WO2021198981A1 - Antiviral compounds and uses thereof - Google Patents

Antiviral compounds and uses thereof Download PDF

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Publication number
WO2021198981A1
WO2021198981A1 PCT/IB2021/052750 IB2021052750W WO2021198981A1 WO 2021198981 A1 WO2021198981 A1 WO 2021198981A1 IB 2021052750 W IB2021052750 W IB 2021052750W WO 2021198981 A1 WO2021198981 A1 WO 2021198981A1
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compound
alkyl
mmol
preparation
cycloalkyl
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PCT/IB2021/052750
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French (fr)
Inventor
Leonid Beigelman
Sandrine Celine Grosse
Kiran MATCHA
David Craig Mc Gowan
Karin Ann Stein
Anh Pham TRUONG
Guangyi Wang
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Janssen Biopharma, Inc.
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Publication of WO2021198981A1 publication Critical patent/WO2021198981A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • This disclosure relates generally to therapeutic agents that may be useful in inhibiting replication of a respiratory syncytial virus (RSV).
  • the therapeutic agents may be used in the treatment of a respiratory syncytial virus infection.
  • Respiratory syncytial virus is a non-segmented negative-strand (NNS) RNA virus and is a member of the order Mononegavirales and the family Pneumoviridae. Pneumoviridae previously was a subfamily within the Paramyxoviridae family, but has recently been reclassified (Afonso et al.2016, Archives of Virology, 161(8):2351-2360). RSV has been classified in two antigenic subtypes: A and B, with subtype A typically associated with more severe symptoms.
  • RSV causes infections that can be relatively mild in the majority of otherwise healthy adults, but that can lead to severe lower respiratory infections in at risk populations, such as immunocompromised people, infants, and the elderly. For infants younger than 5 years old, it has been estimated that 33.8 million RSV infections occurred worldwide each year, at least 3.4 million of these cases required hospitalization, and 66,000 to 199,000 deaths occurred as a result (Nair et al., 2010, Lancet 375:1545-1555; Stein et al., 2017, Pediatric Pulmonology 52:566-569). [0005] Currently available treatments are inadequate. This is particularly true for adults, including the elderly and the immunocompromised, for which no treatment has been approved.
  • Inhaled Ribavirin (Virazole®) was approved in 1986 for treatment of serious RSV infections, but is potentially toxic for exposed medical personnel and lacks clear efficacy data (Fearns et al., 2016, Antiviral Research, 134:63-76). In addition, it is not recommended for use in adults (Virazole® prescribing information).
  • the monoclonal antibody directed against RSV, palivizumab (Synagis®) is approved only for prophylaxis of serious lower respiratory tract disease caused by RSV in high-risk infants, but “therapeutic efficacy has not been established” (Fearns et al., 2016, Antiviral Research, 134:63-76).
  • G 1 is N or O;
  • G 2 is CR 4a (R 4b ) m or N, wherein m is 0 or 1, and when G 2 is N or CR 4a (R 4b ) m and m is 0, G 2 is bound to one of G 1 , G 3 , or G 4 via a double bond;
  • G 3 is CR 5a (R 5b )v or N, wherein v is 0 or 1, and when G 3 is N or CR 5a (R 5b ) v and v is 0, G 3 is bound to G 2 or G 4 via a double bond;
  • G 4 is CR 6a (R 6b )w, N, O, or
  • compositions comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
  • methods of treating a respiratory syncytial virus (RSV) infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the individual has one or more symptoms of an RSV infection.
  • the RSV is RSV Type A.
  • the RSV is RSV Type B.
  • methods of ameliorating one or more symptoms of an RSV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the symptom is one or more of: coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing.
  • the individual has a lower respiratory tract infection.
  • the individual has bronchiolitis, pneumonia, or croup. In some embodiments, the individual has been diagnosed with an RSV infection. In some embodiments, the RSV is RSV Type A. In some embodiments, the RSV is RSV Type B. In some embodiments, the RSV infection has been confirmed by a laboratory test. In some embodiments, the method further comprises obtaining the results of an RSV detecting laboratory test. In some embodiments, the laboratory test comprises detecting RSV in a nasal sample.
  • Also provided are methods of preventing an RSV infection in an individual at risk of developing an RSV infection comprising administering to the individual a prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the individual is between 0 and about 2 years of age. In some embodiments, the individual was born prematurely. In other embodiments, the individual is greater than 65 years of age. In some embodiments, the individual is immunocompromised.
  • the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered orally.
  • the RSV is a resistant RSV.
  • the method further comprises administering an additional anti-RSV agent.
  • the additional anti-RSV agent is an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, an RSV RNA polymerase inhibitor, an inosine-5'- monophosphate dehydrogenase (IMPDH) inhibitor, or an interferon.
  • IMPDH inosine-5'- monophosphate dehydrogenase
  • Also provided are methods of inhibiting an RSV RNA polymerase comprising contacting the RSV RNA polymerase with a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • Also provided are methods of inhibiting an RSV RNA polymerase in an individual in need thereof comprising administering to the individual in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Also provided are methods of inhibiting an RSV RNA polymerase comprising contacting the RSV RNA polymerase with a metabolite of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the RSV RNA polymerase is encoded by a subgenomic replicon.
  • Also provided are methods of inhibiting replication of an RSV in a cell comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof, or a metabolite of any of the foregoing or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a metabolite of any of the foregoing.
  • the cell is infected with the RSV.
  • the cell is subsequently infected with the RSV.
  • the contacting is performed in vitro.
  • the contacting is performed in vivo.
  • the RSV is RSV Type A or RSV Type B.
  • compositions for use in any one of the methods described herein comprising administering to the individual in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • compositions for use in any one of the methods described herein are also provided.
  • Figure 1 shows the single crystal structural analysis of tert-butyl ((S)-3,3,3-trifluoro- 2-((S)-7-(4-fluorophenyl)-3-(hydroxymethyl)-3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2- hydroxypropyl)carbamate (Intermediate 14-3).
  • DETAILED DESCRIPTION Definitions [0018] For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.
  • Alkyl refers to fully saturated straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms.
  • C 1-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes n-propyl and isopropyl; and “butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • a range of values e.g., C 1-6 alkyl
  • each value within the range as well as all intervening ranges are included.
  • C1-6 alkyl includes C1, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 alkyl.
  • Alkenyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one site of olefinic unsaturation (having at least one carbon-carbon double bond).
  • alkenyl group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s).
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en- 2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2- methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3- dien-2-yl).
  • Alkynyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one site of acetylenic unsaturation (having at least one carbon-carbon triple bond).
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).
  • Alkoxy refers to the group R-O-, where R is alkyl; and includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n- pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.
  • cycloalkoxy refers to the group “cycloalkyl-O-” and “aryloxy” refers to the group “aryl-O-”.
  • Substituted alkoxy refers to the group “substituted alkyl-O-”.
  • Substituted cycloalkoxy refers to the group “substituted cycloalkyl-O-”.
  • Substituted aryloxy refers to the group “substituted aryl-O-”.
  • Aryl or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which condensed rings are carbocyclic and may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is aromatic.
  • aryl groups are those having from 6 to 14 annular carbon atoms (a “C 6 -C 14 aryl”).
  • An aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • Cycloalkyl refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C 3 - C 10 means three to ten carbon atoms).
  • Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl.
  • a cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof.
  • Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl").
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
  • Halo or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc.
  • perhaloalkyl refers to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.”
  • a preferred perhaloalkyl group is trifluoromethyl (-CF3).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • haloalkyl refers to an alkyl group with one or more halo substituents, such as one, two, or three halo substituents.
  • haloalkyl groups include –CF 3 , -(CH 2 )F, - CHF 2 , CH 2 Br, -CH 2 CF 3 , - CH 2 CHF 2 , and –CH 2 CH 2 F.
  • Heteroaryl refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur.
  • a heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), which condensed rings may be carbocyclic or may contain one or more annular heteroatom and which may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is both aromatic and contains at least one annular heteroatom.
  • Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • a heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
  • Heterocycle refers to a saturated or an unsaturated non-aromatic cyclic group having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like.
  • a heterocyclic group may have a single ring (e.g., pyrrolidinyl) or multiple condensed rings (e.g., decahydroisoquinolin-1-yl), which condensed rings may or may not be aromatic and which may be carbocylic or contain one or more annular heteroatoms, but which excludes heteroaryl rings.
  • a heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof.
  • one or more of the fused rings can be cycloalkyl or aryl, but excludes heteroaryl groups.
  • the heterocyclyl group may be optionally substituted independently with one or more substituents described herein.
  • Particular heterocyclyl groups are 3 to 14- membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • amino acid side chain or “side chain of an amino acid” refers to a monovalent non-hydrogen substituent that is bonded to an a carbon of an ⁇ -amino acid, including, e.g., natural, non-natural, standard, non-standard, proteinogenic, or non-proteinogenic amino acid.
  • amino acid side chains include, but are not limited to the ⁇ -carbon substituent of alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline, and derivatives thereof.
  • a taxonomic categorization of a virus such as the order Mononegavirales or the family Pneumoviridae, is understood that the term is used in its sense as described in Afonso et al.
  • a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results in treating a viral infection include, but are not limited to, one or more of the following: eliminating or lessening the severity of one or more symptoms resulting from the viral infection (such as but not limited to coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing), increasing the quality of life of those suffering from the viral infection, decreasing the dose of other medications required to treat the viral infection, delaying the progression of the viral infection, and/or prolonging survival of an individual.
  • eliminating or lessening the severity of one or more symptoms resulting from the viral infection such as but not limited to coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing
  • increasing the quality of life of those suffering from the viral infection decreasing the dose of other medications required to treat the viral infection, delaying the progression of the viral infection, and/or prolonging survival
  • preventing is an approach for eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and/or behavioral symptoms of a viral infection. Prevention may be in the context of an individual at risk of developing the viral infection, such as where the at risk individual does not develop the viral infection over a period of time, such as during a viral season or during a period of exposure to the virus, which may be days to weeks to months.An individual “at risk” of developing a viral infection is an individual with one or more risk factors for developing the viral infection but who has not been diagnosed with and does not display symptoms consistent with a viral infection.
  • Risk factors for developing an RSV infection include but are not limited to an individual’s age (young children under age 5 such as children between about 0 and about 2 years of age, including infants, and individuals greater than 65 years of age), premature birth, co-morbidities associated with RSV and individuals who are immunocompromised.
  • a “therapeutically effective dosage” or “therapeutically effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to produce a desired therapeutic outcome.
  • a therapeutically effective amount or a therapeutically effective dosage can be administered in one or more administrations.
  • a therapeutically effective amount or dosage may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in a therapeutically effective amount if, in conjunction with one or more other agents, a desired therapeutic outcome is achieved.
  • Suitable doses of any of the co- administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • a “prophylactically effective dosage” or “prophylactically effective amount” is an amount sufficient to effect the preventative result of eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and/or behavioral symptoms of a viral infection.
  • a prophylactically effective amount or a prophylactically effective dosage can be administered in one or more administrations and over a period of time in which such prevention is desired.
  • the term “individual” is a mammal, including humans. An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is human.
  • the individual may have advanced viral infection or lesser extent of viral infection, such as low viral titer.
  • the term “resistant” refers to a viral strain displaying a delayed, lessened, and/or null response to one or more therapeutic agents.
  • a viral strain may comprise a mutation that decreases the efficacy of one or more therapeutic agents used for treatment or prevention of an infection caused by the viral strain compared the efficacy of the one or more therapeutic agents used for treatment or prevention of an infection caused by a viral strain that does not comprise the mutation.
  • aspects and variations described herein also include “consisting” and/or “consisting essentially of” aspects and variations.
  • a compound of the Formula (I): or a pharmaceutically acceptable salt thereof wherein: Ring and Ring are taken together to form a bicyclic heteroaromatic ring, or Ring is an aromatic ring fused to Ring , wherein Ring is a saturated or partially unsaturated ring; G 1 is N or O; G 2 is CR 4a (R 4b )m or N, wherein m is 0 or 1, and when G 2 is N or CR 4a (R 4b )m and m is 0, G 2 is bound to one of G 1 , G 3 , or G 4 via a double bond; G 3 is CR 5a (R 5b )v or N, wherein v is 0 or 1, and when G 3 is N or CR 5a (R 5b )v and v is 0, G 3 is bound to G 2 or G
  • the compound of Formula (I) contains at least one stereocenter (at the carbon bearing R 8 and OH) and may further contain one or more additional stereocenters.
  • the compound of Formula (I) contains stereocenters as labeled by a single asterisk (*) and double asterisks (**) depicted in the structure of Formula (I) below.
  • the carbon marked by (*) and bearing the R 8 and OH moieties is in an “R” configuration. In other embodiments, the carbon marked by (*) and bearing the R 8 and OH moieties is in an “S” configuration.
  • the carbon marked by (**) and bearing the R 1 and R 2 moieties is in an “R” configuration. In other embodiments, the carbon marked by (**) and bearing the R 1 and R 2 moieties is in an “S” configuration. In some embodiments of the compounds of Formula (I), the carbon marked by (*) and bearing the R 8 and OH moieties is in an “R” configuration and the carbon marked by (**) and bearing the R 1 and R 2 moieties is in an “R” configuration.
  • the carbon marked by (*) and bearing the R 8 and OH moieties is in an “R” configuration and the carbon marked by (**) and bearing the R 1 and R 2 moieties is in an “S” configuration.
  • the carbon marked by (*) and bearing the R 8 and OH moieties is in an “S” configuration and the carbon marked by (**) and bearing the R 1 and R 2 moieties is in an “S” configuration.
  • the carbon marked by (*) and bearing the R 8 and OH moieties is in an “S” configuration and the carbon marked by (**) and bearing the R 1 and R 2 moieties is in an “R” configuration.
  • the compound of Formula (I) has additional stereocenters located on substituent groups R 1 , R 2 , R 3 , R 3a , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R a , R b , R c , R d , R d1 , R d2 , R e and R f .
  • R 4a is , wherein the compound contains an additional stereocenter marked by (#).
  • R 4a the carbon marked by (#) is in an “R” configuration. In other embodiments, the carbon marked by (#) is in an “S” configuration.
  • R 2 is wherein the compound contains two additional stereocenters marked by (@) and (&).
  • R 2 is the carbon marked by (@) is in an “R” configuration. In some embodiments, the carbon marked by (@) is in an “S” configuration. In some embodiments, the carbon marked by (&) is in an “R” configuration. In some embodiments, the carbon marked by (&) is in an “S” configuration.
  • the carbon marked by (@) is in an “R” configuration and the carbon marked by (&) is in an “R” configuration. In some embodiments, the carbon marked by (@) is in an “R” configuration and the carbon marked by (&) is in an “S” configuration. In some embodiments, the carbon marked by (@) is in an “S” configuration and the carbon marked by (&) is in an “R” configuration. In other embodiments, the carbon marked by (@) is in an “S” configuration and the carbon marked by (&) is in an “S” configuration. [0049] In some embodiments of the compounds of Formula (I), G 1 is N. In some embodiments, G 1 is O.
  • G 2 is N.
  • n is 1.
  • G 3 is CR 5a (R 5b ) v .
  • v is 0.
  • R 5a is hydrogen, halo, C 1 -C 6 alkyl, CN, or -NR i R j , wherein the C 1 -C 6 alkyl of R 5a is unsubstituted or substituted by 1, 2, or 3 halo.
  • R 5a is hydrogen, halo, C1-C6 alkyl, or - NR i R j , wherein the C1-C6 alkyl of R 5a is unsubstituted or substituted with 1, 2, or 3 halo.
  • R 5a is -H, -F, -Cl, - Br, -CH 3 , -CH 2 F, -CF 3 , -CN, or -NH 2 . In some embodiments, R 5a is -H, -F, -Cl, -Br, -CH 3 , - CH 2 F, -CF 3 , or -NH 2 .
  • G 3 is N. In some embodiments of the compounds of Formula (I), n is 0. In some embodiments of the compounds of Formula (I), G 4 is CR 6a (R 6b ) w . In some embodiments of the compounds of Formula (I), w is 0.
  • R 6a is hydrogen, halo, C 1 -C 6 alkyl, CN, or -NR i R j .
  • R 6a is -H, -CH3, or -F.
  • R 6a is -H.
  • G 4 is N.
  • G 4 is O.
  • G 4 is S.
  • G 5 is C.
  • G 5 is N.
  • G 6 is C.
  • Ring and Ring are taken together to form a bicyclic heteroaromatic ring.
  • the ring containing is an aromatic ring fused to the ring containing , which is a saturated ring.
  • the ring containing is an aromatic ring fused to the ring containing , which is a partially unsaturated ring.
  • R 1 is -CH3, -CH2F, -CHF2, -CF3, or -CH2OH.
  • R 3 is C1-C6 alkyl, C3- C 8 cycloalkyl, or C 6 -C 14 aryl.
  • R 3 is -OR d , wherein R d is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.
  • R 3 is –OCH 3 or –O-cyclopropyl.
  • R 3 is -OR d , wherein R d and G 1 are taken together with the atoms to which they are attached to form a 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl ring.
  • R 8 is C 1 -C 6 alkyl. In some embodiments, R 8 is C3-C8 cycloalkyl. In some embodiments, R 8 is cyclopropyl. In some embodiments, R 8 is C1-C6 haloalkyl. In some embodiments, R 8 is CHF 2 or CF 3 . [0076] In some embodiments of Formula (I), one or two of R 9 , R 10 , R 11 , R 12 , and R 13 is halo or C1-C6 haloalkyl. In some embodiments, one or two of R 9 , R 10 , R 11 , R 12 , and R 13 is F.
  • R 9 is F or Cl. In some embodiments, R 10 is F, Cl, CF 3 , or CHF 2 . In some embodiments, R 12 is F or Cl. In some embodiments, R 9 and R 10 are each F. In some embodiments, one or two of R 9 , R 10 , R 11 , R 12 , and R 13 is CF3. In some embodiments, R 10 is CF3.
  • the compound of Formula (I) is a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein Ring 1 2 3 4 5 , Ring G , G , G , G , G , G 6 , n, R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are as defined for Formula (I).
  • the carbon bearing R 1 and R 2 is in the “S” configuration.
  • the carbon bearing R 1 and R 2 is in the “R” configuration.
  • the compound of Formula (I) is a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein Ring , Ring , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , n, R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are as defined for Formula (I).
  • the carbon bearing R 1 and R 2 is in the “R” configuration.
  • the carbon bearing R 1 and R 2 is in the “S” configuration.
  • G 2 is CR 4a .
  • G 2 is N.
  • n is 1 and G 3 is CR 5a .
  • R 5a is H, F, Cl, - CH3, -CD3, -CHF2, -CH2F, -CF3, -OCH3, -OCHF2, -OCF3, CN, -cyclopropyl (optionally substituted with fluoro), NH 2 , NHCH 3 , or CONH 2 .
  • n is 1 and G 3 is N.
  • G 4 is CR 6a .
  • R 6a is H or -CH3, optionally wherein R 6a is H.
  • G 4 is N, or wherein G 4 is O, or wherein G 4 is S.
  • R 1 is -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -CH 2 OH.
  • R 3 is F, Cl, -OCH3, -OCD3, -OCHF2, -OCF3, -OCH2CHF2, -O- cyclopropyl, or -O-CH2-cyclopropyl.
  • R 8 is -CHF 2 , -CF 3 , -CH 2 F, cyclobutyl, cyclopropyl, or fluoro- cyclopropyl.
  • R 9 , R 10 , R 11 , R 12 , and R 13 are independently F, - CF 3 , Cl, ethyl, -CF 2 CH 3 , or -CHFCH 3 .
  • R 9 , R 12 , and R 13 are each H.
  • (a) R 10 is F, Cl, -CF3, or -CHF2, or
  • (b) R 11 is H, F, Cl, -CF3, -CF2CH3, or ethyl.
  • R 1 , R 2 , R 3 , R 9 , and R 10 are as defined for Formula (I); G 2 is CR 4a or N; and G 3 is CR 5a or N.
  • R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, -C(O)NHR a , or -CN, wherein the C1-C6 alkyl and C 1 -C 6 haloalkyl of R 1 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -CN, -OH, and oxo, and the C3-C8 cycloalkyl of R 1 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -CN, -OH, and oxo; R 2 is
  • R 3 is —OR d .
  • R 3 is — OR d , wherein R d unsubstituted C 1 -C 6 alkyl (e.g., R d is –CH 3 ).
  • R 3 is –OR d , wherein R d C 1 -C 6 alkyl substituted by 1 or 2 groups selected from halogen and C 3 - C8 cycloalkyl (e.g., R d is –CHF2 or –CH2-cyclopropyl).
  • R 3 is –OR d , wherein R d is C3-C8 cycloalkyl (e.g., R d is cyclopropyl).
  • R 4a is hydrogen.
  • R 4a is C1-C6 alkyl substituted by 1 or 2 groups selected from halo and OH (e.g., R 4a is –CH 2 OH or –CH 2 F).
  • R 5a is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN.
  • R 5a is C 1 -C 6 alkoxy (e.g., -OCH 3 ) or - NR i R j , wherein R i and R j are each hydrogen.
  • R 5a is C1-C6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., - CH 3 , -CH 2 F, CHF 2 , or –CF 3 ).
  • R 5a is hydrogen.
  • R 5a is halo.
  • R 5a is F, Cl, or Br.
  • R 5a is C1-C6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups. In some embodiments, R 5a is CH 3 , CH 2 F, or CF 3 . In some embodiments, R 5a is NH 2 . [0098] In some embodiments of Formula (III), R 6a is hydrogen. In some embodiments, R 6a is hydrogen, halo, C1-C6 alkyl, CN, or -NR i R j .
  • R 6a is -H, -CH 3 , or -F.
  • R 6a is -H.
  • R 3 is –OR d .
  • R 3 is – OR d , wherein R d is C3-C8 cycloalkyl (e.g., R d is cyclopropyl).
  • R 3 is – OR d , wherein R d unsubstituted C 1 -C 6 alkyl (e.g., R d is –CH 3 ).
  • R 3 is –OR d , wherein R d C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., R d is –CHF2 or –CH2-cyclopropyl).
  • R 5a is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN.
  • R 5a is C1-C6 alkoxy (e.g., -OCH3) or - NR i R j , wherein R i and R j are each hydrogen.
  • R 5a is C 1 -C 6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., -CH3, -CH2F, CHF2, or –CF3).
  • R 5a is hydrogen.
  • R 5a is halo.
  • R 5a is F, Cl, or Br.
  • R 5a is C 1 -C 6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups.
  • R 5a is CH 3 , CH2F, or CF3.
  • R 5a is NH2.
  • R 3 is —OR d .
  • R 3 is — OR d , wherein R d unsubstituted C1-C6 alkyl (e.g., R d is –CH3).
  • R 3 is –OR d , wherein R d C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C 8 cycloalkyl (e.g., R d is –CHF 2 or –CH 2 -cyclopropyl).
  • R 3 is –OR d , wherein R d is C 3 -C 8 cycloalkyl (e.g., R d is cyclopropyl).
  • R 4a is hydrogen.
  • R 4a is C3-C8 cycloalkyl (e.g., cyclopropyl).
  • R 4a is -C(O)NR g R h , wherein R g and R h are each hydrogen.
  • R 6a is hydrogen.
  • R 6a is hydrogen, halo, C 1 -C 6 alkyl, CN, or -NR i R j .
  • R 6a is -H, -CH3, or -F.
  • R 6a is -H.
  • R 3 is —OR d .
  • R 3 is — OR d , wherein R d unsubstituted C 1 -C 6 alkyl (e.g., R d is –CH 3 ).
  • R 3 is –OR d , wherein R d C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., R d is –CHF2 or –CH2-cyclopropyl).
  • R 3 is –OR d , wherein R d is C 3 -C 8 cycloalkyl (e.g., R d is cyclopropyl).
  • R 4a is unsubstituted C1-C6 alkyl (e.g., R 4a is – CH3).
  • R 4a is hydrogen.
  • R 5a is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., -CH3, -CH2F, CHF2, or –CF3).
  • R 5a is hydrogen.
  • R 5a is halo.
  • R 5a is F, Cl, or Br.
  • R 5a is C 1 -C 6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups.
  • R 5a is CH 3 , CH 2 F, or CF 3 .
  • R 5a is NH2.
  • R 3 is —OR d .
  • R 3 is —OR d , wherein R d unsubstituted C 1 -C 6 alkyl (e.g., R d is –CH 3 ).
  • R 3 is –OR d , wherein R d C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., R d is –CHF2 or –CH2-cyclopropyl).
  • R 3 is –OR d , wherein R d is C 3 -C 8 cycloalkyl (e.g., R d is cyclopropyl).
  • R 4a is hydrogen.
  • R 4a is C1-C6 alkyl substituted by 1 or 2 groups selected from halo and OH (e.g., R 4a is –CH 2 OH or –CH 2 F).
  • R 4a is C3-C8 cycloalkyl (e.g., cyclopropyl).
  • R 4a is -C(O)NR g R h , wherein R g and R h are each hydrogen.
  • R 3 is —OR d .
  • R 3 is —OR d , wherein R d unsubstituted C1-C6 alkyl (e.g., R d is –CH3).
  • R 3 is –OR d , wherein R d C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C 8 cycloalkyl (e.g., R d is –CHF 2 or –CH 2 -cyclopropyl). In one particular variation, R 3 is –OR d , wherein R d is C3-C8 cycloalkyl (e.g., R d is cyclopropyl). [0116] In some embodiments of Formula (VIII), R 4a is -C(O)NR g R h , wherein R g and R h are each hydrogen. In some embodiments, R 4a is hydrogen.
  • R 6a is -H, -CH3, or -F.
  • R 6a is -H.
  • R 3 is –OR d .
  • R 3 is – OR d , wherein R d unsubstituted C1-C6 alkyl (e.g., R d is –CH3).
  • R 3 is –OR d , wherein R d C 1 -C 6 alkyl substituted by 1 or 2 groups selected from halogen and C 3 - C8 cycloalkyl (e.g., R d is –CHF2 or –CH2-cyclopropyl).
  • R 3 is –OR d , wherein R d is C3-C8 cycloalkyl (e.g., R d is cyclopropyl).
  • R 4a is -C(O)NR g R h , wherein R g and R h are each hydrogen.
  • R 4a is hydrogen.
  • R 4a is C 1 -C 6 alkyl substituted by OH.
  • R 4a is -CH 2 OH.
  • R 4b is -C(O)NR g R h , wherein R g and R h are each hydrogen.
  • R 4b is hydrogen.
  • R 4b is C 1 -C 6 alkyl substituted by OH.
  • R 4b is -CH 2 OH.
  • R 4a and R 4b are each hydrogen.
  • R 5a is unsubstituted C1-C6 alkyl (e.g., –CH3).
  • R 5b is hydrogen.
  • R 5a and R 5b are each unsubstituted C 1 -C 6 alkyl (e.g., –CH 3 ).
  • R 5a and R 5b are each methyl.
  • R 5a is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN.
  • R 5a is C 1 -C 6 alkoxy (e.g., -OCH 3 ) or -NR i R j , wherein R i and R j are each hydrogen.
  • R 5a is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., -CH3, -CH2F, CHF2, or –CF3).
  • R 5a is hydrogen.
  • R 5a is halo.
  • R 5a is F, Cl, or Br.
  • R 5a is C 1 -C 6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups. In some embodiments, R 5a is CH3, CH2F, or CF3. In some embodiments, R 5a is NH2. In some embodiments, R 5b is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN. In some embodiments, R 5b is C 1 -C 6 alkoxy (e.g., -OCH 3 ) or -NR i R j , wherein R i and R j are each hydrogen.
  • R 5b is C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., -CH3, -CH2F, CHF2, or –CF3).
  • R 5b is hydrogen.
  • R 5b is halo.
  • R 5b is F, Cl, or Br.
  • R 5b is C 1 -C 6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups.
  • R 5b is CH3, CH2F, or CF3.
  • R 5b is NH2.
  • every description of R 1 may be combined with every description of R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , and n the same as if each and every combination were specifically and individually listed.
  • every description of R 2 may be combined with every description of R 1 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , and n the same as if each and every description were specifically and individually listed.
  • R 1 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl. In some embodiments, R 1 is methyl.
  • R 1 is C1-C6 haloalkyl, wherein the C1-C6 haloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -CN, -OH, and oxo.
  • R 1 is CF 3 or CH 2 F.
  • R 1 is C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 1 is -C(O)NHR a , wherein R a is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and –CH 2 R c .
  • R 1 is –CN.
  • R 2 is C 1 -C 6 haloalkyl, wherein the C 1 -C 6 haloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo.
  • R 2 is CH2F.
  • R 2 is C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -CN, -OH, and oxo.
  • R 2 is –CN.
  • R 2 is -C(O)NHR b , wherein R b is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, and –CH 2 R c .
  • R 2 is -C(O)NH 2 .
  • R 2 is - C(O)NHR b , wherein R b is C1-C6 alkyl.
  • R 2 is -C(O)NHCH3.
  • R 2 is -C(O)NHR b , wherein R b is C 1 -C 6 haloalkyl.
  • R 2 is -C(O)NHCHF 2 or -C(O)NHCH 2 CHF 2 .
  • R 2 is - C(O)NHR b , wherein R b is C3-C8 cycloalkyl, unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, - OH, and oxo.
  • R 2 is -C(O)NH-cyclopropyl, wherein the cyclopropyl is unsubstituted or substituted with halogen C1-C6 alkyl, C3-C8 cycloalkyl, -CN, - OH, or oxo.
  • R 2 is [0130] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R 2 is CH2F, -C(O)NH2, -C(O)N(H)CH3, -C(O)N(H)CH2CHF2, or –CN. In some embodiments, R 1 is CH 3 and R 2 is -C(O)NH 2 , -C(O)N(H)CH 3 , or - C(O)N(H)CH2CHF2.
  • R 1 is C 1 -C 6 alkyl and R 2 is -C(O)NHR b .
  • R 1 is methyl and R 2 is -C(O)NH 2 .
  • R 1 is methyl and R 2 is - C(O)NHCH2CHF2.
  • R 1 is methyl and R 2 is -C(O)NHCH3.
  • R 1 is methyl and R 2 is [0132] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R 1 is C 1 -C 6 alkyl and R 2 is C 1 -C 6 haloalkyl. For instance, in some embodiments, R 1 is methyl and R 2 is CH2F. [0133] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R 1 and R 2 are each independently C 1 -C 6 haloalkyl.
  • R 1 and R 2 are each CH2F.
  • R 1 is C 1 -C 6 alkyl and R 2 is CN.
  • R 1 is methyl and R 2 is CN.
  • R 1 is CH 3 and R 2 is -C(O)NH 2 , -C(O)N(H)CH 3 , or - C(O)N(H)CH 2 CHF 2.
  • R 1 is CH 2 F and R 2 is CH 2 F or –CN.
  • R 3 is C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C14 aryl.
  • R 3 is -OR d , wherein R d is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.
  • R 3 is –OCH3 or –O-cyclopropyl.
  • R 5a is hydrogen, halo, C 1 -C 6 alkyl, CN, or -NR i R j , wherein the C 1 -C 6 alkyl of R 5a is unsubstituted or substituted by 1, 2, or 3 halo.
  • R 5a is hydrogen, halo, C 1 -C 6 alkyl, or -NR i R j , wherein the C 1 -C 6 alkyl of R 5a is unsubstituted or substituted with 1, 2, or 3 halo.
  • R 5a is -H, -F, -Cl, -Br, -CH 3 , -CH 2 F, -CF 3 , -CN, or -NH 2 . In some embodiments, R 5a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, or -NH2.
  • R 6a is hydrogen, halo, C1-C6 alkyl, CN, or - NR i R j .
  • R 6a is -H, -CH 3 , or -F.
  • R 6a is -H.
  • R 9 and R 10 are each independently hydrogen, halo, or C1-C6 haloalkyl.
  • R 9 is hydrogen. In some embodiments, R 9 is F, Cl, Br or I. In some embodiments, R 9 is C1-C6 haloalkyl. In some embodiments, R 9 is –CF3, -(CH2)F, -CHF2, CH2Br, -CH2CF3, and –CH2CH2F. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is F, Cl, Br or I. In some embodiments, R 10 is C 1 -C 6 haloalkyl. In some embodiments, R 10 is –CF 3 , -(CH 2 )F, - CHF 2 , CH 2 Br, -CH 2 CF 3 , and –CH 2 CH 2 F.
  • R 1 is -CH 2 F and R 2 is selected from the group consisting of -CH 2 F and -CN.
  • R 1 is -CH3 and R 2 is selected from the group consisting of –CH2F and -CN.
  • R 1 is -CH 3 and R 2 is -C(O)NHR b .
  • R b is selected from the group consisting of hydrogen, C1-C6 alkyl (e.g., -CH3), C1-C6 haloalkyl (e.g., -CHF2 or CH2CHF2), and C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl of R b is substituted by 1 or 2 halo groups (e.g., cyclopropyl substituted by 1 or 2 fluoro groups).
  • R 7 is hydrogen.
  • R 8 is -CF 3 or -CHF 2 .
  • R 10 is -F or -CF 3 .
  • R 10 is hydrogen or -F.
  • each variable is independently defined as described herein for any one of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX).
  • any variable definition provided for Formula (X) herein is also applicable as an embodiment for any one of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), where such variable appears in the respective formula.
  • the carbon bearing the R 8 and OH moieties is in an “R” configuration.
  • the carbon bearing the R 8 and OH moieties is in an “S” configuration.
  • G 2 is CR 4a .
  • G 2 is N.
  • n is 1 and G 3 is CR 5a .
  • R 5a is H, F, Cl, - CH 3 , -CD 3 , -CHF 2 , -CH 2 F, -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 , CN, -cyclopropyl (optionally substituted with fluoro), NH 2 , NHCH 3 , or CONH 2 .
  • n is 1 and G 3 is N.
  • G 4 is CR 6a .
  • R 6a is H or -CH3, optionally wherein R 6a is H.
  • G 4 is N, or wherein G 4 is O, or wherein G 4 is S.
  • (a) n is 0, G 5 is C, and G 6 is N, or (b) n is 0, G 5 is N, and G 6 is C, or (c) n is 1 and G 5 and G 6 are each C.
  • R 1 is -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -CH 2 OH.
  • R 3 is F, Cl, -OCH 3 , -OCD 3 , -OCHF 2 , -OCF 3 , -OCH 2 CHF 2 , -O- cyclopropyl, or -O-CH2-cyclopropyl.
  • R 8 is -CHF2, -CF3, -CH2F, cyclobutyl, cyclopropyl, or fluoro- cyclopropyl.
  • one or two of R 9 , R 10 , R 11 , R 12 , and R 13 are independently F, - CF3, Cl, ethyl, -CF2CH3, or -CHFCH3.
  • R 9 , R 12 , and R 13 are each H.
  • R 10 is F, Cl, -CF 3 , or -CHF 2
  • R 11 is H, F, Cl, -CF 3 , -CF 2 CH 3 , or ethyl.
  • Table 1B Additional compounds are presented in Table 1B: [0163] It is understood that compounds of Table 1 and Table 1A have one or more symmetric centers and therefore can exist in different stereochemical forms, such as different enantiomeric and/or diastereomeric forms. Where a specific stereochemistry is indicated, it is understood that the compound designated intends the specific stereoisomer provided. For example, in Table 1, compound 1a intends the compound depicted wherein the carbon indicated by the single asterisk (*) is in the R configuration and the carbon indicated by the double asterisk (**) is in the R configuration.
  • compound 1b intends the compound depicted wherein the carbon indicated by the single asterisk (*) is in the R configuration and the carbon indicated by the double asterisk (**) is in the S configuration.
  • any compound of Table 1 that provides for either the R or S stereochemistry at a given stereocenter for example, any of compounds 1-97 that are not further designated by stereoisomeric forms a-d and list “R or S” for the stereocenter designation of * and **
  • such compound is understood to embrace all possible stereoisomers of the compound depicted, as well as mixtures of stereoisomers in any proportion.
  • a composition comprising a specific stereochemical form of a compound is provided, wherein the composition is substantially free of alternate stereochemical forms of the compound, such as when the composition comprises no more than 5% or 3% or 1% or 0.5% or 0.1% by weight of the corresponding compound having a different stereochemical configuration.
  • a composition comprising compound 1a, wherein the composition is substantially free of alternate stereochemical forms of the compound (and is therefore substantially free of, and in one aspect, comprises no more than 5% or 3% or 1% or 0.1% by weight of, compounds 1b, 1c and/or 1d).
  • compounds 1b, 1c and/or 1d are compounds described in Table 1, or a pharmaceutically acceptable salt thereof, and uses thereof.
  • compounds described in Table 1A, or a pharmaceutically acceptable salt thereof, and uses thereof are compounds described in Table 1A, or a pharmaceutically acceptable salt thereof, and uses thereof.
  • the embodiments and variations described herein are suitable for compounds of any formulae detailed herein, where applicable.
  • any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.
  • the compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
  • the salts of the compounds provided herein are pharmaceutically acceptable salts.
  • tertiary amine moiety is present in the compound
  • the N-oxides are also provided and described.
  • tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
  • Compounds of a formula given herein may have asymmetric centers and therefore exist in different stereochemical forms. The present disclosure includes any or all of the stereochemical forms of the compounds provided. Such compounds may be isolated as specific stereochemical forms or may be present in a mixture of different stereochemical forms in any ratio.
  • compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.
  • the invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl.
  • Certain isotope labeled compounds e.g. 3 H and 14 C
  • Incorporation of heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.
  • Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
  • the invention also includes any or all metabolites of any of the compounds described.
  • the metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.
  • Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided.
  • the container may be a vial, jar, ampoule, preloaded syringe, I.V. bag, and the like.
  • Compounds detailed herein may be formulated or oral administration. Compounds may also be formulated for parenteral (e.g., intravenous) administration.
  • One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of a viral infection.
  • the manufacture of a medicament comprises a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof for use in preventing an RSV infection.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein. [0178] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound.
  • the diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered.
  • a racemate may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility.
  • compounds of the Formula (I) may be synthesized according to Scheme 1.
  • Scheme 1 wherein Ring , Ring , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , n, R 1 , R 2 , R 3 , R 7 , R 8 , 9 10 11 12 R , R , R , R , and R 13 are as defined for Formula (I), or any variation thereof detailed herein.
  • a method of making a compound of Formula (XX, ethyl 8-fluoro- 3-methylcinnoline-6-carboxylate) comprising: coupling a compound of formula (XXa): with 1-(trimethylsilyl)-propyne in the presence of a palladium catalyst to form a compound of formula (XXb): cyclizing the compound of formula (XXb) with di-tert-butyl-hydrazodiformate (Boc-NH-NH- Boc) in the presence of a base, such as Cs2CO3, to form the comound of formula (XXc): and deprotecting the compound of formula (XXc) to form the compound of Formula (XX).
  • compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided.
  • the purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • a compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
  • One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • compositions may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 th ed. (2000), which is incorporated herein by reference.
  • Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Compositions comprising a compound provided herein are also described.
  • the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • the composition is for use as a human or veterinary medicament.
  • the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment or prevention of a viral infection described herein.
  • Methods of Use and Uses Compounds and compositions detailed herein, such as a pharmaceutical composition comprising a compound of any formula provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
  • a method of inhibiting an RSV RNA polymerase comprising contacting the RSV RNA polymerase with a compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof.
  • Also provided are methods of inhibiting an RSV RNA polymerase in an individual in need thereof comprising administering to the individual in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Also provided are methods of inhibiting an RSV RNA polymerase comprising contacting the RSV RNA polymerase with a metabolite of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the RSV RNA polymerase is encoded by a subgenomic replicon.
  • Also provided herein is a method of inhibiting replication of an RSV in a cell comprising contacting the cell with the compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a metabolite of any of the foregoing or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof or metabolite.
  • a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein or a pharmaceutically acceptable salt thereof, or a metabolite of any of the foregoing or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof or metabolite.
  • the cell is infected with the RSV. In some embodiments, the cell is subsequently infected with the RSV. Also provided are methods of inhibiting replication of an RSV in a cell in an individual in need thereof comprising administering to the individual in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. [0196] In some embodiments, the contacting is performed in vitro. In some embodiments, the cell comprises an RSV. In some embodiments, the comprises a subgenomic RSV replicon. In some embodiments, the contacting is performed in vivo.
  • a method of treating a respiratory syncytial virus (RSV) infection in an individual in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, to the individual.
  • RSV respiratory syncytial virus
  • a method of ameliorating one or more symptoms of an RSV infection in an individual in need thereof comprising administering an effective amount of a compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, to the individual.
  • a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, to the individual.
  • the individual has one or more symptoms of an RSV infection, which may include, but are not limited to coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and/or wheezing.
  • the individual has a lower respiratory tract infection, an upper respiratory tract infection, or both an upper and lower respiratory tract infection.
  • the individual has bronchiolitis, pneumonia, or croup.
  • the one or more symptoms of an RSV infection include, but are not limited to, nasal congestion, rhinorrhea, subcostal, itercostal, or tracheosternal retractions, grunting, head bobbing, nasal flaring, or tachypnea, wheezing, cyanosis, cough, or apnea.
  • the individual has symptoms such as feeding difficulties, dehydration, fever, disturbed sleep, or disturbed activity level (e.g., irritable, restless, agistated, or less responsive).
  • the individual has one or more risk factors for severe RSV disease, such as prematurity at birth, bronchopulmonary dysplasia, congenital heart disease, Down syndrome, neuromuscular impairment, cystic fibrosis, recurrent wheezing, asthma, or other congenital disease.
  • the individual has been diagnosed with an RSV infection.
  • the RSV is RSV Type A or RSV Type B.
  • the RSV infection has been confirmed by a laboratory test.
  • the methods disclosed herein comprise obtaining the results of an RSV detecting laboratory test.
  • Laboratory tests can include detection of viral genes or proteins, such as by PCR based assays or antibody based assays, or viral culture or serology. Methods of obtaining samples for laboratory tests are known in the art and may include taking samples from the nose or mouth, or taking a blood sample.
  • the laboratory test comprises detecting RSV in a nasal sample, such as a nasopharyngeal swab, a nasopharyngeal aspirate, or a nasal/nasopharyngeal wash specimen.
  • a method of preventing a respiratory syncytial virus (RSV) infection in an individual at risk of developing an RSV infection comprising administering to the individual a prophylactically effective amount of a compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof.
  • RSV respiratory syncytial virus
  • compositions for use in any one of the methods described herein is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound, in the manufacture of a medicament for treating or preventing an RSV infection in an individual in need thereof.
  • the individual for any of the methods detailed herein may be an infant, a child, or an adult. In some embodiments, the individual is elderly. In some embodiments, the individual is greater than 65 years old, such as greater than 70, 75, or 80 years old. In some embodiments, the individual is 18 to 65 years of age, such as 18 to 60, 55, 50, 45, 30, 25, or 20 years of age.
  • the individual is 0 to 18 years of age, such as 0 and 17, 15, 12, 10, 8, 6, 5, 4, 3, 2, or 1 years of age. In some embodiments, the individual is 2 to 5 years of age. In some embodiments, the individual is 5 to 10 years of age. In some embodiments, the individual is 0 to 2 years of age. In some embodiments, the individual is an infant. In some embodiments, the individual is an infant or child aged one month to 36 months, or an infant aged 28 days or less. [0204] In some embodiments, the individual was born prematurely. In some embodiments, the individual was born at the gestation age of or less than 36 weeks, such as the gestation age of or less than 35, 34, 33, 32, 31, or 30 weeks.
  • the individual was born at the gestation age of or less than 32 weeks.
  • the individual is immunocompromised.
  • the individual has a chronic lung or chronic heart disease.
  • the individual has reactive airway disease, asthma, chronic obstructive pulmonary disease (COPD), or congestive heart failure.
  • the individual has a neuromuscular disorder.
  • the individual has difficulty swallowing or clearing mucus secretions.
  • the methods provided herein further comprise monitoring the effectiveness of the treatment.
  • indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in viral RNA, a reduction in time to seroconversion (virus undetectable in patient serum), and/or a reduction in the severity of the symptoms associated with the infection.
  • treatment results in a reduced viral load compared to the viral load before administration.
  • treatment results in reducing viral load to less than 1.7 log 10 plaque forming units equivalents (PFUe) per mL, or less than 0.3 log 10 PFUe/mL.
  • treatment results in greater than 1.5-log reduction, such as a greater than 2.5-log reduction, 3-log reduction, 4-log reduction, or 5-log reduction compared to the viral load before administration.
  • the viral load may be measured before administration and several hours after receiving the initial dosage, such as 24 hours, 48 hours, 60 hours, or more after receiving the initial dosage.
  • treatment results in a lower risk of hospitalization or ICU admission or a shorter duration of hospitalization or ICU status than without treatment.
  • the treatment results in reduced requirements for supplemental oxygen, mechanical ventilation, or supplemental feeding/hydration than without treatment.
  • treatment provides a reduction in time to resolution or alleviation of key RSV symptoms as compared to no treatment.
  • key RSV symptoms include one or more of cough, shortness of breath, wheezing, or coughing up phlegm (sputum).
  • treatment provides a reduction in progression to complications compared to no treatment.
  • complications include one or more of bronchitis, respiratory distress, respiratory failure, exacerbations of chronic conditions (such as COPD, congestive heart failure, or asthma), hospitalization, or myocardial infarction.
  • the RSV is human RSV or bovine RSV.
  • the RSV is human RSV.
  • the RSV is Type A.
  • the RSV is Type B.
  • the RSV is Type A and Type B.
  • the RSV is RSV A2, RSV B1, or RSV S2.
  • the RSV is a resistant RSV.
  • the RSV is resistant against an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, an RSV RNA polymerase inhibitor, an inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor, or an interferon treatment.
  • the RSV is resistant against ribavirin or palivizumab.
  • Also provided herein are uses of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament.
  • the manufacture of a medicament is for the treatment of a viral infection described herein.
  • the medicament comprises a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof for use in treating an RSV infection.
  • the manufacture of a medicament is for the prevention of a viral infection described herein.
  • the medicament comprises a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof for use in preventing an RSV infection.
  • compositions including pharmaceutical compositions as described herein for the use in treating, preventing, and/or delaying the onset and/or development of a disease described herein and other methods described herein.
  • the composition comprises a pharmaceutical formulation which is present in a unit dosage form.
  • compositions described herein may be administered with an additional agent to treat or prevent any of the viral infections disclosed herein.
  • methods described herein further comprise administering an additional anti-RSV agent.
  • the additional anti-RSV agent is an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, an RSV RNA polymerase inhibitor, an inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor, or an interferon.
  • the dose of a compound administered to an individual may vary with the particular compound or salt thereof, the method of administration, and the particular infection, such as type and stage of infection, being treated.
  • the amount of the compound or salt thereof is a therapeutically effective amount.
  • the amount of the compound or salt thereof is a prophylactically effective amount.
  • the therapeutically or prophylactically effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg.
  • Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection to be treated, the subject’s health status, condition, and weight.
  • An exemplary dose is in the range of about from about 0.1 mg to 10 g daily.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
  • a compound or composition disclosed herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one week, at least about 2 weeks, at least about 3 weeks, at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
  • the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
  • the dosing frequency can be more than once daily, e.g., twice or three times daily.
  • the dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more).
  • Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • the compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal. In some embodiments, the compound or composition is administered orally.
  • the present disclosure further provides articles of manufacture comprising a compound of the disclosure or a salt thereof, composition, and unit dosages described herein in suitable packaging.
  • the article of manufacture is for use in any of the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • kits for carrying out the methods of the disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein.
  • kits employs a compound described herein or a pharmaceutically acceptable salt thereof.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment or prevention of a viral infection described herein.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.
  • the kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a viral infection detailed herein to provide effective treatment or prevention of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods disclosed herein.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • CDI (1,1'- carbonyldiimidazole), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DCE (1,2-dichloroethane), DCM (dichloromethane), DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), DIAD (diisopropyl azodicarboxylate), DIPEA or DIEA (N,N-diisopropylethylamine), DMA (dimethylacetamide), DMF (N,N-dimethylformamide), DMP (Dess–Martin periodinane), DMSO (dimethyl sulfoxide), DPPP (1,3-Bis(diphenylphosphino)propane), EA (ethyl acetate), ESI-MS (electrospray ionisation mass spectrometry),
  • reaction mixture was placed in a 100 mL sealed tube and stirred at 125 °C for 12 h.
  • LC-MS trace showed that Intermediate 1-15 was consumed completely. (Note: 5 reactions could be carried out in parallel).
  • the resulting solution was extracted with EA (200 mL X 2).
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Example 6 Synthesis of Compound 6d [0311] 6.1 Preparation of Intermediate 6-2: [0312] Intermediate 6-1 was prepared essentially as described in Example 5 for the preparation of Compound 5d. A mixture of Intermediate 6-1 (200 mg, 0.59 mmol, 1.0 eq.), trifluoro-potassio-vinyl-boron(1-) (638 mg, 4.76 mmol, 8 eq.), Pd(dppf)Cl 2 (43 mg, 0.06 mmol, 0.10 eq.), Cs2CO3 (388 mg, 1.19 mmol, 2 eq.) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N 2 for 3 times, and then stirred at 90°C for 5 h under N 2 atmosphere.
  • Intermediate 6-1 200 mg, 0.59 mmol, 1.0 eq.
  • trifluoro-potassio-vinyl-boron(1-) (638 mg, 4.76
  • Example 9 Synthesis of Compound 9b [0343] 9.1 Preparation of Intermediate 9-2: [0344] Intermediate 9-1 was prepared essentially as described in Example 5 for the preparation of Compound 5d. To a mixture of Intermediate 9-1 (300 mg, 0.97 mmol, 1.0 eq.), sodium ascorbate (10 mg, 0.048 mmol, 0.05 eq.), CuI (18.4 mg, 0.97 mmol, 0.1 eq.) and N,N- dimethylethane-1,2-diamine (13 mg, 0.15 mmol, 0.15 eq.) in H2O (1.2 mL) and MeOH (2.8 mL) was added NaN3 (252 mg, 3.87 mmol, 4 e.q) in one portion at under N2.
  • NaN3 252 mg, 3.87 mmol, 4 e.q
  • reaction mixture was extracted with EA 150 mL (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 50% Ethyl acetate/Petroleum ether gradient at 20 mL/min). Intermediate 10-4 (585 mg, 93.6% yield) was obtained as a yellow oil.
  • Example 12 Synthesis of Compound 12d [0360] 12.1 Preparation of Intermediate 12-3: [0361] Preparation of Intermediate 12-1 can be referred to the reference: WO2015/26792 A1, 2015. Intermediate 12-3 was prepared essentially as described in Example 1 for the preparation of Compound 1d by using Intermediate 12-1 and (4-(trifluoromethyl)phenyl)boronic acid as starting materials. [0362] 12.2 Preparation of Intermediate 12-5: [0363] Intermediate 12-5 was prepared essentially as described in Example 7 for the preparation of Compound 7b by using Intermediate 12-13 and 3-chloro-2-(chloromethyl)prop-1- ene as starting materials.
  • Example 18 Synthesis of Compound 18d [0431] Intermediate 18-1 was prepared essentially as described in Example 4 for the preparation of Compound 4d. Preparation of Intermediate 18-2 was prepared essentially as described in Example 17 for the preparation of Compound 17d. [0432] Compound 18d was prepared essentially as described in Example 2 the preparation of Compound 2d by using acid 18-1 and amine 18-2 as starting materials. Finally, Compound 18d (29 mg) was obtained as white solid.
  • Example 19 Synthesis of Compound 19d [0433] Intermediate 19-1 was prepared essentially as described in Example 6 for the preparation of Compound 6d. Intermediate 19-2 was prepared essentially as described in Example 17 for the preparation of Compound 17d. [0434] Compound 19d was prepared essentially as described in Example 2 for the preparation of Compound 2d by using acid 19-1 and amine 19-2 as starting materials. Finally, Compound 19d (38 mg) was obtained as white solid.
  • Example 21 Synthesis of Compound 21c [0437] Intermediate 21-1 was prepared essentially as described in Example 6 for the preparation of Compound 6d. Preparation of Intermediate 21-2 was prepared essentially as described in Example 2 for the preparation of Compound 2d. [0438] Compound 21c was prepared essentially as described in Example 2 for the preparation of Compound 2d by using acid 21-1 and amine 21-2 as starting materials. Finally, Compound 21c (30 mg) was obtained as white solid.
  • Example 25 Synthesis of Compound 25d [0507] 25.1 Preparation of Intermediate 25-2: [0508] To a stirring mixture of ester 25-1 (30 mg, 0.093 mmol) in EtOH (0.5 mL) at room temperature was added a solution of NaOH (140 ⁇ L, 2 N). The reaction mixture was stirred at rt for several hours before it was acidified with an aqueous HCl (10%) solution. The crude mixture was azeotroped with toluene (3 x 10 mL) under reduced pressure. The crude product was taken directly to the next reaction without further purification. [0509] Compound 25d was synthesized using the same procedure that was previously described in the synthesis of Compound 5d by using acid 25-2 and amine 25-3.
  • Example 26 Synthesis of Compound 26d [0510] Compound 26d was synthesized using the same procedure that was previously descried to the synthesis of Compound 24d from step 14-17, except 2,2-difluoroethan-1-amine was used in step 17 instead of NH 4 Cl. The crude product was purified via HPLC to afford the desired product as a light-yellow powder.
  • Compound 27d was synthesized using the same procedure that was previously descried to the synthesis of Compound 16d by using acid 27-1 (prepared as described for Compound 22d, using Intermediate 22-2 as starting material, and using zinc cyanide) and amine 27-2.
  • the crude product was purified via HPLC to afford the desire product as a white powder.
  • Compound 28d was synthesized using similar procedure that was described to the synthesis of Compound 26d using acid 28-1 (prepared as described for acid 27-1, using Intermeidate 22-2 as starting material) and amine 28-2 as the starting intermediates. The product was purified via HPLC to afford Compound 28 as a white solid.
  • Example 31 Synthesis of Compound 31e [0530] Compound 31e was synthesized using the same procedure that was previously described to the synthesis of Compound 24d except (1S,2R)-2-fluorocyclopropan-1-amine hydrochloride salt was used in step 17 instead of NH4Cl. The crude product was purified via HPLC to afford the desired product as a white powder.
  • Example 32 Synthesis of Compound 32d [0531] Compound 32d was synthesized using the same procedure that was previously described to the synthesis of Compound 24d. The crude product was purified via HPLC to afford the desired product as a white powder.
  • Example 33 Synthesis of Compound 33d [0532] Compound 33d was synthesized using the same procedure that was previously described to the synthesis of Compound 24d. The crude product was purified via HPLC to afford the desired product as a white powder.
  • Example 35 Synthesis of Compound 35d [0534] Compound 35d was synthesized using the same procedure that was previously descried to the synthesis of Compound 24d.
  • Example 36 Synthesis of Compound 36d [0535] Compound 36d was synthesized using the same procedure that was previously descried to the synthesis of Compound 16d. The crude product was purified via HPLC to afford the desired product as a white solid.
  • Example 37 Synthesis of Compound 37d [0536] Compound 37d was synthesized using the procedure that was previously described to the synthesis of Compound 13d.
  • Example 39b Preparation of Compound 40d: [0547] Compound 40d was synthesized in the same manner as Compound 39d, except that difluoroethylamine (8 ⁇ L) was substituted for the methyl amine. LC/MS: [M+H] 663.05.
  • Example 41 Synthesis of Compound 42e [0558] 41.1 Preparation of Intermediate 41-2: [0559] Intermediate 41-1 was prepared essentially as described in the preparation of Compound 1d. To a solution of Intermediate 41-1 (80 mg, 0.13 mmol, 1.0 eq.) and (2S)-2-(tert- butoxycarbonylamino)-3-methyl-butanoic acid (66 mg, 0.3 mmol, 2.4 eq.) in THF (10 mL) were added DCC (63 mg, 0.3 mmol, 2.4 eq.) and DMAP (15.4 mg, 0.13 mmol, 1 eq.). The resulting mixture was stirred at 50 °C for 20 min.
  • the aqueous phase was extracted with EA (15 mL X 3).
  • the combined organic phases were washed with brine (10 mL X 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the mixture was poured into saturated aqueous NH 4 Cl (10 mL).
  • the aqueous phase was extracted with EA (15 mL X 3).
  • Example 46 Synthesis of Compound 47e [0576] Intermediate 46-1 was prepared essentially as described in the preparation of compound 43d. Compound 47e was prepared essentially as described in the preparation of Compound 42e by using compound 46-1 and acid 46-2 as starting materials. Finally, Compound 47e (80 mg) was obtained as white solid.
  • Intermediate 54-1 was prepared essentially as described in the preparation of Compound 2d.
  • Intermediate 54-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51.
  • the stereoisomers of Compound 55 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 54-1 and amine 54-2 as starting materials.
  • the stereoisomers of Compound 55 were separated by SFC twice according the method of (column: AD (250mm*30mm, 5um); mobile phase: [0.1%NH3H2O IPA]; B%: 25%- 25%, min).
  • Example 61 Synthesis of Compound 62d [0653] Intermediate 61-1 was prepared essentially as described in the preparation of compound 43d. Compound 62d was prepared essentially as described in the preparation of Compound 42e by using Intermediate 61-1 and acid 61-2 as starting materials. Finally, Compound 62d (35 mg) was obtained as white solid.
  • Examples 62a and 62b Synthesis of Stereoisomers of Compound 63
  • Preparation of intermediate 62-1 can be referred to the Reference: EP1595866, 2005, A1.
  • Intermediate 62-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51.
  • the stereoisomers of Compound 63 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 62-1 and amine 62-2 as starting materials.
  • Example 65 Synthesis of Compound 66d Preparation of intermediate 65-1 can be referred to the Reference: WO2010/132615, 2010, A1. Intermediate 65-5 was prepared essentially as described in the preparation of Compound 2d. [0675] Compound 66d was prepared essentially as described in the preparation of Compound 5d by using compound 65-1 and amine 65-5 as starting materials. Finally, Compound 66d (23 mg) was obtained as white solid.
  • Examples 69a and 69b Synthesis of Stereoisomers of Compound 70
  • Intermediate 69-1 was prepared essentially as described in the preparation of compound 49b.
  • Intermediate 69-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51.
  • the stereoisomers of Compound 70 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 69-1 and amine 69-2 as starting material.
  • Example 71 Synthesis of Compound 72e [0694] To a stirring mixture of Compound 35d (15 mg, 0.023 mmol) and acid (15.2 mg) in THF (0.5 mL, 0.05 M) at room temperature were added DCC (14.4 mg, 0.069 mmol) and DMAP (1 crystal). The resulting mixture was stirred at rt for 1.5 h before it was concentrated and purified via a silica gel column to afford the desired product as white solid. To this stirring product was added a solution of HCl in dioxane. The reaction mixture was stirred at room temperature for 30 min before it was concentrated under reduced pressure and directly subjected into the HPLC to afford desired product was a white solid.
  • Example 76 Synthesis of Compound 77b [0725] Intermediate 76-1 was prepared essentially as described in the preparation of Compound 76d. Intermediate 76-2 was prepared essentially as described in the preparation of Compound 7b. [0726] Compound 77b was prepared essentially as described in the preparation of Compound 76d by using acid 76-1 and amine 76-2 as starting materials. Finally, Compound 77b (39 mg) was obtained as white solid.
  • Example 78 Synthesis of Compound 79d [0729] Acid 78-1 was prepared essentially as described in the preparation of Compound 10b. Amine 78-2 was prepared essentially as described in the preparation of Compound 2d. [0730] Compound 79d was prepared essentially as described in the preparation of Compound 2d by using acid 78-1 and amine 78-2 as starting materials. Finally, Compound 79d (51 mg) was obtained as a yellow solid.
  • Example 79 Synthesis of Compound 80b [0731] 79.1 Preparation of Intermediate 79-2: [0732] Intermediate 79-1 was prepared essentially as described in the preparation of Compound 1d. A mixture of Intermediate 79-1 (1 g, 3.53 mmol, 1 eq.), methyl boronic acid (528 mg, 8.81 mmol, 2.5 eq.), K 3 PO 4 (1.50 g, 7.05 mmol, 2 eq.), Cs 2 CO 3 (2.87 g, 8.8 mmol, 2.5 eq.) and Pd(dppf)Cl 2 (288 mg, 0.35 mmol, 0.1 eq.) in toluene (10 mL) and H 2 O (2 mL) was taken up into a microwave tube.
  • Example 82 Synthesis of Compound 83d [0749] Intermediate 82-1 was prepared essentially as described in the preparation of Compound 1d. Intermediate 82-3 was prepared essentially as described in the preparation of Compound 14. [0750] Compound 83d was prepared essentially as described in the preparation of Compound 2d by using ester 82-1 and amine 82-3 as starting materials. Finally, Compound 83d (45 mg) was obtained as white solid.
  • Example 83 Synthesis of Compound 84d [0751] Intermediate 83-1 was prepared essentially as described in the preparation of Compound 4d. Intermediate 83-2 was prepared essentially as described in the preparation of Compound 14d. [0752] Compound 84d was prepared essentially as described in the preparation of Compound 14d by using acid 83-1 and amine 83-2 as starting materials. Finally, Compound 84d (42 mg) was obtained as white solid.
  • Acid 86-1 was prepared essentially as described in the preparation of Compound 85.
  • Amine 86-2 was prepared essentially as described in the preparation of Compound 7b.
  • Compound 87b was prepared essentially as described in the preparation of Compound 85 by using acid 86-1 and amine 86-2 as starting materials. Finally, Compound 87b (49 mg) was obtained as a yellow solid.
  • Example 87 Synthesis of Compound 88d
  • Intermediate 87-1 was prepared essentially as described in the preparation of Compound 6.
  • Intermediate 87-2 was prepared essentially as described in the preparation of Compound 14.
  • Compound 88d was prepared essentially as described in the preparation of Compound 14 by using acid 87-1 and amine 87-2 as the starting materials. Finally, Compound 88d (42 mg) was obtained as white solid.
  • Example 89 Synthesis of Compound 90d [0773] Intermediate 89-1 was prepared essentially as described in the preparation of Compound 4d. Intermediate 89-2 was prepared essentially as described in the preparation of Compound 16d. [0774] Compound 90d was prepared essentially as described in the preparation of Compound 16 by using acid 89-1 and amine 89-2 as the starting materials. Finally, Compound 90d (35 mg) was obtained as white solid.
  • Examples 96a and 96b Synthesis of Stereoisomers of Compound 97
  • Intermediate 96-1 was prepared essentially as described in the preparation of Compound 15d.
  • Intermediate 96-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51.
  • the stereoisomers of Compound 97 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 96-1 and amine 96-2 as starting materials.
  • Figure 1 shows the single crystal structural analysis of tert-butyl ((S)-3,3,3-trifluoro-2-((S)-7-(4-fluorophenyl)-3-(hydroxymethyl)- 3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-hydroxypropyl)carbamate (Intermediate 14-3), with the structure as shown below.
  • Example 98 Synthesis of Compound 98a [0801] 98.1 Scheme showing synthesis of Intermediate 98-1
  • Example 99 Synthesis of Compound 99 [0822] Acid 10-8 was prepared as previously described in Example 10. Amine 99-2 was prepared essentially as described for the preparation of intermediate 17-21 in Example 17. [0823] To a solution of Acid 10-8 (45 mg, 0.18 mmol, 1 eq.) and amine 99-2 (77 mg, 184.24, 0.18 mmol, 1 eq.) in DCM (2 mL) was added T 3 P (propylphosphonic anhydride; 176 mg, 165 uL, 50% in EA, 1.5 eq.). The mixture was stirred at 15 °C for 15 min. Then TEA (56 mg, 0.56 mmol, 3 eq.) was added and stirred at 15 °C for 15 min.
  • T 3 P propylphosphonic anhydride
  • the yellow oil was purified by prep-HPLC (FA) ⁇ column: Boston Green ODS 150*30mm*5um; mobile phase: [water (0.2%FA)-ACN];B%: 35%-65%,8min ⁇ to give yellow solution and then lyophilized to give Compound 99 (56.8 mg, 47.90% yield, 100% purity) as a yellow solid.
  • Example 100 Synthesis of Compound 100 [0824]
  • Amine 100-2 was prepared as described in the preparation of Intermediate 23-20 in Example 23.
  • DMF dimethyl methoxylate
  • HATU 66 mg, 0.17 mmol, 1.05 eq.
  • DIPEA 64 mg, 0.49 mmol, 3 eq.
  • Intermediate 100-2 60 mg, 0.16 mmol, 1 eq. was added.
  • the mixture was stirred at 20 °C for 15 min.
  • Example 101 Synthesis of Compound 101 [0825] Acid 101-1 was prepared essentially as described for Intermediate 10-8 in Example 10.
  • Intermediate 101-2 was prepared essentially as described in the preparation of Intermediate 7-15 in Example 7 by using [4-fluoro-3-(trifluoromethyl)phenyl]boronic acid as starting material.
  • Compound 101 was prepared essentially as described in the preparation of Example 99 using Acid 101-1 and Amine 101-2 as starting materials. Finally, Compound 101 (60 mg) was obtained as white solid.
  • WO2013/185103 2013, A1; 4.1 g, 13.05 mmol, 1 eq.) in THF (50 mL) was added LiAlH4 (743 mg, 19.58 mmol, 1.5 eq.). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by the addition of H 2 O (0.75 mL), NaOH (15% aq.0.75 mL) with stirring at 0 °C for 5 min. Then H2O (2 mL) was added. The mixture was stirred at 0 °C for 50 min, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Example 103 Synthesis of Compound 103 [0832] Acid 102-7 was prepared as described in Example 102. Amine 7-15 was prepared as described in Example 7. Compound 103 was prepared essentially as described in the preparation of Example 100 using acid 102-7 and amine 7-15 as starting materials. Finally, Compound 103 (33 mg) was obtained as yellow solid.
  • Amine 104-1 was prepared essentially as described in the preparation of intermediate 7-15 in Example 7 by using (4-chlorophenyl)boronic acid as starting material.
  • Compound 104 was prepared essentially as described in the preparation of Compound 100 using acid 101-1 and amine 104-1 as starting materials.
  • Compoune 104 38 mg was obtained as yellow solid.
  • Amine 106-3 was prepared essentially as described in the preparation from intermediate 14-3 as a starting material in Example 14.
  • Example 107 Synthesis of Compound 107 [0841] Amine 107-2 was prepared essentially as described in the preparation of intermediate 14-7 in Example 14. Compound 107 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 107-2 as starting materials. Finally, Compound 107 (111.2 mg) was obtained as yellow solid.
  • Example 109 Synthesis of Compound 109 [0843] Amine 109-1 was prepared essentially as described in the preparation of intermediate 1-27 in Example 1 using (4-(trifluoromethyl)phenyl)boronic acid as starting material. Compound 109 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 109-1 as starting materials.
  • Example 110 Synthesis of Compound 110 [0844] Intermediate 110-1 was prepared essentially as described using intermediate 1-18 in Example 1 as a starting material using (4-(trifluoromethyl)phenyl)boronic acid as starting material. Compound 110 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 110-2 as starting materials. Finally. Compound 110 (43 mg) was obtained as yellow solid.
  • Example 111 Synthesis of Compound 111 [0845] Compound 111 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 111-1 as starting materials. Finally, Compound 111 (59 mg) was obtained as yellow solid.
  • Example 112 Synthesis of Compound 112 [0846] Amine 112-1 was prepared essentially as described in the preparation of Intermediate 14-7 in Example 14 by using cyclopropanamine as starting material. Compound 112 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 112-1 as starting materials.
  • Example 113 Synthesis of Compound 113 [0847] Acid 65-4 was prepared as described in Example 65. Amine 98-1 was previously described in the preparation of Compound 98a. Compound 113 was prepared essentially as described in the preparation of Compound 100 by using acid 65-4 and amine 98-1 as starting materials.
  • Example 114 Synthesis of Compound 114 [0848] Amine 114-2 was prepared using the method described for the preparation of intermediate 14-7 in Example 14 by using 2,2,2-trifluoroethanamine as starting material. Compound 114 was prepared essentially as described in the preparation of Compound 100 using acid 101-1 and amine 114-2 as starting materials. Finally, Compound 114 (31 mg) was obtained as yellow solid.
  • Example 118 Synthesis of Compound 118 [0852] Amine 118-2 was prepared essentially as described in preparation of intermediate 98- 1 by using cyclopropyl magnesium bromide and 98-5 as starting materials. Compound 118 was prepared essentially as described in the preparation of Compound 100 using acid 101-1 and amine 118-2 as starting materials. Compound 118 (97 mg) was obtained as a yellow solid.
  • Example 119 Synthesis of Compound 119 [0853] Acid 119-1 was prepared as described in the preparation of intermediate 10-8 in Example 10 by using ethynylcyclopropane as starting material. Amine 119-2 was previously descried in the preparation of Compound 98a. Compound 119 was prepared essentially as described in the preparation of Compound 99 by using acid 119-1 and amine 119-2 as starting materials.
  • Amine 120-5 was prepared essentially as described in the preparation of intermediate 14-7 in Example 14 using methyl amine as a starting material.
  • Compound 120 was prepared essentially as described in the preparation of Compound 100 using acid 120-4 and amine 120-5 as starting materials.
  • Compound 120 (16 mg) was obtained as a light yellow solid.
  • Amine 121-2 was prepared as previously described in the synthesis of Intermediate 50-7 in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51.
  • Compounds 121a (32.9 mg) and 121b (29.7 mg) were prepared as white solids essentially as described in the preparation of the isomers of Compound 97 by using acid 101-1 and amine 121- 2 as starting materials.
  • Example 122 Synthesis of Compound 122 [0860] To a mixture of compound 120-3 (150 mg, 0.68 mmol, 1 eq.) in DMF (2 mL) was added K 2 CO 3 (190 mg, 1.37 mmol, 2 eq.) at 15°C. Then, trideuterio(iodo)methane (214 uL, 5 eq.) was added. The resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into ice-water (10 mL) and stirred for 10 min. The aqueous phase was extracted with EA (15mLX3).
  • Example 123 Synthesis of Compound 123 [0863] Acid 123-1 was prepared essentially as previously described in the preparation of Compound 92d. Compound 123 (15 mg) was obtained as a white solid essentially as described in the preparation of Compound 100 using acid 123-1 and amine 123-2 as starting materials.
  • Example 124 Synthesis of Compound 124 [0864] Compound 124 (86 mg) was obtained as a white solid essentially as described in the preparation of Compound 101 using acid 102-7 and amine 98-1 as starting materials.
  • Example 125 Synthesis of Compound 125 [0865] Amine 125-2 was prepared essentially as described in preparation of intermediate 98- 1 by using cyclobutyl magnesium bromide and 98-5 as starting materials. Compound 125 (43.6 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 125-2 as starting materials.
  • Example 126 Synthesis of Compound 126 [0866] Amine 126-2 was prepared essentially as described in preparation of intermediate 17- 21 by using intermediate 17-8 as a starting material in Example 17. Compound 126 (23 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 99 using acid 101-1 and amine 126-2 as starting materials.
  • Example 127 Synthesis of Compound 127 [0867] Amine 127-2 was prepared essentially as described in the preparation of Compound 23d in Example 23. Compound 127 (27 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 127-2 as starting materials.
  • Example 128 Synthesis of Compound 128 [0868] Amine 128-2 was prepared essentially as described in the preparation of Compound 17d in Example 17. Compound 128 (45 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 128-2 as starting materials.
  • Example 129 Synthesis of Compoung 129 [0869] Amine 129-2 was prepared essentially as described in the preparation of intermediate 14-7 in Example 14 using methyl amine as a starting material. Compound 129 (117 mg) was obtained as a white solid essentially as described in the preparation of Compound 100 by using acid 10-8 and amine 129-2 as starting materials.
  • Example 130 Synthesis of Compound 130 [0870] Acid 130-1 was prepared essentially as described in the preparation of Compound 75d. Compound 130 (40.6 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 130-1 and amine 130-2 as starting materials.
  • Example 131 Synthesis of Compound 131 [0871] Acid 131-1 was prepared essentially as described in the preparation of Compound 75d. Compound 131 (32.5 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 131-1 and amine 131-1 as starting materials.
