NZ616642B2 - Quinazoline derivatives for the treatment of viral infections and further diseases - Google Patents

Quinazoline derivatives for the treatment of viral infections and further diseases Download PDF

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NZ616642B2
NZ616642B2 NZ616642A NZ61664212A NZ616642B2 NZ 616642 B2 NZ616642 B2 NZ 616642B2 NZ 616642 A NZ616642 A NZ 616642A NZ 61664212 A NZ61664212 A NZ 61664212A NZ 616642 B2 NZ616642 B2 NZ 616642B2
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NZ616642A
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Werner EMBRECHTS
Tim Hugo Maria Jonckers
Stefaan Julien Last
Gowan David Mc
Serge Maria Aloysius Pieters
Pierre Jeanmarie Bernard Raboisson
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Janssen Sciences Ireland Uc
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Priority claimed from PCT/EP2012/059234 external-priority patent/WO2012156498A1/en
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Publication of NZ616642B2 publication Critical patent/NZ616642B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

This disclosure relates to 2,4-aminoquinazoline derivatives, processes for their preparation, pharmaceutical compositions, and their use in therapy of disorders in which the modulation of toll - like - receptors is involved, typically in the treatment of viral infections. compounds of the disclosure include: (3S)-3-[(2-amino-5-methylquinazolin-4-yl)amino]hexan-1-ol, (3S)-3-[(2-amino-6,7-dimethoxyquinazolin-4-yl)amino]hexan-1-ol, and (3S)-3-[(2-amino-8-fluoroquinazolin-4-yl)amino]hexan-1-ol include: (3S)-3-[(2-amino-5-methylquinazolin-4-yl)amino]hexan-1-ol, (3S)-3-[(2-amino-6,7-dimethoxyquinazolin-4-yl)amino]hexan-1-ol, and (3S)-3-[(2-amino-8-fluoroquinazolin-4-yl)amino]hexan-1-ol

Description

QUINAZOLINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS AND FURTHER DISEASES This invention relates to quinazoline derivatives, processes for their preparation, pharmaceutical compositions, and their use in therapy.
The present invention relates to the use of quinazoline derivatives in the treatment of viral infections, immune or inflammatory disorders, whereby the modulation, or agonism, of toll-like-receptors (TLRs) is involved. Toll-Like Receptors are primary transmembrane proteins characterized by an extracellular leucine rich domain and a cytoplasmic extension that ns a conserved region. The innate immune system can recognize pathogen- associated molecular patterns via these TLRs expressed on the cell surface of n types of immune cells. Recognition of foreign ens activates the production of cytokines and upregulation of co-stimulatory molecules on phagocytes. This leads to the modulation of T cell behavior.
It has been estimated that most mammalian species have n ten and fifteen types of ike ors. Thirteen TLRs (named simply TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species.
However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein ous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12, and 13, none of which are ented in humans. Other mammals may express TLRs which are not found in humans. Other non-mammalian s may have TLRs distinct from mammals, as demonstrated by TLR14, which is found in the Takifugu pufferfish. This may complicate the process of using experimental animals as models of human innate immunity.
For ed reviews on toll-like receptors see the following journal articles.
Hoffmann, J.A., Nature, 426, p33-38, 2003; Akira, S., Takeda, K., and Kaisho, T., Annual Rev. Immunology, 21, p335-376, 2003; Ulevitch, R. J., Nature Reviews: Immunology, 4, p512-520, 2004.
Compounds indicating activity on Toll-Like receptors have been previously described such as purine derivatives in WC 2006 117670, adenine derivatives in WO 98/01448 and WO 99/28321, and dines in .
However, there exists a strong need for novel Toll-Like receptor modulators having preferred selectivity, higher potency, higher metabolic stability, and an improved safety profile ed to the compounds of the prior art.
In the treatment of certain viral ions, regular injections of interferon (lFNor) can be stered, as is the case for tis C virus (HCV), (Fried et. al.
Peginterferon-alfa plus ribavirin for chronic hepatitis C virus infection, N Engl J Med 2002; 347: 975-82). Orally available small molecule lFN inducers offer the potential advantages of reduced immunogenicity and convenience of administration. Thus, novel lFN inducers are potentially effective new class of drugs for treating virus infections. For an e in the literature of a small molecule lFN inducer having antiviral effect see De Clercq, E.; Descamps, J.; De Somer, P. Science 1978, 200, 563-565. lFNor is also given in combination with other drugs in the ent of certain types of cancer (refer to Eur. J. Cancer 46, 7, and Cancer Res. 1992, 52, 1056 for examples). TLR 7/8 agonists are also of interest as vaccine adjuvants because of their ability to induce pronounced Th1 response .
In ance with the present ion a compound of formula (I) is provided R2 1‘NH R3 \ N R4 N/J\NH2 R5 (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein R1 is Cg_8alkyl, Cg_8alkoxy, 02-6alkenyl or 02-5alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, nitrile, ester, amide, C1_3alkyl, C1_3alkoxy or 03-5cycloalkyl, R2 is hydrogen, halogen, yl, amine, C1_7alkyl, C1_7alkylamino, C1_6alkoxy, (01-4)alkoxy-(C1-4)alkyl, 03-5cycloalkyl, C4-7heterocycle, aromatic, bicyclic heterocycle, kyl, heteroaryl, arylalkyl, carboxylic amide, carboxylic ester each of which is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C1-5alkyl, di-(C1-5)alkyl- amino, C1_6alkylamino, C1-5alkyl, C1-5alkoxy, 03-6cycloalkyl, carboxylic acid, carboxylic ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl, or nitrile, R3 is hydrogen, halogen, hydroxyl, amine, C1_7alkyl, C1_7alkenyl, C1_7alkynyl, C1_7alkylamino, koxy, (C1_4)alkoxy-(C1_4)alkyl, C3-3cycloalkyl, C4-7hetero- cycle, aromatic, bicyclic cycle, arylalkyl, aryl, heteroarylalkyl, y, heteroaryloxy, ketone, nitrile each of which is ally substituted by one or more substituents independently selected from n, hydroxyl, amino, C1_3alkyl, di-(C1_3)alkylamino, C1_3alkylamino, C1_3alkyl, C1_3alkoxy, C3-3cycloalkyl, carboxylic acid, carboxylic ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl, or nitrile.
R4 is hydrogen, halogen, hydroxyl, amine, kyl, C1_7alkylamino, C1_3alkoxy, (C1-4)alkoxy-(C1-4)alkyl, C3-3cycloalkyl, C4-7heterocycle, bicyclic heterocycle, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy each of which is optionally substituted by one or more substituents independently selected from halogen, yl, amino, C1_3alkyl, di-(C1_3)alkylamino, C1_3alkylamino, C1_3alkyl, C1-3alkoxy, C3-3cycloalkyl, carboxylic acid, carboxylic ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl, or nitrile, and R5 is hydrogen, ne, chlorine or methyl with the proviso that R2, R3, R4, and R5 cannot all be H.
In a first embodiment the present invention provides nds of formula (I) wherein R1 is butyl, pentyl or 2-pentyl and n R2, R3, R4 and R5 are as specified above.
In a further embodiment the current invention relates to compounds of formula (I) wherein R1 is C43 alkyl substituted with a hydroxyl, and wherein R2, R3, R4 and R5 are as specified above.
Another embodiment relates to compounds of formula (I) wherein R1, when being C4-3alkyl substituted with hydroxyl, is one of the following: :01(S) [I] /\j\(S) I], \Ai(SIII In another embodiment the present invention provides compounds of formula (I) n R5 is preferably hydrogen or fluorine and R1, R2, R3, and R4 are as described above.
The compounds of formula (I) and their pharmaceutically acceptable salt, solvate or polymorph thereof have activity as pharmaceuticals, in particular as modulators of ike or (especially TLR7 and/or TLR8) activity.
So, in a further aspect the present invention provides a ceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.
Furthermore a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof according to the t invention, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph f can be used as a medicament.
Another aspect of the invention is that a nd of formula (I) or a pharmaceutically able salt, solvate or polymorph thereof, or said pharmaceutical composition comprising said compound of formula (I) or a ceutically acceptable salt, solvate or polymorph thereof can be used accordingly in the treatment of a disorder in which the modulation of TLR7 and/or TLR8 is involved.
The term “alkyl” refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms.
The term “halogen” refers to fluorine, chlorine, e or iodine.
The term yl” refers to an alkyl as defined above consisting of at least two carbon atoms and at least one -carbon double bond.
The term “alkynyl” refers to an alkyl as defined above consisting of at least two carbon atoms and at least one -carbon triple bond.
The term “cycloalkyl” refers to a carbocyclic ring containing the specified number of carbon atoms.
The term “alkoxy” refers to an alkyl (carbon and en chain) group ar bonded to oxygen like for instance a methoxy group or ethoxy group.
The term “aryl” means an aromatic ring structure optionally comprising one or two heteroatoms selected from N, O and S, in particular from N and O. Said aromatic ring structure may have 5, 6 or 7 ring atoms. In particular, said aromatic ring ure may have 5 or 6 ring atoms.
The term “aryloxy” refers to an ic ring structure. Said aromatic group is arly bonded to , like for instance phenol.
The term “heteroaryloxy” refers to an aromatic ring structure optionally comprising one or two heteroatoms selected from N, O and S. Said aromatic group, containing 5 to 7 ring atoms, one of which is singularly bonded to oxygen like for instance hydroxypyridine.
The term “bicyclic heterocycle” means an aromatic ring structure, as defined for the term “aryl” comprised of two fused aromatic rings. Each ring is optionally comprised of heteroatoms selected from N, O and S, in particular from N and The term arylalkyl” means an aromatic ring structure as defined for the term “aryl” optionally substituted with an alkyl group.
The term “heteroarylalkyl” means an aromatic ring structure as defined for the term “heteroaryl” optionally substituted by an alkyl group.
Heterocycle refers to molecules that are saturated or partially saturated and include ethyloxide, tetrahydrofuran, dioxane or other cyclic ethers.
Heterocycles containing nitrogen include, for example azetidine, morpholine, piperidine, zine, pyrrolidine, and the like. Other heterocycles include, for example, thiomorpholine, dioxolinyl, and cyclic sulfones.
Heteroaryl groups are heterocyclic groups which are aromatic in nature. These are monocyclic, bicyclic, or polycyclic containing one or more atoms selected from N, O or S. Heteroaryl groups can be, for example, imidazolyl, isoxazolyl, furyl, oxazolyl, pyrrolyl, pyridonyl, pyridyl, pyridazinyl, pyrazinyl, Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. le base salts are formed from bases which form non-toxic salts.
The compounds of the invention may also exist in unsolvated and solvated forms. The term “solvate” is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for e, ethanol.
The term “polymorph” refers to the ability of the compound of the ion to exist in more than one form or crystal structure.
The compounds of the present invention may be administered as crystalline or amorphous products. They may be obtained for e as solid plugs, powders, or films by methods such as precipitation, llization, freeze drying, spray drying, or evaporative . They may be administered alone or in combination with one or more other compounds of the invention or in ation with one or more other drugs. Generally, they will be administered as a ation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
The compounds of the present ion or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all itions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable r, which carrier may take a wide variety of forms depending on the form of ation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, for example, for oral, rectal, or percutaneous administration. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, , elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets.
Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are sly employed. Also included are solid form ations that can be converted, shortly before use, to liquid forms. In the compositions suitable for percutaneous administration, the carrier optionally comprises a ation enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired itions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
The nds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the nds of the t invention may be administered to the lungs in the form of a solution, a sion or a dry powder.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of stration and uniformity of dosage. Unit dosage form as used herein refers to physically te units suitable as unitary dosages, each unit containing a predetermined quantity of active ient calculated to produce the desired therapeutic effect in association with the ed pharmaceutical carrier. Examples of such unit dosage forms are s (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
Those of skill in the treatment of infectious diseases will be able to determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body WO 56498 weight. It may be appropriate to ster the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub- doses may be formulated as unit dosage forms, for example, ning 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration s on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. rmore, it is evident that the effective amount may be lowered or increased depending on the response of the treated subject and/or depending on the tion of the physician prescribing the compounds of the instant invention. The effective amount ranges mentioned above are therefore only guidelines and are not intended to limit the scope or use of the invention to any .
Preparation of compounds Compounds of formula (I) are ed according to scheme 1. The 2,4-dichloroquinazolines can be reacted in separate steps to afford the 2,4-diaminoquinazolines in acceptable yield. In the first step the 2,4-dichloro- quinazoline is mixed or heated with an amine with or without a transition metal catalyst to afford the 2—chloroaminoquinazoline. After workup of the crude 2—chloroaminoquinazoline, the ediate is heated in a pressure vessel with an ammonia source (for example, ammonia in methanol) and optionally with CuO. 1 I HN/V\ HN/V\ R R R I“ \N I“ / NAG lCfi / NAG / ‘1 Amine NH3 N/ NH2 base CuO heat, pressu re vessel Compounds of formula (I) can also be prepared according to scheme 2.
Substituted anthranilic esters (IV) were heated under acidic conditions in the presence of excess cyanamide, using an alcoholic solvent (e.g. ethanol) or diglyme according to the method described in the literature (O'Hara et. al. JOC (1991) 56, p776). Subsequent amine substitution of the 2-amino hydroxyquinazolines (V) can proceed via several different pathways. In one example, intermediates V can be heated in the presence of orous oxychloride (POCI3) with or without solvent. After removal of solvents, the amine can be added neat, or in the presence of a polar solvent (e.g. acetonitrile) to afford VI at room ature or by heating. A second approach is to react intermediates V with a coupling agent such as BOP or PyBOP in the presence of DBU and the amine. The reaction takes place in a polar t (e.g. DMF). A third method is to protect the 2-amino group in intermediate V with an acyl group. Intermediate V is reacted with anhydride (e.g. acetic anhydride), typically at reflux for several hours. The solvents can be removed under reduced pressure and the crude can undergo subsequent on with POC|3 as described above. Facile removal of the protecting acyl group is done via reaction in a basic solvent (e.g. sodium methoxide in ol).
SCHEME 2 R2 t \ ‘N // A R1 N NH 1.AcZO 2. POCI3 3. RZ-NHZ 4. NaOCH3, CH3OH 0 R2\ ' 0 C6“NANH—>1. POCI3 \ \“ R1/ / I NH2 HCI // A EtOH or diglyme 2 2. RZ-NHZ ACN refulx 16h R1 N m cyanamide 2 IV reflux BOP or PyBOP DBU, R2—NH2 anhydrous DM F, rt Ex tal Section.
Preparation of intermediate A HN/\/\ 0 /O \ / \ N \o NAG A DIPEA, CH3CN, rt \0 N CI To a mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (500 mg, 1.9 mmol), ropylethylamine (0.73 mL, 4.2 mmol), and acetonitrile (0.1 mL) was added a solution of n-butylamine (0.19 mL, 1.9 mmol) in acetonitrile (5 mL) dropwise while stirring. The mixture was allowed to stir for one day at t temperature. Ethyl acetate was added, the organic layer was washed with sat. aq ammonium de. The organic layer was removed, dried over magnesium sulfate. The solids were removed via filtration to afford crude A, used as such in the next step.
Pre aration of Com ound 1 HN/\/\ HN/\/\ /O \N /O \ \O NJ\C|/ NH3 \0 NANHZ 130°C A 1 Intermediate A (0.5 g, 1.7 mmol) was placed into a 20 mL re vessel with 7N ammonia in methanol (15 mL) and to this was added CuO (242 mg, 1.7 mmol). The vessel was sealed and the mixture was heated to 130°C with stirring for 18 hours. The reaction was allowed to cool to room temperature.
The solids were removed via filtration and the solvents of the filtrate were removed under reduced pressure. The crude material was purified via reverse phase column chromatography (Vydac Denali C18 column 10pm, 250g, 5cm).
Mobile phase (0.25% NH4HC03 solution in water, CH3CN).
Preparation of 9 \ \ O O \o are OH NH2 A OH N NH2 1.5 eq cyanamide. reflux Step 1. Into a 500 mL round bottom flask equipped with a magnetic stir bar was placed methyl 2-aminomethoxybenzoate (25 g, 149.6 mmol), ethanol (200 mL), cyanamide (9.43 g, 224 mmol), and concentrated HCI (6 mL). The e was allowed to stir at reflux for 6 hours. At one hour intervals, concentrated HCI (0.5 mL) was added. The on mixture was allowed to cool to room temperature and the solid, V-1, was isolated via filtration and washed with ethanol.
