Classifications

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  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/423—Oxazoles condensed with carbocyclic rings
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
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  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/14—Decongestants or antiallergics
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  • 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]
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P35/00—Antineoplastic agents
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  • 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
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D215/14—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D235/26—Oxygen atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
  • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
  • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present disclosure is directed to specific leukotriene synthesis inhibitor compounds and pharmaceutical compositions comprising the compounds and methods of using the compounds and the pharmaceutical compositions in treating, for example, inflammatory diseases or conditions
• 5-Lipoxygenase is a key enzyme in the production of leukotrienes
• 5-lipoxygenase activating protein FLAP
• 5-LO oxidizes substrate arachidonic acid to HPETE, a transient intermediate that degrades to leukotriene A 4 (LTA 4 ), the immediate precursor of the biologically active molecules, leukotriene C 4 (LTC 4 ) and leukotriene B 4 (LTB 4 ).
• LTA 4 leukotriene A 4
• LTC 4 leukotriene C 4
• LTB 4 leukotriene B 4
• Leukotriene A 4 is converted by LTA 4 hydrolase to LTB 4 , or it can be conjugated with reduced glutathione by LTC4 synthase to yield LTC 4 .
• LTC 4 is converted to leukotriene D 4 (LTD 4 ) which undergoes conversion to leukotriene E 4 (LTE 4 ) by sequential amino acid hydrolysis.
• Leukotrienes C 4 , D 4 and E 4 are collectively known as the cysteinyl leukotrienes.
• Leukotrienes are largely, though not exclusively, produced by leukocytes.
• LTB 4 is produced, for example, by neutrophils, macrophages and mast cells.
• LTC 4 is produced, for example, by macrophages, eosinophils, basophils, and mast cells.
• Transcellular biosynthesis can also occur.
• LTA 4 produced in neutrophils can be delivered to endothelial cells which lack 5- lipoxygenase but express LTC 4 synthase, wherein the endothelial cells metabolize LTA 4 to LTC 4 .
• the amounts of LTB 4 and cysteinyl leukotrienes that various types of cells produce depend on the distal enzymes LTA 4 hydrolase and LTC 4 synthase respectively. Other factors that influence leukotriene synthesis include intracellullar localization of 5-lipoxygeanse.
• Leukotrienes act by binding to specific G-protein coupled receptors that are located on the outer plasma membrane of structural and inflammatory cells. This binding activates signalling pathways within the cells leading to a host of biological responses present in, e.g., inflammatory diseases and conditions. Leukotrienes have a broad array of functional roles in disease including recruitment of leukocytes, increase in mucous release, increase in vascular permeability, and increased proliferation, among others.
• 5-LO is an important drug target for disease indications wherein either or both of LTB 4 and the cysteinyl leukotrienes are involved.
• 5-LO inhibitors in development can be grouped by mechanism of inhibition. Redox inhibitors reduce the active site iron of the enzyme into the inactive ferrous form. However, general redox inhibitors interfere with multiple biological redox systems thereby leading to side effects. Another group of inhibitors are the iron ligand chelators. These compounds bind to the catalytic iron in the 5-LO enzyme such that it is hindered from catalysing the conversion of arachidonic acid to its products.
• Examples of compounds within this group includes hydroxamic acid and N-hydroxyurea derivatives. Potential for side effects of the iron chelators render them a less favorable therapeutic option.
• Non-redox competitive inhibitors offer specific inhibition of the 5-LO enzyme without the potential for side effects associated with the redox and iron chelator classes.
• Zileuton a compound approved for the treatment of asthma, inhibits an estimated 26-86% of endogenous leukotriene production. Its clinical use, however, is limited by the need to monitor hepatic enzyme levels and to administer multiple times per day.
• FLAP was initially discovered as a target for MK886, and since then a number of compounds targeting FLAP have entered the clinic to treat respiratory and cardiovascular disease, but none have reached the market (D. Petterson et al., Bioorg. Med. Chemm Lett. (2015), v25( 13) pp. 2607-2612).
• LTA 4 H leukotriene A 4 hydrolase
• LTA 4 H is a bifunctional enzyme that is pivotal in leukotriene B 4 synthesis.
• the enzyme is classically known as an epoxide hydrolase activity responsible for generating of LTB 4 from LTA 4 . It also possesses an aminopeptidase activity responsible for the breakdown of the tripeptides formed during destruction of collagen and is also chemotactic to neutrophils (A. Gaggar et al., J. Immunol (2008) v. 180(3) pp. 5662-5669; P.
• LTA 4 H is classically recognized for its hydrolase activity for the synthesis of pro-inflammatory LTB 4 production, the aminopeptidase activity of this enzyme may play a compensatory mechanism to resolve inflammation. Therefore, a therapy that aimed at inhibiting LTB 4 production through inhibiting LTA4H must also maintain the
• the present disclosure provides compounds of formula (1).
• the present disclosure provides compositions comprising a compound of formula (1), e.g., pharmaceutical compositions.
• the present disclosure provides methods of treating various diseases and conditions, where the method comprises administering a
• Exemplary embodiments of the present disclosure include the compounds set forth in Table 1, and the following embodiments which are numbered for convenience of reference.
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents;
• L is selected from a direct bond and methylene
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl, Ci-C 6 alkoxy, C3-C6cycloalkoxy, and Ci-C 6 alkoxy substituted with C3-C6cycloalkyl;
• A is selected from a direct bond, -CH2- and -CH2CH2-;
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 ;
• R 2 is selected from methyl, ethyl and phenyl
• R 3 is selected from H, alkyl and substituted alkyl
• R 4 is selected from hydrogen, alkyl and phenyl
• R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalkyl, phenyl and substituted phenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl
• R 7 is hydrogen
• R 8 is hydrogen, methyl or ethyl
• R 7 and R 8 may form a 5 or 6-membered, optionally substituted, heterocycle.
• Ar is a 9- or 10-membered bicyclic ring system comprising two aromatic rings, where Ar is unsubstitued or is substituted with one substituent selected from halide, Ci- 6 alkyl; -S-Ci- ea Ikyl; -0-Ci- 6 alkyl; and -SC> -Ci- alkyl;
• L is selected from a direct bond and -CHr- (methylene);
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, C -C cycloalkoxy and Ci-C 6 alkoxy substituted with C -C cycloalkyl;
• A is selected from a direct bond, -CH - and -CH CH -;
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 ;
• R 2 is selected from methyl, ethyl and phenyl
• R 3 is H
• R 4 is selected from hydrogen, Ci-Cyalkyl and phenyl
• R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalkyl, phenyl and halophenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl
• R 7 is hydrogen and R 8 is hydrogen, methyl or ethyl; or R 7 and R 8 together form a 5- or 6- membered heterocycle which is optionally substituted with a substituent selected from Cr Cea Ikyl and carboxylic acid.
• Ar is 1,3-benzothiazole.
• a pharmaceutical composition comprising a compound of any of embodiments 1-66, or a pharmaceutically acceptable enantiomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
• composition of embodiment 67 in the form of an eyedrop.
• a method of treating an inflammatory disease or inflammatory condition comprising administrating to a subject in need thereof an effective amount of a compound of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating a respiratory disease or condition comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating a neurodegenerative disease, condition or disorder comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating respiratory disease, lung dysfunction or lung conditions comprising administrating to a subject in need thereof an effective amount of a compound of any of embodiments 1-66 or a composition of embodiment 67.
• COPD chronic obstructive pulmonary disease
• cystic fibrosis cystic fibrosis
• bronchopulmonary dysplasia bronchopulmonary dysplasia
• Idiopathic pulmonary fibrosis IPF
• a method of treating an autoimmune disease or autoimmune condition such as arthritis, Otis, and multiple sclerosis comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating an allergic disease comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating a conjunctivitis comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating uveitis comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating dry eye comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating diabetic retinopathy comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any of any of embodiments 1- 66 or a composition of embodiment 67.
• a method of treating age-related macular degeneration comprising administering to a
• a method of treating diabetic macular edema comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any of any of embodiments 1- 66 or a composition of embodiment 67.
• a method of treating skin disorders or skin conditions comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating cancer comprising administrating to a subject in need thereof an
• a method of treating a neuroinflammatory disease or neurodegenerative disease, such as Alzheimer's disease comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating Sjogren-Larsson-Syndrome comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• a method of treating cardiovascular (CV) disease comprising administrating to a subject in need thereof an effective amount of a compound of any of any of embodiments 1-66 or a composition of embodiment 67.
• FIG. 1 shows the effect of Compound 104 on LPS-induced neutrophil infiltration into the lung.
• FIG. 2 shows the effect of Compound 104 on clinical scores in the EIU rat model.
• FIG 3. shows the superior ability of Compound 104 to distribute to the posterior section (vitreous+retina) of the eye compared to standard of care Prednisolone.
• Sprague Dawley rats received a lOpL drop of either Compound 104 (0.4%) or commercially available ophthalmic prednisolone acetate (1%) and tissues were removed 2 hours post administration to measure compound concentration.
• the resulting data in FIG. 3, which represent the mean ⁇ standard deviation, n 5 eyes per drug, shows that Compound 104 was absorbed into the posterior segment at levels approximately 50 times that of prednisolone 2 hours after administration.
