NZ723972B2 - Hepatitis b core protein allosteric modulators - Google Patents

Hepatitis b core protein allosteric modulators Download PDF

Info

Publication number
NZ723972B2
NZ723972B2 NZ723972A NZ72397215A NZ723972B2 NZ 723972 B2 NZ723972 B2 NZ 723972B2 NZ 723972 A NZ723972 A NZ 723972A NZ 72397215 A NZ72397215 A NZ 72397215A NZ 723972 B2 NZ723972 B2 NZ 723972B2
Authority
NZ
New Zealand
Prior art keywords
wilkinson
sarah
annotation
mmol
reaction
Prior art date
Application number
NZ723972A
Other versions
NZ723972A (en
Inventor
Lee Daniel Arnold
Hans Maag
William W Turner
Adam Zlotnick
Original Assignee
Assembly Biosciences Inc
Indiana University Research And Technology Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Assembly Biosciences Inc, Indiana University Research And Technology Corporation filed Critical Assembly Biosciences Inc
Priority claimed from PCT/US2015/020444 external-priority patent/WO2015138895A1/en
Publication of NZ723972A publication Critical patent/NZ723972A/en
Publication of NZ723972B2 publication Critical patent/NZ723972B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/14—[b, e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y10S514/894—

Abstract

ABSTRACT The present disclosure provides, in part, compounds (pictured below) having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound. ound.

