WO2012113103A1 - Asymmetric ureas and medical uses thereof - Google Patents

Asymmetric ureas and medical uses thereof Download PDF

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Publication number
WO2012113103A1
WO2012113103A1 PCT/CN2011/000298 CN2011000298W WO2012113103A1 WO 2012113103 A1 WO2012113103 A1 WO 2012113103A1 CN 2011000298 W CN2011000298 W CN 2011000298W WO 2012113103 A1 WO2012113103 A1 WO 2012113103A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
group
adduct
acceptable salt
Prior art date
Application number
PCT/CN2011/000298
Other languages
French (fr)
Inventor
Silvina Garcia Rubio
Claudio Pietra
Claudio Giuliano
Zhigang Li
Original Assignee
Helsinn Healthcare S.A.
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Publication date
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Priority to PCT/CN2011/000298 priority Critical patent/WO2012113103A1/en
Priority to UAA201311289A priority patent/UA113510C2/en
Priority to PE2013001934A priority patent/PE20141000A1/en
Priority to BR112013021566-6A priority patent/BR112013021566B1/en
Priority to KR1020137025184A priority patent/KR20140014186A/en
Priority to PT127493831T priority patent/PT2678017T/en
Priority to AP2013007123A priority patent/AP3768A/en
Priority to DK12749383.1T priority patent/DK2678017T3/en
Priority to HUE12749383A priority patent/HUE035039T2/en
Priority to EA201300946A priority patent/EA027374B1/en
Priority to JP2013555559A priority patent/JP6077468B2/en
Priority to PL12749383T priority patent/PL2678017T3/en
Priority to MX2013006974A priority patent/MX347587B/en
Priority to KR1020187017910A priority patent/KR101907573B1/en
Priority to CN201611088800.9A priority patent/CN106995403B/en
Priority to GEAP201213239A priority patent/GEP20156319B/en
Priority to MYPI2013003013A priority patent/MY164354A/en
Priority to CA2820767A priority patent/CA2820767C/en
Priority to EP12749383.1A priority patent/EP2678017B1/en
Priority to AU2012220531A priority patent/AU2012220531B2/en
Priority to NZ615283A priority patent/NZ615283B2/en
Priority to SG2013056775A priority patent/SG192138A1/en
Priority to CN201280008805.XA priority patent/CN103874492B/en
Priority to MA36252A priority patent/MA34968B1/en
Priority to MEP-2017-123A priority patent/ME02845B/en
Priority to SI201230981A priority patent/SI2678017T1/en
Priority to RS20170546A priority patent/RS56033B1/en
Priority to ES12749383.1T priority patent/ES2628386T3/en
Priority to PCT/US2012/026315 priority patent/WO2012116176A2/en
Priority to LTEP12749383.1T priority patent/LT2678017T/en
Priority to TW101106171A priority patent/TWI579273B/en
Priority to US13/404,165 priority patent/US8658797B2/en
Priority to ARP120100611A priority patent/AR085398A1/en
Publication of WO2012113103A1 publication Critical patent/WO2012113103A1/en
Priority to IL227941A priority patent/IL227941A/en
Priority to NI201300070A priority patent/NI201300070A/en
Priority to TNP2013000346A priority patent/TN2013000346A1/en
Priority to CL2013002412A priority patent/CL2013002412A1/en
Priority to DO2013000195A priority patent/DOP2013000195A/en
Priority to ZA2013/07071A priority patent/ZA201307071B/en
Priority to EC2013012893A priority patent/ECSP13012893A/en
Priority to CO13226995A priority patent/CO6771450A2/en
Priority to US14/150,360 priority patent/US9751836B2/en
Priority to CY20171100635T priority patent/CY1118947T1/en
Priority to HRP20170997TT priority patent/HRP20170997T1/en
Priority to US15/663,761 priority patent/US10407390B2/en

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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
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    • 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
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds based on asymmetric ureas, and medical uses thereof, particularly in the treatment of medical conditions modulated by the ghrelin receptor.
  • the growth hormone secretagogue receptor regulates a number of physiological processes, including growth hormone (GH) release, metabolism, and appetite.