• FIG. 4A shows the effect of Compound 104 on clinical scores and histological evaluation in the EAU rat model.
• FIG. 4B is data taken from the same experiment as described for FIG. 4A, where FIG. 4B shows histological scores that were obtained 10 days post immunization.
• FIG. 4C is data taken from the same experiments as described for FIG. 4A, where FIG. 4C shows retinal thickness measurements that were determined from histological slides 10 days post immunization.
• alkyl refers to the term “alkyl” used by itself as well as the “alkyl” portion of words that incorporate the alkyl concept, e.g., "hydroxyalkyl”, “haloalkyl”, “O- alkyl”, etc.
• Chemical names, common names, and chemical structures may be used interchangeably to describe the same compound.
• the compounds of formula (1) may be referred to herein by chemical structure and/or by chemical name.
• chemical name In an instance where both the structure and the name of a compound are provided and there is a discrepancy between the name and the structure, then it is to be understood that the structural representation of the compound controls.
• substituted means that one or more hydrogens on a designated or selected atom is replaced with a selection from an indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• stable compound or “stable structure” it is meant that a compound is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic composition. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the atom's normal valence.
• Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to the specified number of carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),
• the alkyl group has 1 carbon. In one embodiment the alkyl group has 2 carbons. In one embodiment the alkyl group has 3 carbons. In one embodiment the alkyl group has 4 carbons. In one embodiment the alkyl group has 4 carbons.
• alkyl group has 5 carbons. In one embodiment the alkyl group has 6 carbons. Two or more of these embodiments may be combined to describe compounds of the disclosure.
• Alkoxy refers to -O-alkyl.
• Cycloalkyl refers to a cyclic aliphatic radical having no unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Cycloalkoxy refers to -O- cycloalkyl.
• Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. In one embodiment the aryl ring system has 6 to 12 carbon atoms. In one embodiment the aryl ring system has 6 to 10 carbon atoms.
• the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
• Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
• an aryl group may be optionally substituted by one or more substituents
• Compounds of the present disclosure and the equivalent term “compounds of the (or this) invention” (unless specifically identified otherwise) refer to compounds of Formula (1), including subsets thereof, and all pure and mixed stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds. Flydrates and solvates of the compounds of this invention / disclosure are also considered within the scope of the term compounds of this invention / disclosure.
• the compounds may exist in one or more crystalline states, i.e., as co-crystals or polymorphs, or they may exist as amorphous solids, or they may exist as oils. All such forms are encompassed by the invention and the claims.
• Compounds of "Formula (1)", “Formula 1", “formula (1)”, “formula 1” and the like may be used interchangeably herein and no difference or distinction is meant.
• Effective amount refers to an amount or dose of the active compound as described herein sufficient to elicit a desired pharmacological or therapeutic effect in a subject. In the case of compounds to treat inflammation, an effective amount will be an anti-inflammatory amount.
• effective amounts can be readily determined by ordinarily skilled artisans following the teachings of this disclosure and employing tools and methods generally known in the art, often based on routine clinical or patient-specific factors. It will be understood, however, that the attending physician, within the scope of sound medical judgment, will decide the total daily dosage of the compound.
• the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the desired result to be obtained, the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
• the total daily dose will typically range from about 0.0001 mg/kg/day to about 100 mg/kg/day in single or in divided doses.
• dosages for humans will range from about 0.1 mg to about 4000 mg per day, in a single or multiple doses
• fused refers to any ring system described herein which is fused to an existing ring structure in the compounds of the disclosure.
• the fused ring system is a heterocyclyl or a heteroaryl, any carbon in the existing ring structure which becomes part of the fused ring system may be replaced with a nitrogen.
• Halo refers to chloro, bromo, fluoro, and iodo.
• halogen refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I).
• the halogen is chlorine.
• the halogen is fluorine.
• the halogen is bromine.
• halophenyl refers to a phenyl group having at least one halogen substituent which replaces a hydrogen normally present on phenyl.
• Halogenated CH refers to a CH group that has at least one halogen substitution in place of hydrogen, e.g., CHF and CF .
• Haloalkyl refers to an alkyl group having at least one halogen substitution in lieu of a C-H bond.
• there is a single halogen substituent on the named group e.g., phenyl, alkyl.
• a subset of haloalkyl is
• fluoroalkyl which refers to alkyl groups that are substituted by one or more fluorine atoms, up to the total number of hydrogen atoms present on the alkyl moiety.
• Ci-Cefluoroalkyl refers to fluorinated alkyl groups, e.g., trifluoromethyl or difluoroethyl (i.e., CF and CH CHF ).
• Ci-Cefluoroalkyl denotes a straight-chain or branched alkyl group containing from 1 to 6, e.g., 1, 2, 3, or 4 carbon atoms.
• Ci-Cefluoroalkyl radicals are methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, where the radical contains 1, 2, 3 4, 5, 6, 7, 8, 9 or 10 or more fluorine substituents, for example, the radical may contain 1, 2 or 3 fluorine substituents.
• Heteroaryl refers to "aryl” as defined herein, wherein the aromatic ring includes one or more heteroatoms, preferably selected from N, O and S.
• a heteroaryl radical refers to an aromatic ring system radical wherein the ring atoms are selected from carbon, nitrogen, oxygen and sulfur, and include at least one of nitrogen, oxygen and sulfur.
• the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
• the heteroaryl radical is a 5-, 6- or 7-membered heteroaryl group.
• heteroaryl groups include 5-membered rings, such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3-thiazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole.
• 5-membered rings such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3-thi
• the heteroaryl group may be a 6-membered ring, such as pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1, 2,4,5- tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, or fused rings including a 6-membered ring such as indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, purine, naphthimidazole, phenanthrimidazole, pyridimidazole, pyrazinimidazole, quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, benzothiazole, benzofuran, isobenzofuran, dibenzofur
• Hydroxyalkyl refers to an alkyl group having at least one hydroxyl (-OH; also called hydroxy) substitution in lieu of a C-H bond. In one embodiment, there is a single hydroxyl substituent on the named group (e.g., phenyl, alkyl). In embodiments, there are two hydroxyl substituents, or 1-2 hydroxyl substituents, or three hydroxyl substituents, or 1-3 hydroxyl substituents. As used herein, "Ci-C 6 hydroxyalkyl” denotes a straight-chain or branched alkyl group containing from 1 to 6, e.g., 1, 2, 3, 4, 5 or 6 carbon atoms.
• Ci-Cehydroxyalkyl radicals are methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, te/t-butyl, where the radical contains 1 or more hydroxyl substituents, for example, as in one embodiment, the radical may contain 1 hydroxyl substituent.
• each substituent is selected without regard to the selection that is made for any other substituent, i.e., each substituent is independently selected.
• each selected substituent may be identical to or different from the other substituent(s) selected from a group of substituents.
• a disclosure that something is selected from a group means that the selection is independently done at each occurrence in the event that the selection is done multiple times. Unless otherwise explicitly stated, and regardless of whether the selection is explicitly stated to be made independently, selections of atoms and/or substituents are independently selected.
• mammal refers to human or animals including livestock and companion animals.
• companion animal or “companion animals” refers to animals kept as pets, e.g., cats, dogs, and horses.
• livestock refers to animals reared or raised in an agricultural setting to make products such as food or fiber, or for its labor, e.g., cattle, goats, horses, pigs, sheep, lambs, and rabbits, as well as birds, such as chickens, ducks and turkeys.
• “Pharmaceutically acceptable” refers to being suitable for use in mammals, companion animals or livestock animals.
• a pharmaceutically acceptable substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
• “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
• “Pharmaceutically acceptable salts” refers to either “pharmaceutically acceptable acid addition salts” or “pharmaceutically acceptable base addition salts” depending upon the actual structure of the compound.
• a “pharmaceutically acceptable salt” may refer to an acid addition salt of the amine group.
• Such salts refer to any non-toxic organic or inorganic acid addition salt of the compounds of this disclosure or any of its intermediates.
• Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
• Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids.
• Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
• Such salts can exist in either a hydrated or substantially anhydrous form.
• the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents.
• Basic nitrogen containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
• lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
• a “pharmaceutically acceptable salt” may refer to a base addition salt of the acid group.
• Such basic salts refer to any non-toxic organic or inorganic base addition salt of the compounds of this disclosure or any of its intermediates.
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as
• the counterion of the carboxylic or other acidic group may be a quarternized nitrogen- containing group.
• Prodrug refers to a compound (e.g., a drug precursor) that is transformed in vivo to provide a compound of the present disclosure or a pharmaceutically acceptable salt of the compound. The transformation may occur by, for example, metabolic or chemical processes, such as through hydrolysis in blood.
• Prodrugs include a bio-reversible derivative of a compound of Formula I of the present disclosure. Prodrugs can alter the solubility, lipophilicity and in-vivo distribution of drugs. By deliberately altering these key properties, it may be possible to improve absorption, enhance onset time, reduce first pass metabolism, allow development of aqueous IV formulations and achieve targeted delivery.
