WO2024026076A2 - Inhibiteurs de tshr substitués de 3,4-dihydroquinolinone - Google Patents

Inhibiteurs de tshr substitués de 3,4-dihydroquinolinone Download PDF

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WO2024026076A2
WO2024026076A2 PCT/US2023/028950 US2023028950W WO2024026076A2 WO 2024026076 A2 WO2024026076 A2 WO 2024026076A2 US 2023028950 W US2023028950 W US 2023028950W WO 2024026076 A2 WO2024026076 A2 WO 2024026076A2
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alkyl
alkoxy
compound
halo
optionally substituted
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PCT/US2023/028950
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WO2024026076A3 (fr
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Steven J. MCKERRALL
Daniel D. Long
Xiaohui Du
Deniz AYDIN
Matthew Volgraf
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Septerna, Inc.
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Publication of WO2024026076A2 publication Critical patent/WO2024026076A2/fr
Publication of WO2024026076A3 publication Critical patent/WO2024026076A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • C07D215/16—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 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 to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • TSH-Receptor This pathological activation of TSH-Receptor (TSHR) leads to uncontrolled production of thyroid hormones (e.g., T3 and T4) causing hyperthyroidism.
  • TSH and the TSHR are important proteins for controlling thyroid function.
  • TSHR is primarily expressed in follicular epithelial cells of the thyroid gland, but also is expressed in a variety of additional cell types, such as retro-orbital fibroblasts, kidney cells, adipocytes and bone cells.
  • TSH binds to its receptor and leads to the stimulation of second messenger pathways involving predominantly cAMP. Inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) pathways are also activated at higher TSH concentrations.
  • IP3 Inositol 1,4,5-triphosphate
  • DAG diacylglycerol
  • thyrostatic drugs that block the production of thyroid hormones. These medications play a role further downstream in the signal cascade of the thyroid upon activation of the TSHR. Since thyroid hormones T3 and T4 are secreted in the thyroid gland, thyrostatic drugs induce an inhibition of their synthesis. Thus, the current primary anti-thyroid treatment does not target the causative molecular activation of the TSHR by autoantibodies and patients are therefore burdened by a rate of at least 5% adverse effects. This demands frequent controls of the thyroid hormone levels and adjustments of thyrostatics dosage. In contrast to these drugs, which regulate the thyroid hormone level, another promising target is the TSHR itself.
  • TSHR pathological activation of TSHR leads to the production of the extracellular matrix by involvement of hyaluronanic acid, fibrosis and swelling of extraocular muscle as well as adipogenesis of orbital fibroblasts (orbital fat expansion).
  • the increase in tissue volume in the orbit often causes diplopia and compression of the optic nerve and exophthalmos.
  • Grave’s ophthalmology and thyroid eye disease Accordingly, there is a need in the art to provide additional means for the treatment of hyperthyroidism, in particular compounds that act as TSHR antagonists.
  • A is (C 6 -C 10 )aryl, 5- to 10-membered heteroaryl, (C 3- C 8 )cycloalkyl, or 4- to 7-membered heterocycloalkyl;
  • n is 0, 1, 2, 3, 4, or 5;
  • R 1 is independently for each occurrence (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3- C8)cycloalkyl, (C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, 4-
  • a compound has the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein A is (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; n is 0, 1, 2, 3, 4, or 5; R 1 is independently for each occurrence (C 1- C 6 )alkyl, (C 2- C 6 )alkynyl, (C 2- C 6 )alkenyl, (C 3- C 8 )cycloalkyl, (C 3- C 8 )cycloalkoxy, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl(C 1- C 6 )alkyl, 4- to 7-membered heterocycloalkyl, (C 1- C 6 )alkoxy, (C 1- C 6 )alkoxy(C 1- C 6 )alkyl, halo,
  • a compound has the structure of Formula (III): or a pharmaceutically acceptable salt thereof, wherein: A is (C 6 -C 10 )aryl, 5- to 10-membered heteroaryl, (C 3- C 8 )cycloalkyl, or 4- to 7-membered heterocycloalkyl; n is 0, 1, 2, 3, 4, or 5; R 1 is independently for each occurrence (C 1- C 6 )alkyl, (C 2- C 6 )alkynyl, (C 2- C 6 )alkenyl, (C 3- C8)cycloalkyl, (C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo, cyano, amino, formyl, carboxy,
  • a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • “or” should be understood to have the same meaning as “and/or” as defined above.
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
  • the phrase “at least one,” in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.
  • Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.”
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer.
  • the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.
  • the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.
  • a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer.
  • prodrug as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum
  • compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate naphthylate
  • mesylate glucoheptonate
  • lactobionate lactobionate
  • laurylsulphonate salts and the like.
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).
  • pharmaceutically acceptable cocrystals refers to solid coformers that do not form formal ionic interactions with the small molecule.
  • a “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.
  • a desired dosage regimen to a mammal, preferably a human
  • the term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions.
  • the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the term “patient” or “subject” refers to a mammal in need of a particular treatment.
  • a patient is a primate, canine, feline, or equine.
  • a patient is a human.
  • An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below.
  • a straight aliphatic chain is limited to unbranched carbon chain moieties.
  • the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.
  • “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made.
  • alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties.
  • Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer.
  • Alkyl goups may be substituted or unsubstituted.
  • heteroalkyl refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.
  • haloalkyl refers to an alkyl group as hereinbefore defined substituted with at least one halogen.
  • hydroxyalkyl refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl.
  • alkylene refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain.
  • alkylene groups include methylene -(CH 2 )-, ethylene -(CH 2 CH 2 )-, n-propylene -(CH 2 CH 2 CH 2 )-, isopropylene - (CH 2 CH(CH 3 ))-, and the like.
  • Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.
  • Cycloalkyl means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. As used herein, the term “halocycloalkyl” refers to an cycloalkyl group as hereinbefore defined substituted with at least one halogen.
  • Cycloheteroalkyl refers to an cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.
  • Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted.
  • lower alkyl means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • preferred alkyl groups are lower alkyls.
  • a substituent designated herein as alkyl is a lower alkyl.
  • Alkenyl refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety.
  • Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).
  • Alkynyl refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.
  • aryl as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl).
  • aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.
  • halo means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.
  • heterocyclyl or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12- membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10- membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, chromane, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, and the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety
  • the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • small molecules refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da).
  • the small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).
  • a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000.
  • a small molecule is an organic compound, with a size on the order of 1 nm.
  • small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.
  • An “effective amount” is an amount sufficient to effect beneficial or desired results.
  • a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day.
  • treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.
  • the terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference.
  • “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter ascompared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment.
  • the terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10- fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.
  • the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response.
  • a “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases.
  • the radiolabelled pharmaceutical agent for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source.
  • RI radioisotope
  • the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents.
  • the radioisotope is a metallic radioisotope
  • a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule.
  • the radioisotope is a non-metallic radioisotope
  • the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
  • A is (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl;
  • n is 0, 1, 2, 3, 4, or 5;
  • R 1 is independently for each occurrence (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3- C 8 )cycloalkyl, (C 3- C 8 )cycloalkoxy, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl(C 1- C 6 )alkyl, 4- to 7-membered heterocycloalkyl, (C 1- C 6 )alkoxy, (C 1- C 6 )alkoxy(C 1- C 6 )alkyl, 4- to 7-membered heterocycloalkyl, (C 1- C 6 )alkoxy, (C 1- C 6 )
  • A is (C6-C10)aryl or 5- to 10-membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; R 1 is independently for each occurrence (C 1- C 6 )alkyl, (C 3- C 8 )cycloalkyl, 4- to 7- membered heterocycloalkyl, (C 1- C 6 )alkoxy, halo, cyano, formyl, carboxy, or alkoxycarbonyl, wherein (C 1- C 6 )alkyl, (C 3- C 8 )cycloalkyl, (C 1- C 6 )alkoxy, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy, or two vicinal occurrences
  • A is (C 6 -C 10 )aryl or 5- to 10-membered heteroaryl; n is 0, 1, 2, 3, 4 or 5; R 1 is independently for each occurrence (C 1- C 6 )alkyl, (C 3- C 8 )cycloalkyl, , 4- to 7- membered heterocycloalkyl, (C1-C6)alkoxy, halo, cyano, formyl, carboxy, or alkoxycarbonyl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, and (C1-C6)alkoxy are each optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy; or two vicinal
  • A is (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl;
  • n is 0, 1, 2, 3, 4, or 5;
  • R 1 is independently for each occurrence (C 1- C 6 )alkyl, (C 2- C 6 )alkynyl, (C 2- C 6 )alkenyl, (C 3- C8)cycloalkyl, (C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo, cyano, amino, formyl, carboxy, or alkoxycarbon
  • A is (C6-C10)aryl or 5- to 10-membered heteroaryl; n is 0, 1, 2, 3, 4 or 5; R 1 is independently for each occurrence (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7- membered heterocycloalkyl, (C 1- C 6 )alkoxy, halo, cyano, formyl, carboxy, or alkoxycarbonyl, wherein (C 1- C 6 )alkyl, (C 3- C 8 )cycloalkyl, 4- to 7-membered heterocycloalkyl, and (C 1- C 6 )alkoxy are each optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy; or two vicinal occurrences
  • A is phenyl. In certain embodiments, A is a 5- to 7-membered heteroaryl comprising 1 or 2 nitrogen atoms. In certain embodiments, A is pyridyl or diazolyl. thiazolyl, pyrazinyl, pyrimidinyl, while in other embodiments, A is pyridyl or diazolyl. In some embodiments, A is wherein A is isoquinolinyl or indazolyl. In other embodiments, A is cyclopentyl, cyclohexyl, or tetrahydropyranyl.