  • Ghrelin a circulating hormone produced predominantly by endocrine cells in the stomach, is its endogenous ligand.
  • Ghrelin is a 28 amino acid peptide with an acyl side chain required for biological activity (Kojima et al., Nature, 402, 656-660, 1999).
  • Ghrelin has been shown to stimulate growth hormone (GH) release and to increase food intake when administered both centrally and peripherally (Wren et al., Endocrinology, 141, 4325-4328, 2000).
  • Ghrelin endogenous levels of ghrelin rise on fasting and fall on re-feeding in humans (Cummings et al., Diabetes, 50, 1714-1719, 2001). Ghrelin also appears to play a role in maintaining long term energy balance and appetite regulation. Chronic administration of ghrelin in rodents leads to hyperphagia and weight gain that are independent of growth hormone secretion (Tschop et al., Nature, 407, 908-913, 2000). Circulating ghrelin levels decrease in response to chronic overfeeding and increase in response to chronic negative energy balance associated with anorexia or exercise. Obese people generally have low plasma ghrelin levels (Tschop et al., Diabetes, 50, 707-709, 2001) accordingly to the physiological response of the body in reducing calories intake. Intravenous ghrelin is effective in
  • ghrelin receptor may reduce appetite, reduce food intake, induce weight loss and treat obesity without affecting or reducing the circulating growth hormone levels.
  • agonists at ghrelin receptor may _be useful in stimulating food intake and thus be useful in treating eating disorders, for example anorexia nervosa, or in treating cachexia resulting from cancer, AIDS or Chronic Obstructive Pulmonary Disease (COPD).
  • Ghrelin agonists may also be useful as gastropfokinetic agents which can enhance gastrointestinal motility by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm.
  • Gastroprokinetic agents are used to relieve gastrointestinal symptoms such as abdominal discomfort, bloating, constipation, heart burn, nausea, and vomiting, and are used to treat a number of gastrointestinal disorders, including but not limiting to, irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.
  • compounds that modulate ghrelin receptor activity can also be used to prevent or treat diseases related to substance abuse, for example, alcohol or drug (e.g., amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, and opioids) abuse, which refers to a maladaptive pattern of use of a substance that is not considered dependent.
  • YIL-781 is a small molecule ghrelin receptor antagonist from Bayer that reportedly improves glucose tolerance, suppress appetite and promote weigh loss (Esler et al., Endocrinology 148 (1 1): 5175-5185); LY44471 1 is an orally active ghrelin receptor agonist from Lilly that reportedly induces adiposity by stimulating food consumption and sparing fat utilization (Bioorg. & Med. Chem.
  • Anamorelin is an orally available ghrelin receptor small molecule agonist from Helsinn Therapeutics that is in clinical trials for the treatment of anorexia and cachexia in cancer patients.
  • Other small molecule ghrelin receptor modulators can be found in WO 2008/092681, US 2009/0253673, WO 2008/148853, WO 2008/148856, US 2007/0270473 and US 2009/0186870.
  • R and R 1 -R14 as defined herein, and pharmaceutically acceptable salts or adducts thereof.
  • Compounds of formula (I), also known as asymmetric ureas, are particularly useful for preventing and/or treating diseases that are pathophysiologically related to the ghrelin receptor in a subject. Accordingly, in another embodiment the invention provides a method of treating a disease that is mediated by the ghrelin receptor, comprising administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof.
  • compositions for preventing and/or treating diseases which are pathophysiologically related to ghrelin receptor in a subject, comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, and one or more pharmaceutically acceptable excipients.