LC-MS m/z = 192(M+H). 1H NMR (400 MHz, DMSO-de) 8 ppm 3.88 (s, 3 H), 6.96 (dd, J=8.2, 3.1 Hz, 2 H), 7.69 (t, J=8.3 Hz, 1 H), 8.28 (br. s., 2 H), 12.67 (br. s.,1 H) Step 2. dbl\ \ NJ\NH2/ DBU, BOP, n-butylamine. dblNANHZ anhydrous DMF, rt V-1 9 Into a 50 mL vial was placed V-1 (250 mg, 1.24 mmol), ous DMF (5 mL), DBU (0.6 g, 3.73 mmol), and BOP (659 mg, 1.49 mmol). The mixture stirred at room temperature for 2 hours, n-butylamine (287 mg, 3.73 mmol) was added and the reaction was allowed to stir at room temperature for 15 hours. The solvent was reduced in volume and the residue purified via silica column chromatography using a dichloromethane to 10% methanol in dichloromethane gradient. The best fractions were pooled, the solvents were d under reduced pressure to afford 9. _12_ The following intermediates were prepared according to the method to prepare V-1.
Br OH N NH2 LC-MS m/z = 240/242 1H NMR (400 MHz, DMSO-de) 3 ppm 3.09 - 3.55 (m, 2 H), 7.09 (br. s., 1 H), 7.26 (dd, J=7.9, 1.3 Hz, 1 H), 7.37 - 7.48 (m, 2H) CI OH LC-MS m/z = 196(M+H) 1H NMR (400 MHz, DMSO-dg) 3 ppm 7.00 (br. s., 2 H) 7.13 (d, J=7.78 Hz, 1 H) 7.18 (d, J=8.28 Hz, 1 H) 7.50 (t, J=8.03 Hz, 1 H), phenol proton not ed.
N NH2 LC-MS m/z = 176(M+H) F OH N NH2 LC-MS m/z = 180(M+H) _13_ 1H NMR (400 MHz, DMSO-de) 8 ppm 6.98 (dd, J=11.0, 8.3 Hz, 1 H), 7.13 (d, J=8.3 Hz, 1 H), 7.51 (br. s., 2 H), 7.64 (td, J=8.3, 5.8 Hz, 1 H), 12.30 (br. s, N NH2 V-19 LC-MS m/z = H) N NH 2 V-14 LC-MS m/z = 239/241 (M+H) 1H NMR (400 MHz, DMSO-dg) 8 ppm 7.32 (d, J=8.8 Hz, 1 H), 7.49 (s, 2 H), 7.71 (br. s.,1 H), 7.81 (dd, J=8.6, 2.4 Hz, 1 H), 8.00 (d, J=2.4 Hz,1 H) /O \N N NH 2 V-20 LC-MS m/z = 192(M+H) N NH 2 V-21 LC-MS m/z = 176(M+H) WO 56498 _14_ v-22 LC-MS m/z = 180(M+H) 1H NMR (400 MHz, DMSO-de) 8 ppm 7.01 - 7.16 (m, 2 H), 7.56 (br. s., 2 H), 7.99 (t, J=7.7 Hz, 1 H), 10.38 - 13.48 (m, 1 H) CI N NH2 v-23 LC-MS m/z = 196(M+H) 1H NMR (400 MHz, DMSO-de) 8 ppm 7.41 (dd, J=8.5, 2.0 Hz, 1 H), 7.55 (d, J=2.0 Hz, 1 H), 7.98 (d, J=8.5 Hz, 1 H), 8.49 (br. s., 2 H), 10.79 - 13.69 (m, 1 H) LC-MS m/z = 176(M+H) 1H NMR (400 MHz, DMSO-de) 8 ppm 2.43 (s, 3 H), 7.22 (d, J=1.0 Hz, 1 H), 7.24 (s, 1 H), 7.89 (d, J=8.0 Hz, 1 H), 8.29 (br. s., 2 H), 12.65 (br. s,1 H) \ A o N NH2 v-24 LC-MS m/z = 192(M+H) 2012/059234 _15_ /O 1 N/ NH2 V-25 LC-MS m/z = 220(M+H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 3.87 - 3.95 (m, 3 H), 7.12 - 7.47 (m, 1 H), 7.83 (dd, J=8.3, 1.4 Hz,1 H), 7.99 (d, J=1.3 Hz,1 H), 8.07 - 8.13 (m, 1 H), 8.43 (br. s., 2 H) F N NH 2 V-26 LC-MS m/z = 198(M+H) @/ H \o N NH2 v-27 LC-MS m/z = 298(M+H) 1H NMR (400 MHz, DMSO-d6) 6 ppm 3.85 (s, 3 H), 5.10 (s, 2 H), 6.17 (br. s., 2 H), 6.70 (s, 1 H), 7.30 - 7.36 (m, 2 H), 7.40 (t, J=7.4 Hz, 2 H), 7.44 - 7.48 (m, 2 H), 10.82 (br. s.,1 H) V-28 LC-MS m/z = 180(M+H) 1H NMR (400 MHz, DMSO-d6) 6 ppm 6.51-6.67 (m, 2H), 7.00-7.08(m, 1H), 7.42(ddd, J =11.2, 7.9 1.3Hz, 1H), 7.69 (dd, J=7.9, 0.6Hz, 1H), 11.08 (br. s., N NH2 V-29 LC-MS m/z = 196 (M+H) N NH2 V-30 LC-MS m/z = 176 (M+H) 1H NMR (400 MHz, DMSO-ds) 8 ppm 2.41 (s, 3 H), 7.15 (t, J=7.5 Hz, 1 H), 7.43 (br. s., 2 H), 7.55 (d, J=7.0 Hz, 1 H), 7.80 (d, J=7.8 Hz, 1 H), 11.17 - 12.49 (m, 1H) Preparation of 10 Pd(PPh3)4 K2CO3 A dioxane/water 130 °C, 16h vs V-6 Step 1. Preparation of V-6. Into a 50 mL vial equipped with a magnetic stir bar was placed V-3 (500 mg, 2.16 mmol), boronic acid (342 mg, 2.8 mmol), ium carbonate (1.19 g, 8.62 mmol), dioxane (5.5 mL), water (1.8 mL), and tetrakis(tripheny|phosphine)palladium (249 mg, 0.215 mmol). Nitrogen gas was bubbled through the reaction e for 10 minutes. The vial was sealed and heated to 130°C. The reaction cooled to room temperature and the solvents were removed under reduced pressure. The crude was purified via reverse phase column chromatography (RP Vydac Denali C18 - 10 pm, 200 g, cm. Mobile phase 0.25% NH4HC03 solution in water, CH3CN) to afford V-6.
LC-MS m/z = 238 (M+H) _17_ O \N O \N A DBU, BOP, (S)aminopentanol A ous DMF, rt V-6 10 Step 2. Into a 50 mL vial equipped with a magnetic stir bar was placed V-6 (148 mg, 0.624 mmol), anhydrous DMF (3.5 mL), DBU (0.373 mL, 2.5 mmol), BOP (345 mg, 0.78 mmol), then (S)aminopentanol (322 mg, 3.12 mmol).
The reaction mixture was allowed to stir at room ature for 3 days. The volatiles were removed under reduced pressure and the crude was partitioned between water and ethyl acetate. The organic layers were combined, dried (magnesium sulfate), the solids were removed by filtration, and the solvents of the filtrate were d under reduced pressure. The crude was purified via e phase column chromatography (RP SunFire Prep C18 OBD-10 pm, 30 x150 mm). Mobile phase (0.25% NH4HC03 solution in water, CH3CN) to afford 10.
Preparation of 11 O H \o OH 1 —’ \l O / ACO2 / N NH2 N NJK reflux15h H V-1 v-9 Step 1. Into a 1L round bottom flask equipped with a magnetic stir bar was placed V-1 (8.8 g, 46.03 mmol) and acetic anhydride (150 mL). The flask was equipped with a reflux condenser and the mixture was heated to reflux with stirring for 15 hours. The precipitate was isolated by filtration and washed with diisopropylether then dried in vacuo to afford a white solid, V-9.
LC-MS m/z = 234 (M+H) -18— \o OH \0 CI \N o —» CEKN O NANJK POCI3 NANJK H CH3CN,rt H v-9 v-1o Step 2. Into a 250 mL round bottom flask equipped with a magnetic stir bar was added V-9 (4.5g, 19.3 mmol), and acetonitrile (100 mL). POCI3 (5.56 mL, 59.8 mmol) was added dropwise over 30 minutes, followed by the addition of DIPEA (10.3 mL, 59.8 mmol). The reaction e became a brown solution and stirred for 2 hours at room temperature. The reaction mixture was poured into 1M NaOH (100 mL) and extracted with ethyl acetate (2 x 100 mL). The ed organic layers were dried over MgSO4, the solids were removed via filtration and the te was used as such in the next step. \o Cl \o HN/V\ \N o CEKN o NANJK n—butylamine NANJK H DIPEA H (ethyl acetate), rt V-10 V-11 Step 3. The filtrate solution from step 2 in ethyl acetate was treated with DIPEA (9.2 mL, 53.6 mmol) and n-butylamine (3.5 mL, 35.8 mmol). The reaction mixture was stirred for 16 hours at ambient temperature. The solvent was removed under reduced pressure and the crude was reconstituted in dichloromethane and washed with water. The organic layer was dried (MgSO4), the solids were removed by filtration, and the solvents of the filtrate were ated to dryness to obtain an orange solid, V-11.
LC-MS m/z = 289 (M+H) \o HN/V\ OH HN/V\ \ N o \ N NANJK pyridine HCI NANHZ H (pyridine) 120°C v-11 VI-1 Step 4. Into a 30 mL pressure tube was placed V-11 (2.8 g, 9.71 mmol), pyridine hloride (6.73 g, 58.26 mmol), and ne (50 mL) and the mixture was heated to 120°C for 16 hours. The pyridine was removed under reduced pessure. The crude was dissolved in a mixture of dichloromethane/methanol: 95/5 and washed with a 1N HCI solution and water.
The organic layer was dried (MgSO4), the solids were removed via filtration and the solvents of the filtrate were removed under reduced pressure to afford Vl-1.
LC-MS m/z = 231 (M-H) 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.92 (t, J=7.37 Hz, 3 H) 1.33 - 1.43 (m, 2 H) 1.50 - 1.59 (m, 2 H) 3.41 - 3.49 (m, 2 H) 5.79 - 5.88 (m, 1 H) 6.02 (d, J=8.14 Hz, 1 H) 6.91 (br. s., 2 H) 6.99 - 7.04 (m, 1 H) 10.78 (br. s.,1 H) 13.35 (br. s., 1 H) H HN \O/\/ Br 0 HN N \N N)\NH2/ CS2C03 NANH2 DMF, rt VI-1 Step 5. Into a 100mL flask was placed Vl-1 (175 mg, 0.753 mmol), cesium ate (0.74 g, 2.26 mmol) and DMF (15 mL). The mixture was stirred at ambient temperature for 30 minutes. 2-bromoethyl methyl ether (0.089 mL, 0.94 mmol) was added and the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the crude residue was purified by HPLC (RP Vydac Denali C18 - 10 pm, 250 g, 5 cm.
Mobile phase (0.25% NH4HC03 on in water, methanol), the best fractions were collected and the solvents were removed under reduced pressure to obtain 11 as a solid. ation of 12 Br OH (\N /> \N i N A A PdCl PPh N NH2 2( 3)2 NH2 PPh3, HNEt2, Cul, DMF 80 °C, 10min V-12 Step 1. V-2 was dissolved in DMF (15 mL) and purged with N2 on an oil bath at 80°C for 10 minutes. Then bis(triphenylphosphine)palladium(|l) dichloride (69 mg, 0.098 mmol), triphenylphosphine (57.6 mg, 0.22 mmol) and copper iodide (42.5 mg, 0.22 mmol) were added. After 5 minutes of purging with N2, diethylamine (3.15 mL, 30.31 mmol) was added followed by the addition of 2-pyridylethyne (168 mg, 1.63 mmol). The vessel was closed and the reaction stirred at 80°C for 16 hours. The reaction e was poured into ice water, and the precipitate was isolated by filtration, washed with water and dried under vacuum. The product was d in dichloromethane for 30 minutes. The precipitate was isolated by filtration, washed with dichloromethane and ropyl ether and dried under vacuo at 50°C to obtain V-12.
LC-MS m/z = 263 (M-H) I \ /N I OH OH \N \N H2, Pd/C / A N NH2 N NH2 V42 V43 Step 2. To a solution of V-12 (300 mg, 1.15 mmol) in THF (50 mL) was placed 10%Pd/C (100 mg) under an N2(g) atmosphere. The reaction mixture stirred for 16 hours at room temperature, and subsequently filtered over packed decalite. The solvent of the filtrate was removed under reduced pressure to afford crude V-13, used as such in the next step.
LC-MS m/z = 267 (M-H) l I A DBU, BOP, n-butylamine A N NH2 anhydrous DMF, rt N NH2 V-13 Step 3. Example 12 was prepared according to the method to prepare 9.
Preparation of 14 Br Br Br / / N O / N O \ k \ k JJ\ I k HN N NH2 A020 HN N N HN N N J) 0% 13 VI-2 VI-3 Step 1. Intermediates Vl-2 and Vl-3 was prepared according to the method to prepare VI-1. VI-3 was isolated after stirring with diisopropylether at room ature.
Vl-2 : LC-MS m/z = 337 (M+H) Vl-3 : LC-MS m/z = 379 (M+H) Br OH fl Nk kI \N HN N PdC|2(PPh3)2 A j H N ““2 PPh3, HNEt2, Cul, DMF Vl-2 14 _22_ Step 2. Compound 14 was prepared according to the method to prepare intermediate V-12.
Preparation of 15 \/o o NH2 \ HO o HCI, EtOH NANHZ OHO 1.5 eq cyanamide reflux V-14 Step 1. Into a 500 mL round bottom flask equipped with a magnetic stir bar was placed 3-aminophthalic acid hydrochloride (25 g, 115 mmol), ethanol (250 mL), cyanamide (7.25 g, 172 mmol), and concentrated HCI (6 mL). The flask was equipped with a reflux condenser and the mixture was allowed to stir at reflux for 6 hours. At one hour als, concentrated HCI (0.5 mL) was added via g|ass pipette. The reaction was allowed to cool to room temperature, the ts were removed under reduced pressure to afford a yellow oil. The crude was dried over silica gel then partially purified via si|ica gel column tography using a dich|oromethane to 10% methanol in dich|oromethane gradient . The crude, yellow solid, V-14, was used as such in the next step.
LC-MS m/z = 234 (M+H).
\/O O OH \H l ’ O ‘ k HN N _ NH2 N NH2 DBU, PyBOP, n—butylamine anhydrous DMF, rt V-14 15 Step 2. Into a 100 mL round bottom flask equipped with a magnetic stir bar was placed V-14 (1.7 g, 7.29 mmol), anhydrous DMF (25 mL), DBU (3.3 g, 21.87 mmol), and PyBOP (4.55 g, 8.75 mmol). The on mixture was allowed to stir for 1 hour at room temperature. Then n-butylamine (2.1 g, 29.2 mmol) was added and the mixture was d to stir for 15 hours at room temperature. The solvent was removed under reduced pressure and the crude _23_ was filtered through silica gel using 20% methanol in dichloromethane. The solvents of the filtrate were removed under reduced pressure and the crude oil (15, 4 g) was purified via reverse phase column chromatography (RP Vydac Denali C18 - 10 pm, 200 g, 5 cm). Mobile phase (0.25% NH4H003 solution in water, CchN).
Preparation of 16 H2N H2N H M N N\H_\— N N\H_\— H2, Pd/C \\ CH OH,3 rt OH OH To a suspension of 10% Pd/C in methanol (25 mL) under a N2 atmosphere was added compound 14 (111 mg, 0.39 mmol). The en atmosphere was removed and ed by hydrogen gas. The mixture was allowed to stir at room temperature until 2 equivalents of hydrogen gas were consumed. The on mixture was filtered over packed decalite. The solvent of the filtrate was removed under reduced pressure. The crude was purified via silica gel column chromatography using a dichloromethane to 10% methanol in dichloromethane gradient to afford 16.
Preparation of 18 O O OH LAH THF rt ’ ’ \ J: \ j: H H 17 18 17 (625 mg, 2.28 mmol) was dissolved in ous THF (10 mL). LAH (1M in THF, 3.42 mL, 3.42 mmol) was added dropwise and the reaction mixture was stirred for 3 hours at room temperature. LC-MS showed complete conversion to the desired product. The reaction mixture was quenched with sat., aq.
NH4CI, the solids were removed by filtration and the solvents of the filtrate were removed under reduced pressure. The e was purified via prep. HPLC yielding the product as a white solid.
Preparation of 19 LEM # E11.Zn(CN)2,Pd(PPh3)4 HN DMF,160°C,10min 2. NaOCH3, CH3OH Vl-2 A mixture of Vl-2 (500 mg, 1.48 mmol), tetrakis(triphenylphosphine)palladium (86 mg, 0.074 mmol) and zinc e (106 mg, 0.89 mmol) in DMF (5 mL) in a 10 mL tube was placed under microwave ation at 160 °C for 10 minutes.