Description

(12) Granted patent specificaon (19) NZ (11) 723972 (13) B2 (47) Publicaon date: 2021.12.24 (54) TIS B CORE PROTEIN ALLOSTERIC MODULATORS (51) Internaonal Patent Classificaon(s): A01N 43/00 A61K 31/55 C07D 498/00 (22) Filing date: (73) Owner(s): 2015.03.13 INDIANA UNIVERSITY RESEARCH AND TECH NOLOGY CORPORATION (23) Complete specificaon filing date: ASSEMBLY ENCES, INC. 3.13 (74) Contact: (30) Internaonal Priority Data: Spruson & Ferguson Pty Ltd US 61/952,467 2014.03.13 US 62/010,025 2014.06.10 (72) Inventor(s): TURNER, William W. (86) Internaonal Applicaon No.: ARNOLD, Lee Daniel MAAG, Hans ZLOTNICK, Adam (87) Internaonal Publicaon number: /138895 (57) ct: ABSTRACT The present disclosure provides, in part, compounds (pictured below) having allosteric effector properes against Hepas B virus Cp. Also provided herein are methods of treang viral infecons, such as s B, comprising administering to a paent in need thereof a disclosed compound. 723972 B2 HEPATITIS B CORE PROTEIN ALLOSTERIC MODULATORS STATEMENT OF GOVERNMENT T This invention was made with government support under AIO67417 awarded by the National Institutes of Health. The government has certain rights in the invention.
RELATED APPLICATIONS This application claims the benefit of and priority to United States Provisional Patent Applications serial nos. ,467, filed March 13, 2014, and 62/010,025, filed June 10, 2014, the contents of each of which are hereby incorporated by reference.
BACKGROUND Hepatitis B (HBV) causes viral Hepatitis that can filrther lead to c liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people have been infected with HBV, around 360 million people are chronically infected, and every year HBV infection causes more than one half million deaths (2009; WHO, 2009). HBV can be spread by body fluids: from mother to child, by sex, and via blood products.
Children born to HBV -positive mothers may also be infected, unless ated at birth.
The virus particle is composed of a lipid ped studded with surface protein (HBsAg) that surrounds the viral core. The core is ed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed ar DNA (cchNA) in the host cell nucleus. The cchNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral rase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the s of the capsid to generate the DNA-filled viral core. For convenience, we divide the assembly process at the point of capsid ly and pgRNA-packaging. Steps preceding this event are "upstream"; steps following RNA-packaging are "downstream".
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson At present, c HBV is primarily treated with nucleos(t)ide s (e.g. entecavir) that ss the virus while the patient remains on ent but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucleotide analogs most must continue taking them or risk the possibility of a life threatening immune response to viral rebound. Further, nucleos(t)ide therapy may lead to the emergence of antiviral drug resistance (Deres and Rubsamen-Waigmann, l999; Tennant et al., 1998; Zhang et al., 2003) and — in rare patients- adverse events have been reported (Ayoub and Keeffe , 2011).
The only FDA approved alternative to s(t)ide s is treatment with interferon or or pegylated interferon 0L. Unfortunately, the adverse event incidence and profile of interferon or can result in poor tolerability, and many patients are unable to complete therapy.
Moreover, only a small percentage of patients are considered riate for interferon therapy, as only a small subset of patients are likely to have asustained clinical response to a course of interferon therapy. As a result, interferon based therapies are used in only a small percentage of all diagnosed patients who elect for treatment.
Thus, current HBV treatments can range from palliative to watchful waiting.
Nucleos(t)ide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon a has severe side s and less bility among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections.
SUMMARY Provided herein are compounds that can have properties such as those described below, where the compounds in some embodiments may be ented by: R4 O R5 NH R10 6 T R Y \ R7 rfl—L—R2 s 9 R R RL Formulal [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson R5 NH R10 / \ R6 Y Tx .. u—L—R2 R8 RL Formula 1 ’ wherein R2, R4, R5, R6, R7, R8, R9, R10, RL, Y, T, and L are defined herein. Also ed herein are methods of treating viral infections, such as hepatitis B, comprising stering to t a disclosed compound.
For example, the present disclosure is directed in part to compounds having allosteric effector properties against Hepatitis B virus Cp, a protein found as a dimer, a multimer, and as the protein shell of the HBV core. Without being bound by theory, disclosed compounds may ultimately target multimerization of viral core proteins, which is l to HBV infection, where the core protein multimerizes into shell, or capsid, and/or disclosed compounds may for example, ultimately target interaction of viral core proteins with other macromolecules, such as host or viral nucleic acid, host proteins, or other viral proteins. For example, sed compounds may be considered in some ments CpAM -- core protein allosteric modifiers. CpAM ction with core n can allosterically favor an assembly-active form of Cp dimer and lead to viral capsid assembly at an inappropriate time or place or lead to andard intersubunit interactions, all resulting in defective capsids. CpAMs may additionally or alternatively affect steps of "upstream" of capsid assembly by altering the concentrations or nature of Cp available as dimer as compared to capsid or other multimeric forms. Disclosed compounds or CpAMs may, in some embodiments, noticeably affect functions upstream of viral assembly such as modulation of cchNA transcription, RNA stability and/or protein-protein interactions.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates synthetic scheme 1.
Figure 2 illustrates synthetic scheme 2.
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ED DESCRIPTION The features and other details of the disclosure will now be more particularly described. Before fiarther description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as tood by a person of skill in the art.
Unless defined otherwise, all technical and ific terms used herein have the same meaning as commonly understood by a person of ry skill in the art.
Definitions As intended herein, the terms "a" and "an" include singular as well as plural references unless the context y dictates otherwise. For e, the term "an assembly effector" can include one or more such effectors.
The term "alkyl" as used herein refers to a saturated straight or ed hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1_6alkyl, C1_4alkyl, and C1_ 3alkyl, respectively. Exemplary alkyl groups include, but are not d to, methyl, ethyl, propyl, isopropyl, 2-methyl-l-butyl, 3-methylbutyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4- methyl-l-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
The term "alkenyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C2_6alkenyl, and C3_4alkenyl, respectively. Exemplary alkenyl groups e, but are not d to, vinyl, allyl, butenyl, pentenyl, etc.
The term "alkoxy" as used herein refers to a straight or branched alkyl group attached to oxygen -O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1_6alkoxy, and koxy, respectively.
Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
[Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson The term "alkynyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary l groups include, but are not limited to, straight or ed groups of 2-6, or 3-6 carbon atoms, referred to herein as C2_6alkynyl, and C3_6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
The terms "cycloalkyl" or a "carbocyclic group" as used herein refers to a saturated or lly unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3_6cycloalkyl or C4_6cycloalkyl, tively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.
The terms "halo" or en" as used herein refer to F, Cl, Br, or I.
] The terms "heteroaryl" or "heteroaromatic group" as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and . Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, azole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.
The terms "heterocyclyl" or "heterocyclic group" are art-recognized and refer to saturated or partially unsaturated 4-7 membered ring structures, Whose ring structures include one to three heteroatoms, such as nitrogen, , and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of cyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, ine, tetrahydrofuran or dihydrofuran etc The terms xy" and "hydroxyl" as used herein refers to the radical —OH.
"Treatment" as used herein includes the alleviation, prevention, reversal, amelioration or control of a pathology, disease, er, process, condition or event, including viral infection.
In this t, the term "treatment" is fiarther to be understood as embracing the use of a drug to inhibit, block, reverse, restrict or control progression of viral infection. ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson As used herein, the term "pharmaceutical ition" refers to compositions of matter comprising at least one pharmaceutical nd and optionally a pharmaceutically acceptable carrier.
] As used herein, the term "pharmaceutical compound" or "drug" refers to a free compound, its therapeutically suitable salts, solvates such as hydrates, specific crystal forms of the compound or its salts, or therapeutically suitable prodrugs of the compound.
Pharmaceutically or pharmacologically acceptable" include molecular entities and itions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.
The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.
The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term "stereoisomers" when used herein consist of all enantiomers or reomers. These compounds may be designated by the symbols "(+)," "(-)," "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center itly. The present invention encompasses various stereoisomers of these nds and mixtures thereof Mixtures of enantiomers or diastereomers may be designated "(::)" in nomenclature, but the d artisan will recognize that a structure may denote a chiral center implicitly.
The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric s ing from the arrangement of substituents around a carbon-carbon double bond. The symbol — denotes a bond that may be a single, double or triple bond as described . Substituents around a carbon-carbon double bond are designated [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson as being in the "Z" or "E" configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise ed, structures depicting double bonds encompass both the "E" and "Z" isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents tuents on opposite sides of the double bond.
Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric s resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the "Z" or "E" configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures ing carbocyclic or heterocyclic rings encompass both "Z" and "E " s. Substituents around a carbocyclic or heterocyclic rings may also be referred to as "cis" or "trans", where the term "cis" represents tuents on the same side of the plane of the ring and the term "trans" represents tuents on opposite sides of the plane of the ring. Mixtures of nds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are ated "cis/trans." Individual enantiomers and diasteriomers of nds of the present invention can be prepared synthetically from commercially ble starting als that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (l) ment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent.
Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a isting one, are well known in the art. selective syntheses [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson ed set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson encompass both o- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
The compounds sed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the nd is a single polymorph. In another ment, the compound is a mixture of polymorphs. In r embodiment, the compound is in a crystalline form.
The ion also embraces ically labeled nds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in . Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, , fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 358, 18F, and 36Cl, respectively. For example, a compound of the invention may have one or more H atom replaced with deuterium.
Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-l4 (i. e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. r, substitution with heavier isotopes such as deuterium (i. e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in viva half-life or d dosage requirements) and hence may be preferred in some circumstances.
Isotopically labeled compounds of the invention can generally be ed by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
The term "therapeutically le salt," refers to salts or zwitterions of pharmaceutical compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders and effective for their intended use. The salts may be prepared, for instance, during the final isolation and purification of the compounds or separately by reacting an amino group of [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson the compounds with a suitable acid. For e, a compound may be ved in a suitable solvent, such as but not limited to methanol and water, and treated with at least one equivalent of an acid, for ce hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be d under reduced pressure to e the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, rate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, filmarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, e, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para- toluenesulfonate, undecanoate, hydrochloric, hydrobromic, ic, phosphoric, and the like.
The amino groups of a compound may also be quatemized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
] Basic addition salts may be prepared, for instance, during the final isolation and purification of ceutical compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, ate, or onate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic y, secondary, or tertiary amine. Quaternary amine salts may derived, for example, from amine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N- ylaniline, N—methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, namine, and N,N'- ylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
The term "therapeutically suitable prodrug," refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of subjects and are effective for their intended use. The term ug" refers to compounds that are transformed in vivo to a pharmaceutical compound, for example, by hydrolysis in blood. The term "prodrug," refers to compounds that contain, but are not limited to, substituents known as "therapeutically suitable esters." The term "therapeutically suitable ester," refers to alkoxycarbonyl groups appended to the parent molecule on an available carbon atom. More specifically, a "therapeutically suitable [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ester," refers to alkoxycarbonyl groups appended to the parent molecule on one or more available aryl, cycloalkyl and/or heterocycle groups. Compounds containing therapeutically suitable esters are an e, but are not intended to limit the scope of nds considered to be gs. Examples of prodrug ester groups include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art. Other examples of prodrug ester groups are found in T. Higuchi and V. , Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., ersible Carriers in Drug Design, American Pharmaceutical Association and on Press, 1987, both of which are incorporated herein by reference.
The terms "pharmaceutically effective amoun " and "effective amount", as used herein, refer to an amount of a pharmaceutical formulation that will elicit the desired therapeutic effect or response when administered in accordance with the desired treatment regimen.
US2011/0144086 describes the use of some diabenzothiazepine molecules (DBTs) as anti- malarial "inhibitors of the plasmodial surface anion channel." However, no study of DBT molecules as anti-virals has yet been reported. 1. Disclosed compounds contemplated herein may in some embodiments be represented by Formula 1: R4 0 RE : fLNH R10 6 T R \ R7 YQ w-L-RZ R8 R9 RL Formula 1 wherein: T is selected from the group consisting of —C(O)-, -CH2-C(O)—, -N(C(O)-CH3)-, -NH-, - 0-, and —S(O)Z-, where z is 0, l or 2; Y is C(R11)2 and 0 wherein y is 0, , S(O)y, NRY l, or 2; RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl; [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson RL is ed from the group consisting of H, methyl, and —C(O)-C1_3alkyl; L is a bond or C1_4 straight chain alkylene optionally tuted by one or two substituents each independently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), ethenyl, hydroxyl, NR’R", phenyl, heterocycle, and halogen and wherein the C1_4 straight chain alkylene may be interrupted by an —O-; R2 is selected from the group consisting of H, phenyl or naphthyl (wherein the phenyl or naphthyl may be optionally substituted with one, two three or more substituents ed from the group consisting of halogen, yl, nitro, cyano, carboxy, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, koxy, NR’R", -C(O)- NR’R", - C(O)-C1_6alkyl, C1_6alkoxy, phenyl (optionally substituted by one, two or three tuents each independently selected from the group consisting of halogen, hydroxyl, cyano, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)- C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), S(O)W-NR’R" (where w is l, 2 or ’- S(O)W, and -S(O)W-NR’R’ ’(where w is l, 2 or 3)), heteroaryl (optionally substituted by one, two or three substituents each independently selected from the group ting of halogen, hydroxyl, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)- C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), NR’-S(O)W, and -S(O)W-NR’R’ ’(where w is l, 2 or 3)), C3_6cycloalkyl, -S(O)W-C1_6alkyl (where w is l, 2 or 3), -S(O)W-NR’R" (where w is l, 2 or 3), and (O)w, (where w is l, 2 or 3)), -6 membered heteroaryl haVing one, two, or three heteroatoms each independently selected from O, N and S (wherein the 5-6 membered heteroaryl may be optionally substituted on a carbon with one, two three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R’ ’, C(O)— NR’R", C1_6alkyl, -C(O)-OH, -C(O)-C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), -NR’-S(O)w, and -S(O)W-NR’R’ ’(where w is l, 2 or 3)), heteroaryl, heterocycle, NR’R’ ’, - C(O)- NR’R", -C(O)-C1_6alkyl, C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), -NR’- S(O)W, and -NR’R"(where w is l, 2 or 3), and on a nitrogen by R’), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson C1_6alkyl, C1_6alkoxy, kenyl, C3_10cycloalkyl (optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, NR’R", -C(O)- NR’R", =CNR’, C1_6alkyl, C1_6alkoxy, -C(O)-C1_6alkyl, and -C(O)-C1_ 6alkoxy, and wherein the C3_1ocycloalkyl may ally be a d cycloalkyl)), and a 4-6 membered heterocycloalkyl having one or two heteroatoms each independently selected from O, N and S (wherein the 4-6 membered heterocycloalkyl may be optionally substituted with one, two three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, NR’R", -C(O)— NR’R", C1_6alkyl, C1_6alkoxy, -C(O)-C1_6alkyl, and -C(O)-C1_ 6alkoxy); R’ is selected, independently for each ence, from H, methyl, ethyl, propyl, phenyl, and benzyl; R" is ed, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, carboxybenzyl, —C(O)-methyl and —C(O)-ethyl, or R’ and R’ ’ taken together may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected for each occurrence from the group consisting of hydrogen, kyl, C2_6alkenyl, C2_6alkynyl, halogen, hydroxyl, nitro, cyano, NR’R", -C(O)— NR’R", -C1_6alkyl (where w is l, 2 or 3), -NR’- S(O)W, and -S(O)W-NR’R"(where w is 0, l or 2), C1_6alkoxy,-C(O)-OH, -C(O)—C1_6alkyl, and - C(O)-C1_6alkoxy; wherein for each occurrence, C1_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, phenyl, NR’R", -C(O)— NR’R", S(O)W-methyl (where w is l, 2 or 3), -NR’-S(O)W, and S(O)w-NR’R’ ’(where w is 0, 1 or 2); C1_6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, phenyl, NR’R’ ’, -C(O)- NR’R", S(O)W-C1_6alkyl (where w is l, 2 or 3), (O)W, and S(O)W-NR’R" (where w is 0, l or 2); and cloalkyl may be optionally tuted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, C1- [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 6alkoxy, -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, and NR’R"; and pharmaceutically acceptable salts thereof.
For example, in certain embodiments, L may be selected from the group consisting of a bond, -CH2-, —CH2-CH2-, or CH2(CH2)-CH2-. For example, in certain embodiments, L is C2- 3alkylene, or in other embodiments, L is selected from the group consisting of —CH2-CH2 — CH2(CH2)—CH2-, —CH2-CH2(OH)-, -CH2-CH2(CH30H)-, and —CH2-CH2(OH)-CH2-. L may be a bond, or for example, L may be kylene-O-. For example, L may be —O-CH2-CH2(OH)-, - CH2-CH2(CH30H)-, or —CH2-CH2(OH)-CH2-. In other embodiments, L is —O-.
] Y, in n embodiments, may be S(O)y (where y is 0, 1 or 2), or NRy. In certain ments y is 0 or 2, for example, Y may be S.
In certain other embodiments, R2 is phenyl, for example, R2 may be phenyl substituted by C1_6alkyl or C1_6alkoxy. In other ments, R2 is phenyl substituted by one or two substituents each ed from the group consisting of fluorine, chlorine, C1_6alkyl (optionally substituted by one, two or three es), C1_6alkoxy (optionally substituted by one, two or three fluorines), hydroxyl, NR’R’ ’, -S(O)2-NR’R", heteroaryl, and phenyl (optionally substituted by halogen or hydroxyl). For example, R2 may be phenyl substituted by an 5-6 membered heteroaryl selected from the group consisting of: Adm[N/Ns,ON Ii,» [2%3N" (NY/j m [NEEI‘I‘Nwho" N N, yu/\\N fN/N\ \ firmF :L_R. O ’R' ,{1 S NwR N[qt/l} ML)E "(1:2 N oxN N / | . Elm] and In an exemplary embodiment R2 is phenyl substituted by [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson In other embodiments, R2 may be a 5-6 membered heteroaryl, for example, R2 may be selected from the group consisting of: s / N \/ \ N , , KN N N N’N N NVN N/\ ‘ /N with‘ lil§\/N I]! \ SEN x O ,R' [I] [j8 NR. 7 7 O‘N/I '/\> LN [3' N:N "",’/\Iv 7 ' E and , "cw l/ )3" M" ' IN\ 934N N ,,N ‘N / ‘N N S\// o\// #N‘ N\//N In another embodiment, R2 may be a 4-6 membered heterocycloalkyl, which may be optionally substituted as described above. For example, R2 may be ed from the group consisting of: wherein R32 is selected from the group consisting of H, halogen, phenyl, and C1_6alkyl (optionally substituted by one, two or three halogens); R52 is selected from the group consisting of H, halogen, phenyl, and C1_6alkyl nally tuted by one, two or three halogens); and R42 is selected from the group consisting of H, n, phenyl, C1_6alkyl (optionally substituted by one, two or three halogens), C1_6alkoxy (optionally substituted by one, two or three halogens), NH2, -OCH3, NHCHg, and 2.
R42 in some embodiments, may be independently selected for each ence from the group consisting of H, methyl, ethyl, propyl, -CF3, -CH2CH3, Cl, F, phenyl, -NH2, -OCH3, NHCHg, and N(CH3)2.
In other embodiments, e.g. when R2 is a heteroaryl, R2 may be ally substituted on a carbon by one or two tutents each selected from the group consisting of fluorine, chlorine, phenyl, -NH2, NH kyl, and N(C1_6alkyl)2, C1_6alkyl, and C1_6alkoxy. In certain embodiments, R11 is CH2 or -CH2(CH3)— [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ] Also contemplated herein is a compound of formula 1 or 1’ wherein R2 is a 4-6 ed heterocycloalkyl or C4_6cycloalkyl, for example, R2 is selected from the group of: ydropyranyl, tetrahydrofuran, cyclopentane, cyclohexane, and cyclobutane. In an embodiment, R2 is selected from the group consisting of: . | OQ orU LU [:3 ("job| A compound represented by: R5 NH R10 R6 Y R7 N—L—R2 Formula 1’’ is also contemplated , wherein Y is S(O)y, wherein y is 0, l, 2; L is a bond or C1_4 straight chain alkylene optionally substituted by one or two substituents each ndently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), hydroxyl and halogen; R2 is selected from phenyl optionally substituted with one, two three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_ 6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)-C1_ 6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently ed from the group consisting of halogen, hydroxyl, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1- 6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)—C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), NR’-S(O)W, and -NR’R’ ’(where w is l, 2 or 3)), 5-6 membered heteroaryl haVing one, two, or three heteroatoms each independently selected from O, N and S (optionally substituted by one, two or three substituents each ndently selected from the group [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson ed set by Sarah.Wilkinson consisting of halogen, hydroxyl, C1_6alkyl, kenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), -NR’-S(O)W, and -S(O)w-NR’R’ ’(where W is l, 2 or 3)), C3_6cycloalkyl, -S(O)W-C1_6alkyl (where w is l, 2 or 3), S(O)w-NR’R" (Where W is l, 2 or 3),-and -NR’-S(O)w, (Where W is l, 2 or 3)), and a 5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (wherein the 5-6 membered heteroaryl may be optionally tuted on a carbon with one, two three or more substituents ed from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C1_6alkyl, kenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, -S(O)W-C1_6alkyl (Where W is l, 2 or 3), S(O)w- NR’R" (Where W is l, 2 or 3),-NR’-S(O)w, and -S(O)w-NR’R’ ’(where W is l, 2 or 3)), heteroaryl, heterocycle, NR’R", -C(O)- NR’R", -C(O)—C1_6alkyl, -C(O)-C1_6alkoxy, -C1_ 6alkyl (where W is l, 2 or 3),-NR’-S(O)W, and -S(O)W-NR’R’ ’(where W is l, 2 or 3), and on a nitrogen by R’); R’ is selected, independently for each occurrence, from H, methyl, ethyl, and propyl, R" is selected, independently for each occurrence, from H, , ethyl, propyl, butyl, — C(O)-methyl and —C(O)-ethyl, or R’ and R’ ’ taken together may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, R10, and R11 are independently ed for each occurrence from the group consisting of hydrogen, kyl, C2_6alkenyl, C2_6alkynyl, halogen, hydroxyl, nitro, cyano, NR’R", -C(O)— NR’R", -S(O)W-C1_6alkyl (where W is l, 2 or 3), NR’- S(O)W, and S(O)W-NR’R"(Where w is 0, l or 2), C1_6alkoxy,-C(O)-OH, -C(O)-C1_6alkyl, and - 1_6alkoxy; wherein for each occurrence, C1_6alkyl may be ally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, phenyl, NR’R", -C(O)— NR’R", S(O)W-methyl (Where W is l, 2 or 3), -NR’-S(O)W, and S(O)w-NR’R’ ’(where w is 0, 1 or 2); C1_6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, phenyl, NR’R’ ’, -C(O)- NR’R", S(O)W-C1_6alkyl (where W is l, 2 or 3), -NR’-S(O)W, and S(O)W-NR’R" (where W is 0, l or 2); and C3_6cycloalkyl may be optionally substituted with one, two, three or more tuents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, kyl, C1- 6alkoxy, -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, and NR’R" and pharmaceutically acceptable salts thereof.
In some embodiments, nds of Formula 1, 1’ and/or 1" may have R7 selected from H and F; and/or R6 is selected from H and F; and/or R5 is selected from H and F. In some embodiments, compounds of a 1, 1’ and/or 1" may have R10 selected from the group ting of H, methyl and F and/or R4, R5, R6, R7, R8, R9, R10, and/or R11 may be H.
] In another embodiment, a compound represented by Formula 2 is provided: R5 NH R10 wherein Rm, and RIn are each independently selected from the group consisting of H, halogen, C1_6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR’R’ ’, and hydroxyl; R22 is selected for each ence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -C(O)-C1_6alkyl, - C(O)-C1_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(O)W-C1_6alkyl (where w is l, 2 or 3), - S(O)W-NR’R" (where w is l, 2 or 3), and -NR’-S(O)w, (where w is l, 2 or 3)); R’ is selected, independently for each occurrence, from H, methyl, ethyl, and propyl; R" is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, —C(O)—methyl and —C(O)-ethyl, or R’ and R’ ’ taken together with the nitrogen to which they are ed may form a 4-6 ed heterocycle; [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, C1_6alkyl, kynyl, kenyl, n, hydroxyl, nitro, cyano, and NR’R’ ’; wherein for each ence, C1_6alkyl may be optionally tuted with one, two, three or more substituents selected from the group ting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -NR’-S(O)W, and S(O)W-NR’R"; C1- 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, kyl, NR’R’ ’, -NR’-S(O)W, and S(O)W-NR’R’ ’; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_ 6alkyl, C1_6alkoxy, -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, and NR’R"; phenyl may be optionally substituted by one, two or three substituents each independently ed from the group consisting of halogen, hydroxyl, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), NR’-S(O)W, and -S(O)W-NR’R’ ’(where w is l, 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C1_6alkyl, C2_6alkenyl, C3_6cycloalkyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)—C1_6alkyl, -C(O)-C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), NR’-S(O)W, and - S(O)W-NR’R’ ’(where w is l, 2 or 3)), C3_6cycloalkyl; and pharmaceutically acceptable salts thereof.
For example, a compound of Formula 2 may have R7 is selected from H and F; and/or R6 is selected from H and F; and/or R5 is ed from H and F; and/or R10 is ed from the group ting of H, methyl and F; and/or each of R4, R5, R6, R7, R8, R9, R10, and R11 may be H.
For example, provided herein is a compound represented by R4 0 R5 NH R10 R6 8 Q R7 ""22 R8 R9 wherein the R moieties are described above.
For example, in an embodiment, provided herein is a compound represented by: [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 0w 8’ <\ > (N \\ H R22 wherein R22 for example,is selected from the group consisting of: Also provided are compounds of Formula 3: 8{V R3 Formula 3 wherein the moiety R3 is selected from the group consisting of phenyl and yl. R3 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, carboxy, alkoxy, amino-cycloalkyl, phenyl, carbonyl-alkoxy, sulfonylalkyl , sulfonyl-amino, and sulfonyl-amino-alkyl.
In on, compounds of Formula 4 are provided: 8W R4 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Formula 4 wherein moiety R4 is selected from the group consisting of pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, dinyl, and piperazinyl. R4 may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, carboxy, alkoxy, amino-cycloalkyl, phenyl, carbonyl-alkoxy, yl-alkyl, sulfonyl-amino, and sulfonylamino- alkyl.
In another embodiment, a compound ented by: R4 0 R5 NH R10 ORm Rm R6 Y R7 N R62 (Formula 5) is provided Y is C(R11)2 and 0 wherein y is 0, , S(O)y, NRY l, or 2; RY is selected from the group consisting of H, , ethyl, propyl, phenyl and benzyl; Rm, and RIn are each independently selected from the group consisting of H, halogen, C1- 6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2_6alkenyl (optionally substituted by one, two or three tuents each independently selected from halogen and hydroxyl), NR’R’ ’, and hydroxyl (e.g., Rm, and RIn may each be H in certain embodiments); R62 is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -C(O)-C1_6alkyl, - C(O)-C1_6alkoxy, phenyl, aryl, cloalkyl, -S(O)W-C1_6alkyl (where w is l, 2 or 3), - S(O)W-NR’R" (where w is l, 2 or 3), and -NR’-S(O)W, (where w is l, 2 or 3)); R’ is selected, independently for each occurrence, from H, methyl, ethyl, and propyl; [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson R" is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, — C(O)-methyl and ethyl, or R’ and R’ ’ taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, C1_6alkyl, kynyl, C2_6alkenyl, halogen, yl, nitro, cyano, and NR’R’ ’; wherein for each occurrence, C1_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -NR’-S(O)W, and S(O)W-NR’R"; C1- 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, NR’R’ ’, -NR’-S(O)W, and S(O)W-NR’R’ ’; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_ 6alkyl, C1_6alkoxy, -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, and NR’R"; phenyl may be ally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C1_6alkyl, kenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), NR’-S(O)W, and -NR’R’ ’(where w is l, 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each ndently selected from the group consisting of halogen, hydroxyl, C1_6alkyl, kenyl, kynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)—C1_ 6alkyl, -C(O)-C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), NR’-S(O)W, and -S(O)W- NR’R’ ’(where w is l, 2 or 3)), and C3_6cycloalkyl; and pharmaceutically acceptable salts thereof.
In an embodiment, a compound of a 5 may have R7 selected from H and F and/or R6 is selected from H and F and/or R5 may be selected from H and F; and/or R10 may be selected from the group ting of H, methyl and F; and/or R4, R5, R6, R7, R8, R9, R10, and R11 may be H.
] In some embodiments,Y of Formula 5 may be S.
A compound represented by: [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson R72 (Formula 6) is also provided wherein Y is C(R11)2 and 0 wherein y is 0, , S(O)y, NRY l, or 2; RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl; Rm, and RIn are each independently ed from the group ting of H, halogen, C1- 6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2_6alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR’R’ ’, and hydroxyl (e.g., Rm, and RIn may each be H in certain embodiments); Rc is H or C1_6alkyl; R72 is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, C2_6alkenyl, kynyl, koxy, NR’R", -C(O)-C1_6alkyl, - C(O)-C1_6alkoxy, , heteroaryl, C3_6cycloalkyl, -S(O)W-C1_6alkyl (where w is l, 2 or 3), - S(O)W-NR’R" (where w is l, 2 or 3), and -NR’-S(O)W, (where w is l, 2 or 3)); R’ is selected, independently for each occurrence, from H, methyl, ethyl, and propyl; R" is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, — C(O)-methyl and —C(O)-ethyl, or R’ and R’ ’ taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, C1_6alkyl, C2_6alkynyl, C2_6alkenyl, halogen, hydroxyl, nitro, cyano, and NR’R’ ’; n for each occurrence, C1_6alkyl may be ally substituted with one, two, three or more tuents selected from the group consisting of halogen, hydroxyl, nitro, cyano, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson carboxy, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -NR’-S(O)W, and S(O)W-NR’R"; C1- y may be optionally substituted with one, two, three or more substituents selected from the group ting of halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, NR’R’ ’, -NR’-S(O)W, and S(O)W-NR’R’ ’; cloalkyl may be optionally tuted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_ 6alkyl, C1_6alkoxy, -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, and NR’R"; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), NR’-S(O)W, and -S(O)W-NR’R’ ’(where w is l, 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, yl, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", C1_ 6alkyl, C1_6alkoxy, -S(O)W-C1_6alkyl (where w is l, 2 or 3), NR’-S(O)W, -S(O)W- NR’R’ ’(where w is l, 2 or 3)), and C3_6cycloalkyl, and pharmaceutically able salts thereof.
In some embodiments, R0 of a compound of formula 6 may be H or methyl, e.g., H; and/or R7 may be ed from H and F; and/or R6 may be selected from H and F; and/or R5 may be selected from H and F; and/or R10 may beselected from the group consisting of H, methyl and F; and/or R4, R5, R6, R7, R8, R9, R10, and R11 may be H.
] In certain embodiments, the Y moiety of a 6 is S.
Provided herein, in certain embodiments, is a compound represented by: R5 NRC R10 Rm Rm R6 R79 R7 M / R8 R9 N R78 Formula7 wherein Y is C(R11)2 and 0 wherein y is 0, , S(O)y, NRY l, or 2; [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson RY is selected from the group consisting of H, , ethyl, , phenyl and benzyl; Rm, and RIn are each independently selected from the group consisting of H, halogen, C1- 6alkyl nally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2_6alkenyl (optionally substituted by one, two or three substituents each independently selected from n and hydroxyl), NR’R’ ’, and yl(e.g., Rm, and RIn may each be H in certain ments); Rc is H or C1_6alkyl; R78 is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -C(O)-C1_6alkyl, -C(O)—C1_6alkoxy, phenyl, heteroaryl, cloalkyl, -S(O)W-C1_6alkyl (Where W is l, 2 or 3), -S(O)W-NR’R" (where W is l, 2 or 3), and -NR’-S(O)w, (where W is l, 2 or 3)); R79 is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -C(O)-C1_6alkyl, -C(O)—C1_6alkoxy, phenyl, aryl, C3_6cycloalkyl, -S(O)W-C1_6alkyl (Where W is l, 2 or 3), -S(O)W-NR’R" (where W is l, 2 or 3), and -NR’-S(O)w, (where W is l, 2 or 3)); R’ is selected, independently for each occurrence, from H, methyl, ethyl, and propyl; R" is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, — C(O)-methyl and —C(O)-ethyl, or R’ and R’ ’ taken together with the nitrogen to which they are attached may form a 4-6 membered cycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, C1_6alkyl, C2_6alkynyl, C2_6alkenyl, halogen, hydroxyl, nitro, cyano, and NR’R’ ’; wherein for each occurrence, C1_6alkyl may be optionally substituted with one, two, three or more substituents ed from the group consisting of halogen, yl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", -NR’-S(O)W, and NR’R"; C1- 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1_6alkyl, NR’R’ ’, -NR’-S(O)W, and S(O)W-NR’R’ ’; C3_6cycloalkyl may be optionally substituted with one, two, three or more [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson substituents ed from the group consisting of halogen, yl, nitro, cyano, carboxy, C1_ 6alkyl, C1_6alkoxy, -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, and NR’R"; phenyl may be optionally substituted by one, two or three tuents each ndently selected from the group consisting of halogen, yl, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)-C1_6alkyl, -C(O)-C1_6alkoxy, -C1_6alkyl (Where W is l, 2 or 3), NR’-S(O)W, and -S(O)W-NR’R’ ’(Where W is l, 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each ndently selected from the group consisting of halogen, hydroxyl, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C1_6alkoxy, NR’R", C(O)- NR’R", -C(O)—C1_6alkyl, -C(O)-C1_6alkoxy, -S(O)W-C1_6alkyl (Where W is l, 2 or 3), NR’-S(O)W, and - S(O)W-NR’R’ ’(Where W is l, 2 or 3), and ceutically acceptable salts thereof.
Rc is H or methyl.
In certain embodiments, compound of formula 7 may have R0 as H; and/or R7 may be selected from H and F; and/or R6 may be selected from H and F; and/or R5 may be selected from H and F; and/or R10 may be selected from the group consisting of H, methyl and F; and/or each of R4, R5, R6, R7, R8, R9, R10, and R" may be H.
For example, the present disclosure also provides, in part, a compound selected from the group consisting a compound of Table l, 2, 3, 4, 5, 6 and 7. Also contemplated herein are compounds: N—((2-methylthiazolyl)methyl)-l l-oxo- l 0, l ldihydrodibenzo [b,f][l,4]thiazepinecarboxamide 5-oxide, aminothiazolyl)methyl)- l l-oxo- l 0,1 l-dihydrodibenzo[b,f] [ l ,4]thiazepinecarboxamide 5-oxide, N—((2-methylthiazolyl)methyl)-l l-oxo- l 0,1 l-dihydrodibenzo [b,f] [ l ,4]thiazepinecarboxamide 5,5 -dioxide, N- inothiazolyl)methyl)-l l-oxo- l 0,1 l-dihydrodibenzo [b,f] [ l ,4]thiazepinecarboxamide ,5-dioxide, l l-oxo-N—(2-phenylbutyl)- l 0,1 drodibenzo[b,f] [ l ,4]thiazepinecarboxamide ,5-dioxide, N—(2-(4,4-difluorocyclohexyl)ethyl)-l l-oxo- l 0,1 l- dihydrodibenzo[b,f] [ l ,4]thiazepinecarboxamide 5 ,5-dioxide, 3'-(5 ,5-dioxido-l l-oxo- l 0,1 l- dihydrodibenzo [b,f] [ l ,4]thiazepinecarboxamido)-[ l , l '-biphenyl] carboxylic acid, 9-methyl- N—((2-methylthiazolyl)methyl)-l l-oxo- l 0, l l-dihydrodibenzo [b,f] [l ,4]thiazepine carboxamide, N—(2-(4'-fluoro-[ l , l '-biphenyl]yl)ethyl)-l l-oxo- l 0,1 l- [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Wilkinson dihydrodibenzo[b,f][1,4]thiazepine-S-carboxamide 5 ,S-dioxide, N—((2-amin0thiazol y1)rnethy1)rnethy1— 1 1-0x0-10,1 1-dihydr0dibenzo[b,f][1,4]thiazepinecarboxarnide, 1 1-0X0- N—(pyrimidin-S -y1rnethy1)— 1 0,1 dr0-5H-dibenzo[b,e][1,4]diazepinecarb0xamide, 1 1- 0X0-N-(2-(pyridiny1)ethy1)—10,1 1-dihydr0-5H-dibenzo[b,e][1,4]diazepine-S-carboxamide, 1 1- oxo-N—(Z-(pyridin-3 -y1)ethy1)— 1 0,1 1-dihydr0-5H-dibenzo[b,e][1,4]diazepine-S-carboxamide, 1 1- 0x0-N-(pyridin-3 -y1rnethy1)-10, 1 1-dihydr0-5H-dibenzo[b,e][1,4]diazepine-S-carboxamide, N-(2- ([1,1'-bipheny1]—4-y1)ethy1)—1 1-0x0-10,1 1-dihydr0-5H-dibenzo[b,e] [1 ,4]diazepine carboxarnide, 1 1-0X0-N—(pyridiny1)-10,1 1-dihydr0-5H-dibenzo[b,e][1,4]diazepine carboxarnide, N-(4-(N,N-dimethylsulfam0y1)phenethy1)-1 1-0x0-10,1 dr0-5H- dibenz0[b,e][1,4]diazepine-S-carboxamide, N—([1,1'-bipheny1]—3-y1)-1 1-oxo-10, 1 1-dihydr0-5H- dibenzo[b,e][1,4]diazepine-S-carboxamide, (Z)-N-((3-(methy1imino)propeny1)oxy)-1 1- 0X0-10, 1 1-dihydr0dibenzo[b,f][1,4]thiazepine-S-carb0xarnide, 1 1-0X0-N-(pyrirnidin-5 )— ,1 1-dihydrodibenzo[b,f][1,4]thiazepinecarboxarnide,1 1-0X0-N—(4-(pyrimidin-5 -y1)benzy1)- ,1 drodibenzo[b,f][1,4]thiazepinecarboxamide,N—(2—(4'-fluoro-[1,1'-bipheny1]—4- y1)ethy1)-1 1-oxo-10, 1 1-dihydr0dibenzo [b,f] [1 ,4]thiazepinecarb0xarnide,2-ch10r0-N—((2- methylthiazol-S -y1)rnethy1)— 1 1-0x0-10,1 1-dihydr0dibenzo [b,f] [1 ,4]thiazepinecarboxamide,2- ch10r0-1 1-0X0-N—(pyridin-3 -y1rnethy1)-10,1 1-dihydr0dibenzo[b,f][1,4]thiazepine-S-carb0xarnide, 2-ch10r0-1 1-0X0-N-(pyrimidin-5 -y1rnethy1)-10, 1 1-dihydr0dibenzo[b,f][1 ,4]thiazepine carboxarnide, 3 0-N-((2-rnethy1thiaz01-5 -y1)rnethy1)— 1 1-0x0-10,1 1- dihydrodibenzo[b,f][1 ,4]thiazepine-S-carboxarnide,3-ch10ro-1 1-0X0-N—(pyridiny1rnethy1)- ,1 1-dihydr0dibenzo[b,f][1,4]thiazepinecarboxarnide, 3 -ch10r0-1 1-0X0-N—(pyrirnidin-5 - y1rnethy1)—10,1 1-dihydr0dibenzo[b,f][1,4]thiazepinecarboxarnide, 1 1-rnethy1—N—((2- methylthiazol-S -y1)rnethy1)—6-oxo-6, 1 1-dihydr0-5H-dibenzo zepine-3 -carb0xarnide, 1 1- methy1oxo-N-(pyridin-3 -y1rnethy1)-6,1 1-dihydr0-5H-dibenzo [b,e]azepine-3 -carb0xarnide, 1 1- rnethyl0xo-N—(pyrimidin-S thy1)-6,1 1-dihydr0-5H-dibenzo [b,e]azepine-3 -carboxarnide, 2-ch10r0-1 1-0X0-N-(thiaz01-5 -y1rnethy1)-10, 1 1-dihydr0dibenzo[b,f][1,4]thiazepine carboxarnide, 3 -ch10r0-1 1-0X0-N-(thiaz01—5 -y1rnethy1)-10, 1 1- dihydrodibenzo[b,f][1,4]thiazepine-S-carboxarnide, 1 1-methy1—6-0X0-N—(thiaz01y1rnethy1)— 6,1 1-dihydro-5H-dibenzo[b,e]azepinecarboxamide, and 1 1-0X0-N—(2-(thiaz01y1)pr0pan ,1 1-dihydr0dibenzo[b,f] [1 ,4]thiazepinecarboxarnide; [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson or a pharmaceutically acceptable salt thereof.
In a second aspect, a method for the synthesis of disclosed compounds is provided.
The method follows tic Scheme 1, as illustrated in FIG. I. A first mixture comprising reagents 1 and 2 is formed for synthetic step A to yield synthetic ediate 3. Synthetic step A may be conducted in an organic solvent, for instance a polar aprotic solvent such as dimethyl sulfoxide , ylformamide (DMF), dioxane, hexamethylphosphorotriamide, and tetrahydrofuran. The reaction may be conducted in the ce of a base, for example a carbonate such as leCOg, N212C03, K2C03, szCOg, CSQCOg, MgCOg, CaCOg, SI‘COg, and BaCOg.
In reagent 1, moiety —YH is selected from the group consisting of —SH, -OH, and — N(R12)H, wherein R12 is selected from the group consisting of hydrogen and alkyl. In intermediates 3, 4, 5, and in product 6, moiety —Y- is selected from the group consisting of —S-, - O-, and -N(R12)-. Moieties P1 and P2 are independently selected carboxyl protecting , such as yl or ethoxyl groups. In some cases, at least one of P3 and P4 is an amino protecting group, for example selected from the group consisting of carbobenzyloxy (Cbz), p- methoxybenzyl-carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9- ylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), sulfonamides (Nosyl and Nps). atively, moiety —N(P3)(P4) may be a group that can be ormed in an amino group by appropriate chemical reactions. By way of example, moiety — N(P3)(P4) may be an —N02 group that is transformed into an amino (—NH2) moiety by reaction with a reductant.
In synthetic step B, ting groups P1 and P2 are removed to yield yl es. In instances where P1 and P2 are alkoxy groups, this may be achieved by hydrolysis, for example in the presence of a base or acid. Group —N(P3)(P4) is transformed into an amino moiety, as exemplified above, to yield intermediate 4. In synthetic step C, the amino group of intermediate 4 is reacted with the y group on the other phenyl moiety, forming the 1,4- thiazepan-S-one moiety of intermediate 5. The formation of this amide bond may be speeded up by the addition of activators. Example activators include carbodiimides, such as N,N’- [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson dicyclohexylcarbodiimide (DCC), N,N’-diisopropylcarbodiimide (DIC), and carbonyl diimidazole (CD1); and triazolols, such as oxy-benzotriazole (HOBt) and l-hydroxy aza-benzotriazole (HOAt). Other activators include HBTU, HATU, HCTU, TBTU, and PyBOP.
In synthetic step D, intermediate 5 is reacted with a molecule of formula RZNHz to create an amide bond and yield products of Formula 6. As with synthetic step C, the formation of the amide bond may be speeded up with an activator. An exemplary Synthetic Scheme is rated in In a fiarther aspect, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising stering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, and additional, different disclosed compound(s). In another embodiment, a method for treating a hepatitis B ion in a patient in need thereof is provided, sing administering to a subject or patient a therapeutically effective amount of a pharmaceutical ition comprising a disclosed compound, or two or more disclosed compounds.
For use in ance with this aspect, the appropriate dosage is expected to vary depending on, for example, the particular compound employed, the mode of administration, and the nature and severity of the infection to be treated as well as the specific ion to be treated and is within the w of the treating physician. Usually, an indicated administration dose may be in the range between about 0.1 to about 1000 ug/kg body weight. In some cases, the administration dose of the compound may be less than 400 ug/kg body weight. In other cases, the administration dose may be less than 200 ug/kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 ug/kg body weight. The dose may be conveniently administered once daily, or in divided doses up to, for example, four times a day or in sustained release form.
A compound may be administered by any conventional route, in particular: enterally, lly, orally, nasally, e.g. in the form of tablets or capsules, via suppositories, or parenterally, e.g. in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub- cutaneous, or intra-peritoneal injection. Suitable formulations and ceutical itions will include those formulated in a conventional manner using one or more physiologically [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting. Thus, the compounds may be formulated for oral, buccal, topical, eral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally).
For oral administration, pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, nylpyrrolidone or hydroxypropyl methylcellulose); fillers (e. g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e. g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch late); or g agents (e.g. sodium lauryl sulphate).
Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable e before use.
Such liquid preparations may be prepared by tional means with pharmaceutically acceptable additives such as suspending agents (e. g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e. g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). Preparations may also contain buffer salts, flavoring, ng and sweetening agents as appropriate.
Preparations for oral administration may also be ly formulated to give lled-release or sustained release of the active compound(s) over an extended period. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan.
A disclosed compound may also be formulated for parenteral administration by injection e.g. by bolus injection or continuous on. Formulations for injection may be presented in unit dosage form e.g. in es or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, ons or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or sing agents. Alternatively, the nd may be in powder form for constitution with a [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson suitable which: tag. sterile pymgewfree watm befora USS. Compounds may aisw be farmulatsd {by rests} administxa'itian as suppositories 01' ion enemas, ago cantaining cem'entionai suppesiiery bases such as cocoa Butts: or Omar glycsridcsu f {WWW} in same cases; a disclosed compomad may be. administémd as part. ofa combination therapy in can}tmctienwfih me or mare: amivirais. Example rals insiuds nudsoside analogs, inierfanm up, and othfir assembly effecmrsj, fer instance: heiamaryidihydmpyrinfidims (HAPS) such as methyl 4%Zach}0m~4mflumopheny'D—6~mefi1y1w2~fipyridin~2~yi}»1 ,4~ Vdihydmpyfimidimfi~carb0xylats {ii-{ARE}. For exampiée, provided herein is a method. tfiag satiem ng fmm hepatitis B c-Ompfismg administefing to a subject a first muslin: Ofa disclosed. campmnfi and a, sacend ammmt cf an antiviral 0r ether anti HB‘V agent, far sxampie at 51 magmas of a sscond campaund sslected fiom the gimp censisfing of: amethcr HBV, caspid assembly pmmmger (such as cartain compmmds sed hammer-for example, €321,554, BAY 4145109, A3133, DVRQB (6.3,), as depicted beiiow), NVR 35778, Z‘WRIZZl (by (30:16); and N890 (as dfipictsd balow}; when" CpAMs such as thész: discyiesed in the fafilowing patent applications hereby rasad by resistance:EVQ2€3E4€33748£L W{329141 84328, W02013065394, WGZGMGSfiQé, WOZGHIOGOI9, WOZGEBIOEGSS, WOZOMIMSSO,‘ W020141843653 MSSS, "702014131847, WO2OE4033176, "702014033167, and ‘WQ2034033170; N'uclsosids anaiegs mtcficring with final pa?yrnemse, such as entecavir (Baraciuds), Lami‘mdine, (Epivir—EfifiV), 'I‘slbiwdine {Tymks Sabivo), Adsfovir dipi‘mxil {Hepssra}, Tcnoibvir }? Tenoibvi: D 30 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson alafenamide filmam 8 {TAP}: prodmgs oftenofavir (fig. AGX~10©9), L~FMAU {Ciewdfinfi}, 1380380 (Besfibvir) and: Pu"...
Nita": "AER 0% 4 L >’ G H N" '95 Q A 3i a» {2—H} x E ,3 ,§3\ ' :7; OWXQ R!,x‘ xx J, 2...): ,1" viral entry inhibitors. such. as Myrciudex B and d iéipopaptide tives; HBsAg smretien inhibitors such as RE? 9A0 and related c acid~bascd aihic 1::01j,v‘mers2 HEROES , {PBHBV"001): PBEBV—Z-E :5 as depicted belew: : ‘; "ANNE! xvi/"14X "‘3"? 232PBHEV~2~15 : _ ’ ' and BMfim as depicted belawz‘ _ ‘ ",ng 2,.....m.,\ ),:--—-\ ‘ . ,, ‘\-. f "-. (23.1% .: ’9 "f ‘,. >_. 4:; \> ‘ \" 2/ K -~ é/ 1" car/DNA ibmatim inhibi‘i'omi such as BSBEQS, (ICC—0346, CCCuOWS (as depicted 'belsw): EB g; r/‘Nxfiern: 1"§"x.(fl\ g N": i‘g Ca 3,; ‘i H ' NJ"; " $~~,\§‘j‘ "RR «*flkk .9» Mi g; g ' y {:3 L\{/’j‘\$(v [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core n inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at //dx.doi.org/l0.1016/j.intimp.2015.01.028; antiviral core protein mutant (such as Cpl 83-Vl24W and related mutations as described in WO/2013/010069, WO2014/074906 each incorporated by reference ); inhibitors of HBX-interactions such as RNAi, antisense and nucleic acid based polymers targeting HBV RNA;, e. g., RNAi (for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid based polymer: (REP 2l39-Ca); immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), Pegylated IFN 2b, IFN lambda la and PEG IFN lambda la, Wellferon, Roferon, en, lymphotoxin beta agonists such as CBEll and BSl); Non- Interferon Immune enhancers such as Thymosin alpha-l (Zadaxin) and eukin-7 (CYT107); TLR—7/9 agonists such as GS-9620, CYT003, imod; Cyclophilin Inhibitors such as NVP018; OCB-030; SCY-635; Alisporivir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, Core n vaccine; SMAC mimetics such as birinapant and other IAP-antagonists; Epigenetic modulators such as KMT inhibitors (EZHl/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. OICR-9429), PARP inhibitors, APE inhibitors, DNMT tors, LSDl inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists; kinase inhibitors such as TKBl antagonists, PLKl inhibitors, SRPK tors, CDK2 inhibitors, ATM & ATR kinase inhibitors; STING Agonists; Ribavirin; N—acetyl cysteine ; 5 (BAM205); Nitazoxanide (Alinia), Tizoxanide; SB 9200 Small Molecule c Acid Hybrid (SMNH); ; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, eutic proteins, gene therapy, and biologics directed against viral components or interacting host proteins.
In some embodiments, the first and second amounts together comprise a ceutically effective amount. The first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies.
Therapeutically effective amounts of a disclosed compound and antiviral may be co- stered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of a disclosed compound first, for example one or more [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination y.
In another embodiment, a disclosed compound may be conjugated (e. g., covalently bound directly or through molecular linker to a free , nitrogen (e. g. an amino group), or oxygen (e. g. an active ester) of a disclosed compound), with a detection moiety, e.g. a fluorophore moiety (such a moiety may for example re-emit a n light frequency upon binding to a virus and/or upon photon excitation. Contemplated fluorophores include AlexaFluor® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, rbocyanine, anthraquinones, cent proteins, aminocoumarin, methoxycoumarin, hydrooxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated to a detection moiety may be used in e.g. a method for detecting HBV or biological pathways ofHBV infection, e. g., in vitro or in viva; and/or methods of assessing new compounds for biological activity.
EXAMPLES ] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, on of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of c synthesis that the functionality t on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction ions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting als for the examples are either cially available or are readily prepared by standard methods from known materials.
Exam le 1: S nthesis of 11-0x0-10 11-dih drodibenzo b 1 4 thiaze inecarb0x lic acid 16) - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (ICOzMe 02N SH F 002MB CL 002Me COzH CEQ002H NH CDI S 3 THF: H20 THF 3UCOZH NH2 NH2 4 5 6 Synthesis of methyl 4-((2-(meth0xycarb0nyl) phenyl) thio)nitr0benzoate (3): COZMe [:1 COZMe S ; To a stirred solution of methyl 4-fluoronitrobenzoate 2 (30 g, 150.67 mmol) in DMF (300 mL) under inert atmosphere were added cesium carbonate (58.76 g, 180.8 mmol) and methyl 2-mercaptobenzoate 1 (22.6 mL, 165.47 mmol) at RT; heated to 55-60 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was d with water (1500 mL) and the precipitated solid was filtered to obtain the crude. The crude was washed with water (500 mL), hexane (200 mL) and dried in vacuo to afford compound 3 (48.8 g, 93%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H NMR (CDC13, 400 MHz): 8 8.85 (s, 1H), 7.99-7.92 (m, 2H), .56 (m, 3H), 6.93 (d, J: 8.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H).
Synthesis of methyl 0((2-(meth0xycarb0nyl) phenyl) thio) benzoate (4): COZMe (:1 COZMe s’ ; To a stirred solution of compound 3 (48 g, 138.32 mmol) in MeOH (1000 mL) under [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson inert atmosphere was added 10% Pd/C (20 g, wet) at RT under hydrogen atmosphere in an autoclave (100 psi pressure) and stirred for 24 h. The reaction was monitored by TLC; after completion of the on, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2C12 (500 mL). The filtrate was removed in vacuo to obtain the crude which as triturated with diethyl ether (200 mL), washed with hexane (200 mL) and dried in vacuo to afford compound 4 (40 g, 91%) as yellow solid. TLC: 10% EtOAc/ s (Rf: 0.3); 1H NMR (DMSO-dg, 400 MHz): 5 7.95 (dd, J: 7.8, 1.4 Hz, 1H), 7.48-7.35 (m, 3H), 7.23 (td, J: 7.5, 1.1 Hz, 1H), 7.15 (dd, J: 8.0, 1.8 Hz, 1H), 6.66 (dd, J: 8.2, 0.8 Hz, 1H), 5.67 (br s, 2H), 3.88 (s, 3H), 3.84 (s, 3H).
Synthesis of 0((2-carb0xyphenyl) thio) benzoic acid (5): : :CozH c02H S ; To a stirred solution of compound 4 (40 g, 126.18 mmol) in THF: H20 (5: 1, 400 mL) was added lithium ide monohydrate (26 g, 619.0 mmol) at 0 0C; warmed to RT and d for 48 h. The on was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~2. The precipitated solid was filtered and dried in vacuo to afford compound 5 (34.6 g, 95%) as an off-white solid.
TLC: 30% EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-dg, 500 MHz): 8 13.00 (br s, 2H), 7.93 (dd, .1: 7.7, 1.0 Hz, 1H), 7.42 (s, 1H),7.40-7.31 (m, 2H), 7.18 (t, .1: 7.4 Hz, 1H), 7.13 (dd, .1: 8.0, 1.6 Hz, 1H), 6.61 (d, .1: 7.8 Hz, 1H), 5.55 (br s, 2H).
Synthesis of 11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—S-carboxylic acid (6): sDcozH [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson ] To a stirred solution of compound 5 (31 g, 107.26 mmol) in THF (600 mL) under inert atmosphere was added CD1 (86.88 g, 536.29 mol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 2 N HCl to pH~4. The obtained solid was filtered and fiarther dried by using toluene (2 x 200 mL) to afford compound 6 (26 g, 90%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H NMR (DMSO-dg, 400 MHz): 5 13.22 (br s, 1H), 10.81 (s, 1H), 7.78 (s, 1H), .64 (m, 3H), 7.57-7.44 (m, 3H).
Exam le 2: S nthesis of 2-chlor00x0-10 11-dih drodibenzo b 1 4 thiaze ine carbox lic acid 14 - a common intermediate \ 0"" CIUCN o s CIUCN TFA —> —> CIUCN F 032003, DMF s’PMB SH 7 9 10 FQ002Me CI CN COZMe CI Fe/AcOH 002Me —> r1 —> S UCN S Cszcog, DMF N02 NH2 11 12 sis of 5-chlor0((4-meth0xybenzyl) thio) itrile (9): CluCN,PMBS To a stirred solution of 5-chlorofluorobenzonitrile 7 (1 g, 6.41 mmol) in DMF (10 mL) under inert atmosphere was added cesium carbonate (2.30 g, 7.05 mmol) at RT; heated to [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 40 0C and to this was added (4-methoxyphenyl) methanethiol 8 (1.08 g, 7.05 mmol); heated to 60 0C and stirred for 2 h. The reaction was red by TLC; after completion of the reaction, the reaction e was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% EtOAc/ hexanes to afford compound 9 (1 g, 54%) as white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.6); 1H-NMR (CDC13, 500 MHz): 8 7.57 (s, 1H), 7.39 (d, J: 8.0 Hz, 1H), 7.28-7.27 (m, 1H), 7.20 (d, J: 9.0 Hz, 2H), 6.81 (d, J: 9.0 Hz, 2H), 4.15 (s, 2H), 3.78 (s, 3H). sis of 5-chlor0mercapt0benz0nitrile (10): CIUCNSH ] A stirred solution of nd 9 (1 g, 3.47 mmol) in trifluoro acetic acid (10 mL) under inert atmosphere was stirred at 70 0C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were d in vacuo to obtain the crude compound 10 (590 mg) which was carried to the next step without further purification. TLC: 30% EtOAc/ s (Rf: 0.2); 1H-NMR(CDC13, 500 MHZ): 5 7.57 (s, 1H), 7.41 (d, J: 9.0 Hz, 1H), 7.34 (d, J: 9.0 Hz, 1H), 4.08 (s, 1H).
Synthesis of methyl 4-((4-chlor0cyan0phenyl) thio)—3-nitr0benzoate (11): CIUCN COzMe s’ ; To a stirred solution of compound 10 (620 mg, 3.11 mmol) in DMF (10 mL) under inert atmosphere was added cesium carbonate (1.1 g, 3.42 mmol) at RT; heated to 40 0C and stirred for 10 min. To this was added methyl 4-fluoronitrobenzoate 2 (582 mg, 3.42 mmol) at 60 0C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson obtain the crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ hexanes to afford compound 11 (600 mg, 55%) as pale yellow solid. TLC: 30% EtOAc/ s (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz): 8 8.66 (s, 1H), 8.33 (s, 1H), 8.05-8.03 (m, 1H), 7.98-7.92 (m, 2H), 7.02 (d, J: 8.4 Hz, 1H), 3.86 (s, 3H).
Synthesis of methyl 3-amin0((4-chlor0cyan0phenyl) thio) benzoate (12): CIUCN31?COZMe To a stirred solution of compound 11 (450 mg, 1.29 mmol) in acetic acid (15 mL) under inert atmosphere was added iron powder (724 mg, 12.9 mmol) at RT; heated to 90 0C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was d with saturated NaHC03 on (15 mL) and extracted with CH2C12 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and trated in vacuo to obtain the crude. The crude was triturated with 3% EtOAc/ hexanes (2 x 5 mL) to afford compound 12 (290 mg, 70%) as pale yellow solid.
TLC: 20% MeOH/ CH2C12 (Rf: 0.7); 1H-NMR (DMSO-dg, 400 MHz): 5 8.05 (s, 1H), 7.63-7.60 (m, 1H), 7.48 (s, 1H), 7.43 (d, J: 8.0 Hz, 1H), 7.14 (d, J: 8.8 Hz, 1H), 6.75 (d, J: 8.8 Hz, 1H), .88 (s, 2H), 3.84 (s, 3H).
Synthesis of 2-((2-amin0carboxyphenyl) thio)-S-chlorobenzoic acid (13): CI ;HZNUCOZH c02H To a stirred solution of nd 12 (450 mg, 1.41 mmol) in MeOH (10 mL) was added potassium hydroxide (792 mg, 14.1 mmol) in water (3 mL) at 0 0C; heated to 90 0C and stirred for 9 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was acidified with l N HCl to pH~4.0. The obtained solid was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 13 (350 mg, 76%) as an off-white solid. TLC: 20% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson (DMSO-dg, 400 MHz): 8 12.92 (br s, 2H), 7.89 (s, 1H), 7.44-7.38 (m, 3H), 7.14 (d, .1: 8.8 Hz, 1H), 6.60 (d, .1: 8.8 Hz, 1H), 5.64 (br s, 2H).
Synthesis of 2-chlor00xo-10, ydrodibenzo [b,f] [1, 4] thiazepine ylic acid (14): sDCOZH To a stirred solution of compound 13 (30 mg, 0.09 mmol) in THF (2 mL) under inert atmosphere was added CD1 (45 mg, 0.27 mmol) at RT and stirred for 7 h. The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo. The residue was acidified with 2 N HCl to pH~4.0. The obtained solid was filtered, washed with ether (2 X 3 mL) and dried in vacuo to afford compound 14 (15 mg, 53%) as an off-white solid.
TLC: 15% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 5 13.05 (br s, 1H), 10.98 (s, 1H), 7.80 (s, 1H), 7.72-7.70 (m, 3H), 7.64 (s, 2H).
Exam le 3: S nthesis of 3-chlor00x0-10 11-dih drodibenzo b 1 4 thiaze ine carbox lic acid 21 - a common intermediate ON" CN C 8 TFA 082C03 DMF CI 8/ Cl SH CSzCOg, DMF fiCN 17 COgMe 002Me Fe/AcOH :QC8% Aq. KOH QQ : —> CI 8 MeOH, CI 8 CDI, THF [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 4-chlor0((4-meth0xybenzyl) thio) benzonitrile (16): CI 8 To a stirred on of 4-chlorofiuorobenzonitrile 15 (1 g, 6.41 mmol) in DMF (25 mL) under inert atmosphere was added cesium carbonate (2.30 g, 7.05 mmol) at RT; heated to 40 0C and to this was added (4-methoxyphenyl) methanethiol 8 (1.08 g, 7.05 mmol); heated to 60 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was d with water (20 mL) and ted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4% EtOAc/ hexanes to afford compound 16 (900 mg, 48%) as white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.6); 1H-NMR , 400 MHZ): 5 7.51 (d, J: 8.4 Hz, 1H), 7.33 (s, 1H), 7.23- 7.20 (m, 3H), 6.84 (d, J: 8.4 Hz, 2H), 4.19 (s, 2H), 3.79 (s, 3H).
Synthesis of 4-chlor0mercaptobenzonitrile (17): £16" CI SH A stirred solution of compound 16 (900 mg, 3.11 mmol) in trifluoro acetic acid (10 mL) under inert atmosphere at RT was heated to 70 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude nd 17 (527 mg) as brown solid. The crude was carried to the next step without further purification. TLC: 5% MeOH/ CH2C12 (Rf: 0.1); 1H-NMR (CDC13, 400 MHZ): 5 7.52 (d, J: 8.4 Hz, 1H), 7.41 (s, 1H), 7.22-7.19 (m, 1H), 4.13 (s, 1H).
Synthesis of methyl 4-((5-chlor0cyan0phenyl) thio)nitr0benzoate (18): gm COZMe CI 8’ ; [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson To a stirred solution of compound 17 (550 mg, 2.76 mmol) in DMF (15 mL) under inert here was added cesium carbonate (988 mg, 3.04 mmol) at RT; heated to 40 0C and stirred for 10 min. To this was added methyl 4-fluoronitrobenzoate 2 (515 mg, 3.04 mmol) at 60 0C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL). The obtained solid was filtered, washed with 15% EtOAc/ hexanes (2 x 5 mL) and dried in vacuo to afford compound 18 (700 mg, 73%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.3); 1H-NMR dg, 500 MHz): 8 8.69 (s, 1H), 8.18-8.15 (m, 2H), 8.10 (d, J: 8.5 Hz, 1H), 7.92 (d, J: 8.5 Hz, 1H), 7.10 (d, J: 9.0 Hz, 1H), 3.90 (s, 3H). sis of methyl 3-amin0((5-chlor0cyan0phenyl) thio) benzoate (19): gm COgMe CI 3’ : To a stirred solution of compound 18 (700 mg, 2.01 mmol) in acetic acid (15 mL) under inert here was added iron powder (1.12 g, 20.11 mmol) at RT; heated to 90 0C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were d in vacuo. The residue was basif1ed with 10% NaHC03 solution (20 mL) and extracted with CH2C12 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 19 (500 mg, 78%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.8); 1H-NMR (DMSO-dg, 500 MHz): 8 7.92 (d, J: 7.5 Hz, 1H), 7.51-7.43 (m, 3H), 7.17 (d, J: 8.0 Hz, 1H), 6.66 (s, 1H), 5.96 (s, 2H), 3.86 (s, 3H).
Synthesis of amin0carboxyphenyl) thio)chlor0benz0ic acid (20): £1 E) CI 8 To a stirred solution of compound 19 (500 mg, 1.57 mmol) in MeOH (6 mL) was [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson added potassium hydroxide (1.32 mg, 23.5 mmol) in water (6 mL) at 0 0C; heated to 90 0C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was d with water (20 mL) and ted with EtOAc (2 x 25 mL). The aqueous layer was acidified with 1 N HCl to pH~6.0. The obtained solid was filtered, washed with ether (2 x 7 mL) and dried in vacuo to afford compound 20 (375 mg, 74%) as an off-white solid. TLC: 20% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (CDC13, 400 MHz): 8 8.05 (d, J: 8.4 Hz, 1H), 7.55-7.47 (m, 3H), 7.17-7.14 (m, 1H), 6.67 (s, 1H).
Synthesis of r00x0-10, ydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xylic acid (21): 3D/cozH To a stirred solution of compound 20 (375 mg, 1.16 mmol) in THF (10 mL) under inert atmosphere was added CDI (564 mg, 3.48 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo.
The e was diluted with water (15 mL) and acidified with 6 N HCl to pH~1.0. The obtained solid was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 21 (285 mg, 81%) as an off-white solid. TLC: 20% MeOH/ CH2C12 (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz): 5 14.56 (br s, 2H), 10.90 (s, 1H), 9.11 (s, 1H), 7.71-7.65 (m, 4H).
Exam le 4: S nthesis of 1-flu0r00x0-10 11-dih drodibenzo b 1 4 thiaze ine carboxylic acid 128) - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson dime COZMe COzMe %Pd/C —> cowe—> C52C03 DMF ’ :2 M60" F;28’ Synthesis of methyl 2-flu0r0((4-meth0xybenzyl) thio) te (23): CESPMB002Me To a stirred solution of methyl 2, 6-difluorobenzoate 22 (10 g, 58.13 mmol) in DMF (100 mL) under inert atmosphere were added (4-methoxypheny1) ethiol 8 (8.96 g, 58.13 mmol), cesium carbonate (20.8 g, 63.95 mmol) at 0 0C; warmed to 10 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was diluted with water (200 mL) and extracted with EtOAc (2 x 800 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.
The crude was purified through silica gel column tography using 10-15% EtOAc/ hexanes to afford nd 23 (7.5 g, 42%) as white solid. TLC: 10% EtOAc/ hexanes(Rf: 0.3); 1H NMR (DMSO-dg, 400 MHz) 8 7.53-7.44 (m, 1H), 7.35 (d, J: 8.0 Hz, 1H), 7.26 (d, J: 8.6 Hz, 2H), 7.15 (t, J: 9.0 Hz, 1H), 6.86 (d, J: 8.7 Hz, 2H), 4.22 (s, 2H), 3.72 (s, 3H), 3.33 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of methyl 2-flu0r0mercapt0benz0ate (24): CECOZMeSH A stirred solution of compound 23 (7.5 g, 24.5 mmol) in ro acetic acid (100 mL) at RT under inert atmosphere was heated to 60-65 0C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed and dried in vacuo to obtain compound 24 (4.6 g) as brown syrup. The crude was carried forward for next step without further purification. TLC: 10% EtOAc/ hexanes (Rf: 0.7).
Synthesis of methyl 2-flu0r0((4-(meth0xycarb0nyl)—2-nitrophenyl) thio) benzoate (25): iC:OZMe 002Me s’ ; To a stirred solution of methyl 4-fluoronitrobenzoate 2 (4.5 g, 22.61 mmol) in DMF (100 mL) under inert atmosphere were added compound 24 (4.6 g, crude), cesium carbonate (11 g, 33.91 mmol) at RT; heated to 60-65 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the on, the on mixture was diluted with water (600 mL) and stirred for 1 h. The precipitated solid was filtered, titurated with 10% EtOAc/ hexanes(2 x 20 mL) and dried in vacuo to afford compound 25 (7 g, 85%) as yellow solid. TLC: % EtOAc/ hexanes (Rf: 0.3); 1H NMR dg, 400 MHz): 8 8.65 (s, 1H), 8.08 (dd, J = 8.6, 1.9 Hz, 1H), 7.79-7.72 (m, 1H), 7.67-7.61 (m, 2H), 7.01 (d, J: 8.6 Hz, 1H), 3.88 (s, 3H), 3.72 (s, 3H).
Synthesis of methyl 2-((2-amin0(methoxycarbonyl) phenyl) thio)flu0r0benz0ate (26): @6021" COZMe s’ ; [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson To a stirred solution of compound 25 (7.09 g, 19.17 mmol) in MeOH (200 mL) under inert atmosphere was added 10% Pd/ C (3.5 g) at RT and stirred under hydrogen at 80 psi for 16 h in an autoclave. The reaction was monitored by TLC; after completion of the on, the on mixture was d through celite and washed with 40% MeOH/ CH2C12 (3 X 500 mL).
The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was triturated with 20% EtOAc/ hexanes (200 mL) and dried in vacuo to afford compound 26 (5 g, 78%) as an ite solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHZ): 5 7.45-7.36 (m, 3H), 7.19-7.11 (m, 2H), 6.68 (d, J: 7.7 Hz, 1H), 5.71 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H).
Synthesis of 2-((2-aminocarboxyphenyl) thio)—6-flu0r0benz0ic acid (27): ofo"; To a stirred solution of compound 26 (5 g, 14.92 mmol) in THF: H20 (5: 1, 90 mL) was added lithium hydroxide monohydrate (3.13 g, 74.62 mmol) at RT and stirred for 16 h and heated to 80 0C for 5 h. The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (200 mL) and acidified with 2 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford nd 27 (4 g, 87%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-dg, 400 MHz): 5 12.89 (br s, 1H), 7.42-7.36 (m, 2H), 7.35-7.31 (m, 1H), 7.14 -7.08 (m, 2H), 6.63 (d, J: 8.0 Hz, 1H), 5.75 (br s, 2H).
Synthesis of 1-flu0r00x0-10, ydr0dibenz0 [b,f] [1, 4] thiazepine-S-carboxylic acid (28): sD/COZH To a stirred solution of compound 27 (4 g, 13.02 mmol) in THF (100 mL) under inert [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson atmosphere was added CD1 (10.56 g, 65.1 mmol) at RT and stirred for 26 h. The reaction was monitored by TLC; after completion of the reaction, the les were removed in vacuo. The residue was diluted with ice cold water (80 mL) and acidified with 2 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 28 (3.3 g, 88%) as an off- white solid. TLC: 15% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 8 13.33 (br s, 2H), 11.00 (s, 1H), 7.77 (s, 1H), 7.69-7.67 (m, 2H), 7.53-7.47 (m, 1H), .39 (m, 1H), 7.35-7.29 (m, 1H).
Exam le 5: S nthesis of 2-flu0r00x0-10 11-dih drodibenzo b 1 4 thiaze ine—8- carbox lic acid 35 - a common intermediate F COZMe W1 8 0/ U F CSzCOsyDMF /\©\ /—> 29 30 002Me 002Me COzMe 002Me C02H Fsm/Q/ —>FS\©L/©/1O%Pd/C COZH LiOH. H20 CDITHF MeOH _>FS\©L©THF 33 34 Synthesis of methylflu0r0((4-meth0xybenzyl) thio) benzoate (30): FUCOZMe 8/00/ To a stirred solution of methyl 2, 5-difluorobenzoate 29 (1 g, 5.80 mmol) in DMF (20 mL) under argon atmosphere were added (4-methoxyphenyl) methanethiol 8 (985 mg, 6.39 mmol), cesium carbonate (2.07 g, 6.39 mmol) at RT and stirred for 3 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (30 mL) and extracted with CH2C12 (2 x 30 mL). The ed organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford nd 30 (700 mg, 40%) as white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H-NMR(CDC13, 400 MHz): 8 7.64-7.61 (m, 1H), .29 (m, 3H), 7.17-7.09 (m, 1H), 6.86-6.82 (m, 2H), 4.09 (s, 2H), 3.90 (s, 3H), 3.79 (s, 3H).
Synthesis of methyl 5-flu0r0mercapt0benz0ate (31): FUCOZMe A stirred solution of compound 30 (700 mg, 2.28 mmol) in trifluoro acetic acid (7 mL) at RT under argon atmosphere was heated to 60-65 0C and d for 5 h. The on was monitored by TLC; after completion of the reaction, the volatiles were removed and dried in vacuo to obtain compound 31 (380 mg, 89%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.7); 1H-NMR (DMSO-dg, 400 MHz): 8 .58 (m, 2H), 7.42-7.35 (m, 1H), 5.42 (s, 1H), 3.86 (s, 3H).
Synthesis of methyl 5-flu0r0((4-(meth0xycarb0nyl)—2-nitrophenyl) thio) benzoate (32): COZMe Fm 002Me s’ ; To a stirred solution of methyl 4-fluoronitrobenzoate 2 (350 mg, 1.75 mmol) in DMF (10 mL) under argon atmosphere were added compound 31 (360 mg, 1.93 mmol), cesium carbonate (1.14 g, 3.51 mmol) at RT; heated to 60-65 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with CH2C12 (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was ed through silica gel column chromatography using 7-10% EtOAc/ hexanes to afford compound 32 (500 mg, 78%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (DMSO-dg, 400 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson MHz): 5 8.64 (s, 1H), 8.04-8.02 (m, 1H), 7.83-7.79 (m, 2H), 7.64-7.59 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.71 (s, 3H).
Synthesis of methyl 2-((2-amin0(methoxycarbonyl) phenyl) 5-flu0r0benzoate (33): F COZMe : COzMe ‘s’ ; To a stirred solution of compound 32 (500 mg, 1.36 mmol) in MeOH (10 mL) under argon atmosphere was added 10% Pd/ C (300 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the on, the reaction mixture was filtered h celite and washed with 20% MeOH/ CH2C12 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, d and concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 8-10% EtOAc/ hexanes to afford compound 33 (300 mg, 66%) as pale yellow solid. TLC: 30% EtOAc/ hexanes(Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 8 7.78 (d, J = 9.6 Hz, 1H), 7.45-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.14 (d, J: 9.6 Hz, 1H), .65 (m, 1H), 5.70 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H).
Synthesis of 2-((2-aminocarboxyphenyl) 5-flu0r0benzoic acid (34): F CO2H : COZH \s’ ; To a stirred solution of compound 33 (300 mg, 0.89 mmol) in THF: H20 (5: 1, 6 mL) under argon atmosphere was added lithium hydroxide monohydrate (188 mg, 4.47 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL) and acidified with 6 N HCl to pH~4. The itated solid was filtered and dried in vacuo to afford compound 34 (180 mg, 66%) as white solid. TLC: 50% EtOAc/ hexanes(Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 12.99-12.96 (m, 2H), 7.69 (d, J: 6.8 Hz, 1H), 7.40 (t, J: 7.2 Hz, 2H), 7.29 (t, J: 7.2 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Hz, 1H), 7.13 (d, .1: 7.2 Hz, 1H), 6.64-6.61 (m, 1H), 5.64-5.61 (m, 2H).
Synthesis of 2-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xylic acid (35): sDcozH To a stirred on of compound 34 (180 mg, 0.58 mmol) in THF (10 mL) under argon atmosphere was added CD1 (284 mg, 1.75 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo.
The e was d with ice cold water (10 mL) and acidified with 6 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 35 (80 mg, 47%) as an off- white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 13.30 (br s, 1H), 10.93 (s, 1H), 7.70 (s, 1H), 7.67 (d, J: 7.6 Hz, 2H), 7.59 (t, J: 7.6 Hz, 1H), 7.48 (t, J: 7.6 Hz, 1H), 7.40-7.35 (m, 1H).