  • Example 132 Synthesis of Compound 132 [0872] Compound 132 (58.9 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 132-2 as starting materials.
  • Example 133 Synthesis of Compound 133 [0873] Amine 133-2 was prepared as described in the preparation of Compound 98a. Compound 133 (25 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 by using acid 120-4 and amine 133-2 as starting materials.
  • Example 135 Synthesis of Compound 135 [0878] To a mixture of intermediate 135-1 (prepared essentially as described for Compound 95c; 120 mg, 0.2 mmol, 1 eq.) in MeOH (5 mL) was added NaOMe (22.3 mg, 0.4 mmol, 2 eq.). The reaction was stirred at 50 °C for 4 h. Then cyanamide (4.32 mL, excess amount) was added and the resulting mixture was stirred at 50 °C for 1 h. The reaction was quenched with H2O (10 mL) and extracted with EA (20 mL X 2). The organic layer was separated, dried and concentrated.
  • Example 137 Synthesis of Compound 137 [0889] Amine 137-2 was prepared essentially as described in the preparation of Compound 14d in Example 14. Compound 137 (28.6 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 137-2 as starting materials.
  • Example 138 Synthesis of Compound 138 [0890] Acid 138-1 was prepared essentially as described in the preparation of Compound 15d in Example 15. Amine 138-2 was prepared essentially as described in the preparation of compound 98a. Compound 138 (37.2 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 by using acid 138-1 and amine 138-2 as starting materials.
  • Example 139 Synthesis of Compound 139 [0891] Acid 138-1 was prepared essentially as described in the preparation of compound intermediate 10-8 in Example 10 but using 3.3.3-trideuterio-1-trimethylsilylpropyne as starting material. Compound 139 (15 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 using acid 139-1 and amine 139-2 as starting materials.
  • Example 142 Synthesis of Compound 142 [0894] Amine 142-2 was prepared essentially as described in the preparation of Compound 98a by using (4-(trifluoromethyl)phenyl)boronic acid as starting material. Compound 142 (32.8 mg) was obtained as a light colored solid essentially as described in the preparation of Compound 100 by using acid 10-8 and amine 142-2 as starting materials.
  • Example 143 Synthesis of Compound 143 [0895] Intermediate 3 (prepared essentially as described in the preparation of Compound 7b in Example 7; 6 g, 19.13 mmol, 1 eq.), t-butyl carbamate (4.48 g, 38.25 mmol, 2 eq.), Pd 2 (dba) 3 (876 mg, 0.96 mmol, 0.05 eq.), Xantphos (1.11 g, 1.91 mmol, 0.1 eq.) and Cs2CO3 (9.35 g, 28.69 mmol, 1.5 eq.) in dioxane (150 mL) was stirred at 110 °C for 5 h under nitrogen.
  • Amine 144-2 was prepared essentially as described in the preparation of Compound 143.
  • Compound 144 (30 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 by using acid 10-8 and amine 144-2 as starting materials.
  • Amine 145-2 was prepared essentially as described in the preparation of intermediate 14-7 in Example 14 by using (1R,2S)-2-fluorocyclopropan-1-amine and intermediate 14-4 as the starting material.
  • Compound 145 was obtained as a white form using methods described herein with acid 10-8 and amine 145-2 as starting materials.
  • Nitrile 149-1 (113 mg, 0.23 mmol) was dissolved in ethylene diamine (2 mL) and transferred to a reaction vial. Carbon disulfide (1 drop) was added and the reaction vial was sealed and heated at 110 o C for 1 h. The reaction mixture was concentrated, and the crude material was purified by HPLC to provide intermediate 149-2 as a clear oil (110 mg). LCMS: ESI-MS: m/z 525 [M+H] + . [0910] Intermediate 149-2 (55 mg, 0.1 mmol) was dissolved in acetonitrile (1.5 mL). Potassium permanganate (82 mg, 0.52 mmol) was added and the reaction was stirred at rt.
  • 6-Carboxy-8-methoxy-3-methylquinoline 1-oxide (1.16 g, 5 mmol) was suspended in ACN (25 mL) and Et 3 N (2.1 mL, 15 mmol) was added. The solution was stirred for 5 min and then TMSCN (1.88 mL, 15 mmol) was added. The reaction mixture was heated at 80°C for 1 h. ACN was evaporated and the residue was taken up in water (50 mL) and 1 mL acetic acid was added.
  • the product was purified via silica column chromatography using a heptane to EA gradient, followed by a 2nd column using dichloromethane to 2% methanol in dichloromethane gradient, impure fractions were discarded, affording the desired product as a pale yellow solid (1.89 g, 26%).
  • the reaction mixture was stirred at rt for 16 h.
  • the mixture was concentrated in vacuo.
  • the residue was dissolved in water and acidified till pH ⁇ 4.5 with HCl (1M in H 2 O) (106.9 mL, 1 M, 106.9 mmol) (monitor with pH meter).
  • the mixture was extracted with DCM/2- propanol mixture twice and the organic layer was concentrated in vacuo.
  • the product was triturated in CH 3 CN, filtered off and washed with CH 3 CN and dipe.
  • the product was dried under vacuum to yield 8-(cyclopropylamino)-3-methylcinnoline-6-carboxylic acid (4.1 g, yield 79%) as a bright yellow solid.
  • the product was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford the title compound (1.08 g, 76%) as a white solid.
  • Triethylamine (3.85 mL, 27.7mmol), 4 ⁇ molecular sieve (2 g) and DPPA (2.6 mL, 12 mmol) was added. The mixture was heated at 90 °C for 16 hours. The suspension was quenched with sat. aq.
  • the aqueous phase was lyophilization afford the crude product which was purified by preparative HPLC over Xtimate C18150 x 25mm x5um (eluent: water (0.05% ammonia hydroxide v/v)-ACN from 8% to 38%, v/v). The pure fractions were collected and the volatiles were removed under vacuum. The residue was re- suspended in water (10 mL) and the resulting mixture was lyophilized to dryness to remove the solvent residue completely. Desired product was obtained as white solid (739 mg, 65% yield).
  • Ethyl 3,4-difluoro-5-(prop-1-yn-1-yl)benzoate (20 g, 1eq.) was charged into a reactor.
  • DMAc (200 mL), NHBocNHBoc (41.5 g, 2.0 eq.), Cs2CO3 (58 g, 2.0eq.) were added and the temperature was adjusted to 50 °C.
  • the reaction mixture was stirred for 15 h. After cooling, EtOAc (10V) and H2O (10V) were added into the mixture.
  • Example 179 Synthesis of Compound 179
  • Example 184 Synthesis of Compound 184
  • Example 198 Synthesis of Compound 198
  • Example 210 Synthesis of Compound 210
  • Example 218 Synthesis
  • Example 227 Synthesis of Compound 227
  • Example 229 Synthesis of Compound 229
  • Example 230 Synthesis of Compound 230 [1005] Step 1. To a stirring mixture of Intermediate 1 (40 mg), in MeOH (1 mL) was added a solution of NH3 in MeOH (2.5 mL). The resulting mixture was stirred under microwave conditions at 110 o C for 3 h. The resulting mixture was cooled and concentrated under reduced pressure and directly loaded into HPLC column to afford the desired product as a white solid (11 mg, 25% yield). LCMS: ESI-MS: m/z 584 [M+H] + . [1006] Step 2. To a stirring mixture of amidine 2 (5.6 mg) in dioxane (1.5 mL) were added Cs2CO3 (15 mg) and 1,2,3-triazine (2 mg).
  • LCMS ESI-MS: m/z 661.1 [M+H] + .
  • Example 238 Synthesis of Compound 238
  • RSV Polymerase Non-nucleoside Inhibition Assay [1019] Standard RSV polymerase assays were conducted in the presence of 10 nM recombinant RSV complex in a reaction buffer containing Tris-HCl pH 7.5, 6 mM MgCl 2 , and other additives and substrates including RNA oligonucleotides and radionucleotides. Standard reactions were incubated in 96-well plate format for 2 hours at 30 °C, in the presence of increasing concentration of test compound. The reaction was stopped with 90 ⁇ L of 0.1M EDTA, and the reaction product was transferred to a "reading" 96-well plate.
  • IC50 concentration at which the enzyme- catalyzed rate was reduced by 50%
  • RSV Replicon Assay 1 The RSV subgenomic replicon cell line APC126 was licensed from Apath (Brooklyn, NY) and was originally developed by Dr. Mark Meeples of Center for Vaccines & Immunity, the Research Institute at Nationalwide Children's Hospital in Columbus, Ohio.
  • RSV replicon In the subgenomic RSV replicon, three glycoprotein genes, those for SH, G, and F, from a full- length recombinant GFP-expressing (rg) RSV antigenomic cDNA were deleted and, in their place, a blasticidin S deaminase (bsd) gene was inserted. A luciferase gene was also inserted into the RSV replicon. Through multiple steps, the RSV replicon was established in baby hamster kidney (BHK) cells to generate the cell line APC126.
  • BHK baby hamster kidney
  • APC126 was maintained in Dulbecco's Modified Eagle Medium (DMEM)/Hams F-1250/50 (Mediatech, Cat No.10-092) supplemented with 10% (v/v) fetal bovine serum (FBS), 1% (v/v) penicillin/streptomycin, 1% non-essential amino acids (Mediatech, Cat No.25-025), 5% (v/v) tryptose phosphate broth (Biomedicals, Cat No.1682149) and 10 ⁇ g/mL blasticidin (InvivoGen, Cat No. Ant-BL). [1021] On the first day, 3.5 x 10 3 APC126 cells per well were seeded in a 96-well plate with 10% FBS supplemented medium.
  • Negative control wells contained 10% FBS supplemented medium only. The next day, test compound was dissolved in 100% DMSO, and cells were treated with serial dilutions of the test compound in triplicates in a 37 ⁇ C, 5% CO2 incubator. The positive control wells were APC126 cells with DMSO only. The final concentration of DMSO for all conditions was 1% (v/v). After a 3-day incubation, luciferase activity was measured using the Promega Renilla-Glo Luciferase Assay kit according to the manufacturer’s instruction (Cat No. E2750) to assess anti-RSV replicon activity.
  • the concentration of the test compound required for reducing RSV replicon RNA by 50% in relation to the untreated cell control value was calculated from the plot of percentage reductions of the optical density (OD) value against the test compound concentrations.
  • the EC50 values were derived from the mean of one or more independent experiments and are shown in Table 3.
  • rgRSV224 virus is an engineered virus that includes an additional GFP gene (Hallak LK, Spillmann D, Collins PL, Peeples ME.
  • the EC 50 was defined as the 50% inhibitory concentration for GFP expression.
  • compounds were incubated for three days in a set of white 384-well microtiter plates (Corning) and the cytotoxicity of compounds in HeLa cells was determined by measuring the ATP content of the cells using the ATPlite kit (Perkin Elmer, Zaventem, Belgium) according to the manufacturer’s instructions.
  • the CC 50 was defined as the 50% concentration for cytotoxicity. TABLE 3B: RSV REPLICON EC 50
  • mice received either a single intravenous dose (2 mg/kg) or a single oral dose (10 mg/kg) of the test compound.
  • Experimental groups of three mice per timepoint were sacrificed at 0.0333, 0.0833, 0.250, 0.500, 1.00, 2.00, 4.00, 6.00, 8.00, and 12.0 hours after dosing and blood samples were harvested. Whole blood was collected into containers with (K2) EDTA.

Abstract

Compounds for inhibiting replication of a respiratory syncytial virus (RSV) are provided. The compounds may find use as therapeutic agents for treating or preventing an RSV infection.

Description

ANTIVIRAL COMPOUNDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/003,735, filed April 1, 2020, the content of which is incorporated by reference herein in its entirety. FIELD OF THE INVENTION [0002] This disclosure relates generally to therapeutic agents that may be useful in inhibiting replication of a respiratory syncytial virus (RSV). The therapeutic agents may be used in the treatment of a respiratory syncytial virus infection. BACKGROUND [0003] Respiratory syncytial virus (RSV) is a non-segmented negative-strand (NNS) RNA virus and is a member of the order Mononegavirales and the family Pneumoviridae. Pneumoviridae previously was a subfamily within the Paramyxoviridae family, but has recently been reclassified (Afonso et al.2016, Archives of Virology, 161(8):2351-2360). RSV has been classified in two antigenic subtypes: A and B, with subtype A typically associated with more severe symptoms. [0004] RSV causes infections that can be relatively mild in the majority of otherwise healthy adults, but that can lead to severe lower respiratory infections in at risk populations, such as immunocompromised people, infants, and the elderly. For infants younger than 5 years old, it has been estimated that 33.8 million RSV infections occurred worldwide each year, at least 3.4 million of these cases required hospitalization, and 66,000 to 199,000 deaths occurred as a result (Nair et al., 2010, Lancet 375:1545-1555; Stein et al., 2017, Pediatric Pulmonology 52:566-569). [0005] Currently available treatments are inadequate. This is particularly true for adults, including the elderly and the immunocompromised, for which no treatment has been approved. Inhaled Ribavirin (Virazole®) was approved in 1986 for treatment of serious RSV infections, but is potentially toxic for exposed medical personnel and lacks clear efficacy data (Fearns et al., 2016, Antiviral Research, 134:63-76). In addition, it is not recommended for use in adults (Virazole® prescribing information). The monoclonal antibody directed against RSV, palivizumab (Synagis®), is approved only for prophylaxis of serious lower respiratory tract disease caused by RSV in high-risk infants, but “therapeutic efficacy has not been established” (Fearns et al., 2016, Antiviral Research, 134:63-76). According to the American Academy of Pediatrics, the “benefit resulting from this drug is limited. Palivizumab prophylaxis has limited effect on RSV hospitalizations on a population basis, no measurable effect on mortality, and a minimal effect on subsequent wheezing,” see Brady et al. Pediatrics, August 2014, 134(2):415- 420. [0006] Accordingly, there is a need for improved therapies for treating an RSV infection. BRIEF SUMMARY [0007] In one aspect, provided is a compound of the formula (I):
Figure imgf000004_0001
or a pharmaceutical wherein: Ring and Ring are taken together to form a bicyclic heteroaromatic ring, or
Figure imgf000004_0002
Figure imgf000004_0003
Ring is an aro atic ring fused to Ring , wherein Rin is a saturated or partially
Figure imgf000004_0004
Figure imgf000004_0005
u urated ring; G1 is N or O; G2 is CR4a(R4b)m or N, wherein m is 0 or 1, and when G2 is N or CR4a(R4b)m and m is 0, G2 is bound to one of G1, G3, or G4 via a double bond; G3 is CR5a(R5b)v or N, wherein v is 0 or 1, and when G3 is N or CR5a(R5b)v and v is 0, G3 is bound to G2 or G4 via a double bond; G4 is CR6a(R6b)w, N, O, or S, wherein w is 0 or 1, and when G4 is CR6a(R6b)w and w is 0, G4 is bound to G2, G3, or G6 via a double bond; G5 and G6 are each independently C or N; wherein at least one of G5 and G6 is C; n is 0 or 1; R1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, -C(O)NHRa, or -CN, wherein the C1-C6 alkyl and C1-C6 haloalkyl of R1 are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo, and the C3-C8 cycloalkyl of R1 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, - CN, -OH, and oxo; R2 is C1-C6 haloalkyl, C3-C8 cycloalkyl, -C(O)NHRb, or -CN, wherein the C1-C6 haloalkyl of R2 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo, and the C3-C8 cycloalkyl of R2 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo; each Ra and Rb are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, or –CH2Rc, wherein the C3-C8 cycloalkyl of Ra and Rb is unsubstituted or substituted with 1, 2, 3, or 4 halo groups, and Rc is 3- to 12-membered heterocyclyl; R3 is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, -ORd, NReRf, CN, nitro, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R3 are independently unsubstituted or substituted with one, two, three, or four R3a; Rd is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C14 aryl, wherein Rd is unsubstituted or substituted by 1, 2, 3, or 4 halogen, OH, NRd1Rd2, or C3-C8 cycloalkyl; or Rd and G1 are taken together with the atoms to which they are attached to form a 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl ring; Rd1, Rd2, Re and Rf are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12- membered heterocyclyl; each R3a is independently halo, OH, oxo, CN, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl of R3a are independently unsubstituted or substituted with one, two, three, or four substituents selected from the group consisting of halo, OH, and oxo; R4a and R5a are each independently hydrogen, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -C(O)NRgRh, -NRiRj, or -CH2-O- [C(=O)CH(RAA)NH]tH, wherein RAA is a side chain of an amino acid, t is an integer from 1- 12, and wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12- membered heterocyclyl of R4a and R5a are unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from the group consisting of halo, OH, oxo, CN, C1-C6 alkyl, and C3- C8 cycloalkyl; or R4a and R5a are taken together with the atoms to which they are attached to form a C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or C6-C14 aryl ring; R4b, R5b, R6a, and R6b are each independently hydrogen, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10- membered heteroaryl, 3- to 12-membered heterocyclyl, -C(O)NRgRh, -NRiRj, -CH2-O- C(=O)C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH, wherein RAA is a side chain of an amino acid, t is an integer from 1-12, and wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R4b, R5b, R6a, and R6b are independently unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from the group consisting of halo, OH, oxo, CN, C1-C6 alkyl, and C3-C8 cycloalkyl; Rg, Rh, Ri, and Rj are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12- membered heterocyclyl; R7 is hydrogen or C1-C6 alkyl; R8 is C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl; and R9, R10, R11, R12, and R13 are each independently hydrogen, halo, or C1-C6 haloalkyl.
[0008] In one aspect, provided is a compound of Formula (X):
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof; wherein G2 is CR4a or N; G3 is CR5a or N; wherein R4a and R5a are each independently H, halo, CN, C1-C6 alkyl, -CD3, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, - C(O)NRgRh, -NRiRj, or -CH2-O-Rk, wherein the C3-C8 cycloalkyl and C3-C8 cycloalkoxy of R4a and R5a are optionally substituted with halo, OH, CN, or C1-C6 alkyl; wherein Rg and Rh are each independently H or C1-C6 alkyl; Ri and Rj are each independently H or C1-C6 alkyl; and Rk is H, -C(O)C1-C6 alkyl, or -C(=O)CH(RAA)NH2, wherein RAA is a side chain of an amino acid; G4 is CR6a, N, O, or S; wherein R6a is hydrogen or C1-C6 alkyl; one of G5 and G6 is C and the other is C or N; n is 0 or 1; R1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; R2 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, - C(O)NHRb, -NRxRy, -C(O)NHRb, -C(=N-CN)NH2, or -CN, wherein the C1-C6 alkyl of R2 is optionally substituted with -OH, oxo, or -NH2, and the C3-C8 cycloalkyl and monocyclic heteroaryl of R2 are each optionally substituted with halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OH; wherein Rb is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, wherein the C3-C8 cycloalkyl or monocyclic heteroaryl of Rb is optionally substituted with halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OH; and Rx and Ry are each independently H or C1-C6 alkyl; or R1 and R2 taken together with the carbon to which they are attached form a C3-6 cycloalkyl or a monocyclic heterocycloalkyl; R3 is halo, -ORd, or -NReRf; wherein Rd is C1-C6 alkyl, -CD3, C1-C6 haloalkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl of Rd is optionally substituted with C3-C8 cycloalkyl; and Re and Rf are each independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R7 is hydrogen or C1-C6 alkyl; R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl optionally substituted with C1-4 alkyl or halo; and R9, R10, R11, R12, and R13 are each independently hydrogen, halo, C1-C6 alkyl, or C1-C6 haloalkyl. [0009] In one aspect, provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. [0010] In other aspects, provided are methods of treating a respiratory syncytial virus (RSV) infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the individual has one or more symptoms of an RSV infection. In some embodiments, the RSV is RSV Type A. In some embodiments, the RSV is RSV Type B. [0011] Also provided are methods of ameliorating one or more symptoms of an RSV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the symptom is one or more of: coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing. In some embodiments, the individual has a lower respiratory tract infection. In some embodiments, the individual has bronchiolitis, pneumonia, or croup. In some embodiments, the individual has been diagnosed with an RSV infection. In some embodiments, the RSV is RSV Type A. In some embodiments, the RSV is RSV Type B. In some embodiments, the RSV infection has been confirmed by a laboratory test. In some embodiments, the method further comprises obtaining the results of an RSV detecting laboratory test. In some embodiments, the laboratory test comprises detecting RSV in a nasal sample. [0012] Also provided are methods of preventing an RSV infection in an individual at risk of developing an RSV infection comprising administering to the individual a prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the individual is between 0 and about 2 years of age. In some embodiments, the individual was born prematurely. In other embodiments, the individual is greater than 65 years of age. In some embodiments, the individual is immunocompromised. [0013] In some embodiments of any of the methods provided herein, the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered orally. In some embodiments of any of the methods provided herein, the RSV is a resistant RSV. In some embodiments, the method further comprises administering an additional anti-RSV agent. In some embodiments, the additional anti-RSV agent is an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, an RSV RNA polymerase inhibitor, an inosine-5'- monophosphate dehydrogenase (IMPDH) inhibitor, or an interferon. [0014] Also provided are methods of inhibiting an RSV RNA polymerase comprising contacting the RSV RNA polymerase with a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Also provided are methods of inhibiting an RSV RNA polymerase in an individual in need thereof comprising administering to the individual in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Also provided are methods of inhibiting an RSV RNA polymerase comprising contacting the RSV RNA polymerase with a metabolite of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the RSV RNA polymerase is encoded by a subgenomic replicon. [0015] Also provided are methods of inhibiting replication of an RSV in a cell comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof, or a metabolite of any of the foregoing or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a metabolite of any of the foregoing. In some embodiments, the cell is infected with the RSV. In other embodiments, the cell is subsequently infected with the RSV. In some embodiments, the contacting is performed in vitro. In other embodiments, the contacting is performed in vivo. In some embodiments, the RSV is RSV Type A or RSV Type B. Also provided are methods of inhibiting replication of an RSV in a cell in an individual in need thereof comprising administering to the individual in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. [0016] Provided in other aspects are compositions for use in any one of the methods described herein. Also provided is the use of any of the compounds provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an RSV infection in an individual in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0017] Figure 1 shows the single crystal structural analysis of tert-butyl ((S)-3,3,3-trifluoro- 2-((S)-7-(4-fluorophenyl)-3-(hydroxymethyl)-3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2- hydroxypropyl)carbamate (Intermediate 14-3). DETAILED DESCRIPTION Definitions [0018] For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more. [0019] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. [0020] "Alkyl" refers to fully saturated straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C1-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, "propyl" includes n-propyl and isopropyl; and "butyl" includes n-butyl, sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. [0021] When a range of values is given (e.g., C1-6 alkyl), each value within the range as well as all intervening ranges are included. For example, “C1-6 alkyl” includes C1, C2, C3, C4, C5, C6, C1-6, C2-6, C3-6, C4-6, C5-6, C1-5, C2-5, C3-5, C4-5, C1-4, C2-4, C3-4, C1-3, C2-3, and C1-2 alkyl. [0022] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one site of olefinic unsaturation (having at least one carbon-carbon double bond). The alkenyl group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en- 2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2- methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3- dien-2-yl). [0023] "Alkynyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one site of acetylenic unsaturation (having at least one carbon-carbon triple bond). Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl). [0024] “Alkoxy" refers to the group R-O-, where R is alkyl; and includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n- pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like. Similarly, “cycloalkoxy” refers to the group “cycloalkyl-O-” and “aryloxy” refers to the group “aryl-O-”. “Substituted alkoxy” refers to the group “substituted alkyl-O-”. “Substituted cycloalkoxy” refers to the group “substituted cycloalkyl-O-”. “Substituted aryloxy” refers to the group “substituted aryl-O-”. [0025] “Aryl” or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which condensed rings are carbocyclic and may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C6-C14 aryl”). An aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position. [0026] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3- C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. [0027] “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (–OCF3). [0028] The term “haloalkyl” refers to an alkyl group with one or more halo substituents, such as one, two, or three halo substituents. Examples of haloalkyl groups include –CF3, -(CH2)F, - CHF2, CH2Br, -CH2CF3, - CH2CHF2, and –CH2CH2F. [0029] “Heteroaryl” as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), which condensed rings may be carbocyclic or may contain one or more annular heteroatom and which may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is both aromatic and contains at least one annular heteroatom. Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom. [0030] “Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocyclic group may have a single ring (e.g., pyrrolidinyl) or multiple condensed rings (e.g., decahydroisoquinolin-1-yl), which condensed rings may or may not be aromatic and which may be carbocylic or contain one or more annular heteroatoms, but which excludes heteroaryl rings. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl or aryl, but excludes heteroaryl groups. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are 3 to 14- membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. [0031] “Oxo” refers to the group (=O) or (O). [0032] “Nitro” refers to the group -NO2. [0033] As used herein, "amino acid side chain" or “side chain of an amino acid” refers to a monovalent non-hydrogen substituent that is bonded to an a carbon of an α-amino acid, including, e.g., natural, non-natural, standard, non-standard, proteinogenic, or non-proteinogenic amino acid. Examples of amino acid side chains include, but are not limited to the α-carbon substituent of alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline, and derivatives thereof. [0034] To the extent the present disclosure refers to a taxonomic categorization of a virus, such as the order Mononegavirales or the family Pneumoviridae, is understood that the term is used in its sense as described in Afonso et al. (2016, Archives of Virology, 161(8):2351-2360). [0035] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. [0036] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For example, beneficial or desired results in treating a viral infection include, but are not limited to, one or more of the following: eliminating or lessening the severity of one or more symptoms resulting from the viral infection (such as but not limited to coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing), increasing the quality of life of those suffering from the viral infection, decreasing the dose of other medications required to treat the viral infection, delaying the progression of the viral infection, and/or prolonging survival of an individual. [0037] As used herein, “preventing” a viral infection is an approach for eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and/or behavioral symptoms of a viral infection. Prevention may be in the context of an individual at risk of developing the viral infection, such as where the at risk individual does not develop the viral infection over a period of time, such as during a viral season or during a period of exposure to the virus, which may be days to weeks to months.An individual “at risk” of developing a viral infection is an individual with one or more risk factors for developing the viral infection but who has not been diagnosed with and does not display symptoms consistent with a viral infection. Risk factors for developing an RSV infection include but are not limited to an individual’s age (young children under age 5 such as children between about 0 and about 2 years of age, including infants, and individuals greater than 65 years of age), premature birth, co-morbidities associated with RSV and individuals who are immunocompromised. [0038] As used herein, a “therapeutically effective dosage” or “therapeutically effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to produce a desired therapeutic outcome. A therapeutically effective amount or a therapeutically effective dosage can be administered in one or more administrations. A therapeutically effective amount or dosage may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in a therapeutically effective amount if, in conjunction with one or more other agents, a desired therapeutic outcome is achieved. Suitable doses of any of the co- administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds. [0039] As used herein, a “prophylactically effective dosage” or “prophylactically effective amount” is an amount sufficient to effect the preventative result of eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and/or behavioral symptoms of a viral infection. A prophylactically effective amount or a prophylactically effective dosage can be administered in one or more administrations and over a period of time in which such prevention is desired. [0040] As used herein, the term “individual” is a mammal, including humans. An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is human. The individual (such as a human) may have advanced viral infection or lesser extent of viral infection, such as low viral titer. [0041] As used herein, the term “resistant” refers to a viral strain displaying a delayed, lessened, and/or null response to one or more therapeutic agents. For example, a viral strain may comprise a mutation that decreases the efficacy of one or more therapeutic agents used for treatment or prevention of an infection caused by the viral strain compared the efficacy of the one or more therapeutic agents used for treatment or prevention of an infection caused by a viral strain that does not comprise the mutation. [0042] It is understood that aspects and variations described herein also include “consisting” and/or “consisting essentially of” aspects and variations. [0043] All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties. Compounds [0044] In one aspect, provided is a compound of the Formula (I):
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring and Ring are taken together to form a bicyclic heteroaromatic ring, or Ring is an aromatic ring fused to Ring
Figure imgf000017_0002
, wherein Ring is a saturated or partially unsaturated ring; G1 is N or O; G2 is CR4a(R4b)m or N, wherein m is 0 or 1, and when G2 is N or CR4a(R4b)m and m is 0, G2 is bound to one of G1, G3, or G4 via a double bond; G3 is CR5a(R5b)v or N, wherein v is 0 or 1, and when G3 is N or CR5a(R5b)v and v is 0, G3 is bound to G2 or G4 via a double bond; G4 is CR6a(R6b)w, N, O, or S, wherein w is 0 or 1, and when G4 is CR6a(R6b)w and w is 0, G4 is bound to G2, G3, or G6 via a double bond; G5 and G6 are each independently C or N; wherein at least one of G5 and G6 are C; n is 0 or 1; R1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, -C(O)NHRa, or -CN, wherein the C1-C6 alkyl and C1-C6 haloalkyl of R1 are independently unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo, and the C3-C8 cycloalkyl of R1 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, - CN, -OH, and oxo; R2 is C1-C6 haloalkyl, C3-C8 cycloalkyl, -C(O)NHRb, or -CN, wherein the C1-C6 haloalkyl of R2 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo, and the C3-C8 cycloalkyl of R2 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo; each Ra and Rb are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, or –CH2Rc, wherein the C3-C8 cycloalkyl of Ra and Rb are independently unsubstituted or substituted with 1, 2, 3, or 4 halo groups, and Rc is 3- to 12-membered heterocyclyl; R3 is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, -ORd, NReRf, CN, nitro, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R3 are independently unsubstituted or substituted with one, two, three, or four R3a; Rd is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C14 aryl, wherein Rd is unsubstituted or substituted by 1, 2, 3, or 4 halogen, OH, NRd1Rd2, or C3-C8 cycloalkyl; or Rd and G1 are taken together with the atoms to which they are attached to form a 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl ring; Rd1, Rd2, Re and Rf are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12- membered heterocyclyl; each R3a is independently halo, OH, oxo, CN, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl of R3a are independently unsubstituted or substituted with one, two, three, or four substituents selected from the group consisting of halo, OH, and oxo; R4a and R5a are each independently hydrogen, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -C(O)NRgRh, -NRiRj, or -CH2-O- [C(=O)CH(RAA)NH]tH, wherein RAA is a side chain of an amino acid, t is an integer from 1- 12, and wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12- membered heterocyclyl of R4a and R5a are unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from the group consisting of halo, OH, oxo, CN, C1-C6 alkyl, and C3- C8 cycloalkyl; or R4a and R5a are taken together with the atoms to which they are attached to form a C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or C6-C14 aryl ring; R4b, R5b, R6a, and R6b are each independently hydrogen, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10- membered heteroaryl, 3- to 12-membered heterocyclyl, -C(O)NRgRh, -NRiRj, -CH2-O- C(=O)C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH, wherein RAA is a side chain of an amino acid, t is an integer from 1-12, and wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R4b, R5b, R6a, and R6b are independently unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from the group consisting of halo, OH, oxo, CN, C1-C6 alkyl, and C3-C8 cycloalkyl; Rg, Rh, Ri, and Rj are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12- membered heterocyclyl; R7 is hydrogen or C1-C6 alkyl; R8 is C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl; and R9, R10, R11, R12, and R13 are each independently hydrogen, halo, or C1-C6 haloalkyl. [0045] The compound of Formula (I) contains at least one stereocenter (at the carbon bearing R8 and OH) and may further contain one or more additional stereocenters. For example, in some embodiments, the compound of Formula (I) contains stereocenters as labeled by a single asterisk (*) and double asterisks (**) depicted in the structure of Formula (I) below.
Figure imgf000019_0001
[0046] In some embodiments of the compounds of Formula (I), the carbon marked by (*) and bearing the R8 and OH moieties is in an “R” configuration. In other embodiments, the carbon marked by (*) and bearing the R8 and OH moieties is in an “S” configuration. In some embodiments of the compounds of Formula (I), the carbon marked by (**) and bearing the R1 and R2 moieties is in an “R” configuration. In other embodiments, the carbon marked by (**) and bearing the R1 and R2 moieties is in an “S” configuration. In some embodiments of the compounds of Formula (I), the carbon marked by (*) and bearing the R8 and OH moieties is in an “R” configuration and the carbon marked by (**) and bearing the R1 and R2 moieties is in an “R” configuration. In some embodiments of the compounds of Formula (I), the carbon marked by (*) and bearing the R8 and OH moieties is in an “R” configuration and the carbon marked by (**) and bearing the R1 and R2 moieties is in an “S” configuration. In some embodiments of the compounds of Formula (I), the carbon marked by (*) and bearing the R8 and OH moieties is in an “S” configuration and the carbon marked by (**) and bearing the R1 and R2 moieties is in an “S” configuration. In some embodiments of the compounds of Formula (I), the carbon marked by (*) and bearing the R8 and OH moieties is in an “S” configuration and the carbon marked by (**) and bearing the R1 and R2 moieties is in an “R” configuration. In some embodiments, the compound of Formula (I) has additional stereocenters located on substituent groups R1, R2, R3, R3a, R4a, R4b, R5a, R5b, R6a, R6b, R7, R8, R9, R10, R11, R12, R13, Ra, Rb, Rc, Rd, Rd1, Rd2, Re and Rf. [0047] For example, in some embodiments of Formula (I), R4a is
Figure imgf000020_0001
, wherein the compound contains an additional stereocenter marked by (#). In some embodiments of Formula (I) wherein R4a is , the carbon marked by (#) is in an “R”
Figure imgf000020_0003
configuration. In other embodiments, the carbon marked by (#) is in an “S” configuration. [0048] As another example, in some embodiments of Formula (I), R2 is wherein
Figure imgf000020_0002
the compound contains two additional stereocenters marked by (@) and (&). In some embodiments of Formula (I), wherein R2 is the carbon marked by (@) is in an “R”
Figure imgf000021_0001
configuration. In some embodiments, the carbon marked by (@) is in an “S” configuration. In some embodiments, the carbon marked by (&) is in an “R” configuration. In some embodiments, the carbon marked by (&) is in an “S” configuration. In some embodiments, the carbon marked by (@) is in an “R” configuration and the carbon marked by (&) is in an “R” configuration. In some embodiments, the carbon marked by (@) is in an “R” configuration and the carbon marked by (&) is in an “S” configuration. In some embodiments, the carbon marked by (@) is in an “S” configuration and the carbon marked by (&) is in an “R” configuration. In other embodiments, the carbon marked by (@) is in an “S” configuration and the carbon marked by (&) is in an “S” configuration. [0049] In some embodiments of the compounds of Formula (I), G1 is N. In some embodiments, G1 is O. In some embodiments of the compounds of Formula (I), G2 is CR4a(R4b)m. In some embodiments of the compounds of Formula (I), m is 0. [0050] In some embodiments of the compounds of Formula (I), R4a is hydrogen, halo, CN, C1-C6 alkyl, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH. In some embodiments, R4a is hydrogen, halo, C1-C6 alkyl, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O- [C(=O)CH(RAA)NH]tH, wherein the C1-C6 alkyl of R4a is unsubstituted or substituted by 1, 2, or 3 groups independently selected from halo and OH, and t is 1 or 2. In some embodiments, R4a is hydrogen, halo, C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH, wherein the C1-C6 alkyl of R4a is unsubstituted or substituted by OH, and t is 1 or 2. In some embodiments, R4a is hydrogen, C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH, wherein the C1-C6 alkyl of R4a is substituted with OH, and t is 1 or 2. [0051] In some embodiments of the compounds of Formula (I), m is 0 and R4a is -H, -F,-Cl, - Br, -CH3,-CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R4a is -H, -F,-Cl, -Br, -CH3,-CH2F, -CF3, -CH2OH, -NH2, or -CH2-O- C(=O)CH(CH(CH3)2)NH2. In some embodiments, R4a is -H, -F, -CH3, -CH2OH, or -CH2-O- C(=O)CH(CH(CH3)2)NH2. [0052] In some embodiments, R4a is -H,-CH2OH, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. [0053] In some embodiments of the compounds of Formula (I), G2 is N. In some embodiments, n is 1. [0054] In some embodiments of the compounds of Formula (I), G3 is CR5a(R5b)v. In some embodiments, v is 0. [0055] In some embodiments of the compounds of Formula (I), R5a is hydrogen, halo, C1-C6 alkyl, CN, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH. In some embodiments, R5a is hydrogen, halo, C1-C6 alkyl, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O- [C(=O)CH(RAA)NH]tH, wherein the C1-C6 alkyl of R4a is unsubstituted or substituted by 1, 2, or 3 groups independently selected from halo and OH, and t is 1 or 2. In some embodiments, R5a is hydrogen, halo, C1-C6 alkyl, CN, or -NRiRj, wherein the C1-C6 alkyl of R5a is unsubstituted or substituted by 1, 2, or 3 halo. In some embodiments, R5a is hydrogen, halo, C1-C6 alkyl, or - NRiRj, wherein the C1-C6 alkyl of R5a is unsubstituted or substituted with 1, 2, or 3 halo. In some embodiments, R5a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O- C(=O)CH(CH(CH3)2)NH2. In some embodiments, R5a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, - CH2OH, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R5a is -H, -F, -Cl, - Br, -CH3, -CH2F, -CF3, -CN, or -NH2. In some embodiments, R5a is -H, -F, -Cl, -Br, -CH3, - CH2F, -CF3, or -NH2. [0056] In some embodiments of the compounds of Formula (I), G3 is N. In some embodiments of the compounds of Formula (I), n is 0. In some embodiments of the compounds of Formula (I), G4 is CR6a(R6b)w. In some embodiments of the compounds of Formula (I), w is 0. [0057] In some embodiments of the compounds of Formula (I), R6a is hydrogen, halo, C1-C6 alkyl, CN, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH. In some embodiments, R6a is hydrogen, halo, C1-C6 alkyl, CN, or -NRiRj. In some embodiments, R6a is - H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R6a is -H, -CH3, or -F. In some embodiments, R6a is -H. [0058] In some embodiments of the compounds of Formula (I), G4 is N. In some embodiments of the compounds of Formula (I), G4 is O. In some embodiments of the compounds of Formula (I), G4 is S. [0059] In some embodiments of the compounds of Formula (I), G5 is C. In some embodiments of the compounds of Formula (I), G5 is N. [0060] In some embodiments of the compounds of Formula (I), G6 is C. [0061] In some embodiments of the compounds of Formula (I), Ring and Ring are taken together to form a bicyclic heteroaromatic ring. [0062] In some embodiments of the compounds of Formula (I), the ring containing is
Figure imgf000023_0001
an aromatic ring fused to the ring containing , which is a saturated ring. [0063] In some embodiments of the compounds of Formula (I), the ring containing is an aromatic ring fused to the ring containing
Figure imgf000023_0002
, which is a partially unsaturated ring. [0064] In some embodiments, R1 is -CH3, -CH2F, -CHF2, -CF3, or -CH2OH. [0065] In some embodiments, R2 is -CH3, -CH2F, -CHF2, -CF3, -CN, -C(CH3)2OH, - cyclopropyl-OH, -C(O)CH3, -CH2OH, -CH2NH2, -NH2, triazolyl, imidazolyl, pyridinyl, pyrimidinyl, -C(=N-CN)NH2, or -C(O)NRb, wherein Rb is H, -CH3, -CH2CHF2, -CH2CF3, cyclopropyl (optionally substituted with one or two F or CH3 groups), or pyridyl (optionally substituted with F, CH3, or CF3). [0066] In some embodiments of the compounds of Formula (I), R3 is C1-C6 alkyl, C3- C8 cycloalkyl, or C6-C14 aryl. In some embodiments, R3 is -ORd, wherein Rd is C1-C6 alkyl or C3-C8 cycloalkyl. In some embodiments, R3 is –OCH3 or –O-cyclopropyl. In some embodiments, R3 is -ORd, wherein Rd and G1 are taken together with the atoms to which they are attached to form a 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl ring.
[0067] In some embodiments of the compounds of Formula
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
[0075] In some embodiments of Formula (I), R8 is C1-C6 alkyl. In some embodiments, R8 is C3-C8 cycloalkyl. In some embodiments, R8 is cyclopropyl. In some embodiments, R8 is C1-C6 haloalkyl. In some embodiments, R8 is CHF2 or CF3. [0076] In some embodiments of Formula (I), one or two of R9, R10, R11, R12, and R13 is halo or C1-C6 haloalkyl. In some embodiments, one or two of R9, R10, R11, R12, and R13 is F. In some embodiments, R9 is F or Cl. In some embodiments, R10 is F, Cl, CF3, or CHF2. In some embodiments, R12 is F or Cl. In some embodiments, R9 and R10 are each F. In some embodiments, one or two of R9, R10, R11, R12, and R13 is CF3. In some embodiments, R10 is CF3. In some embodiments of Formula (I),
Figure imgf000029_0001
Figure imgf000029_0002
[0077] In some embodiments,
Figure imgf000029_0003
Figure imgf000029_0004
[0078] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia),
Figure imgf000029_0005
or a pharmaceutically acceptable salt thereof, wherein Ring 1 2 3 4 5
Figure imgf000029_0006
, Ring G , G , G , G , G ,
Figure imgf000029_0007
G6, n, R1, R2, R3, R7, R8, R9, R10, R11, R12, and R13 are as defined for Formula (I). In some embodiments of formula (Ia), the carbon bearing R1 and R2 is in the “S” configuration. In some embodiments of formula (Ia), the carbon bearing R1 and R2 is in the “R” configuration. [0079] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib),
Figure imgf000030_0003
or a pharmaceutically acceptable salt thereof, wherein Ring
Figure imgf000030_0002
, Ring
Figure imgf000030_0001
, G1, G2, G3, G4, G5, G6, n, R1, R2, R3, R7, R8, R9, R10, R11, R12, and R13 are as defined for Formula (I). In some embodiments of formula (Ib), the carbon bearing R1 and R2 is in the “R” configuration. In some embodiments of formula (Ia), the carbon bearing R1 and R2 is in the “S” configuration. [0080] In some embodiments, G2 is CR4a. In some embodiments, R4a is H, F, Cl, CH3, - OCH3, -CH2F, -CF3, -CN, -CH2-ORk, -NH2, or -NHCH3, wherein Rk is H, -C(O)CH2CH3, or - C(=O)CH(iPr)NH2. [0081] In some embodiments, G2 is N. [0082] In some embodiments, n is 1 and G3 is CR5a. In some embodiments, R5a is H, F, Cl, - CH3, -CD3, -CHF2, -CH2F, -CF3, -OCH3, -OCHF2, -OCF3, CN, -cyclopropyl (optionally substituted with fluoro), NH2, NHCH3, or CONH2. [0083] In some embodiments, n is 1 and G3 is N. [0084] In some embodiments, G4 is CR6a. In some embodiments, R6a is H or -CH3, optionally wherein R6a is H. [0085] In some embodiments, G4 is N, or wherein G4 is O, or wherein G4 is S. In some embodiments, (a) n is 0, G5 is C, and G6 is N, or (b) n is 0, G5 is N, and G6 is C, or (c) n is 1 and G5 and G6 are each C. [0086] In some embodiments, R1 is -CH3, -CH2F, -CHF2, -CF3, or -CH2OH. [0087] In some embodiments, R2 is -CH3, -CH2F, -CHF2, -CF3, -CN, -C(CH3)2OH, - cyclopropyl-OH, -C(O)CH3, -CH2OH, -CH2NH2, -NH2, triazolyl, imidazolyl, pyridinyl, pyrimidinyl, -C(=N-CN)NH2, or -C(O)NRb, wherein Rb is H, -CH3, -CH2CHF2, -CH2CF3, cyclopropyl (optionally substituted with one or two F or CH3 groups), or pyridyl (optionally substituted with F, CH3, or CF3). [0088] In some embodiments, R3 is F, Cl, -OCH3, -OCD3, -OCHF2, -OCF3, -OCH2CHF2, -O- cyclopropyl, or -O-CH2-cyclopropyl. [0089] In some embodiments,
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
[0090] In some embodiments, R8 is -CHF2, -CF3, -CH2F, cyclobutyl, cyclopropyl, or fluoro- cyclopropyl. [0091] In some embodiments, one or two of R9, R10, R11, R12, and R13 are independently F, - CF3, Cl, ethyl, -CF2CH3, or -CHFCH3. In some embodiments, R9, R12, and R13 are each H. In some embodiments, (a) R10 is F, Cl, -CF3, or -CHF2, or (b) R11 is H, F, Cl, -CF3, -CF2CH3, or ethyl. [0092] Provided in other embodiments are compounds of Formula (II):
Figure imgf000031_0004
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R9, and R10 are as defined for Formula (I); G2 is CR4a or N; and G3 is CR5a or N. [0093] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, -C(O)NHRa, or -CN, wherein the C1-C6 alkyl and C1-C6 haloalkyl of R1 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo, and the C3-C8 cycloalkyl of R1 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo; R2 is C1-C6 haloalkyl, C3-C8 cycloalkyl, -C(O)NHRb, or -CN, wherein the C1-C6 haloalkyl of R2 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo, and the C3-C8 cycloalkyl of R2 is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo; Ra and Rb are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, or –CH2Rc, wherein the C3-C8 cycloalkyl of Ra and Rb is unsubstituted or substituted with 1, 2, 3, or 4 halo groups, and Rc is 3- to 12-membered heterocyclyl; R3 is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, -ORd, NReRf, CN, nitro, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R3 are independently unsubstituted or substituted with one, two, three, or four R3a; Rd is C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C14 aryl, wherein Rd is unsubstituted or substituted by 1, 2, 3, or 4 groups selected from the group consisting of halogen, OH, NRd1Rd2, and C3-C8 cycloalkyl; Rd1, Rd2, Re and Rf are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12- membered heterocyclyl; each R3a is independently halo, OH, oxo, CN, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl of R3a are independently unsubstituted or substituted with one, two, three, or four substituents selected from the group consisting of halo, OH, and oxo; R4a and R5a are each independently hydrogen, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -C(O)NRgRh, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH, wherein RAA is a side chain of an amino acid, t is an integer from 1-12, and wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R4a and R5a are unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from the group consisting of halo, OH, oxo, CN, C1-C6 alkyl, and C3-C8 cycloalkyl; Rg, Rh, Ri, and Rj are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12- membered heterocyclyl; R9 and R10 are each independently hydrogen, halo, or C1-C6 haloalkyl. [0094] Provided in other embodiments are compounds of Formula (III):
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R5a, R6a, R9, and R10 are as defined for Formula (I). [0095] In some embodiments of Formula (III), R3 is –ORd. In one particular variation, R3 is – ORd, wherein Rd unsubstituted C1-C6 alkyl (e.g., Rd is –CH3). In another particular variation, R3 is –ORd, wherein Rd C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., Rd is –CHF2 or –CH2-cyclopropyl). In one particular variation, R3 is –ORd, wherein Rd is C3-C8 cycloalkyl (e.g., Rd is cyclopropyl). [0096] In some embodiments of Formula (III), R4a is hydrogen. In some embodiments of Formula (III), R4a is C1-C6 alkyl substituted by 1 or 2 groups selected from halo and OH (e.g., R4a is –CH2OH or –CH2F). In some embodiments of Formula (III), R4a is -CH2-O- [C(=O)CH(RAA)NH]tH. In one particular variation, R4a is -CH2-O-[C(=O)CH(RAA)NH]tH. wherein RAA is -CH(CH3)2. [0097] In some embodiments of Formula (III), R5a is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN. In some embodiments of Formula (III), R5a is C1-C6 alkoxy (e.g., -OCH3) or - NRiRj, wherein Ri and Rj are each hydrogen. In some embodiments of Formula (III), R5a is C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., - CH3, -CH2F, CHF2, or –CF3). In some embodiments, R5a is hydrogen. In some embodiments, R5a is halo. In other embodiments, R5a is F, Cl, or Br. In some embodiments, R5a is C1-C6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups. In some embodiments, R5a is CH3, CH2F, or CF3. In some embodiments, R5a is NH2. [0098] In some embodiments of Formula (III), R6a is hydrogen. In some embodiments, R6a is hydrogen, halo, C1-C6 alkyl, CN, or -NRiRj. In some embodiments, R6a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R6a is -H, -CH3, or -F. In some embodiments, R6a is -H. [0099] Provided in other embodiments are compounds of Formula (IV):
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5a, R6a, R9, and R10 are as defined for Formula (I). [0100] In some embodiments of Formula (IV), R3 is –ORd. In one particular variation, R3 is – ORd, wherein Rd is C3-C8 cycloalkyl (e.g., Rd is cyclopropyl). In one particular variation, R3 is – ORd, wherein Rd unsubstituted C1-C6 alkyl (e.g., Rd is –CH3). In another particular variation, R3 is –ORd, wherein Rd C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., Rd is –CHF2 or –CH2-cyclopropyl). [0101] In some embodiments of Formula (IV), R5a is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN. In some embodiments of Formula (IV), R5a is C1-C6 alkoxy (e.g., -OCH3) or - NRiRj, wherein Ri and Rj are each hydrogen. In some embodiments, R5a is C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., -CH3, -CH2F, CHF2, or –CF3). In some embodiments, R5a is hydrogen. In some embodiments, R5a is halo. In other embodiments, R5a is F, Cl, or Br. In some embodiments, R5a is C1-C6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups. In some embodiments, R5a is CH3, CH2F, or CF3. In some embodiments, R5a is NH2. [0102] In some embodiments of Formula (IV), R6a is hydrogen. In some embodiments, R6a is hydrogen, halo, C1-C6 alkyl, CN, or -NRiRj. In some embodiments, R6a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R6a is -H, -CH3, or -F. In some embodiments, R6a is -H. [0103] Provided in other embodiments are compounds of Formula (V):
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R6a, R9, and R10 are as defined for Formula (I). [0104] In some embodiments of Formula (V), R3 is –ORd. In one particular variation, R3 is – ORd, wherein Rd unsubstituted C1-C6 alkyl (e.g., Rd is –CH3). In another particular variation, R3 is –ORd, wherein Rd C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., Rd is –CHF2 or –CH2-cyclopropyl). In one particular variation, R3 is –ORd, wherein Rd is C3-C8 cycloalkyl (e.g., Rd is cyclopropyl). [0105] In some embodiments of Formula (V), R4a is hydrogen. In some embodiments of Formula (V), R4a is C1-C6 alkyl substituted by OH (e.g., R4a is –CH2OH). In some embodiments of Formula (V), R4a is C1-C6 alkoxy (e.g., -OCH3). R4a is hydrogen. In some embodiments, R4a is C1-C6 alkyl substituted by 1 or 2 groups selected from halo and OH (e.g., R4a is –CH2OH or – CH2F). In some embodiments, R4a is -CH2-O-[C(=O)CH(RAA)NH]tH. In one particular variation, R4a is -CH2-O-[C(=O)CH(RAA)NH]tH. wherein RAA is -CH(CH3)2. In some embodiments, R4a is C3-C8 cycloalkyl (e.g., cyclopropyl). In some embodiments, R4a is -C(O)NRgRh, wherein Rg and Rh are each hydrogen. In some embodiments, R4a is -CH2-O-C(=O)C1-C6 alkyl (e.g., -CH2-O- C(=O)CH2CH3). [0106] In some embodiments of Formula (V), R6a is hydrogen. In some embodiments, R6a is hydrogen, halo, C1-C6 alkyl, CN, or -NRiRj. In some embodiments, R6a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R6a is -H, -CH3, or -F. In some embodiments, R6a is -H. [0107] Provided in other embodiments are compounds of Formula (VI):
Figure imgf000036_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R5a, R9, and R10 are as defined for Formula (I). [0108] In some embodiments of Formula (VI), R3 is –ORd. In one particular variation, R3 is – ORd, wherein Rd unsubstituted C1-C6 alkyl (e.g., Rd is –CH3). In another particular variation, R3 is –ORd, wherein Rd C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., Rd is –CHF2 or –CH2-cyclopropyl). In one particular variation, R3 is –ORd, wherein Rd is C3-C8 cycloalkyl (e.g., Rd is cyclopropyl). [0109] In some embodiments of Formula (VI), R4a is unsubstituted C1-C6 alkyl (e.g., R4a is – CH3). In some embodiments, R4a is hydrogen. In some embodiments, R4a is C1-C6 alkyl substituted by 1 or 2 groups selected from halo and OH (e.g., R4a is –CH2OH or –CH2F). In some embodiments, R4a is -CH2-O-[C(=O)CH(RAA)NH]tH. In one particular variation, R4a is -CH2-O- [C(=O)CH(RAA)NH]tH. wherein RAA is -CH(CH3)2. In some embodiments, R4a is C3- C8 cycloalkyl (e.g., cyclopropyl). In some embodiments, R4a is -C(O)NRgRh, wherein Rg and Rh are each hydrogen. In some embodiments, R4a is -CH2-O-C(=O)C1-C6 alkyl (e.g., -CH2-O- C(=O)CH2CH3). [0110] In some embodiments of Formula (VI), R5a is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN. In some embodiments, R5a is C1-C6 alkoxy (e.g., -OCH3) or -NRiRj, wherein Ri and Rj are each hydrogen. In some embodiments, R5a is C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., -CH3, -CH2F, CHF2, or –CF3). In some embodiments, R5a is hydrogen. In some embodiments, R5a is halo. In other embodiments, R5a is F, Cl, or Br. In some embodiments, R5a is C1-C6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups. In some embodiments, R5a is CH3, CH2F, or CF3. In some embodiments, R5a is NH2. [0111] Provided in other embodiments are compounds of Formula (VII):
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R9, and R10 are as defined for Formula (I). [0112] In some embodiments of Formula (VII), R3 is –ORd. In one particular variation, R3 is –ORd, wherein Rd unsubstituted C1-C6 alkyl (e.g., Rd is –CH3). In another particular variation, R3 is –ORd, wherein Rd C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., Rd is –CHF2 or –CH2-cyclopropyl). In one particular variation, R3 is –ORd, wherein Rd is C3-C8 cycloalkyl (e.g., Rd is cyclopropyl). [0113] In some embodiments of Formula (VII), R4a is hydrogen. In some embodiments of Formula (VII), R4a is C1-C6 alkyl substituted by 1 or 2 groups selected from halo and OH (e.g., R4a is –CH2OH or –CH2F). In some embodiments of Formula (VII), R4a is -CH2-O- [C(=O)CH(RAA)NH]tH. In one particular variation, R4a is -CH2-O-[C(=O)CH(RAA)NH]tH. wherein RAA is -CH(CH3)2. In some embodiments of Formula (VII), R4a is C3-C8 cycloalkyl (e.g., cyclopropyl). In some embodiments of Formula (VII), R4a is -C(O)NRgRh, wherein Rg and Rh are each hydrogen. In some embodiments of Formula (VII), R4a is -CH2-O-C(=O)C1-C6 alkyl (e.g., -CH2-O-C(=O)CH2CH3). [0114] Provided in other embodiments are compounds of Formula (VIII):
Figure imgf000038_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R6a, R9, and R10 are as defined for Formula (I). [0115] In some embodiments of Formula (VIII), R3 is –ORd. In one particular variation, R3 is –ORd, wherein Rd unsubstituted C1-C6 alkyl (e.g., Rd is –CH3). In another particular variation, R3 is –ORd, wherein Rd C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., Rd is –CHF2 or –CH2-cyclopropyl). In one particular variation, R3 is –ORd, wherein Rd is C3-C8 cycloalkyl (e.g., Rd is cyclopropyl). [0116] In some embodiments of Formula (VIII), R4a is -C(O)NRgRh, wherein Rg and Rh are each hydrogen. In some embodiments, R4a is hydrogen. In some embodiments, R4a is CH2-O- [C(=O)CH(RAA)NH]tH. In some embodiments, R4a is -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R4a is C1-C6 alkyl substituted by OH. In other embodiments, R4a is -CH2OH. [0117] In some embodiments of Formula (VIII), R6a is hydrogen. In some embodiments, R6a is hydrogen, halo, C1-C6 alkyl, CN, or -NRiRj. In some embodiments, R6a is -H, -F, -Cl, -Br, - CH3, -CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R6a is -H, -CH3, or -F. In some embodiments, R6a is -H. [0118] Provided in other embodiments are compounds of Formula (IX):
Figure imgf000038_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R4b, R5a, R5b, R9, and R10 are as defined for Formula (I). [0119] In some embodiments of Formula (IX), R3 is –ORd. In one particular variation, R3 is – ORd, wherein Rd unsubstituted C1-C6 alkyl (e.g., Rd is –CH3). In another particular variation, R3 is –ORd, wherein Rd C1-C6 alkyl substituted by 1 or 2 groups selected from halogen and C3- C8 cycloalkyl (e.g., Rd is –CHF2 or –CH2-cyclopropyl). In one particular variation, R3 is –ORd, wherein Rd is C3-C8 cycloalkyl (e.g., Rd is cyclopropyl). [0120] In some embodiments of Formula (IX), R4a is -C(O)NRgRh, wherein Rg and Rh are each hydrogen. In some embodiments, R4a is hydrogen. In some embodiments, R4a is CH2-O- [C(=O)CH(RAA)NH]tH. In some embodiments, R4a is -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R4a is C1-C6 alkyl substituted by OH. In other embodiments, R4a is -CH2OH. In some embodiments of Formula (IX), R4b is -C(O)NRgRh, wherein Rg and Rh are each hydrogen. In some embodiments, R4b is hydrogen. In some embodiments, R4b is CH2-O- [C(=O)CH(RAA)NH]tH. In some embodiments, R4b is -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R4b is C1-C6 alkyl substituted by OH. In other embodiments, R4b is -CH2OH. In some embodiments, R4a and R4b are each hydrogen. [0121] In some embodiments of Formula (IX), R5a is unsubstituted C1-C6 alkyl (e.g., –CH3). In some embodiments, R5b is hydrogen. In some embodiments, R5a and R5b are each unsubstituted C1-C6 alkyl (e.g., –CH3). In one particular embodiment, R5a and R5b are each methyl. In some embodiments, R5a is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN. In some embodiments, R5a is C1-C6 alkoxy (e.g., -OCH3) or -NRiRj, wherein Ri and Rj are each hydrogen. In some embodiments, R5a is C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., -CH3, -CH2F, CHF2, or –CF3). In some embodiments, R5a is hydrogen. In some embodiments, R5a is halo. In other embodiments, R5a is F, Cl, or Br. In some embodiments, R5a is C1-C6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups. In some embodiments, R5a is CH3, CH2F, or CF3. In some embodiments, R5a is NH2. In some embodiments, R5b is hydrogen, halo (e.g., fluoro, chloro, and bromo), or CN. In some embodiments, R5b is C1-C6 alkoxy (e.g., -OCH3) or -NRiRj, wherein Ri and Rj are each hydrogen. In some embodiments, R5b is C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1, 2, or 4 halo groups. (e.g., -CH3, -CH2F, CHF2, or –CF3). In some embodiments, R5b is hydrogen. In some embodiments, R5b is halo. In other embodiments, R5b is F, Cl, or Br. In some embodiments, R5b is C1-C6 alkyl, which is unsubstituted or substituted by 1, 2, 3, or 4 halo groups. In some embodiments, R5b is CH3, CH2F, or CF3. In some embodiments, R5b is NH2. [0122] Any of the embodiments detailed herein with respect to Formula (I), where applicable, apply equally to Formula (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX). It is also understood that the descriptions of any variable of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) may, where applicable, be combined with one or more descriptions of any other variable, the same as if each and every combination of variables were specifically and individually listed. For example, every description of R1 may be combined with every description of R2, R3, R7, R8, R9, R10, R11, R12, R13, G1, G2, G3, G4, G5, G6, and n the same as if each and every combination were specifically and individually listed. Likewise, every description of R2 may be combined with every description of R1, R3, R7, R8, R9, R10, R11, R12, R13, G1, G2, G3, G4, G5, G6, and n the same as if each and every description were specifically and individually listed. Similarly, every description of
Figure imgf000040_0001
may be combined with every description of R1, R2, R7, R8, and
Figure imgf000040_0002
, the same as if each and every description were specifically and individually listed. [0123] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo. In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl. In some embodiments, R1 is methyl. [0124] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is C1-C6 haloalkyl, wherein the C1-C6 haloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo. In some embodiments, R1 is CF3 or CH2F. [0125] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0126] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is -C(O)NHRa, wherein Ra is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and –CH2Rc. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is –CN. [0127] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R2 is C1-C6 haloalkyl, wherein the C1-C6 haloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R2 is CH2F. [0128] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R2 is C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, -OH, and oxo. In some embodiments, R2 is –CN. [0129] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R2 is -C(O)NHRb, wherein Rb is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and –CH2Rc. In some embodiments, R2 is -C(O)NH2. In some embodiments, R2 is - C(O)NHRb, wherein Rb is C1-C6 alkyl. For example, in some embodiments, R2 is -C(O)NHCH3. In some embodiments, R2 is -C(O)NHRb, wherein Rb is C1-C6 haloalkyl. For example, in some embodiments, R2 is -C(O)NHCHF2 or -C(O)NHCH2CHF2. In some embodiments, R2 is - C(O)NHRb, wherein Rb is C3-C8 cycloalkyl, unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -CN, - OH, and oxo. For example, in some embodiments, R2 is -C(O)NH-cyclopropyl, wherein the cyclopropyl is unsubstituted or substituted with halogen C1-C6 alkyl, C3-C8 cycloalkyl, -CN, - OH, or oxo. In one embodiment, R2 is
Figure imgf000041_0001
[0130] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R2 is CH2F, -C(O)NH2, -C(O)N(H)CH3, -C(O)N(H)CH2CHF2, or –CN. In some embodiments, R1 is CH3 and R2 is -C(O)NH2, -C(O)N(H)CH3, or - C(O)N(H)CH2CHF2. [0131] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is C1-C6 alkyl and R2 is -C(O)NHRb. For instance, in some embodiments, R1 is methyl and R2 is -C(O)NH2. In some embodiments, R1 is methyl and R2 is - C(O)NHCH2CHF2. In some embodiments, R1 is methyl and R2 is -C(O)NHCH3. In other embodiments, R1 is methyl and R2 is
Figure imgf000042_0001
[0132] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is C1-C6 alkyl and R2 is C1-C6 haloalkyl. For instance, in some embodiments, R1 is methyl and R2 is CH2F. [0133] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 and R2 are each independently C1-C6 haloalkyl. For instance, in some embodiments, R1 and R2 are each CH2F. [0134] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is C1-C6 alkyl and R2 is CN. For example, in some embodiments, R1 is methyl and R2 is CN. [0135] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is CH3 and R2 is -C(O)NH2, -C(O)N(H)CH3, or - C(O)N(H)CH2CHF2. In some embodiments, R1 is CH2F and R2 is CH2F or –CN. [0136] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R3 is C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C14 aryl. In some embodiments, R3 is -ORd, wherein Rd is C1-C6 alkyl or C3-C8 cycloalkyl. In some embodiments, R3 is –OCH3 or –O-cyclopropyl. [0137] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (V), (VI), (VII), (VIII), and (IX), R4a is hydrogen, halo, CN, C1-C6 alkyl, -NRiRj, -CH2-O-C(=O)C1- C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH. In some embodiments, R4a is hydrogen, halo, C1-C6 alkyl, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH, wherein the C1-C6 alkyl of R4a is unsubstituted or substituted by 1, 2, or 3 groups independently selected from halo and OH. In some embodiments, R4a is hydrogen, halo, C1-C6 alkyl, or -CH2-O- [C(=O)CH(RAA)NH]tH, wherein the C1-C6 alkyl of R4a is unsubstituted or substituted by OH. In some embodiments, R4a is hydrogen, C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH, wherein the C1-C6 alkyl of R4a is substituted with OH. In some embodiments, R4a is -H, -F,-Cl, -Br, - CH3,-CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R4a is -H, -F,-Cl, -Br, -CH3,-CH2F, -CF3, -CH2OH, -NH2, or -CH2-O- C(=O)CH(CH(CH3)2)NH2. In some embodiments, R4a is -H, -F, -CH3, -CH2OH, or -CH2-O- C(=O)CH(CH(CH3)2)NH2. In some embodiments, R4a is -H, -CH2OH, or -CH2-O- C(=O)CH(CH(CH3)2)NH2. [0138] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (VI), and (IX), R5a is hydrogen, halo, C1-C6 alkyl, CN, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or - CH2-O-[C(=O)CH(RAA)NH]tH. In some embodiments, R5a is hydrogen, halo, C1-C6 alkyl, - NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O-[C(=O)CH(RAA)NH]tH, wherein the C1-C6 alkyl of R4a is unsubstituted or substituted by 1, 2, or 3 groups independently selected from halo and OH. In some embodiments, R5a is hydrogen, halo, C1-C6 alkyl, CN, or -NRiRj, wherein the C1-C6 alkyl of R5a is unsubstituted or substituted by 1, 2, or 3 halo. In some embodiments, R5a is hydrogen, halo, C1-C6 alkyl, or -NRiRj, wherein the C1-C6 alkyl of R5a is unsubstituted or substituted with 1, 2, or 3 halo. In some embodiments, R5a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R5a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CH2OH, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R5a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CN, or -NH2. In some embodiments, R5a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, or -NH2. [0139] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (III), (IV), (V), and (VIII), R6a is hydrogen, halo, C1-C6 alkyl, CN, -NRiRj, -CH2-O-C(=O)C1-C6 alkyl, or -CH2-O- [C(=O)CH(RAA)NH]tH. In some embodiments, R6a is hydrogen, halo, C1-C6 alkyl, CN, or - NRiRj. In some embodiments, R6a is -H, -F, -Cl, -Br, -CH3, -CH2F, -CF3, -CH2OH, -CN, -NH2, or -CH2-O-C(=O)CH(CH(CH3)2)NH2. In some embodiments, R6a is -H, -CH3, or -F. In some embodiments, R6a is -H. [0140] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (III), (IV), (V), and (VIII), R9 and R10 are each independently hydrogen, halo, or C1-C6 haloalkyl. In some embodiments, R9 is hydrogen. In some embodiments, R9 is F, Cl, Br or I. In some embodiments, R9 is C1-C6 haloalkyl. In some embodiments, R9 is –CF3, -(CH2)F, -CHF2, CH2Br, -CH2CF3, and –CH2CH2F. In some embodiments, R10 is hydrogen. In some embodiments, R10 is F, Cl, Br or I. In some embodiments, R10 is C1-C6 haloalkyl. In some embodiments, R10 is –CF3, -(CH2)F, - CHF2, CH2Br, -CH2CF3, and –CH2CH2F. [0141] In some embodiments of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is -CH2F and R2 is selected from the group consisting of -CH2F and -CN. [0142] In some embodiments of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is -CH3 and R2 is selected from the group consisting of –CH2F and -CN. [0143] In some embodiments of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R1 is -CH3 and R2 is -C(O)NHRb. In one aspect of the foregoing embodiment, Rb is selected from the group consisting of hydrogen, C1-C6 alkyl (e.g., -CH3), C1-C6 haloalkyl (e.g., -CHF2 or CH2CHF2), and C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl of Rb is substituted by 1 or 2 halo groups (e.g., cyclopropyl substituted by 1 or 2 fluoro groups). [0144] In some embodiments of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R7 is hydrogen. [0145] In some embodiments of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R8 is -CF3 or -CHF2. [0146] In some embodiments of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R10 is -F or -CF3. [0147] In some embodiments of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), R10 is hydrogen or -F. Formula (X) [0148] In some embodiments of Formula (X), each variable is independently defined as described herein for any one of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX). Alternatively, any variable definition provided for Formula (X) herein is also applicable as an embodiment for any one of Formulae (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), where such variable appears in the respective formula. [0149] In some embodiments of Formula (X), the carbon bearing the R8 and OH moieties is in an “R” configuration. In some embodiments, the carbon bearing the R8 and OH moieties is in an “S” configuration. [0150] In some embodiments, G2 is CR4a. In some embodiments, R4a is H, F, Cl, CH3, - OCH3, -CH2F, -CF3, -CN, -CH2-ORk, -NH2, or -NHCH3, wherein Rk is H, -C(O)CH2CH3, or - C(=O)CH(iPr)NH2. [0151] In some embodiments, G2 is N. [0152] In some embodiments, n is 1 and G3 is CR5a. In some embodiments, R5a is H, F, Cl, - CH3, -CD3, -CHF2, -CH2F, -CF3, -OCH3, -OCHF2, -OCF3, CN, -cyclopropyl (optionally substituted with fluoro), NH2, NHCH3, or CONH2. [0153] In some embodiments, n is 1 and G3 is N. [0154] In some embodiments, G4 is CR6a. In some embodiments, R6a is H or -CH3, optionally wherein R6a is H. [0155] In some embodiments, G4 is N, or wherein G4 is O, or wherein G4 is S. In some embodiments, (a) n is 0, G5 is C, and G6 is N, or (b) n is 0, G5 is N, and G6 is C, or (c) n is 1 and G5 and G6 are each C. [0156] In some embodiments, R1 is -CH3, -CH2F, -CHF2, -CF3, or -CH2OH. [0157] In some embodiments, R2 is -CH3, -CH2F, -CHF2, -CF3, -CN, -C(CH3)2OH, - cyclopropyl-OH, -C(O)CH3, -CH2OH, -CH2NH2, -NH2, triazolyl, imidazolyl, pyridinyl, pyrimidinyl, -C(=N-CN)NH2, or -C(O)NRb, wherein Rb is H, -CH3, -CH2CHF2, -CH2CF3, cyclopropyl (optionally substituted with one or two F or CH3 groups), or pyridyl (optionally substituted with F, CH3, or CF3). [0158] In some embodiments, R3 is F, Cl, -OCH3, -OCD3, -OCHF2, -OCF3, -OCH2CHF2, -O- cyclopropyl, or -O-CH2-cyclopropyl.