  • R 1 is independently for each occurrence (C1-C6)alkyl, (C1- C 6 )alkoxy, fluoro, chloro, or cyano, wherein (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one or more substituents independently selected from fluoro and hydroxyl.
  • at least one R 1 is fluoro, chloro, or cyano.
  • at least one R 1 is (C1-C6)alkyl optionally substituted with one or more substituents independently selected from hydroxyl and fluoro.
  • R 1 is 2,2,2-trifluoroethyl-1-hydroxyethyl.
  • At least one R 1 is difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluropropyl, or 4,4,4- trifluorobutyl.
  • at least one R 1 is (C 1 -C 6 )alkoxy optionally substituted with at least one fluoro, preferably (C 1 -C 3 )alkoxy optionally substituted with at least one fluoro, more preferably difluoromethoxy or trifluoromethoxy.
  • R 1 is methoxy or isopropoxy.
  • R 1 is methyl optionally substituted with hydroxy or one or more fluoro.
  • R 1 is (C1-C3)alkoxy optionally substituted with at least one fluoro.
  • at least one R 1 is (C 3- C 8 )cycloalkyl, preferably cyclopropyl or cyclobutyl.
  • at least R 1 is (C 3- C 8 )cycloalkoxy, preferably cyclopentyloxy, cyclohexyloxy.
  • R 1 is (C2-C6)alkynyl optionally substituted with hydroxy.
  • two vicinal occurrences of R 1 taken together with the atoms to which they are attached form a fused 5- to 7-membered cycloalkyl or 5- to 7-membered heterocycloalkyl ring, either of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C 1 -C 6 )alkyl, (C 3 - C 8 )cycloalkyl, and (C 1- C 6 )alkoxy.
  • A is phenyl comprising two vicinal occurrences of R 1 , wherein the two vicinal occurrences of R 1 , taken together with the atoms to which they are attached, form a fused 5- to 7-membered cycloalkyl or 5- to 7-membered heterocycloalkyl ring.
  • n is 2. In certain embodiments, n is 1. In certain embodiments, n is 0.
  • Q is CR 2c . In certain embodiments, Q is N.
  • R 2a , R 2b , and R 2c are each hydrogen.
  • R 2a , R 2b , and R 2c is fluoro, chloro, or cyano.
  • R 3 is (C1-C6)alkyl optionally substituted with hydroxy.
  • R 3 is t-butyl.
  • R 3 is (C 3 -C 8 )cycloalkyl optionally substituted with one or more (C 1- C 6 )alkyl, (C 1- C 6 )fluoroalkyl, fluoro, or (C 1- C 6 )alkoxy(C 1- C 6 )alkyl.
  • the (C 3 -C 8 )cycloalkyl is cyclobutyl, cyclopentyl, cylohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl,bicycle[2.1.1]hexanyl, or bicyclo[3.1.0]hexanyl.
  • the (C3-C8)cycloalkyl is optionally substituted with one or more substituents selected from fluoro, trifluoromethyl, methoxymethyl, methyl, and hydroxyl.
  • R 3 is 4- to 7-membered heterocycloalkyl optionally substituted with one or more substituents selected from (C 1- C 6 )alkyl, (C 1- C 6 )fluoroalkyl, or fluoro.
  • the 4- to 7-membered heterocycloalkyl is etrahydropyranyl or oxetanyl.
  • Z is NR 4 , R 3 and R 4 taken together with the nitrogen to which they are attached form a 4- to 7-member heterocycloalkyl optionally substituted with one or more (C 1- C6)alkyl or halo.
  • the 4- to 7 membered heterocycloalkyl is azetidine or pyrrolidine,
  • X is NR 4 or O.
  • X is NH.
  • Z is NR 4 , or O.
  • Z is NH.
  • one and only one of X and Z is CH 2.
  • X and Z are each NH.
  • L is unsubstituted (C1-C6)alkylene.
  • L is (C1-C6)alkylene substituted with hydroxy.
  • L is (C1-C6)alkylene substituted with 1 to 3 halo atoms.
  • L is –CH2–, –-CH(CH3)–, –CH(CH2CH3)–, or –CH(CH2OH)–.
  • W a –W b represents: –C(R 6 ) 2 –C(R 7 ) 2 –.
  • R 6 is (C 1- C 6 )alkyl, wherein (C 1- C 6 )alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, and (C1-C6)alkoxy.
  • At least one R 7 is (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1- C6)alkoxy, and cyano.
  • each R 6 and each R 7 is hydrogen.
  • W a –W b represents: –O–C(R 8 ) 2 –.
  • R 8 is hydrogen.
  • W a –W b represents: –C(R 8 )2–O–, where each R8 is hydrogen.
  • W a –W b represents: –C(R 8 )2–NR 9 –.
  • each R 8 is hydrogen.
  • R 9 is (C1-C6)alkyl, preferably methyl.
  • R 10 is hydrogen.
  • R 10 is (C 1- C 6 )alkyl.
  • R 10 is methyl.
  • a compound is selected from Table 1: Table 1.
  • the compound is selected from Table 2. Table 2.
  • the compounds are atropisomers.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • the (C1-C4)alkyl or the -O-(C1- C4)alkyl can be suitably deuterated (e.g., -CD3, -OCD3).
  • Any compound of the invention can also be radiolabed for the preparation of a radiopharmaceutical agent.
  • Methods of Treatment One aspect of the invention provides methods of inhibiting a thyroid stimulating hormone receptor, comnprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.
  • Another aspect of the invention comprises treating or preventing a thyroid disease, comnprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.
  • the subject has Graves' disease.
  • the subject has Graves' ophthalmopathy. In certain embodiments, the subject has Graves' dermopathy. In certain embodiments, the subject has thyroid cancer. While not being bound by theory, TSHR in thyroid cells, and likely in fibroblasts and adipocytes in the supporting tissue behind the eye (in the retro-orbital space), also are stimulated by TSHR-stimulating antibodies (TSAbs), resulting in Graves' disease.
  • TSHR-stimulating antibodies TSAbs
  • Graves' disease which is an autoimmune disease that occurs in 1% of the US population, has two important clinical components: 1) hyperthyroidism from stimulation of TSHR on thyroid cells and 2) Graves' orbitopathy (or Graves' ophthalmopathy or thyroid eye disease), which appears to result from stimulation of TSHR on retro-orbital fibroblasts and/or adipocytes.
  • Hyperthyroidism in particular Graves' hyperthyroidism, is a hypermetabolic state that affects virtually every tissue/cell in the body and can lead to, in particular, cardiovascular dysfunction and death.
  • Graves' ophthalmopathy also known as Graves' orbitopathy, occurs in 80% of Graves' hyperthyroid patients as diagnosed by computerized tomographic scan.
  • Graves dermopathy also known as Pretibial myxedema, thyroid dermopathy, Jadassohn- Dössekker disease or Myxoedema tuberosum, is an infiltrative dermopathy, resulting as a complication of Graves' disease, with an incidence rate of about 1-5% in patients.
  • the disease usually presents itself as a waxy, discolored induration of the skin on the anterior aspect of the lower legs.
  • a disease that can be treated o prevented by TSHR antagonists is thyroid cancer.
  • TSHR is expressed in thyroid cancer cells and regulates the growth, proliferation and metastatic potential of thyroid cancer cells.
  • the thyroid gland is, as is well known, one site of metabolic control within the body. Cancer of the thyroid gland is not particularly common, but the high rate of disease re- occurrence necessitates long-term surveillance. Usually, during treatment for cancer of the thyroid, the majority of the thyroid tumor is removed, but a small amount often remains that must be treated by radioactive iodide therapy. Indeed, thyroid cancer is characterized by a high likelihood of relapses in up to 30% of patients, even after successful therapy.
  • TSHR contains a hereditary mutation that makes it more active than the normal TSHR, resulting in hereditary non-immune hyperthyroidism.
  • TSHR antagonists could be effective treatment for these patients also.
  • a “TSHR antagonist” as described herein blocks or inhibits the action of the agonists (TSH or thyroid-stimulating antibodies for TSHR.
  • Small-molecule ligands for the TSHR (antagonists) typically bind to an intra-membrane domain of the receptor, and act by inducing a conformational change rather than simply competing for TSH binding to its extracellular site on the receptor.
  • the antagonists may be selective antagonists for TSHR (i.e, the compounds do not activate or modulate other hormone receptors, particularly luteinizing hormone/chorionic gonadotropin receptor (LHCGR) and follicle-stimulating hormone receptor (FSHR)).
  • the antagonists disclosed herein may be used for treating hyperthyroidism in a subject.
  • the antagonists may inhibit mutant TSHRs with higher than normal basal signaling activities (CAMs) that cause an unusual form of hyperthyroidism.
  • the antagonists may inhibit stimulation by antibodies found in Graves' disease, which is the most common form of hyperthyroidism.
  • the TSHR antagonists are useful for treating TSHR-mediated thyroid cancer or hyperthyroidism by blocking TSHR-stimulating antibodies (TSAbs) in Graves' hyperthyroidism.
  • the compound is administered orally to the subject.