  • R is selected from the group consisting of aryl, arylalkyl, carbocyclic ring,
  • heterocycloalkyl heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, optionally substituted with one or more independent R 103 substituents;
  • Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, - C(0)R 101 , -C(0)OR 101 , aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more independent R 103 substituents; or Ri and R 2 , together with the atoms connecting the same, form a fused or non- fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R 103 substituents;
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R 101 , -C(0)OR 101 , -C(O)NR ,01 R 102 , -S(0) 2 R 102 , -SR 101 and -S(O) 2 NR 101 R 102 , optionally substituted with one or more independent R 103 substituents;
  • R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -OR 103 ,
  • R ⁇ 5, R 7 , R 8 , R9, Rio, R1 1, Ri 2 , R13 and Ru are each independently selected from the group consisting of hydrogen, cyano, -N0 2 , -OR 101 , hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl,
  • R 101 , R 102 and R 103 are each independently selected from the group consisting of hydrogen, cyano, -N0 2 , -OR 101 , hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R 101 , -C(0)OR 101 , -C(O) R 101 R 102 , -NR 101 R 102 , -NR 101 S(O) 2 R 102 , -NR 101 C(O)R 102 , - S(0) 2 R 102 , -SR 101 and -S(O) 2 NR 101 R 102 , each optionally independently substituted with one or more independent R 103 substituents; or R 101 , R 102 , together with the atoms connecting the same, form a fused or
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R is aryl or heteroaryl.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R is R is selected from the group consisting of phenyl, naphthalene, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl, fluorenyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R is phenyl or naphthalene which is optionally independently substituted with from one to six substituents independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, trifluoromethyl, cyano, methoxy, ethoxy, methyl and ethyl.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Ri and R 2 are not both hydrogen; or R] and R 2 , together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Ri is selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, -OR 101 , hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Rj is selected from the group consisting of alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl and heteroarylalkyl.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Rj is selected from the group consisting of methyl, -CH 2 OH, and -CH 2 -0-CH 2 -phenyl.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R 2 is hydrogen, alkyl or cycloalkyl. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R 3 is hydrogen, alkyl or cycloalkyl. 22.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R4 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amino, alkoxy, alkylamino, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and aminoalkyl.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R4 is methyl, ethyl, benzyl, or benzyl substituted with from one to five substituents independently selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl, methoxy, cyano and hydroxy.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R5 is methyl.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R6, R 7 , Rs, R9, Rio, R1 1, R12, R13 and RH are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, , -C(0)OR 101 , and -alkylOR 103 .
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R 8 and R9 are each independently hydrogen, alkyl, cycloalkyl, -C(0)OR 101 , or -alkylOR 103 .
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Rg and R 9 , together with the atom connecting them, form a cycloalkyl ring.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein said cycloalkyl ring as formed by R 8 and R 9 together with the atom connecting them, is cyclopropane. 25.
  • the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein the compound of formula (I) is a compound selected from the group consisting of:
  • the compound may exist in the form of optical isomers (enantiomers).
  • the disclosed compounds and compositions can comprise enantiomers and mixtures, including racemic mixtures of the compounds of formula (I).
  • the disclosed compounds and compositions can comprise diastereomeric forms (individual diastereomers and mixtures thereof) of compounds.
  • Tautomeric Forms 27.
  • the disclosed compositions and compounds comprise the tautomeric forms of compounds of formula (I). Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • the various ratios of the tautomers in solid and liquid form are dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound. 3. Salts
  • compositions and compounds can be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound can be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also can be used as an aid in the isolation, purification, and/or resolution of the compound.
  • salt preferably is pharmaceutically acceptable.
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound, such as the disclosed compounds, with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the disclosed methods because of their greater aqueous solubility relative to the parent compound.
  • salts of the disclosed compounds are non-toxic “pharmaceutically acceptable salts.”
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the disclosed compounds which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the disclosed compounds when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclylic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, ⁇ -hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, cam
  • suitable pharmaceutically acceptable salts thereof can include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., copper, calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine,
  • Organic salts can be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( -methylglucamine), and procaine.
  • secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( -methylglucamine), and procaine.
  • Basic nitrogenrcontaining groups can be quaternized with agents such as lower alkyl (C1-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • C1-C6 halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibuyt
  • hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts.
  • the disclosed compounds can exist in both unsolvated and solvated forms.
  • a "solvate” as used herein is a nonaqueous solution or dispersoid in which there is a noncovalent or easily dispersible combination between solvent and solute, or dispersion means and disperse phase.
  • adducts of the disclosed compounds.
  • An representive type of adduct can be Lewis acid adduct.
  • Lewis acid is a molecular entity (and the corresponding chemical species) that is an electron-pair acceptor and therefore able to react with a Lewis base to form a Lewis adduct, by sharing the electron pair furnished by the Lewis base.