• prodrugs are useful in improving transdermal delivery, masking taste, minimizing pain on injection, improving stability, etc. In situations where the pharmacophore itself leads to poor delivery properties, prodrugs are one of the few strategies that can be used to salvage the highly active compound.
• prodrugs of the compounds of Formula (1) that can be prepared by the standard methods known to one skilled in the art.
• Prodrugs of the compounds of Formula (1) may be prepared following the methods described in, e.g., "Prodrugs of phosphates, phosphonates, and phosphinates", Krise J P, Stella V J, Advanced Drug Delivery Reviews, 19: (2) 287-310 May 22 1996; “Targeted Prodrug Design to Optimize Drug Delivery”. Hyo-Kyung Han and Gordon Am idon. AAPS PharmSci 2000; 2 (1) article 6; "Prodrugs", L Prokai and K.
• Solvate refers to a physical association of a compound of this disclosure with one or more solvent molecules.
• One or more compound of the disclosure may exist in solvated as well as unsolvated forms, where solvated forms are associated with pharmaceutically acceptable solvents such as water, ethanol and the like. All such solvated and unsolvated forms are within the scope of the compounds of Formula (1).
• the physical association involves varying degrees of ionic and covalent bonding including hydrogen bonding. In certain instances the solvate will be capable of isolation. This may happen when the one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid comprising a compound of the present disclosure.
• Reference to "solvate” encompasses both solution-phase and isolatable solvates.
• solvate encompasses hemisolvates.
• Non-limiting examples of solvates including methanolates, ethanolates and hydrates, where hydrates refer to solvates wherein the associated solvent molecule is water.
• a compound of the present disclosure may optionally be converted to a corresponding solvate form by methods known in the art.
• An exemplary, non-limiting process for preparing a solvate involves dissolving the inventive compound in a selected amount of a desired solvent (organic or water or mixtures thereof) at temperature that is higher than room temperature, and then cooling the solution at a rate that is sufficiently slow that crystals are formed, where the crystals may be isolated. See, e.g., M. Caira et al. J.
• Subject refers to mammals, e.g., humans, as well as livestock. The subject may also be referred to as a patient.
• Substituents refer to monovalent groups that may be attached to a mentioned radical.
• a “substituted phenyl” refers to a phenyl ring having 1, 2, 3 or 4 substituents attached to the phenyl ring.
• Substituents may be selected from halogen, Ci-C 6 alkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, -OH, -O(Ci-Cealkyl), -O(Ci-Cehaloalkyl), -O(Ci-Cehydroxyalkyl), -S(Ci-Cealkyl), -S(Ci- Cehaloalkyl), -S(Ci-C 6 hydroxyalkyl), cyano, amino (-NH ), formyl (-CHO), carboxylic acid (-COOH), carboxylate ester (-COOR where R is a C -C alkyl group).
• a 5- or 6-membered substituted heterocycle refers to a heterocyclic radical where at least one of the ring atoms is bonded to a substituent as defined herein.
• “Therapeutically effective amount” refers to the amount of a compound that, when administered to a mammal for a therapeutic purpose, is sufficient to effect such therapy for the disease or condition.
• the “therapeutically effective amount” will vary depending on the compound, the condition and its severity and the age, weight, etc., of the mammal to be treated.
• Treating" or “treatment” of a condition includes: (1) preventing the condition, i.e. causing the clinical symptoms or signs of the disease not to develop in a mammal that may be exposed to or predisposed to the condition but does not yet experience or display symptoms/signs of the condition; (2) inhibiting the condition, i.e., arresting or reducing the development of the condition or its clinical symptoms/signs, such as stopping the recurrence of the condition in a subject that has the condition; or (3) relieving the condition, i.e., causing regression of the condition or its clinical symptoms/signs.
• treating means an alleviation of symptoms associated with a disease, disorder or condition, or halt of further progression or worsening of those symptoms.
• treatment may include one or more of curative, palliative and prophylactic treatment. Treatment can also include administering a pharmaceutical formulation of the present disclosure in combination with other therapies. The compounds of the disclosure can also be administered in conjunction with other drugs and/or therapies.
• a patient, clinician, or another human may in some cases be described in the context of the male gender. It is understood that a medical practitioner can be of any gender, and the terms “he,” “his,” “himself,” and the like as used herein are to be interpreted broadly inclusive of all known gender definitions.
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents;
• L is selected from a direct bond and methylene
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl, Ci-C 6 alkoxy, C 3 -C 6 cycloalkoxy and Ci-C 6 alkoxy substituted with C 3 -C 6 cycloalkyl;
• A is selected from a direct bond, -Ch - and -CH 2 CH 2 -;
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 ;
• R 2 is selected from methyl, ethyl and phenyl;
• R 3 is selected from hydrogen, alkyl and substituted alkyl
• R 4 is selected from hydrogen, alkyl and phenyl
• R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalky, phenyl and substituted phenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl
• R 7 is hydrogen
• R 8 is hydrogen, methyl or ethyl
• R 7 and R 8 may form a 5 or 6-membered, optionally substituted, heterocycle.
• Arl and Ar2 are used in order to refer distinctively to one of the two aromatic rings. Also for each of discussion, Arl, which is 9- or 10-membered bicyclic aromatic ring system, may be referred to as an aromatic ring.
• compounds of formula (1) include pharmaceutically acceptable enantiomers, diastereomers, salts and solvates thereof.
• a compound of formula (1) may exist in either the (R) or (S) configuration and thus give rise to two enantiomeric forms.
• the present disclosure provide a compound of claim 1 as a racemic mixture of two enantiomers of compounds of formula (1).
• the present disclosure provides a compound of formula (1) as a non-racemic mixture of enantiomers of compounds of formula (1), i.e., both the (R) and (S) enantiomers are present together in admixture, but the molar (R):(S) ratio does not equal 1.
• the present disclosure provides a compound of formula (1) as an isolated (S) enantiomer, i.e., not in admixture with the corresponding (R) enantiomer or in admixture with less than 1% of the (R) enantiomer.
• the present disclosure provides a compound of formula (1) as an isolated (R) enantiomer, i.e., not in admixture with the corresponding (S) enantiomer or in admixture with less than 1% of the (S) enantiomer.
• Ar (Arl) represents a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents.
• a bicyclic ring system refers to a moiety having two rings that are fused to one another, and a bicyclic aromatic ring refers to a moiety having two rings fused together where at least one, and optionally two (both) of the rings is an aromatic ring.
• only one of the two rings of the bicyclic aromatic ring system is an aromatic ring.
• both rings of the bicyclic aromatic ring system are aromatic rings. That the ring system is 9- or 10-membered refers to the number of atoms that form the ring system.
• a 6-membered ring fused to a 5-membered ring provides a 9- membered ring system
• a 6-membered ring fused to a 6-membered ring provides a 10- membered ring system
• Arl is a 9-membered bicyclic aromatic ring system, wherein a five membered ring is fused to a six membered ring.
• 9-membered Ar groups include benzofuran, 1,3-benzoxazole, furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-c]pyridine, furo[2,3-b]pyridine, indole, lH-benzimidazole, lH-pyrrolo[3,2-b]pyridine, 1H- pyrrolo[3,2-c]pyridine, lH-pyrrolo[2,3-c]pyridine, lH-pyrrolo[2,3-b]pyridine, benzothiophene, 1,3- benzothiazole, thienol[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3-c]pyridine, benzoxadia
• Ar is a 10-membered bicyclic aromatic ring system wherein a six membered ring is fused to another six membered ring.
• 10-membered Ar groups include naphthalene, quinoline, quinazoline, quinoxaline, 1,5- naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine and 2,7-naphthyridine.
• Each of the listed 10-membered ring systems may be an Ar group in compounds of formula (1), where each of these ring systems is optionally substituted with one, two or three substituents.
• compounds of formula (1) have Ar as 1,3-benzothiazole.
• compounds of formula (1) have Ar selected from 1,3-benzoxazole and quinoline.
• a substituent on Ar refers to a monovalent group that may be attached to any of the ring atoms of the Ar group.
• substituents may be selected from halide, Cr Cialkyl, Ci-Cihaloalkyl, Ci-C alkoxy,Ci-C haloalkoxy, Ci-C thioalkyl, Ci-C thiohaloalkyl, Cr
• Ar does not have any substituents.
• Ar is mono-substituted, where optionally the one substituent may be selected from those listed above.
• Ar contains a single substituent which is Ci-C thioalkyl, e.g., -S-methyl.
• Ar is di-substituted, where optionally the two substituents may be independently selected from those listed above.
• Ar is tri-substituted, where optionally the three substituents may be independently selected from those listed above.
• the compounds of formula (1) have a single substituent on Ar, where that single substituent is -S-CH3.
• the Ar group (sometimes referred to herein as Arl) is joined to a central benzene ring (sometimes referred to herein as Ar2) in compounds of formula (1) via an -L-O- group.
• L is a directed bond, so that the Ar group is joined to a central benzene ring in compounds of formula (1) via an ether (-0-) linkage.
• L is methylene, so that the Ar group is joined to a central benzene ring in compounds of formula (1) via a -CH -O- linkage.
• the central benzene ring in formula (1) is bonded to R 1 , where R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl, Ci-C 6 alkoxy, and Ci-C 6 alkoxy substituted with C - Cecycloalkyl.