The mixture was cooled to room ature and concentrated in vacuo. The residue was partioned between water and romethane. The organic layer was separated, dried (MgSO4), the solvents were removed by filtration and the solvents of the filtrate were concentrated in vacuo. The product was triturated in CH3CN, the solid was isolated by filtration. Acyl deprotection was afforded after treatment with sodium methoxide in ol at 60°C for one hour. The mixture was cooled and the product precipitated. The white solid, 19, was isolated by filtration and dried under vacuum.
Preparation of 20 £4? \N Br \ E/ 0’3 /I": N'\ N o I N \ JJ\ \ k HN N N 1.PdCl2(PPh3)2 A HN N NH2 Ncho3 O DME, water, 90°C, 1h 2. NaOCHg, CHgoH Vl-3 20 Into a 50 mL vial equipped with a magnetic stir bar and sparged with en gas was placed Vl-3 (300 mg, 0.79 mmol), the boronic ester (198 mg, 0.95 mmol), water (3 mL, degassed) and DME (6 mL, degassed), sodium bicarbonate (199 mg, 2.37 mmol) and PdCl2(PPh3)2 (55 mg, 0.079 mmol ) was added and the mixture was heated to 90°C for 1 hour. The mixture was cooled and ethyl acetate was added. The organic layer was ted, dried (MgSO4), the solids were removed by tion and the solvents of the filtrate were removed in vacuo. The residue was purified via silica gel column chromatography using a gradient of dichloromethane to 10% methanol in dichloromethane (containing ammonia). The product fractions were collected and concentrated in vacuo. Acyl deprotection was afforded after treatment with sodium methoxide in methanol at 60°C for one hour. The solvents were removed under reduced pressure and the residue was partitioned between water and dichloromethane. The c layer was separated, dried (MgSO4), the solvents were removed via filtration and the solvents of the filtrate were removed in vacuo. The t was crystallized from CH3CN, ed by filtration and dried in vacuo to obtain a white solid, 20.
Preparation of 21 Br [TL/$— /N N N o HN \ «N=\ \ HN N N N j 1. Pd2(dba)3, 033H53P A O K3PO4 N NH2 toluene/t-buOH 120°C, 12h 2. NaOCH3, CH3OH VI-3 21 In a first vial equipped with a magnetic stir bar and a screw cap septum, a solution of Pd2(dba)3 (6 mg, 0.007 mmol ) and 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2',4',6'-triisopropy l-1,1'-biphenyl (6 mg, 0.013 mmol) in toluene (0.5 mL) was flushed with N2 gas then stirred at 120 °C for 3 minutes. A second vial, ed with a magnetic stir bar and a screw cap septum, was charged with 2-methylimidazole (104 mg, 1.26 mmol ) and K3PO4 (224 mg, 1.05 mmol), then Vl-3 (200 mg, 0.53 mmol) and also flushed with N2(g). The premixed catalyst solution followed by anhydrous e (0.5 mL) and t—butanol (1.0 mL) were added via syringe to the second vial (total 2 mL of toluene: t—BuOH 1:1 on). The reaction was heated to 120 °C for 12 hours.
WO 56498 The mixture was cooled and sodium methoxide (30% in methanol) was added.
The mixture was heated at 60°C for 1 hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was partioned between water and dichloromethane. The organic layer was separated, dried (MgSO4), the solids were removed by filtration and the solvents of the filtrate were trated in vacuo. The crude was purified by Prep HPLC (RP SunFire Prep C18 OBD-10 um,30 x150 mm). Mobile phase (0.25% NH4HC03 solution in water, CH3CN). The product fractions were collected and concentrated in vacuo to afford compound 21.
Preparation of 22 . H \NXNJOK HN 1. yl(1e-thoxyvinyl)tin H PdCI2(PPh3)2 N/JLNH 80°C,16h 2. NaOCH3, CH3OH VI-2 22 A mixture of Vl-2 (500 mg, 1.48 mmol), tributyl(1-ethoxyvinyl)tin (0.626 mL, 1.85 mmol), PdCl2(PPh3)2 (220 mg, 0.31 mmol) in DMF (10 mL) was heated to 80 °C for 16 hours. The reaction mixture was cooled and HCI (1N, 2 mL) was added. The mixture was stirred at room temperature for 2 hours then was poured into sat. aq. NaHC03 (100 mL) and the precipitate was isolated by filtration, tituted in dichloromethane, dried (MgSO4), the solids were removed by filtration and the solvents of the filtrate were concentrated in vacuo. The product was purified via silica gel column chromatography using a gradient of dichloromethane to 5% methanol in dichloromethane, the t fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered and dried under vacuum to become a pale yellow solid.
To the mixture was added ol (6 mL) and sodium methoxide (0.716 mL) and was stirred at 60°C for 1 hour . The mixture was cooled and concentrated in vacuo. The residue was partioned n water and dichloromethane. The organic layer was separated, dried ), the solids were removed by filtration and solvents of the filtrate were trated in vacuo. The product was triturated in DIPE, isolated by filtration and dried under vacuum to become a yellow solid, 22.
WO 56498 2012/059234 Preparation of 23 H H NH H NH 1 \N N/ NH2 NaBH4, CH3OH, rt, 2h N/)\NH2 22 23 22 (59 mg, 0.23 mmol ) was ded in methanol (2 mL) and sodium borohydride (9 mg, 0.23 mmol) was added. The mixture was stirred under N2(g) at room temperature for two hours. The mixture was diluted with dichloromethane (5 mL), then sat., aq. NH4C| (0.5 mL) was added followed by addition of NaHC03. The c layer was dried (MgSO4), the solids were removed via filtration and the solvents of the filtrate were concentrated in vacuo. The product was triturated in DIPE, isolated by filtration and dried under vacuum to become a pale yellow solid, 23.
Preparation of 24 Br H O NH / N O \ I k 0 N Pd OAc l “N N ,dppp m M KO(Ac )2 N NH2 THF,MeOH,CO 120°C,16h V|-2 Vl-4 Step 1. A 75 mL stainless steel autoclave was charged under nitrogen atmosphere with Vl-2 (626 mg, 1.87 mmol), Pd(OAc)2 (8 mg, 0.037 mmol), 1,3-bis(diphenylphosphino)propane (31 mg, 0.074 mmol), potassium acetate (364 mg, 3.71 mmol), THF (20 mL), and methanol (20 mL). The autoclave was closed and pressurized to 30 bar CO(g). The reaction mixture was stirred for 16 hours at 120°C. The reaction mixture was allowed to cool to room ature then concentrated in vacuo. The residue was dissolved in water and extracted with dichloromethane. The organic layer was dried (MgSO4), the solids were removed by filtration and the solvent of the filtrate was -28— trated in vacuo. The product was purified on a silica column using a dichloromethane to 5% methanol in dichloromethane gradient. The product ons were collected and concentrated in vacuo to obtain an off-white solid, VI-4.
HNH OH NH oIXCfi/ \ \N NXNH m N “”2 2 LAH, THF, -75°C VI-4 24 Step 2. To a solution of Vl-4 (190 mg, 0.69 mmol) in anhydrous THF (20 mL) was added LAH (1M in THF, 1.04 mL, 1.04 mmol) at -75°C under a en atmosphere. The reaction was allowed to stir for two hours while it slowly warmed to 0°C. Then the mixture was cooled on a ice-ethanol bath and carefully quenched by adding 15 mL ethyl acetate followed by Na2804 10H20 (2 g). The mixture was stirred for one hour and then dried over MgSO4, the solids were d by filtration and the solvent of the filtrate was removed under reduced pressure. The residue was purified by prep. HPLC (RP Vydac Denali C18 — 10 pm, 200 g, 5 cm). Mobile phase (0.25% NH4HC03 solution in water, CH3CN), followed by SFC purification (Chiralpak Diacel AD 30 X 250 mm). Mobile phase (C02, methanol with 0.2% isopropylamine), the desired fractions were collected, and the solvents were removed under reduced pressure to afford 24.
Preparation of 25 TMS OH \N E—TMS § A N N NH2 \ k PPh3)2 N NH2 PPh3, HNEt2, Cul, DMF v-14 V-15 Step 1. V-14 was reacted with trimethylacetylene according to the method to prepare compound 14, to afford V-15.
LC-MS m/z = 258 (M+H) . "/\OH \\ TMS OH \ AA-10 \NJ\NH2| 1.DBU, BOP,AA-1O HN \NXNHz| anhydrous DMF, rt (3) 2. NaHC03, CH30H "'/\OH v-15 Vl-5 Step 2. Vl-5 was prepared according to the method to prepare compound 9.
Deprotection of the TMS group was performed in a NaHCOB, water, methanol mixture.
LC-MS m/z = H) I \ \ HN N NH2 '3“ N NH2 H2,10%Pd/C ()-,,/\ (3),,” CH3OH,THF,rt " OH Vl-5 25 Step 3. The hydrogenation was performed ing to the method to prepare Preparation of 26 H2N—</ >—< —’ H2N Pd (OAc)2, dppp Br KOAc, THF, water, CO 110°C, 16h 2—aminoisopropylbenzoic acid Step 1. Palladium catalyzed carbonylation of 2—bromoisopropylaniline was performed according to the ure to prepare Vl-4 with the exception that the reaction was run at 110°C to afford 2-aminoisopropylbenzoic acid.
LC-MS m/z = 180 (M+H) H2N \NANHZ| NHZCN, HCI EtOH reflux 2-aminoisopropylbenzoic acid V-16 Step 2. V-16 was prepared according to the method to prepare V-1.
LC-MS m/z = 204(M+H) AA-1O m N \N DBU, PyBOP HN N NH NH2 2 anhydrous DMF, rt (8) . /\ ’ OH V-16 26 Step 3. Example 26 was prepared according to the method to prepare 15.
Preparation of 27 N// j: HCI H2N NH HCI, EtZO, rt Step 1. Cyanamide was dissolved in ether and the mixture was stirred under nitrogen gas. HCI (2M in ether) was added dropwise to the on mixture at ambient temperature and stirring ued for 2 hours at room temperature.
The precipitate, A-2 was ed by filtration and dried in vacuo at 50°C.
C Cl o 5 o F NH2 N F CI F \ k F O O A HCI HO N NH2 \ H2N NH IV-1 V-17 Step 2. SOz(CH3)2 (20.4 g, 217 mmol) was heated to melting. A-2 (3.3 g, 29 mmol) was added and the resulting mixture was stirred and heated to 120°C to dissolve completely. Methyl 5-(2-chlorotrifluoromethylphenoxy)— anthranilate (5 g, 14.5 mmol) was added in one part to the reaction e.
Stirring was continued for 30 s. The reaction e was d with water (10 mL) and stirred for 10 minutes. The precipitate, V-17, a white solid, was isolated by filtration and dried in the vacuum oven.
LC-MS m/z = 356 (M+H) CI 0 AA—10 F F DBU,P BOP F @N\ k F y HN N \ k NH2 F anh ydrous DMF, rt HO N NH2 (S) I/\OH V-17 Step 3. Compound 27 was formed according to the method to prepare 15.
Preparation of 28 O Os 0' O + O \ + o \o \o N‘o 1/0 C| HNO3, H2804 O 0 Cl Cl 0 °C K/O k/O A3 A4 A6 Step 1. A-3 (101 g, 0.44 mol) was dissolved in sulfuric acid (850 mL). This solution was cooled to 0°C. HN03 (18.3 mL, 0.44 mol) in sulfuric acid (200 mL) was added dropwise over 2 hours. The reaction mixture was d for 45 minutes at -10°C, then poured into ice-water (6 L). The solvents were decanted and the residue was dissolved in romethane (1.5 L). The aqueous layer was extracted with dichloromethane (1 L). The combined organic layers were dried (MgSO4), the solids were removed by filtration and the solvent was removed under reduced pressure to afford A-4, and the side product isomer A-5, separated via silica gel column chromatography using a heptane to ethyl acetate gradient.
WO 56498 N02 0 NH2 0 o/ 0 Cl 0 (3' % Pt/C, H2 0y CHgOH (2% thiophene) Oj A-4 lV-2 Step 2. Into a 500 mL erlenmeyer flask equipped with a magnetic stir bar and sparged with nitrogen gas was placed methanol (100 mL, containing 2% thiophene), 5% Pt/C (2 g, 0.513 mmol) then placed under a hydrogen atmosphere. The reaction mixture was d for 16 hours at room temperature. The catalyst was removed by filtration and the volatiles of the filtrate were removed under reduced pressure. The residue was purified on silica using a dichloromethane to dichloromethane: methanol 9:1 gradient yielding a yellow oil, IV-2.
LC-MS m/z = 244 (M+H) 9 Cl NH2 0 /s\ o O/ O > E 0 N 0j A Ho NM H2N NH 2 lV-2 V-18 Step 3. ediate V-18 was prepared according to the method to prepare V-17.
LC-MS m/z = 254 (M+H) O N [O DBU, BOP, n-butylamine_ O N \ k | \ )\ HO N NH anhydrous DMF, rt 2 /\/\ N N NH2 V-18 28 Step 4. The procedure to prepare compound 9 was applied in the synthesis of 28 from V-18. ation of compound 29 H2, Pd/C, CH30H, rt OHNENINNHZ ,1 (HS)N OH ,/\ Step 1. Example 29 was afforded after catalytic hydrogenation of 27, according to the method described in the preparation of 25.
Preparation of 90 O O O OH | LIOH(aq) l MM\N/|\NH2 CH30H,THF,rt /\/\N \ /|\ VI-6 Step 1. 17 (12.515 g, 45.62 mmol) was dissolved in THF (100 mL). LiOH (3.83 g, 91.2 mmol) dissolved in water (20 mL) was added, followed by ol (50 mL). The reaction mixture was stirred ght at room temperature. The volatiles were removed under reduced pressure, the solid was washed with water and triturated with DIPE to afford Vl-6 as off-white solid. 1H NMR (400 MHz, DMSO-de) 6 ppm 0.95 (t, J=7.4 Hz, 3 H), 1.40 (dq, J=14.9, 7.3 Hz, 2 H), 1.68 (quin, J=7.3 Hz, 2 H), 3.54 - 3.65 (m, 2 H), 7.89 - 8.05 (m, 2 H), 8.14 - 8.31 (m, 2 H), 9.11 (br. s., 1 H), 11.10 (br. s.,1 H), 16.37 (br. s.,1 H) O OH GNU N )2CN \ NEt3 DMF 2h rt MN N/|\NH2 VI-6 90 Step 2. Into a 50 mL vial was placed Vl-6 (200 mg, 0.768 mmol), DMF (10 mL), triethylamine (0.641 mL, 4.61 mmol), 3-aminopyridine (181 mg, 1.92 mmol) and diethyl cyanophosphonate (0.233 mL, 1.54 mmol). The reaction was d to stir for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was purified via e phase column chromatography (Sunfire Prep C18, OBD 10um, 30 X 150 mm. Mobile phase (0.25% 3 solution in water, methanol) to afford 90.
Synthetic Scheme for the preparation of AA-9 E\P C Vii/NpH PhP\An/O7< 0 Ph 0 AA-4 AA_2 THF,16h, rt n-BuLi, THF, -78°C AA-1 AA-3 X 8) LAH/THF 10% Pd/C ,50psi, O \\ N (S) —> HO/\\\(L43) N(S) MeOH, 50°C, 24h BOC\ Boc20, Et3N OAc NHZHC' HO‘\—§\—\¥DCM HO‘\:s§-:::\¥—>EtOAC (S AA 9 Synthesis of intermediate AA-3 Ph P/\n/:A7<><\ THF 16h rt AA-1 AA-3 To a solution of valeraldehyde (43 g, 500 mmol) in THF (1 L) was added AA-2 (200 g, 532 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvents were evaporated and the residue was diluted in eum ether and filtered. The solvents of the filtrate were removed under reduced pressure and the residue was purified by silica chromatography using a petroleum ether to 3% ethyl acetate in petroleum ether gradient to give AA-3 (90 g) as a colorless oil. 1H NMR (400 MHz, CDCI3): 6 ppm 6.81-6.77 (m, 1H), 5.68-5.64 (td, J=1.2Hz, .6 Hz, 1H), 2.11-2.09 (m, 2H), 1.406 (s, 9H), 1.38-1.26(m, 4H), 0.85-0.81(t, J=7.2Hz, 3H).
Synthesis of compound AA-5 O @nfi xi n-BuLi, THF, -78°C AA-3 AA-5 n-butyl lithium (290 mL, 725 mmol, 1.5 eq.) was added to a stirred solution of AA-4 (165 g, 781 mmol) in THF (800 mL) at -78°C. The reaction mixture was stirred for 30 minutes then AA-3 (90 g, 488.4 mmol) in THF (400 mL) was added and the reaction was stirred for 2 hours at -78°C. The mixture was quenched with sat., aq. NH4C| solution and warmed to room ature. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and ated. The residue was purified by column chromatography g with 5% ethyl acetate in petroleum ether to afford a colorless oil, AA-5 (132 g). 1H NMR (400 MHz, coolg): 6 ppm .16 (m, 10H), 3.75-3.70 (m, 2H), 3.43- 3.39 (d, J=15.2Hz, 1H), 3.33-3.15 (m, 1H), 1.86-1.80 (m, 2H), 1.47-1.37 (m, 2H), 1.32 (s, 9H), .17 (m, 7H), .79 (t, J=7.2Hz, 3H).
