlorophenyl)methanesulfonyl chloride: To a solution of NCS (11.3 g, 84.8 mmol) and HCl (2 M, 6 mL) in acetonitrile (30 mL) was added 3,4-dichlorobenzyl carbamimidothioate hydrochloride (5.0 g, 21.2 mmol) in acetonitrile (20 mL) dropwise at 0°C. The reaction was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, then water (40 mL) was added to the residue and stirred for 20 min. The resulting solid was collected by filtration and dried under an infrared lamp to afford the title compound (4 g, 74% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.34 (dd, J = 8.3, 2.0 Hz, 1H), 4.80 (s, 2H). [0617] 1-((allyloxy)methyl)-2-iodobenzene (LLL-1): To a solution of (2- iodophenyl)methanol (40 g, 170.9 mmol) in tetrahydrofuran (500 mL ) was added sodium hydride ( 8.1 g, 204.0 mmol, 60%wt) at 0°C, and the mixture was stirred at 0°C for 30 min. 3-Bromoprop-1-ene (24.6 g, 204.0 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours. The reaction was quenched with water (300 mL) and extracted with ethyl acetate (500 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to obtain the title product (46 g, 98.9% yield) as a yellow oil that was suitable for use without further purification. 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.9, 1.1 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.36 (dd, J = 7.5, 1.0 Hz, 1H), 6.98 (m, 1H), 5.99 (m, 1H), 5.36 (m, 1H), 5.23 (m, 1H), 4.50 (s, 2H), 4.11 (m, 2H). [0618] 4-Methyleneisochromane (LLL-2): A mixture of LLL-1 (45.0 g, 164.2 mmol), palladium diacetate (1.84 g, 8.2 mmol), triethylamine (82.9 g, 821.1 mmol) and triphenylphosphine (4.3 g, 16.4 mmol) in acetonitrile (200 mL) was stirred at 80°C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate=4:1) to obtain the title product (11.5 g, 48.1% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.64 (m, 1H), 7.26 – 7.21 (m, 2H), 7.07 – 6.98 (m, 1H), 5.61 (s, 1H), 5.01 (t, J = 1.2 Hz, 1H), 4.81 (s, 2H), 4.45 (t, J = 1.2 Hz, 2H). [0619] Isochroman-4-one (LLL-3): To a solution LLL-2 (11.5 g, 78.6 mmol) in dioxane (80 mL) and water (80 mL) was added sodium periodate (50.4 g, 235.8 mmol) at 0°C, and the mixture was stirred at 0°C for 30 min. Then, K2OsO4.2H2O (1.5 g, 3.9 mmol) was added to the above mixture, which was continued to stir at room temperature for 16 hours. The reaction was poured into water (1000 mL) and extracted with ethyl acetate (1000 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to obtain the title product (10 g ,86.2%) as a colorless oil without further purification. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.6 Hz, 1H), 7.60-7.56 (m, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 4.90 (s, 2H), 4.38 (s, 2H). [0620] 2-(Isochroman-4-ylidene)acetonitrile (LLL-4): To a solution of diethyl (cyanomethyl)phosphonate (23.9 g, 135.0 mmol) in tetrahydrofuran (300 mL) was added sodium hydride (5.4 g, 135.0 mmol, 60%wt) at 0°C. The reaction was stirred at 0°C for 30 min. A solution of LLL-3 (6.7 g, 45.2 mmol) in THF (20 mL) was added dropwise to above solution, which was then stirred at room temperature for 16 hours. After which period, the reaction mixture was poured into H2O (100 mL), extracted with ethyl acetate (100 mL* 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate= 90:10) to give the product (5.3 g, 68.8% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.57 – 8.50 (m, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.47 – 7.36 (m, 2H), 7.33 (dd, J = 11.3, 4.6 Hz, 1H), 7.14 (d, J = 8.2 Hz, 2H), 5.81 (t, J = 1.6 Hz, 1H), 5.28 (t, J = 1.3 Hz, 1H), 4.84 (s, 1H), 4.82 – 4.78 (m, 4H), 4.47 (d, J = 1.3 Hz, 1H). [0621] 2-(Isochroman-4-yl)acetonitrile (LLL-5): To a solution of LLL-4 (5.1 g, 29.7 mmol) in methanol (40 mL) was added 10% Pd/C (1.5 g,), and the reaction was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the crude product (4.1 g, 80.3% yield) as a colorless oil for the next step without further purification. [0622] 2-(Isochroman-4-yl)ethan-1-amine (LLL-6): To a solution of LLL-5 (4.1 g, 23.6 mmol) in NH3/methanol (7 N, 30 mL) was added Raney Ni (500 mg), and the reaction was stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the crude product (3.6 g, 87.8% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.22 – 7.13 (m, 3H), 6.98 (d, J = 6.5 Hz, 1H), 4.78 (q, J = 15.0 Hz, 2H), 3.97-3.86 (m, 2H), 3.16 – 2.63 (m, 3H), 2.10 – 1.78 (m, 2H). [0623] 1-(3,4-Dichlorophenyl)-N-(2-(isochroman-4-yl)ethyl)methanesulfonamide (LLL- 7): To the solution of LLL-6 (1 g, 5.6 mmol) and DIPEA (1.1 g, 8.5 mmol) in DCM (20 mL) was added (3,4-dichlorophenyl)methanesulfonyl chloride (2.2 g, 8.5 mmol) in DCM (10 mL) dropwise. The reaction was stirred at 0°C for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with DCM (100 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate=80:20) to obtain the title product (1.2 g, 54.5% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 8.1, 5.1 Hz, 2H), 7.24 – 7.16 (m, 3H), 7.12 – 7.06 (m, 1H), 7.02 – 6.95 (m, 1H), 4.97 (dd, J = 6.3, 5.9 Hz, 1H), 4.71 (s, 2H), 4.13 (d, J = 1.7 Hz, 2H), 3.99 (dd, J = 11.8, 1.6 Hz, 1H), 3.83 (dd, J = 11.8, 3.7 Hz, 1H), 3.04 (m, 1H), 2.92 (dd, J = 17.5, 9.3 Hz, 1H), 2.82 (d, J = 4.7 Hz, 1H), 2.04 – 1.86 (m, 2H). [0624] 6-((3,4-Dichlorobenzyl)sulfonyl)-3,3a,4,5,6,7-hexahydro-1H-isochromeno[5,4- cd]azepine (LLL-8): To the solution of LLL-7 (1.2 g, 3.0 mmol), 1,3,5-trioxane (672.5 mg, 7.5 mmol) and acetic anhydride (305.2 mg, 3.0 mmol) in ethylene dichloride (20 mL) was added methanesulfonic acid (1.8 g, 18.8 mmol). The reaction was stirred at 20°C for 3.5 hours. After which period, the mixture was poured into water (100 mL), extracted with DCM (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=7:3) to obtain the title product (400 mg, 33.3% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.2 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 6.8 Hz, 1H), 7.05 – 6.98 (m, 2H), 6.94 (d, J = 1.9 Hz, 1H), 4.72 (dd, J = 17.3, 9.6 Hz, 2H), 4.60 (d, J = 15.4 Hz, 1H), 4.27 (d, J = 15.4 Hz, 1H), 4.01 (dd, J = 11.6, 5.3 Hz, 1H), 3.89 (s, 2H), 3.87 – 3.81 (m, 1H), 3.66 (dd, J = 11.7, 5.3 Hz, 1H), 3.31 (m, 1H), 3.08 – 2.98 (m, 1H), 1.65 – 1.60 (m, 1H), 1.36 – 1.28 (m, 1H). [0625] 3,3a,4,5,6,7-Hexahydro-1H-isochromeno[5,4-cd]azepin-6-ium chloride (86): To a solution of LLL-8 (300 mg, 0.7 mmol) in tetrahydrofuran (20 mL) was added LiAlH4 (110.1 mg, 2.9 mmol) at 0°C, and the reaction was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction was quenched with sodium sulfate. The resulting mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (25.5 mg, 18.7% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.29 –7.22 (m, 2H), 7.14 (d, J = 7.3 Hz, 1H), 4.73 (s, 2H), 4.46 (d, J = 14.2 Hz, 1H), 4.30 (d, J = 14.2 Hz, 1H), 4.09 (dd, J = 11.8, 5.4 Hz, 1H), 3.78 (dd, J = 11.8, 5.1 Hz, 1H), 3.55 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H), 2.05 – 1.96 (m, 1H), 1.96 – 1.83 (m, 1H). MS(ESI) calculated for C12H15NO, 189.1; found 190.2. Procedure for Compound 88 1-(2-Aminoethyl)-5-bromoisochroman-8-ol (1)
Figure imgf000237_0001
[0626] To the solution of 4-bromo-3-(2-hydroxyethyl)phenol (11.0 g, 50.6 mmol) and 3,3- dimethoxypropan-1-amine (9.0 g, 75.8 mmol) in DCM (50 mL) was added trifluoromethanesulfonic acid (13.3 mL, 151.0 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 hours and then quenched by saturated aqueous NaHCO3. After removing the organic solvent in vacuo, the residue was used for the next step without further purification. [0627] MS(ESI) calculated for C11H14BrNO2: 271.0; found 272.0, 274.0 tert-Butyl (2-(5-bromo-8-hydroxyisochroman-1-yl)ethyl)carbamate (2)
Figure imgf000237_0002
[0628] To a solution of 1 (13.0 g, 47.7 mmol) in H2O (40 mL) and THF (40 mL) were added sodium carbonate (15.1 g, 143.0 mmol) and Boc2O (20.8 g, 95.4 mmol). The resulting mixture was stirred for at room temperature for 1 hour. The mixture was then filtered through a pad of celite, and the filtrate was extracted with ethyl acetate (80 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 9:1) to obtain the desired compound (15.0 g, 84.7% yield) as a yellow solid. [0629] 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.22 (m, 1H), 6.69 – 6.44 (m, 1H), 5.23 (s, 1H), 5.02 – 4.77 (m, 1H), 4.08 – 3.92 (m, 1H), 3.87 – 3.71 (m, 1H), 3.36 – 3.21 (m, 2H), 2.82 – 2.65 (m, 2H), 2.30 – 2.13 (m, 1H), 2.04 – 1.96 (m, 1H), 1.45 (s, 9H). [0630] MS(ESI) calculated for C16H22BrNO4: 371.1; found 272.1, 274.0 tert-Butyl (2-(8-hydroxyisochroman-1-yl)ethyl)carbamate (3)
Figure imgf000238_0001
[0631] To a solution of 2 (7.3 g, 19.7 mmol) and triethylamine (1.2 g, 11.8 mmol) in methanol (14 mL) was added 10% Pd/C (0.7 g). The resulting mixture was stirred under hydrogen atmosphere at room temperature for 6 hours. The mixture was then filtered through a pad of celite and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate= 4:1) to get the title compound (5.0 g, 86.6% yield) as a yellow solid. [0632] 1H NMR (400 MHz, CDCl3) δ 7.01 (t, J = 7.8 Hz, 1H), 6.69 – 6.59 (m, 2H), 5.14 (brs, 1H), 4.99 (d, J = 6.8 Hz, 1H), 4.06 – 3.96 (m, 1H), 3.83 – 3.66 (m, 1H), 3.32 – 3.20 (m, 2H), 2.78 (t, J = 5.4 Hz, 2H), 2.30 – 2.10 (m, 1H), 2.07 – 1.96 (m, 1H), 1.45 (s, 9H). 1-(2-((tert-Butoxycarbonyl)amino)ethyl)isochroman-8-yl trifluoromethanesulfonate (4)
Figure imgf000238_0002
[0633] To a solution of 3 (5.0 g, 17.1 mmol) and pyridine (13.5 g, 171 mmol) in DCM (40 mL) was added trifluoromethanesulfonic anhydride (5.7 mL, 34.2 mmol) at 0°C. After stirring at 0°C for 3 hours, the reaction mixture was poured into ice water (50 mL) and the phases were separated. The organic layer was washed with HCl (1 M) and brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the title compound (4.0 g, 55.0% yield) as a yellow solid. [0634] 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.22 (m, 2H), 7.18 – 7.09 (m, 2H), 5.11 – 4.99 (m, 1H), 4.87 (brs, 1H), 4.12 – 3.99 (m, 1H), 3.87 – 3.75 (m, 1H), 3.32 – 3.26 (m, 1H), 2.86 (t, J = 5.4 Hz, 2H), 2.12 – 1.97 (m, 2H), 1.44 (s, 9H). Methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)isochromane-8-carboxylate (5)
Figure imgf000239_0001
[0635] To a solution of 4 (2.0 g, 4.7 mmol) and triethylamine (1.0 g, 9.4 mmol) in DMF/MeOH (28 mL, 3:1) was added Pd(OAc)2 (77.7 mg, 0.5 mmol) and [3- (diphenylphosphanyl)propyl]diphenylphosphane (0.2 g, 0.5 mmol) under CO atmosphere. The reaction mixture was stirred at 75°C for 16 hours. After cooling to room temperature, the mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 4:1) to obtain the title compound (1.4 g, 88.9% yield) as a yellow oil. [0636] 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.74 (m, 1H), 7.26 – 7.10 (m, 2H), 5.70 – 5.63 (m, 1H), 5.12 – 4.93 (m, 1H), 4.12 – 4.01 (m, 2H), 3.88 (s, 3H), 3.84 – 3.78 (m, 1H), 3.39 – 3.24 (m, 3H), 2.99 – 2.77 (m, 3H), 1.99 – 1.87 (m, 1H), 1.85 – 1.73 (m, 1H), 1.45 (s, 9H). Methyl 1-(2-aminoethyl)isochromane-8-carboxylate (6)
Figure imgf000239_0002
[0637] To a solution of 5 (1.4 g, 4.2 mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 10 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated to get the crude product, which was used for the next step without further purification. [0638] MS(ESI) calculated for C13H17NO3: 235.1; found 236.1 2,3,8,9,10,10a-Hexahydro-7H-isochromeno[8,1-cd]azepin-7-one (7)
Figure imgf000240_0001
[0639] To a solution of 6 (1.2 g, 5.1 mmol) in dry THF (16 mL) was added trimethylaluminum (2 M, 25.4 mL) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction was quenched with cold HCl (1 M). The phases were separated, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain the desired compound (0.6 g, 58.2% yield) as a white solid. [0640] 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.55 (m, 1H), 7.52 – 7.42 (m, 1H), 7.30 – 7.27 (m, 1H), 5.22 – 5.04 (m, 1H), 4.07 – 3.91 (m, 1H), 3.86 – 3.76 (m, 1H), 3.34 – 3.23 (m, 1H), 3.21 – 3.06 (m, 1H), 3.00 – 2.77 (m, 2H), 2.68 – 2.41 (m, 1H), 2.03 – 1.88 (m, 1H).^ 8-Chloro-3,7,8,9,10,10a-hexahydro-2H-8l5-isochromeno[8,1-cd]azepine (88)
Figure imgf000240_0002
[0641] To a solution of 7 (0.1 g, 0.5 mmol) in dry THF (6 mL) was added LiAlH4 (55.7 mg, 1.5 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was refluxed for 3 hours. After cooling to 0°C, the reaction was quenched with sodium sulfate decahydrate and filtered through a pad of celite. The filtrate was concentrated to dryness; the residue was purified by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (16.8 mg, 17.7% yield) as a white solid. [0642] 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.71 (s, 1H), 7.31 – 7.24 (m, 1H), 7.23 – 7.16 (m, 2H), 5.08 (d, J = 9.8 Hz, 1H), 4.25 – 4.14 (m, 2H), 4.03 – 3.93 (m, 1H), 3.73 – 3.60 (m, 1H), 3.39 (s, 2H), 2.93 – 2.79 (m, 1H), 2.74 – 2.63 (m, 1H), 2.15 – 2.05 (m, 1H), 2.03 – 1.87 (m, 1H). [0643] MS(ESI) calculated for C12H15NO: 189.1; found 190.2 Procedure for Compound 72
Figure imgf000241_0001
General procedure A: 1-(tert-Butyl) 3-ethyl 4-(2-methoxyphenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (1)
Figure imgf000241_0002
[0644] A mixture of 1-bromo-2-methoxybenzene (1.0 g, 5.3 mmol), 1-tert-butyl 3-ethyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,5,6-tetrahydropyridine-1,3-dicarboxylate (4.0 g, 10.6 mmol), palladium(II) acetate (119.0 mg, 0.5 mmol), 2-Dicyclohexylphosphino- 2',6'-dimethoxy-1,1'-biphenyl (435 mg, 1.06 mmol) and potassium carbonate (1.5 g, 10.6 mmol) in dioxane (80 mL) and water (10 mL) was stirred at 80°C for 3 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography(eluted with petroleum ether: ethyl acetate=5:1) to obtain the desired compound (2.1 g, crude). [0645] 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.22 (m, 1H), 7.00 – 6.85 (m, 3H), 4.36 – 4.03 (m, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.66 – 3.39 (m, 2H), 2.54 – 2.28 (m, 2H), 1.51 (s, 9H), 1.36 – 1.32 (m, 3H). 1-(tert-Butyl) 3-ethyl 4-(2-methoxyphenyl)piperidine-1,3-dicarboxylate (2)
Figure imgf000242_0001
[0646] To a solution of 1 (2.0 g, 5.5 mmol) in MeOH (200 mL) was added magnesium (401.0 mg, 16.5 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered; the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=5:1) to obtain the desired compound (0.9 g, 46.3% yield, over two steps) as a white solid. [0647] MS(ESI) calculated for C20H29NO5, 363.2; found 308.1 tert-Butyl (3S,4S)-3-(hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate (3a) and tert-Butyl (3S,4R)-3-(hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate (3b)
Figure imgf000242_0002
[0648] To a solution of 2 (0.9 g, 2.5 mmol) in THF (15 mL) was added borane-THF complex (7.4 mL, 7.4 mmol) at 0°C, and the resulting mixture was stirred at 55°C for 12 hours. After cooling to room temperature, the reaction was quenched with methanol. The mixture was concentrated and purified by column chromatography to obtain tert-butyl (3S,4S)-3- (hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate (3a) (310.0 mg, 37.7% yield).1H NMR (400 MHz, CDCl3) δ 7.25 – 7.16 (m, 1H), 7.03 – 6.97 (m, 1H), 6.96 – 6.83 (m, 2H), 4.41 – 4.22 (m, 2H), 3.82 (s, 3H), 3.51 – 3.35 (m, 2H), 3.19 – 3.06 (m, 1H), 3.04 – 2.84 (m, 2H), 2.39 – 2.25 (m, 1H), 2.13 – 1.96 (m, 1H), 1.54 – 1.51 (m, 1H), 1.50 (s, 9H) and tert-butyl (3S,4R)-3-(hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate (100.0 mg, 12.6% yield). 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.15 (m, 2H), 7.02 – 6.94 (m, 1H), 6.93 – 6.87 (m, 1H), 4.32 – 4.18 (m, 2H), 3.86 (s, 3H), 3.38 – 3.22 (m, 2H), 3.21 – 3.06 (m, 1H), 2.96 – 2.74 (m, 2H), 1.79 – 1.58 (m, 3H), 1.49 (s, 9H). 2-((3S,4S)-3-(Hydroxymethyl)piperidin-4-yl)phenol (4)
Figure imgf000243_0001
[0649] To a solution of 3a (310.0 mg, 1.5 mmol) in DCM (5 mL) was added BBr3 (1 M, 2 mL) dropwise at 0°C, and the resulting mixture was stirred at 0°C for 2 hours. The reaction was quenched with methanol. The mixture was concentrated to obtain the title compound (250 mg, crude) for the next step without further purification. [0650] MS(ESI) calculated for C12H17NO2, 207.1; found 208.2 tert-Butyl (3S,4S)-3-(hydroxymethyl)-4-(2-hydroxyphenyl)piperidine-1-carboxylate (5)
Figure imgf000243_0002
[0651] A mixture of 4 (250.0 mg, crude) and di-tert-butyl dicarbonate (261.0 mg, 1.2 mmol) in saturated sodium bicarbonate (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain the desired compound (370.0 mg, 43.0 % yield, over two steps) as a white solid. [0652] MS(ESI) calculated for C17H25NO4: 307.2; found 308.3 tert-Butyl (4aS,10bS)-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (6)
Figure imgf000243_0003
[0653] Diethyl azodicarboxylate (625.0 mg, 3.6 mmol) was added dropwise to a solution of 5 (370.0 mg, 1.2 mmol) and triphenylphosphine (941.0 mg, 3.6 mmol) in THF (15 mL) at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated and purified by column chromatography (eluted with petroleum ether: ethyl acetate=1:1) to obtain the title compound (190.0 mg, 54.5% yield). [0654] MS(ESI) calculated for C17H23NO3: 289.2; found 290.3 (2S,7S)‐9‐Oxa‐5‐azatricyclo[8.4.0.02,7]tetradeca‐1(10),11,13‐triene hydrochloride (72)
Figure imgf000244_0001
[0655] To a solution of 6 (190.0 mg, 0.7 mmol) in MeOH (5 mL) was added HCl/dioxane (5 mL, 2M). After stirring at room temperature for 2 hours, the mixture was concentrated to dryness. The residue was slurried with ethyl acetate to obtain the desired compound (120.0 mg, 80.9% yield) as a white solid. [0656] 1H NMR (400 MHz, CDCl3) δ 9.89 (brs, 2H), 7.15 – 7.05 (m, 2H), 6.90 – 6.84 (m, 1H), 6.83 – 6.78 (m, 1H), 4.44 – 4.32 (m, 1H), 4.18 – 4.08 (m, 1H), 3.08 – 2.98 (m, 2H), 2.97 – 2.87 (m, 2H), 2.83 – 2.71 (m, 1H), 2.24 – 2.13 (m, 1H), 2.02 – 1.82 (m, 2H). [0657] MS(ESI) calculated for C12H15NO: 189.1; found 190.3 Procedure for Compound 73
Figure imgf000244_0002
(2S,7R)‐9‐Oxa‐5‐azatricyclo[8.4.0.02,7]tetradeca‐1(10),11,13‐triene hydrochloride (73) [0658] The title compound (140 mg, 81.5% yield) was prepared from tert-butyl (3S,4R)-3- (hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate (3b) using General Procedure A described for the preparation of 72. [0659] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 7.25 – 7.18 (m, 1H), 7.17 – 7.08 (m, 1H), 6.93 – 6.84 (m, 1H), 6.77 (dd, J = 8.2, 1.1 Hz, 1H), 4.25 (dd, J = 10.5, 3.5 Hz, 1H), 3.83 (t, J = 10.9 Hz, 1H), 3.51 – 3.42 (m, 1H), 3.40 – 3.34 (m, 1H), 3.11 – 2.96 (m, 1H), 2.84 – 2.69 (m, 2H), 2.59 – 2.52 (m, 1H), 2.09 – 1.94 (m, 1H), 1.59 – 1.44 (m, 1H). [0660] MS(ESI) calculated for C12H15NO: 189.1; found 190.3 Procedure for Compound 12
Figure imgf000245_0001
Bromobenzene-1,3-dicarboxylic acid (1)
Figure imgf000245_0002
[0661] To a solution of 2-bromo-1,3-dimethylbenzene (50.0 g, 271.7mmol) in t-BuOH (300 mL ) and H2O (700 mL ) was added KMnO4 (156.0 g, 987.3 mmol) at 110°C under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 19 hours. EtOH (30 mL) was added. After cooling to room temperature, the mixture was filtered through a pad of celite; the filtrate was acidified with HCl (1 N) to pH~2. The precipitate was collected by filtration and dried over vacuum to obtain the title compound (50.0 g, 75.6% yield) as a pale solid. [0662] 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.53 (dd, J = 7.9, 7.4 Hz, 1H). [2-Bromo-3-(hydroxymethyl)phenyl]methanol (2)
Figure imgf000246_0001
[0663] To a solution of 1 (10.0 g, 40.8 mmol) in THF (500 mL ) was added borane tetrahydrofuran complex (20 mL, 10 M) at 0°C. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere and then quenched with MeOH (500 mL). The mixture was concentrated to get the crude product (8.0 g, 90.2% yield) as a pale solid for the next step without further purification. 2-({2-Bromo-3-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (3)
Figure imgf000246_0002
[0664] To a solution of 2 (8.0 g, 37.0 mmol) and TsOH (1.2 g, 6.9 mmol) in DMF (50 mL ) was added DHP (6.3 g, 75.0 mmol), and the resulting mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified with column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to get the desired product (8.0 g, 23.5% yield) as colorless oil. [0665] 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.5 Hz, 2H), 7.36 – 7.30 (m, 2H), 4.85 (d, J = 13.4 Hz, 2H), 4.79 (t, J = 3.4 Hz, 2H), 4.61 (d, J = 13.4 Hz, 2H), 3.97 – 3.84 (m, 2H), 3.63 – 3.48 (m, 2H), 1.97 – 1.50 (m, 12H).