• R 1 is hydrogen, so that the central benzene ring (Ar2) may be said to be unsubstituted.
• R 1 is not hydrogen, so that the central benzene ring is substituted.
• R 1 is halide, e.g., fluoride.
• R 1 is Ci-C 6 alkyl, e.g., methyl or ethyl.
• R 1 is Ci-Cehaloalkyl, e.g., trifluoromethyl.
• R 1 is Ci-C 6 alkoxy, e.g., methoxy or ethoxy.
• R 1 is C -C cycloalkoxy, e.g., cyclopropyloxy, cyclobutyloxy or cyclopentyloxy.
• R 1 is Ci-C 6 alkoxy substituted with C -C cycloalkyl, such as -O-Ch -cyclopropyl where -O-CH is a Ci alkoxy that is substituted with a C cycloalkyl (cyclopropyl).
• a central aromatic ring (benzene) is substituted with R 1 as descried above, as well as the group denoted as -A-E.
• A links together the E group and the central aromatic ring.
• the A group is selected from a direct bond, methylene and ethylene.
• the E group is selected from -C(0)-R 2 , i.e., a carbonyl group bonded to R 2 , C(OR 3 )R 4 R 5 , i.e., a carbon to which each of OR 3 , R 4 and R 5 is bonded, and CH(R 6 )NR 7 R 8 , i.e., a carbon to which each of hydrogen, R 6 and NR 7 R 8 is bonded.
• A may be a direct bond while E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 , i.e., in one embodiment A-E is -C(0)-R 2 , while in another embodiment A-E is C(OR 3 )R 4 R 5 , and in a further embodiment A-E is CH(R 6 )NR 7 R 8 .
• A may be methylene while E is selected from— C(O)- R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 , i.e., in one embodiment A-E is CH 2 -C(0)-R 2 , while in another embodiment A-E is CH -C(OR 3 )R 4 R 5 , and in a further embodiment A-E is CH -CH(R 6 )NR 7 R 8 .
• A may be ethylene while E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and
• A-E is CH 2 CH 2 -C(0)-R 2
• A-E is CH CH -C(OR 3 )R 4 R 5
• A-E is CH CH -CH(R 6 )NR 7 R 8 .
• A is a direct bond.
• A is -CH -.
• A is -CH CH -.
• R 5 is trifluoromethyl.
• E is -C(0)-R 2 , where R 2 is methyl, ethyl or phenyl, e.g., E may be any of C(0)CH 3 , i.e., acetyl, C(0)CH 2 CH 3 , or C(0)phenyl, i.e., benzoyl.
• -A-E is - C(0)-R 2 when A is a direct bond.
• -A-E is CH 2 -C(0)-R 2 when A is methylene, e.g., -CH 2 -C(0)CH 3 , or -CH 2 C(0)CH 2 CH 3 , or -CH 2 (C(0)phenyl.
• A-E is CH 2 CH 2 C(0)-R 2 when A is ethylene, e.g., -CH 2 CH 2 C(0)CH 3 or -CH 2 CH 2 C(0)CH 2 CH 3 or
• E is C(OR 3 )R 4 R 5 , where R 3 is selected from hydrogen, alkyl and substituted alkyl; R 4 is selected from hydrogen, alkyl and phenyl; and R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalky, phenyl and substituted phenyl. In one embodiment, R 5 is trifluoromethyl and R 3 is hydrogen.
• E is CH(R 6 )NR 7 R 8 , where R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl; R 7 is hydrogen; and R 8 is hydrogen, methyl or ethyl.
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl; R 7 is hydrogen; and R 8 is hydrogen, methyl or ethyl.
• E is selected from CH(R 6 )NH , CH(R 6 )NH(CH ) and CH(R 6 )NH(CH CH ).
• R 7 and R 8 together, along with the nitrogen atom to which they are both attached, may form a 5 or 6-membered, optionally substituted, heterocycle, where the heterocycle will include the nitrogen to which both R 7 and R 8 are attached, as well as one or more, e.g., two, non carbon atoms, e.g., oxygen or nitrogen.
• Exemplary 5-membered rings are pyrrolidine and unsaturated analogs thereof, e.g., 2,5-dihydro-lH- pyrrole.
• -NR 7 R 8 may represent 2, 5-dihydro-lH-pyrrole.
• Exemplary 6-membered heterocyclic rings are piperidine and unsaturated analogs thereof, e.g., 1,2,3,4-tetrahydropyridine, and piperazine.
• the 5-membered heterocyclic ring and 6-membered heterocyclic ring will each have at least one nitrogen atom, and optionally may have a second heteroatom ring atom, e.g, a heteroatom selected from oxygen, nitrogen and sulfur.
• the 5-membered heterocyclic ring and 6-membered heterocyclic ring may be substituted as described herein.
• E is CH(R 6 )NR 7 R 8 , where (i) R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl; and R 7 is hydrogen; and R 8 is selected from hydrogen, methyl and ethyl, or (ii) R 7 and R 8 together, along with the nitrogen atom to which they are both attached, form a 5 or 6-membered heterocycle, which is optionally substituted, where the heterocycle will include the nitrogen to which both R 7 and R 8 are attached, as well as one or more, e.g., two, non-carbon atoms, e.g., oxygen or nitrogen.
• Ar may be unsubstituted aryl, or it may have one, two or three substituents. In one embodiment, Ar has no substituents. In another embodiment, Ar has one substituent. In yet another embodiment, Ar has two substituents. In a further embodiment, Ar has three substituents. When Ar has no substituents, the present disclosure provides compounds of formula (1)
• Ar is a 9- or 10-membered unsubstituted bicyclic aromatic ring system
• L is selected from a direct bond and methylene
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl and Ci-Cealkoxy
• A is selected from a direct bond, -CE - and -CH CH -
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8
• R 2 is selected from methyl, ethyl and phenyl
• R 3 is selected from hydrogen, alkyl and substituted alkyl
• R 4 is selected from hydrogen, alkyl and phenyl
• R 5 is selected from Ci-Cyalkyl, Ci- Cyhaloalkyl (e.g., trifluoromethyl), phenyl and substituted phenyl
• R 6 is selected from hydrogen, methyl, halogenated
• A is ethylene and E is -C(0)-R 2 , while R 1 is selected from halide and alkoxy so as to provide compound, when Ar-L-0 is benzoxazol-2-yloxy so as to provide compounds of the formula
• n ano er suc em o men , s e y ene and E is C(OR 3 )R 4 R 5 where R 3 is hydrogen, R 4 is alkyl, e.g., ethyl, and R 5 is Ci-Cyhaloalky, e.g.,
• R 1 is Ci-C alkoxy, so as to provide compounds, when Ar-L-0 is 1,3- benzothiazol-2-yloxy, of the formula
• A is ethylene and E is C(OR 3 )R 4 R 5 where R 3 is hydrogen, R 4 is alkyl, e.g., methyl, and R 5 is Ci-Cyhaloalky, e.g., trifluoromethyl, while R 1 is Ci-C4alkoxy, so as to provide compounds, when Ar-L-0 is 1,3- benzothiazol-2-yloxy, of the formula
• y and E is C(OR 3 )R 4 R 5 where R 3 is selected from hydrogen, alkyl and substituted alkyl; R 4 is hydrogen, and R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalky, phenyl and substituted phenyl; while R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl and Ci-C 6 alkoxy, so as to provide compounds, e.g., when Ar-L-0 is l,3-benzothiazol-2-yloxy, of the formula
• R 1 may be hydrogen so as to provide compounds of the formula
• R 3 is selected from hydrogen, alkyl and substituted alkyl
• R 4 is selected from hydrogen, alkyl and phenyl
• R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalkyl, phenyl and substituted phenyl; so as to provide compounds, e.g., of the formula
• Ar is unsubstituted and E is -C(OH)(CF )(CH CH ), so as to provide compounds of the formula the compound .
• Other compound of the present disclosure having an unsubstituted Ar group have A equal to ethylene and E is C(0)-phenyl, for example, compounds of the formula
• A is a direct bond, to provide compounds, e.g., having the formula
• Ar may be unsubstituted aryl, or it may have one, two or three substituents.
• the present disclosure provides compounds of formula ( 1) pharmaceutically acceptable salts thereof, wherein : Ar is a 9- or 10-membered substituted bicyclic aromatic ring system, having one, two or three substituents; L is selected from a direct bond and methylene; R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl and Ci-C 6 alkoxy; A is selected from a direct bond, -CH2- and -CH2CH2-; E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )N R 7 R 8 ; R 2 is selected from methyl, ethyl and phenyl; R 3 is selected from hydrogen, alkyl and substituted alkyl; R 4 is selected from hydrogen, alkyl and phen
• R 3 may be, for example, hydrogen, so as to provide compounds of the formula.
• Ar is substituted and R 1 is selected from halide and alkoxy to provide, e.g., a compounds of the formulae
• the compounds of the disclosure include both of hydroxyl and trifluoromethyl as components of the“E" group.