  • the compound is administered parenterally to the subject.
  • the disease is prevented.
  • the disease is treated.
  • Pharmaceutical Compositions, Routes of Administration, and Dosing In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention, e.g. a compound of Formula (1), and a pharmaceutically acceptable carrier.
  • the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier.
  • the invention is directed to a pharmaceutical composition, comprising a compound of Table 1 or 2, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention.
  • the at least one additional pharmaceutically active agent can be an agent useful in the treatment of ischemia-reperfusion injury.
  • compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.
  • an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect.
  • an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition.
  • intravenous administration of a compound may typically be from 0.1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg/kg/day to 2 mg/kg/day.
  • intravenous administration of a compound may typically be from 0.5 mg/kg/day to 5 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 1 mg/kg/day to 10 mg/kg/day.
  • daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams/kg, in one or more administrations per day, will yield therapeutic results.
  • Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.
  • the therapeutically effective amount can be initially determined from animal models.
  • a therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents.
  • the applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well- known in the art is well within the capabilities of the ordinarily skilled artisan.
  • the formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
  • an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface.
  • Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan.
  • Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.
  • a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex.
  • Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.
  • the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.
  • oral dosage forms of the above component or components may be chemically modified so that oral delivery of the derivative is efficacious.
  • the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine.
  • the increase in overall stability of the component or components and increase in circulation time in the body are also desired.
  • moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline.
  • Abuchowski and Davis “Soluble Polymer- Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp.367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982).
  • Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane.
  • polyethylene glycol moieties are suitable.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
  • a coating impermeable to at least pH 5.0 is essential.
  • cellulose acetate trimellitate hydroxypropylmethylcellulose phthalate
  • HPMCP 50 HPMCP 55
  • PVAP polyvinyl acetate phthalate
  • CAP cellulose acetate phthalate
  • shellac shellac
  • These coatings may be used as mixed films.
  • a coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow.
  • Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used.
  • the shell material of cachets could be thick starch or other edible paper.
  • moist massing techniques can be used.
  • the therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm.
  • the formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets.
  • the therapeutic could be prepared by compression. Colorants and flavoring agents may all be included.
  • the compound of the invention may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
  • an edible product such as a refrigerated beverage containing colorants and flavoring agents.
  • One may dilute or increase the volume of the therapeutic with an inert material.
  • These diluents could include carbohydrates, especially mannitol, ⁇ -lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch.
  • Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride.
  • Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.
  • Disintegrants may be included in the formulation of the therapeutic into a solid dosage form.
  • Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used.
  • Another form of the disintegrants are the insoluble cationic exchange resins.
  • Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
  • Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.
  • An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process.
  • Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000. Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
  • Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride.
  • Non- ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.
  • Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
  • compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
  • Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl.5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) ( ⁇ 1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado
  • Pat. No. 5,284,656 granulocyte colony stimulating factor; incorporated by reference.
  • a method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No.5,451,569 (incorporated by reference), issued Sep. 19, 1995 to Wong et al.
  • Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St.
  • each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.
  • Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
  • Formulations suitable for use with a nebulizer will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant.
  • the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof.
  • Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
  • Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • the compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers ( ⁇ m), most preferably 0.5 to 5 ⁇ m, for most effective delivery to the deep lung. Nasal delivery of a pharmaceutical composition of the present invention is also contemplated.
  • Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.
  • Formulations for nasal delivery include those with dextran or cyclodextran.
  • a useful device is a small, hard bottle to which a metered dose sprayer is attached.
  • the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed.
  • the chamber is compressed to administer the pharmaceutical composition of the present invention.
  • the chamber is a piston arrangement.
  • Such devices are commercially available.
  • a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
  • the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
  • the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
  • the compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi- dose containers, with an added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • a compound may also be formulated as a depot preparation.
  • Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example, as an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • the pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin.
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
  • the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).
  • the compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal.
  • a pharmaceutically acceptable salt or cocrystal When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof.
  • Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
  • Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v).
  • Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3- 0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v).
  • Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • the therapeutic agent(s) including specifically but not limited to a compound of the invention, may be provided in particles.
  • Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein.
  • the particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating.
  • the therapeutic agent(s) also may be dispersed throughout the particles.
  • the therapeutic agent(s) also may be adsorbed into the particles.
  • the particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
  • the particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof.
  • the particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state.
  • the particles may be of virtually any shape.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s).
  • Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired.
  • Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al.
  • Macromolecules 26:581-7 the teachings of which are incorporated herein.
  • These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
  • controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations.
  • sustained release also referred to as “extended release” is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
  • Example 1 1-(1-benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert-butyl)urea Synthetic Scheme 1-benzyl-6-nitro-3,4-dihydroquinolin-2(1H)-one To a solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (1 g, 5.204 mmol, 1 equiv) in DMF (20 mL) was added K2CO3 (2.154 g, 15.611 mmol, 3 equiv) and (bromomethyl)benzene (979 mg, 5.724 mmol, 1.1 equiv). The resulting mixture was stirred for 16 h at rt.
  • Example 2 1-(tert-butyl)-3-(2-oxo-1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinolin-6- yl)urea 6-nitro-1-(pyridin-2-ylmethyl)-3,4-dihydroquinolin-2(1H)-one
  • K2CO3 1078.7 mg, 7.805 mmol, 3 equiv
  • 2- (bromomethyl)pyridine 492.3 mg, 2.862 mmol, 1 equiv).
  • 6-amino-1-(pyridin-2-ylmethyl)-3,4-dihydroquinolin-2-one 440 mg, 1.553 mmol, 1 equiv
  • EtOH 10 mL
  • H2O 2.5 mL
  • Fe 867.3 mg, 15.532 mmol, 10 equiv
  • NH 4 Cl 830.8 mg, 15.530 mmol, 10 equiv
  • Example 3 1-(tert-butyl)-3-(2-oxo-1-(1-phenylethyl)-1,2,3,4-tetrahydroquinolin-6-yl)urea 6-nitro-1-(1-phenylethyl)-3,4-dihydroquinolin-2-one
  • K2CO3 1078.7 mg, 7.805 mmol, 3 equiv
  • (1-bromoethyl)benzene 529.6 mg, 2.862 mmol, 1 equiv).
  • 6-amino-1-(1-phenylethyl)-3,4-dihydroquinolin-2-one 400 mg, 1.350 mmol, 1 equiv
  • EtOH 10 mL
  • H2O 2.5 mL
  • Fe 753.8 mg, 13.499 mmol, 10 equiv
  • NH4Cl 722.0 mg, 13.499 mmol, 10 equiv
  • Example 4 1-(tert-butyl)-3-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)urea 1-[(1-methylpyrazol-3-yl)methyl]-6-nitro-3,4-dihydroquinolin-2-one
  • K2CO3 1086.6 mg, 7.805 mmol, 3 equiv
  • 3-(bromomethyl)-1- methylpyrazole 500.9 mg, 2.862 mmol, 1.1 equiv).
  • 6-amino-1-[(1-methylpyrazol-3-yl)methyl]-3,4-dihydroquinolin-2-one To a solution of 6-nitro-1-(1H-pyrazol-3-ylmethyl)-3,4-dihydroquinolin-2-one (300 mg, 1.102 mmol, 1 equiv) in EtOH (10 mL) and H 2 O (2.5 mL) was added Fe (615.3 mg, 11.019 mmol, 10 equiv) and NH 4 Cl (589.3 mg, 11.019 mmol, 10 equiv). The resulting mixture was stirred for 2 h at 60 °C and stirred until the starting material was totally consumed by TLC.
  • reaction mixture was quenched by water and extracted with EA (3 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by silica gel column, eluted with PE / EA (2:1) to afford 6-amino-1-[(1-methylpyrazol-3-yl)methyl]-3,4- dihydroquinolin-2-one (101 mg, 36.03%) as a yellow solid.
  • Example 5 1-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert-butyl)urea Synthetic Scheme 1-benzyl-3-methyl-6-nitro-3,4-dihydroquinolin-2(1H)-one To a solution of 1-benzyl-6-nitro-3,4-dihydroquinolin-2(1H)-one (1 g, 3.54 mmol, 1 equiv) in THF (70 mL) was added 2M LiHMDS (in THF) (2.3 mL, 4.60 mmol, 1.3 equiv) at -20 °C under N2. The resulting mixture was stirred 30 min at -20 °C.
  • the reaction mixture was added MeI (653.6 mg, 4.60 mmol, 1.3 equiv) at -20 °C.
  • the resulting mixture was stirred 30 min at -20 °C and then stirred 16 h at rt.
  • the reaction mixture was quenched by water (50 mL) and extracted with EA (3 x 70 mL).
  • Example 6 1-(tert-butyl)-3-(1-(3-chlorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea 1-(3-chlorobenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • 1-(bromomethyl)-3-chlorobenzene 801.93 mg, 3.903 mmol, 1.5 equiv
  • Example 7 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(tert-butyl)urea 4-benzyl-7-nitro-2H-1,4-benzoxazin-3-one
  • K 2 CO 3 860.4 mg, 6.181 mmol, 3 equiv
  • benzyl bromide 387.6 mg, 2.266 mmol, 1.1 equiv).
  • Example 8 1-(tert-butyl)-3-(1-(2-chlorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea 1-(2-chlorobenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • K 2 CO 3 1086.6 mg, 7.805 mmol, 3 equiv
  • 1-(bromomethyl)-2- chlorobenzene 583.64 mg, 2.862 mmol, 1.1 equiv).