Figure imgf000046_0001
[0160] In some embodiments, R8 is -CHF2, -CF3, -CH2F, cyclobutyl, cyclopropyl, or fluoro- cyclopropyl. [0161] In some embodiments, one or two of R9, R10, R11, R12, and R13 are independently F, - CF3, Cl, ethyl, -CF2CH3, or -CHFCH3. In some embodiments, R9, R12, and R13 are each H. In some embodiments, (a) R10 is F, Cl, -CF3, or -CHF2, or (b) R11 is H, F, Cl, -CF3, -CF2CH3, or ethyl. [0162] Representative compounds are listed in Tables 1 and 1A. Table 1
Figure imgf000046_0002
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
N/A = not applicable Table 1A
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Additional compounds are presented in Table 1B:
Figure imgf000092_0002
[0163] It is understood that compounds of Table 1 and Table 1A have one or more symmetric centers and therefore can exist in different stereochemical forms, such as different enantiomeric and/or diastereomeric forms. Where a specific stereochemistry is indicated, it is understood that the compound designated intends the specific stereoisomer provided. For example, in Table 1, compound 1a intends the compound depicted wherein the carbon indicated by the single asterisk (*) is in the R configuration and the carbon indicated by the double asterisk (**) is in the R configuration. Similarly, in Table 1, compound 1b intends the compound depicted wherein the carbon indicated by the single asterisk (*) is in the R configuration and the carbon indicated by the double asterisk (**) is in the S configuration. In any compound of Table 1 that provides for either the R or S stereochemistry at a given stereocenter (for example, any of compounds 1-97 that are not further designated by stereoisomeric forms a-d and list “R or S” for the stereocenter designation of * and **), such compound is understood to embrace all possible stereoisomers of the compound depicted, as well as mixtures of stereoisomers in any proportion. Thus, racemic mixtures, scalemic mixtures, mixtures of enantiomers in any proportion, mixtures of diastereomers in any proportion, and mixtures of enantiomers and diastereomers in any proportion are embraced, as well as individual, stereochemically pure compounds. In one embodiment, a composition comprising a specific stereochemical form of a compound is provided, wherein the composition is substantially free of alternate stereochemical forms of the compound, such as when the composition comprises no more than 5% or 3% or 1% or 0.5% or 0.1% by weight of the corresponding compound having a different stereochemical configuration. For example, in one embodiment is provided a composition comprising compound 1a, wherein the composition is substantially free of alternate stereochemical forms of the compound (and is therefore substantially free of, and in one aspect, comprises no more than 5% or 3% or 1% or 0.1% by weight of, compounds 1b, 1c and/or 1d). [0164] In some embodiments, provided herein are compounds described in Table 1, or a pharmaceutically acceptable salt thereof, and uses thereof. In some embodiments, provided herein are compounds described in Table 1A, or a pharmaceutically acceptable salt thereof, and uses thereof. [0165] The embodiments and variations described herein are suitable for compounds of any formulae detailed herein, where applicable. [0166] Representative examples of compounds detailed herein, including intermediates and final compounds according to the present disclosure are depicted herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual. [0167] The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described. [0168] Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein. [0169] Compounds of a formula given herein may have asymmetric centers and therefore exist in different stereochemical forms. The present disclosure includes any or all of the stereochemical forms of the compounds provided. Such compounds may be isolated as specific stereochemical forms or may be present in a mixture of different stereochemical forms in any ratio. [0170] Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. For example, compounds of any formula given herein may contain bonds with restricted rotation and therefore exist in different geometric configurations. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture. [0171] The invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, 11C, 13C, 14C 13N, 15O, 17O, 32P, 35S, 18F, 36Cl. Certain isotope labeled compounds (e.g.3H and 14C) are useful in compound or substrate tissue distribution study. Incorporation of heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances. [0172] Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent. [0173] The invention also includes any or all metabolites of any of the compounds described. The metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human. [0174] Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, I.V. bag, and the like. [0175] Compounds detailed herein may be formulated or oral administration. Compounds may also be formulated for parenteral (e.g., intravenous) administration. [0176] One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of a viral infection. In one variation, the manufacture of a medicament comprises a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof for use in preventing an RSV infection. General synthetic methods [0177] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein. [0178] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described. [0179] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction. [0180] Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate [0181] In some embodiments, compounds of the Formula (I) may be synthesized according to Scheme 1. Scheme 1
Figure imgf000096_0001
wherein Ring , Ring , G1, G2, G3, G4, G5, G6, n, R1, R2, R3, R7, R8, 9 10 11 12
Figure imgf000096_0002
Figure imgf000096_0003
R , R , R , R , and R13 are as defined for Formula (I), or any variation thereof detailed herein. [0182] In another aspect is a method of making a compound of Formula (XX, ethyl 8-fluoro- 3-methylcinnoline-6-carboxylate):
Figure imgf000096_0004
comprising: coupling a compound of formula (XXa):
Figure imgf000097_0001
with 1-(trimethylsilyl)-propyne in the presence of a palladium catalyst to form a compound of formula (XXb):
Figure imgf000097_0002
cyclizing the compound of formula (XXb) with di-tert-butyl-hydrazodiformate (Boc-NH-NH- Boc) in the presence of a base, such as Cs2CO3, to form the comound of formula (XXc):
Figure imgf000097_0003
and deprotecting the compound of formula (XXc) to form the compound of Formula (XX). [0183] In some embodiments, the particular conditions are as described in the examples below. [0184] Particular examples are provided in the Example section below. It is understood that the schemes above may be modified to arrive at various compounds of the invention by selection of appropriate reagents and starting materials. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006. Pharmaceutical Compositions and Formulations [0185] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. [0186] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. [0187] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. [0188] A compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. [0189] One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference. [0190] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. [0191] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. [0192] In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment or prevention of a viral infection described herein. Methods of Use and Uses [0193] Compounds and compositions detailed herein, such as a pharmaceutical composition comprising a compound of any formula provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays. [0194] In some embodiments, provided herein is a method of inhibiting an RSV RNA polymerase comprising contacting the RSV RNA polymerase with a compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof. Also provided are methods of inhibiting an RSV RNA polymerase in an individual in need thereof comprising administering to the individual in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Also provided are methods of inhibiting an RSV RNA polymerase comprising contacting the RSV RNA polymerase with a metabolite of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the RSV RNA polymerase is encoded by a subgenomic replicon. [0195] Also provided herein is a method of inhibiting replication of an RSV in a cell comprising contacting the cell with the compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a metabolite of any of the foregoing or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof or metabolite. In some embodiments, the cell is infected with the RSV. In some embodiments, the cell is subsequently infected with the RSV. Also provided are methods of inhibiting replication of an RSV in a cell in an individual in need thereof comprising administering to the individual in need thereof a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. [0196] In some embodiments, the contacting is performed in vitro. In some embodiments, the cell comprises an RSV. In some embodiments, the comprises a subgenomic RSV replicon. In some embodiments, the contacting is performed in vivo. [0197] In some embodiments, provided herein is a method of treating a respiratory syncytial virus (RSV) infection in an individual in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, to the individual. [0198] In some embodiments, provided herein is a method of ameliorating one or more symptoms of an RSV infection in an individual in need thereof comprising administering an effective amount of a compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof, to the individual. [0199] In some embodiments, the individual has one or more symptoms of an RSV infection, which may include, but are not limited to coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and/or wheezing. In some embodiments, the individual has a lower respiratory tract infection, an upper respiratory tract infection, or both an upper and lower respiratory tract infection. In some embodiments, the individual has bronchiolitis, pneumonia, or croup. In some emboidments, the one or more symptoms of an RSV infection include, but are not limited to, nasal congestion, rhinorrhea, subcostal, itercostal, or tracheosternal retractions, grunting, head bobbing, nasal flaring, or tachypnea, wheezing, cyanosis, cough, or apnea. In children and infants, the individual has symptoms such as feeding difficulties, dehydration, fever, disturbed sleep, or disturbed activity level (e.g., irritable, restless, agistated, or less responsive). In some emboidments, the individual has one or more risk factors for severe RSV disease, such as prematurity at birth, bronchopulmonary dysplasia, congenital heart disease, Down syndrome, neuromuscular impairment, cystic fibrosis, recurrent wheezing, asthma, or other congenital disease. [0200] In some embodiments, the individual has been diagnosed with an RSV infection. In some embodiments, the RSV is RSV Type A or RSV Type B. In some embodiments, the RSV infection has been confirmed by a laboratory test. In some embodiments, the methods disclosed herein comprise obtaining the results of an RSV detecting laboratory test. Laboratory tests can include detection of viral genes or proteins, such as by PCR based assays or antibody based assays, or viral culture or serology. Methods of obtaining samples for laboratory tests are known in the art and may include taking samples from the nose or mouth, or taking a blood sample. In some embodiments, the laboratory test comprises detecting RSV in a nasal sample, such as a nasopharyngeal swab, a nasopharyngeal aspirate, or a nasal/nasopharyngeal wash specimen. [0201] In some embodiments, provided herein is a method of preventing a respiratory syncytial virus (RSV) infection in an individual at risk of developing an RSV infection comprising administering to the individual a prophylactically effective amount of a compound of Formula (I) or any embodiment, variation or aspect thereof, including but not limited to a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or any embodiment or variation or aspect thereof, (collectively, a compound of Formula (I) or the present compounds or the compounds detailed or provided or described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof. [0202] In some embodiments is a composition for use in any one of the methods described herein. In some embodiments is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound, in the manufacture of a medicament for treating or preventing an RSV infection in an individual in need thereof. [0203] The individual for any of the methods detailed herein may be an infant, a child, or an adult. In some embodiments, the individual is elderly. In some embodiments, the individual is greater than 65 years old, such as greater than 70, 75, or 80 years old. In some embodiments, the individual is 18 to 65 years of age, such as 18 to 60, 55, 50, 45, 30, 25, or 20 years of age. In some embodiments, the individual is 0 to 18 years of age, such as 0 and 17, 15, 12, 10, 8, 6, 5, 4, 3, 2, or 1 years of age. In some embodiments, the individual is 2 to 5 years of age. In some embodiments, the individual is 5 to 10 years of age. In some embodiments, the individual is 0 to 2 years of age. In some embodiments, the individual is an infant. In some embodiments, the individual is an infant or child aged one month to 36 months, or an infant aged 28 days or less. [0204] In some embodiments, the individual was born prematurely. In some embodiments, the individual was born at the gestation age of or less than 36 weeks, such as the gestation age of or less than 35, 34, 33, 32, 31, or 30 weeks. In some embodiments, the individual was born at the gestation age of or less than 32 weeks. [0205] In some embodiments, the individual is immunocompromised. In some embodiments, the individual has a chronic lung or chronic heart disease. In some embodiments, the individual has reactive airway disease, asthma, chronic obstructive pulmonary disease (COPD), or congestive heart failure. In some embodiments, the individual has a neuromuscular disorder. In some embodiments, the individual has difficulty swallowing or clearing mucus secretions. [0206] In some embodiments, the methods provided herein further comprise monitoring the effectiveness of the treatment. Examples of indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in viral RNA, a reduction in time to seroconversion (virus undetectable in patient serum), and/or a reduction in the severity of the symptoms associated with the infection. [0207] In some embodiments, treatment results in a reduced viral load compared to the viral load before administration. In some embodiments, treatment results in reducing viral load to less than 1.7 log10 plaque forming units equivalents (PFUe) per mL, or less than 0.3 log10 PFUe/mL. In some embodiments, treatment results in greater than 1.5-log reduction, such as a greater than 2.5-log reduction, 3-log reduction, 4-log reduction, or 5-log reduction compared to the viral load before administration. For example, the viral load may be measured before administration and several hours after receiving the initial dosage, such as 24 hours, 48 hours, 60 hours, or more after receiving the initial dosage. In some embodiments, treatment results in a lower risk of hospitalization or ICU admission or a shorter duration of hospitalization or ICU status than without treatment. In some emboidments, the treatment results in reduced requirements for supplemental oxygen, mechanical ventilation, or supplemental feeding/hydration than without treatment. [0208] In some embodiments, treatment provides a reduction in time to resolution or alleviation of key RSV symptoms as compared to no treatment. In some embodiments, key RSV symptoms include one or more of cough, shortness of breath, wheezing, or coughing up phlegm (sputum). In some embodiments, treatment provides a reduction in progression to complications compared to no treatment. In some embodiments, complications include one or more of bronchitis, respiratory distress, respiratory failure, exacerbations of chronic conditions (such as COPD, congestive heart failure, or asthma), hospitalization, or myocardial infarction. [0209] In some embodiments, the RSV is human RSV or bovine RSV. In some embodiments, the RSV is human RSV. In some embodiments, the RSV is Type A. In some embodiments, the RSV is Type B. In some embodiments, the RSV is Type A and Type B. In some embodiments, the RSV is RSV A2, RSV B1, or RSV S2. [0210] In some embodiments, the RSV is a resistant RSV. In some embodiments, the RSV is resistant against an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, an RSV RNA polymerase inhibitor, an inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor, or an interferon treatment. In some embodiments, the RSV is resistant against ribavirin or palivizumab. [0211] Also provided herein are uses of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is for the treatment of a viral infection described herein. In one variation, the medicament comprises a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof for use in treating an RSV infection. In some embodiments, the manufacture of a medicament is for the prevention of a viral infection described herein. In one variation, the medicament comprises a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof for use in preventing an RSV infection. [0212] Also provided herein are compositions (including pharmaceutical compositions) as described herein for the use in treating, preventing, and/or delaying the onset and/or development of a disease described herein and other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation which is present in a unit dosage form. Combination Therapy [0213] As provided herein, compounds or salts thereof described herein and compositions described herein may be administered with an additional agent to treat or prevent any of the viral infections disclosed herein. In some embodiments, methods described herein further comprise administering an additional anti-RSV agent. In some embodiments, the additional anti-RSV agent is an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, an RSV RNA polymerase inhibitor, an inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor, or an interferon. Dosing and Method of Administration [0214] The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular infection, such as type and stage of infection, being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount. In some embodiments, the amount of the compound or salt thereof is a prophylactically effective amount. [0215] The therapeutically or prophylactically effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection to be treated, the subject’s health status, condition, and weight. An exemplary dose is in the range of about from about 0.1 mg to 10 g daily. [0216] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient. [0217] A compound or composition disclosed herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one week, at least about 2 weeks, at least about 3 weeks, at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein. [0218] The compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal. In some embodiments, the compound or composition is administered orally. Articles of Manufacture and Kits [0219] The present disclosure further provides articles of manufacture comprising a compound of the disclosure or a salt thereof, composition, and unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed. [0220] The present disclosure further provides kits for carrying out the methods of the disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment or prevention of a viral infection described herein. [0221] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. [0222] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a viral infection detailed herein to provide effective treatment or prevention of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies). [0223] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods disclosed herein. The instructions included with the kit generally include information as to the components and their administration to an individual. [0224] The invention can be further understood by reference to the following examples, which are provided by way of illustration and are not meant to be limiting. EXAMPLES Synthetic Examples [0225] The following examples are offered to illustrate but not to limit the present disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a salt (e.g., pharmaceutically acceptable salt) thereof. The compounds are prepared using the general methods described above. [0226] The following abbreviations are used throughout the Examples: CDI (1,1'- carbonyldiimidazole), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DCE (1,2-dichloroethane), DCM (dichloromethane), DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), DIAD (diisopropyl azodicarboxylate), DIPEA or DIEA (N,N-diisopropylethylamine), DMA (dimethylacetamide), DMF (N,N-dimethylformamide), DMP (Dess–Martin periodinane), DMSO (dimethyl sulfoxide), DPPP (1,3-Bis(diphenylphosphino)propane), EA (ethyl acetate), ESI-MS (electrospray ionisation mass spectrometry), HATU ((1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HPLC (high-pressure liquid chromatography), IPA (isopropyl alcohol), LCMS (liquid chromatography mass spectrometry), m-CPBA (meta-chloroperoxybenzoic acid), MeI (methyl iodide), ACN or MeCN (acetonitrile), MeOH (methanol), NBS (N- bromosuccinimide), NMO (N-Methylmorpholine N-oxide), NMR (nuclear magnetic resonance), PBSF (perfluoro-1-butanesulfonyl fluoride), PE (petroleum ether), PPh3 (triphenylphosphane), Q-Phos (1,2,3,4,5-Pentaphenyl-1-(di-tert-butylphosphino)ferrocene), RT (room temperature), SEM (2-(trimethylsilyl)ethoxymethyl), SEMCl (2-(trimethylsilyl)ethoxymethyl chloride), t- BuOK (potassium tert-butoxide), TBAAC (tertbutylammonium chloride), TBAF (Tetra-n- butylammonium fluoride), TBS (tert-butyldimethylsilyl), TBSCl (tert-butyldimethylsilyl chloride), TEA (triethylamine), TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl or (2,2,6,6- tetramethylpiperidin-1-yl)oxidanyl), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TIPSCl (triisopropylsilyl chloride) and TLC (thin layer chromatography). Example 1: Synthesis of Compound 1d [0227] 1.1 Preparation of Intermediate 1-2:
Figure imgf000108_0001
[0228] A solution of Wittig reagent 1-1A (Reference: Journal of Molecular Structure, 2013, 1034, 51 – 56) (11.0 g, 24.53 mmol, 1.00 eq.) and Compound 1-1 (2.45 g, 19.62 mmol, 0.8 eq.) in toluene (30.0 mL) was stirred at 120 °C for 12 h. TLC (PE/EA=3/1) indicated that the aldehyde was consumed completely. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 5/1) to give Intermediate 1-2 (5.95 g, 91.7% yield) as a yellow oil. LCMS: ESI-MS: m/z 295.9 [M+H]+. [0229] 1.2 Preparation of Intermediate 1-3:
Figure imgf000108_0002
[0230] A mixture of Intermediate 1-2 (5.95 g, 20.16 mmol, 1.0 eq.) in TFA (20 mL) was stirred at 20 °C for 2 h. LCMS trace indicated that the reaction was completed. The reaction mixture was concentrated under reduced pressure. Intermediate 1-3 (5.0 g, crude) was used into the next step without further purification. LCMS: ESI-MS: m/z 240.0 [M+H]+. [0231] 1.3 Preparation of Intermediate 1-4:
Figure imgf000109_0001
[0232] To a solution of Intermediate 1-3 (5.0 g, 20.16 mmol, 1.0 eq.) in Ac2O (20 mL) was added NaOAc (8.26 g, 100.8 mmol, 5.0 eq.). The mixture was stirred at 135 °C for 4 h. LC-MS trace showed that the reaction was complete and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 1/1) to give Intermediate 1-4 (2.49 g, 45.4% yield) as a white solid. LCMS: ESI-MS: m/z 263.9 [M+H]+. [0233] 1.4 Preparation of Intermediate 1-5:
Figure imgf000109_0002
[0234] To a solution of Intermediate 1-4 (2.49 g, 9.47 mmol, 1.00 eq.) in MeOH (15.00 mL) was added K2CO3 (3.94 g, 28.50 mmol, 3.00 eq.). The mixture was stirred at 25°C for 1 h. TLC indicated that the reaction was consumed completed. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=20/1 to 1/2) to give Intermediate 1-5 (1.97 g, 94.2% yield) as a white solid. LCMS: ESI-MS: m/z 222.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ= 8.85-8.82 (d, J = 2.8 Hz, 1H), 8.18-8.08 (m, 2H), 7.58-7.55 (d, J = 1.6 Hz, 1H), 3.93(s, 3H). [0235] 1.5 Preparation of Intermediate 1-6:
Figure imgf000109_0003
[0236] To a solution of Intermediate 1-5 (1.97 g, 8.91 mmol, 1.00 eq.) in DMF (30.0 mL) was added MeI (10.1 g, 71.28 mmol, 4.45 mL, 8.0 eq.) and K2CO3 (3.69 g, 26.73 mmol, 3.00 eq.). The reaction mixture was stirred at 20 °C for 2 h. LCMS trace showed that the reaction was complete. The reaction mixture was quenched by H2O (100 mL), and then extracted with EA (50 mL X 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA = 1/0 to 2/1). Intermediate 1-6 (1.78 g, 85.4% yield) was obtained as a yellow solid. LCMS: ESI-MS: m/z 236.0 [M+H]+. [0237] 1.6 Preparation of Intermediate 1-7:
Figure imgf000110_0001
[0238] To a solution of Intermediate 1-6 (500 mg, 2.13 mmol, 1.0 eq.) in CHCl3 (5.0 mL) was added m-CPBA (865 mg, 4.26 mmol, 85% purity, 2.0 eq.). The mixture was stirred at 70 °C for 3 h. TLC (PE/EA=3/1) indicated that the reaction was complete. The reaction mixture was diluted with DCM (20 mL). The resulting solution was washed with saturated Na2SO3 solution (10 mL) and concentrated under reduced pressure. The crude Intermediate 1-7 (0.82 g, crude) was used in the next step without further purification. [0239] 1.7 Preparation of Intermediate 1-8:
Figure imgf000110_0002
[0240] A mixture of Intermediate 1-7 (0.82 g, crude, 2.13 mmol, 1.00 eq.) in POCl3 (15.0 mL) was stirred at 90 °C for 3 h. LC-MS trace showed that the reaction was complete. The reaction mixture was slowly added to H2O (50 mL) at 20 °C, and adjusted to pH=7~8 by addition of saturated NaHCO3 solution. The resulting solution was extracted with EA (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 2/1) to give Intermediate 1-8 (445 mg, 77.6% yield) as a yellow solid. LCMS: ESI-MS: m/z 269.9 [M+H]+. [0241] 1.8 Preparation of Intermediate 1-9:
Figure imgf000111_0001
[0242] A mixture of Intermediate 1-8 (400 mg, 1.48 mmol, 1.0 eq.), potassium trifluoro(vinyl)boranuide (596 mg, 4.45 mmol, 3.0 eq.), Pd(dppf)Cl2 (108 mg, 0.148 mmol, 0.10 eq.), and Na2CO3 (314 mg, 2.97 mmol, 2.0 eq.) in a mixed solvent of EtOH (5.0 mL) and H2O (1.0 mL) was degassed and purged with N2 for 3 times. Then the mixture was stirred at 80 °C for 4 h under N2 atmosphere. TLC (PE/EA=3/1) indicated that the reaction was complete. The reaction mixture was diluted with H2O (15 mL) and extracted with EA (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 3/1). Intermediate 1-9 (290 mg, 75% yield) was obtained as a yellow solid. LCMS: ESI-MS: m/z 261.9 [M+H]+. [0243] 1.9 Preparation of Intermediate 1-11:
Figure imgf000111_0002
[0244] To a solution of Intermediate 1-9 (200 mg, 0.76 mmol, 1.0 eq.) in dioxane (1.0 mL) and H2O (0.2 mL) were added OsO4 (19.5 mg, 0.07 mmol, 0.1 eq.) and NMO (89.7 mg, 0.76 mmol, 1.0 eq.). The mixture was stirred at 20 °C for 1 h. TLC (PE/EA=2/1) indicated that the reaction was complete. The crude Intermediate 1-10 in solution was used for next step without further purification. [0245] To the above solution was added NaIO4 (652 mg, 3.05 mmol, 5.0 eq.), and the mixture was then stirred at 20 °C for 1 h. TLC (PE/EA=2/1) indicated that the reaction was complete. The reaction mixture was quenched by addition of saturated Na2SO3 solution (10 mL) at 25 °C, and extracted with EA (10mL X 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=30/1 to 3/1) to give Intermediate 1-11 (130 mg, 81% yield) as a yellow solid. LCMS: ESI-MS: m/z 263.9 [M+H]+. [0246] 1.10 Preparation of Intermediate 1-12:
Figure imgf000112_0003
[0247] To a solution of Intermediate 1-11 (130 mg, 0.49 mmol, 1.0 eq.) in THF (3.0 mL) was added NaBH4 (38 mg, 0.99 mmol, 2.0 eq.). The mixture was stirred at 20 °C for 1 h. TLC (PE/EA=3/1) indicated that the reaction was complete. The reaction mixture was quenched by H2O (15 mL) at 20 °C. The resulting solution was extracted with EA (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=50/1 to 2/1) to give Intermediate 1-12 (120 mg, 91.6% yield) as a yellow oil. LCMS: ESI-MS: m/z = 265.9 [M+H]+. [0248] 1.11 Preparation of Intermediate 1-13:
Figure imgf000112_0001
[0249] To a solution of Intermediate 1-12 (100 mg, 0.38 mmol, 1.0 eq.) in DMF (2.0 mL) were added TIPSCl (87.2 mg, 0.45 mmol, 1.20 eq.) and imidazole (77.0 mg, 1.13 mmol, 3.00 eq.). The mixture was stirred at 25 °C for 1 h. LCMS trace indicated that Intermediate 1-12 was consumed completely. The reaction mixture was diluted with H2O and extracted with EA (10 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 10/1) to give Intermediate 1-13 (148 mg, 93.1% yield) as a yellow oil. LCMS: ESI-MS: m/z = 421.9 [M+H]+. [0250] 1.12 Preparation of Intermediate 1-14:
Figure imgf000112_0002
[0251] To a solution of Intermediate 1-13 (130 mg, 0.31 mmol, 1.0 eq.) in MeOH (3.0 mL) and H2O (0.5 mL) was added NaOH (24.7 mg, 0.62 mmol, 2.0 eq.). The mixture was stirred at 50 °C for 2 h. TLC (PE/EA=5/1) indicated that Intermediate 1-13 was consumed completely. The reaction mixture was acidified to pH=5~6 by HCl solution (0.5 M) and extracted with EA (20mL X 3). The combined organic layers were washed with brine, and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Acid 1-14 (110 mg, 87.5%yield) was obtained as a yellow solid. LCMS: ESI-MS: m/z = 407.9 [M+H]+. 1H-NMR (400 MHz, CD3OD), δ= 8.10-8.06 (m, 2H), 7.68 (s, 1H), 5.13 (s, 2H), 4.08 (s, 3H), 1.22-1.17 (m, 3H), 1.09 (s, 18H). [0252] 1.13 Preparation of Intermediate 1-16:
Figure imgf000113_0001
[0253] A mixture of Intermediate 1-15 (7.0 g, 30.76 mmol, 1.0 eq.), (4-fluorophenyl)boronic acid (8.6 g, 61.52 mmol, 2.0 eq.), Pd(PPh3)4 (1.78 g, 1.54 mmol, 0.05 eq.), and K2CO3 (8.5 g, 61.52 mmol, 2.0 eq.) in dioxane (40 mL) and H2O (20 mL) was degassed and purged with N2 for 3 times. Then the reaction mixture was placed in a 100 mL sealed tube and stirred at 125 °C for 12 h. LC-MS trace showed that Intermediate 1-15 was consumed completely. (Note: 5 reactions could be carried out in parallel). The reaction mixture was acidified to pH=5~6 by adding 2.0 M HCl solution. The resulting solution was extracted with EA (200 mL X 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 4/1) to give crude Intermediate 1-16 (~40 g, crude) as a yellow solid. LCMS: ESI-MS: m/z 287.9 [M+H]+. [0254] 1.14 Preparation of Intermediate 1-17:
Figure imgf000113_0002
[0255] To a solution of Intermediate 1-16 (70 g, 243.7 mmol, 1.0 eq.) in H2O (200 mL) and MeOH (300 mL) were added I2 (185.6 g, 731.2 mmol, 3.0 eq.) and Na2CO3 (77.5 g, 731.17 mmol, 3.0 eq.). The mixture was stirred at 25 °C for 12 h. LCMS indicated that Intermediate 1- 16 was consumed completely. The reaction mixture was quenched by saturated sodium sulfite solution and acidified to pH=5~6 by addition of 2.0 M HCl solution. The resulting solution was extracted with EA (400 mL X 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=50/1 to 10/1). Intermediate 1-17 (75 g, 74.5% yield) was obtained as a yellow solid. LCMS: ESI-MS: m/z 413.9 [M+H]+. [0256] 1.15 Preparation of Intermediate 1-18:
Figure imgf000114_0001
[0257] A mixture of Intermediate 1-17 (25 g, 60.52 mmol, 1.0 eq.), Na2CO3 (51.3 g, 484.13 mmol, 8.0 eq.), NaBr (3.11 g, 30.26 mmol, 972.90 ^L, 0.5 eq.), and 3-chloro-2-methyl-prop-1- ene (38.4 g, 423.62 mmol, 41.25 mL, 7 eq.) in MeCN (100 mL) was stirred at 85 °C for 12 h. NaHCO3 and 3-chloro-2-methyl-prop-1-ene were added in portions until TLC (PE/EA=5/1) showed completion of the reaction. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=0/1 to 10/1). Intermediate 1-18 (~25 g, 88.4% yield) was obtained as a colorless oil. LCMS: ESI-MS: m/z 467.9 [M+H]+. [0258] 1.16 Preparation of Intermediate 1-19:
Figure imgf000114_0002
[0259] To a solution of Intermediate 1-18 (2.1 g, 4.49 mmol, 1.0 eq.) in toluene (50 mL) were added Q-Phos (319 mg, 0.45 mmol, 0.1 eq.) and Pd2(dba)3 (329 mg, 0.36 mmol, 0.08 eq.). The mixture was stirred at 110 °C for 2 h. TLC (PE/EA=5/1) showed that the reaction was complete and the mixture was concentrated under reduced pressure. The residue was purified by flash column (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% EA/PE gradient at 50 mL/min) to give the desired Intermediate 1-19 (2.1 g, crude, containing some Q-Phos) as a brown oil. LCMS: ESI-MS: m/z 467.9 [M+H]+. [0260] 1.17 Preparation of Intermediate 1-20:
Figure imgf000115_0001
[0261] To a solution of Intermediate 1-19 (2.0 g, 4.28 mmol, 1.0 eq.) in DMF (20 mL) was added tetrabutylammonium acetate (5.16 g, 17.12 mmol, 4.0 eq.). The resulting mixture was stirred at 100 °C for 4 h. TLC showed the reaction was complete. The reaction mixture was partitioned between EA (100 mL) and water (100 mL). The organic phase was separated, and the aqueous was extracted with EA (50 mL X 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% EA/PE gradient at 30mL/min) to give Intermediate 1-20 (1.50 g, 87.8% yield) as a pale brown oil. [0262] 1.18 Preparation of Intermediate 1-21:
Figure imgf000115_0002
[0263] To a solution of Intermediate 1-20 (1.5 g, 3.76 mmol, 1.0 eq.) in DCM (20 mL) was added DMP (3.19 g, 7.52 mmol, 2.0 eq.). The resulting mixture was stirred at 25 °C for 2 h. LCMS trace showed that the reaction was complete. The reaction mixture was quenched by addition of saturated Na2SO3 solution (30 mL). The resulting solution was extracted with EA (50 mL X 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% EA/PE gradient at 40 mL/min) to give Intermediate 1-21 (1.4 g, 93.7% yield) a colorless oil. LCMS: ESI-MS: m/z 416.1 [M+H3O]+. [0264] 1.19 Preparation of Intermediate 1-22:
Figure imgf000116_0001
[0265] Methyltriphenylphosphonium bromide (2.7 g, 7.55 mmol, 1.2 eq.), and t-BuOK (776 mg, 6.92 mmol, 1.10 eq.) in THF (20 mL) were charged in a 100 mL bottle flask, and then a solution of Intermediate 1-21 (2.50 g, 6.29 mmol, 1.0 eq.) in THF (5.0 mL) was added . The resulting mixture was stirred at 40 °C for 2 h. TLC showed that Intermediate 1-21 was consumed completely. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% EA/PE gradient at 30 mL/min) to give Intermediate 1-22 (1.8 g, 67.7% yield, 93.6% purity) as a white solid. LCMS: ESI-MS: m/z 353.9 [M+H]+. [0266] 1.20 Preparation of Intermediate 1-23:
Figure imgf000116_0002
[0267] To a solution of Intermediate 1-22 (1.8 g, 4.55 mmol, 1.0 eq.) in MeOH (10 mL) was added K2CO3 (630 mg, 4.55 mmol, 1.0 eq.). The mixture was stirred at 30 °C for 1 h. TLC indicated that Intermediate 1-22 was consumed completely. Then the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0~30% EA/PE gradient at 35 mL/min) to give Intermediate 1-23 (1.6 g, 99.5% yield) as a white solid. [0268] 1.21 Preparation of Intermediate 1-24:
Figure imgf000117_0001
[0269] To a solution of Intermediate 1-23 (1.5 g, 4.25 mmol, 1.0 eq.) in MeCN (14 mL) and H2O (1.8 mL) were added TEMPO (334 mg, 2.12 mmol, 0.5 eq.), PhI(OAc)2 (4.10 g, 12.74 mmol, 3.0 eq.) and NH4OAc (2.29 g, 29.72 mmol, 7.0 eq.). The resulting mixture was stirred at 50 °C for 1 h. TLC showed that the reaction was complete and the reaction was quenched with aqueous NaHCO3 (20 mL). The mixture was extracted with EA (30 mL X 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% EA/PE gradient at 30 mL/min) to give Intermediate 1-24 (1.3 g, 87.8% yield) as a white solid. LCMS: ESI-MS: m/z 348.9 [M+H]+. [0270] 1.22 Preparation of Intermediate 1-25:
Figure imgf000117_0002
[0271] A mixture of Intermediate 1-24 (1.3 g, 3.73 mmol, 1.0 eq.), AD-mix-beta (10.0 g, 12.83 mmol, 3.44 eq.), methanesulfonamide (426 mg, 4.48 mmol, 1.2 eq.) in t-BuOH (20 mL) and H2O (20 mL) was stirred at 0 °C for 48 h. TLC (PE/EA=1/1) indicated that Intermediate 1- 24 was consumed completely and one new spot was formed. The reaction mixture was quenched with aqueous Na2SO3 (30 mL) and extracted with EA (40 mL X 2). The combined organic layers were washed with brine (10 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0~80% ethyl acetate/PE gradient at 30 mL/min). Intermediate 1-25 (1.35 g, 94.6% yield) was obtained as a colorless oil. LCMS: ESI-MS: m/z 382.9 [M+H]+. [0272] 1.23 Preparation of Intermediate 1-27:
Figure imgf000118_0001
[0273] To a solution of Intermediate 1-25 (1.35 g, 3.53 mmol, 1.0 eq.) in THF (100 mL) were added Et3N (1.07 g, 10.59 mmol, 3.0 eq.) and MsCl (404 mg, 3.53 mmol, 1.00 eq.). The reaction mixture was stirred at 20 °C for 1 h. TLC (PE/EA=2/1) indicated that Intermediate 1-25 was consumed completely. The reaction mixture was filtered and the filtrate was concentrated to give a residue as colorless oil. The crude 1-26 (1.63 g) was used for the next step without further purification. [0274] To a solution of crude Intermediate 1-26 (1.60 g, 3.48 mmol, 1.0 eq.) in MeOH (60.00 mL) was added a solution of NH3 in MeOH (7 M, 60 mL). The mixture was stirred at 20 °C for 17 h. LC-MS trace showed that Intermediate 1-26 was consumed completely and one main peak with the desired MS signal was detected. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA = 2/1 to 0/1). Intermediate 1-27 (1.10 g, 78 % yield) was obtained as a white solid. LCMS: ESI-MS: m/z 381.9 [M+H]+. [0275] 1.24 Preparation of Intermediate 1-28:
Figure imgf000118_0002
[0276] To a solution of Intermediate 1-14 (55 mg, 0.135 mmol, 1.0 eq.) in DCM (3 mL) were added HATU (62 mg, 0.16 mmol, 1.2 eq.) and DIPEA (52 mg, 0.4 mmol, 3.0 eq.). The reaction mixture was stirred at 20 °C for 30 min before Intermediate 1-27 (51.46 mg, 134.95 ^mol, 1 eq.) was added. The mixture was stirred at 20 °C for additional 30 min. LC-MS trace showed that the reaction was complete. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, EA/PE = 1/1) to give Intermediate 1-28 (98 mg, 95% yield) as a yellow oil. LCMS: ESI-MS: m/z 771.3 [M+H]+. [0277] 1.25 Preparation of Intermediate 1-29:
Figure imgf000119_0001
[0278] To a solution of Intermediate 1-28 (98 mg, 0.13 mmol) in THF (3 mL) was added TBAF (1 M in THF, 0.2 mL, 1.5 eq.). The mixture was stirred at 20 °C for 1 h. TLC (PE/EA=1/1) indicated that Intermediate 1-28 was consumed completely. The reaction mixture was diluted with H2O (10 mL) and extracted with EA (10 mL X 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 15:1) to give Intermediate 1-29 (71 mg, 88.2% yield, 99.12% purity) as a white solid.1H NMR (400MHz, CD3OD) δ= 8.32-8.27 (m, 2H), 7.91-7.87 (m, 2H), 7.70 (d, J=33.6 Hz, 1H), 7.55 (d, J=28.4 Hz, 1H), 7.18-7.13 (m, 2H), 5.05-5.02 (dd, J=2.4 Hz, 9.6 Hz, 1H), 4.88 (s, 2H), 4.63 (d, J=9.6 Hz, 1H), 4.56-4.51 (m, 1H), 4.11-4.06 (dd, J=6.0 Hz, 14.0 Hz, 1H) 3.99 (d, J=5.6 Hz, 2H), 1.77 (d, J=8.8 Hz, 3H). LCMS: ESI-MS: m/z615.1 [M+H]+. [0279] 1.26 Preparation of Compound 1d:
Figure imgf000120_0001
[0280] To a solution of Intermediate 1-29 (71 mg, 0.11 mmol) in H2O (1 mL) and MeOH (3 mL) were added H2O2 (0.05 mL, 30% purity) and K2CO3 (34 mg, 0.24 mmol, 2.2 eq.). The mixture was stirred at 40 °C for 1 h. TLC indicated that Intermediate 1-29 was consumed completely. The reaction mixture was diluted by H2O (20 mL) and extracted with EA (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM/MeOH = 15/1) and then by prep-HPLC twice (column: Xtimate C18 150*25mm*5µm; mobile phase: [water (0.225%FA)-ACN]; B%: 42%-72%, 13min) to give Compound 1d (which was eluted as the second peak during the HPLC purification). (5.3 mg, 10.3% yield, 100% purity, 95% de).1H NMR (400MHz, CD3OD) ^ = 8.37-8.30 (m, 2H), 7.85 (d, J=10.4 Hz, 1H), 7.83 (s, 1H), 7.64 (s, 1H), 7.27 (s, 1H), 7.18-7.14 (t, J=8.8 Hz, 2H), 5.16 (d, J=9.2 Hz, 1H), 4.90 (s, 2H), 4.56-4.48 (m, 2H), 4.13 (d, J=16.0 Hz, 1H), 3.98 (s, 3H), 1.65 (s, 3H). LCMS: ESI-MS: m/z 633.0 [M+H]+. Example 2: Synthesis of Compound 2d [0281] 2.1 Preparation of Intermediate 2-2:
Figure imgf000120_0002
[0282] To a solution of 4-bromo-2-fluoro-1-nitro-benzene 2-1 (12.0 g, 54.5 mmol, 1.0 eq.) and cyclopropanol (3.8 g, 65.5 mmol, 1.2 eq.) in THF (100 mL) was added NaH (2.6 g, 65.5 mmol, 60% purity, 1.2 eq.) at 0°C. The mixture was stirred at 25°C for 120 min. The reaction mixture was quenched by water at 25 °C and concentrated under reduced pressure to remove THF, and then the residue was recrystallized from water to give the pure product. Intermediate 2- 2 (13.6 g, 97% yield) was obtained as a yellow solid. [0283] 2.2 Preparation of Intermediate 2-3:
Figure imgf000121_0001
[0284] To a solution of Intermediate 2-2 (10.0 g, 38.8 mmol, 1 eq.) in THF (60 mL) and H2O (30 mL) were added Fe (17.3 g, 310.0 mmol, 8 eq.) and NH4Cl (16.6 g, 310.0mmol, 8 eq.). The mixture was stirred at 70 °C for 30 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 10/1). Intermediate 2-3 (7.9 g, 87.58% yield, 97.98% purity) was obtained as a yellow oil.1H NMR (400MHz, CDCl3) ^ = 7.23 (d, J=2 Hz 1H), 6.89-6.86 (dd, J=8.4 Hz, 2 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 3.7 (m, 1H), 3.49 (brs, 2 H), 0.81-0.76 (m, 4H). LCMS: ESI-MS: m/z230.0/232.0 [M+H]+. [0285] 2.3 Preparation of Intermediate 2-4:
Figure imgf000121_0002
[0286] To a solution of Intermediate 2-3 (2.5 g, 11.0 mmol, 1 eq.) in HCl (aq., 1.0 N, 60 mL) was added prop-2-enal (922 mg, 16.5 mmol, 1.1 mL, 1.5 eq.) at 0°C slowly. The resulting mixture was stirred at 80°C for 0.5 hour. Then the mixture was stirred at 100 °C for another 1 hour. The reaction mixture was neutralized with saturated NaHCO3 solution, and then extracted with EA (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=5/1 to 1:1). Intermediate 2-4 (3.2 g, 54.15% yield, 97.98% purity) was obtained as a yellow oil. LCMS: ESI-MS: m/z 264.0/266.0 [M+H]+. [0287] 2.4 Preparation of Intermediate 2-5:
Figure imgf000122_0001
[0288] To a solution of Intermediate 2-4 (3.1 g, 11.7 mmol, 1 eq.) in DMSO (7 mL) and EtOH (20 mL) were added Pd(OAc)2 (527 mg, 2.35 mmol, 0.2 eq.), DPPP (1.94 g, 4.7 mmol, 0.4 eq.), and TEA (7.1 g, 70.4 mmol, 9.8 mL, 6 eq.). The suspension was degassed and purged with CO for 3 times. The mixture was stirred under CO (50 Psi) at 80°C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (80 mL X 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=3/1 to 1:1). Intermediate 2-5 (2.7 g, 84.70% yield, 94.73% purity) was obtained as a light yellow solid. LCMS: ESI-MS: m/z 258.2 [M+H]+. [0289] 2.5 Preparation of Intermediate 2-6:
Figure imgf000122_0002
[0290] To a solution of Intermediate 2-5 (2.4 g, 9.3 mmol, 1 eq.) in EtOH (10 mL) and H2O (10 mL) was added NaOH (1.1 g, 28 mmol, 3 eq.). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with water (50 mL) and acidified with HCl (1 M) to pH=5~6. The resulting solution was extracted with EA (200 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give Intermediate 2-6 (1.95 g, 90% yield, 98.7% purity) as a white solid.1H NMR (400MHz, DMSO- d6) ^ =13.2 (brs, 1H), 8.90-8.89 (m, 1H), 8.48 (d, J=8.4 Hz, 1H), 8.21 (d, J=0.8 Hz 1H), 7.88 (d, J=1.0 Hz 1H), 7.60-7.58 (m, 1H), 4.07-4.03 (m, 1H), 0.90-0.74 (m, 4H). LCMS: ESI-MS: m/z 230.1 [M+H]+. [0291] 2.6 Preparation of Intermediate 2-8:
Figure imgf000123_0001
[0292] Intermediate 2-7 was prepared essentially as described in Example 1 for the preparation of Compound 1d. Intermediate 2-7 (16.0 g, 41.9 mmol) was subjected to SFC separation (column: (S, S) WHELK-O1 (250mm*50mm, 10um); mobile phase: [0.1% NH3H2O IPA]; B%: 25%-25%, min) to obtain fraction 2 as the desired isomer 2-8 in isopropanol solution. The solution was concentrated to dryness and lyophilized to give Intermediate 2-8 as a white powder (6.9 g, 41.6% yield, 96.5% de). LCMS: ESI-MS: m/z 381.9 [M+H]+. [0293] 2.7 Preparation of Intermediate 2-9:
Figure imgf000123_0002
[0294] To a mixture of Intermediate 2-8 (3 g, 7.9 mmol, 1.0 eq.) in DMSO (18 mL) were added K2CO3 (3.3 g, 23.6 mmol, 3 eq.) and H2O2 (1.5 mL, 30% purity, 2 eq.). The mixture was stirred at 25 °C for 40 min. LCMS trace showed that the reaction was complete. The mixture was diluted with H2O (200 mL) and extracted with EA (100 mL X 2). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Intermediate 2- 9 (2.9 g, 96% yield) was obtained as a white solid and used for next step without further purification. LCMS: ESI-MS: m/z 400.0 [M+H]+. [0295] 2.8 Preparation of Compound 2d:
Figure imgf000123_0003
[0296] A mixture of Intermediate 2-6 (207 mg, 0.9 mmol, 1.2 eq.), HATU (288 mg, 0.76 mmol, 1.0 eq.), and DIPEA (243 mg, 1.9 mmol, 2.5 eq.) in DMF (3 mL) was stirred at 25 °C for 10 min. Then Intermediate 2-9 (300 mg, 0.76 mmol, 1 eq.) was added and the mixture was stirred at 25 °C for 20 min. LCMS trace showed that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with EA (30 mL X 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions, column: Xtimate C18150*25mm*5µm; mobile phase: [water (0.225%FA)-ACN]; B%: 40%-70%, 7 min) to give Compound 2d (275 mg, 59.64% yield, 99.47% purity) as a white solid.1H NMR (400MHz, CD3OD) ^ = 8.79 (d, J=4.4 Hz 1H), 8.23-8.20 (m, 3H), 7.84 (s, 1H), 7.58 (s, 1H), 7.55-7.52 (m, 1H), 7.11 (t, J=8.8 Hz 1H), 5.14 (d, J=9.2 Hz 1H), 4.63-4.58 (m, 1H), 4.46 (d, J=8.8 Hz, 1H), 3.95-3.92 (d, J=13.6 Hz, 1H), 3.86-3.83 (m, 1H), 1.65 (s, 3H), 0.81-0.76 (m, 4H). LCMS: ESI-MS: m/z 611.1 [M+H]+. Example 3: Synthesis of Compound 3d [0297] 3.1 Preparation of Intermediate 3-3:
Figure imgf000124_0001
[0298] To a solution of Compound 3-1 (300 mg, 1.66 mmol, 1 eq.) in HCl (aq., 12 mL, 3 M) was added Compound 3-2 (348 mg, 4.97 mmol, 3 eq.). The mixture was stirred at 100 °C for 1 h. The reaction mixture was neutralized with saturated NaHCO3 solution to pH=7~8, and then extracted with EA (80 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1/1 to 0:1). Intermediate 3-3 (285 mg, 74.4% yield) was obtained as a colorless oil. 1H NMR (400MHz, CDCl3) ^ = 8.86 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.558 (s, 1H), 4.14 (s, 3H), 3.99 (s, 3 H), 2.55 (s, 3H). LCMS: ESI-MS: m/z 232.2 [M+H]+. [0299] 3.2 Preparation of Compound 3d:
Figure imgf000125_0001
[0300] Intermediate 3-5 was prepared essentially as described in Example 2 for the preparation of Compound 2d. Compound 3d was prepared essentially as described in Example 2 for the preparation of Compound 2d by using ester 3-3 and amine 3-5 as starting materials. Finally, Compound 3d (25 mg) was obtained as white solid.1H NMR (400MHz, DMSO-d6) ^ = 8.84 (brs, 1H), 8.72 (s, 2H), 8.26-8.22 (m, 2H), 8.01 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.55 (d, J=9.2 Hz 1H), 7.36-7.22 (m, 4H), 5.15 (d, J=9.2 Hz, 1H), 4.36 (d, J=9.2 Hz, 1H), 4.24-4.20 (m, 1H), 4.13-4.08 (m, 1H), 3.90 (s, 3H), 2.43 (s, 3H), 1.47 (s, 3H). LCMS: ESI-MS: m/z 599.1 [M+H]+. Example 4: Synthesis of Compound 4d [0301] 4.1 Preparation of Intermediate 4-2:
Figure imgf000125_0002
[0302] Intermediate 4-1 was prepared essentially as described in Example 1 for the preparation of Compound 1d. A mixture of Intermediate 4-1 (5 g, 21.3 mmol, 1 eq.), bromocyclopropane (25.7 g, 213 mmol, 17.0 mL, 10 eq.), Cs2CO3 (20.8 g, 63.9 mmol, 3 eq.), and KI (706 mg, 4.25 mmol, 0.2 eq.) in DMA (100 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 140 °C for 15 h under N2 atmosphere. TLC (PE/EA=3/1) indicated that the desired compound with lower polarity was formed. The reaction mixture was diluted with water (200 mL) and extracted with EA (100 mL X 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Three bathes of this reaction were combined together and purified by column chromatography (SiO2, PE/EA=20/1 to 10:1). Intermediate 4-2 (3.8 g, ~95% purity) was obtained as a white solid and then subjected to further prep-HPLC purification (column: Phenomenex luna (2) C18 250*5010 ^; mobile phase: [water (0.1%TFA)-ACN]; B%: 35%-60%, 20.5min) to give Intermediate 4-2(3.1 g, 100% purity) as white solid. LCMS: ESI-MS: m/z 599.1 [M+H]+. [0303] 4.2 Preparation of Compound 4d:
Figure imgf000126_0001
[0304] Intermediate 4-4 was prepared essentially as described in Example 2 for the preparation of Compound 2d. Compound 4d was prepared essentially as described in Example 2 for the preparation of Compound 2d by using ester 4-2 and amine 4-4 as the starting materials. Finally, Compound 4d (24 mg) was obtained as white solid.1H NMR (400MHz, DMSO-d6) ^ = 8.89 (d, J=2.8 Hz 1H), 8.68 (br, 1H), 8.27-8.24 (m, 2H), 8.2-8.17 (dd, J=9.2 Hz, 2.8 Hz , 1H), 7.91 (d, J=1.6 Hz 1H), 7.86 (s, 1H), 7.69 (d, J=1.2 Hz 1 H), 7.54 (brs, 1 H), 7.37 (brs, 1 H), 7.33 (t, J=9.2 Hz, 2 H), 7.25 (s, 1 H), 5.17 (d, J=8.8 Hz 1 H), 4.39 (d, J=8.8 Hz 1 H), 4.22-4.21 (m, 1H), 4.17-4.16 (m, 1H), 4.01-3.98 (m, 1H),1.50 (s, 3H), 0.84-0.80 (m, 2H), 0.76-0.72 (m, 2H). LCMS: ESI-MS: m/z 629.2 [M+H]+. Example 5: Synthesis of Compound 5d [0305] 5.1 Preparation of Intermediate 5-2:
Figure imgf000126_0002
[0306] Intermediate 5-1 was prepared essentially as described in Example 2 for the preparation of Compound 2d. To a mixture of Intermediate 5-1 (600 mg, 2.33 mmol, 1 eq.) in AcOH (8 mL) was added NBS (457 mg, 2.57 mmol, 1.1 eq.). The mixture was stirred at 90 °C for 12 h. TLC showed the formation of desired product and incomplete consumption of Intermediate 5-1. The reaction mixture was neutralized with aq. NaHCO3 solution and extracted with EA (30 mL X 2). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=20/1 to 1/1) to give the desired Intermediate 5-2 (230 mg, 29.3% yield) as a yellow solid. LCMS: ESI-MS: m/z 336.0/338.0 [M+H]+. [0307] 5.2 Preparation of Intermediate 5-3:
Figure imgf000127_0001
[0308] A mixture of Intermediate 5-2 (100 mg, 0.3 mmol, 1.0 eq.), CuCl (206 mg, 2.08 mmol, 7 eq.), and pyridine (165 mg, 2.08 mmol, 7 eq.) in DMA (2 mL) was taken up into a microwave tube. The sealed tube was heated at 135 °C for 180 min under microwave irradiation. LCMS trace showed that the desired product was formed. The reaction mixture was quenched by saturated NH4Cl solution (20 mL), diluted with water (20 mL), and extracted with EA (20 mL X 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE/EA=3/1) to give Intermediate 5-3 (65 mg, 74.90% yield) as a white solid. LCMS: ESI-MS: m/z 292.0 [M+H]+. [0309] 5.3 Preparation of Compound 5d:
Figure imgf000127_0002
[0310] Intermediate 5-5 was prepared essentially as described in Example 2 for the preparation of Compound 2d. Compound 5d was prepared essentially as described in Example 2 for the preparation of Compound 2d by using ester 5-3 and amine 5-5 as starting materials. Finally, Compound 5d (11 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^ = 8.73 (d, J=2.4 Hz 1H), 8.26-8.22 (m, 2H), 8.19 (d, J=2.4 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J=1.6 Hz 1 H), 7.58 (d, J=1.6 Hz 1 H), 7.33 (t, J=8.8 Hz, 2 H), 5.16 (d, J=9.2 Hz 1 H), 4.64 (d, J=13.6 Hz 1 H), 4.48 (d, J=9.2 Hz 1H), 3.94 (d, J=13.6 Hz 1H), 3.89-3.86 (m, 1H),1.67 (s, 3H), 0.83- 0.78 (m, 4H), LCMS: ESI-MS: m/z 645.1 [M+H]+. Example 6: Synthesis of Compound 6d [0311] 6.1 Preparation of Intermediate 6-2:
Figure imgf000128_0002
[0312] Intermediate 6-1 was prepared essentially as described in Example 5 for the preparation of Compound 5d. A mixture of Intermediate 6-1 (200 mg, 0.59 mmol, 1.0 eq.), trifluoro-potassio-vinyl-boron(1-) (638 mg, 4.76 mmol, 8 eq.), Pd(dppf)Cl2 (43 mg, 0.06 mmol, 0.10 eq.), Cs2CO3 (388 mg, 1.19 mmol, 2 eq.) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then stirred at 90°C for 5 h under N2 atmosphere. TLC (PE/EA=3/1) indicated that Intermediate 6-1 was consumed completely. The solution was poured into H2O (20 mL) and extracted with EA (20 mL X 3). The combined organic phase was washed with saturated brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2.PE/EA=3/1) to give Intermediate 6-2 (145 mg, 77.4% yield, 90% purity) as light yellow oil. LCMS: ESI-MS: m/z 284.1 [M+H]+. [0313] 6.2 Preparation of Intermediate 6-3:
Figure imgf000128_0001
[0314] To a solution of Intermediate 6-2 (145 mg, 0.51 mmol, 1 eq.) in dioxane (3 mL) and H2O (1 mL) were added NMO (120 mg, 1.02 mmol, 2 eq.) and OsO4 (13 mg, 0.051 mmol, 0.1 eq.). The resulting mixture was stirred at 20°C for 1 h. TLC indicated that Intermediate 6-2 was consumed completely. The reaction mixture was quenched by saturated Na2SO3 solution, and extracted with EA (50mL X 3). The organic phase was concentrated under reduced pressure to give a residue (170 mg, crude) as yellow oil. To a solution of the residue in dioxane (2 mL) and H2O (0.5 mL) was added NaIO4 (334 mg, 1.56 mmol, 3 eq.). The mixture was stirred at 20°C for 1 h. The reaction mixture was quenched by saturated Na2SO3 solution (50mL), and extracted with EA (50mL X 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=30/1 to 1/1) to give Intermediate 6-3 (142 mg, 86.8% yield, 92% purity) as light yellow solid. LCMS: ESI-MS: m/z 286.1 [M+H]+. [0315] 6.3 Preparation of Intermediate 6-4:
Figure imgf000129_0001
[0316] To a solution of Intermediate 6-3 (120 mg, 0.42 mmol, 1 eq.) in DCM (2 mL) was added DAST (339 mg, 2.10 mmol, 0.28 mL, 5 eq.) at -78°C. The mixture was stirred at 20 °C for 1 h. TLC (PE/EA=5/1) indicated that Intermediate 6-3 was consumed completely. The reaction mixture was quenched by saturated NaHCO3 solution (30 mL), and extracted with EA (20 mL X 3). The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=30/1 to 2/1) to give Intermediate 6-4 (81 mg, 62% yield) as light yellow solid. LCMS: ESI-MS: m/z 308.1 [M+H]+. [0317] 6.4 Preparation of Compound 6d:
Figure imgf000130_0001
[0318] Intermediate 6-6 was prepared essentially as described in Example 2 for the preparation of Compound 2d. Compound 6d was prepared essentially as described in Example 2 for the preparation of Compound 2d by using ester 6-4 and amine 6-6 as starting materials. Finally, Compound 6d (41 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^ = 8.93 (d, J=1.6 Hz 1H), 8.38 (d, J=1.6 Hz 1H), 8.25-8.22 (m, 2H), 7.86 (s, 1H), 7.80 (d, J=1.6 Hz 1H), 7.67 (d, J=1.6 Hz 1 H), 7.13 (t, J=9.2 Hz, 2 H), 7.04 (t, J=55.6 Hz, 1 H), 5.17 (d, J=9.2 Hz 1 H), 4.65 (d, J=14.0 Hz 1 H), 4.48 (d, J=9.2 Hz 1H), 3.96 (d, J=14.0 Hz 1H), 3.91-3.88 (m, 1H),1.67 (s, 3H), 0.85-0.78 (m, 4H). LCMS: ESI-MS: m/z 661.2 [M+H]+. Example 7: Synthesis of Compound 7b [0319] 7.1 Preparation of Intermediate 7-3:
Figure imgf000130_0002
[0320] Intermediate 7-1 was prepared essentially as described in Example 1 for the preparation of Compound 1d. To a solution of Intermediate 7-1 (40 g, 96.8 mmol, 1.0 eq.) and Intermediate 7-2 (36.3 g, 290.4 mmol, 33.6 mL, 3.0 eq.) in DMF (400 mL) was added Na2CO3 (30.8 g, 290.4 mmol, 3.0 eq.) in one portion. The mixture was stirred at 80~90 °C for 1 hour. TLC (PE: EA=5:1) showed that the reaction was completed. The reaction mixture was filtered and the filtrate was diluted with EA (500 mL). The organic phase was washed with water (0.5 L), and brine (500 mL), and dried over anhydrous Na2SO4. The resulting solution was concentrated at low pressure. The residue was purified by silica gel chromatography (SiO2, PE: EA=5:1) to give Intermediate 7-3 (41 g, 82% yield) as a yellow oil. MS: m/z = 295.9 [M+H]+. [0321] 7.2 Preparation of Intermediate 7-4:
Figure imgf000131_0001
[0322] To a solution of Intermediate 7-3 (30 g, 60.0 mmol, 1.0 eq.) in DMF (300 mL) was added tetrabutylammonium acetate (90 g, 300 mmol, 5.0 eq.) in one portion. The resulting mixture was stirred at 80~90 °C for 2 hours. LCMS trace showed that the reaction was completed. The mixture was cooled to 20 °C and poured into water (1 L). The aqueous phase was extracted with ethyl acetate (500 mL X 3). The combined organic phase was washed with brine (500 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=5/1) to give Intermediate 7-4 (28 g, 89% yield) was obtained as yellow oil. MS: m/z = 525.9 [M+H]+. [0323] 7.3 Preparation of Intermediate 7-5:
Figure imgf000131_0002
[0324] To a solution of Intermediate 7-4 (12 g, 22.85 mmol, 1.0 eq.) in toluene (150 mL) was Pd2(dba)3 (2.51 g, 2.74 mmol, 0.12 eq.) and Q-Phos (1.95 g, 2.74 mmol, 0.12 eq.) in one portion under N2. The mixture was stirred at 130 °C for 4 hours. TLC (PE: EA=5:1) showed that the reaction was completed. Two reactions were carried in parallel and the resulting mixture was combined, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1) to give Intermediate 7-5 (20.4 g, 85% yield) as Black Brown oil. MS: m/z 525.9 [M+H]+. [0325] 7.4 Preparation of Intermediate 7-6:
Figure imgf000132_0001
[0326] To a solution of Intermediate 7-5 (20 g, 38.1 mmol, 1.0 eq.) in DCM (200 mL) was added DMP (32.3 g, 76.2 mmol, 2.0 eq.) in one portion. The mixture was stirred at 25°C for 30 min. LCMS trace showed that the reaction was completed. The reaction mixture was quenched by saturated Na2SO3 (aq.)/ NaHCO3 (aq.) =1:1 (300 mL) at 25°C, and then extracted with EA (150 mL X 3). The combined organic layers were washed with brine (150 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude 7-6 (20 g) as black brown oil. The crude product was used next step without further purification. MS: m/z 541.9 [M+H3O]+. [0327] 7.5 Preparation of Intermediate 7-7:
Figure imgf000132_0002
[0328] To a mixture of Intermediate 7-6 (20 g, 38.2 mmol, 1.0 eq.) in MeOH (200 mL) was added K2CO3 (15.8 g, 114.6 mmol, 3 eq.). The mixture was stirred at 20 °C for 30 min. TLC (PE: EA=3:1) showed that the reaction was completed. The mixture was poured into water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (200 mL X 3). The combined organic phase was washed with brine (200 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 3/1) to obtain Intermediate 7-7 (16 g, 87% yield) as black brown oil. MS: m/z 499.9 [M+H3O]+. [0329] 7.6 Preparation of Intermediate 7-8:
Figure imgf000133_0001
[0330] To a solution of Intermediate 7-7 (16 g, 33.2 mmol, 1.0 eq.) in toluene (200 mL) was added PBSF (30.1 g, 99.8 mmol, 17.52 mL, 3.0 eq.) at 0°C, then DBU (20.2 g, 133.0 mmol, 20.0 mL, 4.0 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20 °C for 30 min, then heated to 40 °C and stirred for 1 hour. TLC (PE: EA=3:1) showed that the reaction was completed. The mixture was cooled to 20 °C and poured into water (200 mL). The aqueous phase was extracted with EA (200 mL X 3). The combined organic phase was washed with brine (200 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 5/1) to give Intermediate 7-8 (13.5 g, 83% yield) as yellow oil. MS: m/z 501.9 [M+H3O]+. [0331] 7.7 Preparation of Intermediate 7-9:
Figure imgf000133_0002
[0332] To a solution of Intermediate 7-8 (13.5 g, 27.9 mmol, 1.0 eq.) in DMF (150 mL) was added TBAAC (42.1 g, 139.5 mmol, 5.0 eq.). The mixture was stirred at 90 °C for 1 hour. LCMS trace showed that the reaction was completed. The mixture was cooled to 20 °C and poured into water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (200 mL X 3). The combined organic phase was washed with brine (300 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to obtain Intermediate 7-9 (11.5 g, crude) as yellow oil which was used into next step without further purification. MS: m/z 434.0 [M+H3O]+. [0333] 7.8 Preparation of Intermediate 7-10:
Figure imgf000134_0001
[0334] To a solution of Intermediate 7-9 (11.5 g, 27.6 mmol, 1.0 eq.) in MeOH (150 mL) was added K2CO3 (11.4 g, 82.8 mmol, 3 eq.). The mixture was stirred at 20 °C for 30 min. TLC (PE: EA=1:1) showed that the reaction was completed and LCMS showed that the desired product was detected. The mixture was poured into water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (200 mL X 3). The combined organic phase was washed with brine (200 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 1/1) to give Intermediate 7-10 (9.5 g, 92% yield) as yellow oil. MS: m/z 392.0 [M+H3O]+. [0335] 7.9 Preparation of Intermediate 7-11:
Figure imgf000134_0002
[0336] To a mixture of Intermediate 7-10 (9.5 g, 25.4 mmol, 1.0 eq.) and DBU (15.5 g, 101.6 mmol, 15.3 mL, 4 eq.) in THF (100 mL) was added PBSF (23.1 g, 76.2 mmol, 13.4 mL, 3.0 eq.) in one portion at 0 °C. The mixture was stirred at 0 °C for 30 min. TLC (PE: EA=3:1) showed that the reaction was completed and LCMS trace showed that the desired product was detected. The mixture was poured into water (150 mL) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (150 mL X 3). The combined organic phase was washed with brine (150 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0, 1/1) to obtain Intermediate 7-11 (7.5 g, 78.9% yield) as yellow solid. MS: m/z 394.0 [M+H3O]+. [0337] 7.10 Preparation of Intermediate 7-12:
Figure imgf000135_0001
[0338] To a mixture of MePPh3I (9.3 g, 26.0 mmol, 1.3 eq.) and t-BuOK (2.7 g, 24.1 mmol, 1.2 eq.) in THF (100 mL) was added Intermediate 7-11 (7.5 g, 20 mmol, 1.0 eq.) in one portion. The mixture was stirred at 50 °C for 3 hours. TLC (PE: EA=5:1) showed that the reaction was completed. The mixture was filtered and the resulting solution was concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1) to obtain Intermediate 7-12 (6.2 g, 83% yield) as white solid. MS: m/z 374.1 [M+H]+. [0339] 7.11 Preparation of Compound 7b:
Figure imgf000135_0002
[0340] Intermediate 7-16 was prepared essentially as described in Example 1 for the preparation of Compound 1d. Compound 7b was prepared essentially as described in Example 1 for the preparation of Compound 1d by using Intermediate 7-3 and acid 7-16 as the starting materials. Finally, Compound 7b (35 mg) was obtained as white solid.1H NMR (400MHz, MeOD) ^ = 8.31-8.27 (m, 2H), 7.84 (d, J=10 Hz 1H), 7.75 (s, 1H), 7.65 (d, J=1.2 Hz 1H), 7.28 (d, J=1.6 Hz 1H), 7.17 (t, J=8.8 Hz 1H), 4.89 (s, 2 H), 4.77-4.52 (m, 7 H), 4.06 (d, J=14 Hz, 1 H), 3.97 (s, 3 H). MS: m/z = 640.2 [M+H]+. Example 8: Synthesis of Compound 8b
Figure imgf000136_0001
[0341] Intermediate 8-1 was prepared essentially as described in Example 2 for the preparation of Compound 2d. Intermediate 8-2 was prepared essentially as described in Example 7 for the preparation of Compound 7b. [0342] Compound 8b was prepared essentially as described in Example 2 for the preparation of Compound 2d by using acid 8-1 and amine 8-2 as starting materials. Finally, Compound 8b (440 mg) was obtained as white solid.1H NMR (400MHz, MeOD) ^ = 8.82 (dd, J=4.4, 1.6 Hz 1H), 8.32-8.26 (m, 3H), 7.76-7.75 (m, 2H), 7.70 (d, J=2.0 Hz, 1 H), 7.60-7.57 (m, 1H), 7.18 (t, J=9.0 Hz 2H), 4.80-4.56 (m, 7 H), 4.05 (d, J=14.0 Hz 1H), 3.93-3.89 (m, 1 H), 0.87-0.84 (m, 4 H). MS: m/z = 618.2 [M+H]+. Example 9: Synthesis of Compound 9b [0343] 9.1 Preparation of Intermediate 9-2:
Figure imgf000136_0002
[0344] Intermediate 9-1 was prepared essentially as described in Example 5 for the preparation of Compound 5d. To a mixture of Intermediate 9-1 (300 mg, 0.97 mmol, 1.0 eq.), sodium ascorbate (10 mg, 0.048 mmol, 0.05 eq.), CuI (18.4 mg, 0.97 mmol, 0.1 eq.) and N,N- dimethylethane-1,2-diamine (13 mg, 0.15 mmol, 0.15 eq.) in H2O (1.2 mL) and MeOH (2.8 mL) was added NaN3 (252 mg, 3.87 mmol, 4 e.q) in one portion at under N2. The mixture was stirred at 100°C for 48 hours. LCMS showed that the desired mass was detected. The mixture was cooled to 25 °C, and adjusted to PH>9 by adding NaOH solution (1 M) and poured into NaClO solution (10 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (30 mL X 3). The combined organic phase was washed with brine (30 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=3/1 to 0:1) to obtain Intermediate 9-2 (98 mg, 41 % yield) was obtained as yellow solid. MS: m/z 246.9 [M+H]+ [0345] 9.2 Preparation of Compound 9b:
Figure imgf000137_0001
[0346] Intermediate 9-4 was prepared essentially as described in Example 7 for the preparation of Compound 7b. Compound 9b was prepared essentially as described in Example 2 for the preparation of Compound 2d by using ester 9-2 and amine 9-4 as starting materials. Finally, Compound 9b (45 mg) was obtained as white solid.1H NMR (400MHz, MeOD) ^ = 8.39 (d, J=2.8 Hz 1H), 8.30-8.27 (m, 2H), 7.74 (s, 1H), 7.47 (d, J=1.6 Hz 1H), 7.29 (d, J=2.8 Hz 1H), 7.17 (t, J=9 Hz 2H), 7.01 (d, J=1.6 Hz 1 H), 4.79-4.60 (m, 6 H), 4.53 (d, J=10 Hz, 1 H), 4.04 (d, J=10 Hz, 1 H), 3.92 (s, 3 H). MS: m/z = 607.1 [M+H]+. Example 10 Synthesis of Compound 10b [0347] 10.1 Preparation of Intermediate 10-2:
Figure imgf000137_0002
[0348] Preparation of Intermediate 10-1 can be referred to the Reference: WO2018/39386, 2018, A1. To a solution of Intermediate 10-1 (400 mg, 1.93 mmol, 1 eq.) in EtOH (40 mL) were added Ag2SO4 (602 mg, 1.93 mmol, 1 eq.) and I2 (490 mg, 1.93 mmol, 1 eq.). The mixture was stirred at 25 °C for 1 hr .TLC (PE/EA=3/1) showed that the reaction was completed. The reaction mixture was diluted with EA (50 mL) and water (30 mL). The mixture was filtered. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness at low pressure. The crude product 10-2 (640 mg) was obtained as a brown solid and used for the next step without further purification. MS: m/z = 333.9 [M+H]+. [0349] 10.2 Preparation of Intermediate 10-4:
Figure imgf000138_0001
[0350] Intermediate 10-2 (500 mg, 1.5 mmol, 1 eq.) was dissolved in MeCN (5 mL). Then HCl solution (3 M, 2.5 mL, 5 eq.) was added. The suspension was cooled to 0°C, and a solution of NaNO2 (113 mg, 1.65 mmol, 1.1 eq) in co-solvent H2O (3 mL) and MeCN (1 mL) was added slowly at 0 oC for 1h. TLC showed that Intermediate 10-2was consumed completely. To a pre- cooled solution of HNEt2 (550 mg, 7.5 mmol, 5 eq.) and K2CO3 (1.45 g, 10.5 mmol, 7 eq.) in water (40 mL) was added above solution slowly. After addition, the resulting mixture was stirred at 0 oC for 30 min until TLC (PE/EA=3/1) showed that the reaction was completed. The reaction mixture was extracted with EA 150 mL (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient at 20 mL/min). Intermediate 10-4 (585 mg, 93.6% yield) was obtained as a yellow oil.1H NMR (400MHz, CDCl3) ^ = 8.16 (d, J=2.0 Hz 1H), 7.91 (d, J=2.0 Hz 1H), 3.92 (s, 3H), 3.81-3.74 (m 5H), 1.33-1.26 (m, 6H), 0.78-0.72 (m, 4H). MS: m/z = 418.0 [M+H] + [0351] 10.3 Preparation of Intermediate 10-5:
Figure imgf000139_0001
[0352] A mixture of Intermediate 10-4 (580 mg, 1.4 mmol, 1 eq.), trimethyl(prop-1-ynyl) silane (785 mg, 7 mmol, 5 eq.), CuI (27 mg, 1.4 ^mol, 0.1 eq.) , Pd(PPh3)2Cl2 (49 mg, 0.07 mmol, 0.05 eq.) TBAF (1 M, 2.8 mL, 2 eq.) in triethylamine (2 mL) was degassed and purged with N2 for 3 times. The reaction vessel was sealed and heated at 70 °C for 3 hr. LCMS trace showed that the reaction was completed. The mixture was diluted with H2O (30 mL), and extracted with EA (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether gradient at 30 mL/min). Intermediate 10-5 (422 mg, 92.3% yield) was obtained as a yellow oil. MS: m/z = 330.0 [M+H]+. [0353] 10.4 Preparation of Intermediate 10-6:
Figure imgf000139_0002
[0354] To a solution of Intermediate 10-5 (400 mg, 1.21 mmol, 1 eq.) in acetone (5 mL) was added HBr (1.0 g, 3.63 mmol, 0.66 mL, 30% purity, 3 eq.). The mixture was stirred at 20 °C for 5 min. TLC (PE/EA=3/1) indicated that Intermediate 10-5 was consumed completely. The yellow precipitate was filtered and dried under reduced pressure to give the crude product. Intermediate 10-6 (245 mg, crude) was obtained as a yellow solid. MS: m/z = 336.9/338.9 [M+H]+. [0355] 10.5 Preparation of Intermediate 10-7:
Figure imgf000140_0001
[0356] To a solution of Intermediate 10-6 (200 mg, 0.59 mmol, 1 eq.) in THF (20 mL) was added Pd/C (10%, 30 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 0.5 hr. TLC (PE/EA=1/1) indicated that Intermediate 10-6 was consumed completely. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue as a yellow solid. The residue was dissolved in CH2Cl2 (20 mL). The resulting solution was treated with DDQ (270 mg, 1.18 mmol, 2 eq.). The mixture was stirred at 20 °C for 0.5 hr. TLC (PE/EA=1/1) indicated that the reaction was consumed completely. The reaction mixture was purified by prep-TLC (SiO2, DCM: MeOH = 10:1). Intermediate 10-7 (46 mg, 30% yield) was obtained as a yellow solid.1H NMR (400MHz, CDCl3) ^ = 8.07 (s, 1H), 7.96 (s, 1H), 7.68 (s, 1H), 4.01 (s, 3H), 3.93-3.91 (m 1H), 2.97 (s, 3H), 1.09-1.02 (m, 4H). MS: m/z = 258.9 [M+H]+. [0357] 10.5 Preparation of Compound 10b:
Figure imgf000140_0002
[0358] Intermediate 10-9 was prepared essentially as described in Example 7 for the preparation of Compound 7b. Compound 10b was prepared essentially as described in Example 2 for the preparation of Compound 2d by using ester 10-7 and amine 10-9 as starting materials. Finally, Compound 10b (53 mg) was obtained as white solid.1H NMR (400MHz, MeOD) ^ = 8.28-8.25 (m, 2H), 7.74 (s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.56 (s, 1H), 7.14 (t, J=8.8 Hz 2H), 4.76-4.55 (m, 7 H), 4.01 (d, J=14 Hz, 1 H), 3.95-3.92 (m, 1 H), 2.82 (s, 3 H), 0.84 (m, 4 H). MS: m/z = 633.1 [M+H]+. Example 11: Synthesis of Compound 11b
Figure imgf000141_0001
[0359] Intermediate 11-1 was prepared essentially as described in Example 6 for the preparation of Compound 6d. Intermediate 11-2 was prepared essentially as described in Example 7 for the preparation of Compound 7b. Compound 11b was prepared essentially as described in Example 2 for the preparation of Compound 2d by using acid 11-1 and amine 11-2 as starting materials. Finally, Compound 11b (42 mg) was obtained as white solid.1H NMR (400MHz, MeOD) ^ = 8.93 (s, 1H), 8.38 (s, 1H), 8.32-8.28 (m, 2H), 7.80 (d, J=1.2 Hz 1H), 7.76-7.75 (m, 2H), 7.17 (t, J=8.8 Hz 2H), 7.04 (t, J=55.6 Hz 1 H), 4.88-4.57 (m, 7H) 4.05 (d, J=13.6 Hz, 1 H), 3.97-3.90 (m, 1 H), 0.86 (m, 4 H). MS: m/z = 668.2 [M+H]+. Example 12: Synthesis of Compound 12d [0360] 12.1 Preparation of Intermediate 12-3:
Figure imgf000141_0002
[0361] Preparation of Intermediate 12-1 can be referred to the reference: WO2015/26792 A1, 2015. Intermediate 12-3 was prepared essentially as described in Example 1 for the preparation of Compound 1d by using Intermediate 12-1 and (4-(trifluoromethyl)phenyl)boronic acid as starting materials. [0362] 12.2 Preparation of Intermediate 12-5:
Figure imgf000142_0001
[0363] Intermediate 12-5 was prepared essentially as described in Example 7 for the preparation of Compound 7b by using Intermediate 12-13 and 3-chloro-2-(chloromethyl)prop-1- ene as starting materials. [0364] 12.3 Preparation of Intermediate 12-6:
Figure imgf000142_0002
[0365] To a solution of Intermediate 12-5 (5.0 g, 8.69 mmol, 1 eq.) in DMF (50 mL) under nitrogen were added Pd(OAc)2 (195 mg, 0.87 mmol, 0.1 eq.), Na2CO3 (1.84 g, 17.38 mmol, 2 eq.), LiCl (369 mg, 8.69 mmol, 1 eq.) and HCOONa (1.18 g, 17.38 mmol, 2 eq.). The resulting mixture was stirred at 100 °C for 4 h. TLC (PE/EA=3/1) showed that the reaction was complete. Then the reaction was cooled to room temperature, diluted with H2O (120 mL), extracted with EA 120 mL (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% EA/PE gradient at 35 mL/min). Intermediate 12-6 (3.1 g, 79.4% yield) was obtained as a colorless oil. LCMS: ESI-MS: m/z 450.1 [M+H]+. [0366] 12.4 Preparation of Compound 12d:
Figure imgf000143_0001
[0367] Intermediate 12-13 was prepared essentially as described in Example 5 for the preparation of Compound 5d. Compound 12d was prepared essentially as described in Example 1 for the preparation of Compound 1d by using Intermediate 12-13 and acid 12-14 as starting materials. Finally, Compound 12d (48 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) δ = 8.73 (d, J=2.3 Hz, 1H), 8.43 (d, J=8.3 Hz, 2H), 8.25 (d, J=2.3 Hz, 1H), 7.96 (s, 1H), 7.76 - 7.56 (m, 4H), 5.22 (d, J=9.3 Hz, 1H), 4.65 (d, J=13.6 Hz, 1H), 4.53 (d, J=9.3 Hz, 1H), 3.99 (d, J=13.8 Hz, 1H), 3.92 - 3.82 (m, 1H), 1.70 (s, 3H), 0.97 - 0.71 (m, 4H). LCMS: ESI-MS: m/z 695.2 [M+H]+. Example 13: Synthesis of Compound 13d [0368] 13.1 Preparation of Intermediate 13-2:
Figure imgf000143_0002
[0369] Intermediate 13-1 was prepared essentially as described in Example 12 for the preparation of Compound 12d. To a solution of Intermediate 13-1 (1.2 g, 2.98 mmol, 1 eq.) in DMF (10 mL) were added TBSCl (538 mg, 3.57 mmol, 1.2 eq.) and imidazole (608 mg, 8.93 mmol, 3 eq.). The mixture was stirred at 20 °C for 15 h. TLC (PE/EA=5/1) showed that the reaction was complete. The reaction mixture was diluted with H2O (20 mL), extracted with EA 30 mL (10 mL X 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5%EA/PE gradient at 30 mL/min). Intermediate 13-2 (1.5 g, 97.4% yield) was obtained as a colorless oil. LCMS: ESI-MS: m/z 518.1 [M+H]+. [0370] 13.2 Preparation of Intermediate 13-4:
Figure imgf000144_0001
[0371] Intermediate 13-4 was prepared essentially as described in Example 1 for the preparation of Compound 1d by using Intermediate 13-2 as starting material. [0372] 13.3 Preparation of Intermediate 13-6:
Figure imgf000144_0002
[0373] Preparation of Intermediate 13-5 can be referred to the Reference: WO2015/26792 A1, 2015. To a solution of Intermediate 13-5 (81 mg, 0.40 mmol, 1.1 eq.) in DMF (5 mL) were added HATU (166 mg, 0.43 mmol, 1.2 eq.) and DIPEA (235 mg, 1.82 mmol, 5 eq.). The mixture was stirred at 20 °C for 10 min. Then Intermediate 13-4 (200 mg, 0.36 mmol, 1 eq.) was added. The mixture was stirred at 20 °C for 20 min. TLC (PE/EA=1/1) indicated that the reaction was complete. The reaction mixture was diluted with H2O (10 mL), extracted with EA 30 mL (10 mL X 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% EA/PE gradient at 20 mL/min). Intermediate 13-6 (251 mg, 93.5%yield) was obtained as a colorless oil. LCMS: ESI-MS: m/z 736.2 [M+H] + [0374] 13.4 Preparation of Intermediate 13-7:
Figure imgf000145_0001
[0375] To a solution of Intermediate 13-6 (251 mg, 0.34 mmol, 1 eq.) in THF (5 mL) was added TBAF (1 M, 0.68 mL, 2 eq.). The mixture was stirred at 20 °C for 0.5 h. TLC (PE/EA=1/1) indicated that Intermediate 13-6 was consumed completely. The reaction mixture was diluted with H2O (10 mL), extracted with EA 30 mL (10 mL X 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; X g SepaFlash® Silica Flash Column, Eluent of 0~100% EA/PE gradient at 20 mL/min). Intermediate 13-7 (197 mg, 92.9% yield) was obtained as a white solid. LCMS: ESI-MS: m/z 622.1 [M+H]+. [0376] 13.5 Preparation of Intermediate 13-8:
Figure imgf000145_0002
[0377] To a solution of Intermediate 13-7 (180 mg, 0.29 mmol, 1 eq.) in MeCN (3 mL) and H2O (1 mL) were added TEMPO (23 mg, 0.14 mmol, 0.5 eq.), NH4OAc (89 mg, 1.16 mmol, 4 eq.), and PhI(OAc)2 (280 mg, 0.87 mmol, 3 eq.). The mixture was stirred at 75 °C for 2 h. TLC (PE/EA=0/1) showed that Intermediate 13-7 was consumed completely. The reaction mixture was quenched by addition of H2O (10 mL), extracted with EA 30 mL (10 mL X 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% EA/PE gradient at 20 mL/min). Intermediate 13-8 (152 mg, 246.55 mmol, 85.1% yield) was obtained as a yellow oil. LCMS: ESI-MS: m/z 617.2 [M+H]+. [0378] 13.6 Preparation of Compound 13d:
Figure imgf000146_0001
[0379] Compound 13d was prepared essentially as described in Example 1 for the preparation of Compound 1d by using Intermediate 13-8 as starting material. Finally, Compound 13d (175 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) δ = 9.12 (d, J=5.6 Hz 1H), 9.08 (d, J=7.6 Hz, 1H), 8.91 (br, 1H), 8.44 (d, J=8.4 Hz, 2 H), 8.13-8.09 (m, 2H), 7.96 (s, 1H), 7.73-7.70 (m, 3 H), 5.24 (d, J=9.2 Hz 1H), 4.73-4.68 (m, 1 H), 4.56 (d, J=9.2 Hz 1H), 4.17 (s, 3H), 4.03 (dd, J=14, 4.4Hz, 1H ), 1.72 (s, 3H). LCMS: ESI-MS: m/z 635.2 [M+H]+. Example 14: Synthesis of Compound 14d [0380] 14.1 Preparation of Intermediate 14-2:
Figure imgf000146_0002
[0381] Intermediate 14-1 was prepared essentially as described in Example 13 for the preparation of Compound 13d. To a solution of Intermediate 14-1 (1.47 g, 2.94 mmol, 1 eq.) in DCM (10 mL) were added Boc2O (705 mg, 3.23 mmol, 1.1 eq.) and TEA (594.28 mg, 5.87 mmol, 817.45 µL, 2 eq.). The mixture was stirred at 20 °C for 2 h. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (20 mL), extracted with EA (20 mL X 2). The combined organic layers were washed with brine (10 mL X 2), dried over Na2SO4, filtered and, concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0~30% EA/PE gradient at 35 mL/min). Intermediate 14-2 (1.65 g, 93.5% yield) was obtained as colorless oil. LCMS: ESI-MS: m/z 601.2 [M+H]+. [0382] 14.2 Preparation of Intermediate 14-3:
Figure imgf000147_0001
[0383] To a solution of Intermediate 14-2 (1.65 g, 2.75 mmol, 1 eq.) in THF (20 mL) was added TBAF (1 M, 8.24 mL, 3 eq.). The mixture was stirred at 20 °C for 1 h. TLC (PE/EA=3/1) showed that the reaction was complete. The reaction mixture was diluted with H2O (30 ml), extracted with EA (30 mL X 2), the combined organic layers were washed with H2O (30 mL X 3), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~40% EA/PE gradient at 30 mL/min). Intermediate 14-3 (1.17 g, 87.5% yield) was obtained as colorless oil.1H NMR (400MHz, CDCl3) δ = 8.19-8.15 (m, 2H), 7.51 (s, 1H), 7.2- 7.14 (m, 2H), 6.61 (brs, 1H), 4.93-4.90 (m, 1H), 4.67 (d, J=9.2 Hz, 1H), 4.45 (d, J=9.2 Hz, 1H), 4.27-4.21 (m, 1H), 3.78 (d, J=7.8 Hz, 1H), 3.59 (m, 2H), 3.44 (dd, J=14.4, 3.6 Hz, 1 H), 1.46 (s, 3H), 1.12 (s, 9H). LCMS: ESI-MS: m/z 486.2 [M+H]+. [0384] 14.3 Preparation of Intermediate 14-4:
Figure imgf000147_0002
[0385] To a solution of Intermediate 14-3 (1.17 g, 2.41 mmol, 1 eq.) in MeCN (10 mL) and H2O (2 mL) were added TEMPO (0.76 g, 4.81 mmol, 2 eq.) and PhI(OAc)2 (3.87 g, 12.03 mmol, 5 eq.). The mixture was stirred at 40 °C for 0.5 h. LCMS showed that Intermediate 14-3 consumed completely. The reaction mixture was partitioned between EA (40 mL) and H2O (20 mL). The organic phase was separated, washed with brine (30 mL X 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% EA/PE gradient at 40 mL/min). Intermediate 14-4 (1.3 g, 84% yield, 77.6% purity) was obtained as yellow solid. LCMS: ESI-MS: m/z 501.1 [M+H]+. [0386] 14.4 Preparation of Intermediate 14-6:
Figure imgf000148_0001
[0387] To a solution of Intermediate 14-4 (1.30 g, 2.02 mmol, 1 eq.) in DMF (10 mL) were added HATU (1.15 g, 3.03 mmol, 1.5 eq.) and DIEA (0.78 g, 6.05 mmol, 1.05 mL, 3 eq.) . The mixture was stirred at 20 °C for 15 min, then amine 14-5 (0.16 g, 2.02 mmol, 1 eq.) was added. After addition, the reaction was stirred at 20 °C for 15 min. LCMS showed that the reaction was complete. The reaction mixture was partitioned between EA (30 mL) and water (10 mL). The organic phase was separated, washed with brine (10 mL X 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% EA/PEgradient at 40 mL/min). Intermediate 14-6 (920 mg, 80.9% yield) was obtained as a white solid. LCMS: ESI-MS: m/z 564.1 [M+H]+. [0388] 14.5 Preparation of Intermediate 14-7:
Figure imgf000148_0002
[0389] A solution of Intermediate 14-6 (920 mg, 1.63 mmol, 1 eq.) in HCl/EA (4 M, 50 mL) was stirred at 20 °C for 0.5 h. LCMS showed that the reaction was complete. The mixture was neutralized with Sat. NaHCO3 to pH=8, extracted with EA (50 mL X 2). The combined organic layers were dried over Na2SO4, filtered, and filtrate was concentrated under vacuum. The residue was lyophilized to give Intermediate 14-7 as a white solid (740 mg, 97.8% yield).1H NMR (400MHz, CD3Cl) δ = 8.19-8.15 (m, 2H), 7.35 (s, 1H), 7.13 (t, J=8.8 Hz, 2H), 6.24 (brs, 1H), 5.91-5.62 (tt, J=56, 3.6 Hz 1H), 5.50 (d, J=9.6 Hz, 1H), 4.44 (d, J=9.6 Hz, 1H), 3.69-3.61 (m, 1H), 3.44-3.27 (m, 3H), 1.71 (s, 3H). LCMS: ESI-MS: m/z 464.1 [M+H]+. [0390] 14.6 Preparation of Compound 14d:
Figure imgf000149_0001
[0391] Intermediate 14-8 was prepared essentially as described in Example 5 for the preparation of Compound 5d. Compound 14d was prepared essentially as described in Example 2 for the preparation of Compound 2d by using Intermediate 14-7 and acid 14-8 as starting materials. Finally, Compound 14d (45 mg) was obtained as white solid.1H NMR (400MHz, DMSO-d6) δ = 8.82 (d, J=2.4 Hz 1H), 8.67 (t, J=5.6 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.35 (t, J=5.6 Hz, 1H), 8.27-8.23 (m, 2H), 7.84 (d, J=1.6 Hz 1 H), 7.81 (s, 1H), 7.69 (d, J=1.6 Hz 1 H), 7.31 (t, J=9.0 Hz 2H), 7.17 (s, 1H), 6.09-5.79 (tt, J=56, 4 Hz 1H), 5.12 (d, J=9.2 Hz, 1H ), 4.45 (d, J=9.2 Hz, 1H ), 4.26-4.23 (m, 1H), 4.14-4.09 (m, 1H), 3.97-3.95 (m, 1H), 3.47-3.43 (m, 2H), 1.52 (s, 3H), 0.83-0.77 (m, 2H), 0.75-0.70 (m, 2H). LCMS: ESI-MS: m/z 709.1 [M+H]+. Example 15: Synthesis of Compound 15d
Figure imgf000150_0001
[0392] Intermediate 15-5 was prepared essentially as described in Example 6 for the preparation of Compound 6d. Preparation of Intermediate 15-6 was prepared essentially as described in Example 14 for the preparation of Compound 14d. [0393] Compound 15d was prepared essentially as described in Example 14 for the preparation of Compound 14d by using acid 15-5 and amine 15-6 as starting materials. Finally, Compound 15d (25 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) δ = 8.922 (s, 1H), 8.73 (brs, 1H), 8.32 (s, 1H), 8.24-8.20 (m, 2H), 7.97 (t, J=2.0 Hz 1H), 7.80 (s, 1 H), 7.69 (s, 1H), 7.30 (s, 1 H), 7.11 (t, J=9.2 Hz 2H), 7.02 (t, J=55.2 Hz 1H), 6.05-5.75 (tt, J=56, 4 Hz 1H), 5.10 (d, J=9.6 Hz, 1H), 4.66-4.61 (m, 1H ), 4.50 (d, J=9.6 Hz, 1H), 3.94 (s, 3H), 3.88-3.84 (m, 1H), 3.61-3.53 (m, 2H), 1.66 (s, 3H). LCMS: ESI-MS: m/z 699.1 [M+H]+. Example 16: Synthesis of Compound 16d [0394] 16.1 Preparation of Intermediate 16-2:
Figure imgf000150_0002
[0395] Preparation of Intermediate 16-1 was prepared essentially as described in Example 14 for the preparation of Compound 14d. To a solution of Intermediate 16-1 (700 mg, 1.4 mmol, 1 eq.) in DMF (8 mL) were added DIPEA (542 mg, 4.2 mmol, 3 eq.) and HATU (530 mg, 1.4 mmol, 1 eq.).The mixture was stirred at 45 °C for 10 min before adding MeNH2HCl (472 mg, 7.0 mmol, 5 eq.). The mixture was stirred at 45 °C for additional 20 min. LC-MS showed that the desired product was formed. The reaction mixture was quenched by H2O (50 mL), extracted with EA 60 mL (20 mL X 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~70% EA/PE gradient at 30 mL/min). Intermediate 16-2 (294 mg, 41% yield) was obtained as a colorless oil. LCMS: ESI-MS: m/z 514.2 [M+H]+. [0396] 16.2 Preparation of Compound 16d:
Figure imgf000151_0001
[0397] Intermediate 16-4 was prepared essentially as described in Example 6 for the preparation of Compound 6d. Compound 16d was prepared essentially as described in Example 14 for the preparation of Compound 14d by using Intermediate 16-2 and amine 16-4 as starting materials. Finally, Compound 16d (38 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) δ = 8.96 (s, 1H), 8.81 (brs, 1H), 8.37 (s, 1H), 8.27-8.23 (m, 2H), 7.84 (s, 1 H), 7.74 (d, J=0.8 Hz 1H), 7.60 (brs, 1 H), 7.34 (d, J=0.8 Hz, 2H), 7.15 (t, J=8.8 Hz, 2 H), 7.06 (t, J=55.2 Hz, 1H), 5.14 (d, J=9.6 Hz, 1H ), 4.75-4.71 (m, 1H ), 4.49 (d, J=9.6 Hz, 1H), 3.98 (s, 3H), 3.89- 3.85 (m, 1H), 2.81 (d, J=4.4 Hz, 3H), 1.68 (s, 3H). LCMS: ESI-MS: m/z 649.0 [M+H]+. Example 17: Synthesis of Compound 17d [0398] 17.1 Preparation of Intermediate 17-2:
Figure imgf000151_0002
[0399] Preparation of Intermediate 17-1 can be referred to the Reference: Tetrahedron Letters, 2003, 44, 4, 725 –728. A mixture of Intermediate 17-1 (30.0 g, 117.44 mmol, 1.0 eq.), (4-fluorophenyl)-boronic acid (24.65 g, 176.16 mmol, 1.5 eq.), Pd(dppf)Cl2 (3.44 g, 4.70 mmol, 0.04 eq.), and K2CO3 (48.69 g, 352.32 mmol, 3.0 eq.) in dioxane (200 mL) and H2O (40 mL) was degassed and purged with N2 for 3 times and then stirred at 110 °C for 1 h under N2 atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was diluted with H2O (1200 mL), acidified to PH=5~6 by addition of 2 M HCl (200mL), extracted with EA 900 mL (300 mL X 3). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 10/1) to afford Intermediate 17-2 (42 g, 79.96% yield) as a yellow solid. LCMS: ESI-MS: m/z 223.9 [M+H]+. [0400] 17.2 Preparation of Intermediate 17-3:
Figure imgf000152_0001
[0401] To a solution of Intermediate 17-2 (26 g, 116.26 mmol, 1 eq.) in DMF (200 mL) was added NaH (9.30 g, 232.53 mmol, 60% purity, 2 eq.). After addition, the mixture was stirred at 0 °C for 20 min before adding SEMCl (19.38 g, 116.26 mmol, 20.58 mL, 1 eq.). The resulting mixture was stirred at 0°C for 1 h. TLC (PE/EA=10/1) showed that the reaction was complete. The reaction mixture was quenched by H2O (150 mL) at 0 °C, extracted with EA (100mL X 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 5/1) to afford Intermediate 17-3 (36 g, 87.5% yield) as a yellow oil. LCMS: ESI-MS: m/z 354.0 [M+H]+. [0402] 17.3 Preparation of Intermediate 17-4:
Figure imgf000152_0002
[0403] To a solution of Intermediate 17-3 (30 g, 84.77 mmol, 1.00 eq.) in THF (800mL) was added n-BuLi (2.5 M, 50.86 mL, 1.5 eq.) at -78°C. After addition, the reaction was stirred at - 78°C for 20 min, and then a solution of I2 (32.27 g, 127.16 mmol, 25.61 mL, 1.5 eq.) in THF (200 mL) was added dropwise. The reaction solution was stirred at -78 °C for 1 h. TLC indicated that Intermediate 17-3 was consumed completely. The reaction mixture was quenched by saturated sodium sulfite solution, extracted with EA (400 mL X 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by recrystallization from MeOH (60 mL) to afford Intermediate 17-4 (45.1 g, 55.4% yield) as white solid. LCMS: ESI-MS: m/z 479.9 [M+H]+. [0404] 17.4 Preparation of Intermediate 17-5:
Figure imgf000153_0001
[0405] To a solution of Intermediate 17-4 (40 g, 83.37 mmol, 1.0 eq.) in THF (80 mL) was added HCl (4M, 100 mL). The mixture was stirred at 25 °C for 1 h. TLC showed that the reaction was complete. The reaction mixture adjusted to PH=5~6 by aqueous NaHCO3, extracted with EA (400mL X 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, EA/PE=1/10) to afford Intermediate 17-5 (28 g, 96% yield) as yellow oil. LCMS: ESI-MS: m/z 349.9 [M+H]+. [0406] 17.5 Preparation of Intermediate 17-7:
Figure imgf000153_0002
[0407] To a solution of Intermediate 17-5 (23 g, 65.80 mmol, 1 eq.) and Compound 17-6 (16.45 g, 131.61 mmol, 15.23 mL, 2 eq.) in MeCN (100 mL) was added K2CO3 (27.28 g, 197.41 mmol, 3 eq.). The mixture was stirred at 80-90°C for 1 h. LCMS showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=10:1) to afford Intermediate 17-7 (20.7 g, 72% yield) as yellow oil. [0408] 17.6 Preparation of Intermediate 17-8:
Figure imgf000154_0001
[0409] To a solution of Intermediate 17-7 (18 g, 41.09 mmol, 1 eq.) in DMF (100 mL) was added TBAAc (61.94 g, 205.45 mmol, 62.57 mL, 5 eq.). The mixture was stirred at 90°C for 1.5 h. LCMS showed that the reaction was complete. The reaction was cooled to 20 °C and poured into water (100 mL). The aqueous phase was extracted with EA (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=10/1 to 5/1) to give Intermediate 17-8 (17.1 g, 90.15% yield) as a yellow oil. LCMS: ESI-MS: m/z 462.1 [M+H]+. [0410] 17.7 Preparation of Intermediate 17-9:
Figure imgf000154_0002
[0411] To a solution of Intermediate 17-8 (12 g, 25.99 mmol, 1.0 eq.) in MeOH (100 mL) was added K2CO3 (10.78 g, 77.97 mmol, 3.0 eq.) in one portion. The mixture was stirred at 25 °C for 30 min. LCMS showed that the reaction was complete. The mixture was poured into water (100 mL). The aqueous phase was extracted with EA (100 mL X 3). The combined organic phase was washed with brine (100 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, PE/EA=5/1) to afford Intermediate 17-9 (10.2 g, 92% yield) as brown oil. LCMS: ESI- MS: m/z 420.1 [M+H]+. [0412] 17.8 Preparation of Intermediate 17-10:
Figure imgf000155_0001
[0413] To a solution of Intermediate 17-9 (12.6 g, 30.03 mmol, 1 eq.) and Et3N (9.12 g, 90.08 mmol, 12.54 mL, 3 eq.) in THF (100 mL) was added MsCl (5.16 g, 45.04 mmol, 3.49 mL, 1.5 eq.) slowly at 0°C. The mixture was stirred at 20°C for 0.5 h. TLC (DCM/PE=10/1) indicated that Intermediate 17-9 was consumed completely. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=3/1 to 1/1) to afford the corresponding mesylate (27.8 g, 93% yield) as brown oil. [0414] To a solution of mesylate (27.2 g, 54.66 mmol, 1 eq.) in THF (200 mL) was added TBAF (1 M in THF, 220 mL, 4 eq.). The mixture was stirred at 70°C for 2 h. TLC indicated that the reaction was complete. The mixture was filtered and the filtrate was concentrated mesylate. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 5/1) to afford Intermediate 17-10 (20.5 g, 88.97% yield) as a brown oil. LCMS: ESI-MS: m/z 421.9 [M+H]+. [0415] 17.9 Preparation of Intermediate 17-11:
Figure imgf000155_0002
[0416] To a mixture of Intermediate 17-10 (20 g, 47.4 mmol, 1.00 eq.) and Q-phos (3.37 mg, 4.74 mmol, 0.10 eq.) in toluene (200 mL) was added Pd2(dba)3 (4.34 mg, 4.74 mmol, 0.10 eq.) in one portion under N2. Two batches were carried out simultaneously. The mixture was stirred at 110 °C for 4 h. TLC (PE: EA=10:1) showed that the reaction was complete and LCMS indicated the desired mass. The mixture was cooled to 25 °C and poured into water (300 mL). The aqueous phase was extracted with EA (300 mL X 3). The combined organic phase was washed with brine (300 mL X 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, PE/EA=10/1) to afford Intermediate 17-11 (32.8 g, 80~90% purity, 60~70% yield) as black brown oil. LCMS: ESI-MS: m/z 422.1 [M+H]+. [0417] 17.10 Preparation of Intermediate 17-12:
Figure imgf000156_0001
[0418] To a solution of Intermediate 17-11 (3.3 g, 7.83 mmol, 1.0 eq.) in DMF (30 mL) was added TBAAc (11.8 g, 39.15 mmol, 11.92 mL, 5.0 eq.). The mixture was stirred at 90 °C for 1 h. TLC (PE/EA=10/1) showed that the reaction was complete. The mixture was cooled to 25 °C and poured into water (50 mL). The aqueous phase was extracted with EA (50 mL X 3). The combined organic phase was washed with brine (50 mL X 2), dried over Na2SO4, concentrated in vacuum to afford Intermediate 17-12 (3.5 g, crude) as black brown oil, which was used in the next step without further purification. LCMS: ESI-MS: m/z 353.9 [M+H]+. [0419] 17.11 Preparation of Intermediate 17-13:
Figure imgf000156_0002
[0420] To a solution of Intermediate 17-12 (2.3 g, 6.50 mmol, 1.0 eq.) in MeOH (25 mL) was added K2CO3 (2.70 g, 19.50 mmol, 3.0 eq.). The mixture was stirred at 25 °C for 30 min. TLC (PE/EA=5/1) showed that the reaction was complete. The mixture was poured into water (30 mL). The aqueous phase was extracted with EA (30 mL X 3). The combined organic phase was washed with brine (30 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=1/1) to afford Intermediate 17-13 (1.8 g, 89% yield) as a white solid. LCMS: ESI-MS: m/z 311.9 [M+H]+ [0421] 17.12 Preparation of Intermediate 17-14:
Figure imgf000157_0001
[0422] To a solution of Intermediate 17-13 (1.8 g, 1.0 eq.) in MeCN (20 mL) was added IBX (8.08 g, 28.85 mmol, 5.0 eq.). The mixture was stirred at 70 °C for 2 h. LCMS showed that the reaction was complete. The mixture was cooled to 25 °C, diluted with saturated NaHCO3 (20 mL), and stirred for 5 min. The aqueous phase was extracted with EA (20 mL X 3). The combined organic phase was washed with brine (20 mL X 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to afford Intermediate 17-14 (1.6 g, crude) as yellow oil, which was used in the next step without further purification. LCMS: ESI-MS: m/z 332.0 [M+H +Na]+. [0423] 17.13 Preparation of Intermediate 17-15:
Figure imgf000157_0002
[0424] To a solution of Intermediate 17-14 (1.60 g, 5.17 mmol, 1.00 eq.) in EtOH (20 mL) were added Na2CO3 (603 mg, 5.68 mmol, 1.1 eq.) and NH2OH.HCl (395 mg, 5.68 mmol, 1.10 eq.). The resulting mixture was stirred at 40 °C for 1 h. LCMS showed that the reaction was complete. The mixture was cooled to 25 °C, diluted with water (20 mL) and extracted with EA (20 mL X 3). The combined organic phase was washed with brine (20 mL X 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=1/1) to afford Intermediate 17-15 (1.50 g, 89.35% yield) as yellow solid. LCMS: ESI-MS: m/z 324.9 [M+H]+. [0425] 17.14 Preparation of Intermediate 17-16:
Figure imgf000158_0001
[0426] To a solution of Intermediate 17-15 (1.4 g, 4.31 mmol, 1.0 eq.) in MeCN (15 mL) was added CDI (2.1 g, 12.93 mmol, 3.0 eq.). The mixture was stirred at 50 °C for 1 h. LCMS showed that the reaction was complete. The mixture was cooled to 25 °C, diluted with water (15 mL) and extracted with EA (15 mL X 3). The combined organic phase was washed with brine (15 mL X 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=5/1) to afford Intermediate 17- 16 (980 mg, 74% yield) as white solid. LCMS: ESI-MS: m/z 307.0 [M+H]+. [0427] 17.15 Preparation of Intermediate 17-18:
Figure imgf000158_0002
[0428] A mixture of Intermediate 17-16 (0.98 g, 3.2 mmol, 1.0 eq.), Compound 17-17 (3.62 g, 16.3 mmol, 5 eq.), Cs2CO3 (3.13 g, 9.6 mmol, 3.0 eq.) and Pd(dppf)Cl2 (1.19 g, 1.63 mmol, 0.5 eq.) in DME (10.00 mL) and H2O (2.00 mL) was taken up into a microwave tube under N2. The sealed tube was heated at 110 °C for 4 h under microwave irradiation. LCMS showed that the reaction was complete. After cooling to 25°C, water (20 mL) was added. The aqueous layer was extracted with EA (20 mL X 3). The combined organic layers were washed with brine (20 mL X 2), dried over Na2SO4, concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=1/1) to afford Intermediate 17-18 (960 mg, 79 % yield) as yellow solid. LCMS: ESI-MS: m/z 430.2 [M +Na +MeCN]+. [
Figure imgf000159_0001
[0430] Intermediate 17-22 was prepared essentially as described in Example 5 for the preparation of Compound 5d. Compound 17d was prepared essentially as described in Examples 1 and 2 for the preparation of Compound 1d and Compound 2d by using Intermediate 17-18 and acid 17-22 as starting materials. Finally, Compound 17d (45 mg) was obtained as white solid.1H NMR (400MHz, DMSO) δ = 8.87 (d, J=2.8 Hz 1H), 8.74 (t, J=5.6 Hz, 1H), 8.49 (d, J=2.8 Hz, 1H), 8.28-8.25 (m, 2H), 7.99 (s, 1H), 7.89 (d, J=1.2 Hz 1 H), 7.77 (d, J=1.2 Hz 1 H), 7.44 (brs, 1 H), 7.39 (t, J=8.8 Hz 2H), 5.18 (dd, J=10, 2.4 Hz, 1H ), 4.99 (s, 1H ), 4..89-4.99 (m, 2H), 4.28- 4.24 (m, 1H), 4.19-4.15 (m, 1H), 4.04-4.01 (m, 1H), 0.87-0.83 (m, 2H), 0.79-0.76 (m, 2H). LCMS: ESI-MS: m/z 645.0 [M+H]+. Example 18: Synthesis of Compound 18d
Figure imgf000159_0002
[0431] Intermediate 18-1 was prepared essentially as described in Example 4 for the preparation of Compound 4d. Preparation of Intermediate 18-2 was prepared essentially as described in Example 17 for the preparation of Compound 17d. [0432] Compound 18d was prepared essentially as described in Example 2 the preparation of Compound 2d by using acid 18-1 and amine 18-2 as starting materials. Finally, Compound 18d (29 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) δ = 8.74 (d, J=2.8 Hz, 1H), 8.69-8.63 (brs, 1H), 8.30-8.27 (m, 2H), 7.97 - 7.93 (m, 2H), 7.75 (d, J=1.6 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.15-7.12 (t, J=8.8 Hz, 2H), 5.04-5.01 (m, 1H), 4.91 (s, 1H), ,4.83-4.80 (m, 1H), 4.73-4.72 (m, 1H), 4.53-4.49 (m, 1H), 4.52-4.09 (m, 1H), 3.94 - 3.93 (m, 1H), 0.86 - 0.83 (m, 4H). LCMS: ESI-MS: m/z 629.0 [M+H]+. Example 19: Synthesis of Compound 19d
Figure imgf000160_0001
[0433] Intermediate 19-1 was prepared essentially as described in Example 6 for the preparation of Compound 6d. Intermediate 19-2 was prepared essentially as described in Example 17 for the preparation of Compound 17d. [0434] Compound 19d was prepared essentially as described in Example 2 for the preparation of Compound 2d by using acid 19-1 and amine 19-2 as starting materials. Finally, Compound 19d (38 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) δ = 8.96 (d, J=1.5 Hz, 1H), 8.76-8.33 (br, 1 H), 8.44 (s, 1H), 8.33 - 8.29 (m, 2H), 8.00 (s, 1H), 7.88 - 7.85 (m, 2H), 7.21 - 6.93 (m, 3H), 5.06 (dd, J=2.5, 10.0 Hz, 1H), 4.94 (d, J=10.0 Hz, 1H), 4.90 - 4.84 (m, 1H), 4.77 (m, 1H), 4.60 - 4.47 (m, 1H), 4.22 - 4.10 (m, 1H), 3.98 (m,1H), 0.97 - 0.79 (m, 4H). LCMS: ESI-MS: m/z 661.2 [M+H]+. Example 20: Synthesis of Compound 20d
Figure imgf000161_0001
[0435] Intermediate 20-1 was prepared essentially as described in Example 8 for the preparation of Compound 8b. Preparation of Intermediate 20-2 was prepared essentially as described in Example 17 for the preparation of Compound 17d. [0436] Compound 20d was prepared essentially as described in Example 2 for the preparation of Compound 2d by using acid 20-1 and amine 20-2 as starting materials. Finally, Compound 20d (32 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) δ = 8.88-8.86 (dd, J=1.6, 4.5 Hz, 1H), 8.71-8.70 (br 1H), 8.44-8.42 (dd, J=1.5, 8.3 Hz, 1H), 8.31 - 8.28 (m, 2H), 7.97 (s, 1H), 7.87 (d, J=1.6, Hz, 1H), 7.83 (d, J=1.6, Hz, 1H), 7.70-7.67 (m, 1H), 7.19 - 7.13 (m, 2H), 5.05-5.02 (dd, J=2.7, 10.0 Hz, 1H), 4.90 (d, J=10.0 Hz, 1H), 4.86 - 4.81 (m, 1H), 4.75 - 4.72 (m, 1H), 4.55 - 4.51 (m, 1H), 4.15 - 4.129 (m, 1H), 4.01 - 3.98 (m, 1H), 0.92 - 0.85 (m, 4H). LCMS: ESI-MS: m/z 611.1 [M+H]+. Example 21: Synthesis of Compound 21c
Figure imgf000161_0002
[0437] Intermediate 21-1 was prepared essentially as described in Example 6 for the preparation of Compound 6d. Preparation of Intermediate 21-2 was prepared essentially as described in Example 2 for the preparation of Compound 2d. [0438] Compound 21c was prepared essentially as described in Example 2 for the preparation of Compound 2d by using acid 21-1 and amine 21-2 as starting materials. Finally, Compound 21c (30 mg) was obtained as white solid.1H NMR (400MHz, DMSO-d6) δ = 8.94 (d, J=0.8 Hz, 1H), 8.72-8.69 (t, J=6.0 Hz, 1H), 8.43 (s, , 1H), 8.31-8.27 (m, 2H), 7.90 (s, 1 H), 7.88 (d, J=1.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.18-6.91 (s, 3H), 5.03 (d, J=9.6 Hz, 1H), 4.63 (d, J=9.6 Hz, 1H), 4.55-4.50 (m, 1 H), 4.13-4.09 (m, 1 H), 3.98-3.95 (m, 1 H), 1.77 (s, 3H), 0.87- 0.84 (m, 4H). LCMS: ESI-MS: m/z 643.0 [M+H]+. Example 22: Synthesis of Compound 22d [0439] 22.1 Preparation of Intermediate 22-2:
Figure imgf000162_0001
[0440] Preparation of Intermediate 22-1 can be referred to the Reference: WO2015/26792 A1, 2015. To a solution of Intermediate 22-1 (2 g, 8.65 mmol, 1 eq.) in DCE (15 mL) were added I2 (4.39 g, 17.30 mmol, 2 eq.) and 2-hydroperoxy-2-methyl-propane (2.34 g, 25.95 mmol, 2.49 mL, 3 eq.).The mixture was stirred at 110 °C for 3 h. TLC (PE/EA=3/1) showed that the reaction was complete. The reaction mixture was quenched with aqueous Na2SO3 (20 mL) and concentrated under reduced pressure. The aqueous phase was extracted with EA (10 mL X 2). The combined organic phase was washed with brine (15 mL X 2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=20/1 to 3/1) to afford Intermediate 22-2 (1.5 g, 48.6% yield) as yellow solid.1H NMR (400MHz, CD3OD) δ = 9.02 (d, J=2.0 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.12 (s, 1H), 7.68 (s, 1H), 4.45-4.40 (q, J=7.2 Hz, 2 H), 4.09 (s, 3H), 1.44 (t, J=7.2 Hz, 1H). LCMS: ESI-MS: m/z 358.0 [M+H]+. [0441] 22.2 Preparation of Intermediate 22-5:
Figure imgf000162_0002
[0442] Preparation of amine 22-4 was prepared essentially as described in Example 17 for the preparation of Compound 17d. Intermediate 22-5 was prepared essentially as described in Example 1 for the preparation of Compound 1d by using ester 22-2 and amine 22-4 as starting materials. LCMS: ESI-MS: m/z 711.0 [M+H]+. [0443] 22.3 Preparation of Compound 22d:
Figure imgf000163_0001
[0444] A mixture of Intermediate 22-5 (90 mg, 0.13 mmol, 1.0 eq.), Pd(PPh3)4 (58 mg, 0.51 mmol, 0.4 eq.), and Zn(CN)2 (28 mg, 0.26 mmol, 2.0 eq.) in DMF (2 mL) was taken up into a microwave tube. The sealed tube was heated at 120°C for 1 h under microwave irradiation. LCMS showed that the reaction was complete. After cooling to 25°C, the mixture was diluted with H2O (20 mL) and extracted with EA (20 mL X 3). The combined organic layers were washed with brine (20 mL X 2), dried over Na2SO4, and concentrated. The crude product was purified by prep-HPLC (column: Xtimate C18150*25mm*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 64%-86%, 5min) and the solution was lyophilized to give Compound 22d (31 mg, 39.1% yield) as white solid.1H NMR (400MHz, CD3OD) δ = 9.15 (d, J=2.0 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.81 (br t, J=5.9 Hz, 1H), 8.24 (dd, J=5.6, 9.0 Hz, 2H), 7.99 (d, J=1.2 Hz, 1H), 7.96 (s, 1H), 7.60 (d, J=1.2 Hz, 1H), 7.42 (s, 1H), 7.35 (t, J=8.9 Hz, 2H), 5.14 (dd, J=2.4, 10.0 Hz, 1H), 4.99 - 4.94 (m, 1H), 4.90 - 4.84 (m, 2H), 4.27 - 4.21 (m, 1H), 4.19 - 4.12 (m, 1H), 3.97 (s, 3H). LCMS: ESI-MS: m/z 610.0 [M+H]+. Example 23: Synthesis of Compound 23d [0445] 23.1 Preparation of Intermediate 23-2:
Figure imgf000163_0002
[0446] Preparation of Intermediate 23-1 can be referred to the Reference: WO2010/54279, 2010, A1. To a solution of Intermediate 23-1 (20.8 g, 69.4 mmol, 1 eq.) in THF (200 mL) was added NaH (3.33 g, 83.2 mmol, 60% purity, 1.2 eq.) at 0 °C. After stirring for 5 minutes, MOMCl (6.14 g, 76.3 mmol, 5.80 mL, 1.1 eq.) was added dropwise. After addition, the reaction mixture was stirred at 0 °C for 1 h. TLC (PE/EA=3/1) showed that the reaction was complete. The reaction was quenched with water (100 mL), extracted with EA (200 mL X 2). The organic phase was concentrated to dryness. The residue was purified by column chromatography (SiO2, PE/EA=20/1 to 10/1) to give desired Intermediate 23-2 (17.0 g, 71.2% yield) as pale yellow oil.1H NMR (400MHz, CDCl3) δ = 7.57 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 5.23 (s, 2H), 3.48 (s, 3H). [0447] 23.2 Preparation of Intermediate 23-4:
Figure imgf000164_0001
[0448] To a solution of Intermediate 23-2 (13.0 g, 37.8 mmol, 1 eq.) in toluene (130 mL) was added nBuLi (2.5 M, 18.14 mL, 1.2 eq.) dropwise at -78°C. After stirring for 30 min, Compound 23-3 (7.0 g, 56.7 mmol, 1.5 eq.) was added. Then the reaction mixture was stirred at 0 °C for another 30 min. TLC (PE/EA=3/1) showed that desired product was formed. The reaction was quenched with saturated NH4Cl (50 mL), extracted with EA (100 mL X 2). The organic phase was concentrated to dryness. The residue was purified by column chromatography (SiO2, PE/EA=20/1 to 10/1) to give desired Intermediate 23-4 (8.9 g, 79.5% yield) as pale yellow oil. LCMS: ESI-MS: m/z 296.0/298.0 [M+H]+. [0449] 23.3 Preparation of Intermediate 23-5:
Figure imgf000164_0002
[0450] To a solution of Intermediate 23-4 (8.9 g, 30 mmol, 1 eq.) in EtOH (50 mL) was added NaBH4 (1.14 g, 30 mmol, 1 eq.) in portions at 25 °C. The resulting mixture was stirred for 1 h. LCMS showed that the reaction was complete. The reaction mixture was quenched by saturated NaCl (20 mL), extracted with EA (30 mL X 2). The combined organic phase was washed with brine and concentrated to dryness. Intermediate 23- 5 (9 g, crude) was obtained as yellow oil. LCMS: ESI-MS: m/z 297.8/299.8 [M+H]+. [0451] 23.4 Preparation of Intermediate 23-6: [0452] To a mixture of Intermediate 23-5 (9 g, 30.2 mmol, 1 eq.), (4-fluorophenyl)boronic acid (6.4 g, 45.3 mmol, 1.5 eq.), and Cs2CO3 (19.8 g, 60.4 mmol, 2 eq.) in dioxane (100 mL) and H2O (20 mL) was added Pd(dppf)Cl2 (2.2 g, 3.0 mmol, 0.1 eq.). The resulting mixture was stirred at 110 °C for 5 h. LCMS showed that the reaction was complete. The reaction was cooled to room temperature and diluted with water (200 mL), extracted with EA (200 mL X 2). The organic phase was concentrated to dryness. The residue was purified by column chromatography (SiO2, PE/EA=50/1 to 10/1) to give desired Intermediate 23-6 (7.1 g, 74.3% yield) as a pale yellow oil.1H NMR (400MHz, CDCl3) δ = 7.95-7.91 (m, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.17 (t, J=8.8 Hz, 2H), 5.98-5.69 (td, J=56, 3.6 Hz, 1H) 5.23 (s, 2H), 4.9-4.84 (m, 2H), 3.47 (s, 3H). LCMS: ESI-MS: m/z 313.9 [M+H]+. [0453] 23.5 Preparation of Intermediate 23-7:
Figure imgf000165_0001
[0454] To a solution of Intermediate 23-6 (7.1 g, 22.7 mmol, 1 eq.) in dioxane (70 mL) was added HCl (12 M, 30 mL, 15.8 eq.) in one portion. The resulting mixture was stirred at 50 °C for 0.5 h. TLC (PE/EA=3/1) showed that the reaction was complete. The reaction mixture was neutralized to pH=7 by sat NaHCO3 and extracted with EA (100 mL X 2). The combined organic phase was concentrated to dryness. The residue was purified by column chromatography (SiO2, PE/EA=20/1 to 5/1) to give desired phenol (5.2 g, 84.7% yield) as yellow oil. [0455] The above phenol (5.2 g, 19.3 mmol, 1 eq.) and K2CO3 (8.0 g, 57.9 mmol, 3 eq.) were dissolved in MeOH (50 mL) and H2O (50 mL). Then I2 (9.8 g, 38.6 mmol, 2 eq.) were added and stirred at 20 °C for 1 h. LCMS showed that the reaction was complete. The reaction was quenched by Na2SO3 (250mL) and stirred for 2 min. The aqueous phase was extracted with EA (150mL X 3). The combined organic phase was washed with brine (50 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=30/1 to 5/1) to give Intermediate 23-7 (4.1 g, 53.5% yield) as yellow oil. LCMS: ESI-MS: m/z 396.0 [M+H]+. [0456] 23.6 Preparation of Intermediate 23-11:
Figure imgf000166_0001
[0457] Intermediate 23-11 was prepared essentially as described in Example 1 for the preparation of Compound 1d by using Intermediate 23-7 as starting material. [0458] 23.7 Preparation of Intermediate 23-12:
Figure imgf000166_0002
[0459] To a solution of Intermediate 23-11 (2.25 g, 5.93 mmol, 1 eq.) in MeOH (30 mL) was added K2CO3 (410 mg, 2.97 mmol, 0.5 eq.). The mixture was stirred at 15 °C for 1 h. TLC (PE/EA=2/1) showed that the reaction was complete. The reaction mixture was diluted with H2O (100 mL), extracted with EA (100mL X 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=50/1 to 3/1) to give Intermediate 23-12 (1.8 g, 89.9% yield) as light yellow solid. [0460] 23.8 Preparation of Intermediate 23-13:
Figure imgf000167_0001
[0461] To a solution of Intermediate 23-12 (1.8 g, 5.34 mmol, 1.0 eq.) in DMF (40 mL) were added TBSCl (885 mg, 5.87 mmol, 1.1 eq.) and imidazole (727 mg, 10.67 mmol, 2 eq.). The mixture was stirred at 15 °C for 48 h. TLC indicated that the reaction was complete. The reaction mixture was diluted with H2O (50 mL), extracted with EA 120 mL (40mL X 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=100/1 to 3/1) to give Intermediate 23-13 (2.1 g, 87.1% yield) as a light yellow oil. LCMS: ESI-MS: m/z 469.9 [M+H2O+ H]+ . [0462] 23.9 Preparation of Intermediate 23-14:
Figure imgf000167_0002
[0463] To a mixture of MePh3P+Br- (2.96 g, 8.28 mmol, 2.2 eq.) in THF (20 mL) was added t-BuOK (760 mg, 6.78 mmol, 1.8 eq.). Then a solution of Intermediate 23-13 (1.7 g, 3.76 mmol, 1 eq.) in THF (5 mL) was added to the mixture at 0 °C. The resulting mixture was stirred at 50 °C for 1 h. TLC (PE/EA=10/1) showed that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA=100/1) to give Intermediate 23-14 (1.4 g, 82.3% yield) as light yellow oil. LCMS: ESI-MS: m/z 450.2 [M+H]+. [0464] 23.10 Preparation of Intermediate 23-18:
Figure imgf000168_0001
[0465] Preparation from Intermediate 23-14 to Intermediate 23-16 was essentially as described in Example 1 for the preparation of Compound 1d by using Intermediate 23-14 as starting material. [0466] Preparation from Intermediate 23-16 to Intermediate 23-18 was essentially as described in Example 14 for the preparation of Compound 14d by using Intermediate 23-16 as starting material. Single isomer Intermediate 23-18 could be separated by flash column. [0467] 23.11 Preparation of Intermediate 23-19:
Figure imgf000168_0002
[0468] Preparation of Intermediate 23-19 was essentially as described in Example 14 for the preparation of Compound 14d by using Intermediate 23-18 as starting material via 3 steps. [0469] 23.12 Preparation of Intermediate 23-20:
Figure imgf000169_0001
[0470] A mixture of Intermediate 23-19 (370 mg, 0.8 mmol, 1 eq.) in TFA (5 mL) was stirred at 15 °C for 30 min. TLC (PE/EA=3/1) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL), neutralized to pH=7-8 by saturated NaHCO3 solution, extracted with EA (20 mL X 2). The organic phase was concentrated to dryness. The residue was purified by column chromatography (SiO2, PE/EA=20/1 to 0/1) to give Intermediate 23-20 (203 mg, 70% yield) as a light yellow solid. LCMS: ESI-MS: m/z 363.9 [M+H]+. [0471] 23.13 Preparation of Compound 23d:
Figure imgf000169_0002
[0472] Intermediate 23-21 was prepared essentially as described in Example 5 for the preparation of Compound 5d. Compound 23d was prepared essentially as described in Example 1 for the preparation of Compound 1d by using amine 23-20 and acid 23-21 as starting materials. Finally, Compound 23d (45 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) δ = 8.72 (d, J=2.0 Hz, 1H), 8.61-8.58 (br t, J=6.0 Hz, 1H), 8.21-8.19 (m, 2H), 8.10 (d, J=2.4 Hz, 1H), 7.76 (s, 1H), 7.62 - 7.61 (m, 2H), 7.07-7.03 (t, J=8.8 Hz, 2H), 6.64-6.37 (t, J=54.4 Hz, 1H), 5.09 (d, J=9.2 Hz, 1H), 4.42 (d, J=9.2 Hz, 1H), 4.32-4.26 (m, 1H), 3.89-3.87 (m, 1H), 3.86 - 3.78 (m, 1H), 1.59 (s, 3H), 0.86 - 0.77 (m, 4H). LCMS: ESI-MS: m/z 627.0 [M+H]+. Example 24: Synthesis of Compound 24d [0473] 24.1 Preparation of Intermediate 24-2:
Figure imgf000170_0001
[0474] To a stirring mixture of pyridine iodine 24-1 (1.7 g, 6.66 mmol) in dioxane (11 mL, deoxygenated prior to use) was added PdCl2(dppf) (550 mg, 0.67 mmol), K2CO3 (2.8, 20 mmol), 3,4-difluorophenyl boronic acid (1.3 g, 8.0 mmol), water (1.5 mL). The reaction mixture was heated at 100 oC for 10 hours. The reaction mixture was diluted with EtOAc and an aqueous solution of citric acid (10%). A normal aqueous workup with ethyl acetate was followed. The crude product mixture was purified via a silica gel column to afford the desired product as a yellow solid. LC/MS 242 m/z [M+H]+. [0475] 24.2 Preparation of Intermediate 24-3:
Figure imgf000170_0002
[0476] To a stirring mixture of phenol 24-2 (1.0 g, 4.15 mmol) in DMF (17 mL) at 0 oC was added NaH (250 mg, 6.22 mmol, 60% by weight) over 5 min. The reaction mixture was stirred at 0 oC for 30 min before SEMCl (880 ^L) was added. The reaction mixture was stirred at 0 oC for 1 h before it was quenched with water and diluted with ethyl acetate/hex (1:1). A normal aqueous workup with ethyl acetate/hex (1:1) was followed. The crude product was purified a via a silica gel column to afford SEM ether 24-3 as a colorless oil. LC/MS 372 m/z [M+H]+. [0477] 24.3 Preparation of Intermediate 24-4:
Figure imgf000170_0003
[0478] To a stirring mixture of SEM ether 24-3 (1.8 g, 4.84 mmol) in THF (19 mL) at -78 oC was added a solution of n-BuLi (2.9 mL, 2.5 M) in hexane. The resulting mixture was stirred at - 78 oC for 1.5 h before a solution of iodine (1.23 g, 4.84 mmol) in THF (2 mL) was added. The resulting mixture was stirred for 2 h before it was quenched with a saturated NaHCO3 and Na2S2O3 (1:1). A normal aqueous work-up with ethyl acetate was followed. The crude product was purified via a silica gel column to afford the desired product. LC/MS 498 m/z [M+H]+. [0479] 24.4 Preparation of Intermediate 24-5:
Figure imgf000171_0001
[0480] Compound 24-4 was dissolved in a solution of HCl in dioxane (5 mL, 4 N). The reaction mixture was stirred at room temperature for 7 h before it was concentrated under reduced pressure. The crude product was azeotroped with toluene (3x 15 mL). This crude product was taken directly to the next reaction without further purification. [0481] 24.5 Preparation of Intermediate 24-6:
Figure imgf000171_0002
[0482] To a stirring mixture of crude phenol in DMF (10 mL) at room temperature was added Na2CO3 (1.5 g, 1.4 mmol) and 3-bromo-2-methylprop-1-ene (653 mg, 4.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and diluted with ethyl acetate/hexane (1:1). A normal aqueous work with ethyl acetate/hexane was followed. The crude product was purified via a silica gel column to afford the desired product as a colorless oil. LC/MS 422 m/z [M+H]+. [0483] 24.6 Preparation of Intermediate 24-7:
Figure imgf000171_0003
[0484] To a stirring mixture of compound 24-6 (600 mg, 1.42 mmol) in toluene (6 mL) was added Q-phos (200 mg, 0.28 mmol) and Pd2(dba)3 (128 mg). The reaction mixture was stirred at reflux for 15 h before it was concentrated under reduced pressure and purified via a silica gel to afford the desired product as a brownish oil. LC/MS 422 m/z [M+H]+. [0485] 24.7 Preparation of Intermediate 24-8:
Figure imgf000172_0001
[0486] To a stirring mixture of neopentyl iodide 24-7 (400 mg, 0.95 mmol) in DMF (3.8 mL) was added tetrabutylammonium acetate (516 mg, 1.7 mmol). The reaction mixture was heated at 90 oC for 1.5 h under a microwave irradiation condition. The reaction mixture was diluted with ethyl acetate/hex (1:1) and water. A normal aqueous work with ethyl acetate/hexane (1:1) was followed. The crude product was purified via a silica gel column to afford the desired product as a colorless oil. LC/MS 354 m/z [M+H]+. [0487] 24.8 Preparation of Intermediate 24-9:
Figure imgf000172_0002
[0488] Acetate 24-8 (250 mg, 0.7 mmol) was dissolved in a solution of NH3 in MeOH (5 mL, 7N). The reaction mixture was stirred at room temperature for 4 h before it was concentrated and purified via a silica gel column to afford 24-9 as the desired product. LC/MS 312 m/z [M+H]+. [0489] 24.9 Preparation of Intermediate 24-10:
Figure imgf000173_0001
[0490] To a stirring mixture of alcohol 24-9 (200 mg, 0.64 mmol) in DMF (2 mL) at room temperature was added TBSCl (166 mg, 1.1 mmol) and imidazole (150 mg, 2.2 mmol). The reaction mixture was stirred at rt for 6 h before it was diluted with ethyl acetate/hex (1:1) and quenched with water. A normal aqueous work-up with ethylacetate/hexane (1:1) was followed. The crude product was purified via a silica gel column to afford the desired product as a colorless oil. LC/MS 426 m/z [M+H]+. [0491] 24.10 Preparation of Intermediate 24-11:
Figure imgf000173_0002
[0492] To a stirring mixture of 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-7-(3,4- difluorophenyl)-3-methyl-2,3-dihydrofuro[2,3-c]pyridine (150 mg, 0.35 mmol) in DME/water (3.3 mL, 10:1, deoxygenated prior to use) were added 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1- en-2-yl)-1,3,2-dioxaborinane (321 mg, 1.4 mmol), Cs2CO3 (350 mg, 1.1 mmol), PdCl2(dppf) (115 mg, 0.14 mmol). The resulting mixture was heated at 110 oC for 4 h under microwave irradiation condition. The crude mixture was concentrated under reduced pressure and purified via a silica gel column to afford the desired product as a colorless oil (130 mg). LC/MS 486 m/z [M+H]+. [0493] 24.11 Preparation of Intermediate 24-12:
Figure imgf000174_0001
[0494] To a stirring mixture of alkene 24-11 (130 mg, 0.267 mmol) in t-BuOH/water (0.6 mL each) at 0 oC was added AD-mix ^ (910 mg) and NH2SO2Me (29 mg, 0.29 mmol). The resulting mixture was stirred at 0 oC for ~ 12 h and warmed up to room temperature overnight. The reaction mixture was quenched with a saturated Na2S2O3 solution and diluted with ethyl acetate. A normal aqueous workup with EtOAc was followed. The crude mixture was purified via a silica gel column. The less polar (peak 1) diastereomer was separated and taken to the next reaction. LC/MS 520 m/z [M+H]+. [0495] 24.12 Preparation of Intermediate 24-13:
Figure imgf000174_0002
[0496] To a stirring mixture of diol 24-12 (50 mg, 0.096 mmol) in THF (0.8 mL) at 0 oC was added NaH (12 mg, 0.29 mmol, 60% by weight). The reaction mixture was stirred at 0 oC for 30 min before TsCl (20.2 mg, 0.11 mmol) was added. The resulting mixture was stirred for 1 h at 0 oC before it was diluted with ethyl acetate and quenched with water. A normal aqueous workup with EtOAc was followed. The crude mixture was purified via a silica gel column to afford the desired epoxide as a colorless oil. LC/MS 502 m/z [M+H]+. [0497] 24.13 Preparation of Intermediate 24-14:
Figure imgf000175_0001
[0498] To a stirring mixture of epoxide 24-13 (48 mg, 0.095 mmol) in DMF (1.9 mL) at room temperature was added dropwise a solution of NH4OH (160 ^L) dropwise over 10 min. The reaction mixture was stirred at rt for 12 h before it was concentrated under reduced pressure and azeotroped with toluene (3 x 5 mL) and concentrated under reduced pressure. The crude amine was taken directly to the next reaction without further purification. LC/MS 519 m/z [M+H]+. [0499] 24.14 Preparation of Intermediate 24-15:
Figure imgf000175_0002
[0500] To a stirring mixture of 8-cyclopropoxyquinoline-6-carboxylic acid (28 mg, 0.12 mmol) in DMF (1.0 mL) was added HATU (45 mg, 0.12 mmol), followed by DIPEA (39 mg, 0.31 mmol). The resulting mixture was stirred for 5 min before a solution of the crude amine in DMF was added. The mixture was stirred for 15 min before it was subjected directly to a silica gel column to afford the TBS ether as a colorless oil. LC/MS 730 m/z [M+H]+. [0501] 24.15 Preparation of Intermediate 24-16:
Figure imgf000176_0001
[0502] TBS ether 24-15 was dissolved in a solution of HCl in dioxane (5 mL, 4N). The reaction mixture was stirred at rt for 30 min before it was concentrated under reduced pressure and purified via HPLC to afford the desired product as a white powder (45 mg). LC/MS 616 m/z [M+H]+. [0503] 24.16 Preparation of Intermediate 24-17:
Figure imgf000176_0002
[0504] To a stirring mixture of alcohol 24-16 (45 mg, 0.074 mmol) in AcCN/water (1.1 mL; 10:1) were added BAIB (68 mg, 0.22 mmol) and TEMPO (34 mg, 0.22 mmol). The resulting mixture was stirred at rt for 3 h before it was subjected directly to the HPLC to afford the desired acid as a white powder (22 mg). LC/MS 630 m/z [M+H]+. [0505] 24.17 Preparation of Compound 24d:
Figure imgf000176_0003
[0506] To a stirring mixture of acid 24-17 (22mg, 0.035 mmol) in AcCN (1.0 mL) was added HATU (15 mg, 0.039 mmol) and DIPEA (13.5 mg, 0.1 mmol). The resulting mixture was stirred for 5 min before NH4Cl (13 mg, 0.245 mmol) was added. The reaction mixture was stirred for 15 min before it was purified via HPLC to afford the desired product as a white solid (12 mg). 1H NMR (400 MHz, CD3OD): ^ 8.79-8.78 (m, 1H), 8.25- 8.22 (m, 1H), 8.13-8.04 (m, 2H), 7.87 (s, 1H), 7.76-7.75 (m, 1H), 7.62-7.61 (m, 1H), 7.55-7.52 (m, 1H), 7.27-7.22 (m, 1H), 5.16 (d, J = 9 Hz, 1H), 4.57 (d, J = 13.7 Hz, 1H), 4.48 (d, J = 9 Hz, 1H), 3.97 (d, J = 13.7 Hz, 1H), 3.92-3.87 (m, 1H), 1.63 (s, 3H), 0.85- 0.78 (m, 4H); LC/MS 629 m/z [M+H]+. Example 25: Synthesis of Compound 25d [0507] 25.1 Preparation of Intermediate 25-2:
Figure imgf000177_0001
[0508] To a stirring mixture of ester 25-1 (30 mg, 0.093 mmol) in EtOH (0.5 mL) at room temperature was added a solution of NaOH (140 ^L, 2 N). The reaction mixture was stirred at rt for several hours before it was acidified with an aqueous HCl (10%) solution. The crude mixture was azeotroped with toluene (3 x 10 mL) under reduced pressure. The crude product was taken directly to the next reaction without further purification.