• the present disclosure provides compounds of the formula
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents;
• L is selected from a direct bond and methylene;
• R 1 is selected from hydrogen, halide, Ci-C4alkyl, Ci-Cihaloalkyl and Ci-C4alkoxy;
• A is selected from a direct bond, -CH2- and -CH2CH2-;
• E is C(OR 3 )R 4 R 5 where R 3 is hydrogen while R 5 is trifluoromethyl, so that E is C(OH)(CF )R 4 ; and
• R 4 is selected from hydrogen, methyl and ethyl.
• a compound of formula (1) may additionally be characterized by one or more of the following: R 5 is Ci-Cyalkyl; R 5 is methyl; R 5 is ethyl; R 5 is Ci-Cyhaloalkyl; R 5 is phenyl; A is -CH 2 CH 2 - and R is Ci-Cyalkyl; A is -CH 2 CH 2 - and R is methyl; A is -CH 2 CH 2 - and R is ethyl; A is - CH 2 CH 2 - and R is Ci-Cyhaloalkyl; A is -CH 2 CH 2 - and R is phenyl; L is a direct bond, A is -CH 2 CH 2 - and R is Ci-Cyalkyl; L is a direct bond, A is -CH 2 CH 2 - and R is Ci-Cyalkyl; L is a direct bond, A is -CH 2 CH 2 - and R is methyl; L is a direct bond, A is -CH
• R 1 is selected from hydrogen, halide and alkoxy;
• A is selected from a direct bond, -CH - and - CH CH -;
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 ;
• R 2 is selected from methyl, ethyl and phenyl;
• R 3 is selected from H and a hydroxyl protecting group;
• R 4 is selected from hydrogen, methyl and ethyl;
• R 5 is selected from methyl, halogenated methyl (e.g., trifluoromethyl) ethyl and phenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl;
• R 7 is hydrogen; and
• R 8 is methyl or ethyl; with the proviso that together, R 7 and R 8 may form a 5 or 6-membered optionally substituted heterocycle.
• the present disclosure
• Arl is a naphthalene radical, or a heterocyclic analog thereof, where Arl is optionally substituted with one or two substituents, and L is optionally a methylene group (-CH2-), where R 1 is selected from hydrogen, halide and alkoxy; A is selected from a direct bond, -Ch - and -CH2CH2-; E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 ; R 2 is selected from methyl, ethyl and phenyl; R 3 is selected from H and a hydroxyl protecting group; R 4 is selected from hydrogen, methyl and ethyl; R 5 is selected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyl and phenyl; R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl; R 7 is hydrogen; and R
• alkoxy is selected from a direct bond, -CH2- and -CH2CH2-; E is selected from -C(0)-R 2 ,
• R 2 is selected from methyl, ethyl and phenyl;
• R 3 is selected from H and a hydroxyl protecting group;
• R 4 is selected from hydrogen, methyl and ethyl;
• R 5 is selected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyl and phenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl;
• R 7 is hydrogen; and R 8 is methyl or ethyl; with the proviso that together, R 7 and R 8 may form a 5 or 6-membered optionally substituted heterocycle, such as compounds of the formula
• R 1 is selected from hydrogen, halide and alkoxy
• R 3 is selected from H and a hydroxyl protecting group
• R 4 is selected from hydrogen, methyl and ethyl
• R 5 is selected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyl and phenyl, e.g.,
• the present disclosure provides the following exemplary compounds that include naphthyl or heterocyclic analogs of naphthyl as the Ar group, such as compounds of the formula :
• R 1 is selected from hydrogen, halide and alkoxy;
• A is selected from a direct bond, -CH2- and -CH2CH2-;
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH( R 6 )N R 7 R 8 ;
• R 2 is selected from methyl, ethyl and phenyl;
• R 3 is selected from H and a hydroxyl protecting group;
• R 4 is selected from hydrogen, methyl and ethyl;
• R 5 is selected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyl and phenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl;
• R 7 is hydrogen; and
• R 8 is methyl or ethyl; with the proviso that together, R 7 and R 8 may form a 5 or 6-membered optionally substituted heterocycle, including compounds of the formula
• R 1 is selected from hydrogen, halide and alkoxy and R 2 is selected from methyl, ethyl and phenyl, such as the compound of the formula
• the compounds of the disclosure have a nitrogen atom as part of the E group, and more specifically have E is -CH(R 6 )NR 7 R 8 .
• E is -CH(R 6 )NR 7 R 8 .
• the present disclosure provides compounds of the formula (1)
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one or two substituents;
• L is selected from a direct bond and methylene;
• R 1 is selected from hydrogen, halide and alkoxy;
• A is selected from a direct bond, -CH2- and -CH2CH2-;
• E is CH(R 6 )NR 7 R 8 ;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl;
• R 7 is hydrogen; and R 8 is methyl or ethyl; with the proviso that together, R 7 and R 8 may form a 5 or 6-membered optionally substituted heterocycle.
• a compound of formula (1) may additionally be characterized by one or more of the following: R 7 and R 8 form a 5 or 6-membered optionally substituted heterocycle, and R 1 is hydrogen; A is CH2CH2; R 7 and R 8 form a 5 or 6-membered optionally substituted heterocycle, R 1 is hydrogen and A is CH2CH2, to provide, for example, the following compounds:
• (1) may additionally be characterized by specifying that A is a direct bond, so as to provide, for example, compounds of the formula:
• such a compound of formula (1) may additionally be characterized by specifying that R 1 is not hydrogen, R 7 is hydrogen, and R 8 is methyl or ethyl, so as to provide, for example, a compound of the formula.
• the compounds of the disclosure have a carbonyl group (C(O)) as part of the E group, and more specifically have E is -CH(R 6 )NR 7 R 8 .
• the present disclosure provides compounds of the formula (1)
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents;
• L is selected from a direct bond and methylene;
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl and Ci-C 6 alkoxy;
• A is selected from a direct bond, -CH2- and - CH2CH2-;
• E is -C(0)-R 2 ; and R 2 is selected from methyl, ethyl and phenyl.
• the present disclosure provides compounds of the formula
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents;
• L is selected from a direct bond and methylene;
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl
• R 2 is phenyl, including compounds of the formula
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents; L is selected from a direct bond and methylene; R 1 is Ci-C 6 alkoxy and specifically methoxy; A is -CH2CH2-; E is— C(0)-R 2 ; and R 2 is phenyl, and including compounds of the formula
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl and Ci-C 6 alkoxy, such as the compound of the formula
• the compounds of the disclosure have halide substitution on the central aromatic ring, i.e., compounds of formula (1) wherein R 1 is halide.
• the present disclosure provides compounds of the formula (1)
• the present disclosure provides compounds of the formula (1)
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents;
• L is selected from a direct bond and methylene;
• R 1 is halide;
• A is selected from a direct bond, -CH2- and - CH2CH2-;
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 ;
• R 2 is selected from methyl, ethyl and phenyl;
• R 3 is selected from hydrogen, alkyl and substituted alkyl;
• R 4 is selected from hydrogen, alkyl and phenyl;
• R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalkyl (e.g., trifluoromethyl), phenyl and substituted phenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl;
• R 1 is halide and R 2 is selected from methyl, ethyl and phenyl; such as
• R 1 is halide
• R 3 is selected from hydrogen, alkyl and substituted alkyl
• R 4 is selected from hydrogen, alkyl and phenyl
• R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalkyl (e.g., trifluoromethyl), phenyl and substituted phenyl; such as
• isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, C, 13 C, 14 C, 13 N, 1S N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 CI, 123 1, and 125 l, respectively.
• radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to a pharmacologically important site of action.
• Certain isotopically-la belled compounds of the disclosure for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.
• Isotopically- la belled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate isotopically-labelled reagent in place of the non- labeled reagent previously employed.
• solvate refers to an aggregate that comprises one or more molecules of a compound of the disclosure with one or more molecules of solvent.
• the solvent may be water, in which case the solvate may be a hydrate.
• the solvent may be an organic solvent.
• the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
• the compound of the disclosure may be true solvates, while in other cases, the compound of the disclosure may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
• the present disclosure provides the compounds in Table 1, listed singly or in any combination, as well as a pharmaceutically acceptable enantiomer, diastereomer, salt, or solvate thereof.
• Ar is a 9- or 10-membered bicyclic aromatic ring system, where Ar is optionally substituted with one, two or three substituents;
• L is selected from a direct bond and methylene
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl, Ci-C 6 alkoxy, C -C cycloalkoxy and Ci-C 6 alkoxy substituted with C -C cycloalkyl;
• A is selected from a direct bond, -CH 2 - and -CH 2 CH 2 -;
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 ;
• R 2 is selected from methyl, ethyl and phenyl
• R 3 is selected from H, alkyl and substituted alkyl
• R 4 is selected from hydrogen, alkyl and phenyl
• R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalkyl, phenyl and substituted phenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl
• R 7 is hydrogen; and R 8 is hydrogen, methyl or ethyl; with the proviso that together, R 7 and R 8 may form a 5 or 6-membered, optionally substituted, heterocycle.