Methyl (2E)-3-{2,6-bis[(oxan-2-yloxy)methyl]phenyl}prop-2-enoate (4)
Figure imgf000247_0001
[0666] To a mixture of 3 (5.0 g, 12.9 mmol), methyl prop-2-enoate (5.0 g, 58.0 mmol) and PPh3 (0.4 g, 1.5 mmol) in DMF (50 mL ) was added Pd(OAc)2 (0.2 mg, 0.8 mmol) at room temperature. The reaction mixture was stirred at 120°C for 19 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=10:1) to obtain the title compound (2.00 g, 39.7% yield) as a light yellow oil. Methyl (2E)-3-[2-(hydroxymethyl)-6-[(oxan-2-yloxy)methyl]phenyl]prop-2-enoate (5)
Figure imgf000247_0002
[0667] To a solution of 4 (2.0 g, 5.1 mmol) in THF (15 mL ) was added HCl/dioxane (2 mL, 4 M) at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours and basified with saturated NaHCO3 till pH~9. The mixture was then extracted with ethyl acetate (25 mL*4). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=5:1) to obtain the title product (0.9 g, 57.4% yield) as a light yellow oil. [0668] 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 16.2 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.41 – 7.32 (m, 1H), 6.27 (d, J = 16.2 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.73 (dd, J = 7.2, 3.6 Hz, 3H), 4.46 (d, J = 12.0 Hz, 1H), 3.93-3.87 (m, 1H), 3.82 (s, 3H), 3.61 – 3.54 (m, 1H), 1.95 – 1.46 (m, 7H). Methyl 2-{7-[(oxan-2-yloxy)methyl]-1,3-dihydro-2-benzofuran-1-yl}acetate (6)
Figure imgf000248_0001
[0669] To a solution of 5 (0.8 g, 2.6 mmol) in THF (15 mL ) was added Cs2CO3 (2.5 g, 7.8 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated. The residue was purified with column chromatography (eluted with petroleum ether: ethyl acetate=10:1) to get the title product (0.6 g, 75.3% yield) as colorless oil. [0670] 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.21 (m, 2H), 7.17 (d, J = 7.2 Hz, 1H), 5.94 – 5.77 (m, 1H), 5.23 – 4.98 (m, 2H), 4.85-4.76 (m, 1H), 4.69 (dt, J = 14.9, 3.5 Hz, 1H), 4.50 (t, J = 12.2 Hz, 1H), 3.89-3.74 (m, 1H), 3.72 (s, 3H), 3.57-3.53 (m, 1H), 2.99-3.03 (m, 1H), 2.65-2.67 (m, 1H), 1.89 – 1.46 (m, 3H). Methyl 2-[7-(hydroxymethyl)-1,3-dihydro-2-benzofuran-1-yl]acetate (7)
Figure imgf000248_0002
[0671] To a solution of 6 (0.6 g, 2.0 mmol) in MeOH (5 mL) was added HCl/dioxane (2 mL, 4 M) at 0°C and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 2.5 hours. Then, the mixture was concentrated to get the desired product (0.4 g, 95.1% yield) as a light yellow oil. [0672] 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.22 (m, 2H), 7.18 (d, J = 7.3 Hz, 1H), 5.86 (dd, J = 6.1, 2.5 Hz, 1H), 5.18 (dd, J = 12.4, 2.6 Hz, 1H), 5.05 (d, J = 12.3 Hz, 1H), 4.69 (q, J = 12.6 Hz, 2H), 3.69 (s, 3H), 3.04 (dd, J = 15.3, 2.8 Hz, 1H), 2.71 (dd, J = 15.3, 8.6 Hz, 1H). Methyl 2-(7-(chloromethyl)-1,3-dihydroisobenzofuran-1-yl)acetate (8)
Figure imgf000249_0001
[0673] To a solution of 7 (0.4 g, 1.9 mmol) and Et3N (0.4 g, 3.5 mmol) in DMF (5 mL ) was added MsCl (0.3 g, 2.3 mmol) at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to get desired product (0.4 g, 90.2% yield) as a pale solid. [0674] 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.23 (m, 2H), 7.19 (d, J = 7.1 Hz, 1H), 5.86- 5.83 (m, 1H), 5.26 – 4.99 (m, 2H), 4.69-4.49 (m, 2H), 3.69 (s, 3H), 2.94-2.63 (m, 2H). Methyl 2-[7-(azidomethyl)-1,3-dihydro-2-benzofuran-1-yl]acetate (9)
Figure imgf000249_0002
[0675] To a solution of 8 (0.4 g, 1.7 mmol) in acetone (25 mL) was added NaN3 (0.5 g, 8.3 mmol, in 15 mL H2O) at room temperature. The resulting mixture was stirred at 60°C for 4.5 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into ice water (50 mL) and extracted with ethyl acetate (25 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =5:1) to obtain the title compound (0.2 g, 53.6% yield) as a colorless oil. 6,7,9,9a-Tetrahydroisobenzofuro[7,1-cd]azepin-8(2H)-one (10)
Figure imgf000250_0001
[0676] A solution of 9 (0.2 g, 0.9 mmol) and PPh3 (0.5 g, 1.8 mmol) in THF (15 mL ) and H2O (10 mL ) was refluxed for 19 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (elute with ethyl acetate) to get the title compound (60.0 mg, 35.7% yield) as colorless oil. 2,6,7,8,9,9a-Hexahydroisobenzofuro[7,1-cd]azepin-7-ium chloride (12)
Figure imgf000250_0002
[0677] To a solution of 10 (60.0 mg, 0.3 mmol) in THF (10 mL ) was added borane tetrahydrofuran complex (1 mL, 1 M) at 0°C. The resulting mixture was stirred at room temperature for 2.5 hours under nitrogen atmosphere. The reaction was then quenched with MeOH (10 mL), and the resulting mixture was concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (15.0 mg, 27.1% yield) as a pale solid. [0678] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (brs, 1H), 8.91 (brs, 1H), 7.34-7.30 (m, 3H), 5.37-5.34 (m, 1H), 5.14-5.10 (m, 1H), 5.03-5.00 (m, 1H), 4.30 (brs, 2H), 3.52-3.48 (m, 1H), 3.35 – 3.23 (m, 1H), 2.26-2.22 (m, 1H), 1.92-1.83 (m, 1H). [0679] MS(ESI) calculated for C11H13NO: 175.1; found 176.2.
Procedure for Compound 13
Figure imgf000251_0001
7-Chloroisobenzofuran-1(3H)-one(1)
Figure imgf000251_0002
[0680] The mixture of 2-chlorobenzoic acid (10.0 g, 63.8 mmol), Pd(OAc)2 (1.4 g, 6.4 mmol) and KHCO3(16.0 g, 0.2 mol) in dibromomethane (100 mL) was stirred at 120°C under nitrogen atmosphere in a sealed tube for 36 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =5:1) to obtain the title compound (8.1 g, 74.1 % yield) as a colorless oil. [0681] 1H NMR (400 MHz, CDCl3) δ 7.61 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.9, 1H), 7.39 (d, J = 7.6, 1H), 5.26(s, 2 H). 7-Chloro-1,3-dihydroisobenzofuran-1-ol (2)
Figure imgf000251_0003
[0682] To a stirred solution of 1 (8.1 g, 47.5 mmol) in dichloromethane (200 mL) was added DIBAL-H (47.5 mL, 1 M in toluene) dropwise at -78°C, and the resulting mixture was stirred at this temperature for 1 hour. Additional DIBAL-H (6 mL) was added. After stirring at - 78°C for another 30 min, celite was added to the mixture followed by water (1 mL), 15% NaOH (1 mL) and water (2.2 mL). The reaction mixture was slowly warmed to room temperature and stirred for 40 min. Then, it was filtered through a pad of celite, and the filtrate was dried over sodium sulfate. The solution was filtered and concentrated to obtain the title compound (4.7 g, 58.0% yield) as a white solid. 7-chloro-1,3-dihydroisobenzofuran-1-carbonitrile (3)
Figure imgf000252_0001
[0683] To a solution of 2 (4.0 g, 23.4 mmol) in DCM (100 mL) was added trimethylsilanecarbonitrile (11.6 g, 116.9 mmol) and boron trifluoride etherate (10.0 g, 70.2 mmol) at -20° C, and the resulting mixture was stirred at this temperature for 1 h. The reaction was quenched by aqueous NaOH (20 mL, 1 M). The phases were separated; the aqueous layer was extracted with DCM (30 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to obtain the crude product (3.7 g, 88.0% yield) as a yellow oil for the next step without further purification. tert-Butyl ((7-chloro-1,3-dihydroisobenzofuran-1-yl)methyl)carbamate (4)
Figure imgf000252_0002
[0684] To a solution of 3 (3.7 g, 20.6 mmol) in THF (100 mL) was added BH3-THF (61.8 mL, 1 M) at 0°C, and the resulting mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction was quenched by HCl/MeOH (20 mL, 1M) and continued to stir at 70°C for 1 hour. The reaction was concentrated to dryness. The residue was re- dissolved in THF (50 mL), and Boc2O (6.7 g, 30.9 mmol) and saturated aqueous NaHCO3 (50 mL) were added to the above solution. The resulting mixture was stirred at room temperature for 2 hours and then extracted with ethyl acetate (100mL*2). The combined organic layers were washed brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =5:1) to obtain the title compound (4.0 g, 68.4 % yield) as yellow oil. [0685] MS(ESI) calculated for C14H18ClNO3, 283.1: found 284.2, 286.2 tert-Butyl ((7-vinyl-1,3-dihydroisobenzofuran-1-yl)methyl)carbamate (5)
Figure imgf000253_0001
[0686] A solution of 5 (1.5 g, 5.3 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane(1.2 g, 8.0 mmol), tris(dibenzylideneacetone)dipalladium (457.9 mg, 0.5 mmol), tricyclohexylphosphane (280.4 mg, 1.0 mmol) and tripotassium phosphate (3.4 g, 15.8 mmol) in dioxane/H2O (55 mL, 10/1) was stirred at 140°C under nitrogen atmosphere in a sealed tube for 16 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain the title compound (1.2 g, 82.1 % yield) as a colorless oil. [0687] MS(ESI) calculated for C16H21NO3: 275.2; found 220.3, 276.3 tert-Butyl ((7-(1-hydroxyethyl)-1,3-dihydroisobenzofuran-1-yl)methyl)carbamate (6)
Figure imgf000253_0002
[0688] To a solution of 5 (1.0 g, 3.6 mmol) in THF (20 mL) was added BH3-THF (18.0 mL, 1 M) at 0°C and the resulting mixture was stirred at 75°C for 1 hour. After cooling to room temperature, aqueous NaOH (5 mL, 3 N) was added to the solution followed by H2O2 (5 mL, 30% in water). The resulting mixture was stirred at room temperature for 2 hours. The reaction was diluted with water (80 mL) and extracted with ethyl acetate (100.0 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain the title compound (610.2 mg, 57.8 % yield) as a white solid. [0689] MS(ESI) calculated for C16H23NO4: 293.2; found 294.3 tert-Butyl ((7-acetyl-1,3-dihydroisobenzofuran-1-yl)methyl)carbamate (7)
Figure imgf000254_0001
[0690] DMSO (477.5 mg, 6.1 mmol) was added dropwise to the solution of oxalic dichloride (776.2 mg, 6.1 mmol) in DCM (20.0 mL) at -78°C. Then, 6 (600.0 mg, 2.0 mmol) in DCM (30 mL) was added thereto, and the resulting mixture was continued to stir at -78°C for 2 hours before the addition of TEA (618.5 mg, 6.1 mmol). The resulting solution was continued to stir at -78°C for 1 hour and then at room temperature for 1 hour. The reaction mixture was quenched with water (50 mL). The phases were separated and the organic layer was dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain the title compound (269.8 mg, 45.3 % yield) as a white solid. [0691] MS(ESI) calculated for C16H21NO4, 291.2; found 292.3 (6S,8aS)-6-Methyl-6,7,8,8a-tetrahydro-2H-furo[2,3,4-de]isoquinolin-7-ium chloride (13)
Figure imgf000254_0002
[0692] To a solution of 6 (269.8 mg, 0.9 mmol) in DCM (3.0 mL) was added HCl/dioxane (1 mL, 4 M), and the resulting mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was triturated with Et2O to get a yellow solid (150.0 mg). [0693] To a solution of above solid (150.0 mg, 0.8 mmol) in DCM (5 mL) was added sodium cyanoborohydride (73.5 mg, 1.2 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate (25 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (12.0 mg, 6.1% yield) as a white solid. [0694] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (brs, 1H), 9.78 (brs, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 5.26 (m, 1H), 5.07 (dd, J = 12.4, 2.2 Hz, 1H), 4.94 (d, J = 12.5 Hz, 1H), 4.52 (q, J = 6.7 Hz, 1H), 3.82 (dd, J = 10.9, 5.4 Hz, 1H), 2.95 (t, J = 10.8 Hz, 1H), 1.68 (d, J = 6.9 Hz, 3H). [0695] MS(ESI) calculated for C11H13NO: 175.1; found 176.2 Procedure for Compound 87
Figure imgf000255_0001
General procedure B: 2-(3-Methoxyphenyl)ethan-1-ol (1)
Figure imgf000255_0002
[0696] To a solution of 2-(3-methoxyphenyl)acetic acid (30.0 g, 180.7 mmol) in dry THF (200 mL) was added BH3-THF (217 mL, 1 M) dropwise at -78°C under nitrogen atmosphere. The reaction mixture was stirred at -78°C for 30 min, and then at room temperature for 4 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (27.0 g, 98.2% yield) as a yellow oil. [0697] 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.20 (m, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.80 – 6.76 (m, 2H), 3.86 (t, J = 6.5 Hz, 2H), 3.80 (s, 3H), 2.85 (t, J = 6.5 Hz, 2H). 2-(2-Bromo-5-methoxyphenyl)ethan-1-ol (2)
Figure imgf000256_0001
[0698] To a solution of 1 (25.0 g, 164.5 mmol) in dry CH3CN (100 mL) was added N- bromosuccinimide (32.2 g, 180.9 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (29.0 g, 76.6% yield) as a colorless oil. [0699] 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 6.82 6.66 (dd, J = 8.8, 2.8 Hz, 1H), 3.88 (q, J = 6.8 Hz, 2H), 3.78 (s, 3H), 2.99 (t, J = 6.8 Hz, 2H). 4-Bromo-3-(2-hydroxyethyl)phenol (3)
Figure imgf000256_0002
[0700] To a solution of 2 (38.0 g, 164.5 mmol) in dry DCM (200 mL) was added BBr3 (82.1 g, 329.0 mmol) dropwise at 0oC under nitrogen atmosphere. After stirring at 0°C for 1 hour, the mixture was poured into ice water and extracted with dichloromethane (300 mL). The organic layer was washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to obtain the desired compound (22.0 g, 61.8% yield) as a white solid. [0701] MS(ESI) calculated for C8H9BrO2 , 215.9; found 198.9, 200.9 1-(Aminomethyl)-5-bromoisochroman-8-ol (4)
Figure imgf000256_0003
[0702] To a solution of 3 (11 g, 50.6 mmol) and 2,2-dimethoxyethan-1-amine (7.9 g, 75.8 mmol) in DCM (200 mL) was added trifluoromethanesulfonic acid (22.6 g, 151.0 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. The reaction was then quenched with water (150 mL); the organic solvent was removed under reduced pressure. The residue aqueous solution was used for the next step without further purification. tert-Butyl ((5-bromo-8-hydroxyisochroman-1-yl)methyl)carbamate (5)
Figure imgf000257_0001
[0703] To a solution of 4 (crude in water) in dioxane (100 mL) was added di-tert-butyl pyrocarbonate (18.5 g, 85.2 mmol) and sodium carbonate (36.0 g, 340 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The phases were separated, and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =2:1) to obtain the title compound (12 g, 66.6% yield over two steps) as a white solid. [0704] MS(ESI) calculated for C15H20BrNO4: 357.1; found 258.0, 260.0 tert-Butyl ((8-hydroxyisochroman-1-yl)methyl)carbamate (6)
Figure imgf000257_0002
[0705] A solution of 5 (7.0 g, 19.5 mmol), 10% palladium on activated carbon (1.4 g) and TEA (9.9 g, 97.5 mmol) in methanol (150 mL) was stirred at room temperature for 2 hours under hydrogen atmosphere. Then, the mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 2:1) to obtain the desired compound (4.0 g, 73.5% yield) as a white solid. [0706] MS(ESI) calculated for C15H21NO4: 279.1; found 180.0 1-(((tert-Butoxycarbonyl)amino)methyl)isochroman-8-yl trifluoromethanesulfonate (7)
Figure imgf000258_0001
[0707] To a solution of 6 (4.0 g, 14.3 mmol) and pyridine (2.23 g, 28.6 mmol) in dry DCM (100 mL) was added Tf2O (4.82 g, 17.1 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (200 mL) and extracted with DCM (60 mL). The organic layer was washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (5.0 g, 85.1% yield) as a yellow oil. [0708] MS(ESI) calculated for C16H20F3NO6S: 411.1; found 312.1, 356.1 tert-Butyl ((8-vinylisochroman-1-yl)methyl)carbamate (8)
Figure imgf000258_0002
[0709] A solution of 7 (5.0 g, 12.1 mmol), potassium vinyltrifluoroborate (2.4 g, 18.1 mmol), Pd(PPh3)2Cl2 (0.8 g, 1.2 mmol) and sodium carbonate (5.1 g, 48.4 mmol) in dioxane/H2O (180 mL, 5:1) was stirred at 100°C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, and filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (2.5 g, 71.5% yield) as a white solid [0710] MS(ESI) calculated for C17H23NO3: 289.2; found 190.1 tert-Butyl ((8-(2-hydroxyethyl)isochroman-1-yl)methyl)carbamate (9)
Figure imgf000258_0003
[0711] To a solution of 8 (2.4 g, 8.9 mmol) in dry THF (150 mL) was added BH3-THF (12.4 mL, 12.4 mmol) at 0oC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0°C, water (3mL), aqueous NaOH (16.5 mL, 1 N) and H2O2 (8.3 mL, 30% in water) were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (1.0 g, 39.3% yield) as a white solid. [0712] 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.13 (br,1H), 5.04 (d, J = 9.2 Hz, 1H), 4.08-4.02 (m, 1H), 3.96 – 3.84 (m, 2H), 3.81 – 3.75 (m, 1H), 3.69 – 3.64 (m, 1H), 3.27-3.20 (m, 1H), 3.06 – 2.99 (m, 1H), 2.93 – 2.75 (m, 3H), 1.43 (s, 9H). [0713] MS(ESI) calculated for C17H25NO3: 307.1; found 208.1 2-(1-(Aminomethyl)isochroman-8-yl)ethan-1-ol (10)
Figure imgf000259_0001
[0714] To the solution of 9 (0.5 g, 1.6 mmol) in dioxane (4 mL) was added HCl/dioxane (4 mL, 4 M). The resulting mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was used for the next step without further purification. tert-Butyl 2,3,7,8,10,10a-hexahydro-9H-isochromeno[1,8-cd]azepine-9-carboxylate (11)
Figure imgf000259_0002
[0715] To a solution of 10 (crude) in dry CHCl3 (20 mL) was added SOCl2 (487 mg, 4.1mmol) under nitrogen atmosphere, and the resulting mixture was stirred at 50oC for 6 hours. After cooling to room temperature, the mixture was concentrated to dryness. The residue was re-dissolved in THF (40 mL), and aqueous NaOH (68 mL, 3 N) was added. After stirring at room temperature for 2 days, the mixture was adjusted to pH~8 with HCl (3 M) for the next step directly. [0716] MS(ESI) calculated for C12H15NO, 189.1; found 190.1 [0717] To the above solution was added sodium carbonate (1.1 g, 10.5 mmol) and Boc2O (1.2 g, 5.3 mmol). The resulting mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (400.0 mg, 52.5% yield) as a colorless oil. [0718] MS(ESI) calculated for C17H23NO3: 289.1; found 190.1 3,7,8,9,10,10a-Hexahydro-2H-isochromeno[1,8-cd]azepin-9-ium chloride (87)
Figure imgf000260_0001
[0719] To a solution of 11 (200 mg, 0.7 mmol) in dioxane (3 mL) was added HCl/dioxane (6 mL, 4 M), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (60 mg, 38.7% yield) as a yellow solid. [0720] 1H NMR (400 MHz, DMSO-d6) δ 9.70-9.41 (brs, 2H), 7.18-7.14 (m, 1H), 7.10-7.07 (m, 2H), 5.20 (d, J = 9.2 Hz, 1H), 4.01-3.95 (m, 1H), 3.74-3.68 (m, 1H), 3.50-3.46 (m, 1H), 3.39-3.36 (m, 1H), 3.18-3.11 (m, 1H), 3.09-3.01 (m, 1H), 2.95 – 2.89 (m, 1H), 2.87-2.78 (m, 2H), 2.72 – 2.67 (m, 1H). [0721] MS(ESI) calculated for C12H15NO: 189.1; found 190.2 Procedure for Compound 166
Figure imgf000260_0002
tert-Butyl 9,9a-dihydroisobenzofuro[1,7-cd]azepine-8(2H)-carboxylate (1)
Figure imgf000261_0001
[0722] To a solution of tert-butyl N-[(7-ethenyl-1,3-dihydro-2-benzofuran-1- yl)methyl]carbamate (0.5 g, 1.8 mmol) in DMF/H2O (20 mL, 10:1) was added dichloropalladium (641.1 mg, 3.6 mmol), and the resulting mixture was stirred at 80°C for 12 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (40 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain the title compound (220.5 mg, 44.7% yield) as a colorless oil. [0723] 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.21 (m, 1H), 7.15 – 6.83 (m, 3H), 5.64 (brs, 1H), 5.18 – 5.14 (m, 1H), 5.08 – 4.93 (m, 2H), 2.86 (brs, 2H), 1.54 (s, 9H). tert-Butyl 6,7,9,9a-tetrahydroisobenzofuro[1,7-cd]azepine-8(2H)-carboxylate (2)
Figure imgf000261_0002
[0724] To a solution of 1 (220.5 mg, 0.8 mmol) in MeOH (10 mL ) was added 10% palladium on activated carbon (20.0 mg, 199.0 mmol), and the resulting mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. The mixture was then filtered through a pad of celite, and the filtrate was concentrated to obtain the title compound (201.5 mg, 90.2 % yield) as a white solid. [0725] 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 7.4 Hz, 1H), 7.13 – 6.95 (m, 2H), 5.14 (m, 3H), 4.62 – 4.18 (m, 2H), 3.14 – 2.95 (m, 1H), 2.91 – 2.79 (m, 1H), 2.79 – 2.67 (m, 2H), 1.49 (s, 9H). 2,6,7,8,9,9a-Hexahydroisobenzofuro[1,7-cd]azepin-8-ium chloride (166)
Figure imgf000262_0001
[0726] To a solution of 2 (200.0 mg, 0.7 mmol) in DCM (5 mL) was added HCl/dioxane (1 mL, 4 M), and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness; the residue was slurried with Et2O twice to obtain the title compound (120.0 mg, 78.0% yield) as a yellow solid. [0727] 1H NMR (400 MHz, DMSO-d6) δ 9.73 (brs, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 5.57 (dd, J = 10.9, 3.1 Hz, 1H), 5.09 (ddd, J = 29.8, 12.5, 2.3 Hz, 2H), 3.62 – 3.50 (m, 2H), 3.29 (m, 1H), 3.00 – 2.85 (m, 3H). [0728] MS(ESI) calculated for C11H13NO: 175.1; found 176.2 Procedure for Compound 168
Figure imgf000262_0002
2-(2-Bromo-5-chlorophenyl)acetonitrile (1)
Figure imgf000262_0003
[0729] To a solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (2.0 g, 7.0 mmol) in DMF/H2O (16 mL, 1:1) was added KCN (549.6 mg, 8.4 mmol) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (40 mL). The precipitate was collected by filtration and washed with water (5 mL*2), and dried over vacuum to obtain the title compound (1.5 g, 92.5% yield) as a white solid. [0730] 1H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 2H), 7.22 (dd, J = 8.5, 2.5 Hz, 1H), 3.82 (s, 2H). 2-(2-Bromo-5-chlorophenyl)ethan-1-amine (2)
Figure imgf000263_0001