  • Example 9 tert-butyl (1-benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)carbamate Synthetic Scheme tert-butyl (1-benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)carbamate To a solution of 6-amino-1-benzyl-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.396 mmol, 1 equiv) in DCM (6 mL) was added Boc2O (129.7 mg, 0.594 mmol, 1.5 equiv) and DMAP (72.6 mg, 0.594 mmol, 1.5 equiv).
  • Example 10 1-(1-benzyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert- butyl)urea Synthetic Scheme 4,4-dimethyl-6-nitro-3,4-dihydroquinolin-2(1H)-one To a solution of 4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (0.4 g, 2.28 mmol, 1 equiv) in H2O (2 mL) and H2SO4 (9 mL) was added HNO3 (0.3 mL) at -10 °C. The reaction was stirred for 2 h at -10-0 °C.
  • Example 12 1-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3-(tert-butyl)ur ea Synthetic Scheme 2-(benzylamino)-5-nitrobenzonitrile To a solution of 2-fluoro-5-nitrobenzonitrile (5 g, 30.100 mmol, 1 equiv) in ACN (100 mL) was added benzylamine (4.84 g, 45.150 mmol, 1.5 equiv) and K 2 CO 3 (8.32 g, 60.200 mmol, 2 equiv). The reaction was stirred at rt for 1 hour.
  • Example 14 (R)-1-(tert-butyl)-3-(2-oxo-1-(1-phenylethyl)-1,2,3,4-tetrahydroquinolin-6-yl)u (R)-6-nitro-1-(1-phenylethyl)-3,4-dihydroquinolin-2(1H)-one
  • Example 15 1-(1-benzyl-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert-butyl)urea 4-methyl-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • H 2 O 2-mL
  • H 2 SO 4 9 mL
  • HNO 3 0.3 mL
  • the reaction was stirred for 2 h at -10-0 °C.
  • the reaction mixture was quenched by water.
  • Example 16 1-(1-benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-hydroxy-2- methylbutan-2-yl)urea Synthetic Scheme 6-amino-1-benzyl-3,4-dihydroquinolin-2(1H)-one
  • a solution of 1-benzyl-6-nitro-3,4-dihydroquinolin-2-one (400 mg, 1.417 mmol, 1 equiv) in EtOH (10 mL) and H 2 O (2 mL) was treated with Fe (791.29 mg, 14.170 mmol, 10 equiv) and NH 4 Cl (757.92 mg, 14.170 mmol, 10 equiv) for 2 h at 60 °C.The resulting mixture was concentrated under reduced pressure.
  • Desired product could be detected by LCMS.
  • the resulting mixture was concentrated under reduced pressure.
  • the crude product was purified by HPLC with the following conditions Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 41% B in 10 min, 41% B; Wave Length: 254/220 nm; RT1(min): 10; Number Of Runs: 0; to afford 1-(1-benzyl-2-oxo-3,4- dihydroquinolin-6-yl)-3-(4-hydroxy-2-methylbutan-2-yl)urea (23.3 mg, 16.47%) as a white solid.
  • Example 17 1-(tert-butyl)-3-(1-(4-cyanobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea 4-((6-nitro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)benzonitrile
  • 6-nitro-3,4-dihydroquinolin-2(1H)-one 500 mg, 2.602 mmol, 1 equiv
  • DMF 10 mL
  • K2CO3 1086.6 mg, 7.805 mmol, 3 equiv
  • 4- (bromomethyl)benzonitrile 558.09 mg, 2.862 mmol, 1.1 equiv).
  • Example 18 1-(tert-butyl)-3-(1-(3-cyanobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea 3-((6-nitro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)benzonitrile
  • 6-nitro-3,4-dihydroquinolin-2(1H)-one 500 mg, 2.602 mmol, 1 equiv
  • DMF 10 mL
  • K 2 CO 3 1086.6 mg, 7.805 mmol, 3 equiv
  • 3- (bromomethyl)benzonitrile 558.09 mg, 2.862 mmol, 1.1 equiv).
  • Example 1 3-tert-butyl-1- ⁇ 1-[(2-fluorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-6-yl ⁇ urea 1-[(2-fluorophenyl)methyl]-6-nitro-3,4-dihydroquinolin-2-one
  • 6-nitro-3,4-dihydro-1H-quinolin-2-one (2 g, 10.407 mmol, 1 equiv)
  • 1-(bromomethyl)-2-fluorobenzene (3147.60 mg, 16.651 mmol, 1.6 equiv) in dimethylformamide (20 mL) was added K2CO3 (4346.47 mg, 31.221 mmol, 3 equiv).
  • Example 20 1-(tert-butyl)-3-(1-(2-cyanobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea 2-((6-nitro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)benzonitrile
  • 2-(bromomethyl)benzonitrile 612.09 mg, 3.122 mmol, 1.5 equiv
  • potassium methaneperoxoate potassium (869.29 mg, 6.243 mmol, 3 equiv) at rt and stirred for overnight.
  • Example 21 1-(tert-butyl)-3-(1-(3-methylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)urea 6-amino-1-[(3-methylphenyl)methyl]-3,4-dihydroquinolin-2-one
  • K2CO3 1086.6 mg, 7.862 mmol, 3 equiv
  • 1-(bromomethyl)-3- methylbenzene 529.6 mg, 2.862 mmol, 1.1 equiv).
  • Example 22 1-(tert-butyl)-3-(1-(3-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6- 1-[(3-methoxyphenyl)methyl]-6-nitro-3,4-dihydroquinolin-2-one
  • K 2 CO 3 1078.7 mg, 7.862 mmol, 3 equiv
  • 1-(bromomethyl)-3- methoxybenzene 575.4 mg, 2.862 mmol, 1.1 equiv).
  • Example 23 1-(tert-butyl)-3-(2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4- tetrahydroquinolin-6-yl)urea 6-nitro-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one
  • K2CO3 1086.6 mg, 7.862 mmol, 3 equiv
  • 1-(bromomethyl)-3- (trifluoromethyl)benzene 684.1 mg, 2.862 mmol, 1.1 equiv).
  • 6-amino-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one To a solution of 6-nitro-1- ⁇ [3-(trifluoromethyl)phenyl]methyl ⁇ -3,4-dihydroquinolin-2-one (500 mg, 1.427 mmol, 1 equiv) in EtOH (10 mL) and H 2 O (2.5 mL) was added Fe (797.1 mg, 14.274 mmol, 10 equiv) and NH 4 Cl (763.4 mg, 14.274 mmol, 10 equiv).
  • Example 24 3-tert-butyl-1- ⁇ 1-[(2,5-dichlorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-6- yl ⁇ urea 1-[(2,5-dichlorophenyl)methyl]-6-nitro-3,4-dihydroquinolin-2-one
  • 2-(bromomethyl)-1,4-dichlorobenzene 936.34 mg, 3.903 mmol, 1.5 equiv
  • potassium carbonate (724.41 mg, 5.204 mmol, 2 equiv) at room temperature under nitrogen atmosphere.
  • Example 26 1-(tert-butyl)-3-(1-(3-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea 1-(3-fluorobenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • K2CO3 1086.62 mg, 7.806 mmol, 3 equiv
  • bromomethyl)-3- fluorobenzene 737.72 mg, 3.903 mmol, 1.5 equiv
  • Example 28 1-(tert-butyl)-3-(2-oxo-1-(1-phenylpropyl)-1,2,3,4-tetrahydroquinolin-6- yl)urea 6-nitro-1-(1-phenylpropyl)-3,4-dihydroquinolin-2-one
  • K2CO3 863.0 mg, 6.244 mmol, 3 equiv
  • (1-bromopropyl)benzene 455.8 mg, 2.289 mmol, 1.1 equiv).
  • 6-amino-1-(1-phenylpropyl)-3,4-dihydroquinolin-2-one To a solution of 6-nitro-1-(1-phenylpropyl)-3,4-dihydroquinolin-2-one (130 mg, 0.419 mmol, 1 equiv) in EtOH (8 mL) and H2O (2 mL) was added Fe (233.9 mg, 4.189 mmol, 10 equiv) and NH4Cl (224.0 mg, 4.189 mmol, 10 equiv). The resulting mixture was stirred for 2 h at 60 °C.
  • N-(2-bromophenyl)pivalamide To a stirred solution of O-bromoaniline (3 g, 17.439 mmol, 1 equiv) in anhydrous DCM (50 mL) was added triethylamine (2.29 g, 22.671 mmol, 1.3 equiv) followed by 2,2- dimethylpropanoyl chloride (2.10 g, 17.439 mmol, 1 equiv) at 0 °C. The reaction mixture was stirred for 16 h at rt. After completion of reaction, the reaction mixture was quenched by addition of water (50 mL). The aqueous layer was extracted with DCM (50 mL).
  • 6-amino-1-benzyl-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one To a solution of 1-benzyl-3,3-dimethyl-6-nitro-3,4-dihydroquinolin-2(1H)-one (130 mg, 0.419 mmol, 1 equiv) in 10 mL MeOH was added Pd/C (30 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 50 min under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and concentrated under reduced pressure to afford 6-amino-1-benzyl-3,3-dimethyl-4H-quinolin-2-one (100 mg, 85.15%) as a white solid.