Figure imgf000177_0002
[0509] Compound 25d was synthesized using the same procedure that was previously described in the synthesis of Compound 5d by using acid 25-2 and amine 25-3. The crude product was purified via HPLC to afford the desired product as a white solid.1H NMR (400 MHz, CD3OD): ^ 8.76- 8.75 (m, 1H), 8.31-8.3 (m, 1H), 8.23- 8.2 (m, 2H), 7.83 (s, 1H), 7.60 – 7.56 (m, 2H), 7.11- 7.09 (m, 2H), 5.13 (d, J = 9 Hz, 1H), 4.61 (d, J = 13.7 Hz, 1H), 4.45 (d, J = 9 Hz, 1H), 3.91 (d, J = 13.7 Hz, 1H), 3.82- 3.80 (m, 1H), 1.65 (s, 3H), 0.81- 0.76 (m, 4H); LC/MS 691 m/z [M+H]+. Example 26: Synthesis of Compound 26d
Figure imgf000178_0001
[0510] Compound 26d was synthesized using the same procedure that was previously descried to the synthesis of Compound 24d from step 14-17, except 2,2-difluoroethan-1-amine was used in step 17 instead of NH4Cl. The crude product was purified via HPLC to afford the desired product as a light-yellow powder.1H NMR (400 MHz, CD3OD): ^ 8.25-8.22 (m, 2H), 7.81 (s, 1H), 7.68 (s, 1H), 7.50 – 7.45 (m, 2H), 7.14 – 7.10 (m, 2H), 5.89 (tt, J = 56.3, 4.3 Hz, 1H), 5.10 (d, J = 9.3 Hz, 1H), 4.64 (d, J = 13.7 Hz, 1H), 4.5 (d, J = 9.3 Hz, 1H), 3.92- 3.82 (m, 2H), 3.59-3.51 (m, 2 H), 2.83 (s, 3H), 1.67 (s, 3H), 0.88 – 0.8 (m, 4H); LC/MS 690 m/z [M+H]+. Example 27: Synthesis of Compound 27d
Figure imgf000179_0001
[0511] Compound 27d was synthesized using the same procedure that was previously descried to the synthesis of Compound 16d by using acid 27-1 (prepared as described for Compound 22d, using Intermediate 22-2 as starting material, and using zinc cyanide) and amine 27-2. The crude product was purified via HPLC to afford the desire product as a white powder. 1H NMR (400 MHz, CD3OD): ^ 8.97 – 8.97 (m, 1H), 8.97 (d, J= 1.57 Hz, 1H), 8.22- 8.19 (m, 2H), 7.80 (s, 1H), 7.71 (s, 1H), 7.37 (s, 1H), 7.10 (t, J = 9 Hz, 2 H), 5.11 (d, J = 9 Hz, 1H), 4.76 (d, J = 13.7 Hz, 1H), 4.45 (d, J = 9 Hz, 1H), 3.84 (d, J = 13.7 Hz, 1H), 2.77 (s, 3H), 1.64 (s, 3H); LC/MS 624 m/z [M+H]+. Example 28: Synthesis of Compound 28d
Figure imgf000180_0001
[0512] Compound 28d was synthesized using similar procedure that was described to the synthesis of Compound 26d using acid 28-1 (prepared as described for acid 27-1, using Intermeidate 22-2 as starting material) and amine 28-2 as the starting intermediates. The product was purified via HPLC to afford Compound 28 as a white solid.1H NMR (400 MHz, CD3OD): ^ 8.97 (d, J = 1.95 Hz, 1H), 8.60 (d, J = 1.96 Hz, 1H), 8.23 – 8.2 (m, 2H), 7.80 (s, 1H), 7.69 (d, J = 1.57 Hz, 1H), 7.36 (d, J = 1.57 Hz, 1H), 7.13 – 7.08 (m, 2H), 5.91 (tt, J = 56.3, 4.3 Hz, 1H), 5.1 (d, J = 9.38 Hz, 1H), 4.63 (d, J = 13.7 Hz, 1H), 4.49 (d, J = 9.4 Hz, 1H), 3.94 (s, 3H), 3.86 (d, J = 13.7 Hz, 1H), 3.61 – 3.52 (m, 2 H), 1.66 (s, 3H); LC/MS 674 m/z [M+H]+. Example 29: Synthesis of Compound 29d
Figure imgf000181_0001
[0513] 29.1 Preparation of Intermediate 29-2: [0514] 4-tert-Butyl-1-methyl-2-(triphenylphosphoranylidene)succinate (1.3 g) and 3- trifluoromethylnicotinaldehyde (0.50 g) were heated at reflux in toluene (2 mL) for 1 h. The reaction mixture was chromatographed (ethyl acetate). Yield = 0.66 g. LC/MS: [M+H] 345.95. [0515] 29.2 Preparation of Intermediate 29-3: [0516] Trifluroacetic acid (0.51 ml, 3.0 eq) was added to 29-2 (0.66 g) in CH2Cl2 (0.5 mL) and stirred at r.t. for 1 h. The reaction mixture was concentrated, and the product was used without further purification. LC/MS: [M+H] 290.90. [0517] 29.3 Preparation of Intermediate 29-4: [0518] Sodium acetate (0.22 g, 1.2 eq) was added to crude 29-3 in acetic anhydride (2 mL). The reaction was heated in the microwave at 160 oC for 45 minutes. The reaction was concentrated and chromatographed (hexane/ethyl acetate). Yield = 0.25 g. LC/MS: [M+H] 313.99. [0519] 29.4 Preparation of Intermediate 29-5: [0520] Compound 29-4 (0.25 g) was dissolved in methanol (20 mL). Cesium carbonate (100 mg) was added and the reaction was stirred at r.t. for 15 minutes. The reaction was acidified with 2 N HCl and extracted with ethyl acetate. The product was purified by column chromatography (hexane/ethyl acetate). Yield = 0.25g. LC/MS: [M+H] 271.96. [0521] 29.5 Preparation of Intermediate 29-6: [0522] Iodomethane (0.3 mL, 5 eq) was added to a solution of 29-5 (0.25 g) and cesium casrbonate (3.0 g, 15 eq) in DMF (0.5 mL). The reaction was stirred at r.t. for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The product was purified by column chromatography (hexane/ethyl acetate). Yield = 0.25g. LC/MS: [M+H] 285.99. [0523] 29.6 Preparation of Intermediate 29-7: [0524] 2 N NaOH (1 mL) was added to a solution of 29-6 in methanol (5 mL). The reaction was stirred at r.t. for 1 h. The reaction was acidified with 2 N HCl and extracted with ethyl acetate. The product was used without further purification. Yield= 0.19 g. [0525] 29.7 Preparation of Intermediate 29-8: [0526] (R)-5-((S)-3-Amino-1,1,1-trifluoro-2-hydroxypropan-2-yl)-7-(4-fluorophenyl)-3- methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carbonitrile (2-8, 30 mg), 29-7 (25 mg), and HATU (30 mg) were dissolved in DMF (0.5 mL). DIEA (20 µL) was added and the reaction was stirred in DMF for 1h. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate and brine. The crude product was purified by column chromatography (hexane/ethyl acetate). Yield = 40 mg. LC/MS: [M+H] 635.09. [0527] 29.8 Preparation of Compound 29d: [0528] 30% H2O2 (60 µL) was added to a solution of 29-8 (40 mg) and potassium carbonate (60 µL) in DMSO (0.5 mL). The reaction was stirred at r.t. for 2 h. The reaction was purified by reverse-phase HPLC to afford the title compound. Yield = 20.8 mg. LC/MS: [M+H] 653.00. 1H NMR (400 MHz, CDCl3): ^ 9.15 (d, J = 2.0, 1H), 8.83 (s, 1H), 8.75 (t, J = 5.9, 1H), 8.22-8.26 (m, 2H), 8.1 (s, 1H), 7.9 (s, 1H), 7.l6 (s, 1H), 7.5 (s, 1H), 7.14 (s, 1H), 7.25-7.28 (m, 3H), 5.17 (d, J = 8.6, 1H), 4.37 (d, J = 8.6, 1H), 4.25 (dd, J = 14.08, 6.26, 1H), 4.11 (dd, J = 14.08, 5.47, 1H), 3.97 (s, 3H), 1.50 (s, 3H). Example 30: Synthesis of Compound 30d
Figure imgf000183_0001
[0529] Compound 30d was synthesized using the same procedure that was previously descried to the synthesis of Compound 24d except methylamine was used in step 17 instead of NH4Cl. The crude product was purified via HPLC to afford the desired product as a white powder.1H NMR (400 MHz, CD3OD): ^ 8.94 (dd, J = 4.3, 1.56 Hz, 1H), 8.44 (b s, 1H), 8.22 - 8.15 (m, 3H), 7.81 (s, 1H), 7.66 (d, J = 1.56 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.11 – 7.07 (m, 2H), 5.11 (d, J = 9.4 Hz, 1H), 4.69 (d, J = 13.7 Hz, 1H), 4.55 (s, 1H), 4.4 (d, J = 9.4 Hz, 1H), 3.84- 3.80 (m, 2H), 2.75 (s, 3H), 1.64 (s, 3H), 0.79- 0.76 (m, 4H); LC/MS 625 m/z [M+H]+. Example 31: Synthesis of Compound 31e
Figure imgf000183_0002
[0530] Compound 31e was synthesized using the same procedure that was previously described to the synthesis of Compound 24d except (1S,2R)-2-fluorocyclopropan-1-amine hydrochloride salt was used in step 17 instead of NH4Cl. The crude product was purified via HPLC to afford the desired product as a white powder.1H NMR (400 MHz, CD3OD): ^ 8.80 (dd, J = 4.3, 1.6 Hz, 1H), 8.23-8.17 (m, 3H), 7.76 (s, 1H), 7.7 (d, J = 1.96 Hz, 1H), 7.54 (dd, J = 8.22, 4.3 Hz, 1H), 7.26 (d, J = 1.56 Hz, 1H), 7.11- 7.07 (m, 2H), 5.11 (d, J = 9.4 Hz, 1H), 4.83 – 4.65 (m, 1H), 4.56 – 4.47 (m, 3H), 3.96- 3.93 (m, 1H) 3.93 (s, 3H), 2.65 – 2.60 (m, 1H), 1.64 (s, 3H), 1.26- 2.40 (m, 2H); LC/MS 643 m/z [M+H]+. Example 32: Synthesis of Compound 32d
Figure imgf000184_0001
[0531] Compound 32d was synthesized using the same procedure that was previously described to the synthesis of Compound 24d. The crude product was purified via HPLC to afford the desired product as a white powder.1H NMR (400 MHz, DMSO-d6): ^ 9.34 (s, 1H), 8.62- 8.60 (m, 1H), 8.26 – 8.22 (m, 2H), 8.02 (d, J = 1.57 Hz, 1H), 7.83 – 7.82 (m, 1H), 7.78 (s, 1H), 7.32 – 7.27 (m, 3H), 7.21 (s, 1H), 5.11 (d, J = 9 Hz, 1H), 4.38 (d, J = 9.0 Hz, 1H), 4.25 – 4.21 (m, 1H), 4.07 – 4.02 (m, 1H), 3.92 (s, 3H), 2.60 (s, 3H), 1.50 (s, 3H); LC/MS 605 m/z [M+H]+. Example 33: Synthesis of Compound 33d
Figure imgf000184_0002
[0532] Compound 33d was synthesized using the same procedure that was previously described to the synthesis of Compound 24d. The crude product was purified via HPLC to afford the desired product as a white powder.1H NMR (400 MHz, CD3OD): ^ 8.81- 8.79 (m, 1H), 8.32 (d, J = 1.95 Hz, 1H), 8.25 – 8.21 (m, 2H), 7.80 (s, 1H), 7.59 (s, 1H), 7.28 (s, 1H), 7.14- 7.09 (m, 2H), 5.14 (d, J = 9.0 Hz, 1H), 4.6 (d, J = 13.1 Hz, 1H), 4.55 (b s, 1H), 4.45 (d, J = 9 Hz, 1H), 3.94 (s, 3H), 3.90 (d, J = 14 Hz, 1H), 1.65 (s, 3H) ; LC/MS 665 m/z [M+H]+. Example 34: Synthesis of Compound 34d
Figure imgf000185_0001
[0533] Compound 34d was synthesized using the same procedure that was previously descried to the synthesis of Compound 24d except 2,2-difluorocyclopropan-1-amine was used in step 17 instead of NH4Cl. The crude product was purified via HPLC to afford the desired product as a white powder.1H NMR (400 MHz, CD3OD): ^ 8.81 – 8.80 (m, 1H), 8.22 – 8.17 (m, 3H), 7.79- 7.76 (m, 1H), 7.68 – 7.67 (m, 1H), 7.56 – 7.53 (m, 1H), 7.25- 7.23 (m, 1H), 7.1 – 7.05 (m, 2H), 5.11 (d, J = 9 Hz, 1H), 5.05 (d, J = 9.0 Hz, 1H), 4.65 (m, 4H), 3.92 (m, 3H), 3.24 (m, 1H), 1.64 (s, 3H), 1.60- 0.9 (m, 1H); LC/MS 661 m/z [M+H]+. Example 35: Synthesis of Compound 35d
Figure imgf000185_0002
[0534] Compound 35d was synthesized using the same procedure that was previously descried to the synthesis of Compound 24d.1H NMR (400 MHz, DMSO-d6): ^ 8.72 (t, J = 5.47 Hz, 1H), 8.27- 8.23 (m, 2H), 8.12 (d, J = 10.2 Hz, 1H), 7.85 (m, 2H), 7.78 (s, 1H), 7.35 – 7.22 (m, 4H), 5.43 (t, J = 5.48 Hz, 1H), 5.11 (d, J = 9.0 Hz, 1H), 4.71 (d, J = 5.4 Hz, 2H), 4.38 (d, J = 8.6 Hz, 1H), 4.24 (dd, J = 14, 5.9 Hz, 1H), 4.07 (dd, J = 14, 5.9 Hz, 1H), 3.92 (s, 3H), 2.60 (s, 3H), 2.6 (b s 1H), 1.49 (s, 3H); LC/MS 647 m/z [M +H]+. Example 36: Synthesis of Compound 36d
Figure imgf000186_0001
[0535] Compound 36d was synthesized using the same procedure that was previously descried to the synthesis of Compound 16d. The crude product was purified via HPLC to afford the desired product as a white solid.1H NMR (400 MHz, DMSO-d6): ^ 8.84 (d, J = 2.4 Hz, 1H), 8.71 (t, J = 5.87 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.26 – 8.25 (m, 2H), 7.84 – 7.83 (m, 2H), 7.78 (s, 1H), 7.41 – 7.38 (m, 1H), 7.31 (m, 2H), 7.18 (s, 1H), 5.11 (d, J = 9 Hz, 1H), 4.4 (d, J = 9.0 Hz, 1H), 4.26 (dd, J = 13.7, 6.3 Hz, 1H), 4.04 (dd, J = 14, 8.6 Hz, 1H), 3.92 (s, 3H), 2.60 (s, 3H), 1.49 (s, 3H); LC/MS 633 m/z [M+H]+. Example 37: Synthesis of Compound 37d
Figure imgf000186_0002
[0536] Compound 37d was synthesized using the procedure that was previously described to the synthesis of Compound 13d.1H NMR (400 MHz, DMSO-d6): ^ 9.02 (d, J = 1.96 Hz, 1H), 8.72 (t, J = 5.87 Hz, 1H), 8.56 (d, J = 1.2 Hz, 1H), 8.40 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 1.2 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.55 (s, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.30 (tt, J = 55, 3.9 Hz, 1H), 5.18 (d, J = 9 Hz, 1H), 4.41 (d, J = 9 Hz, 1H), 4.26 (dd, J = 14, 6.3 Hz, 1H), 4.11 (dd, J = 13.7, 5.47 Hz, 1H), 3.95 (s, 3H), 1.5 (s, 3H); LC/MS 685 m/z [M+H]+. Example 38: Synthesis of Compound 38d
Figure imgf000187_0001
[0537] Compound 38d was synthesized using the procedure that was previously described to the synthesis of Compound 26d.1H NMR (400 MHz, DMSO-d6): ^ 8.75- 8.74 (m, 1H), 8.39 (d, J = 8.22 Hz, 2H), 7.86 (d, J = 13.3 Hz, 2H), 7.83 – 7.79 (m, 3H), 7.66 (d, J = 1.18 Hz, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 5.17 (d, J = 9 Hz, 1H), 4.4 (d, J = 9 Hz, 1H), 4.24 (dd, J = 8.22, 7.43 Hz, 1H), 2.81 (s, 3H), 1.5 (s, 3H), 0.87- 0.78 (m, 4H); LC/MS 676 m/z [M+H]+. Examples 39a and 39b: Synthesis of Compounds 39d and 40d
Figure imgf000188_0001
[0538] 39.1 Preparation of Intermediate 39-1: [0539] Methacrolein (0.25 g) was added to a suspension of methyl 4-amino-3- methoxybenzoate (300 mg) and the resulting mixture was heated at 100 °C for 4 h. The reaction was concentrated and the crude acid purified by HPLC. LC/MS: [M+H] 218.70. [0540] 39.2 Preparation of Intermediate 39-2: [0541] DIEA (20 µL) was added to a solution 39-1A (55 mg), 39-1 (25 mg) and HATU (39 mg) in DMF (0.5 mL). The solution was stirred at r.t. for 1 h. The reaction was diluted with ethyl acetate, washed with 1N HCl, saturated sodium bicarbonate and brine. It was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (hexane/ethyl acetate). Yield = 60 mg. LC/MS: [M+H] 700.20. [0542] 39.3 Preparation of Intermediate 39-3: [0543] 39-2 (60 mg) was dissolved in 4N HCl/dioxane and the resulting solution was stirred at r.t. for 3h. The reaction was concentrated and purified by HPLC. Yield = 45 mg. LC/MS: [M+H] 586.00. [0544] 39.4 Preparation of Intermediate 39-4: [0545] TEMPO (72 mg) was added to a solution of 39-3 (45 mg) and BAIB (90 mg) in acetonitrile (1 mL) and water (0.1 mL). The reaction was stirred at r.t. for 1 h. The reaction was diluted with ethyl acetate, washed with Na2S2O3 and brine, dried and concentrated. The product was purified by HPLC. LC/MS: [M+H] 600.00. Example 39a: Preparation of Compound 39d: [0546] HATU (14 mg) was added to a solution of 39-4 (20 mg, DIEA (18 mg) and methylamine hydrochloride (7 mg) in DMF (0.5 ml). The reaction was stirred at r.t. for 1 h and then purified by HPLC. Yield = 6.2 mg. LC/MS: [M+H] 613.10. 1H NMR (400 MHz, dmso- d6): ^ 8.69-8.72 (m, 2H), 8.22-8.27 (m, 2H), 7.95 (s, 1H), 7.84-7.85 (m, 1H), 7.77-7.88 (m, 2H), 7.27-7.32 (m, 3H), 5.11 (d, J = 9.0 Hz, 1H), 4.38 (d, J = 9.0 Hz, 1H), 4.25 (dd, J = 13.7, 6.31 Hz, 1H), 4.05 (dd, J = 13.7, 5.1 Hz, 1H), 3.90 (s, 3H), 2.59 (d, J = 4.3 Hz, 1H), 2.43 (s, 3H), 1.45 (s, 3H). Example 39b: Preparation of Compound 40d: [0547] Compound 40d was synthesized in the same manner as Compound 39d, except that difluoroethylamine (8 µL) was substituted for the methyl amine. LC/MS: [M+H] 663.05.1H NMR (400 MHz, dmso-d6): ^ 8.68-8.73 (m, 2H), 8.02-8.35 (m, 1H), 8.23-8.27 (m, 2H), 7.99 (s, 1H), 7.82 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.28-7.32 (m, 3H), 5.81-6.09 (m, 1H), 5.10 (d, J = 9.0 Hz, 1H), 4.43 (d, J = 9.0 Hz, 1H), 4.22 (dd, J = 13.7, 6.3 Hz, 1H), 4.12 (dd, J = 13.7, 5.5 Hz, 1H), 3.42-3.92 (m, 2H), 1.53 (s, 3H). Example 40: Synthesis of Compound 41d
Figure imgf000190_0001
[0548] 40.1 Preparation of Compound 40-2: [0549] Pd(dppf)Cl2 (0.26g) was added to a solution of ethyl 2-chloro-2-fluoro- 8methoxyquinoline-6-carboxylate (0.2 g), cesium carbonate (0.81g) and vinylboronic acid pinacol ester (0.24 ml) in dimethoxyethane (2 ml) and water (0.3 ml). The resulting solution was heated under microwave irradiation at 110 °C for 90 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The product was purified by column chromatography (hexane/ethyl acetate). Yield = 0.11g. LC/MS: [M+H] 275.99. [0550] 40.2 Preparation of Compound 40-3: [0551] Osmium tetroxide (4%, 0.53 mL) was added to a solution of 40-2 (110 mg), 4- methylmorpholine-N-oxide (74 mg), and sodium periodate (0.18g) in t-butanol (2ml) and water (2 ml). The resulting solution was stirred at r.t. for 3h. The reaction was quenched with saturated Na2S2O3 and extracted with ethyl acetate. The ethyl acetate extracts were concentrated, and the crude material was immediately re-dissolved in methanol (1 mL). Sodium borohydride (20 mg) was added and the reaction was stirred at r.t. for 1 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The desired alcohol was purified by column chromatography (hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3): ^ 8.11 (s, 3H), 7.80 (d, J = 1.75 Hz, 1H), 7.61 (s, 1H), 4.99 (s, 2H), 4.41-4.47 (m, 2H), 4.10 (s, 3H), 1.42-1.46 (m, 3H). Yield = 30 mg. [0552] 40.3 Preparation of Compound 40-4: [0553] DAST (17 µL) was added to a solution of 40-3 (30 mg) in CH2Cl2 (1 mL) at -78 oC and slowly warmed to r.t. for 30 minutes. The reaction was diluted with ethyl acetate, washed with 1N HCl, and brine, dried and concentrated. The product was purified by column chromatography. Yield = 7 mg. LC/MS: [M+H] 282.10. [0554] 40.4 Preparation of Compound 40-5: [0555] 2 N NaOH (0.2 mL) was added to a solution of 40-4 (7 mg) in ethanol (0.75 mL) and the resulting solution was stirred at r.t. for 1 h. The reaction was acidified with 2 N HCl and extracted with ethyl acetate. The crude acid was used without further purification. Yield = 4 mg. LC/MS: [M+H] 253.99. [0556] 40.5 Preparation of Compound 41d: [0557] DIEA (4 µL) was added to a solution of (S)-5-((S)-3-amino-1,1,1-trifuloro-2- hydroxypropan-2-yl)-7-(4-fluorophenyl)-3-methyl-2,3-dihydrofuro[2,3-c] pyridine-3- carboxamide (8 mg), 40-5 (4 mg), and HATU (7 mg) in DMF (0.4 mL) and the resulting reaction was stirred at r.t. for 1 h. The reaction was purified by HPLC. Yield = 2.1 mg. LC/MS: [M+H] 635.10. 1H NMR (400 MHz, dmso-d6): ^ 8.75 (t, J = 5.87 Hz, 1H), 8.29 (d, J = 10.17 Hz, 1H), 8.22-8.26 (m, 2H), 7.91 (s, 1H), 7.85 (s, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.27-7.35 (m, 3H), 5.72 (d, J = 46.95 Hz, 2H), 5.15 (d, J = 9.0 Hz, 1H), 4.37 (d, J = 9.0 Hz, 1H), 4.22 (dd, J = 13.69, 6.26 Hz, 1H), 4.11 (dd, J = 14.08, 5.86 Hz, 1H), 3.91 (s, 3H), 1.49 (s, 3H). Example 41: Synthesis of Compound 42e [0558] 41.1 Preparation of Intermediate 41-2:
Figure imgf000191_0001
[0559] Intermediate 41-1 was prepared essentially as described in the preparation of Compound 1d. To a solution of Intermediate 41-1 (80 mg, 0.13 mmol, 1.0 eq.) and (2S)-2-(tert- butoxycarbonylamino)-3-methyl-butanoic acid (66 mg, 0.3 mmol, 2.4 eq.) in THF (10 mL) were added DCC (63 mg, 0.3 mmol, 2.4 eq.) and DMAP (15.4 mg, 0.13 mmol, 1 eq.). The resulting mixture was stirred at 50 °C for 20 min. TLC (PE/EA=3/1) showed that Intermediate 41-1 was consumed completely. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~80% EA/PE gradient @ 30 mL/min). Intermediate 41-2 (61 mg, 57% yield) was obtained as a white solid. LCMS: ESI-MS: m/z 854.5 [M+Na]+. [0560] 41.2 Preparation of Compound 42e:
Figure imgf000192_0002
[0561] A solution of Intermediate 41-2 (50 mg, 0.06 mmol, 1 eq.) in HCl/dioxane (4 M, 1 mL, 66 eq.) was stirred at 20 °C for 5 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeCN (10 mL) and saturated aqueous NaHCO3 (3 mL). The result mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC column: Gemini 150*255u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 45%-75%,10min), then lyophilized to give a free base. The obtained compound was dissolved in MeCN (3 mL) and HCl solution (0.05M, 1mL), and lyophilized. Compound 42e (36 mg, 81.13% yield, 99.12% purity) was obtained as a white solid.1H NMR (400 MHz, CD3CN) δ= 8.24-8.20 (m, 2H), 7.90 (d, J=10.4 Hz, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.29 - 7.10 (m, 3H), 5.64 (d, J=14.0 Hz, 1H), 5.52 (d, J=14.0 Hz, 1H), 5.12 (d, J=9.2 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.45 (d, J=9.2 Hz, 1H), 4.02 - 3.88 (m, 5H), 2.40 - 2.30 (m, 1H), 1.64 (s, 3H), 1.05 (t, J=7.4 Hz, 6H). LCMS: ESI-MS: m/z 754.1 [M+Na]+. Example 42: Synthesis of Compound 43d [0562] 42.1 Preparation of Intermediate 42-2:
Figure imgf000192_0001
[0563] Preparation of Intermediate 42-1 can be referred to the Reference: WO2018/81276, 2018, A1. Intermediate 42-5 was prepared essentially as described in the preparation of Compound 2d. A mixture of Intermediate 42-1 (400 mg, 1.32 mmol, 1.0 eq.), potassium trifluoro(vinyl)boranuide (354 mg, 2.64 mmol, 2.0 eq.), Pd(dppf)Cl2 (193 mg, 0.264 mmol, 0.2 eq) and Cs2CO3 (1.08 g, 3.30 mmol, 2.5 eq.) in co-solvent of dioxane (5.0 mL) and H2O (0.85 mL) was taken up into a microwave tube. The tube was sealed and heated at 110 °C for 30 min. under microwave irradiation. The mixture was cooled to 20°C and poured into 5% Na2CO3 solution (10 mL) and EA (15 mL), and stirred for 2 min. After separation, the aqueous phase was extracted with EA (15 mL X 3). The combined organic phase was washed with brine (10 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography using 20% EA in PE to afford Intermediate 42-2 (245 mg, 74.5% yield) as white solid. LCMS: ESI-MS: m/z 249.9 [M+H]+. [0564] 42.2 Preparation of Intermediate 42-3:
Figure imgf000193_0001
[0565] To a mixture of Intermediate 42-2 (250 mg, 1.0 mmol, 1.0 eq.) and NMO (176 mg, 1.5 mmol, 1.5 eq.) in co-solvent of t-BuOH (3 mL) and H2O (3 mL) was added OsO4 (51 mg, 0.2 mol, 0.2 eq.) in one portion at 20°C. The mixture was stirred at 20 °C for 2 h. Then NaIO4 (428 mg, 2.0 mmol, 2.0 eq.) was added. The mixture was stirred at 20 °C for 2 h before poured into saturated aqueous Na2SO3 (10 mL). The aqueous phase was extracted with EA (15 mL X 3). The combined organic phases were washed with brine (10 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. [0566] The residue was dissolved in MeOH (5.0 mL), then NaBH4 (189 mg, 5.0 mmol, 5.0 eq) was added and the solution was stirred at 20 °C for 0.5 h. TLC (DCM: MeOH = 20:1) showed that the reaction was completed. The mixture was poured into saturated aqueous NH4Cl (10 mL). The aqueous phase was extracted with EA (15 mL X 3). The combined organic phase was washed with brine (10 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography using 5% MeOH in DCM to afford Intermediate 42-3 (220 mg, 85.1% yield) as yellow solid. LCMS: ESI-MS: m/z 253.8 [M+H]+. [0567] 42.3 Preparation of Intermediate 42-4:
Figure imgf000193_0002
[0568] To a solution of Intermediate 42-3 (210 mg, 0.83 mmol, 1.0 eq.) in MeOH (2.0 mL) was added NaOH (2 M, 1.66 mL, 4.0 eq.) in one portion. Then the resulting mixture was stirred at 50 °C for 1 h. LCMS trace showed the reaction was completed. The mixture was adjusted to pH = 3 by HCl solution (1 M). Then the precipitate was filtered and dried in vacuum to afford Intermediate 42-4 (180 mg, 90.7% yield) as yellow solid. LCMS: ESI-MS: m/z 239.8 [M+H]+. [0569] 42.4 Preparation of compound Compound 43d:
Figure imgf000194_0001
[0570] To a mixture of Intermediate 42-4 (105 mg, 0.44 mmol, 3.5 eq.), HATU (71 mg, 0.19 mmol, 1.5 eq.) and DIPEA (49 mg, 0.38 mmol, 3 eq.) in DMF (2 mL) was added Intermediate 42-5 (50 mg, 0.12 mmol, 1 eq.). Then the mixture was stirred at 25 °C for 20 min. LCMS trace showed that the reaction was completed. Then the reaction mixture was diluted with H2O (25 mL), and extracted with EA (10 mL X 3). The resulting solution was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Xtimate C18150*25mm*5um; mobile phase: [water (0.225%FA)- ACN]; B%: 32%-62%,8min) to give Compound 43d (31 mg, 39% yield, 100% purity) as a white solid.1H NMR (400MHz, MeOD) δ = 8.64 (t, J=5.8 Hz, 1H), 8.30 - 8.24 (m, 2H), 8.02 (d, J=1.6 Hz, 1H), 7.89 (s, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.37 - 7.31 (m, 3H), 7.29 (s, 1H), 6.38 - 6.29 (t, J=6.0 Hz, 1H), 5.19 (d, J=9.2 Hz, 1H), 4.84 (d, J=6.0 Hz, 2H), 4.40 (d, J=8.8 Hz, 1H), 4.27 - 4.08 (m, 2H), 3.92 (s, 3H), 1.53 (s, 3H). LCMS: ESI-MS: m/z 621.1 [M+H]+. Example 43: Synthesis of Compound 44c
Figure imgf000195_0001
[0571] Intermediate 43-1 was prepared essentially as described in the preparation of Compound 7b. Compound 44c was prepared essentially as described in the preparation of Compound 42e by using Intermediate 43-1 as starting material. Finally, Compound 44c (95 mg) was obtained as white solid.1H NMR (400MHz, DMSO-d6) ^ ^= 8.88 (br s, 1H), 8.45 (br s, 3H), 8.32 - 8.26 (m, 3H), 7.95 (s, 1H), 7.81 (s, 1H), 7.48 (s, 1H), 7.38 - 7.32 (m, 3H), 5.67 - 5.64 (d, J=12.8 Hz, 1H), 5.53 - 5.50 (d, J=12.8 Hz, 1H), 4.85 - 4.63 (m, 6H), 4.27 - 4.18 (m, 2H), 4.04 (d, J=4.8 Hz, 1H), 3.97 (s, 3H), 2.30 - 2.22 (m, 1H), 1.02-0.98 (m, 6H). LCMS: ESI-MS: m/z 739.4 [M+H]+. Example 44: Synthesis of Compound 45b
Figure imgf000195_0002
[0572] Intermediate 44-1 was prepared essentially as described in the preparation of Compound 3d. Intermediate 44-2 was prepared essentially as described in the preparation of Compound 7b. [0573] Compound 45b was prepared essentially as described in the preparation of Compound 3d by using acid 44-1 and amine 44-2 as starting materials. Finally, Compound 45b (25 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^= 8.71 (d, J=2.0 Hz, 1H), 8.32 - 8.26 (m, 2H), 8.00 (s, 1H), 7.75 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.29 (d, J=1.6 Hz, 1H), 7.20 - 7.09 (m, 2H), 4.80 - 4.71 (m, 3H), 4.70 (d, J=1.8 Hz, 1H), 4.67 (d, J=9.6 Hz, 2H), 4.63 - 4.59 (m, 1H), 4.55 (d, J=13.8 Hz, 1H), 4.02 (d, J=13.8 Hz, 1H), 3.98 (s, 3H), 2.50 (s, 3H). LCMS: ESI-MS: m/z 606.1 [M+H]+.
Figure imgf000196_0001
[0574] Intermediate 45-1 was prepared essentially as described in the preparation of Compound 15d. Intermediate 45-2 was prepared essentially as described in the preparation of Compound 7b. [0575] Compound 46b was prepared essentially as described in the preparation of Compound 3d by using acid 45-1 and amine 45-2 as the starting materials. Finally, Compound 46b (14 mg) was obtained as white solid.1H NMR (400MHz, MeOD) δ = 8.94 (d, J=1.6 Hz, 1H), 8.66 (br, 1H), 8.38 (s, 1H), 8.30-8.26 (m, 2H), 7.76-7.74 (m, 2H), 7.40 (d, J=1.2 Hz, 1H), 7.10 (t, J=8.8 Hz, 2 H), 7.04 (t, J=55.6 Hz, 1 H), 4.78-4.52 (m, 7 H), 4.04-4.0 (m, 1 H), 3.98 (s, 3 H). LCMS: ESI-MS: m/z 642.1 [M+H]+. Example 46: Synthesis of Compound 47e
Figure imgf000196_0002
[0576] Intermediate 46-1 was prepared essentially as described in the preparation of compound 43d. Compound 47e was prepared essentially as described in the preparation of Compound 42e by using compound 46-1 and acid 46-2 as starting materials. Finally, Compound 47e (80 mg) was obtained as white solid.1H NMR (400MHz, DMSO-d6) ^= 8.76 (t, J=5.8 Hz, 1H), 8.25 (dd, J=5.6, 8.8 Hz, 2H), 8.08 (d, J=1.2 Hz, 1H), 7.86 (s, 1H), 7.55 (s, 1H), 7.41 (d, J=0.8 Hz, 1H), 7.37 (s, 1H), 7.34 - 7.28 (m, 3H), 5.74 - 5.53 (m, 2H), 5.16 (d, J=9.0 Hz, 1H), 4.37 (d, J=9.0 Hz, 1H), 4.26 - 4.09 (m, 2H), 3.98 - 3.88 (m, 4H), 2.25 - 2.10 (m, 1H), 1.49 (s, 3H), 0.96 (dd, J=7.2, 8.4 Hz, 6H). LCMS: ESI-MS: m/z 720.2 [M+H]+. Example 47: Synthesis of Compound 48d
Figure imgf000197_0001
[0577] Compound 48d was synthesized using the same procedure that was previously descried to the synthesis of Compound 16d. The crude product was purified via HPLC to afford the desired product as a white solid.1H NMR (400 MHz, DMSO-d6): ^ 8.9 (d, J = 2.4 Hz, 1H), 8.71 (t, J = 5.9 Hz, 1H), 8.6 (d, J = 2.4 Hz, 1H), 8.26 – 8.23 (m, 2H), 7.84 – 7.83 (m, 2H), 7.78 (s, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.31-7.27 (m, 2H), 7.2 (s, 1H), 5.11 (d, J = 9 Hz, 1H), 4.4 (d, J = 9.0 Hz, 1H), 4.25 (dd, J = 13.7 Hz, 6.3 Hz, 1H), 4.05 (dd, J = 13.7, 5.5 Hz, 1H), 3.92 (s, 3H), 2.60 (s, 3H), 1.49 (s, 3H). LC/MS 677 m/z [M+H]+. Example 48: Synthesis of Compound 49b [0578] 48.1 Preparation of Intermediate 48-3:
Figure imgf000197_0002
[0579] Preparation of intermediate 48-1 can be referred to the Reference: WO2018/35061, 2018, A1. To a mixture of Intermediate 48-1 (600 mg, 2.61 mmol, 1 eq.) and pyridine (619 mg, 7.82 mmol, 3.0 eq.) in DCM (10 mL) was added Intermediate 48-2 (534 mg, 3.91 mmol, 1.5 eq.) dropwise at 0°C. The mixture was stirred at 0 °C for 1 h. LCMS trace showed that the reaction was completed. The mixture was poured into water (15 mL) and stirred for 2 min. The aqueous phase was extracted with EA (50 mL X 3). The combined organic phase was washed with brine (50 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=1/1) to give Intermediate 48-3 (720 mg, 83.62% yield) as a white solid. LCMS: ESI-MS: m/z 329.9/331.9 [M+H]+. [0580] 48.2 Preparation of Intermediate 48-4:
Figure imgf000198_0001
[0581] Intermediate 48-4 was prepared essentially as described in the preparation of Compound 7b. A mixture of Intermediate 48-3 (720 mg, 2.18 mmol, 1 eq.) in NH3-EtOH (7 M, 30 mL) was stirred at 120 °C for 4 h. TLC (PE/EA=1/1) showed that the reaction was completed. The mixture was cooled to 25 °C and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=1/1 to 0/1) to give Intermediate 48-4 (520 mg, 88.6% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ= 8.29 (s, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.33 (s, 1H), 5.01 (s, 2H), 4.09 (s, 3H). LCMS: ESI-MS: m/z 286.7/288.7 [M+H3O]+. [0582] 48.3 Preparation of Intermediate 48-5:
Figure imgf000198_0002
[0583] To a mixture of Intermediate 48-4 (500 mg, 1.86 mmol, 1.0 eq.) and imidazole (506 mg, 7.43 mmol, 4.0 eq.) in DMF (5 mL) was added TIPSCl (716 mg, 3.72 mmol, 2.0 eq.) in one portion at 50°C. The mixture was stirred at 50 °C for 30 min. LCMS trace showed that the reaction was completed. The mixture was diluted with water (15 mL). The aqueous phase was extracted with EA (20 mL X 3). The combined organic phase was washed with brine (20 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, PE/EA=20/1) to give Intermediate 48-5 (710 mg, 89.8% yield) as a colorless oil. LCMS: ESI-MS: m/z 443.0/445.0 [M+H3O]+. [0584] 48.4 Preparation of Intermediate 48-6:
Figure imgf000199_0001
[0585] To a mixture of Intermediate 48-6 (700 mg, 1.65 mmol, 1 eq.), TEA (832 mg, 8.23 mmol, 5 eq.) and DPPP (136 mg, 0.33 mmol, 0.2 eq.) in methanol (100 mL) was added Pd(OAc)2 (37 mg, 0.16 mmol, 0.1 eq.) in one portion. The suspension was degassed and purged with carbon monoxide for several times. The mixture was stirred under CO (50 PSI) at 80°C for 20 h. LCMS trace showed that the reaction was completed. The reaction mixture was concentrated at low pressure and the crude product was purified by silica gel chromatography eluting with EA/PE=1/3 to give Intermediate 48-6 (490 mg, 73.5% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ= 9.55 (s, 1H), 8.29 (d, J=0.8 Hz, 1H), 7.81 (s, 1H), 5.10 (s, 2H), 4.08 (s, 3H), 3.96 (s, 3H), 1.09 (d, J=3.2 Hz, 1H). LCMS: ESI-MS: m/z 423.2 [M+H3O]+. [0586] 48.5 Preparation from Intermediate 48-6 to Compound 49b:
Figure imgf000199_0002
[0587] Compound 49b was prepared essentially as described in the preparation of Compound 1d by using ester 48-6 and amine 48-8 as starting materials. Finally, Compound 49b (38 mg) was obtained as white solid.1H NMR (400MHz, DMSO-d6) ^= 9.52 (s, 1H), 8.76 (brs, 1H), 8.28-8.24 (m, 2H), 8.03 (d, J=1.6 Hz, 1H), 7.78 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.32 (t, J=9.2 Hz, 2H), 7.25 - 7.24 (m, 1H), 5.40 (t, J=6.4 Hz, 1H), 4.83-4.63 (m, 8H), 4.18-4.16 (m, 2H), 3.96 (s, 3H), 3.29 - 3.28 (m, 1H). LCMS: ESI-MS: m/z 641.1 [M+H3O]+. Example 49: Synthesis of Compound 50e
Figure imgf000200_0001
[0588] DIEA (8 µM) was added to a solution of 49-1 (11 mg), trans-2-fluoro- cyclopropylamine tosylate salt (6 mg) and HATU (8 mg) in DMF (0.5 ml). The reaction was stirred at r.t. for 1 hr. The reaction was purified by reverse-phase HPLC. Yield = 4mg.1H NMR (400 MHz, dmso-d6): ^ 8.86-8.87 (m, 1H), 8.23-8.29 (m, 3H), 7.96-7.98 (m, 1H), 7.84 (s, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.56 (dd, J = 4,0, 8.0 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.26-7.32 (m, 3H), 5.08 (dd, J=9.2, 3.6 Hz, 1H), 4.47-4.74 (m, 1H), 4.38 (dd, J = 8.8, 1.6Hz, 1H), 4.22-4.28 (m, 1H), 4.07-4.13 (M, 1H), 3.96 (s, 3H), 2.93-3.00 (m, 1H), 1.46 (s, 1H), 1.23-1.33 (m, 1H), 0.83-0.99 (m, 1H). LC/MS: [M+H] 643.05. Examples 50a and 50b: Synthesis of Stereoisomers of Compound 51 [0589] 50.1 Preparation of Intermediate 50-3:
Figure imgf000200_0002
[0590] Intermediate 50-1 was prepared essentially as described in the preparation of Compound 1d. To a solution of Intermediate 50-1 (1.4 g, 3.52 mmol, 1.0 eq.) in MeOH (30 mL) was added NH3 • H2O (5 mL). The reaction mixture was stirred at 60 °C for 4 h. The reaction was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% EA in PE @ 40 mL/min). Intermediate 50-2 (1.15 g, 92% yield) was obtained as a white solid. LCMS: ESI-MS: m/z 374.0 [M+H3O]+. [0591] 50.2 Preparation of Intermediate 50-3:
Figure imgf000201_0001
[0592] To a solution of Intermediate 50-2 (1.1 g, 3.10 mmol, 1.0 eq.) and DBU (1.41 g, 9.3 mmol, 3.0 eq.) in THF (50 mL) was added PBSF (1.87 g, 6.19 mmol, 1.09 mL, 2.0 eq.). The mixture was stirred at 0 °C for 5 h. LCMS trace showed that the reaction was completed. The reaction mixture was partitioned between EA (30 mL) and water (100 mL). The organic phase was separated, and the aqueous was extracted with EA (30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% EA in PE gradient @ 30 mL/min). Intermediate 50-3 (630 mg, 57% yield) was obtained as a colorless oil. LCMS: ESI-MS: m/z 376.0 [M+H3O]+. [0593] 50.3 Preparation of Intermediate 50-4:
Figure imgf000201_0002
[0594] A 250 mL flask was charged with a mixture of methyl triphenyl phosphonium bromide (13.8 g, 38.63 mmol, 1.5 eq.) and t-BuOK (3.76 g, 33.48 mmol, 1.3 eq.), then THF (100 mL) was added. The reaction mixture was stirred at 25 oC, and a solution of Intermediate 50-3 (9.2 g, 25.75 mmol, 1 eq.) in THF (30 mL) was added. The mixture was stirred at 50 °C for 1 h. TLC (PE/EA=10/1) showed that the reaction was completed. The mixture was filtered and the filtrate was concentrated to dryness at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=30/1 to 8/1). Intermediate 50-4 (6.9 g, 75.5% yield) was obtained as a white solid. LCMS: ESI-MS: m/z 356.1 [M+H]+. [0595] 50.4 Preparation from Intermediate 50-4 to Intermediate 50-9:
Figure imgf000202_0001
[0596] Preparation of Intermediate 50-4 to Intermediate 50-9 was essentially as described in the preparation of Compound 1d. Intermediate 50-8 was prepared essentially as described in the preparation of Compound 3d. Finally, Intermediate 50-9 (150 mg) was obtained as a white solid. LCMS: ESI-MS: m/z 588.1 [M+H]+. [0597] 50.5 Preparation of Stereoisomers of Compound 51:
Figure imgf000202_0002
[0598] Intermediate 50-9 (150 mg, 255.30 umol, 1 eq.) was submitted for SFC separation according to the method (column: (s,s) WHELK-O1 (250mm*50mm,10um); mobile phase: [0.1%NH3H2O IPA];B%: 45%-45%,min) to give Stereoisomer 1 of Compound 51 (peak 1, Rt = 8.916 min, 48 mg, 32% yield) as a white solid and Stereoisomer 2 of Compound 51 (peak 2, Rt = 9.439 min, 49 mg, 32.6% yield) as a white solid. [0599] Example 50a: Stereoisomer 1 of Compound 51: 1H NMR (400MHz, CD3OD) ^ ^δ = 8.68 (d, J=2.4 Hz, 1H), 8.32 - 8.28 (m, 2H), 7.89 (d, J=0.8 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.74 (d, J=9.2 Hz, 1H), 4.60 (m, 1H), 4.56 (m, 1H), 4.50 (s, 1H), 4.42 (dd, J=2.0, 9.2 Hz, 1H), 4.38 (s, 1H), 3.98 (d, J=14.0 Hz, 1H), 3.95 (s, 3H), 2.48 (s, 3H), 1.43 (d, J=1.6 Hz, 3H). LCMS: ESI-MS: m/z 588.1 [M+H]+. [0600] Example 50b: Stereoisomer 2 Compound 51: 1H NMR (400MHz, CD3OD) ^ ^δ = 8.67 (d, J=2.0 Hz, 1H), 8.33 - 8.29 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.72 (d, J=9.2 Hz, 1H), 4.58-4.38 (m, 4H), 4.00 (d, J=14.0 Hz, 1H), 3.94 (s, 3H), 2.48 (s, 3H), 1.40 (d, J=1.2 Hz, 3H). LCMS: ESI-MS: m/z 588.1 [M+H]+. Example 51: Synthesis of Compound 52c
Figure imgf000203_0001
[0601] Intermediate 51-1 was prepared essentially as described in the preparation of Compound 28d. Intermediate 51-2 was prepared essentially as described in the preparation of Compound 2d. [0602] Compound 52c was prepared essentially as described in the preparation of Compound 2d by using acid 51-1 and amine 51-2 as starting materials. Finally, Compound 52c (34 mg) was obtained as a white solid.1H NMR (400MHz, DMSO) ^ = 9.14 (d, J=2.0 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.82 (br t, J=5.9 Hz, 1H), 8.26-8.23 (m, 2H), 8.00 (d, J=1.2 Hz, 1H), 7.94 (s, 1H), 7.60 (d, J=1.2 Hz, 1H), 7.41 (s, 1H), 7.34 (t, J=8.9 Hz, 2H), 5.11 (d, J=9.6 Hz, 1H), 4.65 (d, J=9.6 Hz, 1H), 4.27 - 4.21 (m, 1H), 4.15 - 4.10 (m, 1H), 3.97 (s, 3H), 1.69 (s, 3H). LCMS: ESI-MS: m/z 692.0 [M+H]+. Example 52: Synthesis of Compound 53d
Figure imgf000204_0001
[0603] 52.1 Preparation of Intermediate 51-3: DIEA (26 uL) was added to a solution of 52-1 (50 mg), 52-2 (26 mg) and HATU (42 mg) in DMF (0.5 ml) and the resulting solution was stirred at r.t. for 1hr. The reaction was diluted with ethyl acetate, washed with 1N HCl and brine, dried and concentrated. The product was purified by column chromatography (hexane/ethyl acetate). Yield = 70 mg. LC/MS: [M+H] 720. [0604] 52.2 Preparation of Intermediate 51-4: 4N HCl in dioxane (2 ml) was added to 52-2 (70 mg) and the reaction was stirred at r.t. for 30 minutes. The reaction was concentrated, and the product was purified by column chromatography (hexane/ethyl acetate). Yield = 40 mg. L LC/MS: [M+H] 607. [0605] 52.3 Preparation of Intermediate 52-5: (Diacetoxyiodo)benzene (53 mg) was added to a solution of 52-5 (40 mg) and TEMPO (26 mg) in CH3CN (1 ml) and water (0.1 ml). The reaction was stirred at r.t.3h. The reaction was diluted with ethyl acetate and washed with Na2S2O3 and brine, dried and concentrated. The acid was purified by reverse-phase HPLC. Yield = 15 mg. LC/MS: [M+H] 621. [0606] 52.4 Preparation of Compound 53d: DIEA (10 uL) as added to a solution of 52-3 (7 mg), NH4Cl (5 mg), and HATU (10 mg) and the reaction was stirred at r.t. for 20 minutes. The product was purified by reverse-phase HPLC. Yield = 4 mg. 1H NMR (400 MHz, dmso-d6): 8.34 (t, J = 5.6, 1H), 8.21-8.25 (m, 2H), 7.84-7.85 (m, 1H), 7.76 (s, 2H), 7.28-7.32 (m, 2H), 7.23 (s, 1H), 6.91 (d, J = 1.6, 1H), 6.84 (d, J = 1.6, 1H), 5.12 (d, J = 9.0, 1H), 4.38 (d, J = 9.0, 1H), 4.11-4.16 (m, 1H), 3.98-4.02 (m, 1H), 389 (s, 2H), 3.71 (s, 3H), 2.62 (d, J = 4.8 (3H), 1.50 (s, 3H), 1.21 (s, 6H). LC/MS: [M+H] 634. Example 53: Synthesis of Compound 54e
Figure imgf000205_0001
[0607] Intermediate 53-1 was prepared essentially as described in the preparation of Compound 1d. Intermediates 53-4 and 53-5 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. [0608] Compound 54e was prepared essentially as described in the preparation of Compound 42e by using Intermediate 53-5 as starting material. Finally, Compound 54e (125 mg) was obtained as white solid.1HNMR (400MHz, DMSO-d6) ^ ^= 8.89 (br t, J=6.0 Hz, 1H), 8.37 (br s, 3H), 8.28 - 8.24 (m, 2H), 7.92 (d, J=1.2 Hz, 1H), 7.74 (s, 1H), 7.46 (d, J=1.2 Hz, 1H), 7.34 - 7.28 (m, 3H), 5.63 (d, J=12.0 Hz, 1H), 5.50 (d, J=12.0 Hz, 1H), 4.68 - 4.63 (d, J=9.2 Hz, 1H), 4.58 - 4.42 (m, 3H), 4.23-4.19 (m, 2H), 3.98 (d, J=4.4 Hz, 1H), 3.94 (s, 3H), 2.26 - 2.21 (m, 1H), 1.37 (s, 3H), 1.00-0.95 (m, 6H). LCMS: ESI-MS: m/z 743.3 [M+Na]+. Examples 54a and 54b: Synthesis of Stereoisomers of Compound 55
Figure imgf000206_0001
[0609] Intermediate 54-1 was prepared essentially as described in the preparation of Compound 2d. Intermediate 54-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. [0610] The stereoisomers of Compound 55 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 54-1 and amine 54-2 as starting materials. [0611] The stereoisomers of Compound 55 were separated by SFC twice according the method of (column: AD (250mm*30mm, 5um); mobile phase: [0.1%NH3H2O IPA]; B%: 25%- 25%, min). Finally, Stereoisomer 1 of Compound 55 (peak 1, Rt = 4.415 min, 21.2 mg, 32% yield) as a white solid and Stereoisomer 2 of Compound 55 (peak 2, Rt = 4.541 min, 13 mg, 18.5% yield) as a white solid were obtained. [0612] Example 54a: Stereoisomer 1 of Compound 55: 1H NMR (400MHz, CD3CN) ^ ^δ = 8.78-8.76 (m, 1H), 8.23 - 8.20 (m, 2H), 8.09-8.06 (dd, J=8.4 Hz, 2 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.42 - 7.39 (m, 1H), 7.35 (m, 1H), 7.15-7.11 (m, 2H), 6.58 (s, 1H), 4.67 (d, J=9.2 Hz,1H), 4.45-4.32 (m, 4H), 4.05-4.00 (dd, J=14.4 Hz, 4.8 Hz, 1H), 3.81-3.80 (m, 1H), 1.32 (d, J=2 Hz, 3H), 0.76-0.57 (m, 4H). LCMS: ESI-MS: m/z 600.1 [M+H]+. [0613] Example 54b: Stereoisomer 2 of Compound 55: 1H NMR (400MHz, CD3CN) ^ ^δ = 8.77-8.76 (m, 1H), 8.22 - 8.18 (m, 2H), 8.08-8.06 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.65 (d, J=1.2 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.15-7.10 (m, 2H), 6.58 (s, 1H), 4.65 (d, J=9.2 Hz,1H), 4.45-4.32 (m, 4H), 4.05-4.00 (dd, J=14.0 Hz, 4.8 Hz, 1H), 3.80-3.78 (m, 1H), 1.30 (d, J=1.6 Hz, 3H), 0.74-0.57 (m, 4H). LCMS: ESI-MS: m/z 600.1 [M+H]+. Example 55: Synthesis of Compound 56b [0614] 55.1 Preparation of Intermediate 55-3:
Figure imgf000207_0001
[0615] Preparation of intermediate 55-1 can be referred to the Reference: Chemische Berichte, 1916, vol.49, p.16. To a mixture of Intermediate 55-1 (400 mg, 1.84 mmol, 1 eq.) in DMF (5 mL) were added K2CO3 (636 mg, 4.60 mmol, 2.5 eq.) and Intermediate 55-2 (1.24 g, 9.21 mmol, 5 eq.). The mixture was stirred at 60 °C for 15 h. LCMS trace showed that the reaction was completed. The reaction was diluted with H2O (60 mL) and EA (80 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=10/1 to 1/1) to give Intermediate 55-3 (360 mg, 69.9% yield, 97% purity) as a white solid. LCMS: ESI-MS: m/z 272.1 [M+H]+. [0616] 55.2 Preparation from Intermediate 55-3 to Compound 56b:
Figure imgf000207_0002
[0617] Intermediate 55-5 was prepared essentially as described in the preparation of Compound 7b. Compound 56b was prepared essentially as described in the preparation of Compound 3d by using ester 55-3 and amine 55-5 as starting materials. Finally, Compound 56b (45 mg) was obtained as white solid.1H-NMR (400MHz, CD3OD) ^ = 8.87-8.86 (dd, J=4.4, 1.6 Hz, 1H), 8.33-8.27 (m, 3H), 7.75 (s, 2H), 7.64-7.61 (m, 1H), 7.18-7.13 (m, 2H), 4.77 - 4.55 (m, 7H), 4.04-3.97 (m, 3H), 1.42-1.36 (m, 1H), 0.66-0.61 (m, 2H), 0.38-0.35 (m, 2H). LCMS: ESI- MS: m/z 632.1 [M+H]+. Example 56: Synthesis of Compound 57d
Figure imgf000208_0001
[0618] Intermediate 56-1 was prepared essentially as described in the preparation of Compound 15d. Intermediate 56-2 was prepared essentially as described in the preparation of Compound 2d. [0619] Compound 57d was prepared essentially as described in the preparation of Compound 2d by using acid 56-1 and amine 56-2 as the starting materials. Finally, Compound 57d (41 mg) was obtained as white solid.1H NMR (400MHz, MeOD) ^ = 8.93 (s, 1H), 8.36 (s, 1H), 8.26-8.23 (m, 2H), 7.86 (s, 1H), 7.78 (s, 1H), 7.37 (s, 1H), 7.13 (t, J=8.8 Hz, 2 H), 7.04 (t, J=55.6 Hz, 1 H), 5.17 (d, J=9.2 Hz 1 H), 4.67 (d, J=6.4 Hz, 1 H), 4.48 (d, J=9.2 Hz, 1 H), 3.98 (s, 3 H), 3.94 (d, J=6.4 Hz, 1 H), 1.68 (s, 3H). LCMS: ESI-MS: m/z 635.2 [M+H]+. Example 57a and 57b: Synthesis of Stereoisomers of Compound 58 [0620] 57.1 Preparation of Intermediate 57-3:
Figure imgf000208_0002
[0621] Intermediate 57-1 was prepared essentially as described in the preparation of Compound 15. To a stirred solution of Intermediate 57-1 (4.6 g, 24.47 mmol, 1 eq.) in DCM (300 mL) was added Intermediate 57-2 (10.53 g, 48.93 mmol, 2 eq.) at 0°C. After stirring for 0°C for 2 h. A new spot was observed on TLC (PE/EA=1/1) with some Intermediate 57-1 remaining. The resulting precipitate was filtered and the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without any further purification. The desired Intermediate 57-3 (10 g, crude) was obtained as a light yellow oil. [0622] 57.2 Preparation of Intermediate 57-5:
Figure imgf000209_0001
[0623] To a solution of Intermediate 57-3 (6.5 g, 16.12 mmol, 1 eq.) in DMF (50 mL) was added Intermediate 57-4 (6.87 g, 48.35 mmol, 3 eq.) and Na2CO3 (5.12 g, 48.35 mmol, 3 eq.). The resulting mixture was stirred at 20 °C for 2. TLC (PE/EA=1/1) showed that the reaction was completed. The reaction was quenched with water (60 mL) and extracted with EA (50 mL X 3). The combined organic layers were washed by brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (Silica gel, PE/EA=50/1 to 1/1) to give Intermediate 57-5 (0.8 g, 10.85% yield, 75% purity) as a yellow solid. LCMS: ESI-MS: m/z 342.8/344.8 [M+H]+. [0624] 57.3 Preparation of Intermediate 57-6:
Figure imgf000209_0002
[0625] To a solution of Intermediate 57-5 (0.8 g, 2.33 mmol, 1 eq.) in H2SO4 (10 mL). The mixture was stirred at 120 °C for 30 min. TLC (DCM/MeOH=10/1) showed that most of Intermediate 57-5 was consumed. The reaction mixture was poured into ice-water (20 mL) and extracted by EA (20 mL X 3). The combined organic layers were washed by brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was used directly in the next step without any further purification. The desired product Intermediate 57-6 (0.5 g, crude) was obtained as a yellow solid. [0626] 57.4 Preparation of Intermediate 57-7:
Figure imgf000210_0001
[0627] To a mixture of Intermediate 57-6 (0.5 g, 1.84 mmol, 1 eq.) in DMF (15 mL) was added K2CO3 (510 mg, 3.69 mmol, 2 eq.) at 15°C, and then CH3I (5.24 g, 36.89 mmol, 20 eq.) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 1 h. TLC(PE/EA=1/1) showed that the reaction was completed. The solution was poured into ice- water (30 mL) and stirred for 10 min. The aqueous phase was extracted with EA (30 mL X 3). The combined organic phase was washed with H2O (50 mL X 3), saturated brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=30/1, 3/1) to give Intermediate 57-7 (198 mg, 38% yield) as yellow solid. [0628] 57.5 Preparation of Intermediate 57-8:
Figure imgf000210_0002
[0629] To a solution of Intermediate 57-7 (150 mg, 0.52 mmol, 1 eq.) in MeOH (5 mL) was added NH3 • H2O (180 mg, 10.4 mmol, 20 eq.). The mixture was stirred at 80 °C for 1 h. LCMS trace showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (DCM:MEOH=20:1) to give Intermediate 57-8 (90 mg, 63.3% yield) as a yellow solid. LCMS: ESI-MS: m/z 270.0/272.0 [M+H]+. [0630] 57.6 Preparation of Intermediate 57-9:
Figure imgf000210_0003
[0631] To a solution of Intermediate 57-8 (90 mg, 0.33 mmol, 1 eq.) in DMSO (1 mL) and MeOH (5 mL) were added Pd(OAc)2 (30 mg, 0.13 mmol, 0.4 eq.), DPPP (69 mg, 0.17 mmol, 0.5 eq.) and TEA (169 mg, 1.67 mmol, 5 eq.). The resulting mixture was degassed and refilled with carbon monoxide. Then the reaction was stirred at 80 °C for 16 h under carbon monoxide (50 PSI). LCMS trace showed that the reaction was completed. The reaction was quenched with water (30 mL) and extracted with EA (20 mL X 3). The combined organic layers was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE/EA=0/1) to give Intermediate 57-9 (60 mg, 61.4% yield, 85% purity) as a light yellow solid. LCMS: ESI-MS: m/z 250.1 [M+H]+. [0632] 57.7 Preparation of Intermediate 57-10:
Figure imgf000211_0001
[0633] To a solution of Intermediate 57-9 (60 mg, 0.24 mmol, 1.0 eq.) in MeOH (2 mL) and H2O (0.4 mL) was added NaOH (14 mg, 0.36 mmol, 1.5 eq.). The mixture was stirred at 30 °C for 1 h. LCMS trace showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove MeOH. The aqueous phase was acidified by 1.0 N HCl solution to pH = 3~4. The aqueous phase was extracted with EA (10 mL X 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was used for next step without further purification. Intermediate 57-10 (45 mg, 75.5% yield, 95% purity) was obtained as a light yellow solid. LCMS: ESI-MS: m/z 236.1 [M+H]+. [0634] 57.8 Preparation from Intermediate 57-10 to Stereoisomers of Compound 58:
Figure imgf000211_0002
[0635] The stereoisomers of Compound 58 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 57-10 and amine 57-11 as starting materials. Intermediate 57-11 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. [0636] The stereoisomers of Compound 58 were separated by SFC according the method of (column: AD (250mm*30mm, 5um); mobile phase: [0.1%NH3 in H2O/ETOH]; B%: 30%-30%, min). Finally, Stereoisomer 1 of Compound 58 (peak 1, Rt=4.643 min, 20 mg, 12.8% yield) as a white solid and Stereoisomer 2 of Compound 58 (peak 2, Rt=5.207 min, 25 mg, 16.0% yield) as a white solid were obtained. [0637] Example 57a: Stereoisomer 1 of Compound 58: 1H NMR (400MHz, CD3OD) ^ ^δ = 8.32-8.28 (m, 2H), 7.67 (s, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.19-7.14 (m, 2H), 7.09 (s, 1H), 6.58 (d, J=1.6 Hz, 1H), 4.79-4.77 (d, J=8.8 Hz, 1H), 4.58-4.42 (m, 4H), 4.12 (s, 3H), 4.01 (d, J=13.6 Hz,1H), 1.46 (d, J=1.6 Hz, 3H). LCMS: ESI-MS: m/z 606.1 [M+H]+. [0638] Example 57b: Stereoisomer 2 of Compound 58: 1H NMR (400MHz, DMSO) ^ ^δ = 8.76-8.74 (m, 1H), 8.35-8.32 (m, 2H), 7.89 (s, 1H), 7.82-7.81 (m, 2H), 7.59 (s, 1H), 7.41-7.36 (m, 2H), 7.23 (s, 1H), 7.16 (s, 1H), 6.75 (d, J=1.6 Hz, 1H), 4.79-4.51 (m, 4H), 4.30-4.212 (m, 2H), 4.17 (s, 3H), 1.46 (s, 3H). LCMS: ESI-MS: m/z 606.2 [M+H]+. Example 58: Synthesis of Compound 59d [0639] 58.1 Preparation of Intermediate 58-2:
Figure imgf000212_0001
[0640] Preparation of Intermediate 58-1 can be referred to the Reference: US2016/244460, 2016, A1. To a solution of Intermediate 58-1 (100 mg, 0.4 mmol, 1 eq.) in DCM (2 mL) was added DAST (130 mg, 0.8 mmol, 2 eq.) at -78°C. The mixture was stirred at - 78 °C for 30 min, then warmed to 25 °C and stirred for 30 min. LCMS trace showed that the reaction was completed. The reaction was quenched by saturated NaHCO3 solution (3 mL) and stirred for 5 min, and diluted with water (5 mL). The aqueous phase was extracted with DCM (10 mL X 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=1/0 to 1/1) to give Intermediate 58-2 (110 mg, 72.7% yield) as yellow solid. LCMS: ESI-MS: m/z 250.2 [M+H]+. [0641] 58.2 Preparation from Intermediate 58-2 to Compound 59d:
Figure imgf000213_0001
[0642] Intermediate 58-4 was prepared essentially as described in the preparation of Compound 2d. Compound 59d was prepared essentially as described in the preparation of Compound 2d by using ester 58-2 and amine 58-4 as starting materials. Finally, Compound 59d (40.3 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^ = 8.29 - 8.19 (m, 3H), 7.84 (s, 1H), 7.73 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.11 (t, J=8.8 Hz, 2H), 5.67 (s, 1H), 5.55 (s, 1H), 5.15 (d, J=9.2 Hz, 1H), 4.65 - 4.58 (m, 1H), 4.47 (d, J=9.2 Hz, 1H), 3.98 - 3.93 (m, 4H), 1.66 (s, 3H). LCMS: ESI-MS: m/z 617.1 [M+H]+. Example 59: Synthesis of Compound 60d [0643] 59.1 Preparation of Intermediate 59-2:
Figure imgf000213_0002
[0644] Preparation of Intermediate 59-1 can be referred to the Reference: WO2018/81276, 2018, A1. A mixture of Intermediate 59-1 (300 mg, 1 mmol, 1.0 eq.), cyclopropylboronic acid (213 mg, 2.5 mmol, 2.5 eq.), Pd(dppf)Cl2 (81 mg, 0.1 mmol, 0.10 eq.), K2CO3 (343 mg, 2.5 mmol, 2.5 eq.), K3PO4 (421 mg, 2.0 mmol, 2 eq.) in toluene (5 mL) and H2O (0.5 mL) was taken up into a microwave tube. The tube was sealed and heated at 100 °C for 30 min under microwave irradiation. TLC (PE/EA=5/1) indicated that Intermediate 59-1 was consumed completely. The solution was poured into H2O (20 mL) and extracted with EA (20 mL X 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, PE/EA=20/1 to 5/1) to give Intermediate 59-2 (258 mg, 97% yield,) as white solid. LCMS: ESI- MS: m/z 264.1 [M+H]+. [0645] 59.2 Preparation from Intermediate 59-2 to Compound 60d:
Figure imgf000214_0001
[0646] Compound 60d was prepared essentially as described in the preparation of Compound 2d by using ester 59-2 and amine 59-4 as starting materials. Intermediate 59-4 was prepared essentially as described in the preparation of Compound 2d. Finally, Compound 60d (55 mg) was obtained as white solid.1H NMR (400MHz, DMSO) ^ = 8.58 (t, J=5.6 Hz, 1H), 8.28 - 8.20 (m, 2H), 7.92 (d, J=1.6 Hz, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.34 - 7.28 (m, 3H), 7.25 (s, 1H), 5.17 (d, J=9.0 Hz, 1H), 4.38 (d, J=8.8 Hz, 1H), 4.24 - 4.04 (m, 2H), 3.89 (s, 3H), 1.51 (s, 3H), 1.23 - 1.19 (m, 2H), 1.13 - 1.08 (m, 2H). LCMS: ESI-MS: m/z 632.2 [M+H]+. Example 60: Synthesis of Compound 61b [0647] 60.1 Preparation of Intermediate 60-2:
Figure imgf000214_0002
[0648] Intermediate 60-1 was prepared essentially as described in the preparation of Compound 15. To a mixture of Intermediate 60-1 (650 mg, 2.51 mmol, 1 eq.) in MeOH (5 mL) was added NaBH4 (285 mg, 7.52 mmol, 3 eq.) at 25°C in portions. The mixture was stirred at 25°C for 20 min. LCMS trace showed that the reaction was completed. The mixture was quenched with H2O (20 mL) and extracted with EA (10 mL X 3). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, PE/EA=5/1 to 0/1) to give Intermediate 60-2 (590 mg, 90.7% yield) as a yellow solid. LCMS: ESI-MS: m/z 262.1 [M+H]+. [0649] 60.2 Preparation of Intermediate 60-3:
Figure imgf000215_0001
[0650] To a solution of Intermediate 60-2 (450 mg, 1.72 mmol, 1 eq.) in DCM (5 mL) was added DAST (555 mg, 3.44 mmol, 2 eq.) at -78 °C. Then the reaction was warmed to 25 °C and stirred for 1 h. LCMS trace showed that the reaction was completed. The reaction mixture was quenched by saturated aqueous NaHCO3 solution and extracted with EA (15 mL X 2). The combined organic phase was washed with brine (10 mL X 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, PE/EA=10/1 to 0/1) to give compound Intermediate 60-3 (195 mg, 43.3% yield) as a yellow solid. LCMS: ESI-MS: m/z 264.2 [M+H]+. [0651] 60.3 Preparation from Intermediate 60-3 to Compound 61b:
Figure imgf000215_0002
[0652] Compound 61b was prepared essentially as described in the preparation of Compound 3d by using ester 60-3 and amine 60-5 as starting materials. Intermediate 60-5 was prepared essentially as described in the preparation of Compound 7b. Finally, Compound 61b (21 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^ = 8.86 (s, 1H), 8.31 - 8.27 (m, 2H), 8.21 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.35 (d, J=1.2 Hz, 1H), 7.14 (t, J=8.4 Hz, 2H), 5.65 (s, 1H), 5.53 (s, 1H), 4.76-4.52 (m, 7H), 4.04 - 3.99 (m, 1H), 3.98 (s, 3H). LCMS: ESI-MS: m/z 624.2 [M+H]+. Example 61: Synthesis of Compound 62d
Figure imgf000216_0001
[0653] Intermediate 61-1 was prepared essentially as described in the preparation of compound 43d. Compound 62d was prepared essentially as described in the preparation of Compound 42e by using Intermediate 61-1 and acid 61-2 as starting materials. Finally, Compound 62d (35 mg) was obtained as white solid.1H NMR (400MHz, DMSO) ^= 8.62 (t, J=6.0 Hz, 1H), 8.28 - 8.21 (m, 2H), 8.02 (d, J=1.2 Hz, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.36 (d, J=1.1 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.23 (s, 1H), 5.47 (s, 2H), 5.16 (d, J=8.8 Hz, 1H), 4.38 (d, J=9.0 Hz, 1H), 4.26 - 4.05 (m, 2H), 3.92 (s, 3H), 2.47 - 2.41 (m, 2H), 1.51 (s, 3H), 1.07 (t, J=7.5 Hz, 3H). LCMS: ESI-MS: m/z 677.1 [M+H]+. Examples 62a and 62b: Synthesis of Stereoisomers of Compound 63
Figure imgf000216_0002
[0654] Preparation of intermediate 62-1 can be referred to the Reference: EP1595866, 2005, A1. Intermediate 62-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. [0655] The stereoisomers of Compound 63 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 62-1 and amine 62-2 as starting materials. [0656] The stereoisomers of Compound 63 were separated by SFC twice according the method of (column: AD (250mm*30mm, 5um); mobile phase: [0.1%NH3H2O ETOH]; B%: 30%-30%, min). Finally, Stereoisomer 1of Compound 63 (peak 1, Rt = 4.635 min, 31 mg, 31% yield) as a white solid and Stereoisomer 2 of Compound 63 (peak 2, Rt = 4.802 min, 35 mg, 35% yield) as a white solid were obtained. [0657] Example 62a: Stereoisomer 1of Compound 63: 1H NMR (400MHz, CD3OD) ^ ^δ = 9.1 (s, 1H), 8.22-8.17 (m, 2H), 7.74 (d, J=1.6 Hz, 1H), 7.56 (s, 1H), 7.10 (d, J=1.6 Hz, 1H), 7.07- 7.03 (m, 2H), 4.66-4.64 (d, J=9.6 Hz, 1H), 4.48-4.29 (m, 4H), 3.91 (d, J=14.0 Hz, 1H), 3.82 (s, 3H), 1.33 (d, J=1.6 Hz, 3H). LCMS: ESI-MS: m/z 580.2 [M+H]+. [0658] Example 62b: Stereoisomer 2of Compound 63: 1H NMR (400MHz, CD3OD) ^ ^δ = 9.11 (s, 1H), 8.22-8.18 (m, 2H), 7.72 (d, J=1.6 Hz, 1H), 7.57 (s, 1H), 7.11 (s, 1H), 7.08-7.03 (t, J=8.8 Hz, 2H), 4.64-4.62 (d, J=9.2 Hz, 1H), 4.48-4.29 (m, 4H), 3.93 (d, J=14.0 Hz, 1H), 3.83 (s, 3H), 1.32 (s, 3H). LCMS: ESI-MS: m/z 580.0 [M+H]+. Examples 63a and 63b: Synthesis of Stereoisomers of Compound 64 [0659] 63.1 Preparation of Intermediate 63-2:
Figure imgf000217_0001
[0660] Preparation of intermediate 63-1 can be referred to the Reference: Chemical and Pharmaceutical Bulletin, 1962, vol.10, p.856 - 865. To a mixture of Intermediate 63-1 (400 mg, 1.72 mmol, 1 eq.) and CuBr2 (958 mg, 4.29 mmol, 2.5 eq.) in MeCN (5 mL) was added isoamyl nitrite (603 mg, 5.15 mmol, 3.0 eq.) in one portion at 70°C. The mixture was stirred at 70 °C for 5 h. TLC (PE/EA=3/1) showed that the reaction was completed. The mixture was cooled to 25 °C, and diluted with ice-water (10 mL) and extracted with EA (10 mL X 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=3/1) to give Intermediate 63-2 (150 mg, 29.4% yield) as a yellow solid. [0661] 63.2 Preparation of Intermediate 63-3:
Figure imgf000218_0001
[0662] To a mixture of Intermediate 63-2 (150 mg, 0.5 mmol, 1 eq.) in MeOH (5 mL) was added MeONa (136 mg, 2.5 mmol, 5 eq.) in one portion. The mixture was stirred at 70 °C for 16 h. LCMS trace showed that the reaction was completed. The mixture was was diluted with water (10 mL) and acidified to pH=3 by adding HCl solution (1 M). The precipitate was filtered and dried in vacuum to give Intermediate 63-3 (101 mg, 85% yield) as yellow solid. LCMS: ESI-MS: m/z 234.9 [M+H]+. [0663] 63.3 Preparation from Intermediate 63-3 to Stereoiosmers of Compound 64:
Figure imgf000218_0002
[0664] Intermediate 63-4 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. The stereoisomers of Compound 64 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 63-3 and amine 63-4 as starting materials. [0665] The stereoisomers of Compound 64 were separated by SFC according the method of (column: AD (250mm*30mm, 5um); mobile phase: [0.1% NH3 in H2O/ETOH]; B%: 25%-25%, min). Finally, Stereoisomer 1of Compound 64 (peak 1, Rt = 4.355 min, 25 mg, 25% yield) as a white solid and Stereoisomer 2 of Compound 64 (peak 2, Rt = 4.636 min, 35 mg, 35% yield) as a white solid were obtained. [0666] Example 63a: Stereoisomer 1of Compound 64: 1H NMR (400MHz, CD3OD) ^ ^δ = 9.04 (s, 1H), 8.20-8.17 (m, 2H), 7.67 (d, J=2.0 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.07-7.02 (t, J=8.8 Hz, 2H), 4.66-4.64 (d, J=8.8 Hz, 1H), 4.49-4.30 (m, 4H), 4.00 (s, 3H), 3.92 (d, J=14.0 Hz, 1H), 3.83 (s, 3H). LCMS: ESI-MS: m/z 605.1 [M+H]+. [0667] Example 63b: Stereoisomer 2 of Compound 64: 1H NMR (400MHz, CD3OD) ^ ^δ = 9.06 (s, 1H), 8.22-8.18 (m, 2H), 7.67 (d, J=2.0 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J=1.6 Hz, 1H), 7.08-7.03 (m, 2H), 4.64-4.62 (d, J=9.2 Hz, 1H), 4.49-4.29 (m, 4H), 4.01 (s, 3H), 3.95 (d, J=14.4 Hz, 1H), 3.85 (s, 3H). LCMS: ESI-MS: m/z 605.1 [M+H]+. Examples 64a and 64b: Synthesis of Stereoisomers of Compound 65 [0668] 64.1 Preparation of Intermediate 64-2:
Figure imgf000219_0001
[0669] Preparation of intermediate 64-1 can be referred to the Reference: WO2018/35061, 2018, A1. Intermediate 64-1 (500 mg, 2.17 mmol, 1 eq.) and acetic acid methanimidamide (905 mg, 8.69 mmol, 4 eq.) in MeOH (5 mL) were taken up into a microwave tube. The sealed tube was heated at 100 °C for 1 hour under microwave irradiation. TLC (PE/EA=3/1) showed that the reaction was completed and LCMS trace showed that the desired product was formed. After cooling to 25°C, EA (10 mL) and saturated NaHCO3 (5 mL) were added. The aqueous layer was extracted with EA (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=1/0 to 1/1) to give Intermediate 64-2 (410 mg, 78.9% yield) as a white solid. MS: m/z 258.9 [M+H3O]+. [0670] 64.2 Preparation from Intermediate 64-2 to Stereoisomers of Compound 65:
Figure imgf000220_0001
[0671] The stereoisomers of Compound 65 were prepared essentially as described in Example 57a and 57b in the preparation of the stereoisomers of Compound 58 by using bromide 64-2 and amine 64-5 as starting materials. Intermediate 64-5 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. [0672] The stereoisomers of Compound 65 were separated by SFC twice according the method of (column: OJ (250mm*30mm, 5um); mobile phase: [0.1% NH3 in H2O/EtOH]; B%: 20%-20%, min) and (column: OJ (250mm*30mm, 5um); mobile phase: [0.1% NH3 in H2O/EtOH]; B%: 15%-15%, min). Finally, Stereoisomer 1 of Compound 65 (peak 1, Rt=3.474 min, 16.22 mg, 12.48% yield) as a white solid and Stereoisomer 2 of Compound 65 (peak 2, Rt=3.648 min, 32.62 mg, 24.69% yield) as a white solid were obtained. [0673] Example 64a: Stereoisomer 1 of Compound 65: 1H NMR (400MHz, CD3OD) δ 9.41 (s, 1H), 9.25 (s, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.71 (s, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.21 - 7.14 (m, 2H), 4.80 - 4.77 (m, 1H), 4.66 - 4.64 (m, 1H), 4.55 (d, J=5.3 Hz, 1H), 4.59 - 4.51 (m, 1H), 4.49 - 4.45 (m, 1H), 4.44 (d, J=5.6 Hz, 1H), 4.05 (d, J=13.6 Hz, 1H), 4.01 (s, 3H), 1.47 (d, J=1.2 Hz, 3H). LCMS: ESI-MS: m/z 575.0 [M+H]+. [0674] Example 64b: Stereoisomer 2 of Compound 65: 1H NMR (400MHz, CD3OD) δ 9.28 (s, 1H), 9.14 (s, 1H), 8.23 - 8.17 (m, 2H), 7.73 (d, J=1.8 Hz, 1H), 7.60 (s, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.08 - 7.01 (m, 2H), 4.64 (d, J=9.2 Hz, 1H), 4.50 (br s, 1H), 4.45 (d, J=8.8 Hz, 1H), 4.37 - 4.29 (m, 2H), 3.95 (d, J=14.0 Hz, 1H), 3.90 (s, 3H), 1.33 (d, J=1.6 Hz, 3H). LCMS: ESI-MS: m/z 575.1 [M+H]+. Example 65: Synthesis of Compound 66d
Figure imgf000221_0001
Preparation of intermediate 65-1 can be referred to the Reference: WO2010/132615, 2010, A1. Intermediate 65-5 was prepared essentially as described in the preparation of Compound 2d. [0675] Compound 66d was prepared essentially as described in the preparation of Compound 5d by using compound 65-1 and amine 65-5 as starting materials. Finally, Compound 66d (23 mg) was obtained as white solid.1H NMR (400MHz, DMSO) ^ ^= 8.72 (d, J=6.4 Hz, 1H), 8.27 - 8.23 (m, 2H), 8.16 (d, J=2.4 Hz, 1H), 7.85 (s, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.28 (d, J=1.6 Hz 1H), 7.15 - 7.10 (m, 2H), 5.16 (d, J=9.2 Hz, 2H), 4.61 (d, J=15.6 Hz, 1H), 4.48 (d, J=9.2 Hz, 1H), 3.95 (s, 3H), 3.91 (d, J=15.6 Hz, 1H), 1.67 (s, 3H). LCMS: ESI-MS: m/z 619.2 [M+H]+. Example 66: Synthesis of Compound 67d
Figure imgf000222_0001
[0676] Compound 67d was prepared essentially as described in the preparation of Compound 2d by using Intermediate 66-1 and aldehyde 66-4 as starting materials. Finally, Compound 67d (28 mg) was obtained as white solid.1H NMR (400MHz, DMSO) ^= 8.76 (s, 1H), 8.69 (m, 1H), 8.31 (m, 2H), 8.02 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.68 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.36 - 7.32 (m, 3H), 5.20 (d, J=9.2 Hz, 2H), 4.43 (d, J=8.8 Hz, 1H), 4.27-4.14 (m, 2H), 4.0 (m, 1H), 1.54 (s, 3H), 0.86-0.76 (m, 4H). LCMS: ESI-MS: m/z 625.1 [M+H]+.