[0731] Borane tetrahydrofuran complex (1.0 M, 8.7 mL) was added to a solution of 1 (1.0 g, 4.3 mmol) in THF (10 mL). The mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was quenched with HCl (3 M). The mixture was concentrated and the residue was dissolved in water, adjusted with NaOH (12 N) to pH~11. The resulting mixture was extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The crude product (970 mg) was used for the next step directly without further purification. [0732] MS(ESI) calculated for C8H9BrClN: 233.0; found 234.2, 236.2 N-(2-Bromo-5-chlorophenethyl)-2,2,2-trifluoroacetamide (3)
Figure imgf000263_0002
[0733] To a solution of 2 (970 mg, 4.1 mmol) and TEA (1.7 mL) in DCM (15 mL) was added TFAA (0.4 mL, 6.2 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The mixture was then diluted with DCM (50 mL), washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=4:1) to obtain the title compound (750.0 mg, 52% yield over 2 steps) as a white solid. [0734] 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 8.5, 2.5 Hz, 1H), 6.37 (brs, 1H), 3.64 (q, J = 6.8 Hz, 2H), 3.02 (t, J = 7.1 Hz, 2H). N-Allyl-N-(2-bromo-5-chlorophenethyl)-2,2,2-trifluoroacetamide (4)
Figure imgf000263_0003
[0735] A solution of 3 (750.0 mg, 2.3 mmol) in toluene (10 mL) was treated with K2CO3 (407.7 mg, 3.0 mmol), KOH (381.9 mg, 6.8 mmol), n-Bu4NBr (73.2 mg, 0.2 mmol), and allyl bromide (411.8 mg, 3.4 mmol) sequentially. The mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was acidified with 10% aqueous HCl. The phases were separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product (780 mg, 92.7% yield) as brown oil. 1-(7-Chloro-1-methylene-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-2,2,2-trifluoroethan-1- one (5)
Figure imgf000264_0001
[0736] A solution of 4 (780 mg, 2.1 mmol), Pd(OAc)2 (47.3 mg, 0.2 mmol), KOAc (661.0 mg, 6.7 mmol), n-Bu4NBr (746.4 mg, 2.3 mmol) and PPh3 (110.4 mg, 0.4 mmol) in DMF (15 mL) was stirred at 110°C under nitrogen atmosphere for 4 hours. After cooling to room temperature, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=4:1) to obtain the title compound (100 mg, 16.4% yield). [0737] 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.19 (m, 2H), 7.13 (t, J = 2.2 Hz, 1H), 5.49 – 5.27 (m, 2H), 4.43 – 4.39 (m, 2H), 3.93 – 3.76 (m, 2H), 3.03 – 2.99 (m, 2H). tert-Butyl 7-chloro-1-methylene-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate (6)
Figure imgf000264_0002
[0738] Potassium hydroxide (5 M, 0.7 mL) was added dropwise to a solution of 5 (100 mg, 0.3 mmol) in methanol (1 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was removed by vacuum, and the residue was re-dissolved in water (5 mL) and tetrahydrofuran (5 mL). Boc2O (327.4 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=5:1) to obtain title compound (85 mg, 83.8% yield) as a yellow oil. [0739] MS(ESI) calculated for C16H20ClNO2: 293.1; found 194.2, 196.2, 238.2, 240.2 tert-Butyl 7-chloro-1-(hydroxymethyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate (7)
Figure imgf000265_0001
[0740] Borane tetrahydrofuran complex (1.0 M in THF, 1 mL) was added dropwise to a solution of 6 (85 mg, 0.3 mmol) in tetrahydrofuran (3 mL) at 0°C. The mixture was stirred at room temperature for 1 h and then cooled to 0°C. NaOH (0.5 mL, 3 N) and H2O2 (0.3 mL) were added dropwise. After addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=4:1) to obtain title compound (50 mg, 53.3% yield) as a colorless oil. [0741] 1H NMR (400 MHz, CDCl3) δ 7.15 – 7.09 (m, 2H), 7.06 (s, 1H), 5.30 (s, 1H), 4.51 (d, J = 12.6 Hz, 1H), 4.25 (d, J = 11.3 Hz, 1H), 3.67 – 3.61 (m, 1H), 3.52 – 3.48 (m, 1H), 3.15 – 2.97 (m, 3H), 2.95 – 2.83 (m, 1H), 2.69 (dd, J = 15.5, 4.9 Hz, 1H), 1.51 (s, 9H). [0742] MS(ESI) calculated for C16H22ClNO3: 311.1; found 212.2, 214.2. 9-Chloro-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (Compound 168)
Figure imgf000265_0002
[0743] To a solution of 7 (50.0 mg, 0.16 mmol) and paraformaldehyde (24.0 mg, 0.8 mmol) in DCM (2 mL) was added CF3SO3H (72.0 mg, 0.48 mmol) at 0 oC. After addition, the reaction mixture was stirred at 0°C for an additional 30 min before stirring at room temperature for 1 hour. The mixture was filtered through a pad of celite, and the filtrate was concentrated and purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (9.9 mg, 23.8% yield) as a white solid. [0744] 1H NMR (400 MHz, DMSO-d6) δ 9.15 (brs, 2H), 7.23 (d, J = 2.1 Hz, 1H), 7.13 (d, J = 1.9 Hz, 1H), 4.72 – 4.58 (m, 2H), 3.98-3.93 (m, 1H), 3.80-3.75 (m, 1H), 3.52-3.47 (m, 1H), 3.37-3.36 (m, 1H), 3.30 – 3.26 (m, 1H), 3.22-3.19 (m, 1H), 2.98-2.91 (m, 1H), 2.87-2.80 (m, 2H). [0745] MS(ESI) calculated for C12H14ClNO: 223.1; found 224.2 Procedure for Compound 169
Figure imgf000266_0001
General procedure D: 2-(2-Bromophenyl)propan-2-ol (1)
Figure imgf000266_0002
[0746] To a solution of ethyl 2-bromobenzoate (15 g, 65.4 mmol) in THF (250 mL) was added bromo(methyl)magnesium (65.0 mL, 196.0 mmol) at 0°C, and the resulting mixture was stirred under nitrogen atmosphere for 16 hours. The reaction was quenched with HCl (1M) till pH~6, and the mixture was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether) to obtain the desired compound (14.0 g, 99.4% yield) as yellow oil. [0747] 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 7.9, 1.7 Hz, 1H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H), 7.33 – 7.22 (m, 1H), 7.13 – 7.06 (m, 1H), 2.77 (s, 1H), 1.75 (s, 6H). 1-(2-(Allyloxy)propan-2-yl)-2-bromobenzene (2)
Figure imgf000267_0001
[0748] Sodium hydride (7.8 g, 195.0 mmol) was suspended in dry THF (100 mL), and 1 (14.0 g, 65.1 mmol)) in THF (100 mL) was added slowly under stirring. After the gas evolution ceased, 3-bromoprop-1-ene (10.2 g, 84.5 mmol) was added and stirred for 30 min, then tetrabutylammonium iodide (2.4 g, 6.5 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. After then, the mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (14.2 g, 85.5% yield) as colorless oil. [0749] 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 7.9, 1.3 Hz, 1H), 7.37 (dd, J = 7.9, 1.7 Hz, 1H), 7.25 – 7.14 (m, 1H), 7.09 – 6.96 (m, 1H), 6.00 – 5.85 (m, 1H), 5.28 – 5.16 (m, 1H), 5.12 – 5.01 (m, 1H), 3.71 – 3.61 (m, 2H), 1.64 (s, 6H). 1,1-Dimethyl-4-methyleneisochromane (3)
Figure imgf000267_0002
[0750] A mixture of 2 (11.2 g, 43.8 mmol), palladium acetate (244.0 mg, 1.1 mmol), tetraethylammonium chloride (7.3 g, 43.8 mmol), potassium carbonate (6.1 g, 43.8 mmol) and potassium acetate (4.3 g, 43.8 mmol) in DMF(300 mL) was stirred at 105°C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was diluted with water (1000 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the desired compound (4.1 g, 53.7% yield) as a colorless oil. [0751] 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 7.7, 1.3 Hz, 1H), 7.29 – 7.18 (m, 2H), 7.14 (dd, J = 7.6, 1.4 Hz, 1H), 5.56 (s, 1H), 5.01 (s, 1H), 4.43 (s, 2H), 1.55 (s, 6H). (1,1-Dimethylisochroman-4-yl)methanol (4)
Figure imgf000268_0001
[0752] To a solution of 3 (4.1 g, 23.5 mmol) in tetrahydrofuran (100 mL) was added borane- tetrahydrofuran complex (70.4 mL, 70.4 mmol) at 0°C, and the resulting mixture was stirred for 2 hours. The reaction was cooled to 0°C. NaOH (39 mL, 3 N) was added dropwise followed by hydrogen peroxide (11.8 mL, 30% in water). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (4.2 g, 92.8% yield) as a white solid. [0753] 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.15 (m, 3H), 7.15 – 7.10 (m, 1H), 4.18 – 3.98 (m, 2H), 3.98 – 3.82 (m, 2H), 2.82 – 2.70 (m, 1H), 1.54 (s, 3H), 1.52 (s, 3H). N-(2,2-Dimethoxyethyl)-N-((1,1-dimethylisochroman-4-yl)methyl)-1,1,1- trifluoromethanesulfonamide (5)
Figure imgf000268_0002
[0754] To a solution of 4 (4.2 g, 21.8 mmol), N-(2,2-dimethoxyethyl)-1,1,1- trifluoromethanesulfonamide (6.2 g, 26.1 mmol) and triphenylphosphine (17.1 g, 65.3 mmol) in tetrahydrofuran (40 mL) was added diethyl azodicarboxylate (11.3 g, 65.3 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours and then concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (6.6 g, 73.4% yield) as a yellow oil. [0755] 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.22 (m, 1H), 7.21 – 7.16 (m, 1H), 7.15 – 7.09 (m, 2H), 4.53 (t, J = 5.3 Hz, 1H), 4.00 – 3.87 (m, 2H), 3.86 – 3.71 (m, 1H), 3.71 – 3.61 (m, 1H), 3.55 – 3.28 (m, 8H), 3.12 – 2.99 (m, 1H), 1.54 (s, 3H), 1.50 (s, 3H). 1,1-Dimethyl-5-((trifluoromethyl)sulfonyl)-3,3a,4,5-tetrahydro-1H-isochromeno[4,5- cd]azepine (6)
Figure imgf000269_0001
[0756] To a solution of 5 (3.0 g, 7.3 mmol) in DCM (10 mL) was added aluminum chloride (7.8 g, 58.3 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 1 hour. The reaction was quenched by NaOH (1N) and extracted with DCM (30 mL*3). The organic layer was dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 4:1) to obtain the desired compound (1.2 g, 47.3% yield) as a yellow oil. [0757] 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.17 (m, 1H), 7.11 – 7.07 (m, 1H), 7.06 – 7.01 (m, 1H), 6.65 – 6.56 (m, 1H), 5.86 (d, J = 10.4 Hz, 1H), 4.21 – 4.05 (m, 2H), 3.73 – 3.64 (m, 1H), 3.36 – 3.27 (m, 1H), 3.18 – 3.09 (m, 1H), 1.54 (s, 3H), 1.51 (s, 3H). 1,1-Dimethyl-5-((trifluoromethyl)sulfonyl)-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5- cd]azepine (7)
Figure imgf000269_0002
[0758] To a solution of 6 (1.2 g, 3.5 mmol) in methanol (15 mL) was added 10% palladium on activated carbon (350 mg), and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was then filtered through a pad of celite; the filtrate was concentrated to obtain the crude product (1.1 g, 90.0%) for the next step without further purification. [0759] 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 7.6 Hz, 1H), 7.11 – 7.05 (m, 1H), 7.05 – 6.99 (m, 1H), 4.22 – 3.93 (m, 3H), 3.90 – 3.76 (m, 1H), 3.45 – 2.86 (m, 5H), 1.53 (s, 3H), 1.52 (s, 3H). 1,1-Dimethyl-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (Compound 169)
Figure imgf000270_0001
[0760] To a solution of 7 (500.0 mg, 1.4 mmol) in tetrahydrofuran (10 mL) was added sodium bis(2-methoxyethoxy)aluminum hydride (1.2 g, 4.3 mmol, 70% in toluene), and the resulting mixture was refluxed for 1 hour. After cooling to 0°C, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL *3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (24.8 mg, 6.9% yield) as a white solid. [0761] 1H NMR (400 MHz, DMSO-d6) δ 9.74 – 9.54 (m, 1H), 9.44 – 9.27 (m, 1H), 7.21 – 7.13 (m, 2H), 7.11 – 7.04 (m, 1H), 3.99 (dd, J = 12.2, 4.9 Hz, 1H), 3.74 (dd, J = 12.2, 3.6 Hz, 1H), 3.52 – 3.44 (m, 1H), 3.43 – 3.24 (m, 3H), 2.97 – 2.84 (m, 2H), 2.82 – 2.71 (m, 1H), 1.45 (s, 3H), 1.44 (s, 3H). [0762] MS(ESI) calculated for C14H19NO: 217.1; found 218.2
Procedure for Compound 171
Figure imgf000271_0001
6‐Chloro‐2‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (171) [0763] Following the same procedure described in General Procedure B, the title compound was synthesized (33.6 mg, 59.9% yield) as a white solid. [0764] 1H NMR (400 MHz, DMSO-d6) δ 9.44 (brs, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 5.20 (d, J = 9.8 Hz, 1H), 4.03-3.93 (m, 1H), 3.78-3.74 (m, 1H), 3.49-3.45 (m, 1H), 3.42-3.37 (m, 1H), 3.15-3.09 (m, 2H), 2.98-2.93 (m, 1H), 2.83 – 2.70 (m, 3H). [0765] MS(ESI) calculated for C12H14ClNO: 223.1; found 224.2, 226.2 Procedure for Compound 15
Figure imgf000271_0002
[0766] Following the same procedure described in General Procedure D, 15 was synthesized from 2-fluoro-6-iodophenyl)methanol (1) as a white solid. (2-Fluoro-6-iodophenyl)methanol (1)
Figure imgf000272_0001
[0767] To a solution of 2-fluoro-6-iodobenzoic acid (15.0 g, 56.3 mmol), trimethylborate (17.4 g, 168.0 mmol) in THF (100 mL) was added BH3-THF (225 mL, 1M) at 0oC, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with methanol and then concentrated to dryness. The residue was diluted with water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (13.0 g, 91.7% yield) as a colorless oil. [0768] MS(ESI) calculated for C7H6FIO: 251.9; found 235.1 10-Fluoro-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (15)
Figure imgf000272_0002
[0769] 1H NMR (400 MHz, DMSO-d6) δ 9.67 (brs, 1H), 9.43 (brs, 1H), 7.19-7.15 (m, 1H), 7.04-7.00 (m, 1H), 4.73-4.64 (m, 2H), 3.98-3.93 (m, 1H), 3.82-3.78 (m, 1H), 3.50-3.46 (m, 1H), 3.45-3.38 (m, 1H), 3.37-3.26 (m, 2H), 2.96 – 2.85 (m, 2H), 2.81-2.72 (m, 1H). [0770] MS(ESI) calculated for C12H14FNO: 207.1; found 208.2 Procedure for Compound 16
Figure imgf000272_0003
Methyl ((9,10-dihydroanthracen-9-yl)methyl)carbamate (1)
Figure imgf000273_0001
[0771] To a solution of 1-(9,10-dihydroanthracen-9-yl)methanamine (700 mg, 3.3 mmol) and triethylamine (506 mg, 5.0 mmol) in methylene chloride (20 mL ) was added ethyl carbonochloridate (377 mg, 4.0 mmol) dropwise at 0°C, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (eluted with petroleum ether : ethyl acetate = 4:1) to obtain the title product (600 mg, 67.4% yield) as a white solid. [0772] MS(ESI) calculated for C17H17NO2: 267.1; found 268.2 1,2,7,11b-Tetrahydro-3H-dibenzo[de,h]isoquinolin-3-one (2)
Figure imgf000273_0002
[0773] Compound 1 (500 mg, 1.8 mmol) was added to POCl3 (12 mL) under nitrogen atmosphere at 0°C. The solution was allowed to warm to room temperature and heated to reflux for 2 hours. The reaction mixture was then cooled to 0°C, and SnCl4 (2.8 mL, 1 M in DCM) was added dropwise thereto. The resulting mixture was stirred at 0°C for 1 h and slowly allowed to warm to room temperature for 1 hour. The reaction was poured into ice, and stirred for 0.5 h. The suspension was extracted with ethyl acetate (80 mL*3). The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluted with DCM: MeOH= 90:10) to obtain the title product (100 mg, 23.6% yield) as a white solid. [0774] 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 1H), 7.52-7.50 (m, 1H), 7.43 – 7.26 (m, 5H), 4.34 – 4.22 (m, 2H), 4.06 (d, J = 1.8 Hz, 2H), 3.75-3.67 (m, 1H). 2,3,7,11b-Tetrahydro-1H-dibenzo[de,h]isoquinolin-2-ium chloride (16)
Figure imgf000274_0001
[0775] To a solution of 2 (80 mg, 340 μmol) in tetrahydrofuran (3 mL) was added BH3/THF (1.7 mL, 1 M) at 0°C, and the resulting mixture was stirred at 60°C for 5 hours. After cooling to room temperature, the reaction was quenched with methanol. The solvent was removed under reduced pressure, and the residue was dissolved in HCl/MeOH (10 mL, 4 M) and heated to reflux for 1 hour. The mixture was concentrated and purified by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title product (51 mg, 66.6% yield) as a white solid. [0776] 1H NMR (400 MHz, DMSO-d6) δ 10.00 (brs, 1H), 9.67 (brs, 1H), 7.41-7.14 (m, 7H), 4.45 – 4.31 (m, 3H), 4.19 – 4.08 (m, 1H), 4.01 (d, J = 17.2 Hz, 1H), 3.89-3.84 (m, 1H), 3.46 (t, J = 12.7 Hz, 1H). [0777] MS(ESI) calculated for C16H15N: 221.1; found 222.2 Procedure for Compound 17
Figure imgf000274_0002
6‐Methoxy‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (17) [0778] Following the same procedure described in General Procedure D, the title compound was synthesized (111.5 mg, 86.2% yield) from 2-bromo-6-methoxybenzoic acid as a white solid. [0779] 1H NMR (400 MHz, DMSO-d6) δ 9.30 (brs, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.61 – 4.50 (m, 2H), 3.89 (dd, J = 11.7, 5.2 Hz, 1H), 3.78 (d, J = 4.5 Hz, 1H), 3.76 (s, 3H), 3.54 – 3.42 (m, 1H), 3.38 – 3.36 (m, 1H), 3.31 – 3.27 (m, 1H), 3.25 – 3.14 (m, 1H), 2.91 – 2.84 (m, 2H), 2.78 – 2.67 (m, 1H). [0780] MS(ESI) calculated for C13H17NO2: 219.1; found 220.2 Procedure for Compound 18
Figure imgf000275_0001
Methyl 2-bromo-6-chlorobenzoate (1)
Figure imgf000275_0002
[0781] To the solution of 2-bromo-6-chlorobenzoic acid (15 g, 63.7 mmol) in dimethylformamide (60 mL) was added potassium carbonate (13.1 g, 95.5 mmol) and methyl iodide (18.0 g, 127.0 mmol) at room temperature under nitrogen atmosphere. After stirring at room temperature for 16 hours, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (80 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=10:1) to obtain the desired compound (13.0 g, 82.2% yield) as a yellow solid. [0782] 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.0, 1.0 Hz, 1H), 7.36 (dd, J = 8.0, 1.0 Hz, 1H), 7.24 – 7.15 (t, J = 8.0 Hz, 1H), 3.97 (s, 3H). (2-Bromo-6-chlorophenyl)methanol (2)
Figure imgf000276_0001
[0783] DIBAL-H (104 mL, 104 mmol) was added dropwise to a solution of 1 (13.0 g, 52.1 mmol) in dry DCM (80 mL) at -78°C under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 16 hours. After cooling to -78°C, the reaction was quenched by 1 N HCl (100 mL). The mixture was allowed to warm to room temperature and separated. The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (8.1 g, 70.4% yield) as a white solid. [0784] 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 8.0, 1.0 Hz, 1H), 7.37 (dd, J = 8.1, 1.0 Hz, 1H), 7.15 – 7.07 (t, J = 8.0 Hz, 1H), 4.99 (s, 2H). 2-((Allyloxy)methyl)-1-bromo-3-chlorobenzene (3)
Figure imgf000276_0002
[0785] To a solution of 2 (8.1 g, 36.5 mmol) in THF (30 mL) was added NaH (1.8 g, 43.8 mmol) at 0°C. After stirring for 30 min, 3-bromoprop-1-ene (5.3 g, 43.8 mmol) was added slowly^ the resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (60 mL) and extracted with ethyl acetate (60 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 20:1) to obtain the title compound (9.0 g, 94.3% yield) as yellow oil. [0786] 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 8.0, 1.1 Hz, 1H), 7.35 (dd, 1H), 7.10 (t, 1H), 6.07 – 5.90 (m, 1H), 5.39 – 5.30 (m, 1H), 5.26 – 5.16 (m, 1H), 4.79 (s, 2H), 4.15 – 4.08 (m, 2H). 8-Chloro-4-methyleneisochromane (4)
Figure imgf000277_0001
[0787] To a solution of 3 (9.0 g, 34.4 mmol) in DMF (50 mL) was added triphenylphosphine (2.7 g, 10.3 mmol), tetraethylammonium chloride (10.2 g, 61.9 mmol), palladium acetate (569 mg, 3.4 mmol) and potassium acetate (16.7 g, 171.0 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 105°C for 16 hours. After cooling to room temperature, the solution was diluted with water (300 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether) to get the title compound (3.5 g, 56.3% yield) as yellow oil. [0788] 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.56 (m, 1H), 7.28 – 7.24 (m, 1H), 7.21 – 7.13 (m, 1H), 5.64 (s, 1H), 5.08 (s, 1H), 4.84 (s, 2H), 4.37 (s, 2H). (8-Chloroisochroman-4-yl)methanol (5)
Figure imgf000277_0002
[0789] To a solution of 4 (2.5 g, 13.8 mmol) in THF (20 mL) was added BH3-THF (1 M, 41.4 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 2 hours. Aqueous NaOH (23.0 mL, 3 N) was added thereto followed by H2O2 (10 mL, 30% in water). After addition, the mixture was continued to stir for 2 hours. The layers were then separated and the aqueous layer was extracted with ethyl acetate (40 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 77:23) to obtain the desired compound (1.7 g, 62.0% yield) as a white solid. [0790] 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.22 (m, 1H), 7.20 – 7.11 (m, 2H), 4.96 – 4.84 (m, 1H), 4.69 – 4.59 (m, 1H), 4.26 (dd, J = 11.6, 1.8 Hz, 1H), 3.94 – 3.84 (m, 2H), 3.80 (dd, J = 11.6, 3.3 Hz, 1H), 2.90 – 2.78 (m, 1H), 1.88 (brs, 1H). N-(2,2-Dimethoxyethyl)-4-nitrobenzenesulfonamide (6)
Figure imgf000278_0001
[0791] To a solution of 2,2-dimethoxyethan-1-amine (2.8 g, 27.0 mmol) and triethylamine (4.6 g, 45.0 mmol) in methylene chloride (30 mL ) was added 4-nitrobenzene-1-sulfonyl chloride (5.0 g, 22.5 mmol) by portions. After stirring at room temperature for 16 hours, the reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (3.0 g, 45.9% yield) as a yellow solid. [0792] 1H NMR (400 MHz, CDCl3) δ 8.40 – 8.34 (m, 2H), 8.08 – 8.03 (m, 2H), 4.86 (t, J = 5.9 Hz, 1H), 4.36 (t, J = 5.2 Hz, 1H), 3.33 (s, 6H), 3.17 – 3.07 (m, 2H). N-((8-Chloroisochroman-4-yl)methyl)-N-(2,2-dimethoxyethyl)-4-nitrobenzenesulfonamide (7)
Figure imgf000278_0002
[0793] Diethyl azodicarboxylate (2.6 g, 15.1 mmol) was added dropwise to a solution of 5 (1.5 g, 7.6 mmol), 6 (2.6 g, 9.1 mmol) and triphenylphosphine (4.0 g, 15.1 mmol) in dry THF (20 mL) at 0°C. After stirring at room temperature for 3 hours, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 4:1) to afford the desired compound (2.4 g, 67.6% yield) as a yellow oil. [0794] 1H NMR (400 MHz, CDCl3) δ 8.37 – 8.30 (m, 2H), 8.04 – 8.00 (m, 2H), 7.23 (dd, J = 7.9, 1.0 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.08 – 7.03 (m, 1H), 4.97 – 4.84 (m, 1H), 4.65 – 4.56 (m, 1H), 4.49 (t, J = 5.1 Hz, 1H), 4.19 – 4.13 (m, 1H), 3.78 – 3.61 (m, 2H), 3.36 (d, J = 2.9 Hz, 6H), 3.34 – 3.30 (m, 2H), 3.25 – 3.18 (m, 1H), 3.17 – 3.07 (m, 1H). 10-Chloro-5-((4-nitrophenyl)sulfonyl)-3,3a,4,5-tetrahydro-1H-isochromeno[4,5-cd]azepine (8)