• Ar is a 9- or 10-membered bicyclic ring system comprising two aromatic rings, where Ar is unsubstitued or is substituted with one substituent selected from halide, Ci-ealkyl; -S-Ci- 6 alkyl; - 0-Ci- 6 alkyl; and -SC> -Ci- alkyl;
• L is selected from a direct bond and -CH - (methylene);
• R 1 is selected from hydrogen, halide, Ci-C 6 alkyl, Ci-Cehaloalkyl and Ci-C 6 alkoxy;
• A is selected from a direct bond, -CH 2 - and -CH 2 CH 2 -;
• E is selected from -C(0)-R 2 , C(OR 3 )R 4 R 5 and CH(R 6 )NR 7 R 8 ;
• R 2 is selected from methyl, ethyl and phenyl
• R 3 is H
• R 4 is selected from hydrogen, Ci-Cyalkyl and phenyl
• R 5 is selected from Ci-Cyalkyl, Ci-Cyhaloalkyl, phenyl and halophenyl;
• R 6 is selected from hydrogen, methyl, halogenated methyl and ethyl
• R 7 is hydrogen and R 8 is hydrogen, methyl or ethyl; or R 7 and R 8 together form a 5- or 6- membered heterocycle which is optionally substituted with a substituent selected from Ci- Cea Ikyl and carboxylic acid.
• a pharmaceutical composition comprising a compound of embodiments 1 or 2, or a pharmaceutically acceptable enantiomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
• a method of treating an inflammatory disease or inflammatory condition comprising
• condition is an ocular inflammatory disease or an ocular inflammatory condition, respectively.
• a method of treating a respiratory disease or condition comprising administering to a
• a method of treating a neurodegenerative disease, condition or disorder comprising
• the compounds and compositions of the present disclosure may be used in therapeutic methods.
• the therapeutic method may provide either a therapeutically effective amount of the compound/composition, or a prophylactically-effective amount of the compound/composition.
• a compound of the disclosure may be administered pre-surgery to minimize post-surgery trauma.
• the following are exemplary therapeutic methods where the compounds and compositions may be used.
• the present disclosure provides a method of treating inflammation comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating inflammation prophylactically comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• a prophylactically-effective amount of a compound as set forth above for example, in conditions such as asthma and allergy, the compounds as set forth herein may be administered prophylactically to prevent exacerbation or flare of the condition.
• the present disclosure provides a method of treating a respiratory disease or condition, comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating asthma comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the subject being treated has mild to moderate asthma. In another embodiment, the subject being treated has severe asthma.
• the present disclosure provides a method of treating asthma comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the subject being treated has mild to moderate asthma. In another embodiment, the subject being treated has severe asthma.
• the present disclosure provides a method of treating allergic disease including but not limited to dermal and ocular indications comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating allergic disease including but not limited to dermal and ocular indications comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating conjunctivitis.
• the present disclosure provides a method of treating allergic conjunctivitis comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the conjunctivitis may be secondary to an infection such as a viral or bacterial infection.
• the conjunctivitis may be caused by contact lens use.
• the present disclosure provides a method of treating conjunctivitis.
• the present disclosure provides a method of treating allergic conjunctivitis comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the conjunctivitis may be secondary to an infection such as a viral or bacterial infection.
• the conjunctivitis may be caused by contact lens use.
• the present disclosure provides a method of treating uveitis comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the subject may have, for example, anterior, intermediate, posterior or pan uveitis.
• the present disclosure provides a method of treating uveitis comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the subject may have, for example, anterior, intermediate, posterior or pan uveitis.
• the present disclosure provides a method of treating atopic dermatitis comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating atopic dermatitis comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating psoriasis comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating psoriasis comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating acne vulgaris comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating acne vulgaris comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating tendinopathy comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating tendinopathy comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating
• bronchopulmonary dysplasia comprising administering to a subject in need thereof a
• the present disclosure provides a method of treating bronchopulmonary dysplasia comprising administering to a subject in need thereof a
• the present disclosure provides a method of treating chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the subject may have, for example, early stage or mild/moderate COPD.
• the present disclosure provides a method of treating chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the subject may have, for example, early stage or mild/moderate COPD.
• the present disclosure provides a method of treating lung dysfunction comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the subject may have, for example, occupational lung dysfunction related to environmental pollutants/hazards.
• the present disclosure provides a method of treating lung dysfunction comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the subject may have, for example, occupational lung dysfunction related to environmental pollutants/hazards.
• the present disclosure provides a method of treating pulmonary hypertension (e.g., neonatal) comprising administering to a subject in need thereof a
• the present disclosure provides a method of treating pulmonary hypertension (e.g., neonatal) comprising administering to a subject in need thereof a
• the present disclosure provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• An exemplary cancer is a solid tumor.
• the cancer may be, for example breast cancer or ovarian cancer.
• the method may provide presentation of metastases of an existing cancer.
• the present disclosure provides a method of treating neuroinflammatory disease comprising administering to a subject in need thereof a therapeutically- effective amount of a compound as set forth above.
• the present disclosure provides a method of treating neuroinflammatory disease comprising administering to a subject in need thereof a prophylactically- effective amount of a compound as set forth above.
• the present disclosure provides a method of treating a
• neurodegenerative disease, condition or disorder comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating multiple sclerosis comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating multiple sclerosis comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating cystic fibrosis comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the cystic fibrosis may be related to lung inflammation (e.g., be at a non-infectious stage).
• the present disclosure provides a method of treating cystic fibrosis comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the cystic fibrosis may be related to lung inflammation (e.g., be at a non-infectious stage).
• the present disclosure provides a method of treating idiopathic pulmonary fibrosis (IPF) comprising administering to a subject in need thereof a therapeutically- effective amount of a compound as set forth above.
• IPF idiopathic pulmonary fibrosis
• the present disclosure provides a method of treating idiopathic pulmonary fibrosis (IPF) comprising administering to a subject in need thereof a prophylactically- effective amount of a compound as set forth above.
• IPF idiopathic pulmonary fibrosis
• the present disclosure provides a method of treating Alzheimer's disease, particularly early stage Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating Sjogren-
• Larsson-Syndrome comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating cardiovascular (CV) disease, e.g., ACS or plaque formation, comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• CV cardiovascular
• the population being treated may have an ischemia/reperfusion injury.
• the present disclosure provides a method of treating otitis comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the otitis may be, for example, secondary to an infection.
• the present disclosure provides a method of treating inflammation that is associated with ocular surgery comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating inflammation that is associated with ocular surgery comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating dry eye, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as set forth above.
• the present disclosure provides a method of treating inflammation associated with cataract surgery comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating inflammation associated with cataract surgery comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating arthritis comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the arthritis may be, for example, at the early onset stage.
• the present disclosure provides a method of treating arthritis comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the arthritis may be, for example, at the early onset stage.
• the present disclosure provides a method of treating inflammation associated with laser eye surgery comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating inflammation associated with laser eye surgery comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating allograft rejection comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating allograft rejection comprising administering to a subject in need thereof a prophylactically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating trauma, e.g., a cerebral ischemia, comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• trauma e.g., a cerebral ischemia
• the present disclosure provides a method of treating diabetic retinopathy comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• the present disclosure provides a method of treating age-related macular degeneration comprising administering to a subject in need thereof a therapeutically- effective amount of a compound as set forth above.
• the present disclosure provides a method of treating diabetic macular edema comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as set forth above.
• compositions may be used to treat the above-mentioned medical condition.
• Those compositions may optionally include one or more active agents other than compounds of formula (1), which, e.g., supplement, augment or complement the activity of a compound of formula (1).
• the present disclosure provides pharmaceutical compositions comprising a compound of formula (1).
• the compounds of the present disclosure may be formulated into a pharmaceutical composition.
• the present disclosure provides a pharmaceutical composition comprising a compound of formula (1) as set forth above, and at least one pharmaceutically acceptable carrier, excipient or diluent.
• compositions can be administered for use in human or veterinary medicine, by analogy with other bioactive agents such as anti-inflammatory agents.
• bioactive agents such as anti-inflammatory agents.
• Such methods are known in the art and include administration by any route known in the art, such as subdermal, by-inhalation, oral, topical or parenteral.
• the compositions may be administered in intravenous (bolus or infusion), intraperitoneal, topical (e.g., ocular, eye drop), subcutaneous, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
• compositions are formulated into a form suitable for the desired route of administration.
• a form of the compositions is selected, in part, based on the desired route of administration.
• the compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations.
• a brief summary includes oral administration, which is readily accomplished with solid (e.g., tablet, capsule, gel-cap, powder, granule, lozenge, delayed-release solid form, slow or sustained release solid form, encapsulated solid form) or liquid (e.g., liquid gel cap, suspension, solution, syrup, elixir, liposomal solution) compositions.
• the composition may be in liquid (e.g., nebulized solution/suspension) or solid (e.g., metered dose inhaler, dry powder inhaler) form.
• the composition may be delivered via an implant, where examples are an ocular implant (e.g., a slow or sustained release depot solid form matrix) and a subcutaneous implant (e.g., a slow or sustained release depot pump).
• the composition may be a liquid (e.g., solution, nano-suspension, liposomal suspension, micellar suspension) or a solid (e.g., a lyophilized product) which may be reconstituted to provide a liquid form.
• the composition may be a liquid (e.g., solution, nano-suspension, liposomal suspension, micellar suspension, oil-based formulation) or a solid (e.g., a lyophilized product) which may be reconstituted to provide a liquid form.