  • An illustrative example is given by the reaction of trimethylboron and ammonia to give the adduct Me 3 BNH 3 .
  • Typical Lewis acids are boron trihalides, for example, boron trifluoride.
  • the disclosed compounds encompass boron trihalides adduct, for example, boron trifluoride adduct.
  • isotopically labeled compounds which are identical to those compounds recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, I3 C, n C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Disclosed compounds, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are contemplated.
  • Certain isotopically labeled disclosed compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon- 14, i.e. , 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds of formula (I) can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. 6.
  • the compounds of the formula (I) can be prepared by the methods as illustrated by examples described in the "Examples” section, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are commercially available or can be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the Compendium of Organic Synthesis Methods, Vol. I-VI (published by Wiley-Interscience)). Preferred methods include, but are not limited to, those described below.
  • alkyl refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; in one embodiment from one to twelve carbon atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms.
  • substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like.
  • alkenyl refers to a linear or branched-chain hydrocarbyl substituent containing one or more double bonds and from two to twenty carbon atoms; in another embodiment, from two to twelve carbon atoms; in another embodiment, from two to six carbon atoms; and in another embodiment, from two to four carbon atoms.
  • alkenyl include ethenyl (also known as vinyl), allyl, propenyl (including 1-propenyl and 2- propenyl) and butenyl (including 1 -buteny], 2-butenyl and 3-butenyl).
  • alkenyl embraces substituents having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • benzyl refers to methyl radical substituted with phenyl, i.e., the
  • carbocyclic ring refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to form the ring).
  • a carbocyclic ring typically contains from 3 to 10 carbon ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
  • a "carbocyclic ring system” alternatively may be 2 or 3 rings fused together, such as naphthalenyl,
  • tetrahydronaphthalenyl also known as “tetralinyl”
  • indenyl isoindenyl
  • indanyl is also known as tetralinyl
  • bicyclodecanyl anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”), fluorenyl, and decalinyl.
  • heterocyclic ring refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 ring atoms ("ring atoms" are the atoms bound together to form the ring), in which at least one of the ring atoms is a heteroatom that is oxygen, nitrogen, or sulfur, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • cycloalkyl refers to a saturated carbocyclic substituent having three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkyl also includes substituents that are fused to a C6-C 1 0 aromatic ring or to a 5- 10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group.
  • substituents that are fused to a C6-C 1 0 aromatic ring or to a 5- 10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group.
  • cycloalkenyl refers to a partially unsaturated carbocyclic substituent having three to fourteen carbon atoms, typically three to ten carbon atoms.
  • Examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • a cycloalkyl or cycloalkenyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. Alternatively, 2 or 3 rings may be fused together, such as bicyclodecanyl and decalinyl.
  • aryl refers to an aromatic substituent containing one ring or two or three fused rings.
  • the aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms.
  • aryl may refer to substituents such as phenyl, naphthyl and anthracenyl.
  • aryl also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C4-C 10 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4- 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group.
  • substituents such as phenyl, naphthyl and anthracenyl that are fused to a C4-C 10 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4- 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group.
  • aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as "phenalenyl”), and fluorenyl.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -C y -,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -C y - refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C 3 -C6-cycloalkyl refers to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.
  • the number of atoms in a cyclic substituent containing one or more heteroatoms is indicated by the prefix "X-Y- membered", wherein wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent.
  • X-Y- membered the number of atoms in a cyclic substituent containing one or more heteroatoms
  • heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one ore more heteroatoms, in the cyclic moiety of the heterocycloalkyl.
  • hydrogen refers to hydrogen substituent, and may be depicted as -H.
  • hydroxy refers to -OH.
  • prefix indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents.
  • Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phenol.
  • hydroxyalkyl refers to an alkyl that is substituted with at least one hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
  • nitro means -N0 2 .
  • carbonyl means -C(0)-, which also may be depicted as:
  • amino refers to - ⁇ 2 .
  • alkylamino refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom.
  • alkylamino substituents include monoalkylamino such as methylamino (exemplified by the
  • halogen refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -CI), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I).
  • the halogen is chlorine.