Synthesis of AA-6 (S) LiAIH4 s N (S) —> Ho/\\“' ()N (S) 0°C (>2 AA-6 AA-5 (130 g, 328 mmol) was dissolved in THF (1.5 L) and LAH (20 g, 526 mmol) was added at 0°C in small portions. The resulting mixture was stirred at the same temperature for 2 hours and then allowed to warm to room temperature. The mixture was quenched with a sat. aq. NH4C| solution. The product was partitioned between ethyl e and water. The organic phase was washed with brine, dried and evaporated. The combined organic layers were dried over sodium sulfate, the solids were removed via filtration and trated to afford crude AA-6 (100 g), which was used in the next step without further purification. 1H NMR (400 MHz, coolg): 8 ppm .14 (m, 10H), 3.91-3.86 (m, 1H), 3.80- 3.77 (d, J=13.6Hz, 1H), 3.63-3.60 (d, J=13.6Hz, 1H), 3.43-3.42 (m, 1 H), 3.15- 3.10 (m, 1H), 2.70-2.63 (m, 2H), 1.65-1.28 (m, 10H), 0.89-0.81 (m, 3H).
Synthesis of AA-9 % Pd/C 50psi (300)20EtsN DCM 50°C, 24h AA-7 AA-8 HCI/EIOAC EIOAC k HOwNH2 HCI AA-9 A solution of AA-6 (38 g, 116.75 mmol) and 10% Pd/C in ol (200 mL) was hydrogenated under 50 PSI hydrogen at 50°C for 24 hours. The reaction mixture was filtered and the solvent was evaporated to give crude product AA-7 (17 g).
The crude product was dissolved in dichloromethane (200 mL), triethylamine (26.17 g, 259.1 mmol) and di-tert—butyl dicarbonate (84.7g, 194.4 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was partitioned n dichloromethane and water. The organic phase was washed with brine, dried and evaporated. The residue was ed by silica gel tography eluting with 20% ethyl e in petroleum ether to give AA-8 (13 g) as colorless oil. 1H NMR (400 MHz, coolg): 8 ppm 4.08-4.03 (br, 1H), 3.68 (m, 1H), 3.58-3.55 (m, 2H), 3.20-2.90(br, 1H), 1.80-1.73 (m, 1H), 1.42-1.17 (m, 15 H), 0.85-0.82(t, J=6.8Hz, 3H).
AA-8 (42 g, 0.182 mol) was dissolved in dioxane (200 mL) and dioxane/HCI (4M, 200 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 2h. The solvent was evaporated to afford the crude product. A dichloromethane/ petroleum ether e (50 mL, 1:1, v/v) was added to the crude product, and the supernatant was decanted. This procedure was repeated two times to obtain an oil, AA-9 (26.6 g). 1H NMR (400 MHz, DMSO-da): 6 ppm 8.04 (s, 3H), 3.60-3.49 (m, 2H), 3.16- 3.15 (m, 1H), 1.71-1.67 (m, 2H), 1.60-1.55(m, 2H), 1.33-1.26 (m, 4H), 0.90- 0.87 (t, J=6.8Hz, 3H).
Preparation of AA-10 HOWNH2 HCI AA-10 AA-10 was prepared according to the preparation of AA-9, using butyraldehyde instead of valeraldehyde. 1H NMR (400 MHz, DMSO-de):6 ppm 8.07 (s, 3H), 4.85 (br, 1H), 3.57-3.45 (m, 2H), 3.14-3.12 (m, 1H), 1.70-1.64 (m, 2H), 1.56-1.49 (m, 2H), .30 (m, 2H), 0.90-0.80 (t, J=6.8Hz, 3H). -38— Table 1. Com ounds of formula I .
# Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (360 MHz, e) 5 N)_N ppm 0.93 (t, J=7.3 Hz, 3 H), 1.31 N/ \ N\_\— - 1.43 (m, 2 H), 1.60 (t, J=7.1 HZ, 1 2 H), 3.40 - 3.48 (m, 2 H), 3.79 A, 0-67 —o /o (s, 3 H), 3.79 (s, 3 H), 5.67 (s, 2 H), 6.63 (s, 1 H), 7.40 (s, 1 H), 7.44 - 7.50 (m, 1 H) 1H NMR (360 MHz, DMSO-de) 5 N)_N /—/_/ ppm 0.85 - 0.93 (m, 3 H), 1.27 - Same / \ 1.37 (m, 4 H), 1.57 _ 1.68 (m, 2 N N method as 2 H), 3.39 - 3.49 (m, 2 H), 3.78 (s, A, 0-86 to prepare 3 H), 3.79 (s, 3 H), 5.67 (s, 2 H), _0 /° 1_ 6.63 (s, 1 H), 7.40 (s, 1 H), 7.47 (t, J=5.7 Hz, 1 H) 1H NMR (360 MHz, DMSO-de) 5 ppm 0.79 - 0.91 (m, 3 H), 1.29 o (m, J=3.3 Hz, 4 H), 1.59 (m, J=6.6 N)_ {f Hz, 2 H), 1.64 - 1.70 (m, 1 H), Same ~ N\ ~ 1.72 _ 1.79 (m, 1 H), 3.40 _ 3.50 method as 3 A, 074 (m, 2 H), 3.80 (s, 3 H), 3.80 (s, 3 to prepare —° ,° H), 4.33 - 4.43 (m, 1 H), 4.48 (t, 1- J=5.1 Hz, 1 H), 5.68 (s, 2 H), 6.63 (s, 1 H), 7.09 (d, J=8.4 Hz, 1 H), 7.44 (s, 1 H) 1H NMR (400 MHz, 0 CHLOROFORM-d) 5 ppm 0.91 (t, N <_/_/ )/_N\ Same J=7.0 Hz, 3 H), 1.28 - 1.48 (m, 5 N N methOd as 4 H), 1.58 - 1.77 (m, 2 H), 3.48 (s, 1 A, 068 H), 3.72 (dd, J=11.0, 6.3 Hz, 1 H), to prepare _° /° 3.88 (s, 3 H), 3.91 (s, 3 H), 4.34 (td, J=6.8, 2.8 Hz, 1 H), 4.78 (br. s., 2 H), 5.64 (d, J=7.0 Hz, 1 H), _39_ Method, Synthetic STRUCTURE H NMR Rt Method 6.81 (s, 1 H), 6.81 (s, 1 H) 1H NMR (360 MHz, DMSO-de) 5 ppm 0.88 (t, J=7.3 Hz, 3 H), 1.23 - N>/_N\ 1.42 (m, 2 H), 1.48 Same - 1.81 (m, 4 g—L H), 3.39 - 3.48 (m, 2 H), 3.79 (s, 3 method as A, 069 H), 3.80 (s, 3 H), 4.38-4.46 (m, 1 to prepare _° /° o H), 4.49 (t,J=5.3 Hz, 1 H), 5.68 (s, 1- 2 H), 6.63 (s, 1 H), 7.08 (d, J=8.4 Hz, 1 H), 7.44 (s, 1 H) 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 0.95 (t, J=7.3 Hz, 3 H), 1.35 - 1.52 (m, 2 N>/_N\ H), 1.60 - 1.71 (m, 2 H), 3.48 (5, Same 2—\_ 1 H), 3.71 (dd, , 6.3 Hz, 1 method as A, 069 o H), 3.85 (s, 3 H), 3.85-3.88(m, to prepare _° /0 1 H), 3.90 (s, 3 H), 4.37 (td, 1- J=6.7, 3.3 Hz, 1 H), 4.85 (br. s., 2 H), 5.82 (d, J=7.3 Hz, 1 H), 6.78 (s, 1 H), 6.85 (s, 1 H) 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 0.89 - 0.96 (m, 4 H), 1.01 (d, J=1.0 Hz, N>/_N 4 H), 1.25 (ddd, J=13.7, 8.5, 7.4 Same N \ H Hz, 1 H), 1.47 - 1.65 (m, 1 H), method as 1.77 - 1.92 (m, 1 H), 3.48 (s, 0 o to prepare —0 /o H), 3.81 - 3.84 (m, 1 H), 3.87 (s, 3 H), 3.87 (s, 3 H), 4.21 - 4.31 (m, 1 H), 5.15 (br. s., 2 H), 6.04 - 6.11 (m, 1 H), 6.74 (s, 1 H), 6.86 (s, 1 H) Method, tic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 - 0.96 (m, 3 H), 1.31 - 1.43 (m, 2 H), 1.57 - 1.67 (m, 2 Same H), 3.44 - 3.52 (m, 2 H), 6.04 (s, method as 2 H), 7.01 (ddd, J=8.1, 7.0, 1.0 A, 0.64 to prepare Hz, 1 H), 7.20 (dd, J=8.4, 0.9 Hz, 1 H), 7.46 (ddd, J=8.3, 6.9, 1.4 Hz, 1 H), 7.75 (t, J=5.4 Hz, 1 H), 7.98 (dd, J=8.2, 0.9 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.4 Hz, 3 H), 1.29 - 1.44 (m, 2 H), 1.63 (t, J=7.3 Hz, C,0.83 2 H), 3.55 - 3.64 (m, 2 H), 4.02 (s, 3 H), 6.99 (dd, J=8.3, 1.8 Hz, 2 H), 7.69 (t, J=8.3 Hz, 1 H), 7.81 - 8.29 (m, 2 H), 9.10 (s, 1 H), 12.49 (s, 1 H) 1H NMR (360 MHz, DMSO-de) 5 ppm 0.80 (t, J=1.00 Hz, 3 H) 0.83 - 0.93 (m, 1 H) 0.96 - 1.17 (m, 2 H) 1.20 - 1.35 (m, 1 H) 3.10 - 3.26 (m, 2 H) 3.36 (br. s., 2 H) C,0.88 4.12 (td, J=8.23, 4.39 Hz, 1 H) 4.56 - 4.74 (m, 1 H) 5.96 (d, J=8.42 Hz, 1 H) 7.18 (d, J=1.00 Hz, 1 H) 7.37 - 7.64 (m, 6 H) 7.81 (t,J=1.00 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.28 Hz, 3 H) 1.36 - 1.46 (m, 2 H) 1.55 - 1.63 (m, 2 11 H) 3.37 (s, 3 H) 3.44 (td, J=6.96, C,0.85 experimen tal section .14 Hz, 2 H) 3.74 - 3.80 (m, 2 H) 4.24 (dd, J=5.27, 3.76 Hz, 2 H) 6.04 (br. s, 2 H) 6.57 (d, J=7.53 W0 2012/156498 _41_ # Method, Synthetic STRUCTURE H NMR Rt Method Hz, 1 H) 6.77 - 6.81 (m, 1 H) 7.34 (t, J=8.16 Hz, 1 H) 7.97 (t, J=5.02 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.90 (t, J=7.37 Hz, 3 H) 1.32 - 1.42 (m, 2 H) 1.63 - 1.71 (m, 2 N:>/_N\ H/_/— H) 3.05 — 3.12 (m, 2 H) 3.38 - c,0.99 See 3.48 (m, 2 H) 3.52 - 3.59 (m, 2 H) 12 experimen /N_\ 5.93 (s, 2 H) 6.88 (dd, J=7.15, tal section 1.21 Hz, 1 H) 7.07 (dd, J=8.25, 1.21 Hz, 1 H) 7.23 - 7.34 (m, 4 H) 7.71 - 7.76 (m, 1 H) 8.53 - 8.56 (m, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 - 0.93 (m, 3 H), 1.25 - “”$_N 1.40 (m, 4 H), 1.61 (t, J=6.9 Hz, 2 Same N/ \ NH H), 3.39 - 3.48 (m, 2 H), 6.13 (s, method as 13 @099 2 H), 7.11 (d, J=9.0 Hz, 1 H), 7.55 to prepare Br (dd, J=8.8, 2.3 Hz, 1 H), 7.79 9 7.90 (m, 1 H), 8.25 (d, J=2.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.92 (t, J=7.15 Hz, 3 H) 1.29 NH - 1.45 (m, 5 H) 1.51 - 1.67 (m, 2 c,0.74 See H) 3.40 - 3.51 (m, 2 H) 4.60 (br. 14 experimen \:S 5., 1 H) 5.41 (br. s., 1 H) 6.18 (br. tal section ., 2 H) 7.11 (d, J=8.58 Hz, 1 H) 7.41 (d, J=8.36 Hz, 1 H) 7.83 - 7.96 (m, 1 H) 8.14 (br. s., 1 H) 1H NMR (400 MHz, e) 5 ~H—/_/ 599 ppm 0.92 (m, J=7.3, 7.3, 2.3 Hz, N/ \ NH° 6 H), 1.29- 1.45(m,4H),1.47- 90-97 experime” “Hf“ \‘\_ “J" seCt‘O” 1.60 (m, 4 H), 3.24 - 3.30 (m, 2 H), 3.39 (td, J=6.8, 5.0 Hz, 2 H), Method, Synthetic STRUCTURE H NMR Rt Method 6.10 (s, 2 H), 6.96 (dd, J=7.0, 1.3 Hz, 1 H), 7.29 (dd, J=8.4, 1.4 Hz, 1 H), 7.46 (t, J=8.4 Hz, 1 H), 7.95 (t, J=4.8 Hz, 1 H), 8.88 (t, J=5.6 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.37 Hz, 3 H) 1.10 (d, J=6.16 Hz, 3 H) 1.30 - 1.42 (m, 2 H) 1.56 - 1.72 (m, 4 H) 2.53 - 2.75 (m, 2 H) 3.40 - 3.50 (m, 2 16 H) 3.57 - 3.66 (m, 1 H) 4.46 (d, C,0.75 experimen J=4.62 Hz, 1 H) 5.83 (s, 2 H) 7.10 tal section (d, J=8.58 Hz, 1 H) 7.31 (dd, J=8.58, 1.76 Hz, 1 H) 7.65 (t, J=5.39 Hz, 1 H) 7.76 - 7.84 (m, 1 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.4 Hz, 3 H), 1.37 (dq, J=14.9, 7.4 Hz, 2 H), 1.66 Same (quin, J=7.3 Hz, 2 H), 3.52 - 3.63 method as 17 4:1: (m, 2 H), 3.71 (br. to s, 2 H), 3.93 C,0.78 prepare (s, 3 H), 7.88 (dd, J=8.5, 1.5 Hz, 1 9 from V- H), 8.01 (d, J=1.5 Hz, 1 H), 8.46 25 (d, J=8.5 Hz, 1 H), 9.67 (t, J=5.4 Hz, 1 H), 12.84 (s, 1 H)(HC| salt) 1H NMR (400 MHz, e) 5 ppm 0.92 (t, J=7.3 Hz, 3 H), 1.36 (dq, J=14.9, 7.4 Hz, 2 H), 1.60 \ NH (quin, J=7.3 Hz, 2 H), 3.41 - 3.49 c,0.58 18 3;; \-\_N (m, 2 H), 4.53 (s, 2 H), 6 5.24 (br. experimen tal section 0H s., 1 H), 5.98 (s, 2 H), 6.96 (dd, J=8.3,1.5 Hz, 1 H), 7.13 (s, 1 H), 7.69 (t, J=5.4 