Figure imgf000222_0002
[0677] Intermediate 67-1 was prepared essentially as described in Example 66 for the preparation of Compound 67d. Intermediate 67-2 was prepared essentially as described in the preparation of Compound 7b. [0678] Compound 68b was prepared essentially as described in the preparation of Compound 3d by using acid 67-1 and amine 67-2 as starting materials. Finally, Compound 68b (32 mg) was obtained as white solid.1H NMR (400MHz, DMSO) ^= 8.76 (d, J=2.0 Hz, 1H), 8.68 (t, J=5.6 Hz, 1H), 8.31-8.28 (m, 2H), 8.02 (s, 1H), 7.82 (s, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.38-7.33 (m, 3H), 4.86-4.65 (m, 6H), 4.26-4.15 (m, 2H), 4.01-3.98 (m, 1H), 0.86-0.82 (m, 2H), 0.78-0.76 (m, 2H). LCMS: ESI-MS: m/z 632.2 [M+H] +. Example 68: Synthesis of Compound 69b [0679] 68.1 Preparation of Intermediate 68-2:
Figure imgf000223_0001
[0680] Preparation of intermediate 68-1 can be referred to the Reference: WO2018/81276, 2018, A1. To a solution of Intermediate 68-1 (300 mg, 0.99 mmol, 1 eq.) in THF (5 mL) and H2O (5 mL) was added NaOH (100 mg, 2.48 mmol, 2.5 eq.). The mixture was stirred at 25 °C for 1 h. LCMS trace showed that the reaction was completed. The reaction mixture was acidified to pH=5~6 by HCl (2 M) and extracted with EA (50 mL X 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was used for next step without purification. Acid 68-2 (240 mg, 79.7% yield) was obtained as a yellow solid. LCMS: ESI-MS: m/z 288.1/290.1 [M+H]+. [0681] 68.2 Preparation of Intermediate 68-4:
Figure imgf000223_0002
[0682] Intermediate 68-3 was prepared essentially as described in the preparation of Compound 7b. To a mixture of Intermediate 68-2 (128 mg, 0.44 mmol, 1.2 eq.) in DMF (5 mL) was added HATU (154 mg, 0.41 mmol, 1.1 eq.), DIPEA (143.0 mg, 1.11 mmol, 3 eq.). The reaction mixture was stirred at 25°C for 30 min, then a solution of amine 68-3 (150 mg, 0.37 mmol, 1 eq.) in DMF (1 mL) was added. The resulting mixture was stirred at 25°C for another 30 min. LCMS trace showed that the reaction was completed. The residue was poured into water (20 mL) and the aqueous phase was extracted with EA (20 mL X 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=10/1 to 3/1) to give Intermediate 68-4 (230 mg, 92.1% yield) as yellow solid. LCMS: ESI-MS: m/z 675.9/677.9 [M+H]+ [0683] 68.3 Preparation of Intermediate 68-5:
Figure imgf000224_0001
[0684] A mixture of Intermediate 68-4 (150 mg, 0.22 mmol, 1 eq.), Zn(CN)2 (130 mg, 1.11 mmol, 5 eq.) and Pd(PPh3)4 (25.6 mg, 0.022 mmol, 0.1 eq.) in DMF (2 mL) was taken up into a microwave tube. The sealed tube was heated at 150°C for 2.5 h under microwave irradiation. LCMS trace showed that the reaction was completed. After cooling to 25°C, the reaction mixture was diluted with H2O (25 mL) and extracted with EA (30 mL X 3). The combined organic phase was washed with brine (25 mL X 3), dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, PE/EA=20/1 to 1/1) give the desired product 68-5 (79 mg, 57.95% yield) as a yellow oil. LCMS: ESI-MS: m/z 623.1 [M+H]+. [0685] 68.4 Preparation of Compound 69b:
Figure imgf000224_0002
[0686] To a solution of Intermediate 68-5 (79 mg, 0.13 mmol, 1 eq.) in DMSO (1 mL) were added H2O2 (43 mg, 0.39 mmol, 30% purity, 3 eq.) and K2CO3 (53 mg, 0.39 mmol, 3 eq.). The reaction was stirred at 50 °C for 30 min. LCMS trace showed that the reaction was completed. The reaction was diluted with water (15 mL) and extracted with EA (25 mL X 2). The combined organic phase was washed with saturated Na2SO3 (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep- HPLC (column: Xtimate C18150*25mm*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 50%-70%, 7min) to give the desired product Compound 69b (25 mg, 30.37% yield, 100% purity) as a white solid.1H NMR (400MHz, DMSO) ^ ^= 8.67 (t, J=3.0 Hz, 1H), 8.46 (s, 1H), 8.32 - 8.26 (m, 2H), 8.10 - 8.07 (m, 2H), 7.82 (s, 1H), 7.41 (d, J=0.8 Hz, 1H), 7.36 (t, J=8.8 Hz, 2H), 7.29 (s, 1H), 4.89 - 4.65 (m, 6H), 4.26-4.12 (m, 2H), 3.99 (s, 3H). LCMS: ESI-MS: m/z 641.1 [M+H]+. Examples 69a and 69b: Synthesis of Stereoisomers of Compound 70
Figure imgf000225_0001
[0687] Intermediate 69-1 was prepared essentially as described in the preparation of compound 49b. Intermediate 69-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. [0688] The stereoisomers of Compound 70 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 69-1 and amine 69-2 as starting material. [0689] The stereoisomers of Compound 70 were separated by SFC twice according the method of (column: AD (250mm*30mm, 5um); mobile phase: [0.1% NH3 • H2O IPA]; B%: 25%-25%, min) and (column: AD (250mm*30mm, 5um); mobile phase: [0.1% NH3 • H2O IPA]; B%: 30%-30%, min). Finally, Stereoisomer 1 of Compound 70 (peak 1, Rt = 4.336 min, 45 mg, 34.31% yield) as a white solid and Stereoisomer 2 of Compound 70 (peak 2, Rt = 4.473 min, 55 mg, 41.53% yield) as a white solid were obtained. [0690] Example 69a: Stereisomer 1 of Compound 70: 1H NMR (400MHz, CD3OD) ^ ^δ = 9.34 (s, 1H), 8.30-8.27 (m, 2H), 7.82 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.16 - 7.12 (t, J=9.2 Hz, 2H), 4.88 (s, 2H), 4.76 (d, J=8.8 Hz, 1H), 4.62-4.39 (m, 4H), 4.02 (d, J=14.4 Hz, 1H), 3.98 (s, 3H), 1.43 (s, 3H). LCMS: ESI-MS: m/z 623.1 [M +H3O] + [0691] Example 69b: Stereisomer 2 of Compound 70: 1H NMR (400MHz, CD3OD) ^ ^δ = 9.34 (s, 1H), 8.32-8.28 (m, 2H), 7.81 (s, 1H), 7.69 (s, 1H), 7.54 (s, 1H), 7.17 - 7.13 (m, 2H), 4.88 (s, 2H), 4.74 (d, J=8.8 Hz, 1H), 4.58-4.40 (m, 4H), 4.05 (d, J=14.4 Hz, 1H), 3.99 (s, 3H), 1.41 (s, 3H). LCMS: ESI-MS: m/z 623.1 [M+H3O] + Example 70: Synthesis of Compound 71b
Figure imgf000226_0001
[0692] Intermediate 70-1 was prepared essentially as described in the preparation of Compound 29. Intermediate 70-2 was prepared essentially as described in the preparation of Compound 7b. [0693] Compound 71 was prepared essentially as described in the preparation of Compound 3d by using acid 70-1 and amine 70-2 as starting materials. Finally, Compound 71b (37 mg) was obtained as a green yellow solid.1H NMR (400MHz, DMSO) ^ = 9.17 (d, J=2 Hz, 1H), 8.84 (s, 1H), 8.74 (t, J=5.6 Hz, 1H), 8.27-8.23 (m, 2H), 8.05 (d, J=1.2 Hz, 1H), 7.79 (s, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.33-7.28 (m, 3H), 4.83-4.64 (m, 6H), 4.29-4.24 (m, 1H), 4.16-4.11 (m, 1 H), 3.97 (s, 3H). LCMS: ESI-MS: m/z 660.0 [M+H]+. Example 71: Synthesis of Compound 72e
Figure imgf000227_0002
[0694] To a stirring mixture of Compound 35d (15 mg, 0.023 mmol) and acid (15.2 mg) in THF (0.5 mL, 0.05 M) at room temperature were added DCC (14.4 mg, 0.069 mmol) and DMAP (1 crystal). The resulting mixture was stirred at rt for 1.5 h before it was concentrated and purified via a silica gel column to afford the desired product as white solid. To this stirring product was added a solution of HCl in dioxane. The reaction mixture was stirred at room temperature for 30 min before it was concentrated under reduced pressure and directly subjected into the HPLC to afford desired product was a white solid.1H NMR (400 MHz, DMSO-d6): ^ 8.74 (m, 1H), 8.3-8.2 (m, 3H), 7.87-7.84 (m, 3H), 7.36 – 7.27 (m, 3H), 7.22 (s, 1H), 5.41 (d, J = 12.91 Hz, 1H), 5.34 (d, J = 12.91 Hz, 1H), 5.11 (d, J = 9 Hz, 1H), 4.38 (d, J = 9 Hz, 1H), 4.24 (dd, J = 14.1, 6.67 Hz, 1H), 4.06 (dd, J = 14.1, 5.5 Hz, 1H), 3.91 (s, 3H), 3.16 (d, J = 5.47 Hz, 1H), 2.6 (d, J = 4.3 Hz, 1H), 2.59 (s, 3H), 1.9 – 1.85 (m, 1H), 1.48 (s, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.8 (d, J = 6.7 Hz, 3H). LC/MS 746 m/z [M+H]+. Example 72: Synthesis of Compound 73d [0695] 72.1 Preparation of Intermediate 72-2:
Figure imgf000227_0001
[0696] Intermediate 72-1 was prepared essentially as described in the preparation of Compound 10. A mixture of Intermediate 72-1 (4.0 g, 11.0 mmol, 1 eq.), ethynyltrimethylsilane (1.62 g, 16.5 mmol, 1.5 eq.), CuI (210 mg, 1.10 mmol, 0.1 eq.), Pd(PPh3)2Cl2 (386 mg, 0.55 mmol, 0.05 eq.) in TEA (20 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 50 °C for 2 h under nitrogen. LCMS trace showed that the reaction was completed. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EA (30 mL), and the resulting solution washed with brine. The organic solution was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® Silica Flash Column, Eluent of 0~40% EA in PE gradient @ 20 mL/min) to give Intermediate 72-2 (3.6 g, 98% yield) as a brown oil. LCMS: ESI-MS: m/z 334.2 [M+H]+. [0697] 72.2 Preparation of Intermediate 72-3:
Figure imgf000228_0001
[0698] To a solution of Intermediate 72-2 (3.6 g, 10.8 mmol, 1 eq.) in MeOH (10 mL) and THF (50 mL) was added K2CO3 (4.47 g, 32.4 mmol, 3 eq.). The mixture was stirred at 20 °C for 4 h. TLC indicated that the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® Silica Flash Column, Eluent of 0~40% EA in PE gradient @ 20 mL/min) to give Intermediate 72-3 (2.1 g, 74.5% yield) as a yellow solid. LCMS: ESI-MS: m/z 334.2 [M+H]+. [0699] 72.3 Preparation of Intermediate 72-4:
Figure imgf000228_0002
[0700] A solution of Intermediate 72-3 (2 g, 7.65 mmol, 1 eq.) in 1,2-dichlorobenzene (15 mL) was stirred at 190 °C for 6 hr . LCMS trace showed that the reaction was complete. The crude mixture was purified by flash silica gel chromatography (ISCO®; SepaFlash® Silica Flash Column, Eluent of 0~100% EA/PE gradient @ 35 mL/min) to give Intermediate 72-4 (0.5 g, 29.0% yield) as a brown solid. LCMS: ESI-MS: m/z 218.9 [M+H]+. [0701] 72.4 Preparation of Intermediate 72-5:
Figure imgf000229_0001
[0702] To a solution of Intermediate 72-4 (500 mg, 2.29 mmol, 1 eq.) in DCM (20 mL) was added BBr3 (2.83 g, 11.47 mmol, 5 eq.) at 0 oC. Then the mixture was warming to 25 °C and stirred for 12 h. LCMS trace showed that the reaction was complete and the desired product was observed. The reaction mixture was concentrated to dryness and the crude product was used into the next step without further purification. Intermediate 72-5 (0.5 g, crude) was obtained as a brown solid. [0703] 72.5 Preparation of Intermediate 72-6:
Figure imgf000229_0002
[0704] To a solution of Intermediate 72-5 (0.5 g, crude, 2.29 mmol, 1 eq.) in EtOH (15 mL) was added SOCl2 (0.6 mL, 3 eq.) dropwise. Then the reaction mixture was stirred at reflux for 1 h. TLC (PE/EA=1/1) indicated that the reaction was completed. The reaction mixture was neutralized to pH=7~8 with saturated aqueous NaHCO3 solution and extracted with EA (20 mL X 2). The organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% EA/PE gradient @ 30 mL/min) to give Intermediate 72-6 (451 mg, 58.17% yield, 74% purity) as a brown solid. LCMS: ESI-MS: m/z 219.0 [M+H]+. [0705] 72.6 Preparation of Intermediate 72-8:
Figure imgf000229_0003
[0706] To a solution of Intermediate 72-6 (450 mg, 2.45 mmol, 1 eq.) in DMA (8 mL) were added Cs2CO3 (2.39 g, 7.35 mmol, 3 eq.), Intermediate 72-7 (294 mg, 2.45 mmol, 10 eq.) and KI (81.0 mg, 489.76 umol, 0.2 eq.). The mixture was stirred at 140 °C for 15 h. LCMS trace showed that the desired product was formed. The reaction mixture was diluted with H2O (100 mL) and extracted with EA (100 mL X 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% EA/PE gradient @ 25 mL/min) to give Intermediate 72-8 (50 mg, 7.91% yield) as a brown solid. LCMS: ESI-MS: m/z 259.1 [M+H]+. [0707] 72.7 Preparation from Intermediate 72-8 to Compound 73d:
Figure imgf000230_0001
[0708] Intermediate 72-10 was prepared essentially as described in the preparation of Compound 2d. Compound 73d was prepared essentially as described in the preparation of Compound 2d by using ester 72-8 and amine 72-9 as starting materials. Finally, Compound 73d (21 mg) was obtained as a green yellow solid.1H NMR (400MHz, CD3OD) ^ = 9.35 (d, J=6.0 Hz, 1H), 8.28-8.09 (m, 2H), 8.11 (d, J=6.0 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J=1.2 Hz,1H), 7.66 (d, J=1.6 Hz,1H), 7.16-7.11 (m, 2H), 5.20 (d, J=9.6 Hz, 1H), 4.70-4.65 (m, 1H), 4.51 (d, J=9.2 Hz, 1 H), 4.02-3.94 (m, 2H), 1.70 (s, 3 H), 0.89-85 (m, 4 H). LCMS: ESI-MS: m/z 612.1 [M+H]+. Example 73: Synthesis of Compound 74e
Figure imgf000230_0002
[0709] Compound 74e was synthesized using the same procedure that was previously descried to the synthesis of Compound 72e. The crude product was purified via HPLC to afford the desired product as a white solid.1H NMR (400 MHz, DMSO-d6): ^ 8.76 (d, J = 5.87 Hz, 1H), 8.26 – 8.19 (m, 3H), 7.88 (s, 1H), 7.77 (s, 1H), 7.38 (s, 1H), 7.33-7.30 (m, 3H), 5.43 (d, J = 12.92 Hz, 1H), 5.34 (d, J = 13.2 Hz, 1H), 4.81 – 4.6 (m, 6H), 4.22 (dd, J = 14.1, 5.87 Hz, 1H), 4.12 (dd, J = 14.1, 5.48 Hz, 1H), 3.91 (s, 3H), 3.18 (d, J = 5.1 Hz, 1H), 1.93-1.84 (m, 1H), 0.85 (d, J = 6.7 Hz, 3H), 0.8 (d, J = 6.6 Hz, 3H). LC/MS 739.1 m/z [M+H]+. Example 74: Synthesis of Compound 75d [0710] Intermediate 74-1 was prepared essentially as described in the preparation of Compound 4d. Intermediate 74-4 was prepared essentially as described in the preparation of Compound 2d. [0711] 74.1 Preparation of Intermediate 74-2:
Figure imgf000231_0001
[0712] A solution of Intermediate 74-1 (98 mg, 0.36 mmol, 1.0 eq.) and NaOMe (96 mg, 1.78 mmol, 5.0 eq.) in DMF (4 mL) was taken up into a microwave tube. The sealed tube was heated at 140 °C for 1.5 h under microwave. LCMS trace showed that the main peak was the desired product. The mixture was diluted with H2O (6 mL) and acidified by 1M HCl solution to pH=3~4. The resulting solution was extracted with EA (10 mL X 2). The organic layer was washed brine, dried over anhydrous Na2SO4 and concentrated at low pressure. The crude product was used for next step without purification. The crude Intermediate 74-2 (82 mg, crude mixture with corresponding ethyl ester) was obtained as a white solid. LCMS: ESI-MS: m/z 260.1 [M+H]+. [0713] 74.2 Preparation of Intermediate 74-3:
Figure imgf000232_0001
[0714] To a mixture of Intermediate 74-2 (mixture with corresponding ethyl ester; 80 mg, 0.31 mmol, 1 eq.) in EtOH (3 mL) was added H2SO4 (0.2 mL) slowly. The resulting mixture was stirred at 70 °C for 1 h. TLC showed that the reaction was completed. The mixture was acidified to pH=5~6 by 1 M HCl solution and extracted with EA (10 mL X 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=15/1 to 2/1) to give Intermediate 74-3 (35 mg, 41% yield) as a white solid. LCMS: ESI-MS: m/z 288.1 [M+H]+. [0715] 74.3 Preparation from Intermediate 74-3 to Compound 75d:
Figure imgf000232_0002
[0716] Compound 75d was prepared essentially as described in the preparation of Compound 2d by using ester 74-3 and amine 74-4 as starting materials. Finally, Compound 75d (40 mg) was obtained as a white solid.1H NMR (400MHz, CD3OD) ^ = 8.46 (d, J=2.8 Hz, 1H), 8.25-8.21 (m, 2H), 7.83 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.50 (d, J=1.2 Hz,1H), 7.12 (t, J=8.8 Hz, 2H), 5.14 (d, J=9.2 Hz, 1H), 4.61 (d, J=14 Hz, 1H), 4.46 (d, J=9.2 Hz, 1 H), 3.94 (d, J=14 Hz, 1H), 3.90 (s, 3H), 3.82-3.79 (m, 1H), 1.65 (s, 3 H), 0.78-0.74 (m, 4 H). LCMS: ESI-MS: m/z 641.1 [M+H]+. Example 75: Synthesis of Compound 76d [0717] 75.1 Preparation of Intermediate 75-6:
Figure imgf000233_0002
[0718] Intermediate 75-4 was prepared essentially as described in the preparation of Compound 2d using methyl 3-fluoro-4-nitrobenzoate as staring material. Intermediate 75-10 was prepared essentially as described in the preparation of Compound 2d. To a mixture of Intermediate 75-4 (100 mg, 0.48 mmol, 1 eq.) in HCl solution (6 M, 1 mL) was added crotonaldehyde (68 mg, 0.96 mmol, 2 eq.) slowly at 25 °C. Then the mixture was heated to 100 °C for 2 h. LCMS trace showed that the reaction was completed. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EtOH (2 mL), then concentrated H2SO4 (1 mL) was added slowly. The resulting mixture was stirred at 70 °C for 0.5 h. LCMS trace showed that the reaction was completed. The reaction mixture was cooled to room temperature and neutralized to pH=7~8 by saturated aqueous NaHCO3 and extracted with EA (10 mL X 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=15/1 to 1/1) to give Intermediate 75-6 (81 mg, 65.3% yield) as a yellow oil. LCMS: ESI-MS: m/z 272.1 [M+H]+. [0719] 75.2 Preparation of Intermediate 75-7:
Figure imgf000233_0001
[0720] To a mixture of Intermediate 75-6 (80 mg, 0.29 mmol, 1 eq.) in dioxane (1 mL) and H2O (0.1 mL) was added SeO2 (43 mg, 0.38 mmol, 1.3 eq.) in one portion at 25 °C. Then the mixture was heated to 80 °C for 1 h. LCMS trace showed that the reaction was completed. The reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL X 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=15/1 to 2/1) to give Intermediate 75-7 (62 mg, 73% yield) as a yellow oil. LCMS: ESI-MS: m/z 286.2 [M+H]+. [0721] 75.3 Preparation of Intermediate 75-8:
Figure imgf000234_0001
[0722] To a mixture of Intermediate 75-7 (62 mg, 0.21 mmol, 1 eq.) in EtOH (1 mL) was added NaBH4 (16 mg, 0.42 mmol, 2 eq.) in one portion at 25 °C. Then the mixture was heated to 25 °C for 0.5 h. LCMS trace showed that the reaction was completed. The reaction mixture was diluted with water (5 mL), and extracted with EA (10 mL X 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure.. The residue was purified by column chromatography (SiO2, PE/EA=15/1 to 0/1) to give Intermediate 75-8 (40 mg, 67% yield) as a yellow oil. LCMS: ESI-MS: m/z 287.9 [M+H]+. [0723] 75.4 Preparation from Intermediate 75-8 to Compound 76d:
Figure imgf000234_0002
[0724] Compound 76d was prepared essentially as described in the preparation of Compound 2d by using ester 75-8 and amine 75-10 as starting materials. Finally, Compound 76d (40 mg) was obtained as a white solid.1H NMR (400MHz, CD3OD) δ = 8.26 - 8.20 (m, 3H), 7.85 (s, 1H), 7.76 - 7.72 (m, 2H), 7.61 (d, J=1.5 Hz, 1H), 7.10 (t, J=8.8 Hz, 2H), 5.15 (d, J=9.6 Hz, 1H), 4.85 (s, 2H), 4.62 (m, 1H), 4.47 (d, J=9.2 Hz, 1H), 3.98-3.93 (m, 1H), 3.89 - 3.83 (m, 1H), 1.66 (s, 3H), 0.87 - 0.76 (m, 4H). LCMS: ESI-MS: m/z 641.1 [M+H]+. Example 76: Synthesis of Compound 77b
Figure imgf000235_0001
[0725] Intermediate 76-1 was prepared essentially as described in the preparation of Compound 76d. Intermediate 76-2 was prepared essentially as described in the preparation of Compound 7b. [0726] Compound 77b was prepared essentially as described in the preparation of Compound 76d by using acid 76-1 and amine 76-2 as starting materials. Finally, Compound 77b (39 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^= 8.3-8.22 (m, 3H), 7.75 - 7.72 (m, 3H), 7.69 (s, 1H), 7.13 (t, J=8.8 Hz, 2H), 4.85 (s, 2H), 4.79 - 4.57 (m, 7H), 4.08 - 4.01 (m, 1H), 3.92 - 3.86 (m, 1H), 0.83-0.82 (m, 4H). LCMS: ESI-MS: m/z 670.2 [M+Na]+. Example 77: Synthesis of Compound 78b
Figure imgf000235_0002
[0727] Intermediate 77-1 was prepared essentially as described in the preparation of Compound 2d. Preparation from Intermediate 77-1 to Intermediate 77-4 can be referred to the Reference: WO2018/81276, 2018, A1. Intermediate 77-7 was prepared essentially as described in the preparation of compound 43. Intermediate 77-8 was prepared essentially as described in the preparation of Compound 7b. [0728] Compound 78b was prepared essentially as described in the preparation of Compound 3d by using acid 77-7 and amine 77-8 as starting materials. Finally, Compound 78b (45 mg) was obtained as a yellow solid.1H NMR (400MHz, CD3OD) ^ = 8.30-8.27 (m, 2H), 7.78 (d, J=1.2 Hz, 1H), 7.74 (s,1H), 7.50 (d, J=1.2 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 4.89 (s, 2H), 4.78-4.51 (m, 7H), 4.01 (d, J=13.8 Hz, 1H), 3.91-3.79 (m, 1H), 0.86-0.73 (m, 4H). LCMS: ESI- MS: m/z 654.1 [M+H]+. Example 78: Synthesis of Compound 79d
Figure imgf000236_0001
[0729] Acid 78-1 was prepared essentially as described in the preparation of Compound 10b. Amine 78-2 was prepared essentially as described in the preparation of Compound 2d. [0730] Compound 79d was prepared essentially as described in the preparation of Compound 2d by using acid 78-1 and amine 78-2 as starting materials. Finally, Compound 79d (51 mg) was obtained as a yellow solid.1H NMR (400MHz, CD3OD) δ = 8.23-8.19 (m, 2H), 7.84 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.50 (s,1H), 7.09 (t, J=8.4 Hz, 2H), 5.15 (d, J=9.2 Hz, 1H), 4.64-4.59 (m, 1H), 4.46 (d, J=9.6 Hz, 1 H), 3.92-3.89 (m, 1H), 2.93 (s, 3H), 1.65 (s, 3 H), 0.83-0.82 (m, 4 H). LCMS: ESI-MS: m/z 626.1 [M+H]+. Example 79: Synthesis of Compound 80b [0731] 79.1 Preparation of Intermediate 79-2:
Figure imgf000236_0002
[0732] Intermediate 79-1 was prepared essentially as described in the preparation of Compound 1d. A mixture of Intermediate 79-1 (1 g, 3.53 mmol, 1 eq.), methyl boronic acid (528 mg, 8.81 mmol, 2.5 eq.), K3PO4 (1.50 g, 7.05 mmol, 2 eq.), Cs2CO3 (2.87 g, 8.8 mmol, 2.5 eq.) and Pd(dppf)Cl2 (288 mg, 0.35 mmol, 0.1 eq.) in toluene (10 mL) and H2O (2 mL) was taken up into a microwave tube. The sealed tube was heated at 115°C for 1.5 h under microwave. LCMS trace showed that the reaction was completed. Two batches were combined, diluted with H2O (100ml) and extracted with 150 mL (50 mL X 3). The separated organic layer was washed by brine (50 ml), dried over anhydrous Na2SO4 and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA= 3/1) to give Intermediate 79-2 (1.2 g, 64.6% yield) as a red solid. LCMS: ESI-MS: m/z 264.1 [M+H]+. [0733] 79.2 Preparation of Intermediate 79-3:
Figure imgf000237_0001
[0734] To a solution of Intermediate 79-2 (1.2 g, 4.56 mmol, 1 eq.) in DCM (5 mL) was added BBr3 (11.4 g, 45.6 mmol, 10 eq.). The mixture was stirred at 20 °C for 15 h. LCMS trace showed that the reaction was completed. The reaction was quenched by addition of MeOH (30 mL) at 20°C, diluted with H2O (100 mL) and extracted with EA (50 mL X 3). The separated organic layer was washed by brine (50 ml), dried over anhydrous Na2SO4 and concentrated at low pressure. The residue was used for next step without purification. The crude Intermediate 79-3 (1.02 g, crude) was obtained as a black brown solid. LCMS: ESI-MS: m/z 221.9 [M+H]+. [0735] 79.3 Preparation from Intermediate 79-4:
Figure imgf000237_0002
[0736] To a solution of Intermediate 79-3 (1 g, 4.52 mmol, 1 eq.) in EtOH (10 mL) was added H2SO4 (0.24 mL, 1 eq.). The mixture was stirred at 75 °C for 1 h. LCMS trace showed that the reaction was completed. The resulting solution was neutralized with saturated NaHCO3 solution to pH=7-8 and extracted with EA (50 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product of Intermediate 79-4 (1 g, 63.90% yield, 72% purity) was obtained as a yellow solid. The crude was used for next step without puritication. LCMS: ESI- MS: m/z 249.9 [M+H]+. [0737] 79.4 Preparation of Intermediate 79-5:
Figure imgf000238_0001
[0738] To a solution of Intermediate 79-4 (500 mg, 2.01 mmol, 1 eq.) in DMA (5 mL) were added bromocyclopropane (2.43 g, 20.06 mmol, 1.61 mL, 10 eq.) and Cs2CO3 (1.31 g, 4.01 mmol, 2 eq.), KI (100 mg, 0.6 mmol, 0.3 eq.). The reaction mixture was stirred at 140 °C for 15 h. LCMS trace showed that the reaction was completed. The reaction mixture was cooled to 25 °C and diluted with H2O(100 mL). The resulting solution was extracted with EA (50 mL X 3). The separated organic layer was washed by brine (50 ml), dried over anhydrous Na2SO4 and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=5/1) to give Intermediate 79-5 (150 mg, 12.92% yield) as a yellow oil. LCMS: ESI-MS: m/z 289.9 [M+H]+. [0739] 79.5 Preparation from Intermediate 79-5 to Compound 80b:
Figure imgf000238_0002
[0740] Intermediate 79-9 was prepared essentially as described in the preparation of Compound 7b. Compound 80b was prepared essentially as described in the preparation of Compound 76 by using Intermediate 79-5 and amine 79-9 as starting materials. Finally, Compound 80b (15 mg) was obtained as a white solid.1H-NMR (400MHz, CD3OD), ^ = 8.32- 8.29 (m, 2H), 7.87 (d, J=9.6 Hz, 1H), 7.69 (s, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.16 (t, J=7.2 Hz, 2H), 4.89 (s, 2H), 4.78-4.59 (m, 7H), 4.04 (d, J=12.8 Hz, 1 H), 3.92-3.88 (m, 1H), 0.88-0.81 (m, 4H). LCMS: ESI-MS: m/z 666.1 [M+H]+. Example 80: Synthesis of Compound 81b [0741] 80.1 Preparation of Intermediate 80-2:
Figure imgf000239_0001
[0742] Intermediate 80-1 was prepared essentially as described in the preparation of Compound 43. To a mixture of Intermediate 80-1 (450 mg, 1.63 mmol, 1 eq.) and NMO (287 mg, 2.45 mmol, 1.5 eq.) in t-BuOH (8 mL) and H2O (8 mL) was added OsO4 (83 mg, 0.33 mmol, 0.2 eq.) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 0.5 h. Then NaIO4 (0.7 g, 3.27 mmol, 2 eq.) was added to the mixture and stirred at 25 °C for another 0.5 h. TLC (PE/EA=3/1) showed that the reaction was completed. The mixture was poured into Na2SO3 aq. (20 mL). The aqueous phase was extracted with EA (15 mL X 2). The combined organic phase was washed with brine (10 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. Crude Intermediate 80-2 (300 mg) was obtained as a black solid which was used for next step without further purification. LCMS: ESI-MS: m/z 277.9 [M+H]+. [0743] 80.2 Preparation of Intermediate 80-3:
Figure imgf000239_0002
[0744] To a solution of Intermediate 80-2 (120 mg, 0.43 mmol, 1 eq.) in DCM (2 mL) was added DAST (280 mg, 1.73 mmol, 0.23 mL, 4 eq.) at -78°C. The mixture was allowed to warm up to 25°C with stirring for 1 h. TLC (PE/EA=0/1) showed that the reaction was completed. The reaction mixture was quenched by aq. NaHCO3 and extracted with EA (20 mL X 3). The organic phase was concentrated under reduced pressure. Crude Intermediate 80-3 (50 mg, 38.60% yield) was obtained as white solid which was used for next step without purification. LCMS: ESI-MS: m/z 299.9 [M+H]+. [0745] 80.3 Preparation from Intermediate 80-3 to Compound 81b:
Figure imgf000240_0001
[0746] Intermediate 80-5 was prepared essentially as described in the preparation of Compound 7b. Compound 81b was prepared essentially as described in the preparation of 43 by using ester 80-3 and amine 80-5 as starting materials. Finally, Compound 81b (13.5 mg) was obtained as a white solid.1H NMR (400MHz, CD3OD) δ = 8.34-8.30 (m, 2H), 7.90 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.18 (t, J=8.4 Hz, 2H), 7.10 (t, J=54 Hz, 1 H), 4.75 - 4.55 (m, 8H), 4.03 (d, J=14.0 Hz, 1H), 3.95 (m, 1H), 0.82 - 0.80 (m, 4H). LCMS: ESI-MS: m/z 674.1 [M+H]+. Example 81: Synthesis of Compound 82d
Figure imgf000240_0002
[0747] Intermediate 81-1 was prepared essentially as described in the preparation of Compound 67. Intermediate 81-2 was prepared essentially as described in the preparation of Compound 14. [0748] Compound 82d was prepared essentially as described in the preparation of Compound 14 by using acid 81-1 and amine 81-2 as starting materials. Finally, Compound 82d (28 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^= 8.69 (s, 1H), 8.25-8.22 (m, 2H), 8.00 (s, 1H), 7.81 (s, 1H), 7.58 (d, J=0.8 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.16 (t, J=9.2 Hz, 2H), 6.05-5.74 (tt, J=56.4 Hz, 4.0 Hz, 1H), 5.11 (d, J=9.2 Hz, 8H), 4.66 (d, J=14.0 Hz, 1H), 4.50 (d, J=9.2 Hz, 1H), 3.88-3.83 (m, 2H), 3.60 - 3.52 (m, 2H), 2.49 (s, 3H), 1.66 (s, 3H), 0.79-0.76 (m, 4H). LCMS: ESI-MS: m/z 711.2 [M+Na]+. Example 82: Synthesis of Compound 83d
Figure imgf000241_0001
[0749] Intermediate 82-1 was prepared essentially as described in the preparation of Compound 1d. Intermediate 82-3 was prepared essentially as described in the preparation of Compound 14. [0750] Compound 83d was prepared essentially as described in the preparation of Compound 2d by using ester 82-1 and amine 82-3 as starting materials. Finally, Compound 83d (45 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^ ^= 8.75 (d, J=2.8 Hz, 1H), 8.27-8.24 (m, 2H), 8.01 (br, 1H), 7.89-7.86 (dd, J=2.8 Hz, 8.8 Hz, 1H), 7.84 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 7.15-7.10 (m, 2H), 6.09-5.79 (tt, J=56.4 Hz, 4.0 Hz, 1H), 5.14(d, J=9.6 Hz, 1H), 4.68 (d, J=14.0 Hz, 1H), 4.53 (d, J=9.2 Hz, 1H), 3.94-3.88 (m, 4H), 3.65- 3.57 (m, 2H), 1.69 (s, 3H). LCMS: ESI-MS: m/z 667.1 [M+H]+. Example 83: Synthesis of Compound 84d
Figure imgf000241_0002
[0751] Intermediate 83-1 was prepared essentially as described in the preparation of Compound 4d. Intermediate 83-2 was prepared essentially as described in the preparation of Compound 14d. [0752] Compound 84d was prepared essentially as described in the preparation of Compound 14d by using acid 83-1 and amine 83-2 as starting materials. Finally, Compound 84d (42 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^= 8.74 (d, J=2.8 Hz, 1H), 8.28-8.24 (m, 2H), 7.88-7.85 (m, 2H), 7.65 (d, J=1.6 Hz, 1H), 7.50 (d, J=0.8 Hz, 1H), 7.16-7.12 (t, J=8.8 Hz, 2H), 6.08-5.78 (tt, J=56.4 Hz, 4.0 Hz, 1H), 5.15 (d, J=9.6 Hz, 1H), 4.69 (d, J=13.6 Hz, 1H), 4.53 (d, J=9.2 Hz, 1H), 3.91-3.82 (m, 2H), 3.61-3.55 (m, 2H), 1.70 (s, 3H), 0.81-0.77 (m, 4H). LCMS: ESI-MS: m/z 715.1 [M+Na]+. Example 84: Synthesis of Compound 85d [0753] 84.1 Preparation of Intermediate 84-2:
Figure imgf000242_0001
[0754] Intermediate 84-1 was prepared essentially as described in the preparation of Compound 2d using 4-bromo-2-methoxyaniline as staring material. To a solution of Intermediate 84-1 (1 g, 3.97 mmol, 1 eq.) in DCM (15 mL) was added BBr3 (4.97 g, 19.83 mmol, 5 eq.) slowly. The mixture was stirred at 25 °C for 12 h. TLC (PE/EA=3/1) showed that the reaction was completed. The reaction was quenched by MeOH (5 mL) and concentrated under reduced pressure. The residue was diluted with aqueous NaHCO3 solution (50 mL) and extracted with EA (40 mL X2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=1/0 to 0/1) to give Intermediate 84-2 (510 mg, 54 % yield) as a white solid. LCMS: ESI- MS: m/z 238.0/239.0 [M+H]+. [0755] 84.2 Preparation of Intermediate 84-4:
Figure imgf000242_0002
[0756] To a mixture of Intermediate 84-2 (400 mg, 1.68 mmol, 1 eq.) and Na2CO3 (356 mg, 3.36 mmol, 2 eq.) in DMF (5 mL) was added Intermediate 84-3 (512 mg, 3.36 mmol, 2 eq.). The mixture was stirred at 80 °C for 1 h. TLC (PE/EA=3/1) showed that the reaction was completed. The mixture was diluted with H2O (30 mL) and extracted with EA (25 mL X 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=50/1 to 1/1) to give Intermediate 84-4 (302 mg, 62% yield) as a white solid. LCMS: ESI-MS: m/z 288.0/290.0 [M+H]+. [0757] 84.3 Preparation from Intermediate 84-4 to Compound 85d:
Figure imgf000243_0001
[0758] Intermediate 84-8 was prepared essentially as described in the preparation of Compound 2d. Compound 85d was prepared essentially as described in the preparation of Compound 2d by using intermediate 84-4 and amine 84-8 as starting materials. Finally, Compound 85d (51 mg) was obtained as a white solid.1H NMR (400MHz, CD3OD) ^ = 8.77 (d, J=1.2 Hz , 1H), 8.25-8.21 (m, 2H), 7.93 (s, 1H), 7.88 (s, 1H), 7.81 (s,1H), 7.58 (s, 1H), 7.29- 6.92 (m, 3H), 5.13 (d, J=8.8 Hz, 1H), 4.59-4.55 (d, J=13.6 Hz, 1H), 4.46 (d, J=9.2 Hz, 1 H), 3.94 (d, J=13.6 Hz, 1H), 2.49 (s, 3H), 1.65 (s, 3 H). LCMS: ESI-MS: m/z 635.1 [M+H]+. Example 85: Synthesis of Compound 86d [0759] 85.1 Preparation of Intermediate 85-2:
Figure imgf000243_0002
[0760] Preparation of intermediate 85-1 can be referred to the Reference: Bioorganic and Medicinal Chemistry, 2016, vol.24, # 18, p.4281 - 4290. To a solution of Intermediate 85-1 (300 mg, 1.57 mmol, 1 eq.) in EtOH (15 mL) was added SOCl2 (1 mL) slowly. The mixture was stirred at 80 °C for 3 h. LCMS trace showed that the reaction was completed. The reaction was neutralized to pH=7~8 with aqueous NaHCO3 and extracted with EA (20 mL X 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=10/1 to 3/1) to give Intermediate 85-2 (102 mg, 29% yield) as a yellow oil. LCMS: ESI-MS: m/z 220.2 [M+H]+. [0761] 85.2 Preparation from Intermediate 85-2 to Compound 86d:
Figure imgf000244_0001
[0762] Intermediate 85-6 was prepared essentially as described in the preparation of Compound 2d. Compound 86d was prepared essentially as described in the preparation of Compound 5d by using intermediate 85-2 and amine 85-6 as starting materials. Finally, Compound 86d (10 mg) was obtained as a green-yellow solid.1H NMR (400MHz, CD3OD) ^ = 8.87 (d, J=2 Hz , 1H), 8.29-8.24 (m, 3H), 7.92 (s, 1H), 7.85 (s, 1H), 7.70-7.66 (dd, J=10.8 Hz, 1.6 Hz, 1H), 7.14 (t, J=8.8 Hz 1H), 5.17 (d, J=9.2 Hz, 1H), 4.64 (d, J=14.0 Hz, 1H), 4.48 (d, J=9.6 Hz, 1 H), 3.95 (d, J=4.0 Hz, 1H), 1.68 (s, 3 H). LCMS: ESI-MS: m/z 607.1 [M+H]+. Example 86: Synthesis of Compound 87b
Figure imgf000245_0001
[0763] Acid 86-1 was prepared essentially as described in the preparation of Compound 85. Amine 86-2 was prepared essentially as described in the preparation of Compound 7b. [0764] Compound 87b was prepared essentially as described in the preparation of Compound 85 by using acid 86-1 and amine 86-2 as starting materials. Finally, Compound 87b (49 mg) was obtained as a yellow solid.1H NMR (400MHz, CD3OD) ^ = 8.75 (d, J=1.6 Hz, 1H ), 8.28-8.25 (m, 2H), 7.93 (s, 1H), 7.88 (s, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.12 (t, J=8.8 Hz, 2H), 7.10 (t, J=74.4 Hz, 1 H), 4.77 - 4.60 (m, 6H), 4.53 (d, J=14.0 Hz, 1H), 4.02 (d, J=14.0 Hz, 1H), 2.48 (s, 3H). LCMS: ESI-MS: m/z 642.1 [M+H]+. Example 87: Synthesis of Compound 88d
Figure imgf000245_0002
[0765] Intermediate 87-1 was prepared essentially as described in the preparation of Compound 6. Intermediate 87-2 was prepared essentially as described in the preparation of Compound 14. [0766] Compound 88d was prepared essentially as described in the preparation of Compound 14 by using acid 87-1 and amine 87-2 as the starting materials. Finally, Compound 88d (42 mg) was obtained as white solid.1H NMR (400MHz, DMSO) ^ = 9.05 (d, J=1.6 Hz, 1H), 8.71 (t, J=5.6 Hz, 1H), 8.54 (s, 1H), 8.38 (t, J=5.6 Hz, 1H), 8.31-8.27 (m, 2H), 8.02 (s, 1H), 7.86 (s, 1H), 7.81(d, J=1.6 Hz, 1H), 7.46-7.19 (m, 4H), 6.138-5.83 (tt, J=56.0 Hz, 4.0 Hz, 1H), 5.16 (d, J=9.2 Hz, 1H), 4.49 (d, J=9.2 Hz, 1H), 4.29-4.27 (m, 1H), 4.15-4.14 (m, 1H), 4.03- 4.01(m, 1H), 3.55-3.47 (m, 2H), 1.56 (s, 3H), 0.86-0.74 (m, 4H). LCMS: ESI-MS: m/z 725.2 [M+H]+. Example 88: Synthesis of Compound 89b [0767] 88.1 Preparation from Intermediate 88-1 to Intermediate 88-5:
Figure imgf000246_0001
[0768] Preparation of intermediate 88-1 can be referred to the Reference: US2009/306089, 2009, A1. Intermediate 88-5 was prepared essentially as described in the preparation of Compound 1d by using Intermediate 88-1 as starting material. [0769] 88.2 Preparation of Intermediate 88-7:
Figure imgf000246_0002
[0770] To a mixture of Intermediate 88-5 (190 mg, 0.71 mmol, 1 eq.) and Intermediate 88-6 (307 mg, 3.58 mmol, 5 eq.) in DCE (5 mL) were added Cs2CO3 (699 mg, 2.15 mmol, 3.0 eq.), Cu(OAc)2 (390 mg, 2.15 mmol, 3.0 eq.) and 1,10-phenanthroline (129 mg, 0.71 mmol, 1.0 eq.) in one portion. The mixture was stirred at 50 °C for 4 h. LCMS trace showed that the reaction was completed. The mixture was cooled to 25 °C and poured into water (20 mL) and stirred for 5 min. The aqueous phase was extracted with EA (20 mL X 3). The combined organic phase was washed with brine (20 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, PE/EA=5/1) to give Intermediate 88-7 (110 mg, 50.3% yield) as a white solid.1H NMR (400MHz, CDCl3) ^ = 8.15 (s, 1H ), 8.07 (d, J=1.6 Hz, 1H), 8.01 (s, 1H), 4.44 (q, J=10.8 Hz, 2H), 4.40-3.95 (m, 1H), 2.84 (s, 3H), 1.43 (t, J=10.8 Hz, 2H), 1.02-0.94 (m, 4 H). LCMS: ESI-MS: m/z 305.9 [M+H]+. [0771] 88.3 Preparation from Intermediate 88-7 to Compound 89b:
Figure imgf000247_0001
[0772] Compound 89b was prepared essentially as described in the preparation of Compound 1d by using intermediate 88-7 and amine 88-11 as starting materials. Intermediate 88-11 was prepared essentially as described in the preparation of Compound 7b. Finally, Compound 89b (18 mg) was obtained as a white solid.1H NMR (400MHz, CD3OD) ^ = 8.31- 8.28 (m , 2H), 8.18 (s, 1H), 7.74 (s, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.15 (t, J=9.2 Hz, 1H), 4.90 (s, 2H), 4.76-4.54 (m, 7H), 4.01 (d, J=14.0 Hz, 1 H), 3.91 (m, 1H), 0.85- 0.82 (m, 4H). LCMS: ESI-MS: m/z 682.1 [M+H]+. Example 89: Synthesis of Compound 90d
Figure imgf000247_0002
[0773] Intermediate 89-1 was prepared essentially as described in the preparation of Compound 4d. Intermediate 89-2 was prepared essentially as described in the preparation of Compound 16d. [0774] Compound 90d was prepared essentially as described in the preparation of Compound 16 by using acid 89-1 and amine 89-2 as the starting materials. Finally, Compound 90d (35 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^= 8.76 (d, J=2.4 Hz, 1H), 8.26-8.22 (m, 2H), 7.93-7.90 (dd, J=2.8 Hz, 8.8 Hz, 1H), 7.85 (s, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 7.16-7.11 (t, J=8.8 Hz, 2H), 5.16 (d, J=9.2 Hz, 1H), 4.76-4.71 (m, 1H), 4.49 (d, J=9.2 Hz, 1H), 3.86-3.81 (m, 2H), 2.79 (s, 3H), 1.69 (s, 3H), 0.83-0.78 (m, 4H). LCMS: ESI-MS: m/z 643.3 [M+H]+. Example 90: Synthesis of Compound 91d
Figure imgf000248_0001
[0775] Intermediate 90-1 was prepared essentially as described in the preparation of Compound 5d. Intermediate 90-2 was prepared essentially as described in the preparation of Compound 16d. [0776] Compound 91d was prepared essentially as described in the preparation of Compound 16d by using acid 90-1 and amine 90-2 as the starting materials. Finally, Compound 91d (30 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^= 8.72 (d, J=2.0 Hz, 1H), 8.26-8.22 (m, 2H), 8.15-8.14 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.15-7.11 (t, J=8.8 Hz, 2H), 5.15 (d, J=8.8 Hz, 1H), 4.76-4.71 (m, 1H), 4.48 (d, J=9.2 Hz, 1H), 3.86-3.82 (m, 2H), 2.79 (s, 3H), 1.69 (s, 3H), 0.81-0.78 (m, 4H). LCMS: ESI-MS: m/z 659.0 [M+H]+. Example 91: Synthesis of Compound 92d [0777] 91.1 Preparation of Intermediate 89-4:
Figure imgf000249_0001
[0778] Preparation of intermediate 91-1 can be referred to the Reference: US2016/244460, 2016, A1. To a solution of Intermediate 91-1 (1 g, 5.1 mmol, 1 eq.) in AcOH (25 mL) and toluene (25 mL) was added Intermediate 91-2 (1.1 g, 15.29 mmol, 3 eq.). The resulting mixture was stirred at 40 °C for 2 h. LCMS showed that the reaction was completed. The mixture was neutralized to pH=7~8 with aqueous NaHCO3 and extracted with EA (20 mL X 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (SiO2, PE/EA=3/1 to 1/1) to give a mixture of Intermediates 91-3 and 91-4 (710 mg) as a yellow solid. Then the mixture of Intermediates 91-3 and 91-4 was separated by SFC according (column: DAICEL CHIRALPAK AD-H (250mm*30mm,5um);mobile phase: [0.1% NH3 • H2O MEOH];B%: 30%-30%,min) to give Intermediate 91-4 (120 mg, 10% yield) as yellow solid.1H NMR (400MHz, CD3OD) ^ = 8.80 (s, 1H), 8.19 (d, J=1.6 Hz, 1H), 7.66 (s, 1H), 4.10 (s, 3 H), 3.98 (s, 3 H). LCMS: ESI-MS: m/z 232.9 [M+H]+. [0779] 91.2 Preparation from Intermediate 91-4 to Compound 92d:
Figure imgf000249_0002
[0780] Intermediate 91-6 was prepared essentially as described in the preparation of Compound 2d. Compound 92d was prepared essentially as described in the preparation of Compound 2d by using ester 91-4 and amine 91-6 as starting materials. Finally, Compound 92d (39 mg) was obtained as a white solid.1H NMR (400MHz, CD3OD) ^ = 8.76 (s , 1H), 8.27-8.24 (m, 2H), 7.87 (s, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.31 (s,1H), 7.13 (t, J=8.8 Hz, 2H), 5.19 (d, J=9.6 Hz, 1H), 4.68-4.63 (m, 1H), 4.51 (d, J=9.2 Hz, 1 H), 3.99 (s, 3H), 3.99-3.96 (m, 1H), 2.75 (s, 3H), 1.70 (s, 3 H). LCMS: ESI-MS: m/z 600.3 [M+H]+. Example 92: Synthesis of Compound 93d
Figure imgf000250_0001
Figure imgf000251_0001
[0781] 92.1 Preparation of Compound 93d: [0782] Intermediate 92-13 was prepared essentially as described in the preparation of Compound 1d using Intermediate 92-1 and (4-(trifluoromethyl)phenyl) boronic acid as starting materials. Intermediate 92-14 was prepared essentially as described in the preparation of Compound 6d. [0783] Compound 93d was prepared essentially as described in the preparation of Compound 1d by using acid 92-14 and amine 92-13 as starting materials. Finally, Compound 93d (28 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^= 8.91 (d, J=1.6 Hz, 1H), 8.40-8.31 (m, 2H), 7.92 (s, 1H), 7.82 (d, J=1.2 Hz, 1H), 7.68-7.65 (m, 3H), 7.16-6.88 (t, J=55.4 Hz, 1H), 5.19 (d, J=9.2 Hz, 8H), 4.64 (d, J=9.6 Hz, 1H), 4.50 (d, J=6.4 Hz, 1H), 3.99 (d, J=14.0 Hz, 1H), 3.90-3.88 (m, 1H), 1.66 (s, 3H), 0.83-0.78 (m, 4H). LCMS: ESI-MS: m/z 711.1 [M+H]+. Example 93: Synthesis of Compound 94d
Figure imgf000251_0002
[0784] Intermediate 93-1 was prepared essentially as described in the preparation of Compound 4d. Intermediate 93-2 was prepared essentially as described in the preparation of Compound 23d. [0785] Compound 94d was prepared essentially as described in the preparation of Compound 23d by using acid 93-1 and amine 93-2 as starting materials. Finally, Compound 94d (22 mg) was obtained as white solid.1H NMR (400MHz, CD3OD) ^ ^= 8.75 (d, J=2.4 Hz, 1H), 8.60 (br, 1H), 8.24-8.21 (m, 2H), 7.88-7.86 (d, J=9.2 Hz, 1H), 7.77 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.09-7.05 (t, J=8.8 Hz, 2H), 6.65-6.37 (t, J=54.8 Hz, 1H), 5.12(d, J=9.2 Hz, 1H), 4.45 (d, J=9.2 Hz, 1H), 4.33-4.28 (m, 1H), 3.89-3.81 (m, 2H), 1.60 (s, 3H), 0.84-0.81 (m, 4H). LCMS: ESI-MS: m/z 611.0 [M+H]+.
Figure imgf000252_0001
[0786] Intermediate 94-1 was prepared essentially as described in the preparation of Compound 4d. Intermediate 94-2 was prepared essentially as described in the preparation of Compound 2d. [0787] Compound 95c was prepared essentially as described in the preparation of Compound 2d by using acid 94-1 and amine 94-2 as starting materials. Finally, Compound 95c (32 mg) was obtained as a white solid.1H NMR (400MHz, CD3OD) ^ = 8.75 (d, J=2.8 Hz, 1H), 8.39-8.20 (m, 2H), 7.97-7.93 (dd, J=9.2 Hz, 2.8 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.17-7.12 (m, 2H), 5.06 (d, J=9.6 Hz, 1H), 4.66 (d, J=9.6 Hz, 1H), 4.58-4.53 (m, 1H), 4.13-4.10 (m, 1H), 3.96-3.92 (m, 1H), 1.78 (s, 3H), 0.88-0.80 (m, 4H). LCMS: ESI-MS: m/z 611.0 [M+H]+. Examples 95a and 95b: Synthesis of Stereoisomers of Compound 96
Figure imgf000253_0001
[0788] Intermediate 95-1 was prepared essentially as described in the preparation of Compound 6d. Intermediate 95-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. [0789] The stereoisomers of Compound 96 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 95-1 and amine 95-2 as starting materials. [0790] The stereoisomers of Compound 96 were separated by SFC according the method of (column: Phenomenex-Amylose-1 (250mm*30mm, 5um); mobile phase: [0.1% NH3 • H2O ETOH]; B%: 25%-25%, min). Finally, Stereoisomer 1 of Compound 96 (peak 1, Rt=3.605 min, 44 mg, 27.43% yield) as a white solid and Stereoisomer 2 of Compound 96 (peak 2, Rt=3.826 min, 45 mg, 27.87% yield) as a white solid were obtained. [0791] Example 95a: Stereoisomer 1 of Compound 96: 1H NMR (400MHz, CD3OD) ^ ^δ = 8.91 (d, J=2.0 Hz, 1H), 8.35 (d, J=1.6 Hz, 1H), 8.30-8.26 (m, 2H), 7.77 (d, J=1.2 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.67 (s, 1H), 7.15 - 7.10 (t, J=8.8 Hz, 2H), 7.16 - 6.88 (t, J=55.2 Hz, 1H), 4.75 (d, J=9.6 Hz, 1H), 4.63 (d, J=13.6 Hz, 1H), 4.49 (s, 1H), 4.43-4.40 (dd, J=9.2 Hz 1.6 Hz, 1H), 4.37 (s, 1H), 3.99 (d, J=10.4 Hz, 1H), 3.88 (m, 1H), 1.42 (d, J=1.2 Hz, 3H).0.81-0.80 (m, 4H). LCMS: ESI-MS: m/z 650.1 [M+H]+. [0792] Example 95b: Stereoisomer 2 of Compound 96: 1H NMR (400MHz, CD3OD) ^ ^δ = 8.92 (s, 1H), 8.35 (d, J=1.2 Hz, 1H), 8.31-8.28 (m, 2H), 7.75 (d, J=1.6 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.68 (s, 1H), 7.16 - 7.11 (m, 2H), 7.16 - 6.88 (t, J=55.6 Hz, 1H), 4.73 (d, J=9.6 Hz, 1H), 4.60-4.38 (m, 4H), 4.02 (d, J=10.0 Hz, 1H), 3.90-3.88 (m, 1H), 1.40 (d, J=1.6 Hz, 3H).0.83-0.81 (m, 4H). LCMS: ESI-MS: m/z 650.1 [M+H]+. Examples 96a and 96b: Synthesis of Stereoisomers of Compound 97
Figure imgf000254_0001
[0793] Intermediate 96-1 was prepared essentially as described in the preparation of Compound 15d. Intermediate 96-2 was prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. [0794] The stereoisomers of Compound 97 were prepared essentially as described in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51 by using acid 96-1 and amine 96-2 as starting materials. [0795] The stereoisomers of Compound 97 were separated by SFC twice according the method of (column: Phenomenex-Amylose-1 (250mm*30mm,5um); mobile phase: [0.1%NH3H2O ETOH]; B%: 20%-20%, min) and (column: Phenomenex-Amylose-1 (250mm*30mm,5um); mobile phase: [0.1% NH3 • H2O ETOH]; B%: 20%-20%, min). [0796] Finally, Stereoisomer 1 of Compound 97 (peak 1, Rt=2.805 min, 52 mg, 24.76% yield) as a white solid and Stereoisomer 2 of Compound 97 (peak 2, Rt=3.796 min, 70 mg, 33.3% yield) as a white solid were obtained. [0797] Example 96a: Stereoisomer 1 of Compound 97: 1H NMR (400MHz, DMSO) ^ ^δ = 9.04 (s, 1H), 8.74 (t, J=5.6 Hz, 1H), 8.55 (s, 1H), 8.27-8.24 (m, 2H), 8.00 (s, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 7.33-7.28 (m, 2H), 7.23 (s, 1H), 7.45 - 7.17 (t, J=55.2 Hz, 1H), 4.68 (d, J=9.2 Hz, 1H), 4.60 - 4.41 (m, 3H), 4.25 - 4.14 (m, 2H), 3.96 (s, 3H), 1.38 (s, 3H). LCMS: ESI-MS: m/z 624.1 [M+H]+. [0798] Example 96b: Stereoisomer 2 of Compound 97: 1H NMR (400MHz, DMSO) ^ ^δ = 9.04 (d, J=2.0 Hz, 1H), 8.74 (t, J=5.6 Hz, 1H), 8.56 (s, 1H), 8.28-8.24 (m, 2H), 8.02 (d, J=1.2 Hz, 1H), 7.74 (s, 1H), 7.50 (s, 1H), 7.33-7.28 (m, 2H), 7.24 (s, 1H), 7.45 - 7.17 (t, J=55.2 Hz, 1H), 4.70 (d, J=9.2 Hz, 1H), 4.63 - 4.40 (m, 3H), 4.25 - 4.12 (m, 2H), 3.96 (s, 3H), 1.31 (s, 3H). LCMS: ESI-MS: m/z 624.1 [M+H]+. Example 97: Single crystal X-ray diffraction studies [0799] The absolute stereochemistry of compounds were determined by X-ray diffraction. The single crystal X-ray diffraction studies were carried out on a Bruker D8 Platinum135 CCD diffractometer equipped with Cu K ^ radiation ( ^ = 1.5478). A 0.357 x 0.134 x 0.126 mm piece of a colorless block was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using ^ and ^ scans. Crystal-to-detector distance was 45 mm using variable exposure time (0.5s-1s) depending on ^ ^with a scan width of 2.0°. Data collection was 99.9% complete to 68.00° in ^. A total of 16881 reflections were collected covering the indices, -10<=h<=11, -14<=k<=14, -23<=l<=23. 4240 reflections were found to be symmetry independent, with a Rint of 0.0408. Indexing and unit cell refinement indicated a primitive, orthorhombic lattice. The space group was found to be P212121. The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SHELXT) produced a complete phasing model consistent with the proposed structure. [0800] All nonhydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-2014. All other hydrogen atoms (H-bonding) were located in the difference map. Their relative positions were restrained using DFIX commands and their thermals freely refined. The absolute stereochemistry of the molecule was established by anomalous dispersion using the Parson’s method with a Flack parameter of 0.017(39). Figure 1 shows the single crystal structural analysis of tert-butyl ((S)-3,3,3-trifluoro-2-((S)-7-(4-fluorophenyl)-3-(hydroxymethyl)- 3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-hydroxypropyl)carbamate (Intermediate 14-3), with the structure as shown below.
Figure imgf000256_0001
Example 98: Synthesis of Compound 98a [0801] 98.1 Scheme showing synthesis of Intermediate 98-1
Figure imgf000256_0002
Figure imgf000257_0001
[0802] 98.2 Synthesis of Intermediate 98-3 [0803] Intermediate 98-3 was prepared essentially as described in the preparation of Compound 7-11 by using Compound 17-13 as starting material. Finally, Intermediate 98-3 (3.8 g, 94%) was obtained as a white solid. [0804] 98.3 Synthesis of Intermediate 98-4 [0805] A mixture of Intermediate 98-3 (5 g, 15.94 mmol, 1 eq.), potassium vinyltrifluoroborate (6.40 g, 47.82 mmol, 3 eq), Pd(dppf)Cl2 (1.17 g, 1.59 mmol, 0.1 eq), K2CO3 (6.61 g, 47.82 mmol, 3 eq.) in EtOH (40 mL) and H2O (10 mL) was degassed and purged with N2 for 3 times. The resulting mixture was stirred at 85 °C for 4 hr under N2 atmosphere. TLC indicated Intermediate 98-3 was consumed completely. The reaction mixture was quenched by addition H2O 100 mL, and then extracted with EA (100 mL X 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; Silica Flash Column, Eluent of 0~10% EA/PA gradient @ 40 mL/min). Intermediate 98-4 (4.1 g, 84.26% yield) was obtained as a white solid. [0806] 98.4: Synthesis of Intermediate 98-5 [0807] Intermediate 98-5 was prepared essentially as described in the preparation of Compound 6-3 by using intermediate 98-4 as starting material. Finally, Intermediate 98-5 (3.8 g, 94%) was obtained as a white solid. [0808] 98.5: Synthesis of Intermediate 98-7 [0809] To a solution of Intermediate 98-5 (1.1 g, 3.58 mmol, 1 eq.) and TMSCF2H (98-6) (4.89 g, 39.38 mmol, 11 eq.) in DMF (11 mL) was added TBAF (1 M, 5.37 mL, 1.5 eq.) dropwise at 0 oC. The mixture was stirred at 0 °C for 1 hr. TLC indicated compound 98-5 was consumed completely. The reaction was clean according to TLC. The reaction mixture was diluted by H2O (50 mL), then extracted with EA (20 mL X 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO® Silica Flash Column, Eluent of 0~25% EA/PE gradient @ 30 mL/min). Intermediate 98-7 (1.01 g, 78.52% yield) was obtained as a light yellow oil. [0810] 98.6: Synthesis of Intermediate 98-8 [0811] Intermediate 98-8 was prepared essentially as described in the preparation of Compound 17-4 by using Intermediate 98-7 as starting material. Finally, Intermediate 98-7 (842 mg, 94%) was obtained as a white solid. [0812] 98.7: Synthesis of Intermediate 98-9 [0813] Intermediate 98-9 was prepared essentially as described in the preparation of Compound 23-14 by using Intermediate 98-8 as starting material. Finally, Intermediate 98-7 (601 mg, 85%) was obtained as a white solid. [0814] 98.8: Synthesis of Intermediate 98-10 [0815] Intermediate 98-10 was prepared essentially as described in the preparation of Compound 1-25 by using Intermediate 98-9 as starting material. Finally, Intermediate 98-10 (602 mg, 91%) was obtained as a white solid. [0816] 98.9: Synthesis of Intermediate 98-11 [0817] Intermediate 98-11 was prepared essentially as described in the preparation of Compound 1-26 by using intermediate 98-10 as starting material. Finally, Intermediate 98-7 (620 mg, crude) was obtained as a yellow oil. [0818] 98.9: Synthesis of Intermediate 98-1 [0819] Intermediate 98-1 was prepared essentially as described in the preparation of Compound 1-27 by using Intermediate 98-11 as starting material. Finally, Intermediate 98-1 (230 mg, 53%, 98.6% purity) was obtained as a yellow oil. [0820] 98.10: Synthesis of Compound 98a
Figure imgf000259_0001
[0821] Compound 98a was prepared essentially as described in the preparation of Compound 41d by using acid 10-8 and amine 98-1 as starting materials.1H NMR (400MHz, METHANOL- d4) δ = 8.27 - 8.23 (m, 2H), 7.71 (d, J=2.4 Hz, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.58 (d J=1.6 Hz, 1H), 7.12 - 7.06 (t, J=9.2 Hz, 2H), 6.68 - 6.41 (t, J=55.2 Hz, 1H), 4.78 - 4.62 (m, 6H), 4.25 (d, J=13.6 Hz, 1H), 4.02 - 3.99 (m, 1H), 3.88 (d, J=13.6 Hz, 1H), 2.88 (s, 3H), 0.91 - 0.89 (m, 4H). Example 99: Synthesis of Compound 99
Figure imgf000259_0002
[0822] Acid 10-8 was prepared as previously described in Example 10. Amine 99-2 was prepared essentially as described for the preparation of intermediate 17-21 in Example 17. [0823] To a solution of Acid 10-8 (45 mg, 0.18 mmol, 1 eq.) and amine 99-2 (77 mg, 184.24, 0.18 mmol, 1 eq.) in DCM (2 mL) was added T3P (propylphosphonic anhydride; 176 mg, 165 uL, 50% in EA, 1.5 eq.). The mixture was stirred at 15 °C for 15 min. Then TEA (56 mg, 0.56 mmol, 3 eq.) was added and stirred at 15 °C for 15 min. LCMS trace showed that Acid 10-8 was consumed and one main peak (Rt = 0.873 min) with desired MS (ESI-MS: m/z 644.3 [M+1]+) was observed. The reaction mixture was quenched by addition of water (10 mL), extracted with EA (10 mL X 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to give a yellow oil (110 mg). The yellow oil was purified by prep-HPLC (FA) {column: Boston Green ODS 150*30mm*5um; mobile phase: [water (0.2%FA)-ACN];B%: 35%-65%,8min} to give yellow solution and then lyophilized to give Compound 99 (56.8 mg, 47.90% yield, 100% purity) as a yellow solid. LCMS: ESI-MS: m/z 644.2 [M+H]+. 1H NMR (METHANOL-d4, 400MHz): δ = 8.27-8.16 (m, 2H), 7.89 (s, 1H), 7.73 (s, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.10 (t, J=8.8 Hz, 2H), 5.03 (dd, J=9.8, 2.4 Hz, 1H), 4.97 (d, J=9.6 Hz, 1H), 4.81 (br s, 1H), 4.75-4.68 (m, 2H), 4.60 (d, J=13.7 Hz, 1H), 3.98-3.92 (m, 1H), 3.90 (d, J=13.6 Hz, 1H), 2.84 (s, 3H), 0.99-0.68 ppm (m, 4H). Example 100: Synthesis of Compound 100
Figure imgf000260_0001
[0824] Amine 100-2 was prepared as described in the preparation of Intermediate 23-20 in Example 23. To a mixture of Acid 10-8 (42 mg, 0.17 mmol, 1.05 eq.) in DMF (2 mL) were added HATU (66 mg, 0.17 mmol, 1.05 eq.) and DIPEA (64 mg, 0.49 mmol, 3 eq.). After 15 min, Intermediate 100-2 (60 mg, 0.16 mmol, 1 eq.) was added. Then the mixture was stirred at 20 °C for 15 min. LC-MS trace showed that Acid 10-8 was consumed completely and one main peak (Rt=0.932 min) that contained desired mass. The reaction mixture was diluted with H2O(50 mL), extracted with EA (20 mL X 3). The separated organic layer was washed with brine (20 ml), dried over Na2SO4 and concentrated to dryness. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(0.2%FA)-ACN];B%45%- 75%, 8min) to give the title compound (42 mg, 42.28% yield, 98% purity) as light yellow solid. LCMS: ESI-MS: m/z 590.0 [M+H]+. 1H NMR (400MHz, METHANOL-d4) δ = 8.22 (dd, J=5.5, 9.0 Hz, 2H), 7.84 (s, 1H), 7.71 (s, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.61 (d, J=1.3 Hz, 1H), 7.08 (t, J=8.9 Hz, 2H), 6.81 - 6.42 (m, 1H), 4.99 (d, J=9.5 Hz, 1H), 4.60 (d, J=9.5 Hz, 1H), 4.17 (d, J=13.9 Hz, 1H), 4.05 - 3.96 (m, 1H), 3.88 (d, J=13.7 Hz, 1H), 2.87 (s, 3H), 1.72 (s, 3H), 0.94 - 0.85 (m, 4H). Example 101: Synthesis of Compound 101
Figure imgf000261_0001
[0825] Acid 101-1 was prepared essentially as described for Intermediate 10-8 in Example 10. Intermediate 101-2 was prepared essentially as described in the preparation of Intermediate 7-15 in Example 7 by using [4-fluoro-3-(trifluoromethyl)phenyl]boronic acid as starting material. Compound 101 was prepared essentially as described in the preparation of Example 99 using Acid 101-1 and Amine 101-2 as starting materials. Finally, Compound 101 (60 mg) was obtained as white solid. LCMS: ESI-MS: m/z 675.1 [M+H]+. 1H NMR (400MHz, MeOD-d6) δ = 8.59-8.56 (m, 2H), 7.83 (s, 1H), 7.60 (s, 1H), 7.40-7.36 (t, J=9.6 Hz, 1H, ), 7.30 (s, 1H), 4.78- 4.50 (m, 6H), 4.62-4.53 (m, 1H), 4.06-4.03 (m, 4H), 2.86 (s, 3H). Example 102: Preparation of Compound 102
Figure imgf000261_0002
[0826] To a solution of Intermediate 102-1 (prepared as described in PCT Publ. No. WO2013/185103, 2013, A1; 4.1 g, 13.05 mmol, 1 eq.) in THF (50 mL) was added LiAlH4 (743 mg, 19.58 mmol, 1.5 eq.). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by the addition of H2O (0.75 mL), NaOH (15% aq.0.75 mL) with stirring at 0 °C for 5 min. Then H2O (2 mL) was added. The mixture was stirred at 0 °C for 50 min, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~80% EA in PE gradient @ 40 mL/min) to give Intermediate 102-2 (1.1 g, 32.78% yield) as a yellow solid. LCMS: ESI-MS: m/z 257.0 [M+H]+. [0827] To a solution of Intermediate 102-2 (2 g, 7.78 mmol, 1 eq.) in DCM (15 mL) was added MnO2 (4.06 g, 46.68 mmol, 6 eq.). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was quenched by addition of H2O (50 mL). Then the reaction mixture was extracted with EA (30 mL X 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~40% EA in PE gradient @ 25 mL/min) to give Intermediate 102-3 (751 mg, 37.85% yield) as a yellow solid. LCMS: ESI-MS: m/z 255.0 [M+H]+. [0828] To a solution of Intermediate 102-3 (750 mg, 2.94 mmol, 1 eq.) in DCM (15 mL) was added DAST (1.42 g, 8.82 mmol, 1.17 mL, 3 eq.) at -30 °C in 10 min with stirring. The reaction mixture was quenched by addition H2O (30 mL), extracted with EA (20 mL X 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~30% EA in PE gradient @ 25 mL/min) to give intermediate 102-4 (420 mg, 51.55% yield) as a yellow solid. LCMS: ESI-MS: m/z 277.0 [M+H]+; 1H NMR (400MHz, CHLOROFORM-d) δ = 9.47 (s, 1H), 8.26 (s, 1H), 7.40 - 7.25 (m, 1H), 7.13 (d, J=1.7 Hz, 1H), 7.02 (s, 1H). [0829] To a solution of intermediate 102-4 (420 mg, 1.52 mmol, 1 eq.) in MeOH (8 mL) was added NaOMe (246 mg, 4.55 mmol, 3 eq.). The mixture was stirred at 55 °C for 1 h. The reaction mixture was quenched by addition H2O (10 mL), extracted with EA (10 mL X 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~40% EA in PE gradient @ 25 mL/min) to give intermediate 102-5 (213 mg, 48.60% yield) as a yellow solid. LCMS: ESI-MS: m/z 289.2 [M+H]+. [0830] Intermediates 102-6 and 102-7 were prepared essentially as described in the preparation of Intermediate 2-5 in Example 2. Intermediate 102-8 was prepared essentially as in the preparation of Intermediate 23-20 in Example 23. [0831] Compound 102 was prepared essentially as described in the preparation of Compound 100 by using acid 102-7 and amine 102-8 as starting materials. Finally, Compound 100 (35 mg) was obtained as gray solid. LCMS: ESI-MS: m/z 589.1 [M+H]+. 1H NMR (400MHz, MeOD- d6) δ = 8.23 (dd, J=5.6, 8.6 Hz, 2H), 8.18 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.39 - 7.07 (m, 1H), 7.03 (t, J=8.7 Hz, 2H), 6.66 - 6.31 (m, 1H), 4.42 - 4.34 (m, 2H), 4.23 (d, J=13.9 Hz, 1H), 4.05 (s, 3H), 3.87 (d, J=13.7 Hz, 1H), 1.34 (d, J=7.1 Hz, 6H). Example 103: Synthesis of Compound 103
Figure imgf000263_0001
[0832] Acid 102-7 was prepared as described in Example 102. Amine 7-15 was prepared as described in Example 7. Compound 103 was prepared essentially as described in the preparation of Example 100 using acid 102-7 and amine 7-15 as starting materials. Finally, Compound 103 (33 mg) was obtained as yellow solid. LCMS: ESI-MS: m/z 643.1 [M +H]+; 1H NMR (400MHz, METHANOL-d4) δ 8.35 - 8.20 (m, 3H), 7.75 (s, 2H), 7.45 (d, J=1.2 Hz, 1H), 7.39 - 7.15 (m, 1H), 7.14 - 7.08 (m, 2H), 4.81 - 4.60 (m, 6H), 4.57 (d, J=13.8 Hz, 1H), 4.07 (s, 3H), 4.01 (d, J=13.8 Hz, 1H). Example 104: Synthesis of Compound 104
Figure imgf000263_0002
[0833] Intermediate 101-1 was prepared as described in Example 10. Amine 104-1 was prepared essentially as described in the preparation of intermediate 7-15 in Example 7 by using (4-chlorophenyl)boronic acid as starting material. Compound 104 was prepared essentially as described in the preparation of Compound 100 using acid 101-1 and amine 104-1 as starting materials. Finally, Compoune 104 (38 mg) was obtained as yellow solid. LCMS: ESI-MS: m/z 623.2 [M+H]+; 1H NMR (400MHz, METHANOL-d4) δ = 8.26 (d, J=6.8 Hz, 2H), 7.84 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.42 (d, J=6.8 Hz, 2H), 7.30 (s, 1H), 4.79 - 4.67 (m, 7H), 4.05-3.99 (m, 4H), 2.88 (s, 3H).