Figure imgf000279_0001
[0795] To a solution of 7 (2.4 g, 5.1 mmol) in DCM (20 mL) was added AlCl3 (6.8 g, 50.9 mmol) under nitrogen atmosphere at 0°C, and the resulting mixture was stirred at 0°C for 4 hours. The reaction was quenched with NaOH (20 mL, 1 N) and extracted with DCM (20 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 4:1) to obtain the title compound (0.9 g, 43.4% yield) as a yellow solid. [0796] 1H NMR (400 MHz, CDCl3) δ 8.45 – 8.34 (m, 2H), 8.04 – 7.96 (m, 2H), 7.17 – 7.12 (m, 1H), 7.02 – 6.97 (m, 1H), 6.86 (dd, J = 10.4, 1.8 Hz, 1H), 5.72 (d, J = 10.5 Hz, 1H), 4.80 – 4.72 (m, 1H), 4.64 – 4.55 (m, 1H), 4.24 – 4.14 (m, 2H), 3.56 – 3.50 (m, 1H), 3.02 – 2.95 (m, 1H), 2.72 – 2.62 (m, 1H). 10-Chloro-5-((4-nitrophenyl)sulfonyl)-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5- cd]azepine (9)
Figure imgf000279_0002
[0797] Triethylsilane (0.2 mL, 1.3 mmol) was added dropwise to a solution of 8 (0.5 g, 1.2 mmol) in trifluoroacetic acid (5 mL) at -10°C. After stirring at room temperature for 5 hours, the reaction mixture was poured into ice-cold water, basified with aqueous NaHCO3, and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 2:1) to afforded the desired compound (350 mg, 70.0% yield) as yellow solid. [0798] 1H NMR (400 MHz, CDCl3) δ 8.34 – 8.21 (m, 2H), 7.88 – 7.79 (m, 2H), 7.12 – 7.06 (m, 1H), 6.95 – 6.87 (m, 1H), 4.71 – 4.54 (m, 2H), 4.23 – 4.10 (m, 1H), 4.08 – 4.02 (m, 1H), 3.98 – 3.86 (m, 3H), 3.22 – 3.02 (m, 2H), 2.92 – 2.77 (m, 2H). 10-Chloro-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (18)
Figure imgf000280_0001
[0799] A solution of 9 (0.3 g, 0.6 mmol), potassium carbonate (0.4 g, 3.1 mmol) and thiophenol (0.1 mL) in dry DMF (5 mL) was stirred at room temperature for 3 hours. Then, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: MeOH = 95:5) to obtain the crude compound which was further purified by prep- HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (65.0 mg, 47.7% yield) as a white solid. [0800] 1H NMR (400 MHz, DMSO-d6) δ 9.71 (brs, 1H), 9.41 (brs, 1H), 7.32 – 7.26 (m, 1H), 7.21 – 7.14 (m, 1H), 4.70 – 4.58 (m, 2H), 3.96 – 3.89 (m, 1H), 3.89 – 3.81 (m, 1H), 3.51 – 3.28 (m, 4H), 3.02 – 2.85 (m, 2H), 2.85 – 2.71 (m, 1H). [0801] MS(ESI) calculated for C12H14ClNO: 223.1; found, 224.2, 226.2 Procedure for Compound 19
Figure imgf000281_0001
Ethyl 2-(3-bromo-5-chlorophenyl)-2-cyanoacetate (1)
Figure imgf000281_0002
[0802] To a solution of ethyl 2-cyanoacetate (40.4 g, 0.4 mol) in NMP (300 mL) was added sodium hydride (14.3 g, 60% in mineral oil) at 0°C under nitrogen atmosphere. The reaction was stirred at room temperature for 2.5 hours.1-Bromo-3-chloro-5- fluorobenzene (15.0 g, 71.6 mmol) was added dropwise. The resulting mixture was stirred at 110°C for 19 hours. After cooling to room temperature, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether : ethyl acetate: = 10:1) to obtain the title compound (15.0 g, 69.1% yield) as colorless oil. [0803] 1H NMR (400 MHz, CDCl3) δ 7.57 (t, J = 1.7 Hz, 1H), 7.52 (t, J = 1.5 Hz, 1H), 7.42 (t, J = 1.6 Hz, 1H), 4.66 (s, 1H), 4.34 – 4.22 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H). 2-(3-Bromo-5-chlorophenyl)acetic acid (2)
Figure imgf000282_0001
[0804] A solution of 1 (15.0 g, 49.5 mmol) and sodium hydroxide (7.9 g, 0.2 mmol) in H2O (300 mL) was stirred at 110°C for 19 hours. After cooling to room temperature, the solvent was removed by rotary vacuum; the residue was acidified with HCl (2N) to pH ~3. The mixture was extracted with ethyl acetate (100 mL*4). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to obtain the title compound (12.0 g, 97.5 % yield) as a pale solid. [0805] 1H NMR (400 MHz, CDCl3) δ 11.11 (s, 1H), 7.45 (t, J = 1.7 Hz, 1H), 7.34 (s, 1H), 7.23 (d, J = 1.5 Hz, 1H), 3.61 (s, 2H). 2-(3-Bromo-5-chlorophenyl)ethan-1-ol (3)
Figure imgf000282_0002
[0806] To a solution of 2 (10.0 g, 40.0 mmol) in THF (300 mL) was added borane tetrahydrofuran complex (80 mL, 1M) at 0°C under nitrogen atmosphere. After stirring at room temperature for 19 hours, the reaction was quenched by MeOH. The mixture was concentrated to get the desired product (8.1 g, 85.9 % yield), which was suitable for the next step without further purification. Ethyl 8-bromo-6-chloro-3,4-dihydro-1H-2-benzopyran-1-carboxylate (4)
Figure imgf000282_0003
[0807] To a solution of 3 (8.0 g, 33.9 mmol) and ethyl 2,2-dimethoxyacetate (5.5 g, 37.2 mmol) in DCM (100 mL ) was added trifluoromethanesulfonic acid (15.1 g, 0.1 mol) at 0°C under nitrogen atmosphere. After stirring at room temperature for 2.5 hours, the reaction mixture was poured into water (250 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether :ethyl acetate: = 5:1) to obtain the mixture of title compound and ethyl 6-bromo-8-chloroisochromane-1- carboxylate (6.50 g, 60.1% yield) as a colorless oil. Ethyl 8-[(1Z)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]-6-chloro-3,4-dihydro-1H-2-benzopyran- 1-carboxylate (5)
Figure imgf000283_0001
[0808] A solution of 4 and its isomer (6.5 g, 20.3 mmol), t-BuOH (3.9 g, 30.4 mmol), Et3N (6.2 g, 60.9 mmol), PPh3 (0.3 g, 1.2 mmol) and Pd(OAc)2 (4.6 g, 20.3 mmol) in DMF (150 mL) was stirred at 110°C under nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (500 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with petroleum ether : ethyl acetate: =10:1) to obtain the title compound (5.0 g, 67.2 % yield) as a colorless oil. Ethyl 8-[3-(tert-butoxy)-3-oxopropyl]-6-chloro-3,4-dihydro-1H-2-benzopyran-1-carboxylate (6)
Figure imgf000283_0002
[0809] To a solution of 5 (2 g, 5.5 mmol) in ethyl acetate/THF/EtOH (60 mL, 1:1:1) was added 10% palladium on activated carbon (0.2 g), and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 2.5 hours. The mixture was then filtered through a pad of celite, the filtrate was concentrated to obtain the title compound (1.5 g, 74.6% yield) as a colorless oil. 3-[6-Chloro-1-(ethoxycarbonyl)-3,4-dihydro-1H-2-benzopyran-8-yl]propanoic acid (7)
Figure imgf000284_0001
[0810] To a solution of 6 (0.7 g, 1.9 mmol) in DCM (15 mL ) was added TFA (1.1 g, 9.4 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 19 hours. After which period, the solution was concentrated to get crude product (0.5 g, 84.6 % yield) which was suitable for the next step without further purification. Methyl 2-[7-(chloromethyl)-1,3-dihydro-2-benzofuran-1-yl]acetate (8)
Figure imgf000284_0002
[0811] To a solution of 7 (0.5 g, 1.6 mmol) and Et3N (0.5 g, 4.8 mmol) in t-BuOH (35 mL ) was added DPPA (0.6 g, 2.4 mmol). The resulting mixture was stirred at 90°C for 8.5 hours. After cooling to room temperature, the solvent was removed by reduced pressure, and the residue was purified by column chromatography to obtain the title compound (0.4 g, 65.5 % yield) as a colorless oil. [0812] 1H NMR (400 MHz, CDCl3) δ 7.08-7.04 (m, 2H), 5.40 (s, 1H), 4.30 – 4.20 (m, 2H), 4.18 – 4.04 (m, 1H), 3.99 – 3.89 (m, 1H), 3.46 – 3.20 (m, 2H), 2.98-2.94 (m, 1H), 2.88 – 2.71 (m, 2H), 2.70-2.64 (m, 1H), 1.45 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H).
2-(6-Chloro-1-(ethoxycarbonyl)isochroman-8-yl)ethan-1-aminium chloride (9)
Figure imgf000285_0001
[0813] To a solution of 8 (0.3 g, 0.8 mmol) in MeOH (15 mL) was added HCl/dioxane (2 mL, 4 M). After stirring at room temperature for 5.5 hours, the mixture was concentrated to obtain the title compound (0.2 g, 88.0% yield) as a colorless oil. 5-Chloro-2,3,7,8,9,10a-hexahydro-10H-isochromeno[1,8-cd]azepin-10-one (10)
Figure imgf000285_0002
[0814] AlMe3 (1.1 mL, 2.1 mmol) was added to a solution of 9 (0.2 g, 0.7 mmol) in toluene (15 mL ) at 0°C, and the resulting mixture was stirred at 50°C for 1.5 hours. After cooling to room temperature, the reaction was quenched with HCl (50 mL, 1 N). The mixture was extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluted with ethyl acetate) to obtain the title compound (0.1 g, 59.8 % yield) as a pale solid. [0815] 1H NMR (400 MHz, CDCl3) δ 7.05-7.02 (m, 2H), 6.05 (brs, 1H), 5.73 (s, 1H), 4.27- 4.21 (m, 1H), 4.18 – 3.98 (m, 1H), 3.78-3.71 (m, 1H), 3.43 – 3.29 (m, 1H), 3.23-3.16 (m, 1H), 3.09 – 2.86 (m, 2H), 2.81-2.75 (m, 1H). 5-Chloro-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepin-9-ium chloride (19)
Figure imgf000285_0003
[0816] To a solution of 10 (0.1 g, 0.4 mmol) in THF (5 mL) was added borane- tetrahydrofuran complex (2 mL, 1 M) at 0°C, and the resulting mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the reaction was quenched by MeOH, and concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to get the title compound (20.0 mg, 21.2 % yield) as a pale solid. [0817] 1H NMR (400 MHz, DMSO-d6) δ 9.76 (brs, 1H), 9.45 (brs, 1H), 7.21-7.20 (m, 2H), 5.20 (d, J = 9.4 Hz, 1H), 3.99-3.94 (m, 1H), 3.74 – 3.63 (m, 1H), 3.49-3.44 (m, 1H), 3.39- 3.35 (m, 1H), 3.20 – 2.90 (m, 3H), 2.90 – 2.62 (m, 3H). [0818] MS(ESI) calculated for C12H14ClNO: 223.1; found 224.2, 226.2 Procedure for Compound 20
Figure imgf000286_0001
General procedure E: tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,7,8,10,10a-hexahydro-9H- isochromeno[1,8-cd]azepine-9-carboxylate (1)
Figure imgf000286_0002
[0819] A solution of tert-butyl 4-chloro-2,3,7,8,10,10a-hexahydro-9H-isochromeno[1,8- cd]azepine-9-carboxylate (690 mg, 1.9 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.7 g, 2.8 mmol), Pd(PPh3)4 (215.3 mg, 0.2 mmol), Xphos (266.3 mg, 0.5 mmol) and KOAc (0.5 g, 5.5 mmol) in dioxane (40 mL) was stirred at 105oC under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain the desired compound (0.8 g, 90.9% yield) as a yellow solid. [0820] MS(ESI) calculated for C23H34BNO5, 415.3; found 316.1 tert-Butyl-4-methoxy-2,3,7,8,10,10a-hexahydro-9H-isochromeno[1,8-cd]azepine-9- carboxylate (2)
Figure imgf000287_0001
[0821] To a solution of 1 (150 mg, 0.36 mmol) in methanol (3 mL) and DCM (3 mL) was added Cu(OAc)2 (130 mg, 0.72 mmol), N,N-dimethylpyridin-4-amine (52.7 mg, 0.43 mmol) and 4Å molecular sieves (about 2 g). After stirring at 40°C for 5 hours, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=88:12) to obtain the title product (80 mg, 69.5% yield) as colorless oil. [0822] MS(ESI) calculated for C18H25NO4: 319.7; found 264.2 4-Methoxy-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepin-9-ium chloride (20)
Figure imgf000287_0002
[0823] To a solution of 1 (80 mg, 0.3 mmol) in methylene chloride (2 mL) was added HCl/MeOH (4 mL,4 M), and the resulting mixture was stirred at 30°C for 2 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (25.2 mg, 46.6% yield) as a white solid. [0824] 1H NMR (400 MHz, DMSO-d6) δ 9.69 (brs, 2H), 7.06 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.19 (d, J = 9.6 Hz, 1H), 4.02 – 3.91 (m, 1H), 3.78 (s, 3H), 3.74 – 3.61 (m, 1H), 3.46 (d, J = 4.9 Hz, 2H), 3.19 – 2.96 (m, 2H), 2.90-2.84(m, 1H), 2.72 (t, J = 12.5 Hz, 1H), 2.58 (d, J = 8.6 Hz, 2H). [0825] MS(ESI) calculated for C13H17NO2: 219.1; found 220.2 Procedure for Compound 172
Figure imgf000288_0001
General procedure F: (9-(tert-Butoxycarbonyl)-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepin-4- yl)boronic acid (1)
Figure imgf000288_0002
[0826] To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,3,7,8,10,10a-hexahydro-9H-isochromeno[1,8-cd]azepine-9-carboxylate (100.0 mg, 0.2 mmol) in acetone/H2O (3 mL, 2:1) was added NaIO4 (103.0 mg, 0.4 mmol) and NH4OAc (37.0 mg, 0.4 mmol). After stirring at room temperature for 48 hours, the mixture was concentrated to dryness. The residue was dissolved in ethyl acetate (10 mL) and filtered through a pad of celite. The filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (60.0 mg, 75.0% yield) as a yellow oil. [0827] MS(ESI) calculated for C17H24BNO5: 333.1; found 278.1
tert-Butyl 4-fluoro-2,3,7,8,10,10a-hexahydro-9H-isochromeno[1,8-cd]azepine-9-carboxylate (2)
Figure imgf000289_0001
[0828] A solution of 1 (60.0 mg, 0.2 mmol) and NaOH (9.6 mg, 0.2 mmol) in dry MeOH (2 ml) was stirred at room temperature for 15 minutes, then cooled to 0°C. AgOTf (154.2 mg, 0.6 mmol) was added thereto and stirring continued at 0°C for 30 min. The solvent was removed in vacuo at 0oC, and the residue was re-dissolved in dry acetone (2 ml). Selectfluor (89.0 mg, 0.2 mmol) was added to the above solution. After stirring at room temperature for 30 min, the mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was diluted with water (5 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (30.0 mg, 54.5%) as a yellow oil. [0829] 1H NMR (400 MHz, CDCl3) δ 6.97 – 6.91 (m, 1H), 6.85-6.80 (m, 1H), 4.79-4.69 (m, 1H), 4.31-4.61 (m, 2H), 4.14 – 4.08 (m, 1H), 3.74-3.65 (m, 1H), 3.05-2.96 (m, 1H), 2.87 – 2.73 (m, 5H), 1.47 (s, 9H). [0830] MS(ESI) calculated for C17H22FNO3: 307.2; found 252.1 4-Fluoro-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepin-9-ium chloride (172)
Figure imgf000289_0002
[0831] To a solution of 2 (30.0 mg, 0.1 mmol) in DCM (1 mL) was added HCl/dioxane (0.2 mL, 4 M), and the resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (12.9 mg, 54.4% yield) as a white solid. [0832] 1H NMR (400 MHz, DMSO-d6) δ 9.52 (brs, 2H), 7.16-7.10 (m, 1H), 7.09-7.01 (m, 1H), 5.20 (d, J = 9.3 Hz, 1H), 4.04 – 3.95 (m, 1H), 3.77 – 3.66 (m, 1H), 3.50-3.43 (m, 1H), 3.42-3.35 (m, 1H), 3.16 – 3.04 (m, 2H), 2.99-2.91 (m, 1H), 2.83-2.75 (m, 1H), 2.73-2.634 (m, 2H). [0833] MS(ESI) calculated for C12H14FNO: 207.2; found 208.2 Procedure for Compound 173
Figure imgf000290_0001
General procedure G: 2-(2-Bromo-6-chlorophenyl)acetonitrile (1)
Figure imgf000290_0002
[0834] To a solution of 1-bromo-2-(bromomethyl)-3-chlorobenzene (8.0 g, 28.1 mmol) and trimethylsilanecarbonitrile (4.2 g, 42.1 mmol) in CH3CN (150 mL) was added Bu4NF (42mL, 1M in THF) at room temperature, and the resulting mixture was stirred for 2 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (6.0 g, 92.9% yield) as a white solid.. [0835] 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 4.06 (s, 2H). tert-Butyl (2-bromo-6-chlorophenethyl)carbamate (2)
Figure imgf000291_0001
[0836] To a solution of 1 (7.0 g, 30.3 mmol) in THF (50 mL) was added BH3-THF (151 mL, 1M) at room temperature, and the resulting mixture was stirred at 70°C for 4 hours. After cooling to room temperature, the reaction was quenched with the addition of methanol and concentrated to dryness. The residue was redissolved in HCl/methanol (50 mL, 1 M) and stirred at 70oC for 2 hours. The mixture was concentrated to obtain the crude compound (7.5 g) as colorless oil. [0837] To a solution of the above compound (7.5 g, 27.9 mmol) in CH3CN/water (50 mL/25 mL) was added sodium carbonate (15.7 g, 149.0 mmol), Boc2O (13.5 g, 59.6 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (7.0 g, 69% yield over 2 steps) as a white solid. [0838] MS(ESI) calculated for C13H17BrClNO2: 333.0; found 233.9, 235.9 tert-Butyl allyl(2-bromo-6-chlorophenethyl)carbamate (3)
Figure imgf000291_0002
[0839] To a solution of 2 (7.0 g, 20.9 mmol), potassium carbonate (3.7 g, 27.1 mmol), KOH (3.5 g, 62.6 mmol) and Bu4NBr (0.7 g, 2.1 mmol) in toluene (200 mL) was added 3- bromoprop-1-ene (7.6 g, 62.6 mmol). The resulting mixture was stirred at 80°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the title compound (7.0 g, 89.3% yield) as a colorless oil. [0840] 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 5.77 (br, 1H), 5.12 (br, 2H), 3.90-3.75 (m, 1H), 3.90-3.75 (m, 2H), 3.41 (br, 1H), 3.20 (br, 1H). tert-Butyl 6-chloro-1-methylene-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate (4)
Figure imgf000292_0001
[0841] A solution of 3 (4.0 g, 10.6mol), Pd(OAc)2 (235 mg, 1.1 mmol), triphenylphosphine (552 mg, 2.1 mmol), KOAc (3.1 g, 31.8 mmol) and Bu4NBr (3.4 g, 10.6 mmol) in DMF (60 mL) was stirred at 120°C for 3 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (0.7 g, 22.5% yield) as a colorless oil. [0842] 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 5.21-5.17 (m, 2H), 4.20-4.14 (m, 2H), 3.66-3.53 (m, 2H), 3.10-2.97 (m, 2H), 1.27 (s, 4H), 1.19 (s, 5H). tert-Butyl 6-chloro-1-(hydroxymethyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate (5)
Figure imgf000292_0002
[0843] To a solution of 4 (300 mg, 1.0 mmol) in dry THF (3 mL) was added BH3-THF (2.0 mL, 1 M) dropwise at 0°C under nitrogen atmosphere. The solution was stirred at room temperature for 1 hour. The reaction was cooled to 0oC, and water (2 mL), aqueous NaOH (1 mL, 1 N) and H2O2 (1 mL, 30% in water) were added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (200 mg, 62.9% yield) as colorless oil. [0844] 1H NMR (400 MHz, CDCl3) δ 7.28-7.26 (m, 1H), 7.11-7.05 (m, 2H), 4.48-4.43 (m, 1H), 4.27-4.22 (m, 1H), 3.75-3.69 (m, 1H), 3.61-3.52 (m, 2H), 3.21-3.10 (m, 2H), 2.91-2.85 (m, 1H), 2.81-2.75 (m, 1H), 1.48 (s, 9H). 8-Chloro-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (173)
Figure imgf000293_0001
[0845] To a solution of 5 (150 mg, 0.5 mmol) and paraformaldehyde (138.7 mg, 4.8 mmol) in dichloromethane (15 mL) was added trifluoromethanesulfonic acid (346.5 mg, 2.4 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. Then, the reaction was quenched with addition of saturated aqueous NaHCO3 (60 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (64.6 mg, 24.8% yield) as a white solid. [0846] 1H NMR (400 MHz, DMSO-d6) δ 9.29 (br, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.69-4.60 (m, 2H), 3.93-3.89 (m, 1H), 3.85-3.81 (m, 1H), 3.58-3.36 (m, 4H), 3.22-3.15 (m, 1H), 2.97-2.91 (m, 1H), 2.82 (t, J = 12.0 Hz, 1H), [0847] MS(ESI) calculated for C12H14ClNO: 223.1; found 224.2, 226.2 Procedure for Compound 90-1 (Trans isomer, enantiomer 1)
Figure imgf000294_0001
General procedure I: (E)-2-(2-Nitrovinyl)phenol (1)
Figure imgf000294_0002
[0848] To a mixture of 2-hydroxybenzaldehyde (400.0 mg, 3.3 mmol), nitromethane (2.4 g, 39.3 mmol) and acetic acid (1.8 g, 29.9 mmol) was added pyrrolidine (696.8 mg, 9.8 mmol) dropwise at 0°C. After stirring at room temperature for 16 hours, the mixture was poured into water, and the orange oil in the bottom layer was collected and washed with petroleum ether (20 mL*2) to obtain the desired product (400.5 mg, 73.9 % yield) as an orange solid. [0849] 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 13.6 Hz, 1H), 7.95 (d, J = 13.6 Hz, 1H), 7.44 (dd, J = 7.7, 1.5 Hz, 1H), 7.35 (td, J = 8.1, 1.6 Hz, 1H), 7.02 (td, J = 7.6, 0.8 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 5.66 (s, 1H). (3S,4S)-4-(Nitromethyl)chromane-3-carbaldehyde (2)
Figure imgf000294_0003
[0850] To a solution of 1 (400.0 mg, 2.4 mmol) and (2S)-2- {diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine (78.7 mg, 0.2 mmol) in toluene (10 mL), freshly distilled prop-2-enal (405.8 mg, 7.3 mmol, in 10 mL toluene) was added via a syringe pump over a period of 12 hours. After stirring at room temperature for 2 days, the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =3:1) to obtain the desired product (222.3 mg, 41.3 % yield) as an orange oil. [0851] 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.17 (m, 2H), 6.99 – 6.93 (m, 1H), 6.84 (t, J = 8.8 Hz, 1H), 4.80 – 4.71 (m, 2H), 4.65 – 4.58 (m, 1H), 4.26 (dd, J = 12.1, 2.9 Hz, 1H), 4.21 – 4.12 (m, 1H), 2.90 (dd, J = 5.0, 2.8 Hz, 1H).^ Ethyl (E)-3-((3S,4S)-4-(nitromethyl)chroman-3-yl)acrylate (3)
Figure imgf000295_0001
[0852] A mixture of 2 (1.5 g, 6.8 mmol) and ethyl 2-(triphenyl-l5- phosphanylidene)acetate (2.8 g, 8.1 mmol) in toluene (20 mL) was stirred at 110°C for 2 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (eluted with petroleum ether: ethyl acetate =3:1) to obtain the desired product (1.3 g, 66.8% yield) as a yellow oil. [0853] 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.16 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.95 (td, J = 7.6, 1.1 Hz, 1H), 6.92 – 6.82 (m, 2H), 6.02 (dd, J = 15.8, 1.1 Hz, 1H), 4.73 – 4.61 (m, 2H), 4.26 – 4.21 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.69 – 3.59 (m, 1H), 2.83 (dd, J = 6.9, 3.3 Hz, 1H), 1.27 (dd, J = 8.8, 5.5 Hz, 3H).^ Ethyl 3-((3S,4S)-4-(aminomethyl)chroman-3-yl)propanoate (4)
Figure imgf000295_0002
[0854] A solution of 3 (1.2 g, 4.1 mmol) and 10% palladium on activated carbon (120.0 mg) in ethyl acetate (15 mL) was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the desired product (1.0 g, 92.7% yield) as yellow oil. (5aS,11bS)-1,4,5,5a,6,11b-Hexahydrochromeno[4,3-c]azepin-3(2H)-one (5)