Hz, 1 H), 7.92 (d, J=8.5 Hz, 1 H) W0 2012/156498 _43_ # Method, Synthetic URE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.37 Hz, 3 H) 1.31 :S/_N\ - 1.44 (m, 2 H) 1.55 - 1.65 (m, 2 19 \—\_ H) 3.42 - 3.51 (m, 2 H) 6.57 (br. @083 experimen s., 2 H) 7.20 (d, J=8.80 Hz, 1 H) tal section 7.71 (dd, J=8.58, 1.76 Hz, 1 H) 8.02 (br. s., 1 H) 8.55 (d, J=1.76 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.40 Hz, 3 H) 1.33 HT - 1.45 (m, 2 H) 1.64 (m, J=7.30, 7.30, 7.30, 7.30 Hz, 2 H) 3.41 - B,4.24 See 3.57 (m, 2 H) 3.88 (s, 3 H) 5.93 experimen HN \NflNHZ )2 (s, 2 H) 7.16 (d, J=8.78 Hz, 1 H) ta' section 7.62 - 7.74 (m, 2 H) 7.86 (s, 1 H) 8.04 (s, 1 H) 8.18 (d, J=1.76 Hz, 1 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.4 Hz, 3 H), 1.39 (dq, J=14.9, 7.4 Hz, 2 H), 1.59 - N),—~\ 1.67 (m, 2 H), 2.18 (d, J=0.9 Hz, NH see L\_ 3 H), 3.48 (td, J=7.0, 5.6 Hz, 2 H), 21 3,45 experimen 6.11 (s, 2 H), 7.26 (d, J=8.9 Hz, 1 (:1 tal section N H), 7.39 (t, J=1.2 Hz, 1 H), 7.71 (dd, J=9.0, 2.5 Hz, 1 H), 7.78 (t, J=5.4 Hz, 1 H), 8.05 (d, J=1.5 Hz, 1 H), 8.18 (d, J=2.3 Hz, 1 H) 1H NMR (400 MHz, e) 5 ~H>_ ppm 0.94 (t, J=7.26 Hz, 3 H) 1.26 N/ \ NH - 1.49 (m, 2 H) 1.64 (quin, J=7.21 C,0.73 22 LL Hz, 2 H) 2.58 (s, 3 H) 3.50 (q, experime“ 0 tal section J=6.53 Hz, 2 H) 6.43 (br. s., 2 H) 7.17 (d, J=8.80 Hz, 1 H) 7.96 (d, J=8.80 Hz, 1 H) 8.19 (br. s., 1 H) Method, Synthetic STRUCTURE H NMR Rt Method 8.67 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.37 Hz, 3 H) 1.30 - 1.42 (m, 5 H) 1.61 (quin, J=7.32 Hz, 2 H) 3.42 see - 3.50 (m, 2 H) 4.70 23 -4.77 (m, 1 H) 5.07 - 5.16 (m, 1 C,0.66 experimen H) 5.93 (s, 2 H) 7.15 (d, J=8.36 tal section Hz, 1 H) 7.48 (dd, J=8.58, 1.54 Hz, 1 H) 7.79 (t, J=5.28 Hz, 1 H) 7.91 (d, J=1.54 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.92 (t, J=7.32 Hz, 3 H) 1.25 - 1.44 (m, 2 H) 1.60 (quin, J=7.23 Hz, 2 H) 3.38 - 3.50 (m, 2 H) 4.49 C,0.56 see 24 (d, J=5.12 Hz, 2 H) 5.14 (t, J=5.49 men tal section OH Hz, 1 H) 5.92 (s, 2 H) 7.14 (d, J=8.42 Hz, 1 H) 7.43 (d, J=8.05 Hz, 1 H) 7.74 (t, J=4.76 Hz, 1 H) 7.90 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 (t, J=7.28 Hz, 3 H) 1.17 - 1.29 (m, 3 H) 1.29 - 1.39 (m, 2 H) 1.54 - 1.71 (m, 2 H) 1.76 - 1.86 (m, 2 H) 2.71 (q, J=7.61 Hz, see 2 H) 3.46 (t, J=6.65 Hz, 2 H) 4.54 C,0.81 experimen -4.63 (m, 1 H) 7.36 - 7.40 (m, 1 tal section H) 7.66 (dd, J=8.41, 1.63 Hz, 1 H) 7.81 (br. s., 2 H) 8.21 (s, 1 H) 8.87 (d, J=8.53 Hz, 1 H) 12.31 (s, 1 H) _45_ # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.90 (t, J=7.32 Hz, 3 H) 1.27 (d, J=6.95 Hz, 6 H) 1.29 - 1.40 “)5N (m’ 2 H ) 1.57- 1.74 (m’ 2 H ) 1.74 N C,0.85 see 3 - 1.90 (m, 2 H) 2.93 - 3.05 (m, 1 26 . experimen OH H) 3.41 - 3.53 (m, 2 H) 4.54 - tal section 4.65 (m, 1 H) 7.38 (d, J=8.42 Hz, 1 H) 7.70 (dd, J=8.60, 1.65 Hz, 1 H) 8.27 (s, 1 H) 8.98 (d, J=8.42 Hz, 1 H) 12.49 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.87 (t, J=7.4 Hz, 3 H), 1.23 - 1.38 (m, 2 H), 1.49 - 1.62 (m, 2 % H), 1.63 - 1.79 (m, 2 H), 3.44 (t, N \ NH 27 db J=6.4 Hz, 2 H), 4.33 - 6 4.42 (m, see 1 H), 4.42 - 4.52 (m, 1 H), 6.43 c,1.1 experimen 5g (br. t6" section s., 2 H), 6.99 (d, J=8.8 Hz, 1 H), 7.34 (d, J=9.0 Hz, 1 H), 7.41 (dd, J=9.0, 2.5 Hz, 1 H), 7.58 - 7.68 (m, 2 H), 8.02 (d, J=2.0 Hz, 1 H), 8.06 (d, J=2.5 Hz, 1 H) 1H NMR (400 MHz, d-DMF) 5 ppm 1.36 (t, J=7.4 Hz, 3 H), 1.79 <— ' (dq, J=14.9, 7.4 Hz, 2 H), 1.97 - ° C’O'SS —\—\NH 207 (m, 2H )’ 388 (tdJ-7058_ 28 ' ' ’ ' ’ ' men ) N / Hz, 2 H), 4.74 - 4.80 (m, 2 H), tal section. 4.86 - 4.92 (m, 2 H), 6.38 (s, 2 H), 7.25 (s, 1 H), 8.07 (t, J=5.5 Hz, 1 H) 1% 1H NMR (400 MHz, DMSO-de) 5 dgs—LW see ppm 0.87 (t, J=7.4 Hz, 3 H), 1.22 29 W - 1.39 (m, 2 H), 1.46 - 1.61 (m, 2 91-05 exper'me” tal section H), 1.61 - 1.79 (m, 2 H), 3.43 (t, J=6.5 Hz, 2 H), 4.28 - 6 4.50 (m, W0 2012/156498 # Method, Synthetic STRUCTURE H NMR Rt Method 2 H), 6.07 (s, 2 H), 7.10 (d, J=8.8 Hz, 2 H), 7.24 - 7.40 (m, 3 H), 7.71 (d, J=8.5 Hz, 2 H), 7.98 (d, J=2.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.28 Hz, 3 H) 1.35 - 1.45 (m, 2 H) 1.56 - 1.65 (m, 2 Same O _ = as ./ \ .H 335,2135325129333 £2' ' ' ' ' _N to e "“2 \_\_ Hz, 2 H) 6.38 (br. s., 2 H) 6.69 (d, J=8.03 Hz, 1 H) 6.86 (d, J=7.78 Hz, 1 H) 7.42 (t, J=8.28 Hz, 1 H) 8.04 (br. s., 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.40 Hz, 3 H) 1.38 (d, J=6.02 Hz, 6 H) 1.40 - 1.47 NHfi—N Same 31 Ex 64:35:31.3; 1:53:13 ° ' ’ ' ' ’ >— to prepare H) 6.08 (br. s., 2 H) 6.61 (d, J=8.03 Hz, 1 H) 6.76 (dd, J=8.28, 0.75 Hz, 1 H) 7.35 (t, J=8.16 Hz, 1 H) 7.97 (br. s., 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 (t, J=7.40 Hz, 3 H) 1.36 MHz (dq, J=14.90, 7.41 Hz, 2 H) 1.56 - Same N/ \ /_/_ 1.66 (m, 2 H) 2.82 - 2.93 (m, 2 H) NH c,1.1 method as 32 3.34 - 3.43 (m, 2 H) 3.43 - 3.52 O to prepare (m, 2 H) 5.95 (s, 2 H) 6.60 (t, J=5.14 Hz, 1 H) 6.83 - 6.89 (m, 1 H) 7.07 (dd, J=8.28, 1.25 Hz, 1 H) 7.16 - 7.35 (m, 6 H) _47_ # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 8 ppm 0.89 (t, J=7.4 Hz, 3 H), 1.21 - 1.45 (m, 2 H), 1.48 - 1.71 (m, 2 "”2 Same N H), 3.49 (qd, J=10.4, 5.8 Hz, 2 H), N>/—\ N” method as 33 2'“— 4.31 - 4.43 (m, 1 H), 6 4.54 (s, 2 @051 to prepare W H), 4.71 (br. s., 1 H), 5.27 (br. 5., 1 H), 6.26 (br. 24 s., 2 H), 7.00 (dd, J=8.4, 1.4 Hz, 1 H), 7.16 (s, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 8.03 (d, J=8.5 Hz, 1 H) OH 1H NMR (400 MHz, e) 8 ppm 0.89 (t, J=7.15 Hz, 3 H) 1.34 (td, J=14.81, 7.78 Hz, 2 H) 1.48 - NH: 1.74 (m, 2 H) 3.48 (m, 1:11.70, >/_N\ Same N “If—\— 5.40 Hz, 2 H) 4.38 (m, 1-4.00 Hz, method as 34 1 H) 4.50 (d, J=4.02 Hz, 2 H) 4.68 33-04 OH to prepare (t, J=1.00 Hz, 1 H) 5.12 (t, J=1.00 OH 24 Hz, 1 H) 5.87 (br. s., 2 H) 7.15 (d, J=8.53 Hz, 1 H) 7.26 (d, J=8.03 Hz, 1 H) 7.44 (dd, J=8.50 Hz, 1 H) 7.98 (br. s., 1 H) 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.95 (t, J=7.4 Hz, 3 H), 1.42 (dq, J=15.1, N’ N) NH 7.4 Hz, 2 H ) 1.58 - 1.70 ( ) Same L\_ , m, 2 H, c,1.15 3.56 (td,J=7.2, 5.6 Hz, 2 H), 4.96 meth0d as O 96 (s, 2 H), 5.70 (t, J=4.8 Hz, 1 H), to prepare 1 r 6.87 (d, J=8.5 Hz, 1 H), 7.25 - 7.30 (m, 2 H), 7.38 (dd, J=8.5, 1.5 Hz, 1 H), 7.43 - 7.48 (m, 1 H), 7.70 (d, J=2.0 Hz, 1 H) # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.40 Hz, 3 H) 1.30 ~H$_ - 1.47 (m, 2 H) 1.55 - 1.70 (m, 2 Same N N\ _ method as 36 ~H\_\_ H) 2.72 (s, 3 H) 3.42 3.53 (m, 2 @076 H)5.95 (s, 2 H) 6.44-6.60 (m, 1 to prepare H) 6.78 (d, J=7.03 Hz, 1 H) 7.04 9 (d, J=7.78 Hz, 1 H) 7.29 (dd, J=8.28, 7.28 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.6 Hz, 3 H), 1.36 (dq, , 7.4 Hz, 2 H), 1.55 - NH, Same N),—~\ 1.66 (m, 2 H), 3.42 - 3.51 (m, 2 C075 NH method as 37 H), 6.24 (br. s., 2 H), 6 6.94 (td, F to prepare 1:7.9, 5.0 Hz, 1 H), 7.29 (ddd, J=11.4,7.8,1.1 Hz, 1 H), 7.79 (d, J=8.3 Hz, 1 H), 7.84 (t, J=5.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.4 Hz, 3 H), 1.37 (dq, J=14.9, 7.4 Hz, 2 H), 1.56 - “HS—N Same N/ \ 1.67 (m, 2 H), 3.43 - 3.51 (m, 2 method as 38 NL\_ H), 6.38 (br. c 0 76 s., 2 H), 6 7.26 (dd, , - to prepare , 1:9.0, 5.3 Hz, 1 H), 7.42 (td, J=8.8, 3.0 Hz, 1 H), 7.93 (dd, J=10.2, 2.9 Hz, 1 H), 8.00 (t, J=5.0 Hz, 1 H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.93 (t, J=7.37 Hz, 3 H) NH>-~ 1.28 Same — 1.45 (111,2 H) 1.50 — 1.80 N/ \ NH 6071 \‘\_ (111,2 H) 3.40 met 0d as - 3.53 (111,2 H) 3.80 (s, 3 H) 6.07 (br. to s, 2 H) prepare 6.57 — 6.70 (m, 1 H) 6.64 (s, 1 H) 7.58 (s, 1 H) 7.81 — 8.04 (m, 1 H) W0 2012/156498 _49_ # Method, tic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 NH$_N ppm 0.94 (t, J=7.3 Hz, 3 H), 1.38 Same N/ \ (dq, J=14.9, 7.4 Hz, 2 H), 1.57 - method as 40 ~H\_\_ 1.69 (m, 2 H), 3.44-3.51(m, 2 00-71 to prepare / H), 3.56 (s, 3H), 5.87 (s, 2 H), 7.14 - 6 7.19 (m, 2 H), 7.50 (s, 1 H), 7.76 (t, J=5.4 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.32 Hz, 3 H) 1.29 NH: - 1.44 (m, 2 H) 1.63 (quin, J=7.23 Same method as 41 gNLL Hz, 2 H) 3.47 - 3.57 (m, 2 H) 6.67 3578 6. (br. to s., 2 H) 7.14 (dd, J=7.50, prepare 0.91 Hz, 1 H) 7.21 (dd, J=8.42, 9 1.10 Hz, 1 H) 7.40 - 7.51 (m, 1 H) 7.88 (br. s., 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.3 Hz, 2 H), 1.36 “Hg—~\ (dq, , 7.4 Hz, 2 H), 1.60 Same c 0.87 “ “”\_\_ ’ (quin,J=7.3 Hz, 2 H), 3.40-3.48 method as (m, 2 H), 6.15 (s, 2 H), 6 7.08 to prepare F F (dd, J=12.5, 7.8 Hz, 1 H), 7.71 (t, 9 J=5.3 Hz, 1 H), 8.10 (dd, J=12.0, 9.0 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.78 - 0.95 (m, 3 H), 1.15 - 1.42 (m, 2 H), 1.47 - 1.74 (m, 3 NH: H), 2.37 (s, 3 H), 3.22 - 3.27 (m, Same N/ N\ method as 43 N?“— 1 H), 3.42 - 3.60 (m, 2 H), 4.37 @064 (d, J=5.3 Hz, 1 H), 4.68 (br. to s., 1 prepare H), 6.89 (t, J=7.5 Hz, 1 H), 7.18 9 (d, J=8.3 Hz, 1 H), 7.33 (d, J=7.0 Hz, 1 H), 7.89 (d, J=8.0 Hz, 1 H).
LC-MS m/z = 261 (M+H) _50_ # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.20 - 1.44 (m, 2 H), 1.55 (td, J=9.1, 4.4 Hz, 1 H), 1.61 - 1.71 (m, 1 H), "”57“ 2.33 (s, 3 H), 3.41 - 3.57 (m, 2 Same N \ NH C,0.64 method as 44 25—\_ H), 4.24-4.43 (m, 1 H), 4.71 (br.