Figure imgf000264_0001
[0834] Intermediate 105-1 was synthesized using similar conditions to those previously described for the preparation for Intermediate 7-11, using Intermediate 17-13 as a starting material. [0835] A mixture of intermediate 105-1 (3 g, 9.56 mmol, 1 eq.), tributyl(1- ethoxyvinyl)stannane (10.46 g, 28.96 mmol, 3.03 eq.) and Pd(PPh3)2Cl2 (671 mg, 0.95 mmol, 0.1 eq.) in toluene (80 mL) was stirred at 100 °C for 3 h under nitrogen. TLC (PE/EA=5/1) showed intermediate 105-1 was consumed and one new main point was formed. The residue was purified by column chromatography (SiO2, 0~20% EA in PE) to give Intermediate 105-2 (1.8 g, 58.58% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ = 8.35-8.31 (m, 2H), 7.96 (s, 1H), 7.21- 7.16 (m, 2H), 4.77-4.72 (m, 4H), 4.66-4.60 (m, 2H), 2.78 (s, 3H). [0836] To a mixture of Intermediate 105-2 (1.8 g, 5.60 mmol, 1 eq.) in DCM (50 mL) were added DIPEA (3.26 g, 25.21 mmol, 4.5 eq.) and TMSOTf (2.49 g, 11.20 mmol, 2 eq.) at 0 °C. Then the mixture was stirred at 25 °C for 2 h. TLC (PE/EA=3/1) showed the reaction was completed. The mixture was quenched by aq.NaHCO3 (100 mL) and extracted with DCM (100 mL). The organic layer was separated, dried and concentrated to give crude product 105-3 (1.7 g, crude) as a brown oil. [0837] To a mixture of Select F (2.85 g, 8.03 mmol, 1.5 eq.) in MeCN (30 mL) and H2O (15 mL) was added a solution of Intermediate 105-3 (1.7 g, crude) in MeCN (15 mL) under nitrogen. The mixture was stirred at 25 °C for 30 min. The mixture was extracted with EA (50 mL). The organic layer was concentrated. The residue was purified by column chromatography (SiO2, 0~15% EA in PE) to give Intermediate 105-4 (1.1 g, 59.33% yield, 98% purity) as a white solid. LCMS: ESI-MS: m/z 340.0 [M+H]+. [0838] The preparation of Intermediates 105-5, 105-6, 105-7, and 105-8 was essentially as described in the preparation of intermediate 7-15 in Example 7. [0839] Acid 101-1 was prepared as described in Example 101. Compound 105 was prepared essentially as described in for Compound 100, Example 100, using amine 105-8 and acid 101-1 as starting materials. Finally, Compound 105 (28 mg) was obtained as yellow solid; LCMS: ESI-MS: m/z 571.2 [M+H]+. 1H NMR (400MHz, METHANOL-d4) δ = 8.29 - 8.18 (m, 2H), 7.71 (s, 1H), 7.67 (s, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.31 (d, J=1.1 Hz, 1H), 7.06 (t, J=8.8 Hz, 2H), 5.01 (d, J=9.5 Hz, 1H), 4.87 (d, J=2.9 Hz, 1H), 4.78 - 4.72 (m, 2H), 4.66 - 4.60 (m, 4H), 4.05 (s, 3H), 4.02 (d, J=13.9 Hz, 1H), 3.83 (d, J=13.7 Hz, 1H), 2.87 (s, 3H). Example 106: Synthesis of Compound 106
Figure imgf000266_0002
[0840] Amine 106-3 was prepared essentially as described in the preparation from intermediate 14-3 as a starting material in Example 14. Compound 106 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 106-3 as starting materials. Finally, Compound 106 (55 mg) was obtained as light yellow solid; 1H NMR (400MHz, METHANOL-d4) ^= 8.29 (dd, J=5.6, 8.9 Hz, 2H), 7.66 (d, J=3.5 Hz, 2H), 7.51 (d, J=1.3 Hz, 1H), 7.22 (s, 1H), 7.17 (t, J=8.8 Hz, 2H), 4.90 - 4.89 (m, 1H), 4.70 (d, J=13.9 Hz, 1H), 4.29 (d, J=9.5 Hz, 1H), 4.00 (s, 3H), 3.86 (d, J=13.7 Hz, 1H), 2.85 (s, 3H), 1.47 (s, 3H), 1.13 (s, 3H), 1.04 (s, 3H). LCMS: ESI-MS: m/z 615.3 [M+H]+. Example 107: Synthesis of Compound 107
Figure imgf000266_0001
[0841] Amine 107-2 was prepared essentially as described in the preparation of intermediate 14-7 in Example 14. Compound 107 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 107-2 as starting materials. Finally, Compound 107 (111.2 mg) was obtained as yellow solid. 1H NMR (400MHz, METHANOL-d4) ^= 8.25 (dd, J=5.5, 8.9 Hz, 2H), 7.82 (s, 1H), 7.71 (s, 1H), 7.50 (d, J=1.2 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 6.12 - 5.74 (m, 1H), 5.12 (d, J=9.3 Hz, 1H), 4.65 (d, J=13.7 Hz, 1H), 4.51 (d, J=9.3 Hz, 1H), 4.01 (s, 3H), 3.86 (d, J=13.7 Hz, 1H), 3.59 (dt, J=4.2, 14.6 Hz, 2H), 2.86 (s, 3H), 1.69 (s, 3H). LCMS: ESI-MS: m/z 664.0 [M+H]+. Example 108: Synthesis of Compound 108
Figure imgf000267_0002
[0842] Amine 98-1 was previously described in the preparation of Compound 98a. Compound 108 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 98-1 as starting materials. Finally, Compound 108 (102 mg) was obtained as yellow solid. 1H NMR (400MHz, METHANOL-d4) ^= 8.25 - 8.13 (m, 2H), 7.57 (s, 1H), 7.46 (s, 1H), 7.34 (s, 1H), 7.24 (s, 1H), 7.16 (t, J=8.7 Hz, 2H), 6.73 - 6.66 (m, 1H), 6.11 - 5.80 (m, 1H), 4.79 - 4.54 (m, 6H), 4.47 (dd, J=7.9, 13.9 Hz, 1H), 4.09 (s, 3H), 3.96 (dd, J=4.1, 14.2 Hz, 1H), 2.93 (s, 3H). LCMS: ESI-MS: m/z 589.0 [M+H]+. Example 109: Synthesis of Compound 109
Figure imgf000267_0001
[0843] Amine 109-1 was prepared essentially as described in the preparation of intermediate 1-27 in Example 1 using (4-(trifluoromethyl)phenyl)boronic acid as starting material. Compound 109 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 109-1 as starting materials. Finally, Compound 109 (45 mg) was obtained as yellow solid; 1H NMR (400MHz, METHANOL-d4) ^= 8.46 (d, J=8.3 Hz, 2H), 8.00 (s, 1H), 7.86 (s, 1H), 7.74 (d, J=8.5 Hz, 2H), 7.69 (d, J=1.3 Hz, 1H), 7.38 (d, J=1.3 Hz, 1H), 5.10 (d, J=9.5 Hz, 1H), 4.70 (d, J=9.5 Hz, 1H), 4.57 (d, J=14.1 Hz, 1H), 4.12 (d, J=14.1 Hz, 1H), 4.07 (s, 3H), 2.88 (s, 3H), 1.81 (s, 3H); LCMS: ESI-MS: m/z 632.1 [M+H]+. Example 110: Synthesis of Compound 110
Figure imgf000268_0001
[0844] Intermediate 110-1 was prepared essentially as described using intermediate 1-18 in Example 1 as a starting material using (4-(trifluoromethyl)phenyl)boronic acid as starting material. Compound 110 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 110-2 as starting materials. Finally. Compound 110 (43 mg) was obtained as yellow solid. 1H NMR (400MHz, METHANOL-d4) ^= 8.51 (d, J=8.3 Hz, 2H), 7.80 (s, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.71 (s, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H), 4.62 (d, J=13.8 Hz, 1H), 4.49 (s, 2H), 4.07 - 4.02 (m, 4H), 2.88 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H). LCMS: ESI-MS: m/z 621.2 [M +H]+. Example 111: Synthesis of Compound 111
Figure imgf000268_0002
[0845] Compound 111 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 111-1 as starting materials. Finally, Compound 111 (59 mg) was obtained as yellow solid.1H NMR (400MHz, METHANOL-d4) ^= 8.30 (dd, J=5.5, 8.9 Hz, 2H), 7.81 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.27 (s, 1H), 7.16 (t, J=8.8 Hz, 2H), 5.20 (d, J=9.5 Hz, 1H), 4.68 - 4.60 (m, 1H), 4.43 (d, J=9.5 Hz, 1H), 4.04 (s, 3H), 3.96 (d, J=13.9 Hz, 1H), 2.87 (s, 3H), 2.18 (s, 3H), 1.60 (s, 3H). LCMS: ESI-MS: m/z 599.1 [M+H]+. Example 112: Synthesis of Compound 112
Figure imgf000269_0002
[0846] Amine 112-1 was prepared essentially as described in the preparation of Intermediate 14-7 in Example 14 by using cyclopropanamine as starting material. Compound 112 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 112-1 as starting materials. Finally, Compound 112 (111 mg) was obtained as yellow solid; 1H NMR (400MHz, METHANOL-d4) ^= 8.29 - 8.20 (m, 2H), 7.76 (d, J=11.0 Hz, 2H), 7.55 (d, J=1.5 Hz, 1H), 7.23 (d, J=1.3 Hz, 1H), 7.18 - 7.08 (m, 2H), 5.11 (d, J=9.3 Hz, 1H), 4.59 (d, J=13.8 Hz, 1H), 4.47 (d, J=9.3 Hz, 1H), 4.03 (s, 3H), 3.91 (d, J=13.6 Hz, 1H), 2.87 (s, 3H), 2.67 (t, J=3.9 Hz, 1H), 1.63 (s, 3H), 0.73 - 0.54 (m, 4H); LCMS: ESI-MS: m/z 640.1 [M+H]+. Example 113: Synthesis of Compound 113
Figure imgf000269_0001
[0847] Acid 65-4 was prepared as described in Example 65. Amine 98-1 was previously described in the preparation of Compound 98a. Compound 113 was prepared essentially as described in the preparation of Compound 100 by using acid 65-4 and amine 98-1 as starting materials. Finally, Compound 113 (120 mg) was obtained as yellow solid; 1H NMR (400MHz, METHANOL-d4) ^= 8.75 (d, J=2.4 Hz, 1H), 8.26 - 8.20 (m, 2H), 8.13 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.72 - 6.40 (m, 1H), 4.73 - 4.56 (m, 6H), 4.18 (d, J=13.7 Hz, 1H), 3.97 (s, 3H), 3.84 (d, J=13.9 Hz, 1H). LCMS: ESI- MS: m/z 608.1 [M+H]+. Example 114: Synthesis of Compound 114
Figure imgf000270_0001
[0848] Amine 114-2 was prepared using the method described for the preparation of intermediate 14-7 in Example 14 by using 2,2,2-trifluoroethanamine as starting material. Compound 114 was prepared essentially as described in the preparation of Compound 100 using acid 101-1 and amine 114-2 as starting materials. Finally, Compound 114 (31 mg) was obtained as yellow solid. 1H NMR (400MHz, METHANOL-d4) ^= 8.28-8.25 (m, 2H), 7.82 (s, H), 7.74 (s, 1H), 7.52 (s, 1H), 7.19-7.12 (m, 3H), 5.11 (d, J=9.2 Hz, 1H), 4.62-4.52 (m, 2H), 4.02 (s, 3H), 4.39 – 3.89 (m, 3H), 2.87 (s, 3H); LCMS: ESI-MS: m/z 682.2 [M+H]+. Example 115: Synthesis of Compound 115
Figure imgf000270_0002
[0849] Amine 7-15 was previously described in Example 7. Compound 115 was prepared essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 7-15 as starting materials. Finally, Compound 115 (57 mg) was obtained as yellow solid. 1H NMR (400MHz, METHANOL-d4) ^= 8.30-8.27 (m, 2H), 7.79 (s, H), 7.75 (s, 1H), 7.57 (s, 1H), 7.27 (s, 1H), 7.15 (t, J=8.8 Hz, 2H), 4.80-4.54 (m, 7H), 4.03 (s, 3H), 4.02– 3.99 (m, 1H), 2.86 (s, 3H); LCMS: ESI-MS: m/z 607.1 [M+H]+. Example 116: Synthesis of Compound 116
Figure imgf000271_0001
[0850] Intermediate 116-4 was prepared as described in US2010/311760A1. Preparation of Intermediate 116-5 can be done as described in Tetrahedron 2004, 60(36), 7983-7984. Compound 116 was prepared essentially as described for Compound 100 using Acid 116-6 and Amine 7-15 as starting materials.
Figure imgf000271_0002
[0851] Compound 117 (16 mg) was obtained from Compound 116 as a light yellow solid by using a similar procedure as described in the preparation of Compound 22d in Example 22. 1H NMR (400MHz, METHANOL-d4) ^= 8.80-8.77 (brs, 1H), 8.57 (s, 1H), 8.35-8.26 (m, 2H), 7.75 (s, H), 7.72 (s, 1 H), 7.56 (d, J=1.2 Hz, 1H), 7.16-7.12 (t, J=8.8 Hz, 1H), 4.80-4.57 (m, 7 H), 4.09 (s, 3 H), 4.06-4.02 (m, 1H), 3.18-3.30 (m, 4 H). LCMS: ESI-MS: m/z 618.2 [M+H]+. Example 118: Synthesis of Compound 118
Figure imgf000272_0001
[0852] Amine 118-2 was prepared essentially as described in preparation of intermediate 98- 1 by using cyclopropyl magnesium bromide and 98-5 as starting materials. Compound 118 was prepared essentially as described in the preparation of Compound 100 using acid 101-1 and amine 118-2 as starting materials. Compound 118 (97 mg) was obtained as a yellow solid. 1H NMR (400MHz, METHANOL-d4) ^= 8.28 (dd, J=5.5, 8.8 Hz, 2H), 7.70 (s, 1H), 7.65 (s, 1H), 7.56 (d, J=1.1 Hz, 1H), 7.30 (d, J=1.1 Hz, 1H), 7.12 (t, J=8.8 Hz, 2H), 4.82 - 4.61 (m, 6H), 4.19 (d, J=13.5 Hz, 1H), 4.05 (s, 3H), 3.82 (d, J=13.5 Hz, 1H), 2.88 (s, 3H), 0.92 - 0.85 (m, 1H), 0.73 - 0.25 (m, 4H); LCMS: ESI-MS: m/z 579.1 [M+H]+. Example 119: Synthesis of Compound 119
Figure imgf000272_0002
[0853] Acid 119-1 was prepared as described in the preparation of intermediate 10-8 in Example 10 by using ethynylcyclopropane as starting material. Amine 119-2 was previously descried in the preparation of Compound 98a. Compound 119 was prepared essentially as described in the preparation of Compound 99 by using acid 119-1 and amine 119-2 as starting materials. Compound 119 (53 mg) was obtained as a yellow solid; 1H NMR (400MHz, METHANOL-d4) ^= 8.31 - 8.18 (m, 2H), 7.69 (s, 1H), 7.61 (s, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.22 (d, J=1.3 Hz, 1H), 7.13 - 7.00 (m, 2H), 6.72 - 6.38 (m, 1H), 4.81 - 4.55 (m, 6H), 4.18 (d, J=13.7 Hz, 1H), 4.02 (s, 3H), 3.84 (d, J=13.7 Hz, 1H), 2.40 (quin, J=6.6 Hz, 1H), 1.29 - 1.17 (m, 4H). LCMS: ESI-MS: m/z 615.2 [M+H]+. Example 120: Synthesis of Compound 120
Figure imgf000273_0001
[0854] To a solution of acid 101-1 (400 mg, 1.72 mmol, 1 eq.) in DCM (10 mL) was added BBr3 (2.16 g, 8.61 mmol, 0.83 mL, 5 eq.). The mixture was stirred at 20 °C for 15 h. The reaction mixture was quenched by addition of MeOH (30 mL) slowly at 25 °C. Then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude mixture of 120-2 and 120-3 (380 mg, crude) was obtained as yellow solid and used for the next step without further purification. [0855] To a solution of the crude mixture of 120-2 and 120-3 (380 mg, 1 eq.) in MeOH (10 mL) was added SOCl2 (0.27 mL, 2 eq.). The resulting mixture was stirred at 85 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and basified with aqueous Na2CO3 solution to adjust pH = 8. The aqueous phase was extracted with ethyl acetate (20 mLX3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (eluent: PE/EA=5/1) to give 120-3 (170 mg, 41.86% yield) as a yellow solid; LCMS: ESI-MS: m/z 219.1 [M+H]+.
Figure imgf000273_0002
[0856] To a mixture of compound 120-3 (100 mg, 0.46 mmol, 1 eq.) in DMF (2 mL) was added K2CO3 (127 mg, 0.92 mmol, 2 eq.) at 25 °C. Then, 1,1-difluoro-2-iodoethane (177 mg, 2 eq.) was added. The resulting mixture was heated to 80 °C for 12 h. The reaction mixture was poured into ice-water (10 mL) and stirred for 10 min. The aqueous phase was extracted with EA (15 mL X 3). The combined organic phase was washed with H2O (10 mL X 3), saturated brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (eluent PE/EA=0/1) to give desired 120-6 (70 mg, 54.8% yield) as a light yellow solid; LCMS: ESI-MS: m/z 283.1 [M+H]+. [0857] To a solution of intermediate 120-6 (70 mg, 0.25 mmol, 1.0 eq.) in MeOH (2 mL) and H2O (1 mL) was added NaOH (20 mg, 0.5 mmol, 2.0 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. Then the aqueous phase was acidified to pH = 3~4 by addition of 1N HCl. The resulting mixture was concentrated in vacuum. The crude acid 120-4 (60 mg, crude) was obtained as a yellow solid. [0858] Acid 120-4 was prepared as described in the preparation of 120-3 by using 1,1- difluoro-2-iodoethane as starting material. Amine 120-5 was prepared essentially as described in the preparation of intermediate 14-7 in Example 14 using methyl amine as a starting material. Compound 120 was prepared essentially as described in the preparation of Compound 100 using acid 120-4 and amine 120-5 as starting materials. Compound 120 (16 mg) was obtained as a light yellow solid. 1H NMR (400MHz, METHANOL-d4) ^= 8.27 (dd, J=5.6, 8.9 Hz, 2H), 7.82 (s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.30 (s, 1H), 7.10 (t, J=8.9 Hz, 2H), 6.71 - 6.40 (m, 1H), 4.85 - 4.61 (m, 9H), 4.22 (d, J=13.6 Hz, 1H), 4.01 (s, 3H), 3.86 (d, J=14.3 Hz, 1H), 2.49 (s, 3H), 1.35 - 1.28 (m, 4H); LCMS: ESI-MS: m/z 664.1 [M+H]+. Example 121: Synthesis of Compound 121a and Compound 121b
Figure imgf000275_0001
[0859] Amine 121-2 was prepared as previously described in the synthesis of Intermediate 50-7 in Examples 50a and 50b for the preparation of the stereoisomers of Compound 51. Compounds 121a (32.9 mg) and 121b (29.7 mg) were prepared as white solids essentially as described in the preparation of the isomers of Compound 97 by using acid 101-1 and amine 121- 2 as starting materials. Compound 121a: 1H NMR (400MHz, METHANOL-d4) ^= 8.29 (dd, J=8.9, 5.5 Hz, 2H), 7.76 (s, 1H), 7.66 (s, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.24 (d, J=1.2 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 4.75 (d, J=9.3 Hz, 1H), 4.59 (d, J=13.9 Hz, 1H), 4.51 (d, J=3.7 Hz, 1H), 4.34-4.47 (m, 2H), 4.02 (s, 3H), 3.95 (d, J=13.7 Hz, 1H), 2.85 (s, 3H), 1.43 ppm (d, J=1.2 Hz, 3H); LCMS: ESI-MS: m/z 589.1 [M+H]+. Compound 121b: 1H NMR (400MHz, METHANOL-d4) ^= = 8.32 (dd, J=8.8, 5.4 Hz, 2H), 7.77 (s, 1H), 7.70 (s, 1H), 7.56 (s, 1H), 7.27 (s, 1H), 7.17 (t, J=8.8 Hz, 2H), 4.74 (d, J=9.3 Hz, 1H), 4.38-4.65 (m, 4H), 3.96-4.10 (m, 4H), 2.88 (s, 3H), 1.43 ppm (s, 3H); LCMS: ESI-MS: m/z 589.1 [M+H]+. Example 122: Synthesis of Compound 122
Figure imgf000275_0002
[0860] To a mixture of compound 120-3 (150 mg, 0.68 mmol, 1 eq.) in DMF (2 mL) was added K2CO3 (190 mg, 1.37 mmol, 2 eq.) at 15°C. Then, trideuterio(iodo)methane (214 uL, 5 eq.) was added. The resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into ice-water (10 mL) and stirred for 10 min. The aqueous phase was extracted with EA (15mLX3). The combined organic phase was washed with H2O (10 mLX3), saturated brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (eluent PE/EA=0/1) to give desired Compound 122-1 (40 mg, 24.73% yield) as a light yellow solid. LCMS: ESI-MS: m/z 236.1[M+H]+. [0861] To a solution of 122-1 (40 mg, 0.17 mmol, 1.0 eq.) in MeOH (2 mL) and H2O (1 mL) was added NaOH (15.3 mg, 0.38 mmol, 2.2 eq.). The mixture was stirred at 45 °C for 10 min. The reaction mixture was concentrated under reduced pressure to remove MeOH. Then the aqueous phase was acidified to pH = 3~4 by addition of 1N HCl. The resulting mixture was concentrated in vacuum. The crude acid 122-2 (35 mg, crude) was obtained as a yellow solid.
Figure imgf000276_0001
[0862] Compound 122 (35 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 122-2 and amine 122-3 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.31 (dd, J=5.4, 8.8 Hz, 2H), 7.78 (d, J=11.7 Hz, 2H), 7.58 (s, 1H), 7.29 (d, J=1.0 Hz, 1H), 7.17 (t, J=8.9 Hz, 2H), 4.81 - 4.63 (m, 6H), 4.57 (d, J=13.9 Hz, 1H), 4.07 - 3.97 (m, 1H), 2.88 (s, 3H). LCMS: ESI-MS: m/z 610.1 [M+H]+. Example 123: Synthesis of Compound 123
Figure imgf000276_0002
[0863] Acid 123-1 was prepared essentially as previously described in the preparation of Compound 92d. Compound 123 (15 mg) was obtained as a white solid essentially as described in the preparation of Compound 100 using acid 123-1 and amine 123-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.74 (s, 1H), 8.27 (dd, J=8.8, 5.6 Hz, 2H), 7.74 (s, 2H), 7.32 (s, 1H), 7.13 (t, J=8.8 Hz, 2H), 4.52-4.78 (m, 7H), 4.03 (d, J=13.9 Hz, 1H), 3.98 (s, 3H), 2.72 (s, 3H); LCMS: ESI-MS: m/z 607.1 [M+H]+. Example 124: Synthesis of Compound 124
Figure imgf000277_0001
[0864] Compound 124 (86 mg) was obtained as a white solid essentially as described in the preparation of Compound 101 using acid 102-7 and amine 98-1 as starting materials. 1H NMR (400MHz, METHANOL-d4) δ = 8.27 - 8.19 (m, 3H), 7.74 (d, J=1.1 Hz, 1H), 7.70 (s, 1H), 7.46 (s, 1H), 7.43 - 7.11 (m, 1H), 7.05 (t, J=8.8 Hz, 2H), 6.75 - 6.39 (m, 1H), 4.79 - 4.55 (m, 6H), 4.20 (d, J=13.7 Hz, 1H), 4.08 (s, 3H), 3.87 (d, J=13.9 Hz, 1H); LCMS: ESI-MS: m/z 625.1 [M+H]+. Example 125: Synthesis of Compound 125
Figure imgf000277_0002
[0865] Amine 125-2 was prepared essentially as described in preparation of intermediate 98- 1 by using cyclobutyl magnesium bromide and 98-5 as starting materials. Compound 125 (43.6 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 125-2 as starting materials. 1H NMR (400MHz, METHANOL- d4) ^= 8.45 (s, 1H), 8.25 (dd, J=5.6, 8.8 Hz, 2H), 7.64 (s, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.26 (s, 1H), 7.10 (t, J=8.8 Hz, 2H), 4.78 - 4.57 (m, 6H), 4.02 (s, 3H), 3.97 (dd, J=7.5, 13.3 Hz, 1H), 3.59 (dd, J=4.5, 13.3 Hz, 1H), 3.22 (t, J=8.7 Hz, 1H), 2.85 (s, 3H), 2.32 (q, J=9.5 Hz, 1H), 2.09 - 1.54 (m, 6H). LCMS: ESI-MS: m/z 593.3 [M+H]+. Example 126: Synthesis of Compound 126
Figure imgf000278_0001
[0866] Amine 126-2 was prepared essentially as described in preparation of intermediate 17- 21 by using intermediate 17-8 as a starting material in Example 17. Compound 126 (23 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 99 using acid 101-1 and amine 126-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^=8.11 (dd, J=5.6, 8.7 Hz, 2H), 7.65 (s, 1H), 7.18 - 7.09 (m, 3H), 7.03 (s, 1H), 6.92 (s, 1H), 6.78 (s, 1H), 6.58 (d, J=10.4 Hz, 1H), 4.90 (dd, J=10.1, 13.2 Hz, 1H), 4.64 (d, J=9.5 Hz, 1H), 4.44 (d, J=9.3 Hz, 1H), 4.04 - 3.97 (m, 6H), 3.96 - 3.90 (m, 1H), 3.62 (dd, J=2.8, 13.8 Hz, 1H), 3.51 (dd, J=3.5, 8.4 Hz, 1H), 2.86 (s, 3H), 2.17 (m, 1H). LCMS: ESI-MS: m/z 603.3 [M+H]+. Example 127: Synthesis of Compound 127
Figure imgf000278_0002
[0867] Amine 127-2 was prepared essentially as described in the preparation of Compound 23d in Example 23. Compound 127 (27 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 127-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.25 - 8.18 (m, 2H), 7.84 (s, 1H), 7.77 - 7.69 (m, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.30 (d, J=1.3 Hz, 1H), 7.07 (t, J=8.8 Hz, 2H), 6.78 - 6.44 (m, 1H), 4.99 (d, J=9.5 Hz, 1H), 4.65 - 4.61 (m, 1H), 4.15 (d, J=13.7 Hz, 1H), 4.05 (s, 3H), 3.88 (d, J=13.9 Hz, 1H), 2.88 (s, 3H), 1.72 (s, 3H); LCMS: ESI-MS: m/z 564.1 [M+H]+. Example 128: Synthesis of Compound 128
Figure imgf000279_0001
[0868] Amine 128-2 was prepared essentially as described in the preparation of Compound 17d in Example 17. Compound 128 (45 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 128-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.31 - 8.27 (m, 2H), 7.96 (s, 1H), 7.85 (s, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.37 (d, J=1.2 Hz, 1H), 7.17 (t, J=8.8 Hz, 2H), 5.06-5.02 (m, 1H), 4.93 (m, 1H), 4.85 - 4.83 (m, 1H), 4.79-4.74 (m, 1H), 4.52 (d, J=14.4 Hz, 1H), 4.11 (d, J=14.4 Hz, 1H), 4.08 (s, 3H), 2.89 (s, 3H); LCMS: ESI-MS: m/z 600.2 [M+H]+. Example 129: Synthesis of Compoung 129
Figure imgf000279_0002
[0869] Amine 129-2 was prepared essentially as described in the preparation of intermediate 14-7 in Example 14 using methyl amine as a starting material. Compound 129 (117 mg) was obtained as a white solid essentially as described in the preparation of Compound 100 by using acid 10-8 and amine 129-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.24 (dd, J=5.5, 8.8 Hz, 2H), 7.83 (s, 1H), 7.72 (s, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 7.13 (t, J=8.8 Hz, 2H), 5.13 (d, J=9.3 Hz, 1H), 4.71 (d, J=13.6 Hz, 1H), 4.46 (d, J=9.3 Hz, 1H), 3.94 - 3.88 (m, 1H), 3.82 (d, J=13.6 Hz, 1H), 2.86 (s, 3H), 2.77 (s, 3H), 1.67 (s, 3H), 0.89 - 0.79 (m, 4H); LCMS: ESI-MS: m/z 640.2 [M+H]+. Example 130: Synthesis of Compound 130
Figure imgf000280_0001
[0870] Acid 130-1 was prepared essentially as described in the preparation of Compound 75d. Compound 130 (40.6 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 130-1 and amine 130-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.30 (dd, J=5.5, 8.9 Hz, 2H), 7.75 (s, 1H), 7.52 (s, 1H), 7.37 (d, J=1.7 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.08 (s, 1H), 4.82 - 4.69 (m, 4H), 4.69 - 4.67 (m, 1H), 4.66 - 4.53 (m, 4H), 4.21 (s, 3H), 4.03 - 4.01 (m, 2H), 4.05 - 3.97 (m, 1H). LCMS: ESI- MS: m/z 623.3 [M+H]+. Example 131: Synthesis of Compound 131
Figure imgf000280_0002
[0871] Acid 131-1 was prepared essentially as described in the preparation of Compound 75d. Compound 131 (32.5 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 131-1 and amine 131-1 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.46 - 8.16 (m, 2H), 7.78 (s, 1H), 7.58(d, J=1.2 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.18 (t, J=8.8 Hz, 2H), 4.86 - 4.58 (m, 8H), 4.24 (s, 3H), 4.10 - 3.94 (m, 2H), 0.94 - 0.80 (m, 4H); LCMS: ESI-MS: m/z 649.2 [M+H]+. Example 132: Synthesis of Compound 132
Figure imgf000280_0003
[0872] Compound 132 (58.9 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 132-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.25 (dd, J=5.5, 8.9 Hz, 2H), 7.82 (s, 1H), 7.73 (s, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 5.13 (d, J=9.3 Hz, 1H), 4.69 (d, J=13.7 Hz, 1H), 4.47 (d, J=9.3 Hz, 1H), 4.02 (s, 3H), 3.84 (d, J=13.9 Hz, 1H), 2.87 (s, 3H), 2.78 (s, 3H), 1.67 (s, 3H); LCMS: ESI-MS: m/z 614.1 [M+H]+. Example 133: Synthesis of Compound 133
Figure imgf000281_0001
[0873] Amine 133-2 was prepared as described in the preparation of Compound 98a. Compound 133 (25 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 by using acid 120-4 and amine 133-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.25 (dd, J=5.6, 8.9 Hz, 2H), 7.78 - 7.76 (m, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.36 (s, 1H), 7.09 (t, J=8.8 Hz, 2H), 6.73 - 6.53 (m, 1H), 6.45 - 6.25 (m, 1H), 4.80 - 4.45 (m, 8H), 4.21 (d, J=13.6 Hz, 1H), 3.87 (d, J=13.6 Hz, 1H), 2.91 (s, 3H). LCMS: ESI- MS: m/z 639.1 [M+H]+. Example 134: Synthesis of Compound 134
Figure imgf000282_0001
[0874] To a mixture of 134-1 (1.5 g, 3.0mmol, 1 eq.) in MeOH (6 mL) and THF (24 mL) was added TMSCHN2 (2 M, 3.0 mL, 2 eq.) dropwise at 0 °C under N2. The mixture was stirred at 20 °C for 1 h. The mixture was poured into water (30 mL) and stirred for 2 min. The aqueous phase was extracted with EA (50 mL X 3). The combined organic phase was washed with brine (30 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, 0~50% EA in PE) to afford 134-2 (1.12 g, 72.63% yield) as a white solid. [0875] To a mixture of intermediate 134-2 (1.12 g, 2.18 mmol, 1 eq.) in THF (15 mL) was added Ti(Oi-Pr)4 (123.75 mg, 0.44 mmol, 0.2 eq.) in one portion a 0 °C under N2. The mixture was stirred at 0 °C for 30 min, then EtMgBr (2 M, 10.89 mL, 10 eq.) was added dropwise. After addition, the resulting mixture was stirred at 20 °C for 11.5 h. The mixture was quenched with water (20 mL) and stirred for 2 min. The aqueous phase was extracted with EA (35 mLX3). The combined organic phase was washed with brine (20 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was used for next step reaction without purification. Intermediate 134-3 (1.1 g, crude) was obtained as a light-yellow oil. LCMS: ESI- MS: m/z =513.1 [M+H]+.
Figure imgf000283_0001
[0876] To a mixture of Compound 134-3 (1.1 g, 2.15 mmol, 1 eq.) in DCM (30 mL) was added TFA (15.9 mL) in one portion at 20 °C under N2. The mixture was stirred at 20 °C for 1 hour. The pH of the mixture was adjusted to ~7.0 by adding NaHCO3 solution. The aqueous phase was extracted with ethyl acetate (100 mL X 3). The combined organic phase was washed with brine (50 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue (0.61 g, crude) was obtained as a light yellow oil and used for next step without purification. LCMS: ESI-MS: m/z 413.3 [M + H]+. [0877] Compound 134 (15.4 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 by using amine 134-4 and acid 101-1 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^=8.27 (dd, J=5.6, 8.6 Hz, 2H), 7.66 (s, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.22 - 7.12 (m, 3H), 4.82 (d, J=9.0 Hz, 1H), 4.66 (d, J=13.7 Hz, 1H), 4.34 (d, J=9.0 Hz, 1H), 4.00 (s, 3H), 3.87 (d, J=13.7 Hz, 1H), 2.85 (s, 3H), 1.43 (s, 3H), 0.74 - 0.62 (m, 2H), 0.60 - 0.46 (m, 2H); LCMS: ESI-MS: m/z 613.1 [M+H]+. Example 135: Synthesis of Compound 135
Figure imgf000283_0002
[0878] To a mixture of intermediate 135-1 (prepared essentially as described for Compound 95c; 120 mg, 0.2 mmol, 1 eq.) in MeOH (5 mL) was added NaOMe (22.3 mg, 0.4 mmol, 2 eq.). The reaction was stirred at 50 °C for 4 h. Then cyanamide (4.32 mL, excess amount) was added and the resulting mixture was stirred at 50 °C for 1 h. The reaction was quenched with H2O (10 mL) and extracted with EA (20 mL X 2). The organic layer was separated, dried and concentrated. The residue was purified by prep-HPLC twice (column: Venusil ASB Phenyl 150*30mm*5um;mobile phase: [water(0.05%HCl)-ACN];B%: 55%-85%,12min) (column: Boston Green ODS 150*30mm*5um;mobile phase: [water(0.2%FA)-ACN];B%: 32%- 62%,8min) to give Compound 135 (37 mg, 74.00% yield, 98% purity) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ = 8.80 (s, 1H), 8.75 (t, J=5.9 Hz, 1H), 8.67 (s, 1H), 8.23 (dd, J=5.7, 8.9 Hz, 2H), 7.90 (s, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.37 (s, 1H), 7.30 (t, J=8.8 Hz, 2H), 7.25 (s, 1H), 5.09 (d, J=9.3 Hz, 1H), 4.42 (d, J=9.5 Hz, 1H), 4.24 - 4.16 (m, 1H), 4.13 - 4.05 (m, 1H), 4.02 (s, 3H), 2.82 (s, 3H), 1.51 (s, 3H). LCMS: ESI-MS: m/z 624.1 [M+H]+. Example 136: Synthesis of Compound 136
Figure imgf000284_0001
[0879] To a solution of intermediate 3 (2 g, 4.33 mmol, 1 eq.) in toluene (10 mL) was added Pd2(dba)3 (397 mg, 0.433 mmol, 0.1 eq.) and Q-phos (277 mg, 0.39 mmol, 0.09 eq.). The mixture was stirred at 110 °C 6 h. The reaction mixture was cooled to room temperature and quenched by addition of H2O (10 mL). Then the mixture was extracted with EA (15 mLX3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (eluent: PE/EA=50/1 to 3/1) to give intermediate 4 (1.1 g, 55.0% yield) as a black brown oil. LCMS: ESI-MS: m/z 461.9[M+H]+.
Figure imgf000285_0003
[0880] To a solution of intermediate 4 (1.1 g, 2.38 mmol, 1 eq.) in DMF (10 mL) was added NaOAc (586 mg, 7.15 mmol, 3 eq.) and TBAAc (1.44 g, 4.77 mmol, 2 eq.). The mixture was stirred at 90 °C 1 h. The reaction mixture was cooled to room temperature and quenched by addition of H2O (10 mL). The resulting mixture was extracted with EA (15 mLX3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (eluent: PE/EA=50/1 to 3/1) to give intermediate 5 (0.8 g, 85.3% yield) as a yellow solid. LCMS: ESI-MS: m/z 394.1[M+H]+.
Figure imgf000285_0001
[0881] To a solution of intermediate 5 (700 mg, 1.78 mmol, 1 eq.) in MeOH (10 mL) was added K2CO3 (737 mg, 5.34 mmol, 3 eq.). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (20 mL), extracted with EA (20 mLX3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (eluent: PE/EA=50/1 to 3/1) to give intermediate 6 (0.4 g, 72.6% yield) as a yellow solid; LCMS: ESI-MS: m/z 310.1[M+H]+.
Figure imgf000285_0002
[0882] To a solution of intermediate 6 (2 g, 6.46 mmol, 1 eq.) in pyridine (20 mL) was added TosCl (1.48 g, 7.75 mmol, 1.2 eq.). The reaction mixture was stirred at 25 °C for 30 min. The reaction was diluted with H2O (30 mL), extracted with EA (10 mLX3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (eluent: PE/EA=50/1 to 3/1) to give intermediate 7 (1.7 g, 56.7% yield) as a yellow solid. LCMS: ESI-MS: m/z 464.1 [M+H]+.
Figure imgf000286_0001
[0883] To a solution of intermediate 7 (0.85 g, 1.83 mmol, 1 eq.) in t-BuOH (5 mL) was added t-BuOK (1.03 g, 9.16 mmol, 5 eq.). The reaction mixture was stirred at 85 °C for 0.5 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL). Then the mixture was extracted with EA (10 mLX3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (eluent: PE/EA=50/1 to 3/1) to give intermediate 8 (0.16 g, 15% yield) as a yellow solid. LCMS: ESI-MS: m/z 292.1 [M+H]+.
Figure imgf000286_0002
[0884] To a mixture of intermediate 8 (220 mg, 0.75 mmol, 1 eq.), reagent 8a (586 mg, 2.64 mmol, 3.5 eq.) and Cs2CO3 (737 mg, 2.26 mmol, 3 eq.) in DME (1.2 mL) and H2O (0.3 mL) in a was added Pd(dppf)Cl2 (221 mg, 0.3 mmol, 0.4 eq.). The tube was sealed and heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL). Then the mixture was extracted with EA (10 mLX3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (eluent: PE/EA=50/1 to 3/1) to give intermediate 9 (180 mg, 67.9% yield) as a yellow solid. LCMS: ESI-MS: m/z 352.1 [M+H]+.
Figure imgf000287_0001
[0885] To a solution of intermediate 9 (180 mg, 0.51 mmol, 1 eq.) in t-BuOH (20 mL) and H2O (20 mL) was add methanesulfonamide (54 mg, 0.56 mmol, 1.1 eq.) and AD-mix-Beta (0.9 g, 0.51 mmol, 1 eq.). The mixture was stirred at 0 °C for 50 h. The reaction mixture was diluted with H2O (50 mL). Then the mixture was extracted with EA (10 mLX3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (eluent: PE/EA=50/1 to 2/1) to give intermediate 10 (94 mg, 47.8% yield) as a yellow solid; LCMS: ESI-MS: m/z 386.1 [M+H]+.
Figure imgf000287_0002
[0886] To a solution of intermediate 10 (94 mg, 0.24 mmol, 1 eq.) in THF (10 mL) were added MsCl (28 mg, 0.24 mmol, 1 eq.) and TEA (123 mg, 1.22 mmol, 5 eq.). The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with water (10 mL). The mixture was extracted with EA (10 mLX2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product (81 mg, crude) as a yellow oil. The residue was used for next step reaction without purification. LCMS: ESI-MS: m/z 464.1 [M+H]+. [0887] To a solution of above crude product (81 mg, 0.17 mmol, 1 eq.) in MeOH (5 mL) was added NH3/MeOH (5 M, 0.7 mL, 20 eq.). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added to the residue. The mixture was extracted with ethyl acetate (10 mLX2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate 11 (40 mg, 60.3% yield) as a yellow oil. LCMS:
Figure imgf000288_0002
[0888] Compound 136 (37 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 11 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.30 (dd, J=5.6, 9.0 Hz, 2H), 8.12 (s, 1H), 7.75 (s, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.27 (s, 1H), 7.16 (t, J=8.8 Hz, 2H), 4.96 (s, 2H), 4.93 - 4.89 (m, 4H), 4.62 (d, J=13.7 Hz, 1H), 4.58 (s, 2H), 4.04 (s, 3H), 2.87 (s, 3H). LCMS: ESI-MS: m/z 585.2 [M+H]+. Example 137: Synthesis of Compound 137
Figure imgf000288_0001
[0889] Amine 137-2 was prepared essentially as described in the preparation of Compound 14d in Example 14. Compound 137 (28.6 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 137-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.33 - 8.24 (m, 2H), 7.68 (s, 1H), 7.63 (s, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 7.18 - 7.12 (m, 2H), 4.73 (d, J=9.0 Hz, 1H), 4.58 (d, J=13.8 Hz, 1H), 4.39 (d, J=9.0 Hz, 1H), 4.01 (s, 3H), 3.93 (d, J=13.8 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.60 - 3.53 (m, 1H), 2.85 (s, 3H), 1.40 (s, 3H). LCMS: ESI-MS: m/z 587.2 [M+H]+. Example 138: Synthesis of Compound 138
Figure imgf000289_0001
[0890] Acid 138-1 was prepared essentially as described in the preparation of Compound 15d in Example 15. Amine 138-2 was prepared essentially as described in the preparation of compound 98a. Compound 138 (37.2 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 by using acid 138-1 and amine 138-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.97 (s, 1H), 8.36 (s, 1H), 8.25 (dd, J=5.5, 8.9 Hz, 2H), 7.78 (s, 1H),7.71 (s, 1H), 7.44 (s, 1H), 7.25 - 6.91 (m, 3H), 6.79 - 6.31 (m, 1H), 4.81 - 4.69 (m, 2H), 4.66 (m, 2H), 4.64 - 4.53 (m, 2H), 4.22(d, J=13.9 Hz, 1H), 4.02 (s, 3H), 3.89 (d, J=13.7 Hz, 1H); LCMS: ESI-MS: m/z 624.2 [M+H]+. Example 139: Synthesis of Compound 139
Figure imgf000289_0002
[0891] Acid 138-1 was prepared essentially as described in the preparation of compound intermediate 10-8 in Example 10 but using 3.3.3-trideuterio-1-trimethylsilylpropyne as starting material. Compound 139 (15 mg) was obtained as a yellow solid essentially as described in the preparation of Compound 100 using acid 139-1 and amine 139-2 as starting materials. 1H NMR (400MHz, METHANOL-d4) ^= 8.30 (dd, J=8.8, 5.4 Hz, 2H), 7.78 (s, 1H), 7.76 (s, 1H), 7.58 (d, J=1.0 Hz, 1H), 7.28 (s, 1H), 7.16 (t, J=8.8 Hz, 2H), 4.54-4.85 (m, 7H), 3.97-4.11 (m, 4H). LCMS: ESI-MS: m/z 610.2 [M+H]+. Example 140: Synthesis of Compound 140
Figure imgf000290_0001
[0892] Compound 140 (315 mg) was obtained as a white solid essentially as described in the preparation of Compound 100 by using acid 101-1 and amine 140-2 (WO2015/26792, 2015, A1). 1H NMR (400MHz, METHANOL-d4) ^= 8.35-8.34 (m, 2H), 7.76 (s, 1H), 7.62 (s, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 7.19 (t, J=8.8 Hz, 2H), 4.63 (d, J=13.6 Hz, 1H), 4.45 (d, J=2.0 Hz, 1H), 4.05 (s, 3H), 3.97 (d, J=13.6 Hz, 1H), 2.89 (s, 3H), 1.42 (s, 3H), 1.37 (s, 3H). LCMS: ESI-MS: m/z 571.1 [M+H]+. Example 141: Synthesis of Compound 141
Figure imgf000290_0002
[0893] Amine 141-2 was prepared essentially as described in the preparation of Compound 98a by using (4-(trifluoromethyl)phenyl)boronic acid as starting material. Compound 141 (35 mg) was obtained as a white solid essentially as described in the preparation of Compound 99 using acid 101-1 and amine 141-2 as starting materials. LCMS: ESI-MS: m/z 639.2 [M+H]+. 1H NMR (400MHz, MeOD-d6) δ = 8.39 (d, J=8.1 Hz, 2H), 7.77 (s, 1H), 7.75 (s, 1H), 7.62 (d, J=8.1 Hz, 2H), 7.57 (d, J=1.2 Hz, 1H), 7.28 (d, J=1.2 Hz, 1H), 6.60 (t, J=55.2 Hz, 1H), 4.54-4.81 (m, 6H), 4.19 (d, J=13.7 Hz, 1H), 4.04 (s, 3H), 3.87 (d, J=13.7 Hz, 1H), 2.86 (s, 3H). Example 142: Synthesis of Compound 142
Figure imgf000291_0001
[0894] Amine 142-2 was prepared essentially as described in the preparation of Compound 98a by using (4-(trifluoromethyl)phenyl)boronic acid as starting material. Compound 142 (32.8 mg) was obtained as a light colored solid essentially as described in the preparation of Compound 100 by using acid 10-8 and amine 142-2 as starting materials. 1H NMR (400MHz, MeOD-d6) δ = 8.39 (d, J=8.3 Hz, 2H), 7.78 (s, 1H), 7.72 (s, 1H), 7.65 - 7.59 (m, 3H), 7.57 (s, 1H), 6.65 (t, J=55.2 Hz, 1H), 4.81 - 4.54 (m, 6H), 4.21 (d, J=13.7 Hz, 1H), 3.98 (t, J=4.3 Hz, 1H), 3.87 (d, J=13.7 Hz, 1H), 2.84 (s, 3H), 0.87 (d, J=5.6 Hz, 4H); LCMS: ESI-MS: m/z 665.3 [M+H]+. Example 143: Synthesis of Compound 143
Figure imgf000291_0002
[0895] Intermediate 3 (prepared essentially as described in the preparation of Compound 7b in Example 7; 6 g, 19.13 mmol, 1 eq.), t-butyl carbamate (4.48 g, 38.25 mmol, 2 eq.), Pd2(dba)3 (876 mg, 0.96 mmol, 0.05 eq.), Xantphos (1.11 g, 1.91 mmol, 0.1 eq.) and Cs2CO3 (9.35 g, 28.69 mmol, 1.5 eq.) in dioxane (150 mL) was stirred at 110 °C for 5 h under nitrogen. The mixture was concentrated to dryness and the residue was purified by column chromatography (eluent: PE/EA=30/1 to 5/1) to give intermediate 4 (5.9 g, 78.2% yield) as a yellow solid. LCMS: ESI- MS: m/z 395.1 [M+H]+.
Figure imgf000292_0001
[0896] To a mixture of intermediate 4 (5.9 g, 14.96 mmol, 1 eq.) in DCM (100 mL) was added TFA (30.8g, 20 mL, 18.06 eq.). The mixture was stirred at 25 °C for 3 h. The reaction was concentrated and then diluted with aq. NaHCO3 (150 mL) and extracted with EA (150 mLX2). The organic layer was separated, dried and concentrated. The residue was purified by column chromatography (eluent: PE/EA=20 /1 to 0/1) to give intermediate 5 (3.1 g, 70.4% yield) as a yellow solid. LCMS: ESI-MS: m/z 295.1 [M+H]+.
Figure imgf000292_0002
[0897] To a mixture of intermediate 5 (2.1 g, 7.14 mmol, 1 eq.) in diiodomethane (20 mL) was added KI (4.74 g, 28.55 mmol, 4 eq.), CuI (1.36 g, 7.14 mmol, 1 eq.), I2 (5.43 g, 21.41 mmol, 4.31 mL, 3 eq.) and isopentyl nitrite (4.18 g, 35.68 mmol, 5 eq.). The mixture was stirred at 65 °C for 3 h. The mixture was cooled to room temperature and quenched by addition of Na2S2O3 (800 mL) and extracted with EA (500 mLX2). The organic layer was separated, dried and concentrated. The residue was purified by column chromatography (eluent: PE/EA=1/0 to 10/1) to give intermediate 6 (2.3 g, 79.5% yield) as a white solid. LCMS: ESI-MS: m/z 406.0 [M+H]+.
Figure imgf000293_0001
[0898] To a mixture of intermediate 2 (prepared as described in WO2019/12063A1; 2.29 g, 15.55 mmol, 4.5 eq.) and intermediate 6 (1.4 g, 3.46 mmol, 1 eq.) in THF (30 mL) was added i- PrMgCl-LiCl (1.3 M, 10.63 mL, 4 eq.) under nitrogen at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was quenched by addition of aqueous NH4Cl (50 mL) and extracted with EA (60 mLX2). The organic layer was separated, dried and concentrated. The residue was purified by column chromatography (eluent: PE/EA=1/0 to 0/1) to give intermediate 7 (920 mg, 72.9% yield) as a white solid. LCMS: ESI-MS: m/z 366.1 [M+H]+. [0899] Intermediates 8 to 11 were prepared essentially as described in the preparation of Compound 136.
Figure imgf000293_0002
[0900] Compound 143 (85 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 using acid 101-1 and amine 11 as starting materials. LCMS: ESI-MS: m/z 597.3 [M+H]+. 1H NMR (400MHz, MeOD-d6) δ = 8.30 (dd, J=5.6, 8.9 Hz, 2H), 7.76 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.29 (s, 1H), 7.17 (t, J=8.8 Hz, 2H), 4.86 - 4.60 (m, 7H), 4.06 (s, 3H), 3.91 (d, J=13.6 Hz, 1H), 2.89 (s, 3H), 1.27 - 0.81 (m, 4H).
Figure imgf000294_0002
[0901] Amine 144-2 was prepared essentially as described in the preparation of Compound 143. Compound 144 (30 mg) was obtained as a light yellow solid essentially as described in the preparation of Compound 100 by using acid 10-8 and amine 144-2 as starting materials. 1H NMR (400MHz, MeOD-d6) δ = 8.31 (dd, J=5.4, 8.9 Hz, 2H), 7.76 (s, 1H), 7.74 (s, 1H), 7.60 (d, J=5.5 Hz, 2H), 7.18 (t, J=8.8 Hz, 2H), 4.85 - 4.61 (m, 7H), 4.02 - 3.95 (m, 1H), 3.91 (d, J=13.8 Hz, 1H), 2.89 (s, 3H), 1.20 - 0.85 (m, 8H); LCMS: ESI-MS: m/z 623.2 [M+H]+.
Figure imgf000294_0001
[0902] Amine 145-2 was prepared essentially as described in the preparation of intermediate 14-7 in Example 14 by using (1R,2S)-2-fluorocyclopropan-1-amine and intermediate 14-4 as the starting material. Compound 145 was obtained as a white form using methods described herein with acid 10-8 and amine 145-2 as starting materials. 1H NMR (400 MHz, DMSO-d6): ^ 8.73 (t, J = 7.87, 1H0, 8.25-8.31 (m, 2H), 8.04 (d, J = 3.52, 1H), 7.87 (s,1H), 8.04 (s, 1H), 7.66 (s, 1H), 7.26-7.28 (7, J = 9.0, 1H), 5.08 (d, J = 9.0, 1H), 4.44-4.71 (m, 1H), 4.21 (d, J = 9.0, 1H), 4.07- 4.19 (m, 2H), 4.01-4.05 (m, 1H), 2.81 (s, 3H), 2.48-2.50 (m, 1H), 1.45 (s, 3H), 0.96-1.03 (m, 2H), 0.77-0.97 (m, 4H). LCMS: ESI-MS: m/z 684 [M+H]+. Example 146: Synthesis of Compound 146
Figure imgf000295_0001
[0903] Intermediate 146-1 (prepared as described in WO2015/16972A1; 71 mg, 0.15 mmol) was dissolved in methanol (1 mL). Ammonium acetate (46 mg), glyoxal (87 uL, 0.6 mmol), and formaldehyde (49 uL, 0.6 mmol) were added and the reaction was stirred at 80 oC for 1 h. The reaction was diluted with ethyl acetate and washed with water and brine. The product was purified by column chromatography (MeOH/CH2Cl2) to provide intermediate 146-2 (75 mg) as a clear oil. LCMS: ESI-MS: m/z 523 [M+H]+. [0904] Compound 146 was obtained as a white foam using methods described herein and using amine 146-3 and acid 101-1. 1H NMR (400 MHz, DMSO-d6): ^ 8.73 (t, J = 5.87, 1H), 8.51 (br s, 1H), 8.25-8.31 (m, 2H), 7.88 (d, J = 6.26, 2H), 7.65 (s, 1H), 7.54 (2, 1H), 7.30-7.34 (m, 2H), 7.17 (s, 1H), 5.05 (d, J = 10.96, 1H), 4.76 (d, J = 10.96, 1H), 4.26-4.28 (m, 1H), 4.40- 4.42 (m, 1H), 2.50 (s, 3H), 2.03 (s, 3H). LCMS: ESI-MS: m/z 623 [M+H]+. Example 147: Synthesis of Compound 147
Figure imgf000295_0002
[0905] Compound 147 was obtained as a white foam essentially as described in the preparation of Compound 146, using amine 147-2 and acid 10-8 as starting materials. 1H NMR (400 MHz, DMSO-d6): ^ 8.73 (t, J = 5.87, 1H), 8.51 (br s, 1H), 8.25-8.31 (m, 2H), 7.88 (d, J = 6.26, 2H), 7.65 (s, 1H), 7.54 (2, 1H), 7.30-7.34 (m, 2H), 7.17 (s, 1H), 5.05 (d, J = 10.96, 1H), 4.76 (d, J = 10.96, 1H), 4.26-4.28 (m, 1H), 4.40-4.42 (m, 1H), 3.08 (m, 1H), 3.06-3.08 (m, 1H), 2.50 (s, 3H), 2.03 (s, 3H), 0.73-0.86 (m, 4H). LCMS: ESI-MS: m/z 649 [M+H]+. Example 148: Synthesis of Compound 148
Figure imgf000296_0001
[0906] Acid 148-1 (30 mg, 0.06 mmol) was dissolved in dichloromethane (0.2 mL). Propanephosphonic anhydride (57 mg, 0.09 mmol) and triethylamine (25 ul, 0.18 mmol) were added and the reaction was stirred at r.t. for 5 min. 5-Amino-2-(trifluoromethyl)pyridine (48 mg, 0.3 mmol) was added and the reaction was stirred at r.t. for 2 h. The reaction was diluted with ethyl acetate, washed with 1 N HCl and brine, dried and concentrated. The product was chromatographed on silica gel, eluting with ethyl acetate/hexane to provide intermediate 148-2 (13 mg) as a clear oil. LCMS: ESI-MS: m/z 645 [M+H]+. [0907] Intermediate 148-2 (35 mg, 0.054 mmoles) was dissolved in HCl (4 M in dioxane, 1 ml) and the reaction was stirred at r.t. for 1h. The reaction was concentrated to a clear oil and the product was used without further purification. LCMS: ESI-MS: m/z 545 [M +H]+. [0908] Compound 148 was obtained as a white foam essentially as described in the preparation of Compound 146 by using amine 148-3 and acid 101-1 as starting materials. 1H NMR (400 MHz, DMSO-d6): ^ 10.19 (s, 1H), 8.95 (d, J = 2.4, 1H), 8.75 (t, J = 6.0, 1H), 8.17- 8.30 (m, 3H), 7.90 (s, 1H), 7.80-7.84 (m, 2H), 7.70 (d, J = 1.2, 1H), 7.29-7.33 (m, 3H), 7.18 (br. S, 1H), 5.24 (d, J=9.2, 1H), 4.57 (d, J=9.2, 1H), 4.28 (dd, J = 6.0, 13.6, 1H), 4.11 (dd, J = 6.0, 13.6, 1H), 3.98 (s, 3H), 2.47 (s, 3H), 1.67 (s, 3H). LCMS: ESI-MS: m/z 745.0 [M+H]+.
Figure imgf000297_0001
[0909] Nitrile 149-1 (113 mg, 0.23 mmol) was dissolved in ethylene diamine (2 mL) and transferred to a reaction vial. Carbon disulfide (1 drop) was added and the reaction vial was sealed and heated at 110 oC for 1 h. The reaction mixture was concentrated, and the crude material was purified by HPLC to provide intermediate 149-2 as a clear oil (110 mg). LCMS: ESI-MS: m/z 525 [M+H]+. [0910] Intermediate 149-2 (55 mg, 0.1 mmol) was dissolved in acetonitrile (1.5 mL). Potassium permanganate (82 mg, 0.52 mmol) was added and the reaction was stirred at rt. for 4 h. The reaction mixture was quenched with Na2S2O3 solution and extracted with ethyl acetate. The product was purified by HPLC. The dried product fractions were then re-dissolved in ethyl acetate, washed with NaHCO3 solution and brine, then dried and concentrated to provide intermediate 149-3 as a clear oil (45mg). LCMS: ESI-MS: m/z 523 [M+H]+. [0911] Intermediate 149-3 (4.0 mg, 7.8 x 10-3 mmoles) was dissolved in HCl (4 M in dioxane, 1 ml) and the reaction was stirred at r.t. for 1h. The reaction was concentrated to a clear oil and the product was used without further purification. LCMS: ESI-MS: m/z 423 [M +H]+. [0912] Compound 149 was obtained as a white foam essentially as described in the preparation of Compoudn 146 by using amine 149-4 and acid 101-1 as starting materials. 1H NMR (400 MHz, DMSO-d6): ^ 8.20-8.23 (m, 2H), 7.88 (s, 1H), 7.61-7.87 (m, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.35-7.47 (m, 2H), 7.10 (s, 1H), 7.01 (s, 1H), 5.16 (d, J – 8.6, 1H), 4.71-4.77 (m, 1H), 4.63 (d, J 8.6, 1H), 3.96 (s, 3H), 3.81-3.86 (m, 1H), 2.82 (s, 3H), 1.78 (s, 3H). LCMS: ESI- MS: m/z 622 [M+H]+. [0913] Additional intermediate acids used in the preparation of compounds described herein are described below. Synthesis of 2-cyano-8-methoxy-3-methylquinoline-6-carboxylic acid:
Figure imgf000298_0001
[0914] 8-Methoxy-3-methyl-quinoline-6-carboxylic acid (4.34 g, 20 mmol) was suspended in DCM (200 mL) and 3-chloroperoxybenzoic acid (6.9 g, 40 mmol) was added. The mixture was stirred at rt for 16 h. The precipitate was filtered off, washed with some DCM and then dried in vacuo at 50°C overnight to afford 6-carboxy-8-methoxy-3-methylquinoline 1-oxide (4.23 g, 91% yield) used as such in the next step. [0915] 6-Carboxy-8-methoxy-3-methylquinoline 1-oxide (1.16 g, 5 mmol) was suspended in ACN (25 mL) and Et3N (2.1 mL, 15 mmol) was added. The solution was stirred for 5 min and then TMSCN (1.88 mL, 15 mmol) was added. The reaction mixture was heated at 80°C for 1 h. ACN was evaporated and the residue was taken up in water (50 mL) and 1 mL acetic acid was added. The water layer was stirred for two hours, the yellowish precipitate was collected by filtration and dried overnight in vacuo at 40°C to afford 2-cyano-8-methoxy-3-methylquinoline- 6-carboxylic acid (1.06 g, 88% yield). Synthesis of 2-cyclopropyl-4-methoxybenzo[d]oxazole-6-carboxylic acid:
Figure imgf000298_0002
[0916] To a solution of 4-bromo-2,6-dimethoxyaniline (6.5 g, 28 mmol), cyclopropanecarboxylic acid (4.8 g, 56 mmol), HATU (21.3 g, 56 mmol,) and DIPEA (7.24 g, 56 mmol) in DMF (150 mL). The resulting mixture was maintained under nitrogen and stirred at 70°C for 16 h. After cooling to rt, the reaction was quenched with water (800 ml). The resulting mixture was extracted with ethyl acetate (3x300 ml). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated. The residue obtained was purified by silica gel chromatography(0-50% ethyl acetate/petroleum ether) to afford the N-(4-bromo- 2,6-dimethoxyphenyl)cyclopropanecarboxamide as a yellow solid (7.0 g, 83% yield). [0917] To a solution of N-(4-bromo-2-hydroxy-6-methoxyphenyl)cyclopropanecarboxamide (7 g, 23.322 mmol, 1.0 eq) in DCM (100 mL) was added tribromoborane in DCM (23 mL) at -30ºC. The resulting mixture was maintained under nitrogen and stirred at rt for 3 h. The reaction was poured into ice water (150 ml) and extracted with ethyl acetate (3x250 ml). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-40% ethyl acetate/petroleum ether) to afford the N-(4-bromo-2-hydroxy-6-methoxyphenyl)cyclopropanecarboxamide as a light yellow solid (5.5 g, 82% yield). [0918] To a solution of N-(4-bromo-2-hydroxy-6-methoxyphenyl)cyclopropanecarboxamide (5.5 g, 19.2 mmol) and 4-methylbenzenesulfonic acid (3.3 g,19.2 mmol, 1.0 eq) in toluene (100 mL) The resulting mixture was maintained under nitrogen and stirred at 100ºC for 16 h. After cooling to rt, the reaction was quenched with water (150 ml). The resulting mixture was extracted with ethyl acetate (3x250 ml). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to afford the 6-bromo-2- cyclopropyl-4-methoxybenzo[d]oxazole as a light-yellow oil (2.5 g, 49% yield). [0919] A mixture of 6-bromo-2-cyclopropyl-4-methoxybenzo[d]oxazole (2.5 g, 9.26 mmol, 1.0 eq), Pd(dppf)Cl2.DCM (0.756 g, 0.926 mmol, 0.1 eq) and Et3N (1.874 g, 18.519 mmol, 2.0 eq) in MeOH (100 mL) was stirred overnight at 70ºC under a CO(g) (60 psi) atmosphere. The reaction was filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-40% ethyl acetate/petroleum ether) to afford methyl 2-cyclopropyl-4- methoxybenzo[d]oxazole-6-carboxylate as a light-yellow oil (1.9 g, 83% yield). [0920] To a solution of methyl 2-cyclopropyl-4-methoxybenzo[d]oxazole-6-carboxylate (1.9 g, 7.7 mmol) in MeOH (20 ml) was added NaOH (1.54 g, 38.4 mmol) in H2O (10 ml). The resulting mixture was maintained under nitrogen and stirred at rt for 3 h. The MeOH was removed under vacuum and the PH value of the aqueous phase was adjusted to 5 used HCl solution(1M). The resulting mixture was extracted with ethyl acetate (3x150 ml). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated. The crude was dissolved in DMF. The residue obtained was purified by C18 (0-40% MeCN/Water) to afford 2-cyclopropyl-4-methoxybenzo[d]oxazole-6-carboxylic acid as a light pink solid (1.2 g, 99% yield). Synthesis of 2-(1-fluorocyclopropyl)-8-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid:
Figure imgf000300_0001
[0921] To a solution of 5-bromo-3-methoxypyridin-2-amine (5 g, 24.63 mmol) in EtOH (50 mL) was added ethanone, 2-chloro-1-(1-fluorocyclopropyl) (3.36 g, 24.6 mmol). The reaction mixture was stirred at 120 °C for 2 h in the microwave. The reaction cooled to rt, and the solvent was removed under reduced pressure. The product was purified via silica column chromatography using a heptane to EA gradient, followed by a 2nd column using dichloromethane to 2% methanol in dichloromethane gradient, impure fractions were discarded, affording the desired product as a pale yellow solid (1.89 g, 26%). [0922] A 75-ml stainless steal autoclave was charged under N2 atmosphere with the aryl halide (1.89 g, 6.496 mmol), 1,3-bis(diphenylphosphino)propane (dppp, 54 mg, 0.13 mmol), KOAc (1.275 g, 12.993 mmol), DIPEA (4.478 mL, 25.985 mmol), methanol (30 mL), and Pd(OAc)2 (15 mg, 0.065 mmol). The autoclave was sealed and pressurized to 25 bar CO and heated at 100°C for 18 h. The reaction vessel cooled to rt and the gas released under the safety of the hood. The solids were removed by filtration over packed diatomaceous earth and washed with methanol. The solvents of the filtrate were concentrated under reduced pressure and the crude was purified by silica column chromatography using a heptane to EA gradient. The best fractions were pooled and the solvents were removed under reduced pressure to afford a white solid, methyl 2-(1-fluorocyclopropyl)-8-methoxyimidazo[1,2-a]pyridine-6-carboxylate (1.28 g, 75%). [0923] To a solution of methyl 2-(1-fluorocyclopropyl)-8-methoxyimidazo[1,2-a]pyridine-6- carboxylate (1280 mg, 4.84 mmol) in water (5 mL) and 1,4-dioxane (20 mL) was added LiOH (233 mg, 9.73 mmol) at room temperature. The mixture was allowed to stir for two hours at 50°C and overnight at room temperature. The mixture was evaporated, diluted with 20 mL water and neutralised with 1 N HCl solution in water. After two hours of stirring the white precipitate was collected by filtration and dried overnight in vacuo to afford 2-(1-fluorocyclopropyl)-8- methoxyimidazo[1,2-a]pyridine-6-carboxylic acid (1.02 g, 84%). Synthesis of 8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridine-6-carboxylic acid:
Figure imgf000301_0001
[0924] 8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridine-6-carboxylic acid was prepared following a similar procedure to the one described for compound 2-(1-fluorocyclopropyl)-8- methoxyimidazo[1,2-a]pyridine-6-carboxylic acid starting from 1-chloro-3,3,3-trifluoroacetone. Synthesis of 8-(cyclopropylamino)-3-methylcinnoline-6-carboxylic acid:
Figure imgf000301_0002
[0925] A reactor was charged with ethyl 8-fluoro-3-methyl-cinnoline-6-carboxylate (5 g, 21.3 mmol), cyclopropylamine (14.8 mL, 213.5 mmol), DIPEA (11.2 mL, 0.7 g/mL, 64 mmol) in NMP (24 mL) and the reaction mixture was stirred at 110 ºC for 16 h. The mixture was dissolved in water and was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo. A purification was performed by column chromatography system using a gradient from 0% till 30% EtOAc in Heptane (12cv). The product fractions were collected and concentrated in vacuo to afford ethyl 8-(cyclopropylamino)-3-methylcinnoline-6-carboxylate (5.8 g, yield 100%) as a yellow oil which solidified on standing. [0926] Ethyl 8-(cyclopropylamino)-3-methylcinnoline-6-carboxylate (5.8 g, 21.4 mmol) was dissolved in THF (128 mL) and a solution of LiOH (2.6 g, 106.9 mmol) in water, distilled (35 mL) was added. The reaction mixture was stirred at rt for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in water and acidified till pH~4.5 with HCl (1M in H2O) (106.9 mL, 1 M, 106.9 mmol) (monitor with pH meter). The mixture was extracted with DCM/2- propanol mixture twice and the organic layer was concentrated in vacuo. The product was triturated in CH3CN, filtered off and washed with CH3CN and dipe. The product was dried under vacuum to yield 8-(cyclopropylamino)-3-methylcinnoline-6-carboxylic acid (4.1 g, yield 79%) as a bright yellow solid. Synthesis of 3,8-dimethoxyquinoline-6-carboxylic acid:
Figure imgf000302_0001
[0927] Methyl 4-amino-3-methoxybenzoate (10 g, 55 mmol), 2,2,3-tribromopropanal (18 g, 61 mmol) and AcOH (80 mL) were added to 250 mL bottled flask. The resultant mixture was stirred at 100 °C for 3 hours. LCMS showed 69% the acid and 27% of the ester. The suspension isolated via filtration. The filter cake was washed with petroleum ether: ethyl acetate = 10:1 (100 mL x 2) before drying under reduced pressure to afford the crude product (20 g, crude), which was used directly for the next step without purification. [0928] SOCl2 (1.4 mL, 19 mmol) was added to a solution consisting of previous crude and methanol (50 mL). The resultant mixture was stirred at 80 °C for 1.5 hours. The mixture was concentrated to dryness under reduced pressure to give the crude product (4 g, crude), which was used directly in the next step without purification. [0929] Methyl 3-bromo-8-methoxyquinoline-6-carboxylate (4 g, crude), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.9 g, 27 mmol), potassium acetate (4.0 g, 41 mmol), and 1,4-dioxane (40 mL) were added to a 250 mL bottled flask. The mixture was spared with N2 for 5 minutes and then treated with Pd(dppf)Cl2 (988 mg, 1.35 mmol). The mixture was spared with N2 for another 5 minutes and then stirred at 80 °C for 16 hours. The reaction mixture was filtered and filtrate was concentrated to dryness under reduced pressure to afford the title product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 10:1 to 0:1 TLC: petroleum ether: ethyl acetate = 0:1) to afford methyl 8-methoxy-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinoline-6-carboxylate (3.2 g, 94% yield) as a yellow oil. [0930] H2O2 (2.1 mL, 27 mmol) was added to a solution consisting of methyl 8-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-6-carboxylate (3.2 g, 9.3 mmol), LiOH•H2O (2.4 g, 57 mmol) and methanol (30 mL). The resultant mixture was stirred at room temperature for 16 hours. The mixture was poured into H2O (20 mL) and washed with ethyl acetate (50 mL * 3). The aqueous phase used 2 M HCl adjust to pH = 5. The suspension isolated via filtration. The filter cake was washed with ethyl acetate (10 mL x 2) before drying under reduced pressure to afford the 3-hydroxy-8-methoxyquinoline-6-carboxylic acid (1.5 g, 69%) as a yellow solid. [0931] MeI (8.0 g, 56 mmol) was added to a 0 °C solution consisting of 3-hydroxy-8- methoxyquinoline-6-carboxylic acid (1.3 g, 5.9 mmol), K2CO3 (3.3 g, 24 mmol) and DMF (15 mL). The resultant mixture was stirred at room temperature for 1 hour. MeI (8.0 g, 56 mmol) was added the mixture then stirred at room temperature for 1 hour. The mixture was quenched with sat.NH4Cl (20 mL) and and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 10:1 to 0:1 TLC: petroleum ether: ethyl acetate = 0:1) to afford the title compound (1.6 g) as a yellow solid. [0932] NaOH (725 mg, 18.1 mmol) was added to a solution consisting of methyl 3,8- dimethoxyquinoline-6-carboxylate (1.5 g, 6.1 mmol), methanol (10 mL) and H2O (2 mL). The reaction mixture was stirred at room-temperature for 2 hours. The mixture was poured into H2O (10 mL) and washed with ethyl acetate (15 mL * 3). The aqueous layer was used 2 M HCl adjust pH = 5, which was purified by preparative HPLC using a Phenomenex Synergi Max-RP 250*50mm*10 um (eluent: 2% to 35% (v/v) CH3CN and H2O with 0.225% HCOOH) to afford pure product. The product was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford the title compound (1.08 g, 76%) as a white solid. Synthesis of 1-fluoro-8-methoxyisoquinoline-6-carboxylic acid:
Figure imgf000304_0001
[0933] A cooled (0°C) solution of 4-bromo-2-fluoroaniline (29.8 g, 157 mmol) in water (300 mL) was subsequently treated with concentrated hydrochloric acid (35.6 mL) and sodium nitrite (13.0 g, 188 mmol). After 20 min at 0°C, concentrated hydrochloric acid (53.4 mL) and sodium tetrafluoroborate (70.0 g, 638 mmol) were added. After 40 min at 0°C, the intermediate diazonium was filtered, washed with water, and used without further purification. A solution of the diazonium (78.4 mmol) in acetonitrile (500 mL) was treated with ethyl 3-morpholinoacrylate (32.0 g, 173 mmol). [0934] After 1 h at RT, silica gel was added. The reaction mixture was stirring at RT for 16 h. The volatiles were removed in vacuo and the residue was purified by FCC (petroleum ether: ethyl acetate 1:0 to 9:1) to afford ethyl 2-((Z)-(4-bromo-2-methoxyphenyl)diazenyl)-3- hydroxyacrylate (17 g, 32%) as a highly coloured solid and as a mixture of tautomers. [0935] Concentrated H2SO4 (180 mL) was added to ethyl 2-((Z)-(4-bromo-2- methoxyphenyl)diazenyl)-3-hydroxyacrylate (6.5 g, 20 mmol). The resultant mixture was stirred at 100 °C for 7 hours. The mixture was diluted with water (200 mL) before cooling to 0 °C and a solid was filtered off. The filtrate was extracted with ethyl acetate (300 mL x 2) The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the crude product which was purified by FCC (petroleum ether: ethyl acetate =1:10 to 1:1) to dryness to afford 6-bromo-8-fluorocinnoline-3-carboxylic acid (2.5 g, 38%) as a yellow solid. [0936] 6-Bromo-8-fluorocinnoline-3-carboxylic acid (2.5 g, 9.2 mmol) was dissolved in t- BuOH (50 mL) and added to a 100 mL round-bottomed flask. Triethylamine (3.85 mL, 27.7mmol), 4 Å molecular sieve (2 g) and DPPA (2.6 mL, 12 mmol) was added. The mixture was heated at 90 °C for 16 hours. The suspension was quenched with sat. aq. NaHCO3 (100 mL), extracted with ethyl acetate (100mL x 3) and the combined organic phases were dried, and concentrated to dryness to afford the crude product which was purified by FCC (petroleum ether: ethyl acetate = 5:1 to 1:1) to afford tert-butyl (6-bromo-8-fluorocinnolin-3-yl)carbamate (2.3 g, 73%) as white solid. [0937] NaOMe (1.9 g, 35 mmol) was added to a mixture of tert-butyl (6-bromo-8- fluorocinnolin-3-yl)carbamate (4.0 g, 12 mmol) and MeOH (80 mL). The resultant mixture was stirred at 60 °C for 1.5 hours. The mixture was added with a.q. NH4Cl (100 mL), extracted with dichloromethane (100 mL x 3) and the combined organic phases were dried, and concentrated to dryness to afford the crude product which was purified by FCC (petroleum ether: ethyl acetate = 5 : 1 to 0:1) to afford tert-butyl (6-bromo-8-methoxycinnolin-3-yl)carbamate (2.0 g, 48%) as white solid. [0938] Et3N (4.0 mL, 29 mmol) was added to a mixture consisting of tert-butyl (6-bromo-8- methoxycinnolin-3-yl)carbamate (2.0 g, 5.6 mmol), and MeOH (40 mL). The resultant mixture was purged with N2 for 5 minutes. Pd(OAc)2 (127 mg, 0.566 mmol) and dcpp•2HBF4 (692 mg, 1.13 mmol) were added and the flask was evacuated and backfilled with CO three times. The mixture was stirred at 80 °C under CO atmosphere (50 Psi) for 24 hours. The reaction mixture was concentrated to dryness under reduced pressure to afford crude product. The crude product was purified by FCC (eluent: petroleum ether: ethyl acetate = 5:1 to ethyl acetate:dichloromethane = 1:1) to afford the methyl 3-((tert-butoxycarbonyl)amino)-8- methoxycinnoline-6-carboxylate (1.8 g, 79%) as a yellow solid. [0939] HCl/EA (90 mL, 360 mmol) was added to a mixture of methyl 3-((tert- butoxycarbonyl)amino)-8-methoxycinnoline-6-carboxylate (1.8 g, 5.4 mmol) and MeOH (50 mL). The mixture was stirred at r.t. for 16 hours. The mixture was concentrated to dryness to afford methyl 3-amino-8-methoxycinnoline-6-carboxylate. [0940] A solution of NaNO2 (1.54 g, 22.3 mmol) in water (3 mL) was added drop-wise to a 0 °C (ice/water) solution of methyl 3-amino-8-methoxycinnoline-6-carboxylate (1.2 g, 4.5 mmol) and HF/pyridine (30 mL). The resultant mixture was stirred for 0.5 hours with gradual warming to room-temperature. The resultant mixture was stirred at room temperature for 1 hour. The mixture was pouring it into H2O (50 mL) and extracting ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to afford the crude title product which was purified by FCC (petroleum ether: ethyl acetate = 1:10 to 1:1) to afford methyl 1-fluoro-8-methoxyisoquinoline-6- carboxylate. [0941] LiOH•H2O (214 mg, 5.10 mmol) was added into to a 0 °C (ice/water) mixture consisting of methyl 1-fluoro-8-methoxyisoquinoline-6-carboxylate (1.2 g, 5.1 mmol), 1,4- dioxane (72 mL) and H2O (70 mL). The resultant mixture was stirred at room-temperature for 1.5 hours. The mixture was added ethyl acetate (70 mL). The aqueous phase was lyophilization afford the crude product which was purified by preparative HPLC over Xtimate C18150 x 25mm x5um (eluent: water (0.05% ammonia hydroxide v/v)-ACN from 8% to 38%, v/v). The pure fractions were collected and the volatiles were removed under vacuum. The residue was re- suspended in water (10 mL) and the resulting mixture was lyophilized to dryness to remove the solvent residue completely. Desired product was obtained as white solid (739 mg, 65% yield). Synthesis of ethyl 8-fluoro-3-methylcinnoline-6-carboxylate:
Figure imgf000307_0001
[0942] Ethyl 3,4-difluoro-5-iodobenzoate was charged into a reactor. EtOH (300 mL) and CsF (43.5 g, 3.0eq.) were added and the reactor was swap with N2 three times. CuI (3.6 g, 0.2 eq.), Pd(PPh3)2Cl2 (3.3 g, 0.05eq.) were added and the reactor was swap with N2 three times. The reaction mixture was cooled down to 0°C and trimethyl(prop-1-ynyl)silane (21 g, 2.0 eq.) was added. After swapping the reactor N2 three times, the reaction mixture was stirred between 10 and 20°C for 18 h before being filtered through diatomite and wash with EtOH (10V). The filtrate was concentrated under vacuum to remove EtOH, and EtOAc (10V) and H2O (10V) were added. The two phases were separated and the organic layer was filtered through silica gel and Na2SO4. After a washing with EtOAC, the organic layer was concentrated to afford ethyl 3,4- difluoro-5-(prop-1-yn-1-yl)benzoate as a crude mixture (20 g) which was used as such in the next step. [0943] Ethyl 3,4-difluoro-5-(prop-1-yn-1-yl)benzoate (20 g, 1eq.) was charged into a reactor. DMAc (200 mL), NHBocNHBoc (41.5 g, 2.0 eq.), Cs2CO3 (58 g, 2.0eq.) were added and the temperature was adjusted to 50 °C. The reaction mixture was stirred for 15 h. After cooling, EtOAc (10V) and H2O (10V) were added into the mixture. The organic layers were washed with brine (10V) twice and concentrated under vacuum to obtain 53 g of 1,2-di-tert-butyl 6-ethyl 8- fluoro-3-methylcinnoline-1,2,6-tricarboxylate as a solid. [0944] 1,2-di-tert-butyl 6-ethyl 8-fluoro-3-methylcinnoline-1,2,6-tricarboxylate (20 g, 1eq.) was charged into a reactor was charged into a reactor. DCM (530 mL, 10V) and FeBr3 (54 g, 1.5eq.) were added and the reaction mixture was stirred for 3 h at 10-20°C. H2O (530 mL, 10V) was added into the mixture and the the two phases were separated. The organic layer was filtered and the solid was washed with DCM (160 mL, 3V). The organic layer was concentrated to afford 31.5g of sticky solid. EtOAc (90 mL, 3V) was added into the solid and warm to 50 °C to dissolve the solid. MCYH (210 mL, 7V) into the mixture and stir for 1 h. (NOTE: Some black sticky solid was observed at the bottom of mixture.). the mixture was concentrated under vacuum to remove the solvent and ACN (60 mL, 2V) was added to dissolve the solid. H2O (30 mL, 1V) was then added into the mixture drop wise. The reaction mixture was stirred at 20-30 °C for 10 min before being filtered and washed with ACN: H2O=2:1 (15 mL) solution. The wet cake at 45 °C for 16 h to obtain 5.5 g of ethyl 8-fluoro-3-methylcinnoline-6-carboxylate. Hydrolysis of the ethyl ester using methods described herein yields the corresponding acid. [0945] Compounds 150 to 174 were made using the following method. Stock solutions were made for all acids (0.12 mmol) and amines (0.11 mmol). Stock solution of HATU (94.11 mg, 0.25 mmol x (x) number of compounds) in DMF was made. 5 X 24 well blocks were used. The acids were mapped into their destination vials and to these solutions was added 0.5 mL of HATU stock solution followed by DIPEA (92.72 µL, 0.66 mmol). The resulting mixtures were stirred at room temperature for 30 minutes. Then the amines were mapped into their destination vials and the resulting mixtures were stirred for 5 hours at room temperature. The DMF was removed by evaporation using a Genevac. The crudes were redissolved in DCM/EtOAc 2/1 (2.2 mL).1 mL of citric acid (1 M) was added and the mixtures were stirred for 10 minutes. Then they were left standing for 10 minutes. 2 mL of the organics were removed using a pipet and these were filtered over a fritted filter. The remaining water layer was extracted another time using 2 mL of the DCM/EtOAc mixture. Again 2 mL was removed and filtered over the same fritted filter. The obtained filtrates were concentrated in vacuo using a Genevac. The obtained crudes were redissolved in MeOH / ACN 1/1 (3 mL) and purified by reverse phase column chromatography (Instrument: Waters Acquity® UPLC® DAD and DQD; Column: Waters BEH (1.8 µM, 2.1*50 mm); Mobile Phase: A: 10 mM CH3COONH4 in 95% H2O + 5% CH3CN; B: CH3CN; Gradient: 100% A to 5% A in 1.3 min, hold 0.7 min; Flow: 0.8 mL/min; Column temperature 55 °C; Run time, 2.0 min).