• Intramuscular administration may also be accomplished with a suitably positioned implant.
• the composition may be administered subcutaneously, in which case the same forms that are suitable for intramuscular administration may be used for subcutaneous administration.
• Intraperitoneal administration may be used to deliver a compound or composition of the present disclosure, where a suitable form intraperitoneal administration is liquid (e.g., solution, nano-suspension, liposomal suspension, micellar suspension) or solid (Lyophilized product for reconstitution).
• Intrathecal is another suitable route of administration, in which case the formulation may be a liquid (e.g., solution, nano-suspension, liposomal suspension, micellar suspension) or solid (e.g., lyophilized product for reconstitution).
• composition may be administered topically to the skin of the subject, where suitable forms are liquid (e.g., solution, suspension, emulsion, cream, gel, ointment - with carriers). Topical administration may also be for delivery to the eye of the subject, where suitable forms are liquid (e.g., solution, suspension, liposomal suspension, emulsion, ointment) or solid (e.g., coated implant, implant pump).
• suitable forms e.g., solution, suspension, liposomal suspension, emulsion, ointment
• solid e.g., coated implant, implant pump
• the compounds of the disclosure may be formulated into a transdermal patch, which may provide slow or sustained release of the compound to the subject.
• Rectal administration may be accomplished with a suppository, such as a solid/solid wax or solid oil- based; or solid/semi-solid wax oil based with semi-solid liquid or gel composition.
• a suppository such as a solid/solid wax or solid oil- based; or solid/semi-solid wax oil based with semi-solid liquid or gel composition.
• the present disclosure also provides lyophilized preparations for reconstitution with a suitable vehicle.
• Lyophilization refers to the removal of liquid components of a formulation to provide a solid phase. Lyophilization may be accomplished by techniques known in the art, e.g., placing the composition under vacuum and moderate heating to evaporate the liquid components.
• the active ingredients will typically be administered in admixture with carrier materials selected with a view to the intended form of administration, such as oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, liquids, solutions and suspensions including sterile solutions or suspensions for topical administration.
• the composition is administered to an eye of the subject, and the composition may take the form of a liquid composition that may be dropped onto the surface of the eye.
• Each of such compositions may be made in a manner consistent with conventional pharmaceutical practices.
• the composition is a solid form preparation.
• the composition may be in the form of tablets, dispersible granules, and capsules.
• the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier. Examples include saccharides such as lactose, mannitol, sucrose and other sugars, starches and cellulose; and inorganic compounds such as calcium sulfate, magnesium stearate and dicalcium phosphate.
• the solid may be formulated as a suppository.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
• Suitable binders include starches, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
• lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
• Disintegrants include starches, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate for a dosage form intended for oral administration.
• binding agents for example acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone
• fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
• tableting lubricants for example magnesium stearate, talc, polyethylene glycol or silica, disintegrants, for example potato starch
• acceptable wetting agents such as sodium lauryl sulphate.
• the solid form preparation may contain from between about 0.5 to about 100 weight percent of active ingredient including a compound of formula (1).
• the compounds of the present disclosure may be formulated into a liquid
• Liquid form preparations include solutions, suspensions and emulsions.
• Liquid compositions include at least one material that is a liquid at room temperature, where water is one such material.
• Other liquid materials that may be included in the liquid composition include propylene glycol parenteral injection.
• liquid compositions may be administered orally, topically, parenterally, intravenously and intranasally, to name a few.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
• the liquid form of the pharmaceutical composition may be formulated with the intent that the compositions will be delivered by topical administration, e.g., as an eyedrop.
• the eyedrop formulation may optionally contain one or more of cyclodextrin, methyl cellulose and EDTA in addition to a compound of formula (1), which may be present in the eyedrop at a concentration of between about 0.1% to 1% (weight basis) in the eyedrop solution.
• the eyedrop formulation may optionally contain hydroxypropyl-beta-cyclodextrin in a range of 1% to 40% and hydroxypropyl methyl cellulose in a range of 0.1% to 1%.
• the eye drop formulation may optionally contain 10%, 20%, or 30% by weight of hydroxypropyl-beta-cyclodextrin.
• the amount, timing and mode of delivery of compounds the disclosure will be routinely adjusted on an individual basis, depending on such factors as weight, age, gender, and condition of the individual, the condition being induced or treated, whether the administration is prophylactic or therapeutic, and on the basis of other factors known to effect drug delivery, absorption, pharmacokinetics, including half-life, and efficacy.
• the suitable ocular dose range for use is from about 0.01 mg to 1000 mg per day, or from 0.05 mg to about 1000 mg per day, about 0.1 mg to about lOOOmg a day, about 0.5 mg to about 1000 mg a day, about 2mg to about lOOOmg a day, about 0.05mg to about 500 mg per day, 0.10 mg to 300 mg per day, 0.10 mg to 100 mg per day, 75mg to 450mg per day, 150mg to 400mg per day, about 300 mg to about 1500mg per day, about 600 to about 1500 mg per day.
• a topical dose is typically between 0.5 mg and 3mg /day where a dose of 3 mg / day may be administered in the form of six applications of 0.5 mg each.
• a typical oral dose is between lOOmg and 3500mg x 2 per day.
• fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being typical.
• the compound of formula (1) depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent.
• the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
• the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• Parenteral solutions and suspensions may be used for topical administration.
• the liquid form preparation may contain from between about 0.05 to about 95 weight percent of active ingredient including a compound of formula (1).
• compositions of the present disclosure include solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
• liquid forms include solutions, suspensions and emulsions.
• compositions of the present disclosure may be formulated in a sustained release form to provide a rate controlled release of any one or more of the components or active ingredients to optimize therapeutic effects.
• Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
• the one or more Compounds of Formula (1) are administered orally.
• the one or more Compounds of Formula (1) are administered topically.
• a pharmaceutical preparation comprising at least one compound of formula (1) is in unit dosage form.
• the preparation is subdivided into unit doses containing effective amounts of the active components.
• compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.5 wt% to about 95 wt% of one or more compounds of formula (1). In various embodiments, the present compositions can contain, in one embodiment, from about 1% to about 70% or from about 5% to about 60% of the compound of formula (1).
• the compounds of Formula I may be administered orally in a dosage range of 0.001 to 150 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
• mammal e.g., human
• One preferred dosage range is 0.01 to 100 mg/kg body weight per day orally in a single dose or in divided doses.
• Another preferred dosage range is 0.1 to 50 mg/kg body weight per day orally in single or divided doses.
• the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
• the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
• the compounds of Formula I may be administered to the eye in the form of eye drops as dosage range of 0.01 to 50 mg per day in a single dose or in divided doses in the form of one or more eye drops as a solution of 0.1% to 2% by weight of compound.
• One preferred dosage range is 0.1 to 10 mg per day in a single dose or in divided doses in the form of one or more eye drops as a solution of 0.1% to 2% by weight of compound.
• Another preferred dosage range is 0.3 to 3 mg per day in a single dose or in divided doses in the form of one or more eye drops as a solution of 0.1% to 2% by weight of compound.
• compositions can be provided in the form of eye drops containing 0.01 to 3 milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, and 3 milligrams of the active ingredient per eye drop for the symptomatic adjustment of the dosage to the subject to be treated.
• the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and duration of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
• the total daily dosage may be divided and administered in portions during the day if desired. In one embodiment, the daily dosage is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24 hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24 hour period. In still another embodiment, the total daily dosage is administered in four divided doses over a 24 hour period.
• compositions of the disclosure can further comprise one or more additional therapeutic agents.
• additional active agent may, for example, augment the biological activity of a compound of formula (1), or it may complement that activity, or it may supplement that biological activity.
• the compounds of formula (1) may be prepared in a number of different ways from known or readily prepared starting materials. In describing suitable synthetic methodology, it is helpful to identify the Ar group of formula (1) as Arl, and the central benzene ring of formula (1) as Ar2, as shown below.
• One factor that may be considered when preparing a compound of formula (1) is the identity of the group that links together the Arl and Ar2 groups. That linking group is represented in formula (1) by -L-O- where O is oxygen and L is selected from a direct bond and methylene (i.e., - CH -). Thus, the linking group may take the form of O or CH O.
• linking groups may be formed by reacting together appropriately substituted Arl and Ar2 containing compounds under suitable reaction conditions.
• compounds of formula (1) where L is CH may be prepared as shown in Scheme 1, where phenol or a Ri-substituted phenol (either of which is represented by hydroxyl substituted Ar2) is reacted with an X-substituted benzyl compound (having the Arl group) where X is a leaving group.
• This reaction may be conducted in the presence of a suitable base such as potassium carbonate in combination with sodium iodide, and in the presence of a suitable solvent such as acetone.
• Arl is shown as a benzene ring, however that is for illustrative purposes only.
• Arl is more generally identified as Ar, and represents a 9- or 10-membered bicyclic aromatic ring system which is optionally substituted with one, two or three substituents.
• Arl may be quinoline (introduced via
• linking group -L-O- has L as a direct bond
• linking group is oxygen (O).