  • Example 30 1-(tert-butyl)-3-(1-(2-hydroxy-1-phenylethyl)-2-oxo-1,2,3,4-tetrahydroquinoli n-6-yl)urea Synthetic Scheme Into a 40 mL round-bottom flask was added 2-bromo-2-phenylethan-1-ol (3 g, 21.713 mmol, 1 equiv) and bromotrimethylsilane (3.66 g, 23.884 mmol, 1.1 equiv) at rt. The resulting mixture was stirred for additional overnight at rt. The resulting mixture was concentrated under reduced pressure.
  • Example 31 1-(1-benzyl-2-oxo-3H-indol-5-yl)-3-tert-butylurea Synthetic Scheme 1-benzyl-5-nitroindole-2,3-dione To a solution of 1H-indole-2,3-dione, 5-nitro (1 g, 5.205 mmol, 1 equiv) and benzyl bromide (979.24 mg, 5.726 mmol, 1.1 equiv) in dimethylformamide (10 mL) was added K2CO3 (1438.66 mg, 10.41 mmol, 2 equiv). The reaction was stirred at rt for 3h.
  • Example 33 3-tert-butyl-1- ⁇ 4-[(3-chlorophenyl)methyl]-3-oxo-2H-1,4-benzoxazin-7-yl ⁇ urea 4-[(3-chlorophenyl)methyl]-7-nitro-2H-1,4-benzoxazin-3-one
  • Example 34 and Example 35 (R)-1-(tert-butyl)-3-(3-oxo-4-(1-phenylethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)urea and (S)-1-(tert-butyl)-3-(3-oxo-4-(1-phenylethyl)-3,4-dihydro -2H-benzo[b][1,4]oxazin-7-yl)urea Synthetic Scheme 7-nitro-4-(1-phenylethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of 7-nitro-2,4-dihydro-1,4-benzoxazin-3-one (500 mg, 2.575 mmol, 1 equiv) in DMF (20 mL) was added Cs 2 CO 3 (1683.41 mg, 5.150 mmol, 2 equiv) and
  • the reaction was stirred at rt for 1 days. Quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined extracts were washed with water, brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • Example 36 and Example 37 (R)-1-(tert-butyl)-3-(4-(1-(3-chlorophenyl)ethyl)-3-oxo-3,4-di hydro-2H-benzo[b][1,4]oxazin-7-yl)urea and (S)-1-(tert-butyl)-3-(4-(1-(3-chlorophenyl)ethy l)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea 1-(1-bromoethyl)-3-chlorobenzene To a solution of 1-(3-chlorophenyl)ethanol (1.5 g, 9.578 mmol, 1 equiv) in Et2O (10 mL) was added PBr 3 (5.19 g, 19.156 mmol, 2 equiv) at 0 o C.
  • the reaction was stirred at rt for 1 day. Quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined extracts were washed with water, brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • Example 38 1-(3-benzyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-(tert-butyl)urea 3-benzyl-6-nitrobenzo[d]oxazol-2(3H)-one
  • 6-nitrobenzo[d]oxazol-2(3H)-one 300 mg, 1.666 mmol, 1 equiv
  • CH3CN 6 mL
  • KI 76.49 mg, 1.666 mmol, 1 equiv
  • K2CO3 788.35 mg, 5.664 mmol, 3.4 equiv
  • benzyl bromide 112.4 mg, 0.657 mmol, 1.1 equiv.
  • Example 39 1-(tert-butyl)-3-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahyd roquinolin-6-yl)urea 1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • Cs 2 CO 3 1.695 g, 5.20 mmol, 2 equiv
  • 2-(bromomethyl)-1-fluoro- 4-(trifluoromethyl)benzene 735.1 mg, 2.860 mmol, 1.1 equiv).
  • Example 40 1-(tert-butyl)-3-(4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazi n-7-yl)urea 4-(3-methylbenzyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one
  • 1-(bromomethyl)-3- methylbenzene 619.59 mg, 3.348 mmol, 1.3 equiv
  • Cs 2 CO 3 (2.52 g, 7.725 mmol, 3 equiv
  • Example 41 and Example 42 (R)-1-(4-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazin-7-yl)-3-(tert-butyl)urea and (S)-1-(4-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b ][1,4]oxazin-7-yl)-3-(tert-butyl)urea Synthetic Scheme 4-benzyl-2-methyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of 2-methyl-7-nitro-2,4-dihydro-1,4-benzoxazin-3-one (300 mg, 1.441 mmol, 1 equiv) in DMF (10 mL) was added Cs2CO3 (941.99 mg, 2.882 mmol, 2 equiv) and benzyl bromide (369
  • Example 43 and Example 44 (R)-1-(tert-butyl)-3-(4-(3-chlorobenzyl)-2-methyl-3-oxo-3,4-di hydro-2H-benzo[b][1,4]oxazin-7-yl)urea and (S)-1-(tert-butyl)-3-(4-(3-chlorobenzyl)-2-met hyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea 4-(3-chlorobenzyl)-2-methyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of 2-methyl-7-nitro-2,4-dihydro-1,4-benzoxazin-3-one (500 mg, 2.402 mmol, 1 equiv) in DMF (10 mL) was added Cs 2 CO 3 (1569.98 mg, 4.804
  • Example 45 and Example 45 3-tert-butyl-1- ⁇ 3-methyl-2-oxo-1-[(1S)-1-phenylethyl]-4H- quinazolin-6-yl ⁇ urea and 3-tert-butyl-1- ⁇ 3-methyl-2-oxo-1-[(1R)-1-phenylethyl]-4H- quinazolin-6-yl ⁇ urea 3-methyl-6-nitro-1-(1-phenylethyl)-4H-quinazolin-2-one To a solution of 3-methyl-6-nitro-1,4-dihydroquinazolin-2-one (600 mg, 2.896 mmol, 1 equiv) and (1-bromoethyl)benzene (800 mg, 4.323 mmol, 1.49 equiv) in dimethylformamide (30 mL) was added Cs2CO3 (2802.47 mg, 8.575 mmol, 2.96 equiv).
  • Example 46 and Example 52 (S)-1-(tert-butyl)-3-(1-(1-(4-chlorophenyl)ethyl)-3-methyl-2- oxo-1,2,3,4-tetrahydroquinazolin-6-yl)urea and (R)-1-(tert-butyl)-3-(1-(1-(4- chlorophenyl)ethyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)urea 1-(1-(3-chlorophenyl)ethyl)-3-methyl-6-nitro-3,4-dihydroquinazolin-2(1H)-one To a stirred mixture of 3-methyl-6-nitro-1,4-dihydroquinazolin-2-one (500 mg, 2.413 mmol, 1 equiv) and Cs2CO3 (1.57 g, 4.826 mmol, 2 equiv
  • Example 47 1-(tert-butyl)-3-(1-(3-chlorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazo lin-6-yl)urea 3-methyl-6-nitro-3,4-dihydroquinazolin-2(1H)-one
  • KNO 3 0.50 g, 4.933 mmol, 0.8 equiv
  • Desired product could be detected by LCMS.
  • the mixture was diluted with water (100 mL).
  • the resulting mixture was extracted with EA (3 x 100 mL).
  • the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-methyl-6- nitro-3,4-dihydroquinazolin-2(1H)-one (400 mg, 31.31%) as a white solid.
  • Desired product could be detected by LCMS.
  • the mixture was diluted with water (50 mL).
  • the resulting mixture was extracted with EA (3 x 50 mL).
  • the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 6-amino-1-(3-chlorobenzyl)-3- methyl-3,4-dihydroquinazolin-2(1H)-one (160 mg, 44.53%) as a yellow solid.
  • Example 48 1-(tert-butyl)-3-(1-(2-fluoro-3-methylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin 1-(2-fluoro-3-methylbenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • 6-nitro-3,4-dihydro-1H-quinolin-2-one 300 mg, 1.561 mmol, 1 equiv
  • DMF 1-(bromomethyl)-2-fluoro-3-methylbenzene (412.08 mg, 2.029 mmol, 1.3 equiv) and Cs 2 CO 3 (1.53 g, 4.683 mmol, 3 equiv) at rt and stirred for overnight.
  • Example 49 1-(tert-butyl)-3-(1-(2-fluoro-5-methylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin 1-(2-fluoro-5-methylbenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • 2-(bromomethyl)-1-fluoro-4-methylbenzene 412.08 mg, 2.029 mmol, 1.3 equiv
  • Cs 2 CO 3 (1.53 g, 4.683 mmol, 3 equiv
  • Example 50 1-(tert-butyl)-3-(3-oxo-4-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-yl)urea 7-nitro-4-(3-(trifluoromethyl)benzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one
  • Cs2CO3 1.678 g, 5.150 mmol, 2 equiv
  • 1- (bromomethyl)-3-(trifluoromethyl)benzene (676.8 mg, 2.832 mmol, 1.1 equiv).
  • Example 51 1-(1-benzyl-3-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert- butyl)urea Synthetic Scheme 1-benzyl-6-nitro-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid
  • 1-benzyl-6-nitro-3,4-dihydroquinolin-2- one 500 mg, 1.771 mmol, 1 equiv
  • tetrahydrofuran 5 mL, 0.069 mmol, 0.04 equiv
  • 2M LDA in THF
  • Example 53 3-tert-butyl-1- ⁇ 1-[(2-cyano-3-methylphenyl)methyl]-2-oxo-3,4-dihydroquinoli 2-methyl-6-[(6-nitro-2-oxo-3,4-dihydroquinolin-1-yl)methyl]benzonitrile
  • 2-(bromomethyl)-6-methylbenzonitrile 400 mg, 1.904 mmol, 1 equiv
  • 6-nitro-3,4-dihydro-1H-quinolin-2-one 548.88 mg, 2.856 mmol, 1.5 equiv
  • K 2 CO 3 (662.69 mg, 4.760 mmol, 2.5 equiv) in portions at room temperature under nitrogen atmosphere.