Exam le 6: S nthesis of 3-flu0r00x0-10 11-dih drodibenzo b 1 4 thiaze ine carboxylic acid 142) - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson COZMe TFA —> QCOZMe 032003, f)2C|2, SPMB F SH 1,4-Dioxane COzMe COZMe C02" <111 <111c02H THF H20 Cszcog, DMF OZH dew Synthesis of methyl 4-flu0r0((4-meth0xybenzyl) thio) benzoate (37): F/CESPMBCOzMe To a stirred solution of methyl 2-bromofluorobenzoate 36 (2 g, 8.58 mmol) in 1,4- dioxane (50 mL) under inert atmosphere were added (4-methoxypheny1) methanethiol 8 (1.58 g, .25 mmol), cesium carbonate (4.18 g, 12.80 mmol) at RT and purged under argon here for 30 min. To this was added Pd(dppf)2C12 (306 mg, 0.42 mmol); heated to 120 0C and stirred for 16 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7% EtOAc/ hexanes to afford compound 37 (1.6 g, 61%) as an off-white solid. TLC: 10% EtOAc/ hexanes(Rf: 0.4); 1H NMR(CDC13, 400 MHZ): 5 8.01 (dd, J: 8.7, 6.2 Hz, 1H), 7.34 (d, J: 7.9 Hz, 2H), 7.04 (dd, J: 10.3, 2.4 Hz, 1H), 6.88-6.80 (m, 3H), 4.09 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of methyl 4-fluoro-Z-mercaptobenzoate (38): F SH A d on of compound 37 (2.2 g, 7.18 mmol) in trifluoro acetic acid (30 mL) at RT under inert atmosphere was heated to 90 0C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain compound 38 (1.33 g, crude) as brown syrup. The crude was carried forward for next step without further purification. TLC: 10% EtOAc/ hexanes (Rf: 0.8).
Synthesis of methyl 4-flu0r0((4-(meth0xycarb0nyl)—2-nitrophenyl) thio) benzoate (39): COZMe £131?002%; 8] To a stirred solution of methyl 4-fluoronitrobenzoate 2 (1.29 g, 6.93 mmol) in DMF (50 mL) under inert atmosphere were added cesium carbonate (2.93 g, 9.01 mmol) and compound 38 (1.2 g, 6.03 mmol) at RT; heated to 55-60 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was d with water (20 mL), the precipitated solid was filtered to obtain the crude. The crude was washed with e (2 x 20 mL) and dried in vacuo to afford compound 39 (1.5 g, 68%) as yellow solid.
TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 8.63 (s, 1H), 8.13- 8.04 (m, 2H), 7.53-7.46 (m, 2H), 7.24 (d, J: 8.4 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H).
Synthesis of 2-((4-carb0xynitr0phenyl) thio)flu0r0benz0ic acid (40): C02H £181?COZH To a stirred solution of compound 39 (1.5 g, 4.10 mmol) in THF: H20 (4: 1, 20 mL) was added lithium hydroxide monohydrate (690 mg, 16.4 mmol) at RT, heated to 80 0C and [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~6. The itated solid was filtered and dried in vacuo to afford compound 40 (1.2 g, 86%) as an off- white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 13.46 (br s, 2H), 8.58 (s, 1H), 8.08-8.01 (m, 2H), 7.45-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.29 (d, J: 8.4 Hz, 1H).
Synthesis of 2-((2-amin0carboxyphenyl) thio)—4-flu0r0benz0ic acid (41): C02H 0] To a stirred solution of compound 40 (1.2 g, 3.56 mmol) in MeOH (50 mL) under inert atmosphere was added 10% Pd/ C (300 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was filtered through celite, washed with MeOH (20 mL). The e was removed in vacuo to obtain the crude which as triturated with 10% EtOAc/ n-pentane (50 mL) to afford compound 41 (1 g, 91%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 12.96 (br s, 2H), 8.06-8.02 (m, 1H), 7.46 (s, 1H), 7.40 (d, J: 8.0 Hz, 1H), 7.16 (d, J: 8.0 Hz, 1H), 7.07-7.02 (m, 1H), 6.24 (d, J: 8.0 Hz, 1H), 5.67 (br s, 2H).
Synthesis of 3-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine-S-carboxylic acid (42): 8Doom To a stirred solution of compound 41 (1 g, 3.25 mmol) in THF (30 mL) under inert atmosphere was added CD1 (1.61 g, 9.77 mmol) at RT and stirred for 16 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 2 N HCl to pH~4. The obtained solid was filtered, washed with water (20 mL), ether (2 x 5 mL) and [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson dried in vacuo to afford compound 42 (760 mg, 80%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 13.24 (br s, 1H), 10.83 (s, 1H), 7.78-7.74 (m, 2H), .66 (m, 2H), 7.47-7.44 (m, 1H), 7.35-7.30 (m, 1H).
Exam le 7: S nthesis of 4-flu0r00x0-10 11-dih drodibenzo b 1 4 thiaze ine—8- carbox lic acid 50 - a common intermediate COZMe 002Me 002Me 002Me o N2 Uco M2 e 0—s>200339 LiOHH20 F THF: H20 002" COZH FOS/O—COZH COOH COZMe T COzMe 002Me H2804 TFA MeOH C82C03, DMF SPMB SH Synthesis of methyl 2, 3-diflu0r0benz0ate (44): ; :COZMe F To a stirred solution of 2, 3-difluorobenzoic acid 43 (1 g, 6.28 mmol) in MeOH (10 mL) under inert atmosphere was added Conc. H2SO4 (5 mL) at 0 0C and heated to reflux for 36 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and pH adjusted to ~8 with ted sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic ts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 44 (800 mg, 74%) as an off-white solid. TLC: 40% EtOAc/ [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson hexanes (Rf: 0.8); 1H NMR dg, 500 MHz) 8 7.80 - 7.65 (m, 2H), 7.41-7.23 (m, 1H), 3.88 (s, 3H).
Synthesis of methyl 3-flu0r0((4-meth0xybenzyl) thio) benzoate (45): ; COZMe SPMB To a stirred solution of compound 44 (800 mg, 4.65 mmol) in DMF (10 mL) under inert atmosphere were added (4-methoxypheny1) methanethiol 8 (282 mg, 5.11 mmol), cesium carbonate (1.66 g, 5.11 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was diluted water (25 mL) and extracted with ether (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 45 (750 mg, 53%) as an off- white solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 500 MHz): 8 7.49-7.36 (m, 3H), 7.10 (d, J: 8.9 Hz, 2H), 6.79 (d, J: 8.9 Hz, 2H), 4.06 (s, 2H), 3.81 (s, 3H), 3.70 (s, 3H); Synthesis of methyl 3-flu0r0mercapt0benzoate (46): ; COgMe A d on of compound 45 (750 mg, 2.45 mmol) in trifluoro acetic acid (7 mL) at RT under inert atmosphere was heated to 70 0C and stirred for 2 h. The reaction was red by TLC; after tion of the reaction, the volatiles were removed in vacuo to obtain compound 46 (1.1 g, crude) as colorless liquid. The crude was carried forward for next step. TLC: 30% EtOAc/ hexanes (Rf: 0.8).
Synthesis of methyl 3-flu0r0((4-(meth0xycarb0nyl)—2-nitrophenyl) thio) benzoate (47): [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 002Me 002% F N02 To a stirred on of compound 46 (5.96 g, 3.20 mmol) in DMF (100 mL) under inert atmosphere were added methyl 4-fluoronitrobenzoate 2 (5.8 g, 2.91 mmol), cesium carbonate (10.41 g, 3.20 mmol) at RT; heated to 80 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (25 mL). The obtained solid was filtered, washed with hexane (2 x 10 mL) and dried in vacuo to afford compound 47 (7.8 g, 73%) as an pale yellow solid. TLC: 30% EtOAc/ hexanes(Rf: 0.5); 1H NMR (DMSO-dg, 500 MHz): 8 8.67 (s, 1H), 8.05 (dd, J: 8.7, 1.7 Hz, 1H), 7.94-7.75 (m, 2H), 7.73-7.67 (m, 1H), 7.00 (d, J: 8.4 Hz, 1H), 3.88 (s, 3H), 3.77-3.64 (m, 3H).
Synthesis of methyl 2-((2-amin0(methoxycarbonyl) phenyl) thio)—3-flu0r0benz0ate (48): 002Me $01?002Me F NH2 To a stirred solution of nd 47 (670 mg, 1.83 mmol) in MeOH (10 mL) under inert atmosphere was added 10% Pd/C (150 mg) at RT and stirred under hydrogen atmosphere (balloon re) for 12 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford compound 48 (500 mg, 81%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 5 7.58-7.50 (m, 2H), 7.48-7.41 (m, 1H), 7.33 (s, 1H), 7.04 (s, 2H), 5.59 (br s, 2H), 3.82 (s, 3H), 3.79 (s, 3H).
Synthesis of 2-((2-aminocarboxyphenyl) thio)—3-flu0r0benz0ic acid (49): ; C:02"; .002H F NH2 To a d solution of compound 48 (500 mg, 1.49 mmol) in THF: H20 (4: 1, 20 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson mL) was added m hydroxide monohydrate (376 mg, 8.95 mmol) at RT; heated to 80 0C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and washed with diethyl ether (2 x 25 mL). The aqueous layer was acidified with 2 N HCl to pH~4 and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude which was washed with diethyl ether (2 x 5 mL) and dried in vacuo to afford compound 49 (300 mg, 65%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-dg, 500 MHz): 8 12.68 (br s, 2H), 7.54-7.45 (m, 2H), 7.39-7.32 (m, 1H), 7.28 (s, 1H), 7.09-7.06 (m, 1H), .96 (m, 1H), 5.56 (br s, 2H); Synthesis of 4-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xylic acid (50): To a stirred solution of compound 49 (300 mg, 0.97 mmol) in THF (15 mL) under inert atmosphere was added CDI (474 mg, 2.92 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo.
The pH of the residue was ed with 4 N HCl to ~2. The obtained solid was filtered, washed with diethyl ether (2 x 5 mL) and dried in vacuo to afford compound 50 (150 mg, 53%) as an off-white solid. TLC: 15% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 400 MHz): 5 13.38 (br s, 1H), 10.92 (s, 1H), 7.79 (s, 1H), 7.75-7.66 (m, 2H), 7.55-7.46 (m, 3H).
Exam le 8: S nthesis of 7-flu0r00x0-10 11-dih drodibenzo b 1 4 thiaze ine ylic acid 155) - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of methyl 2-flu0r0((2-(methoxycarbonyl) phenyl) thio)nitr0benzoate (52): ©8136.02N OMe COOMe To a stirred solution of methyl 2, 4-difluoronitrobenzoate 51 (9.0 g, 41.45 mmol) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (6.97 g, 41.45 mmol), cesium carbonate (14.82 g, 45.60 mmol) at 0 0C; warmed to 10 0C and stirred for 2 h. The on was monitored by TLC; after completion of the reaction, the reaction e was diluted with water (800 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried under sodium sulfate, filtered and concentrated in vacuo to obtain the crude.
The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 52 (11 g, 73%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 8 8.69 (d, J: 6.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.81-7.69 (m, 3H), 6.60 (d, J: 11.5 Hz, 1H), 3.88 (s, 3H), 3.73 (s, 3H).
Synthesis of methyl 0flu0r0((2-(meth0xycarbonyl) phenyl) thio) benzoate (53): gsHzNfiOMeF COOMe [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson To a stirred solution of compound 52 (11 g, 30.13 mmol) in MeOH (400 mL) under inert atmosphere was added 10% Pd/ C (5 g) at RT and stirred under en atmosphere (balloon pressure) for 24 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with 30% MeOH/ CH2C12 (3 X 60 mL). The filtrate was removed in vacuo to afford compound 53 (6.5 g, 64%) as an ite solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 8 8.01-7.88 (m, 1H), 7.45-7.40 (m, 1H), 7.34-7.24 (m, 3H), 6.72 (dd, J: 8.2, 0.8 Hz, 1H), 5.51 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H).
Synthesis of 5-amin0((2-carb0xyphenyl) thio)—2-flu0r0benz0ic acid (54): (EsHZNIXKOHF COOH To a d solution of compound 53 (6.5 g, 19.4 mmol) in THF: H20 (4: 1, 90 mL) was added lithium hydroxide monohydrate (4 g, 97.01 mmol) at RT and stirred for 16 h. The reaction was red by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~4. The precipitated solid was filtered and dried in vacuo to afford compound 54 (4.5 g, 75.6%) as an off-white solid. TLC: % EtOAc/ hexane (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 5 13.19 (br s, 2H), 7.96 (dd, J = 7.7, 1.5 Hz, 1H), 7.39 (t, J: 7.3 Hz, 1H), 7.30 (d, J: 6.6 Hz, 1H), 7.27-7.20 (m, 2H), 6.68 (dd, J = 8.2, 0.7 Hz, 1H), 5.42 (br s, 2H). sis of 7-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine-S-carboxylic acid (55): To a stirred solution of compound 54 (4.5 g, 14.65 mmol) in THF (100 mL) under inert atmosphere was added CD1 (11.88 g, 73.28 mol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson was quenched with 2 N HCl to pH~4; the precipitated solid was filtered, dried in vacuo to afford compound 55 (3.5 g, 83%) as an off-white solid. TLC: 15% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 8 13.61 (br s, 1H), 10.75 (s, 1H), 7.74-7.65 (m, 2H), 7.59-7.45 (m, 4H).
Exam le 9: S nthesis of 7 9-diflu0r00x0-10 11-dih drodibenzo b 1 4 thiaze ine- 8-carb0x lic acid 62 - a Common Intermediate CESHCOOMe OMe 1—> 032003, DMF Pd/C LiOH. H20 MeOH THF: H20 COOH'42:?EEOH To 2, 4, 6-trifluorobenzoic acid 56 (15 g, 85.22 mmol) at 0 0C, filming nitric acid (20 mL) was added dropwise for 10 min; warmed to RT and d for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (500 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford nd 57 (20 g) as pale yellow liquid. TLC: 5% MeOH/ CH2C12 + 0.05 mL CH3COOH (Rf: 0.2); 1H NMR [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (DMSO-d6, 400 MHz): 5 14.12 (br s, 1H), 7.83 (td, .1: 10.5, 2.1 Hz, 1H). sis of methyl 2, 4, 6-trifluoronitr0benz0ate (58): F 0 F F To a stirred solution of compound 57 (20 g) in MeOH (200 mL) under argon atmosphere was added concentrated sulfuric acid (20 mL) dropwise for 20 min at 0 0C and heated to reflux for 48 h. The reaction was red by TLC; after tion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (500 mL) and extracted with EtOAc (4 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column tography using 5-8% EtOAc/ hexanes to afford compound 58 (14 g, 70% for 2 steps) as pale yellow syrup. TLC: 20% EtOAc/ hexane (Rf: 0.8); 1H NMR (DMSO-dg, 400 MHz): 5 7.88 (td, J: 10.6, 2.2 Hz, 1H), 3.93 (s, 3H).
Synthesis of methyl 2, 6-diflu0r0((2-(meth0xycarb0nyl) phenyl) thio)—3-nitr0benz0ate (59): ] To a stirred solution of compounds 58 (14 g, 59.57 mmol) in DMF (300 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (11.1 g, 66.07 mmol), cesium carbonate (38.77 g, 119.14 mmol) at 0 0C; warmed to RT and stirred for 2 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic ts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography to afford compound 59 (14.5 g, 64%) as yellow syrup. TLC: 10% EtOAc/ ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson hexanes (Rf: 0.2); 1H NMR (DMSO-dg, 500 MHZ): 5 7.98 (dd, J: 7.7, 1.3 Hz, 1H), 7.66-7.61 (m, 1H), 7.59-7.55 (m, 1H), 7.46 (d, J: 7.8 Hz, 1H), 7.19 (d, J: 9.3 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H).
Synthesis of methyl 3-amin0-2, 6-diflu0r0((2-(meth0xycarbonyl) ) thio) benzoate (60): To a stirred solution of compound 59 (18 g, 46.99) in MeOH (400 mL) under inert atmosphere was added Pd/C (9 g, 50% wet) at RT and stirred under hydrogen atmosphere in an autoclave (5 kg/cm2 pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (500 mL). The filtrate was trated in vacuo to afford compound 60 (15.1 g, 91%) as colorless semi solid.
TLC: 20% EtOAc/ hexanes (Rf: 0.5); 1H NMR (DMSO-ds, 500 MHz): 8 8.00-7.93 (m, 1H), 7.48-7.42 (m, 1H), .21 (m, 2H), 6.76-6.64 (m, 1H), 5.54-5.47 (m, 2H), 3.91 (s, 3H), 3.89 (s, 3H).
Synthesis of o((2-carboxyphenyl) thio)-2, 6-diflu0r0benz0ic acid (61): F o 656$HZN OH COOH To a stirred solution of compound 60 (15.1 g, 39.42 mmol) in THF: H20 (4: 1, 250 mL) was added lithium hydroxide monohydrate (8.3 g, 197.61 mmol) at RT and stirred for 16 h.
The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, d with water (100 mL) and washed with EtOAc (2 x 100 mL). The pH of the aqueous layer was acidified with 4 N HCl to ~4. The precipitated solid was d, washed with water (100 mL), pentane (100 mL). The obtained solid was further dried using toluene (150 mL) to afford compound 61 (11 g, 79%) as an off-white solid. TLC: 20% EtOAc/ [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson hexanes (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHZ): 5 13.24 (br s, 1H), 7.97 (dd, J: 7.7, 1.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.28-7.19 (m, 2H), 6.66 (d, J: 8.2 Hz, 1H), 5.39 (br s, 2H).
Synthesis of 7, 9-diflu0r0oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepinecarboxylic acid (62): To a stirred solution of compound 61 (10 g, 30.76 mmol) in THF (200 mL) under argon atmosphere was added CD1 (14.9 g, 81.97 mmol) at RT and stirred for 24 h. The on was monitored by TLC; after completion of the reaction, the volatiles were d in vacuo.
The e was diluted with water (300 mL) and the pH was adjusted to ~3 with 2 N HCl. The obtained solid was filtered, washed with water (100 mL), pentane (50 mL) and diethyl ether (150 mL) and dried in vacuo to obtain compound 62 (2.83 g, 30%) as brick red solid. TLC: 15% MeOH/ CH2C12 (Rf: 0.3); 1H NMR (DMSO-ds, 500 MHz): 8 14.19 (br s, 1H), 10.64 (s, 1H), 7.73-7.66 (m, 2H), 7.58- 7.48 (m, 3H).
Exam le 10: 2-meth0x 0x0-10 11-dih drodibenzo b 1 4 thiaze inecarb0x lic acid 170) - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson triflic "U anhydride COZMe \0 OH ne CS2C03 Pd(dppf)2C|2 1 4—dioxane 63 64 O2Nj©/COZ2Me/OF COZMe:©/002Me i}/O\©[:02Me 10% Pd/C MeOH CS2C03 DMF COZMe COZH LIOH. H2O CDI THF THF: H20 "as!" OSND/COZH 69 70 Synthesis of methyl 5-meth0xy(((trifluoromethyl) sulfonyl) oxy) benzoate (64): /o\©[c02Me To a stirred solution of methyl 2-hydroxymethoxybenzoate 63 (2 g, 10.97 mmol) in pyridine (8 mL) under inert atmosphere was added triflic anhydride (3.56 g, 12.62 mmol) at 0 0C; warmed to RT and stirred for 2 h; heated to 40 0C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (40 mL) and extracted with ether (3 x 40 mL). The combined organic extracts were washed with l N HCl (40 mL), water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified h silica gel column chromatography using 5-10% EtOAc/ hexanes to afford compound 64 (2.9 g, 85%) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf: 0.6); 1H-NMR (CDC13, 500 MHz): 8 7.50 (s, 1H), 7.09 (d, J: 7.5 Hz, 1H), 7.03 (d, J: 7.5 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H).
Synthesis of methylmeth0xy((4-meth0xybenzyl) thio) benzoate (65): [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson /oUSPMBCOgMe 0] To a stirred solution of compound 64 (500 mg, 1.59 mmol) in 1, 4-dioxane (10 mL) under inert atmosphere were added (4-methoxyphenyl) methanethiol 8 (270 mg, 1.75 mmol), cesium ate (1.035 g, 3.18 mol) at RT and degassed for 20 min. To this was added Pd(dppf)2C12 (29.1 mg, 0.039 mmol); heated to 110 0C and d for 10 h. The reaction was monitored by TLC; after completion of the reaction, the on mixture was d with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column tography using 10-15% EtOAc/ hexanes to afford compound 65 (280 mg, 55%) as pale yellow solid. TLC: 10% EtOAc/ hexanes(Rf: 0.4); 1H-NMR (CDC13, 500 MHz): 5 7.42 (s, 1H), 7.28-7.25 (m, 3H), 6.98 (d, J: 8.5 Hz, 1H), 6.84 (d, J: 8.5 Hz, 2H), 4.08 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H).
Synthesis of methyl 2-mercapt0meth0xybenzoate (66): /O\(:[C02MeSH A stirred solution of compound 65 (280 mg, 0.88 mmol) in trifluoro acetic acid (10 mL) at RT under inert atmosphere was heated to 70 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain compound 66 (170 mg, crude) as brown syrup. TLC: 10% MeOH/ CH2C12 (Rf: 0.8); 1H- NMR (DMSO-dg, 400 MHz): 5 7.68 (d, J: 8.0 Hz, 1H), 7.48 (d, J: 7.2 Hz, 1H), 7.39 (s, 1H), .13 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H).
Synthesis of methyl 5-meth0xy((4-(methoxycarb0nyl)nitr0phenyl) thio) benzoate (67): /O\©LCOzMe COZMG S ; [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson To a stirred solution of nd 66 (150 mg, 0.75 mmol) in DMF (5 mL) under inert atmosphere were added methyl 4-fiuoronitrobenzoate 2 (164 mg, 0.82 mmol), cesium ate (490 mg, 1.50 mmol) at RT; heated to 55-60 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was diluted with water (20 mL) and extracted with CH2C12 (2 x 30 mL). The combined c ts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15-25% EtOAc/ hexanes to afford compound 67 (200 mg, 70%) as yellow solid. TLC: 10% EtOAc/ hexanes(Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 8.64 (s, 1H), 8.02 (d, J: 8.4 Hz, 1H), 7.69 (d, J: 8.8 Hz, 1H), 7.59-7.54 (m, 1H), 7.31 (d, J: 8.8 Hz, 1H), 6.94 (d, J: 8.8 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.68 (s, 3H).
Synthesis of methyl 2-((2-amin0(methoxycarbonyl) phenyl) thio)—5-meth0xybenzoate (68): /o\ Synthesis of 2-((2-amin0carboxyphenyl) thio)—5-meth0xybenz0ic acid (69): ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson <11 1602"S To a stirred solution of compound 68 (120 mg, 0.34 mmol) in THF: H20 (4: 1, 5 mL) was added lithium hydroxide monohydrate (72.5 mg, 1.72 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The e was diluted with water (10 mL) and ed with 6 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 69 (80 mg, 73%) as an off- white solid. TLC: 40% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 12.99 (br s, 2H), 7.41 (d, J: 8.4 Hz, 2H), 7.35 (d, J: 7.6 Hz, 1H), 7.12 (d, J: 7.6 Hz, 1H), 7.01 (d, J: 8.8 Hz, 1H), 6.61 (d, J: 8.8 Hz, 1H), 5.54 (br s, 2H), 3.74 (s, 3H).
Synthesis of 2-meth0xy0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—8-carb0xylic acid (70): To a stirred solution of compound 69 (80 mg, 0.25 mmol) in THF (5 mL) under inert here was added CDI (122 mg, 0.75 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (10 mL) and acidified with 6 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 70 (40 mg, 53%) as an off-white solid.
TLC: 10% MeOH/ CH2C12 (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz): 5 13.15 (br s, 1H), 10.79 (s, 1H), 7.78 (s, 1H), 7.69-7.66 (m, 2H), 7.44-7.42 (m, 1H), 7.20-7.19 (m, 1H), 7.08-7.05 (m, 1H), 3.77 (s, 3H).
Exam le 11: 7-meth0x 0x0-10 11-dih drodibenzo b 1 4 thiaze inecarb0x lic acid 176] - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson CECOZMe O N2 flCO Me2 FOIVI/CEeco2Me HN03 o2N co2Me SH 1 10% Pd/C —> —> s OMe H SO2 4 F OMe C82C03, DMF MeOH 002Me 71 73 H2N 002MB COZH LiOH. H2o co2H S ome THF: H20 co2Hs 8 COZMe OMe 75 76 Synthesis of methyl 4-flu0r0meth0xynitr0benz0ate (72): flVIG F OMe To a stirred on of methyl 4-fluoromethoxybenzoate 71 (500 mg, 2.50 mmol) in sulfilric acid (1 mL) under inert atmosphere was added the mixture of nitric acid (0.125 mL), sulfuric acid (0.5 mL) at -5 0C and stirred for 10 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2C12 (2 x 30 mL). The combined organic extracts were washed with 10% NaHC03 solution (20 mL), dried over sodium sulfate, filtered and trated in vacuo to obtain the crude. The crude was triturated with diethyl ether (2 x 5 mL) to afford compound 72 (200 mg, 33%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (CDC13, 400 MHz): 8 8.69 (d, J: 8.8 Hz, 1H), 6.83 (d, J: 12.8 Hz, 1H), 4.01 (s, 3H), 3.92 (s, 3H).
Synthesis of methyl 2-meth0xy((2-(methoxycarbonyl) phenyl) thio)—5—nitr0benzoate (73): QsOzNflCOZMeOMe COZMG To a stirred solution of compound 72 (200 mg, 0.81 mmol) in DMF (4 mL) under [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson inert atmosphere were added methyl 2-mercaptobenzoate 1 (151 mg, 0.89 mmol), cesium carbonate (318 mg, 0.97 mmol) at RT; heated to 80 0C and stirred for 2 h. The reaction was monitored by TLC; after tion of the reaction, the reaction e was diluted with ice water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 73 (200 mg, 61%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (CDC13, 400 MHz): 8 8.80 (s, 1H), 7.94-7.92 (m, 1H), 7.70 (t, J: 8.0 Hz, 1H), 7.61-7.59 (m, 2H), 6.30 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.52 (s, 3H).
Synthesis of methyl 0meth0xy((2-(methoxycarbonyl) ) thio) benzoate (74): ; HZNKICOZMES OMe COZMe 8] To a stirred solution of compound 73 (200 mg, 0.53 mmol) in MeOH (15 mL) under inert atmosphere was added 10% Pd/C (100 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford nd 74 (110 mg, 60%) as yellow sticky solid. TLC: % EtOAc/ hexanes (Rf: 0.6); 1H-NMR(CDC13, 400 MHz): 8 7.99 (d, J: 8.0 Hz, 1H), 7.54 (s, 1H), 7.34-7.31 (m, 1H), 7.20 (t, J: 8.0 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J: 8.4 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.80 (s, 3H).
Synthesis of 5-amin0((2-carb0xyphenyl) thio)-Z-methoxybenzoic acid (75): ; H2N: Synthesis of 7-meth0xy0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—8-carb0xylic acid (76): sHoozH To a stirred on of compound 75 (70 mg, 0.21 mmol) in THF (2 mL) under inert atmosphere was added CD1 (106 mg, 0.65 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with ice water (15 mL), acidified with 6 N HCl, the obtained solid was filtered, washed with % EtOAc/ hexanes and dried in vacuo to afford compound 76 (40 mg, 61%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 12.88 (br s, 1H), .64 (s, 1H), 7.71-7.69 (m, 1H), 7.58-7.42 (m, 4H), 7.28 (s, 1H), 3.81 (s, 3H).
Exam le 12: S nthesis of 6-meth l0x0-10 11-dih enzo b 1 4 thiaze ine—8- carboxylic acid 182) - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson COzMe 002Me CE:02Me—> Pd/C LiOH. H20 C52C03 DMF 002M: MeOH CO©:Me THF: H20 KNO3 H2804: TFA Synthesis of methyl 4-br0m0methylnitr0benz0ate (78): 02NBr:©/002Me To a d solution of methyl omethy1benzoate 77 (500 mg, 2.18 mmol) in sulfuric acid: trifluoro acetic acid (1: 0.1, 6.6 mL) under inert atmosphere was added ium nitrate (231 mg, 2.29 mmol) at 0 0C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude nd 78 (540 mg, 95%) as yellow oil. TLC: 10% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz): 5 8.25 (s, 1H), 8.17 (s, 1H), 3.89 (s, 3H), 2.53 (s, 3H).
Synthesis of methyl 4-((2-(meth0xycarb0nyl) phenyl) thi0)methylnitr0benzoate (79): (piggcoflweCOM2 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson To a stirred solution of methyl 2-mercaptobenzoate 1 (575 mg, 2.18 mmol) in DMF (6 mL) under inert atmosphere were added cesium carbonate (1.42 g, 4.37 mmol), compound 78 (385 mg, 2.29 mmol) at RT; heated to 65 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was d with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined c extracts were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude. The crude was recrystallized using CH2C12: ane (1: 4, 5 mL) to afford compound 79 (120 mg, 16%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz): 5 8.32 (s, 1H), 8.24 (s, 1H), 7.63-7.59 (m, 1H), 7.49-7.45 (m, 1H), 7.23 (t, J: 8.0 Hz, 1H), 6.61 (d, J: 8.0 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.35 (s, 3H).
Synthesis of methyl 3-amin0((2-(meth0xycarb0nyl) ) thi0)methylbenz0ate (80): (23);}H2N COzMe COZMe To a stirred solution of compound 79 (200 mg, 0.55 mmol) in MeOH (5 mL) under inert atmosphere was added Pd/C (70 mg) at RT and stirred under hydrogen atmosphere for 6 h.
The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 80 (175 mg, 96%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.7); 1H-NMR (DMSO-dg, 400 MHZ): 5 7.96 (d, J: 7.6 Hz, 1H), 7.38- 7.31 (m, 2H), .20 (m, 1H), 7.14 (s, 1H), 6.56 (d, J: 8.0 Hz, 1H), 5.67 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.25 (s, 3H).
Synthesis of 3-amin0((2-carb0xyphenyl) thio)—5-methylbenz0ic acid (81): N C02H COZH To a stirred solution of compound 80 (160 mg, 0.48 mmol) in THF: H20 (3: 1.5, 4.5 mL) was added lithium hydroxide (118 mg, 2.90 mmol) at RT and d for 24 h; heated to reflux and stirred for 12 h. The reaction was monitored by TLC; after tion of the reaction, ation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson the volatiles were removed in vacuo. The residue was diluted with water (15 mL), filtered the itated solid and dried in vacuo to afford the crude compound 81 (140 mg, 96%) as an off- white solid. TLC: 30% EtOAc/ s (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 13.00 (br s, 2H), 7.95 (d, J: 8.0 Hz, 1H), 7.35-7.29 (m, 2H), 7.19 (t, J: 7.6 Hz, 1H), 7.13 (s, 1H), 6.54 (d, J: 8.0 Hz, 1H), 5.30 (br s, 2H), 2.25 (s, 3H).
Synthesis of 6-methyl0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—8-carb0xylic acid (82): To a stirred solution of compound 81 (140 mg, 0.46 mmol) in THF (5 mL) under inert atmosphere was added CD1 (375 mg, 2.31 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the les were removed in vacuo and neutralized with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford the crude compound 82 (120 mg, 91%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.4); 1H- NMR (DMSO-dg, 400 MHz): 8 13.05 (br s, 1H), 10.73 (s, 1H), 7.69-7.58 (m, 4H), 7.51-7.44 (m, 2H), 2.56 (s, 3H).
Exam le 13: S nthesis of 7-meth x0-10 11-dih drodibenzo b 1 4 thiaze ine—8- carboxylic acid 188) - a common intermediate ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Wilkinson 34 LiOH.H20 052003, DMF S THF:H20 COZMe NO2 02NJCE002H OZN COOH F F 84 (major) 89 Synthesis of 4-fluoro-Z-methyl-S-nitrobenzoic acid (84): OZNJCECOZH To a stirred solution of 4-fluoromethylbenzoic acid 83 (500 mg, 3.24 mmol) in concentrated ic acid (2.5 mL) under inert atmosphere was added potassium nitrate (655 mg, 6.49 mmol) at 0 0C; warmed to RT and d for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL), filtered the precipitated solid and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 84 (300 mg, 60%) as brown syrup. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 500 MHz): 5 1356 (br s, 1H), 8.52 (d, J: 8.0 Hz, 1H), 7.61 (d, J: 12.5 Hz, 1H), 2.63 (s, 3H).
Synthesis of 4-((2-(meth0xycarb0nyl) phenyl) thi0)methyl-S-nitrobenzoic acid (85): QS/Efi/COW COZMe N02 To a stirred solution of methyl 2-mercaptobenzoate 1 (5 14 mg, 3.08 mmol) in DMF (10 mL) under inert atmosphere were added cesium carbonate (1.81 g, 5.57 mmol), compound 1003594907 84 (560 mg, 2.78 mmol) at RT; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure.
The residue was d with water (20 mL) and pH was adjusted to ~2 with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford compound 85 (500 mg, 52%) as an off-white solid.
TLC: 5% MeOH/ CH2Cl2 (Rf: 0.4); 1H-NMR (DMSO-d 6, 400 MHz): δ 13.47 (br s, 1H), 8.59 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.68-7.60 (m, 3H), 6.83 (s, 1H), 3.72 (s, 3H), 2.40 (s, 3H). sis of (carboxyphenyl)thio)methylnitrobenzoic acid (86): To a stirred solution of compound 85 (500 mg, 1.45 mmol) in THF: H2O (2:1, 15 mL) was added lithium hydroxide monohydrate (300 mg, 7.31 mmol) at RT and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL), and pH was adjusted to ~2 with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford crude compound 86 (500 mg) as an off-white solid. TLC: 5% MeOH/ CH2Cl2 (Rf: 0.1); 1H-NMR (DMSO-d 6, 400 MHz): δ 13.51 (br s, 2H), 8.57 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), .58 (m, 2H), 7.53 (t, J = 8.0 Hz, 1H), 6.89 (s, 1H), 2.41 (s, 3H).
Synthesis of 5-amino((2-carboxyphenyl) thio)methylbenzoic acid (87): To a stirred on of compound 86 (500 mg) in MeOH (15 mL) under inert atmosphere was added Pd/ C (250 mg) at RT and stirred under hydrogen atmosphere for 16 h.
The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford crude compound 87 (430 mg) as an off-white solid. TLC: MeOH/ CH2Cl2 (Rf: 0.1); LC-MS: 84.24%; 304.5 (M++1); (column; X-Select CSH C-18, (50 × 3.0 mm, 3.5 µm); RT 3.75 min. 0.05% TFA (Aq): ACN; 0.8 mL/min). 4907 Synthesis of 7-methyloxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepinecarboxylic acid (88): To a stirred solution of compound 87 (430 mg) in THF (20 mL) under inert atmosphere was added CDI (1.15 g, 7.09 mmol) at RT and d for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and neutralized with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford the crude nd 88 (290 mg) as an off-white solid. TLC: 10% MeOH/ CH2Cl2 (Rf: 0.5); 1H-NMR (DMSO-d6, 500 MHz): δ 13.15 (br s, 1H), 10.68 (s, 1H), 7.69-7.68 (m, 2H), 7.67-7.44 (m, 4H), 2.44 (s, 3H).
Example 14: 9-methyloxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepinecarboxylic acid (97) - a common intermediate and Synthesis of 7-methyloxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepinecarboxylic acid (88) a common intermediate - Alternate Approach [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson +02:1—>:fi>/COOH 84 (major) 89 (minor) COZMG COZMG COZMG 082003, DMF 002""? 002Me 002" <1 C02H —> S THF 95 96 Synthesis of mixture of 4-fluoro-Z-methylnitr0benzoic acid (89) and 4-flu0r0methyl nitrobenzoic acid (84): COOH OgN COOH 84 ) 89 (minor) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson To a stirred solution of 4-fluoromethylbenzoic acid 83 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphere was added fuming nitric acid (50 mL) at RT and heated to 80 0C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered and dried in vacuo to afford e of compounds 84 and 89 (5.3 g, 40%) as white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 5 13.30 (br s, 2H), 8.52 (d, J = 8.0 Hz, 2H), 8.10 (dd, J: 8.9 5.9, Hz, 1H), 7.60 (d, J: 12.5 Hz, 2H), 7.56 (t, J: 9.3 Hz, 1H), 2.63 (s, 6H), 2.48 (s, 3H); (1H NMR showed mixture of compounds 84 and 89 in the ratio of 2: 1).
Synthesis of methyl 4-flu0r0methylnitr0benz0ate (91) and methyl 4-flu0r0methyl- -nitrobenz0ate (90): COzMe OZN COZMe F F 90 91 To a stirred solution of compound 84 and 89 (10 g) in MeOH (100 mL) under argon atmosphere was conc. sulfiJric acid (20 mL) at 0 0C and heated to reflux for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and ted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford e of compounds 90 & 91 (6 g) as colorless thick syrup. TLC: 30% EtOAc/ hexane (Rf: 0.5); 1H NMR (DMSO-ds, 500 MHz): 8 8.51 (d, J=7.8 Hz, 1H), 8.09 (dd, J: 8.8, 5.6 Hz, 0.5H), 7.63 (d, J: 12.4 Hz, 1H), 7.58 (t, J: 9.1 Hz, 0.5H), 3.87 (s, 4.5H), 2.62 (s, 3H), 2.45 (s, 15H); (1H NMR showed mixture of compounds 90: 91 in the ratio of 2: 1).
Synthesis of methyl 4-((2-(meth0xycarb0nyl) phenyl) 2-methyl—3-nitr0benzoate (93) and methyl 4-((2-(meth0xycarb0nyl) ) thio)—2-methylnitr0benzoate (92): COZMe 002Me COzMe COZMe or o S 8 N02 N02 92 93 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson To a stirred solution of compounds 90 and 91 (11 g) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (10.4 g, 61.97 mmol), cesium carbonate (18.5 g, 56.81 mmol) at 0 0C; heated to 80 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium e, filtered and concentrated in vacuo to afford a mixture of compounds 93 and 92 (12 g) as a yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.2); LC-MS: 12.57% + 81.14%; 370.8 (M++l); (column; X-Select CSH C18, (50 X 3.0 mm, 3.5 um); RT 2.77 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); RT 4.05, 4.14 min.
Synthesis of methyl 3-amin0((2-(meth0xycarb0nyl) phenyl) thi0)methylbenzoate (95) and Synthesis of methyl 5-amin0((2-(meth0xycarb0nyl) phenyl) thi0)methylbenzoate (94): 002Me COzMe 002m COZMe CL, (181:1 NH2 NH2 94 95 To a stirred solution of compound 93 and 92 (14 g, crude) in MeOH (500 mL) under inert atmosphere was added Pd/C (l .4 g, 50% wet) at RT and stirred under hydrogen atmosphere in an autoclave (6 kg/ cm2 pressure) for 18 h. The reaction was monitored by TLC; after tion of the reaction, the reaction mixture was filtered through , washed with MeOH (100 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was recrystallized with EtOH (20 mL) and further purified through silica gel column chromatography column chromatography using 10% EtOAc/ hexanes to afford compound 95 (3 g, 30%) and 94 (8 g, 63%) as sticky off-white solids. TLC: 30% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz) (95): 8 7.94 (d, J: 7.1 Hz, 1H), 7.40 (t, J: 7.3 Hz, 1H), 7.33-7.26 (m, 2H), 7.22 (dt, .1: 7.6, 1.1 Hz, 1H), 6.67 (dd, J: 8.2, 0.8 Hz, 1H), 5.41 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.33 (s, 3H). 1H NMR (DMSO-dg, 400 MHz) (94): 8 7.94 (dd, J: 7.8, 1.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.22 (td, J=7.5, 1.0 Hz, 1H), 6.67 (dd, J: 8.1, 0.8 Hz, 1H), 5.41 (s, 2H), 3.88 (s, 2H), 3.82 (s, 3H), 2.33 (s, 3H).
[Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 3-amin0((2-carb0xyphenyl) thi0)methylbenz0ic acid (96): C02H <1 IEM8 To a d solution of compound 95 (2 g, 6.04 mmol) in THF: H20 (4: 1, 50 mL) was added lithium hydroxide monohydrate (2.5 g, 10.0 mmol) at 0 0C; warmed to RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (10 mL) and washed with diethyl ether (2 x 50 mL). The pH of the s layer was acidified with 4 N HCl to ~1. The precipitated solid was filtered and dried in vacuo to afford compound 96 (1.2 g, 66%) as white solid. TLC: 20% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-ds, 400 MHz): 5 13.01 (br s, 2H), 7.94 (d, J: 7.4 Hz, 1H), 7.36 (t, J: 7.8 Hz, 1H), 7.28 (d, J: 8.0 Hz, 1H), 7.20 (dt, J: 7.4, 6.3 Hz, 1H), 6.95 (d, J: 8.0 Hz, 1H), 6.61 (d, J: 7.4 Hz, 1H), 5.25 (br s, 2H), 2.27 (s, 3H). sis of 9-methyl0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—8-carb0xylic acid (97): COzH To a stirred solution of compound 96 (2.6 g, 4.30 mmol) in THF (30 mL) under argon atmosphere was added CD1 (3.5 g, 21.50 mmol) at RT; heated to 80 0C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and pH was ed with 4 N HCl to ~2.
The obtained solid was filtered, washed with diethyl ether and dried in vacuo to obtain compound 97(1.6 g, 67%) as an off white solid. TLC: 15% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-d6, 400 MHz): 8 13.20 (br s, 1H), 10.23 (s, 1H), .60 (m, 1H), 7.56-7.51 (m, 2H), 7.50-7.42 (m, 3H), 2.47 (s, 3H).
Exam le 15: S nthesis of 3-carbam0 l0x0-10 11-dih drodibenzo b 1 4 thiazepinecarb0xylic acid (135) - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1:(:[:02Me\—>\SO/©/8\H /E6:[:02M: TFA MeOzC Pd(dppf)2C|2,052003, Me02C Me02C 1, ane /E7:[::2Me COZtBU C02M9 r1 COZ'BU COZMG COz'Bu N02 128 MeOZC S MeOZCr; MeOH —> N02 082C03, DMF 129 130 COZH I —', H020 3 051/394")OBU, I NH2 OB"I HATU, DIPEA DC Synthesis of yl 2-((4-meth0xybenzyl) thio) terephthalate (126): ,PMB MeOZC s To a stirred solution of dimethyl 2-bromoterephthalate 125 (l g, 3.66 mmol) in l, 4- dioxane (50 mL) under inert atmosphere were added (4-methoxyphenyl) methanethiol 8 (620 mg, 4.02 mmol), cesium carbonate (2.38 g, 7.32 mmol), Pd(dppf)2C12 (67 mg, 0.09 mmol) at RT and stirred under argon for 30 min; heated to 110 0C and d for 20 h in a sealed tube. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.
The crude was d through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 126 (680 mg, 54%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (CDCI3, 500 MHz): 8 8.06 (s, 1H), 7.99 (d, J: 8.5 Hz, 1H), 7.77 (d, J: 8.0 Hz, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.34 (d, .1: 8.5 Hz, 2H), 6.85 (d, .1: 8.5 Hz, 2H), 4.18 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.79 (s, 3H).
Synthesis of dimethyl 2-mercapt0terephthalate (127): MeOZC SH A stirred solution of compound 126 (1.47 g, 4.24 mmol) in trifluoro acetic acid (25 mL) under inert atmosphere at RT was heated to 80 0C and stirred for 5 h. The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 127 (950 mg) as pale green semi-solid which was carried to the next step without any purification. TLC: 15% EtOAc/ hexanes (Rf: 0.7). sis of dimethyl (tert-but0xycarb0nyl)nitr0phenyl) thio) terephthalate (129): COZME COztBu MeOZC 8 To a stirred solution of tert-butyl 4-fluoronitrobenzoate 128 (400 mg, 1.65 mmol) in DMF (20 mL) under inert atmosphere were added compound 127 (525 mg, crude), cesium carbonate (1.07 g, 3.31 mmol) at RT; heated to 60 0C and d for 1 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was diluted water (25 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound 129 (400 mg, 54%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf: 0.4); 1H-NMR , 400 MHz): 8 8.76 (s, 1H), 8.25 (s, 1H), 8.20-8.17 (m, 1H), 7.98 (d, J: 8.4 Hz, 1H), 7.92 (d, J: 8.4 Hz, 1H), 6.91 (d, J: 8.4 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 1.58 (s, 9H).
Synthesis of dimethyl 2-((2-amin0(tert—butoxycarbonyl) phenyl) thio) terephthalate (130): ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson COZMe COZIBU Meozc’ : ‘s’ ; To a stirred solution of compound 129 (1 g, 2.23 mmol) in MeOH (50 mL) under inert atmosphere was added 10% Pd/C (500 mg) at RT and d under hydrogen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was trated in vacuo to obtain the crude. The crude was triturated with 2% EtOAc/ n-pentane (2 x 5 mL) and dried in vacuo to afford compound 130 (800 mg, 86%) as an off-white solid. TLC: 15% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHZ): 5 8.05 (d, J: 8.0 Hz, 1H), 7.76-7.73 (m, 1H), 7.43-7.40 (m, 2H), 7.27 (s, 1H), 7.13-7.10 (m, 1H), 5.68 (br s, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 1.55 (s, 9H).
Synthesis of 2-((2-amin0(tert-but0xycarb0nyl) ) thio) terephthalic acid (131): C02H £1 1 1m" H020 s To a d solution of compound 130 (250 mg, 0.59 mmol) in THF: H20 (4: 1, 10 mL) under inert atmosphere was added lithium hydroxide monohydrate (123 mg, 2.99 mmol) at RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and extracted with diethyl ether (2 x 25 mL). The aqueous layer was acidified with 2 N HCl to pH~6. The obtained solid was filtered and dried in vacuo to afford compound 131 (180 mg, 77%) as yellow solid.
TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 5 13.16 (br s, 2H), 8.02 (d, J: 8.0 Hz, 1H), 7.70 (d, J: 8.4 Hz, 1H), 7.44-7.40 (m, 2H), 7.16 (s, 1H), 7.13-7.09 (m, 1H), .64 (br s, 2H), 1.55 (s, 9H).
Synthesis of 8-(tert—but0xycarb0nyl)—11-0xo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine—3- carboxylic acid (132): [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson o S/O/«otsu To a stirred solution of compound 131 (180 mg, 0.46 mmol) in THF (9 mL) under inert atmosphere was added CDI (225 mg, 1.39 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo.
The residue was diluted with water (15 mL) and acidified with HCl. The obtained solid was d and dried in vacuo to afford nd 132 (150 mg, 87%) as an off-white solid. TLC: 7% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 13.32 (br s, 1H), 10.93 (s, 1H), 8.02 (d, J: 8.4 Hz, 1H), 7.97-7.94 (m, 1H), 7.81-7.77 (m, 2H), 7.71-7.62 (m, 1H), 7.43-7.42 (m, 1H), 1.55-1.51 (m, 9H).
Synthesis of tert-butyl 3-carbamoyl—11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] pine—S- carboxylate (134): SWotBu To a stirred solution of compound 132 (150 mg, 0.40 mmol) in DMF (9 mL) under inert atmosphere were added HATU (307 mg, 0.80 mmol), ammonium chloride 133 (43 mg, 0.80 mmol), diisopropyl ethyl amine (0.3 mL, 1.60 mmol) at 0 0C; warmed to RT and stirred for 16 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL). The obtained solid was filtered, triturated with 10% EtOAc/ hexanes (2 x 5 mL) and dried in vacuo to afford compound 134 (95 mg, 63%) as white solid.
TLC: 7% MeOH/ CH2C12 (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 5 10.89 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.89 (d, J: 8.0 Hz, 1H), 7.77-7.76 (m, 2H), .69 (m, 1H), 7.64 (d, J: 8.0 Hz, 1H), 7.58 (br s, 1H), 1.52 (s, 9H).
Synthesis of 3-carbam0yl0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine-S-carboxylic acid (135): [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson To a stirred solution of nd 134 (95 mg, 0.25 mmol) in EDC (10 mL) under inert atmosphere was added trifluoroacetic acid (293 mg, 2.56 mmol) at RT; heated to 80 0C and stirred for 5 h. The reaction was monitored by TLC; after completion of the on, the reaction mixture was filtered. The obtained solid was triturated with 5% CH2C12 (2 X 5 mL) and dried in vacuo to afford compound 135 (70 mg, 87%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 500 MHz): 5 10.93 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, J: 8.5 Hz, 1H), .76 (m, 2H), 7.72-7.68 (m, 2H), 7.59 (s, 1H).
Exam le 16: 11-0x0-10 11-dih drodibenzo b 1 4 thiaze ine-7—carb0x lic acid 140 - a common intermediate 002Me COZH FQSNO052003 LiOH H20 10% Pd/C THF' ©1838NO MeOH C02|V|e COZH To a stirred solution of methyl onitrobenzoate 136 (100 mg, 0.50 mmol) in DMF (3 mL) under argon atmosphere was added cesium carbonate (180 mg, 0.55 mmol) at RT [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson and heated to 40 0C. To this was added methyl 2-mercaptobenzoate 1 (93 mg, 0.55 mmol) in DMF (1 mL) drop wise for 3 min and stirred for 2 h. The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was diluted with water (30 mL) and ted with CH2C12 (2 x 30 mL). The ed organic extracts were dried over sodium sulfate, filtered and trated in vacuo to afford compound 137 (120 mg, 69%) as yellow crystalline solid. TLC: 20% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 8.30 (d, J: 8.4 Hz, 1H), 7.99-7.93 (m, 2H), 7.65-7.60 (m, 3H), 7.49 (d, J: 7.6 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H).
Synthesis of 3-((2-carb0xyphenyl) thio)nitr0benz0ic acid (138): C02H COzH No2 To a stirred solution of compound 137 (100 mg, 0.26 mmol) in THF (7 mL) under argon atmosphere was added lithium hydroxide drate (28 mg, 0.66 mmol) in water (3 mL) at RT; heated to reflux and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (20 mL) and pH was ed to ~2 with l N HCl. The obtained solid was filtered and dried in vacuo to afford compound 138 (72 mg, 85%) as yellow solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 13.49 (br s, 2H), 8.25 (d, J: 8.4 Hz, 1H), 7.96-7.91 (m, 2H), 7.66 (s, 1H), 7.60-7.54 (m, 2H), 7.40 (d, J: 7.6 Hz, 1H).
Synthesis of 4-amin0((2-carb0xyphenyl) thio) benzoic acid (139): COZH 002H NH2 To a d solution of compound 138 (70 mg, 0.20 mmol) in MeOH (5 mL) under argon atmosphere was added 10% Pd/C (10 mg) and stirred under hydrogen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the reaction, the [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson reaction e was filtered through celite, washed with MeOH (2 x 5 mL) and the filtrate was trated in vacuo to afford compound 139 (53 mg, 90%) as an off-white solid. TLC: 20% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 12.91 (br s, 2H), 7.94 (d, J: 6.4 Hz, 1H), 7.86 (s, 1H), 7.76 (d, J: 8.4 Hz, 1H), 7.37 (t, J: 8.0 Hz, 1H), 7.19 (t, J: 7.6 Hz, 1H), 6.83 (d, J: 8.8 Hz, 1H), 6.63 (d, J: 8.0 Hz, 1H), 6.14 (br s, 2H).
Synthesis of 11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—7—carb0xylic acid (140): COZH To a stirred solution of compound 139 (50 mg, 0.17 mmol) in dry THF (3 mL) under argon atmosphere was added CD1 (84 mg, 0.51 mmol) at 0 0C; warmed to RT and stirred for 12 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was quenched with 1 N HCl (3 mL), water (10 mL). The obtained solid was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 140 (28 mg, 61%) as white solid.
TLC: 20% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 5 13.10 (br s, 1H), 10.97 (s, 1H), 8.05 (s, 1H), 7.89 (d, J: 8.4 Hz, 1H), 7.69 (d, J: 7.6 Hz, 1H), 7.57 (d, J: 7.6 Hz, 1H), 7.53-7.44 (m, 2H), 7.31 (d, J: 8.4 Hz, 1H).
[Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 17: S nthesis of 8-aminodibenzo b 1 4 thiaze in-11 10 -one 145 -a common intermediate COOMe N02 :1)"(1:30"C. Sfij COOH NO COOHS NH % Pd/C HOBt EDCI. HCI MeOH DIPEA THF sUNHZ Synthesis of methyl 2-((4-aminonitrophenyl) thio) benzoate (142): COOMe N02 To a stirred solution of 4-fluor0nitr0aniline 141 (500 mg, 3.20 mmol) in DMF (6 mL) under inert atmosphere was added cesium carbonate (1.14 g, 3.50 mmol) at RT and heated to 40 0C. To this was added methyl 2-mercapt0benz0ate 1 (592 mg, 3.50 mmol) in DMF (1 mL) drop wise for 3 min and stirred for 3 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was diluted with water (35 mL) and extracted with CH2C12 (2 x mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 142 (600 mg, 62%) as brown syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 8 7.91 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.30-7.20 (m, 2H), 7.10 (s, 1H), 6.87-6.84 (m, 1H), 6.79 (d, J: 8.0 Hz, 1H), 6.24 (s, 2H), 3.84 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 2-((4-amin0nitrophenyl) thio) benzoic acid (143): COOH No2 To a stirred solution of compound 142 (600 mg, 1.98 mmol) in THF: H20 (10: 3, 13 mL) under inert atmosphere was added lithium hydroxide monohydrate (406 mg, 9.90 mmol) at RT; heated to 60 0C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The aqueous layer was acidified with HCl to pH~2. The obtained solid was filtered and dried in vacuo to afford nd 143 (350 mg, 61%) as orange solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 500 MHz): 8 13.18 (s, 1H), 7.89 (d, J: 7.5 Hz, 1H), 7.38 (t, J: 7.0 Hz, 1H), 7.28 (d, J: 9.0 Hz, 1H), 7.19 (t, J: 8.0 Hz, 1H), 7.07 (s, 1H), 6.84 (d, J: 8.5 Hz, 1H), 6.71 (d, J: 8.5 Hz, 1H), 6.23 (s, 2H).
Synthesis of 2-((2, 4-diamin0phenyl) thio) benzoic acid (144): COOH NH2 To a d on of compound 143 (350 mg, 1.20 mmol) in MeOH (10 mL) under inert atmosphere was added 10% Pd/C (100 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was filtered and the filtrate was concentrated in vacuo to obtain the crude. The crude was washed with n-pentane (2 x 10 mL) and dried in vacuo to afford compound 144 (250 mg, 80%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz):512.60(br s, 1H), 7.87 (d, J: 7.6 Hz, 1H), 7.32 (t, J: 8.4 Hz, 1H), 7.12 (t, J: 6.8 Hz, 1H), 6.90 (d, J: 8.0 Hz, 1H), 6.72 (d, J: 8.0 Hz, 1H), 6.02 (s, 1H), 5.93 (d, J: 8.4 Hz, 1H), .02-4.98 (m, 4H).
Synthesis of 0dibenz0 [b,f] [1, 4] pin-11 (10H)-0ne (145): [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson sUNHg To a stirred solution of compound 144 (150 mg, 0.57 mmol) in DMF (4 mL) under inert atmosphere were added HOBt (233 mg, 1.73 mmol), EDCI.HCl (330 mg, 5.19 mmol), diisopropyl ethyl amine (0.5 mL, 2.87 mmol) at 0 0C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (30 mL). The obtained solid was filtered, washed with hexanes (2 x mL) and dried in vacuo to afford compound 145 (80 mg, 57%) as an off-white solid. TLC: % MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 8 10.40 (s, 1H), 7.63 (d, J: 6.8 Hz, 1H), 7.45-7.37 (m, 3H), 7.12 (d, J: 8.4 Hz, 1H), 6.39 (s, 1H), 6.31 (d, J: 8.4 Hz, 1H), 5.46 (s, 2H).
Exam le 18: S nthesis of 11-0x0-10 11-dih enzo b 1 4 thiaze inecarb0x lic acid 5-0xide 156 - a common intermediate Synthesis of 11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xylic acid 5-0xide (156): To a stirred solution of 6 (2.5 g, 9.21 mmol) in CH2C12 (50 mL) under inert here was added m-chloro perbenzoic acid (1.59 g, 9.21 mol) at RT and stirred for 48 h.
The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson the volatiles were removed in vacuo to obtain the crude. The crude was triturated with 10% MeOH/ CH2C12 (2 x 5 mL), isopropanol (10 mL) to afford nd 156 (2.3 g, 87%) as white solid. TLC: 10% MeOH/ CH2C12 + 0.05 mL CH3COOH (Rf: 0.4); 1H NMR (DMSO-ds, 500 MHz): 8 13.36 (br s, 1H), 11.08 (s, 1H), 7.96 (d, J: 7.8 Hz, 1H), 7.92-7.87 (m, 1H), 7.85-7.66 (m, 3H), 7.63 (t, J: 7.8 Hz, 1H), 7.53 (t, J: 7.8 Hz, 1H); Exam le 19: S nthesis of 11-0x0-10 11-dih drodibenzo b 1 4 thiaze inecarb0x lic acid 5 5-di0xide 159 - a common intermediate NH O CH2N2 SD/(OH MeOH Ergo 031::Djome LiOH. H20 THF: MeOH: H20 H 008\\O Synthesis of methyl 11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xylate (157): NH O 4] To a stirred solution of 6 (500 mg, 1.84 mmol) in MeOH: CH2C12 (1: 1, 20 mL) under argon atmosphere was added CH2N2 (prepared in situ using N—nitrosomethyl urea (0.95 g, 9.2 mmol) + KOH (0.51 g, 9.22 mmol) at 0 0C; warmed to RT and stirred for 1 h. The on was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 157 (450 mg, 86%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (DMSO-dg, 500 MHz): 8 10.82 (s, 1H), 7.82 (s, 1H), 7.75-7.69 (m, 3H), 7.58-7.63 (m, 3H), 3.82 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of methyl 11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xylate 5, 5- dioxide (158): NH O l/ \\ To a stirred solution of 157 (5 g, 17.54 mmol) in acetic acid (25 rnL) was added 30% aqueous hydrogen peroxide (100 rnL) at 0 0C; warmed to 50 0C and stirred for 72 h. The reaction was monitored by TLC; after completion of the reaction, the ed solid was filtered, washed with water (100 rnL), 10% EtOAc/ hexanes (100 rnL) and dried in vacuo to afford compound 158 (3.5 g, 64%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.3); 1H NMR (DMSO-dg, 500 MHz): 5 11.58 (s, 1H), 8.09 (d, J: 8.4 Hz, 1H), 8.01-7.95 (m, 3H), 7.93-7.83 (m, 3H), 3.88 (s, 3H).
Synthesis of 11-0x0-10, ydr0dibenz0 [b,f] [1, 4] thiazepine—8-carb0xylic acid 5, 5- dioxide (159): To a stirred solution of compound 158 (3.5 g, 11.04 mmol) in a mixture of THF: MeOH: H20 (2: 2: 1, 25 rnL) was added lithium hydroxide monohydrate (1.3 g, 33.12 mmol) portion wise for 10 min at 0 0C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the on, the volatiles were removed in vacuo. The residue was diluted with water (20 rnL) and acidified with 1 N HCl to pH~2. The obtained solid was filtered, washed with isopropyl alcohol (15 rnL) and dried in vacuo to obtain compound 159 (2.8 g, 84%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.1); 1H NMR (DMSO-dg, 400 MHz): 8 13.65 (br s, 1H), 11.55 (s, 1H), 8.07 (d, J: 8.3 Hz, 1H), 8.03-7.82 (m, 6H).
Exam le 20: S nthesis of 5-meth l0x0-10 11-dih -dibenzo b e 1 4 diazepine—8-carb0xylic acid (164) - a common intermediate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson cone co Me E): CLNO 2 DIPEA CH3| CS2C03 NH2 02:1: co2Me MP W C02Me @NN COZMe F8IA OHC L'OHH20 COOMe COZH THF: H20 Synthesis of methyl (meth0xycarb0nyl) phenyl) amino)—3-nitr0benzoate (161): To a stirred solution of methyl 2-aminobenzoate 160 (5 g, 33.07 mmol) in NMP (13 mL) under inert atmosphere were added diisopropylethylamine (18 rnL, 103.46 mmol), methyl 4-fluoronitrobenzoate 2 (9.87 g, 49.61 mmol) at RT; heated to 120 0C in a sealed tube and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with diethyl ether (50 mL) and d for 1 h. The obtained solid was filtered, washed with diethyl ether (10 mL) and dried in vacuo to afford compound 161 (3.2 g, 29%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H NMR dg, 400 MHz): 11.13 (s, 1H), 8.67 (s, 1H), 8.11-7.94 (m, 2H), 7.70-7.62 (m, 2H), 7.58 (d, J: 9.0 Hz, 1H), 7.32-7.27 (m, 1H), 3.87 (s, 6H).
Synthesis of methyl 4-((2-(meth0xycarb0nyl) phenyl) (methyl) amino)—3-nitr0benzoate (162): CEOECOZME To a stirred solution of nd 161 (3 g, 9.09 mmol) in DMF (30 mL) under inert atmosphere were added cesium carbonate (5.9 g, 18.15 mmol), methyl iodide (0.84 rnL, 13.59 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the on, the reaction mixture was diluted with ice-cold water (60 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 162 (2.73 g, 88%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 8 8.07 (s, 1H), 8.06 (d, J: 7.8 Hz, 1H), 7.71 (dd, J: 7.8, 1.5 Hz, 1H), 7.62 (t, J: 7.3 Hz, 1H), 7.40-7.26 (m, 3H), 3.84 (s, 3H), 3.53 (s, 3H), 3.38 (s, 3H).
Synthesis of methyl 5-methyl0x0-10, 11-dihydr0-5H—dibenzo [b, e] [1, 4] diazepine carboxylate (163): To a stirred solution of nd 162 (2.73 g, 7.93 mmol) in acetic acid (36 mL) under inert atmosphere was added iron powder (7 g, 127.2 mmol) at RT; heated to 80 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the on mixture was diluted with CH2C12 (50 mL), stirred for 2 h and filtered through celite and the e was concentrated in vacuo to obtain the crude. The crude was dissolved in CH2C12 (200 mL), washed with saturated aqueous NaHC03 solution (100 mL), brine (100 mL). The c extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 163 (2 g, 91%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 500 MHz): 8 10.33 (s, 1H), 7.68 (dd, J: 8.5, 1.9 Hz, 1H), 7.65-7.61 (m, 2H), 7.50 (t, J: 7.8 Hz, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.21 (d, J: 8.1 Hz, 1H), 7.10 (t, J: 7.4 Hz, 1H), 3.80 (s, 3H), 3.33 (s, 3H).
Synthesis of 5-methyl0x0-10, 11-dihydr0-5H—dibenzo [b, e] [1, 4] diazepine—8-carb0xylic acid (164): ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ND/COZH To a stirred solution of compound 163 (2 g, 7.09 mmol) in THF: H20 (1: 1, 80 mL) was added lithium hydroxide monohydrate (900 mg, 21.42 mol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 with 2 N HCl. The precipitated solid was filtered and dried in vacuo to afford nd 164 (1.7 g, 89%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 5 12.82 (br s, 1H), 10.33 (s, 1H), 7.70-7.60 (m, 3H), 7.51 (t, J: 7.8 Hz, 1H), 7.27 (d, J: 8.5 Hz, 1H), 7.21 (d, J: 7.8 Hz, 1H), 7.11 (t, J: 7.2 Hz, 1H), 3.32 (s, 3H).
Exam le 21: S nthesis of 5-eth l0x0-10 11-dih -dibenzo b e 1 4 diaze ine- 8-carb0x lic acid 167 - a common intermediate COZMe 002Me COZMe (ELM/$2 COZMe 0.32003 Etl CLE/Q/ Fe/AcOH OED/COW"; 165 166 LiOH. H20 COH2 THF: H20 OND/ Synthesis of methyl 4-(ethyl (2-(meth0xycarb0nyl) phenyl) amino)—3-nitr0benzoate (165): To a stirred solution of nd 161 (2.9 g, 8.78 mmol) in DMF (40 mL) under inert atmosphere were added cesium carbonate (6 g, 18.46 mmol), ethyl iodide (1.06 mL, 12.82 [Annotation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mmol) at RT and d for 5 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (60 mL), extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude which was titurated with n-pentane (20 mL) to afford nd 165 (2.8 g, 89%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.5); 1H NMR (DMSO-dg, 500 MHz): 8 8.05 (dd, J: 9.0, 2.0 Hz, 1H), 8.02 (s, 1H), 7.62-7.57 (m, 2H), 7.45 (d, J: 9.0 Hz, 1H), 7.33 (d, J: 8.1 Hz, 1H), 7.28 (t, J: 7.5 Hz, 1H), 3.94 (q, J: 7.1 Hz, 2H), 3.82 (s, 3H), 3.44 (s, 3H), 1.20 (t, J: 7.1 Hz, 3H).
Synthesis of methyl 5-ethyl0x0-10, 11-dihydr0-5H—dibenz0 [b, e] [1, 4] diazepine—8- carboxylate (166): To a d solution of compound 165 (2.8 g, 7.82 mmol) in acetic acid (40 mL) under inert atmosphere was added iron powder (6.8 g, 125.1 mmol) at RT; heated to 80 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the on mixture was diluted with CH2C12 (50 mL), stirred for 2 h and filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was d with CH2C12 (200 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 166 (2.2 g, 96%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.3); 1H NMR (DMSO-dg, 500 MHz): 5 10.35 (br s, 1H), 7.70 (dd, J = 8.5, 1.9 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J: 7.5 Hz, 1H), 7.51 (t, J: 8.1 Hz, 1H), 7.29 (d, J: 8.4 Hz, 1H), 7.22 (d, J: 8.1Hz, 1H), 7.12 (t, J: 7.4 Hz, 1H), 3.31 (s, 5H), 1.11 (t, J: 6.9 Hz, 3H).
Synthesis of 5-ethyl0x0-10, 11-dihydr0-5H—dibenzo [b, e] [1, 4] diazepinecarb0xylic acid (167): [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson To a stirred solution of compound 166 (2.1 g, 7.09 mmol) in THF: H20 (1: 1, 60 mL) was added m hydroxide monohydrate (890 mg, 21.26 mol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified to ~2 with 2 N HCl. The precipitated solid was filtered, washed with water (50 mL) and dried in vacuo to afford compound 167 (1.6 g, 80%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHZ): 5 12.82 (br s, 1H), 10.33 (s, 1H), 7.69-7.59 (m, 3H), 7.53-7.48 (m, 1H), 7.24 (dd, J: 19.7, 8.2 Hz, 2H), 7.12 (t, J: 7.5 Hz, 1H), 3.79 (br s, 2H), 1.12 (t, J: 7.0 Hz, 3H).
Exam le 22: S s of 5-benz l0x0-10 11-dih dro-SH—dibenzo b e 1 4 diaze ine- 8-carb0x lic acid 170 - a common intermediate COzMe C02Me ©/\Br @810 (3020/13<1thCOZMe Fe’ACOH @W COOMe 032C03 DMF D 161 168 169 LiOH.H20 THF: H20 Synthesis of methyl 4-(benzyl (2-(meth0xycarb0nyl) phenyl) amino)—3-nitr0benzoate (168): Bn N02 To a stirred solution of compound 161 (2.5 g, 7.57 mmol) in DMF (40 mL) under inert here were added cesium carbonate (4.92 g, 15.15 mmol), benzyl bromide (1.34 mL, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 11.36 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the on, the reaction mixture was diluted with ice-cold water (60 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 168 (3 g, 91%) as ess thick syrup. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 500 MHz): 8 8.04 (s, 1H), 7.97 (dd, J: 8.8, 1.9 Hz, 1H), .57 (m, 1H), 7.56- 7.50 (m, 3H), 7.40 (t, J: 8.2 Hz, 2H), 7.34 (t, J: 7.7 Hz, 2H), 7.28-7.23 (m, 2H), 5.20 (s, 2H), 3.81 (s, 3H), 3.39 (s, 3H).
Synthesis of methyl 5-benzyl0x0-10, 11-dihydr0-5H—dibenzo [b, e] [1, 4] diazepine—8- carboxylate (169): To a stirred solution of compound 168 (950 mg, 2.26 mmol) in acetic acid (10 mL) under inert atmosphere was added iron powder (2 g, 36.36 mmol) at RT; heated to 80 0C and stirred for 4 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2C12 (50 mL), filtered h celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was dissolved in CH2C12 (200 mL), washed with ted aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic extract was dried over sodium sulfate, d and concentrated in vacuo to afford compound 169 (800 mg, 98%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 500 MHz): 5 10.42 (s, 1H), 7.66 (s, 1H), 7.62 (d, J: 8.1 Hz, 2H), 7.48- 7.34 (m, 4H), 7.33-7.21 (m, 3H), 7.15 (t, J: 7.2 Hz, 1H), 7.09 (t, J: 7.4 Hz, 1H), 5.04 (br s, 2H), 3.79 (s, 3H).
Synthesis of 5-benzyl0x0-10, 11-dihydr0-5H—dibenzo [b, e] [1, 4] diazepinecarb0xylic acid (170): [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson To a stirred solution of compound 169 (2 g, 5.58 mmol) in THF: H20 (1: 1, 80 mL) was added lithium hydroxide monohydrate (703 mg, 16.73 mol) at RT and d for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 6 N HCl to pH ~2 and stirred for 1 h. The itated solid was filtered and dried in vacuo to afford compound 170 (1.5 g, 78%) as an off- white solid. TLC: 50% EtOAc/ hexanes (Rf: 0.2); 1H NMR (DMSO-dg, 500 MHz): 8 12.87 (br s, 1H), 10.39 (s, 1H), 7.65-7.55 (m, 3H), 7.47- 7.21 (m, 7H), 7.16-7.04 (m, 2H), 5.02 (br s, 2H).
Exam le 23: S nthesis of 3-meth0x 0x0-10 11-dih drodibenzo b 1 4 thiaze ine—8- carboxylic acid gP-421 \O/E:[::2'V'e—>triflic ide C02M9 PMB-SH pyridine Pd(dppf)2C'21 \ 082C303 1, 4-dioxane P-35 P-36 02N COZMS COZMG COZMG CO Me COzMe FUD/CL:EE:C02W10%MEG/(18:53: 2 SH C52C03 DMF MeOH P-38 COZH _.£1fly";dygw Synthesis of methyl 4-meth0xy(((trifluoromethyl) sulfonyl) oxy) te (P- 36): To a stirred solution of methyl 2-hydroxymethoxybenzoate P-35 (1 g, 5.49 mmol) in pyridine (5 mL) under argon atmosphere was added triflic anhydride (1 mL, 6.31 mmol) drop wise at 0 0C; warmed to RT and stirred for 2 h; heated to 40 0C and stirred for 16 h. The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo.
The residue was diluted with water (25 mL) and extracted with diethyl ether (2 x 30 mL). The [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson combined organic extracts were washed with 1 N HCl (15 mL), water (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound P-36 (1.58 g, 92%) as colorless syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.6); 1H-NMR (CDC13, 500 MHz): 5 8.06 (d, J: 9.0 Hz, 1H), 6.95 (d, J: 8.5 Hz, 1H), 6.78 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H).
Synthesis of methylmeth0xy((4-meth0xybenzyl) thio) benzoate (P-37): To a d solution of compound P-36 (1 g, 3.18 mmol) in 1, ane (15 mL) under argon atmosphere were added hoxyphenyl) ethiol (539 mg, 3.50 mmol), cesium carbonate (2 g, 6.36 mmol) at RT and degassed under argon for 20 min. To this was added Pd(dppf)2C12 (233 mg, 0.31 mmol); heated to 80 0C and stirred for 8 h. The reaction was monitored by TLC; after tion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound P-37 (340 mg, 30%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf; 0.4); 1H-NMR(CDC13, 500 MHz): 5 7.96 (d, J: 8.5 Hz, 1H), 7.38-7.37 (m, 1H), 7.35 (d, J: 9.0 Hz, 1H), 6.85 (d, J: 8.0 Hz, 2H), 6.82 (s, 1H), 6.64 (d, J: 8.5 Hz, 1H), 4.10 (s, 2H), 3.86 (s, 3H), 3.79 (s, 6H).
Synthesis of methyl 2-mercapt0meth0xybenzoate (P-38): A stirred solution of compound P-37 (330 mg, 1.03 mmol) in trifluoroacetic acid (5 mL) under argon atmosphere was heated to reflux and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound P-38 (340 mg) as brown syrup which was carried to the next step without any further purification. TLC: 10% EtOAc/ s (Rf: 0.7).
Synthesis of methyl 4-meth0xy((4-(methoxycarb0nyl)nitr0phenyl) thio) benzoate (P-39): To a d on of compound P-38 (200 mg, 1.01 mmol) in DMF (5 mL) under argon atmosphere were added methyl 4-fluoronitrobenzoate (201 mg, 1.01 mmol), cesium carbonate (656 mg, 2.02 mmol) at RT; heated to 40 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo.
[Annotation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and trated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound P-39 (280 mg, 74%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (CDC13, 400 MHz): 8 8.84 (d, J = 7.2 Hz, 1H), 8.03 (d, J: 8.8 Hz, 1H), 7.96-7.92 (m, 1H), 7.78 (s, 1H), 7.17-7.12 (m, 1H), 7.08-6.93 (m, 1H), 3.96-3.93 (m, 3H), 3.85 (s, 3H), .74 (m, 3H).
Synthesis of methyl 2-((2-amin0(methoxycarbonyl) phenyl) thi0) methoxybenzoate (P-40): To a stirred solution of compound P-39 (270 mg, 0.71 mmol) in MeOH (10 mL) under argon atmosphere was added 10% Pd/C (80 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through , washed with CH2C12 (2 x 25 mL) and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ s to afford compound P-40 (180 mg, 79%) as colorless syrup. TLC: 20% EtOAc/ hexanes (Rf: 0.5); 1H- NMR (CDCI3, 400 MHz): 8 8.03 (d, J: 8.8 Hz, 1H), 7.54-7.40 (m, 1H), 7.08 (d, J: 8.8 Hz, 1H), 6.79-6.72 (m, 1H), 6.66-6.63 (m, 1H), 6.21-6.14 (m, 1H), 3.95-3.88 (m, 5H), 3.85 (s, 3H), 3.65 (s, 3H).
Synthesis of 2-((2-amin0carboxyphenyl) thio)—4-meth0xybenz0ic acid (P-41): To a stirred solution of compound P-40 (160 mg, 0.46 mmol) in THF: H20 (2: 1, 6 mL) under argon atmosphere was added lithium hydroxide monohydrate (96 mg, 2.30 mmol) at RT and d for 16 h. The reaction was monitored by TLC; after completion of the reaction, the les were removed in vacuo, d with water (20 mL), acidified with 1 N HCl to pH~6.
The obtained precipitate was filtered and dried in vacuo to afford compound P-41 (85 mg, crude) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHZ): 5 12.84 (br s, 2H), 7.95 (d, J: 8.8 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J: 8.0 Hz, 1H), 6.13 (s, 1H), .58 (br s, 2H), 3.80-3.69 (m, 2H), 3.60 (s, 3H).
Synthesis of 3-meth0xyoxo-10, 11-dihydrodibenzo [b,f] [1, 4] pine—S- carboxylic acid (P-42): To a stirred solution of compound 41 (80 mg, 0.25 mmol) in THF (8 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mL) under argon atmosphere was added CD1 (203 mg, 1.25 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (20 mL), acidified with dilute HCl. The obtained precipitate was filtered and dried in vacuo to afford compound P-42 (50 mg, crude) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 5 13.18 (br s, 1H), 10.64 (s, 1H), 7.77 (s, 1H), 7.66 (s, 2H), .07 (m, 1H), 7.01 (d, J: 8.8 Hz, 1H), 6.82-6.79 (m, 1H), 3.80 (s, 3H).
Exam le 24: S nthesis of 2-meth l0x0-10 11-dih drodibenzo b 1 4 thiaze ine—8- carboxylic acid gP-Slz UZOOH—>MeOH, H2804 COzMe Triflic anhydride COzMe PMB-SH —>—> OH pyridine OTf Pd(dppf)20|2, 052003, 1, 4-dioxane P-43 P-44 P-45 OzND/COZMG COZMe COZMe co Me2 % Pd/C —> U:Ozme—> \CLS/Q/COZW —>\©L 052003, DMF MeOH SO P-47 P-4s P-49 COZH LiOH H20 CDI, THF THF: H20 \QSN P-50 :SQCOOH 4] sis of methyl 2-hydroxy-S-methylbenzoate (P-44): To a stirred on of 2- hydroxymethylbenzoic acid P-43 (2 g, 13.15 mmol) in MeOH (65 mL) under argon atmosphere was added sulphuric acid (0.65 mL) at RT; heated to reflux and stirred for 20 h. The reaction was monitored by TLC; after completion of the on, the volatiles were removed in vacuo. The residue was diluted with ice water (50 mL) and extracted with ether (3 x 40 mL). The combined organic extracts were washed with 10% aqueous NaHC03 solution (until the pH s neutral), dried over sodium e, filtered and concentrated in vacuo to obtain compound P-44 (2 g, 92%) as colorless liquid. TLC: 10% EtOAc/ s (Rf: 0.7); 1H-NMR (CDC13, 500 MHz): 8 10.57 (s, 1H), 7.65 (s, 1H), 7.29 (d, J: 7.5 Hz, 1H), 6.90 (d, J: 8.0 Hz, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1H), 3.96 (s, 3H), 2.30 (s, 3H).
] Synthesis of methyl 5-methyl(((trifluoromethyl) sulfonyl) oxy) benzoate (P- 45): To a stirred solution of compound P-44 (2 g, 12.04 mmol) in pyridine (8 rnL) under argon atmosphere was added trifiuoro methane sulfonic anhydride (2.3 mL, 13.85 mmol) at 0 0C; warmed to RT and stirred for 2 h; heated to 40 0C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (50 rnL) and extracted with ether (3 x 50 rnL). The combined organic ts were washed with water (50 rnL), brine (50 rnL), 1 N HCl (40 rnL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 3-5% EtOAc/ hexanes to afford nd P-45 (2.6 g, 72%) as colorless liquid. TLC: 7% EtOAc/ hexanes (Rf: 0.6); 1H-NMR (CDC13, 500 MHz): 8 7.88 (s, 1H), 7.40 (d, J: 8.5 Hz, 1H), 7.17 (d, J: 8.0 Hz, 1H), 3.96 (s, 3H), 2.42 (s, 3H). sis of methyl 2-((4-meth0xybenzyl) thi0)methylbenzoate (P-46): To a stirred solution of compound P-45 (1 g, 3.35 mmol) in 1, ane (15 rnL) under argon atmosphere were added (4-methoxyphenyl) methanethiol (568 mg, 3.69 mmol), cesium ate (2.18 g, 6.71 mmol) at RT and ed for 20 min. To this was added Pd(dppf)2C12 (61.4 mg, 0.083 mmol); heated to 110 0C and d for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 rnL) and extracted with EtOAc (2 x 40 rnL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% EtOAc/ hexanes to afford compound P-46 (290 mg, 29%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (CDC13, 400 MHz): 5 7.75 (s, 1H), 7.30 (d, J: 8.8 Hz, 2H), 7.22-7.21 (m, 2H), 6.83 (d, J: 8.8 Hz, 2H), 4.09 (s, 2H), 3.89 (s, 3H), 3.79 (s, 3H), 2.32 (s, 3H).
Synthesis of methyl 2-mercapt0methylbenzoate (P-47): A stirred solution of compound P-46 (200 mg, 0.66 mmol) in trifiuoro acetic acid (10 rnL) at RT under argon atmosphere was heated to 70-75 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound P-47 (100 mg, crude) as yellow syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.7); 1H-NMR (DMSO-dg, 500 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson MHz): 5 7.74 (s, 1H), 7.44 (d, .1: 8.0 Hz, 1H), 7.26 (d, .1: 7.5 Hz, 1H), 5.20 (s, 1H), 3.82 (s, 3H), 2.28 (s, 3H).
Synthesis of methyl 2-((4-(meth0xycarb0nyl)nitr0phenyl) 5- methylbenzoate (P-48): To a stirred solution of compound P-47 (100 mg, 0.50 mmol) in DMF (5 mL) under argon atmosphere were added methyl 4-fiuoronitrobenzoate (100 mg, 0.55 mmol), cesium ate (326 mg, 1.00 mmol) at RT; heated to 60 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (30 mL) and extracted with CH2C12 (2 x 30 mL). The combined c extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ s to afford nd P-48 (100 mg, 55%) as yellow solid. TLC: 10% EtOAc/ s (Rf: 0.3); 1H-NMR dg, 400 MHz): 5 8.63 (s, 1H), 8.03 (d, J: 8.8 Hz, 1H), 7.78 (s, 1H), 7.61 (d, J: 7.6 Hz, 1H), 7.55-7.53 (m, 1H), 6.99 (d, J: 8.4 Hz, 1H), 3.87 (s, 3H), 3.68 (s, 3H), 2.43 (s, 3H).
Synthesis of methyl 2—((2-amin0(methoxycarbonyl) phenyl) thi0) methylbenzoate (P-49): To a stirred solution of compound P-48 (400 mg, 1.10 mmol) in MeOH (20 mL) under argon atmosphere was added 10% Pd/ C (200 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after tion of the reaction, the reaction mixture was filtered through celite and washed with 50% MeOH/ CH2C12 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7-10% EtOAc/ hexanes to afford compound P-49 (220 mg, 60%) as pale yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.5); 1H-NMR dg, 500 MHz): 8 7.77 (s, 1H), 7.44 (s, 1H), 7.40 (d, J: 7.5 Hz, 1H), 7.21 (d, J: 8.0 Hz, 1H), 7.16-7.14 (m, 1H), 6.57 (d, J: 8.5 Hz, 1H), 5.63 (br s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H). 0] Synthesis of 2—((2-amin0carboxyphenyl) thi0)methylbenzoic acid (P-50): To a stirred solution of compound P-49 (220 mg, 0.66 mmol) in THF: H20 (5: l, 6 mL) under argon atmosphere was added lithium hydroxide monohydrate (139 mg, 3.32 mmol) at RT and stirred for 20 h. The reaction was red by TLC; after completion of the reaction, the volatiles were [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson removed in vacuo. The residue was diluted with water (15 mL) and acidified with 6 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford nd P-50 (110 mg, 55%) as an ite solid. TLC: 20% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 500 MHz): 8 12.96 (br s, 2H), 7.76 (s, 1H), 7.42 (s, 1H), 7.37 (d, J: 8.0 Hz, 1H), 7.18 (d, J: 8.0 Hz, 1H), 7.15-7.13 (m, 1H), 6.54 (d, J: 8.0 Hz, 1H), 5.54 (br s, 2H), 2.26 (s, 3H).
Synthesis of 2-methyl—11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—S- carboxylic acid : To a stirred solution of compound P-50 (110 mg, 0.36 mmol) in THF (10 mL) under argon atmosphere was added CDI (176 mg, 1.08 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice cold water (20 mL) and acidified with 6 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound P-51 (60 mg, 58%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 5 13.21 (br s, 1H), 10.76 (s, 1H), 7.76 (s, 1H), 7.65 (s, 2H), 7.50 (s, 1H), 7.41 (d,.]= 8.0 Hz, 1H), 7.30 (d, J: 8.0 Hz, 1H), 2.29 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson Exam le 25: S nthesis of 3-meth l0x0-10 11-dih drodibenzo b 1 4 thiaze ine—8- carboxylic acid gP-81 QCO2Me—>triflic anhydride CO2Me If" H3CO OH Pyndme Pd/<18/?002M8—>10%Pd/CflTEE: 2 e Cs2CO3 DMF MeOH CO2H LiOH. H2o CDI THF THF: H2o P-7 95% Synthesis of methyl yl(((trifluoromethyl) sulfonyl) oxy) benzoate (P-2): To a stirred solution of methyl 2-hydroxymethy1benzoate P-1 (950 mg, 5.70 mmol) in pyridine (9.5 mL) under argon atmosphere was added triflic anhydride (1.05 mL, 6.20 mmol) drop wise at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 6 N HCl and extracted with l ether (2 x 50 mL). The combined organic ts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column Chromatography using 2% EtOAC/ hexanes to afford compound P-2 (1.2 g, 71%) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf: 0.7); 1H-NMR (CDC13, 400 MHz): 8 7.98 (d, J = 8.0 Hz, 1H), 7.28 (d, J: 8.0 Hz, 1H), 7.09 (s, 1H), 3.94 (s, 3H), 2.45 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of methyl meth0xybenzyl) thi0)methylbenzoate (P-3): To a d solution of compound 2 (600 mg, 2.01 mmol) in 1, 4-dioxane (12 mL) under argon atmosphere were added (4-methoxyphenyl) methanethiol (341 mg, 2.21 mmol), cesium carbonate (1.3 g, 4.02 mmol) at RT and degassed under argon for 20 min. To this was added Pd(dppf)2C12 (36.8 mg, 0.05 mmol); heated to 100 0C and stirred for 48 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% EtOAc/ hexanes to afford compound 3 (200 mg, 33%) as sticky solid. TLC: 10% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (CDC13, 500 MHz): 8 7.85 (d, J: 8.5 Hz, 1H), 7.32 (d, J: 8.0 Hz, 2H), 7.14 (s, 1H), 6.94 (d, J: 8.5 Hz, 1H), 6.84 (d, J: 8.0 Hz, 2H), 4.10 (s, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 2.34 (s, 3H). 4] Synthesis of methyl apt0methylbenzoate (P-4): A d solution of compound P-3 (200 mg, 0.65 mmol) in trifiuoro acetic acid (4 mL) under argon atmosphere at RT was heated to 80 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound P- 4 (115 mg) which was carried to the next step without any further purification. TLC: 10% EtOAc/ hexanes (Rf: 0.8).
Synthesis of methyl 2-((4-(meth0xycarb0nyl)nitr0phenyl) thi0) methylbenzoate (P-5): To a stirred solution of methyl onitrobenzoate (120 mg, 0.60 mmol) in DMF (4 mL) under argon atmosphere were added compound P-4 (115 mg, crude), cesium carbonate (392 mg, 1.20 mol) at RT; heated to 60 0C and stirred for 2 h. The reaction was red by TLC; after completion of the on, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound P-5 (120 mg, 55%) as yellow solid. TLC: 15% EtOAc/ hexanes (Rf: 0.7); 1H-NMR (CDC13, 400 MHz): 8 8.85 (s, 1H), 7.95-7.89 (m, 2H), 7.46 (s, 1H), 7.38 (d, J: 8.8 Hz, 1H), 6.93 (d, J: 8.4 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 2.42 (s, 3H).
[Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of methyl 2-((2-amin0(methoxycarbonyl) phenyl) thi0) methylbenzoate (P-6): To a stirred solution of compound P-5 (120 mg, 0.33 mmol) in MeOH (10 mL) under argon atmosphere was added 10% Pd/C (60 mg) at RT and stirred under en atmosphere (balloon pressure) for 16 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was filtered h celite, washed with n-pentane (2 x 5 mL) and dried in vacuo to afford compound P-6 (90 mg, 82%) as yellow sticky solid. TLC: 15% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHZ): 5 7.86 (d, J: 8.0 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J: 8.0 Hz, 1H), 7.15 (d, J: 8.0 Hz, 1H), 7.05 (d, J: 8.0 Hz, 1H), 6.44 (s, 1H), .65 (br s, 2H), 3.85-3.84 (m, 6H), 2.13 (s, 3H).
Synthesis of 2-((2-amin0carboxyphenyl) thi0)methylbenz0ic acid (P-7): To a stirred solution of compound P-6 (90 mg, 0.27 mmol) in THF: H20 (2: 1, 3 mL) under argon here was added lithium hydroxide monohydrate (56 mg, 1.35 mmol) at RT and stirred for h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The aqueous layer was acidified with 2 N HCl, the obtained solid was filtered, washed with n-hexane (2 x 5 mL) and dried in vacuo to afford compound P-7 (60 mg, 73%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 500 MHz): 5 12.95 (br s, 2H), 7.85 (d, J: 8.0 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J: 8.0 Hz, 1H), 7.15 (d, J: 7.5 Hz, 1H), 7.02 (d, J: 8.0 Hz, 1H), 6.42 (s, 1H), 5.57 (br s, 2H), 2.13 (s, 3H).
Synthesis of 3-methyl0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—8- carboxylic acid (P-8): To a d on of compound P-7 (60 mg, 0.19 mmol) in THF (4 mL) under argon atmosphere was added CD1 (96 mg, 0.59 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (20 mL), acidified with dil. HCl to pH~ 3. The obtained precipitate was filtered and dried in vacuo to afford compound P-8 (45 mg, 80%) as an off-white solid.
TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 5 13.12 (br s, 1H), 10.72 (s, 1H), 7.76 (d, J: 8.0 Hz, 2H), 7.59 (d, J: 8.0 Hz, 2H), 7.37 (s, 1H), 7.26 (s, 1H), 2.30 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson e 26: Preparation of nds Acids r to compound 6 (compounds 14, 21, 28, 35, 42, 50, 55, 62, 70, 76, 82, 88, 97, 135, 140, 145, 150, 155, 156, 159, 164, 167, 170, P-8, P-42, P-51) were synthesized as mentioned above and converted to final products either using commercially available amines or by using prepared amines employing Procedures A, B, C, D, E, F, G, H and the results are captured in Table l.
Procedure A: To a stirred solution of 6 (50 mg, 0.18 mmol) in DMF (3 mL) under argon atmosphere were added EDCI.HCl (50 mg, 0.22 mmol), HOBt (35 mg, 0.22 mmol), 2-(5-methyl- l, 3, diazolyl) l-amine hydrochloride 187 (50 mg, 0.22 mmol) and diisopropyl ethyl amine (0.1 mL, 0.55 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and stirred for l h. The crude was extracted with EtOAc or the precipitated al was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired nd.
Procedure B: To a stirred on of 6 (40 mg, 0.14 mmol) in DMF (4 mL) under argon atmosphere were added pyridinamine 182 (15 mg, 0.16 mmol), HATU (84 mg, 0.22 mmol), diisopropyl ethyl amine (0.05 mL, 0.29 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (15 mL), the obtained precipitate was d, or extracted with EtOAc (2 x 30 mL). The combined organic ts were dried over sodium sulfate, filtered, concentrated in vacuo to obtain the crude. The crude was extracted with EtOAc or the precipitated material was directly dried in vacuo, triturated or purified through silica gel column [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson chromatography to afford the desired compound.
Procedure C: To a stirred solution of compound 35 (50 mg, 0.17 mmol) in CH2C12 (5 mL) were added oxalyl chloride (0.03 mL, 0.34 mmol) or (0.06 mL, 0.69 mmol), DMF (0.01 mL) under argon atmosphere at 0 0C; warmed to 10 0C and d for 2-3 h. After tion of the on, the volatiles were removed in vacuo to obtain the crude. The crude was carried to the next step without further purification. 3] To a d solution of crude acid chloride (70 mg, crude) in CH2C12 (5 mL) under argon atmosphere were added 2-chlorofluoroaniline 184 (25 mg, 0.17 mmol) and pyridine (0.07 mL, 0.86 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2C12 (2 x 30 mL). The combined organic extracts were washed with 1 N HCl (20 mL), 10% NaHC03 solution (30 mL), brine (15 mL) dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude. The precipitated al was either directly dried in vacuo or triturated or purified through silica gel column chromatography /preparative HPLC or by acid-base treatment to afford the d compound.
Procedure D: To a stirred solution of 6 (40 mg, 0.14 mmol) in DMF (3 mL) under argon atmosphere was added CD1 (71.7 mg, 0.17 mmol) at 0 0C; warmed to RT and stirred for 2 h. To this were added (4-(trifluoromethoxy) phenyl) methanamine 172 (33.8 mg, 0.17 mmol), and diisopropyl ethyl amine (0.05 mL, 0.29 mmol) and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mass was diluted with water (15 mL) and stirred for 1 h. The precipitate was filtered or extracted with EtOAc or CH2C12 and the obtained solid was dried in vacuo or purified by column chromatography or triturated to afford the desired Procedure E: A stirred solution of 6 (40 mg, 0.14 mmol) in thionyl chloride (1 mL) under argon atmosphere was heated to 90 0C and stirred for 1 h. The reaction was monitored by TLC; after ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson completion of the reaction, the volatiles were removed in vacuo to obtain acid chloride (50 mg, crude) which was carried to the next step t further purification. To a stirred solution of 2- amino pyridine 181 (15 mg, 0.16 mmol) in CH2C12 (5 mL) under argon atmosphere were added pyridine (0.035 mL), acid chloride (50 mg, crude) at 0 0C; warmed to RT and stirred for 16 h.
The reaction was monitored by TLC; after completion of the reaction, the les were removed in vacuo to obtain the crude which was purified through silica gel column chromatography using 2% MeOH/ CH2C12 to afford the desired product.
Procedure F: To a d solution of compound 35 (50 mg, 0. 17 mmol) in CH2C12 (5 mL) under argon atmosphere were added ethyl 2-amino(pyridinyl) acetate hydrochloride 249 (26 mg, 0. 17 mmol), phosphonic anhydride (~50% solution in EtOAc, 0.22 mL, 0.34 mmol), NMM (0.037 mL, 0.34 mmol) at 0 0C; warmed to RT and d for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and diluted with water (20 mL) or the pH of the reaction mixture was adjusted to ~8 and extracted with CH2C12 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified either h silica gel column chromatography or triturated to afford the desired product.
Procedure G: To a stirred solution of compound 159 (100 mg, 0.33 mmol) in CH3CN (2 mL) under argon atmosphere was added thiazolamine 231 (36 mg, 0.36 mmol), propylphosphonic anhydride (~50% solution in EtOAc, 0.8 mL, 1. 32 mmol) and NMM (0.14 mL, 132 mol) at RT in a microwave vial and heated at 100 0C and stirred for l h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were d in vacuo and diluted with water (20 mL) and the precipitated solid was filtered. The obtained solid was either ly dried in vacuo or titurated or purified by column tography to afford the desired product.
Procedure H: To a stirred solution of compound 159 (100 mg, 0.33 mmol) in CH2C12 (12 mL) under argon atmosphere were added EDCI.HCl (188.8 mg, 0.98 mmol), 6-fluorobenzo [d] [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson thiazolamine 241 (61 mg, 0.36 mmol) and DMAP (120.7 mg, 0.98 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after tion of the reaction, the precipitated solid was filtered washed with water and titurated to afford the desired product.
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Representative Commercially Available Amines Used for Synthesis [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson CIH_H2N/\[_s/ /) L")/ H2N CI /N NED MUF Mm" 240 241 242 H2N «N \ NH2_2HC| H2N \N H2N \ O \ N | | EtOZC I / \ // /-N N // 244 245 246 247 248 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Preparation of amines for compound sis Synthesis of 2-cyclohexylethanamine hydrochloride (261): NH2 10% Pd/C NH2_HC| MeOH To a stirred solution of 2-(cyc10heX-l-en-l-yl) ethanamine 260 (500 mg, 4.00 mmol) in MeOH (10 mL) under argon atmosphere was added 10% Pd/C (50 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the on, the reaction mixture was filtered through celite, washed with MeOH (2 x 5 mL) and the filtrate was concentrated in vacuo. The residue was triturated with CH2C12: EtOAc (l: l, 2 mL), diethyl ether in l N HCl (4 mL) to afford compound 261 (250 mg, 38%) as white solid. TLC: 20% EtOAc/ s (Rf: 0.3); 1H-NMR (DMSO-dg, 500 MHz): 8 7.79 (br s, 2H), 2.77 (t, J: 7.5 Hz, 2H), 1.66-1.59 (m, 5H), 1.45-1.41 (m, 2H), .28 (m, 1H), 1.23-1.11 (m, 3H), 0.91-0.84 (m, 2H).
Synthesis of 2-(4-fluorophenoxy) ethanamine hydrochloride (265) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson CIACN 263 /—CN HCI,Pd/C OH —> F—O—O —> K2C03, acetone MeOH Synthesis of 2-(4-flu0r0phen0xy) acetonitrile (264): To a stirred solution of 4- fiuorophenol 262 (1.74 mL, 18.96 mmol) in acetone (50 mL) under argon atmosphere were added ium carbonate (6.5 g, 47.40 mmol), chloro acetonitrile 263 (1 mL, 15.80 mol) at RT; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered and the filtrate was trated in vacuo. The residue was extracted with diethyl ether (3 x 40 mL). The ed organic extracts were washed with NaOH solution (30 mL), water (30 mL), dried over sodium e, filtered and concentrated in vacuo to afford compound 264 (2.4 g, 90%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (CDCI3, 400 MHz): 5 7.06-7.01 (m, 2H), 6.98-6.89 (m, 2H), 4.73 (s, 2H).
Synthesis of 2-(4-flu0r0phen0xy) ethan-l-amine hydrochloride (265): To a stirred solution of compound 264 (200 mg, 1.32 mmol) in MeOH (10 mL) under argon atmosphere were added HCl (0.3 mL), Pd/C (90 mg) and stirred under hydrogen atmosphere (balloon pressure) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ted sodium potassium tartrate solution (20 mL) and extracted with diethyl ether (2 x 20 mL). The combined organic extracts were dried over sodium e, filtered and concentrated in vacuo to afford compound 265 (130 mg, 65%) as an ite solid. TLC: 10% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHZ): 5 8.31-8.28 (m, 2H), .12 (m, 2H), 7.02-6.98 (m, 2H), 4.16 (t, J: 5.2 Hz, 2H), 3.17 (t, J: 5.2 Hz, 2H).
Synthesis of 2-(4-flu0r0cyclohexyl) ethan-l-amine hydrochloride (269) [Annotation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 2] Synthesis of 2-(4-hydr0xycyclohexyl) acetonitrile (267): To a stirred solution of 2- (4-oxocyclohexyl) acetonitrile 266 (200 mg, 1.45 mmol) in EtOH (10 mL) under argon atmosphere was added sodium borohydride (82.7 mg, 2.18 mmol) at 0 0C; warmed to 10-15 0C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (2 mL) and the volatiles were removed in vacuo. The e was diluted with water (20 mL) and extracted with CH2C12 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and trated in vacuo to afford compound 267 (180 mg, 89%) as colorless syrup. TLC: 50% EtOAc/ s (Rf: 0.4); 1H-NMR (CDC13, 400 MHz): 5 3.62-3.55 (m, 1H), 2.30-2.24 (m, 2H), 2.06-2.01 (m, 2H), 1.92- 1.88 (m, 2H), 1.80-1.78 (m, 1H), 1.70-1.63 (m, 2H), 1.59-1.56 (m, 1H), 1.40-1.16 (m, 2H).
Synthesis of 2-(4-flu0r0cyclohexyl) acetonitrile (268): To a stirred solution of compound 267 (180 mg, 1.29 mmol) in CH2C12 (5 mL) under argon atmosphere was added DAST (313 mg, 1.94 mmol) at -20 0C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL) and extracted with CH2C12 (2 x 30 mL). The combined c extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ s to afford nd 268 (35 mg, 19%) as colorless syrup. TLC: 20% EtOAc/ s (Rf: 0.4); 1H-NMR (CDC13, 500 MHz): 5 4.88-4.79 (m, 1H), 2.27 (d, J: 7.0 Hz, 2H), 2.10-2.08 (m, 2H), 1.77-1.70 (m, 3H), 1.57-1.33 (m, 4H).
Synthesis of 2-(4-flu0r0cyclohexyl) ethan-l-amine hydrochloride (269): To a stirred solution of compound 268 (35 mg, 0.24 mmol) in ether (5 mL) under argon atmosphere was added lithium aluminium hydride (18.8 mg, 0.49 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mixture was quenched with saturated sodium potassium tartrate solution (10 mL) at 0-5 0C and extracted with ether (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was dissolved in ether (3 mL), slowly added 2 N HCl in ether (10 mL) and d for 1 h. The precipitated solid was filtered and dried in vacuo to afford nd 269 (12 mg, 33%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 7.81 (br s, 2H), 4.87 (br s, 1H), 4.75 (br s, 1H), 2.82-2.77 (m, 2H), 1.89-1.84 (m, 2H), 1.59-1.40 (m, 6H), 1.20 (t, J: 10.0 Hz, 2H).
Synthesis of 3-meth0xymethylbutan-l-amine (273) >420H TsCI >420" News —> —> MeO MeO MeO ne DMF 270 271 H2, Pd/C —> sz EtOH MeO Synthesis of 3-meth0xymethylbutyl 4-methylbenzenesulf0nate (271): To a stirred solution of 3-methoxymethylbutanol 270 (1 g, 8.46 mmol) in pyridine (15 mL) under argon here was added tosyl chloride (1.6 g, 8.46 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was quenched with saturated NaHC03 solution (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 271 (1.8 g, 78%) as colorless syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.7); 1H-NMR (CDC13, 400 MHz): 8 7.79 (d, J = 8.4 Hz, 2H), 7.34 (d, J: 7.6 Hz, 2H), 4.13 (t, J: 7.2 Hz, 2H), 3.10 (s, 3H), 2.45 (s, 3H), 1.87 (t, J: 7.6 Hz, 2H), 1.12 (s, 6H).
Synthesis of 1-azid0meth0xymethylbutane (272): To a stirred solution of compound 271 (1 g, 3.67 mmol) in DMF (10 mL) under argon here was added sodium azide (478 mg, 7.34 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson red by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulphate, d and concentrated in vacuo to afford compound 272 (525 mg, 76%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.7); 1H-NMR(CDC13, 400 MHz): 8 3.34 (t, J = 7.6 Hz, 2H), 3.18 (s, 3H), 1.78 (t, J=8.0 Hz, 2H), 1.18 (s, 6H).
Synthesis of 3-methoxymethylbutanamine (273): To a stirred solution of compound 272 (400 mg, 2.79 mmol) in EtOH (5 mL) under argon atmosphere was added 10% Pd/C (250 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was filtered h celite and the filtrate was trated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 80% EtOAc/ hexanes to afford compound 273 (320 mg, 33%) as colorless syrup. TLC: 70% EtOAc/ hexanes (Rf: 0.3); 1H- NMR (CDC13, 400 MHz): 8 3.18 (s, 3H), 2.80 (t, J: 8.0 Hz, 0.5 H), 2.70 (t, J: 7.6 Hz, 1H), 2.49 (t, J: 8.0 Hz, 0.5H), 1.71 (t, J: 7.6 Hz, 2H), 1.56 (s, 6H).
Synthesis of 3-phenyl(pyrrolidin-l-yl) propan-l-amine (277) ©/\/\ CN O LAH, H2804 Q ceric ammloinigm nitrate, ©A/CN THF 2 WNW 274 276 277 Synthesis of 3-phenyl(pyrrolidin-l-yl) propanenitrile (276): To a stirred solution of cinnamonitrile 274 (500 mg, 3.87 mmol) in H20 (15 mL) were added pyrrolidine 275 (412 mg, 5.80 mmol), ceric ammonium nitrate (2.1 g, 3.87 mmol) at RT, heated to 60 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined c extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column tography using 25% EtOAc/ hexanes to afford compound 276 (300 mg, 39%) as colorless syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (CDC13, 400 MHz): 5 7.39-7.31 (m, 5H), 3.50-3.35 (m, 1H), 2.80-2.70 (m, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 2H), 2.60-2.45 (m, 4H), 1.89-1.72 (m, 4H).
Synthesis of yl(pyrrolidinyl) propan-l-amine (277): To a stirred solution of compound 276 (150 mg, 0.75 mmol) in THF (10 mL) under argon atmosphere were added lithium aluminium hydride (57 mg, 1.50 mmol), H2SO4 (0.04 mL, 0.75 mmol) at 0 0C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated sodium sulphate and the reaction mixture was filtered through celite, washed with EtOAc (2 x 5 mL).The volatiles were removed in vacuo to afford compound 277(100 mg, 65%) as an off-white solid. TLC: 10% MeOH/ EtOAc (Rf: 0.3); 1H-NMR , 400 MHz): 8 7.31-7.30 (m, 5H), 3.26-3.22 (m, 1H), 2.59- 2.40 (m, 4H), 2.39-2.37 (m, 2H), 2.14-2.10 (m, 1H), 2.10 -2.04 (m, 1H), 1.98-1.72 (m, 6H).
Synthesis of 2-(5-methyl-1, 3, 4-0xadiazolyl) ethan-l-amine hydrochloride (283) EDC|.HCI, HOBt, Eth, CH20|2 4N HCI in 1, 4-Dioxane Eth, CHZCI2 CHZCI2 Synthesis of 3-((tert-but0xycarb0nyl) amino) propanoic acid (279): To a stirred solution of 3-aminopropanoic acid 278 (5 g, 51.02 mmol) in THF (50 mL) were added 1 M aqueous sodium hydroxide solution (25 mL) and Boc-anhydride (11.3 mL, 51.02 mmol) at 0 0C; warmed to RT and d for 12 h. The reaction was monitored by TLC; after completion of the reaction, the les were removed in vacuo. The aqueous layer was washed with l ether (2 x 50 mL) and the pH was adjusted to ~6 with 4 M HCl and extracted with diethyl ether (4 x 50 mL). The ed organic extracts were washed with brine (100 mL), dried over sodium sulphate, d and concentrated in vacuo to obtain compound 279 (8 g, 79%) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (DMSO-dg, 500 MHz): 5 12.18 (br s, 1H), 6.81 (t, J: 4.8 Hz, 1H), 3.11 (q, .1: 6.9 Hz, 2H), 2.34 (t, J: 7.1 Hz, 2H), 1.36 (s, 9H).
[Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of tert-butyl (3-(2-acetylhydrazinyl)0x0pr0pyl) carbamate (281) To a stirred solution of compound 279 (1 g, 5.29 mmol) in CH2C12 (15 ML) under argon atmosphere were added EDCI.HCl (1.3 g, 6.87 mmol), HOBt (714 mg, 5.29 mmol), triethyl amine (0.99 ML, 6.87 mmol), acetic acid hydrazide 280 (430 mg, 5.82 mmol) at 0 0C; warmed to RT and stirred for 1.5 h. The reaction was monitored by TLC; after completion of the reaction, the on mixture was diluted with ice cold water (5 mL) and extracted with CH2C12 (4 x 20 mL). The combined organic ts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 281 (610 mg, 50%) as an off white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 5 9.70 (s, 2H), 6.73 (t, J = 4.7 Hz, 1H), 3.13 (q, J: 6.6 Hz, 2H), 2.27 (t, J: 7.4 Hz, 2H), 1.83 (s, 3H), 1.37 (s, 9H).
Synthesis of tert-butyl methyl-1, 3, 4-0xadiazolyl) ethyl) carbamate (282): To a stirred solution of triphenyl phosphine (428 mg, 1.63 mmol) in CH2C12 (5 mL) under argon atmosphere were added iodine (414 mg, 1.63 mmol) and stirred for 15 min. To this were added triethyl amine (0.47 mL, 3.26 mmol), compound 281 (200 mg, 0.81 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 4% EtOAc/ hexanes to afford crude compound 282 (360 mg) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.7); 1H NMR shows mixture of compound and TPPO as major impurity. 1H-NMR (DMSO-dg, 400 MHz): 5 7.68-7.49 (m, PO as impurity), 6.97 (t, J: 5.0 Hz, 1H), 3.27 (q, .1: 6.5 Hz, 2H), 2.89 (t, J: 6.7 Hz, 2H), 2.43 (s, 3H), 1.35 (s, 9H).
Synthesis of 2-(5-methyl-1, 3, 4-0xadiazolyl) l-amine hydrochloride (283): To a stirred solution of compound 282 (350 mg) in CH2C12 (5 mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (4 mL) at 0 0C; warmed to RT and stirred for 4 h.
The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was titurated with CH2C12 (2 mL), diethyl ether (5 mL) and n-pentane (5 mL) and dried in vacuo to afford crude compound 283 (60 mg) as brown solid. TLC: 10% EtOAc/ hexanes (Rf: 0.1).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of (2-ethylthiazolyl) amine hydrochloride (292) H2N Et 287 I \ LiAIH4 tBuOK, M9804, EtOH \/O\'(ES>§Et Dry THF Diisopropyl Ether M5CL EtsN >\EtN TPP, THF: H20 / NaN3, DMF >~ —> DMAP, CH2C|2 4N HCI in 1, 4—dioxane Synthesis of ethyl 2-chlorooxopropanoate (286): To a stirred solution of ethyl 2- chloroacetate 284 (5 g, 40.98 mmol) and 285 (3.03 g, 40.98 mmol) in diisopropyl ether (100 mL) under argon atmosphere was added ium tert—butoxide (5.49 g, 45.08 mmol) portion wise for 10 min at 0 0C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was adjusted to ~ 6 using 5 N HCI.
The obtained solid was d, washed with diethyl ether (200 mL) and dried in vacuo to afford compound 286 (6 g) as pale brown syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.2); LC-MS: 21.49% + 75.58%; 149.0 (Mil); (column; X-Select C-l8, (50 X 3.0 mm, 3.5 um); RT 0.56 min, 0.77 min. 5 Mm Aq.NH4OAc: ACN 0.8 ).
Synthesis of ethyl 2-ethylthiazolecarboxylate (288): To a stirred solution of compound 286 (l g) in ethanol (25 mL) under argon atmosphere were added propanethioamide 287 (594 mg, 6.67 mmol), dry magnesium sulfate (4 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with EtOAc (2 X 100 mL). The ed organic extracts were washed with saturated sodium bicarbonate on (2 x 100 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 6% EtOAc/ hexanes to afford compound 288 (330 mg, 27%) as [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson brown syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz): 8 8.29 (s, 1H), 4.30 (q, .1: 7.1 Hz, 2H), 3.04 (q, .1: 7.5 Hz, 2H), 1.31 (t, J: 7.3 Hz, 3H), 1.29 (t, J: 7.3 Hz, 3H).
Synthesis of (2-ethylthiazolyl) methanol (289) (SAP-MA1426-31): To a stirred suspension of lithium aluminium e (205 mg, 5.40 mmol) in dry THF (15 mL) under inert atmosphere was added compound 288 (500 mg, 2.70 mol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 0C, quenched with 20% s sodium ide solution (3 mL), filtered through celite and washed with EtOAc (3 x 100 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford nd 289 (310 mg, 80%) as pale yellow solid. TLC: 50% EtOAc/ hexanes (Rf: 0.4).1H-NMR(CDC13, 400 MHz): 5 7.51 (s, 1H), 4.82 (s, 2H), 3.01 (q, J: 7.5 Hz, 2H), 1.38 (t, J: 7.6 Hz, 3H).
Synthesis of 5-(chloromethyl)ethylthiazole (290) (SAP-MA1426-34): To a stirred solution of compound 289 (300 mg, 2.09 mmol) in CH2C12 (15 ML) under inert here were added triethyl amine (0.6 mL, 4.20 mmol), DMAP (25.6 mg, 0.21 mmol) and mesyl chloride (0.19 mL, 2.51 mmol) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2C12 (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 290 (500 mg, crude) as pale yellow syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.8); LC-MS: ; 162.0 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 urn); RT 2.14 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of 5-(azidomethyl)ethylthiazole (291) (SAP-MA1426-35): To a d solution of compound 290 (500 mg, 2.26 mmol) in DMF (20 mL) under inert atmosphere was added sodium azide (294 mg, 4.52 mmol) at RT and heated to 80 0C for 16 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium e, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 15% EtOAc/ hexanes to afford [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson compound 291 (250 mg, 71%) as pale yellow syrup. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H- NMR (CDC13, 400 MHz): 5 7.56 (s, 1H), 4.49 (s, 2H), 3.03 (q, .1: 7.6 Hz, 2H), 1.40 (t, J: 7.6 Hz, 3H); sis of (2-ethylthiazolyl) methanamine hloride (292): To a stirred solution of compound 291 (250 mg, 1.48 mmol) in THF: H20 (5:1, 12 mL) was added triphenyl phosphine (780 mg, 2.97 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo to obtain the crude. The obtained solid was fiarther dried using toluene (2 x 5 mL) to obtain the crude amine.
The above compound was dissolved in CH2C12 (5 mL) added 4 N HCl in 1, 4- e (4 mL) under inert atmosphere at 0 0C and stirred for 30 min. The volatiles were removed in vacuo to obtain the crude, which was titurated with EtOAc (2 mL), l ether (2 mL) and pentane (5 mL) to afford compound 292 (180 mg, 68%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-dg, 500 MHz): 8 8.48 (br s, 3H), 7.74 (s, 1H), 4.25 (q, J: 5.5 Hz, 2H), 2.98 (q, J: 7.5 Hz, 2H), 1.28 (t, J: 7.5 Hz, 3H); Synthesis of (2-is0propylthiazol-S-yl) methanamine hydrochloride (298) MsCL EtsN | N; —> NaNg‘ DMF TPP, THF: H20 —> N\ I —> 3 < N3 DMAP, CH20|2 S 4N HCI in 1, 4-Dioxane 296 297 CIH_H2N\/[:\>‘< Synthesis of ethyl 2-is0propylthiazole-S-carboxylate (294): To a stirred solution of compound 286 (3.05 g) in ethanol (60 mL) under argon atmosphere were added 2- [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson methylpropanethioamide 293 (1.5 g, 14.56 mmol), dry magnesium sulfate (5 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with saturated sodium bicarbonate on (100 mL), extracted with EtOAc (3 x 100 mL). The ed organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 2% EtOAc/ hexanes to afford compound 294 (550 mg, 17%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.5); 1H NMR (500 MHz, DMSO-dg) 5 8.31 (s, 1H), 4.30 (q, .1: 7.0 Hz, 2H), 3.36-3.29 (m, 1H), 1.34 (d, J: 6.9 Hz, 6H), 1.29 (t, J: 7.1 Hz, 3H).
Synthesis of (2-is0propylthiazol-S-yl) methanol (295): To a stirred solution of compound 294 (550 mg, 2.76 mmol) in dry THF (10 mL) under inert atmosphere was added lithium aluminium hydride (210 mg, 5.52 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 0C, quenched with 15% aqueous sodium hydroxide solution (3 mL), filtered through celite and washed with EtOAc (100 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 295 (360 mg, 83%) as pale yellow syrup. TLC: 50% EtOAc/ hexanes (Rf: 0.3). 1H NMR (400MHz, DMSO-dg) 5 7.47 (s, 1H), 5.43 (t, J: 5.7 Hz, 1H), 4.61 (dd, J: 5.6, 0.6 Hz, 2H), 3.26-3.19 (m, 1H), 1.30 (d, J: 6.9 Hz, 6H).
Synthesis of or0methyl)is0pr0pylthiazole (296): To a stirred solution of compound 295 (350 mg, 2.23 mmol) in CH2C12 (20 mL) under inert atmosphere were added yl amine (0.64 mL, 4.45 mmol), DMAP (27.2 mg, 0.22 mmol) and mesyl de (0.2 mL, 2.67 mmol) at 0 0C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2C12 (2 x 100 mL). The combined c extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 296 (500 mg, crude) as pale yellow syrup.
TLC: 40% EtOAc/ hexanes (Rf: 0.8); LC-MS: 70.54%; 175.8 ; (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.34 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of domethyl)—2-is0propylthiazole (297): To a stirred solution of [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson compound 296 (500 mg, 2.26 mmol) in DMF (20 mL) under inert atmosphere was added sodium azide (445 mg, 6.85 mmol) at RT and heated to 80 0C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was d with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 8% EtOAc/ hexanes to afford compound 297 (255 mg, 63%) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf: 0.4); 1H NMR (500 MHz, DMSO-dg): = 7.67 (s, 1H), 4.69 (s, 2H), .24 (m, 1H), 1.32 (d, J: 6.9 Hz, 8H).
Synthesis of (2-is0propylthiazol-S-yl) methanamine hydrochloride (298): To a stirred solution of compound 297 (250 mg, 1.37 mmol) in THF: H20 (5:1, 12 mL) was added nyl phosphine (720 mg, 2.74 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were d in vacuo to obtain the crude. The obtained solid was further dried using toluene (2 x 5 mL) to obtain the crude amine.
The above crude compound was dissolved in CH2C12 (5 mL) added 4 N HCl in 1, 4- e (10 mL) under inert atmosphere at 0 0C and stirred for 30 min. The volatiles were removed in vacuo to obtain the crude, which was titurated with EtOAc (2 mL), diethyl ether (2 mL) and pentane (5 mL) to afford compound 298 (170 mg, 65%) as low melting hygroscopic solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (500 MHz, g): 8 8.29 (br s, 2H), 7.72 (s, 1H), 4.25 (d, J: 5.8 Hz, 2H), .24 (m, 1H), 1.30 (d, J: 6.9 Hz, 6H) Synthesis of (2-meth0xythiazolyl) methanamine (300) Synthesis of (2-meth0xythiazolyl) methanamine (300): Sodium metal (46.6 mg, 2.02 mmol) was added slowly to MeOH (5 mL) under argon atmosphere and stirred for 15 min in a sealed tube. To this was added (2-chlorothiazolyl) methanamine 299 (100 mg, 0.67 mmol) and the on mixture was heated to 80 0C for 3 h. The reaction was monitored by TLC; after completion the reaction, the reaction mixture was extracted with 20% MeOH/ CH2C12 (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson concentrated in vacuo to obtain the crude compound 300 (32 mg, 33%). The crude was carried forward for next step without purification. TLC: 5% MeOH/ CH2C12 (Rf: 0.2); LC-MS: 90.34%; 145.0 (M++1); (column; X-Select CSH C18, (50 X 3.0 mm, 3.5 um); RT 0.88 min. 2.5 mM Aq.NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq. NH4OOCH; 1.2 mL/min).
Synthesis of 5-(amin0methyl) thiazol-Z-amine dihydrochloride (303) N . . N [N (Boc)20 l >*NHBoc 4 N HCI In 1, ane l >‘NH2 HCI s s NC S)‘NH2 NaBH4, CH20|2 NHBoc NH2_ HCI MeOH 301 302 303 Synthesis of tert-butyl ((2-((tert-butoxycarbonyl) amino) thiazol-S-yl) methyl) carbamate (302): To a stirred solution of 2-aminothiazolecarbonitrile 301 (300 mg, 2.40 mmol) in MeOH (50 mL) were added Boc-anhydride (1.5 mL, 7.20 mmol), nickel(H) chloride (571 mg, 2.40 mmol) at 0 0C. To this was added sodium borohydride (638 mg, 16.80 mmol) portion wise for10 min at 0 0C; warmed to RT and d for 18 h. The reaction was red by TLC; after tion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (100 mL) and water (75 mL), filtered through celite. The organic layer was dried over sodium te, filtered and concentrated in vacuo to obtain compound 302 (300 mg) as colorless syrup. TLC: 10% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 500 MHz): 8 11.24 (br s, 1H), 7.38 (br s, 1H), 7.11 (s, 1H), 4.17 (d, J: 5.5 Hz, 2H), 1.39 (s, 9H), 1.37 (s, 9H).
Synthesis of 5-(amin0methyl) l-Z-amine dihydrochloride (303): To a stirred solution of compound 302 (300 mg) in CH2C12 (10 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under argon atmosphere at 0-5 0C; warmed to RT and stirred for 4 h. The on was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The obtained solid was washed with CH2C12 (5 mL), EtOAc (5 mL) and dried in vacuo to afford compound 303 (120 mg, HCl salt) as yellow solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-dg, 500 MHz): 8 9.31 (br s, 1H), 8.53 (br s, 2H), 8.14 (br s, 1H), 7.37 (br s, 1H), 7.27 (br s, 1H), 7.17 (br s, 1H), 4.07 (d, J: 5.5 Hz, 2H).
Synthesis of 4-(aminomethyl)-N-methylthiazol-Z-amine hydrochloride (308) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson NH2 (Boc)2O,E13N NHBOC MeNHz 306 '7 \ '1 Cl/Ks CHZCIZ Cl/Ks\ DIPEA 304 305 4 N HCI in 1,4—Dioxane CH2C|2 0] Synthesis of tert-butyl ((2-chlor0thiazolyl) methyl) carbamate (305): To a stirred solution of (2-chlorothiazolyl) methanamine 304 (200 mg, 1.35 mmol) in CH2C12 (10 mL) were added triethylamine (0.6 mL, 4.14 mmol) and Boc-anhydride (0.6 mL, 2.7 mol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was red by TLC; after completion of the reaction, the volatiles were removed in vacuo. The aqueous layer was washed with CH2C12 (50 mL), washed with water (50 mL). The organic extract was dried over sodium sulphate, filtered and trated in vacuo to obtain compound 305 (200 mg, 60%) as pale yellow sticky solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 8 7.56 (br s, 1H), 7.49 (s, 1H), 4.24 (d, J: 5.9 Hz, 3H), 1.39 (s, 9H). sis of tert-butyl ((2-(methylamin0) thiazolyl) methyl) carbamate (307): A mixture of compound 305 (100 mg, 0.41 mmol) and methyl amine 306 (5 mL, 33% solution in EtOH) in a sealed tube under argon atmosphere was added diisopropyl ethylamine (0.2 mL, 1.21 mmol) under argon here at RT and heated to 120 0C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was purified through silica gel column chromatography using 70% EtOAc/ hexanes to afford compound 307 (90 mg, 92%) as colorless sticky solid. TLC: 50% EtOAc/ hexanes (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 5 7.26 (d, J: 5.6 Hz, 2H), 6.77 (s, 1H), 4.05 (d, J: 5.7 Hz, 2H), 2.76 (d, J: 4.8 Hz, 3H), 1.38 (s, 9H).
Synthesis of 4-(aminomethyl)-N-methylthiazolamine hydrochloride (308) To a stirred solution of compound 307 (90 mg, 0.37 mmol) in CH2C12 (3 mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 0C; warmed to RT and stirred for 4 h. The [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was titurated with diethyl ether (5 mL) and dried in vacuo to afford compound 308 (70 mg, HCl salt) as brown solid. TLC: 30% EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO- d6, 400 MHz): 8 9.73-9.27 (m, 1H), 8.39 (br s, 3H), 7.35 (s, 1H), 4.08 (q, J: 5.3 Hz, 2H), 2.95 (s, 3H).
Synthesis of 4-(amin0methyl)—N, N—dimethylthiazol—Z-amine hydrochloride (310) NH(Me) HCI 3092 4 N HCIIn 1 4—Dioxane CIA;N{NHBOC —» DIPEACchN CHZCI2 Synthesis of tert-butyl ((2-(dimethylamin0) thiazolyl) methyl) carbamate (310): To a stirred solution of compound 305 (100 mg, 0.41 mmol) in CH3CN (3 mL) under argon atmosphere were added dimethyl amine hydrochloride 310 (648 mg, 8.06 mmol) and diisopropyl mine (0.2 mL, 1.21 mmol) in a sealed tube at RT and heated to 120 0C for 54 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (2 x 50 mL) washed with water (20 mL). The organic t was dried over sodium sulphate, d and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 310 (80 mg, 77%) as an off-white solid. TLC: 30% EtOAc/ s (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 5 7.29 (t, J: 4.8 Hz, 1H), 6.89 (s, 1H), 4.08 (d, J: 5.9 Hz, 2H), 2.97 (s, 6H), 1.38 (s, 9H). sis of n0methyl)—N, N—dimethylthiazol—Z-amine hydrochloride (311): To a stirred solution of nd 310 (100 mg, 0.38 mmol) in CH2C12 (3 mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 0C; warmed to RT and stirred for 4 h. The reaction was red by TLC; after completion of the reaction, the volatiles were [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson removed in vacuo. The crude was ted with diethyl ether (5 mL) and dried in vacuo to afford compound 311 (75 mg, HCl salt) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-dg, 400 MHz): 8 8.44 (br s, 3H), 7.38 (s, 1H), 4.10 (q, J: 5.6 Hz, 2H), 3.14 (s, 6H).
Synthesis of (4-ethylthiazolyl) methanamine hydrochloride (319) TPP THF: H20 v 3 C ZCIZ I Ii 8 CI IL; N3 Dioxane ] Synthesis of ethyl 2-chlor00x0pentanoate (313): To a stirred solution of ethyl 3- oxopentanoate 312 (l g, 6.94 mmol) in CH2C12 (20 mL) under argon atmosphere was added sulfuryl chloride (0.56 ML, 6.94 mmol) at 0 0C; warmed to RT and stirred for 6 h. The on was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford nd crude 313 (l g) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf: 0.5); 1H NMR (DMSO-dg, 400 MHz): 8 5.66-5.55 (m, 1H), 5.66-5.55 (m, 1H), 4.22 (q, J: 7.1 Hz, 3H), 2.73-2.67 (m, 2H), 1.22 (t, J: 7.1 Hz, 3H), 0.99 (t, J: 7.2 Hz, 3H).
Synthesis of ethyl 4-ethylthiazolecarb0xylate (315): To a stirred solution of compound 313 (l g, crude) in EtOH (10 mL) under inert atmosphere was added thioformamide 314 (3.3 g, 55.55 mmol) at RT; heated at 80 0C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the les were removed in vacuo to obtain the crude. The crude was purified through column tography using 40% EtOAc/ hexanes to ation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson afford compound 315 (300 mg, 30%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); LC- MS: 51.18%; 185.9 (M++l); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.24 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 ). 7] Synthesis of (4-ethylthiazolyl) methanol (316): To a stirred solution of compound 315 (300 mg, 1.62 mmol) in THF (10 mL) under inert atmosphere was added lithium aluminium hydride (123 mg, 3.24 mmol) at 0 0C; warmed to RT and stirred for l h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated 10% NaOH solution (1 mL), filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 30% EtOAc/ hexanes to afford compound 316 (200 mg, 86%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHZ): 5 8.86 (s, 1H), 5.45 (t, J: 5.5 Hz, 1H), 4.62 (d, J: 5.5 Hz, 2H), 2.67 (q, .1: 7.5 Hz, 2H), 1.17 (t, J: 7.5 Hz, 3H). sis of 5-(ch10r0methyl)ethylthiazole (317): To a stirred solution of compound 316 (200 mg, 1.39 mmol) in CH2C12 (10 mL) under inert atmosphere were added yl amine (0.4 mL, 4. 17 mmol), mesyl chloride (0.3 mL, 2.79 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was ed with saturated NaHC03 solution (5 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in vacuo to obtain compound 317 (200 mg, crude) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.7); 1H NMR (DMSO-dg, 400 MHz): 5 9.01 (s, 1H), 5.08 (s, 2H), 2.76 (q, J: 7.5 Hz, 2H), 1.20 (t, J: 7.5 Hz, 3H).
Synthesis of 5-(azid0methyl)ethylthiazole (318): To a stirred solution of compound 317 (400 mg, 2.48 mmol) in DMF (10 mL) under argon atmosphere was added sodium azide (322 mg, 4.96 mol) at RT; warmed to 80 0C and d for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic ts were dried over sodium sulphate, filtered and concentrated in vacuo to afford crude compound 318 (350 mg) as yellow liquid. The crude was carried forward for next step without further purification. TLC: 20% EtOAc/ hexanes (Rf: 0.5).
Synthesis of (4-ethylthiazolyl) methanamine hloride (319): To a stirred [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson solution of compound 318 (350 mg) in THF: H20 (4: 1, 20 mL) was added nyl phosphine (1.3 g, 5.20 mol) at RT and stirred for 3 h. The on was red by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude.
The crude was diluted with CH2C12 (2 mL) cooled to 0 0C; added 4 N HCl 1, 4- dioxane (5 mL) under argon atmosphere and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was titurated with diethyl ether (2 x 5 mL) dried in vacuo to afford compound 319 (136 mg) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf: 0.2); LC-MS: 89.95%; 142.9 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 1.29 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of (4-is0propylthiazol-S-yl) methanamine hydrochloride (327) {£023 MsCI, E13N NaNs CHZCI2 DMF Synthesis of ethyl 2-chlor0methyl0x0pentanoate (321): To a stirred solution of ethyl 4-methyloxopentanoate 320 (5 g, 31.64 mmol) in Toluene (50 mL) under argon atmosphere was added sulfuryl chloride (4.26 g, 31.64 mmol) at 0 0C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after tion of the reaction, the les were removed in vacuo to afford compound crude 321 (6 g) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.8).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of ethyl 4-is0propylthiazole-S-carboxylate (323): To a stirred solution of compound 321 (2.1 g) in ethanol (30 mL) under argon atmosphere was added thioformamide 322 (0.667 g, 10.93 mmol) at RT and heated to reflux for 30 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The e was diluted with EtOAc (200 mL), washed with saturated sodium bicarbonate on (100 mL). The organic extract was dried over sodium e, filtered and concentrated in vacuo to afford crude compound 323 (230 mg, 11%) as brown syrup. TLC: 10% EtOAc/ s (Rf: 0.5); LC-MS: 93.64%; 199.9 (M"+1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.49 min. 0.025% Aq. TFA -- 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of (4-is0propylthiazol-S-yl) methanol (324): To a stirred solution of compound 323 (230 mg, 1.15 mmol) in THF (10 mL) under inert atmosphere was added lithium aluminium e (87 mg, 2.28 mmol) at 0 0C; warmed to RT and stirred for 4 h. The on was monitored by TLC; after completion of the on, the reaction mixture was cooled to 0 0C, quenched with ice-cold water (10 mL), 15% aqueous sodium hydroxide solution (5 mL), filtered through celite and washed with EtOAc (100 mL). The filtrate was dried over sodium e, filtered and concentrated in vacuo to afford crude compound 324 (112 mg) as an off-white solid.
TLC: 20% EtOAc/ hexanes (Rf: 0.2).1H NMR dg, 400 MHz): 8 8.85 (s, 1H), 5.45 (t, J = 5.5 Hz, 1H), 4.64 (d, J: 5.5 Hz, 2H), 3.14-3.07 (m, 1H), 1.19 (d, J: 6.8 Hz, 6H).
Synthesis of 5-(chloromethyl)isopropylthiazole (325): To a d solution of compound 324 (112 mg) in CH2C12 (10 mL) under inert atmosphere were added triethyl amine (0.21 mL, 2.13 mmol), mesyl chloride (0.08 mL, 0.97 mmol) at 0 0C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2C12 (50 mL) washed with NaHC03 solution (50 mL), brine (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 325 (126 mg) as brown thick syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.8); LC- MS: 87.83%; 175.8 (M"+1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.30 min. 0.025% Aq. TFA -- 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of 5-(azidomethyl)—4-isopropylthiazole (326): To a stirred solution of compound 325 (126 mg, 0.53 mmol) in DMF (10 mL) under inert atmosphere was added sodium [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson azide (70 mg, 1.07 mmol) at RT and heated to 80 0C for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (75 mL) washed with water (50 mL). The c extract were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 326 (82 mg, 63%) as thick syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.7); 1H NMR (DMSO-dg, 500 MHz): 5 9.01 (s, 1H), 4.74 (s, 2H), 3.30- 3.21 (m, 1H), 1.21 (d,.]= 6.8 Hz, 6H); Synthesis of (4-is0propylthiazol-S-yl) methanamine hydrochloride (327): To a stirred on of compound 326 (80 mg, 0.43 mmol) in THF: H20 (4: 1, 10 mL) was added triphenyl phosphine (230 mg, 0.87 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The obtained solid was further dried using toluene (2 X 5 mL) to obtain the crude. 8] The crude nd was dissolved in CH2C12 (3 mL) added 4 N HCl in 1, 4-dioxane (2 mL) under inert atmosphere at 0 0C and stirred for 1 h. The volatiles were removed in vacuo to obtain the crude, which was washed with diethyl ether (2 mL) to afford compound 327 (42 mg, 50%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 9.02 (s, 1H), 8.26 (br s, 2H), 4.24 (q, J: 5.6 Hz, 2H), .17 (m, 1H), 1.19 (d, J: 6.8 Hz, 6H).
Synthesis of (4-chlor0thiazolyl) methanamine hydrochloride (337) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson N/gi HO\/\OH _ , )LS CH0 PTSA, e N aq HCI LAH IL; 2:] ’ N \ IL CHO Dry THF MsCI, EtsN /§: TPP THF: H20 —> N \ CH2C|2 L 4N HCI H Ls S N/:I_\N3 in 1 4—Dioxane 9] Synthesis of thiazolidine—2, 4-di0ne (329): To a stirred solution of roacetic acid 328 (5 g, 52.9 mmol) in H20 (10 mL) was added thiourea 314 (3.80 g, 52.9 mmol) at 0 0C d for 30 min added concentrated HCl (6 mL) dropwise for 15 min; heated at 110 0C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 0C and d for 30 min. The precipitated solid was filtered and dried in vacuo to afford compound 329 (3.2 g, 47%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.2); 1H NMR (400 MHz, DMSO-dg): 5 12.01 (br s. 1H), 4.15 (s, 2H).
Synthesis of 2, 4-dichlorothiazole-S-carbaldehyde (330): A mixture of compound 329 (2.7 g, 23.07 mmol) in DMF (1.23 mL, 15.98 mmol) at 0 0C under argon atmosphere was added phosphorous oxychloride (8.15 mL, 87.17 mmol) dropwise for 15 min at 0 0C; warmed to RT and stirred for l h; heated to 120 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice cold water slowly and extracted with CH2C12 (3 x 100 mL). The combined c ts were washed with saturated NaHC03 solution (100 mL), water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 5% EtOAc/ hexanes to afford compound 330 (1.4 g, 33%) as brown color ation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson oil. TLC: 30% EtOAc/ s (Rf: 0.8); 1H NMR (500 MHz, DMSO-dg): 8 9.87 (s, 1H).
Synthesis of 2,4-dichlor0(1, 3-di0xolanyl) thiazole (331): To a stirred solution of compound 330 (1.4 g, 7.73 mmol) in e (20 mL) under argon atmosphere was added ethane-1, 2-diol (1.43 g, 23.20 mmol), p-toluenesulfonic acid (133 mg, 0.77mmol) at 0 0C; heated at 110 0C and stirred for 5 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was quenched with 10% aqueous NaHC03 solution (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 10% EtOAc/ hexanes to afford compound 331 (1.7 g, 98%) as yellow oil. TLC: 10% EtOAc/ hexanes (Rf: 0.2); 1H NMR (400 MHz, CDC13)C 8 6.04 (s, 1H), 4.14-4.07 (m, 2H), 4.06-4.00 (m, 2H).
Synthesis of 4-chlor0(1, 3-di0xolanyl) le (332): To a stirred on of nd 331 (1.7 g, 7.55 mmol) in THF (20 ML) under argon atmosphere was added n-butyl lithium (3.9 mL, 9.82 mmol, 2.5 M solution in THF) dropwise for 10 min at -78 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 5% EtOAc/ s to afford compound 332 (1.1 g, 76%) as yellow oil. TLC: 10% EtOAc/ hexanes (Rf: 0.2); 1H NMR (CDC13,500 MHz): 8 8.74 (s, 1H), 6.16 (s, 1H), 4.19-4.15 (m, 2H), 4.08-4.04 (m, 2H).
Synthesis of 4-chlorothiazole—S-carbaldehyde (333): To a stirred solution of nd 332 (1.1 g, 5.75 mmol) in THF (10 mL) was added 5 N aqueous HCl in 1, 4-dioxane (6 mL) at 0 0C; warmed to RT and stirred for 3 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was poured into brine (20 mL) extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 333 (800 mg, 95%) as yellow oil. TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H NMR (CDC13,500 MHz): 5 10.11 (s, 1H), 9.00 (s, 1H).
[Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of (4-chlorothiazolyl) methanol (334): To a stirred solution of compound 333 (750 mg, 5.10 mmol) in dry THF (20 mL) under inert atmosphere was added lithium aluminium hydride (193 mg, 5.10 mmol) at 0 0C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the on, the on mixture was cooled to 0 0C, quenched with 30% aqueous sodium hydroxide solution (3 mL) extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and trated in vacuo to afford compound 334 (520 mg, 68%) as yellow oil. TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H NMR (CDC13,500 MHz): 5 8.69 (m, 1H), 4.88 (s, 2H).
Synthesis of orothiazolyl) methyl methanesulfonate (335): To a stirred solution of compound 334 (520 mg, 3.48 mmol) in CH2C12 (15 mL) under inert atmosphere were added triethyl amine (1.23 mL, 8.71 mmol) and mesyl chloride (0.34 mL, 4.18 mol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2C12 (2 x 50 mL). The combined organic extracts were washed with saturated NaHC03 (50 mL) dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 335 (600 mg, crude) as brown liquid. TLC: 10% EtOAc/ hexanes (Rf: 0.81H NMR (CDC13,500 MHz): 8 8.74 (s, 1H), 4.79 (s, 2H), 1.44 (s, 3H).
Synthesis of 5-(azidomethyl)chlorothiazole (336): To a d solution of compound 335 (600 mg, 2.64 mmol) in DMF (10 mL) under inert atmosphere was added sodium azide (343 mg, 5.28 mmol) at RT and heated to 100 0C for 4 h. The reaction was monitored by TLC; after completion of the on, the on mixture was diluted with ice cold water (100 mL) and extracted with diethyl ether (2 x 50 mL). The combined c extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 336 (250 mg, 54%) as yellow oil. TLC: 8% EtOAc/ hexanes (Rf: 0.5); 1H NMR (CDClg, 400 MHz) 5 8.74 (s, 1H), 4.58 (s, 2H).
Synthesis of (4-chlorothiazolyl) methanamine hydrochloride (337): To a stirred solution of compound 336 (250 mg, 1.43 mmol) in THF: H20 (3:1, 13 ML) was added triphenyl phosphine (752 mg, 2.87 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the residue was [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson acidified with 4 N HCl in l, 4-dioxane (2 mL) at 0 0C. The volatiles were d in vacuo and the obtained solid was washed with EtOAc (2 mL), diethyl ether (2 mL) to afford compound 337 (l 10 mg) as yellow solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 9.19 (s, 1H), 8.52 (br s, 3H), 4.24 (q, J: 5.6 Hz, 2H); Synthesis of 0xetanylmethanamine (341) o N2 o N CH3N02 2 o MsCI, E13N Pd(OH)2 —> —> / —> OH CHZCIZ MeOH O o 339 340 Synthesis of 3-(nitr0methyl) oxetanol (339): To a stirred solution of one 338 (500 mg, 0.69 mmol) in nitromethane (l .25 mL) under argon atmosphere was added triethyl amine (0.25 mL) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ hexanes to afford compound 339 (750 mg, 81%) as an off white solid. TLC: 30% EtOAc/ s (Rf: 0.3); 1H NMR (DMSO-dg, 400 MHz): 5 6.47 (s, 1H), 4.93 (s, 2H), 4.64 (d, J: 7.5 Hz, 2H), 4.49 (d, J: 7.3 Hz, 2H).
Synthesis of 3-(nitr0methylene) oxetane (340): To a stirred solution of compound 339 (750 mg, 5.63 mmol) in CH2C12 (10 mL) under inert atmosphere were added triethyl amine (3.17 mL, 22.55 mmol), mesyl chloride (1.20 mL, 15.50 mmol), at 0 0C; cooled -78 0C and stirred for l h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain crude. The crude was d through silica gel column chromatography using 25% EtOAc/ s to afford compound 340 (380 mg, 58%) as an off white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.51H NMR (CDClg, 400 MHZ): 5 6.94-6.92 (m, 1H), 5.68-5.64 (m, 2H), .36 (m, 2H).
Synthesis of 0xetanylmethanamine (341): To a stirred solution of compound 340 (500 mg, 4.34 mmol) in MeOH (10 mL) under inert atmosphere was added Pd(OH)2 (100 mg) at RT; heated at 45 0C stirred under hydrogen atmosphere (balloon pressure) for 5 h. The reaction was monitored by TLC; after completion of the reaction, the on mixture was filtered 1003594907 through celite and washed with MeOH (20 mL). The filtrate was evaporated in vacuo to obtain the crude which was triturated with diethyl ether (2 x 10 mL) to afford crude compound 341 (100 mg) as pale brown solid. TLC: 10% MeOH / CH2Cl2 (Rf: 0.2); Mass (m/z) (Agilent 6310 Ion Trap): 88.5 (M++1).
Synthesis of 2-(oxazolyl)ethanamine, TFA salt (347) 2] Synthesis of oxazolylmethanol (343): To a stirred solution of ethyl oxazole carboxylate 342 (2 g, 14.18 mmol) in EtOH (20 mL) under argon atmosphere was added sodium borohydride (1.07 g, 28.36 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (25 mL) and extracted with 5% MeOH/ CH2Cl2 (2 x 20 mL). The combined c extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2Cl2 to afford compound 343 (810 mg, 58%) as colorless syrup. TLC: 5% MeOH/ CH2Cl2 (Rf: 0.3); 1H-NMR (DMSO-d 6, 500 MHz): δ 8.28 (s, 1H), 7.04 (s, 1H), 5.36 (t, J = 6.0 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H). sis of 5-(chloromethyl) oxazole (344): To a stirred solution of compound 343 (800 mg, 8.08 mmol) in CH2Cl2: n-hexane (1: 1, 10 mL) under argon atmosphere was added thionyl chloride (1.2 mL, 16.16 mmol) at 0 °C; heated to reflux and stirred for 3 h. The reaction was monitored by TLC; after tion of the reaction, the reaction e was lized with saturated NaHCO3 solution (20 mL) and extracted with ether (2 x 20 mL). The combined organic ts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 344 (700 mg) as colorless syrup. TLC: 40% EtOAc/ hexanes (Rf: 0.5); 1H- NMR (CDCl3, 400 MHz): δ 7.89 (s, 1H), 7.10 (s, 1H), 4.62 (s, 2H). 1003594907 Synthesis of zolyl) acetonitrile (345): To a stirred solution of nd 344 (700 mg, 5.95 mmol) in DMF (8 mL) under argon atmosphere was added sodium e (1.02 g, 20.85 mmol) at RT; heated to 70 °C and stirred for 4 h. The reaction was red by TLC; after completion of the reaction, the reaction e was diluted with water (20 mL) and extracted with ether (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, ed and concentrated in vacuo to obtain the crude compound 345 (650 mg) as colorless syrup. TLC: 40% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (CDCl 3, 400 MHz): δ 7.89 (s, 1H), 7.10 (s, 1H), 3.84 (s, 2H).
Synthesis of tert-butyl (2-(oxazolyl) ethyl) carbamate (346): To a stirred solution of compound 345 (50 mg, 0.46 mmol) in MeOH (3 mL) under argon atmosphere were added Boc-anhydride (0.21 mL, 0.92 mmol), nickel chloride hexahydrate (11 mg, 0.04 mmol), sodium borohydride (122 mg, 3.24 mmol) portion wise for 5 min at 0 °C; warmed to RT and d for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with MeOH (10 mL), filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 346 (68 mg, 71%) as colorless syrup. TLC: 50% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (CDCl 3, 400 MHz): δ 7.82 (s, 1H), 6.85 (s, 1H), 4.64 (br s, 1H), 3.42-3.40 (m, 2H), 2.89 (t, J = 6.4 Hz, 2H), 1.43 (s, 9H).
Synthesis of zolyl)ethanamine, TFA salt (347): To a stirred solution of compound 346 (65 mg, 0.30 mmol) in CH2Cl2 (3 mL) under argon atmosphere was added trifluoro acetic acid (0.14 mL, 1.83 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 347 (50 mg) as colorless syrup. TLC: 60% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-d 6, 500 MHz): δ 8.30 (s, 1H), 7.85-7.79 (m, 2H), 7.02 (s, 1H), 3.10- 3.05 (m, 2H), 2.98 (t, J = 7.5 Hz, 2H).
Synthesis of 2-(thiazolyl)ethanamine, TFA salt (352) [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson OH CH3302C| CI NaCN CN N N DIPEA, CHZCI2 S EtOH: H20 S 348 349 NiCI2_ 6H20, NaBH4 N/\>_/—NHBoc TFA, CHZCIZ N|/\>_/_ Ls| ’ BOCQO, MeOH LS Synthesis of 5-(chlor0methyl) thiazole (349): To a stirred solution of thiazol ylmethanol 348 (1 g, 8.69 mmol) in CH2C12 (50 mL) under argon atmosphere were added mesyl de (1.09 g, 9.56 mmol) drop wise for 15 min, diisopropyl ethyl amine (1.23 g, 9.56 mmol) at 0-5 0C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were d in vacuo to obtain the crude. The crude was washed with saturated NaHC03 solution (20 mL) and d through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 349 (650 mg, 57%) as yellow liquid. TLC: 5% MeOH/ CH2C12 (Rf: 0.7); 1H-NMR (CDC13, 500 MHz): 8 8.84 (s, 1H), 7.86 (s, 1H), 4.84 (s, 2H).
Synthesis of 2-(thiazolyl) acetonitrile (350): To a stirred solution of nd 349 (650 mg, 4.92 mmol) in EtOH: H20 (4: 1, 10 mL) under argon atmosphere was added sodium cyanide (361 mg, 7.38 mmol) at RT; heated to 80 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 70% EtOAc/ hexanes to afford nd 350 (250 mg, 41%) as colorless olid. TLC: 70% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (CDC13, 500 MHz): 8 8.81 (s, 1H), 7.85 (s, 1H), 3.84 (s, 2H).
Synthesis of tert-butyl (2-(thiazolyl) ethyl) carbamate (351): To a stirred solution of compound 350 (50 mg, 0.40 mmol) in MeOH (3 mL) under argon atmosphere were added Boc-anhydride (175 mg, 0.80 mmol), nickel chloride drate (9.75 mg, 0.04 mmol), sodium borohydride (107 mg, 2.82 mmol) portion wise for 5 min at 0-5 0C; warmed to RT and [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the on mixture was filtered, washed with EtOAc (2 x 10 mL) and the e was concentrated in vacuo to obtain the crude. The crude was purified h silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 351 (20 mg, 22%) as brown solid. TLC: 70% EtOAc/ hexanes (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 5 8.92 (s, 1H), 7.65 (s, 1H), 6.98-6.96 (m, 1H), 3.15 (q, 2H), 2.95 (t, J: 6.8 Hz, 2H), 1.39 (s, 9H). sis of 2-(thiazol—5-yl) ethan-l-amine (352): To a stirred solution of compound 351 (20 mg, 0.08 mmol) in CH2C12 (3 mL) under argon atmosphere was added trifluoro acetic acid (60 mg, 0.53 mmol) at 0-5 0C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 352 (10 mg) as colorless liquid. The crude was carried to the next step without any further purification. TLC: 70% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 9.01 (s, 1H), 7.95-7.89 (m, 2H), 7.76 (s, 1H), 3.16-3.10 (m, 4H).
Synthesis of 2-(4-(pyrimidinyl) phenyl) ethan-l-amine (359) 6)?NH:56 Na co ,Pd(PPh N/ 2 m3"; 3") P(0-to|y|)3, Pd(OAC)2, H20 DIPEA, DMF g I % Pd/C NH2 Phl(OAC)2 Eth EtOH NaOH, THF: H20 Synthesis of 5-(4-br0m0phenyl) pyrimidine (355): To a stirred solution of 5- bromopyrimidine 353 (l g, 6.32 mmol) in DMF: H20 (4: l, 25 mL) were added sodium carbonate (1 g, 9.43 mmol) and (4-bromophenyl) boronic acid 354 (1.26 g, 6.32 mmol), purged under argon atmosphere for 30 min. To this was added Pd(PPh3)4 (731 mg, 0.63 mmol) at RT; heated to 80 0C and stirred for 2.5 h. The on was monitored by TLC; after completion of the reaction, the reaction mass was d through celite; the filtrate was diluted with water (100 [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 355 (1 g, 67%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (DMSO-dg, 500 MHz): 8 9.20 (s, 1H), 9.15 (s, 2H), 7.93 (d, J: 8.5 Hz, 2H), 7.74 (d, J: 9.0 Hz, 2H). sis of (E)(4-(pyrimidinyl) phenyl) acrylamide (357): To a stirred solution of 5-(4-bromophenyl) dine 355 (1 g, 4.27 mmol) in DMF (10 mL) under inert atmosphere was added acrylamide 356 (364 mg, 5.12 mmol) at RT and purged under argon for min. To this were added 0-tolyl phosphine (142 mg, 0.47 mmol), Pd(OAc)2 (4.78 mg, 0.021 mmol), and diisopropyl ethyl amine (0.9 mL, 7.32 mmol) at RT; heated to 130 0C and stirred for h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite washed with 50% MeOH/ CH2C12 (2 x 10 mL), the e was concentrated under d pressure to afford the crude. The crude was washed with 50% MeOH/ CH2C12 (2 x 15 mL), dried in vacuo to afford compound 357 (600 mg, 62%) as white solid. TLC: 40% EtOAc/ hexanes (Rf: 0.2); 1H NMR (400MHz, DMSO-ds) 8 9.23-9.16 (m, 3H), 7.88 (d, J: 8.3 Hz, 2H), 7.72 (d, J: 8.3 Hz, 2H), 7.56 (br s, 1H), 7.48 (d, J: 15.9 Hz, 1H), 7.14 (br s, 1H), 6.70 (d, J: 15.9 Hz, 1H).
Synthesis of 3-(4-(pyrimidinyl) ) propanamide (358): To a stirred solution of compound 357(150 mg, 0.64 mmol) in EtOH (4 mL) under inert atmosphere were added 10% Pd/ C (50 mg) and triethylamine (0.092 mL, 0.64 mol) at RT and stirred under H2 (balloon re) for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The e was concentrated in vacuo to obtain the crude which was purified by silicagel column chromatography using 3% MeOH/ CH2C12 to afford compound 358 (65 mg, 43%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.2); 1H- NMR (DMSO-dg, 400 MHz): 5 9.16 (s, 1H), 9.12 (s, 2H), 7.72 (d, J: 8.0 Hz, 2H), 7.37 (d, J: 8.0 Hz, 2H), 7.29 (br s, 1H), 6.76 (br s, 1H), 2.87 (t, J: 8.0 Hz, 2H), 2.39 (t, J: 8.0 Hz, 2H).
Synthesis of 2-(4-(pyrimidinyl) phenyl) ethan-l-amine (359): To a stirred solution of compound 358 (65 mg, 0.28 mmol) in THF: H20 (1 :1, 3 mL) were added NaOH (128 mg, 0.91 mmol), phenyl-lt3-iodanediyl diacetate (92 mg, 0.28 mmol) at 0 0C and stirred for 1 h.
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson The reaction was monitored by TLC; after completion of the reaction, the pH of the on mixture was adjusted to ~ 2 using 3 N HCl and extracted with CH2C12 (2 x 50 mL). The pH of the aqueous layer was basified to ~ 8 with 3 N NaOH, extracted with THF (2 x 100 mL). The combined organic extracts were dried over sodium sulphate, d and concentrated in vacuo to afford crude compound 359 (40 mg) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H- NMR (DMSO-dg, 400 MHz): 8 9.16 (s, 1H), 9.11 (s, 2H), 7.72 (d, J: 8.4 Hz, 2H), 7.37 (d, J: 8.0 Hz, 2H), 2.81-2.66 (m, 2H), 1.78-1.69 (m, 2H).
Synthesis of 2-(2-phenylpyrimidin-S-yl) ethan-l-amine hloride (366) B(OH)2 HI, CH N— 2CI2 G362 w)8.
N Pd(PPh3)4 N32C03 DMF 0::}B.
% Pd/C E13N EtOH 51¢qu P(Mob/031 Pd(OAC)2,DMF NTNHBoc 4N HCIin1,4-Dioxane NH2_HCI Phl(OAc)2,NaOH ©. CH2CI2 (BOC)20, THF. H20 Q/KN ] Synthesis of 5-bromoiodopyrimidine (361): To a stirred solution of 5-bromo chloropyrimidine 360 (1 g, 5.16 mmol) in CH2C12 (10 mL) was added hydrogen iodide (5 mL, 57% aqueous solution) at -10 0C; warmed to 0 0C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was quenched with solid K2C03 (2 g), diluted with water (100 mL) and extracted with CH2C12 (2 x 100 mL). The ed organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude compound 361 (1.4 g, 94%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf: 0.7); 1H-NMR (DMSO-dg, 400 MHz): 5 8.55 (s, 2H).
Synthesis of 5-br0mo-Z-phenylpyrimidine (363): To a stirred solution of compound [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 361 (1.4 g) in DMF: H20 (4:1, 20 mL) were added sodium carbonate (783 mg, 7.39 mmol) and phenylboronic acid 362 (451 mg, 3.69 mmol), purged under argon for 30 min. To this was added Pd(PPh3)4 (570 mg, 0.49 mmol) at RT; heated to 80 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mass was filtered through celite; the e was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated in vacuo to obtain the crude. The crude was purified through silica gel column tography using 2% EtOAc/ hexanes to afford compound 363 (400 mg, 35%) as white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.9); 1H-NMR (DMSO-dg, 400 MHz): 8 8.83 (s, 2H), 8.41-8.39 (m, 2H), 7.50-7.48 (m, 3H).
Synthesis of (E)—3-(2-phenylpyrimidin-S-yl) acrylamide (364): To a stirred on of nd 363 (300 mg, 1.28 mmol) in DMF (20 mL) under inert atmosphere was added acrylamide 356 (109 mg, 1.53 mmol) at RT and purged under argon for 10 min. To this were added 0-tolyl ine (42 mg, 0.07 mmol), palladium acetate (15.7 mg, 0.07 mmol), and diisopropyl ethyl amine (0.28 mL, 1.53 mmol) at RT; heated to 140 0C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted water (100 mL) and extracted with 10% MeOH/ CH2C12 (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude compound was triturated with 50% EtOAc/ hexanes (10 mL) and dried in vacuo to afford compound 364 (50 mg, 17%) as an off-white solid. TLC: 70% EtOAc/ s (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 9.10 (s, 2H), 8.43-8.41 (m, 2H), 7.64 (br s, 1H), 7.55-7.54 (m, 3H), 7.47 (d, J: 16.0 Hz, 1H), 7.22 (br s, 1H), 6.85 (d, J: 16.0 Hz,1H).
Synthesis of 3-(2-phenylpyrimidinyl) propanamide (365): To a stirred solution of compound 364 (50 mg, 0.22 mmol) in EtOH (2 mL) under inert atmosphere were added triethyl amine (0.032 mL, 0.22 mmol), 10% Pd/ C (17 mg, dry) at RT and stirred under hydrogen atmosphere (balloon pressure) for 4 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude which was triturated with 10% EtOAc/ n-pentane (2 x 5 mL) and dried in vacuo to afford compound 365 (30 mg, 60%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 8 8.76 (s, 2H), .35 (m, 2H), 7.52-7.50 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (m, 3H), 7.31 (br s, 1H), 6.80 (br s, 1H), 2.85 (t, .1: 7.2 Hz, 2H), 2.46 (t, .1: 7.2 Hz, 2H).
Synthesis of tert-butyl (2-(2-phenylpyrimidin-S-yl) ethyl) carbamate (366): To a stirred solution of compound 365 (15 mg, 0.06 mmol) in THF (2 mL) were added sodium hydroxide (8 mg, 0.2 mmol) in water (0.5 mL), phenyl-lf—iodanediyl diacetate (21 mg, 0.06 mmol) at 0 0C and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 366 (10 mg, 51%) as sticky solid. TLC: 50% EtOAc/ hexanes (Rf: 0.9); 1H-NMR (CDC13, 400 MHz): 8 8.65 (s, 2H), 8.42-8.40 (m, 2H), 7.49-7.47 (m, 3H), 4.62 (br s, 1H), 3.43-3.38 (m, 2H), 2.84 (t, J: 7.2 Hz, 2H), 1.43 (s, 9H).
Synthesis of 2-(2-phenylpyrimidinyl) l-amine hydrochloride (367): To a d solution of compound 366 (80 mg, 0.35 mmol) in CH2C12 (3 ML) was added 4N HCl in 1, 4-Dioxane (0.7 mL) under argon atmosphere at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude and was washed with 20% CH2C12/ n-pentane (2 x 5 mL) and dried in vacuo to afford compound 367 (50 mg, HCl salt) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.1); 1H-NMR dg, 400 MHz): 5 8.84 (s, 2H), 8.40-8.37 (m, 2H), 8.07 (br s, 2H), 7.54- 7.52 (m, 3H), 3.19-3.14 (m, 2H), 2.97 (t, J: 7.2 Hz, 2H).
Synthesis of (4-(pyrimidinyl) phenyl) methanamine (372) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson MsCI, Et3N CH2C|2 THF: H20 Synthesis of (4-(pyrimidinyl) phenyl) methanol (369): To a stirred solution of 4- (pyrimidiny1) benzaldehyde 368 (500 mg, 2.71 mmol) in MeOH (20 mL) under argon atmosphere and sodium borohydride (155 mg, 39.99 mmol) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, les were removed in vacuo. The residue was diluted with brine solution (100 mL), extracted with EtOAc (2 x 50 mL). The ed organic extracts were dried over sodium te, filtered and concentrated in vacuo to obtain the crude. The crude was purified h silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 369 (260 mg, 51%) as white solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (CDCI3, 500 MHz): 8 9.20 (s, 1H), 8.93 (s, 2H), 7.58 (d, J: 8.5 Hz, 2H), 7.53 (d, J: 8.0 Hz, 2H), 4.79 (s, 2H).
Synthesis of 4-(pyrimidinyl) benzyl methanesulfonate (370): To a stirred solution of compound 369 (260 mg, 1.39 mmol) in CH2C12 (10 mL) under argon atmosphere were added triethyl amine (0.3 mL, 2.09 mmol), methane sulfonyl chloride (0.16 mL, 2.09 mmol) at 0 0C; warmed to RT and stirred for 14 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL), washed with % NaHC03 solution (30 mL), dried over sodium sulfate, d and concentrated in vacuo to obtain crude nd 370 (300 mg) as thick syrup. The crude was carried to the next step without further purification. TLC: 5% MeOH/ CH2C12 (Rf: 0.4).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 5-(4-(azid0methyl) phenyl) pyrimidine (371): To a stirred solution of compound 370 (300 mg, crude) in DMF (6 mL) under argon atmosphere was added sodium azide (74 mg, 1.13 mmol) at RT; heated to 60 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude. The crude was purified h silica gel column tography using 20% EtOAc/ hexanes to afford nd 371 (45 mg) as colorless thick syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.6); 1H-NMR(CDC13, 400 MHz): 5 9.22 (s, 1H), 8.96 (s, 2H), 7.61 (d, J: 8.4 Hz, 2H), 7.48 (d, J: 8.0 Hz, 2H), 4.43 (s, 2H).
Synthesis of (4-(pyrimidinyl) phenyl) methanamine (372): To a stirred solution of compound 371 (40 mg, 0.18 mmol) in THF: H20 (9:1, 2 mL) was added triphenyl phosphine (74 mg, 0.28 mmol) at RT and stirred for 16 h. The on was monitored by TLC; after tion of the reaction, the volatiles were d in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH2C12 to afford compound 372 (23 mg, 66%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H- NMR (DMSO-d6, 400 MHz): 5 9.21 (s, 1H), 9.17 (s, 2H), 8.27 (br s, 2H), 7.87 (d, J: 8.0 Hz, 2H), 7.64 (d, J: 8.4 Hz, 2H), 4.07 (s, 2H).
Synthesis of (2-phenylpyrimidinyl) methanamine (377) ©_<\N3%: NaBH4 MeOH N:/>_/OH—>MsCI Et3NCH20|2 flyomsN_ 374 375 DMF <34:DJ THF: H20 (3%:\N— Synthesis of (2-phenylpyrimidinyl) methanol (374): To a stirred solution of 2- phenylpyrimidine-S-carbaldehyde 373 (200 mg, 1.08 mmol) in MeOH (20 mL) under argon [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson atmosphere was added sodium borohydride (74 mg, 2.17 mmol) at 0 0C; warmed to RT and d for 2 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL), extracted with EtOAc (2 x 50 mL). The combined c extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 374 (135 mg, 65%) as colorless solid. TLC: 40% EtOAc/ MeOH (Rf: 0.3); 1H-NMR dg, 500 MHz): 5 8.83 (s, 2H), 8.40-8.38 (m, 2H), 7.53-7.51 (m, 3H), 5.45 (t, J: 5.5 Hz, 1H), 4.58 (d, J: 5.5 Hz, 2H). sis of (2-phenylpyrimidinyl) methyl methanesulfonate (375): To a stirred solution of compound 374 (130 mg, 0.69 mmol) in CH2C12 (5 mL) under argon atmosphere were added triethyl amine (0.4 mL, 2.09 mmol) and methane sulfonyl chloride (0.07 mL, 0.84 mmol) at 0 0C; warmed to RT and stirred for 30 min. The reaction was red by TLC; after completion of the reaction, the reaction mixture was diluted CH2C12 (50 mL), washed with water (2 x 20 mL). The organic t was dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude compound 375 (150 mg) as yellow oil. The crude was carried to the next step without further ation. TLC: 50% EtOAc/ hexanes (Rf: 0.5); 1H- NMR (DMSO-dg, 500 MHz): 9.00 (t, J: 10.0 Hz, 2H), 8.42-8.41 (m, 2H), 7.56-7.55 (m, 3H), .40 (s, 2H), 3.32 (s, 3H).
Synthesis of 5-(azidomethyl)—2-phenylpyrimidine (376): To a stirred solution of compound 375 (150 mg) in DMF (6 mL) under argon here was added sodium azide (56 mg, 0.76 mmol) at RT; heated to 60 0C and stirred for 2 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with diethyl ether (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 376 (60 mg, 49%) as colorless syrup. TLC: 40% EtOAc/ hexanes (Rf: 0.9); 1H NMR (DMSO-dg, 400 MHz): 8 8.94 (s, 2H), 8.41 (dd, J: 6.8, 3.0 Hz, 2H), 7.56-7.53 (m, 3H), 4.63 (s, 2H).
Synthesis of (2-phenylpyrimidinyl) methanamine (377): To a stirred solution of compound 376 (90 mg, 0.42 mmol) in THF: H20 (9:1, 4 mL) was added triphenyl phosphine ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (167 mg, 0.63 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified h silica gel column chromatography using 10% MeOH/ CH2C12 to afford compound 377 (30 mg, 38%) as yellow solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-da 500 MHz): 5 8.96 (s, 2H), 8.40 (d, J: 3.9 Hz, 2H), 7.59-7.45 (m, 3H), 6.84 (br s, 2H), 4.01 (s, 2H).
Synthesis of thiazol—S-amine hydrochloride (380) "/OF1N DPPA, Et N N 4N HCI in 1,4-Dioxane 3 41—3(\ t—BuOH s NHBoc MeOH 378 379 Synthesis of tert-butyl thiazol—S-ylcarbamate (379): To a stirred solution of thiazolecarboxylic acid 378 (400 mg, 3.1 mmol) in t—butanol (6 mL) were added diphenylphosphonic azide (1.34 mL, 6.18 mmol) and triethyl amine (0.89 mL, 6.18 mmol) at RT and heated to 100 0C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the les were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 379 (300 mg, 48%) as white solid. TLC: 50% EtOAc/ hexanes (Rf: 0.8); 1H-NMR (DMSO-dg, 400 MHz): 8 10.60 (br s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 1.49 (s, 9H).
Synthesis of thiazol—S-amine hydrochloride (380): To a d solution of compound 379 (300 mg, 1.5 mmol) in MeOH (5 mL) was added 4 N HCl in 1, 4-Dioxane (5 mL) under argon atmosphere at 0 0C; warmed to RT and stirred for 3 h. The on was monitored by TLC; after completion of the reaction, the volatiles were d in vacuo to obtain the crude. The crude was washed with n-pentane (2 X 5 mL) and dried in vacuo to afford compound 380 (150 mg, HCl salt) as pale yellow solid. TLC: 50% EtOAc/ hexanes (Rf: 0.1); 1H-NMR (DMSO-dg, 500 MHz): 5 9.10 (s, 1H), 7.22 (s, 1H).
Synthesis of imidinyl) aniline (383) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 5-(3-nitr0phenyl) pyrimidine (382): To a stirred on of 5- bromopyrimidine 353 (2 g, 12.58 mmol) and (3-nitrophenyl) boronic acid 381 (2.3 g, 13.84 mmol) in 1, 2-dimethoxy ethane: H20 (4: 1, 20 mL) under inert atmosphere were added sodium carbonate (2.66 g, 25.17 mmol) at RT and purged under argon here for 20 min. To this was added Pd(PPh3)4 (726 mg, 0.62 mmol) and heated to 110 0C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, d and concentrated in vacuo to obtain the crude. The obtained solid was filtered, dried in vacuo to obtain the crude which was purified through gel column chromatography in 50% EtOAc/ hexanes to afford nd 382 (2.5 g, 68%) as an off-white solid. TLC: 60% EtOAc/ hexanes (Rf: 0.3); 1H NMR (DMSO-dg, 400 MHz): 8 9.27 (s, 3H), 8.66-8.63 (m, 1H), 8.37-8.25 (m, 2H), 7.84 (t, J: 8.0 Hz, 1H).
Synthesis of 3-(pyrimidinyl) aniline (383): To a stirred solution of compound 382 (1.7 g, 8.45 mmol) in EtOH (30 mL) under inert atmosphere was added 10% Pd/C (500 mg) under argon atmosphere and stirred under H2 atmosphere (balloon pressure) for 5 h. After completion of the reaction, the reaction mixture was filtered through celite, washed with 5% MeOH/ CH2C12 (50 mL). The filtrate was concentrated in vacuo to obtain the crude which was triturated with mixture of ether: pentane (1:1, 10 ML) and dried in vacuo to afford compound 383 (1.2 g, 86%) as an ite solid. TLC: 70% % EtOAc/ hexanes (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 5 9.15 (s, 1H), 9.00 (s, 2H), 7.17 (t, J: 7.8 Hz, 1H), 6.91 — 6.86 (m, 2H), 6.69-6.64 (m, 1H), 5.27 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 3-(pyrimidinyl) aniline (386) Pd(PPh3)4 Na2003, DME CI NaOAc, EtOAc Synthesis of 2, 4-dichlor0(3-nitrophenyl) pyrimidine (385): To a d solution of 2, 4, hloropyrimidine 384 (500 mg, 2.76 mmol) and (3-nitrophenyl) boronic acid 382 (594 mg, 2.76 mmol) in 1, thoxy ethane (10 mL) under inert atmosphere were added sodium carbonate (878 mg, 8.28 mol) at RT and purged under argon atmosphere for 20 min.
To this was added Pd(PPh3)4 (159 mg, 0.13 mmol) and heated to 80 0C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was d through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 10% EtOAc/ s to afford crude compound 385 (200 mg) as yellow solid which was carried forward for next step. TLC: 10% EtOAc/ hexanes (Rf: 0.7).
Synthesis of 3-(pyrimidinyl) e (386): To a stirred on of compound 385 (200 mg, crude) in EtOAc (50 mL) under inert atmosphere were added sodium acetate (304 mg, 3.71 mmol), 10% Pd/C (100 mg, wet) under argon atmosphere and stirred under H2 atmosphere (balloon pressure) for 6 h. After completion of the reaction, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2C12 (50 mL). The filtrate was concentrated in vacuo to obtain the crude which was purified through silicagel column chromatography in 90% EtOAc/ hexanes to afford compound 386 (100 mg, 78%) as an off-white solid. TLC: 70% % EtOAc/ hexanes (Rf: 0.4); 1H NMR (400 MHZ, DMSO-dg): 5 9.19 (s, 1H), 8.80 (d, J: 5.4 Hz, 1H), 7.91 (dd, J: 5.4, 1.4 Hz, 1H), 7.45-7.43 (m, 1H), 7.30 (d, J: 7.7 Hz, 1H), 7.18 (t, J: 7.8 Hz, 1H), 6.74 (d, J: 7.5 Hz, 1H), 5.31 (s, 2H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 3-(thiazolyl) aniline (389) 3)4, N82C03 2-methyl THF To a stirred solution of 5-bromothiazole 387 (350 mg, 2.13 mmol) in 2-methy1THF (5 mL) under inert atmosphere were added 3-aminopheny1boronic acid pinacol ester 388 (600 mg, 2.35 mmol), sodium ate (565 mg, 5.33 mmol), at RT and stirred under argon atmosphere for 20 min. To this was added f)2C12 (78 mg, 0.106 mmol) and heated to 110 0C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 80% EtOAc/ hexanes to afford compound 389 (200 mg, 52%) as yellow syrup. TLC: 70% EtOAc/ hexanes (Rf: 0.4); LC-MS: 84.49%; 176.8 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 1.40 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of 3’-amin0-[1, 1’-biphenyl]ol (392) H2N Br 5'; Nazcos, Pd(0Ac)2, U ‘OH—> O MeOH O HO H0 390 391 To a stirred solution of 3-bromoani1ine 390 (400 mg, 2.32 mmol) and (4- yphenyl) boronic acid 391 (353 mg, 2.55 mmol) in MeOH (4 mL) under inert atmosphere were added sodium carbonate (493 mg, 4.65 mmol) at RT and purged under argon here for 20 min. To this was added Pd(OAc)2 (156 mg, 0.23 mmol) and heated to 80 0C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (20 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography in 20% EtOAc/ hexanes to afford compound 392 (160 mg) as brick red solid. TLC: 30% EtOAc/ ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson hexanes (Rf: 0.4); LC-MS: 67.89%; 185.9 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.10 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min) .
Synthesis of 5-phenyloxazolamine (396) 4-Dioxane sis of 2-br0m0phenylacetaldehyde (394): To a stirred on of 2- phenylacetaldehyde 393 (500 mg, 4.16 mmol) in 1, 4-Dioxane (2 mL) under inert atmosphere was added bromine (0.27 mL, 4.99 mmol) at 0 0C and stirred for 20 min; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford crude compound 394 (800 mg) as green syrup. The crude was carried forward for next step without fiarther purification. TLC: 10% EtOAc/ hexanes (Rf: 0.7); Synthesis of 5-phenyloxazolamine (396): To a stirred solution of compound 394 (800 mg, crude) in EtOH (10 mL) under inert atmosphere was added urea 395 (482 mg, 8.04 mmol) at RT; heated at 80 0C and stirred for 6 h. The reaction was red by TLC; after completion of the on, the volatiles were removed in vacuo and the residue was diluted with water (60 mL). The pH was neutralized with 10% aqueous NaHC03 solution (10 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column tography using 2-3% MeOH/ CH2C12 to afford compound 396 (200 mg, 32%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (400 MHz, DMSO- d6): 5 7.45 (d, J: 7.2 Hz, 2H), 7.36 (t, J: 7.8 Hz, 2H), 7.21-7.16 (m, 2H), 6.81 (s, 2H); Synthesis of 5-phenylthiazolamine (397) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 5-phenylthiazolamine (397): To a d solution of 2-bromo phenylacetaldehyde 394 (860 mg, crude) in EtOH (20 mL) under inert atmosphere was added thiourea (658 mg, 8.64 mmol) at RT; heated at 80 0C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were d in vacuo to obtain the crude. The pH of the residue was neutralized with 10% aqueous NaHC03 solution (10 mL) and extracted with EtOAc (2 x 200 mL). The ed organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 2-3% MeOH/ CH2C12 to afford compound 397 (500 mg, 66%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.6); 1H NMR (400 MHz, DMSO-dg): 5 7.43-7.38 (m, 3H), 7.32 (t, J: 7.8 Hz, 2H), 7.17 (tt, J: 7.5, 0.9 Hz, 1H), 7.12 (s, 2H).
Synthesis of 1-meth0xy(pyrimidinyl) propan-Z-amine hloride (401) Triethyl benzyl N \ OMe N \ OH ammonium chloride m / NHBoc m / NHBOC N N Mel, 50% aq.NaOH, 398 399 4N HCI m 1,4 Dloxane. . _ \ N \ OMe l / rum/Wow/ NH2_HC| NHBoc CH20|2 N Synthesis of utyl (1-hydroxy(pyrimidinyl) propan-Z-yl) carbamate (399): To a stirred solution of methyl 2-((tert—butoxycarbonyl) amino)—3-(pyrimidinyl) propanoate 398 (200 mg, 0.71 mmol) in MeOH (5 mL) under inert atmosphere was added sodium borohydride (105 mg, 2.84 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with 10% MeOH/ CH2C12 (5 x 25 mL). The combined [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8% MeOH/ CH2C12 to afford nd 399 (110 mg, 61%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 8 8.99 (s, 1H), 8.61 (s, 2H), 6.70 (d, J: 9.0 Hz, 1H), 4.82 (t, J: 5.4 Hz, 1H), 3.61 (br s, 2H), 3.45-3.34 (m, 2H), 2.93-2.82 (m, 1H), 1.26 (s, Synthesis of tert-butyl (1-meth0xy(pyrimidinyl) propan-Z-yl) carbamate (400): To a stirred solution of compound 399 (100 mg, 0.39 mmol) in THF (10 mL) were added triethyl benzyl ammonium chloride (9 mg, 0.03 mmol), 50% aqueous sodium hydroxide solution (3.5 mL) and methyl iodide (0.02 mL, 0.39 mmol) at 0 0C; warmed to RT and stirred for 24 h.
The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried over sodium sulfate, ed and concentrated in vacuo to obtain the crude.
The crude was purified through silica gel column chromatography using 3% MeOH/ CH2C12 to afford compound 400 (70 mg, 67%) as ess syrup. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 400 MHz): 8 9.00 (s, 1H), 8.62 (s, 2H), 6.84 (d, J: 8.8 Hz, 1H), 3.78 (brs, 2H), 3.29-3.23 (m, 5H), 2.85 (dd, J: 13.8, 4.1 Hz, 1H), 1.28-1.21 (m, 9H). 2] sis of 1-meth0xy(pyrimidinyl) propan-Z-amine hydrochloride (401): To a stirred solution of compound 400 (60 mg, 0.22 mmol) in CH2C12 (3 mL) was added 4 N HCl in 1, 4-Dioxane (1 mL) under argon atmosphere at 0 0C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the on, the volatiles were removed in vacuo to obtain the crude. The crude was washed with n-pentane (2 x 5 mL) and dried in vacuo to afford compound 401 (40 mg, HCl salt) as brown solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.1); 1H NMR (DMSO-dg, 400 MHz): 8 9.11 (s, 1H), 8.75 (s, 2H), 8.24 (br s, 2H), 3.68-3.59 (m, 1H), 3.53-3.48 (m, 1H), 3.39 (dd, J: 10.5, 5.7 Hz, 1H), 3.30 (s, 3H), 2.95 (t, J: 7.3 Hz, 2H). sis of 4-(2-amin0ethyl)—N, N—dimethylbenzenesulfonamide hydrochloride (406) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H.HC| /N\ 309 ne, THF i) TPP, THF: H20 ii) 1, 4—Dioxane—HCI Synthesis of 4-(2-bromoethyl) benzenesulfonyl chloride (403): To a stirred solution of (2-bromoethyl) benzene 402 (5 g, 27.02 mmol) in CH2C12 (15 mL) under argon atmosphere was added chlorosulfonic acid (5.4 mL, 81.08 mmol) at 0 0C; warmed to RT and d for 3 h. The reaction was monitored by TLC; after completion the reaction, the on mixture was poured into ice-cold water (100 mL) extracted with CH2C12 (2 x 150 mL). The combined organic extracts were washed with brine (100 mL), separated dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 403 (5 g) as colorless thick syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 8 8.00 (d, J = 8.4 Hz, 2H), 7.47 (d, J: 8.8 Hz, 2H), 3.62 (t, J: 7.2 Hz, 2H), 3.30 (t, J: 7.2 Hz, 2H).