• O oxygen
• Arl is illustrated as a benzothiazole compound having a leaving group X at the 2-position, however other Arl groups may be used in this synthesis in lieu of benzothiazole.
• a few examples are 2-chlorobenzoxazole, 2-chloroquinoline and 3-chloroisoquinoline.
• Ar2 is shown as substituted with (A/E) where this designation is meant to denote collectively -A-E as identified herein, and precursors thereto which can be converted to an A-E group after the Arl and Ar2 rings are coupled together.
• the Arl- and Ar2-containing compounds may be combined under suitable reaction conditions, e.g., in the presence of a suitable base such as potassium carbonate, and in a suitable solvent such as dimethylformamide, to provide the corresponding coupled compound of Formula (1).
• Ar2 comprises a hydroxyl group while Arl comprises a leaving group X.
• compounds of the present disclosure may be prepared by a process wherein the relative placement of the hydroxyl group and the leaving group is switched between Arl and Ar2 as shown in Scheme 3.
• a phenolic compound comprising Arl is reacted with a fluoroaryl compound comprising Ar2 under suitable reaction conditions, such as in the presence of a suitable base such as potassium carbonate and in the presence of a suitable solvent such as
• Arl is shown as a benzene ring, however that is for illustrative purposes only.
• Arl is more generally identified as Ar, and represents a 9- or 10-membered bicyclic aromatic ring system that is optionally substituted with one, two or three substituents.
• Ar2 is shown as substituted with (A/E) where this designation is meant to denote collectively -A-E as identified herein, and precursors thereto which can be converted to an A-E group after the Arl and Ar2 rings are coupled together.
• reaction outlined in Scheme 3 is favored when A/E is an electron withdrawing group, e.g., carbonyl, in which case the (A/E) substituents in (F)(R 1 )Ar2(A/E) is a precursor to -A-E.
• A/E is an electron withdrawing group, e.g., carbonyl
• the compounds of the present disclosure may have a variety of substituents on the Arl and Ar2 moieties. These substituents may be prepared by standard methodology known in the art. Such methodology includes benzylation, condensation, hydrogenolysis, O-alkylation, Grignard reaction, trifluoromethylation, reduction, reductive amination of aromatic/aliphatic ketones, reductive amination of aliphatic ketones, and reductive amination of aromatic ketones, any one or more of which may optionally be used in the preparation of compounds of formula (1). These techniques may also be modified according to the knowledge of those skilled in the art. The following provides General Procedures that are further exemplified in the specific Examples which follow.
• Grignard reactions can be carried out using commercially available alkyl or aryl magnesium bromides or prepared freshly as follows.
• (1) Preparation of Grignard Reagent To freshly crushed magnesium turnings (2.5 to 5.0 eq) under argon in THF (1.5 mmol of Mg per mL of tetrahydrofuran (TFH F)) is added 1,2 dibromoethane (50 pL) and stirred for 5 minutes and followed by ethyl magnesium bromide (50 pL, 3.0M in ether) and stirred for another 5 min. Alkyl or aryl bromide (1 eq) is then added and the reaction is cooled occasionally with a water bath over 1 hr.
• THF F tetrahydrofuran
• Grignard Additions To a 0°C solution of ketone (1 eq) as a solution in dry TFH F under argon is added Grignard reagent (generally 1 to 2 eq). The reaction is stirred for approximately 1 hr. and quenched with water and/or 5% aqueous HCI. The mixture is extracted with water, washed with brine, dried (MgSOi), filtered, and the solvent is removed under reduced pressure. The material is purified using flash column chromatography.
• Trifluoromethylation To a solution of ketone (1 eq) in dry DM F at room temperature or reduced temperature (e.g. 0 °C) is added CF3-TMS (1.5 to 2 eq) followed by a catalytic amount of K2CO3 ( ⁇ 0.1 to 0.3 eq) and stirred under argon for a desired length of time, typically 18-72 hours.
• CF3-TMS 1.5 to 2 eq
• K2CO3 ⁇ 0.1 to 0.3 eq
• the reaction is diluted with water and washed with brine.
• the organic layer is dried (MgSOi), filtered, and the solvent removed in vacuo.
• To the residue in methanol is added cone. HCI, and the solution is stirred until the reaction is complete ( ⁇ lhr).
• the reaction is diluted with ethyl acetate and extracted with brine.
• the organic layer is dried (MgSOi), filtered, and the solvent removed under reduced pressure.
• the material is purified using flash column chromatography.
• the material is purified by flash chromatography.
• Reductive amination to form primary and secondary alkyl amines To a stirred mixture of N H4CI (1 eq) in methanol (MeOH) at room temperature under argon are added Et N (1 eq), ketone (1 eq), and Ti(OiPr ( ⁇ 2 eq). The reaction mixture is stirred for 18 h. Another 1 equivalent of Et N and N H4CI may be added and the reaction mixture then stirred for 3 h. NaBFU (1.2 eq) is added, and the reaction mixture is stirred for 1.5 h. Another portion of NaBFU (0.5 eq) may optionally be added, and the reaction mixture is stirred for 1 h. It is quenched with water and extracted with EtOAc. The organic layer is washed with water, dried over anhydrous MgS , filtered, and the solvent is removed under reduced pressure. The residue is purified by flash chromatography.
• molecules with a single chiral center unless otherwise noted, exist as a racemic mixture.
• Those molecules with two or more chiral centers unless otherwise noted, exist as a racemic mixture of diastereomers.
• Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art. For example, enantiomers may be separated from one another by FIPLC using a chiral column such as a ChiralPakTM column (Daicel Corp., Japan), e.g., ChiralPak ADTM which has a size of 4.6 x 250 mm and contains particles having an average diameter of 5 pm.
• the mobile phase may be a mixture of iso-propanol in hexane, where the /-PrOFI/hexane ratio may be varied to impact the degree of separation of the enantiomers.
• An exemplary flow rate is 1 mL/min and an exemplary injection volume is 50 pL, working with a sample concentration of 5 mg/mL.
• the run time may likewise be adjusted to enhance separation, where an exemplary run time is 11 minutes.
• Enantiomer 2 had a retention time of 9.368 min, and >99% purity.
• Compound 122 was prepared from Compound 110 (0.46 mmol, prepared as in Example 10), sodium borohydride (0.91 mmol), and methanol (3 mL). Flash column chromatography of the crude mixture on silica gel (40% EtOAc in Hex) yielded 0.156 g of Compound 122 as an oil.
• Compound 124 was prepared from Compound 110 (0.100 g, 0.305 mmol, prepared as in Example 10), TFH F (1.0 mL), and methyl magnesium bromide (0.20 mL, 3 M in Et 2 0). Flash column chromatography of the crude mixture on silica gel (50-70% EtOAc in Flex) yielded 0.115 g of Compound 124 as an oil.
• Compound 140 was prepared from 4-[4-(l,3-benzothiazol-2-yloxy)phenyl]butan-2-one (135 mg, 0.45 mmol), CF TMS (200 pL, 1.35 mmol), K CO (20 mg, 0.14 mmol) and DMF (3 mL). Flash column chromatography of the crude mixture on silica gel (30% EtOAc in Flex) yielded 137 mg of Compound 140 as an oil.
• Compound 141 was prepared from 4-[4-(l,3-benzothiazol-2-yloxy)phenyl]butan-2-one (113 mg, 0.38 mmol, prepared as in Example 40), NaBH4 (25 mg, 0.59 mmol), CeCI 3 x 7H2O (125 mg, 0.34 mmol), and MeOH (3 m L). Flash column chromatography of the crude mixture on silica gel (50% EtOAc in Hex) yielded 100 mg of Compound 141 as a colourless oil.
• Compound 142 was prepared from 4-[4-(l,3-benzothiazol-2-yloxy)phenyl]butan-2-one (128 mg, 0.43 mmol, prepared as in Example 40), TFH F (2.0 m L), and isopropyl magnesium bromide (0.45 mL, 2 M in TFH F). Flash column chromatography of the crude mixture on silica gel (30% EtOAc in Flex) yielded 52 mg of Compound 142 as an oil.
• Compound 144 was prepared from 4-[4-(l,3-benzothiazol-2-yloxy)phenyl]butan-2-one (195 mg, 0.66 mmol, prepared as in Example 40), TFH F (2.0 mL), and phenyl magnesium bromide (0.32 mL, 3 M in Et 2 0). Flash column chromatography of the crude mixture on silica gel (30% EtOAc in Flex) yielded 222 mg of Compound 144 as an oil.
• Compound 146 was prepared from 4-[4-(l,3-benzoxazol-2-yloxy)phenyl]butan-2-one (101 mg, 0.36 mmol), TFH F (3.0 m L), and ethyl magnesium bromide (0.150 mL, 3 M in Et 2 0). Flash column chromatography of the crude mixture on silica gel (30% EtOAc in Flex) yielded 80 mg of Compound 146.
• Compound 175 was prepared from Compound 174 (105 mg, 0.36 mmol), CF TMS (97 pL, 0.65 mmol), K CO (15 mg, 0.11 mmol) and DMF (2 mL) then MeOH (5 mL) and HCI (250 pL). Flash column chromatography of the crude mixture on silica gel (20% EtOAc in Hex) yielded 109 mg of Compound 175 as an oil.

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