  • Example 54 1-(tert-butyl)-3-(1-(2-fluoro-3-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)urea 1-(2-fluoro-3-(trifluoromethyl)benzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • K2CO3 431.50 mg, 3.122 mmol, 2 equiv
  • 1- (bromomethyl)-2-fluoro-3-(trifluoromethyl)benzene (601.86 mg, 2.341 mmol, 1.5 equiv).
  • Example 55 3-tert-butyl-1-(1- ⁇ [2-cyano-5-(trifluoromethyl) phenyl] methyl ⁇ -2-oxo-3,4- dihydroquinolin-6-yl) urea Synthetic Scheme 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene To a stirred solution of [2-bromo-5-(trifluoromethyl) phenyl] methanol (2 g, 7.842 mmol, 1 equiv) in DCM (20 mL) was added phosphorus tribromide (2.12 g, 7.842 mmol, 1 equiv) in portions at 0°C under air atmosphere.
  • Example 58 3-tert-butyl-1- ⁇ 1-[(1S)-1-(2-fluorophenyl)ethyl]-2-oxo-3,4-dihydroquinolin-6-y l ⁇ ure 1-[(1S)-1-(2-fluorophenyl)ethyl]-6-nitro-3,4-dihydroquinolin-2-one
  • 6-amino-1-[(1S)-1-[3-(trifluoromethyl)phenyl]ethyl]-3,4-dihydroquinolin-2-one To a solution of 6-nitro-1-[(1S)-1-[3-(trifluoromethyl)phenyl]ethyl]-3,4-dihydroquinolin-2-one (285 mg, 0.782 mmol, 1 equiv) in methanol (3 mL) was added Pd/C (150 mg). The reaction was stirred at rt under H2 for 1h. The resulting mixture was stirred for 1 h at room temperature under hydrogen atmosphere. Desired product could be detected by LCMS.
  • Example 61 (S)-1-(tert-butyl)-3-(1-(1-(2-cyanophenyl)ethyl)-2-oxo-1,2,3,4-tetrahydroquino lin-6-yl)urea (S)-1-(1-(2-bromophenyl)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • (1R)-1-(2-bromophenyl)ethanol (1 g, 4.974 mmol, 1 equiv) in THF (10 mL) was added 6-nitro-3,4-dihydro-1H-quinolin-2-one (1.05 g, 5.471 mmol, 1.1 equiv), PPh 3 (1.30 g, 4.974 mmol, 1 equiv) at rt.
  • the crude product 50 mg was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 54% B in 7 min; Wave Length: 220 nm; RT1(min): 6.5; Number Of Runs: 0 ) to afford (S)-1-(tert-butyl)-3-(1-(1-(2-cyanophenyl)ethyl)- 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea (22.5 mg, 23.93%) as white solid.
  • Example 62 (S)-1-(tert-butyl)-3-(3-oxo-4-(1-(3-(trifluoromethyl)phenyl)ethyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)urea (S)-7-nitro-4-(1-(3-(trifluoromethyl)phenyl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one
  • (1R)-1-[3-(trifluoromethyl)phenyl]ethanol 500 mg, 2.629 mmol, 1 equiv
  • 7-nitro-2,4-dihydro-1,4-benzoxazin-3-one 510.47 mg, 2.629 mmol, 1 equiv
  • PPh3 1034.46 mg, 3.944 mmol, 1.5 equiv
  • Example 64 1-(tert-butyl)-3-(1-(cyclohexylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)u rea 1-(cyclohexylmethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • DMF liquid-free fatty acid
  • Cs2CO3 1.53 g, 4.683 mmol, 3.0 equiv
  • (bromomethyl)cyclohexane (276.44 mg, 1.561 mmol, 1 equiv) at rt and stirred for overnight.
  • 6-amino-1-(cyclohexylmethyl)-3,4-dihydroquinolin-2(1H)-one To a solution of 1-(cyclohexylmethyl)-6-nitro-3,4-dihydroquinolin-2-one (100 mg, 0.347 mmol, 1 equiv) in methanol (5 mL) was added Pd/C (30 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 50 min under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. This resulted in 6-amino-1-(cyclohexylmethyl)-3,4-dihydroquinolin-2(1H)-one as a white solid.
  • the residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26% B to 50% B in 9 min, 50% B; Wave Length: 254/220 nm; RT1(min): 8.9;) to afford 1-(tert-butyl)-3-(1- (cyclohexylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea (26.5 mg, 38.18%) as a white solid.
  • Example 65 1-(1-benzyl-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert-butyl)urea Synthetic Scheme 7-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • HNO 3 200.6 mg,3.185 mmol, 1.0 equiv)at 0 °C.
  • the resulting mixture was stirred at 0 °C until the starting material was totally consumed by LCMS, the reaction mixture was quenched by water and extracted with EA (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash
  • reaction progress was monitored by LCMS.
  • the reaction mixture was quenched by water and extracted with EA (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to afford 100 mg crude product as a white solid.
  • Example 66 1-(1-benzyl-7-chloro-2-oxo-3,4-dihydroquinolin-6-yl)-3-tert-butylurea Synthesis of 7-chloro-6-nitro-3,4-dihydro-1H-quinolin-2-one To a stirred solution of 7-chloro-3,4-dihydro-1H-quinolin-2-one (2 g, 11.012 mmol, 1 equiv) in H2SO4 was added KNO3 (1.11 g, 11.012 mmol, 1 equiv) at 0°C. The final reaction mixture was stirred overnight at room temperature. The reaction was monitored by LCMS.
  • 6-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one To a stirred solution of ethyl 3-(3-amino-6-chloropyridin-2-yl)propanoate (900 mg, 3.936 mmol, 1 equiv) in HCl (2M, in EA) (30 mL) at rt and stirred for 2 h. The precipitated solids were collected by filtration and washed with diethyl ether (3 x 50 mL). This resulted in 6-chloro-3,4- dihydro-1H-1,5-naphthyridin-2-one (600 mg, 83.49%) as a white solid.
  • 6-amino-1-benzyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one Into a 20 mL bar were added tert-butyl N-(5-benzyl-6-oxo-7,8-dihydro-1,5-naphthyridin- 2-yl)carbamate (80 mg, 0.226 mmol, 1 equiv) and HCl (10 mL, 10.000 mmol, 44.18 equiv) at rt and strried for 3 h. The crude product/ resulting mixture was used in the next step directly without further purification.
  • Example 68 1-(1-benzyl-2-oxo-1,2-dihydroquinoxalin-6-yl)-3-(tert-butyl)urea Synthetic Scheme 1-benzyl-6-nitroquinoxalin-2(1H)-one To a solution of 6-nitro-1H-quinoxalin-2-one (500 mg, 2.616 mmol, 1 equiv) in DMF (20 mL) was added benzyl bromide (671.10 mg, 3.924 mmol, 1.5 equiv) and K 2 CO 3 (728.31 mg, 5.232 mmol, 2 equiv). The reaction was stirred at rt for 1 hour.
  • Example 69 1-(1-benzyl-8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert-butyl)urea 8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one
  • HNO3 (190.7 mg, 3.027 mmol, 1.0 equiv)at -10 °C.
  • the resulting mixture was stirred at -10 °C until the starting material was totally consumed by LCMS,
  • the reaction mixture was quenched by water and adjusting PH with saturaed sodium bicarbonate aqueous solution and then extracted with EA (3 x 20 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na 2
  • Example 70 1-(tert-butyl)-3-(3-methyl-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahyd roquinazolin-6-yl)urea 3-methyl-6-nitro-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-2(1H)-one
  • 3-methyl-6-nitro-1,4-dihydroquinazolin-2-one 120 mg, 0.579 mmol, 1 equiv) in DMF (10 mL) was added 1-(bromomethyl)-3-(trifluoromethyl)benzene (152.29 mg, 0.637 mmol, 1.1 equiv) and Cs2CO3 (378.58 mg, 1.158 mmol, 2 equiv).
  • the residue was purified by silica gel column chromatography, eluted with EA (35%-46%) to afford crude product.
  • the residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 61% B in 9 min, 61% B; Wave Length: 220/254 nm) to afford1-(tert- butyl)-3-(4-(3-(difluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea (4 mg, 6.03%) as a white solid.
  • reaction was stirred at 90°C for 2 hours. After cooling down to rt, the reaction was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated.
  • Example 157 3-tert-butyl-1-[(2R)-2-methyl-4-[(3-methylphenyl)methyl]-3-oxo-2H-1,4- benzoxazin-7-yl]urea.
  • Synthetic Scheme (2R)-7-bromo-2-methyl-4-[(3-methylphenyl)methyl]-2H-1,4-benzoxazin-3-one To a stirred solution of (2R)-7-bromo-2-methyl-2,4-dihydro-1,4-benzoxazin-3-one (400 mg, 1.652 mmol, 1 equiv) in DMF (4 mL) was added 1-(bromomethyl)-3-methylbenzene (458.70 mg, 2.478 mmol, 1.5 equiv) and Cs2CO3 (1080.10 mg, 3.304 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere.