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
[0946] The following compounds in Examples 175-178 and 180-187 were prepared using methods analogous to those described herein. Compound 179 may be prepared using analogous methods. Example 175: Synthesis of Compound 175
Figure imgf000314_0001
[0947] 1H NMR (400MHz, MeOD-d6) δ 8.7 (d, J = 2 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H, ), 7.61-7.57 (m, 3H), 7.28 (d, J= 1.6 Hz, 1H), 6.59 (t, J = 55 Hz, 1H), 4.78 – 4.6 (m, 6H), 4.19 (d, J = 16 Hz, 1H), 3.94 (s, 3H), 3.88 (d, J = 13.6 Hz, 1H). LCMS: ESI-MS: m/z 658.1 [M+H]+. Example 176: Synthesis of Compound 176
Figure imgf000314_0002
[0948] 1H NMR (400MHz, MeOD-d6) δ 8.99 (s, 1H), 8.46-8.49 (m, 3H), 7.87 (s, 1H), 7.84 (d, J = 1.6, 1H), 7.73-7.75 (m, 2H), 7.46 (d, J = 1.6 Hz, 1H), 7.1 (t, J = 58 Hz, 1H), 4.58-4.77 (m, 7H), 4.06-4.12 (m, 1H), 4.03 (s, 3H). LCMS: ESI-MS: m/z 692.1 [M+H]+. Example 177: Synthesis of Compound 177
Figure imgf000314_0003
[0949] 1H NMR 8.42 (d, J=8.0 Hz, 2H), 7.74 (s, 1H), 7.71 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 1.2, 1H), 7.28 (d, J = 1.2 Hz, 1H), 4.63-4.72 (m, 6H), 4.18 (d, J = 13.2 Hz, 1H), 4.0 (s, 3H), 3.83 (d, J = 13.2 Hz, 1H), 2.8 (s, 3H), 1.52-1.62 (m, 1H), 0.66-0.68 (m, 1H), 0.51-0.53 (m, 1H), 0.39-0.41 (m, 1H), 0.29-0.31 (m, 1H). LCMS: ESI-MS: m/z 629.1 [M+H]+. Example 178: Synthesis of Compound 178
Figure imgf000315_0001
[0950] 1H NMR 8.31-8.28 (m, 2H), 7.76-7.74 (m, 2H), 7.59 – 7.58 (m, 2H), 7.17- 7.12 (m, 2H), 4.77 – 4.55 (m, 7H), 4.0 – 3.94 (m, 2H), 0.86- 0.85 (m, 4H). LCMS: ESI-MS: m/z 636.2 [M+H]+. Example 179: Synthesis of Compound 179
Figure imgf000315_0002
Example 180: Synthesis of Compound 180
Figure imgf000315_0003
[0951] 1H NMR (400MHz, METHANOL-d4) δ 8.19 – 8.08 (m, 2 H), 7.93 (s, 1H), 7.87 (s, 1H), 7.7 (s, 1H), 7.37 – 7.27 (m, 2H), 5.05 (d, J = 9.4 Hz, 1H), 4.67 (d, J = 9.8 Hz, 1H), 4.52 (d, J = 14.1 Hz, 1H), 4.09 (d, J = 13.7 Hz, 1H), 4.07 (s, 3H), 2.88 (s, 3H), 1.77 (s, 3H). LCMS: ESI- MS: m/z 600 [M+H]+. Example 181: Synthesis of Compound 181
Figure imgf000316_0001
[0952] 1H NMR (400MHz, METHANOL-d4) δ 8.3 – 8.26 (m, 2H), 7.89 (s, 1H), 7.82 (s, 1H), 7.66 (d, J = 1.57 Hz, 1H), 7.35 (d, J = 3.13 Hz, 1H), 7.17- 7.12 (m, 1H), 5.03 (d, J = 9.4 Hz, 1H), 4.63 (d, J = 9.8 Hz, 1H), 4.53 (d, J = 14.1 Hz, 1H), 4.0h (d, J = 14 Hz, 1H), 4.06 (s, 3H), 2.87 (s, 3H), 1.78 (s, 3H). LCMS: ESI-MS: m/z 582 [M+H]+. Example 182: Synthesis of Compound 182
Figure imgf000316_0002
[0953] 1H NMR (400 MHz, CD3OD): ^ 8.45 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.73 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), 7.62 (s, 1H), 4.63-4.82 (m, 6H), 4.22 (d, J = 13.6 Hz, 1H), 4.00-4.01 (m, 1H), 3.85 (d, J = 13.6 Hz, 1H), 2.87 (s, 3H), 1.57-1.64 (m, 1H), 0.89-0.90 (m, 4H), 0.68-0.70 (m, 1H), 0.54-0.56 (m, 1H), 0.42-0.44 (m, 1H), 0.28-0.32 (m, 1H). LCMS: ESI-MS: m/z 655.1 [M+H]+. Example 183: Synthesis of Compound 183
Figure imgf000317_0001
[0954] 1H NMR (400 MHz, CD3OD): ^ 8.44 (d, J = 8.4 Hz, 2H), 8.08 (s, 1H), 7.73 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.36 (s, 1H), 4.64-4.74 (m, 7H), 4.22 (d, J = 13.6 Hz, 1H), 4.05 (s, 3H), 3.85 (d, J = 13.6 Hz, 1H), 1.57-1.64 (m, 1H), 0.66-0.69 (m, 1H), 0.53-0.57 (m, 1H), 0.41-0.43 (m, 1H), 0.31-0.32 (m, 1H). LCMS: ESI-MS: m/z 649.2 [M+H]+. Example 184: Synthesis of Compound 184
Figure imgf000317_0003
Example 185: Synthesis of Compound 185
Figure imgf000317_0002
[0956] 1H NMR (400 MHz, DMSO-d6): ^ 8.60 (t, J = 5.6 Hz, 1H), 8.25-8.29 (m, 2H), 7.85 (s, 1H), 7.77 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.30 (t, J = 8.8 Hz, 2H), 5.41 (s, 1H), 4.62-4.82 (m, 6H), 4.11-4.12 (m, 1H), 3.92 (d, J = 5.6 Hz, 2H), 2.85 (s, 3H), 1.57-1.60 (m, 1H), 0.84-0.91 (m, 4H), 0.56-0.57 (m, 1H), 0.40-0.41 (m, 1H), 0.28-0.30 (m, 1H), 0.15-0.17 (m, 1H). LCMS: ESI-MS: m/z 605.3 [M+H]+. Example 186: Synthesis of Compound 186
Figure imgf000318_0001
[0957] 1H NMR (400 MHz, CD3OD): ^ 9.02 (m, 1H), 8.56 – 8.53 (m, 2H), 8.22 (s, 1H), 8.18 (s, 1H), 8.1 – 7.94 (m, 2H), 7.43 – 7.41 (m, 2H), 5.32 (d, J = 9.6 Hz, 1H), 4.91 (d, J = 9.6 Hz, 1H), 4.85-4.80 (m, 1H), 4.38-4.33 (m, 1H), 4.31 – 4.26 (m, 1H), 3.12 (s, 3H), 2.10 (s, 3H), 1.15- 1.14 (m, 4H). LCMS: ESI-MS: m/z 608.1 [M+H]+. Example 187: Synthesis of Compound 187
Figure imgf000318_0002
[0958] 1H NMR (400MHz, MeOD-d6) δ 8.34 – 8.31 (m, 2H), 8.0 (s, 1H), 7.86 (s, 1H), 7.73 (d, J = 1.2 Hz, 1H), 7.70 (d, J= 1.2 Hz, 1H), 7.22 (m, 2H), 5.09 – 5.05 (m, 1H), 5.0 – 4.88 (m, 2H), 4.81- 4.76 (m, 1H), 4.12 (d, J = 14.8 Hz, 1H), 4.08 – 4.04 (m, 1H), 2.91 (s, 3H), 0.94 – 0.93 (m, 4H). LCMS: ESI-MS: m/z 626.2 [M+H]+. [0959] The following compounds were prepared using methods analogous to those described herein. Satisfactory analytical data were obtained for each compound. Example 188: Synthesis of Compound 188
Figure imgf000319_0001
Example 189: Synthesis of Compound 189
Figure imgf000319_0002
Figure imgf000319_0003
[0960] Compound 190a: 1H NMR (400MHz, METHANOL-d4) δ 8.30 - 8.26 (m, 2H), 7.77 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.115 – 7.11 (t, J=8.8 Hz, 2H), 4.74 (d, J=9.3 Hz, 1H), 4.64 - 4.58 (m, 1H), 4.53 - 4.46 (m, 1H), 4.45 - 4.36 (m, 2H), 4.01 - 3.90 (m, 2H), 2.84 (s, 3H), 1.43 (s, 3H), 0.92 - 0.79 (m, 4H); LCMS: ESI-MS: m/z 615.1 [M +H]+. [0961] Compound 190b: 1H NMR (400MHz, METHANOL-d4) δ 8.31 - 8.27 (m, 2H), 7.73 (s, 1H), 7.67 (s, 1H), 7.55 (dd, J=1.5, 7.1 Hz, 2H), 7.14 (t, J=8.9 Hz, 2H), 4.72 (d, J=9.3 Hz, 1H), 4.59 - 4.37 (m, 4H), 4.05 - 3.91 (m, 2H), 2.84 (s, 3H), 1.40 (s, 3H), 0.89 - 0.81 (m, 4H); LCMS: ESI-MS: m/z 615.1 [M+H]+. Example 191: Synthesis of Compound 191
Figure imgf000320_0001
[0962] 1H NMR (400MHz, MeOD-d4) δ 8.26 (dd, J=5.5, 8.9 Hz, 2H), 8.04 (d, J=1.6 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.14 (t, J=8.9 Hz, 2H), 5.16 (d, J=9.0 Hz, 1H), 4.64-4,59 (m, 1H), 4.48 (d, J=9.3 Hz, 1H), 3.94 (d, J=13.9 Hz, 1H), 2.93 (s, 3H), 1.68 (s, 3H); LCMS: ESI-MS: m/z 604.1 [M+H]+. Example 192: Synthesis of Compound 192
Figure imgf000320_0002
[0963] 1H NMR (400MHz, MeOD-d6) δ 8.28 - 8.24 (m, 2H), 7.90 (d, J=1.2 Hz, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.46 - 7.03 (t, J=74 Hz, 1H), 7.12 (t, J=9 Hz, 2H), 4.79 - 4.51 (m, 7H), 4.01 (d, J = 13.7 Hz, 1H), 2.89 (s, 3H); LCMS: ESI-MS: m/z 643.1 [M+H]+. Example 193: Synthesis of Compound 193
Figure imgf000321_0002
[0964] 1H NMR (400MHz, MeOD-d6) δ = 8.31 - 8.27 (m, 2H), 8.06 (d, J=1.7 Hz, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.16 (t, J=8.8 Hz, 2H), 4.81 - 4.73 (m, 2H), 4.72 - 4.68 (m, 2H), 4.68 - 4.62 (m, 2H), 4.54 (d, J=13.9 Hz, 1H), 4.03 (d, J=13.9 Hz, 1H), 2.93 (s, 3H); LCMS: ESI-MS: m/z 611.0 [M+H]+. Example 194: Synthesis of Compound 194
Figure imgf000321_0001
[0965] 1H NMR (400MHz, MeOD-d4) δ 8.60 (d, J=2.6 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.04 (d, J=2.6 Hz, 1H), 7.68 (s, 1H), 7.52 - 7.44 (m, 3H), 7.16 (d, J=1.6 Hz, 1H), 6.57 - 6.27 (t, J=55,2 Hz, 1H), 6.38 (s, 1H), 4.99 (d, J=9.4 Hz, 1H), 4.33 (d, J=9.0 Hz, 1H), 4.11 (d, J=13.6 Hz, 1H), 3.82 (s, 3H), 3.69 (d, J=13.4 Hz, 1H), 1.46 (s, 3H); LCMS: ESI-MS: m/z 651.0 [M+H]+. Example 195: Synthesis of Compound 195
Figure imgf000321_0003
[0966] 1H NMR (400MHz, MeOD-d4) δ 8.75 (d, J=2.4 Hz, 1H), 8.33 - 8.21 (m, 2H), 8.13 (d, J=2.2 Hz, 1H), 8.52 - 8.04 (m, 1H), 7.64 (s, 1H), 7.62 (J=1,6 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.12 (t, J=8.8 Hz, 2H), 4.82 - 4.57 (m, 6H), 4.18 (d, J=13.4 Hz, 1H), 3.98 (s, 3H), 3.82 (d, J=13.4 Hz, 1H), 1.59 (tt, J=5.3, 8.3 Hz, 1H), 0.69 - 0.30 (m, 4H); LCMS: ESI-MS: m/z 598.2 [M+H]+. Example 196: Synthesis of Compound 196
Figure imgf000322_0001
[0967] 1H NMR (400MHz, MeOD-d4) δ 8.75 (d, J=2.9 Hz, 1H), 8.28 (dd, J=5.6, 8.8 Hz, 2H), 7.86 (dd, J=2.8, 8.9 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.64 (s, 2H), 7.12 (t, J=8.8 Hz, 2H), 4.79 - 4.62 (m, 6H), 4.19 (d, J=13.7 Hz, 1H), 3.96 - 3.90 (m, 1H), 3.89 (d, J=6.0 Hz, 1H) 1.66 - 1.48 (m, 1H), 0.91 - 0.75 (m, 4H), 0.70 - 0.27 (m, 4H); LCMS: ESI-MS: m/z 608.2 [M+H]+. Example 197: Synthesis of Compound 197
Figure imgf000322_0002
[0968] 1H NMR (400MHz, MeOD-d4) δ 8.45 (d, J=2.2 Hz, 1H), 8.08 - 7.95 (m, 2H), 7.82 (d, J=2.2 Hz, 1H), 7.47 - 7.32 (m, 3H), 6.85 (t, J=8.9 Hz, 2H), 4.55 - 4.34 (m, 6H), 3.93 (d, J=13.4 Hz, 1H), 3.71 (m, 2H), 3.51 (d, J=13.4 Hz, 1H), 1.31 (tt, J=5.3, 8.3 Hz, 1H), 0.71 – 0.51 (m, 4H), 0.45-0.09 (m, 4H); LCMS: ESI-MS: m/z 624.2 [M+H]+. Example 198: Synthesis of Compound 198
Figure imgf000323_0003
[0969] 1H NMR (400MHz, MeOD-d4) δ 8.27-8.23 (m, 2H), 7.86 (s, 1H), 7.75 (s, 1H), 7.56 (s, 1H), 7.23 (s, 1H), 7.12 (t, J=8.6 Hz, 2H), 5.18 (d, J=9.6 Hz, 1H), 4.67-4.62 (m, 1H), 4.49 (d, J=9.6 Hz, 1H), 4.09 (s, 3H), 3.96 (d, J=13.6 Hz, 1H), 2.85 (s, 3H), 1.69 (s, 3H); LCMS: ESI-MS: m/z 600.1 [M+H]+. Example 199: Synthesis of Compound 199
Figure imgf000323_0001
[0970] 1H NMR (400MHz, METHANOL-d4) δ 8.76 (d, J=1.6 Hz, 1H), 8.28 - 8.24 (m, 2H), 7.93 (s, 1H), 7.88 (s, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.28 – 6.91 (t, J=74 Hz, 1H), 7.12 (t, J=8.8 Hz, 2H), 4.79 - 4.60 (m, 7H), 4.53 (d, J=14.0 Hz, 1H), 4.01 (d, J=14.0 Hz, 1H), 2.48 (s, 3H); LCMS: ESI-MS: m/z 642.1 [M+H]+. Example 200: Synthesis of Compound 200
Figure imgf000323_0002
[0971] 1H NMR (400MHz, DMSO-d6) δ 9.0 (s, 1H), 8.69 (t, J=5.6 Hz, 1H), 8.50 (s, 1H), 8.26-8.23 (m, 2H), 7.99 (d, J=1.2 Hz, 1H), 7.85-7.84 (m, 1H), 7.79 (s, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.43-7.15 (t, J=55.2 Hz, 1H), 7.3-7.26 (m, 2H), 5.12 (d, J=8.8 Hz, 1H), 4.40 (d, J=8.8 Hz, 1H), 4.31-4.26 (m, 1H), 4.08-4.03 (m, 1H), 4.0-3.98 (m, 1H), 2.60 (d, J=4.4 Hz, 3H), 1.48 (s, 3H), 0.82-0.69 (m, 4H); LCMS: ESI-MS: m/z 675.1 [M+H]+. Example 201: Synthesis of Compound 201
Figure imgf000324_0001
[0972] 1H NMR (400MHz, DMSO, d6) δ 8.87 (d, J=2.8 Hz 1H), 8.74 (t, J=5.6 Hz, 1H), 8.49 (d, J=2.8 Hz, 1H), 8.28-8.25 (m, 2H), 7.99 (s, 1H), 7.89 (d, J=1.2 Hz 1 H), 7.77 (d, J=1.2 Hz 1 H), 7.44 (br s, 1 H), 7.39 (t, J=8.8 Hz 2H), 5.18 (dd, J=10, 2.4 Hz, 1H ), 4.99 (s, 1H ), 4..89-4.99 (m, 2H), 4.28-4.24 (m, 1H), 4.19-4.15 (m, 1H), 4.04-4.01 (m, 1H), 0.87-0.83 (m, 2H), 0.79-0.76 (m, 2H); LCMS: ESI-MS: m/z 645.0 [M+H]+. Example 202: Synthesis of Compound 202
Figure imgf000324_0002
[0973] 1H NMR (400MHz, MeOD-d4) δ 9.03 (s, 1H), 8.74 (t, J=5.6 Hz, 1H), 8.64 (s, 1H), 8.31-8.23 (m, 2H), 7.97 (s, 1H), 7.89 (s, 1 H), 7.56 (s, 1 H), 7.18-7.13 (t, J=8.8 Hz, 2H), 5.05 (dd, J=10, 2.4 Hz, 1H ), 4.93 (m, 2H), 4.79-4.72 (m, 2H), 4.57-4.52 (m, 1H), 4.14-4.12 (m, 1H), 4.04 (s, 3H). LCMS: ESI-MS: m/z 653.0 [M+H]+. Example 203: Synthesis of Compound 203
Figure imgf000325_0001
[0974] 1H NMR (400MHz, MeOD-d4) δ 8.28 (dd, J=7.3, 2.3 Hz, 1H), 8.22-8.19 (m, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.65 (d, J=1.2 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.26 (t, J=8.8 Hz, 1H), 5.18 (d, J=9.0 Hz, 1H), 4.60 (d, J=13.8 Hz, 1H), 4.51 (d, J=9.3 Hz, 1H), 3.89-4.03 (m, 2H), 2.89 (s, 3H), 1.69 (s, 3H), 0.93-0.85 (m, 4H); LCMS: ESI-MS: m/z 660.1 [M+H]+. Example 204: Synthesis of Compound 204
Figure imgf000325_0002
[0975] 1H NMR (400MHz, MeOD-d4) δ 8.10-7.96 (m, 2H), 7.84 (s, 1H), 7.70 (s, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.49 (d, J=1.2 Hz, 1H), 7.05 (t, J=9.2 Hz, 1H), 5.15 (d, J=9.3 Hz, 1H), 4.63 (d, J=13.7 Hz, 1H), 4.47 (d, J=9.0 Hz, 1H), 3.96-3.89 (m, 1H), 3.82 (d, J=13.7 Hz, 1H), 2.85 (s, 3H), 2.59 (q, J=7.4 Hz, 2H), 1.68 (s, 3H), 1.12 (t, J=7.6 Hz, 3H), 0.87-0.74 (m, 4H); LCMS: ESI-MS: m/z 654.1 [M+H]+. Example 205: Synthesis of Compound 205
Figure imgf000325_0003
[0976] 1H NMR (400MHz, MeOD-d4) δ 8.27 - 8.23 (m, 2H), 7.63 (s, 1H), 7.59 (d, J=1.6 Hz, 1H) 7.55 (s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.07 (t, J=8.8 Hz, 2H), 6.73 - 6.28 (t, J=55.2 Hz, 1H), 4.38 (s, 2H), 4.25 (d, J=13.9 Hz, 1H), 4.02 - 3.91 (m, 1H), 3.82 (d, J=13.7 Hz, 1H), 2.85 (s, 3H), 1.34 (d, J=8.4 Hz, 6H), 0.94 - 0.77 (m, 4H); LCMS: ESI-MS: m/z 579.2 [M+H]+. Example 206: Synthesis of Compound 206
Figure imgf000326_0001
[0977] 1H NMR (400MHz, MeOD-d4) δ 8.19 (dd, J=5.5, 8.8 Hz, 2H), 7.72 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.06 (t, J=8.7 Hz, 2H), 6.62 - 6.30 (t, J=55.0 Hz 1H), 5.06 (d, J=9.3 Hz, 1H), 4.41 (d, J=9.0 Hz, 1H), 4.36 (d, J=13.7 Hz, 1H), 3.91 (m, 1H), 3.73 (d, J=13.7 Hz, 1H), 2.84 (s, 3H), 2.74 (s, 3H), 1.59 (s, 3H), 0.84 (d, J=5.3 Hz, 4H); LCMS: ESI-MS: m/z 622.1 [M +H]+. Example 207: Synthesis of Compound 207
Figure imgf000326_0002
[0978] 1H NMR (400MHz, MeOD-d4) δ 8.68 (dd, J=5.5, 8.9 Hz, 2H), 8.41 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 8.02 (d, J=1.0 Hz, 2H), 7.53 (t, J=8.8 Hz, 2H), 7.07 - 6.79 (t, J=55.2 Hz, 1H), 5.49 (d, J=9.0 Hz, 1H), 4.88 (d, J=9.3 Hz, 1H), 4.73 (d, J=13.7 Hz, 1H), 4.39 (m, 1H), 4.30 (d, J=13.7 Hz, 1H), 3.31 (s, 3H), 2.01 (s, 3H), 1.74 (s, 3H), 1.32 (d, J=4.6 Hz, 4H), 1.22 - 1.11 (m, 2H), 1.07 - 0.97 (m, 2H); LCMS: ESI-MS: m/z 662.1 [M+H]+. Example 208: Synthesis of Compound 208
Figure imgf000327_0001
[0979] 1H NMR (400MHz, MeOD-d4) δ 8.22 (dd, J=5.5, 8.8 Hz, 2H), 7.71 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.07 (t, J=8.8 Hz, 2H), 6.67 - 6.31 (t, J=55 Hz, 1H), 5.05 (d, J=9.3 Hz, 1H), 4.44 (d, J=9.0 Hz, 1H), 4.29 (d, J=13.7 Hz, 1H), 3.95 (m, 1H), 3.80 (d, J=13.5 Hz, 1H), 2.88 (s, 3H), 2.67 (tt, J=3.7, 7.3 Hz, 1H), 1.58 (s, 3H), 0.88 (d, J=4.4 Hz, 4H), 0.74 - 0.49 (m, 4H); LCMS: ESI-MS: m/z 648.3 [M+H]+. Example 209: Synthesis of Compound 209
Figure imgf000327_0002
[0980] 1H NMR (400MHz, MeOD-d4) δ 8.73 (d, J=2.4 Hz, 1H), 8.28 - 8.20 (m, 2H), 8.11 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.07 (t, J=8.9 Hz, 2H), 6.73 - 6.32 (t, J=55.2 Hz, 1H), 4.78 - 4.57 (m, 6H), 4.21 (d, J=13.7 Hz, 1H), 3.95 - 3.88 (m, 1H), 3.84 (d, J=13.9 Hz, 1H), 0.84 (m, 4H); LCMS: ESI-MS: m/z 634.0 [M+H]+. Example 210: Synthesis of Compound 210
Figure imgf000328_0001
[0981] To a solution of Intermediate 1 (2 g, 4.11 mmol, 1 eq.) in DCM (30 mL) was added DMP (2.62 g, 6.17 mmol, 1.91 mL, 1.5 eq.). The mixture was stirred at 25 °C for 2 h. The reaction was quenched with sat. Na2SO3 sol. (40 mL) and neutralized by sat. NaHCO3 soln. The mixture was extracted with EA (50 mLX3). The organic portions were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~25% EA/PE gradient @ 40 mL/min) to give Compound 2 (1.8 g, 90.4% yield) as a yellow oil. LCMS: ESI-MS: m/z 485.2 [M+H]+. [0982] To a solution of intermediate 2 (1 g, 2.06 mmol, 1 eq.) in MeOH (15 mL) was added K2CO3 (428 mg, 3.10 mmol, 1.5 eq.) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (397 mg, 2.06 mmol, 1 eq.). The mixture was stirred at 25 °C for 8 h. The reaction was diluted with water (30 mL) and extracted with EA (20 mL X 3). The organic portions were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% EA/PE gradient @ 40 mL/min) to give Intermediate 3 (850 mg, 85.7% yield) as a yellow oil. 1H NMR (400MHz, METHANOL-d4) δ 8.37 - 8.26 (m, 2H), 7.69 (s, 1H), 7.25 - 7.14 (m, 2H), 4.75 (d, J=8.8 Hz, 1H), 4.63 (d, J=8.8 Hz, 1H), 4.14 - 4.09 (m, 1H), 3.82 - 3.70 (m, 1H), 2.89 (s, 1H), 1.65 (s, 3H), 1.32 (s, 9H). [0983] To a solution of Intermediate 3 (470 mg, 0.98 mmol, 1 eq.) in MeOH (0.8 mL) and DMF (6 mL) were added TMSN3 (135 mg, 1.17 mmol, 1.2 eq.) and CuI (9.3 mg, 0.05 eq.). The mixture was stirred at 100 °C for 8 h under N2 atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with EA (20 mL X 3). The organic portions were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 60~70% EA/PE gradient @ 30 mL/min) to give Intermediate 4 (0.5 g, 97.6% yield) as a yellow oil. LCMS: ESI-MS: m/z 524.1 [M+H]+. [0984] To a mixture of intermediate 4 (500 mg, 0.95 mmol, 1 eq.) in DCM (2 mL) was added TFA (2.18 g, 1.41 mL, 20 eq.) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 1 hr. The mixture was washed with saturate NaHCO3 solution (15 mL) and stirred for 2min.The aqueous phase was extracted with ethyl acetate (20 mL X 3). The combined organic phase was washed with brine (10 mL X 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude intermediate 5 (380 mg, crude) was obtained as white solid was used for next step without purification; LCMS: ESI-MS: m/z 424.1 [M+H]+. [0985] Compound 210 was prepared essentially as described in the preparation of Compound 100 by using acid 6 and amine 5 as starting materials. 1H NMR (400MHz, MeOD-d4) δ 8.33 (dd, J = 5.7, 7.9 Hz, 2H), 7.99 (s, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.16 (t, J=8.6 Hz, 2H), 5.11 - 4.97 (m, 1H), 5.02 (d, J=8.6 Hz, 1H), 5.01 - 4.96 (m, 1H), 4.72 (d, J=8.8 Hz, 1H), 4.59 (br d, J=14.2 Hz, 1H), 4.04 - 3.90 (m, 2H), 2.86 (s, 3H), 1.81 (s, 3H), 0.90-0.83 (m, 4H); LCMS: ESI-MS: m/z 650.1 [M+H]+. Example 211: Synthesis of Compound 211
Figure imgf000330_0002
[0986] 1H NMR (400MHz, CHLOROFORM-d) δ 8.14 - 8.06 (m, 2H), 7.66 (s, 1H), 7.30 (s, 1H), 7.19 (s, 1H), 7.16 - 7.03 (m, 3H), 6.77 (s, 1H), 6.60 (d, J=9.9 Hz, 1H), 4.90 (dd, J=10.4, 13.7 Hz, 1H), 4.64 (d, J=9.3 Hz, 1H), 4.43 (d, J=9.7 Hz, 1H), 4.11 - 3.90 (m, 4H), 3.84 - 3.78 (m, 1H), 3.63 (dd, J=2.5, 13.8 Hz, 1H), 3.52 (dd, J=6.4, 11.5 Hz, 1H), 2.85 (s, 3H), 2.26 (m, 1H), 0.95 - 0.79 (m, 4H); LCMS: ESI-MS: m/z 629.3 [M+H]+. Example 212: Synthesis of Compound 212
Figure imgf000330_0003
[0987] 1H NMR (400MHz, METHANOL-d4) δ 8.28 (dd, J=5.6, 8.9 Hz, 2H), 7.81 (s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.31 (s, 1H), 7.12 (t, J=8.9 Hz, 2H), 6.74 - 6.42 (t, J=55.2, 1H), 4.88 - 4.86 (m, 2H), 4.80 - 4.72 (m, 6H), 4.24 (d, J=13.8 Hz, 1H), 4.01 (s, 3H), 3.88 (d, J=13.8 Hz, 1H), 2.49 (s, 3H); LCMS: ESI-MS: m/z 618.1 [M+H]+. Example 213: Synthesis of Compound 213
Figure imgf000330_0001
[0988] 1H NMR 400MHz, METHANOL-d4) δ 8.29 - 8.17 (m, 3H), 7.80 (d, J=1.5 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H), 7.71 (s, 1H), 7.49 - 7.11 (t, J=54.8 Hz, 1H), 7.10 - 7.01 (m, 2H), 6.76 - 6.33 (t, J=55.2 Hz, 1H), 4.75 - 4.62 (m, 6H), 4.22 (d, J=13.7 Hz, 1H), 4.08 - 3.99 (m, 1H), 3.86 (d, J=13.7 Hz, 1H), 0.96 - 0.87 (m, 4H); LCMS: ESI-MS: m/z 651.2 [M+H]+. Example 214: Synthesis of Compound 214
Figure imgf000331_0001
[0989] 1H NMR (400MHz, METHANOL-d4) δ 8.31 (dd, J=5.5, 8.8 Hz, 2H), 7.81 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.32 (s, 1H), 7.13 (t, J=8.8 Hz, 2H), 6.71 - 6.33 (t, J=55.0 Hz,1H), 4.41 (s, 2H), 4.28 (d, J=13.8 Hz, 1H), 4.01 (s, 3H), 3.86 (d, J=13.8 Hz, 1H), 2.49 (s, 3H), 1.36 (d, J=11.8 Hz, 6H); LCMS: ESI-MS: m/z 582.3 [M+H]+. Example 215: Synthesis of Compound 215
Figure imgf000331_0002
[0990] 1H NMR (400MHz, METHANOL-d4) δ 8.34 (d, J = 1.17 Hz, 1H), 8.29 – 8.25 (m, 2H), 7.72 (s, 1H), 7.6 (s, 1H), 7.2 – 7.11 (m, 2H), 7.06 (s, 1H), 4.83 – 4.60 (m, 6H), 4.49 (d, J = 14 Hz, 1H), 3.99 (d, J = 14 Hz, 1H), 3.96 (s, 3H), 2.03- 1.97 (m, 1H), 1.06 – 1.02 (m, 2H), 0.88 – 0.84 (m, 2H); LCMS: ESI-MS: m/z 621 [M+H]+. Example 216: Synthesis of Compound 216
Figure imgf000332_0002
[0991] 1H NMR (400MHz, METHANOL-d4) δ 8.65 (s, 1H), 8.39 (d, J = 8.2 Hz, 2H), 7.90 (m, 3.52 Hz, 2H), 7.67 (d, J = 8.22 Hz, 2H), 7.60 (s, 1H), 7.21 (s, 1H), 5.16 (d, J= 9 Hz, 1 H), 4.6 – 4.56 (m, 2H), 4.48 (d, J = 9.47 Hz, 1H), 2.46 (s, 3H), 1.65 (s, 3H). LCMS: ESI-MS: m/z 649.1 [M+H]+. Example 217: Synthesis of Compound 217
Figure imgf000332_0001
[0992] 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.68 (t, J = 5.6, 1H), 8.52 (s, 1H), 8.15-8.20 (m, 1H), 8.12-8.15 (m, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.99 (d, J = 1.6, 1H), 7.47-7.56 (m, 2H), 7.26-7.38 (m, 3H), 5.16 (d, J = 8.8, 1H), 4.39 (d, J = 8.8, 1H), 4.10-4.27 (m, 1H), 4.01- 4.02 (m, 1H), 3.98-4.01 (m, 1H), 1.48 (s, 3H), 0.81-0.84 (m, 2H), 0.74-0.77 (m, 2H). LCMS: ESI-MS: m/z 679.1 [M+H]+. Example 218: Synthesis of Compound 218
Figure imgf000333_0003
[0993] 1H NMR (400 MHz, DMSO-d6): ^ 8.92 (s, 1H), 8.37 (s, 1H), 8.19-8.37 (m, 2H), 7.90 (s, 1H), 7.78 (d, J = 1.6, 1H), 7.67 (d, J = 1.6, 1H), 6.89-7.17 (m, 3H), 5.02-5.04 (m, 1H), 4.08- 5.01 (m, 2H), 4.59-4.72 (m, 3H), 3.87-3.94 (m, 2H), 0.78-0.88 (m, 4H); LCMS: ESI-MS: m/z 679.1 [M+H]+. Example 219: Synthesis of Compound 219
Figure imgf000333_0001
[0994] 1H NMR (400 MHz, CD3OD): ^ 8.50-8.56 (m, 2H), 7.92 (s, 1H), 7.81 (s, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.35 (t, J = 9.6 Hz, 1H), 5.19 (d, J = 9.2 Hz, 1H), 4.58 (d, J = 14.0 Hz, 1H), 4.52 (d, J = 9.2 Hz, 1H), 3.98 – 4.01 (m, 2H), 3.07 (s, 3H), 1.66 (s, 3H), 0.82-0.91 (m, 4H); LCMS: ESI-MS: m/z 694.1 [M+H]+. Example 220: Synthesis of Compound 220
Figure imgf000333_0002
[0995] 1H NMR (400 MHz, CD3OD): ^ 8.25-8.28 (m, 1H), 8.18-8.21 (m, 1H), 7.85 (s, 1H), 7.75 (d, J = 2.8 Hz, 1H), 7.58 (s, 1H), 7.50 (t, J = 1.6 Hz, 1h), 7.08-7.15 (m, 1h), 5.73-5.91 (m, 1H), 5.15 (d, J = 9.2 Hz, 1H), 4.57-4.63 (m, 1H), 4.48 (d, J = 9.2 Hz, 1H), 3.87-3.92 (m, 2H), 2.84 (s, 3H), 1.67 (s, 3H), 1.51-1.61 (m, 3H), 0.81-0.87 (m, 4H); LCMS: ESI-MS: m/z 672.1 [M+H]+. Example 221: Synthesis of Compound 221
Figure imgf000334_0001
[0996] 1H NMR (400 MHz, CD3OD): ^ 8.35-8.41 (m, 2H), 7.89 (s, 1H), 7.81 (s, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.5563 (d, J = 1.2 Hz, 1H), 7.21-7.26 (m, 1H), 5.18 (d, J = 8.0 Hz, 1H), 4.59-4.81 (m, 1H), 4.51 (d, J = 8.0 Hz, 1H), 3.93-3.97 (m, 2H), 2.87 (s, 3H), 1.94 (t, J = 18.8 Hz, 3H), 1.68 (s, 3H), 0.85-0.90 (m, 4H); LCMS: ESI-MS: m/z 690.1 [M+H]+. Example 222: Synthesis of Compound 222
Figure imgf000334_0002
[0997] 1H NMR (400 MHz, CD3CN): ^ 8.75 (d, J = 2.4 Hz, 1H), 8.06-8.14 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.47 (s, 1H), 7.34 -7.39 (m, 2H), 7.05-7.09 (m, 2H), 5.81-6.11 (m, 2H), 5.35 (br. s, 1H), 4.99 (d, J = 9.2 Hz, 1H), 4.37-4.40 (m, 2H), 3.74-3.78 (m, 1H), 3.53-3.70 (m, 2H), 3.43 (dd, J = 13.6 Hz, 4.0, 1H), 2.51 (s, 3H), 1.66 (s, 3H); LCMS: ESI-MS: m/z 624 [M+H]+. Example 223: Synthesis of Compound 223
Figure imgf000335_0001
[0998] 1H NMR (400 MHz, DMSO-d6): ^ 10.2 (s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.77 (t, J = 5.6 Hz, 1H), 8.24-8.30 (m, 3H), 7.91 (s, 1H), 7.79-7.83 (m, 2H), 7.31 (d, J = 0.8 Hz, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.51-7.34 (m, 3H), 5.24 (d, J = 8.8 Hz, 1H), 4.76 (d, J = 8.8 Hz, 1H), 4.26- 4.31 (m, 1H), 4.02-4.12 (m, 2H), 2.81 (s, 3H), 1.66 (s, 3H), 0.78-0.84 (m, 4H); LCMS: ESI-MS: m/z 771 [M+H]+. Example 224: Synthesis of Compound 224
Figure imgf000335_0002
[0999] 1H NMR (400 MHz, DMSO-d6): ^ 8.78 (t, J = 5.87 Hz, 1H), 8.39 (d, J = 8.21 Hz, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.82 (s, 1H), 7.75 (d, J = 1.17 Hz, 1H) 7.55 (d, J = 1.56 Hz, 1H), 7.30 (s, 1H), 4.83- 4.62 (m, 6H), 4.26 (dd, J = 14.1, 6.65 Hz, 1H), 4.1 (dd, J = 14.1, 5.81 Hz, 1H), 4.01 (s, 3H), 2.82 (s, 3H); LCMS: ESI-MS: m/z 657 [M+H]+. Example 225: Synthesis of Compound 225
Figure imgf000336_0002
[1000] 1H NMR (400 MHz, CD3OD) ^ 8.24- 8.21 (m, 3H), 7.80 (s, 1H), 7.7 (d, J = 1.18 Hz, 1H), 7.37 – 7.35 (m, 1H), 7.23 (t, J = 54.8 Hz, 1H), 7.12 – 7.08 (m, 2H), 5.11 (d, J = 9 Hz, 1H), 4.68 (d, J = 13.7 Hz, 1H), 4.45 (d, J = 9 Hz, 1H), 4.03 (s, 3H), 3.83 (d, J = 13.7 Hz, 1H), 2.76 (s, 3H), 1.65 (s, 3H); LCMS: ESI-MS: m/z 650 [[M+H]+. Example 226: Synthesis of Compound 226
Figure imgf000336_0001
[1001] 1H NMR (400 MHz, CD3OD) ^ 8.74 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 8 Hz, 2H), 8.22 (d, J = 2 Hz, 1H), 7.95 (s, 1H), 7.71 (d, J = 8 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 1.2 Hz, 1H), 5.21 (d, J = 9.2 Hz, 1H), 4.63 – 4.62 (m, 2H), 4.53 (d, J = 9.2 Hz, 1H), 3.99 (d, J = 15.2 Hz, 1H), 3.95 (s, 3H), 1.70 (s, 3H); LCMS: ESI-MS: m/z 669 [M+H]+. Example 227: Synthesis of Compound 227
Figure imgf000337_0001
[1002] 1H NMR (400 MHz, CD3OD) ^ 8.44 (d, J= 8.2 Hz, 2H), 8.33 (s, 1H), 7.83 (s, 1H), 7.78 (d, J = 1.56 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 1.57 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 4.83 – 4.56 (m, 7H), 4.08 (s, 3H), 4.05 (d, J = 13.7, 1H); LCMS: ESI-MS: m/z 693 [M+H]+. Example 228: Synthesis of Compound 228
Figure imgf000337_0002
[1003] 1H NMR (400 MHz, CD3OD) ^ 8.43 (d, J = 8.2 Hz, 2H), 7.83 (s, 1H), 7.77 (s, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 4.80 – 4.56 (m, 7H), 4.03 (d, J = 14.1 Hz, 1H), 3.97 – 3.95 (m, 1H), 2.83 (s, 3H), 0.86 – 0.84 (m, 4H); LCMS: ESI- MS: m/z 683 [M+H]+. Example 229: Synthesis of Compound 229
Figure imgf000338_0001
[1004] 1H NMR (400 MHz, DMSO-d6) ^ 8.83 (d, J = 2.3, 1H), 8.71 (t, J = 5.9, 1H), 8.47 (J = 2.3, 1H), 8.39 (d, J = 8.2, 1H), 7.81-7.88 (m, 5H), 7.39 (d, J = 1.6, 1H), 7.23 (s, 1H), 5.15 (d, J = 9.0, 1H), 4.42 (d, J = 9.0, 1H), 4.24-4.28 (m, 1H), 4.03-4.08 (m, 1H), 3.91 (s, 3H), 2.30 (d, J = 4.3, 1H), 1.49 (s, 3H); LCMS: ESI-MS: m/z 683 [M+H]+. Example 230: Synthesis of Compound 230
Figure imgf000338_0002
[1005] Step 1. To a stirring mixture of Intermediate 1 (40 mg), in MeOH (1 mL) was added a solution of NH3 in MeOH (2.5 mL). The resulting mixture was stirred under microwave conditions at 110 oC for 3 h. The resulting mixture was cooled and concentrated under reduced pressure and directly loaded into HPLC column to afford the desired product as a white solid (11 mg, 25% yield). LCMS: ESI-MS: m/z 584 [M+H]+. [1006] Step 2. To a stirring mixture of amidine 2 (5.6 mg) in dioxane (1.5 mL) were added Cs2CO3 (15 mg) and 1,2,3-triazine (2 mg). The resulting mixture was stirred at 130 oC for 1.5 h. The resulting mixture was concentrated under pressure and directly subjected to the HPLC column to afford desired product as a white powder (2 mg). 1H NMR (400 MHz, CD3OD) ^ 8.83 – 8.82 (m, 1H) 8.52 (d, J = 5.1 Hz, 2H), 8.36 – 8.32 (m, 2H), 8.2 – 8.17 (m, 1H), 7.74 (s, 1H), 7.56 – 7.53 (m, 2H), 7.19 – 7.14 (m, 2H), 7.1 (s, 1H) 7.14-7.03 (m, 1H), 5.51 (d, J = 9 Hz, 1H), 4.69 (d, J = 9.4 Hz, 1H), 4.50 (d, J = 14.1 Hz, 1H), 3.95 (d, J = 14.1 Hz, 1H), 3.91 (s, 3H), 1.8 (s, 3H); LCMS: ESI-MS: m/z 620 [M+H]+. Example 231: Synthesis of Compound 231
Figure imgf000339_0001
[1007] 1H NMR (400MHz, METHANOL-d4) ^ 8.79 (d, J = 2.4 Hz, 1H), 8.34 – 8.28 (m, 2H), 8.28 (s, 1H), 7.93 (s, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.18 (m, 1H), 5.07 (d, J= 9.2 Hz, 1H), 4.67 (, d, J= 9.6 Hz, 1H), 4.59 – 4.55 (m, 1H), 4.02 (s, 3H), 1.81 (s, 3H); LCMS: ESI-MS: m/z 601.0 [M+H]+. Example 232: Synthesis of Compound 232
Figure imgf000339_0002
[1008] 1H NMR (400MHz, METHANOL-d4) ^ 8.45 (d, J = 8 Hz, 2H), 7.85 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 1.6 Hz, 1H), 7.02 (t, J = 54 Hz, 1H), 4.80 - 4.53 (m, 7H), 4.05 (d, J = 14 Hz, 1H), 3.91 (s, 3H); LCMS: ESI-MS: m/z 698.2 [M+H]+. Example 233: Synthesis of Compound 233
Figure imgf000340_0001
[1009] 1H NMR (400MHz, METHANOL-d4) ^ 8.31 – 8.27 (m, 2H), 7.85 (d, J = 1.2 Hz, 1H), 7.75 (s, 1H), 7.26 (d, J = 1.2 Hz, 2H), 7.17 – 7.13 (m, 2H), 7.06 (t, J = 40 Hz, 1H), 4.82 – 4.52 (m, 7H), 4.03 (d, J = 14 Hz, 1H), 3.95 (s, 3H); LCMS: ESI-MS: m/z 648.2 [M+H]+. Example 234: Synthesis of Compound 234
Figure imgf000340_0002
[1010] 1H NMR (400MHz, METHANOL-d4) ^ 8.28 (m, 2H), 8.06 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.36 (s, 1H), 7.11 (t, J = 8.8 Hz, 1H), 5.92 (s, 1H), 5.81 (s, 1H), 4.75 – 4.53 (m, 7H), 4.03 (s, 3H), 3.98 (d, J = 14 Hz, 1H. LCMS: ESI-MS: m/z 625.3 [M+H]+. Example 235: Synthesis of Compound 235
Figure imgf000340_0003
[1011] 1H NMR (400MHz, METHANOL-d4) ^ 8.57 (s, 1H), 8.30 -8.27 (m, 2H), 7.86 (d, J = 1.2 Hz, 1H), 7.76 (d, J = 12 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 4.77 – 4.57 (m, 7H), 4.04-3.99 (m, 2H), 0.89-0.88 (m, 4H). LCMS: ESI-MS: m/z 644.2 [M+H]+. Example 236: Synthesis of Compound 236
Figure imgf000341_0001
[1012] 1H NMR (400MHz, METHANOL-d4) ^ 8.48 (s, 1H), 8.32 – 8.27 (m, 2H), 7.80 (d, J = 0.8 Hz, 1H), 7.77 (s, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.16 (t, J = 9.2 Hz, 2H), 4.89 – 4.58 (m, 7H), 4.11 (s, 3H), 4.05 (d, J = 14 Hz, 1H). LCMS: ESI-MS: m/z 661.1 [M+H]+. Example 237: Synthesis of Compound 237
Figure imgf000341_0002
[1013] 1H NMR (400MHz, METHANOL-d4) ^ 8.47 (s, 1H), 7.85 (s, 1H), 7.74-7.70 (m, 3H), 7.56 (s, 1H), 7.24 (s, 1H), 4.87-4.56 (m, 7H), 4.06 (d, J = 17 Hz, 1H), 4.03 (s, 3H), 2.43-2.36 (m, 1H), 1.22-1.2 (m, 4H). LCMS: ESI-MS: m/z 683.3 [M+H]+. Example 238: Synthesis of Compound 238
Figure imgf000342_0001
[1014] 1H NMR (400MHz, METHANOL-d4) ^ 8.43 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.32- 8.28 (m, 2H), 7.78 (s, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.13 (t, J = 8.4 Hz, 2H), 4.86 – 4.56 (m, 7H), 4.07 (d, J = 14 Hz, 1H), 3.9 (s, 3H), 3.87 (s, 3H). LCMS: ESI-MS: m/z 622.1 [M+H]+. Example 239: Synthesis of Compound 239
Figure imgf000342_0002
[1015] 1H NMR (400MHz, METHANOL-d4) ^ 8.51 (d, J = 2.8 Hz, 1H), 8.34 – 8.30 (m, 2H), 7.76 (s, 1H), 7.61 (d, J = 1.6Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.17 (t, J = 8.8 Hz, 2H), 4.88 – 4.6 (m, 7H), 4.03 (d, J = 12Hz, 1H), 4.0 (s, 3H), 3.93-3.86 (m, 1H), 0.82- 0.81 (m, 4H). LCMS: ESI-MS: m/z 648.1 [M+H]+. Example 240: Synthesis of Compound 240
Figure imgf000342_0003
[1016] 1H NMR (400MHz, METHANOL-d4) ^ 8.3 – 8.26 (m, 2H), 7.86 (t, J = 72 Hz, 1H), 7.68 (d, J = 38 Hz, 3H), 7.21 (d, J = 1.2 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 4.80 – 4.53 (m, 7H), 4.03 (s, 3H), 4.0 (d, J = 14 Hz, 1H). LCMS: ESI-MS: m/z 659.1 [M+H]+. Example 241: Synthesis of Compound 241
Figure imgf000343_0001
[1017] 1H NMR (400MHz, METHANOL-d4) ^ ^8.26 - 8.23 (m, 2H), 7.83 (s, 1H), 7.73 (s, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.19 (d, J = 1.2 Hz, 1H), 7.14 (t, J = 8.8 Hz, 2H), 5.11 (d, J = 9.6 Hz, 1H), 4.67 – 4.63 (m, 1H), 4.52 – 4.50 (m, 2H), 4.40 (t, J = 5.2 Hz, 1H), 3.86 (d, J = 13.6 Hz, 1H), 4.01 (s, 3H), 3.6 – 3.5 (m, 2H), 2.87 (s, 3H), 1.7 (s, 3H). LCMS: ESI-MS: m/z 646.2 [M+H]+. [1018] The following compounds in Examples 242-249 were prepared using methods analogous to those described in the preceding examples.
Figure imgf000343_0002
Figure imgf000344_0001
Figure imgf000345_0001
Biological Examples Example B1. RSV Polymerase Non-nucleoside Inhibition Assay [1019] Standard RSV polymerase assays were conducted in the presence of 10 nM recombinant RSV complex in a reaction buffer containing Tris-HCl pH 7.5, 6 mM MgCl2, and other additives and substrates including RNA oligonucleotides and radionucleotides. Standard reactions were incubated in 96-well plate format for 2 hours at 30 °C, in the presence of increasing concentration of test compound. The reaction was stopped with 90 µL of 0.1M EDTA, and the reaction product was transferred to a "reading" 96-well plate. After washing of the plate, radiolabeled RNA products were detected according to standard procedures with a Trilux Topcount scintillation counter. The compound concentration at which the enzyme- catalyzed rate was reduced by 50% (IC50) was calculated by fitting the data to a non-linear regression (sigmoidal). The IC50 values were derived from the mean of one or more independent experiments and are shown in Table 2. TABLE 2: RSV POLYMERASE IC50
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Key: +++ = IC50 ≤ 1 nM; ++ = 1 nM < IC50 ≤ 2.5 nM; + = 2.5 nM < IC50 ≤ 5 nM; * = 5 nM < IC50 < 100 nM; ** = 100 nM < IC50 < 250 nM Example B2. RSV Replicon Assays [1020] Assay 1: The RSV subgenomic replicon cell line APC126 was licensed from Apath (Brooklyn, NY) and was originally developed by Dr. Mark Meeples of Center for Vaccines & Immunity, the Research Institute at Nationwide Children's Hospital in Columbus, Ohio. Briefly, in the subgenomic RSV replicon, three glycoprotein genes, those for SH, G, and F, from a full- length recombinant GFP-expressing (rg) RSV antigenomic cDNA were deleted and, in their place, a blasticidin S deaminase (bsd) gene was inserted. A luciferase gene was also inserted into the RSV replicon. Through multiple steps, the RSV replicon was established in baby hamster kidney (BHK) cells to generate the cell line APC126. APC126 was maintained in Dulbecco's Modified Eagle Medium (DMEM)/Hams F-1250/50 (Mediatech, Cat No.10-092) supplemented with 10% (v/v) fetal bovine serum (FBS), 1% (v/v) penicillin/streptomycin, 1% non-essential amino acids (Mediatech, Cat No.25-025), 5% (v/v) tryptose phosphate broth (Biomedicals, Cat No.1682149) and 10 µg/mL blasticidin (InvivoGen, Cat No. Ant-BL). [1021] On the first day, 3.5 x 103 APC126 cells per well were seeded in a 96-well plate with 10% FBS supplemented medium. Negative control wells contained 10% FBS supplemented medium only. The next day, test compound was dissolved in 100% DMSO, and cells were treated with serial dilutions of the test compound in triplicates in a 37 ^C, 5% CO2 incubator. The positive control wells were APC126 cells with DMSO only. The final concentration of DMSO for all conditions was 1% (v/v). After a 3-day incubation, luciferase activity was measured using the Promega Renilla-Glo Luciferase Assay kit according to the manufacturer’s instruction (Cat No. E2750) to assess anti-RSV replicon activity. EC50, the concentration of the test compound required for reducing RSV replicon RNA by 50% in relation to the untreated cell control value was calculated from the plot of percentage reductions of the optical density (OD) value against the test compound concentrations. The EC50 values were derived from the mean of one or more independent experiments and are shown in Table 3. TABLE 3A: RSV REPLICON EC50
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Key: +++ = EC50 ≤ 1 nM; ++ = 1 nM < EC50 ≤ 10 nM; + = 10 nM < EC50 ≤ 50 nM; * = 50 nM < EC50 ≤ 200 nM; ** = 200 nM < EC50 ≤ 1 uM Assay 2: Black 384-well clear-bottom microtiter plates (Corning, Amsterdam, The Netherlands) were filled via acoustic drop ejection using the echo liquid handler (Labcyte, Sunnyvale, California).200 nL of compound stock solutions (100% DMSO) were transferred to the assay plates. 9 serial 4-fold dilutions of compound were made, creating per quadrant the same compound concentration. The assay was initiated by adding 10 µL of culture medium to each well (RPMI medium without phenol red, 10% FBS-heat inactivated, 0.04% gentamycin (50 mg/mL). All addition steps are done by using a multidrop dispenser (Thermo Scientific, Erembodegem, Belgium). Next, rgRSV224 virus (MOI = 1) diluted in culture medium was added to the plates. rgRSV224 virus is an engineered virus that includes an additional GFP gene (Hallak LK, Spillmann D, Collins PL, Peeples ME. Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection; Journal of virology (2000), 74(22), 10508-13) and was in-licensed from the NIH (Bethesda, MD, USA). Finally, 20 µL of a HeLa cell suspension (3,000 cells/well) were plated. Medium, virus- and mock-infected controls were included in each test. The wells contain 0.05% DMSO per volume. Cells were incubated at 37°C in a 5% CO2 atmosphere. Three days post-virus exposure, viral replication was quantified by measuring GFP expression in the cells by an in house developed MSM laser microscope (Tibotec, Beerse, Belgium). The EC 50 was defined as the 50% inhibitory concentration for GFP expression. In parallel, compounds were incubated for three days in a set of white 384-well microtiter plates (Corning) and the cytotoxicity of compounds in HeLa cells was determined by measuring the ATP content of the cells using the ATPlite kit (Perkin Elmer, Zaventem, Belgium) according to the manufacturer’s instructions. The CC 50 was defined as the 50% concentration for cytotoxicity. TABLE 3B: RSV REPLICON EC50
Figure imgf000352_0002
Figure imgf000353_0001
EC50 ≤ 200 nM; ** = 200 nM < EC50 ≤ 1 uM Example B3. Mouse Pharmacokinetics [1022] Tested compounds were formulated at 1 mg/mL in 20% PEG400 in water. [1023] Female Balb/c mice received either a single intravenous dose (2 mg/kg) or a single oral dose (10 mg/kg) of the test compound. [1024] Experimental groups of three mice per timepoint were sacrificed at 0.0333, 0.0833, 0.250, 0.500, 1.00, 2.00, 4.00, 6.00, 8.00, and 12.0 hours after dosing and blood samples were harvested. Whole blood was collected into containers with (K2) EDTA. An aliquot of 20 µL sample was protein precipitated with 300 µL internal standard, and the mixture was vortex- mixed for 1 min and centrifuged at 4000 rpm for 15 min.7 µL supernatant was injected for LC- MS/MS analysis. [1025] PK parameters were calculated for test compounds from the concentration-time data using Phoenix WinNonlin software (v6.3) by noncompartmental analysis. The steady state volume of distribution (Vdss) and clearance (Cl) are shown for IV administration in Table 4. The area under the concentration-time curve (AUC0-last) and the half-life of the compound (T1/2) are shown for oral administration in Table 5. TABLE 4: MOUSE IV PK
Figure imgf000353_0002
Figure imgf000354_0001
TABLE 5: MOUSE ORAL PK OR PD
Figure imgf000354_0002
Figure imgf000355_0001
1Compound 1 detected, PD shown; 2Compound 43 detected, PD shown; NR = not reportable due to R2 <0.9 Example B4. Pharmacokinetics in other mammals [1026] Pharmacokinetics were determined in other mammals using a similar method to that described in Example B4. The steady state volume of distribution (Vdss) and clearance (Cl) are shown for IV administration in rats (2 mg/kg)(Table 6), dogs (1 mg/kg)(Table 8), and monkey (1 mg/kg)(Table 10). The area under the concentration-time curve (AUC0-last) and the half-life of the compound (T1/2) are shown for oral administration in rats (10 mg/kg)(Table 7), dogs (5 mg/kg) (Table 9), and monkey (5 mg/kg)(Table 11). TABLE 6: RAT IV PK
Figure imgf000356_0001
* N=2 TABLE 7: RAT PO PK
Figure imgf000356_0002
Figure imgf000357_0001
* N=2; NR = not reportable due to R2 <0.9 TABLE 8: DOG IV PK
Figure imgf000357_0002
TABLE 9: DOG PO PK
Figure imgf000357_0003
Figure imgf000358_0003
TABLE 10: MONKEY IV PK
Figure imgf000358_0002
TABLE 11: MONKEY PO PK
Figure imgf000358_0001

Claims

CLAIMS What is claimed is: 1. A compound of Formula (X):
Figure imgf000359_0001
or a pharmaceutically acceptable salt thereof; wherein G2 is CR4a or N; G3 is CR5a or N; wherein R4a and R5a are each independently H, halo, CN, C1-C6 alkyl, -CD3, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, - C(O)NRgRh, -NRiRj, or -CH2-O-Rk, wherein the C3-C8 cycloalkyl and C3-C8 cycloalkoxy of R4a and R5a are optionally substituted with halo, OH, CN, or C1-C6 alkyl; wherein Rg and Rh are each independently H or C1-C6 alkyl; Ri and Rj are each independently H or C1-C6 alkyl; and Rk is H, -C(O)C1-C6 alkyl, or -C(=O)CH(RAA)NH2, wherein RAA is a side chain of an amino acid; G4 is CR6a, N, O, or S; wherein R6a is hydrogen or C1-C6 alkyl; one of G5 and G6 is C and the other is C or N; n is 0 or 1; R1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; R2 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, - C(O)NHRb, -NRxRy, -C(O)NHRb, -C(=N-CN)NH2, or -CN, wherein the C1-C6 alkyl of R2 is optionally substituted with -OH, oxo, or -NH2, and the C3-C8 cycloalkyl and monocyclic heteroaryl of R2 are each optionally substituted with halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OH; wherein Rb is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, wherein the C3-C8 cycloalkyl or monocyclic heteroaryl of Rb is optionally substituted with halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OH; and Rx and Ry are each independently H or C1-C6 alkyl; or R1 and R2 taken together with the carbon to which they are attached form a C3-6 cycloalkyl or a monocyclic heterocycloalkyl; R3 is halo, -ORd, or -NReRf; wherein Rd is C1-C6 alkyl, -CD3, C1-C6 haloalkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl of Rd is optionally substituted with C3-C8 cycloalkyl; and Re and Rf are each independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R7 is hydrogen or C1-C6 alkyl; R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl optionally substituted with C1-4 alkyl or halo; and R9, R10, R11, R12, and R13 are each independently hydrogen, halo, C1-C6 alkyl, or C1-C6 haloalkyl. 2. The compound of claim 1, wherein the carbon bearing the R8 and OH moieties is in a “R” configuration. 3. The compound of claim 1, wherein the carbon bearing the R8 and OH moieties is in an “S” configuration. 4. The compound of claim 1, wherein G2 is CR4a. 5. The compound of claim 4, wherein R4a is H, F, Cl, CH3, -OCH3, -CH2F, -CF3, -CN, - CH2-ORk, -NH2, or -NHCH3, wherein Rk is H, -C(O)CH2CH3, or -C(=O)CH(iPr)NH2. 6. The compound of claim 1, wherein G2 is N. 7. The compound of any one of claims 1 to 5, wherein n is 1 and G3 is CR5a. 8. The compound of claim 7, wherein R5a is H, F, Cl, -CH3, -CD3, -CHF2, -CH2F, -CF3, - OCH3, -OCHF2, -OCF3, CN, -cyclopropyl (optionally substituted with fluoro), NH2, NHCH3, or CONH2. 9. The compound of any one of claims 1 to 5, wherein n is 1 and G3 is N. 10. The compound of any one of claims 1 to 9, wherein G4 is CR6a. 11. The compound of claim 10, wherein R6a is H or -CH3, optionally wherein R6a is H.
12. The compound of any one of claims 1 to 9, wherein G4 is N, or wherein G4 is O, or wherein G4 is S. 13. The compound of claim 1, wherein (a) n is 0, G5 is C, and G6 is N, or (b) n is 0, G5 is N, and G6 is C, or (c) n is 1 and G5 and G6 are each C. 14. The compound of any one of claims 1 to 13, wherein R1 is -CH3, -CH2F, -CHF2, -CF3, or -CH2OH. 15. The compound of any one of claims 1 to 14, wherein R2 is -CH3, -CH2F, -CHF2, -CF3, - CN, -C(CH3)2OH, -cyclopropyl-OH, -C(O)CH3, -CH2OH, -CH2NH2, -NH2, triazolyl, imidazolyl, pyridinyl, pyrimidinyl, -C(=N-CN)NH2, or -C(O)NRb, wherein Rb is H, -CH3, -CH2CHF2, - CH2CF3, cyclopropyl (optionally substituted with one or two F or CH3 groups), or pyridyl (optionally substituted with F, CH3, or CF3). 16. The compound of any one of claims 1 to 15, wherein R3 is F, Cl, -OCH3, -OCD3, - OCHF2, -OCF3, -OCH2CHF2, -O-cyclopropyl, or -O-CH2-cyclopropyl.
Figure imgf000361_0001
18. The compound of claim 17, wherein or
Figure imgf000362_0001
Figure imgf000362_0002
19. The compound of any one of claims 1 to 18, wherein R8 is -CHF2, -CF3, -CH2F, cyclobutyl, cyclopropyl, or fluoro-cyclopropyl. 20. The compound of any one of claims 1 to 19, wherein one or two of R9, R10, R11, R12, and R13 are independently F, -CF3, Cl, ethyl, -CF2CH3, or -CHFCH3. 21. The compound of any one of claims 1 to 20, wherein R9, R12, and R13 are each H. 22. The compound of any one of claims 1 to 21, wherein (a) R10 is F, Cl, -CF3, or -CHF2, or (b) R11 is H, F, Cl, -CF3, -CF2CH3, or ethyl. 23. A compound of Table 1 or Table 1A, or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 23, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. 25. A method of treating a respiratory syncytial virus (RSV) infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of any one of claims 1 to 23, or the pharmaceutical composition of claim 24. 26. A method of ameliorating one or more symptoms of an RSV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of any one of claims 1 to 23, or the pharmaceutical composition of claim 24, wherein the one or more symptoms are optionally selected from coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing. 27. The method of claim 25 or claim 26, wherein the individual (a) has a lower respiratory tract infection, bronchiolitis, pneumonia, or croup, or (b) is immunocompromised, or (c) has been diagnosed with an RSV infection, optionally wherein the RSV infection has been confirmed by a laboratory test, optionally wherein the laboratory test comprises detecting RSV in a nasal sample. 28. A method of preventing an RSV infection in an individual at risk of developing an RSV infection comprising administering to the individual a prophylactically effective amount of the compound of any one of claims 1 to 23, or the pharmaceutical composition of claim 24, optionally wherein the individual is immunocompromised. 29. The method of any one of claims 25 to 28, further comprising administering an additional anti-RSV agent, optionally wherein the additional anti-RSV agent is an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, an RSV RNA polymerase inhibitor, an inosine- 5'-monophosphate dehydrogenase (IMPDH) inhibitor, or an interferon. 30. A method of inhibiting replication of an RSV in a cell comprising contacting the cell with the compound of any one of claims 1 to 23, or the pharmaceutical composition of claim 24, optionally wherein the cell is infected with the RSV or wherein the cell is subsequently infected with the RSV. 31. A method of making a compound of Formula (XX, ethyl 8-fluoro-3-methylcinnoline-6- carboxylate):
Figure imgf000363_0001
comprising: coupling a compound of formula (XXa):
Figure imgf000363_0002
with 1-(trimethylsilyl)-propyne in the presence of a palladium catalyst to form a compound of formula (XXb):
Figure imgf000363_0003
cyclizing the compound of formula (XXb) with di-tert-butyl-hydrazodiformate (Boc-NH-NH- Boc) in the presence of a base to form the comound of formula (XXc):
Figure imgf000364_0001
and deprotecting the compound of formula (XXc) to form the compound of Formula (XX).
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