W s., 1 H), 5.88 (s, 2 H), 6.84 (dd, prepare J=8.3, 1.3 Hz, 1 H), 6.98 (s, 1 H), 9 7.19 (d, J=8.3 Hz, 1 H), 7.94 (d, J=8.3 Hz, 1 H) supports structure. LC-MS m/z = 261 (M+H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.80 - 0.92 (m, 3 H) 1.22 - 1.43 (m, 2 H) 1.48 - 1.70 (m, 2 H) ”:34 2.34 (s, 3 H) 3.47 (ddt, J=16.81, Same NH method as 45 25—\_ 10.98, 5.43, 5.43 Hz, 2 H) 4.30 - @065 4.40 (m, 1 H) 4.66 (t, J=5.40 Hz, to prepare 1 H) 5.79 (s, 2 H) 7.09 (d, J=8.28 9 Hz, 1 H) 7.15 (d, J=8.28 Hz, 1 H) 7.30 (dd, , 1.76 Hz, 1 H) 7.86 (s, 1 H) wembrech_1457_2 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 - 0.94 (m, 3 H) 1.31 - 1.45 (m, 2 H) 1.53 - 1.68 (m, 2 H) NH, Same N),—~\ 1.90 (s, 3 H) 2.73 (s, 3 H) 351- NH method as 46 6:5? 3.56 (m, 2 H) 4.30 - 4.39 (m, 1 H) 00-66 to prepare H 6.00 (s, 2 H) 6.28 (d, J=8.03 Hz, 1 H) 6.81 (d, J=7.03 Hz, 1 H) 7.05 (d, J=8.28 Hz, 1 H) 7.30 (t, J=8.00 Hz, 1 H) wembrech_1405_2 2012/059234 _51_ # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 (t, J=7.4 Hz, 3 H), 1.20 - 1.45 (m, 2 H), 1.47 - 1.72 (m, 2 NH, Same N),—~\ H), 3.41 - 3.56 (m, 2 H), 4.31 - C,0.64 NH method as 47 F625—\_ 4.43 (m, 1 H), 4.69 (br. 6 s., 1 H), to prepare 0H 6.24 (br. s., 2 H), 6.95 (td, J=7.9, .0 Hz, 1 H), 7.31 (dd, J=11.3, 7.8 Hz, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 7.90 (d, J=8.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.90 (t, J=7.3 Hz, 3 H), 1.20 NH, - 1.45 (m, 2 H), 1.51 - 1.73 (m, 2 Same N>/_“\ H), 3.54 (br. s., 2 H), 4.45 (td, "“5 method as 48 2_\_ J=8.5, 5.5 Hz, 1 H), 4.82(br. s., 1 00-65 to prepare F H), 7.18 (dd, J=10.0, 2.5 Hz, 1 H), 7.25 (td, J=8.8, 2.5 Hz, 1 H), 7.63 (br. s., 2 H), 8.41 (dd, J=9.0, 5.8 Hz, 1 H), 8.60 (d, J=8.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.90 (t, J=7.4 Hz, 3 H), 1.22 - 1.45 (m, 2 H), 1.49 - 1.72 (m, 2 "”37“ H), 3.43 - 3.55 (m, 2 H), 4.36 (td, Same N \ NH C063 method as 49 25—\_ J=8.7, 5.0 Hz, 1 H), 6 4.69 (br. 5., 1 H), 5.98 (s, 2 H), 7.22 (dd, to prepare J=9.0, 5.5 Hz, 1 H), 7.27 (d, J=8.3 9 Hz, 1 H), 7.37 (td, J=8.8, 2.8 Hz, 1 H), 7.98 (dd, , 2.8 Hz, 1 1H NMR (400 MHz, DMSO-de) 5 “”$_N Same ppm 0.92 (t, J=7.4 Hz, 3 H), 1.26 methOd -1.42 (m, 2 H), 1.59- 1.70 (m, 2 as 50 '8?“Ft}— C075 H), 3.53-3.67 (m, 3 H), 4.47 (d, to prepare J=5.3 Hz, 1 H), 7.21 - 7.36 (m, 2 H), 7.80 (td, J=8.3, 6.0 Hz, 1 H), _52_ # Method, Synthetic URE H NMR Rt Method 7.93 (dd, J=14.8, 8.5 Hz, 1 H), 8.38 (br. s., 1 H), 13.06 (br. s., 1 H). LC-MS m/z = 265 (M+H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.79 - 0.92 (m, 3 H) 1.19 - {L/J 1.39 (m, 4 H) 1.55 - 1.75 (m, 2 H) NH: Same N),—~\ :H 2.41 (s, 3 H) 3.46 - 3.61 (m, 2 H) c,0.73 method as 51 4.40 - 4.51 (m, 1 H) 7.36 (d, to prepare J=8.53 Hz, 1 H) 7.62 (d, J=8.28 Hz, 1 H) 7.80 (s, 2 H) 8.29 (s, 1 H) 8.87 (d, J=8.28 Hz, 1 H) 12.51 (s, 1 H) wembrech_1457_1 1H NMR (400 MHz, DMSO-de) 5 ppm 0.78 - 0.90 (m, 3 H) 1.20 - 1.39 (m, 4 H) 1.53 - 1.70 (m, 2 H) Same NH: CH “>79 1.90 (s, 3 H) 2.73 (s, 3 H) 350- .65 method as 2 i 3.57 (m, 2 H) 4.28 - 4.36 (m, 1 H) 00-75 to prepare .98 (s, 2 H) 6.28 (d, J=8.28 Hz, 1 H) 6.81 (d, J=7.03 Hz, 1 H) 7.05 (d, J=7.78 Hz, 1 H) 7.30 (t, J=8.30 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.23 ”HS—N - 1.39 (m, 2 H), 1.52 - 1.71 (m, 2 Same N/ \ H), 1.74 - 1.91 (m, 2 H), 2.43 (s, C,0.69 ““5 method as 53 $1 3 H), 3.45 (t, J=6.5 Hz, 2 H), 4.48 to prepare -4.60 (m, 2 H), 7.18 - 7.29 (m, 2 0H 9 H), 7.37 - 8.21 (m, 2 H), 8.35 (d, J=8.3 Hz, 1 H), 8.99 (d, J=8.3 Hz, 1 H), 12.78 (br. s., 1 H) _53_ # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.00 (s, 1 H) 0.79 - 0.97 (m, 3 H) 1.19 - 1.39 (m, 2 H) 1.51 - ":3_,,\ 1.74 (m, 2 H) 1.74 - 1.93 (m, 2 H) Same NH method §s_\¥ 2.40 (s, 3 H) 3.41 - 3.52 (m, 2 H) as 54 c,0.72 4.51-4.63 (m, 1 H)7.35 (d, to prepare J=8.53 Hz, 1 H) 7.57 - 7.65 (m, 1 9 H) 7.83 (s, 2 H) 8.25 (s, 1 H) 8.91 (d, J=8.28 Hz, 1 H) 12.57 (s, 1 H) wembrech_1457_4 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 - 0.95 (m, 3 H) 1.29 - 1.42 (m, 2 H) 1.53 - 1.78 (m, 2 H) “”§_N 1.79 - 1.86 (m, 2 H) 2.78 (s, 3 H) Same .66 (m, 2 H)4.57-4.70 method as 55 8:”sb‘ c,0.75 (m, 1 H) 7.21 (d, J=7.28 Hz, 1 H) to prepare 7.29 (d, J=8.03 Hz, 1 H) 7.62 (t, 9 J=7.91 Hz, 1 H) 7.75 (d, J=8.03 Hz, 2 H) 7.87 (d, J=8.03 Hz, 1 H) 12.36 (s, 1 H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.88 (t, J=7.3 Hz, 3 H), 1.18 — 1.43 (111,2 H), 1.54 (td, ”:§/_N\ J=9.1, 4.4 Hz, 1 H), 1.60 Same — 1.71 NH method as 56 d251— (m, 1 H), 3.39 — 3.54 (111,2 H), @063 3.79 (s, 3 H), 4.33 (td, J=8.6, 5.1 to prepare Hz, 1 H), 4.66 (t, J=5.4 Hz, 1 9 H), 5.87 (s, 2 H), 6.56 — 6.65 (m, 2 H), 7.11 (d, J=8.3 Hz, 1 H), 7.95 (d, J=8.8 Hz, 1 H) W0 2012/156498 _54_ # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.90 (t, J=7.3 Hz, 3 H), 1.25 - 1.45 (m, 2 H), 1.57 (dtd, N),—~\ J=13.7, 9.1, 9.1, 5.0 Hz, 1 H), Same method as 57 25—\_ 1.63- 1.75 (m, 1 H), 3.44-3.55 @064 0H 6(m,2 H), 3.81 (s, 3 H), 4.39 (td, to prepare J=8.5, 5.3 Hz, 1 H), 4.70 (br. 9 s., 1 H), 5.74 (s, 2 H), 7.11 - 7.17 (m, 2 H), 7.23 (d, J=8.3 Hz, 1 H), 7.54 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.92 (t, J=7.3 Hz, 3 H), 1.29 “”§_N - 1.43 (m, 2 H), 1.56 - 1.71 (m, 2 Same N/65%—\ N C,0.66 H), 3.53-3.65 (m, 2 H), 4.04 (5, method as 3 H), 4.27 - 4.43 (m, 1 H), 4.66 to prepare (br. 9 s., 3 H), 7.02 (d, J=8.3 Hz, 2 H), 7.71 (t, J=8.3 Hz, 1 H), 8.90 (d, J=8.3 Hz, 1 H), 12.85 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 (t, J=6.5 Hz, 3 H), 1.19 - 1.39 (m, 4 H), 1.48 - 1.62 (m, 1 H), 1.62 - 1.77 (m, 1 H), 3.40 - V Same >_N\ s 3.56 (m, 2 H), 4.35 (td, 6 J=8.7, method as 59 N” .0 Hz, 1 H), 4.69 (t, J=5.4 Hz, 1 00-74 to prepare F “2 i H), 6.24 (br. s., 2 H), 6.95 (td, J=8.0, 5.0 Hz, 1 H), 7.31 (dd, , 7.7 Hz, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 7.90 (d, J=8.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 NH: {H—F/ Same N)r~\ NS; ppm 0.86 (t, J=6.7 Hz, 3 H), 1.20 C,0.77 method as - 1.39 (m, 4 H), 1.54 - 1.76 (m, 2 to prepare H), 3.55 (d, J=5.8 Hz, 4 H), 4.37 - F 9 4.50 (m, 1 H), 7.26 (dd, J=9.8, # Method, Synthetic STRUCTURE H NMR Rt Method 2.5 Hz, 1 H), 7.30 - 7.36 (m, 1 H), 8.50 - 8.57 (m, 1 H), 8.99 (d, J=8.0 Hz, 1 H), 12.48 (br. s., 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.86 (t, J=6.5 Hz, 3 H), 1.17 - 1.40 (m, 4 H), 1.47 - 1.62 (m, 1 NH: Same _ _ .H W 31:3er 21136123111361 as 61 ' ' ' ' ' ' c,0.73 H), 4.69 (br. s., 1 H), 6.13 (br. to ., prepare r 2 H), 7.23 (dd, J=9.2, 5.4 Hz, 1 9 H), 7.39 (br. s, 1 H), 7.39 (td, J=8.6, 2.4 Hz, 1 H), 8.00 (dd, J=10.3, 2.8 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.82 - 0.92 (m, 3 H), 1.25 - 1.40 (m, 4 H), 1.53 - 1.73 (m, 2 1:)35 HzH 3.51 - 3.60 m4.92 (b3. 5.2 H 4.37 m Same ”Hg—t EL/J I C’0'83 1 H) 1 H) methOd as 62 Nd;NH ' ' ' ' 6.74(br. to s., 2 H), 6.92 (dd, prepare , 8.0 Hz, 1 H), 7.01 - 7.08 9 (m, 1 H), 7.08 - 7.12 (m, 1 H), 7.54 (td, J=8.2, 6.5 Hz, 1 H). LC- MS m/z = 279 (M+H). 1H NMR (400 MHz, DMSO-de) 5 ppm 0.88 (t, J=7.4 Hz, 3 H), 1.22 - 1.40 (m, 2 H), 1.47 - 1.66 (m, 2 ":§/_N\ H), 1.66 - 1.80 (m, 2 H), 3.41 - Same N method 2 i EFL 3.49 (m, 2 H), 4.33 as - 6 4.52 (m, 2 63 @069 H), 6.26 (br.s., 2 H), 6.95 (td, to prepare J=8.0, 4.9 Hz, 1 H), 7.31 (dd, 9 J=11.3, 7.8 Hz, 1 H), 7.48 (d, J=8.5 Hz, 1 H), 7.87 (d, J=8.3 Hz, 1 H) 2012/059234 # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.88 (t, J=7.4 Hz, 3 H), 1.21 "”57“ - 1.41 (m, 2 H), 1.48 - 1.66 (m, 2 Same N \ NH s H), 1.68 _ 1.81 (m, 2 H), 3.42 _ method as 64 @073 3.48 (m, 2 H), 4.30-4.55 (m, 2 to prepare F °” H), 6.69 (br. s., 2 H), 6.89 - 7.07 9 (m, 2 H), 7.86 (d, J=8.3 Hz, 1 H), 8.21 (dd, J=8.9, 6.1 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.88 (t, J=7.4 Hz, 3 H), 1.25 NH$_N - 1.40 (m, 2 H), 1.50 - 1.65 (m, 2 Same N/ \ H), 1.65 - 1.81 (m, 2 H), 3.45 (t, C,0.68 "“5 method as 65 gx J=6.5 Hz, 2 H), 4.32 - 6 4.52 (m, to prepare 2 H), 6.00 (s, 2 H), 7.22 (dd, , 0H 9 J=9.0, 5.5 Hz, 1 H), 7.28 - 7.42 (m, 2 H), 7.95 (dd, J=10.2, 2.9 Hz, 1 H) 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 0.95 (t, J=7.3 Hz, 3 H), 1.34 - 1.58 (m, 4 H), 1.59 - 1.72 (m, 2 H), 1.92 - ““34 Same N/ \ 2.07 (m, 1 H), 3.55 - 3.73 (m, 2 N method as 66 i H), 4.42 - 4.59 (m, 1 H), 5.10 (br. 00-79 to prepare 0H s., 2 H), 6.62 (dd, J=18.7, 8.4 Hz, 1 H), 6.81 (dd, J=13.1, 8.0 Hz, 1 H), 7.21 (d, J=8.5 Hz, 1 H), 7.42 - 7.55 (m, 1 H). LC-MS m/z = 279 (M+H) 1H NMR (400 MHz, DMSO-de) 5 “”54 Same ppm 0.86 (t, J=7.5 Hz, 3 H), 0.93 N \ methOd “SH (d, J=6.8 Hz, 3 H), 1.08 - 1.24 (m, as 67 @072 F to 1 H), 1.43 - 1.59 (m, 1 H), 1.84 prepare (ddt, J=11.2, 7.7, 4.0, 6 4.0 Hz, 1 9 H), 3.54 - 3.68 (m, 2 H), 4.20 - _57_ # Method, Synthetic STRUCTURE H NMR Rt Method 4.30 (m, 1 H), 4.56 (t, J=5.4 Hz, 1 H), 6.20 (br. s., 2 H), 6.95 (td, J=8.0, 5.0 Hz, 1 H), 7.30 (ddd, J=11.4, 7.7, 0.8 Hz, 1 H), 7.39 (d, J=8.5 Hz, 1 H), 7.95 (d, J=8.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.86 (t, J=7.4 Hz, 3 H), 0.92 (d, J=6.8 Hz, 3 H), 1.11 - 1.24 (m, 1 H), 1.44 - 1.59 (m, 1 H), 1.83 m)_ Same N/ ”\ NH (ddt, J=11.3, 7.7, 3.9, 6 3.9 Hz, 1 c,0.71 68 52—(1 H), 3.53 - 3.69 (m, 2 H), 4.16 - EetngL: F 4.28 (m, 1 H), 4.55 (br. s., 1 H), .94 (s, 2 H), 7.21 (dd, J=9.2, 5.4 Hz, 1 H), 7.28 (d, J=8.3 Hz, 1 H), 7.37 (td, J=8.8, 2.8 Hz, 1 H), 8.04 (dd, , 2.8 Hz, 1 H) F 6 1H NMR (400 MHz, DMSO-de) 5 ppm 0.88 (t, J=7.28 Hz, 3 H) 1.20 - 1.43 (m, 2 H) 1.49 - 1.70 (m, 2 NH, Same H) 3.40 - 3.54 (m, 2 H) 4.30 - N, N\ N method as 69 4.42 (m, 1 H) 4.68 (t, J=5.02 Hz, 00-71 c. ;?