  • the resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere.
  • the reaction was monitored by LCMS.
  • the mixture was allowed to cool down to room temperature. Quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated.
  • Example 183 1-(tert-butyl)-3-((R)-4-((S)-1-(3-chlorophenyl)ethyl)-2-methyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea Synthetic Scheme (R)-7-bromo-4-((S)-1-(3-chlorophenyl)ethyl)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of(2R)-7-bromo-2-methyl-2,4-dihydro-1,4-benzoxazin-3-one (270 mg, 1.115 mmol, 1 equiv) in DCM (10 mL) was added 1-[(1R)-1-bromoethyl]-3-chlorobenzene (9.07 mg, 0.041 mmol, 1 equiv) and PPh 3 (438.83 mg
  • reaction was stirred at 90 °C under N 2 for 3h. After cooling down to rt, the reaction was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated.
  • Example 191 1-(1-benzyl-2-oxo-1,2-dihydroquinoxalin-6-yl)-3-(1-methylcyclobutyl)urea Synthetic Scheme benzyl-6-nitroquinoxalin-2(1H)-one To a solution of 6-nitro-1H-quinoxalin-2-one (3 g, 15.695 mmol, 1 equiv) and benzyl bromide (5368.79 mg, 31.390 mmol, 2 equiv) in dimethylformamide (100 mL) was added Cs2CO3 (15388.46 mg, 47.085 mmol, 3 equiv). The reaction was stirred at rt for 3 h.
  • the reaction was added TEA (201.35 mg, 1.990 mmol, 5 equiv) and stirred at rt under N 2 for 1h.
  • the reaction was added 1-methylcyclobutan-1-amine (67.77 mg, 0.796 mmol, 2 equiv) and stirred at rt under N 2 for 1h. Quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated.
  • the reaction was stirred at 0 °C under N 2 for 1 h.
  • the reaction was added TEA (188.57 mg, 1.865 mmol, 5 equiv) and stirred at rt under N 2 for 1 h.
  • the reaction was added 3-amino-3- methylbutan-1-ol (153.80 mg, 1.492 mmol, 4 equiv) and stirred at rt under N 2 for 1 h. Quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated.
  • 6-nitro-1-(3-(trifluoromethoxy)benzyl)quinoxalin-2(1H)-one To a mixture of 6-nitroquinoxalin-2(1H)-one (1.8 g, 9.417 mmol, 1.2 equiv) and 1-(bromomethyl)- 3-(trifluoromethoxy)benzene (2.00 g, 7.848 mmol, 1 equiv) in DMF (30 mL) was stirred and added K2CO3 (2.18 g, 15.695 mmol, 2 equiv). The reaction was stirred at rt for 1 h. The reaction mixture was quenched by ice water (30 mL) and extracted with EA (3 x 30 mL).
  • 6-amino-1-(3-(trifluoromethoxy)benzyl)quinoxalin-2(1H)-one To a mixture of 6-nitro-1-(3-(trifluoromethoxy)benzyl)quinoxalin-2(1H)-one (1.0 g, 2.738 mmol, 1 equiv) in EtOH (25 mL) and water (5 mL). Fe (1.53 g, 27.380 mmol, 10 equiv) and NH 4 Cl (1.46 g, 27.380 mmol, 10 equiv) was added into the mixture. The resulting solution was stirred at 60 °C for 1 h. The reaction was quenched with water (30 mL) at rt.
  • the reaction was stirred at rt for 1 h.
  • TEA 53 mg, 0.522 mmol, 2.5 equiv
  • the reaction was stirred at rt for 1 h.1-amino- 2-methylpropan-2-ol (23 mg, 0.251 mmol, 1.2 equiv) was added into the mixture at 0 °C.
  • the reaction was stirred at rt for 1 h.
  • the reaction mixture was quenched by 1N hydrochloric acid (5 mL) and extracted with DCM (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • Example 246 1-(tert-butyl)-3-(1-(1-(3-cyclobutylphenyl)ethyl)-2-oxo-1,2- dihydroquinoxalin-6-yl)urea Synthetic Scheme 1-(3-cyclobutylphenyl)ethan-1-one In a 100-mL round bottom flask, to a solution of 1-bromo-3-cyclobutylbenzene (500 mg, 2.369 mmol, 1 equiv) in tetrahydrofuran (5 mL) was added dropwise n-BuLi (2.5 M, 1.1 mL, 2.843 mmol, 1.2 equiv) at -78 °C under N 2 atmosphere.
  • 1-bromo-3-cyclobutylbenzene 500 mg, 2.369 mmol, 1 equiv
  • tetrahydrofuran 5 mL
  • n-BuLi 2.5 M, 1.1 mL, 2.843
  • the resulting mixture was stirred for overnight at rt.
  • the reaction mixture was quenched by water (10 mL).
  • the resulting mixture was extracted with EA (5 mL x 3).
  • the combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product 30 mg was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 42% B in 9 min, 42% B; Wave Length: 254/220 nm; RT1(min): 8.9; Number Of Runs: 0) to affored 3-tert-butyl-1- ⁇ 1-[1-(3- cyclobutylphenyl)ethyl]-2-oxoquinoxalin-6-yl ⁇ urea (7.8 mg, 14.70%) as a yellow solid.
  • the final reaction mixture was stirred overnight at 90 °C.
  • the reaction was monitored by LCMS.
  • the mixture was allowed to cool down to room temperature. Quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined extracts were washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated.
  • Example 268 and Example 269 1-(tert-butyl)-3-((S)-2-methyl-3-oxo-4-((S)-1-phenylethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea and 1-(tert-butyl)-3-((R)-2-methyl-3-oxo-4- ((S)-1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea Synthetic Scheme 2-methyl-7-nitro-4-((S)-1-phenylethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of 2-methyl-7-nitro-2,4-dihydro-1,4-benzoxazin-3-one (350 mg, 1.681 mmol, 1 equiv) in DCM (10 mL) was added (R)-1-
  • reaction mixture was quenched by water (10 mL) and extracted with EA (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated under vacuum.
  • the crude product was purified by silica gel column to afford 3-methyl-6-nitro-1-(1-(3- (trifluoromethyl)phenyl)ethyl)-3,4-dihydroquinazolin-2(1H)-one (100 mg, 27.31%) as a yellow solid.
  • Example 274 1-(tert-butyl)-3-(6-oxo-5-(3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-2-yl)urea Synthetic Scheme 6-chloro-1-(3-(trifluoromethyl)benzyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one To a stirred solution of 6-chloro-3,4-dihydro-1H-1,5-naphthyridin-2-one (300 mg, 1.643 mmol, 1 equiv) in anhydrous dimethylformamide (5 mL) was added 1-(bromomethyl)-3- (trifluoromethyl)benzene (432 mg, 1.807 mmol, 1.1 equiv) and Cs 2 CO 3 (1.6 g, 4.929 mmol, 3 equiv) at rt and stirred for 2
  • reaction mixture was quenched by water (20 mL) and extracted with EA (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum.
  • the crude product was purified by flash chromatography with PE/EA (3:1) to afford 6-chloro-1-(3- (trifluoromethyl)benzyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one (390 mg, 69.67%) as a light- yellow solid.
  • reaction mixture was quenched by water (20 mL) and extracted with EA (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum.
  • the crude product was purified by flash chromatography with PE/EA (3:1) to afford tert-butyl (6-oxo-5-(3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-2-yl)carbamate (0.5 g, 96.01%) .
  • Example 276 (S)-1-(1-benzyl-3-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3- (tert-butyl)urea (S)-1-(1-benzyl-3-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert-butyl)urea
  • 2-(6-amino-1-benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile 70 mg, 0.240 mmol, 1 equiv
  • 2-isocyanato-2-methylpropane 72 mg, 0.720 mmol, 3.0 equiv
  • TEA 122 mg, 1.200 mmol, 5.0 equiv
  • reaction mixture was quenched by addition of water (15 mL).
  • the aqueous layer was extracted with ethyl acetate (3 x 30 mL).
  • the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure.
  • the residue was purified by silica gel column, eluted with PE/EA (3:1) to give 2-ethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (1.3 g, 90.17%) as a yellow solid.
  • reaction mixture was quenched by addition of water (15 mL).
  • the aqueous layer was extracted with DCM (3 x 20 mL).
  • the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure.
  • the residue was purified by silica gel column, eluted with PE/EA (2:1) to give crude product.
  • Example 278 (S)-1-(4-benzyl-2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3- (tert-butyl)urea (S)-1-(4-benzyl-2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(tert-butyl)urea A solution of 7-amino-4-benzyl-2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (150 mg, 0.531 mmol, 1 equiv), TEA (269 mg, 2.655 mmol, 5 equiv) and 2-isocyanato-2-methylpropane (263 mg, 2.655 mmol, 5 equiv) in DCM (10 mL) was stirred for overnight at r
  • reaction mixture was quenched by addition of water (15 mL).
  • the aqueous layer was extracted with DCM (3 x 20 mL).
  • the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure.
  • the residue was purified by silica gel column, eluted with PE/EA (2:1) to give crude product.