Synthesis of 4-(2-bromoethyl)-N, N—dimethylbenzenesulfonamide (404): To a stirred on of compound 403 (5 g, crude) in THF (100 mL) under argon atmosphere were added pyridine (14.37 mL, 176.05 mmol), dimethylamine hydrochloride 309 (7.1 g, 88.02 mmol) at 0 0C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion the reaction, the volatiles were removed in vacuo. The residue was diluted with CH2C12 (500 mL) and washed with 1 N HCl (15 mL). The c layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude. The crude was titurated with pentane (30 mL) and dried in vacuo to afford compound 404 (3.5 g, 68%) as an off-white solid. TLC: 20% EtOAc/ hexane (Rf: 0.5); 1H NMR (CDC13, 400 MHZ): 5 7.74 (d, J: 8.4 Hz, 2H), 7.39 (d, J: ation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 8.5 Hz, 2H), 3.60 (t, .1: 7.2 Hz, 2H), 3.25 (t, .1: 7.3 Hz, 2H), 2.72 (s, 6H). ] sis of 4-(2-azid0ethyl)-N, thylbenzenesulfonamide (405): To a stirred solution of compound 404 (500 mg, 1.71 mmol) in DMF (10 mL) under inert atmosphere was added sodium azide (335 mg, 5.15 mmol) at RT and heated to 80 0C for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was d with ice-cold water (20 mL) and extracted with CH2C12 (2 x 200 mL). The combined organic extracts were dried under sodium sulfate, d and concentrated in vacuo to afford compound 405 (350 mg, 80%) as thick syrup. TLC: 20% EtOAc/ hexane (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 5 7.73 (d, J: 8.4 Hz, 2H), 7.40 (d, J: 6.8 Hz, 2H), 3.56 (t, J: 6.8 Hz, 2H), 2.97 (t, J: 6.8 Hz, 2H), 2.71 (s, 6H).
Synthesis of 4-(2-amin0ethyl)-N, thylbenzenesulfonamide hydrochloride (406): To a stirred solution of compound 405 (350 mg, 1.37 mmol) in a mixture of THF: H20 (4:1, 10 mL) was added triphenyl phosphine (1.08 g, 4.13 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% MeOH/ CH2C12 to afford free amine (200 mg) as thick syrup.
To a stirred solution of the free amine (200 mg) in CH2C12 (2 mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (0.5 mL) at 0 0C and stirred for 10 min. The volatiles were removed in vacuo to obtain the crude which was washed with diethyl ether (2 x 5 mL) and dried in vacuo to afford compound 406 (125 mg, 35%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 8.04 (br s, 2H), 7.70 (d, J: 8.4 Hz, 2H), 7.54 (d, J: 8.4 Hz, 2H), 3.15-3.05 (m, 2H), 3.01-2.98 (m, 2H), 2.60 (s, 6H).
Synthesis of 4-(3-amin0pr0pyl)—N, N—dimethylbenzenesulfonamide hydrochloride (410) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H.HC| Br /N\ pyridine, THF N3 i) TPP, THF: H20 ii) 1, ane—HCI Synthesis of 4-(3-bromopropyl) benzenesulfonyl chloride (407): To a d solution of (2-bromoethy1) benzene 402 (5 g, 27.02 mmol) in CHC13 (15 mL) under argon atmosphere was added chlorosulfonic acid (5.4 mL, 81.08 mmol) at 0 0C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion the reaction, the reaction mixture was poured into ice-cold water (100 mL) extracted with CH2C12 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 407 (5 g) as colorless thick syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.4); 1H NMR (CDC13, 400 MHz): 5 7.97 (d, J: 8.8 Hz, 2H), 7.45 (d, J: 8.8 Hz, 2H), 3.40 (t, J: 6.4 Hz, 2H), 2.93 (t, J: 7.2 Hz, 2H), .17 (m, 2H).
Synthesis of 4-(3-chloropropyl)—N, N—dimethylbenzenesulfonamide (408): To a d solution of compound 407 (5 g, crude) in THF (100 mL) under argon atmosphere were added pyridine (14.42 mL, 176.6 mmol), dimethylamine hydrochloride 309 (7.2 g, 88.33 mm01) at 0 0C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion the reaction, the volatiles were d the in vacuo. The residue was diluted with water (100 mL) and extracted with CH2C12 (2 x 100 mL). The combined organic ts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 408 (3 g) as white sticky solid. TLC: 20% EtOAc/ hexanes (Rf: 0.5); 1H NMR (CDC13, 400 MHz): 8 7.71 (d, J: 8.4 Hz, 2H), 7.37 (d, J: 8.0 Hz, 2H), 3.53 (t, J: 6.4 Hz, 1H), 3.40 (t, J: 6.4 Hz, 1H), 2.87 (t, J: 7.2 Hz, 2H), 2.71 (s, 6H), 2.23-2.08 (m, 2H).
Synthesis of 4-(3-azidopropyl)—N, N—dimethylbenzenesulfonamide (409): To a stirred on of compound 408 (3 g, 9.83 mmol) in DMF (50 mL) under inert atmosphere was [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson added sodium azide (1.91 g, 29.50 mmol) at RT and heated to 70-80 0C for 2 h. The on was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice- cold water (20 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried under sodium sulfate, filtered and concentrated in vacuo to afford compound 409 (2 g, 76%) as colorless thick syrup. TLC: 20% EtOAc/ hexane (Rf: 0.6); 1H NMR (CDC13, 500 MHz): 8 7.71 (d, J: 8.1 Hz, 2H), 7.36 (d, J: 8.1 Hz, 2H), 3.32 (t, J: 6.7 Hz, 2H), 2.82-2.77 (m, 2H), 2.71 (s, 6H), 1.98-1.91 (m, 2H).
Synthesis of 4-(3-amin0pr0pyl)—N, N—dimethylbenzenesulfonamide hydrochloride (410): To a stirred solution of compound 409 (2.35 g, 8.76 mmol) in a mixture of THF: H20 (4: 1, 100 mL) was added triphenyl phosphine (6.89 g, 26.30 mmol) at RT and d for 16 h. The reaction was monitored by TLC; after completion of the on, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column tography using 15% MeOH/ CH2C12 to afford free amine (2 g) as thick syrup.
To a stirred solution of the above compound (2 g) in CH2C12 (20 mL) under argon here was added 4 N HCl in 1, 4-dioxane (10 mL) at 0 0C and stirred for 10 min. The solvent was decanted and the obtained solid was dried in vacuo to afford compound 410 (1.5 g, 70%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 5 8.08 (br s, 3H), 7.68 (d, J: 8.4 Hz, 2H), 7.50 (d, J: 8.4 Hz, 2H), 2.81-2.75 (m, 4H), 2.59 (s, 6H), 1.94-1.86 (m, 2H).
Synthesis of 3'-methoxy-[1, 1'-biphenyl]amine (412) HZNB\©/+M€000; Pd(PPh3)4, Na2003 e: MeOH To a stirred solution of 3-bromoaniline 390 (1 g, 5.81 mmol) and (3 -methoxyphenyl) boronic acid 411 (883 mg, 5.81 mmol) in Toluene: MeOH (1 :1, 20 mL) under inert atmosphere were added sodium carbonate (2.15 g, 20.34 mmol in 10 mL of H20) at RT and purged under argon atmosphere for 20 min. To this was added Pd(PPh3)4 (335 mg, 0.28 mmol) and heated to [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 100 0C for 16 h. The reaction was monitored by TLC; after tion of the reaction, the reaction mixture was filtered h celite, washed with 50% MeOH/ CH2C12 (150 mL). The filtrate was evaporated in vacuo to obtain the crude which was purified through silica gel column chromatography in 70% EtOAc/ hexanes to afford compound 412 (500 mg, 54%) as yellow thick syrup. TLC: 70% EtOAc/ hexanes (Rf: 0.5); 1H NMR (400 MHz, CDC]3)C 8 7.35-7.30 (m, 1H), 7.25-7.19 (m, 1H), 7.17-7.13 (m, 1H), 7.10-7.08 (m, 1H), 7.00-6.96 (m, 1H), 6.92-6.85 (m, 2H), 6.68-6.65 (m, 1H), 3.85 (s, 3H), 3.72 (br s, 2H); Synthesis of 3'-amin0-[1, 1'-biphenyl]ol (413) A e of compound 412 (400 mg, 2.01 mmol) in hydrogen iodide (5 mL, 57% aqueous solution) was refluxed for 5 h. The on was monitored by TLC; after completion of the reaction, the on mixture was quenched with ice-cold water and the pH was neutralized with 10% sodium bicarbonate solution (5 mL) and extracted with EtOAc (2 x 50 mL). The combined c extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The obtained solid was filtered, dried in vacuo to obtain the crude which was purified through silicagel column chromatography in 80% EtOAc/ hexanes to afford compound 413 (200 mg, 54%) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf: 0.4); 1H NMR (400 MHz, g): 5 9.41 (s, 1H), 7.20 (t, J: 7.8 Hz, 1H), 7.06 (t, J: 7.8 Hz, 1H), 6.99-6.88 (m, 2H), 6.78-6.76 (m, 1H), 6.73-6.68 (m, 2H), 6.55-6.52 (m, 1H), 5.12 (s, 2H).
Synthesis of 2-(tetrahydr0furanyl) ethan-l-amine hydrochloride (415) i) LAH, ether,RT, 16 h C|H_H2N ii) 4 N HCI in 1, 4-Dioxane 6] To a stirred solution of 2-(tetrahydrofi1ranyl) acetonitrile 414 (2 g, 17.99 mmol) in [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ether (20 mL) under argon atmosphere was added lithium aluminium hydride (1.36 g, 35.83 mmol) at 0 0C; warmed to RT and d for 16 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was quenched with saturated sodium potassium tartrate solution (30 mL) at 0-5 0C and extracted with ether (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.
The crude was dissolved in CH2C12 (5 mL) cooled to 0 0C and added 4 N HCl in 1, 4- dioxane (10 mL) under argon atmosphere and d at the same temperature for 30 min. The volatiles were removed in vacuo. The obtained solid was titurated with CH2C12 (2 x 5 mL) and in vacuo to afford compound 415 (500 mg, HCl salt) as sticky solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2).
Synthesis of 2-(4-(2H-1, 2, 3-triazolyl) phenyl) ethan-l-amine hydrochloride (421) N \ F K2CO3, DMF CH0 2 CHgCOONH4 10% Pd/C —>N\ —>N\ CH2N02, ACOH HCI, MeOH Synthesis of 4-(2H-1, 2, 3-triazolyl) benzaldehyde & 4-(1H-1, 2, 3-triazolyl) benzaldehyde (418 & 419): To a d solution of 4-fluorobenzaldehyde 417 (2 g, 16 mmol) in DMF (50 mL) under argon atmosphere were added 1H—1, 2, 3-triazole 417 (1.32 g, 19.2 mmol), potassium carbonate (3.3 g, 24 mmol) at RT; heated to 100 0C and d for 5 h. The on was monitored by TLC; after completion of the on, the reaction mixture was diluted with ice cold water (35 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 418 (800 mg, 29%) and using 40% EtOAc/ hexanes to afford compound 419 (1 g, 36%) as yellow solids.
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Compound 418 analytical data: TLC: 20% EtOAc/ hexanes (Rf: 0.8); 1H-NMR (DMSO-dg, 400 MHz): 8 10.05 (s, 1H), 8.27 (s, 2H), 8.25 (d, J: 8.8 Hz, 2H), 8.11 (d, J: 8.8 Hz, 2H).
Compound 419 analytical data: TLC: 20% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz):510.07(s, 1H), 8.98 (s, 1H), 8.19 (d, J: 8.8 Hz, 2H), 8.13 (d, J: 8.8 Hz, 2H), 8.04 (s, 1H). sis of (4-(2-nitrovinyl) phenyl)-2H-1, 2, 3-triazole (420): To a stirred on of compound 418 (400 mg, 2.31 mmol) in AcOH (10 mL) under argon atmosphere were added nitromethane (1.41 mL, 23.12 mmol), ammonium acetate (267 mg, 3.46 mol) at RT; heated to 100 0C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the les were removed in vacuo and diluted with water (20 mL). The obtained solid was filtered, washed with n-hexane and dried in vacuo to afford compound 420 (400 mg, 80%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 5 .18 (m, 4H), 8.13-8.05 (m, 4H).
Synthesis of 2-(4-(2H-1, 2, 3-triazol—2-yl) phenyl) ethanamine hydrochloride (421): To a stirred solution of compound 420 (200 mg, 0.92 mmol) in MeOH (10 mL) under argon here were added 10% Pd/C (100 mg), HC1 (0.2 mL) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was triturated with 2 M HC1 in EtZO (2 x 5 mL) and dried in vacuo to afford compound 421 (100 mg, 48%) as an off-white solid. TLC: % EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 5 8.16 (s, 2H), 8.12 (br s, 2H), 7.98 (d, J: 8.4 Hz, 2H), 7.46 (d, J: 8.4 Hz, 2H), 3.10-3.05 (m, 2H), 2.96 (t, J: 8.4 Hz, 2H).
Synthesis of benzyl (4-(4-(2-aminoethyl) phenoxy) butyl) carbamate hydrochloride (427) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (Boc)20, 1 M aq.NaOH 1 4—Dioxane ONNHCbz 4 N HCI in 1, 4—Dioxane Cbz—CI, Eth CH20|2 Synthesis of tert-butyl (4-hydr0xyphenethyl) carbamate (423): To a stirred on of 4-(2-aminoethyl) phenol 422 (1 g, 7.29 mmol) in 1, 4-dioxane: H20 (1: 1, 30 mL) were added 2 M aqueous sodium hydroxide solution (2 mL) and Boc-anhydride (1.9 mL, 8.25 mmol) at 0 0C; warmed to RT and stirred for 3 h. The on was monitored by TLC; after completion of the reaction, the pH of the reaction mixture cooled to 0 0C, acidified with 1 M HCl to ~3 and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium te, filtered and concentrated in vacuo to afford compound 423 (1.5 g, 87%) as an ite solid. TLC: 50% EtOAc/ hexanes (Rf: 0.8); 1H NMR (DMSO-dg, 500 MHz): 8 9.15 (s, 1H), 6.95 (d, J: 8.4 Hz, 2H), 6.83 (t, J: 5.4 Hz, 1H), 6.64 (d, J: 8.1 Hz, 2H), 3.09-3.00 (m, 2H), 2.56-2.51 (m, 2H), 1.35 (s, 9H).
Synthesis of benzyl r0xybutyl) carbamate (425): To a stirred solution of 4- aminobutan-l-ol 424 (1.0 g, 11.23 mmol) in CH2C12 (15 mL) under argon atmosphere were added yl amine (1.78 mL, 12.35 mmol) and benzyl chloroformate (1.76 mL, 12.35 mmol, 50% solution in toluene) at 0 0C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride (50 mL) at 0 0C. The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 425 (2.1 g, 84%) as colorless . TLC: 50% EtOAc/ hexanes (Rf: 0.5); 1H NMR (DMSO-dg, 500 MHz): 8 7.40- 7.22 (m, 6H), 4.98 (s, 2H), 4.37 (t, J: 5.1 Hz, 1H), 3.36 (q, .1: 5.8 Hz, 2H), 2.97 (q, .1: 6.3 Hz, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 2H), 1.51-1.28 (m, 4H).
Synthesis of tert-butyl (4-(4-(((benzyloxy) carbonyl) amino) butoxy) phenethyl) carbamate (426): To a stirred solution of compound 423 (1.5 g, 6.32 mmol) and compound 425 (1.4 g, 6.32 mmol) in THF (50 mL) under argon atmosphere at 0 0C were added triphenyl phosphine (1.65 g, 6.32 mmol), diisopropyl azodicarboxylate (1.4 mL, 6.96 mmol) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was dissolved in % EtOAc/ hexanes (5 mL) and the precipitated solid was filtered, washed with hexane (20 mL), dried in vacuo to afford nd 426 (1.9 g, 68%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.7); 1H NMR (DMSO-dg, 500 MHz): 5 8.89 (s, 1H), 7.68-7.51 (m, 5H), 7.40-7.24 (m, 2H), 7.07 (d, J: 8.4 Hz, 1H), 6.88-6.78 (m, 2H), 5.00 (s, 2H), 4.80-4.73 (m, 2H), 3.91 (t, J: 6.4 Hz, 2H), 3.11-3.02 (m, 2H), 2.60 (t, J: 7.5 Hz, 2H), 1.72-1.64 (m, 2H), 1.56- 1.52 (m, 2H), 1.18 (d, J: 6.1 Hz, 9H). 6] Synthesis of benzyl (4-(4-(2-aminoethyl) phenoxy) butyl) carbamate hydrochloride (427): To a stirred solution of compound 426 (500 mg, 1.13 mmol) in CH2C12 (5 mL) was added 4 N HCl in 1, 4-di0xane (3 mL) under argon atmosphere at 0-5 0C; warmed to RT and d for 3 h. The on was red by TLC; after completion of the on, the les were d under reduced pressure. The obtained solid was washed with diethyl ether (10 mL), n-pentane (10 mL) and dried in vacuo to afford compound 427 (200 mg, 47%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.4); 1H NMR (DMSO-dg, 500 MHz): 8 7.88 (br s, 3H), 7.39-7.28 (m, 5H), 7.15 (d, J: 8.7 Hz, 2H), 6.88 (d, J: 8.7 Hz, 2H), 5.00 (s, 2H), 3.93 (t, J = 6.4 Hz, 2H), 3.04 (q, J: 6.7 Hz, 2H), 2.97 (d, J: 6.4 Hz, 2H), .76 (m, 2H), 1.73-1.65 (m, 2H), 1.57-1.51 (m, 2H).
Synthesis of 4-phenyloxazolamine (429) [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson {000347} Synfhssis (3f yiaxazai-2namfine (4293: T75 a SEEYI‘SfE soEuEien (53737577051104— 775716713735:31277137 ~00: 4328 (100 mg 0. 50 mm:3m CHgCN (5 ml) under inert amnesphels was added urea 3.535 (303 mg, 502 mmoi) a: RT; iteawdat 80%Land stirred for 36 h. The: reaction was 5007550 by ELC; after comp} 57071 05" the rsamion 3’15: V’3‘38EEESS W‘f‘fé) removed 7’77 vaczm to 0775257711756 crude. The (trade was: purified thmugh flash coiumn 7.550735100170573 us:11g 343% EEOAC/ hexanes to 2573:0773 compound 429 {50 mg 63%) as an offwwhitr: solid. TLC: 50% 331075.07" hexanes (EV: 0.63; EH NMR (400 MHZ, 330188-6153: <3 7.36 (s. 1H), 7.63 (d, .]= 7.0 H95, 2H37’.53 {3, J 7.6 Hz, 21-33,?26-722 (m. EH3, 6.70 (s, 2H).
Tabie 1: Synthesis 0f ndts {mm mmpounds 5, 3.49 23.. 28, 35, 42, 50, 55, 623, '70, 76, 82, 88 537.303,332,318,124, 135, 340, 145. 150. 355. 356. 359,164,367, 370, P42 and varifius amines K’E NMR 7EEEE; ; ; V312. DM80 E E d5) 8 10.178 (S, - 5.- 3333.33.62.05 4’73": ‘ ; ; 5.6532, 1553, 3 E i ‘ 7 E 75 E 1101 3,5 5: 7475.77.77.71y £2,175,570 E E 5733367-57 932;;.E E E Agsz. E T ,‘f’ E ‘ 7 (m, 6H), 7.26 ("U37+; 52+. . : 7 (. . ; i ; ; 5915354775 ; E I 6642,3775 ; e 287: 77 5 - 7 552.277).
."""""""" E" E "7 1H NMR 7477:) M552, DMSO— .56) 5 10.725 7's. .-— ‘ . 5;, 11:3. 8 6\/' EE. .EM 554.55 573752; ‘35). "=70? D 75 5 5043048 r 150170 77145707 " " 7 "’ " (N. 555, 75547.70 ; 75337537 7m.675).5,50 * ’ 7713:5355; 2133.23] (7.5 7.1 152,275), 2.52.715. 63-33.
D 365 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson IENMRMOO 1 MHz" 1319133 E 1 1 1 (11.15 10.711 (3, 1 I 1 I 1 111), 8,611 (1,11: 1 I 1 I I 5.5 HZ, 1H), 1 I 1 I 1 I 7.717.59{m, 1 I 1 I 1 I 453.0943 3H), 7.53 (d, J 1 I ‘ for 1 : 1 8.3 Hz, 1 i 11111 1 ‘ . 1 1 1 1 i 1), (1 213 453.0936 7.51. "1' 1 1723112111213 1 I 1:11:( 1 I 432 1 I 1 I (14114)+ 1 1 I 1 I 1 I 1 I 1 I 1 I 1 I 1 I 1 I 1 I 3111.3441:1, 1 I 1 I 1 I =6914-2, 2111, 1 I 1 I 1 I 2.81) (1,J= 7.4 1 I 1 I 1 : Hz, 211). 1 1131111111450" 1 i MHZ, 131111310~ 1 I 1 1 11115 111.7119, 1 1 1 1 1 1 1 1 1 111), 8251.1 (1,! 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 373.1016 1 1 1 1 1 1 1 .i ' Fer L 1 I I 04 1 373.1129A i (3 I 1 1 1 1 1 1 1 1 1 (322141 713120 1 1 1 1 1 1 1 1 1 1 1 1 280114-111 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1411:; [11111.01 4118 10576111, 1H), 3.43 {1, .6 Hz 111), I I I —739 (m, 1 381.1637 13H),758»7401 0,11 110‘ 8613 for 1m 4H1328~ 3,17 (1111,2111 28(M-1E-111" I 1.73 4531111, 6H), 1.37 (11,2 : 7.9 Hz, 2141, 1.324 1.1.13 (111, 3H), 0.8.7 11:11.: 115,111 Hz, 2H).
[Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson I H NMR (400 MHZ D‘1V480- ('-)(710.7 7(5, "DEI0801,. 361 [UN for ,lH‘I. 44.; (d.., = 6. (7 Hz, 2H). 171‘4MU400 Mil-{2, DMSO I 173- I (13:) 5 .76 (s, I 1H), 8.52 (1,1 I §I I I I I I 5.6 Hz, I I 17-17;, I I I I I 389.1324 I I I 7'11760{.1 I II 7 I I I for I 1108 I 3 I I H), 7.60 07 3.42 __2A22v,,_,_,_,_,_,______________________.I__ I I gC33H3N30 I I I I I (m 4H),7 I I I ; 23(41417 7.73 (m, 5H), . 23 (q, .12 6.6 Hz, 2H), 2. 59 (t J:77 Hz ..7. ~ 7.74 (711.27%). 403.1480 SE 403.1496 (3/:ng3NQ; 3.7171++H)" xi }:7’ 41{L9 2H), 1.03 — L44? (m, 4H).
. I‘m (460 MHZ, DI'VY1‘1SO— d,)5 10.77I is. 17-1), 8.65 (t, J= .6 Hz, 7H), 7 .33 (I. .7: 87: 65 1447,1162!'("7473130 {,2 3H),?.78 3SNa (MNa‘:l [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 1 3 ‘ 1111-1231130: ‘ = (1615107811, 473.1399 "935313" 1 g for j D, 6 L» 0*. 47311319 3 (3131112950 ZSNa i 3 (mm? 1 21-11, 2.215 (1,1: 1 7211;221-11, ‘ """"""""""i"—"""""""""WMW . , 1 g : £59814" 1 1161910781 1 1'61" 5 ‘1 1 £16, . i .,- .AEIH\912(1:: 82 5459.11:4 1 ququNa "’ ' ."I i . g ‘ i" " "U = 6.0Hz,-1H1, :SN93 " 5 = g7./6~-7.29(m,§, WWI/} L». Y; {(311)1443‘1d13 1 17:91:12,211): 1111 (14155": i ‘ 1111150: (161510.711 (s, 1 11-11,8,57(1,1= ‘ { 5711z,11-11, 1 7.65(ddd,3= 415.9892: 179,115,311 1 1 far 1 E112,3111,7.57:§ Q6 83 415.0894 63211171130 7.491m,4111, '1 ‘ 2311911 7.2311911: a1" 8.4,5.6Hz, : 2111,7118 11,1: 3.3112, 2111., j 3431111139 112:, 2111, 2.79 "I '\ P1,. . m In} x / .4 AL, 73111:" 5411.4).
MHz, 11111130: g 11611310.:ws, 1 E E 1111,115711,1= 1 1 1 5131125111 E E 427.1092 3 , F, g g 1 [A7 —/.€)G(m, ; : i 1 for _ :1.\.: ma: 1114. ‘ 19,6 714 427.199 (3231120950 "WW: ’5‘?" . E i SN? 3 {111,431, /.13— (Mv‘N 111+ D 1 168 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson MHz, DMSQ- 1 ‘ 1 1 (idé 10.78 (S, 1 1 1575, 9:4 (5, 7 1 1 1 i 1 1H), 4.55 (7,7: 561712., 11-0, 730 {m 1 ' :4 7,55"- 7.40 7 MHz, D5480; 46)§10..8(s, 1575457577, .7744, 7575, 1 7.8474,7=4.7 455.7045 0,771» 1 for ' 1 7.6004315), 45,4 45 455.7049 (3244207420. 7.57 — 7.40135, i 4.5.574 1 1 (54455747 4575, 7.36 <4, 7 = 4.9 Hz, 2H), 7 3.5173, 3775, 1 4.425757%.7 Hz.2775,7 4.4:7 1 Hz 145754404 1 5 .554405440— ,7 - 4,54 775.7874, '7 . 1 1515 921.3 (4 171-75459757 .6 Hz, 5745. 413.9936 , 9(5), 7118 75,5 1 74 147374937 025514sz7 1 3775,754440 . , ,1 1055 56: 1 (57:15:) 1J=77H21H5 1 1 659td5~90,1 7 i 1 1 69742. 3:15 1 54577., 755440» 4,5479.74<, , 7545,4597452: $759159, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson v.4 'i ~4 u?) ’HNMH (400 MHz, DMSO- 1 ; d,551037x(s, , 1H). 8.57m: .61-12,1H), j 7.7. ~~~~7.t’30 (m, 39557534550 _ (m,4H),7.064 (MH—H" 6.96(m,2H), ', ‘ 6.87—cs.78(m, 2H53A2H332§ (13,2H),3.04 (t, J-=5.4Hz,4H5, 2,680,127.55 . H7 213,163» 1.43 (m, (SH). rH NMR (400 MHz, DMSO» dz) 5 1078 (s, 1H), 8.58 (fit, J 2 .6 Hz, 1H), 486.9883 . 7.65 (ddd, .5 2 E for 17.0, 5.8, 2.} 0,6 49 486.9872 CZQHWNZO Hz, 3H), 7.57 7.49 (,m (SH), (j'M~+CE)' 7.17 (d, 3 =- 8.3 Hz, 2H), 3.43 (a .5 e7 Hz , g 2H5, 2.77 (5, J =- ' 7 1 Hz 2H5 E E (ii 107' (s, . E EH}, 8.45 (d, .r E E g 15.7 Hz, EH), g t i 3' "'"r ‘, ‘1)": a 1 361.0778 3 m1" 1.54m: 1 for. e 3555/59" 7,4\3 E i i n q} 1 15231 . : : -},‘+.in AH\ ,H ...~.
:A V . [1-5. g 3/ 361.078 ELMHMHZHE9 E ‘ E E *1'1‘ 5 (€19 ', :‘ (fz’H/3J7 in, ' E 2"" 5 " 5 9H5 14"» T =’M+CD‘ * )2" "'9‘ , E =7.3HzZE—i), ‘ 1.27am?- , . 20.8, 10.6 Hz . 2H5, 0.86 (td J : 72,234 Hz, E 3H5.
D 170 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 55555555545555 MHz, 55575355- 55555 5.55.78 (5, 1H), 8.59 55, .52 .6552, 151), 772—7655;»..f, 3H5758—750; "26, 539.2 ,7 5748 5 575.1"1M 5 5555,75H5,7.58-(5, .. 5M+C15,. 55255.0Hz,5 5,5,5 5 6.85—6.715’555, g 355527055. 5 3H), 3.55 (q, 5 7.5 H25 255), 2.75 (5, 5 7.5 552,255).
Wfi.___________________________ 7 55555555555555 MHZ. 55575855.. 5755255557855, :5,55.55<5,52 ; 555522.555), 7752-7555(5), 22 §3H57582740 (m,5H)6.89-—- D, 6 59‘ § 433.1206 5 6.76 (m, 2H). 05555575570 55 ' 5.7055552 22,255 Hz ‘ 5H5,3.6555d,5 2255-52655), , 356(555252 55:5, 255), 2.73 <5, 5 2 7.3 Hz, 2555.
[HNMRMOO MHz,DMSO- (5255 50.755 (5, 5H), 8.55 (d, 5 ‘ 255.3Hz,555), g 7.752755555555, 3H), 757 27555 . m, 5H), 7.222 i 7.07(m,2H), .95. (d, 5' 55.3 552, 55-5,). 6.84 ('5, 27,6 Hz, 5H), 3.76 (5,5 275 512,315), 3.505q.527.55 Hz,25-5j;7,:2,82 ‘ 27555552555, 5 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7111511111455 5111.., 111.150- .) 5 11775 15 111), 8.150 (1, 1 .5112, 111), '5 1 N1 7.7.5 7,57 115, . 59-111,Q . 1 ,.. .. 1 7, 7.5 1 139 1 ~01 1135 11,5 41 1 391.1191 5 1 132255120 1m 41-1). 7.35 1111. .1 =81), 5.2 112;, 111,», 755 .55 151, 311,1, 3.5515,.1=11.7 Hz, 2111, 2.117 11, .1 = 7.2 Hz 1.1115,, 1551511— 5615117.7515, 3 , 111)., : 1 571-12, 111), ‘ ,125.1 454.1533 1 5211-1177 1149 13,5 211 E451.1135 1.2%;1 5’0""f2), ZS ,..)24-« 1 71-1 115111 1 1111-112, 15 1 55511137515, 11~1),5.5511,1= .7112., 11-1), 405.1955 7 .71 7 «15 ‘ 1‘15, for n 75" 961:" C21H29N217 55.5115 = 2s 1.55 51111 5H)1Mp, J 1 , , 142115211), 1 ‘ 3:_1 03km > : \11),11.511,1~§ 11.1 112. 2H1. ..................................... ‘11 NI1111111111 355.1480 51115135130- for 116151177515, C711H25N7Q 1H}, 3.516(YJ; ‘ " .71112,5 ' 2‘5, 1111, 77 7.411151, __________ m in???)1:3»sz:{\U"__4 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson "W""""""""""""""WW"""""";"gym;"""" .=4"‘(335‘°94z _ . 142,234), 1.32 120113, 6i{) 0.0330,807.33. 7 z = ................................................................................. »»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»4——+——~ : z ’H NMR (400 5 3042, 034303 (3.) 5 10.75 (3. ). 8.46 0,3 ‘4 571-12111}. 383.1793 7.17. W740(n,§ 711).33.4993:03 ' 0334337730 i 1.5001.42(m.6442.211). 38 : 2H). 1.23 (0.} —46, 4.0 ‘43:, .20}I.) )83(. =6.6 .421. 3H). ..............................................i.,....................... .,__............._.....4._ H N34ii‘E1400 34312:, 0— 0.) 3 10.78 (3., 1143, 8,570.3 = . S 6 Hz 1H). 5771—70Mn 462.1851 _ . f'\ E}. \r a..." H DC: .3 Hz. .1154 f0r 13,6 21‘) r'3 462' {86. . 233). 083 (0.3 C2077237730 = 82. Hz: 21-2) ] ES 3. 98 (1,3 .—7-« .3 8 g H}... 3%.). 3 .44- 4 334 (:m, 2H). ! 2. 72 (t I"7 .4 Hz. 2H),;7 .58 (t, J"5.8 Hz. 2H). 2.19 (:3. 6H). : - : .m..___.__._______3............................3....................................... 31-2 NMR (400 34373:, 53480- 0.)?) 107933 . 11%,:043‘ES, 1E .13), 0.00 0, = E 47('3.2008 5.0 1-12. 33-10.
D. 6 40 47020075 for 7.7 3 7.40 (m, E C2777303930. ’ 7.13(0.3 03 S = 32. 143:. 214). 03440.J=02 Hz, 214). 3.09 0,7=0.:3—33, z 2.33:'3 40.03 .7 =03 1-13. 21-3) 1’73 [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson E I 5 I SIGwLJ: ' I 5 EIEZSAHaII E ’ I 52mg7u¢5II I I If'riOflagHL 1 I I 210w%J: I IZAGJHa I 2H) _._.___4_ 1 .................+.w"‘.m—------------------»a. .»»I . CDhfiSC%5Q,4OO I: Mfimfi10% I§(M&1HL&M I(Ma]HLifl— I --I .. .612 (m, 3H), I I7..55—7.45 (m, I Mu7111m (m, 2H). 6.93 . , . 4mg 5 HL L1" 59 IMIU E IHL632&J= . I_‘ , 'gw gé ; I { 72H5Hfi * I % 54$}3wom ’ j :QXHL2H) 2.78 I": J : 6.8 H;flfifi32 @J268H; QEWWW (DMM}&AMI Mflmfllflfi OX&EHL859 8.58011. 1H), 7.69—7.63 (m, I I 3Hl7jfiflfl4 : §Um4HL716Q g nggaHaiHI ; I se i 5 > I % (q,2II),3.46~ 3.43 (m, 2H), 276$J376 , Hamflfljé I I @J253H; = Eh (DMSOwdlfi 500 W,_~_._.I.____________«V,_________________"A...__________________HH"H"HH"HA i MHZ): 6 10.76 I (5, EH), 8.6sz (I. m6 m g U I i 10 .
I : 340~33IInI .mmmmmmmmmImmmmm_.____fl____mm_i 2Efi,277(LJ‘ ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson U) U} 8M+Hfi 440(d"}:43 Hz, 2H), 3.80 3H); H3888£H8g,400 Nflh)510% 8:\S(g: 3;. \,399% ,1: 44HH5H5 869159(ng 8.343 H65 515 (m3}1} 7m (81,88384152 f 2H)886HLJ‘ :84HHH-H, ,HHHHJH56E ‘ H;2H8378‘ H» 8 " * 51360812 EH), 7,71-'61015 8 A? 25M5§ H5/ 8 HH557xEHH3H5758H 81:85H25H3 E ‘ l 708705885 HH840H,J :60H12HL ZXMH3H) I (DMZO58g 6‘00 MHH8 80H (5., 1H), 9.03» 902-381., EH), '51. 41:.
{Ix/+1i) 7787’ ~7.60 (m, 4H} 7,554.45 (m, EH), 7816 8§.J:SOH; [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson -E... 4' 80402}: l 4.38 (d, J 0.0 * Hz. 2H),, 2.25 (s. 3H) 40400 MHZ):6EO.76 l (0m, 2109.03 . ‘ i (0J4: 6.0.1421, 1 §}»I),7.71~7.60 . 8"‘4 H),7‘.55~ . .. 417.4 i 1165 g Aw 05. g . . 7.43 . (mflH), s : a {\4WHJY. . , . .4 M . . g Lana (d, J... 8.4 § . 2 £12.31), 7.20 . (d, .1: 8.4 Hz, 2H), 4.39 ((1,..7 ; r- 8.0 Hz, 2H), x 1.24 (s, 9H}; t _. — .. M_—_?_—_—._.____T'_____.__..,,,,, E J g 1 {Dix/180437404775 { I g I MHZ): 5 10.7.: (5, 41-1), 9,17 (4, J 2 4.8 Hz, 144;». 420.4 7,724.07 (m, we° g (MHT;_ 3 3H), .59 (m, 6H), 7.57~ 7.43 (m, 2H), 11.52 (d, J: 4.3 l Hz; 2H); 4301804 400 : MHZ): 5 10.77 (s,1H).9.11 (t. .1: 6.0Hz, 1H). 7.72-7.62 (m, 4H), .41~ (111,311). 7.36 (t. .1: 8.0 Hz, 1H,), 7.107.044 (m. 3H), 4.45 (a, J r 6.0 Hz, 210; "(904800... 400 MHZ):610.75 (I34 2H). 8.46 (-t, J 6.0 Hz 1H): 7694.62 (m, 3H). 7574.51 (10., 2.03, 7.49— i 7.43 (m, 2H}, 4 3.07-3.04 (m, 3 2H}. 1.074 .50 (10.48:), 1.59- }.48 (m. 2H), 1.17-1.18011'1,".3 /’ ....E..._3lila ‘1193'0887 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson ——---------~--w——wm----------------------------------------4 (m. 2H): 4 443344.50do, 4434 54.47.1510,4 T (s, 444355344, 4 2:543 Hz. 444). 7,72~7,69(m, i 443;: 7.56—7.52 (133,244). 7.48~ 7.44 (m, 2H; 3.44—3.34; (m. 444), 3.24 (jg, (4.4344343 (10. 4043 334444235444,. (s, 34-4),5.43(4, J=4.54~4z, 444), 3643-75455, D, (3 82 % (MW; 344,4 254-7 443 T044 441) 4634*. 1—4533,..4) .43 (m, T 2344325323 (Iv-Mia) T (DR/4805,5400 4 MHZ):510.75 ’(s, 334) 554344, .,«44333;,34) """"""" T (435480a}4043 V442) 30(3.75 (43 44.344848- ‘ 44454444, 344), 7.59-7.63 (m, 1 344),:457-‘743 339.1 (m 4H) 3.26-- A, 6 4 \TWT)/. A; ‘ ? .323 (m 244), 2.50i2.49(4n, ‘ 4344430 4 fm 2H)y I. 82-- 1 76 (33 244:: [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson M112: 1119150- 11111111117515, . 111;1,8.47(1,1=== 581171111, 7.64 1111111; 1 — .5,19 : 11,755 7.39 (111., 411), 1 1 7.27 (1, .1: g 112:, 2111, 7.15 4113.1 117-5 1 (1197.31.11, D76 39 5 11111117" .1111, 5.411 1111151. 1 =24.8,13.3.6.4 11721112715 § 1111,1=119,511§ 1121111172 ‘ (11111,1=13.11, 7.1917112 11111521111111, , 1-==15.5,14.1, % 7 7 1 , 771151111, 1 E 3 1 1159111143 :3 E i E 19127,:4PL) ——'M —‘ " ""i’"»"»"»"" _ "~~~"wE~ {I 1 Y Y """';':"'\""" 11 1919111 {41111 1:11-12, 111M110- 1 11615017511. 1111 9.191., 1111, 11.32 (11,5 452112 1111, "67 11111 1— 1 1 7 1517.5 117 1 1 49 (111, .1 i i (3:13)1. ‘ 5112: 1% 1 17. :i4111,10711.- 1 791111111 """"""" 6.60 (11,12 77.5 1 117.211j1,4.17_ ? ‘ 40711111111, 7 715' 71111» 13 1 73111 11111 111 .— (1.5 Hz: 5H) 111114115117 I 1 111,3. 7 - 7 A 6 . 46 [179/ 8.58(111,‘1H), ‘ E 191717; ’ 7.65 (11. 7:70 1 11511117132 1 1:1, J 7.5 112., 2111, 7.51-7.42 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson ed set by Sarah.Wilkinson "H,24¢ —8uHH-~.
EIIIHI:(* ; H74""8z I ¢J=7OHH I ZHH IDIISHIH,400 Mfiafilam HIHI934H J=60HHIHI 77H7H NMR (DMSO (.75, 400 MHz): 5 .75 ("m s, 1H), 8.92 (hr 3, 2 1H,), 7.72-7.65 (m, 4H), 753- 745 (m. 3H), 2719-7. E4 (m, §4HL%mfiwai 1 2H), 2.29 (s, 7 3H); MHZ):5}U.76 i),9.02(t, 1:6.01—12. 1H), f 7.71«7.6{)(m, ‘ 4H),7.55~7.43 (m,3{~{),7.19 . 389.1 , g > S 1 ";;~"":,,"\ I " (NEH): . (d,.1=8.02—Iz, E ; 2H),",7,13(d,J 38.0 H2.,2H), ; 139‘ngth 132,2H),2.58v 2.54(m52H)-, E E.14(t,..r’=’7.6 H3318; ‘ ******{gnu—7W MHZ): 519.79 (s, 1H), 8.6% ‘ 3.66 (m, EH), 77.694264 (m, 3H), 7.57-7.45 13.6 52 (m, 4H). 7.31 ((1,273: 4. Hz, 1H), .89 (m, 2H). 3.48-- 3.4é§ (m, 2H), 3.02.2.0: (m, 2H); D 180 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Wilkinson ............................................................................................................ 31333330333333 M'Hz):333.73 (s,1H).,S.48- ‘ 8.47 (m, EH), , 7.3937.33(m, . 3333,353333 3332 339 332 A, 6 ' " i 3.78 (333,211), 3 3.233.23(m, 3 4333333 E =9.3'33;z,233), ‘ g i.45--L40(m, g 3333333339 (33,233); 3 : i 3 ...............+»»»..»»»»..»»»:............................{r-wflnmmmmm. : : 3 , 33033 MHZ):6‘30.75 i : (3.33333533— 3333333, 333), : 7333—73333, 3333753333 3 3393f (3343333333, A, 6 3 M.8Hz,2H) I 2332,0333, 3 _ 3333333333 (33,233),3.53— ‘ 3.4333333), £.2.S~1.‘37(m, 23-3.); 3 ---------------33.2., g i 3 33333330333333 3333333373 E (s, 333). 333 3.30 (m, 333), 7.39—7.33 (m, 333), .53 (333,213), 7.53» 3.33 (m, 233), 3 7.2.9 31cm 2 3.3 33.2., 233), 3.33 (d, J: 8.4 Hz, 23-3), 3.33-3.43 ) (333, 23-3), 2.73 § 2.73 (323, 23-3), 3 3 .23 (3,9153); """"" (333330—36, .333 MHZ): 5 10.77 (s, 333)., 3.39 3:, J 3.0 332, 333), 3.3.3 (3, J 7.5 333, 333), 7.32 (d, J =2 8.0 Hz, 2333)., 7.53—7.32 (m, 333'), 3.53- [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson 3.46 (m, 2H), 2922.87 (m, ' 2H); (192915092, 590 g 19191321973 [ i 5 (s 1H), 925a» EH), 8.95(:,J§ 26913291"), 9 , 3 9 792-2646;], A,6 4.3 2 ; 491972554744 '= ‘ ‘ ‘ x 2 3), 7202; (d,JI8,5Hz, 9 2H),6.66(d,.i :35 H2291), 4,314.29 (1119 E 2H); § (DMSO-a’fi, 409 ' E i 2911-2391976 g (3,191,332,039, 3 14.5142, 1H), '1197; , 9 9999 : 793697.691 (m: A6 36 9 E ‘ {7999:9999 , 94h): 1.535.743 = ' z (m,3H),7.32(t, J=6i> H2219), .10(H1, 3 211441919 =5.01~+:'z,2H); E (191913099500 g 2 9 MHZ):5IO.85 i (31H),8.43(t5 2255142191), a 1 5 8.022(932191), 1 1 7.73(d,.1= 8.5 : 112,11223267 ‘ g (d,J:=7.5Hz, " 1199i 380.9 7.55~7.43 A, 6 54 (MM) (mm-njzs ‘ (2391:2999 Hz, 1H), 325-321 (143,213), 1.69- }.57 (m 5H), ; a 5 2.4-0 l ,.36 (m, i i 21%), 228-199 1 g g (173,499,099- : i i i 0.83{m,2H); I . .8045, 4100 MHZ): 6 10976 (5, EH) 3259- 858011, 1H), 7.69—7.64 (m, g 31%),753—73 ‘ (m, SH), 725— [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 144444 .3444404 Efifififi$2m 4, 24; I 034434444,590 g 444)5 OW‘ 34444945 EH) (103 (‘ "?hIIz EH) gl/Zwfiqm 41‘1'f,2,55~7.45 I») \l ‘4 ,.._1 A, 6 {A} I3" 3+4—4 ._/ (n153II),'7.{48(t, §J=80H4Hfi ' 44444J= E IQIOHZJH), @4444J245j 'Hauu44 ‘ (<1, J? 63") Hz, ‘2H); (DVI‘zUdimMr)".
IVIH'7‘155 I4 77 I, 3y III),91.; t, : J —' 4.3152, III/L 7.7I--7,6] (m, I Immé 4H), 7455-7743 (144,414), 7,31 {11,}: 3.0 HZ, E III} 723 ((3,.1’ -S47.12 41.3 g4444.1=60’ ; iMmsmM i :45,43444 41HL ETWMMm :441444 ‘44440 Iwm (4]:32H4 3444 IHLB263£G 4mmmw, 41'444 2444;; flPHfmi 1391.134 (m, mmmlw 4LUH;094 O.34tm,4H w.v __._ 4 ..........I [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson @1st 400 MHz):§11.{15~ ’ 5 , 11.04551111—5), ‘ 8.54-8.53-(111, i 31—7.73 (1:1,3H}, 75$ 7.50 (m, 4H). 1295 All] 3.2.5325 (m, 3H), 1204.52 (m, 5H), L30- i.37 (m, 2H), "\‘4 (m, 2H‘, .85 (m,2H); (13545046, 4.00 MHZ):810.75 (5,1H),8.49(t, J"5.6HZ,1H). 7.69~7.63(m, ‘ 3H), .45 i : (m, 4H). 3.77- i : i 1 E 369.} 3.70 (m, 2H), 1‘09 i MM x- . 359-354(511, E 1:H),3.25-5.24 (m,2H),1.93- % {90011, 1H), , 1.8347/6m1, 2H),:59—153 (m,2H),1.43- 1.34 (m, EH); «D‘vi‘aoj 5:50 MH;»:):510.7. ; ($.1H),9.14(E, .125.01»iz,1H), 8.49(s,1H), A, 6 .55 (m, , $755-$414 3 (m,3H),7.28~ g 7.23 (511.281), 4.513(5,.z::5.5 ................. (05130—016550 MHZ):510.76 g H,1H),9.12H, J: 5012 EH) ':~:,1H), 8.458.413. (m, 11-1),7,7o(5,.1 g 2 15.055z,1H), 7.517.5mm, 4H;),7.55-7.44 (m,31‘1),7.33(t, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 4411:, .5 888-82.,8, DMSO- ' do)810.76(8 1H).54(t,71; 5888; EH), 7.78 7888888, 389.1 44 E=15’.37.85882, (8481 )+ E488), 7234888888, .1": 3,1.68 : 8898888.8 1812,3848") 8-1NMR (400 MHZ, DMSO- 41,) 83 10.7448, , 888), 828 88,8: 6.4 Hz 1H), 7. 78 -2 7 .158m 403 1 .384) 757—735 733,6 54 (M8 if \m, 6H), 7 .29 {t .4: 7.68132, 2H), 7.17 (8, J :- 7.3 Hz, 1H), 3.41 (d, J = 6.3 Hz, 2H), 8.26813, 6.14).
I 8 8 .V._4................L.22...2...2__........». ..._.._, l 8 ... i 8 88880 4,44-88 MHZ):5 888. 77 "Winn/1306... 400 MHZ): 5 10.77 (s, 1H), 8.50 (t, J " 5.6 Hz 1H), 7.69-7.63 (m, 2 3H). 7.58~7.43 (m. 4H). 3.40— 3.37 (m, 2H), 3.28 {5,21%}. 1.10 (s, 9H,); (DMSQ-dé, 4(30 MHZ): é £0.77 (3. 1H), 8.53 (t, J r 6.8 Hz, 1H). 7.69—7.63 (m, 3H}, 7.57—7.43 (111,4H),7.3S~ 1, 4H), 7.23 (t, J =~ 6.8 Hz, 1H), 5.46 (d, J 4.8: Hz, 1H}, 1 (rm 1H), 3.47" 3.41 (m. 1H); (36150-62, 400 MHz): 3 10,74 (s. 1H). 3.40 (1;, J = 51'in 1H). ‘ 7.69:7.63rm, 7H) +68 (d, J 4.8 Hz EH).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson rIIEIIIIIIIIE.I! ’ 3M; .’ S GUf "\ MHZ}: 5 10.74 L H f 9 6 \ L! * i r0 ‘ .0 78 fl) L.R4»? 11 5.x .3 0 7, 5 .5! L. it ...‘....,...._.........................ww. W........_..... 44. K in]? /.\ RA,.fllMaT I; \/ .5 }£2, W )7 6.9'7/ @1r?‘ H; LLv1!H ‘l/.L53 I! I :ssH;flY1 ‘DMSOwl 'x :16; 4%" 33Hm;‘I4 4 xI\ I. flu. 11 \F, ‘ 1-; 7! [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson 1H), 6.95 (t J 7611L111), 3,81 (3,4 ‘11 NMR (400 M112, DMSO~ £1575 10.79 (5, 1.1119118 (H? ' 5.9 117:, 111), 1),6 i 50 3.1 7.74 — 7.59071, 4111,758—725 ((7.1,m.7H),4.507~= 57772 I A ; 56.3."a x ~577" 7 7; 7 7),» *3 , (M-H" 222.... +- +qusud M112): 5 10.79 (1:75.111) 84S (1,77: 50’ 112:, 111), 7.67- 7.73 (m, 11-1). 7.66-- 7.63 (m, 211), 7.58~7 560,11 ., 1 399.5 111) 746-7‘" ’ ' ----- , . , 351-4); (177,111), 7.35— 7.301771, 111), 273.22 (in, 211), 1711158 x (171,511), 1.41— 1.35 (171,211), .09 (127, 41-1), (1.95—0.83 (m 2H); HmSO00,, 4’30 1vfl12:):511.54 (br s, 111'), 8.72. 1,5, 1,11), 8.65 ((1, .71 4.8111, ,. ,2 . 382 3 -257 A" 6 7 1 .- 111:).
. (MRI),. 3.46 (if./= 56 1 11‘7’69- l 7.57 (m, 2117, .58 (m, 2H) 3."7~322 1.117277) 70— ation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson 518 (m, 4113, 1.41-1.35 (111, 2H), 1,274.14 (111, 4H3, O.93~ 0.33 (111,313); LC.MS: , 31.3 (NI+13; 1 (Q1)MSO-43',,,, 488 1 841-171 5 113.7 (51,} 971/1 1 "1111,1113 i 7! 7.7 "1 5,1113, 148) E -\7./ :41 x): $ 1 L'3H3, 7.2(1, 438.4 J 7.6Hz,2113,§ 1 .240 A, '3" ,4, (Ni+~1-13; 6.913(47’386x ~17 1113,1184 5 (t,J‘—6.8Hz 3 1113441338,.13 :56HZ,37713, i 1 33 03'3"i__1124113187 4' 7360112 , 4113; (11818011', 588 78/177336 1875 , 1S (8, EH); 8.38 (1, 1 J=6.0 112, 1 111,1, : I 7.67—7.45 3 (111, 3 ~11 \ n -_ E 71 ).7.16 @211"1‘ 405.4 1241 A, 6 1.34 1.)) 1 311.4433;, 7 .5 HZ, 2H), 1 691—689 (m, 1 3113,3991'1 1 : 6O H2:, RH), (m, 2H), 1.94 (t, J 6.5 171,273); 11111283111804 833518.778, 1113.923 1,1,1: 3345 5.9Hz,1H3, ' 8.933(5, 1:13, , 779(51113, 7171—7404111, E .1113, 41,4488 i 5811211 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson r"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""T"""""""""""""T‘~~~~~~~~~~~~~~~ 1(D8430—ig400 MHZ): 8 113,78 1gJHL8fifi, 1 I— 6.0 132,111) 1 1 1 1 1 1 1 1 1 A.» r) 1 8.2113 111), 1 1 ,4 1 13/16u A16 : , .1106 ,__. 1 1 : 1 + 1 1 1 1 1 1 7613-7641111 I (1111\ 1:}.\ I 1 , : 1 1 I : 1 : 1 1 1 1 1 - 1 : 1 I: 1 \ 1 1 1 1 : . 1 (sflh3‘86 1 i 1 1 1 I 1 1 1 1 E 1 1 1Aazsnm-— 1 1 I 1 1 : 1 1 1 1 1 1 : 1 1 1 1 68Haflm 1 1 1 a -------------------------------+mww»»»»»»»»»»»»»»»»»»»»»»»»1»»»»»»»»»»»»»»»»» z i 1 1 g 1 (138-180—116) 400 1 g 1 1 g 1 1 1 1 MHZ): 8 10,79 1 1 1 1 E 1 1s, 1H): 8 9013, 1 1 1 1 1 113) 8698 1'8 1 1 1 1 "3 1 . 1 6-1g" 4.3-.
A6 140 . , (m, 1H} 7.68 ,mhp‘g 1 1- T 1-: 1 7,65 (m, 1:113)? 1 1 1 1 7.56—7.45 (m, 1 1 1 1 1 1 1 1 411)) 311-716;, 1 1 1 1 = 1 211), 3.09 (1, J: 68 Hz, 2H); \L A " : 8 113 77 (s, 111). 86011, 1726.4 Hz, 1H), 81915:1113: 441.4 86 48m (MUu; I M11!) 8-'0"'8 I 1 I (3111) 922159 I ‘ I 1H). 8.628161 , (m, 111), 8.213 I 1&flHL7fiui 1 J = 8.4 31-12;, 21-1), 1 '7 .21697 6.3 (m, 1 3H) 73"5 73.8 (111361117.53 ' 1 1 3.17gm, RH), 1 287 (1,11: 60 1 113,211"); D 1. 90 ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (C1103 1 {7113011, 400 M112}: 8 7.71 (d, J: 8.0 11.7., 111), 7.56 (d, J : 8.11 112,111), 7.517.411 (m, 4111, 7.34—7.28 112m 1 444.4 (m, 611}, 4.111 AJ3 {A} ‘4) (M1111; (dd,.7:13.2, 4.8 1-12, 1111, _—.707 3661m.
Hfl3hL45‘, - (mHH;i&~ szgmsz , 263QJQHH 12H): SHJ: 61Hx4hh __________________ ......................1 . . ~————-1, E (_DMSO~6’6,4OO 1 1 M112): 5 111.76 ' (g1H1969 . (3,111), 9.111111, , 1J~60Hz1H11 772(3,1111 011, 5 . M37. 23171),7.62(d,.]:= . 8.011z,1111, . . w A, 6 : m1+h 7.55-7.51 (m, 311), 7.50--743 (311,211), 73:35.. 7.311(m,2111, 7,10 (1, .7: 7.? Hz, 1111, 4.41 (d, J: 5.61121, 2111,2118 (5, M11211} . (by8,1111%.""1 1 (br2, 1111,11 08 was 3111 792\("(1,J AG i "21/1125, 3 Hf+n; 2111, 7.697.65 1111,3111754- ‘ 7.40 (m, 6111, 3 50-349 (m 121,388287 (1m, 2111; 1(DMSOIZ?V‘ Ehflfi181096 1K51H18,7% _LJm)gm1J1E/fi [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1..«4......_.____.___.____. ,. 112, .1) 7.711 f g (s, 1111), 7.66161, 1 J: 11.01116, 11:1). 7. 611--" 56(111 213.27-3./.4 : {11,.".13 1.71." 1.581111511), 1.=11:- 1.36 (111. 2111,1291 .119 (111 411110,0.91 11.33 111. ; 11/1112):<31‘{1.75‘1‘); 4.1.11344511.
J=5.611.z, 111,1, 1 3.6814,J=3.2 11:3, 111). 7.61 1 1 (111, {"8032 464.9 1310753," A36 1 "13’,4 (M41); 331.410.17.14 1 1 1 1 715011.511}. 167 472 1111.6 571.01 21-11, 345.4366, 21113 1—02.98 {m 1H) {DMSO11 V113) 113,74 ’ 1 (4, 1111.843 4. 1.1-:5451-{7 1111 363(4 3:60 1'11. 1111,7431 ; g 111,]: 8.0115, 404.9 059 21117544742 ‘3’" "4 ' {M341}; 4111,4111 7.211. ' 1 .,\.. 031 U‘ C? 6-, 11 "4) 2H) .406-2 9'.) (m, 1H); {317911. 400 11111113357 73 761~1z.
H1), .1.52 (13.1; 1 =801111:, 2111), 39.5%...
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ___.,________ L54 = 7.:‘ 555, 251), 2.55 (t. J: 7.5 Hz, 2513:, 2.55 (5. 25)., .55 (t, J: 7.5 Hz, 3H); 1H .5555. (5-5 MHz, DMSO- d5) 5 10.74 (5, 3H), 9.04 (t, 5 = .24 (5, EH), 1264 1 ___.0.m_m-MAKAw._.,,"if______Vn_V_V_"V""VWVVWhnnn.,5. 7.68 A 1, 3H), 7.55 (55 5 .2. 1.9 Hz, ), 7.53 4.35 (m, :55). 7.55 l ('3, Hi), 4.47 (d, g 3 = 5.5 111,211).
(DMSO—dg, 4-00 MHZ): 8 {0.78 (s, 1H), 8.7"; 1H), 8.6.0 (I, J z 1255 44.7.5 A, .5 7.55 I51 M (M521); :52 :11), 7 5m ..........W (35550-5, 455 s MHZ): 5 10.80 I (3, EH), 9.1% {s I 2H), 8.63—8.61 I (m m), 7.75 I 7.57 (m, 55), I 7.56~7.36 (m, I 5H), 3,525.55 I (m, 2H), 2.91- I 2.89 (m, 2H,); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ____________________________________________________________ (DMSOWE, 409 Zji5 12.59 12.36 (1’11, 111), 3077(8,1H). 130 (1)1 S 1}}1'), ",1 '4 IiE , : "41563 7.697.61 177'" 41 4 -535. ( A10 44,1 71 , 4 454414;, 3474, 7517.34 M"1771" 4 415,544}, 5.55 (111' s, 1H), 3.49~ 3.44 ("m 2H), 2.82—2784141 2H); 0-576, 45-5 M1141): 5 441.59 4 (s,111),8.43(1, J25.51—12,444), 7.55—7.59454, 3.4134, 7.55 (5,1 :2 5.4 411:, 444), 7 415 45, 4411, 744415 1: 88 4 441 g 4 ‘4.21."‘4 41,,33-41", i ,5"7 ,' E E 1114,55‘ - s 4 , , _{ 4 (WHY 4 ""14 E (s, 341'), 326- ...... 323445.,244), 1145444 3 5444 744143) - 4 (15,2141125 1.23 (111,171), 1.19-1.09 (111, 31-1), 0,91»0.83 (111 211); 4411550414. 455 54:44424 54(-455 ; (7)7" 343: (1 "Shh: , 4 441),7.547.53 ,5 (54,444), 715 45, 444472545, Q 7‘?W 395.9 , 1~7541144 i A’M. "'9 .. (M741); 725—32455 . E 4 i 5 2444,2555, 4 4 4 , 1.14.55 4 (54, $141,444 ,1 f i 7 i ‘ 4354512444, ‘ 4 4 4 4 4 1445-4, ' E 4 4144, 41.94—41.53 ' (4421—11; (11454505’7, 4:101 9141-1512515744f 515,144), 5.41. (41:52 11:25, i [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson .6 32,213), 7.54(c1,.;=7.2 9121223,.729 Q cs1H;,7.AQ(d, #75122112), 7.29 (01321116 3,322 321011, 2H), 2.29 (s, 3H), 1.70-1.62 (m, Ski-EL 340.225 (m 2H), 32.6- 109 (m, 4H), 09502.22 (m; 3 3 i 2H); a (123,230-226,509 3 3 MHZ);520.89 3 3 (s, 19:), 8.52- 3 8.61021, 1H), 3 8.14(s,1H), 820032122), 3 7.890221%,0 3 H213 1222,7275 i A .2 (X) (X; 1:25 (<2,J=3.92~2z, A 59 3 ; 7.65 (22,] ij, : 75536321=735 HZ2H)7.29~ 7.26 (m 2H) 3 7.2242702}; 31212472243 3 ,2.SG(t, J=7.5 122,212); ................................................................................ .............................3 122430-22 400 3 MHz):51177 (35132390433 —123H\, '7.7i~'7.6i{m, 3 2H),7.5547.A3 3 ‘iii 3‘ 389.5 1283 0‘" (n153H),7.21(t, > up Ln 3 (MM); 33’9"].61'12518‘, = i 722—793(m, 1 392354241ng =5.61‘{2,2H), 3 259—25503, 3 3222), 2.:5(t,.1=3 7‘6 Hz,3H); ‘ [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson DMKUQmmb M22212: 820 88 ; (2,2,22,242222 ? J = 6.8 Hz, 1H,}, '766JL62(nL 2H), 7258-7755 (m, 2H}, 7.46 "(d 7:777? 2 72PH_7. 80:91" y." {2} (:26 u; 22,1722: 3.3.3.24 (m, 2H), 1.74n'lj6 2 (211,512), 1.42— 2 1.38022, 2222, 12812.26 (m, 1H), 1224.08 (m, 3H), 0.94— 0.35 (212.27%); .2 s """"""""" """..%mT'" i 5 ______________________’ ,,,,,,,,,,,,,,,j................. 2 7, : fiwfl—V’"____________________________2 (2222230 2 502: MdQALOJ/ j (3, 123, 2 ‘ 1H),8.66(5, i E 4W") 2' E n:\ Wffim' 1292:» A5 2 :29 2 2 2;, ‘ 47’1""? 2‘12""??if‘732' ,X- i 2 (M +12; g (111,422), 25.:- L, ' ‘ 7443,1422), 3.5435162}, , 2H), 2.85 (2, 2:2 .6 Hz,2H); (222430-226, 400 M222): 5 25.222 (hrs 1H) m2: (s 2222 8. 6! (t J 2 5 2222, 2222,3255 g g 2 (hrs, 211),"776 44%? 1292 A’é 6"A 8.022z, (A 1‘21); 2H),7.t’39~7.63 i 2 (111,322), 7.5:» 7.43 17), . 2.30 (d, — 8.4 7), 3.522- .45 (221,211), 2.2222 (2, 2.2 r 7.2 212,222); {DR/1804125400 390.2020,w 222222222027 . (s,2H),9.GS(t, (MW (2; Lzi"2(:1\70 .6- H" H) E " 7.72:7 (2%(n: [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson J= 8.0 Hz, 1H), .79 (m, 3H), 4.41 (d, J = 5.6 Hz, 2H), 3.71 (s, 3H); 1H—NMR DMSO'dg, 400 MHZ): 5 10.78 (s, 1H), 9.13 (t, 444.08 for J: 6.0 HZ, 1H), C22H15F3N 7.72-7.61 (m, 203 4H), 7.55-7.39 (m, 5H), 7.30 (d, J= 8.0 Hz, 2H), 4.46 (d, J = 6.0 Hz, 2H); H-NMR DMSO-dg, 400 MHZ): 5 10.76 (s, 1H), 9.07- 378.08 for 9.04 (m, 1H), 7.71-7.61(m, C21H15FN2 4H),7.55-7.43 025 (m, 3H), 7.34- 7.27 (m, 2H), 7.19-7.12 (m, 2H), 4.47 (d, J = 4.8 Hz, 2H); H-NMR DMSO-dg, 400 MHZ): 5 10.77 (br s, 1H), 8.40 (t, J= 4.8 Hz, 1H), 7.69-7.62 432.19 for (m, 3H), 7.55_ C26IiZ§NZO 7.43 (m, 4H), 3.25—3.20 (m, 2H), 1.91-1.90 (m, 3H), 1.67- 1.58 (m, 6H), 1.49-1.47 (m, 6H), 1.30-1.26 (m12H); 1H—NMR DMSO'dg, 400 MHZ): 5 10.74 418.17 for (s,1H), 8.29 (t, C25H26N20 J: 6.0 HZ, 1H), ZS 7.69-7.63 (m, 3H), 7.59-7.43 (m, 4H), 2.94 (d, J= 6.4 Hz, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 2H), 1.93-1.91 (m, 3H), 1.66- 1.56 (m, 6H), 1.46 (s, 6H); 1H—NMR DMSO'dg, 400 MHZ): 5 10.77 (s, 1H), 8.74 (t, J= 6.0 Hz, 1H), 7.69-7.64 (m, 390.10 for 3H), 7.60-7.58 C22H18N20 (m, 1H), 7.54— 38 7.43 (m, 3H), 7.28 (t, J= 8.4 Hz, 2H), 6.92 (t, J= 8.4 Hz, 3H), 4.07 (t, J= 6.0 Hz, 2H), 3.59 (q, 2H); 1H—NMR DMSO-dg, 400 MHZ): 5 10.77 (s, 1H), 8.43 (t, J= 4.8 Hz, 1H), 3 83.13 for .64 (m, C20H21N30 3H), 7.56-7.43 38 (m, 4H), 3.55— 3.53 (m, 4H), 3.35—3.33 (m, 2H), 2.50 (s, 2H), 2.44—2.38 (m, 4H); 1H—NMR DMSO-dg, 400 MHZ): 5 10.77 (s, 1H), 8.72 (t, J= 5.2 Hz, 1H), 7.69-7.58 (m, 3H), 7.55 (s, 408.09 for 1H), 7.53—7.45 C22H17FN2 (m, 3H), 7.09 (t, 038 J= 8.8 Hz, 2H), 6.96-6.93 (m, 2H), 4.06 (t, J= .2 Hz, 2H), 3.58 (d, J= 5.6 Hz, 2H); 1H—NMR (DMSO-dg, 400 398.15 for MHZ): 5 10.76 (s, 1H), 8.45 (t, C22H23FN2 J= 5.6 Hz, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson .63 (m, 3H), 7.56-7.45 (m, 4H), 4.84- 4.72 (m, 1H), 3.30-3.29 (m, 2H), 1.87-1.78 (m, 3H), 1.54- 1.51 (m, 2H), 1.42-1.41 (m, 4H),1.21-1.18 (m, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.74 (s, 1H), 8.41 (t, J= 5.6 Hz,1H), 370.14 for 7.69-7.63 (m, ConzzNzO 3H),7.55-7.41 (m, 4H), 3.28- 3.22 (m, 2H), 3.10 (s, 3H), 1.66 (t, J= 8.4 Hz, 2H), 1.11 (s, 6H); H-NMR (CDC13 + CD3OD, 400 MHZ): 5 7.73 (d, J= 7.6 Hz, 1H), 7.61 (d, 8.0 Hz, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.48- 7.46 (m, 3H), 457.18 for 7.45-7.31 (m, 4H), 7.26 (d, J = 6.8 Hz, 1H), 3.31-3.30 (m, 1H), 3.25-3.17 (m, 1H), 3.06- 3.00 (m, 1H), 2.68-2.67 (m, 2H), 2.44-2.42 (m, 2H), 2.36- 2.28 (m, 1H), 2.13-2.04 (m, 1H), 1.78 (t, J= 6.4 Hz, 4H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H-NMR (DMSO-dg, 400 MHZ): 5 10.75 (s, 1H), 9.50 (s, 1H), 8.91(t, J= 6.0Hz, 1H), C21H16NZO .65 (m, 4H), 7.55—7.43 (m, 3H), 7.08- 7.03 (m, 2H), 6.79 (d, J= 7.6 Hz, 1H), 6.72 (t, J= 7.2 Hz, 1H), 4.38 (d, J = 5.6 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.80 (s, 1H),10.25 (s, C20H14NZO 1H), 7.75-7.71 (m, 6H), 7.55 (br s, 1H), 7.49 (t, J= 8.8 Hz, 2H), 7.32 (t, J= 6.8Hz, 2H), 7.10 (t, J= 7.2 Hz, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.81 (s, 1H), 9.71 (br s, 1H), 9.51 (br s, 1H), 7.76 (s, NZO 1H), 7.71 (s, 3H), 7.64 (d, J = 8.4 Hz, 1H), 7.57-7.45 (m, 3H), 7.02 (t, J= 6.8 Hz, 1H), 6.90 (d, J= 7.2 Hz, 1H), 6.81 (t, J= 8.0 Hz, 1H); 1H—NMR (DMSO-dg, 500 MHZ):510.85- C19H13N3O .82 (m, 2H), 8.38 (br s, 1H), 8.14 (d, J= 8.0 Hz, 1H), 7.83- 7.67 (m, 5H), 7.57-7.47 (m, [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 3H), 7.16 (t, J= 7.5 Hz, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.85 (s, 1H), 10.48 (s, 1H), 8.88 (s, 1H), 8.31 (s, 1H), 8.15 (d,J = 8.4 Hz, 1H), 7.78-7.70 (m, 4H), 7.57-7.45 (m, 3H), 7.40- 7.37 (m, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.85 (s, 1H), 9.85 (s, N3O 1H), 9.61 (s, 1H), 7.76 -7.68 (m, 4H), 7.57 (t, J= 6.8 Hz, 2H), 7.53-7.47 (m, 3H), 7.19 (t, J = 4.4 Hz, 2H), 2.05 (s, 3H); H-NMR (DMSO-dg, 400 MHZ): 5 10.82 (br s, 1H), .29 (br s, 1H), 9.95 (br s, C22H17N3O 1H), 8.06 (s, 1H), 7.75-7.70 (m, 4H), 7.57- 7.47 (m, 3H), 7.37 (d, J= 7.6 Hz, 1H), 7.32 (d, J= 7.2 Hz, 1H), 7.23 (t, J= 7.6 Hz, 1H), 2.03 (s, 3H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.85 C19H13N3O (s, 1H), 10.62 (s, 1H), 8.48 (d, J= 6.1 Hz, 2H), 7.79-7.69 (m, 6H), 7.60-7.45 (m, 3H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H-NMR (DMSO-dg, 400 MHZ): 5 10.85 (s, 1H), 10.36 NZO (s, 1H), 8.07- 8.04 (m, 1H), 7.80-7.70 (m, 5H), 7.65-7.61 (m, 2H), 7.57 (dd, J= 7.7, 1.6 Hz, 1H), 7.54- 7.35 (m, 7H); H-NMR (DMSO-dg, 400 MHZ): 5 10.79 (s, 1H), 8.72 (t, C19H16N4O J: 5.3 , 7.71-7.63 (m, 3H), 7.59-7.41 (m, 4H), 3.59 (q, J= 6.3 Hz, 2H), 3.29-3.25 (m, 2H), 2.66 (s, 3H); H-NMR (DMSO-dg, 400 MHZ): 5 10.78 (s, 1H), 8.69 (t, C18H15N50 J: 5.4 HZ,1H), 7.74-7.63 (m, 3H), 7.60-7.43 (m, 4H), 6.97 (s, 2H), 3.51 (q, J= 6.6 Hz, 2H), 3.03 (t, J= 6.7 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.78 (s, 1H), 8.71 (t, J= 5.4 Hz, 1H), ConnNsO 7.74-7.62 (m, 4H), 7.56-7.41 (m, 4H), 7.32 (br s, 1H), 3.99 (s, 2H), 3.58 (q, J= 6.5 Hz, 2H), 3.06 (t, J= 6.6 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H-NMR (DMSO-dg, 400 MHZ): 5 10.76 (s, 1H), 9.07 6N4O (dd, J= 4.4, 2.0 Hz, 1H), 8.64 (t, J= 5.5 Hz, 1H), .41 (m, 9H), 3.68- 3.62 (m, 2H), 3.14 (t, J= 7.0 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 13.67 (br s, 1H), .77 (s, 1H), 8.64 (br s, 1H), C18H15N50 8.42 (br s, 0.4H), 7.82 (br s, 0.6H), 7.71- 7.62 (m, 3H), 7.58-7.42 (m, 4H), 3.55 (q, J = 6.7 Hz, 2H), 3.00-2.82 (m, 2H); H-NMR (DMSO-dg, 500 MHZ): 5 13.24 (d, J= 9.8 Hz, 1H), 10.77 (br s, 1H), 8.69- C19H17N5O 8.57 (m, 1H), 7.71-7.63 (m, 3H), 7.58-7.43 (m, 4H), 3.56- 3.47 (m, 2H), 2.87 (t, J= 7.1 Hz, 1H), 2.76 (t, J= 7.5 Hz, 1H), 2.31-2.16 (s, 3H); 1H—NMR (DMSO-dg, 400 MHZ): 5 13.80 C22H17N5O (br s, 1H), .77 (s, 1H), 8.69 (br s, 1H), 7.74 (br s, 1H), 7.70-7.65 (m, 2H), 7.64 (s, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson 1H), 7.58-7.43 (m, 4H), 6.84 (br s, 1H), 6.59 (br s, 1H), 3.62- 3.55 (m, 2H), 3.00-2.91 (m, 2H); 1H—NMR (DMSO-dg, 400 MHZ): 5 13.62 (br s, 1H), .75 (s, 1H), 9.01 (br s, 1H), 8.38 (br s, 0.5H), 7.77 (br C24H19N50 s, 0.5H), 7.71- 7.62 (m, 3H), 7.60-7.42 (m, 4H), 7.37-7.32 (m, 2H), 7.27 (t, J= 7.5 Hz, 2H), .17 (m, 1H), 5.47 (q, J = 7.7 Hz, 1H), 3.39—3.33 (m, 1H), 3.27—3.17 (m, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.79 (s, 1H), 9.53- C17H12N4O 9.48 (m, 2H), 7.73-7.67 (m, 3H), 7.62 (dd, J = 8.0, 1.8 Hz, 1H), 7.57-7.43 (m, 3H), 4.86 (d, J= 5.9 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.77 (s, 1H), 9.10 (t, C18H13N3O J= 5.7 Hz,1H), 9.04 (s, 1H), 7.74-7.62 (m, 4H), 7.57-7.42 (m, 4H), 4.58 (d, J= 5.6 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson H-NMR (DMSO-dg, 400 MHZ): 5 13.77 (br s, 1H), N50 10.79 (br s, 1H), 9.06 (br s, 1H), 8.33 (br s, 1H), .60 (m, 4H), 7.57- 7.42 (m, 3H), 4.51 (d, J= 4.8 Hz, 2H); H-NMR (DMSO-d6, 400 MHZ): 5 10.78 (s, 1H), 9.16 (t, J= 5.9 Hz, 1H), Conlsto 8.48 (d, J= 5.9 Hz, 2H), 7.76- 7.63 (m, 4H), 7.57-7.42 (m, 3H), 7.27 (d, J = 5.5 Hz, 2H), 4.46 (d, J=5.7 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.79 (s, 1H), 9.22 (t, J= 5.3 Hz,1H), 9.09 (s, 1H), C19H14N40 8.71 (d, J= 5.2 Hz, 1H), 7.74 (s, 1H), 7.72- 7.65 (m, 3H), 7.57-7.44 (m, 3H), 7.39 (d, J = 4.9 Hz, 1H), 4.52 (d, J= 5.9 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.78 (s, 1H), 9.22 (t, C19H14N4O J: 5.7 HZ, 1H), 8.61 (s, 1H), 8.58- 8.56 (m, 1H), 8.54-8.51 (m, 1H), 7.73 (s, 1H), 7.71- 7.63 (m, 3H), 7.57-7.43 (m, ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 3H), 4.59 (d, J = 5.7 Hz, 2H); H-NMR dg, 400 MHZ): 5 10.80 (s, 1H), 9.10 (t, J= 5.8 Hz,1H), C19H14N4O 8.74 (d, J= 4.9 Hz, 2H), 7.73 (s, 1H), 7.71- 7.65 (m, 3H), 7.57-7.43 (m, 3H), 7.38 (t, J= 4.9 Hz, 1H), 4.63 (d, J= 5.9 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.77 (s, 1H), 9.17 (t, C19H15N3O J= 5.7 Hz,1H), ZSZ 7.71-7.64 (m, 3H), 7.59-7.42 (m, 5H), 4.55 (d, J= 5.6 Hz, 2H), 2.57 (s, 3H); H-NMR (DMSO-d6, 400 MHZ): 5 10.77 (s, 1H), 9.28 (t, J= 5.7 , 7.72-7.64 (m, 3H), 7.61-7.42 (m, 5H), 4.55 (d, J= 5.4 Hz, 2H); H-NMR (DMSO-dé, 400 MHZ): 5 10.78 (s, 1H), 9.28 (t, J= 5.7 Hz,1H), C24H17N30 7.90-7.86 (m, 2H), 7.79 (s, 1H), 7.73-7.66 (m, 3H), 7.61 (dd, J= 8.2,1.8 Hz, 1H), 7.56- 7.42 (m, 6H), 4.66 (d, J= 5.6 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H-NMR (DMSO-d6, 400 MHZ): 5 10.76 (s, 1H), 9.15 (t, .7 Hz, 1H), 8.83 (s, 1H), 7.70-7.64 (m, 3H), 7.59-7.43 (m, 4H), 4.55 (d, J= 5.7 Hz, 2H), 2.39 (s, 3H); HNMR (DMso—dé, 400 MHZ): 5 10.78 (s, 1H), 9.34 (t, J= 5.5 Hz, 1H), C24H17N30 9.02 (s, 1H), 7.74-7.66 (m, 5H), 7.60 (dd, J = 8.1, 1.8 Hz, 1H), 7.56-7.39 (m, 6H), 4.74 (d, J= 5.5 Hz, H-NMR (DMSO-dg, 400 C14H10NZO MHZ): 5 10.77 (s, 1H), 7.99 (br s, 1H), 7.72- 7.58 (m, 4H), 7.56-7.43 (m, 4H); 1H—NMR (DMSO'dg, 400 MHZ): 5 10.75 (br s, 1H), 8.55 (t, J= 5.4 Hz, 1H), 7.71-7.62 C19H18N20 (m, 3H), 7.60- 7.43 (m, 4H), 3.98-3.89 (m, 1H), 3.79-3.72 (m, 1H), 3.65- 3.57 (m, 1H), .25 (m, 2H), 1.93-1.73 (m, 3H), 1.61- 1.49 (m, 1H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson H-NMR (DMSO-dg, 400 MHZ): 5 10.75 (br s, 1H), 8.60 (t, J= 5.5 Hz, 1H), 7.71-7.63 (m, 3H), 7.59 - C19H18NZO 7.43 (m, 4H), .56 (m, 3H), 3.43 (dd, J = 8.5, 5.4 HZ, 1H), 3.26-3.14 (m, 2H), 2.47- 2.38 (m, 1H), 1.96-1.86 (m, 1H),1.63-1.51 (m, 1H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.75 (s, 1H), 8.51 (t, J= 5.6 Hz, 1H), .62 (m, 3H), .43 CZOHZONZO (m, 4H), 3.82 (dd, J= 11.2, 2.5 Hz, 2H), 3.27-3.20 (m, 2H), 3.12 (t, J= 6.3 Hz, 2H), 1.81-1.69 (m, 1H),1.6171.51 (m, 2H), 1.24- 1.10 (m, 2H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.79 (s, 1H), 9.26 (t, J= 5.7 Hz, 1H), C18H14N4O 7.72-7.67 (m, 3H), 7.62 (dd, J = 7.9, 1.8 Hz, 1H), 7.57-7.43 (m, 3H), 4.63 (d, J= 5.6 Hz, 2H), 2.45 (s, 1H—NMR C19H16N4O 381.0 (DMSO-dg, 400 1603 dLDAN/\ANINS A,6,283 70 3S H (M++1), MHz):510.78 380.09 (s,1H),8.69(t, J=5.7 Hz, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson .62 (m, 3H), 7.56-7.42 (m, 4H), 3.58 (q, J= 6.6 Hz, 2H), 3.03 (t, J= 6.8 Hz, 2H), 2.43 (s, 3H); 1H-NMR , 400 MHZ): 5 10.77 (s, 1H), 9.18 (t, J= 5.7 Hz,1H), C20H17N3O 7.71-7.64 (m, 3H), 7.60-7.43 (m, 5H), 4.56 (d, J= 5.6 Hz, 2H), 2.90 (q, J = 7.5 Hz, 2H), 1.24 (t, J= 7.5 Hz, 3H); 1H NMR (DMSO-d,, 400 MHZ): 5 10.77 (s, 1H), 9.18 (t, J= 5.7 Hz, 1H), C21H19N3O 7.72-7.64 (m, 3H), 7.61-7.42 (m, 5H), 4.57 (d, J= 5.6 Hz, 2H), 3.22-3.15 (m, 1H), 1.27 (d, J= 6.9 Hz, 6H); 1H NMR (DMSO-d, 400 MHZ): 5 10.76 (s, 1H), 9.15 (t, C19H15N3O J= 5.6 Hz, 1H), 7.71-7.63 (m, 3H), 7.60-7.42 (m, 4H), 7.06 (s, 1H), 4.44 (d, J= 5.6 Hz, 2H), 3.95 (s, 3H); 1H NMR (DMSO-d, 400 N4O MHZ): 5 10.76 (s, 1H), 9.00 (t, J= 5.5 Hz, 1H), 7.72-7.42 (m, 7H), 6.88 (br s, 2H), 6.81 (s, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1H), 4.35 (d, J = 5.5 Hz, 2H); H NMR (DMSO-d6, 500 MHZ): 5 10.77 (s, 1H), 9.03 (t, J= 5.6 Hz,1H), C19H16N4O 7.69-7.62 (m, 3H), 7.59-7.42 (m, 4H), 7.34- 7.30 (m, 1H), 6.87 (s, 1H), 4.36 (d, J= 5.8 Hz, 2H), 2.72 (d, J= 4.9 Hz, 3H); H NMR (DMSO-dg, 400 MHZ): 5 10.75 (s, 1H), 9.05 (t, C201112§N4O J= 5.7 Hz,1H), 7.72-7.62 (m, 3H), 7.59-7.42 (m, 4H), 6.99 (s, 1H), 4.41 (d, J= 5.5 Hz, 2H), 2.95 (s, 6H); H-NMR dg, 400 MHZ): 5 10.78 (s, 1H), 8.69 (t, C20H17N3O J= 5.7 Hz,1H), 7.70-7.62 (m, 3H), 7.56-7.42 (m, 4H), 3.58 (q, J= 6.6 Hz, 2H), 3.03 (t, J= 6.8 Hz, 2H), 2.43 (s, 3H); H NMR (DMSO-dg, 400 MHZ): 5 10.77 (s, 1H), 9.15 (t, J= 5.8 Hz,1H), A, 6, 327 C21H19N3O 8.84 (s, 1H), (Reaction 7.70-7.64 (m, time 24h) 3H), 7.59-7.42 (m, 4H), 4.58 (d, J= 5.9 Hz, 2H), 3.32-3.29 (m, 1H), 1.21 (d, J= 6.8 Hz, [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson HNMR (DMSO-dg, 400 MHZ): 5 10.77 (s, 1H), 9.31 (t, J= 5.5 Hz, 1H), €18H12C1N 9.01 (s, 1H), 30252 7.73-7.65 (111, 401.01 3H), 7.59 (dd, J = 7.9, 1.8 Hz, 1H), 7.56-7.42 (m, 3H), 4.57 (d, J= 5.7 Hz, 2H); H NMR (DMSO-d6, 400 MHZ): 5 10.75 (s, 1H), 8.62 (t, J= 5.5 Hz, 1H), 7.70-7.63 (m, A, 6, 341 C18H16N20 3H),7.59-7.43 (Reaction (m, 4H), 4.60 time 12 h) (dd, J= 7.8, 6.0 Hz, 2H), 4.31 (t, J= 6.0 Hz, 2H), 3.50 (dd, J = 7.8, 6.0 Hz, 2H), 3.17-3.09 (m, 1H). 1H-NMR (CDC13, 400 MHZ): 5 8.16 (br s, 1H), 7.81 (s, 1H), 7.61 (d, J= 8.0 Hz, 1H), 7.57 (s, 1H), 7.45-7.42 (m, C22H23C1N 2H),7.39-7.36 A, 14, 261 202S (m, 1H), 5.99- 41412 5.98(1’1’1,1H), 3.48-3.43 (m, 2H), 1.75-1.67 (m, 5H), 1.57- 1.46 (m, 2H), 1.34-1.31 (m, 1H), 1.27-1.16 (m, 3H), 0.98- 0.92 (m, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H-NMR (CDC13, 400 MHZ): 5 8.70 (s, 1H), 7.77 (d, J= 8.4 Hz, 1H), 7.63-7.60 (m, 2H), 7.51 (s, 1H), 7.45 (d, J A, 21, 261 = 9.6 Hz, 1H), (285 mg) 7.35 (d, J= .0 Hz, 1H), 6.07 (t, J= 6.0 Hz, 1H), 3.48- 3.43 (m, 2H), 1.73-1.45 (m, 8H), 1.30-1.14 (m, 3H), 1.00- 0.91 (m, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.94 (br s, 1H), 9.20 (t, J= 5.7 Hz, 1H), 9.08 (s, C19H13FN4 1H), 8.75 (s, A, 28, 212 028 2H), .60 (75 mg) (m, 3H), 7.53— 380.07 7.46 (m, 1H), 7.41 (dd, J= 7.8, 0.9 Hz, 1H), 7.32-7.28 (m, 1H), 4.47 (d, J= 5.6 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.95 (s, 1H), 9.25 (t, J= 5.7 Hz, 1H), 8.96 (s, 1H), 7.80 (s, 1H), 7.71-7.65 (m, A, 28, 213 2H), 7.60 (dd, J = 8.0, 2.0 Hz, 1H), 7.52-7.46 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.34—7.28 (m, 1H), 4.65 (d, J= 5.7 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-dg, 400 MHZ): 5 10.95 (s, 1H), 9.09 (t, J= 5.4 Hz, 1H), 8.27 (s, 1H), 7.72-7.65 (m, 2H), 7.61 (dd, J 1542 A, 28, 214 = 8.0, 1.9 Hz, 1H), 7.53-7.46 (m, 1H), 7.40 (d, J= 7.2 Hz, 1H), .27 (m, 1H), 7.03 (s, 1H), 4.51 (d, J= 5.4 Hz, 2H); 1H NMR (DMSO'dg, 400 MHZ): 5 10.96 (s, 1H), 9.01 (s, 1H), 8.69-8.60 (m, 3H), 7.66 (d, J= 8.0 Hz, 1H), 7.62 (s, 1H), 7.51 (dd, J 1543 A, 28, 215 = 8.2. 2.0 Hz, 1H), 7.49-7.46 (m, 1H), 7.40 (d, J= 7.8 Hz, 1H), 7.28-7.33 (m, 1H), 3.53 (q, J= 6.4 Hz, 2H), 2.84 (t, J= 6.6 Hz, 2H); 1H NMR (DMSO-d6, 400 MHZ): 5 10.96 (s, 1H), 8.63 (t, J= 5.5 Hz, 1H), 8.52—8.47 (m, 1H), 7.71-7.64 (m, 3H), 7.55 C21H16FN3 393.9 (dd, J= 8.2,1.8 1471 A, 28, 216 22 028 (M++1); Hz, 1H), 7.51— 393.09 7.49 (m, 1H), 7.40 (d, J= 7.4 Hz, 1H), 7.31 (t, J= 9.2 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.23-7.19 (m, 1H), 3.59 (q, J = 6.8 Hz, 2H), [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 2.96 (t, J= 7.3 Hz, 2H); H NMR dg, 400 MHZ): 5 10.97 (s, 1H), 8.64 (t, J= 5.5 Hz, 1H), 8.43 (s, 1H), 8.40 (dd, J= 4.8, 1.6 Hz, FN3 1H), 7.68-7.61 A, 28, 217 028 (m, 3H), 7.53 (dd, J= 8.0, 2.0 39309 Hz, 1H), 7.51— 7.46 (m, 1H), 7.40 (d, J= 7.8, Hz, 1H), 7.34— 7.27 (m, 2H), 3.49 (q, J= 7.0 Hz, 2H), 2.84 (t, J= 7.0 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.96 (s, 1H), 9.15 (t, J= 5.7 Hz,1H), 8.52 (s, 1H), 8.45 (dd, J= 4.7, 1.4 Hz, 1H), 7.73-7.66 A, 28,218 (m, 3H), 7.63 (dd, J= 8.2,1.8 Hz, 1H), 7.54- 7.44 (m, 1H), 7.40 (d, J= 7.3 Hz, 1H), 7.36- 7.28 (m, 2H), 4.46 (d, J= 5.6 Hz, 2H); H NMR (DMSO'dg, 400 MHZ): 5 11.04 (s, 1H), 10.63 (s, 1H), 8.48 (d, A, 28, 185 J= 6.0 Hz, 2H), 7.80-7.69 (m, 5H), 7.43 (d, J = 7.6 Hz, 2H), 7.33 (t, J= 9.1 Hz, 1H); [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-dg, 400 MHZ): 5 11.04 FN2 (s, 1H), 10.38 A, 28, 186 OZS (s, 1H), 8.07- 8.04 (m, 1H), 440.10 7.82-7.72 (m, 4H), 7.67-7.61 (m, 2H), 7.55- 7.30 (m, 8H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.98 (s, 1H), 8.68 (t, J= 5.6 Hz, 1H), 8.22 (s, 1H), 7.69-7.64 (m, 2H), 7.55 (dd, J = 8.0, 1.9 Hz, A, 28, 347 1H), 7.53—7.46 (m, 1H), 7.40 (dd, J= 7.6, 0.9 Hz, 1H), 7.36- 7.28 (m, 1H), 6.92 (s, 1H), 3.49 (q, J= 6.2 Hz, 2H), 2.90 (t, J= 6.7 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.98 (br s, 1H), 8.91 (s, 1H), 8.70 (t, J= 5.6 Hz, 1H), 7.68 (d, J= 7.9 C19H14FN3 Hz, 3H), 7.57 (dd, J= 8.0, 1.9 A, 28, 352 0282 Hz, 1H), 7.53— 399.05 7.47 (m, 1H), 7.41 (d, J= 7.1 Hz, 1H), 7.35— 7.29 (m, 1H), 3.48 (q, J= 5.9 Hz, 2H), 3.10 (t, J= 6.7 Hz, 2H); H NMR C28Hz1FNz (DMSO-dg, 400 A, 28, 219 OZS MHZ): 5 10.97 468.13 (s, 1H), 8.66 (t, J= 5.3 Hz,1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.77-7.24 (m, 15H), 3.50 (q, J = 7.0 Hz, 2H), 2.86 (t, J= 7.0 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.97 (s, 1H), 8.63 (t, J= 5.5 Hz, 1H), 7.69-7.61 (m, C24H22FN3 4H),7.54-7.46 A, 28, 406 0452 (m, 4H), 7.40 49910 (d, J: 7.0 HZ, 1H), 7.34-7.28 (m, 1H), 3.56- 3.46 (m, 2H), 2.93 (t, J= 7.0 Hz, 2H), 2.54 (s, 6H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.89 (s, 1H), 9.16 (t, J= 5.6 Hz, 1H), 9.07 (s, 1H), C19H13FN4 8.74 (S, 2H), A, 35, 212 Ozs 7.71-7.66 (m, 2H), 7.64-7.58 380.07 (m, 2H), 7.47 (dd, J= 9.2, 2.8 Hz, 1H), 7.37 (dt, J= 11.6, 3.2 Hz, 1H), 4.47 (d, J= 5.6 Hz, 2H); H-NMR (DMSO-d6, 400 MHZ): 5 10.89 (br s, 1H), 9.24 (t, J= 5.6 Hz, 1H), 8.95 (br s, 1H), 7.80 (br s, B, 35, 213 1H), 7.70-7.65 (m, 2H), 7.61- 7.57 (m, 2H), 7.47 (d, J= 6.4 Hz, 1H), 7.39- 7.37 (m, 1H), 4.64 (d, J= 5.6 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson H-NMR (DMSO-dg, 400 MHZ): 5 10.89 (s, 1H), 8.62 (t, J= 5.6 Hz,1H), 8.47 (d, J= 8.0 Hz, 1H), 7.70- 7.61 (m, 3H), 7.59-7.54 (m, A, 35,216 2H), 7.48 (dd, J = 9.2, 2.8 Hz, 1H), 7.36 (dt, J = 11.6, 3.2 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.22-7.19 (m, 1H), 3.61-3.50 (m, 2H), 2.96 (t, J= 7.2 Hz, 2H); 1H—NMR dg, 400 MHZ): 5 10.89 (br s, 1H), 9.07 (t, J= 5.2 Hz, 1H), 8.27 (s, 1H), 7.70 (s, C18H12FN3 1H), 7.66 (d, J A, 35, 214 038 = 8.0 Hz, 1H), 369.06 7.62-7.57 (m, 2H), 7.48 (dd, J = 9.2, 2.8 Hz, 1H), 7.37 (dt, J =11.6, 3.2 Hz, 1H), 7.03 (s, 1H), 4.50 (d, J = 5.2 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.89 (br s, 1H), 9.01 C20H15FN4 (s, 1H), 8.65- A, 35, 215 028 8.62 (m, 3H), 394.09 7.65-7.35 (m, 6H), 3.52 (t, J= 6.4 Hz, 2H), 2.84 (t, J= 6.4 Hz, 2H); H-NMR C26H25FN2 (DMSO-dg, 400 A, 35, 220 03 S MHZ): 5 10.88 464.16 (s, 1H), 8.72 (d, J= 8.0 Hz, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 7.70 (s, 1H), 7.66 (s, 2H), 7.62-7.58 (m, 1H), 7.47 (dd, J = 8.8, 2.8 Hz, 1H), 7.37 (611, J = 11.6, 3.2 Hz, 1H), 7.32—7.25 (m, 4H), 5.01— 4.95 (m, 1H), 4.86 (t, J= 6.0 Hz, 1H), 3.68- 3.57 (m, 2H), 1.24 (s, 9H), H-NMR (DMSO-dg, 400 MHZ): 5 10.96 (s, 1H), 10.35 FZN (s, 1H), 7.76- 2025 7.72 (m, 5H), A, 35, 221 7.63-7.60 (m, 382.06 1H), 7.50 (dd, J = 9.2, 2.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.19 (t, J= 8.8 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.94 (s, 1H), 10.40 (s, 1H), 7.78- 7.70 (m, 5H), 7.63-7.60 (m, 1H), 7.50 (dd, J = 9.2, 3.2 Hz, 1H), 7.41-7.37 (m, 3H); H-NMR (DMSO-dg, 400 MHZ): 5 10.90 (s, 1H), 9.15 (s, 1H), 9.11 (s, 1H), 8.64 (t, J= C26H19FN4 .2 Hz, 1H), A, 35, 359 028 7.73 (d, J= 8.0 470.12 Hz, 2H), 7.67- 7.61 (m, 2H), 7.59-7.55 (m, 2H), 7.48 (dd, J = 9.2, 2.8 Hz, 1H), 7.40-7.34 (m, 2H), 3.50 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson (q, 2H), 2.89 (t, J= 7.2 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.88 (s, 1H), 8.75 (s, 2H), 8.64 (t, J= 6.0 Hz, 1H), C26H19FN4 8.36-8.34 (m, 2H), 7.65-7.63 A, 35, 367 028 (m, 2H), 7.60- 470.12 7.57 (m, 2H), 7.55-7.45 (m, 4H), 7.39-7.34 (m, 1H), 3.56 (q, J= 6.4 Hz, 2H), 2.88 (t, J= 6.8 Hz, 2H); 1H-NMR (DMSO-dg, 400 MHZ): 5 10.91 (s, 1H), 9.20 (t, J= 6.0 Hz, 1H), 9.17 (s, 1H), C25H17FN4 9.11 (s, 2H), A, 35, 372 028 .74 (m, 3H), 7.67 (s, 456.11 2H), 7.62-7.58 (m, 1H), 7.50- 7.40 (m, 3H), 7.38 (td, J= 11.6, 3.2 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H); 1H-NMR (DMSO-dg, 400 MHZ): 5 10.89 (s, 1H), 9.17 (t, J= 5.6 Hz, 1H), 8.84 (s, 2H), 8.38-8.35 (m, C25H17FN4 2H), 7.72 (s, A, 35, 377 028 1H), 7.69-7.60 (m, 2H), 7.59- 456.11 7.58 (m, 1H), 7.52-7.51 (m, 3H), 7.49-7.46 (m, 1H), 7.37 (td, J= 11.6, 2.8 Hz, 1H), 4.50 (d, J= 6.0 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H-NMR (DMSO-dg, 400 MHZ): 5 10.96 (s, 1H), 10.46 (s, 1H), 7.76- FZN 7.68 (m, 4H), 2025 7.64-7.60 (m, 382.06 1H), 7.52-7.49 (m, 2H), 7.41- 7.35 (m, 2H), 6.93 (dt, J= .0, 1.6 Hz, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.94 (s, 1H), 10.26 (s, 1H), 7.78 (s, 1H), 7.75-7.70 N202S (m, 2H), 7.64- A, 35, 224 7.60 (m, 2H), 416.02 7.54-7.51 (m, 2H), 7.39 (dt, J = 11.6, 3.2 Hz, 1H), 7.31 (dd, J = 8.8, 1.2 Hz, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.94 (s, 1H), 10.18 (s, 1H), 7.78 (s, 1H), 7.75-7.74 ConlezN (m, 2H), 7.64- ZOZS 7.55 (m, 2H), 382.06 7.50 (dd, J= 9.2, 2.8 Hz, 1H), 7.39 (dt, J = 8.8, 2.8 Hz, 1H), 7.31-7.26 (m, 2H), 7.24- 7.19 (m, 1H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.94 C20H1 1C1F2 (s, 1H), 10.16 C, 35, 226 N202S (s, 1H), 7.80 (s, 1H), 7.77-7.72 416.02 (m, 2H), 7.63- 7.60 (m, 1H), 7.57-7.53 (m, 2H), 7.50 (dd, J [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson = 9.2, 2.8 Hz, 1H), 7.39 (td, J = 11.2, 2.8 HZ, 1H), 7.27 (td, J = 11.2, 2.8 HZ, 1H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.98 (br s, 1H), C20H10F4N 10.60 (br s, 202S 1H), .66 (m, 5H), 7.63- 418.04 7.60 (m, 1H), 7.51 (dd, J= 9.2, 2.8 Hz, 1H), 7.41-7.37 (m, 1H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.93 F (s, 1H), 10.19 F (s, 1H), 7.78 (s, C20H11F3N A, 35, 228 1H), 7.73 (s, ZOZS 2H), 7.63-7.48 400.05 (m, 3H), 7.41— 7.32 (m, 2H), 7.11 (t,J= 8.8 Hz, 1H); 1H—NMR (DMSO'dg, 400 MHZ): 5 10.95 (s, 1H), 10.29 (s, 1H), 7.76 (s, 1H), 7.73-7.72 C20H13FNz (m, 4H), 7.64- A, 35, 179 028 7.60 (m, 1H), 364.07 7.51 (dd, J= 9.2, 2.8 Hz, 1H), 7.40 (dd, J = 8.4, 2.8 Hz, 1H), 7.37-7.32 (m, 2H), 7.10 (t, J= 7.6 Hz, 1H); 1H—NMR (DMSO-dg, 400 C18H11FN4 MHZ): 5 10.99 A, 35, 229 028 (s, 1H), 10.69 (s, 1H), 9.13 (s, 366.06 2H), 8.93 (s, 1H), 7.80 (s, 1H), 7.77 (s, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson 2H), 7.64-7.60 (m, 1H), 7.51 (dd, J= 9.2, 3.2 Hz, 1H), 7.39 (dt, J= 11.2, 2.8 Hz, 1H); 1H NMR (DMSO'dg, 400 MHZ): 5 11.29 (s, 1H), 10.94 (s, 1H), 8.95 (s, 1H), 8.72 (d, J = 5.8 Hz, 1H), C18H11FN4 8.17 (d, J= 5.7 C, 35, 230 028 Hz, 1H), 7.83- 366.06 7.76 (m, 2H), 7.75-7.67 (m, 1H), 7.62 (dd, J = 8.5, 5.1 Hz, 1H), 7.51 (dd, J = 9.1, 2.8 Hz, 1H), 7.39 (t, J= 8.0 Hz, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 12.70 (br s, 1H), .98 (s, 1H), 7.87-7.86 (m, 2H), 7.72 (d, J A, 35, 231 = 8.4 Hz, 1H), 7.63-7.60 (m, 1H), 7.51 (dt, J = 9.2, 2.8 Hz, 2H), .37 (m, 1H), 7.28- 7.25 (m, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 11.79 (br s, 1H), .98 (s, 1H), 8.62 (s, 1H), 7.79-7.73 (m, A, 35, 380 2H), 7.61-7.58 (m, 2H), 7.50- 7.47 (m, 1H), 7.47 (d, J= 9.2, 2.8 Hz, 1H), 7.37 (td, J= 11.2, 3.2 Hz, 1H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H-NMR dg, 400 MHZ): 5 11.62 (br s, 1H), .94 (br s, 1H), 7.95-7.85 (m,1H),7.81- A, 35, 232 7.69 (m, 3H), .59 (m, 1H), 7.50 (d, J = 6.4 Hz, 1H), 7.40-7.37 (m, 1H), 7.20 (br s, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.97 (s, 1H), 10.63 (s, 1H), 8.48- 8.47 (m, 2H), C, 35, 185 7.77-7.73 (m, 5H), 7.64-7.60 (m, 1H), 7.51 (dd, J= 9.2, 2.8 Hz, 1H), 7.39 (td, J= 11.2, 2.8 Hz, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.98 (s, 1H), 10.93 (s, 1H), 8.39- 8.35 (m, 1H), 8.17 (dd, J= 9.2, 4.0 Hz, C, 35, 233 1H), 7.82-7.77 (m, 3H), 7.69 (d, J= 8.0 Hz, 1H), 7.63-7.60 (m, 1H), 7.50 (dd, J= 9.2, 2.8 Hz, 1H), 7.38 (td, J= 11.6, 3.2 Hz, 1H); 1H—NMR (DMSO-dg, 400 C19H11F2N MHZ): 5 10.98 B, 35,234 3028 (br s, 1H), .73 (br s, 383.05 1H), 8.74 (s, 1H), 8.34 (s, 1H), 8.16 (d,J [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson = 9.2 Hz, 1H), 7.78 (s, 1H), 7.76 (s, 2H), 7.64-7.60 (m, 1H), 7.51 (dd, J = 9.2, 3.2 Hz, 1H), 7.39 (dt, J = 11.6, 3.2 HZ, 1H); 1H—NMR (DMSO'dg, 400 MHZ): 5 11.01 (br s, 2H), 8.43 (br s,1H), 8.18 (d, J= 8.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), C, 35, 235 .77 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.61-7.60 (m, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.38 (t, J= 8.0 Hz, 1H); H-NMR (DMSO-dg, 400 MHZ): 5 10.97 (br s, 1H), .71 (br s, 1H), 8.82 (br s, 1H), 8.36 (d, J C, 35,236 = 7.6 Hz, 2H), 7.78-7.76 (m, 3H), 7.62 (t, J= 7.6 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.39 (t, J= 7.2 Hz, 1H); H-NMR (DMSO'dg, 400 MHZ): 5 10.97 (s, 1H), 10.55 C21H12FN3 (s, 1H), 8.68 (s, A, 35, 237 038 1H), 8.31 (s, 1H), 7.79-7.75 405.06 (m, 4H), 7.60- 7.61 (m, 2H), 7.51 (dd, J= 9.2, 2.8 Hz, 1H), 7.39 (dt, J [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson = 11.6, 3.2 Hz, 1H); H-NMR DMSO-dg, 400 MHZ): 5 12.44 (br s, 1H), .94 (s, 1H), Ca 238 , 35, 7.92 (br s, 1H), (a= Et3N, 7.86-7.84 (m, DMAP) 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62-7.60 (m, 2H), .49 (m, 2H), 7.40- 7.30 (m, 3H); H-NMR (DMSO-dg, 400 MHZ): 5 10.97 (s, 1H), 10.56 (s, 1H), 9.30 (s, 1H), 8.65 (s, 1H), 8.05 (d, J A, 35,239 = 8.8 Hz, 1H), 7.79-7.73 (m, 4H), 7.64-7.61 (m, 1H), 7.51 (dd, J= 9.2, 2.8 Hz, 1H), 7.39 (dt, J= 11.2, 2.8 Hz, 1H), 1H—NMR (DMSO-dg, 400 MHZ): 5 12.09 (br s, 1H), .98 (s, 1H), C21H12FN3 8.00 (d, J: 8.0 O 8 Hz, 1H), 7.93- A, 35, 240 2 2 7.91 (m) 2H), 42104 7.79-7.74 (m, 2H), 7.64-7.60 (m, 1H), 7.53- 7.44 (m, 2H), 7.41—7.32 (m, 2H); 1H—NMR (DMSO-dg, 400 C21H11FzN MHZ); 5 1291 C9 35» 241 30252 (br s, 1H), .96 (s, 1H), 439'03 7.93-7.90 (m, 2H), 7.78 (d, J = 6.8 Hz, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson 7.68-7.59 (m, 3H), 7.50 (dd, J = 9.2, 2.8 Hz, 1H), 7.38 (td, J = 11.6, 3.2 Hz, 1H), 7.23-7.17 (m, 1H); 1H—NMR (DMSO'dg, 400 MHZ): 5 13.01 (br s, 1H), 11.00 (s, 1H), 8.16 (s, 1H), 7.91 (d, J= 8.0 C, 35, 242 Hz, 2H), 7.79- 7.70 (m, 2H), 7.64-7.60 (m, 1H), 7.53-7.47 (m, 2H), 7.39 (td, J= 8.4, 3.2 Hz, 1H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.96 (s, 1H), 10.39 (s, 1H), 7.84 (d, C26H17FN2 J= 8.8 Hz, 2H), 028 7.78 (s, 1H), A, 35, 243 7.74 (s, 2H), 440.10 7.68-7.61 (m, 4H), 7.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.47-7.45 (m, 1H), 7.43- 7.32 (m, 4H); 1H NMR (400 MHz, DMSO- d6) 5 10.97 (s, C26H17FN2 1H), 10.38 (s, A, 35, 186 028 1H), 8.05 (s, 1H), 7.83 7 7.73 440.10 (m, 4H), 7.68 — 7.61 (m, 3H), 7.52 7 7.37 (m, 7H); 1H NMR (DMSO-dg, 400 C21H16FN3 MHZ): 5 10.91 A, 35,217 OZS (s, 1H), 8.62 (t, 393.09 J= 5.5 Hz,1H), 8.44—8.38 (m, 2H), 7.67-7.57 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (m, 4H), 7.54 (dd, J= 8.2, 1.8 Hz, 1H), 7.48 (dd, J= 9.2, 2.9 Hz, 1H), 7.37 (dt, J= 8.5, 2.9 Hz, 1H), 7.29 (dd, J= 7.7, 4.8 Hz, 1H), 3.54- 3.44 (m, 2H), 2.84 (t, J= 7.0 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.90 (br s, 1H), 8.66 (t, J= 5.5 Hz, 1H), 8.21 (s, 1H), 7.68-7.63 (m, 2H), 7.60 (dd, J= 8.6, 5.3 B, 35, 347 Hz, 1H), 7.55 (dd, J= 8.2, 1.7 Hz, 1H), 7.48 (dd, J= 9.2, 2.9 Hz, 1H), 7.37 (dt, J= 8.5, 3.0 Hz, 1H), 6.92 (s, 1H), 3.49 (q, 2H), 2.90 (t, J= 6.7 Hz, 2H); 1H NMR (DMSO'dg, 400 MHZ): 5 10.92 (br s, 1H), 8.91 (br s, 1H), 8.70 C19H14FN3 (br s, 1H), 7.73- B, 35, 352 0282 7.54 (m, 5H), 399.05 7.49 (d, J= 7.2 Hz, 1H), 7.42- 7.36 (m, 1H), 3.52-3.45 (m, 2H), 3.13-3.10 (m, 2H); 1H NMR (400 MHZ, DMSO- C20H14F d6): 5 10.89 (s, A, 35,218 N302S 1H), 9.15 (t, J= .4 Hz, 1H), 379.08 8.52 (s, 1H), 8.45 (dd, J = 4.8, 1.5 Hz, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson 1H), .57 (m, 5H), 7.48 (dd, J = 9.2, 2.9 Hz, 1H), 7.41- 7.36 (m, 1H), 7.34 (dd, J = 7.9, 4.9 Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H); 1H NMR (DMSO-d6, 400 MHZ): 5 10.91 (s, 1H), 8.65 (t, J = 5.4 Hz, 1H), C28H21F .53 (m, A, 35,219 N202S 8H), 7.50-7.41 468.13 (m, 3H), 7.40- 7.28 (m, 4H), 3.50 (q, J = 6.7 Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H); 1H NMR (DMSO-d6, 400 MHZ): 5 10.91 (br s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 7.67-7.62 (m, 4H), 7.59 (dd, J = 8.6, 5.3 C24H22F Hz, 1H), 7.53 A, 35, 406 N304S2 (dd, J = 8.2, 1.7 499.10 Hz, 1H), 7.51- 7.46 (m, 3H), 7.37 (td, J= 8.5, 3.0 Hz, 1H), 3.51 (q, J = 6.6 Hz, 2H), 2.93 (t, J = 7.0 Hz, 2H), 2.54 (s, 6H); 1H NMR (400 MHz, DMSO- d6): 5 10.98 (br s, 1H), 10.44 (s, C25H16F 1H), 8.68 (d, J A, 35, 244 N302S = 5.1 Hz, 1H), 441.09 8.50 (s, 1H), 7.94-7.89 (m, 2H), 7.87-7.84 (m, 1H), 7.83- 7.77 (m, 3H), [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson 7.76-7.72 (m, 1H), 7.63 (dd, J = 8.6, 5.3 Hz, 1H), 7.52 (dd, J = 9.1, 2.7 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.43—7.35 (m, 2H); 1H NMR (400 MHZ, DMSO- d6): 5 10.98 (s, 1H), 10.42 (s, 1H), 8.85 (br s, 1H), 8.59 (d, J = 3.7 Hz, 1H), C25H16F 8.08 (s, 1H), A, 35, 245 N3OZS 8.03 (d, J = 8.0 441.09 Hz, 1H), 7.85- 7.72 (m, 4H), 7.63 (dd, J = 8.5, 5.2 Hz, 1H), 7.54—7.45 (m, 4H), 7.40 (td, J = 8.4, 2.9 Hz, 1H); HNMR (400 MHZ, DMSO- d6): 5 10.99 (s, 1H), 10.46 (s, 1H), 8.66 (d, J = 6.0 Hz, 2H), 8.18-8.16 (m, C25H16F 1H), 7.85 (dt, J A, 35, 246 N3OZS = 7.6, 1.6 Hz, 441.09 1H), 7.81-7.78 (m, 1H), 7.77- 7.74 (m, 2H), 7.68-7.61 (m, 3H), 7.56-7.49 (m, 3H), 7.40 (td, J= 8.5, 2.5 Hz, 1H); 1H NMR (400 MHz, DMSO- d6): 5 10.98 (s, C23H14FN3 1H), 10.44 (s, A, 35, 247 038 1H), 8.46 (s, 431.07 1H), 8.16 (s, 1H), 7.83-7.69 (m, 4H), 7.69- 7.59 (m, 2H), [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.55—7.43 (m, 3H), 7.40 (rd, J = 8.5, 3.0 Hz, 1H); 1H NMR (400 MHZ, DMSO- d6): 10.89 (s, 1H), 9.20 (d, J = 7.3 HZ, 1H), 8.57—8.54 (m, 1H), 7.84 (td, J = 7.7, 1.8 HZ, 1H), 7.74 (s, C23H18FN3 1H), 7.70-7.64 048 (m, 2H), 7.60 F, 35, 248 (dd, J= 8.6, 5.3 451.10 Hz, 1H), 7.53 (d, J= 7.9 HZ, 1H), 7.48 (dd, J = 9.2, 2.9 HZ, 1H), .33 (m, 2H), 5.77 (d, J= 7.3 HZ, 1H), 4.16-4.09 (m, 2H), 1.14 (t, J= 7.1 HZ, 3H); HNMR (400 MHZ, DMSO- d6): 5 10.90 (s, 1H), 9.38 (d, J = 7.5 HZ, 1H), 8.58 (d, J= 5.0 HZ, 2H), 7.73 (s, 1H), 7.71- 7.65 (m, 2H), F, 35, 249 7.61 (dd, J= 8.6, 5.2 HZ, 1H), 7.52-7.44 (m, 3H), 7.38 (td, J= 8.4, 3.0 Hz, 1H), 5.71 (d, J= 7.4 HZ, 1H), 4.19-4.10 (m, 2H), 1.15 (t, J= 7.1 HZ, 3H); 1H NMR (400 MHZ, DMSO- d6): 5 10.91 (s, F, 35, 250 1H), 8.87 (br s, 1H), 7.94 (s, 1H), 7.87 (dd, J = 8.0, 1.7 Hz, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1H), 7.61 (d, J = 9.0 Hz, 1H), .56 (m, 1H), 7.48 (dd, J = 9.2, 2.9 Hz, 1H), 7.35 (td, J = 8.5, 3.0 Hz, 1H); 1H NMR (400 MHz, DMSO- d6) 5 12.26 (br s, 1H), 10.97 (br s, 1H), 9.02 (s, 1H), 7.84- 7.71 (m, 3H), F, 35, 251 7.62 (dd, J: 8.4, 5.3 Hz, 1H), 7.51 (dd, J = 9.2, 2.7 Hz, 1H), 7.39 (td, J = 8.4, 2.9 Hz, 1H); 1H NMR (400 MHz, DMSO- d6): 5 11.95 (br s, 1H), 10.97 F", 35, 252 (br s, 1H), 7.85- C17H11FN4 7.70 (m, 3H), (a = 038 7.62 (dd, J: Microwave 8.6, 5.2 Hz, 100 OC 370.05 1H), 7.50 (dd, J temp, 1h) = 9.2, 2.8 Hz, 1H), 7.39 (td, J = 8.5, 2.9 Hz, 1H), 2.45 (s, 3H); H NMR (400 MHZ, DMSO- d6): 5 12.97 (br s, 1H), 11.00 (br s, 1H), 7.86 (br s, 2H), 7.73 F, 35,253 (d, J= 8.2 Hz, 1H), 7.60 (br s, 2H), 7.51 (d, J = 7.7 Hz, 1H), 7.43-7.35 (m, 1H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-dg, 400 MHZ): 5 10.99 (s, 1H), 10.47 (s, 1H), 9.21 (s, 1H), 9.09 (s, 2H), 8.13-8.11 C24111513184 (m, 1H), 7.88- A, 35, 383 028 7.85 (m, 1H), 442.09 7.80 (s, 1H), 7.77-7.75 (m, 2H), 7.63 (dd, J = 8.6, 5.3 Hz, 1H), 7.56-7.50 (m, 3H), 7.40 (td, J= 8.5, 3.0 Hz, 1H); 1H NMR (400 MHZ, DMSO- d6): 5 10.99 (s, 1H), 10.52 (s, 1H), 9.27 (s, 1H), 8.88 (d, J = 5.3 Hz, 1H), 8.66-8.63 (m, C24H15FN4 1H), 8.04 (dd, J A, 35, 386 028 = 5.4, 1.3 Hz, 442.09 1H), 7.98-7.91 (m, 2H), 7.83- 7.73 (m, 3H), 7.63 (dd, J= 8.6, 5.3 Hz, 1H), .49 (m, 2H), 7.40 (td, J= 8.5, 3.0 Hz, 1H); H NMR (400 MHZ, DMSO- d6): 5 10.99 (s, 1H), 10.42 (s, 1H), 9.10 (s, 1H), 8.27 (s, A, 35, 389 1H), 8.06 -8.04 (m, 1H), 7.82- 7.71 (m, 4H), 7.63 (dd, J= 8.6, 5.2 Hz, 1H), 7.57-7.35 (m, 4H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson ation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-da 400 MHz): 5 10.99 (br s, 1H), .33 (s, 1H), 9.57 (s, 1H), 7.96 (s, 1H), 7.79 (s, 1H), 7.75-7.74 (m, C26H17FN2 2H), 7.68 (d, J = 8.7 Hz, 1H), B, 35, 392 038 7.63 (dd, J= 456.09 8.6, 5.3 Hz, 1H), 7.52 (dd, J = 9.2, 2.