Figure imgf000296_0001
[0855] AlMe3 (2.0 mL, 2 M in toluene) was added to a solution of 4 (200.0 mg, 0.8 mmol) in toluene (10 mL), and the resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with HCl (1N), diluted with water (15 mL) and extracted with ethyl acetate (10 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to purify by column chromatography (eluted with DCM: MeOH=15:1) to obtain the desired product (179.9 mg, 98.0 % yield) as a white solid. [0856] MS(ESI) calculated for C13H15NO2: 217.1; found 218.2 (5aS,11bS)-1,2,3,4,5,5a,6,11b-Octahydrochromeno[4,3-c]azepin-2-ium chloride (90-1 (enantiomer 1))
Figure imgf000296_0002
[0857] To a solution of 5 (179.9 mg, 0.8 mmol) in THF (5 mL) was added BH3-THF (4.1 mL, 1M); the resulting mixture was refluxed for 3 hours. After cooling to room temperature, the reaction was quenched with MeOH (2 mL) and concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (50.0 mg, 29.6 % yield) as a white solid. [0858] 1H NMR (400 MHz, DMSO-d6) δ 9.18 (brs, 2H), 7.32 (d, J = 7.7 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 6.93 (td, J = 7.7, 1.2 Hz, 1H), 6.81 (dd, J = 8.1, 1.1 Hz, 1H), 4.13 (dd, J = 10.8, 4.0 Hz, 1H), 3.73 (dd, J = 13.1, 3.8 Hz, 1H), 3.53 (t, J = 11.2 Hz, 1H), 3.26 – 3.10 (m, 3H), 2.88 (dd, J = 12.9, 11.0 Hz, 1H), 2.18 – 2.03 (m, 1H), 2.03 – 1.82 (m, 2H), 1.78 (m, 1H), 1.36 – 1.16 (m, 1H). [0859] MS(ESI) calculated for C13H17NO: 203.1; found 204.2 Procedure for Compound 90-2 (Trans isomer, enantiomer 2)
Figure imgf000297_0001
8‐Oxa‐14‐azatricyclo[8.5.0.02,7]pentadeca‐2(7),3,5‐triene (90-2 (enantiomer 2)) [0860] Following the same procedure described in General Procedure I, the title compound was synthesized (44.0 mg, 26.7% yield) from (2R)-2- {diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine as a white solid. [0861] 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.26 (s, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.19 – 7.08 (m, 1H), 6.93 (td, J = 7.6, 1.3 Hz, 1H), 6.81 (dd, J = 8.1, 1.2 Hz, 1H), 4.13 (dd, J = 10.8, 4.1 Hz, 1H), 3.72 (m, 1H), 3.53 (t, J = 11.2 Hz, 1H), 3.29 – 3.09 (m, 3H), 2.98 – 2.77 (m, 1H), 2.10 (m, 1H), 2.02 – 1.84 (m, 2H), 1.78 (m, 1H), 1.36 – 1.17 (m, 1H). [0862] MS(ESI) calculated for C13H17NO: 203.1; found 204.2
Procedure for Compound 176
Figure imgf000298_0001
2-(2-Bromo-5-chlorophenyl)acetonitrile (1)
Figure imgf000298_0002
[0863] To a solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (20.0 g, 70.3 mmol) and TMSCN (11.4 mL, 91.3 mmol) in acetonitrile (200 mL) was added tetrabutylammonium fluoride (91.3 mL, 1 M in THF) at 0°C. After stirring at room temperature for 3 hours, the mixture was poured into ice water and the phases were separated. The aqueous layer was extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the title compound (18.5 g, crude) as a white solid. [0864] 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.51 (m, 2H), 7.22 (dd, J = 8.5, 2.4 Hz, 1H), 3.82 (s, 2H). Ethyl 2-(2-bromo-5-chlorophenyl)acetate (2)
Figure imgf000299_0001
[0865] To a solution of 1 (18.5 g, crude) in EtOH (100 mL) was added concentrated HCl (100 mL) slowly at 0°C, and the resulting mixture was refluxed for 16 hours. After cooling to room temperature, the mixture was poured into ice water (500 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (18.1 g, 81.3% yield, two steps) as a white solid. [0866] 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 8.5, 2.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H). Ethyl 2-(2-bromo-5-chlorophenyl)-2-methylpropanoate (3)
Figure imgf000299_0002
[0867] To a solution of 2 (17.1 g, 61.6 mmol) in tetrahydrofuran (200 mL) was added LiHMDS (183 mL, 1 M) dropwise at 0°C, and the resulting mixture was stirred at 0°C for 30 min. Methyl iodide (11.4 mL, 184 mmol) was added to the above solution dropwise. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate (100 mL*3). The combined layers were dried over sodium sulfate, filtrated and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10: 1) to give the title compound (13.9 g, 73.9% yield) as yellow oil. [0868] 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 8.4, 2.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 1.62 (s, 6H), 1.20 (t, J = 7.1 Hz, 3H). 2-(2-Bromo-5-chlorophenyl)-2-methylpropan-1-ol (4)
Figure imgf000300_0001
[0869] To a solution of 3 (10.0 g, 32.7 mmol) in THF (100 mL ) was added BH3.Me2S (19.5 mL, 10 M) at 0°C, and the resulting mixture was heated to reflux for 19 hours. After cooling to room temperature, the reaction was quenched with MeOH; the mixture was concentrated to obtain the desired product (7.0 g, 81.3 % yield) as a colorless oil. [0870] 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.06 (dd, J = 8.4, 2.5 Hz, 1H), 4.03 (s, 2H), 1.49 (s, 6H). Ethyl 5-bromo-8-chloro-4,4-dimethyl-3,4-dihydro-1H-2-benzopyran-1-carboxylate (5)
Figure imgf000300_0002
[0871] To a solution of 4 (7.0 g, 26.5 mmol) and ethyl 2,2-dimethoxyacetate (4.3 g, 29.0 mmol) in DCM (50 mL) was added trifluoromethanesulfonic acid (11.9 g, 79.5 mmol) dropwise at 0°C. After stirring at room temperature for 3.5 hours, the reaction mixture was poured into water (150 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10: 1) to obtain the desired product (6.6 g, 71.6 % yield) as a colorless oil. [0872] 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 5.38 (s, 1H), 4.35 – 4.19 (m, 2H), 3.69 (d, J = 11.7 Hz, 1H), 3.53 (d, J = 11.7 Hz, 1H), 1.50 (s, 3H), 1.48 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). Ethyl 8-chloro-4,4-dimethyl-3,4-dihydro-1H-2-benzopyran-1-carboxylate (6)
Figure imgf000301_0001
[0873] To a solution of 5 (6.5 g, 18.6 mmol) in THF (100 mL ) was added n-BuLi (2.5 M, 11.1 mL) dropwise at -60°C under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 1 hour. The solution was poured into saturated aqueous NH4Cl and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =20:1) to obtain the desired product (4.0 g, 80.1 % yield) as colorless oil. [0874] 1H NMR (400 MHz, CDCl3) δ 7.31-7.19 (m, 3H), 5.39 (s, 1H), 4.38 – 4.13 (m, 2H), 3.75 (d, J = 11.4 Hz, 1H), 3.58 (d, J = 11.4 Hz, 1H), 1.34-1.26 (m, 9H). Ethyl 8-ethenyl-4,4-dimethyl-3,4-dihydro-1H-2-benzopyran-1-carboxylate (7)
Figure imgf000301_0002
[0875] A solution of ethyl 8-chloro-4,4-dimethyl-3,4-dihydro-1H-2-benzopyran-1- carboxylate 6 (2.8 g, 10.4 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.20 g, 20.8 mmol), K3PO4 (6.6 g, 31.2 mmol), Cy3P (174 mg, 624 μmol) and Pd2(dba)3 (285 mg, 0.3 mmol) in DMF (50 mL) was stirred at 140°C for 19 hours under nitrogen atmosphere in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to obtain the desired product (1.2 g, 44.4 % yield) as a light yellow oil. [0876] 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.16 (m, 3H), 6.69 (dd, J = 17.1, 10.9 Hz, 1H), 5.60 (dd, J = 17.1, 1.3 Hz, 1H), 5.43 (s, 1H), 5.39 – 5.17 (m, 1H), 4.35 – 4.10 (m, 2H), 3.83 (d, J = 11.3 Hz, 1H), 3.58 (d, J = 11.3 Hz, 1H), 1.30-1.27 (m, 9H). Ethyl 8-(2-hydroxyethyl)-4,4-dimethyl-3,4-dihydro-1H-2-benzopyran-1-carboxylate (8)
Figure imgf000302_0001
[0877] To a solution of 7 (1.0 g, 3.8 mmol) in THF (15 mL) was added borane tetrahydrofuran complex (11.5 mL, 1 M) at 0°C, and the resulting mixture was stirred at room temperature for 2.5 hours. Aqueous NaOH (15.3 mL, 1N) was added, followed by H2O2 (2.17 mL, 30% in water) and the reaction was stirred for 1 hour at room temperature. The resulting mixture was extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to obtain the desired product (0.6 g, 46.9 % yield) as a colorless oil. [0878] 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.21 (m, 2H), 7.14 – 7.06 (m, 1H), 5.48 (s, 1H), 4.26 (qd, J = 7.1, 2.7 Hz, 2H), 3.85 (t, J = 6.7 Hz, 2H), 3.78 (d, J = 11.4 Hz, 1H), 3.59 (d, J = 11.4 Hz, 1H), 2.81 –2.65 (m, 2H), 1.39 – 1.16 (m, 9H). Ethyl 8-[2-(methanesulfonyloxy)ethyl]-4,4-dimethyl-3,4-dihydro-1H-2-benzopyran-1- carboxylate (9)
Figure imgf000302_0002
[0879] To a solution of 8 (0.5 g, 1.8 mmol) and Et3N (0.5 g, 5.4 mmol) in DCM (25 mL) was added MsCl (0.5 g, 4.0 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 2.5 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to obtain crude desired product (0.5 g, 78.7 % yield) as a light-yellow oil. Ethyl 8-(2-azidoethyl)-4,4-dimethyl-3,4-dihydro-1H-2-benzopyran-1-carboxylate (10)
Figure imgf000303_0001
[0880] A solution of 9 (0.5 g, 1.4 mmol), NaN3 (0.2 g, 2.8 mmol) and Et3N (0.4 g, 4.2 mmol) in DMF (25 mL) and H2O (5 mL) was stirred at 80°C for 2.5 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=10:1) to obtain the desired product (0.35 g, 82.3 % yield) as a colorless oil. [0881] 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.21 (m, 2H), 7.05 (dd, J = 6.7, 2.1 Hz, 1H), 5.44 (s, 1H), 4.27 (tt, J = 7.2, 3.7 Hz, 2H), 3.79 (d, J = 11.4 Hz, 1H), 3.59 (d, J = 11.4 Hz, 1H), 3.47 (t, J = 7.6 Hz, 2H), 2.85 – 2.62 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 1.30 (s, 3H), 1.26 (s, 3H). 3,3-Dimethyl-2,3,7,8,9,10a-hexahydro-10H-isochromeno[1,8-cd]azepin-10-one (11)
Figure imgf000303_0002
[0882] A solution of 10 (0.35 g, 1.2 mmol) and PPh3 (0.6 g, 2.3 mmol) in THF (15 mL ) and H2O (5 mL) was stirred at 70°C for 19 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to obtain the desired product (0.2 g, 75.4 % yield) as a colorless oil. [0883] 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 7.1 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 3.98 (d, J = 11.4 Hz, 1H), 3.77 – 3.63 (m, 2H), 3.39 – 3.17 (m, 2H), 3.03 – 2.86 (m, 1H), 1.31 (s, 3H), 1.25 (s, 3H). 3,3-Dimethyl-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepin-9-ium chloride (176)
Figure imgf000304_0001
[0884] To a solution of 11 (0.2 g, 0.9 mmol) in THF (10 mL) was added borane tetrahydrofuran complex (3 mL, 1M) at 0°C under nitrogen atmosphere. After refluxing for 2.5 hours, the reaction was quenched with MeOH (10 mL); the resulting mixture was concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired product (65.0 mg, 31.9%) as a pale solid. [0885] 1H NMR (400 MHz, DMSO-d6) δ 10.09 (brs, 1H), 9.60 (brs, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 5.31 (d, J = 8.7 Hz, 1H), 3.59 (d, J = 11.1 Hz, 2H), 3.45 (d, J = 11.1 Hz, 1H), 3.38 (d, J = 12.7 Hz, 1H), 3.27 – 3.12 (m, 1H), 3.09- 3.01 (m, 1H), 2.91 (dd, J = 15.7, 5.3 Hz, 1H), 2.83-2.74 (m, 1H), 1.24 (s, 3H), 1.16 (s, 3H). [0886] MS(ESI) calculated for C14H19NO: 217.1; found 218.2 Procedure for Compound 177
Figure imgf000304_0002
General Procedure J: tert-Butyl 4-bromo-2,3,7,8,10,10a-hexahydro-9H-isochromeno[1,8-cd]azepine-9-carboxylate (1)
Figure imgf000304_0003
[0887] A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,3,7,8,10,10a-hexahydro-9H-isochromeno[1,8-cd]azepine-9-carboxylate (150 mg, 0.4 mmol) and CuBr2 (267.6 mg, 1.2 mmol) in MeOH/H2O (2 mL, 1:1) was stirred at 70oC for 16 hours. After cooling to room temperature, the mixture was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (75.0 mg, 56.4% yield) as a yellow oil. [0888] 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.91-4.69 (m, 1H), 4.30 – 4.06 (m, 3H), 3.78 – 3.63 (m, 1H), 3.08 – 2.98 (m, 1H), 2.90 – 2.72 (m, 5H), 1.46 (s, 9H). [0889] MS(ESI) calculated for C17H22BrNO3: 367.1; found 270.0, 272.0 4-Bromo-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepin-9-ium chloride (177)
Figure imgf000305_0001
[0890] To a solution of 1 (75.0 mg, 0.2 mmol) in DCM (2 mL) was added HCl/dioxane (1 mL, 4 M), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated and slurried with EA/MeOH (20:1) to obtain the desired compound (48.1 mg, 77.7% yield) as a white solid. [0891] 1H NMR (400 MHz, DMSO-d6) δ 9.68 (brs, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 5.25 (d, J = 9.3 Hz, 1H), 4.05-3.94 (m, 1H), 3.81 – 3.69 (m, 1H), 3.52-3.42 (m, 1H), 3.40-3.35 (m, 1H), 3.20 – 3.06 (m, 2H), 2.99-2.89 (m, 1H), 2.77 (t, J = 12.3 Hz, 1H), 2.72-2.65 (m, 2H). [0892] MS(ESI) calculated for C12H14BrNO: 267.0; found 270.2, 272.0
Procedure for 178
Figure imgf000306_0001
8‐Methoxy‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (178) [0893] Following the same procedure describe in General Procedure E, the title compound was synthesized (15.0 mg, 27.3% yield) from tert‐butyl 8‐chloro‐3‐oxa‐12‐ azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene‐12‐carboxylate as a white solid. [0894] 1H NMR (400 MHz, DMSO-d6) δ 9.28 (brs, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.64-4.56 (m, 2H), 3.84-3.89 (m, 1H), 3.79-3.75 (m, 4H), 3.52-3.45 (m, 2H), 3.36-3.28 (m, 2H), 2.92-2.76 (m.2H), 2.75-2.67 (m.2H). [0895] MS(ESI) calculated for C13H17NO2: 219.1; found 220.2 Procedure for Compound 186
Figure imgf000306_0002
(6-Bromo-2H-1,3-benzodioxol-5-yl)methanol (1)
Figure imgf000306_0003
[0896] 1-Bromopyrrolidine-2,5-dione (23.3 g, 131.0 mmol) was added to a solution of benzo[d][1,3]dioxol-5-ylmethanol (20 g, 131.0 mmol) in DCM (300 mL) at 0°C, and the resulting mixture was stirred at 20°C for 2.5 hours. The reaction mixture was washed with saturated aqueous Na2SO3 and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain the desired product (19.0 g, 62.9 % yield) as a white solid. [0897] 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 6.97 (s, 1H), 5.98 (s, 2H), 4.64 (s, 2H), 2.76 (s, 1H). 5-Bromo-6-[(prop-2-en-1-yloxy)methyl]-2H-1,3-benzodioxole (2)
Figure imgf000307_0001
[0898] To a solution of 1 (20.0 g, 86.5 mmol) in DMF (300 mL) was added NaH (4.1 g, 0.1 mol, 60% in mineral oil) at 0°C, and the resulting mixture was stirred at 20°C for 1 hour. 3- bromoprop-1-ene (15.6 g, 0.1 mol) was added to above solution slowly. After addition, the mixture was stirred for 2.5 hours. After which period, the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether :ethyl acetate: =10:1) to obtain the desired product (20.0 g, 85.2% yield) as a colorless oil. [0899] 1H NMR (400 MHz, CDCl3) δ 6.99 (s, 2H), 6.07 – 5.88 (m, 3H), 5.41 – 5.14 (m, 2H), 4.49 (s, 2H), 4.07 (dt, J = 5.6, 1.4 Hz, 2H). 8-Methylene-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene (3)
Figure imgf000307_0002
[0900] A solution of 2 (15.0 g, 55.3 mmol), tetraethylammonium chloride (13.7 g, 82.9 mmol), PPh3 (868.0 mg, 3.3 mmol), Pd(OAc)2 (370.0 mg, 1.6 mmol) and potassium acetate (27.0 g, 0.3 mol) in DMF (150 mL) was stirred at 120°C for 19 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into water (250 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to obtain the desired product (3.0 g, 28.5 % yield) as a colorless oil. [0901] 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 6.47 (s, 1H), 5.94 (s, 2H), 5.39 (s, 1H), 4.90 (s, 1H), 4.71 (s, 2H), 4.39 (s, 2H). (7,8-Dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-8-yl)methanol (4)
Figure imgf000308_0001
[0902] To a solution of 3 (3.0 g, 15.7 mmol) in THF (100 mL ) was added borane- tetrahydrofuran complex (47.0 mL, 1 M) at 0°C, and the resulting mixture was stirred at room temperature for 1.5 hours. Aqueous NaOH (78.4 mL, 1 N) and H2O2 (8.9 mL, 30% in water) were added. After stirring at room temperature for 3 hours, the mixture was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=1:1) to obtain the desired product (2.2 g, 67.9 % yield) as colorless oil. [0903] 1H NMR (400 MHz, CDCl3) δ 6.69 (s, 1H), 6.46 (s, 1H), 5.91 (dd, J = 4.9, 1.4 Hz, 2H), 4.73 – 4.57 (m, 2H), 4.21 (dd, J = 11.5, 2.1 Hz, 1H), 3.93 – 3.72 (m, 3H), 2.71 (brs, 1H), 2.04 (brs, 1H). N-((7,8-Dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-8-yl)methyl)-N-(2,2-dimethoxyethyl)- 1,1,1-trifluoromethanesulfonamide (5)
Figure imgf000308_0002
[0904] DEAD (2.5 g, 14.4 mmol) was added dropwise to a solution of 4 (1.5 g, 7.20 mmol), N-(2,2-dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (2.6 g, 10.8 mmol) and triphenylphosphine (3.8 g, 14.4 mmol) in THF (50 mL ) at 0°C. The resulting mixture was stirred at room temperature for 2.5 hours and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate: =10:1) to obtain the desired product (2.2 g, 71.6 % yield) as a colorless oil. [0905] 1H NMR (400 MHz, CDCl3) δ 6.61 (s, 1H), 6.45 (s, 1H), 5.92 (s, 2H), 4.74– 4.63 (m, 2H), 4.54 (t, J = 5.3 Hz, 1H), 4.17 – 4.04 (m, 1H), 3.81-3.75 (s, 1H), 3.69 (dd, J = 11.8, 2.7 Hz, 1H), 3.57 – 3.39 (m, 9H), 3.01-2.98 (m, 1H). 3-((Trifluoromethyl)sulfonyl)-3,4,4a,7-tetrahydro-5H-[1,3]dioxolo[4',5':6,7]isochromeno[4,5- cd]azepine (6)
Figure imgf000309_0001
[0906] TfOH (2.1 g, 14.0 mmol) was added to a solution of 5 (2.0 g, 4.7 mmol) and DIPEA (6.0 g, 46.6 mmol) in DCM (30 mL) at 0°C, and the resulting mixture was stirred at 20°C for 2 hours. The solution was diluted with DCM (50 mL), washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to obtain the desired compound (0.5g, 29.5 % yield) as a pale solid. [0907] 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J = 10.5 Hz, 1H), 6.38 (s, 1H), 6.04 – 5.90 (m, 3H), 4.71 – 4.56 (m, 2H), 4.23 (dd, J = 11.4, 6.3 Hz, 1H), 4.16 – 4.05 (m, 1H), 3.49 (dd, J = 11.3, 9.8 Hz, 1H), 3.32-3.26 (m, 1H), 3.15-3.09 (m, 1H). 3-((Trifluoromethyl)sulfonyl)-1,2,3,4,4a,7-hexahydro-5H- [1,3]dioxolo[4',5':6,7]isochromeno[4,5-cd]azepine (7)
Figure imgf000309_0002
[0908] A solution of 6 (0.5 g, 1.4 mmol) and 10% palladium on activated carbon (0.2 g ) in DMF (1 mL) and MeOH (15 mL) was stirred at 20°C for 2.5 hours under hydrogen atmosphere. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the desired product (349.1 mg, 69.8 % yield) as a light-yellow oil. 1,2,3,4,4a,7-Hexahydro-5H-[1,3]dioxolo[4',5':6,7]isochromeno[4,5-cd]azepin-3-ium chloride (186)
Figure imgf000310_0001
[0909] To a solution of 7 (0.4 g, 1.1 mmol) in THF (25 mL ) was added LiAlH4 (414.2 mg, 10.9 mmol) at 0°C, and the resulting mixture was stirred at 70°C for 2 hours. After cooling to room temperature, the reaction was quenched with sodium sulfate. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (0.1g, 34.0 % yield) as a white solid. [0910] 1H NMR (400 MHz, DMSO-d6) δ 9.62 (brs, 1H), 9.43 (brs, 1H), 6.58 (s, 1H), 5.98 (dd, J = 7.9, 0.7 Hz, 2H), 4.53 (s, 2H), 3.93-3.89 (m, 1H), 3.73-3.68 (m, 1H), 3.58-3.48 (m, 1H), 3.35-3.30 (m, 2H), 3.07-3.03 (m, 2H), 2.88-2.78 (m, 2H). [0911] MS(ESI) calculated for C13H15NO3: 233.1; found 234.2 Procedure for Compound 187
Figure imgf000310_0002
Methyl 2-phenylacrylate (1)
Figure imgf000310_0003
[0912] To a solution of methyl 2-phenylacetate (30.0 g, 200.0 mmol) in dry THF (300 mL) was added paraformaldehyde (24.0 g, 800.0 mmol), TBAB (3.2 g, 10 mmol) and K2CO3 (82.8 g, 600.0 mmol) under nitrogen atmosphere. After stirring at 30°C for 16 hours, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (11.0 g, 34.0% yield) as a yellow oil. [0913] 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.39 (m, 2H), 7.36 (m, 3H), 6.37 (d, J = 1.2 Hz, 1H), 5.90 (d, J = 1.2 Hz, 1H), 3.83 (s, 3H). Methyl 3-(benzylamino)-2-phenylpropanoate (2)
Figure imgf000311_0001
[0914] To a solution of 1 (11.0 g, 67.9 mmol) in MeOH (110 mL) was added benzylamine (10.9 g, 101.9 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated to dryness and the residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (12.0 g, 65.6% yield) as a yellow oil. [0915] 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.21 (m, 10H), 3.85 (dd, J = 8.6, 6.5 Hz, 1H), 3.80 (s, 2H), 3.67 (s, 3H), 3.34-3.24 (m, 1H), 2.97-2.88 (m, 1H). [0916] MS(ESI) calculated for C17H19NO2: 269.1; found 270.2 Methyl 4-(benzyl(3-methoxy-3-oxo-2-phenylpropyl)amino)butanoate (3)
Figure imgf000311_0002
[0917] To a solution of 2 (12.0 g, 44.6 mmol) in dioxane/H2O (120 mL, 5:1) was added methyl 4-bromobutanoate (12.1 g, 66.9 mmol), KI (0.7 g, 4.46 mmol) and K2CO3 (12.3 g, 89.2 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 100oC for 16 hours. After cooling to room temperature, the mixture was concentrated to dryness. The residue was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (13.0 g, 78.8% yield) as a yellow oil. [0918] 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.19 (m, 10H), 3.85-3.80 (mz, 1H), 3.72 – 3.69 (m, 1H), 3.67 (s, 3H), 3.61 (s, 3H), 3.54-3.49 (m, 1H), 3.29-3.21 (m, 1H), 2.75-2.61 (m, 1H), 2.53-2.44 (m, 1H), 2.43-2.35 (m, 1H), 2.28 – 2.10 (m, 2H), 1.78-1.69 (m, 2H). [0919] MS(ESI) calculated for C22H27NO4: 369.2; found 370.2 Methyl 4-((tert-butoxycarbonyl)(3-methoxy-3-oxo-2-phenylpropyl)amino)butanoate (4)