  • Example 279 1-(1-benzyl-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(tert-butyl)urea Synthetic Scheme 1-benzyl-6-nitro-2-oxo-1,2,3,4-tetrahydroquinoline-5-carbonitrile To a solution of 1-benzyl-5-chloro-6-nitro-3,4-dihydroquinolin-2-one (180 mg, 0.568 mmol, 1 equiv) in dimethylformamide (2 mL) was added zinc (5.57 mg, 0.085 mmol, 0.15 equiv), zinc cyanide (80.07 mg, 0.682 mmol, 1.2 equiv), Brettphos Pd G 3 (103.03 mg, 0.114 mmol, 0.2 equiv) and Brettphos (61.01 mg, 0.114 mmol, 0.2 equiv).
  • Example 280 (R)-1-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)-3-(tert-butyl)urea Synthetic Scheme ethyl (R)-2-((6-chloro-3-nitropyridin-2-yl)oxy)propanoate To a solution of 2,6-dichloro-3-nitropyridine (2.0 g, 10.364 mmol, 1 equiv) in tetrahydrofuran (20 mL) was added 60% NaH (0.5 g, 12.437 mmol, 1.2 equiv) at 0 °C.
  • 6-chloro-1-(3-chlorobenzyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one 300 mg, 1.643 mmol, 1 equiv
  • 6-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one 300 mg, 1.643 mmol, 1 equiv
  • 1-(bromomethyl)-3-chlorobenzene (371 mg, 1.807 mmol, 1.1 equiv) and Cs2CO3 (1.6 g, 4.929 mmol, 3 equiv) at rt and stirred for 2 h.
  • Example 282 (S)-1-(tert-butyl)-3-(6-oxo-5-(1-(3-(trifluoromethyl)phenyl)ethyl)-5,6,7,8- tetrahydro-1,5-naphthyridin-2-yl)urea Synthetic Scheme 6-chloro-1-(1-(3-(trifluoromethyl)phenyl)ethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one To a solution of 6-chloro-3,4-dihydro-1H-1,5-naphthyridin-2-one (400 mg, 2.190 mmol, 1 equiv) in DMF (10 mL) was added K 2 CO 3 (908 mg, 6.571 mmol, 3 equiv) and 1-(1-bromoethyl)-3- (trifluoromethyl)benzene (831 mg, 3.286 mmol
  • reaction progress was monitored by LCMS.
  • the reaction mixture was quenched by water (10 mL) and extracted with EA (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to afford 100 mg crude product as a white solid.
  • Example 283 (R)-1-(tert-butyl)-3-(6-oxo-5-(1-(3-(trifluoromethyl)phenyl)ethyl)-5,6,7,8- tetrahydro-1,5-naphthyridin-2-yl)urea (R)-1-(tert-butyl)-3-(6-oxo-5-(1-(3-(trifluoromethyl)phenyl)ethyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-2-yl)urea To a stirred solution of 6-amino-1-(1-(3-(trifluoromethyl)phenyl)ethyl)-3,4-dihydro-1,5- naphthyridin-2(1H)-one (100 mg, 0.298 mmol, 1 equiv) in DCM (10.00 mL) was added 2- isocyanato-2-methylpropane
  • reaction progress was monitored by LCMS.
  • the reaction mixture was quenched by water (10 mL) and extracted with EA (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to afford 100 mg crude product as a white solid.
  • Example 284 3-(1-benzyl-2-oxo-3,4-dihydroquinolin-6-yl)-1-phenylurea 3-(1-benzyl-2-oxo-3,4-dihydroquinolin-6-yl)-1-phenylurea
  • 6-amino-1-benzyl-3,4-dihydroquinolin-2-one 150 mg, 0.594 mmol, 1 equiv
  • triphosgene 59.98 mg, 0.202 mmol, 0.34 equiv
  • Example 285 N-(1-benzyl-2-oxo-3,4-dihydroquinolin-6-yl)-3,3-dimethylbutanamide N-(1-benzyl-2-oxo-3,4-dihydroquinolin-6-yl)-3,3-dimethylbutanamide
  • N-(1-benzyl-2-oxo-3,4-dihydroquinolin-6-yl)-3,3-dimethylbutanamide To a stirred solution of 3,3-dimethylbutanamide (35.15 mg, 0.305 mmol, 1.1 equiv) and HATU (137.13 mg, 0.360 mmol, 1.3 equiv) in DMF (1 mL) were added 6-amino-1-benzyl-3,4- dihydroquinolin-2-one (70 mg, 0.277 mmol, 1 equiv) and DIEA (107.57 mg, 0.831 mmol, 3 equiv) in portions
  • Example 286 (S)-1-(tert-butyl)-3-(1-(3-chlorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-6-yl)urea Synthetic Scheme (S)-6-chloro-1-(3-chlorobenzyl)-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one A solution of (S)-6-chloro-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (100 mg, 0.503 mmol, 1 equiv) in DMF (5 mL) was added 1-(bromomethyl)-3-chlorobenzene (155 mg, 0.754 mmol, 1.5 equiv) and Cs 2 CO 3 (492 mg, 1.509 mmol, 3.0 equiv)
  • the resulting mixture was stirred for overnight at rt.
  • the reaction mixture was quenched by water (10 mL) and extracted with DCM (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • Example 287 (R)-1-(tert-butyl)-3-(1-(3-chlorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-6-yl)urea (R)-1-(tert-butyl)-3-(1-(3-chlorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-6-yl)urea A solution of (R)-6-amino-1-(3-chlorobenzyl)-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)- one (60 mg, 0.198 mmol, 1 equiv) in DCM (5 mL) was added 2-isocyanato-2-methylpropane (195 mg, 1.980 mmol, 10
  • the resulting mixture was stirred for overnight at rt.
  • the reaction mixture was quenched by water (10 mL) and extracted with DCM (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • the crude product 40 mg was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IF, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 23 min; Wave Length: 220/254 nm; RT1(min): 13.384; RT2(min): 18.251; Sample Solvent: EtOH--HPLC; Injection Volume: 0.6 mL; Number Of Runs: 7) to afford (S)-1-(4-benzyl-2-(methoxymethyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(tert-butyl)urea (20.0 mg, 21.32%) as a white solid.
  • the crude product 40 mg was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IF, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 23 min; Wave Length: 220/254 nm; RT1(min): 13.384; RT2(min): 18.251; Sample Solvent: EtOH--HPLC; Injection Volume: 0.6 mL; Number Of Runs: 7) to afford (S)-1-(4-benzyl-2-(methoxymethyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(tert-butyl)urea (20.0 mg, 21.32%) as a white solid.
  • tert-butyl (5-(1-(3-chlorophenyl)ethyl)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-2- yl)carbamate
  • 6-chloro-1-(1-(3-chlorophenyl)ethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one 200 mg, 0.623 mmol, 1 equiv
  • Xantphos (36.0 mg, 0.062 mmol, 0.1 equiv)
  • Pd2(dba)3 (57.0 mg, 0.062 mmol, 0.1 equiv)
  • Cs2CO3 (608.6 mg, 1.868 mmol, 3 equiv).
  • the resulting mixture was placed at 90°C under a nitrogen atmosphere and stirred overnight until the starting material was totally consumed by LCMS. After cooled to room temperature the reaction mixture was quenched by ice water (10 mL) and extracted with EA (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 292 1-(4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3- (tert-butyl)urea Synthetic Scheme 4-benzyl-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one To a stirred solution of 2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 1.350 mmol, 1 equiv) in anhydrous DMF (10 mL) was added K 2 CO (373 mg, 2.700 mmol, 2 equiv) and BnBr (346 mg, 2.025 mmol, 1.5 equiv) at rt.
  • K 2 CO 373 mg, 2.700 mmol, 2 equiv
  • BnBr 346 mg, 2.025 mmol, 1.5 equiv
  • reaction was stirred for overnight at rt.
  • the reaction mixture was quenched by water (10 mL) and extracted with DCM (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • Example 293 1-(tert-butyl)-3-(4-(1-(5-chloro-2-cyanophenyl)ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)urea Synthetic Scheme 1-bromo-2-(1-bromoethyl)-4-chlorobenzene To a mixture of 1-(2-bromo-5-chlorophenyl)ethan-1-ol (300 mg, 1.047 mmol, 1 equiv) in DCM (5 mL) was added PBr 3 (567 mg, 2.094 mmol, 2 equiv) at 0 °C.
  • the reaction was stirred for overnight at rt.
  • the reaction mixture was quenched by ice water (10 mL) and the pH value of the aqueous phase was adjusted to 8 with NaHCO3 (aq.).
  • the mixture was extracted with DCM (3 x 10 mL).
  • the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • the residue was purified by silica gel column, eluted with PE/EA (20:1) to give 1- bromo-2-(1-bromoethyl)-4-chlorobenzene (218 mg, 69.76%) as yellow oil.
  • reaction mixture was quenched by water (10 mL) and extracted with DCM (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum The residue was purified by silica gel column, eluted with PE/EA (3:1) to afford 4-(1-(2-bromo-5-chlorophenyl)ethyl)-7-nitro-2H-benzo[b][1,4]oxazin- 3(4H)-one (150 mg, 81.55%) as a yellow solid.

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Abstract

L'invention concerne des composés qui sont des antagonistes du récepteur de l'hormone de stimulation de la thyroïde, et des méthodes utiles pour prévenir ou traiter une maladie thyroïdienne.
PCT/US2023/028950 2022-07-29 2023-07-28 Inhibiteurs de tshr substitués de 3,4-dihydroquinolinone WO2024026076A2 (fr)

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