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.43-7.36 (m, 2H), 7.33-7.29 (m, 1H), 6.86 (d, J= 8.7 Hz, 2H); H NMR (400 MHZ, DMSO- Pb, 35, 396 C23H14FN3 d6):511.78(br 038 s, 1H), 10.96 (b = EDC (br s, 1H), 7.90- solvent) 431.07 7.45 (m, 10H), 7.44-7.33 (m, 2H); 1H NMR (DMso-dg, 400MHz): 5 .98 (s, 1H), .37 (s, 1H), 8.02 (s, 1H), 7.83-7.70 (m, 4H), 7.63 (dd, J C23H14FN3 = 8.6, 5.3 Hz, A, 35, 429 038 1H), 7.52 (dd, J 431.07 = 9.2, 2.9 Hz, 1H), 7.47-7.36 (m, 4H), 7.20 (d, J= 7.8 Hz, 1H), 7.16-7.14 (m, 1H), 6.96 (dd, J= 8.0, 2.2 Hz, 1H), 3.82 (s, 3H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (400 MHZ, DMSO- d6): 5 12.82 (br s, 1H), 11.01 (s, FC, 35’ 397 1H), 7.97 (s, 1H), 7.93-7.85 (c = CH3CN (m, 2H), 7.76- solvent, 7.71 (m, 1H), MW, 100 OC, 7.68-7.60 (m, 2h 3H), 7.52 (dd, J = 9.2, 2.9 Hz, 1H), 7.47-7.37 (m, 3H), 7.35- 7.30 (m, 1H); H NMR (DMSO-d6 400 MHZ): 5 10.87 (s, 1H), 8.96 (s, 1H), 8.64 (s, 2H), 8.41 (d, J = 8.7 Hz, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.51 (dd, J= B, 35, 401 C22H19FN4 8.1, 1.8 Hz, ion O38 1H), 7.47 (dd, J 111116511) 438.12 =9.1,3.0 HZ, 1H), 7.37 (dt, J = 8.5, 3.0 Hz, 1H), 4.42—4.29 (m, 1H), 3.43 (d, J= 6.1 Hz, 2H), 3.28 (s, 3H), 2.94 (dd, J = 14.0, 4.1 HZ, 1H), 2.74 (dd, J = 14.0, 10.1, Hz, 1H); H NMR (DMSO-dé, 400 MHZ): 5 10.81 (s, 1H), 9.17 (t, o J=5.6Hz,1H), C19H13FN4 9.08 O (s, 1H), 1347 FdwSW A, 42, 212 46 38109 02S 8.75 (s, 2H), "(E/"N (M +1) 7.79-7.59 (111, 380 07' Ma 4H), 7.45 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.32 (td, J= 8.6, 2.6 Hz, 1H), 4.48 (d, J= 5.6 Hz, [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson HNMR (DMSO-dg, 400 MHZ): 5 10.81 (s, 1H), 9.25 (t, J= 5.9 Hz, 1H), 8.96 (s, 1H), 7.80 (s, 1H), 7.75 (dd, J= 8.7, 5.9 Hz, F, 42,213 1H), 7.71-7.70 (m, 1H), 7.68- 7.65 (m, 1H), 7.63-7.58 (m, 1H), 7.45 (dd, J = 8.5, 2.6 Hz, 1H), 7.32 (td, J = 8.5, 2.6 Hz, 1H), 4.65 (d, J = 5.7 Hz, 2H); 1H NMR (DMSO'dg, 400 MHZ): 5 10.81 (s, 1H), 8.62 (t, J= 5.5 Hz, 1H), 8.49 (dd, J= 0.8, 4.0 Hz, 1H), 7.75 (dd, J = 8.7, 6.0 Hz, 1H), 7.71-7.61 (m, 3H), 7.55 A, 42, 216 (dd, J= 1.8, 8.1 Hz, 1H), 7.45 (dd, J= 8.5 Hz, 2.6 Hz, 1H), 7.32 (dt, J= 8.5, 2.6 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.22-7.19 (m, 1H), 3.67-3.50 (m, 2H), 2.96 (t, J= 7.3 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.79 C18H12FN3 (br s, 1H), 9.08 A, 42, 214 038 (t, J= 5.5 Hz, 369.06 1H), 8.27 (s, 1H), 7.91-7.89 (m, 1H), 7.75 (dd, J= 8.7, 6.0 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson Hz, 1H), 7.68- 7.60 (m, 2H), 7.45 (dd, J= 8.5, 2.5 Hz, 1H), 7.32 (td, J = 8.5, 2.6 Hz, 1H), 7.03 (s, 1H), 4.51 (d, J = 5.4 Hz, 2H); 1H NMR (DMSO-d, 400 MHZ): 5 10.81 (s, 1H), 9.01 (s, 1H), 8.68-8.60 (m, 3H), 7.75 (dd, J= 8.7, 6.0 Hz, 1H), 7.67- C20H15FN4 7.59 (m, 2H), A, 42, 215 028 7.52 (dd, J: 394.09 8.0, 1.8 Hz, 1H), 7.44 (t, J= 6.4 Hz, 1H), 7.32 (dt, J: 8.5, 2.5 Hz, 1H), 3.52 (q, J = 6.4 Hz, 2H), 2.84 (t,J= 6.6 Hz, 2H); 1H NMR (DMSO-d, 400 MHZ): 5 10.82 (s, 1H), 8.62 (t, J= 5.5 Hz, 1H), 8.43-8.42 (m, 1H), 8.40 (d, J = 5.0 Hz, 1H), C21H16FN3 7.75 (t, J= 6.7 A, 42, 217 028 Hz, 1H), 7.68- 7.60 (m, 3H), 393.09 7.54 (dd, J: 8.0, 1.8 Hz, 1H), 7.45 (dd, J = 8.6, 2.6 Hz, 1H), 7.38-7.24 (m, 2H), 3.57- 3.42 (m, 2H), 2.84 (t, J= 7.0 Hz, 2H); 1H NMR A, 42, 347 dg, 400MHz): 5 .82 (s, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 8.66 (t, J= 5.6 Hz, 1H), 8.21 (s, 1H), 7.75 (dd, J= 8.7, 6.0 Hz, 1H), 7.69- 7.62 (m, 2H), 7.55 (dd, J= 8.1, 1.7 Hz, 1H), 7.45 (dd, J = 8.5, 2.5 Hz, 1H), 7.32 (td, J = 8.5, 2.5 Hz, 1H), 6.92 (s, 1H), 3.58-3.42 (m, 2H), 2.91 (t, J= 6.7 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.83 (s, 1H), 8.91 (s, 1H), 8.69 (t, J= .4 Hz, 1H), 7.76 (dd, J= 8.6, 5.9 Hz, 1H), 7.71-7.63 A, 42,352 (m, 3H), 7.58 (d, J= 8.2 Hz, 1H), 7.45 (dd, J = 8.5, 2.5 Hz, 1H), 7.33 (td, J = 8.6, 2.5 Hz, 1H), 3.48 (q, J = 6.4 Hz, 2H), 3.10 (t,J= 6.7 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.81 (s, 1H), 9.15 (t, J= 6.1 Hz, 1H), 8.56-8.49 (m, 1H), 8.45 (dd, J A, 42,218 = 4.7, 1.4 Hz, 1H), 7.78-7.60 (m, 5H), 7.45 (dd, J= 8.6, 2.5 Hz, 1H), 7.39- 7.27 (m, 2H), 4.47 (d, J= 5.7 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-dg, 400 MHZ): 5 10.82 (s, 1H), 8.65 (t, J= 5.5 Hz,1H), FNz 7.76 (t, J= 6.9 Hz, 1H), 7.69- A, 42, 219 OZS 7.54 (m, 7H), 468.13 7.49-7.39 (m, 3H), 7.38-7.26 (m, 4H), 3.57- 3.35 (m, 2H), 2.86 (t, J= 7.2 Hz, 2H); H-NMR dg, 400 MHZ): 5 10.82 (s, 1H), 8.62 (t, J= 5.6 Hz,1H), 7.76 (dd, J= 8.7, 6.0 Hz, 1H), 7.66-7.62 A, 42, 406 (m, 4H), 7.55- 7.43 (m, 4H), 7.33 (td, J= 8.6, 2.6 Hz, 1H), 3.54-3.48 (m, 2H), 2.93 (t, J= 7.1 Hz, 2H), 2.57—2.52 (m, 6H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.89 (s, 1H), 10.64 C19H12FN3 (s, 1H), 8.48 (d, A, 42,185 028 J= 5.2 Hz, 2H), 365.06 7.84-7.67 (m, 6H), 7.48 (dd, J = 8.5, 2.6 Hz, 1H), 7.34 (t, J= 8.3 Hz, 1H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.89 C26H17FN2 (s, 1H), 10.38 A, 42, 186 OZS (s, 1H), 8.05 (s, 1H), 7.82-7.71 440.10 (m, 5H), 7.63 (d, J= 7.2 Hz, 2H), 7.54—7.31 (m, 7H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-dg, 400 MHZ): 5 10.81 (s, 1H), 8.55 (t, J= 5.7 Hz,1H), 7.76 (dd, J= 8.7, 6.0 Hz, 1H), 7.70-7.63 (m, 4H), 7.58 (dd, J= 8.0, 1.7 A, 42, 410 Hz, 1H), 7.53— 7.42 (m, 3H), SOzN(cH3)z 7.33 (td, J= 8.6, 2.6 Hz, 1H), 3.28-3.23 (m, 2H), 2.72 (t, J= 7.6 Hz, 2H), 2.57 (s, 6H), 1.99-1.78 (m, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.88 (s, 1H), 9.17 (t, J= 5.7 Hz, 1H), FN4 9.08 (s, 1H), 8.74 (s, 2H), A, 50, 212 028 7.71 (dd, J= 380.07 4.9 Hz, 3.1 Hz, 2H), 7.67-7.59 (m, 1H), 7.54- 7.43 (m, 3H), 4.47 (d, J= 5.7 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.89 (s, 1H), 9.25 (t, J= 5.7 Hz, 1H), 8.96 (s, 1H), C18H12FN3 7.80 (s, 1H), A, 50, 213 0252 7.71 (dd, J= 385.04 4.8, 3.1 Hz, 2H), 7.60 (dd, J = 8.1, 1.8 Hz, 1H), 7.54—7.45 (m, 3H), 4.65 (d, J= 5.6 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-dg, 400 MHZ): 5 10.88 (s, 1H), 9.08 (t, J= 5.5 Hz,1H), 8.27 (s, 1H), A, 50,214 7.75-7.66 (m, 2H), 7.61 (dd, J = 8.0, 1.5 Hz 1H), 7.54-7.44 (m, 3H), 7.03 (s, 1H), 4.51 (d, J= 5.3 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.89 (s, 1H), 9.01 (s, 1H), 8.68-8.61 C20H15FN4 (m, 3H), 7.69 A, 50,215 028 (d, J= 8.0 Hz, 394.09 1H), 7.63 (s, 1H), .45 (m, 4H), 3.55- 3.49 (m, 2H), 2.84 (t, J= 6.6 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.89 (s, 1H), 8.63 (t, J= 5.3 Hz,1H), .47 (m, 1H), 7.72-7.63 (m, 3H), 7.55 A, 50,216 (dd, J= 8.1,1.8 Hz, 1H), 7.53- 7.44 (m, 3H), 7.25 (d, J= 7.8 Hz, 1H), 7.23- 7.18 (m, 1H), 3.62-3.55 (m, 2H), 2.96 (t, J= 7.3 Hz, 2H); 1H NMR (DMSO-dg, 500 MHZ): 5 10.88 C21H16FN3 (s, 1H), 8.61 (t, A, 50,217 OZS J= 5.4 Hz, 1H), 393.09 8.44-8.36 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.65-7.59 (m, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 2H), 7.54-7.43 (m, 4H), 7.28 (dd, J= 7.4, 5.1 Hz, 1H), 3.47 (q, J= 6.7 Hz, 2H), 2.82 (t, J= 6.9 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.88 (s, 1H), 9.15 (t, J= 5.8 Hz, 1H), 8.56-8.49 (m, C20H14FN3 1H), 8.45 (d, J = 5.2 Hz, 1H), A, 50,218 02S 7.74-7.67 (m, 379.08 3H), .62 (m, 1H), 7.54— 7.43 (m, 3H), 7.34 (dd, J= 7.7, 4.9 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.97 C19H12FN3 (s, 1H), 10.63 A, 50, 185 028 (s, 1H), 8.48 (d, J= 5.3 Hz, 2H), 365.06 7.82-7.76 (m, 2H), 7.76-7.71 (m, 3H), 7.56- 7.47 (m, 3H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.97 C26H17FN2 (s, 1H), 10.38 A, 50, 186 028 (s, 1H), 8.05 (s, 1H), .70 440.10 (m, 4H), 7.63 (d, J= 7.2 Hz, 2H), .36 (m, 8H); 1H NMR (DMSO-d, 500 MHZ): 10.88 (s, C19H14FN3 1H), 8.65 (t, J= A, 50, 347 038 .5 Hz, 1H), 383.07 8.20 (s, 1H), 7.68 (d, J= 8.1 Hz, 1H), 7.64 (s, 1H), 7.57- [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson 7.43 (m, 4H), 6.90 (s, 1H), 3.47 (q, J= 6.7 Hz, 2H), 2.89 (t, J= 6.8 Hz, 2H); 1H NMR (DMSO-da 400 MHZ): 5 10.92 (br s, 1H), 8.91 (s, 1H), 8.71 (t, C19H14FN3 J= 5.4 Hz, 1H), 0282 7.74-7.67 (m, A, 50, 352 3H), 7.57 (dd, J 399.05 = 8.1, 1.8 Hz, 1H), 7.54-7.44 (m, 3H), 3.48 (q, J= 6.5 Hz, 2H), 3.10 (t, J= 6.7 Hz, 2H); 1H NMR (DMSO-d,, 400 MHZ): 5 10.90 (s, 1H), 8.66 (t, J= 5.6 Hz, 1H), 7.72-7.67 (m, C28H21FN2 2H), 7.65-7.61 A, 50, 219 028 (m, 2H), 7.60- 468.13 7.56 (m, 3H), 7.54-7.42 (m, 5H), 7.36-7.29 (m, 3H), 3.49 (q, J= 6.8 Hz, 2H), 2.86 (t, J= 7.3 Hz, 2H); 1H NMR (DMSO-d, 400 MHz) 5 10.90 (s, 1H), 8.63 (t, C24H22FN3 J= 5.6 Hz, 1H), A, 50, 406 0482 7.71-7.61(m, 4H), 7.56-7.44 499.10 (m, 6H), 3.58- 3.45 (m, 2H), 2.92 (t, J= 7.0 Hz, 2H), 2.54 (s, 6H); 1H NMR C19H13FN4 (DMSO-d,, 400 A, 55, 212 028 MHZ): 5 10.70 380.07 (s, 1H), 9.09 (s, 1H), 8.99 (t, J= [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson .1 Hz, 1H), 8.74 (s, 2H), 7.69 (d, J= 6.5 Hz, 1H), 7.59 (d, J= 9.5 Hz, 1H), 7.56-7.45 (m, 4H), 4.48 (d, J= 5.6 Hz, 2H); 1H NMR (DMSO-d,, 400 MHZ): 5 10.71 (s, 1H), 9.03 (t, J= 5.1 Hz, 1H), 8.98 (s, 1H), 7.79 (s, 1H), 7.69 (dd, J= A, 55, 213 7.4, 1.4 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.56-7.47 (m, 3H), 7.46-7.42 (m, 1H), 4.64 (d, J= 5.7 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.71 (s, 1H), 8.89 (t, J= 5.1 Hz, 1H), 8.29 (s, 1H), 7.69 (dd, J= 7.4, 1.5 Hz, A, 55,214 1H), 7.58 (d, J = 9.4 Hz, 1H), 7.56-7.45 (m, 3H), 7.43 (d, J = 6.5 Hz, 1H), 7.02 (s, 1H), 4.50 (d, J= 5.5 Hz, 2H); 1H NMR (DMSO-d,, 400 MHZ): 5 10.73 (s, 1H), 9.02 (s, C20H15FN4 1H), 8.67 (s, A, 55,215 028 2H), 8.44 (t, J= 394.09 5.1 Hz, 1H), 7.69 (d, J= 6.9 Hz, 1H), 7.58— 7.45 (m, 4H), 7.34 (d, J= 6.5 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson Hz, 1H), 3.52 (q, 2H), 2.82 (t, J= 6.6 Hz, 2H); lHNMR da400 MHZ): 5 10.73 (brs,1}D,8.53- 84mmflH) 8458w0m FN3 1H)7n467 AfiiZM 028 (mflHLTW- 74MmAHL 393.09 TMMdJ=66 IhJHLT% (¢J=77HL IHLTMJ22 (mJHL3fl (%2HL2%(L J= 7.2 Hz, 2H); lHNMR (DMSO-dg, 400 MHZ): 5 10.74 (s, 1H), 8.42 (d, J=87}h,fiD, 7.69 (d, J= 7.0 C21H16FN3 Hz, 1H), 7.64 028 (d, J= 7.8 Hz, AfiiZU 1H), 7.60-7.44 393.09 (m, 4H), 7.36 (d, J= 6.5 Hz, 1H), 7.30 (dd, J = 7.5, 4.9 Hz, 1H), 3.48 (q, 2H), 2.81 (t, J= 6.8 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.70 (br s, 1H), 8.95 @J=51HL 1H), 8.52 (s, C20H14FN3 1H), 8.46 (d, J Ajizm 02S = 3.9 Hz, 1H), 379.08 7.75-7.64 (m, 2H), 7.59 (d, J = 9.5 Hz, 1H), 7.56-7.44 (m, 4H), 7.35 (dd, J = 7.7, 4.9 Hz, 1H), 4.46 (d, J [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson = 6.0 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.73 (s, 1H), 8.46 (t, J= 4.9 Hz, 1H), 8.22 (s, 1H), 7.71-7.67 (m, A, 55, 347 1H), 7.58-7.45 (m, 4H), 7.39 (d, J= 6.5 Hz, 1H), 6.92 (s, 1H), 3.48 (q, J = 6.6 Hz, 2H), 2.89 (t, J= 6.7 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 10.75 (s, 1H), 8.93 (s, 1H), 8.49 (t, J= 4.5 Hz, 1H), 7.72-7.64 (br s, A, 55, 352 2H), 7.59-7.44 (m, 4H), 7.41 (d, J= 6.5 Hz, 1H), 3.47 (q, J = 6.4 Hz, 2H), 3.08 (t, J= 6.6 Hz, 2H); 1H NMR (DMSO-d, 400 MHZ): 5 10.75 (s, 1H), 8.45 (t, J= 4.5 Hz, 1H), 7.69 (dd, J: 7.4, 1.3 Hz, 1H), 7.64 (d, J A, 55,219 CZBISZISFNZ = 7.3 Hz, 2H), 2 7.61—7.42 (111, 468.13 8H), 7.40 (d, J = 6.5 Hz, 1H), 7.37-7.30 (m, 3H), 3.48 (q, J = 6.8 Hz, 2H), 2.84 (t, J= 7.2 Hz, 2H) 1H NMR (DMSO-d, 400 A, 55» 406 MHZ): 8 10.75 (s, 1H), 8.42 (t, J= 5.1 Hz, 1H), ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.71-7.63 (m, 3H), 7.57-7.45 (m, 6H), 7.35 (d, J= 6.5 Hz, 1H), 3.50 (q, J = 6.7 Hz, 2H), 2.91 (t, J= 6.9 Hz, 2H), 2.56 (s, 6H); 1H NMR d, 400 MHZ): 5 10.79 FN3 (s, 2H), 8.48 (d, A, 55, 185 028 J= 6.0 Hz, 2H), .66 (m, 365.06 2H), 7.62 (d, J = 6.3 Hz, 2H), 7.59-7.45 (m, 4H); 1H NMR (DMSO-d, 400 MHZ): 5 10.79 (s, 1H), 10.51 C26H17FN2 (s, 1H), 7.98 (s, A, 55, 186 028 1H), 7.71 (dd, J = 7.4, 15 Hz, 440.10 1H), 7.68-7.59 (m, 4H), 7.58— 7.44 (m, 6H), 7.43—7.35 (m, 3H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.68 (s, 1H), 9.38 (t, C19H12FZN J= 6.0 Hz, 1H), 9.10 (s, 1H), B, 62, 212 8.73 (s, 2H), 7.72-7.68 (m, 1H), 7.59-7.46 (m, 4H), 4.50 (d, J= 5.9 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.66 C18H11F2N (s, 1H), 9.39 (t, B, 62,213 30282 J= 5.9 Hz, 1H), 403.03 9.00 (s, 1H), 7.79 (s, 1H), 7.72-7.68 (m, 1H), 7.59-7.45 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (m, 4H), 4.66 (d, J= 5.7 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 10.66 (s, 1H), 9.26 (t, F2N J= 5.6 Hz,1H), B, 62,214 3038 8.31 (s, 1H), 387.05 .66 (m, 1H), 7.58-7.46 (m, 4H), 7.02 (s, 1H), 4.51 (d, J= 5.5 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 10.66 (s, 1H), 9.03 (s, C20H14FzN 1H), 8.80 (t, J= B, 62,215 402S 5.9 Hz, 1H), 8.67 (s, 2H), 412.08 7.78-7.62 (m, 1H), 7.58-7.43 (m, 4H), 3.53 (q, 2H), 2.81 (t, J= 6.5 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 10.64 (s, 1H), 8.78 (t, J= 5.5 Hz,1H), 8.49 (d, J= 4.2 C21H15F2N Hz, 1H), 7.77- B, 62,216 3028 7.62 (m, 2H), 411.09 7.59-7.41 (m, 4H), 7.35-7.13 (m, 2H), 3.58 (q, 2H), 2.92 (t, J= 7.2 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 10.66 (s, 1H), 8.80 (t, C21H15F2N J= 5.6 Hz,1H), B, 62, 217 3028 8.51-8.34 (m, 411.09 2H), 7.72-7.68 (m, 1H), 7.65 (td, J= 1.9, 7.8 Hz, 1H), 7.57- 7.45 (m, 4H), ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.31 (dd, J= 7.7, 4.8 Hz, 1H), 3.49 (q, 2H), 2.80 (t, J= 6.8 Hz, 2H); 1H NMR (DMSO-dé, 400 MHZ): 5 10.66 (s, 1H), 8.94 (s, C19H13FZI\I 1H), 8.88 (t,.]= B, 62, 352 30282 5.5 Hz, 1H), 7.72-7.69 (m, 417.04 1H), 7.68 (s, 1H), 7.58-7.46 (m, 4H), 3.48 (q, 2H), 3.06 (t, J= 6.6 Hz, 2H); 1H NMR dé, 400 MHZ): 5 10.67 (s, 1H), 9.31 (t, J= 6.0 Hz, 1H), 8.52 (s, 1H), 8.48 (dd, J= B, 62,218 4.8, 1.6 Hz, 1H), 7.74-7.64 (m, 2H), 7.58- 7.46 (m, 4H), 7.39-7.36 (m, 1H), 4.48 (d, J = 5.9 Hz, 2H); 1H NMR (DMSO-dé, 400 MHZ): 5 10.63 (s, 1H), 8.81 (t, J= 5.9 Hz, 1H), C28H20F2N 7.71-7.65 (m, 202S 1H), 7.63- 7.60 B, 62, 219 (m, 2H), 7.58- 486.12 7.50 (m, 3H), 7.50-7.40 (m, 5H), 7.35-7.28 (m, 3H), 3.46 (q, 2H), 2.80 (t, J= 7.1 Hz, 2H); 1H-NMR (DMSO-dg, 400 C23H26NZO MHZ): 5 10.74 A, 70, 261 (s, 1H), 8.42 (t, J= 6.4 Hz, 1H), 7.64-7.60 (m, 2H), 7.54 (s, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.18 (s, 1H), 7.05 (d, J= 8.8 Hz, 1H), 3.76 (s, 3H), 3.24— 3.21 (m, 2H), 1.70-1.58 (m, 5H), 1.40—1.35 (m, 2H), 1.26— 1.09 (m, 4H), 0.91-0.83 (m, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.55 (s, 1H), 8.08 (t, J= 5.6 Hz,1H), 7.67 (t, J= 5.6 Hz, 1H), 7.54- C23H26NZO 7.43 (m, 4H), A, 76, 261 7.27 (s, 1H), 3.85 (s, 3H), 3.26-3.21 (m, 2H), 1.70-1.59 (m, 5H), 1.39- 1.33 (m, 2H), 1.29-1.12 (m, 4H), 0.93-0.85 (m12H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.69 (s, 1H), 8.37 (t, J= 5.6 Hz, 1H), 7.68-7.59 (m, NZO 3H), .43 (m, 3H), 3.25— A, 82,261 3.20 (m, 2H), 2.55 (s, 3H), 1.70-1.58 (m, 5H), 1.40—1.35 (m, 2H), 1.26— 1.14 (m, 4H), 0.91-0.85 (m, 1H—NMR C23H26NZO (DMSO-dg, 400 A, 88, 261 MHZ): 5 10.66 (br s, 1H), 8.20 (br s, 1H), 7.66 (d, J= 7.2 Hz, [Annotation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1H), 7.53-7.44 (m, 4H), 7.10 (s, 1H), 3.22- 3.17 (m, 2H), 2.22 (s, 3H), 1.70-1.58 (m, 5H), .09 (m, 6H), 0.90- 0.82 (m, 2H); 1H NMR (DMSO-d,, 400 MHZ): 5 10.62 (s, 1H), 9.10 (s, 1H), 8.91 (t,.]= C20H16N4O 5.7 Hz, 1H), 8.75 (s, 2H), A, 88, 212 7.67 (dd, J= 1.6, 7.4, 1.6 Hz, 1H), 7.57-7.42 (m, 4H), 7.23 (s, 1H), 4.44 (d, J= 5.9 Hz, 2H), 2.23 (s, 3H) H NMR (DMSO-dg, 400 MHZ): 5 10.63 (s, 1H), 9.00- 8.95 (m, 2H), 7.79 (s, 1H), C19H15N3O 7.66 (dd, J= A, 88, 213 7.5, 1.5 Hz, 1H), 7.54-7.41 (m, 4H), 7.15 (s, 1H), 4.61 (d, J= 5.7 Hz, 2H), 2.23 (s, 3H); H NMR (DMSO-dg, 400 MHZ): 5 10.63 (s, 1H), 8.87 (t, J= 5.9 Hz, 1H), 8.53 (s, 1H), C21H17N3O 8.47 (dd, J= A, 88,218 4.8, 1.5 Hz, 1H), 7.74-7.65 (m, 2H), 7.56- 7.41 (m, 4H), 7.36 (dd, J= 7.4, 5.1 Hz, 1H), 7.20 (s, 1H), 4.42 (d, J ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson = 6.0 Hz, 2H), 2.23 (s, 3H) H NMR (DMSO-dé, 400 MHZ): 5 10.24 (s, 1H), 9.09 (s, 1H), 8.93 (t, J= .9 Hz, 1H), A, 97, 212 C201116N4O 8.75 (s, 2H), (Reaction 7.69-7.59 (m, time 18 h) 1H), 7.56-7.39 (m, 4H), 7.14 (d, J= 7.9 Hz, 1H), 4.44 (d, J = 5.7 Hz, 2H), 2.26 (s, 3H); H NMR (DMSO-d6, 400 MHZ): 5 10.23 (s, 1H), 9.01 (t, J= 5.9 Hz, 1H), 8.98 (s, 1H), 7.79 (s, 1H), 7.71-7.59 (m, A, 97, 213 1H), 7.55—7.48 (m, 2H), 7.47- 7.40 (m, 2H), 7.06 (d, J= 7.9 Hz, 1H), 4.61 (d, J= 5.7 Hz, 2H), 2.27 (s, 3H); 1H NMR (DMSO-d, 400 MHZ): 5 10.21 (s, 1H), 8.83 (t, J= 5.7 Hz, 1H), C19H15N3O 8.26 (s, 1H), 7.83-7.56 (m, B, 97, 214 1H), 7.56-7.36 (m, 4H), 7.06 (d, J= 7.9 Hz, 1H), 7.01 (s, 1H), 4.44 (d, J = 5.6 Hz, 2H), 2.24 (s, 3H), 1H NMR C21H18N4O (DMSO-dé, 400 A, 97, 215 MHZ): 5 10.20 (s, 1H), 9.03 (s, 1H), 8.68 (s, 2H), 8.38 (t, J= [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson .3 Hz, 1H), 7.69-7.60 (m, 1H), 7.53-7.39 (m, 4H), 6.96 (d, J= 7.9 Hz, 1H), 3.51 (q, 2H), 2.81 (t, J= 6.6 Hz, 2H), 2.13 (s, 3H); 1H NMR (DMso—dé, 400 MHZ): 5 10.20 (s, 1H), 8.48 (d, J= 4.0 Hz, 1H), 8.34 (br s, 1H), 7.76-7.58 (m, C22H19N30 2H),7.55—7.35 (m, 4H), 7.26 A, 97, 216 (d, J= 7.8 Hz, 1H), 7.23-7.18 (m, 1H), 7.00 (d, J= 7.8 Hz, 1H), 3.55 (d, J = 5.5 Hz, 2H), 2.93 (t, J= 7.1 Hz, 2H), 2.19 (s, 3H); HNMR (DMso—d, 500 MHZ): 5 10.20 (s, 1H), 8.46- 8.39 (m, 2H), 8.36 (t,.]= 5.4 Hz, 1H), 7.65 (td, J= 6.2, 3.0 C22H19N30 Hz, 2H), 7.58- A, 97, 217 23 7.38 (m, 4H), 7.31 (dd, J= 7.7, 4.8 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 3.47 (d, J= 5.5 Hz, 2H), 2.80 (t, J= 6.8 Hz, 2H), 2.15 (s, 1H NMR C20H17N3O (DMSO-d6, 400 A, 97, 347 MHZ): 5 10.22 (s, 1H), 8.41 (t, J= 5.7 Hz, 1H), 8.22 (s, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.72- 7.58 (m, 1H), 7.56-7.35 (m, 4H), 7.01 (d, J= 7.9 Hz, 1H), 6.92 (s, 1H), 3.45 (d, J = 6.2 Hz, 2H), 2.98—2.81 (m, 2H), 2.22 (s, 3H); 1H NMR (DMSO-d6, 400 MHZ): 5 10.22 (s, 1H), 8.93 (s, 1H), 8.44 (t, J= .9 Hz, 1H), C20H17N3O 7.68 (s, 1H), 7.67-7.63 (m, A, 97, 352 1H), 7.54-7.47 (m, 2H), 7.46- 7.42 (m, 2H), 7.02 (d, J= 7.9 Hz, 1H), 3.45 (q, 2H), 3.07 (t, J= 6.6 Hz, 2H), 2.21 (s, 3H), H NMR dé, 400 MHZ): 5 10.24 (s, 1H), 8.90 (t, J= 6.1 Hz, 1H), 8.54-8.51 (m, 1H), 8.46 (d, J = 5.3 Hz, 1H), C21H17N3O 7.70 (dt, J= 7.8, 1.9 Hz, A, 97,218 1H), 7.67-7.63 (m, 1H), 7.54- 7.40 (m, 4H), 7.36 (dd, J= 7.5, 5.1 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 4.42 (d, J= 6.0 Hz, 2H), 2.27 1H NMR C29Hz4NzO (DMSO-d6, 400 A, 97, 219 MHZ): 5 10.20 (s, 1H), 8.37 (t, J= 5.1 Hz, 1H), 7.64 (d, J= 7.2 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson Hz, 3H), 7.59 (d, J= 8.0 Hz, 2H), 7.53-7.40 (m, 6H), 7.39- 7.26 (m, 3H), 7.00 (d, J= 7.9 Hz, 1H), 3.48 (q, 2H), 2.83 (t, J= 6.9 Hz, 2H), 2.19 (s, 3H); 1H NMR (DMSO-d, 400 MHZ): 5 10.73 (br s, 1H), .34 (br s, C20H15N3O 1H), 8.45 (d, J B, 97, 185 = 4.6 Hz, 2H), 7.71-7.53 (m, 5H), 7.50—7.44 (m, 2H), 7.26 (d, J= 7.9 Hz, 1H), 2.34 (s, 3H); H NMR (DMSO-dé, 400 MHZ): 5 10.21 (s, 1H), 8.36 (t, J= 5.6 Hz,1H), 7.69-7.62 (m, C25H25N3O 3H), 7.57-7.40 B, 97, 406 (m, 6H), 6.96 (d, J= 7.9 Hz, 1H), 3.50 (d, J = 5.3 Hz, 2H), 2.90 (t, J= 6.7 Hz, 2H), 2.58 (s, 6H), 2.14 (s, 3H); H NMR (DMSO-d6, 400 MHZ): 5 10.42 (s, 1H), 10.31 (s, 1H), 8.00 (s, C27H20NZO 1H), 7.70-7.63 (m, 2H), 7.62- B, 97, 186 7.53 (m, 4H), 7.51-7.43 (m, 4H), 7.43-7.35 (m, 3H), 7.26 (d, J= 7.9 Hz, 1H), 2.37 (s, 3H); ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H-NMR (DMSO-dg, 500 MHZ): 5 10.86 (br s, 1H), 8.45- 8.44 (m, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.89 (d, J= 8.0 Hz, 1H), 7.75 C23H25N3O (d, J= 8.0 Hz, A, 135, 261 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.57 (d, J= 8.5 Hz, 2H), 3.24- 3.23 (m, 2H), 1.70-1.58 (m, 5H), 1.37 (t, J= 6.5 Hz, 2H), 1.18-1.09 (m, 5H), 0.86 (t, J= 6.5 Hz, 2H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.85 (s, 1H), 8.60 (t, J= 4.8 Hz, 1H), 8.01 (s, 1H), C22H18NZO 7.78 (d, J= 8.4 A, 140, 211 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.54—7.44 (m, 3H), 7.30- 7.17 (m, 6H), .42 (m, 2H), 2.82 (t, J= 7.6 Hz, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.67 (s, 1H), 10.03 (s, 1H), 7.66 (d J= 7.2 Hz, A, 145, 3- C22H24NZO 1H), 7.60 (s, cyclohexylp 1H), 7.50-7.40 ropanoic (m, 4H), 7.31 acid (d, J= 8.4 Hz, 1H), 2.32-2.27 (m, 2H), 1.69- 1.60 (m, 5H), 1.48-1.43 (m, 2H),1.18-1.13 (m, 4H), 0.90- [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 0.85 (m, 2H); H-NMR (DMSO-dg, 400 MHZ): 5 10.77 (br s, 1H), 8.58- 8.54 (m, 1H), 8.12 (s, 1H), 7.90 (d, J= 8.0 Hz, 1H), 7.62- C22Hz4NzO 7.56 (m, 2H), A, 150, 261 7.38-7.34 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.16 (t, J= 6.8 Hz, 1H), 3.27- 3.24 (m, 2H), 1.72-1.58 (m, 5H), 1.26-1.11 (m, 5H), 0.96- 0.82 (m, 2H); 1H—NMR (DMSO-dg, 400 MHZ): 5 10.64 (s, 1H), 10.08 (s, 1H), 7.95 (s, 1H), 7.68—7.65 (m, 1H), 7.53 (d, J= 7.2 Hz, 1H), 7.43 (d, J C22Hz4NzO = 8.4 Hz, 1H), 7.34 (t, J= 8.0 cyclohexylp Hz, 1H), 7.22 ic (d, J= 7.2 Hz, acid 1H), 7.13 (t,.]= 7.6 Hz, 1H), 2.32—2.27 (m, 2H), 1.69—1.60 (m, 4H), 1.49- 1.41 (m, 2H), 1.28-1.13(m, 4H), 0.90—0.85 (m, 3H); 1H NMR (DMSO-d, 500 MHZ): 5 11.03 A, 1 5 6, 2 12 C19H14N4O (br s, 1H), 9.21 (Reaction (t, J= 5.4 Hz, time24 h) 1H), 9.06 (s, 1H), 8.73 (s, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.83-7.76 (m, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 2H), 7.74-7.67 (m, 3H), 7.63- 7.59 (m, 1H), 4.46 (d, J= 4.9 Hz, 2H); 1H NMR 400MHz): 5 C18H13N30 11.05 (s, 1H), 9.31 (t, J= 6.3 A, 156,213 Hz, 1H), 8.96 (s, 1H), 7.88- 7.60 (m, 8H), 4.65 (d, J= 5.6 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 11.05 (s, 1H), 9.14 (t, J= 5.6 Hz,1H), 8.27 (s, 1H), C18H13N30 7.88 (dd, J= 8.2, 1.5 Hz, A, 156, 214 1H), 7.84-7.78 (m, 2H), 7.76- 7.67 (m, 3H), 7.63 (dd, J= 7.7, 1.0 Hz, 1H), 7.04 (s, 1H), 4.51 (d, J = 5.5 Hz, 2H); 1H NMR (DMSO-dé, 400 MHZ): 5 11.06 (s, 1H), 9.01 (s, 1H), 8.69 (t, J= .6 Hz, 1H), 8.66 (s, 2H), C20H16N4O .77 (m, B, 156,215 3H), 7.74 (d, J = 7.0 Hz, 1H), 7.67 (d, J= 8.2 Hz, 1H), 7.65- 7.60 (m, 2H), 3.53 (q, J= 6.3 Hz, 2H), 2.84 (t, J= 6.6 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson HNMR (DMSO-d6, 400 MHZ): 5 11.06 (s, 1H), 8.69 (t, J= 5.6 Hz,1H), 8.51-8.47 (m, 1H), 7.85-7.78 C21H17N3O (m, 3H), 7.74 A, 156,216 (d, J= 6.9 Hz, 1H), .60 (m, 4H), 7.25 (d, J= 7.7 Hz, 1H), 7.23-7.18 (m, 1H), 3.59 (q, J= 6.5 Hz, 2H), 2.96 (t, J= 7.3 Hz, 2H); 1H NMR (DMSO-d, 400 MHZ): 5 11.06 (s, 1H), 8.69 (t, J= 5.2 Hz, 1H), 8.44-8.37 (m, C21H17N3O 2H), 7.84-7.72 A, 156,217 (m, 4H), 7.70- 7.60 (m, 4H), 7.29 (dd, J= 7.5, 5.0 Hz, 1H), 3.49 (q, J = 6.5 Hz, 2H), 2.83 (t, J= 7.0 Hz, 2H); 1H NMR (DMSO-dé, 400 MHZ): 5 11.13 (br s, 1H), .69 (s, 1H), C19H13N3O 8.53—8.43 (m, A, 156, 185 2H), 7.99 (dd, J = 8.1, 1.5 Hz, 1H), 7.86-7.75 (m, 5H), 7.75- 7.70 (m, 2H), .62 (m, 1H); 1H NMR (DMSO-dé, 400 MHZ): 5 11.13 A, 156, 186 (s, 1H), 10.44 (s, 1H), 8.07- 7.98 (m, 2H), 7.87-7.72 (m, [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 6H), 7.68-7.60 (m, 3H), 7.52- 7.35 (m, 5H); HNMR (DMSO-d6, 400 MHZ): 5 11.05 (s, 1H), 9.21 (t, J= 5.9 Hz, 1H), 8.53 (s, 1H), 8.45 (dd, J= C20H15N3O 4.7, 1.4 Hz, 1H), 7.90 (dd, J A, 156,218 = 8.2, 1.5 Hz, 1H), 7.85-7.68 (m, 6H), 7.63 (td, J= 7.5,1.3 Hz, 1H), 7.34 (dd, J= 7.8, 4.8 Hz, 1H), 4.47 (d, J= 5.2 Hz, 2H); 1H NMR (DMSO-dé, 400 MHZ): 5 11.06 (s, 1H), 8.73 (t, J= 5.6 Hz,1H), 8.21 (s, 1H), 7.85 -7.78 (m, C19H15N3O 3H), 7.74 (dd, J A, 156, 347 = 9.5, 2.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.63 (td, J= .1, 1.1 Hz, 1H), 6.92 (s, 1H), 3.53-3.46 (m, 2H), 2.90 (t, J= 6.7 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 11.07 (br s, 1H), 8.90 (s, 1H), 8.76 (t, C19H15N3O J= 5.5 Hz,1H), A, 156, 352 78 (m, 3H), 7.75 (d, J = 7.3 Hz, 1H), 7.71-7.67 (m, 3H), 7.66-7.60 (m, 1H), 3.52- 3.45 (m, 2H), 3.10 (t, J= 6.7 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-d6, 400 MHZ): 5 11.07 (s, 1H), 8.72 (t, J= 5.4 Hz, 1H), 7.87-7.78 (m, 3H), .73 ngHZZNZO (1T1, 1H), 7.71- 7.67 (m, 2H), A, 156,219 .60 (m, 3H), 7.58 (d, J = 8.2 Hz, 2H), 7.47-7.41 (m, 2H), 7.36-7.29 (m, 3H), 3.50 (q, J= 6.7 Hz, 2H), 2.86 (t, J= 7.2 Hz, 2H); 1H NMR (DMso—dé, 400 MHZ): 5 11.06 (s, 1H), 8.68 (t, J= 5.5 Hz, 1H), 7.85-7.77 (m, C24H23N30 /\/©AOZMM 3H), 7.76-7.73 A, 156,406 (m, 1H), 7.68- 7.61 (m, 5H), 7.48 (d, J= 8.4 Hz, 2H), 3.61- 3.45 (m, 2H), 2.92 (t, J= 7.0 Hz, 2H), 2.53 (s, 6H); 1H—NMR DMSO'dg, 400 C14H10NzO MHZ): 5 11.05 B, 156, 133 35 (br s, 1H), 8.06 (br s, 1H), 7.93- 7.58 (m, 7H), 7.52 (br s, 1H); 1H NMR (DMSO-dé, 400 MHZ): 5 11.51 (s, 1H), 9.34 (t, C19H14N4O J= 5.8 Hz, 1H), A, 159, 212 9.08 (s, 1H), 8.76 (s, 2H), 8.06 (d, J= 8.2 Hz, 1H), 8.01- 7.95 (m, 2H), 7.92-7.80 (m, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 4H), 4.50 (d, J = 5.6 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 11.50 (s, 1H), 9.42 (t, J= 5.9 Hz, 1H), 8.97 (s, 1H), C18H13N3O 8.05 (d, J= 8.3 A, 159,213 Hz, 1H), 7.98 (td, J= 7.4,1.1 Hz, 2H), 7.90 (td, J= 7.5,1.4 Hz, 1H), 7.87- 7.77 (m, 4H), 4.67 (d, J= 5.6 Hz, 2H); 1H NMR dé, 400 MHZ): 5 11.51 (br s, 1H), 9.26 (t, J= 5.6 Hz, 1H), 8.29 (s, C18H13N3O 1H), 8.05 (d, J A, 159, 214 = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.90 (td, J = 7.5, 1.5 Hz, 1H), 7.88-7.78 (m, 3H), 7.06 (s, 1H), 4.53 (d, J= 5.3 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 11.51 (s, 1H), 9.01 (s, 1H), 8.80 (t, J= .7 Hz, 1H), 8.67 (s, 2H), C20H16N4O 8.03 (d, J= 8.2 Hz, 1H), 8.01- A, 159,215 7.96 (m, 2H), 7.94-7.82 (m, 2H), 7.76 (s, 1H), 7.71 (dd, J = 8.3, 1.6 Hz, 1H), 3.55 (q, J = 6.3 Hz, 2H), 2.86 (t, J= 6.6 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson HNMR (DMSO-d6, 400 MHZ): 5 11.51 (s, 1H), 8.80 (t, J= 5.5 Hz, 1H), 8.51-8.48 (m, 1H), 8.03 (d, J = 8.3 Hz, 1H), 8.00-7.96 (m, C21H17N3O 2H),7.93-7.83 (m, 2H), 7.79- 1447 A, 159, 216 7.78 (m, 1H), 7.74 (dd, J= 8.3, 1.6 Hz, 1H), 7.69 (td, J = 7.7, 1.8 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.23-7.19 (m, 1H), 3.64-3.57 (m, 2H), 2.97 (t, J= 7.3 Hz, 2H), HNMR (DMSO-dé, 400 MHZ): 5 11.52 (s, 1H), 8.81 (t, J= 5.6 Hz,1H), 8.48-8.36 (m, 2H), 8.03 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 0 N3O 2H), 7.93-7.83 NH O / 407.9 (m, 2H), 7.79— 1448 (3 A, 159,217 22 48 7.78 (m) 1H), ,8 (flaw (M++1) 0% 40709 7.73 (dd, J= 8.3, 1.5 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.29 (dd, J: 7.8, 4.7 Hz, 1H), 3.51 (q,J = 6.5 Hz, 2H), 2.85 (t, J= 7.0 Hz, 2H); 1H NMR (DMSO-dé, 400 MHZ): 5 11.49 @D’E 393.9 C2°H1§N3O (bf S» 1H)» 9-33 1449 u A, 159, 218 15 4 ,S\ (M++1) (t, J: 5.5 Hz, , 393.08 1H), 8.60-8.39 (m, 2H), 8.05 (d, J= 8.2 Hz, 1H), 8.02—7.94 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (m, 2H), 7.93— 7.81 (m, 4H), 7.70 (d, J= 7.7 Hz, 1H), 7.34 (dd, J= 7.6, 4.8 Hz, 1H), 4.49 (d, J= 5.5 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 11.60 (s, 1H), 10.80 (s, 1H), 8.50 (d, C19H13N30 J= 6.1 Hz, 2H), A, 159, 185 45 8.13 (d,J= 8.2 Hz, 1H), 8.01 (td, J= 7.9, 1.0 Hz, 2H), 7.96- 7.84 (m, 4H), 7.73 (d, J= 6.3 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 11.57 (s, 1H), 10.53 (s, 1H), 8.10 (d, C26H18N20 J= 8.2 Hz, 1H), A, 159, 186 45 8.04- 7.96 (m, 3H), 7.95-7.82 (m, 4H), 7.73 (d, J= 7.6 Hz, 1H), 7.66-7.56 (m, 2H), 7.50— 7.33 (m, 5H), 1H NMR (DMSO-dg, 400 MHZ): 5 11.52 (s, 1H), 8.84 (t, J= 5.7 Hz,1H), 8.22 (s, 1H), 8.04 (d, J= 8.2 C19H15N3O HZ, 1H), 8.00- A, 159, 347 7.96 (m, 2H), 7.91 (dd, J= 7.4, 1.5 Hz, 1H), 7.89-7.79 (m, 2H), 7.74 (dd, J= 8.3,1.5 Hz, 1H), 6.92 (s, 1H), 3.51 (q, J= 6.5 Hz, 2H), 2.92 (t, J= 6.8 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-d6, 400 MHZ): 5 11.53 (s, 1H), 8.91 (s, 1H), 8.87 (t, J= .5 Hz, 1H), 8.05 (d, J= 8.3 C19H15N30 HZ, 1H), 8.01- 7.96 (m, 2H), A,159,352 7.92-7.83 (m, 2H), 7.81 (s, 1H), 7.76 (dd, J = 8.3, 1.4 Hz, 1H), 7.69 (s, 1H), 3.50 (q, J = 6.0 Hz, 2H), 3.11 (t,J= 6.6 Hz, 2H); lHNMR (DMSO-dg, 400 MHZ): 5 11.49 (br s, 1H), 8.83 @J=54HL 1H), 8.04 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.80 C28H22N20 (m, 3H), 7.76 (dd, J= 8.3,1.4 B, 159, 219 Hz, 1H), 7.64- ( Reaction 7.61 (m, 2H), time 24 7.58 (d, J= 8.3 Hz, 2H) 7.44 (t, h) J= 7.6 Hz, 2H), 7.36-7.30 (m, 3H), 3.52 (q, J = 6.5, 2H), 2.87 (t, J= 7.1 Hz, 2H); H NMR (thSCLda400 MHZ): 5 11.52 (brs,111),8.80 NH O C24H23N3O (I, J: 5.2 HZ, DANwsozN(CHa)z 406 1mxmmJ as?) H =82HL1HL MHJ96®L 210,793-782 fim2HL777 (g1HL772m, J=82HL1HL ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.65 (d, J= 8.2 Hz, 2H), 7.49 (d, J= 8.2 Hz, 2H), 3.59—3.49 (m, 2H), 2.94 (t, J= 6.8 Hz, 2H), 2.54 (s, 6H). 1H NMR (DMSO-d6, 400 MHZ): 5 11.44 (br s, 1H), 9.27 (t, J= 5.9 Hz, 1H), 8.05 (d, J NZO = 8.2 Hz, 1H), A, 159, 254 7.98 (td, J= 7.7, 1.4, Hz, 2H), 7.93-7.82 (m, 4H), 7.35— 7.28 (m, 4H), 7.27-7.21 (m, 1H), 4.47 (d, J = 6.1 Hz, 2H); 1H NMR (DMSO-d, 400 MHZ): 5 11.45 (br s, 1H), 9.24 (t, J= 5.9 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.98 (td J= A, 159, 255 , 7.7, 1.1 Hz, 2H), 7.93-7.81 (m, 4H), 7.22- 7.18 (m, 1H), 7.13 - 7.04 (m, 3H), 4.43 (d, J = 5.6 Hz, 2H), 2.27 (s, 3H); HNMR dg, 400 MHZ): 5 11.26 (br s, 1H), 9.31 (t, J= 6.0 Hz, C21H15FN2 1H), 8.06 (d, J A, 159, 256 048 = 8.2 Hz, 1H), 7.98 (td, J= 410.07 7.8, 1.3 Hz, 2H), 7.93-7.83 (m, 4H), 7.36 (td, J= 7.8, 6.3 Hz, 1H), 7.16- 7.04 (m, 3H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 4.48 (d, J= 6.0 Hz, 2H); HNMR (DMSO-dg, 400 MHZ): 5 11.49 (br s, 1H), 9.26 (t, J= 5.9 Hz, 1H), 8.04 (d, J ClelsFNz = 8.3 Hz, 1H), A, 159,257 045 8.00-7.94 (111, 410.07 2H), 7.92-7.78 (m, 4H), 7.34 (dd, J= 8.7, 5.6 Hz, 2H), 7.18- 7.10 (m, 2H), 4.44 (d, J= 5.9 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 11.52 (s, 1H), 9.34 (t, J= 5.9 Hz, 1H), 8.07 (d, J= 8.2 CZZHISFSN HZ, 1H), 8.01- 2053 7.96 (m, 2H), A, 8 7.93-7.82 (111, 47607 4H), 7.46 (t, J= 7.9 Hz, 1H), 7.33 (d, J= 7.7 Hz, 1H), 7.30- 7.22 (m, 2H), 4.51 (d, J= 5.9 Hz, 2H) 1H NMR (DMSO-d,, 400 MHZ): 5 12.90 (br s, 1H), CanNsO 11.61 (s, 1H), G, 159, 231 8.12-7.98 (m, 5H), 7.96-7.84 (m, 2H), 7.58 (d, J= 3.7 Hz, 1H), 7.31 (d, J = 3.0 Hz, 1H); 1H NMR (DMSO-d,, 500 C25H18N4O MHZ): 5 11.51 A, 159, 377 (s, 1H), 9.35 (t, J= 5.7 Hz, 1H), 8.85 (s, 2H), 8.39-8.35 (m, 2H), 8.06 (d, J [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.92-7.81 (m, 4H), 7.54- 7.49 (m, 3H), 4.53 (d, J= 5.5 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 11.52 (s, 1H), 8.99 (br s, 1H), 8.05 (d, J= 8.5 Hz, 1H), 8.01-7.96 (m, C27H26NZO 2H), 7.93-7.83 A, 159,259 (m, 2H), 7.79- 7.73 (m, 2H), 7.26 (d, J= 4.8 Hz, 4H), 7.21- 7.16 (m, 1H), 4.54 (br s, 1H), 3.14-2.98 (m, 2H), 1.34 (s, 9H); HNMR (DMSO-dg, 400 MHZ): 5 11.48 (br s, 1H), 8.94 (t, J= 5.4 Hz, 1H), 8.04 (d, J C22H18NZO = 8.3 Hz, 1H), 8.01-7.95 (m, A, 159, 176 2H), 7.93-7.78 (m, 4H), 7.31- 7.24 (m, 2H), 6.97-6.89 (m, 3H), 4.10 (t, J= .7 Hz, 2H), 3.63 (q, J= 5.6 Hz, 2H); H NMR (DMSO-dg, 400 MHZ): 5 11.51 (s, 1H), 8.92 (s, C22H17FN2 1H), 8.04 (d, J A, 159, 265 058 = 8.2 Hz, 1H), 7.98 (td, J= 440.08 7.5, 0.9 Hz, 2H), 7.93-7.77 (m, 4H), 7.10 (t, J= 9.3 Hz, 2H), 7.00-6.91 (m, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 2H), 4.08 (t, J= .5 Hz, 2H), 3.61 (q, J= 5.6 Hz, 2H); 1H NMR (DMSO-d, 400 MHZ): 5 13.19 (br s, 1H), 11.62 (s, 1H), A, 159,253 8.10 (d, J= 8.2 Hz, 1H), 8.07- 7.97 (m, 4H), 7.95-7.85 (m, 2H), 7.63 (s, 1H); HNMR (DMSO-dg, 400 MHZ): 5 11.52 (s, 1H), 9.34 (t, J= 5.9 Hz, 1H), 9.17 (s, 1H), 9.12 (s, 2H), C25H18N4O 8.07 (d, J= 8.2 A, 159, 372 Hz, 1H), 7.99 (td, J= 7.8,1.1 Hz, 2H), 7.94- 7.83 (m, 4H), 7.77 (d, J= 8.3 Hz, 2H), 7.46 (d, J= 8.2 Hz, 2H), 4.53 (d, J = 5.7 Hz, 2H); 1H NMR (DMSO-d, 400 MHZ): 5 13.22 (br s, 1H), 11.63 (s, 1H), C21H12FN3 8.15-8.08 (m, 0482 2H), 8.06-7.98 H, 159, 241 (m, 3H), 7.98- 453.03 7.84 (m, 3H), 7.79 (dd, J= 7.9, 4.8 Hz, 1H), 7.33 (td, J = 8.9, 2.4 Hz, 1H); 1H NMR C1N (DMSO-d, 400 C, 159, 235 3048 MHZ): 5 11.56 (br s, 1H), 413.02 11.26 (br s, 1H), 8.46 (br s, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.10-7.83 (m, 8H); 1H NMR (DMSO-dg, 400 MHZ): 5 11.57 (br s, 1H), .54 (s, 1H), 8.11 (d, J= 8.3 Hz, 1H), 8.00 (td, J= 9.0, 1.0 C28H20NZO Hz, 2H), 7.95- A, 159, 519 7.84 (m, 4H), 7.76- 7.72 (m, 3H), 7.64 (td, J = 9.1, 1.5 Hz, 1H), 7.50 (td, J = 7.6, 1.3 Hz, 1H), 7.46- 7.39 (m, 2H), 7.08- 7.03 (m, 1H), 3.61 (s, 3H); H NMR (DMSO-d6, 400 MHZ): 5 11.60 (s, 1H), 10.60 (s, 1H), 8.86 (br s, 1H), 8.60 (d, A, 159, 246 C25H17N3O J= 3.7 Hz, 1H), ion 8.13 (d, J= 8.3 time RT-1 8 Hz, 1H), 8.08 h) (s, 1H), 8.06- 7.98 (m, 3H), 7.97-7.85 (m, 4H), 7.81 (d, J = 6.7 Hz, 1H), 7.55-7.48 (m, 3H); H NMR (DMSO-dG, 400 MHZ): 5 10.28 (s, 1H), 9.07 (s, 1H), 9.01 (t, J= C20H17N5O .7 Hz, 1H), A, 164, 212 2 8.74 (s, 2H), 359.14 7.66-7.60 (m, 2H), 7.56 (s, 1H), 7.53-7.47 (m, 1H), 7.26 (d, J= 8.6 Hz, 1H), 7.20 (d, J [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson = 8.0 Hz, 1H), 7.10 (t, J= 7.2 Hz, 1H), 4.47 (d, J= 5.6 Hz, 2H), 3.29 (s, 3H); 1H NMR (DMso—dé, 500 MHZ): 5 10.26 (s, 1H), 9.05 (t, J= 5.7 Hz, 1H), 8.93 (s, 1H), C19H16N4O 7.77 (s, 1H), A,164,213 7.66-7.44 (m, 4H), 7.20 (dd, J = 18.1, 8.2 Hz, 2H), 7.08 (t, J= 7.4 Hz, 1H), 4.62 (d, J= 5.6 Hz, 2H), 3.28 (s, 3H); ), 1H NMR (DMSO-dé, 400 MHZ): 5 10.28 (s, 1H), 8.90 (t, J= 5.6 Hz,1H), 8.27 (s, 1H), 7.66-7.59 (m, 2H), 7.55 (s, 1H), 7.52-7.47 A, 164, 214 (m, 1H), 7.24 (d, J= 8.5 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.10 (t, J= 7.5 Hz, 1H), 7.02 (s, 1H), 4.50 (d, J= 5.3 Hz, 2H), 3.30 (s, 3H); H NMR dé, 400 MHZ): 5 10.28 (s, 1H), 9.01 (s, 1H), 8.65 (s, C21H19N5O 2H), 8.46 (t, J= A, 164,215 2 .7 Hz, 1H), 373.15 7.63 (dd, J= 7.7, 1.6 Hz, 1H), 7.53-7.47 (m, 3H), 7.21 (dd, J= 11.2, 8.3 Hz, 2H), [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.10 (t,.]= 7.5 Hz, 1H), 3.52 (q, J= 6.4 Hz, 2H), 3.29 (s, 3H), 2.85 (t, J= 6.6 Hz, 2H), 1H NMR (DMSO-dé, 400 MHZ): 5 10.29 (s, 1H), 8.50 (d, J= 4.0 Hz, 1H), 8.46 (t, J= 5.4 Hz, 1H), 7.69 (td, J= 7.6,1.9 C22H20N4O Hz, 1H), 7.64 A, 164,216 2 (dd, J= 7.7, 1.7 372.16 HZ, 1H), 7.57- 7.47 (m, 3H), 7.27-7.18 (m, 4H), 7.10 (t, J= 7.2 Hz, 1H), 3.57 (q, J= 7.0 Hz, 2H), 3.30 (s, 3H), 2.96 (t, J= 7.3 Hz, 2H), H NMR (DMSO-d, 400 MHZ): 5 10.29 (s, 1H), 8.48- 8.42 (m, 2H), 8.40 (dd, J= 4.7, 1.5 Hz, 1H), 7.63 (dd, J = 7.7, 1.6 Hz, C22H20N4O 2H), 7.57 -7.45 A, 164,217 2 (m, 3H), 7.29 372.16 (dd, J= 7.7, 4.8 Hz, 1H), 7.21 (dd, J= 11.0, 8.4 Hz, 2H), 7.10 (t, J= 7.4 Hz, 1H), 3.48 (q, J= 7.1 Hz, 2H), 3.30 (s, 3H), 2.84 (t, J= 7.0 Hz, 2H), 1H NMR C20H18N4O (DMSO-da 400 A, 164, 352 MHZ): 5 10.30 (s, 1H), 8.91 (s, 1H), 8.53 (t, J= .7 Hz, 1H), [Annotation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson 7.69 (s, 1H), 7.64 (dd, J= 7.7, 1.7 Hz, 1H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.54-7.47 (m, 2H), 7.22 (dd, J= 16.5, 8.1 Hz, 2H), 7.10 (t,J=7.1 Hz, 1H), 3.47 (q, J= 6.8 Hz, 2H), 3.31 (s, 3H), 3.10 (t, J= 6.7 Hz, 2H); HNMR (DMSO-d6, 400 MHZ): 5 10.29 (s, 1H), 8.98 (t, J= 5.8 Hz,1H), 8.51 (s, 1H), 8.44 (dd, J= 4.8, 1.6 Hz, 1H), 7.68 (tt, J = 7.9, 1.9 Hz, 1H), 7.63 (tt, J Zq:0 C21H18N4O = 8.0, 1.9 Hz, 358.9 1499 Z A, 164, 218 30 2 (M++1) 2H), 7.57 (s, 2 I CH3 358.14 1H), 7.53-7.47 (m, 1H), 7.34 (dd, J= 7.3, 4.8 Hz, 1H), 7.25 (d, J= 8.5 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.10 (t,J=7.1 Hz, 1H), 4.46 (d, J= 5.9 Hz, 2H), 3.30 (s, 3H); 1H NMR (DMSO-d, 500 MHZ): 5 10.28 (s, 1H), 8.47 (t, J= 5.4 Hz, 1H), diubd‘O C29H25N3O 448.1 7.65-7.54 (m, 1521 36 2 IZ A, 164, 219 (M++1) 6H), 7.52 (s, CH3 447.19 1H), 7.48 (t, J= 7.8 Hz, 1H), 7.43 (t, J= 7.7 Hz, 2H), 7.35- 7.28 (m, 3H), 7.20 (dd, J= [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 16.8, 8.4 Hz, 2H), 7.08 (t, J= 7.5 Hz, 1H), 3.47 (q, J= 6.4 Hz, 2H), 3.28 (s, 3H), 2.84 (t, J= 7.2 Hz, 2H); 1H NMR (DMSO-dé, 400 MHZ): 5 10.29 (s, 1H), 9.07 (s, 1H), 9.02 (t, J= .7 Hz, 1H), 8.74 (s, 2H), 7.65-7.55 (m, C21H19N5O 3H), 7.52-7.46 AC, 167, 212 2 (m, 1H), 7.25 (6: 373.15 (d, J= 8.5 Hz, 1H), 7.20 (d, J Reaction = 8.2 Hz, 1H), Time 12 h- 7.11 (t,.]= 7.4 Hz, 1H), 4.46 (d, J= 5.6 Hz, 2H), 3.83-3.75 (m, 2H), 1.12 (t, J= 6.9 Hz, 3H); H NMR (DMSO-dé, 400 MHZ): 5 10.29 (s, 1H), 9.07 (t, J= 5.9 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.63-7.54 (m, C20H18N4O 3H), 7.52-7.46 AC, 167,213 (m, 1H), 7.24 (d, J= 8.5 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.10 (t, J= 7.2 Hz, 1H), 4.64 (d, J= 5.7 Hz, 2H), 3.84-3.75 (m, 2H), 1.12 (t, J= 7.0 Hz, 3H); 1H NMR (DMSO-dé, 400 MHZ): 5 10.29 AC, 167, 214 (s, 1H), 8.90 (t, J= 5.6 , 8.27 (s, 1H), 7.63-7.55 (m, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 3H), 7.52-7.47 (m, 1H), 7.24 (d, J= 8.5 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.11 (t,J=7.3 Hz, 1H), 7.01 (s, 1H), 4.50 (d, J= 5.4 Hz, 2H), 3.83-3.76 (m, 12(t,.]= 7.0 Hz, 3H); HNMR (DMSO-d6, 500 MHZ): 5 10.27 (s, 1H), 8.99 (s, 1H), 8.64 (s, 2H), 8.44 (t, J= .4 Hz, 1H), 7.58 (d, J= 6.7 Hz, 1H), 7.52— NH o N50 7.45 (m, 3H), (j EVH®QNN 388 0 1565 N ’) AC, 167, 215 36 1‘ 2 7.19 (dd,J= (M +1) 387.17 14.6, 8.2 Hz, 2H), 7.08 (t, J= 7.5 Hz, 1H), 3.81-3.72 (m, 2H), 3.50 (q, J = 6.1 Hz, 2H), 2.83 (t,.]= 6.7 Hz, 2H), 1.10 (t, J= 6.9 Hz, 3H); 1H NMR (DMSO-dé, 400 MHZ): 5 10.29 (s, 1H), 8.49 (d, J= 4.1 Hz, 1H), 8.45 (t, J= 5.3 Hz, 1H), 7.69 (td, J= 77,18 0 C23H22N4O HZ, 1H), 7.60 387 0 1522 ( S I y’L ’ AC 167’ 216 29 ‘ 2 (dd,J=7.7, 1.6 N \ / 9 E, (Mm) Hz, 1H), 7.57- 386 17' 7.47 (m, 3H), 7.27-7.18 (m, 4H), 7.10 (t, J= 7.4 Hz, 1H), 3.83-3.74 (m, 2H), 3.57 (q, J = 6.9 Hz, 2H), 2.96 (t, J= 7.3 Hz, 2H), 1.12 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR (DMSO-d6, 500 MHZ): 5 10.28 (s, 1H), 8.47- 8.34 (m, 3H), 7.65-7.56 (m, 2H), 7.54—7.45 (m, 3H), 7.28 C23H22N4O (dd, J= 7.5, 4.9 Hz, 1H), 7.19 AC, 167,217 2 (dd, J= 13.7, 386.17 8.2 Hz, 2H), 7.09 (t, J= 7.2 Hz, 1H), 3.76 (br s, 2H), 3.46 (q, J= 6.7 Hz, 2H), 2.82 (t, J= 7.1 Hz, 2H), 1.10 (t, J= 6.9 Hz, 3H); 1H NMR (DMSO-d6, 500 MHZ): 5 10.29 (s, 1H), 8.89 (s, 1H), 8.51 (t,.]= .4 Hz, 1H), 7.67 (s, 1H), 7.61-7.43 (m, C21HzoN4O 4H), 7.22 (d, J = 8.4 Hz, 1H), AC, 167, 352 7.18 (d, J= 8.1 Hz, 1H), 7.09 (t, J= 7.4 Hz, 1H), 3.82-3.74 (m, 2H), 3.45 (q, J= 6.5 Hz, 2H), 3.08 (t, J= 6.7 Hz, 2H), 1.11(t,.]=6.8 Hz, 3H); 1H NMR dé, 400 MHZ): 5 10.29 C22H20N4O (s, 1H), 8.98 (t, AC, 167,218 2 J= 5.9 Hz, 1H), 8.52 (s, 1H), 372.16 8.44 (dd, J= 4.7, 1.6 Hz, 1H), 7.68 (dt, J = 7.9, 1.8 Hz, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1H), 7.65-7.56 (m, 3H), 7.49 (td, J= 7.7,1.7 Hz, 1H), 7.36- 7.32 (m, 1H), 7.25 (d, J: 8.5 Hz, 1H), 7.20 (d, J= 7.9 Hz, 1H), 7.10 (td, J = 7.5, 0.8 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.82-3.75 (m, 2H),1.12(t,J= 7.0 Hz, 3H), HNMR (DMSO-d6, 400 MHZ): 5 10.30 (s, 1H), 8.48 (t, J= 5.5 Hz, 1H), 7.68-7.41 (m, O 10H), 7.36-7.29 dflqj C30H27N30 ,7.21 2 OME 0 462.1 (dd,J—13.5, 1524 1,: [531679219 15 2 Et (Mm) 8.3 Hz, 2H), 461.21 7.10 (t,J=7.5 Hz, 1H), 3.82- 3.75 (m, 2H), 3-48 (q, J= 6.9 Hz, 2H), 2.86 (t, J= 7.2 Hz, 2H), 1.12 (w: 6.9 Hz, 3H), 1H NMR (DMso—dé, 500 MHZ): 5 10.36 (s, 1H), 9.06 (s, 1H), 8.97 (t, J: .8 Hz, 1H), 8.72 (s, 2H), 7.61 (dd, J: NH O C26H21N50 7.7, 1.3 Hz, 1482 ( X Z j’LN H17) A, 170, 212 36 4391 2 1H), 757451 N (M +1) (m) 2H), 7.47- 435 17 N/ ‘ 7.39 (m, 3H), 7.33 (d, J: 8.4 Hz, 1H), 7.30- 7.23 (m, 3H), 7.15 (t,J= 7.8 Hz, 1H), 7.08 (t, J= 7.4 Hz, 1H), 5.03 (s, 2H), 4.44 (d, J [Annotation] Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson -——=55 mm; H NMR (DMSO-dG, 400 MHZ): 5 10.37 (s, 1H), 9.04 (t, J= 5.8 Hz,1H), 8.94 (s, 1H), 7.77 (s, 1H), 7.61 (dd, J= 7.7, 1.6 Hz, C25H20N4O 1H), 7.56 (S, 1H), 7.50 (dd, J A, 170,213 = 8.5, 1.9 Hz, 1H), 7.47-7.39 (m, 3H), 7.32 (d, J= 8.6 Hz, 1H), 7.29-7.22 (m, 3H), 7.14 (t, J= 7.2 Hz, 1H), 7.08 (t, J= 7.3 Hz, 1H), 5.03 (s, 2H), 4.61 (d, J= 5.6 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 10.37 (s, 1H), 8.87 (t, J: 5.6 HZ,1H), 8.25 (s, 1H), 7.61 (dd, J= 7.7, 1.6 Hz, 1H), 7.55 (s, C25H20N4O 1H), 7.51 (dd, J = 8.4, 2.0 Hz, A, 170, 214 3 1H), 7477.39 424.15 (m, 3H), 7.32 (d, J= 8.5 Hz, 1H), 7.30-7.23 (m, 3H), 7.17- 7.12 (m, 1H), 7.08 (t, J= 7.2 Hz, 1H), 7.00 (s, 1H), 5.03 (s, 2H), 4.47 (d, J = 5.4 HZ, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 10.36 A, 170, 215 (s, 1H), 9.01 (s, 1H), 8.64 (s, 2H), 8.42 (t, J= .5 Hz, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.60 (dd, J= 7.7, 1.6 Hz, 1H), 7.49-7.38 (m, 5H), 7.33- 7.21 (m, 4H), 7.15 (t,.]= 7.1 Hz, 1H), 7.08 (t, J= 7.4 Hz, 1H), 5.02 (s, 2H), 3.49 (q, J = 6.4 Hz, 2H), 2.82 (t, J= 6.7 Hz, 2H); H NMR d, 500 MHZ): 5 10.35 (s, 1H), 8.47 (d, J= 3.8 Hz, 1H), 8.41 (t, J= 5.4 Hz, 1H), 7.68- 7.64 (m, 1H), 7.59 (d, J= 7.8 C28H24N4O Hz, 1H), 7.52- A, 170,216 7.49 (m, 1H), 7.47-7.37 (m, 4H), 7.31-7.17 (m, 6H), 7.16- 7.11 (m, 1H), 7.07 (t, J= 7.2 Hz, 1H), 5.01 (s, 2H), 3.53 (q, J= 6.7 Hz, 2H), 2.92 (t, J= 7.2 Hz, 2H); 1H NMR d, 500 MHZ): 5 10.36 (s, 1H), 8.43- 8.39 (m, 2H), 8.37 (dd, J= 4.6, 1.2 Hz, C28H24N4O 1H),7.75-7.54 A, 170,217 2 (m, 2H), 7.49 (s, 1H), 7.46- 448" 7.36 (m, 4H), 7.33—7.21 (m, 5H), 7.18-7.10 (m, 1H), 7.06 (t, J= 7.4 Hz, 1H), .01 (s, 2H), 3.47—3.41 (m, 2H), 2.80 (t, J= [Annotation] Sarah.Wilkinson None set by Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 6.9 Hz, 2H); H NMR (DMSO-dé, 400 MHZ): 5 10.37 (s, 1H), 8.47 (t, J= 5.6 Hz,1H), 8.20 (s, 1H), 7.61 (dd, J= 7.7, 1.6 Hz, C26H22N4O 1H), 7.51 (S 1H), 7.47-7.40 A, 170, 347 3 (m, 4H), 7.33- 43817 7.23 (m, 4H), 7.18-7.12 (m, 1H), 7.08 (t, J= 7.4 Hz, 1H), 6.90 (s, 1H), 3.46 (q, J= 6.6 Hz, 2H), 2.88 (t, J= 6.8 Hz, 1H NMR (DMSO-dé, 500 MHZ): 5 10.37 (s, 1H), 8.89 (s, 1H), 8.49 (t, J= .5 Hz, 1H), 7.66 (s, 1H), 7.60 (dd, J= 7.7, 1.3 Hz, C26H22N4O 1H), 7.52 (S, 1H), 7.49-7.38 A, 170, 352 (m, 4H), 7.31 (d, J= 8.7 Hz, 1H), 7.28-7.22 (m, 3H), 7.14 (t, J= 7.2 Hz, 1H), 7.07 (t, J= 7.4 Hz, 1H), 5.02 (s, 2H), 3.43 (q, J= 6.5 Hz, 2H), 3.06 (t, J= 6.7 Hz, 2H); 1H NMR (DMso—dé, 400 MHZ): 5 10.37 C27H22N4O (s, 1H), 8.95 (t, A, 170,218 2 J= 5.9 Hz, 1H), 434.17 8.51-8.49 (m, 1H), 8.43 (dd, J = 4.8, 1.6 Hz, 1H), 7.66 (td, J [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson = 7.5, 1.7 Hz, 1H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.58-7.52 (m, 2H), 7.47- 7.38 (m, 3H), 7.35-7.22 (m, 5H), 7.18-7.12 (m, 1H), 7.08 (t, J= 7.1 Hz, 1H), .03 (s, 2H), 4.43 (d, J= 5.7 Hz, 2H); H NMR (DMSO-dé, 500 MHZ): 5 10.38 (s, 1H), 8.45 (t, J= 5.5 Hz,1H), 7.66-7.52 (m, C35H29N3O 6H), 7.51-7.39 (m, 6H), 7.37- A, 170, 219 2 7.23 (m, 7H), 523.23 7.18-7.13 (m, 1H), 7.08 (t, J= 7.4 Hz, 1H), .03 (s, 2H), 3.49-3.43 (m, 2H), 2.84 (t, J= 7.2 Hz, 2H); ), 1H NMR (DMSO-dé, 400 MHZ): 5 10.45 (d, J = 4.4 Hz, 2H), 8.53-8.38 (m, 2H), 7.74- C26H20N4O 7.70 (m, 2H), 7.67-7.62 (m, A, 170, 185 2 3H), 7.50-7.39 420.16 (m, 4H), 7.31 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.20-7.08 (m, 2H), 5.07 (s, 2H); 1H NMR (DMSO-dé, 400 MHZ): 5 10.35 A, 170, 406 (s, 1H), 8.40 (t, J= 5.6 Hz, 1H), .53 (m, 3H), 7.52-7.36 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson (m, 7H), 7.31- 7.18 (m, 4H), 7.13 (t, J= 7.3 Hz, 1H), 7.06 (t, J= 7.4 Hz, 1H), 5.00 (s, 2H), .41 (m, 2H), 2.88 (t, J= 7.0 Hz, 2H), 2.51 (s, 6H); 1H NMR (DMSO-d, 400 MHZ): 5 10.44 (s, 1H), 10.20 (s, 1H), 8.05- 8.03 (m, 1H), C33H25N3O 7.75 (d, J= 8.4 Hz, 1H), 7.69- A, 170, 186 2 7.58 (m, 5H), 49519 7.51—7.35 (m, 9H), 7.34—7.24 (m, 3H), 7.17 (t, J= 7.7 Hz, 1H), 7.11 (t, J= 7.5 Hz, 1H), 5.07 (s, 2H); HNMR (400 MHZ, DMSO- d6): 5 10.97 (s, 1H), 10.36 (S, 1H), 9.53 (S, 1H), 8.03-8.01 (m,1H), 7.81 - 7.71 (m, 4H), C26H17FN2 7.63 (dd, J: A, 35, 413 038 8.6, 5.3 HZ, 1H), 7.51 (dd, J 456.09 = 9.2, 2.9 Hz, 1H), 7.45-7.36 (m, 2H), 7.35- 7.32 (m, 1H), 7.26 (t, J= 7.8 HZ, 1H), 7.06- 7.00 (m, 2H), 6.79- 6.75 (m, 1H); 1H NMR C27H19FN2 (DMSO-d, A, 35, 412 O38 400MHz): 5 .98 (s, 1H), 470.11 .37 (s, 1H), 8.02 (s, 1H), ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.83-7.70 (m, 4H), 7.63 (dd, J = 8.6, 5.3 Hz, 1H), 7.52 (dd, J = 9.2, 2.9 Hz, 1H), 7.47-7.36 (m, 4H), 7.20 (d, J= 7.8 Hz, 1H), 7.16-7.14 (m, 1H), 6.96 (dd, J= 8.0, 2.2 Hz, 1H), 3.82 (s, 3H); H NMR (DMSO-da 400 MHZ): 5 11.50 (s, 1H), 8.69 (t, J= 5.4 Hz, 1H), 8.03 (d, J= 8.3 Hz, 1H), 8.01- 7.96 (m, 2H), 7.93-7.82 (m, CZOHZONZO 2H), 7.80 - 7.76 (m, 2H), 3.81- A, 159,415 3.71 (m, 2H), .54 (m, 1H), 3.45-3.40 (m, 1H). 3.29- 3.25 (m, 1H), 2.00-1.90 (m, 1H),1.86-1.73 (m, 2H), 1.68 (q, J= 7.0 Hz, 2H), 1.46-1.35 (m, 1H); H NMR (DMSO-dg, 400 MHZ): 5 11.52 (s, 1H), 8.81 (t, J= 5.5 Hz,1H), 8.09 (s, 2H), C24H19NsO 8.04 (d, J= 8.3 A, 159, 421 Hz, 1H), 8.00- 7.82 (m, 6H), 7.80-7.72 (m, 2H), 7.42 (d, J = 8.6 Hz, 2H), 3.57-3.49 (m, 2H), 2.90 (t, J= 7.0 Hz, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson H NMR da 400 MHZ): 5 11.52 (s, 1H), 8.76 (t, J= 5.5 Hz, 1H), 8.03 (d, J= 8.3 Hz, 1H), 8.00- 7.96 (m, 2H), 7.92-7.83 (m, 2H), 7.79 (s, 1H), 7.75 (dd, J = 8.2, 1.4 Hz, C34H33N3O 1H), 7.44-7.22 628.1 78 (m, 6H), 7.11 A, 159, 427 51 NHCbz (M++1) (d, J= 8.6 Hz, 627.20 2H), 6.82 (d, J = 8.5 Hz, 2H), .00 (s, 2H), 3.90 (t, J= 6.2 Hz, 2H), 3.43 (q, J= 6.7 Hz, 2H), 3.04 (q, J = 6.7 Hz, 2H), 2.74 (t, J= 7.3 Hz, 2H), 1.71- 1.63 (m, 2H), 1.58-1.49 (m, 2H); ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 27: S nthesis of Com ounds 1268 and 1269 \OJLO/ BocHN BocHN (Boc)20 I NICI2 6H20 ©/\CN . Chiral Separation \ —, o\—» NaBH4' MeOH NaH, Toluene O 433 434 (Fr-l) (Racemic) & 435 (Fr-ll) TFA_H2N NH LiOH.H20 (R) —, 434 (Fr-l) —> CHZCIZ "iii/(k EDCI.HCI, HOBt, THF:H20 O DIPEA, DMF @634 435 (Frll)—» O"?sD/EN/\(/©—>LiOH.H20 EDCI HCI HOBt THF- H20 DIPEA DMF Synthesis of methyl 2-cyan0phenylacetate (432): To a stirred solution of sodium hydride (60%, 2.5 g, 63.82 mmol) in ous toluene (50 rnL) under argon atmosphere was added 2-pheny1 acetonitrile 430 (5 g, 42.55 mmol) at 0 0C and stirred for 30 min. To this dimethyl ate 431 (5.74 g, 63.82 mmol) in anhydrous toluene (30 rnL) was added drop wise for 10 min and stirred at 0 0C for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated ammonium de (20 rnL) and extracted with EtOAc (2 x 50 rnL). The combined c extracts were washed with brine (50 rnL), dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 432 (4.8 g, 64%) as colorless syrup. TLC: 30% EtOAc/ hexanes [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (Rf: 0.7); 1H-NMR (CDClg, 400 MHz): 5 7.47—7.39 (m, 5H), 4.74 (s, 1H), 3.81 (s, 3H). sis of methyl 3-amin0phenylpropanoate (433): To a stirred solution of compound 432 (1 g, 5.71 mmol) in MeOH (50 mL) under argon atmosphere were added Bocanhydride (2.49 g, 11.42 mmol), nickel dichloride hexahydrate (135 mg, 0.57 mmol) and sodium borohydride (1.5 g, 39.99 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after tion of the reaction, the on mixture was diluted with MeOH (30 mL), filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 30% EtOAc/ s to afford racemic compound 433 (550 mg, 36%) as an off white solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (DMSO-dg, 500 MHZ): 5 7.34 (t, J: 7.0 Hz, 2H), 7.30-7.25 (m, 3H), 6.93 (t, J: 6.0 Hz, 1H), 3.85 (t, J: 7.5 Hz, 1H), 3.60 (s, 3H), 3.28-3.23 , 1.34 (s, 9H). The racemic compound 433 was purified through chiral preparative HPLC to afford compound 434 Fr-I (120 mg) and compound 435 Fr-II (90 mg) as off-white .
Compound 434 Fr-I analytical data: Chiral HPLC: 99.27%, R: 9.58 min (Chiralcel AD-H, 250 x 4.6 mm, 5 urn); mobile phase (A) 0.1% DEA in n-Hexane (B) EtOH (A: B: 98: 2); Flow Rate: 1.0 mL/min).
Compound 435 Fr-II analytical data: Chiral HPLC: 99.29%, Rt=10.87 min(Chira1ce1AD-H, 250 x 4.6 mm, 5 urn); mobile phase (A) 0.1% DEA in n-Hexane (B) EtOH (A: B: 98: 2); Flow Rate: 1.0 mL/min).
Synthesis of methyl (R)phenyl((2, 2, 2-triflu0r0acetyl)—k4-azanyl) propanoate (436): To a stirred solution of nd 434 (Fr-l) (50 mg, 0.17 mmol) in CH2C12 (2 mL) under inert atmosphere was added trifluoroacetic acid (0.026 mL, 0.35 mmol) at 0 0C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 436 (20 mg, TFA salt) as off-white solid. TLC: 70% EtOAc/ s (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHZ): 5 8.10 (br s, 2H), 7.41-7.28 (m, 5H), 4.03 (t, J: 6.0 Hz, 1H), 3.63 (s, 3H), 3.48 (t, J: 9.2 Hz, 1H), 3.12-3.08 (m, 1H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson sis of methyl (R)—3-(11-0x0-10, 11-dihydr0dibenzo [b,f] [1, 4] thiazepine- 8-carb0xamid0)—2-phenylpr0panoate (437): To a stirred solution of compound 6 (70 mg, 0.25 mmol) in DMF (5 mL) under argon atmosphere were added EDCI.HC1 (73.9 mg, 0.38 mmol), HOBt (30 mg, 0.38 mmol), compound 436 (70 mg, 0.38 mmol), diisopropyl ethyl amine (0.09 mL, 0.51 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was diluted with water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium te, d and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 90% EtOAc/ Hexanes to afford compound 437 (70 mg, 63%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 5 .75 (s, 1H), 8.65 (t, J: 5.6 Hz, 1H), 7.68 (d, J: 7.2 Hz, 2H), 7.67-7.60 (m, 4H), 7.54-7.49 (m, 2H), 7.49-7.44 (m, 3H), 7.35-7.25 (m, 1H), 4.02 (t, J: 7.2 Hz, 1H), 3.80-3.73 (m, 1H), 3.55 (t, J: 6.4 Hz, 1H), 3.47 (s, 3H).
Synthesis 0f(R)(11-0x0-10, ydr0dibenz0 [b,f] [1, 4] thiazepine carboxamido)—2-phenylpropanoic acid (1268): To a stirred solution of compound 437 (40 mg, 0.092 mmol) in THF: H20 (4: 1, 2.5 mL) was added LiOH.H20 (7.7 mg, 0.18 mmol) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, diluted with water (5 mL), pH was adjusted to ~ 6 using 1 N HC1 and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford 1268 (25 mg, 65%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 5 12.49 (br s, 1H), 10.76 (s, 1H), 8.62 (t, J: .6 Hz, 1H), 7.68 (d, J: 7.2 Hz, 1H), 7.66-7.61 (m, 2H), 7.54-7.42 (m, 4H), 7.34-7.23 (m, 5H), 3.92 (t, J: 7.6 Hz, 1H), 3.77-3.72 (m, 1H), 3.57-3.50 (m, 1H); LC-MS: 90.53%; 419.4 (M++1); (column; X-bridge C-18, (50 x 3.0 mm, 3.5 urn); RT 3.76 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 93.78%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.04 min. ACN : 0.025% TFA (Aq); 0.5 mL/min). sis of methyl (S)phenyl((2, 2, 2-triflu0r0acetyl)—k4-azanyl) propanoate (438): To a stirred solution of compound 435 (Fr-ll) (90 mg, 0.32 mmol) in CH2C12 (3 mL) under inert atmosphere was added roacetic acid (0.073 mL, 0.64 mmol) at 0 0C; warmed to RT and d for 3 h. The reaction was monitored by TLC; after completion of the [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson reaction, the volatiles were removed in vacuo to obtain the crude compound 438 (90 mg, TFA salt) as an off-white solid. TLC: 70% EtOAc/ Hexanes (Rf: 0.2); 1H-NMR dg, 400 MHz): 5 8.10 (br s, 2H), 7.41-7.28 (m, 5H), 4.03 (t, J: 6.0 Hz, 1H), 3.63 (s, 3H), 3.48 (t, J: 9.2 Hz, 1H), 3.12-3.08 (m, 1H).
Synthesis of methyl (S)(11-0x0-10, 11-dihydr0dibenzo [b,f] [1, 4] thiazepine carb0xamid0)—2-phenylpr0panoate (439): To a stirred solution of nd 6 (70 mg, 0.25 mmol) in DMF (5 mL) under argon atmosphere were added EDCI.HCl (73.9 mg, 0.38 mmol), HOBt (52 mg, 0.38 mmol), compound 438 (70 mg, 0.38 mmol), ropyl ethyl amine (0.09 mL, 0.51 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 80% EtOAc/ hexanes to afford compound 439 (70mg, 63%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 5 10.77 (s, 1H), 8.65 (t, J: 5.6 Hz, 1H), 7.69 (d, J: 7.2 Hz, 1H), 7.65-7.61 (m, 2H), 7.55-7.45 (m, 4H), 7.37-7.34 (m, 2H), .27 (m, 3H), 4.02 (t, J: 7.2 Hz, 1H), 3.80-3.74 (m, 1H), 3.59 (s, 3H), 3.56-3.53 (m,1H). sis of (S)(11-0x0-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-S- carboxamido)—2-phenylpropanoic acid (1269): To a stirred solution of compound 439 (40 mg, 0.09 mmol) in THF : H20 (4: 1, 2.5 mL) was added lithium hydroxide monohydrate (7.7 mg, 0.18 mmol) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, diluted with water (5 mL), the pH was adjusted to ~ 6 using 1 N HCl and extracted with EtOAc (2 x 10 mL). The combined c extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford 1269 (25 mg, 65%) as white solid. TLC: % MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 12.51 (br s, 1H), 10.76 (s, 1H), 8.62 (t, J: 5.6 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.66-7.61 (m, 2H), 7.54-7.43 (m, 4H), 7.34-7.23 (m, 5H), 3.92 (t, J: 7.6 Hz, 1H), 3.77-3.72 (m, 1H), 3.57-3.50 (m, 1H); LC-MS: 96.04%; 417.8 (M-1)+; (column; X-select C-18, (50 X 3.0 mm, 3.5 um); RT 2.38 min. 5.0 mM NH4OAc : ACN; 0.8 mL/min); UPLC (purity): 96.12%; n : Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.03 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 28: S nthesis of Com ound 1239 O DMAP , Raney—Ni DIPEA CH2CI2 methanolic ammonia 4 N HCI in 1, 4—dioxane HCI EDCI.HCI HOBt DIPEA, DMF Synthesis of tert-butyl (2-cyan0phenyl) carbamate (441): To a stirred solution of 2- aminobenzonitrile 440 (l g, 8.47 mmol) in CH2Cl2 (15 mL) under argon atmosphere were added Boc-anhydride (1.84 g, 4.76 mmol) and triethyl amine (0.83 mL, 5.96 mmol), DMAP (0.1 mg, catalytic amount) at 0 0C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude.
The crude was purified through silica gel column chromatography using 30% EtOAc/ s to afford compound 441 (500 mg, 28%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.8); 1H- NMR (DMSO-dg, 400 MHz): 8 9.25 (br s, 1H), 7.85 (d, J: 7.6 Hz, 1H), 7.73 (t, J: 7.6 Hz, 1H), 7.53 (d, J: 8.0 Hz, 1H), 7.45 (t, J: 7.6 Hz, 1H), 1.35 (br s, 9H).
Synthesis of tert-butyl (2-cyanophenyl) l) carbamate (442): To a stirred solution of compound 441 (500 mg, 2.29 mmol) in DMF (10 mL) under argon atmosphere were added sodium hydride (60%, 55 mg, 2.29 mmol), methyl iodide (325 mg, 2.29 mmol) at 0 0C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the on, the reaction mixture was quenched with ice cold water (10 mL), ted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulphate, filtered and ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 442 (480 mg, 88%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 8 7.85 (d, J = 7.6 Hz, 1H), 7.73 (t, J: 7.6 Hz, 1H), 7.53 (d, J: 7.6 Hz, 1H), 7.45 (t, J: 7.6 Hz, 1H), 3.18 (s, 3H), 1.35 (br s, 9H).
Synthesis of tert-butyl (2-(amin0methyl) phenyl) (methyl) carbamate (443): To a stirred solution of compound 442 (50 mg, 0.21 mmol) in MeOH (3 mL) under argon atmosphere was added Raney Nickel (20 mg), methanolic ammonia (1.5 mL) at RT and stirred under hydrogen atmosphere on pressure) for 6 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (2 x 5 mL) and the filtrate was concentrated in vacuo to obtain the crude. The crude was washed with diethyl ether (2 x 10 mL) and dried in vacuo to afford compound 443 (40 mg, 80%) as white solid. TLC: 50% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 7.52 (d, J = 7.2 Hz, 1H), .20 (m, 2H), 7.12 (t, J: 5.6 Hz, 1H), 3.60-3.57 (m, 2H), 3.14 (br s, 3H), 1.25 (s, 9H).
Synthesis of tert-butyl methyl (2-((11-0x0-10, ydr0dibenz0 [b,f] [1, 4] pinecarboxamido) methyl) phenyl) carbamate (444): To a d solution of compound 6 (40 mg, 0.14 mmol) in DMF (3 mL) under argon atmosphere were added EDCI.HCl (42 mg, 0.22 mmol), HOBt (30 mg, 0.22 mmol), compound 443 (37.6 mg, 0.16 mmol), diisopropyl ethyl amine (0.05 mL, 0.29 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after tion of the reaction, the on mixture was diluted with ice-cold water (20 mL). The precipitate was filtered and the ed solid was dried in vacuo to afford compound 444 (40 mg, 55%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); LC-MS: 93.49%; 390.3 (M++l) (Des-Boc).
Synthesis of N—(2-(methylamin0) benzyl)—11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide (1239): A stirred solution of compound 444 (40 mg, 0.08 mmol) in 4 N HCl in l, 4-dioxane (2 mL) under argon atmosphere at 0-5 0C was stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated NaHC03 solution (20 mL) and extracted with EtOAc (2 x 20 mL). The [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ed organic extracts were washed with water (15 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford 1239 (10 mg, 32%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz):5 10.74 (s, 1H), 8.96 (t, J: 6.0 Hz, 1H), 7.72-7.60 (m, 4H), 7.55-7.43 (m, 3H), 7.08 (t, J: 7.6 Hz, 1H ), 7.02 (d, J: 7.2 Hz, 1H), 6.53 (t, J: 7.2 Hz, 2H), 5.38-5.37 (m, 1H), 4.29 (d, J: 7.2 Hz, 2H), 2.72 (d, J: 4.8 Hz, 3H); LC-MS: 93.74%; 390.3 (M++1); (column; X-select CSH C-18, (50 x 3.0 mm, 3.5 um); RT 3.44 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 94.35%; (column : y UPLC BEH C-18 (2.1 X 50 mm, 1.7 u); RT 1.87 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Exam le 29: S nthesis of Com ound 1244 446 OEt CN 6N—> D/KOH6 LiHMDS Dry THF EDCI. HCI HOBt DIPEA DMF sis of tert-butyl 4-(cyan0methylene) piperidine—l-carboxylate (447): To a stirred solution of diethyl (cyanomethyl) phosphonate 445 (978 mg, 5.52 mmol) in anhydrous THF (10 mL) under argon atmosphere was added LiHMDS (1 mL, 5.52 mmol, 1M in THF) was added drop wise for 10 min at -78 0C. To this was added tert—butyl 4-oxopiperidine carboxylate 446 (1 g, 5.01 mmol) in THF (2 mL) dropwise for 10 min and stirred for 3 h at the same temperature. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 447 (900 mg, 82%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.5); 1H NMR [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (CDC13, 400 MHz) 8 5.19 (s, 1H), 3.54-3.49 (m, 4H), 2.56 (t, J: 5.8 Hz, 2H), 2.33 (t, J: 5.6 Hz, 2H), 1.48 (s, 9H); Synthesis of tert-butyl 4-(2-amin0ethyl) piperidine-l-carboxylate (448): To a d solution of 447 (100 mg, 0.45 mmol) in AcOH (5 mL) under argon atmosphere was added % Pd/C (50 mg) at RT and stirred under en atmosphere (balloon pressure) for 16 h. The reaction was red by TLC; after completion of the reaction, the reaction mass was filtered through celite and washed with EtOAc (3 x 15 mL) and the volatiles were removed in vacuo to afford compound 448 (70 mg, mixture of isomers) as pale brown syrup. TLC: 6% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 3.89 (d, J: 12.4 Hz, 2H), 2.70-2.68 (m, 2H), 1.68-1.65 (m, 2H), 1.59 (d, J: 12.0 Hz, 1H), 1.38 (s, 9H), 1.33-1.28 (m, 4H), 0.99-0.89 (m, 2H).
Synthesis of tert-butyl 4-(2-(11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine- 8-carb0xamid0) ethyl) piperidine-l-carboxylate (449): To a stirred solution of compound 6 (40 mg, 0.14 mmol) in DMF (3 mL) under argon here were added EDCI.HCl (42 mg, 0.22 mmol), HOBt (30 mg, 0.22 mmol), compound 448 (40 mg, 0.17 mmol), ropyl ethyl amine (0.05 mL, 0.29 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was ated with EtOAc: H20 (1: 5, 12 mL), filtered and the precipitate was dried in vacuo to afford compound 449 (36 mg, 51%) as white solid. TLC: 7% MeOH/ CH2C12 (Rf: 0.7); 1H-NMR (DMSO-dg, 400 MHz): 8 10.76 (s, 1H), 8.47 (br s, 1H), 7.69-7.63 (m, 3H), 7.57-7.53 (m, 2H), 7.47 (t, J: 8.8 Hz, 2H), 3.89 (d, J: 10.8 Hz, 2H), 3.26- 3.25 (m, 2H), 2.67 (s, 3H), 1.64 (d, J: 10.8 Hz, 2H), 1.42-1.41 (m, 2H), 1.37 (s, 9H), 0.97-0.95 (m, 2H).
Synthesis of 11-0X0-N—(2-(piperidinyl) ethyl)-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide (1244): To a stirred solution of compound 449 (36 mg, 0.07 mmol) in CH2C12 (3 mL) under argon atmosphere was added trifluoro acetic acid (0.03 mL, 0.37 mmol) at 0 0C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was neutralized with 10% NaHC03 solution (15 mL) and extracted with EtOAc (3 x 15 mL).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1244 (15 mg, 53%) as an off-White solid. TLC: 7% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR dg, 400 MHz): 5 10.77 (br s, 1H), 8.48 (t, J: 5.6 Hz, 1H), 7.69-7.64 (m, 3H), .43 (m, 4H), 3.26-3.25 (m, 3H), 3.16-3.12 (m, 2H), 2.68 (t, J: 10.0 Hz, 2H), .74 (m, 2H), 1.44 (t, J: 6.8 Hz, 3H); 1.23-1.13 (m, 2H); LC-MS: 90.01%; 382.4 (M++1); (column; X-select CSH C-18, (50 X 3.0 mm, 3.5 um); RT 2.97 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 92.90%; (column : Acquity UPLC BEH C-18 (2.1 X 50 mm, 1.7 u); RT 1.60 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 30: Synthesis of Compounds 1651 and 1652 EDCI.HCI, HOBt, DIPEA, CH2CI2 2", ACOH HC| "IL/HMS . . N-OH MeOH EDCI.HC| HOBt pyrIdIne, MeOH DIPEA DMF 453 454 (Racemic) if:bin: 0 NH 0 CH3 SeparationChiral CWCH3 8 H / S\//N 455 (Racemic)S1651 O + NH 0 DAN?CH3 C is H / S\//N 1652 Synthesis of N—methoxy-N—methylthiazole—5-carboxamide (451): To a stirred solution of thiazolecarboxylic acid 378 (1.5 g, 11.61 mmol) in CH2C12 (30 mL) under argon here were added EDCI.HCl (2.45 g, 12.78 mmol), HOBt (785 mg, 135.13 mmol), N,0— yl hydroxylamine hydrochloride 450 (1.36 g, 97.6 mmol) and diisopropyl ethyl amine (10 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson mL, 58.09 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and ted with CH2C12 (3 x 50 mL). The combined organic extracts were washed with 1 N HCl (20 mL), saturated NaHC03 solution (30 mL), brine (50 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through combi flash chromatography using 30-40% EtOAc/ hexanes to afford compound 451 (1.2 g, 60%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (Rf: 0.6); 1H NMR (DMSO-dg, 400 MHz): 9.32 (s, 1H), 8.52 (s, 1H), 3.77 (s, 3H), 3.30 (s, 3H).
Synthesis of 1-(thiazolyl) ethan-l-one (452): To a stirred solution of compound 451 (1.2 g, 6.97 mmol) in THF (20 mL) under argon atmosphere was added methyl magnesium bromide (3.2 mL,10.46 mmol, 3 M solution in EtzO) dropwise for 10 min at -10 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after tion of the reaction, the on mixture was quenched with ted ammonium chloride (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through combi flash chromatography using 25-30% EtOAc/ hexanes to afford compound 452 (800 mg, 90%) as white solid. TLC: 50% EtOAc/ hexanes (Rf: 0.6); 1H NMR dg, 400 MHz): 8 9.40 (s, 1H), 8.71 (s, 1H), 2.60 (s, 3H).
Synthesis of 1-(thiazolyl) ethan-l-one oxime (453): To a d on of compound 452 (800 mg, 6.29 mmol) in MeOH (20 mL) under inert atmosphere was added hydroxyl amine hydrochloride (875 mg, 12.59 mmol) and pyridine (2 mL) dropwise for 5 min at 0 0C warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo diluted with water (50 mL) and stirred for 30 min. The precipitated solid was filtered dried in vacuo to afford compound 453 (800 mg, 90%) as white solid. TLC: 40% EtOAc/ hexanes (Rf: 0.4, 0.6); 1H NMR (DMSO-dg, 400 MHz) (Mixture of E/Z isomers): 5 11.86 (s, 1H), 11.41 (s, 0.6 H), 9.19 (s, 1H), 9.01 (s, 0.56 H), 8.35 (s, 1H), 8.15 (s, 0.65 H), 2.31 (s, 3H), 2.21 (s, 2H). 0] Synthesis of 1-(thiazolyl) ethan-l-amine (454): To a stirred solution of compound 453 (800 mg, 5.63 mmol) in MeOH: acetic acid (1: 1, 20 mL) under inert atmosphere [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson were zinc powder (2.2 g, 33.80 mmol) at RT; heated at 50 0C and stirred for 4 h. The reaction was monitored by TLC; after completion of the on, the reaction mixture was filtered through celite washed with MeOH (3 x 10 mL). The filtrate were removed in vacuo, the e was diluted with water (20 mL), basified with aqueous ammonia (15 mL) and extracted with EtOAc (3 x 50 mL). The combined organic ts were dried over sodium sulfate, filtered and trated in vacuo to obtain the crude compound 454 (racemic) (700 mg, 92%) as brown syrup. TLC: 5% MeOH/ CH2C12 (Rf: 0.4, 0.6); 1H NMR (DMSO-dg, 400 MHz): 8 8.90 (s, 1H), 7.71 (s, 1H), 4.33-4.28 (m, 1H), 3.38 (t, J: 6.4 Hz, 1H), 1.87 (s, 3H).
Synthesis of 1l-oxo-N-(l-(thiazolyl) ethyl)-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide (455 c): Using Procedure A the title nd was prepared with id (150 mg, 0.55 mmol) and compound 454 racemic (109 mg, 0.66) to afford compound 455 ic) (100 mg, 48%); TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 400 MHz): 8 10.87 (br s, 1H), 9.14 (d, J: 8.0 Hz, 1H), 8.95 (s, 1H), 7.79 (d, J: 3.6 Hz, 2H), 7.70-7.58 (m, 3H), 7.56-7.42 (m, 3H), 5.48-5.41 (m, 1H), 1.60 (s, 3H); LC-MS: 98.31%; 381.9 (M"+1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.03 min. 0.025% Aq. TFA -- 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.68%; (column; Eclipse XDB C-18 (150 x 4.6 mm, 5.0 um); RT 7.58 min. ACN : 0.05% TFA (Aq); 1.0 ) (IP14012554); Chiral HPLC: 35.10%, R: 9.01 min (Chiralpak-IA, 250 x 4.6 mm, 5 um); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH (50: 50) (A: B:: 63: 35); Flow Rate: 1.0 mL/min).
The racemic compound 455 (100 mg) was separated by preparative HPLC using a PAK-IC column (250 x 20 mm x 5 um) (10 mg loading; mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH: DMF (65: 35: 05) (A: B:: 75: 25) to afford 1651 (10 mg) and 1652 (15 mg) as an off-white solids.
Analytical Data of 1651: TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 400 MHz): 8 10.75 (s, 1H), 9.02 (d, J: 7.8 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.72-7.64 (m, 3H), 7.62-7.58 (m, 1H), 7.56- 7.41 (m, 3H), 5.45 (t, J: 7.0 Hz, 1H), 1.57 (d, J: 6.8 Hz, 3H); LC-MS: 96.06%; 381.8 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.03 min. 0.025% Aq. TFA + 5% [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.02%; (column; Zorbax SB C-18 (150 X 4.6 mm, 3.5 um); RT 7.79 min. ACN : 0.05% TFA (Aq); 1.0 mL/min) (IP15010530); Chiral HPLC: 96.24%, R: 14.33 min (Chiralpak-IA, 250 x 4.6 mm, 5 um); mobile phase (A) 0.1% DEA in ne (B) CH2C12: MeOH: DMF (65: 35: 05) (A: B:: 75: 25); Flow Rate: 1.0 mL/min). Note: Alternatively the racemic compound 454 was resolved and one fraction had led to 1651.
Analytical Data of 1652: TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 400 MHz): 5 10.75 (s, 1H), 9.03 (d, J: 8.3 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.71-7.63 (m, 3H), .58 (m, 1H), 7.56- 7.42 (m, 3H), .47(m, 1H), 1.57 (d, J: 6.9 Hz, 3H); LC-MS: 96.65%; 381.9 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.68 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.53%; (column; Zorbax SB C-18 (150 X 4.6 mm, 3.5 um); RT 7.76 min. ACN : 0.05% TFA (Aq); 1.0 mL/min) (IP15010229). Chiral HPLC: 99.87%, R: 16.90 min (Chiralpak-IA, 250 x 4.6 mm, 5 um); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH: DMF (65: 35: 05) (A: B:: 75: 25); Flow Rate: 1.0 mL/min).
Exam le 31: S s of Com ounds 1653 and 1633 $ngBoc 4 N HCIIn 1 ,4-Dioxane EDCI HOBt 450 7Hfligaoc CH2CI2 DIPEA, DMF NH O | Et3N 1633 Synthesis of tert-butyl 2-((11-0X0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—8- carboxamido) methyl) pyrrolidine—l-carboxylate (457): Using Procedure A the title compound was prepared with compound 6 (300 mg, 1.10 mmol), tert—butyl 2-(aminomethyl) ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson pyrrolidinecarboxylate 456 (0.24 mL, 1.21 mmol) and was obtained in 50% yield as an off- white solid; TLC: 10% MeOH/ CH2C12 (Rf: 0.7); 1H NMR (DMSO-dg, 400 MHz): 8 10.76 (br s, 1H), 8.53 (t, J: 5.5 Hz, 1H), 7.71-7.63 (m, 3H), 7.56-7.43 (m, 4H), 3.95-3.79 (m, 1H), 3.52-3.35 (m, 1H), 3.26-3.19 (m, 3H), 1.86-1.71 (m, 4H), 1.38 (s, 9H).
Synthesis of 11-oxo-N-(pyrrolidin-Z-ylmethyl)—10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide hydrochloride (1633): To a stirred solution of compound 457 (250 mg, 0.55 mmol) in CH2C12 (5 mL) under argon atmosphere was added 4 N HCl in 1, ane (1 mL) at 0 0C; warmed to RT and stirred for 5 h. The on was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 1633 (150 mg, 77%; HCl salt) as an ite solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.1); 1H NMR (DMSO-dg, 400 MHz): 8 10.82 (br s, 1H), 8.88 (br s, 3H), 7.74-7.62 (m, 4H), 7.56-7.43 (m, 3H), 3.67-3.57 (m, 1H), 3.56-3.46 (m, 2H), 3.24-3.07 (m, 2H), 2.07-1.95 (m, 1H), 1.95-1.78 (m, 2H), .59 (m, 1H); LC-MS: 96.49%; 354.0 (M++1) (-HCl); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 1.64 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.28%; n; Zorbax SB C-18 (150 X 4.6 mm, 3.5 um); RT 6.64 min. ACN : 0.05% TFA (Aq); 1.0 mL/min).
Synthesis of N—((l-acetylpyrrolidin-Z-yl) methyl)0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] pinecarb0xamide : To a stirred solution of compound 1633 (100 mg, 0.25 mmol) in CH2C12 (5 mL) under argon atmosphere were added triethylamine (0.12 mL, 0.77 mmol), acetyl chloride (0.02 mL, 0.30 mmol) at 0 0C; warmed to RT, stirred for 12 h. The reaction was monitored by TLC; after completion the reaction, the reaction the volatiles were removed in vacuo; the residue was basif1ed with saturated NaHC03 solution and extracted with CH2C12 (2 x 50 mL). The combined c ts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford 1653 (20 mg, 20%) as an off-white solid.
TLC: 10% MeOH/ CH2C12 (Rf: 0.6); 1H NMR dg, 400 MHz): 8 10.84-10.73 (m, 1H), 8.87-8.55 (m, 1H), 7.72-7.63 (m, 3H), 7.60-7.43 (m, 4H), 4.17-3.94 (m, 1H), 3.53-3.33 (m, 3H), 3.32-3.30 (m, 0.5H), 3.20-3.09 (m, 0.5H), 2.08-1.92 (m, 3H), 1.88-1.70 (m, 4H); LC-MS: 99.36%; 396.4 (M++1); (column; X-Select C-18, (50 X 3.0 mm, 3.5 um); RT 3.34 min, 0.77 min. mM Aq.NH4OAc: ACN 0.8 mL/min). HPLC (purity): 98.67%; (column; Eclipse XDB C-18 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (150 X 4.6 mm, 5.0 urn); RT 7.28 min. ACN: 5 mM Aq. NH4OAc; 1.0 mL/min).
Exam le 32: S nthesis of Com ounds 1615 and 1608 :tjD/EOH Boc dT/bjn/EE 4N HCIIn 1 4—Dioxane EDCI HOBt CH20I2 DIPEA DMF NH 0 DA CHgCOCI E13N s H CH2C|2 08ij N Hm 1608 1615 Synthesis of tert-butyl 3-((11-0X0-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine carboxamido) methyl) pyrrolidine—1-carb0xylate (459): Using ure A the title compound was prepared with 6 (300 mg, 1.10 mmol), tert—butyl 3-(aminomethyl) pyrrolidine-lcarboxylate 458 (0.24 mL, 1.21 mmol) and was obtained in 60% yield as an off-white solid; TLC: 10% MeOH/ CH2C12 (Rf: 0.5); 1H NMR ds, 400 MHz): 5 10.76 (s, 1H), 8.61 (t, J = 5.0 Hz, 1H), 7.72-7.63 (m, 3H), 7.60-7.42 (m, 4H), 3.34-3.18 (m, 1H), 3.28-3.13 (m, 4H), .92 (m, 1H), 2.42-2.34 (m, 1H), .82 (m, 1H), 1.64-1.50 (m, 1H), 1.37 (s, 9H).
Synthesis of 11-0X0-N—(pyrrolidinylmethyl)-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide hloride (1608): To a stirred solution of compound 459 (300 mg, 0.66 mmol) in CH2C12 (5 rnL) under argon atmosphere was added 4 N HCl in l, 4-dioxane (l rnL) at 0 0C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 1608 (200 mg, 78%; HCl salt) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.1); 1H-NMR (DMSO-dg, 400 MHz): 5 10.78 (s, 1H), 8.88 (br s, 2H), 8.70 (t, J: 5.7 Hz, 1H), 7.71-7.65 (m, 3H), 7.59 (dd, J: 8.2, 2.0 Hz, 1H), 7.56-7.43 (rn, 3H), 3.27-3.15 (m, 5H), 3.15-3.04 (m, 1H), 2.94-2.80 (m, 1H), 2.04-1.92 (m, 1H), 1.69-1.56 (m, 1H); LC-MS: ; 353.9 (M++1) (- HCl); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 urn); RT 1.64 min. 0.025% Aq. TFA + % ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 97.21%; (column; ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.55 min. ACN : 0.025% TFA (Aq); 0.5 ) 20205).
Synthesis of N—((1-acetylpyrrolidinyl) methyl)oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepinecarb0xamide (1615): To a stirred solution of compound 1608 (100 mg, 0.28 mmol) in CH2C12 (5 mL) under argon atmosphere were added triethylamine (0.12 mL, 0.84 mmol), acetyl chloride (0.02 mL, 0.33 mmol) at 0 0C; warmed to RT, stirred for 12 h. The reaction was monitored by TLC; after completion the reaction, the reaction the volatiles were removed in vacuo; the residue was basifled with saturated NaHC03 solution and extracted with CH2C12 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford 1615 (30 mg, 26%) as an off-white solid.
TLC: 10% MeOH/ CH2C12 (Rf: 0.6); 1H NMR (DMSO-dg, 400 MHz): 5 10.71 (m, 1H), 8.69 - 8.58 (m, 1H), 7.72-7.63 (m, 3H), 7.61-7.41 (m, 4H), 3.55-3.34 (m, 3H), 3.29-3.19 (m, 2H), 3.17- 3.13 (m, 0.5H), 3.00 (dd, J: 11.8, 7.3 Hz, 0.5H), .34 (m, 1H), 2.02-1.84 (m, 4H), 1.73- 1.49 (m, 1H); LC-MS: 95.89%; 396.0 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 1.87 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.29%; (column; Eclipse XDB C-18 (150 x 4.6 mm, 5.0 um); RT 7.05 min. ACN: 5 mM Aq. ; 1.0 mL/min).
Exam le 33: S nthesis of Com ound 1654 d13* T mom DIPEA DMF —’d:DAufiNH.TFA 1654 Synthesis of tert-butyl 3-((11-0x0-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine—8- [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson carboxamido) methyl) azetidine-l-carboxylate (461): To a stirred solution of compound 6 (600 mg, 2.21 mmol) in DMF (5 mL) under argon atmosphere were added EDCI.HCl (634 mg, 3.32 mmol), HOBt (435 mg, 3.32 mmol), tert—butyl nomethyl) azetidine-l-carboxylate 460 (453 mg, 2.43 mmol) and diisopropyl ethyl amine (1.14 mL, 6.64 mol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 461 (600 mg, 61%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.6); 1H NMR dg, 400 MHz): 5 10.76 (s, 1H), 8.64 (t, J: 5.6 Hz, 1H), 7.71-7.64 (m, 3H), 7.59-7.43 (m, 4H), 3.84 (t, J: 7.0 Hz, 2H), 3.66-3.50 (m, 2H), 3.41 (t, J: 6.3 Hz, 2H), 2.72-2.64 (m, 1H), 1.33 (s, 9H).
Synthesis of -N—((1-(2, 2, 2-triflu0r0acetyl)—114-azetidinyl) methyl)-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—S-carboxamide (1654): To a stirred on of 461 (350 mg, 0.79 mmol) in CH2C12 (10 mL) under argon atmosphere were added 20 (0.18 mL, 1.59 mmol), molecular sieves (20 mg) at 0 0C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2C12 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.
The crude was purified using preparative HPLC purification to afford nd 1654 (20 mg, 7%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.6); 1H NMR (DMSO-dg, 400 MHz): 8 10.79 (s, 1H), 8.70 (t, J: 5.6 Hz, 1H), 8.62-8.39 (m, 1H), 7.73-7.66 (m, 3H), 7.59 (dd, J: 8.1, 1.7 Hz, 1H), .43 (m, 3H), 3.99-3.88 (m, 2H), .69 (m, 2H), 3.45 (t, J: 6.1 Hz, 2H), 3.04-2.94 (m, 1H); LC-MS: ; 339.9 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 1.70 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq.
TFA, 1.2 mL/min); HPLC (purity): 98.60%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 um); RT 6.54 min. ACN : 0.05% TFA (Aq); 1.0 mL/min).
[Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 34: S nthesis of Com ounds 1601 and 1609 4N HCI in 1, 4-Dioxane H —> EDCI HOBt CHZCI2 DPEA DMF Et3N CHZCIZ NH.HCI 1609 Synthesis of tert-butyl 4-((11-0X0-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine carboxamido) methyl) piperidine-l-carboxylate (463): Using Procedure A the title compound was prepared with nd 6 (200 mg, 0.73 mmol), tert—butyl 4-(aminomethyl) piperidine-l- carboxylate 462 (0.17 mL, 0.81 mmol) and was ed in 86% yield as pale brown solid; TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-ds, 400 MHz): 8 10.75 (br s, 1H), 8.52 (t, J: 5.6 Hz, 1H), 7.72-7.61 (m, 3H), 7.60-7.42 (m, 4H), .88 (m, 2H), 3.12 (t, J: 6.0 Hz, 2H), 2.71-2.59 (m, 2H), 1.74-1.57 (m, 3H), 1.38 (s, 9H), 1.06-0.92 (m, 2H) Synthesis of 11-0x0-N—(piperidinylmethyl)-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide hydrochloride (1609): To a stirred solution of compound 463 (300 mg, 0.64 mmol) in CH2C12 (5 rnL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (1 rnL) at 0 0C; warmed to RT and stirred for 5 h. The reaction was red by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 1609 (200 mg, 85%; HCl salt) as pale brown solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR (DMSO- dg, 400 MHz): 5 10.77 (s, 1H), 8.67-8.58 (m, 2H), 8.32 (br s, 1H), 7.71 -7.64 (m, 3H), 7.61-7.43 (m, 4H), 3.27-3.20 (m, 2H), 3.18-3.12 (m, 2H), .76 (m, 2H), 1.82-1.72 (m, 3H), .23 (rn, 2H); LC-MS: 98.23%; 368.0 (M++1) (-HCl); (column; is Express C18, (50 X 3.0 mm, 2.7 urn); RT 1.67 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 97.67%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 u); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson RT 1.59 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
] Synthesis 0fN—((1-acetylpiperidinyl) methyl)—11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide (1601): To a stirred solution of compound 1609 (100 mg, 0.24 mmol) in CH2C12 (5 mL) under argon atmosphere were added triethylamine (0.1 mL, 0.74 mmol), acetyl chloride (0.02 mL, 0.29 mmol) at 0 0C; warmed to RT, stirred for 12 h. The reaction was monitored by TLC; after completion the on, the reaction the volatiles were removed in vacuo; the e was basifled with ted NaHC03 solution and ted with CH2C12 (2 x 15 mL). The combined organic ts were dried over sodium sulfate, d and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1% MeOH/ CH2C12 to afford 1601 (20 mg, 20%) as an off-white solid.
TLC: 10% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 8 10.75 (s, 1H), 8.53 (t, J: 5.5 Hz, 1H), 7.71-7.63 (m, 3H), 7.61-7.43 (m, 4H), 4.36-4.29 (m, 1H), 3.81-3.73 (m, 1H), 3.19-3.06 (m, 2H), 3.00-2.91 (m, 1H), 2.53-2.46 (m, 1H), 1.96 (s, 3H), 1.82-1.58 (m, 3H), 1.14- 0.89 (m, 2H); LC-MS: 99.33%; 410.0 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 1.99 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 99.57%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.79 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
Exam le 35: S nthesis of Com ounds 1357 1655 and 1367 O O NH CH2N2 NH D'BAL c02H —> COZMe MeOH/ CH2C|2 S S 474 474-A NH '42pr Dom NaCNBH3 AcOH 3 MeOH OSUN/\/© 475 1357 (CH3CO)20 . . N pyrldlne, CH2C|2 8 /\/© [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of methyl 11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine carboxylate (474): To a stirred solution of compound 6 (500 mg, 1.84 mmol) in MeOH: CH2C12 (1: 1, 20 mL) under argon atmosphere was added CH2N2 u prepared using N—nitrosomethyl urea (0.95 g, 9.2 mmol) + KOH (0.51 g, 9.22 mmol) ) at 0 0C; warmed to RT and stirred for 1 h.
The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 474 (450 mg, 86%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (DMSO-dg, 500 MHz): 8 10.82 (s, 1H), 7.82 (s, 1H), 7.75-7.69 (m, 3H), 7.58-7.63 (m, 3H), 3.82 (s, 3H).
Synthesis of 8-(hydr0xymethyl) dibenzo [b,f] [1, 4] thiazepin-11(10Ifl-0ne (474- A): To a stirred solution of compound 474 (500 mg, 1.75 mmol) in dry THF (3 mL) under argon atmosphere was added diisobutylaluminium hydride (1 M sol. in Toluene, 5 mL, 5.26 mmol) dropwise for 5 min at -25 0C; warmed to RT and stirred for 3 h. The reaction was red by TLC; after completion of the reaction, the reaction mixture was cooled to 0 0C, quenched with saturated sodium potassium tartrate solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined c extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude, which was titurated with MeOH: diethyl ether (1: 4, 5 mL) to afford 474-A (300 mg, 66%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-d6, 400 MHz): 5 10.66 (s, 1H), 7.67 (dd, J: 7.5, 1.6 Hz, 1H), 7.55-7.38 (m, 4H), 7.19 (s, 1H), 7.07 (dd, J: 7.9, 1.7 Hz, 1H), 5.26 (t, J: 5.7 Hz, 1H), 4.44 (d, J: 5.6 Hz, 2H); LC-MS: 97.26%; 257.8 ; (column; Ascentis s C18, (50 X 3.0 mm, 2.7 urn); RT 1.94 min. 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 ); UPLC (purity): 96.65%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.80 min. ACN: 0.025% TFA (Aq); 0.5 mL/min) .
Synthesis of 11-0x0-10, 11-dihydr0dibenzo [b,f] [1, 4] thiazepinecarbaldehyde (475): To a stirred solution of compound 474-A (60 mg, 0.23 mmol) in CH2C12 (5 mL) under argon atmosphere was added artin periodinane (300 mg, 0.70 mmol) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2C12 (50 mL) and washed with saturated hypo on (20 mL). The organic t was dried over sodium sulfate, filtered and concentrated in vacuo to [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson obtain the crude. The crude was purified using silicagel column chromatography using 30% EtOAc/ hexanes to afford compound 475 (41 mg, 68%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.8); 1H NMR (DMSO-ds, 400 MHz): 8 10.89 (s, 1H), 9.96 (s, 1H), 7.81 (d, J: 7.6 Hz, 1H), .66 (m, 3H), 7.59-7.45 (m, 3H).
Synthesis of 8-((phenethylamin0) methyl) dibenzo [b,f] [1, 4] thiazepin-l 1(10110— one : To a stirred solution of compound 475 (100 mg, 0.39 mmol) in MeOH (4 mL) under argon here were added 2-phenylethanamine 211 (57 mg, 0.47 mmol) and acetic acid (1 mL) at RT and stirred for 1 h. To this was added sodium cyanoborohydride (72 mg, 1.16 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was d with water with EtOAc (100 mL), washed with saturated sodium bicarbonate solution (20 mL) and water (20 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified using silicagel column tography using 2% MeOH/ CH2C12 to afford compound 1357 (25 mg, 18%) as an off-white solid. TLC: 100% EtOAc (Rf: 0.3); 1H NMR ds, 400 MHz): 5 10.65 (s, 1H), 7.67 (dd, J: 7.4, 1.6 Hz, 1H), 7.54-7.39 (m, 4H), 7.28-7.23 (m, 2H), 7.21-7.14 (m, 4H), 7.10 (d, J: 7.2 Hz, 1H), 3.70 (br s, 2H), 2.72 (br s, 4H); LC-MS: 95.70%; 361.0 (M++1); (column; X-select CSH C18, (50 X 3.0 mm, 3.5 um); RT 2.65 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 95.01%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.87 min. ACN: 0.025% TFA (Aq); 0.5 mL/min) .