Figure imgf000312_0001
[0920] A solution of 3 (7.0 g, 19.0 mmol), Boc2O (12.4 g, 57.0 mmol) and Pd(OH)2/C (0.5 g, 3.8 mmol) in EtOH (70 mL) was stirred at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (6.0 g, 83.3% yield) as a yellow oil. [0921] MS(ESI) calculated for C20H29NO6: 379.2; found 280.2 tert-Butyl 4-oxo-3-phenylazepane-1-carboxylate (5)
Figure imgf000312_0002
[0922] LiHMDS (1M, 39.5 mL) was added dropwise to a solution of 4 (6.0 g, 15.8 mmol) in dry THF (200 mL) at -78°C under nitrogen atmosphere, and the resulting mixture was stirred at -78°C for 30 min, then at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL), and the phases were separated; the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was re-dissolved in THF (150 mL) and H2O (150 mL). K2CO3 (2.6g, 19.0 mmol) was added and the resulting mixture was stirred at 80°C for 3 h. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was adjusted to pH ~ 5.5 with HCl (1 N). The mixture was extracted with ethyl acetate (150 mL), washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (760.0 mg, 16.5% yield) as yellow oil. [0923] MS(ESI) calculated for C17H23NO3: 289.2; found 190.1 tert-Butyl 4-hydroxy-3-phenylazepane-1-carboxylate (6)
Figure imgf000313_0001
[0924] To a solution of 5 (600.0 mg, 2.1 mmol) in MeOH (4 mL) was added NaBH4 (119.7 mg, 3.15 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 2 hours. The mixture was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (400.0 mg, 66.2% yield) as a yellow oil. [0925] 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.20 (m, 5H), 4.10-4.00 (m, 1H), 3.98 – 3.80 (m, 1H), 3.75-3.63 (m, 1H), 3.56-3.43 (m, 1H), 3.32 – 3.14 (m, 1H), 3.09-2.91 (m, 1H), 2.23- 2.02 (m, 2H), 1.84 – 1.63 (m, 2H), 1.41 (s, 9H). [0926] MS(ESI) calculated for C17H25NO3: 291.2; found 191.1 1,2,3,4,5,5a,7,11b-Octahydroisochromeno[4,3-c]azepine (7)
Figure imgf000313_0002
[0927] To a solution of 6 (400.0 mg, 1.4 mmol) and paraformaldehyde (210.0 mg, 7.0 mmol) in dry DCM (4 mL) was added CF3SO3H (1.1 g, 7.0 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 min, then warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous NaHCO3, and the mixture was extracted with DCM (20 mL). The organic layer was washed with saturated brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was used for the next step without further purification. [0928] MS(ESI) calculated for C13H17NO: 203.1; found 204.2 tert-Butyl 3,4,5,5a,7,11b-hexahydroisochromeno[4,3-c]azepine-2(1H)-carboxylate (8)
Figure imgf000314_0001
[0929] A solution of 7 (crude) and Boc2O (457.8 mg, 2.1 mmol) in THF (5 mL) and saturated aqueous NaHCO3 (5 mL) was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (20 mL). The combined organic phase washed with saturated brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (250.0 mg, 60.1% yield) as a yellow oil. [0930] 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.27 (m, 1H), 7.25 – 7.13 (m, 2H), 7.02-6.94 (m, 1H), 4.90-4.76 (m, 2H), 3.95 – 3.77 (m, 2H), 3.75-3.59 (m, 1H), 3.32 – 3.01 (m, 2H), 2.97-2.77 (m, 1H), 2.27 – 2.08 (m, 2H), 1.76 – 1.65 (m, 2H), 1.59 (s, 9H). [0931] MS(ESI) calculated for C18H25NO3: 303.2; found 248.2 1,2,3,4,5,5a,7,11b-Octahydroisochromeno[4,3-c]azepin-2-ium chloride (187)
Figure imgf000314_0002
[0932] To a solution of 8 (60.0 mg, 0.2 mmol) in dry DCM (2 mL) was added HCl/dioxane (1 mL, 4 M), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness. The residue was slurried with EA/MeOH (20:1) to obtain the desired compound (162.8 mg, 56.5% yield) as a white solid. [0933] 1H NMR (400 MHz, DMSO-d6) δ 9.37 (brs, 2H), 7.38 (d, J = 7.1 Hz, 1H), 7.30 – 7.20 (m, 2H), 7.06 (d, J = 7.0 Hz, 1H), 4.83-4.76 (m, 1H), 4.73-4.65 (m, 1H), 3.98-3.88 (m, 1H), 3.40-3.34 (m, 1H), 3.30-3.18 (m, 2H), 3.12-2.96 (m, 2H), 2.21-2.10 (m, 1H), 2.04 -1.91 (m, 1H), 1.91-1.80 (m, 1H), 1.77-1.64 (m, 1H). [0934] MS(ESI) calculated for C13H17NO: 203.1; found 204.2 Procedure for Compound 205
Figure imgf000315_0001
General Procedure K: tert-Butyl 8-cyano-3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)-carboxylate (1)
Figure imgf000315_0002
[0935] To a solution of (5-(tert-butoxycarbonyl)-3,3a,4,5,6,7-hexahydro-1H- isochromeno[4,5-cd]azepin-8-yl)boronic acid (150 mg, 0.4 mmol) and CuCN (40.0 mg, 0.4 mmol) in DMF (3 mL) was added K2CO3( 186 mg, 1.3 mmol), and the resulting mixture was stirred at 60oC for 2 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (70.0 mg, 37.2%) as a white solid. [0936] MS(ESI) calculated for C18H22N2O3: 314.2; found 215.1 8-Cyano-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (205)
Figure imgf000315_0003
[0937] To a solution of 1 (70.0 mg, 0.2 mmol) in dioxane (1 mL) was added HCl/dioxane ( 2 mL, 4 M), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain the title compound (9.5 mg, 17.2% yield) as a white solid. [0938] 1H NMR (400 MHz, DMSO-d6) δ 9.16 (brs, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 4.78-4.68 (m, 2H), 3.97-3.93 (m, 1H), 3.86-3.82 (m, 1H), 3.63-3.58 (m, 1H), 3.43-3.36 (m, 3H), 3.30-3.25 (m.1H), 2.97-2.90 (m.2H). [0939] MS(ESI) calculated for C13H14N2O: 214.1; found 215.2 Procedure for Compound 183
Figure imgf000316_0001
8‐Bromo‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (183) [0940] Following the same procedure described in General Procedure G, the title compound was synthesized (66.7 mg, 80.4% yield) from 2,6-di-bromophenylacetonitrile as a white solid. [0941] 1H NMR (400 MHz, DMSO-d6) δ 9.47 (brs, 2H), 7.51 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 4.70 – 4.56 (m, 2H), 3.95-3.87 (m, 1H), 3.86-3.80 (m, 1H), 3.59-3.51 (m, 1H), 3.50-3.42 (m, 2H), 3.41-3.35 (m, 1H), 3.31 – 3.24 (m, 1H), 2.99-2.89 (m, 1H), 2.86-2.76 (m, 1H). [0942] MS(ESI) calculated for C12H14BrNO: 267.0; found 268.1, 270.1 Procedure for Compound 203
Figure imgf000317_0001
8‐Fluoro‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (203) [0943] Following the same procedure describe in General procedure F, the title compound was synthesized (55.8 mg, 70.3% yield) from (5-(tert-butoxycarbonyl)-3,3a,4,5,6,7- hexahydro-1H-isochromeno[4,5-cd]azepin-8-yl)boronic acid as a white solid. [0944] 1H NMR (400 MHz, DMSO-d6) δ 9.27 (brs, 2H), 7.14 – 7.01 (m, 2H), 4.63 (s, 2H), 3.98-3.91 (m, 1H), 3.82-3.73 (m, 1H), 3.59-3.48 (m, 1H), 3.43-3.34 (m, 2H), 3.31 – 3.30-3.24 (m, 1H), 3.04 – 2.90 (m, 2H), 2.89-2.80 (m, 1H). [0945] MS(ESI) calculated for C12H14FNO: 207.1; found 208.2 Procedure for Compound 181
Figure imgf000317_0002
7‐Bromo‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (181) [0946] Following the same procedure describe in General procedure G, the title compound was synthesized (169.0 mg, 82.2% yield) from 2-iodo-6-bromoacetonitrile as a white solid.
Figure imgf000318_0001
[0947] 1H NMR (400 MHz, DMSO-d6) δ 9.21 (brs, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 1.7 Hz, 1H), 4.68 – 4.60 (m, 2H), 3.95 – 3.93 (m, 1H), 3.79 – 3.75 (m, 1H), 3.50– 3.46 (m, 1H), 3.36– 3.33 (m, 1H), 3.30– 3.20 (m, 2H), 2.97– 2.82 (m, 3H),. [0948] MS(ESI) calculated for C12H14BrNO: 267.0; found, 268.1, 270.1 Procedure for Compound 189
Figure imgf000318_0002
General procedure L: tert-Butyl 8-methyl-3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)-carboxylate (1)
Figure imgf000318_0003
[0949] To a solution of tert-butyl 8-bromo-3a,4,6,7-tetrahydro-1H-isochromeno[4,5- cd]azepine-5(3H)-carboxylate (100 mg, 0.3 mmol) and methylboronic acid (18.0 mg, 0.3 mmol) in dioxane/water (2 mL/0.5 mL) was added tetrakis(triphenylphosphane) palladium (34.7 mg, 0.03 mmol) and potassium carbonate (110.6 mg, 0.8 mmol). The solution was stirred at 100°C under nitrogen for 5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and then concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to get the title compound (123.0 mg, 99.2% yield). [0950] 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 7.7 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 4.74 – 4.66 (m, 2H), 4.05 – 3.75 (m, 4H), 3.24 – 2.98 (m, 4H), 2.73 – 2.65 (m, 1H), 2.31 (s, 3H), 1.38 (s, 9H). 8-Methyl-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (189)
Figure imgf000319_0001
[0951] To a solution of 1 (123.0 mg, 0.4 mmol) in methylene chloride (2 mL) was added HCl/dioxane (2 mL, 4 M). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was slurried with EA/MeOH (20:1) to obtain the title compound (27 mg, 32.9% yield). [0952] 1H NMR (400 MHz, DMSO-d6) δ 9.28 (brs, 2H), 7.06 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 4.66 – 4.57 (m, 2H), 3.92 – 3.88 (m, 1H), 3.92 – 3.88 (m, 1H), 3.51 – 3.46 (m, 1H), 3.37 – 3.33 (m, 2H), 3.18 – 3.13 (m, 1H), 3.07 – 3.01 (m, 1H), 2.89 – 2.83 (m, 1H), 2.76 – 2.70 (m, 1H), 2.28 (s, 3H). [0953] MS(ESI) calculated for C13H17NO: 203.1; found, 204.2 Procedure for Compound 193
Figure imgf000319_0002
General Procedure M: 5-Methyl-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (193)
Figure imgf000319_0003
[0954] To a solution of tert-butyl 8-bromo-3a,4,6,7-tetrahydro-1H-isochromeno[4,5- cd]azepine-5(3H)-carboxylate (100.0 mg, 0.3 mmol) in dry THF (3 mL) was added LiAlH4 (57.0 mg, 1.5 mmol) at 0°C under nitrogen atmosphere, and the resulting mixture was stirred at 66oC for 3 hours. After cooling to room temperature, the reaction was quenched with sodium sulfate. The resulting mixture was filtered through a pad of celite; the filtrate was concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (23.0 mg, 35.4% yield) as a white solid. [0955] 1H NMR (400 MHz, DMSO-d6) δ 11.34 (brs, 1H), 7.20-7.16 (m, 1H), 7.13-7.11 (m, 1H), 7.02-7.00 (m, 1H), 4.69-4.64 (m, 2H), 4.01-3.94 (m, 1H), 3.83-3.75 (m, 1H), 3.64-3.55 (m, 1H), 3.52-3.43 (m, 2H), 3.43 – 3.36 (m, 1H), 3.10-2.99 (m, 1H), 2.98-2.83 (m, 2H), 2.77 (s, 3H). [0956] MS(ESI) calculated for C13H17NO: 203.1; found 204.4 Procedure for Compound 180
Figure imgf000320_0001
General Procedure N: 2-(3,5-Dibromophenyl)ethan-1-ol (1)
Figure imgf000320_0002
[0957] To a solution of 2-(3,5-dibromophenyl)acetic acid (5 g, 17.0 mmol) in THF (75 mL) was added BH3-THF (51 mL, 1 M) at room temperature under nitrogen atmosphere. After stirring at room temperature for 12 hours, the reaction was quenched with MeOH (10 mL) and concentrated to dryness. The residue was diluted with ethyl acetate (60 mL) and washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain the title compound (4.2 g, 88.2% yield) as a yellow solid. N-(3,5-Dibromophenethyl)-N-(2,2-dimethoxyethyl)-4-nitrobenzenesulfonamide (2)
Figure imgf000321_0001
[0958] DEAD (4.1 mL, 25.6 mmol) was added dropwise to a solution of 1 (4.0 g, 14.3 mmol), N-(2,2-dimethoxyethyl)-4-nitrobenzenesulfonamide (3.8 g, 13.0 mmol) and PPh3 (6.8 g, 26.0 ) in THF (30 mL) at 0°C under nitrogen atmosphere. The resulting mixture was slowly warmed to room temperature and stirred for 1 hour. The solvent was removed by vacuum; the resulting residue was purified by column chromatography to obtain the title compound (2.3 g, 32.1% yield). N-(3-Bromo-5-vinylphenethyl)-N-(2,2-dimethoxyethyl)-4-nitrobenzenesulfonamide (3)
Figure imgf000321_0002
[0959] A solution of 2 (2 g, 3.6 mmol), potassium vinyltrifluoroborate (0.5 g, 3.6 mmol), Pd(PPh3)4 (0.4 g, 0.4 mmol) and K3PO4 (2.3 g, 10.9 mmol) in dioxane/water (30 mL, 2:1) was stirred at 100°C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine. The solution was dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=2:1) to obtain the title compound (1.0 g, 55.3% yield) as a yellow solid. [0960] 1H NMR (400 MHz, CDCl3) δ 8.38 – 8.24 (m, 2H), 7.99 – 7.82 (m, 2H), 7.37 (s, 1H), 7.11 (s, 1H), 7.03 (s, 1H), 6.56 (dd, J = 17.6, 10.9 Hz, 1H), 5.72 (d, J = 17.6 Hz, 1H), 5.30 (d, J = 10.9 Hz, 1H), 4.50 (t, J = 5.1 Hz, 1H), 3.55 – 3.48 (m, 2H), 3.42 (s, 6H), 3.38 – 3.30 (m, 2H), 2.94 – 2.80 (m, 2H). N-(3-Bromo-5-(2-hydroxyethyl)phenethyl)-N-(2,2-dimethoxyethyl)-4- nitrobenzenesulfonamide (4)
Figure imgf000322_0001
[0961] To a solution of 3 (0.7 g, 1.4 mmol) in THF (10 mL) was added BH3-THF (2.1 mL, 2.1 mmol) dropwise at 0°C under nitrogen atmosphere. After stirring at room temperature for 3 hours, aqueous NaOH (2.3 mL, 3 M) was added to the above mixture followed by H2O2 (1.0 mL, 30% in water). After stirring at room temperature for an additional 2 hours, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (170 mg, 23.4% yield) as a yellow oil. [0962] 1H NMR (400 MHz, CDCl3) δ 8.35 – 8.28 (m, 2H), 7.97 – 7.91 (m, 2H), 7.25 – 7.21 (m, 1H), 7.11 – 7.06 (m, 1H), 6.98 – 6.94 (m, 1H), 4.45 (t, J = 5.1 Hz, 1H), 3.85 (t, J = 6.3 Hz, 2H), 3.56 – 3.47 (m, 2H), 3.39 (s, 6H), 3.30 (d, J = 5.1 Hz, 2H), 2.91 – 2.84 (m, 2H), 2.79 (t, J = 6.3 Hz, 2H). 5-Bromo-9-((4-nitrophenyl)sulfonyl)-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8- cd]azepine (5)
Figure imgf000322_0002
[0963] To a solution of 4 (170 mg, 0.3 mmol) in DCM (8 mL) was added trifluoromethanesulfonic acid (0.1 mL, 1.3 mmol) at 0°C, and the resulting mixture was stirred at this temperature for 2 hours. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 4:1) to obtain the desired product (90 mg, 60.8% yield) as a yellow solid. [0964] 1H NMR (400 MHz, CDCl3) δ 8.35 – 8.29 (m, 2H), 7.96 – 7.89 (m, 2H), 7.16 – 7.12 (m, 1H), 7.12 – 7.07 (m, 1H), 4.90 – 4.82 (m, 1H), 4.18 – 4.09 (m, 2H), 4.08 – 4.00 (m, 1H), 3.75 – 3.63 (m, 1H), 3.02 – 2.79 (m, 3H), 2.77 – 2.68 (m, 1H), 2.67 – 2.56 (m, 2H). 5-Bromo-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepine hydrochloride (180)
Figure imgf000323_0001
[0965] To a solution of 5 (90 mg, 0.2 mmol) and potassium carbonate (136.0 mg, 1.0 mmol) in dry DMF (6 mL) was added thiophenol (0.03 mL, 0.3 mmol). After stirring at room temperature for 3 hours, the mixture was diluted with water (60 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (15.4 mg, 29.0% yield) as a white solid. [0966] 1H NMR (400 MHz, DMSO-d6) δ 9.64 (brs, 1H), 9.38 (brs, 1H), 7.37 – 7.29 (m, 2H), 5.16 (d, J = 9.7 Hz, 1H), 4.03 – 3.87 (m, 1H), 3.75 – 3.59 (m, 1H), 3.50 – 3.43 (m, 1H), 3.38 (brs, 1H), 3.21 – 3.02 (m, 2H), 2.98 – 2.93 (m, 1H), 2.88 – 2.76 (m, 2H), 2.75 – 2.64 (m, 1H). [0967] MS(ESI) calculated for C12H14BrNO: 267.0; found, 268.2, 270.2 Procedure for Compound 191
Figure imgf000323_0002
8‐Ethyl‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (191) [0968] Following the same procedure described in General Procedure L, the title compound was synthesized (21.0 mg, 65.8% yield) from triethylborane as a white solid. [0969] 1H NMR (400 MHz, DMSO-d6) δ 9.36 (brs, 2H), 7.06 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 4.69 – 4.58 (m, 2H), 3.92 – 3.82 (m, 2H), 3.55 – 3.51 (m, 1H), 3.39 – 3.36 (m, 1H), 3.32 – 3.24 (m, 1H), 3.20 – 3.15 (m, 1H), 3.04 – 2.88 (m, 2H), 2.76 – 2.60 (m, 3H), 1.08 (t, J = 7.5 Hz, 3H). [0970] MS(ESI) calculated for C14H19NO: 217.1; found, 218.2 Procedure for Compound 195
Figure imgf000324_0001
N-(5-Bromo-2-chlorophenethyl)-N-(2,2-dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (1)
Figure imgf000324_0002
[0971] DEAD (1.5 g, 8.5 mmol) was added dropwise to a solution of 2-(5-bromo-2- chlorophenyl)ethan-1-ol (1.0 g, 4.2 mmol), N-(2,2-dimethoxyethyl)-1,1,1- trifluoromethanesulfonamide (1.0 g, 4.2 mmol) and PPh3 (2.2 g, 8.5 mmol ) in THF (30 mL) at 0°C under nitrogen atmosphere. The resulting mixture was slowly warmed to room temperature and continued to stir for 1 hour. The solvent was removed by vacuum; the resulting residue was purified by column chromatography to obtain the title compound (1.4 g, 73.1% yield) as a yellow oil. [0972] 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 2.3 Hz, 1H), 7.34 – 7.31 (m, 1H), 7.23 (d, J = 8.5 Hz, 1H), 4.53 (t, J = 5.3 Hz, 1H), 3.67 – 3.63 (m, 2H), 3.45 – 3.44 (m, 8H), 3.12 – 2.98 (m, 2H).^ N-(2-Chloro-5-vinylphenethyl)-N-(2,2-dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (2)
Figure imgf000325_0001
[0973] A solution of 1 (0.5 g, 1.1 mmol), potassium vinyltrifluoroborate (0.2 g, 1.1 mmol), Pd(PPh3)4 (0.1 g, 0.1 mmol) and K3PO4 (0.2 g, 1.6 mmol) in dioxane/water (10 mL, 2:1) was stirred at 100°C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine. The solution was dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate=2:1) to obtain the title compound (0.3 g, 73.5% yield) as a yellow solid. [0974] 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 1H), 7.27 – 7.20 (m, 2H), 6.68 – 6.61 (m, 1H), 5.76 – 5.71 (m, 1H), 5.30 – 5.27 (m, 1H), 4.59 – 4.46 (m, 1H), 3.75 – 3.56 (m, 3H), 3.45 (s, 6H), 3.16 – 2.99 (m, 3H). N-(2-Chloro-5-(2-hydroxyethyl)phenethyl)-N-(2,2-dimethoxyethyl)-1,1,1- trifluoromethanesulfonamide (3)
Figure imgf000325_0002
[0975] To a solution of 2 (0.3 g, 0.8 mmol) in THF (10 mL) was added BH3-THF (2.4 mL, 2.4 mmol) dropwise at 0°C under nitrogen atmosphere. After stirring at room temperature for 3 hours, aqueous NaOH (1.3 mL, 3 M) was added to above mixture followed by H2O2 (1.0 mL, 30% in water). After stirred at room temperature for another 2 hours, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (170.5 mg, 50.8% yield) as a yellow oil. 6-Chloro-9-((trifluoromethyl)sulfonyl)-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8- cd]azepine (4)
Figure imgf000326_0001
[0976] To a solution of 3 (170.5 mg, 0.4 mmol) in DCM (8 mL) was added trifluoromethanesulfonic acid (72.6 mg, 0.5 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 2 hours. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 4:1) to obtain the desired product (60.0 mg, 41.6% yield) as a yellow solid. [0977] 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 5.03 – 4.92 (m, 1H), 4.15 –4.04 (m, 3H), 3.83 – 3.65 (m, 2H), 3.30 –2.95 (m, 2H), 2.99 – 2.83 (m, 1H), 2.77 – 2.58 (m, 2H). 6-Chloro-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepin-9-ium chloride (195)
Figure imgf000326_0002
[0978] To a solution of 4 (60.0 mg, 0.2 mmol) in dry THF (3 mL) was added LiAlH4 (12.7 mg, 0.3 mmol) at 0°C under nitrogen atmosphere, and the resulting mixture was stirred at 70°C for 3 hours. After cooling to room temperature, the reaction was quenched with Na2SO4·10H2O. The resulting mixture was filtered through a pad of celite; the filtrate was concentrated to purify by Prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the title compound (22.0 mg, 58.5% yield) as a white solid. [0979] 1H NMR (400 MHz, DMSO-d6) δ 9.63 (brs, 1H), 9.32 (brs, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 5.25 (d, J = 8.0 Hz, 1H), 4.00 – 3.90 (m, 1H), 3.77 – 3.65 (m, 1H), 3.59 – 3.46 (m, 2H), 3.45 – 3.35 (m, 1H), 3.17 – 3.06 (m, 1H), 3.03 – 2.96 (m, 1H), 2.87 – 2.75 (m, 2H), 2.75 – 2.65 (m, 1H). [0980] MS(ESI) calculated for C12H14ClNO,223.1; found 224.2, 226.2 Procedure for Compound 91
Figure imgf000327_0001
General procedure O: Methyl 3-(2-formylphenoxy)benzoate (1)
Figure imgf000327_0002
[0981] A solution of 2-fluorobenzaldehyde (10.0 g, 80.6 mmol), methyl 3-hydroxybenzoate (13.5 g, 88.6 mmol) and K2CO3 (11.1 g, 80.6 mmol) in DMF (200 mL) was stirred at 50°C for 2 hours. After cooling to room temperature, the mixture was diluted with water (400 mL) and extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =5:1) to obtain the title compound (12.1 g, 58.1 % yield) as a white solid. [0982] MS(ESI) calculated for C15H12O4: 256.1; found 257.2 Methyl 3-(2-vinylphenoxy)benzoate (2)
Figure imgf000327_0003
[0983] A solution of 1(10.0 g, 39.0 mmol), methyltriphenylphosphonium iodide (18.9 g, 46.8 mmol) and K2CO3 (5.4 g, 39.0 mmol) in dioxane (100 mL) was stirred at 100°C for 16 hours. After cooling to room temperature, the mixture was filtered through a pad of celite; the filtrate was diluted with water (100 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =5:1) to obtain the title compound (8.5 g, 85.9% yield) as colorless liquid. [0984] MS(ESI) calculated for C16H14O3: 254.1; found 255.2 3-(2-Vinylphenoxy)benzoic acid (3)
Figure imgf000328_0001
[0985] To a stirred solution of 2 (8.2 g, 32.2 mmol) in MeOH (30 mL) was added NaOH (24 mL, 4 M) at room temperature. After stirring for 16 hours, the solvent was removed under vacuum. The residue was dissolved in HCl (2 N), and the aqueous layer was extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to obtain the title compound (7.0 g, 90.5% yield) as a white solid. [0986] 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.76 (m, 1H), 7.66 – 7.57 (m, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.31 – 7.21 (m, 1H), 7.21 – 7.14 (m, 2H), 6.98 – 6.86 (m, 2H), 5.79 (dd, J = 17.7, 1.2 Hz, 1H), 5.28 (dd, J = 11.1, 1.2 Hz, 1H).