\_ to prepare 0H 1 H) 6.25 (br. s., 2 H) 6.96 (t, J=7.91 Hz, 1 H) 7.41 (d, J=8.28 Hz, 1 H) 7.62 (d, J=7.53 Hz, 1 H) 8.04 (d, J=8.28 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.80 - 0.95 (m, 3 H), 1.16 - N:§/_N\ Same 1.43 (m, 2 H), 1.46 - 1.74 (m, 2 NH C072 methOd —\_ H), 1.91 (t, J=5.8 Hz, 0 H), 3.43 as 70 - 0H 3.60 (m, 2 H), 3.50-3.50(m, 0 prepare 0' 9 H), 4.35 (td, J=8.4, 5.3 Hz, 1 H), 4.79 (br. s., 1 H), 6.17 (br. s., 2 H), 7.00 (dd, J=8.8, 2.0 Hz, 1 H), # Method, Synthetic STRUCTURE H NMR Rt Method 7.16 (d, J=2.0 Hz, 1 H), 7.54 (d, J=8.0 Hz, 1 H), 8.18 (d, J=8.8 Hz, 1 H). LC-MS m/z = 281 (M+H) supports structure. LC-MS m/z = 281 (M+H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.91 (t, J=7.28 Hz, 3 H) 1.23 - 1.44 (m, 2 H) 1.52 - 1.68 (m, 2 NH$_ H) 3.54 (t, J=4.14 Hz, 2 H) 4.33 Same (ddt, J=10.60, 7.22, 3.76, 3.76 method as 71 81%— 3498 or Hz, 1 H) 4.90 (t, J=5.14 Hz, 1 H) to prepare 6.22 (br. s., 2 H) 7.05 (dd, 9 J=7.65, 1.13 Hz, 1 H) 7.15 (dd, J=8.41,1.13 Hz, 1 H) 7.33 - 7.42 (m, 1 H) 7.60 (d, J=8.03 Hz, 1 H) 1H NMR (400 MHz, e) 5 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.22 NH, - 1.44 (m, 2 H), 1.47 - 1.59 (m, 1 N>/_”\ NH H), 1.59 - 1.72 (m, 1 H), 3.41 - c,0.74 rigid as 72 52—\_ 3.53 (m, 2 H), 4.28 - 6 4.40 (m, 1 to prepare F F H), 4.68 (t, J=5.4 Hz, 1 H), 6.11 (s, 2 H), 7.07 (dd, J=12.5, 7.8 Hz, 1 H), 7.29 (d, J=8.3 Hz, 1 H), 8.22 (dd, J=12.0, 9.0 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 (t, J=6.8 Hz, 3 H), 1.19 - 1.40 (m, 4 H), 1.56 - 1.72 (m, 2 Same NH, {—F/ H), 1.74 - 1.92 (m, 2 H), 2.44 (s, N>/_“\ ,f‘ 3 H), 2.49 - 2.55 (m, 1 H), 3.46 method as 73 @077 (t, J=6.5 Hz, 2 H), 4.47 to - 4.63 (m, prepare 1 H), 7.19 - 7.28 (m, 2 H), 7.92 9 (d, J=8.5 Hz, 2 H), 8.37 (d, J=8.3 Hz, 1 H), 9.01 (d, J=8.3 Hz, 1 H), 12.80 (s, 1 H) _59_ # , Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.82 - 0.90 (m, 3 H) 1.22 - 1.37 (m, 4 H) 1.60 - 1.68 (m, 2 H) {—F/ 1.75 - 1.83 (m, 2 H) 2.42 (s, 3 H) Same N>/_"\ c 0 75 NS; ’ ' 3.43 - 3.48 (m, 2 H)4.51-4.59 method as (m, 1 H) 7.36 (d, J=8.53 Hz, 1 H) to prepare 7.62 (d, J=8.53 Hz, 1 H) 7.74 (br. 9 s., 2 H) 8.19 (s, 1 H) 8.84 (d, J=8.28 Hz, 1 H) 12.27 (s, 1 H) wembrech_1457_3 1H NMR (400 MHz, DMSO-de) 5 ppm 0.82 - 0.91 (m, 3 H) 1.28 - 1.40 (m, 4 H) 1.59 - 1.77 (m, 2 H) {f 1.83 (q, J=5.94 Hz, 2 H) 2.78 (s, 3 Same N)—~\ Msfi. H) 3.50 _ 3.66 (m, 2 H) 4.55 _ method as 75 @083 4.66 (m, 1 H) 7.21 (d, J=7.53 Hz, to prepare 1 H) 7.29 (d, J=8.28 Hz, 1 H) 7.62 9 (t, J=7.91 Hz, 1 H) 7.77 (br. s., 2 H) 7.88 (d, J=8.03 Hz, 1 H) 12.38 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 (t, 12640 Hz, 3 H) 1.17 - 1.38 (m, 4 H) 1.45 - 1.58 (m, 1 NH, {HJJ H) 1.62 - 1.73 (m, 1 H) 3.37 - Same N),—~\ 5%. 3.52 (m, 2 H) 3.79 (s, 3 H) 4.30 c,0.72 method as 76 (dd, J=8.53, 5.02 Hz, 1 H) 4.60 - to prepare 4.68 (m, 1 H) 5.87 (s, 2 H) 6.59 - 0 9 6.60 (m, 1 H) 6.60 - 6.65 (m, 1 H) 7.12 (d, J=8.28 Hz, 1 H) 7.96 (d, J=8.78 Hz, 1 H) wembrech_1505_1 # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 8 ppm 0.86 (t, J=6.5 Hz, 3 H), 1.22 - 1.40 (m, 4 H), 1.49 - 1.63 (m, 1 "HS—N g—F/ Same N/ \ Mr: H), 1.65 - 1.80 (m, 1 H), 3.44 - method as 77 3.56 (m, 2 H), 3.81 (s, 3 6 H), 00-73 to prepare 4.37 (td, J=8.5, 5.3 Hz, 1 H), 4.70 /° 9 (br. s., 1 H), 5.73 (s, 2 H), 7.12 - 7.17 (m, 2 H), 7.23 (d, J=8.3 Hz, 1 H), 7.54 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 8 ppm 0.87 (t, J=7.40 Hz, 3 H) 1.22 - 1.39 (m, 2 H) 1.48 - 1.78 (m, 4 "”ng H) 3.37 - 3.50 (m, 2 H) 3.78 (s, 3 Same N \ NH _ _ method as 78 S H) 4.34 4.49 (m, 1 H) 4.34 @067 4.49 (m, 1 H) 5.92 (s, 2 H) 6.60 to prepare _° °” (d, J=2.51 Hz, 1 H) 6.61 - 6.66 9 (m, 1 H) 7.21 (d, J=8.53 Hz, 1 H) 7.94 (d, J=8.78 Hz, 1 H) wembrech_1505_4 1H NMR (400 MHz, DMSO-de) 8 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.26 )/—N\ - 1.41 (m, 2 H), 1.51 - 1.66 (m, 2 Same N N _ _ method as 79 5:1 H), 1.66 1.83 (m, 2 H), 3.42 @067 3.47 (m, 1 H), 3.81 (s, 3 H), 4.38 to e 0 0H -4.52 (m, 2 H), 5.87 (s, 2 H), 9 7.14 - 7.19 (m, 2 H), 7.35 (d, J=8.5 Hz, 1 H), 7.53 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 8 ““3_N\ ppm 0.86 (t, J=7.4 Hz, 3 H), 0.94 Same N NR (d, J=6.8 Hz, 3 H), 1.11 - 1.24 (m, method as 80 c 0 7 1 H), 1.53 (ddd, J=13.4, 7.5, 3.9 , - W to prepare / Hz, 1 H), 1.87 (ddt, 6 J=11.2, 7.7, 9 4.0, 4.0 Hz, 1 H), 3.58 - 3.66 (m, 2 H), 3.82 (s, 3 H), 4.20 - 4.31 WO 56498 # Method, Synthetic STRUCTURE H NMR Rt Method (m, 1 H), 4.58 (br. s., 1 H), 5.69 (s, 2 H), 7.12 - 7.17 (m, 2 H), 7.24 (d, J=8.5 Hz, 1 H), 7.59 (s, 1 1H NMR (400 MHz, DMSO-de) 5 ppm 0.84 (t, J=6.5 Hz, 3 H), 1.20 - 1.37 (m, 4 H), 1.52 - 1.65 (m, 2 0244 H), 1.65 Same - 1.80 (m, 2 H), 3.44 (q, method as - 6 4.49 (m, 81 N),—~\ ~55 J=6.2 Hz, 2 H), 4.35 F6 @079 2 H), 6.25 (br. to s., 2 H), 6.95 (td, prepare J=7.9, 5.0 Hz, 1 H), 7.31 (dd, 9 J=11.3, 7.8 Hz, 1 H), 7.48 (d, J=8.3 Hz, 1 H), 7.87 (d, J=8.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 0” ppm 0.79 - 0.89 (m, 3 H), 1.19 - Same NH, {—F/ 1.37 (m, 4 H), 1.59 (d, J=6.5 Hz, 8: 2 H), 1.65 method as - 1.79 (m, 2 H), 3.43 82 @081 (t, J=6.3 Hz, 2 H), 4.31 -4.53 (m, to prepare F 2 H), 6.24 (s, 2 H), 6.80 - 6.98 (m, 2 H), 7.51 (d, J=8.5 Hz, 1 H), 8.14 (dd, J=8.8, 6.5 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 (t, J=6.3 Hz, 3 H), 1.20 °2_/_/ - 1.37 (m, 4 H), 1.53 - 1.64 (m, 2 Same >/_,,\ s H), 1.64- 1.82 (m, 2 H), 3.45 (t, method as 83 ”C?“ J=6.4 Hz, 2 H), 4.34-64.48(m, 00-77 to prepare 2 H), 6.01 (s, 2 H), 7.22 (dd, J=9.2, 5.4 Hz, 1 H), 7.29 - 7.42 (m, 2 H), 7.95 (dd, J=10.3, 2.8 Hz, 1 H) # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.89 (t, J=7.0 Hz, 3 H), 1.19 - 1.46 (m, 4 OH H), 1.50 - 1.79 (m, 4 H), 1.92 - Same NH$_N L4 2.12 (m, 1 H), 3.59 - 3.75 (m, 2 method as 84 N/6;\ Nfi‘s H), 3.96 (br. s., 2 H), 4.40 - 4.56 00-88 to prepare (m, 1 H), 6.72 (dd, J=18.6, 8.5 Hz, 1 H), 6.81 (ddd, J=12.8, 8.0, 0.8 Hz, 1 H), 7.19 (d, J=8.5 Hz, 1 H), 7.48 (td, J=8.2, 6.4 Hz, 1 H).
LC-MS m/z = 293 (M+H) 1H NMR (400 MHz, METHANOL- d4) 8 ppm 0.99 (t, J=7.3 Hz, 3 H), ”Hg—~\ 1.38 - 1.50 (m, 2 H), 1.71 (quin, Same “ method as 85 “”\_\_ J=7.4 Hz, 2 H), 3.66 (t, J=7.3 Hz, c,0.9 2 H), 7.33 (d, J=8.8 Hz, 1 H), 7.87 to e (dd, J=8.8, 1.8 Hz, 1 H), 8.00 (br. 9 s., 1 H), 8.35 (d, J=2.0 Hz, 1 H), exchangeable protons not seen 1H NMR (400 MHz, e) 8 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.24 NH: - 1.44 (m, 2 H), 1.50 - 1.73 (m, 2 s ame N/ N\ NH H), 3.50 (tq, J=11.1,5.3 Hz, 2H), method as 86 {:_\_ 3.88 (s, 3 H), 4.38 6 (td,J=8.6, 00-68 to prepare /o 5.1 Hz, 1 H), 4.69 (t, J=5.1 Hz, 1 o 9 H), 6.17 (br. s., 2 H), 7.50 (dd, J=8.5,1.8 Hz, 2 H), 7.74 (d, J=1.8 Hz, 1 H), 8.19 (d, J=8.5 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 8 Same NH, {—F/ ppm 0.76 - 0.89 (m, 3 H) 1.28 (d, N>/_"\ NS: methOd J=5.02 Hz, 4 H) 1.48 - 1.78 (m, 4 as 87 @074 H)3.36-3.48(m, 2 H)3.69- to prepare 3.84 (m, 3 H) 4.32 - 4.46 (m, 1 H) 4.32 - 4.46 (m, 1 H) 5.90 (s, 2 H) # Method, Synthetic STRUCTURE H NMR Rt Method 6.60 (d, J=2.51 Hz, 1 H) 6.63 (s, 1 H) 7.20 (d, J=8.53 Hz, 1 H) 7.94 (d, J=9.03 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 0, ppm 0.85 (t, J=6.7 Hz, 2 H), 1.22 my {_/_/ Same - 1.36 (m, 4 H), 1.56 - 1.65 (m, 2 N/ N\ :a H), 1.65 method as _ 1.84 (m, 2 H), 3.40 _ 88 @076 3.50 (m, 2 H), 3.81 (s, 3 6 H), to e 7° 4.38 - 4.49 (m, 2 H), 5.74 (s, 2 9 H), 7.15 (s, 2 H), 7.27 (d, J=8.5 Hz, 1 H), 7.51 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.4 Hz, 3 H), 1.31 N)“ Same L\_ - 1.44 (m, 2 H), 1.55 - 1.66 (m, 2 H), 3.40 method as _ 3.50 (m, 2 H), 3.80 (s, 89 @094 _o $3 3 H), 5.05 (s, 2 H), 5.67 (s, 2 H), to prepare 6.66 (s, 1 H), 7.32 - 7.46 (m, 4 9 H), 7.48 - 7.50 (m, 1 H), 7.51 (m, J=1.5 Hz, 1 H), 7.59 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.94 (t, J=7.4 Hz, 3 H), 1.38 (dq, J=15.0, 7.3 Hz, 2 H), 1.63 (quin, J=7.4 Hz, 2 H), 3.43 - 3.54 N, (m, 2 H), 6.19 (s, 2 H), 6 7.37 - D See 90 éL 7.44 (m, 1 H), 7.52 (dd, J=8.4, c, 073 experimen N, \th 1.8 Hz, 1 H), 7.82 (d, J=1.5 Hz, 1 H), 7.93 (t, J=5.4 Hz, 1 H), 8.12 (d, J=8.6 Hz, 1 H), 8.19 - 8.25 (m, 1 H), 8.32 (dd, J=4.7, 1.4 Hz, 1 H), 8.97 (d, J=2.2 Hz, 1 H), 10.54 (s, 1 H) Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, e) 5 ppm 0.93 (t, J=7.4 Hz, 3 H), 1.36 (dq, J=14.9, 7.4 Hz, 2 H), 1.55 - @i. 1.66 (m, 2 H), 3.43 - 3.50 (m, 2 Same as to 91 H), 3.50 - 3.74 (m, 4 H), 6 6.21 C, 0.65 prepare 90 (br. s., 2 H), 6.99 (dd, J=8.3, 1.7 Hz, 1 H), 7.12 (d, J=1.5 Hz, 1 H), 7.88 (t, J=5.4 Hz, 1 H), 8.04 (d, J=8.4 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.4 Hz, 3 H), 1.37 (dq, J=15.0, 7.4 Hz, 2 H), 1.62 (quin, J=7.3 Hz, 2 H), 2.19 (s, 6 @N H), 2.41 (t, J=6.8 Hz, 2 H), 3.30 - Same as to 92 3.42 (m, 2 H), 3.42 - 3.51 (m, 2 C, 0.8 NH \NJNHz prepare 90 f H), 6.13 (s, 2 H), 7.40 (dd, J=8.4, 1.8 Hz, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 7.85 (t, J=5.4 Hz, 1 H), 8.03 (d, J=8.6 Hz, 1 H), 8.45 (t, J=5.6 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.4 Hz, 3 H), 1.37 (dq, J=14.9, 7.4 Hz, 2 H), 1.62 (quin, J=7.3 Hz, 2 H), 3.44 - 3.52 \ NH O (m, 2 H), 4.58 (d, J=5.9 6 Hz, 2 H), 6.16 (br. Same as to s., 2 H), 7.27 (dd, 93 @ij C, 0.71 J=7.2, 5.0 Hz, 1 H), 7.34 (d, J=7.9 prepare 90 Hz, 1 H), 7.49 (dd, J=8.5, 1.7 Hz, 1 H), 7.71 - 7.80 (m, 2 H), 7.88 (t, J=5.4 Hz, 1 H), 8.07 (d, J=8.4 Hz, 1 H), 8.52 (dd, J=4.8, 0.7 Hz, 1 H), 9.18 (t, J=5.9 Hz, 1 H) 2012/059234 Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.4 Hz, 3 H), 1.37 (dq, J=14.9, 7.4 Hz, 2 H), 1.55 - 1.67 (m, 2 H), 2.90 (s, 3 H), 2.99 Same as to 94 @984”, (s, 3 H), 3.43 - 3.52 (m, 2 H), C, 0.65 prepare 90 6.26 (br. s., 2 H), 6.99 (dd, J=8.3, 1.7 Hz, 1 H), 7.12 (d, J=1.5 Hz, 1 H), 7.93 (t, J=5.2 Hz, 1 H), 8.04 (d, J=8.4 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.93 (t, J=7.4 Hz, 3 H), 1.31 - 1.43 (m, 2 H), 1.62 (quin, J=7.3 Hz, 2 H), 3.43 - 3.51 (m, 2 H), 4.49 (d, J=5.9 Hz, 2 H), 6 6.22 Same as to 95 @J. (br. s., 2 H), 7.20 - 7.29 (m, 1 H), C, 0.87 prepare 90 7.30 - 7.35 (m, 4 H), 7.48 (dd, J=8.4, 1.8 Hz, 1 H), 7.72 (d, J=1.8 Hz, 1 H), 7.93 (t, J=5.3 Hz, 1 H), 8.07 (d, J=8.6 Hz, 1 H), 9.13 (t, J=5.9 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 8 ppm 0.90 (t, J=7.37 Hz, 3 H) 1.31 - 1.41 (m, 2 H) 1.57 - 1.65 (m, 2 H) 2.78 — 2.84 (m, 2 H) 3.36 - 3.37 (m, 2 H) Same as to 96 C, 1.08 3.43 - 3.51 (m, 2 H) 3.72 prepare 12 (s, 3 H) 6.03 (br. s., 2 H) 6.63 (br. s., 1 H) 6.82 — 6.88 (m, 3 H) 7.05 - 7.14 (m, 3 H) 7.30 — 7.34 (m, 1 H) # Method, Synthetic STRUCTURE H NMR Rt Method 1H NMR (400 MHz, DMSO-de) 8 ppm 0.89 (t, J=7.37 Hz, 3 H) 1.32 - 1.39 (m, 2 H) 1.58 - 1.64 (m, 2 H) 2.82 - 2.87 (m, N: N\ NH/—/— 2 H) 3.35 - 3.41 (m, 2 H) Same as to 3.45 - 3.51 (m, 2 H) 3.72 97 C, 1.06 prepare 12 O (s, 3 H) 6.03 (br. s., 2 H) 6.67 (br. s., 1 H) 6.74 - 6.80 (m, 3 H) 6.89 (cl, J=7.04 Hz, 1 H) 7.08 (cl, J=7.26 Hz, 1 H) 7.19 (t, J=8.03 Hz, 1 H) 7.33 (t, J=7.70 Hz, 1 H) 1H NMR (400 MHz, DMSO-dg) 8 ppm 0.94 (t, J=7.37 Hz, 3 H) 1.34 N:$/_N\ NH/_/_ - 1.47 (m, 2 H) 1.60 - 1.71 (m, 2 s ame as to 98 d: H) 3.42-3.56 (m, 2 H) 3.79 (s, 3 c, 084 °\_<° H) 4.93 (s, 2 H) 6.03 (s, 2 H) 6.48 prepare 11 - 6.57 (m, 1 H) 6.81 (dd, J=8.36, 0.66 Hz, 1 H) 7.33 (t, J=8.25 Hz, 1 H) 8.25 - 8.34 (m, 1 H) Analytical Methods.