Synthesis 0fN-((11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepin-S-yl) methyl)-N-phenethyl acetamide (1367): To a d solution of compound 1357 (40 mg, 0.11 mmol) in CH2C12 (2 mL) under argon atmosphere were added pyridine (0.013 mL, 0.16 mmol), acetic anhydride (0.011 mL, 0.12 mmol) at 0-5 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion the reaction, the reaction mixture was diluted with CH2C12 (20 mL) washed with 1 N HCl (5 mL) and brine (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% EtOAc/ hexanes to afford 1367 (25 mg, 57%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.8); 1H NMR (DMSO-dg, 500 MHz): 5 10.62-10.60 (m, 1H), 7.67-7.64 (m, 1H), 7.57-7.38 (m, 4H), 7.29-6.94 (m, 7H), 4.45 (d, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson J: 9.8 Hz, 2H), 3.41-3.35 (m, 2H), 2.82-2.66 (m, 2H), 1.97-1.87 (m, 3H); LC-MS: 92.67%; 403.5 (M++1); n; X-select CSH C18, (50 X 3.0 mm, 3.5 um); RT 4.37 min. 5 mM Aq.NH4OAc: ACN; 0.8 mL/min); UPLC (purity): 93.63%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.41 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
Exam le 36: S nthesis of Com ound 1501 NH PMB—CI TEBAC OjD/\OHCH20|2PPh3 CBr4 OH 50% aq.NaOH S THF 1655 o @780" TFA ? NH SUOQ 1501 Synthesis of 8-(hydr0xymethyl)—10-(4-methoxybenzyl) dibenzo [b,f] [1, 4] thiazepin-11(10H)-0ne (476): To a stirred solution of 1655 (1 g, 3.89 mmol) in THF (50 mL) were added Benzyltriethylammonium chloride (88 mg, 0.38 mmol), 50% aqueous sodium hydroxide solution (4 mL) at 0-5 0C and stirred for 20 min. To this was added 4-methoxybenzy chloride (0.52 mL, 3.89 mol) at 0-5 0C and heated to reflux for 16 h. The reaction was red by TLC; after completion of the reaction, the on mixture was diluted with ice water (40 mL) and ted with EtOAc (2 x 100 mL). The combined organic ts was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified using silicagel column chromatography using 2% MeOH/ CH2C12 to afford compound 476 (800 mg, 57%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.6); 1H NMR (DMSO-ds, 500 MHz): 8 7.64-7.59 (m, 1H), 7.53 (s, 1H), 7.51-7.44 (m, 2H), 7.41-7.35 (m, 2H), 7.22 (d, J: 8.7 Hz, 2H), 7.06 (d, J: 7.8 Hz, 1H), 6.81 (d, J: 8.7 Hz, 2H), 5.67 (d, J: 15.3 Hz, 1H), 5.21 ( [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson ation] Sarah.Wilkinson ed set by Sarah.Wilkinson br s, 1H), 4.85 (d, .1: 15.3 Hz, 1H), 4.41 (s, 2H), 3.68 (s, 3H). sis of 8-(br0m0methyl)—10-(4-methoxybenzyl) dibenzo [b,f] [1, 4] thiazepin-11(10H)-0ne (477): To a stirred solution of compound 476 (800 mg, 2.12 mmol) in CH2C12 (20 mL) under argon atmosphere were added triphenyl phosphine (1.1 g, 4.24 mmol), CBr4 (0.3 mL, 3.18 mmol) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 477 (600 mg, 66%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.8); 1H NMR (DMSO-dg, 500 MHz): 5 7.73 (s, 1H), 7.63 (dd, J: 7.1, 1.9 Hz, 1H), 7.53-7.44 (m, 2H), 7.43-7.36 (m, 2H), 7.22-7.15 (m, 3H), 6.79 (d, J: 8.7 Hz, 2H), 5.77-5.71 (m, 1H), 4.80 (d, J: 15.0 Hz, 1H), 4.60 (s, 2H), 3.67 (s, 3H).
Synthesis of 10-(4-meth0xybenzyl)(phenethoxymethyl)dibenzo [b,f] [1, 4] thiazepin-11(10H)-0ne (479): To a stirred solution of 2-phenylethanol 477 (100 mg, 0.81 mmol) in THF (10 mL) inert atmosphere was added was added sodium hydride (60%, 49 mg, 2.5 mmol) under portion wise for 5 min at 0 0C; warmed to RT and stirred for 2 h. To this was added compound 478 (359 mg, 0.81 mol) at RT; heated to 65 0C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 50 mL). The ed organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 479 (150 mg) as yellow solid. TLC: 70% EtOAc/ s (Rf: 0.5); LC-MS: 58.75%; 482.0 ; (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 3.25 min. 0.025% Aq. TFA -- 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of 8-(pheneth0xymethyl) dibenzo [b,f] [1, 4] thiazepin-11(10H)-0ne : A mixture of compound 479 (140 mg, crude) and trifiuoro acetic acid (2 mL) under inert atmosphere at RT was heated to 80 0C and stirred for 6 h in a sealed tube. The reaction was monitored by TLC; after completion of the on, the volatiles were removed in vacuo, the residue was quenched with 20% aqueous sodium bicarbonate solution (10 mL) and ted with EtOAc (2 x 20 mL). The combined organic extracts was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified using silicagel column [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson tography using 70% EtOAc/ hexanes to afford compound 1501 (35 mg, 33%) as white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 8 10.65 (s, 1H), 7.67 (dd, J: 7.5, 1.6 Hz, 1H), 7.54-7.40 (m, 4H), 7.29-7.13 (m, 6H), 7.04 (dd, J: 7.9, 1.7 Hz, 1H), 4.44 (s, 2H), 3.63 (t, J: 6.9 Hz, 2H), 2.84 (t, J: 6.9 Hz, 2H); LC-MS: 96.49%; 361.9 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.79 min. 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.59%; n; Eclipse XDB-C-l8 (150 x 4.6 mm, 5.0 um); RT 10.25 min. ACN: 0.025% TFA (Aq); 1.0 mL/min) .
Exam le 37: S nthesis of 10-meth l0x0-10 11-dih drodibenzo b 1 4 thiaze ine—8- carbox lic acid 486 - a common intermediate To a stirred solution of compound 6 (500 mg, 1.84 mmol) in DMF (10 mL) was added sodium hydride (60%, 442 mg, 18.45 mmol) under inert atmosphere at 0 0C and stirred for l h. To this was methyl iodide (1.14 mL, 18.45 mmol) at 0-5 0C, warmed to RT and stirred for 1.5 h. The reaction was monitored by TLC; after tion of the reaction, the on mixture was d with water (20 mL) and washed with EtOAc (2 x 20 mL). The aqueous layer was separated and the pH was adjusted to ~2 with 4 N HCl. The precipitated solid was filtered, washed with n-hexane (10 mL) and dried in vacuo to obtain the compound 486 (400 mg, 76%) a white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR dg, 500 MHz): 8 13.31 (br s, 1H), 7.99 (s, 1H), 7.75-7.68 (m, 2H), 7.65-7.61 (m, 1H), 7.54-7.49 (m, 1H), 7.44-7.39 (m, 2H), 3.53 (s, 3H).
Exam le 38: S nthesis of com ounds from com ound 486 and s commercial] available amines Compound 486 was converted to final products using commercially available amines or by employing Procedure A and the results are captured in the Table 2: [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Table 2: Synthesis of compounds from compound 486 and various commercially available amines H-NMR (DMSO'dg, 400 MHZ): 5 9.27 (t, J= 5.7 Hz, 1H), 8.96 (s, 1H), 7.96 (s, 1H), 381.06 for 7.82 (S, 1H), A, 486, 213 ' 7.74-7.70 (m, 1H), 7.68-7.61 (m, 2H), 7.54— 7.49 (m, 1H), 7.45-7.38 (m, 2H), 4.67 (t, J= .4 Hz, 2H), 3.54 (s, 3H); 1H—NMR dg, 400 MHZ): 5 9.16 (t, J= 5.7 Hz, 1H), 8.54 (s, 1H), 8.45 (dd, J= 4.6, 1.3 Hz, 375.10 for 1H), 7.98 (S, A, 486, 218 C21H17N302 1H), .61 s (m, 4H), 7.55— 7.49 (m, 1H), 7.46—7.38 (m, 2H), 7.33 (dd, J = 7.3, 4.8 Hz, 1H), 4.55—4.41 (m, 2H), 3.55 (s, 3H); 376.10 for O lH-NMR N 0 376.9 N402 (DMSO-d69 400 1574 @WH \N A, 486,212 36 I (M++1), s MHZ).59.19(L ’J J=5.7 Hz, 1H), 9.08 (s, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson 8.76 (s, 2H), 7.98 (s, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.68- 7.60 (m, 2H), 7.55-7.49 (m, 1H), .38 (m, 2H), 4.57 - 4.39 (m, 2H), 3.55 (s, 3H); 1H NMR (400 MHz, DMSO- d6) 5 9.25 (s, 1H), 8.63 (t, J= .6 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.73 4 405.1273 7.56 (m, 3H), 405.127 for 7.55 4 7.47 (m, 1133 D, 486 70 2 C23H21N203 1H), 7.47 4 7.36 S (m, 2H), 7.05 (t, J = 7.7 Hz, 1H), 6.60 (td, J = 9.2, 7.1 Hz, 3H), 3.53 (s, 3H), 3.46 4 3.38 (m, 2H), 2.71 (t, J= 7.4 Hz, 2H).
[Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 39: S nthesis of Com ounds 1342 and 1361 BocHN 0 o —’0506 50/ my C 4N HCI in 1,4-Dioxane N \ \ OMe 0—» N \ OMe —> KO'Bu,CHZCI2 l / NHBOC MeOH { , NHBOC CH2CI2 N N OMe @259: NH2_HC| HATU DIPEA RCKHIH OMeN \Nx) 1342 Synthesis of methyl (Z)((tert-butoxycarbonyl) —3-(pyrimidinyl) acrylate (507): To a stirred solution of methyl 2-((tert—butoxycarbony1) (dirnethoxyphosphoryl) acetate 506 (3.3 g, 11.11 mmol) in CH2C12 (15 mL) under inert atmosphere was added potassium t—butoxide (13.8 mL, 13.88 mmol, 1M solution in THF), portion wise for 15 min at -30 0C. To this was added dinecarba1dehyde 505 (1 g, 9.25 mmol) in CH2C12 (5 mL) drop wise for 10 min at -30 0C, d for 2 h; warmed to 0 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2C12 (2 x 100 mL). The combined c extracts were washed with water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 507 (1.8 g, 72%) as an off- white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.8); 1H NMR (500MHz, DMSO-dg): 8 9.11 (s, 1H), 9.02 (brs, 1H), 8.98 (s, 2H), 6.46 (s, 1H), 3.76 (s, 3H), 1.42-1.38 (m, 9H).
Synthesis of methyl 2-((tert-butoxycarbonyl) amino)—3-(pyrimidinyl) propanoate (508): To a d solution of compound 507 (1.8 g, 6.45 mmol) in MeOH (25 mL) under inert atmosphere was added 5% Pd/C (500 mg) at RT and stirred under hydrogen [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson atmosphere (at 100 psi) for 16 h in a steel bomb. The reaction was red by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 10% MeOH/ CH2C12 (2 x 50 mL). The filtrate was concentrated in vacuo to obtain the crude compound 508 (1.3 g, 72%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR dg, 500 MHz): 5 9.03 (s, 1H), 8.68 (s, 2H), 7.40 (d, J: 7.8 Hz, 1H), .25 (m, 1H), 3.65 (s, 3H), 3.09 (dd, J: 14.4, 4.4 Hz, 1H), 2.89-2.81 (m, 1H), 1.33-1.22 (m, 9H). 9] Synthesis of methyl 2-amino(pyrimidinyl) propanoate hydrochloride (509): To a stirred solution of compound 508 (1.3 g, 4.62 mmol) in CH2C12 (5 mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (5 mL) at 0 0C; warmed to RT and stirred for 3.5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 509 (850 mg) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO-dg, 400 MHz): 8 9.15-9.08 (m, 1H), 8.75 (s, 4H), 4.45-4.44 (m, 1H), 3.73 (s, 3H), 3.22 (dd, J: 6.6, 2.4 Hz, 2H). 0] Synthesis of methyl 2-(2-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamid0)—3-(pyrimidinyl) propanoate (1342): Using Procedure B the title compound was prepared with compound 35 (200 mg, 0.69 mmol), compound 509 (165 mg, 0.76 mmol) and was obtained in 67% yield as an off-white solid; TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 500 MHz): 5 10.89 (s, 1H), 8.99 (t, J: 4.0 Hz, 2H), 8.69 (s, 2H), 7.66 (d, J: 8.1 Hz, 1H), 7.61-7.56 (m, 2H), 7.52 (dd, J: 8.1, 1.4 Hz, 1H), 7.46 (dd, J: 9.1, 2.7 Hz, 1H), 7.36 (td, J: 8.4, 2.9 Hz, 1H), 4.81-4.70 (m, 1H), 3.64 (s, 3H), 3.22 (dd, J: 14.2, 4.9 Hz, 1H), 3.05 (dd, J: 14.0, 10.6 Hz, 1H); LC-MS: 98.59%; 453.4 (M++1); n; X-select CSH C18, (50 X 3.0 mm, 3.5 um); RT 3.45 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC y): 99.40%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.89 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
Synthesis of 2-flu0r0-N—(1-hydr0xy(pyrimidinyl) propan-Z-yl)—11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide (1361): To a stirred solution of 1342 (200 mg, 0.44 mmol) in MeOH (5 mL) under inert atmosphere was added sodium borohydride (65 mg, 1.76 mmol) at 0 0C; warmed to RT and d for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (25 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mL) and extracted with 5% MeOH/ CH2C12 (5 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and trated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8% MeOH/ CH2C12 to afford compound 1361 (140 mg, 75%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.4); 1H NMR (DMSO-d6, 400 MHz): 5 10.87 (s, 1H), 8.96 (s, 1H), 8.64 (s, 2H), 8.30 (d, J: 8.7 Hz, 1H), 7.66-7.63 (m, 1H), .57 (m, 2H), 7.53 (dd, J: 8.1, 1.8 Hz, 1H), 7.47 (dd, J: 9.2, 2.9 Hz, 1H), 7.37 (td, J: 8.5, 3.0 Hz, 1H), 4.93 (t, J: 5.6 Hz, 1H), .11 (m, 1H), 3.53-3.40 (m, 2H), 2.98 (dd,.]= 13.9, 4.2 Hz, 1H), 2.73 (dd,.]= 14.0, 10.1 Hz, 1H); LC-MS: 99.82%; 425.4 (M++1); n; X-select CSH C18, (50 X 3.0 mm, 3.5 um); RT 3.68 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 99.77%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.65 min. ACN: 0.025% TFA (Aq.); 0.5 mL/min).
Exam le 40: S s of Com ound 1346 LiOH H20 (Boo)20 DMAP THF: H20 GfNOO \Nx) tBuOH Synthesis of 2-(2-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine-S- carboxamido)—3-(pyrimidinyl) propanoic acid (510): To a stirred solution of compound 1342 (150 mg, 0.33 mmol) in a mixture of THF: H20 (4: 1, 5 mL) was added lithium hydroxide monohydrate (35 mg, 0.82 mmol) at RT and d for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (3 mL) and the pH was adjusted to ~5 with 1 N HCl. The precipitated solid was filtered and dried in vacuo to afford compound 510 (75 mg, 52%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H NMR (DMSO d6, 400 MHz): 5 10.90 (s, 1H), 8.98 (s, 1H), 8.78 (d, J: 7.6 Hz, 1H), 8.68 (s, 2H), 7.66 (d, J: 8.0 Hz, 1H), 7.62-7.57 (m, 2H), 7.53 (dd, J: 8.1, 1.7 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Wilkinson Hz, 1H), 7.47 (dd, .1: 9.2, 2.9 Hz, 1H), 7.37 (dt, .1: 8.5, 2.9 Hz, 1H), 7.40—7.34 (m, 1H), 4.69- 4.58 (m, 1H), 3.23 (dd, .1: 14.1, 4.6 Hz, 1H), 3.03 (dd, .1: 14.0, 10.3 Hz, 1H).
Synthesis of tert-butyl 2-(2-flu0r00x0-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-S-carb0xamid0)—3-(pyrimidinyl) propanoate (1346): To a stirred solution of compound 510 (70 mg, 0.15 mmol) in t—butanol (4 mL) under inert atmosphere were added Boc- anhydride (0.11 mL, 0.47 mmol) and DMAP (30 mg, 0.03 mol) at 5 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with CH2C12 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through ative TLC (50% EtOAc/ s) to afford 1346 (25 mg, 32%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.4); 1H NMR (DMSO-dg, 400 MHz): 5 10.91 (s, 1H), 9.01 (s, 1H), 8.89 (d, J: 7.8 Hz, 1H), 8.71 (s, 2H), 7.67 (d, J: 8.0 Hz, 1H), 7.64-7.58 (m, 2H), 7.55 (dd, J: 8.0, 1.9 Hz, 1H), 7.48 (dd, J: 9.2, 2.9 Hz, 1H), 7.38 (td, J: 8.5, 2.9 Hz, 1H), 4.65-4.59 (m, 1H), 3.21-3.13 (m, 1H), .99 (m, 1H), 1.39-1.31 (m, 9H); LC-MS: 98.60%; 495.6 (M++1); (column; X-select CSH C18, (50 X 3.0 mm, 3.5 um); RT 3.91 min. 0.05% Aq. TFA: CAN; 0.8 mL/min); UPLC (purity): 98.29%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.15 min. CAN: 0.025% TFA (Aq); 0.5 mL/min).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 41: S nthesis of Com ounds 1420 and 1419 \0kg O 3)4,Na2C03 O + OH OZN ?/ —>Toulene/ H20 Br OH 511 382 0 F-DBT Acid F\do;ib/ENO 0 CI HOBt MeOH: H20 \ DIPEA DMF O 0002"" 513 1420 cibigh Synthesis of methyl 3'-nitr0-[1, 1'-biphenyl]carb0xylate (512): To a stirred solution of methyl 4-bromobenzoate 511 (2.5 g, 14.97 mmol) and (3-nitropheny1) boronic acid 382 (3.8 g, 17.96 mmol) in e (20 mL) under inert atmosphere were added sodium carbonate (3.17 g, 29.96 mmol in 25 mL of H20) at RT and purged under argon here for min. To this was added 3)4 (691 mg, 0.59 mmol) and heated to 80 0C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 512 (800 mg, 21%) as yellow liquid. TLC: 15% EtOAc/ hexanes (Rf: 0.5); 1H NMR (400 MHz, : 8 8.54-8.52 (m, 1H), 8.29-8.26 (m, 1H), 8.15 (d, J: 8.7 Hz, 2H), 8.12-8.09 (m, 1H), 7.84 (d, J: 8.6 Hz, 2H), 7.74 (t, J: 8.0 Hz, 1H), 3.94 (s, 3H).
Synthesis of methyl 3'-amin0-[1, 1'-biphenyl]carb0xylate (513): To a stirred solution of compound 512 (800 mg, 3.11 mmol) in EtOH (50 mL) under inert atmosphere was ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson added 10% Pd/C (500 mg, wet) under argon atmosphere and stirred under H2 atmosphere (balloon pressure) for 5 h. After completion of the on, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2C12 (150 mL). The filtrate was concentrated in vacuo to obtain the crude which was purified through silicagel column chromatography in 5% MeOH/ CH2C12 to afford compound 513 (600 mg, 67%) as an off-white solid. The crude was carried for next step without further purification. TLC: 5% MeOH/ CH2C12 (Rf: 0.4).
Synthesis of methyl flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] pinecarboxamido)—[1, 1'-biphenyl]carb0xylate (1420): Using Procedure A the title compound was prepared with 35 (50 mg, 0.17 mmol), compound 513 (43 mg, 0.19 mmol) and was obtained in 58% yield as white solid; TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 400 MHz): 5 10.99 (s, 1H), 10.43 (s, 1H), 8.14 (s, 1H), 8.07 (d, J: 7.9 Hz, 2H), 7.85-7.72 (m, 6H), 7.63 (dd, J: 8.6, 5.3 Hz, 1H), 7.54-7.45 (m, 3H), 7.40 (td, J: 8.5, 3.0 Hz, 1H), 3.88 (s, 3H); LC-MS: 98.86%; 498.1 (M++1); (column; X-select CSH C18, (50 X 3.0 mm, 3.5 um); RT 4.15 min. 0.05% Aq. TFA: ACN; 0.8 ); UPLC (purity): 95.09%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.75 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Synthesis of 3'-(2-flu0r00x0-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-S- carboxamido)—[1, 1'-biphenyl]carb0xylic acid (1419): To a stirred solution of 1420 (50 mg, 0.10 mmol) in MeOH: H20 (3:1, 8 mL) was added potassium hydroxide (56 mg, 1.00 mmol) at RT in a sealed tube and heated to 90 0C and d for 5 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was acidified with 4 N HCl to pH ~2. The obtained solid was filtered, ated with 10% EtOAc/ hexanes (10 mL) and dried in vacuo and to afford compound 1419 (20 mg, 41%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.2); 1H NMR (400 MHz, DMSO-dg): 5 12.98 (br s, 1H), 11.00 (s, 1H), 10.51 (s, 1H), 8.15 (s, 1H), 8.04 (d, J: 8.4 Hz, 2H), 7.87-7.70 (m, 6H), 7.63 (dd, J: 8.6, 5.3 Hz, 1H), 7.54-7.46 (m, 3H), 7.40 (td, J: 8.5,2.9 Hz, 1H); LC-MS: 91.15%; 485.0 (M++1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.48 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 93.75%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.43 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 42: S s of Com ounds 1422 and 1421 Pd(PPh3)4, NaZCO3 Toubne/HZO 0/, EDCI.HC|,HOBt, F::OH:: MeOH: H20 DPEA, DMF 516 1422 aimMg 1421 Synthesis of methyl 3'-nitr0-[1, 1'-biphenyl]carb0xylate (515): To a stirred solution of methyl 3-bromobenzoate 514 (2.5 g, 14.99 mmol) and (3-nitropheny1) boronic acid 382 (3.8 g, 17.99 mmol) in toluene (20 mL) under inert atmosphere were added sodium carbonate (3.17 g, 29.99 mmol in 20 mL of H20) at RT and purged under argon atmosphere for min. To this was added Pd(PPh3)4 (693 mg, 0.59 mmol) and heated to 80 0C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was d h silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 515 (1 g, 26%) as yellow liquid. TLC: 15% EtOAc/ hexanes (Rf: 0.5); 1H NMR (400 MHz, g): 8 8.48-8.46 (m, 1H), 8.30-8.25 (m, 2H), 8.22-8.18 (m, 1H), 8.11-8.07 (m, 1H), 8.04 (dt, J: 7.8, 1.3 Hz, 1H), 7.80 (t, J: 8.0 Hz, 1H), 7.69 (t, J: 7.8 Hz, 1H), 3.91 (s, 3H).
Synthesis of methyl n0-[1, 1'-biphenyl]carb0xylate (516): To a stirred solution of compound 515 (1 g, 3.89 mmol) in EtOH (100 mL) under inert atmosphere was added 10% Pd/C (600 mg, wet) under argon atmosphere and stirred under H2 atmosphere [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson (balloon pressure) for 16 h. After completion of the reaction, the reaction e was filtered through celite and the celite pad was washed with 50% MeOH/ CH2C12 (150 mL). The filtrate was evaporated in vacuo to obtain the crude which was purified through silicagel column chromatography in 20% EtOAc/ hexanes to afford compound 516 (600 mg, 67%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf: 0.3); 1H NMR (400 MHz, DMSO-dg): 8 8.15- 8.08 (m, 1H), 7.92 (d, J: 7.7 Hz, 1H), 7.84 (d, J: 8.2 Hz, 1H), 7.59 (t, J: 7.7 Hz, 1H), 7.13 (t, J: 7.8 Hz, 1H), 6.90-6.87 (m, 1H), 6.81 (d, J: 7.6 Hz, 1H), 6.60 (dd, J: 8.0, 1.4 Hz, 1H), 5.22 (s, 2H), 3.32 (s, 3H).
Synthesis of methyl 3'-(2-flu0r00x0-10, ydr0dibenz0 [b,f] [1, 4] thiazepinecarboxamido)—[1, 1'-biphenyl]carb0xylate (1422): Using Procedure A the title nd was ed with compound 35 (70 mg, 0.24 mmol), compound 516 (55 mg, 0.24 mmol) and was ed in 41% yield as white solid; TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (400 MHz, DMSO-dg): 5 10.99 (s, 1H), 10.43 (s, 1H), 8.12-8.19 (m, 1H), 8.10-8.08 (m, 1H), 7.96 (dd, J: 12.8, 7.9 Hz, 2H), 7.85 (dt, .1: 7.1, 1.8 Hz, 1H), 7.81-7.73 (m, 3H), 7.69-7.59 (m, 2H), 7.54-7.45 (m, 3H), 7.40 (td, J: 8.5, 2.9 Hz, 1H), 3.90 (s, 3H); LC-MS: 99.82%; 499.0 (M+1)+; (column; X-select CSH C18, (50 X 3.0 mm, 3.5 um); RT 4.10 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 98.72%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.78 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Synthesis of 3'-(2-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine carboxamido)—[1, 1'-biphenyl]carb0xylic acid (1421): To a stirred solution of 1422 (35 mg, 0.07 mmol) in MeOH: H20 (3: 1, 5 mL) under inert atmosphere was added potassium hydroxide (40 mg, 0.70 mmol) at RT in a sealed tube and heated to 80 0C and stirred for 3 h. The reaction was red by TLC; after completion of the reaction, the pH of the reaction mixture was acidified with 4 N HCl to pH ~2 and extracted with EtOAc (2 x 10 mL). The combined organic ts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.
The obtained solid was filtered, dried in vacuo and triturated with 10% EtOAc/ hexanes (10 mL) to afford compound 1421 (20 mg, 58%) as white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.2); 1H NMR (400 MHz, DMSO-dg): 5 12.99 (br s, 1H), 10.98 (s, 1H), 10.43 (s, 1H), .19 (m, 1H), 8.11-8.09 (m, 1H), 7.96 (d, J: 7.7 Hz, 1H), 7.87 (dd, J: 19.5, 7.3 Hz, 2H), 7.82-7.73 (m, 3H), 7.66-7.58 (m, 2H), 7.54-7.44 (m, 3H), 7.40 (td, J: 8.5, 2.9 Hz, 1H); LC-MS: 99.07%; [Annotation] Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 484.9 (M++1); (column; X-select CSH C18, (50 X 3.0 mm, 3.5 um); RT 3.73 min. 0.05% Aq.
TFA: ACN; 0.8 mL/min); UPLC (purity): 96.90%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.46 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Exam le 43: S nthesis of Com ounds 1436 and 1435 / 0 3)4, N32C03 OH Toulene/H20 517 382 NH O F o KOH N O —’ NH2 —.’ S H EDCI.HCI, HOBt, MGOH- "20 DIPEA, DMF O 1436 1435 Synthesis of methyl 3'-nitr0-[1, 1'-biphenyl]carb0xylate (518): To a stirred solution of methyl 2-bromobenzoate 517 (2.5 g, 14.97 mmol) and (3-nitrophenyl) boronic acid 382 (3.8 g, 17.96 mmol) in toluene (20 mL) under inert here were added sodium carbonate (3.17 g, 29.94 mmol in 20 mL of H20) at RT and purged under argon atmosphere for min. To this was added Pd(PPh3)4 (691 mg, 0.59 mmol) and heated to 80 0C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified h silica gel column chromatography using 15% EtOAc/ hexanes to afford nd 518 (600 mg, 17%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.6); 1H NMR (400 MHz, DMSO-dg): 8 8.27-8.23 (m, 1H), 8.11-8.09 (m, 1H), 7.89 (dd, J: 7.7, 1.3 Hz, 1H), 7.79-7.67 (m, 3H), 7.59 (td, J: 7.6, 1.1 Hz, 1H), 7.52 (dd, J: 7.6, 0.6 Hz, 1H), 3.31 (s, 3H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Wilkinson Synthesis of methyl 3'-amin0-[1, 1'-biphenyl]carb0xylate (519): To a stirred solution of compound 518 (600 mg, 2.33 mmol) in EtOH (50 mL) under inert atmosphere was added 10% Pd/C (300 mg, wet) under argon atmosphere and stirred under H2 atmosphere (balloon pressure) for 16 h. After tion of the reaction, the reaction mixture was filtered through celite and the celite pad was washed with 50% MeOH/ CH2C12 (100 mL). The filtrate was evaporated in vacuo to afford compound 519 (500 mg, 87%) as an off-white solid. TLC: % EtOAc/ hexanes (Rf: 0.6); 1H NMR (400 MHz, DMSO-dg): 8 7.63 (dd, J = 7.7, 1.0 Hz, 1H), 7.56 (td, J: 9.0, 1.8 Hz, 1H), 7.43 (td, J: 7.6, 1.1Hz, 1H), 7.37 (dd, J: 7.7, 0.8 Hz, 1H), 7.03 (t, J: 7.7 Hz, 1H), 6.57-6.52 (m, 1H), 6.52-6.49 (m, 1H), 6.39 (d, J: 7.5 Hz, 1H), 5.14 (br s, 2H), 3.59 (s, 3H).
Synthesis of methyl 3'-(2-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarboxamido)—[1, 1'-biphenyl]carb0xylate (1436): Using Procedure A the title compound was prepared with compound 35 (100 mg, 0.34 mmol), compound 519 (78 mg, 0.34 mmol) and was obtained in 35% yield as white solid; TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (400 MHz, DMSO-dg): 5 10.97 (s, 1H), 10.37 (s, 1H), 7.78-7.72 (m, 6H), .60 (m, 2H), 7.54-7.48 (m, 2H), 7.46-7.36 (m, 3H), 7.04 (d, J: 7.3 Hz, 1H), 3.61 (s, 3H); LC-MS: 93.05%; 499.0 (M"+1); (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 urn); RT 2.74 min. 0.025% Aq. TFA -- 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 91.54%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.72 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Synthesis of 3'-(2-flu0r00x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine carboxamido)—[1, 1'-biphenyl]carb0xylic acid (1435): To a stirred solution of 1436 (35 mg, 0.07 mmol) in MeOH: H20 (3:1, 8 mL) was added potassium hydroxide (40 mg, 0.70 mmol) at RT in a sealed tube and heated to 80 0C and stirred for 3 h. The on was monitored by TLC; after completion of the reaction, the pH of the on mixture was acidified with 4 N HC1 to pH ~2 and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The obtained solid was filtered, triturated with 10% EtOAc/ s (5 mL) and dried in vacuo to afford compound 1435 (20 mg, 58%) as white solid. TLC: 70% EtOAc/ hexanes (Rf: 0.2); 1H NMR (400 MHz, g): 5 11.00 (br s, 1H), 10.36 (s, 1H), 7.81-7.69 (m, 5H), 7.67-7.59 (m, 2H), 7.54-7.48 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (m, 2H), 7.44-7.31 (m, 4H), 7.07 (d, J: 7.8 Hz, 1H); LC-MS: 91.40%; 484.9 ; (column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.49 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 92.47%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.36 min. ACN : 0.025% TFA (Aq); 0.5 ).
Exam le 44: S nthesis of 11-0x0-10 11-dih drodibenzo b 1 4 thiaze ine sulfonamide compounds HCOONa Pd(OAc)2 TPP, O K28205 TEAB NH 1 ,1-0Phenanthroline, DMSO R--NH2, NBS, THF To a d solution of nd 491 (80 mg, 0.26 mmol) in DMSO (1.5 mL) under inert atmosphere were added ium metabisulfate (116 mg, 0.52 mmol), tetraethyl um bromide (60 mg, 0.28 mmol), sodium formate (40 mg, 0.57 mmol), palladium acetate (18 mg, 0.026 mmol) and 1, 10-phenanthroline (14 mg, 0.078 mmol) at RT in a microwave vial and purged under argon atmosphere for 10 min; heated to 90 0C for 4 h. The reaction was monitored by TLC; after completion of the reaction, the crude compound was carried forward to next step. TLC: 30% EtOAc/ hexanes (Rf: 0.4).
The above crude compound and commercially available amines were converted to corresponding sulfonamide employing the Procedure L and the results are captured in the Table Procedure L: To a stirred solution of above crude nd (100 mg, crude) in THF (2 mL) under argon atmosphere were added piperidine 521 (0.05 mL, 0.54 mmol) in THF (1 mL), N- bromosuccinimide (96 mg, 0.54 mmol) in THF (1 mL) at 0 0C; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson The crude was purified through silica gel column chromatography to afford the d compound.
Commercially available amines used for the preparation of compounds: Table 3: sis of compounds from compound 520 and various commercially available amines 1H NMR (DMSO-dg, 400 MHZ): 5 .86 (s, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.72 374.08 for (dd, J= 7.6, 1.4 C18H18NZO Hz, 1H), 7.59- 382 7.55 (m, 2H), 7.54—7.43 (m, 3H), 2.93-2.84 (m, 4H), 1.57- 1.48 (m, 4H), 1.42—1.31 (m, 2H); 1H NMR (DMSO-dg, 390.07 for 400 MHZ): 5 C18H18NZO .87 (s, 1H), 7.81 (d, J= 8.2 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Hz, 1H), 7.72 (dd, J= 7.4, 1.4 Hz, 1H), 7.60- 7.53 (m, 3H), 7.52—7.45 (m, 2H), 4.66 (d, J = 4.0 Hz, 1H), 3.53—3.49 (m, 1H), 3.19—3.12 (m, 2H), 2.76— 2.69 (m, 2H), 1.77-1.68 (m, 2H), .35 (m12H); HNMR (DMSO-dg, 400 MHZ): 5 .85 (s, 1H), 360.06 for 7.79 (d, J= 8.0 Hz, 1H), 7.74- C17H16NZO 7.70 (m, 1H), 382 7.63 (s, 1H), 7.60-7.45 (m, 4H), 3.16-3.11 (m, 4H), 1.75— 1.56 (m, 4H), HNMR (DMSO-dg, 400 MHZ): 5 .83 (s, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.74- 7.68 (m, 1H), 376.06 for 7.63 (s, 1H), C17H16NZO 7.59-7.45 (m, 452 4H), 4.86 (d, J = 3.4 Hz, 1H), 4.17—4.14 (m, 1H), 3.27—3.18 (m, 3H), 3.10— 2.93 (m, 1H), 1.81-1.69 (m, 1H),1.68-1.58 (m, 1H); 1H NMR (DMSO-dg, 362.04 for 400 MHZ): 5 .90 (s, 1H), C16H14NZO 7.86 (d, J= 8.2 Hz, 1H), 7.73 (dd, J= 7.5, 1.5 Hz, 1H), 7.64- ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 7.62 (m, 1H), 7.60-7.47 (m, 4H), 5.71 (d, J = 6.3 Hz, 1H), 4.30—4.22 (m, 1H), 3.89 (dd, J = 8.5, 6.8 Hz, 2H), 3.40—3.34 (m, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 .89 (s, 1H), 7.77 (d, J= 8.2 348.06 for Hz, 1H), 7.73- C16H16NzO 7.68 (m, 2H), 352 7.65-7.63 (m, 1H), .44 (m, 4H), 3.27- 3.16 (m, 1H), 0.94 (d, J= 6.5 Hz, 6H); 1H NMR (DMSO-dg, 400 MHZ): 5 .90 (s, 1H), .42 (s, 1H), 7.73 (d, J= 8.2 Hz, 1H), 7.68 382.04 for (dd, J= 6.9, 15.
C19H14N20 Hz, 1H), 7.65- 7.63 (m, 1H), 7.55-7.43 (m, 4H), 7.24-7.18 (m, 2H), 7.08- 7.04 (m, 2H), 7.01 (t, J= 7.7 Hz, 1H); H NMR (DMSO'dg, 400 MHZ): .90 (s, 1H), .37 (s, 1H), 400.04 for 7.74 (d, J= 8.3 C19H13FN2 Hz, 1H), 7.69 0352 (dd, J= 6.9, 1.5 Hz, 1H), 7.60- 7.56 (m, 1H), 7.55-7.45 (m, 3H), 7.43 (dd, J = 8.2, 2.0 Hz, 1H), 7.09-7.04 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson HNMR (DMSO'dg, 400 MHZ): 5 .83 (s, 1H), 8.28 (t, J= 6.3 Hz, 1H), 7.74 (dd, J= 6.8, 1.5 Hz, 1H), 7.69 396.06 for (d, J= 8.2 Hz, C20H16N20 1H), 7.59-7.49 352 (m, 4H), 7.47 (dd, J= 8.2, 2.0 Hz, 1H), 7.15- 7.10 (m, 2H), 7.06 (t, J= 7.4 Hz, 2H), 7.02- 6.96 (m, 1H), 3.99 (d, J= 6.3 Hz, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 .86 (s, 1H), 8.28 (t, J= 6.2 Hz, 1H), 7.76- 414.05 for 7.67 (m, 2H), C20H15FN2 7.63-7.60 (m, 03 S2 1H), 7.58-7.44 (m, 4H), 7.18 (dd, J= 8.6, 5.6 Hz, 2H), 6.92 (t, J= 8.9 Hz, 2H), 4.04—3.92 (m, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 .86 (s, 1H), 398.05 for 8.76 (s, 1H), 399.0 8.59 (s, 2H), 1473 L,212 19 (M++1) C18H14N4O 8.43 (br s, 1H), 352 7.78-7.70 (m, 2H), 7.60-7.54 (m, 3H), 7.54— 7.48 (m, 2H), 4.07 (s, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of 11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepinesulfonyl chloride (520): 8 —> Pd2(dba)3, Xantphos 052003, 1,4-dioxane Ar—NH2 pyridine, CH20|2 Synthesis of 8-(benzylthio) dibenzo [b,f] [1, 4] thiazepin-11(10H)-one (527): To a stirred on of compound 491 (1 g, 3.26 mmol) in 1, 4-dioxane (20 mL) under argon atmosphere were added phenylmethanethiol 526 (0.4 mL, 3.59 mmol), CS2C03 (921 mg, 3.92 mmol) at RT, purged under argon atmosphere for 20 min. To this were added Pd2(dba)3 (75 mg, 0.081 mmol), Xantphos (94 mg, 1.06 mmol) at RT and heated to 0 0C and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was filtered and the filtrate was removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-40% EtOAc/ hexanes to afford compound 527 (700 mg, 61%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.4); 1H NMR dg, 400 MHz): 5 10.63 (s, 1H), .65 (m, 1H), 7.53-7.41 (m, 4H), 7.39-7.34 (m, 2H), 7.32-7.20 (m, 3H), 7.17 (s, 1H), 7.10 (dd, J: 8.2, 2.1 Hz, 1H), 4.24 (s, 2H).
Synthesis of 11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] pinesulfonyl chloride (520): To a stirred solution of 527 (700 mg, 2.00 mmol) in acetic acid: H20 (3: 1, 16 mL) under was added rosuccinimide (668 mg, 5.61 mmol) at 0 0C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was diluted with water (100 mL) and extracted with diethyl ether (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 520 (700 mg) as yellow solid. The crude compound was carried forward for next step without fiarther purification. TLC: 20% EtOAc/ hexanes (Rf: 0.6); LC-MS: 68.55%; 325.9 (M++1); column; Ascentis Express C18, (50 X 3.0 mm, 2.7 um); RT 2.51 min. 1003594907 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min). e 45: Synthesis of compounds from compound 520 and various commercially available amines O O NH O O O Ar NH2 NH S S O Cl pyridine, CH2Cl2 S HN S Ar Compound 520 and commercially available amines were converted to ponding sulfonamides employing Procedure M and the results are captured in Table 4.
Procedure M: To a stirred solution of 2, 4-difluoroaniline 228 (100 mg, 0.77 mmol) in CH2Cl2 (5 mL) under argon atmosphere were added compound 520 (252 mg, crude), ne (3.87 mL, .26 mmol) at 0 °C; warmed to RT and d for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and trated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography to afford the desired compound.
Commercially available amines used for the synthesis of compounds Table 4: sis of compounds from compound 520 and various commercially available amines Procedure, Rx. Mass Mass Spec.
No. Structure Intermediate, Yield Spec. 1H-NMR Calculated Amine (%) Found [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson HNMR (DMSO-dg, 400 MHZ): 5 .89 (s, 1H), .25 (s, 1H), 7.77 (d, J= 8.2 418.03 for Hz, 1H), 7.70 M, 520, 228 C19H12F2N2 (dd, J= 7.5, 1.2 0382 Hz, 1H), 7.58- 7.45 (m, 4H), 7.43 (dd, J= 8.2, 2.0 Hz, 1H), 7.25-7.17 (m, 2H), 7.06- 6.98 (m, 1H) HNMR (DMSO-dg, 400 MHZ): 5 .90 (s, 1H), .43 (s, 1H), 434.00 for 7.77 (d, J= 8.2 M, 520, 224 C19H12C1F Hz, 1H), 7.70 NZO3SZ (d, J= 7.0 Hz, 1H), 7.61-7.43 (m, 5H), 7.42— 7.37 (m, 1H), 7.26-7.18 (m, 2H); 1H NMR (DMSO-dg, 400 MHZ): 5 11.02 (br s, 1H), 10.90 (s, 384.04 for 1H), 8.90 (s, M, 520, 229 1H), 8.52 (s, 2H), 7.78 (d, J = 8.2 Hz, 1H), 7.71-7.64 (m, 2H), 7.57-7.44 (m, 4H); H NMR (DMSO-dg, M, 520, 229 400 MHz): 5 (excess equiv. 11.15 (s, 1H), 400.03 for 11.08 (br s, 1H), 8.91 (s, C17H12N4O 1H), 8.52 (s, 2H), 7.86-7.77 (m, 4H), 7.73 (d, J= 7.0 Hz, 1H), 7.68 (s, 1H), 7.66-7.61 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson HNMR (DMSO-dg, 400 MHZ): 5 .86 (s, 1H), 8.76 (s, 1H), 8.44 (t, J= 6.0 403.01 for Hz, 1H), 7.76 C17H13N3O (d, J= 8.2 Hz, SSS 1H), 7.74-7.71 (m, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.59-7.47 (m, 4H), 4.25 (d, J= 5.9 Hz, 2H); H NMR (DMSO'dg, 400 MHZ): 5 .87 (br s, 1H), 8.91 (s, 412.07 for 1H), 8.59 (s, C19H16N4O 2H), 7.90-7.85 352 (m, 1H), 7.78- 7.70 (m, 2H), 7.61-7.44 (m, 5H), 3.10-3.03 (m, 2H), 2.76- 2.63 (m, 2H); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 46: S nthesis of Com ound 1228 NH2 OzND/802Cl CI 528 —> \ —> pyridine, CH2C|2 Cszcos, DMF, OZN 0V0 2 O 0 Us: "/0 10% Pd/C 3‘ 20 N —> —> s H MeOH THF: H20 002Me Synthesis of 4-chlor0-N—(2-cyclohexylethyl)nitr0benzenesulf0namide (529): To a stirred solution of 2-cyclohexylethanamine 261 (500 mg, 3.93 mmol) in CH2C12 (10 mL) under inert atmosphere were added pyridine (0.9 mL), 4-chloro-3 benzenesulfonyl chloride 528 (l g, 3.93 mmol) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2C12 (2 x 30 mL). The combined c extracts were dried over sodium e, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 529 (1.36 g, 52%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.6); 1H-NMR(CDC13, 400 MHz): 5 8.33 (s, 1H), 7.97 (d, J: 8.4 Hz, 1H), 7.71 (d, J: 8.4 Hz, 1H), 4.52 (t, J: 5.6 Hz, 1H), 3.03 (q, 2H), .56 (m, 4H), 1.40-1.35 (m, 2H), 1.28-1.08 (m, 5H), 0.89-0.83 (m, 2H).
Synthesis of methyl 2-((4-(N-(2-cyclohexylethyl) sulfamoyl)—2-nitr0phenyl) thio) benzoate (530): To a d solution of nd 529 (200 mg, 0.57 mmol) in DMF (4 mL) under inert atmosphere was added cesium carbonate (281 mg, 0.86 mmol) at RT; heated to 40 0C, then added methyl thio salicylate (106 mg, 0.63 mmol) and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water ation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (20 mL), dried over sodium e, filtered and trated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 530 (210 mg, 76%) as yellow syrup. TLC: 30% EtOAc/ s (Rf: 0.4); 1H-NMR (CDC13, 400 MHz): 8 8.67 (s, 1H), 7.99-7.97 (m, 1H), 7.73 (d, J: 8.4 Hz, 1H), 7.65-7.59 (m, 3H), 6.97 (d, J: 8.8 Hz, 1H), 4.44 (t, J: 6.0 Hz, 1H), 3.81 (s, 3H), 3.03-2.98 (m, 2H), 1.67-1.58 (m, 5H), 1.42-1.33 (m, 3H), 1.29-1.09 (m, 3H), 0.91-0.87 (m, 2H).
Synthesis of methyl 2-((2-amin0(N-(2-cyclohexylethyl) sulfamoyl) phenyl) thio) benzoate (531): To a stirred solution of compound 530 (200 mg, 0.41 mmol) in MeOH (10 mL) under inert atmosphere was added 10% Pd/ C (60 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered h celite and the e was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ Hexanes to afford compound 531 (120 mg, 64%) as an off-white solid. TLC: % EtOAc/ Hexanes (Rf: 0.3); 1H-NMR(CDC13, 400 MHz): 8 8.03 (d, J: 7.6 Hz, 1H), 7.59 (d, J: 8.4 Hz, 1H), 7.30-7.29 (m, 2H), 7.21-7.16 (m, 2H), 6.71 (d, J: 8.0 Hz, 1H), 4.36 (br s, 1H), 3.97 (s, 3H), 3.04 (t, J: 6.4 Hz, 2H), 1.68-1.61 (m, 5H), 1.39-1.35 (m, 2H), 1.29-1.13 (m, 4H), 0.90-0.84 (m, 2H).
Synthesis of 2-((2-amin0(N-(2-cyclohexylethyl) sulfamoyl) phenyl) thio) benzoic acid (532): To a stirred solution of compound 531 (110 mg, 0.24 mmol) in THF: H20 (2: 1, 6 mL) was added lithium hydroxide monohydrate (20 mg, 0.49 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The e was diluted with water (15 mL), acidified with dil. HCl. The ed precipitate was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 532 (85 mg, 80%) as white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 5 13.19 (br s, 1H), 7.94 (d, J: 7.6 Hz, 1H), 7.50-7.47 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.24-7.18 (m, 2H), 6.94 (d, J: 8.0 Hz, 1H), 6.61 (d, J: 8.0 Hz, 1H), 5.82 (br s, 2H), 2.85-2.80 (m, 2H), 1.59-1.52 (m, 5H), 1.27-1.23 (m, 3H), 1.16-1.11 (m, 3H), 0.83-0.78 (m, 2H).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Synthesis of N—(2-cyclohexylethyl)—1 1-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinesulf0namide (1228): To a stirred solution of nd 532 (80 mg, 0.18 mmol) in THF (5 mL) under inert atmosphere was added CD1 (89 mg, 0.55 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after tion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL), acidified with dil.HCl. The ed precipitate was filtered, washed with ether (2 X 5 mL) and dried in vacuo to afford 1228 (35 mg, 46%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.6); 1H-NMR dg, 400 MHz): 5 10.89 (s, 1H), 7.77 (d, J: 8.0 Hz, 1H), 7.71-7.69 (m, 1H), 7.64-7.62 (m, 2H), .45 (m, 4H), 2.78-2.73 (m, 2H), 1.48-1.42 (m, 5H), 1.19-1.07 (m, 6H), 0.71-0.66 (m, 2H); LC-MS: 98.00%; 417.6 (M++1); (column; X-Select CSH C-18, (50 X 3.0 mm, 3.5 um); RT 4.76 min. 0.05% TFA (Aq) : ACN; 0.8 ); UPLC (purity): 95.34%; (column : Acquity BEH C-18 (50 X 2.1 mm, 1.7 u); RT 2.74 min. ACN : 0.025% TFA (Aq.); 0.5 mL/min).
Exam le 47: S nthesis of Com ound 1289 02:ND/802CI ©:1\/NHz 528 pyridine CH20|2 032003, DMF Ogi/v©—,10% Pd/C Q\S,,0 LiOH. H20 H THF: H20 MeOH CO2Me 002Me 534 535 CDITHF SN "0 C02H H 1289 Synthesis of 4-chlor0nitr0-N—phenethylbenzenesulfonamide (533): To a stirred solution of 2-phenylethanamine 211 (250 mg, 2.06 mmol) in CH2C12 (5 mL) under inert atmosphere were added 4-chloronitrobenzenesulfonyl chloride 528 (528 mg, 2.06 mmol), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson pyridine (0.5 mL) at 0 0C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2C12 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified h silica gel column tography using 15% EtOAc/ hexanes to afford compound 533 (410 mg, 58%) as colorless syrup. TLC: 30% EtOAc/ hexanes (Rf: 0.6); 1H-NMR (CDCI3, 400 MHz): 5 8.21 (s, 1H), 7.85 (d, J: 8.4 Hz, 1H), 7.64 (d, J: 8.4 Hz, 1H), 7.27 (s, 1H), 7.25-7.22 (m, 2H), 7.08 (d, J: 8.0 Hz, 2H), 4.59 (t, J: 6.0 Hz, 1H), 3.32 (q, 2H), 2.81 (t, J: 6.8 Hz, 2H).
Synthesis of methyl 2-((2-nitr0(N-phenethylsulfamoyl) phenyl) thio) te (534): To a stirred solution of compound 533 (100 mg, 0.29 mmol) in DMF (3 mL) under inert atmosphere were added methyl thio salicylate (54 mg, 0.32 mmol), cesium carbonate (143 mg, 0.44 mmol) at RT; heated to 40 0C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined c extracts were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 534 (90 mg, 65%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (CDC13, 400 MHz): 5 8.56 (s, 1H), 7.98 (t, J: 6.8 Hz, 1H), 7.64-7.60 (m, 4H), 7.23-7.20 (m, 3H), 7.07 (d, J: 8.4 Hz, 2H), 6.91 (d, J: 8.4 Hz, 1H), 4.50 (t, J: 6.0 Hz, 1H), 3.80 (s, 3H), 3.28 (q, 2H), 2.79 (t, J: 6.8 Hz, 2H).
Synthesis of methyl 2-((2-amin0(N-phenethylsulfamoyl) phenyl) thio) benzoate (535): To a d solution of compound 534 (330 mg, 0.69 mmol) in MeOH (15 mL) under inert atmosphere was added 10% Pd/ C (100 mg) at RT and stirred under hydrogen here (balloon pressure) for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with CH2C12 (2 x 5 mL) and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 535 (210 mg, 68%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.3); 1H-NMR(CDC13, 400 MHz): 8 8.03 (d, J: 8.0 Hz, 1H), 7.56 (d, J: 8.0 Hz, 1H), 7.28 (d, J: 8.0 Hz, 3H), 7.25-7.23 (m, 1H), 7.19- 7.11 (m, 5H), 6.69 (d, J: 8.0 Hz, 1H), 4.37 (t, J: 6.4 Hz, 1H), 4.12 (q, 1H), 3.97 (s, 3H), 3.31 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (q, 2H), 2.81 (t, .1: 6.8 Hz, 2H), 2.04 (s, 1H).
Synthesis of 2-((2-amin0(N-phenethylsulfamoyl) phenyl) thio) benzoic acid (536): To a stirred solution of compound 535 (200 mg, 0.45 mmol) in THF: H20 (2: 1, 6 mL) was added lithium hydroxide drate (38 mg, 0.90 mmol) at RT and stirred for 16 h; heated to 40 0C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL), acidified with dil. HCl. The obtained precipitate was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 536 (130 mg, 67%) as white solid. TLC: 40% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHZ): 5 7.93 (d, J: 7.6 Hz, 1H), 7.68 (t, J: 6.0 Hz, 1H), 7.47 (d, J: 8.0 Hz, 1H), 7.32-7.25 (m, 4H), 7.21-7.16 (m, 4H), 6.95 (d, J: 8.0 Hz, 1H), 6.60 (d, J: 8.4 Hz, 1H), 5.81 (br s, 2H), 3.03 (q, 2H), 2.70 (t, J: 8.0 Hz, 2H). sis of 11-0x0-N—phenethyl-10, ydr0dibenz0 [b,f] [1, 4] thiazepine amide (1289): To a stirred solution of compound 536 (100 mg, 0.23 mmol) in THF (5 mL) under inert atmosphere was added CDI (113 mg, 0.70 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the on, the volatiles were removed in vacuo. The residue was diluted with water (20 mL), acidified with 1N HCl. The obtained precipitate was filtered, washed with ether (2 X 5 mL) and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% MeOH/ CH2C12 to afford 1289 (35 mg, 37%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 8 10.86 (s, 1H), 7.81 (br s, 1H), 7.73 (d, J: 8.0 Hz, 2H), 7.71 (s, 1H), .45 (m, 4H), 7.18-7.14 (m, 2H), .07 (m, 3H), 2.97 (q, 2H), 2.64 (t, J: 7.6 Hz, 2H); LC-MS: 97.83%; 411.5 (M++1); (column; X-Select CSH C-18, (50 X 3.0 mm, 3.5 um); RT 4.33 min. 0.05% TFA (Aq): ACN; 0.8 mL/min); UPLC y): 98.00%; (column: Acquity BEH C-18 (50 X 2.1 mm, 1.7 u); RT 2.43 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Exam le 48: S nthesis of Com ounds 1277 and 1282 £1(gag—pTFA DCE002Me t fly MGOZC —>Me02C/[ 108:3:ij EDCI.HC| HOBt DIPEA DMF NH LiOH. H20 [ I o [ :[0 M9020 S/O—ITHF H20 H020 S/©_4NHQ 538 1282 CH3NH2, HATU DIPEA, DMF Synthesis of 3-(meth0xycarb0nyl)—11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xylic acid (537): To a stirred solution of dimethyl 2-((2-amino(tert- butoxycarbonyl) phenyl) thio) terephthalate 130 (200 mg, 0.47 mmol) in 1, 2-dichloro ethane (10 mL) under inert atmosphere was added ro acetic acid (1.09 g, 9.59 mmol) at RT; heated to 80 0C and d for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was d through silica gel column chromatography using 6% MeOH/ CH2C12 to afford compound 537 (60 mg, 38%) as an ite solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHZ): 5 13.17 (br s, 1H), 10.99 (s, 1H), 8.02 (s, 1H), 7.97 (d, J: 8.0 Hz, 1H), 7.82 (d, J: 8.0 Hz, 1H), 7.79 (s, 1H), 7.70-7.65 (m, 2H), 3.86 (s, 3H).
Synthesis of methyl 8-((2-cyclohexylethyl) carbamoyl)—11-oxo-10, 11- dihydrodibenzo [b,f] [1, 4] thiazepinecarb0xylate (538): To a stirred on of compound 537 (60 mg, 0.18 mmol) in DMF (2.4 mL) under inert here were added 2- cyclohexylethan-l-amine 261 (28 mg, 0.21 mmol), HOBt (37 mg, 0.27 mmol), EDCI. HCl (52 mg, 0.27 mmol), diisopropyl ethyl amine (0.08 mL, 0.36 mmol) at RT and stirred for 16 h. The [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson reaction was monitored by TLC; after completion of the reaction, the reaction mixture was d with water (20 mL). The ed solid was filtered and dried in vacuo to afford compound 538 (45 mg, 56%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.6); 1H- NMR (DMSO-dg, 400 MHz): 5 10.94 (s, 1H), 8.46-8.45 (m, 1H), 8.02 (s, 1H), 7.97 (d, J: 8.0 Hz, 1H), 7.81 (d, J: 8.0 Hz, 1H), 7.68 (d, J: 7.6 Hz, 2H), 7.57 (d, J: 8.4 Hz, 1H), 3.87 (s, 3H), 3.26-3.21 (m, 2H), 1.70-1.62 (m, 5H), .35 (m, 2H), 1.26-1.09 (m, 4H), 0.91-0.83 (m, 2H).
Synthesis of 8-((2-cyclohexylethyl) carbamoyl)—11-0x0-10, 11-dihydr0dibenz0 [b, j] [1, 4] thiazepine—3-carb0xylic acid (1282): To a d solution of compound 538 (125 mg, 0.28 mmol) in THF: H20 (4: 1, 5 mL) was added m hydroxide monohydrate (59.9 mg, 1.42 mmol) at RT and stirred for 5 h. The reaction was red by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was diluted with water (20 mL), neutralized with HCl, the obtained solid was filtered and dried in vacuo to afford 1282 (90 mg, 74%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.3); 1H-NMR (DMSO-dg, 400 MHz): 8 13.44 (br s, 1H), 10.92 (s, 1H), 8.45 (t, J: 5.6 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J: 8.0 Hz, 1H), 7.79 (d, J: 8.0 Hz, 1H), 7.68-7.66 (m, 2H), 7.58-7.56 (m, 1H), 3.26-3.21 (m, 2H), 1.70-1.58 (m, 5H), 1.40-1.35 (m, 2H), 1.30-1.22 (m, 4H), 0.91-0.83 (m, 2H). LC-MS: 99.29%; 425.9 (M++1); (column; X-Select CSH C-18, (50 X 3.0 mm, 3.5 um); RT 4.40 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): ; n : Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.32 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Synthesis ofNs-(Z-cyclohexylethyl)-N3-methyl0x0-10,11-dihydr0dibenzo [b, j] [1, 4] thiazepine—3, 8-dicarb0xamide (1277): To a stirred solution of 1282 (30 mg, 0.07 mmol) in DMF (1.2 mL) under inert atmosphere were added methyl amine 306 (2 M in THF, 0.07 mL, 0.14 mmol), HATU (54.7 mg, 0.14 mmol), ropyl ethyl amine (0.05 mL, 0.28 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (10 mL). The obtained solid was filtered, washed with EtOAc (2 x 5 mL) and dried in vacuo to afford 1277 (11 mg, 35%) as white solid. TLC: 7% MeOH/ CH2C12 (Rf: 0.8); 1H-NMR (DMSO-dg, 400 MHz): 10.86 (s, 1H), 8.63-8.62 (m, 1H), 8.44 (t, J: 5.2 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J: 8.0 Hz, 1H), 7.75 (d, J: 8.4 Hz, 1H), 7.65 (d, J: 8.4 Hz, 2H), 7.58-7.55 (m, 1H), 3.26-3.21 (m, 2H), 2.77 (s, 3H), 1.70-1.58 (m, 5H), 1.40-1.35 (m, 2H), 1.26-1.14 (m, 4H), 0.91-0.83 (m, 2H); LC- [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson MS: ; 438.8 ; (column; X-Select CSH C-18, (50 X 3.0 mm, 3.5 um); RT 4.05 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 98.69%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.28 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Exam le 49: S nthesis of Com ound 1278 NH >N.H HCI s HATU DIPEA OH HNfi/O ONN/O Synthesis 0fNs-(Z-cyclohexylethyl)—N3, N3-dimethyl0x0-10, 11— dihydrodibenzo [b,f] [1, 4] pine-3, 8-dicarb0xamide (1278): To a stirred solution of 1282 (40 mg, 0.09 mmol) in DMF (2 mL) under inert atmosphere were added dimethylamine hydrochloride (23 mg, 0.28 mmol), HATU (73 mg, 0.18 mmol), diisopropyl ethyl amine (0.09 mL, 0.47 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL). The obtained solid was d, triturated with EtOAc (2 x 5 mL) and dried in vacuo to afford 1278 (19 mg, 48%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 8 10.84 (s, 1H), 8.44 (t, J: 5.2 Hz, 1H), 7.72 (d, J: 8.0 Hz, 1H), 7.67-7.63 (m, 2H), .47 (m, 2H), 7.45 (d, J: 8.0 Hz, 1H), 3.27-3.22 (m, 2H), 2.96 (s, 3H), 2.88 (s, 3H), 1.70- 1.58 (m, 5H), 1.41-1.35 (m, 2H), 1.28-1.26 (m, 1H), 1.25-1.14 (m, 3H), 0.91-0.83 (m, 2H); LC- MS: 98.41%; 452.7 (M++1); (column; X-Select CSH C-18, (50 X 3.0 mm, 3.5 um); RT 4.11 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 99.60%; (column : Acquity BEH C-18 (50 X 2.1mm, 1.7 u); RT 2.33 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 50: S nthesis of Com ounds 1280 and 1281 /E:E::7NH —>/©E:: LiOH. H20 THF: HO DIPEA DMF CH3NH2 360 HATU DIPEA / 310 HATU, DIPEA, DMF Synthesis of methyl 11-0x0(phenethylcarbamoyl)—10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine—3-carb0xylate (539): To a stirred solution of compound 537 (75 mg, 0.22 mmol) in DMF (3 mL) under inert atmosphere were added 2-pheny1ethan-l-amine 211 (30 mg, 0.25 mmol), HOBt (46 mg, 0.34 mmol), EDCI. HCl (65 mg, 0.34 mmol), diisopropyl ethyl amine (0.08 mL, 0.45 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (20 mL). The obtained solid was filtered, washed with 20% EtOAc/ Hexanes (2 x 5 mL) and dried in vacuo to afford compound 539 (80 mg, 81%) as white solid. TLC: 7% MeOH/ CH2C12 (Rf: 0.8); 1H-NMR (DMSO-dg, 400 MHz): 8 10.96 (s, 1H), 8.61 (t, J: 5.6 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J: 8.0 Hz, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.68 (d, J: 8.0 Hz, 2H), 7.57- 7.54 (rn, 1H), 7.29-7.25 (rn, 2H), .16 (rn, 3H), 3.87 (s, 3H), .42 (rn, 2H), 2.80 (t, J: 7.2 Hz, 2H).
Synthesis of 11-0x0(phenethylcarbamoyl)—10, 11-dihydrodibenzo [b,f] [1, 4] thiazepinecarb0xylic acid (540): To a stirred solution of compound 539 (80 mg, 0.18 mmol) in THF: H20 (4: l, 3 mL) was added m hydroxide monohydrate (39 mg, 0.92 mmol) at RT and d for 5 h. The reaction was monitored by TLC; after completion of the reaction, the [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson volatiles were removed in vacuo. The residue was diluted with water (15 mL), acidified with HCl, the obtained solid was filtered, washed with 20% EtOAc/ hexanes (2 X 5 mL) and dried in vacuo to afford compound 540 (65 mg, 84%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1H-NMR dg, 400 MHz): 8 13.44 (br s, 1H), 10.94 (s, 1H), 8.62 (t, J: 5.6 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J: 8.0 Hz, 1H), 7.79 (d, J: 8.0 Hz, 1H), 7.68 (d, J: 8.0 Hz, 2H), 7.57- 7.54 (m, 1H), 7.29-7.25 (m, 2H), 7.22-7.16 (m, 3H), 3.47-3.42 (m, 2H), 2.80 (t, J: 7.2 Hz, 2H).
Synthesis of N3-methyl-1 l-oxo-Ns-phenethyl-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepine-3, 8-dicarb0xamide : To a stirred solution of compound 540 (35 mg, 0.08 mmol) in DMF (2 mL) under inert here were added methyl amine (2 M in THF, 0.24 mL, 0.50 mmol), HATU (130 mg, 0.32 mmol), diisopropyl ethyl amine (0.10 mL, 0.50 mmol) at 0 0C; warmed to RT and stirred for 44 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (15 mL). The obtained solid was filtered, washed with EtOAc (2 x 5 mL) and dried in vacuo to afford 1280 (12 mg, 28%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz): 8 10.89 (s, 1H), 8.63-8.60 (m, 2H), 7.96 (s, 1H), 7.85 (d, J: 8.0 Hz, 1H), 7.76 (d, J: 8.0 Hz, 1H), .65 (m, 2H), 7.56-7.54 (m, 1H), 7.29-7.26 (m, 2H), 7.22-7.16 (m, 3H), .42 (m, 2H), .73 (m, 5H); LC-MS: 95.22%; 432.6 (M++1); (column; X-Select CSH C-18, (50 X 3.0 mm, 3.5 um); RT 3.61 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 94.66%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 um); RT 1.97 min. ACN : 0.025% TFA (Aq); 0.5 mL/min). 0] Synthesis ofN3, N3-dimethyl0x0-Ns-phenethyl-10, 11-dihydr0dibenz0 [11,1] [1, 4] thiazepine—3, 8-dicarb0xamide (1281): To a stirred solution of 540 (30 mg, 0.07 mmol) in DMF (2 mL) under inert atmosphere were added dimethyl amine hydrochloride 310 (17.5 mg, 0.21 mmol), HATU (55.5 mg, 0.14 mmol), diisopropyl ethyl amine (0.07 mL, 0.35 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was diluted with water (10 mL). The obtained solid was filtered, washed with EtOAc (2 x 5 mL) and dried in vacuo to afford 1281 (17 mg, 53%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 8 10.86 (s, 1H), 8.61 (t, J: 5.2 Hz, 1H), 7.72 (d, J: 8.0 Hz, 1H), 7.67-7.64 (m, 2H), 7.57-7.53 (m, 2H), 7.46 (d, J: 8.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.20-7.16 (m, 3H), 3.48-3.43 (m, 2H), 2.96 (s, 3H), 2.86 (s, 3H), 2.82-2.79 (m, 2H); LC-MS: 97.11%; 446.7 (M++1); (column; X-Select CSH C-18, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (50 X 3.0 mm, 3.5 um); RT 3.68 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 98.02%; n : Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 2.03 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Exam le 51: S nthesis of Com ounds 1225 and 1224 NH ©(DOC5410 ONNH2 UNH2 DIPEA CHZCIZ OSUN(El/0% TEA DMSO 145 542 Synthesis of phenyl 0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinyl) carbamate (542): To a stirred solution of nd 145 (40 mg, 0.16 mmol) in CH2C12 (3 mL) under inert atmosphere were added diisopropyl ethyl amine (0.06 mL, 0.33 mmol), phenyl carbonochloridate 541 (28 mg, 0.18 mol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with CH2C12 (2 x 25 mL). The combined organic ts were dried over sodium sulfate, filtered and trated in vacuo to obtain the crude.
The crude was ated with 15% EtOAc/ hexanes to afford compound 542 (50 mg, 83%) as an off-white solid. TLC: 70% EtOAc/ Hexanes (Rf: 0.8); 1H-NMR (DMSO-dg, 400 MHz): 8 10.73 (s, 1H), 10.45 (s, 1H), 7.68-7.65 (m, 1H), 7.52-7.40 (m, 7H), 7.28-7.24 (m, 2H), 7.21 (d, J = 7.6 Hz, 2H).
Synthesis of 1-(2-cyclohexylethyl)—3-(11-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinyl) urea (1225): To a stirred solution of compound 542 (50 mg, 0.13 mmol) in DMSO (3 mL) under inert atmosphere were added 2-cyclohexylethanamine 161 (21 mg, 0.16 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mmol), triethyl amine (0.04 mL, 0.27 mol) at 0 0C; warmed to RT and stirred for 5 h. The reaction was red by TLC; after tion of the reaction, the reaction mixture was diluted with water (15 mL). The obtained solid was filtered, washed with EtOAc (2 x 5 mL) and dried in vacuo to afford 1225 (17 mg, 31%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 500 MHz): 5 10.58 (s, 1H), 8.58 (s, 1H), 7.64 (d, J: 7.5 Hz, 1H), 7.48- 7.40 (m, 3H), 7.34 (d, J: 7.5 Hz, 2H), 7.13-7.11 (m, 1H), 6.10-6.07 (m, 1H), 3.08-3.04 (m, 2H), 1.67-1.57 (m, 5H), 1.31-1.11 (m, 6H), 0.86-0.84 (m, 2H); LC-MS: 95.28%; 396.4 (M++1); (column; X-Bridge C-18, (50 X 3.0 mm, 3.5 um); RT 3.76 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 96.65%; (column : Acquity UPLC BEH C-18 (2.1 X 50 mm, 1.7 u); RT 2.65 min. ACN : 0.025% TFA (Aq); 0.5 mL/min). 1224 In a similar manner 1224 (1-(11-0x0-10,11-dihydr0dibenz0[b,f] [1,4]thiazepin yl)—3-phenethylurea) was prepared. Yield: 27% LC-MS: 390.3 ; 1H-NMR (DMSO-dg, 400 MHz): 8 10.59 (s, 1H), 8.69 (s, 1H), 7.65 (d, J: 7.2 Hz, 1H), 7.49-7.41 (m, 3H), 7.35 (d, J: 7.6 Hz, 2H), 7.29 (d, J: 7.2 Hz, 2H), 7.22-7.13 (m, 4H), 6.14 (t, J: 6.0 Hz, 1H), 3.30 (s, 2H), 2.73 (t, J: 6.8 Hz, 2H).
Exam le 52: S s of Com ounds 1535 and 1536 NH O Chiral Separation 1535 1536 The racemic compound of 1388 (18 mg) was separated using a CHIRALPAK-IC column (250 x 20 mm x 5 um) (10 mg loading; 0.1% DEA in n-hexane: CH2C12: MeOH (50: 50) ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (A: B = 25: 75) as mobile phase) HPLC to afford 1535 (2.5 mg) and 1536 (2.5 mg) as off-white solids.
Compound 1535 analytical data (Fr-I): LC-MS: 99.81%; 383.9 (M++l); (column; Ascentis Express C-l8, (50 X 3.0 mm, 2.7 mm); RT 1.69 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
UPLC (purity): 96.76%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.49 min. ACN: 0.025% TFA (Aq); 0.5 mL/min). Chiral HPLC: , R: 99.16 min lpak- IC, 250 x 4.6 mm, 5 pm); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH (50: 50) (A: B:: 25: 75); Flow Rate: 1.0 mL/min).
Compound 1536 analytical data (Fr-II): LC-MS: 99.39%; 383.9 (M++l); (column; is Express C-l8, (50 X 3.0 mm, 2.7 mm); RT 1.70 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 ).
UPLC (purity): 99.56%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.49 min. ACN: 0.025% TFA (Aq); 0.5 mL/min). Chiral HPLC: 98.30%, R: 13.33 min (Chiralpak- IC, 250 x 4.6 mm, 5 pm); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH (50: 50) (A: B:: 25: 75); Flow Rate: 1.0 mL/min).
Exam le 53: S nthesis of Com ound 1206 —NH2>&NHD/ENEDCI. HCI HOBtDIPEA DMF (VO—> Synthesis of N—(2-cyclohexylethyl)—1 1-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] thiazepinecarb0xamide (545): To a stirred solution of 6 (100 mg, 0.36 mmol) in DMF (6 mL) under argon atmosphere were added EDCI.HCl (105 mg, 0.54 mmol), HOBt (74 mg, 0.54 [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mmol), 2-cyclohexylethanamine 261 (56 mg, 0.44 mmol), and ropyl ethyl amine (95 mg, 0.73 mmol) at 0-5 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was d with water (20 mL), filtered and washed with water (2 x 5 mL) to obtain the crude. The crude was triturated with EtOAc (2 x 5 mL) to afford 545 (70 mg, 50%) as white solid. TLC: % MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 8 10.75 (s, 1H), 8.43 (t, J: 5.6 Hz, 1H), 7.69-7.62 (m, 3H), .43 (m, 4H), 3.26-3.21 (m, 2H), 1.70-1.58 (m, 5H), 1.40-1.35 (m, 2H), 1.28-1.09 (m, 4H), 0.91-0.83 (m, 2H).
Synthesis of yclohexylethyl)—1 1-0x0-10, 11-dihydr0dibenz0 [b,f] [1, 4] pine-S-carboxamide 5, 5-di0xide : To a stirred solution of 545 (40 mg, 0.10 mmol) in chloroform (20 mL) under inert atmosphere was added m-chloro perbenzoic acid (36.3 mg, 0.21 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate solution (15 mL) and extracted with CH2C12 (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.
The crude was ed through silica gel column chromatography using 30% EtOAc/ hexanes to afford 1206 (16 mg, 37%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.4); 1H-NMR (DMSO-dg, 400 MHz): 8 11.49 (s, 1H), 8.63 (t, J: 4.8 Hz, 1H), .96 (m, 3H), 7.91-7.83 (m, 2H), 7.77 (t, J: 6.4 Hz, 2H), 3.25-3.24 (m, 2H), 1.71-1.58 (m, 5H), 1.42-1.37 (m, 2H), 1.28- 1.14 (m, 4H), 0.92-0.84 (m, 2H); LC-MS: 97.31%; 413.2 (M++1); (column; X-bridge C-18, (50 X 3.0 mm, 3.5 um); RT 3.78 min. 0.05% TFA in water: ACN; 0.8 mL/min); UPLC (purity): 96.73%; (column : Acquity UPLC BEH C-18 (2.1 x 50 mm, 1.7 u); RT 2.52 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Exam le 54: S nthesis of Com ound 1656 Boczo, DIPEA H N2 CH2C|2 Pd(PPh3)2CI2I TEA, DMF TBAF, THF BocHN @3322?008" KO’Bu DMSO 02¢ EDCI HCI HOBt DIPEA DMF 00/8;ij5:,\/Cii&jlh—>—N Synthesis of tert-butyl (4-br0m0phenethyl) carbamate (547): To a stirred solution of 2-(4-bromophenyl) ethan-l-amine 546 (500 mg, 2.50 mmol) in CH2C12 (5 mL) under argon atmosphere were added Boc-anhydride (594 mg, 2.75 mmol), diisopropyl ethyl amine (1 mL, 7.50 mmol) at RT and d for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction e was diluted with water (25 mL) and extracted with CH2C12 (2 x mL). The combined organic extracts were washed with water (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-8% EtOAc/ hexanes to afford compound 547 (500 mg, 65%) as white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 5 7.46 (d, J: 8.0 Hz, 2H), 7.12 (d, J: 8.0 Hz, 2H), .82 (m, 1H), 3.12-3.08 (m, 2H), 2.68-2.64 (m, 2H), 1.32 (s, 9H). sis of tert-butyl (4-((trimethylsilyl) ethynyl) phenethyl) carbamate (548): To a stirred on of compound 547 (500 mg, 1.66 mmol) in DMF (10 mL) under argon [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Wilkinson atmosphere were added ltrimethylsilane (1.8 mL, 16.66 mmol), triethyl amine (2.32 mL, 16.66 mmol) and purged under argon for 15 min. To this were added Pd(PPh3)2C12 (118 mg, 0.16 mmol), copper iodide (33 mg, 0.16 mmol) and purged under argon for 15 min; heated to 70 0C and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 548 (500 mg, 95%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.6); 1H-NMR (DMSO-dg, 400 MHz): 8 7.38 (d, J: 8.0 Hz, 2H), 7.18 (d, J: 8.0 Hz, 2H), 6.85 (t, J: 7.2 Hz, 1H), 3.16-3.11 (m, 2H), 2.70-2.66 (m, 2H), 1.34 (s, 9H), 0.23 (s, 9H).
Synthesis of tert-butyl (4-ethynylphenethyl) carbamate (549): To a stirred solution of compound 548 (500 mg, 1.70 mmol) in THF (5 mL) under argon atmosphere was added TBAF (2.08 mL, 2.08 mmol) in THF (3 mL) at RT and d for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was purified through silica gel column chromatography using 5-10% EtOAc/ hexanes to afford compound 549 (450 mg, 95%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf: 0.4); 1H-NMR (DMSO-dg, 500 MHZ): 5 7.39 (d, J: 7.5 Hz, 2H), 7.20 (d, J: 7.5 Hz, 2H), 6.87-6.85 (m, 1H), 4.10 (s, 1H), 3.15-3.12 (m, 2H), 2.71-2.69 (m, 2H), 1.30 (s, 9H). 2] Synthesis of tert-butyl (4-(1-benzyl-1H—1, 2, 3-triazolyl) phenethyl) ate (551): To a stirred solution of compound 549 (200 mg, 0.82 mmol) in MeOH: DMF (1: 1, 20 mL) under argon atmosphere were added (azidomethyl) benzene 550 (410 mg, 3.06 mmol), copper iodide (202 mg, 1.02 mmol) at RT; heated to reflux and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 551 (200 mg, 68%) as white solid. TLC: 30% EtOAc/ s (Rf: 0.3); 1H-NMR (DMSO-dg, 500 MHz): 8 8.59 (s, 1H), 7.75 (d, J: 8.5 Hz, 2H), 7.41-7.34 (m, 5H), 7.25 (d, J: 8.0 Hz, 2H), 6.90-6.88 (m, 1H), 5.64 (s, 2H), 3.17-3.13 (m, 2H), 2.70 (t, J: 7.5 Hz, 2H), 1.36 (s, 9H).
Synthesis of 1-benzyl-1H—1, 2, 3-triazolyl) phenyl) l-amine (552): To a stirred solution of compound 551 (190 mg, 0.50 mmol) in CH2C12 (4 mL) under argon [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson atmosphere was added trifluoro acetic acid (1 mL) at RT and stirred for 3 h. The on was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude to obtain nd 552 (180 mg, crude) as dark brown syrup which was carried to the next step without any purification. TLC: 100% EtOAc (Rf: 0.2); 1H-NMR (DMSO-dg, 400 MHz): 8 8.61 (s, 1H), 7.81 (d, J: 8.0 Hz, 2H), 7.78-7.76 (m, 3H), 7.39-7.32 (m, 6H), 5.64 (s, 2H), 3.09-3.04 (m, 2H), 2.87 (t, J: 7.6 Hz, 2H).
Synthesis of N—(4-(1-benzyl—1H—1, 2, 3-triazolyl) phenethyl)—11-0x0-10, 11- dihydrodibenzo [b,f] [1, 4] thiazepine-S-carboxamide 5, 5-di0xide (553): To a stirred solution compound 552 (200 mg, 0.66 mmol) in DMF (10 mL) under argon atmosphere were added EDCI. HCl (189 mg, 0.98 mmol), HOBt (189 mg, 0.98 mmol), compound 6 (297 mg, 0.79 mmol), diisopropyl ethyl amine (0.35 mL, 1.98 mmol) at 0 0C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (2 x 50 mL) washed with water (50 mL), brine, dried over sodium e, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified through column tography using 2% MeOH/ CH2C12 to afford compound 553 (180 mg, 49%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR (DMSO-dg, 400 MHz): 811.46(br s, 1H), 8.80 (t, J: 5.5 Hz, 1H), 8.56 (s, 1H), 8.03 (d, J: 8.3 Hz, 1H), 8.00- 7.95 (m, 2H), 7.92-7.83 (m, 2H), 7.79 (s, 1H), 7.75 (d, J: 8.2 Hz, 3H), 7.42-7.31 (m, 5H), 7.29 (d, J: 8.3 Hz, 2H), 5.63 (s, 2H), 3.50 (q, J: 6.8 Hz, 2H), 2.85 (t, J: 7.2 Hz, 2H).
Synthesis of N—(4-(1H-1, 2, 3-triazolyl) phenethyl)—11-0x0-10, 11- dihydrodibenzo [b,f] [1, 4] thiazepine-S-carboxamide 5, 5-di0xide (1656): To a stirred solution of compound 553 (180 mg, 0.31 mmol) in DMSO (10 mL) under argon atmosphere was added ium ry butoxide (1 M in THF, 2.5 mL, 2.55 mmol) at RT. The reaction mixture was stirred under oxygen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the on, the on mixture was d with water (5 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified through column tography using 2% MeOH/ CH2C1251yophilized and washed EtOAc (5 mL), filtered washed with n-pentane (5 mL)and dried in vacuo to afford 1656 (20 mg, 13%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf: 0.3); 1H NMR (DMSO-dg, 400 MHz): 8 14.91 (br s, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1H), 11.52 (br s, 1H), 8.81 (t, J: 5.5 Hz, 1H), 8.21 (br s, 1H), 8.04 (d, J: 8.3 Hz,1H),8.01- 7.95 (m, 2H), .85 (m, 2H), 7.82-7.73 (m, 4H), 7.31 (d, J: 7.9 Hz, 2H), 3.51 (q, J: 6.6 Hz, 2H), 2.86 (t, J: 7.1 Hz, 2H); LC-MS: 96.04%; 473.9 (M++1); n; Ascentis Express C-18, (50 X 3.0 mm, 2.7 um); RT 2.01 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq.
TFA, 1.2 mL/min). HPLC (purity): 95.54%; (column; Zorbax SB C-18 (150 X 4.6 mm, 3.5 um); RT 7.59 min. ACN: 0.05% TFA (Aq); 1.0 mL/min).
Exam le 55: S nthesis of com ounds from com ound 575 usin various commercial] available amines Readily ble acids similar to 575, 576 and 577 were converted to the desired compounds using commercially available amines employing Procedures A and B and the results are captured in Tables 5 and 6.
Carbon d compounds: NH O OH —> NHAr EDC|.HCI, HOBt, O O£1.70 DIPEA, DMF Table 5: Synthesis of compounds from compound 575 using various commercially available amines H-NMR (DMSO-dg, 400 MHZ): 5 9.27 (t, J= 5.7 Hz, 1H), 8.96 (s, 1H), 7.96 (s, 343'" for A, 575,218 1H), 7.82 (s, C21H17N3O 1H), 7.74-7.70 (RT 12 h) 2 (m, 1H), 7.68- 7.61 (m, 2H), 7.54-7.49 (m, 1H), 7.45-7.38 (m, 2H), 4.67 (t, J= 5.4 Hz, 2H), 3.54 (s, [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 311x (DMSO-dg, 400 MHz): 5 .51 (s, 1H), 8.30—8.29 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.51-7.46 (m, 363.2 2H), 7.41—7.31 1198 A, 575 64 (M++1), (m, 3H), 3.94 (s, 2H), 3.23 (d, J= 6.4 Hz, 2H), 1.70—1.62 (m, 5H), 1.39- 1.37 (m, 2H), 1.26-1.14(m, 4H), 0.91—0.86 (m, 2H); H-NMR (DMSO-dg, 400 MHz): 5 .52 (s, 1H), 9.10—9.01 (m, 2H), 8.74 (s, 2H), 7.70 (d, J = 7.5 Hz, 1H), 344.13 for A, 575,212 7.62 (s, 1H)» 3449 1576 44 7.57 (d, J= 7.9 (RT 12 h) (M++1) C20H16N4O Hz, 1H), 7.51— 7.43 (m, 2H), 7.38 (d, J= 7.3 Hz, 1H), 7.33 (t, J = 7.5 Hz,1H), 4.46 (d, J = 5.5 Hz, 2H), 3.96 (s, 2H); 1H—NMR (DMSO-dg, 400 MHz): 5 .52 (s, 1H), 9.10 (t, J= 5.8 349.09 for Hz, 1H), 8.95 1577 A, 575,213 26 (s, 1H), 7.79 (s, C19H1§N3O 1H), 7.70 (dd, J = 7.7, 1.1 Hz, 1H), 7.61 (s, 1H), 7.54 (dd, J = 7.9, 1.6 Hz, 1H), 7.48 (td, J = 8.8, 1.8 Hz, [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.38 (d, J= 6.9 Hz, 1H), 7.33 (td, J= 7.6,1.6 Hz, 1H), 4.64 (d, J= 5.7 Hz, 2H), 3.96 (s, 2H); Oxygen-bridged compounds: ArNH2 EDCI.HCI HOBt @6194 DIPEA DMF Oxygen-bridged Targets Table 6: Synthesis of compounds from compound 576 and various commercially available amines H-NMR (DMSO-dg, 400 MHZ): 5 .63 (s, 1H), 9.17 (t, J= 5.8 Hz, 1H), 8.96 351.07 for (s, 1H), 7.82- B, 576, 213 C18H13N303 7.76 (m, 2H), S 7.68 (s, 1H), 7.66-7.59 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.38-7.31(m, 2H), 4.65 (d, J = 5.6 Hz, 2H) 1H—NMR (DMSO-dg, 400 MHZ): 5 345.11 for 10.62 (s, 1H), A, 576, 218 9.07 (t, J= 5.8 C20H15N3O3 Hz, 1H), 8.53 (s, 1H), 8.45 (d, J= 4.1 Hz, 1H), 7.78 (dd, J ation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson = 7.7, 1.6 Hz, 1H), 7.72-7.60 (m, 4H), 7.43 (d, J= 8.4 Hz, 1H), 7.39-7.31 (m, 3H), 4.47 (d, J= 5.7 Hz, 1H—NMR (DMSO-dg, 400 MHZ): 5 .62 (s, 1H), 9.13—9.05 (m, 2H), 8.75 (s, 2H), 7.78 (dd, J 346.11 for = 7.79 1.6 HZ, A, 576, 212 C19H14N403 1H), 7.68 (s, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J= 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 4.48 (d, J= 5.6 Hz, Nitrogen-bridged compounds: C|H_H2N)8 —'dL"2 EDC|.HC| HOBt N DIPEA DMF Synthesis of 11-oxo-N—(thiazol—S-ylmethyl)—10, 11-dihydr0-5H—dibenz0 [b, e] [1, 4] diazepine—S-carboxamide (1602): Using Procedure A the title compound was prepared using cornpound 577 (35 mg, 0.13 rnrnol) and thiazolylmethanamine hydrochloride 213 (20 mg, 0.13 rnrnol) and diisopropyl ethyl amine (0.05 rnL, 0.27 rnrnol) and was ed in 31% yield as an off-white solid; TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H-NMR (DMSO-dg, 400 MHz): 8 9.89 (s, 1H), 8.99-8.94 (rn, 2H), 8.15 (s, 1H), 7.79 (s, 1H), 7.69 (dd, J: 7.8, 1.3 Hz, 1H), 7.50 -7.42 (rn, 2H), 7.38-7.32 (rn, 1H), 7.00 (dd, J: 10.9, 8.3 Hz, 2H), 6.91 (t, J: 7.4 Hz, 1H), 4.63 (d, J: .6 Hz, 2H); LC-MS: 93.15%; 351.0 ; colurnn; Ascentis Express C18, (50 X 3.0 mm, 2.7 urn); RT 1.76 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 rnL/rnin); [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson UPLC (purity): 93.21%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 u); RT 1.57 min.
ACN: 0.025% TFA (Aq); 0.5 mL/min).
Exam le 56: Assa Measurin Activi of Com ounds on Viral Production in and on ity of AD38 Cells AD38 cells grown in a 175 cm flask with "Growth Medium" (DMEM/F12 (1:1) (cat# SH30023.01, Hyclone, 1X Pen/step (cat#: 30CL, Mediatech, Inc), 10% FBS (cat#: 101, Tissue Culture Biologics), 250 ug/mL G418 (cat#: 30CR, Mediatech, Inc), 1 ug/mL Tetracycline (cat#: T3325, Teknova)) were detached with 0.25% trypsin. ycline-free ment medium" (15 mL DMEM/F12 (1 :1) (cat# SH30023.01, Hyclone, 1x Pen/step (cat#: 30CL, Mediatech, Inc), with 2% FBS, Tet-system approved (cat#: 631106, Clontech) were then added to mix and spun at 1300 rpm for 5 min. Pelleted cells were then re- suspended/washed with 50 mL of 1X PBS 2 times and 10 mL Treatment Medium one time.
AD38 cells were then pended with 10 mL of Treatment Medium and counted. Wells of a en coated 96-well NUNC microtiter plate were seeded at 50,000/well in 180 uL of ent Medium, and 20 uL of in treatment media with either 10% DMSO ol) or a 10X on of compound in 10% DMSO was added. Plates were incubated for 6 days at 37 oC.
Viral load production was assayed by quantitative PCR of the core sequence. Briefly, uL of clarified supernatant was added to a PCR reaction mixture that contained forward primers HBV-f 5'-CTGTGCCTTGGGTGGCTTT-3', Reverse primers HBV-r 5'- AAGGAAAGAAGTCAGAAGGCAAAA-3' and Fluorescent TaqManTM Probes HBV-probe 5'- FAM/AGCTCCAAA/ZEN/TTCTTTATAAGGGTCGATGTCCATG/3IABkFQ -3’ in Quanta Biosciences Ta® qPCR Toughmix®, and was subsequently on an d Biosystems VIIA7 in a final volume of 20 uL. The PCR mixture was incubated at 45 CC for 5 minutes, then 95 0C for 10 min, followed by 40 cycles of 10 seconds at 95 oC and 20 seconds at 60 oC. Viral load was quantitated against known standards by using ViiATM 7 Software. Viral load in the supernatant from wells with treated cells were compared against viral load in supernatant from DMSO control wells (2 3 per plate).
At the end of compound ent period cell viability was assessed using a Promega CellTiter-Glo protocol. All supernatant was removed the previously d 96-well microtiter [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson plate, and 50 uL Tetracycline-free treatment medium (DMEM/F12 (1 :1), 1X Pen/step (cat#: 30- 002-CL, Mediatech, Inc), with 2% FBS, Tet-system approved (cat#: 631106, ch), and 1% DMSO was added back to each well. Another 50 uL of CellTiter—Glo reagent solution (Promega, G7573) was then added at room temperature and the contents mixed for 2 minutes on an l shaker to induce cell lysis. This was followed by incubation at room temperature for minutes to stabilize the luminescent signal. The luminescence was recorded for 0.2 s per well on a Tecan multimode platereader (Infinite M1000 pro). The luminescent signal from each well was normalized against that of untreated (DMSO) control wells. All results were reported percent Viability (with controls being 100%).
Table 7 1101 15 107 1102 1 100 1103 2 87 1104 1 85 1105 1 101 1107 2 106 1108 1 105 1109 6 99 1110 2 119 1111 2 89 1112 4 73 1113 1 99 1114 1 104 1115 1 106 1117 67 108 1118 61 95 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1120 7 94 1121 6 109 1122 21 86 1123 62 95 1124 80 99 1125 20 108 1127 22 94 1130 2 101 1133 94 99 1149 5 118 1150 1 22 1151 1 50 1152 1 45 1154 90 50 1155 18 103 1156 16 106 1157 1 48 1158 37 120 1159 8 92 1160 2 105 1161 1 99 1162 61 99 1163 3 104 1164 27 103 1165 5 82 1166 10 119 1167 57 124 1168 10 117 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1169 39 107 1170 1 95 1171 49 103 1172 51 107 1173 39 105 1174 35 109 1175 30 123 1176 2 104 1177 47 118 1182 13 55 1183 2 36 1184 1 0 1185 1 0 1186 1 39 1187 1 73 1188 4 83 1189 1 85 1190 1 70 1191 14 121 1192 3 81 1193 4 90 1194 1 45 1195 0 48 1196 2 95 1197 1 88 1198 3 60 1199 19 109 1200 18 125 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1201 1 50 1202 7 107 1203 3 89 1204 2 97 1205 2 89 1206 10 106 1207 24 99 1208 11 103 1209 1 102 1210 25 116 1211 1 106 1212 1 72 1213 2 55 1214 2 94 1216 1 125 1217 1 37 1218 12 104 1219 5 100 1220 2 94 1221 19 106 1222 32 100 1223 2 28 1224 3 65 1225 10 87 1226 1 80 1227 10 92 1228 22 101 1229 45 76 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1230 46 102 1231 12 93 1232 42 94 1233 1 93 1234 3 79 1235 6 61 1237 4 66 1238 26 104 1239 33 106 1240 26 92 1241 12 86 1242 91 78 1243 20 118 1244 14 103 1245 1 101 1246 6 96 1247 8 103 1248 3 106 1249 34 108 1250 14 113 1251 8 99 1252 14 94 1253 15 103 1256 1 102 1257 26 113 1258 12 105 1259 11 84 1260 8 100 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1264 8 104 1266 1 74 1267 77 93 1268 77 106 1269 63 107 1270 1 94 1271 6 100 1272 24 102 1273 6 96 1274 11 88 1275 3 93 1276 24 89 1277 43 89 1278 3 88 1279 55 84 1280 74 94 1281 29 86 1282 102 105 1283 1 97 1285 3 108 1286 36 114 1287 11 96 1288 5 49 1289 40 96 1290 33 94 1291 1 102 1293 95 97 1308 1 99 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1309 1 107 1310 1 89 1311 8 95 1312 5 83 1313 17 108 1314 69 101 1315 4 103 1316 32 89 1317 50 95 1318 14 70 1319 16 83 1320 43 93 1321 15 74 1322 28 94 1323 96 60 1324 10 24 1325 26 90 1326 23 95 1328 54 105 1329 62 109 1330 41 109 1331 43 88 1332 70 103 1333 20 73 1334 33 83 1335 87 104 1336 70 90 1337 77 91 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1338 70 118 1339 113 70 1340 64 116 1342 113 95 1343 8 91 1344 96 102 1345 115 93 1346 105 97 1347 3 94 1348 0 107 1349 12 102 1353 50 97 1354 98 70 1356 3 101 1357 39 115 1358 15 72 1361 79 113 1362 19 98 1364 1 102 1365 2 105 1366 12 93 1367 33 88 1370 5 94 1371 6 94 1372 60 103 1373 10 100 1374 1 98 1375 11 89 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1376 3 63 1377 5 65 1381 40 93 1382 47 117 1383 1 87 1384 4 79 1385 26 51 1386 61 95 1387 2 78 1388 5 71 1389 15 89 1390 2 92 1391 2 71 1392 2 85 1393 41 87 1394 55 94 1395 64 79 1396 63 95 1397 73 95 1398 5 60 1399 105 92 1400 34 105 1401 31 79 1402 12 81 1403 15 82 1405 14 94 1407 3 103 1408 17 94 [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1409 4 83 1410 35 50 1411 66 91 1412 48 87 1413 92 78 1414 39 89 1415 27 77 1417 11 75 1418 12 73 1419 113 89 1420 29 86 1421 78 95 1422 64 95 1423 37 91 1424 65 96 1427 7 85 1428 28 93 1429 38 90 1430 58 92 1431 115 92 1432 79 91 1433 82 94 1434 85 98 1435 77 99 1436 10 104 1440 71 91 1441 28 90 1442 85 99 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1443 64 95 1444 6 65 1445 24 38 1446 3 84 1447 1 85 1448 3 85 1449 2 86 1450 73 94 1451 30 92 1452 15 62 1453 48 97 1454 27 95 1455 3 89 1456 15 101 1457 26 92 1458 12 49 1459 4 92 1462 35 99 1463 31 97 1464 49 98 1465 39 106 1466 7 88 1467 1 92 1468 76 97 1471 16 97 1472 37 95 1473 81 97 1474 51 101 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 1475 47 107 1476 1 86 1477 67 16 1478 2 94 1480 72 95 1481 46 100 1482 46 98 1483 65 98 1484 26 100 1485 30 96 1486 53 94 1487 15 96 1488 84 97 1490 7 79 1491 39 80 1492 39 79 1493 51 80 1494 115 60 1495 9 77 1496 2 18 1497 9 49 1498 1 82 1499 2 84 1501 37 71 1503 40 87 1505 81 85 1506 72 85 1507 11 96 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1508 31 81 1509 15 29 1510 62 82 1511 38 85 1512 27 99 1513 2 82 1514 13 84 1515 2 82 1516 30 82 1517 2 78 1518 67 85 1519 73 81 1520 1 81 1521 1 22 1522 1 82 1523 1 70 1524 2 18 1525 78 85 1526 57 92 1527 19 116 1528 4 85 1529 12 111 1530 70 93 1531 53 96 1532 17 112 1533 2 105 1534 5 109 1535 108 85 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 1536 2 120 1537 36 98 1540 12 87 1541 11 117 1542 34 95 1543 72 90 1544 40 97 1545 59 88 1546 65 89 1547 16 90 1548 28 85 1549 7 109 1550 1 87 1551 51 91 1552 64 93 1553 86 93 1555 36 81 1556 67 86 1557 54 86 1558 51 88 1559 68 92 1560 13 92 1561 8 118 1562 25 89 1563 41 93 1564 10 119 1565 4 103 1566 31 91 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1567 1 109 1568 1 100 1569 1 114 1570 2 115 1571 35 117 1572 5 116 1573 46 126 1574 78 109 1575 90 108 1576 8 108 1577 6 120 1578 33 100 1580 59 89 1581 3 97 1582 8 112 1583 41 121 1584 52 95 1585 66 87 1586 23 112 1587 78 92 1588 0 98 1589 1 85 1590 1 96 1591 13 111 1592 50 102 1593 3 133 1594 4 109 1595 3 108 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1597 64 87 1598 61 93 1599 72 101 1600 12 108 1601 62 106 1602 38 116 1603 6 91 1604 0 105 1605 25 106 1606 7 104 1607 14 93 1608 63 103 1609 68 99 1611 0 130 1612 0 112 1613 0 122 1614 2 45 1615 32 123 1616 5 115 1617 1 118 1618 0 44 1619 12 122 1620 3 111 1621 1 117 1622 0 120 1623 1 128 1624 1 136 1625 2 111 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson 1626 0 118 1627 5 115 1628 17 138 1629 3 95 1631 9 112 1632 2 122 1633 66 124 1634 45 125 1635 1 93 1636 0 111 1637 32 123 INCORPORATION BY REFERENCE All publications and s mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
EQUIVALENTS 2] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this cation. The full scope of the invention should be determined by reference to the claims, along with their filll scope of equivalents, and the specification, along with such variations.
Unless otherwise indicated, all s expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being d in all instances by the term "about." Accordingly, unless indicated to the contrary, the cal parameters set forth in this specification and attached claims are approximations that may vary depending upon the d properties sought to be obtained by the present invention. 1003630346