3-(2-Vinylphenoxy)benzoyl chloride (4)
Figure imgf000329_0001
[0987] To a stirred solution of 3 (6.0 g, 24.9 mmol) in DCM (20 mL) was added oxalic dichloride (2.5 mL, 29.8 mmol) and DMF (two drops) dropwise at 0°C under nitrogen atmosphere. After stirring at room temperature for 3 hours, the mixture was concentrated to dryness, and used for the next step without further purification. N-(Pivaloyloxy)-3-(2-vinylphenoxy)benzamide (5)
Figure imgf000329_0002
[0988] 3 (crude, in 10 mL EtOAc) was added dropwise to a solution of O- pivaloylhydroxylamine (3.5 g, 29.6 mmol) and Na2CO3 (5.2 g, 49.4 mmol) in ethyl acetate (38 mL) and H2O (18 mL) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The phases were separated and the aqueous layer was extracted with ethyl acetate (15 mL*2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =8:1) to obtain the title compound (7.0 g, 83.5% yield) as a yellow oil. [0989] 1H NMR (400 MHz, CDCl3) δ 9.37 (brs, 1H), 7.65 – 7.55 (m, 1H), 7.51 – 7.45 (m, 1H), 7.39 – 7.34 (m, 2H), 7.28 – 7.22 (m, 1H), 7.20 – 7.14 (m, 1H), 7.14 – 7.06 (m, 1H), 6.96 – 6.83 (m, 2H), 5.78 (dd, J = 17.7, 1.2 Hz, 1H), 5.27 (dd, J = 11.1, 1.2 Hz, 1H), 1.34 (s, 9H). 1,11b-Dihydrochromeno[4,3,2-de]isoquinolin-3(2H)-one (6)
Figure imgf000329_0003
[0990] A solution of 5 (0.6 g, 1.8 mmol), [Cp*RhCl2]2 (27.1 mg, 44.0 μmol) and CsOPiv (823 mg, 3.5 mmol) in acetonitrile (10 mL) was stirred at room temperature under nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to obtain the title compound (220 mg, 52.7% yield) as a yellow solid. [0991] 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.6, 1.2 Hz, 1H), 7.42 – 7.35 (m, 1H), 7.33 – 7.26 (m, 2H), 7.22 – 7.15 (m, 1H), 7.16 – 7.09 (m, 2H), 6.32 (brs, 1H), 4.57 – 4.44 (m, 1H), 4.16 – 4.05 (m, 1H), 3.78 – 3.67 (m, 1H). 2-Chloro-1,2,3,11b-tetrahydro-2l5-chromeno[4,3,2-de]isoquinoline (91)
Figure imgf000330_0001
[0992] To a solution of 6 (0.2 g, 0.8 mmol) in dry THF (3 mL) was added BH3-THF (4.2 mL, 4.2 mmol) at 0°C under nitrogen atmosphere, and the resulting mixture was refluxed for 16 hours. After cooling to room temperature, the reaction was quenched by methanol, and the resulting solution was concentrated to dryness. The residue was purified by column chromatography (eluted with DCM: MeOH= 7:3) to get the crude product. The crude was further slurried with EtOAc/MeOH (10:1) to obtain the desired compound (20.8 mg, 11.1% yield) as a yellow solid. [0993] 1H NMR (400 MHz, DMSO-d6) δ 9.64 (brs, 2H), 7.44 – 7.30 (m, 3H), 7.23 – 7.17 (m, 2H), 7.15 – 7.10 (m, 1H), 7.10 – 7.04 (m, 1H), 4.52 – 4.27 (m, 4H), 3.37 – 3.33 (m, 1H). [0994] MS(ESI) calculated for C15H13NO: 223.1; found 224.2.
Procedure for Compound 179
Figure imgf000331_0001
6‐Bromo‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (179) [0995] Following the procedure described in General Procedure G, the title compound was synthesized (136 mg, 69.8% yield) from 2-iodo-4-bromotoluene as a white solid. [0996] 1H NMR (400 MHz, DMSO-d6) δ 9.43 (brs, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 4.63 – 4.52 (m, 2H), 3.94 – 3.83 (m, 2H), 3.51 – 3.46 (m, 1H), 3.40 – 3.37 (m, 2H), 3.33 – 3.26 (m, 1H), 2.96 – 2.90 (m, 2H), 2.82 – 2.76 (m, 1H). [0997] MS(ESI) calculated for C12H14BrNO: 267.0; found, 268.1, 270.1 Procedure for Compound 188
Figure imgf000331_0002
6-Methyl-3,7,8,9,10,10a-hexahydro-2H-isochromeno[1,8-cd]azepin-9-ium chloride (188) [0998] Following the same procedure described in General procedure L, the title compound was synthesized (20.0 mg, 86.9% yield) from tert‐butyl 8‐chloro‐2‐oxa‐12‐ azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene‐12‐carboxylate as a white solid. [0999] 1H NMR (400 MHz, DMSO-d6) δ 9.76 (brs, 1H), 9.37 (brs, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 5.24 (d, J = 8.9 Hz, 1H), 3.99 – 3.88 (m, 1H), 3.75 – 3.61 (m, 1H), 3.46 (dd, J = 12.7, 5.7 Hz, 1H), 3.48 – 3.44 (m, 1H), 3.38 – 3.35 (m, 1H), 3.18 – 3.13 (m, 1H), 3.04 – 2.99 (m, 1H), 2.92 – 2.82 (m, 1H), 2.82 – 2.60 (m, 3H), 2.27 (s, 3H). [1000] MS(ESI) calculated for C13H17NO: 203.1; found 204.2 Procedure for Compound 192
Figure imgf000332_0001
12‐Methyl‐2‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene (192) [1001] Following the same procedure described in General Procedure M, the title compound was synthesized (49 mg, 37.5% yield) from tert‐butyl 2‐oxa‐12‐ azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene‐12‐carboxylate as a white solid. [1002] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (brs, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.3 Hz, 2H), 5.31 (d, J = 9.7 Hz, 1H), 4.00 – 3.95 (m, 1H), 3.74 – 3.68 (m, 1H), 3.59 – 3.48 (m, 2H), 3.29 – 3.16 (m, 2H), 2.97 – 2.81 (m, 6H), 2.73 – 2.68 (m, 1H). [1003] MS(ESI) calculated for C13H17NO: 203.1; found, 204.2
Procedure for Compound 185
Figure imgf000333_0001
Methyl 2-(3,4-dihydroxyphenyl)acetate (1)
Figure imgf000333_0002
[1004] To a solution of 2-(3,4-dihydroxyphenyl)acetic acid (20.0 g, 119.0 mmol) in methanol (300 mL) was added SOCl2 (1.4 g, 11.8 mmol) at 0°C. After refluxing for 1.5 hour, the mixture was concentrated to give the desired compound (20.0 g, 93.4 % yield) as a brown oil. [1005] 1H NMR (400 MHz, CDCl3) δ 6.76 – 6.74 (m, 2H), 6.65 (dd, J = 8.1, 2.0 Hz, 1H), 6.02 (brs, 1H), 5.79 (brs, 1H), 3.71 (s, 3H), 3.52 (s, 2H). Methyl 2-(3-bromo-4,5-dihydroxyphenyl)acetate (2)
Figure imgf000333_0003
[1006] To a solution of 1 (15.0 g, 82.3 mmol) in THF (300 mL ) was added NBS (14.6 g, 82.3 mmol) at 0°C^ and the resulting mixture was stirred at room temperature for 19 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate: =5:1) to get desired compound (15.0 g, 70.0 % yield) as a pale solid. Methyl 2-(7-bromo-2H-1,3-benzodioxol-5-yl)acetate (3)
Figure imgf000334_0001
[1007] To a solution of 2 (7.5 g, 28.7 mmol) and CH2I2 (11.5 g, 43.0 mmol) in DMF (50 mL ) and ACN (200 mL ) was added K2CO3 (11.8 g, 86.1 mmol) at 0°C. The resulting mixture was stirred at 90°C for 19 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into ice water (500 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to obtain the desired compound (4.6 g, 58.7 % yield) as a pale solid. [1008] 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 6.78 (s, 1H), 5.97 (s, 2H), 3.72 (s, 3H), 3.70 (s, 2H). 2-(7-Bromo-2H-1,3-benzodioxol-5-yl)ethan-1-ol (4)
Figure imgf000334_0002
[1009] To a solution of 3 (4.5 g, 16.4 mmol) in THF (50 mL) was added borane tetrahydrofuran complex (49.1 mL, 1 M) at 0°C, and the resulting mixture was stirred at 80°C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched by MeOH, and the mixture was concentrated to obtain the title compound (3.6 g, 89.7 % yield) as a colorless oil. [2-(7-Bromo-2H-1,3-benzodioxol-5-yl)ethoxy](tert-butyl)dimethylsilane (5)
Figure imgf000334_0003
[1010] To a solution of 4 (3.5 g, 14.2 mmol) and 1H-imidazole (1.9 g, 28.4 mmol) in DCM (50 mL) was added TBSCl (2.4 g, 15.6 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. After which period, the reaction solution was poured into ice water (100 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =5:1) to obtain the title compound (4.0 g, 78.4 % yield) as colorless oil. [1011] 1H NMR (400 MHz, CDCl3) δ 6.98 (s, 1H), 6.75 (s, 1H), 5.94 (s, 2H), 3.76 (t, J = 7.0 Hz, 2H), 2.87 (t, J = 7.0 Hz, 2H), 0.87 (s, 9H), 0.00 (s, 6H). tert-Butyl[2-(7-ethenyl-2H-1,3-benzodioxol-5-yl)ethoxy]dimethylsilane (6)
Figure imgf000335_0001
[1012] A solution of 5 (3.5 g, 9.7 mmol), tributyl(ethenyl)stannane (6.1 g, 19.4 mmol) and Pd(PPh3)4 (0.5 mg, 0.5 mmol) in toluene (45 mL) was stirred at 110°C for 6 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into ice water (30 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =20:1) to get title compound (2.2 g, 73.8 % yield) as a colorless oil. [1013] 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 6.93 (dd, J = 17.3, 10.9 Hz, 1H), 6.66 (s, 1H), 5.93 (s, 2H), 5.52 (dd, J = 17.3, 1.1 Hz, 1H), 5.20 (dd, J = 10.9, 1.2 Hz, 1H), 3.71 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.3 Hz, 2H), 0.88 (s, 9H), 0.00 (s, 6H). 2-(6-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-2H-1,3-benzodioxol-4-yl)ethan-1-ol (7)
Figure imgf000335_0002
[1014] To a solution of 6 (2.2 g, 7.2 mmol) in THF (50 mL) was added borane tetrahydrofuran complex (21.5 mL, 1.0 M) at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. Aqueous NaOH (3N, 10 mL) was then added to the above solution followed by H2O2 (10 mL, 30% in water). After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =10:1) to have the desired compound (1.5 g, 71.0 % yield) as a colorless oil. [1015] 1H NMR (400 MHz, CDCl3) δ 6.68-6.67 (m, 2H), 5.90 (s, 2H), 3.81 – 3.74 (m, 4H), 2.89 – 2.75 (m, 4H), 0.86 (s, 9H), 0.00 (s, 6H). N-[2-(6-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-2H-1,3-benzodioxol-4-yl)ethyl]-N-(2,2- dimethoxyethyl)-4-nitrobenzene-1-sulfonamide (8)
Figure imgf000336_0001
[1016] DIAD (1.4 g, 6.9 mmol) was added to a solution of 7 (1.5 g, 4.6 mmol), N-(2,2- dimethoxyethyl)-4-nitrobenzene-1-sulfonamide (1.6 g, 5.5 mmol) and PPh3 (1.8 g, 6.9 mmol) in THF (50 mL). The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. The mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =4:1) to have the desired compound (2.0 g, 72.7 % yield) as a pale solid. [1017] 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 6.56 (s, 1H), 5.91 (s, 2H), 4.53 (t, J = 5.1 Hz, 1H), 3.76 (t, J = 6.9 Hz, 2H), 3.44 (s, 6H), 3.40-3.37 (m, 4H), 2.90-2.86 (m, 2H), 2.77 (t, J = 6.9 Hz, 2H), 0.88 (s, 9H), 0.00 (s, 6H). N-(2,2-Dimethoxyethyl)-N-{2-[6-(2-hydroxyethyl)-2H-1,3-benzodioxol-4-yl]ethyl}-4- nitrobenzene-1-sulfonamide (9)
Figure imgf000336_0002
[1018] To a solution of 8 (1.2 g, 2.0 mmol) in THF (25 mL) was added TBAF (1M, 3.01 mL) at 0°C. After stirring at room temperature for 19 hours under nitrogen atmosphere, the mixture was poured into ice water (50 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =1:1) to give the desired compound (0.8 g, 82.5 % yield) as a colorless oil. [1019] 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.9 Hz, 2H), 8.00 (d, J = 8.9 Hz, 2H), 6.68 (s, 1H), 6.57 (s, 1H), 5.90 (s, 2H), 4.49 (dd, J = 6.0, 4.1 Hz, 1H), 3.81 (t, J = 6.6 Hz, 2H), 3.41 (s, 6H), 3.39 – 3.32 (m, 4H), 2.90 (dd, J = 9.6, 6.9 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H). 3-((4-Nitrophenyl)sulfonyl)-2,3,4,4a,6,7-hexahydro-1H- [1,3]dioxolo[4',5':6,7]isochromeno[1,8-cd]azepine (10)
Figure imgf000337_0001
[1020] To a solution of 9 (0.8 g, 1.6 mmol) in DCM (10 mL ) was added TfOH (0.7 g, 4.7 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hour under nitrogen atmosphere. The solution was poured into ice water (50 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate =5:1) to get the desired compound (25.0 mg, 3.9 % yield) as a colorless oil. [1021] 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 6.45 (s, 1H), 5.87 (d, J = 2.9 Hz, 2H), 4.83 (d, J = 8.3 Hz, 1H), 4.14-4.11 (m, 2H), 4.03-4.00 (m, 1H), 3.68-3.66 (m, 1H), 3.27 – 3.12 (m, 1H), 2.85-2.80 (m, 1H), 2.75 – 2.44 (m, 4H). 2,3,4,4a,6,7-Hexahydro-1H-[1,3]dioxolo[4',5':6,7]isochromeno[1,8-cd]azepin-3-ium chloride (185)
Figure imgf000338_0001
[1022] To a solution of 10 (20.0 mg, 47.8 μmol) and K2CO3 (10.0 mg, 71.6 μmol) in DMF (1 mL) was added 4-tert-butylbenzene-1-thiol (9.5 mg, 57.3 μmol) at 0°C. After stirring at room temperature for 2 hours under nitrogen atmosphere, the mixture was poured into ice water (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified with prep-HPLC (CH3CN/H2O, 0.1%HCl) to give the desired compound (1.5 mg, 11.7 % yield). [1023] 1H NMR (400 MHz, CD3OD) δ 6.59 (s, 1H), 5.94 (d, J = 0.7 Hz, 2H), 5.05 (d, J = 8.9 Hz, 1H), 4.11 – 3.96 (m, 1H), 3.80 – 3.66 (m, 1H), 3.66 – 3.56 (m, 1H), 3.55-3.51 (m, 1H), 3.29-3.27 (m, 1H), 3.12-3.06 (m, 1H), 2.94 (t, J = 12.7 Hz, 1H), 2.89 – 2.73 (m, 2H), 2.61 (dt, J = 16.1, 3.4 Hz, 1H). [1024] MS(ESI) calculated for C13H15NO3: 233.1; found 234.2 Procedure for Compound 190
Figure imgf000338_0002
8‐ethyl‐2‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (190) [1025] Following the same procedure described in General procedure L, the title compound was synthesized (18.0 mg, 56.3% yield) from tert‐butyl 8‐chloro‐2‐oxa‐12‐ azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene‐12‐carboxylate and triethylborane as a white solid. [1026] 1H NMR (400 MHz, DMSO-d6) δ 9.45 (brs, 1H), 9.17 (brs, 1H), 7.07 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 5.20 (d, J = 8.9 Hz, 1H), 3.98 – 3.89 (m, 1H), 3.72 – 3.67 (m, 1H), 3.53 – 3.48 (m, 1H), 3.40 – 3.35 (m, 1H), 3.20 – 3.15 (m, 1H), 3.11 – 3.02 (m, 1H), 2.89 – 2.59 (m, 6H), 1.08 (t, J = 7.5 Hz, 3H). [1027] MS(ESI) calculated for C14H19NO: 217.2; found 218.3 Procedure for Compound 201
Figure imgf000339_0001
General Procedure P: tert-Butyl 8-(trifluoromethyl)-3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)- carboxylate (1)
Figure imgf000339_0002
[1028] To a solution of tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)-carboxylate (100 mg, 0.2 mmol) and Cu(OAc)2 (45.6 mg, 0.2 mmol) in DMSO (2 mL) was added potassium trimethoxy(trifluoromethyl)boranuide (102.0 mg, 0.5 mmol). The resulting mixture was stirred at 60oC for 2 hours under oxygen atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (15.0 mg, 17.4% yield) as a white solid. [1029] MS(ESI) calculated for C18H22F3NO3: 357.2; found 258.2 8-(Trifluoromethyl)-3,3a,4,5,6,7-hexahydro-1H-isochromeno[4,5-cd]azepin-5-ium chloride (201)
Figure imgf000339_0003
[1030] To a solution of 1 (15 mg, 0.04 mmol) in dioxane (1 mL) was added HCl/dioxane (2 mL, 4 M), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1% HCl) to obtain title compound (4.1 mg, 34.9% yield) as a white solid. [1031] 1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.85-4.76 (m, 2H), 4.04-3.96 (m, 2H), 3.67-3.62 (m, 1H), 3.53-3.49 (m, 1H), 3.46-3.36 (m, 2H), 3.29-3.24 (m, 1H), 3.16-3.10 (m.1H), 2.99-2.92 (m, 1H). [1032] MS(ESI) calculated for C13H14F3NO: 257.1; found 258.2 Procedure for Compound 182
Figure imgf000340_0001
8‐Bromo‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (182) [1033] Following the same procedure described in General Procedure J, the title compound was synthesized (13 mg, 15.5% yield for two steps) from tert-butyl 8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine- 5(3H)-carboxylate as a white solid. [1034] 1H NMR (400 MHz, CD3OD) δ 7.52 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 5.24 – 5.22 (m, 1H), 4.09 – 4.03 (m, 1H), 3.80 – 3.72 (m, 2H), 3.63 – 3.51 (m, 2H), 3.20 – 3.14 (m, 1H), 3.07 – 2.84 (m, 3H), 3.20 – 3.14 (m, 1H). [1035] MS(ESI) calculated for C12H14BrNO: 267.0; found 268.1
Procedure for Compound 93
Figure imgf000341_0001
[1036] To a solution of 9H-xanthen-9-one (10.0 g, 51.0 mmol) in dry THF (100 mL) was added ZnCl2·TMEDA (12.9 g, 51.0 mmol) at 0°C, and the reaction was stirred at 0oC for 30 min. LiTMP (general procedure: to a solution of 2,2,6,6-tetramethylpiperidine (7.2 g, 76.5 mmol) in dry THF (50 mL) was added BuLi (2.5 M, 30.6 mL) dropwise at 0oC and the mixture was stirred for 10 min.) was added dropwise thereto. After stirring at 0oC for 2 hours, a solution of I2 (13.0 g, 51.0 mmol) in dry THF (50 mL) was added dropwise to the above mixture. After addition, the mixture was slowly warmed to room temperature and stirred for 16 hours. After which period, the reaction was quenched with the saturated aqueous Na2S2O3 (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (8.0 g, 50.0% yield) as a yellow oil. [1037] 1H NMR (400 MHz, CDCl3) δ 8.35-8.32 (m, 1H), 8.05-8.01 (m, 1H), 7.75-7.69 (m, 1H), 7.53-7.49 (m, 1H), 7.44 (dd, J = 8.4, 0.5 Hz, 1H), 7.41 – 7.38 (m, 1H), 7.32-7.27 (m, 1H). [1038] MS(ESI) calculated for C13H7IO2: 322.0; found 323.0 1-Iodo-9H-xanthen-9-ol (2)
Figure imgf000342_0001
[1039] To a solution of 1 (8.0 g, 24.8 mmol) in MeOH/THF (80 mL. 1/1) was added NaBH4 (1.4 g, 37.2 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (1.0 g, 12.5% yield) as a yellow oil. [1040] 1H NMR (400 MHz, CDCl3) δ 7.70-7.66 (m, 1H), 7.61-7.57 (m, 1H), 7.42 – 7.37 (m, 1H), 7.24 – 7.19 (m, 3H), 7.09 – 7.05 (m, 1H), 5.90 (d, J = 5.7 Hz, 1H), 2.48 (d, J = 5.7 Hz, 1H). [1041] MS(ESI) calculated for C13H9IO2: 324.0; found 307.0 1-Iodo-9H-xanthene-9-carbonitrile (3)
Figure imgf000342_0002
[1042] To a solution of 2 (1.0 g, 3.1 mmol) in toluene (10 mL) was added TMSCN (0.5 g, 4.7 mmol) and ZnI2 (98.9 mg, 0.3 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (0.8 g, 77.7% yield) as a yellow oil. [1043] 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 7.7, 1.2 Hz, 1H), 7.45 (dd, J = 7.6, 1.5 Hz, 1H), 7.39-7.36 (m, 1H), 7.21 – 7.16 (m, 3H), 7.09 (t, J = 8.0 Hz, 1H), 5.32 (s, 1H). tert-Butyl ((1-iodo-9H-xanthen-9-yl)methyl)carbamate (4)
Figure imgf000343_0001
[1044] To a solution of 3 (0.8 g, 2.4 mmol) in dry THF (10 mL) was added BH3- THF (12 mL, 1M), and the resulting mixture was stirred at 66oC for 3 hours. After cooling to room temperature, the reaction was quenched with methanol and concentrated to dryness. The residue was dissolved in THF (15 mL) and saturated aqueous NaHCO3 (15 mL); Boc2O (784.8 mg, 3.6 mmol) was added thereto. After stirring at room temperature for 1 hour, the resulting mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (0.8 g, 76.2% yield) as a yellow oil. [1045] 1H NMR (400 MHz, CDCl3) δ 7.64-7.60 (m, 1H), 7.25-7.23 (m, 1H), 7.15-7.07 (m, 4H), 6.95 (t, J = 8.0 Hz, 1H), 4.32-4.22 (m, 1H), 3.47 – 3.39 (m, 1H), 3.34-3.25 (m, 1H), 1.35 (s, 9H). [1046] MS(ESI) calculated for C19H20INO3: 437.1; found 382.1 tert-Butyl ((1-vinyl-9H-xanthen-9-yl)methyl)carbamate (5)
Figure imgf000343_0002
[1047] A solution of 4 (800.0 mg, 1.8 mmol), potassium vinyltrifluoroborate (482.4 mg, 3.6 mmol), Pd(dppf)Cl 2 (147.1 mg, 0.2 mmol) and Cs2CO3 (1.2 g, 3.6 mmol) in dioxane/H2O (10 mL, 10/1) was stirred at 100°C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (420.0 mg, 68.1% yield) as a yellow oil. [1048] 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.31 (m, 2H), 7.25 – 7.15 (m, 3H), 7.14 – 7.09 (m, 2H), 7.08 – 7.04 (m, 1H), 5.80 – 5.73 (m, 1H), 5.48 – 5.39 (m, 1H), 4.57 – 4.26 (m, 1H), 3.45 – 3.33 (m, 1H), 3.12 – 2.99 (m, 1H), 1.43 (s, 9H). [1049] MS(ESI) calculated for C21H23NO3: 337.2; found 238.2 tert-Butyl ((1-(2-hydroxyethyl)-9H-xanthen-9-yl)methyl)carbamate (6)
Figure imgf000344_0001
[1050] To a solution of 5 (420.0 mg, 1.2 mmol) in dry THF (10 mL) was added BH3-THF (2.4 mL, 1 M) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 min, and then at room temperature for another hour. After cooling to 0°C, NaOH (2 mL, 1N) was added followed by H2O2 (4 mL, 30% in water). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with saturated brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain the desired compound (270.0 mg, 61.1% yield) as a yellow oil. [1051] 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.23 (m, 1H), 7.22-7.17 (m, 2H), 7.14-7.05 (m, 2H), 7.04-6.97 (m, 2H), 4.69 (s, 1H), 4.40-4.27 (m, 1H), 4.01 – 3.84 (m, 2H), 3.48 – 3.33 (m, 1H), 3.19-3.10 (m, 1H), 3.10-3.00 (m, 2H), 1.41 (s, 9H). [1052] MS(ESI) calculated for C21H25NO4: 355.2; found 256.2 2-(9-(Aminomethyl)-9H-xanthen-1-yl)ethan-1-ol (7)
Figure imgf000344_0002
[1053] To a solution of 6 (270.0 mg, 0.8 mmol) in DCM (3 mL) was added HCl/dioxane (1.1 mL, 1M). The resulting mixture was stirred at room temperature for 2 hours and then concentrated. The residue was used for the next step without further purification. [1054] MS(ESI) calculated for C16H17NO2: 255.1; found 256.1 tert-Butyl 1,3,4,12b-tetrahydro-2H-xantheno[9,1-cd]azepine-2-carboxylate (9)
Figure imgf000345_0001
[1055] A solution of 7 (crude) and SOCl2 (161.8 mg, 1.4 mmol) in dry CHCl3 (5 mL) was stirred at 50°C under nitrogen atmosphere in a sealed tube for 5 hours. After cooling to room temperature, the mixture was concentrated to dryness. The residue was re-dissolved in DMF (5 mL), and K2CO3 (579.6 mg, 4.2 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated to get crude product for the next step without further purification. [1056] MS(ESI) calculated for C16H15NO: 237.1; found 238.1 [1057] To a solution of the above crude material and Boc2O (392.0 mg, 1.8 mmol) in THF (5 mL) was added saturated aqueous NaHCO3 (5 mL). The resulting mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated brine (10 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10:1) to obtain the desired compound (100.0 mg, 30.2% yield over 3 steps) as a yellow oil. [1058] MS(ESI) calculated for C21H23NO3: 337.2; found 282.2 2,3,4,12b-Tetrahydro-1H-xantheno[9,1-cd]azepin-2-ium chloride (93)
Figure imgf000345_0002