All compounds were terized by LC-MS. The following LC-MS s were used: Method A. Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 um, 2.1 X 50 mm; Waters Acquity) with a flow rate of 0.8 mL/min. Two mobile phases (10 mM ammonium acetate in HZO/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a nt condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.7 minutes. An ion volume of 0.75 ul was used. Cone voltage was 30 V for positive ionization mode and 30 V for negative ionization mode.
Method B. Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 pm, 4.6 X 100 mm) with a flow rate of 1.6 mL/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50 % B and 50 % C in 6.5 minutes, to 100 % B in 0.5 minute, 100 % B for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An ion volume of 10 ul was used.
Method C. Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 pm, 2.1 X 50 mm; Waters Acquity) with a flow rate of 0.8 mL/min. Two mobile phases (mobile phase A: 10mM ammonium e in etonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.2 minutes. An ion volume of 0.5 ul was used.
Biolo ical Activit of com ounds of formula | ption of Biological Assays Assessment of TLR7 and TLR8 activity The ability of compounds to activate human TLR7 and/or TLR8 was assessed in a cellular reporter assay using HEK293 cells transiently transfected with a TLR7 or TLR8 sion vector and NFKB-IUC reporter uct. In one instance the TLR sion construct expresses the respective wild type sequence or a mutant sequence comprising a deletion in the second leucinerich repeat of the TLR. Such mutant TLR proteins have previously been shown to be more susceptible to agonist activation (US 7498409).
Briefly, HEK293 cells were grown in culture medium (DMEM supplemented with 10% FCS and 2 mM ine). For transfection of cells in 10 cm dishes, cells were detached with Trypsin-EDTA, transfected with a mix of CMV-TLR7 or TLR8 plasmid (750 ng), NFKB-IUC plasmid (375 ng) and a transfection reagent and incubated 24 hours at 37°C in a humidified 5% C02 atmosphere.
Transfected cells were then detached with Trypsin-EDTA, washed in PBS and resuspended in medium to a density of 1.67 x 105 cells/mL. Thirty microliters of cells were then dispensed into each well in 384-well plates, where 10 uL of compound in 4% DMSO was already present. ing 6 hours incubation at 37°C, 5% C02, the luciferase activity was determined by adding 15 ul of 2012/059234 -68— Steady Lite Plus substrate (Perkin Elmer) to each well and readout performed on a ViewLux ultraHTS microplate imager (Perkin Elmer). Dose response curves were generated from measurements performed in quadruplicates.
Lowest effective concentrations (LEC) values, defined as the concentration that induces an effect which is at least two fold above the standard deviation of the assay, were determined for each compound.
Compound toxicity was determined in parallel using a similar dilution series of compound with 30 uL per well of cells transfected with the CMV-TLR7 construct alone (1.67 X 105 cells/mL), in 384-well plates. Cell viability was measured after 6 hours incubation at 37°C, 5% C02 by adding 15 uL of ATP lite (Perkin Elmer) per well and reading on a ViewLux ultraHTS microplate imager (Perkin Elmer). Data was reported as CC50.
Suppression of HCV replicon ation Activation of human TLR7 results in robust tion of interferon by plasmacytoid dendritic cells present in human blood. The potential of compounds to induce interferon was evaluated by looking at the antiviral activity in the HCV replicon system upon incubation with conditioned media from peripheral blood mononuclear cells (PBMC). The HCV replicon assay is based on a bicistronic sion construct, as described by Lohmann et al.
(Science (1999) 285: 110-113; Journal of Virology (2003) 77: 3007-15 3019) with modifications described by Krieger et al. al of Virology (2001) 75: 4614-4624). The assay utilized the stably transfected cell line Huh-7 luc/neo harboring an RNA encoding a bicistronic sion construct comprising the wild type NSB-NS5B regions of HCV type 1b translated from an al Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a er gene (Firefly-luciferase) and a selectable marker gene (neoR, neomycine phosphotransferase). The uct is d by 5’ and 3’ NTRs (non-translated regions) from HCV type 1b. Continued e of the on cells in the presence of G418 (neoR) is dependent on the replication of the HCV RNA. The stably transfected replicon cells that replicate HCV RNA mously and to high levels, encoding inter alia luciferase, were used for profiling of the conditioned cell e media.
Briefly, PBMCs were prepared from buffy coats of at least two donors using a standard Ficoll centrifugation protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 105 cells/well were dispensed into 384-well plates containing compounds (70 uL total volume). After overnight incubation, 10 uL of supernatant was transferred to 384-well plates containing 2.2 X 103 replicon well in 30 uL (plated the day before). Following 24 hours of incubation, replication was measured by assaying luciferase activity using 40 uL/well Steady Lite Plus substrate (Perkin Elmer) and measured with ViewLuX ultraHTS microplate imager n Elmer). The inhibitory ty of each nd on the Huh7-luc/neo cells were reported as E050 values, defined as the compound tration applied to the PBMCs resulting in a 50% reduction of rase activity which in turn indicates the degree of replication of the replicon RNA on transfer of a defined amount of PBMC culture medium. Recombinant interferon d-2a (Roferon-A) was used as a standard control compound.
Biological activity of compounds of formula (I). All compounds showed CC50 of >24uM in the HEK 293 TOX assay described above.
Activation of ISRE promoter elements The potential of compounds to induce lFN-l was also evaluated by ing the activation of interferon-stimulated responsive elements (ISRE) by conditioned media from PBMC. The ISRE element of sequence GAAACTGAAACT is highly responsive to the STAT1-STAT2-IRF9 transcription factor, activated upon binding of lFN-l to their receptor IFNAR (Clontech, PT3372-5W). The plasmid plSRE-Luc from Clontech (ref. 631913) contains 5 copies of this ISRE element, followed by the firefly luciferase ORF. A HEK293 cell line stably transfected with plSRE-Luc SREluc) was established to profile of the conditioned PBMC cell culture media.
Briefly, PBMCs were ed from buffy coats of at least two donors using a standard Ficoll centrifugation protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 X 105 cells/well were dispensed into 384-well plates containing compounds (70 uL total volume). After overnight incubation, 10 uL of supernatant was transferred to 384-well plates containing 5 X 103 HEK-lSREluc cells/well in 30 uL (plated the day before). Following 24 hours of incubation, activation of the ISRE elements was measured by assaying luciferase activity using 40 l Steady Lite Plus substrate n Elmer) and measured with ViewLuX TS microplate imager (Perkin Elmer). The ating activity of each compound on the HEK- lSREluc cells was reported as LEC value, defined as the compound concentration applied to the PBMCs resulting in a rase activity at least two fold above the rd deviation of the assay. The LEC in turn indicates the degree of ISRE activation on transfer of a defined amount of PBMC culture medium. Recombinant interferon 0i-2a (Roferon-A) was used as a standard control compound.
For a given compound, the LEC value obtained from this assay were in the same range as the E050 values obtained from the “suppression of HCV replication assay.” Thus, it is possible to compare the ial of compounds to induce lFN-l by PBMC, ed by either of the 2 assays.
# TLR7- TLR7- TLR8— TLR8— PBMC- STRUCTURE wt_LE leR2_LE wt_LE leR2_LE HUH7_EC5 c c c c 0 N>/—\N N 1 L\_ 5.0 0.4 1.1 0.6 1.9 —O /0 N N /—/—/ N 2 NA 1.2 1.5 0.6 4.4 —0 /D 3 4.0 * 0.9 5.5 2.4 0.6 —0 /D N>/—N €—/—/ N \ N§ 4 NA 2.4 2.6 1.7 3.0 —O /O _71_ TLR7- TLR7- TLR8— TLR8— PBMC- STRUCTURE wt_LE dIRR2_LE wt_LE LE HUH7_EC5 c c c c 0 N>/—\N N $1 NA 2.6 6.7 2.6 3.3 —0 /0 0 N>/—\N N 2_\_ NA 3.4 4.4 2.3 3.0 —0 /0 N>/—\N N2i NA 3.8 13.8 9.0 12.4 —0 /0 N>/—\N N \_\_ 0.1 0.02 0.1 0.02 NA * Assay run at 48 hours _72_ # Structure t(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) 9 \N 0.41 0.13 0.10 N NH2 O OH 6.08 >25 2.14 N NH2 11 O HNM 0.08 0.17 0.12 N NH2 NH “HF/— 12 1.66 0.79 NA N>/—N\ NH 13 0.76 0.30 0.57 N>/—N\ NH 14 0.65 4.77 NA 2012/059234 _73_ # Structure TLR7-wt (LEC) TLR8—wt(LEC) HEK-ISREIuc (LEC) NHJJ 0.49 3.27 NA N/ \ N Ni 16 0.57 0.73 NA 17 4—1 5.10 1.66 0.75 N>/—N\ NH 18 \—\_ 0.13 0.13 0.05 N>/—N\ NH 19 \‘\_ >25 7.05 NA N\ 1 N >25 2.55 NA HN \N NH2 WO 56498 _74_ # Structure TLR7-wt(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) N>/—N\ NH 21 di >25 2.55 12.06 N>/—N\ NH 22 \‘\_ 6.07 1.95 NA N NH 23 1 10.23 5.05 NA N>/—N\ NH 24 \‘\_ 0.93 0.22 0.14 NH N 21 0.57 0.45 0.16 N>/—N\ NH 26 EL 3.60 1.97 3.07 Nth NH 27 C? .
M 12.95 >25 14.21 WO 56498 _75_ # Structure TLR7-wt(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) <—0 | 28 _\—\° 2.06 0.88 1.11 NH \N_/<N N}N\ :<<\ g—LNH 29 11.13 >25 >23.81 N/ \ 0.05 0.10 0.04 N>/—N\ NH 31 p 0.09 0.24 0.04 NH ”HF/— 32 0.13 0.47 0.27 N>/—N\ NH 33 25—\_ 1.88 0.15 0.14 2012/059234 # Structure TLR7-wt (LEC) TLR8—wt(LEC) HEK-ISRE luc (LEC) N>/—N\ 34 2—\_ 10.77 0.27 0.39 TH NH \‘\_ 4.15 >25 >23.81 N>/—N\ NH \_\_ 0.47 0.26 0.32 N “\ NH 37 0.16 0.25 0.07 F \‘\_ N>/—N\ NH 38 \—\_ 0.29 0.10 0.11 N>/—N\ NH 39 \—\_ 0.94 0.31 0.15 2012/059234 # Structure TLR7-wt(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) N>/—N\ NH 40 \‘\_ 5.64 1.83 2.44 41 c.\—\_ 0.99 0.13 0.17 42 \—\_ 1.81 0.14 0.26 N \ 43 “§_\_ 4.54 0.12 0.59 44 25—\_ 0.43 0.03 0.09 45 25—\_ 0.41 0.03 0.04 WO 56498 # Structure TLR7-wt(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) NH z”’1: 46 0.77 0.04 0.07 N \ 47 ”;_\_ 0.67 0.03 0.05 4g 25—\_ 0.54 0.01 0.02 49 25—\_ 2.09 0.03 0.13 50 “sh 0.32 0.00 0.01 51 0.60 0.04 0.09 WO 56498 # Structure TLR7-wt (LEC) TLR8—wt(LEC) HEK-ISREIuc (LEC) N <_/_/ N/ ..
\ Nfis 52 0.41 0.03 0.03 N>/—N\ 53 g—L 0.06 0.05 0.02 N>/—N\ 54 g—L 0.54 0.43 0.18 N>/—N\ NH 55 SEL 0.22 0.14 0.06 N/ N\ NH 56 25—\_ 0.39 0.04 0.09 N>/—N\ 57 2—\_ 10.77 0.53 2.08 # Structure TLR7-wt(LEC) t(LEC) HEK-ISREIuc(LEC) N/ N\ N 58 sh 0.18 0.03 0.04 (I? OH 59 N \ Mn 0.29 0.04 0.05 “H “n 60 0.23 0.01 0.02 N/>—~ W\ Nfi 61 0.57 0.05 0.12 62 N \ Mn 0.75 0.01 0.03 N>/—N\ NH 63 gs—L 0.29 0.15 0.04 # ure TLR7-wt(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) 64 21‘ 0.11 0.03 0.04 F 0H N>/—N\ 65 g—L 0.94 0.44 0.56 F OH 65 sh 0.22 0.02 0.06 N ”\ 67 2.50 0.11 0.21 F “SH N>/—N\ NH 68 s2—<s_ 4.57 0.33 0.64 N>/—N\ NH 69 2 gb— 7.48 0.38 0.73 # Structure TLR7-wt(LEC) t(LEC) HEK-ISREIuc(LEC) N/ N\ N 70 ;—\_ 0.41 0.01 0.01 71 5%— 1.02 0.01 0.03 N>/—N\ NH 72 s2—\_ 2.59 0.02 0.05 F F )7“ 5:. 73 ~ \ Mn 0.03 0.06 0.02 74 ~ \ Mn 0.44 0.25 0.14 75 ”)7“: NS; 0.14 0.06 0.02 2012/059234 # Structure TLR7-wt(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) N \ Nfi 76 0.26 0.04 0.09 N \ Nfi 77 3.48 0.62 1.93 N/ N\ NH 78 2—L 0.20 0.13 0.04 —0 OH 79 5:1 11.87 2.97 2.07 N>/—N\ NHSS 80 2—<_ >25 4.10 >24 >_“ 53' 31 0.11 0.16 0.05 # Structure t(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) )/—N s. 82 N \ Ni 0.04 0.03 0.04 83 N \ Mn 1.59 0.42 0.37 84 N>/—“\ Nfi-‘s 0.44 0.10 0.09 N/ N\ NH 85 \—\_ 0.51 0.10 0.21 N>/—N\ NH 86 25—\_ 2.01 0.22 0.28 /° 0 )/_N s. 87 \i—Nfi 0.16 0.16 0.04 2012/059234 # Structure TLR7-wt (LEC) TLR8-wt (LEC) HEK-ISRE luc (LEC) 88 1.85 2.81 0.88 N, N\ NH \‘\_ 89 1.84 2.22 >24 _o 5 90 éL 0.42 NA NA NJ». 91 é; 0.13 0.53 NA 92 éL 1.53 5.87 NA NH \Ni‘Hz :IN NH 0 93 ii 0.77 1.69 NA WO 56498 # Structure TLR7-wt(LEC) TLR8—wt(LEC) HEK-ISREIuc(LEC) 94 (ER 0.07 0.48 NA \NJ‘NHz 95 ii 0.54 0.42 NA /“\ /_/— N NH 95 2.7 16 NA >/—“\ /—/— N NH 97 0.6 0.83 NA N NH 98 d: 0.21 0.31 NA 0 i0

Claims (7)

Claims 1.
1. A compound of formula (I) R2 NH R4 N NH2 R5 (I) or a pharmaceutically acceptable salt thereof, n R1 is one of the following: (S) (S) (S) (S) ; R2 is hydrogen, halogen, hydroxyl, amine, C1-7alkyl, C1-7alkylamino, C1-6alkoxy or (C1-4)alkoxy-(C1-4)alkyl, R3 is hydrogen, halogen, hydroxyl, amine, C1-7alkyl, C1-7alkenyl, kynyl, C1-7alkylamino, C1-6alkoxy or (C1-4)alkoxy-(C1-4)alkyl, R4 is hydrogen, halogen, hydroxyl, amine, C1-7alkyl, C1-7alkylamino, C1-6alkoxy or (C1-4)alkoxy-(C1-4)alkyl, and R5 is hydrogen, fluorine, chlorine or methyl, with the o that R2, R3, R4, and R5 cannot all be H.
2. A compound of formula (I) according to claim 1, wherein R5 is en or fluorine.
3. A compound of formula (I) ing to claim 1, selected from the group consisting of N LF/ / .- N \ if —0 o / .~ N \ N“ —o o N \ N N\ N H N H 2 N N\ N H N H 2 N N\ N H N N\ N H or a pharmaceutically acceptable salt f.
4. A compound of formula (I) ing to claim 1 having the structure: or a pharmaceutically acceptable salt f.
5. A pharmaceutical composition comprising a compound of formula (I) ing to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.
6. A compound of formula (I) according to claim 1, substantially as herein described with reference to any one of the Examples thereof.
7. A pharmaceutical composition according to claim 5, wherein the compound of formula (I) is substantially as herein described with reference to any one of the Examples thereof.
NZ616642A 2011-05-18 2012-05-18 Quinazoline derivatives for the treatment of viral infections and further diseases NZ616642B2 (en)

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Application Number Priority Date Filing Date Title
EP11166538.6 2011-05-18
EP11166538 2011-05-18
PCT/EP2012/059234 WO2012156498A1 (en) 2011-05-18 2012-05-18 Quinazoline derivatives for the treatment of viral infections and further diseases

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NZ616642B2 true NZ616642B2 (en) 2015-09-29

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