Claims (16)

1. A compound represented by: wherein Y is S(O)y, wherein y is 2; Rm’ and Rm are each independently selected from the group consisting of H, n, C1-6 alkyl, C2-6 alkenyl, NR’R’’, and hydroxyl; Rc is H; R78 is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR’R’’, -C(O)-C1-6 alkyl, -C(O)-C1-6 alkoxy, phenyl, heteroaryl, C3-6 cycloalkyl, -S(O)w-C1-6 alkyl (where w is 1, 2 or 3), - S(O)w-NR’R’’ (where w is 1, 2 or 3), and -NR’-S(O)w, (where w is 1, 2 or 3); R79 is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, , -C(O)-C1-6 alkyl, -C(O)-C1-6 alkoxy, , heteroaryl, C3-6 cycloalkyl, -S(O)w-C1-6 alkyl (where w is 1, 2 or 3), - S(O)w-NR’R’’ (where w is 1, 2 or 3), and -NR’-S(O)w, (where w is 1, 2 or 3); R’ is selected, independently for each occurrence, from H, methyl, ethyl, and ; R’’ is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, – C(O)-methyl and -C(O)-ethyl, or R’ and R’’ taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group ting of en, C1-6 alkyl, C2-6 alkynyl, C2-6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR’R’’; or 1003630346 pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein C1-6 alkyl is substituted by one, two or three substituents each independently selected from halogen and hydroxyl.
3. The compound of claim 1 or 2, wherein C2-6 alkenyl is substituted by one, two or three substituents each independently selected from halogen and hydroxyl.
4. The compound of claim 1 or 3, wherein C1-6 alkyl is tuted with one, two, or three substituents ed from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, NR’R’’, -NR’-S(O)w, (where w is 1, 2 or 3) and S(O)w-NR’R’’ (where w is 1, 2 or 3).
5. The compound of any one of claims 1 to 4, wherein C1-6 alkoxy is substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1-6 alkyl, NR’R’’, -NR’-S(O)w (where w is 1, 2 or 3), and S(O)w-NR’R’’ (where w is 1, 2 or 3).
6. The nd of any one of claims 1 to 5, n C3-6 cycloalkyl is substituted with one, two, or three substituents ed from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C1-6 alkyl, C1-6 alkoxy, -C(O)-C1-6 alkyl, -C(O)-C1-6 alkoxy, and
7. The nd of any one of claims 1 to 6, wherein phenyl is substituted with one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 , NR’R’’, C(O)- NR’R’’, - C(O)-C1-6 alkyl, -C(O)-C1-6 alkoxy, -S(O)w-C1-6 alkyl (where w is 1, 2 or 3), NR’-S(O)w (where w is 1, 2 or 3), and -S(O)w-NR’R’’(where w is 1, 2 or 3).
8. The compound of any one of claims 1 to 7, wherein heteroaryl is substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, NR’R’’, C(O)- NR’R’’, -C(O)-C1-6 alkyl, C1-6 alkoxy, -S(O)w-C1-6 alkyl (where w is 1, 2 or 3), O)w (where w is 1, 2 or 3), and -S(O)w-NR’R’’(where w is 1, 2 or 3).
9. The compound of any one of claims 1 to 8, wherein each of R5, R6 and R7 are 1003630346 individually selected from H and F.
10. The compound of any one of claims 1 to 9, wherein R10 is selected from the group consisting of H, methyl and F.
11. The compound of any one of claims 1 to 10, wherein each of R4, R5, R6, R7, R8, R9 and R10 are H.
12. A pharmaceutically acceptable composition comprising a compound of any one of claims 1 to 11, and a pharmaceutically able excipient.
13. Use of an effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically able composition according to claim 12 in the preparation of a medicament for the treatment of a tis B infection in a patient in need thereof.
14. The use according to claim 13, further comprising use of one or more additional compounds ing to any one of claims 1 to 11.
15. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable composition according to claim 12, and another HBV capsid assembly promoter in the preparation of a medicament for the treatment of a hepatitis B infection in a patient in need thereof.
16. Use of an effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable composition according to claim 12, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion tors, disruptors of nucleocapsid formation, cccDNA formation tors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-
NZ723972A 2014-03-13 2015-03-13 Hepatitis b core protein allosteric modulators NZ723972B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201461952467P 2014-03-13 2014-03-13
US61/952,467 2014-03-13
US201462010025P 2014-06-10 2014-06-10
US62/010,025 2014-06-10
PCT/US2015/020444 WO2015138895A1 (en) 2014-03-13 2015-03-13 Hepatitis b core protein allosteric modulators

Publications (2)

Publication Number Publication Date
NZ723972A NZ723972A (en) 2021-08-27
NZ723972B2 true NZ723972B2 (en) 2021-11-30

Family

ID=

Similar Documents

Publication Publication Date Title
CA2942533C (en) Hepatitis b core protein allosteric modulators
CA2998741C (en) Hepatitis b core protein modulators
CA2881057C (en) Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b
US10987360B2 (en) Hepatitis B core protein modulators
JP6581745B2 (en) Pyrazole-oxazolidinone compound of anti-hepatitis B virus
BRPI0611853A2 (en) n- (pyridin-2-yl) sulfonamide derivatives
CA3095451A1 (en) Ox2r compounds
CA3057736A1 (en) Liver x receptors (lxr) modulators
WO2022166923A1 (en) Phenyldihydropyrimidine compound and use thereof
NZ723972B2 (en) Hepatitis b core protein allosteric modulators
BR112016020895B1 (en) HEPATITIS B CORE PROTEIN ALLOSTERIC MODULATORS, THEIR USES, AND PHARMACEUTICAL COMPOSITION
OA18052A (en) Hepatitis B core protein allosteric modulators.