[1059] To a solution of 9 (100 mg, 0.2 mmol) in DCM (2 mL) was added HCl/dioxane (0.25 mL, 4M), and the resulting mixture was stirred at room temperature for 2 hours. Then, the mixture was concentrated to dryness. The residue was slurried with EA/MeOH (20:1) to obtain the desired compound (32.7 mg, 40.4% yield) as a white solid. [1060] 1H NMR (400 MHz, DMSO-d6) δ 9.88 (brs, 1H), 9.36 (brs, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.28-7.21 (m, 1H), 7.19 (t, J = 6.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 7.6 Hz, 2H), 4.96 (d, J = 10.1 Hz, 1H), 3.64 – 3.55 (m, 1H), 3.53-3.40 (m, 2H), 3.26-3.16 (m, 1H), 3.03-2.94 (m, 1H), 2.87-2.77 (m, 1H). [1061] MS(ESI) calculated for C16H15NO: 237.1; found 238.1 Procedure for Compound 194
Figure imgf000346_0001
8‐Methoxy‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (194) [1062] Following the same procedure described in General Procedure E, The title compound was synthesized (13 mg, 21.0% yield for two steps) from tert-butyl 8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine- 5(3H)-carboxylate as a white solid. [1063] 1H NMR (400 MHz, CD3OD) δ 7.09 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 5.15 (d, J = 8.3 Hz, 1H), 4.04 (dt, J = 11.1, 4.5 Hz, 1H), 3.82 (s, 3H), 3.78 – 3.70 (m, 2H), 3.61 – 3.48 (m, 2H), 3.11 (dd, J = 12.9, 9.7 Hz, 1H), 2.92 – 2.77 (m, 2H), 2.72 – 2.54 (m, 2H). [1064] MS(ESI) calculated for C13H17NO2: 219.1; found 220.2 Procedure for Compound 204
Figure imgf000346_0002
8‐Cyano‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (204) [1065] Following the same procedure describe in General procedure K, the title compound was synthesized (8.0 mg, 80% yield) from tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)-carboxylate as a white solid. [1066] 1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 5.22 (d, J = 8.8 Hz, 1H), 4.10 (ddd, J = 11.3, 5.0, 4.1 Hz, 1H), 3.79 (ddd, J = 11.4, 9.1, 3.6 Hz, 1H), 3.70 (dd, J = 13.2, 5.6 Hz, 1H), 3.63 – 3.50 (m, 2H), 3.21 (m, 2H), 3.09 – 2.93 (m, 2H), 2.83 (dt, J = 17.0, 3.7 Hz, 1H). [1067] MS(ESI) calculated for C13H14N2O: 214.1; found 215.2 Procedure of Compound 200
Figure imgf000347_0001
8‐(Trifluoromethyl)‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (200) [1068] Following the same procedure described in General procedure P, the title compound was synthesized (10 mg, 7.1% yield) from tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)-carboxylate as a white solid. [1069] 1H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 5.42 – 5.26 (m, 1H), 4.11 – 4.06 (m, 1H), 3.83 – 3.77 (m, 1H), 3.69 – 3.57 (m, 2H), 3.44 – 3.38 (m, 1H), 3.22 – 3.16 (m, 1H), 3.10 – 2.91 (m, 3H), 2.88 – 2.80 (m, 1H). [1070] MS(ESI) calculated for C13H14F3NO: 257.1; found 258.2 Procedure for Compound 202
Figure imgf000347_0002
8‐Fluoro‐3‐oxa‐12‐azatricyclo[7.4.1.05,14]tetradeca‐5(14),6,8‐triene hydrochloride (202) [1071] Following the same procedure describe in General Procedure F, the title compound was synthesized (30 mg, 45.7% yield) from tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3a,4,6,7-tetrahydro-1H-isochromeno[4,5-cd]azepine-5(3H)-carboxylate as a white solid. [1072] 1H NMR (400 MHz, DMSO-d6) δ 9.70 (brs, 1H), 7.16 – 7.07 (m, 2H), 5.25 (d, J = 9.8 Hz, 1H), 4.00 – 3.94 (m, 1H), 3.72 – 3.67 (m, 1H), 3.53 – 3.49 (m, 1H), 3.40 – 3.37 (m, 1H), 3.30 – 3.26 (m, 1H), 3.12 – 3.07 (m, 1H), 2.91 – 2.76 (m, 3H), 2.71 – 2.65 (m, 1H). [1073] MS(ESI) calculated for C12H14FNO: 207.1; found, 208.2. Procedure for Compound 206-1
Figure imgf000348_0001
tert-Butyl thiophen-3-ylcarbamate (1)
Figure imgf000348_0002
[1074] To a solution of thiophene-3-carboxylic acid (25 g, 195 mmol) in 2-methylpropan- 2-ol (300 mL) was added diphenylphosphinoyl azide (71.0 g, 292 mmol) and triethylamine (108.5 mL, 780 mmol). The mixture was refluxed for 16 hours. After cooling to room temperature, the reaction was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (25 g, 64.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (brs, 1H), 7.38 (dd, J = 5.1, 3.2 Hz, 1H), 7.17 (brs, 1H), 6.98 (d, J = 5.1 Hz, 1H), 1.46 (s, 9H). tert-Butyl (2-formylthiophen-3-yl)carbamate (2)
Figure imgf000349_0001
[1075] To a solution of 1 (10 g, 50.1 mmol) in tetrahydrofuran (100 mL ) was added n- BuLi (40 mL, 100.0 mmol) at -78°C under nitrogen. The resulting solution was stirred at - 78°C for 1 h. N,N-Dimethylformamide (5.8 mL, 75.1 mmol) was added dropwise to above solution, and the resulting solution was stirred for another 2 hours. Saturated NH4Cl was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography to obtain title compound (10.0 g, 87.6% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.81 (brs, 1H), 9.67 (s, 1H), 7.94 (d, J = 5.3 Hz, 1H), 7.66 (d, J = 5.3 Hz, 1H), 1.53 (s, 9H). MS(ESI) calculated for C10H13NO3S, 227.1; found 128.2, 172.2 Ethyl (Z)-3-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)acrylate (3)
Figure imgf000349_0002
[1076] To a solution of ethyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (12.8 g, 38.5 mmol) and 18-crown-6 ether (35.6 g, 132.4 mmol) in tetrahydrofuran (20 mL) was added sodium bis(trimethylsilyl)azanide (14 mL, 28.0 mmol) dropwise at -78°C, and the reaction mixture was stirred for 30 min. tert-Butyl N-(2-formylthiophen-3-yl)carbamate (6.2 g, 27.2 mmol) was dissolved in tetrahydrofuran (5 mL) and added dropwise, and the mixture was continued to stir at -78°C for 1h. The reaction was quenched with saturated NH4Cl, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography to obtain desired product (5.7 g, Z/E=1:1, 70.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 5.2 Hz, 1H), 7.42 (s, 1H), 7.28 (d, J = 5.5 Hz, 1H), 6.93 (d, J = 12.5 Hz, 1H), 5.77 (d, J = 12.5 Hz, 1H), 4.29 – 4.21 (m, 2H), 1.53 (d, J = 6.4 Hz, 9H), 1.32 (td, J = 7.1, 1.6 Hz, 3H). MS(ESI) calculated for C14H19NO4S, 297.1; found 198.0,242.0,298.0 Ethyl (3S,4R)-1-benzyl-4-(3-((tert-butoxycarbonyl)amino)thiophen-2-yl)pyrrolidine-3- carboxylate (4)
Figure imgf000350_0001
[1077] A solution of 3 (5.6 g, 18.8 mmol, Z/E=1:1), benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (9.6 mL, 37.6 mmol) and lithium fluoride (1.95 g, 75.2 mmol) in dimethylformamide (50 mL ) was stirred at 110°C under nitrogen for 1 hour. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to purify by column chromatography to obtain the desired compound (2.80 g, 69.1% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 7.51 – 7.44 (m, 3H), 7.36 – 7.30 (m, 2H), 7.30 – 7.23 (m, 1H), 6.99 (d, J = 5.5 Hz, 1H), 3.93 – 3.63 (m, 5H), 3.53 – 3.49 (m, 1H), 3.42 – 3.36 (m, 1H), 3.11 – 3.09 (m, 1H), 2.73 – 2.68 (m, 1H), 2.45 (t, J = 9.3 Hz, 1H), 1.50 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H). MS(ESI) calculated for C23H30N2O4S, 430.2; found 431.2 (5aS,8aR)-5-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-d]thieno[3,2-b]pyridin-7-ium chloride (Compound 206-1)
Figure imgf000350_0002
[1078] A solution of 4 (1.7 g, 3.9 mmol) in ethylene dichloride (50 mL) was cooled to 0°C. 1-chloroethyl carbonochloridate (2 mL, 18.5 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 1 h, then continued to stir at 50°C for 30 min. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was dissolved in ethanol (30 mL) and stirred at 90°C for 1 hour. The reaction mixture was concentrated to purify by column chromatography (eluted with DCM: MeOH=5:1) to obtain 600 mg gray solid. The solid was slurried with methanol (10 mL), filtered and washed with methanol (2 mL) to obtain title compound (400 mg, 52.6% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.71 (brs, 1H), 9.46 (brs, 1H), 7.45 (d, J = 5.3 Hz, 1H), 6.72 (d, J = 5.3 Hz, 1H), 3.87 – 3.75 (m, 1H), 3.70 – 3.50 (m, 3H), 3.48 – 3.42 (m, 1H), 2.96 – 2.77 (m, 1H). MS(ESI) calculated for C9H10N2OS, 194.1; found 195.0 Procedure for Compound 206-2
Figure imgf000351_0001
Ethyl (E)-3-(3-bromothiophen-2-yl)acrylate (1)
Figure imgf000351_0002
[1079] Ethyl 2-(diethoxyphosphoryl)acetate (117.4 g, 523.6 mmol) in THF(100 mL) was added dropwise to a suspension of sodium hydride (21.9 g, 523.6 mmol, 60%wt) in THF (200 mL) at 0°C and the reaction mixture was stirred at 0°C for 1 hour. 3-Bromothiophene-2- carbaldehyde (50 g, 261.8 mmol) in THF (300 mL) was added to the above solution. The mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. The mixture was poured into H2O (300 mL) and extracted with ethyl acetate (300 mL* 2). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate= 90:10) to obtain the product (50.0 g, 73.5% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 15.8, 0.8 Hz, 1H), 7.33 (dd, J = 5.3, 0.7 Hz, 1H), 7.03 (d, J = 5.3 Hz, 1H), 6.30 (d, J = 15.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). Ethyl (E)-3-(3-((diphenylmethylene)amino)thiophen-2-yl)acrylate (2)
Figure imgf000352_0001
[1080] A solution of 1 (50 g, 191.5 mmol), diphenylmethanimine (69.0 g, 383.0 mmol), BINAP (9.0 g, 14.4 mmol), Pd2(dba)3 (4.4 g, 4.8 mmol) and CS2CO3 (124.8 g, 383.0 mmol) in toluene (200 mL ) was stirred at 110°C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was concentrated to purify by column chromatography (eluted with petroleum ether: ethyl acetate=95:5) to obtain the title product (25 g, 36.2% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.79 (m, 3H), 7.53-7.51 (m, 1H), 7.45-7.43 (m, 2H), 7.38 – 7.30 (m, 3H), 7.16-7.14 (m, 2H), 7.04 (d, J = 5.2 Hz, 1H), 6.20 (d, J = 5.3 Hz, 1H), 6.07 (d, J = 15.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.31 – 1.28 (m, 3H). Ethyl (3S,4R)-1-benzyl-4-(3-((diphenylmethylene)amino)thiophen-2-yl)pyrrolidine-3- carboxylate (3)
Figure imgf000352_0002
[1081] To a solution of 2 (4.0 g, 11.1 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (5.2 g, 22.0 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (125.0 mg, 1.1 mmol) at 0oC, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (2.6 g, 47.4% yield) as a brown solid. MS(ESI) calculated for C31H30N2O2S, 494.2; found 495.2. Ethyl (3S,4R)-4-(3-aminothiophen-2-yl)-1-benzylpyrrolidine-3-carboxylate (4)
Figure imgf000353_0001
[1082] To a solution of 3 (2.6 g, 5.3 mmol) in dioxane (20 mL) was added HCl/dioxane (4 M, 20 mL), and the mixture was stirred at room temperature for 1 hour. After which period, the reaction mixture was adjusted to pH~8 with basic anion exchange resin and filtered. The filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 1:10) to obtain the desired compound (1.0 g, 57.1% yield) as a brown solid. MS(ESI) calculated for C18H22N2O2S, 330.1; found 331.2. (5aR,8aR)-7-Benzyl-4,5a,6,7,8,8a-hexahydro-5H-pyrrolo[3,4-d]thieno[3,2-b]pyridin-5- one (5)
Figure imgf000353_0002
[1083] To a solution of 4 (0.8 g, 2.4 mmol) in toluene (50 mL) was added trimethylaluminium (7.3 mL, 1.0 M in toluene) at 0oC, and the resulting mixture was stirred at 0oC for 2 hours. Then, the reaction mixture was poured into a solution of silica gel in methanol (50 mL) and filtered. The filtrate was concentrated to dryness. The residue was purified by column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain the desired compound (550.0 mg, 80.7% yield) as a brown solid. MS(ESI) calculated for C16H16N2OS, 284.1; found 285.2. (5aR,8aR)-5-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-d]thieno[3,2-b]pyridin-7-ium chloride (Compound 206-2)
Figure imgf000354_0001
[1084] To a solution of 5 (450.0 mg, 1.6 mmol) and cesium carbonate (2.6 g, 7.9 mmol) in 1,2-dichloroethane (30 mL) was added 1-chloroethyl chloroformate (1.1 g, 7.9 mmol). The resulting mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in methanol (30 mL) and refluxed for 3 hours. The reaction mixture was cooled to room temperature and concentrated to purify by prep-HPLC (CH3CN/H2O, 0.1%HCl) to obtain the desired compound (80.0 mg, 21.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.60 (brs, 1H), 9.47 (brs, 2H),7.46 (d, J = 5.2 Hz, 1H), 6.71 (d, J = 5.2 Hz, 1H), 3.81 (q, J = 8.8 Hz, 1H), 3.67-3.60 (m, 2H), 3.58-3.50 (m, 1H), 3.47-3.42 (m, 1H), 2.92-2.83 (m, 1H). MS(ESI) calculated for C9H10N2OS, 194.1; found 195.0. Example 2. TAAR1 % Activation Assay [1085] The compounds of the present disclosure were evaluated for their TAAR1 activation properties. TAAR1 Assay Protocol [1086] TAAR1 functional agonism was determined using the Cisbio Homogenous Time- Resolved Fluorescence (HTRF) cAMP assay (F. Degorce et al., Curr. Chem. Genomics 2009, 3: 22–32). CHO-K1 cells expressing human recombinant TAAR1 receptor grown prior to the test in media without antibiotic are detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g/l BSA, supplemented with 1mM IBMX). 12 μl of cells are mixed with 12 μl of the test compound in 96-well plates at a concentration of 10 μM and then incubated 30 min at room temperature. After addition of the lysis buffer and 1 hour incubation, cAMP concentrations are estimated, according to the manufacturer specification, with the HTRF kit. Agonist activity of test compound was expressed as a percentage of the activity of the reference agonist (tyramine) at its EC100 concentration. Assays were run in duplicate (n=2) and the results reported are the average value. [1087] TAAR1 % activation data at a concentration of 10 uM are shown in Table 2 below. Table 2. TAAR1 % activation
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
Equivalents and Scope [1088] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the appended claims. [1089] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process. [1090] It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the term “consisting of” is thus also encompassed and disclosed. [1091] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [1092] In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the disclosure (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art. [1093] It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the disclosure in its broader aspects. [1094] While the present disclosure has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with references to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope of the disclosure.

Claims

CLAIMS 1. A compound of Formula (II-1):
Figure imgf000361_0001
a tautomer, or a pharmaceutically acceptable salt thereof, wherein X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), each R1, R2, R5a, and R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which is optionally substituted; and wherein n is 1 and m is 1 or 2, or n is 0 and m is 2.
2. The compound of claim 1, wherein n is 0 and m is 2.
3. The compound of claim 1, wherein n is 1 and m is 1.
4. The compound of claim 1, wherein n is 1 and m is 2.
5. The compound of claim 1, wherein R11 is halogen, CN, alkoxy, a methyl group substituted with amine, or a methyl group substituted with halogen(s).
6. The compound of any one of claims 1-5, wherein R21 or R22 are independently H or Me.
7. The compound of any of claims 1-6, wherein one of R12 is H.
8. The compound of any of claims 1-6, wherein the compound is selected from the group consisting of Compounds 11, 23, 84-85, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 2, wherein the compound is Compound 11 or a pharmaceutically acceptable salt thereof.
10. The compound of claim 3, wherein the compound is selected from the group consisting of Compounds 23, 85, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 4, wherein the compound is Compound 84 or a pharmaceutically acceptable salt thereof.
12. A compound of Formula (II-2): a tautomer, or a
Figure imgf000362_0001
pharmaceutically acceptable salt thereof, wherein X1 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), each R1, R2, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R21 and R22 are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), CN, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and wherein n is 0 and m is 1 or 2, or n is 1 and m is 1.
13. The compound of claim 12, wherein n is 0 and m is 1.
14. The compound of claim 12, wherein n is 0 and m is 2.
15. The compound of claim 12, wherein n is 1 and m is 1.
16. The compound of claim 12, wherein R11 is halogen, CN, alkoxy, a methyl group substituted with amine, or a methyl group substituted with halogen(s).
17. The compound of any one of claims 12-16, wherein R21 or R22 are independently H or Me.
18. The compound of any of claims 12-17, wherein one of R12 is H.
19. The compound of any of claims 12-17, wherein the compound is selected from the group consisting of Compounds 12, 13, 15, 17, 18, 83, 166, 168, 169, 173, 178, 179, 181, 183, 186, 191, 193, 197, 199, 201, 203, 205, or a pharmaceutically acceptable salt thereof.
20. The compound of claim 13, wherein the compound is selected from the group consisting of Compounds 13, 166, 201, or a pharmaceutically acceptable salt thereof.
21. The compound of claim 14, wherein the compound is Compound 12 or a pharmaceutically acceptable salt thereof.
22. The compound of claim 15, wherein the compound is selected from the group consisting of Compounds 17, 18, 83, 168, 169, 173, 178, 179, 181, 183, 186, 191, 193, 197, 199, 201, 203, 205, or a pharmaceutically acceptable salt thereof.
23. A compound of Formula (II-3): a tautomer, or a
Figure imgf000363_0001
pharmaceutically acceptable salt thereof, wherein X2 is C(R1)(R2); X5 (when m>1, each X5 independently) is C(R5a)(R5b), each R1, R2, R21, R22, R5a, R5b are independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), halogen, hydroxyl, ether, CN, amine, or CF3; each R11 is independently H, optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, amino alkyl, arylalkyl, or heteroarylalkyl), optionally substituted cycloalkyl (such as a 3-8 membered cycloalkyl), halogen, hydroxyl, alkoxyl, aryloxyl, ether, CN, CF3, amine, aryl, or heteroaryl; R12 or R13 each is independently H or optionally substituted alkyl (including but not limited to lower alkyl, haloalkyl, alkoxy, or amino alkyl), and one of R12 or R13 is attached to the aromatic ring and form a 6-7 membered heterocycle which may be optionally substituted; and wherein n is 0 or 1 and m is 1 or 2.
24. The compound of claim 23, wherein n is 0 and m is 1.
25. The compound of claim 23, wherein n is 0 and m is 2.
26. The compound of claim 23, wherein n is 1 and m is 1.
27. The compound of claim 23, wherein n is 1 and m is 2.
28. The compound of claim 23, wherein R11 is halogen, CN, alkoxy, a methyl group substituted with amine, or a methyl group substituted with halogen(s).
29. The compound of any one of claims 23-28, wherein R21 or R22 are independently H or Me.
30. The compound of any of claims 23-29, wherein one of R12 is H.
31. The compound of any of claims 23-30, wherein the compound is selected from the group consisting of Compounds 19, 20, 87, 88, 171, 172, 176, 180, 182, 185, 188, 190, 192, 194- 196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof.
32. The compound of claim 26, wherein the compound is selected from the group consisting of Compounds 19, 20, 87, 171, 172, 176, 180, 182, 185, 188, 190, 192, 194-196, 198, 200, 202, 204, or a pharmaceutically acceptable salt thereof. 33. The compound of claim 27, wherein the compound is Compound 88 or a pharmaceutically acceptable salt thereof. 34. A compound selected from Compounds 7-13, 15, 17-25,
33,
34, 36, 37, 40-46, 61-63, -77, 80, 82-88, 90-1, 90-2, 92, 95-109, 111-166, 168, 169, 171-173, 176-206 or a pharmaceutically acceptable salt thereof.
35. A pharmaceutical composition comprising the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
36. A method of activating TAAR1 in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of any one of claims 1-34 or a therapeutically effective amount of the pharmaceutical composition of claim 35.
37. A method of activating TAAR1 in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound selected from Compounds 1- 206.
38. The method of claim 36 or claim 37, wherein 5HT1A, 5HT2A, 5HT2C, 5HT6, or 5HT7 of the subject is also modulated.
39. A method of treating, preventing, or managing a CNS disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of any one of claims 1-34 or a therapeutically effective amount of the pharmaceutical composition of claim 35.
40. A method of treating, preventing, or managing a CNS disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound selected from Compounds 1-206.
41. The method of claim 39 or claim 40, wherein the CNS disorder is a neurological or psychiatric disorder.
42. The method of claim 39 or claim 40, wherein the CNS disorder is depression, anxiety, cognitive impairment, psychosis, schizophrenia, bipolar disorder, obsessive compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), addiction, social disorder, attention deficit hyperactivity disorder (ADHD), or autism.
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