  • the halogen is a fluorine.
  • halo indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents.
  • haloalkyl refers to an alkyl that is substituted with at least one halogen substituent. Where more than one hydrogen is replaced with halogens, the halogens may be the identical or different.
  • haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl.
  • haloalkoxy refers to an alkoxy that is substituted with at least one halogen substituent.
  • haloalkoxy substituents include chloromethoxy, 1 -bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 2,2,2-trifluoroethoxy. It should be recognized that if a substituent is substituted by more than one halogen substituent, those halogen substituents may be identical or different (unless otherwise stated).
  • the prefix "perhalo" indicates that each hydrogen substituent on the substituent to which the prefix is attached is replaced with an independently selected halogen substituent. If all the halogen substituents are identical, the prefix may identify the halogen substituent. Thus, for example, the term “perfluoro” means that every hydrogen substituent on the substituent to which the prefix is attached is replaced with a fluorine substituent. To illustrate, the term “perfluoroalkyl” refers to an alkyl substituent wherein a fluorine substituent is in the place of each hydrogen substituent.
  • perfluoroalkyl substituents examples include trifluoromethyl (-CF 3 ), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl.
  • perfluoroalkoxy refers to an alkoxy substituent wherein each hydrogen substituent is replaced with a fluorine substituent.
  • perfluoroalkoxy substituents include trifluoromethoxy (-O-CF 3 ), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy.
  • oxy refers to an ether substituent, and may be depicted as -0-.
  • alkoxy refers to an alkyl linked to an oxygen, which may also be represented as -O-R, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
  • alkylthio means -S-alkyl.
  • methylthio is -S-CH 3 .
  • alkylthio include ethylthio, propylthio, butylthio, and hexylthio.
  • alkylcarbonyl means -C(0)-alkyl.
  • ethylcarbonyl may
  • alkylcarbonyl examples include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcabonyl, and hexylcarbonyl.
  • aminoalkylcarbonyl means -C(0)-alkyl-NH 2 .
  • aminomethylcarbonyl may be depicted as:
  • alkoxycarbonyl means -C(0)-0-alkyl.
  • ethoxycarbonyl means -C(0)-0-alkyl.
  • alkoxycarbonyl examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl.
  • the carbon atom of the carbonyl is attached to a carbon atom of a second alkyl, the resulting functional group is an ester.
  • thio and thia mean a divalent sulfur atom and such a substituent may be depicted as -S-.
  • a thioether is represented as "alkyl-thio-alkyl” or, alternatively, alkyl-S-alkyl.
  • thiol refers to a sulfhydryl substituent, and may be depicted as -SH.
  • alkyl-sulfonyl-alkyl refers to alkyl-S(0) 2 -alkyl.
  • alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
  • aminosulfonyl means -S(0) 2 -NH 2 , which also may be depicted
  • alkylsulfinylalkyl or “alkylsulfoxidoalkyl” refers to alkyl-S(0)-alkyl.
  • exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.
  • heterocycloalkyl refers to a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being
  • a heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (e.g., nitrogen, oxygen, or sulfur).
  • the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • heterocycloalkyl substituents that are fused to a Ce-Cio aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bound to a heteroatom of the
  • heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group.
  • the one or more substituents are each bound to a heteroatom of the
  • heteroaryl refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothioiuranyl, isobenzothioiuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzox
  • the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • heteroaryl also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.
  • heteroaryls examples include furanyl, dihydrofuranyl,
  • thiophenyl also known as "thiofuranyl"
  • dihydrothiophenyl tetrahydrothiophenyl
  • pyrrolyl isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiaediazolyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl,
  • oxadiazolyl also known as "azoximyl", 1 ,2,5-oxadiazolyl (also known as “furazanyl”), or 1 ,3,4-oxadiazolyl
  • oxatriazolyl including 1 ,2,3,4-oxatriazolyl or 1 ,2,3,5-oxatriazolyl
  • dioxazolyl including 1 ,2,3-dioxazolyl, 1 ,2,4-dioxazolyl, 1 ,3,2-dioxazolyl, or 1 ,3,4-dioxazolyl
  • oxathiazolyl oxathiolyl, oxathiolanyl
  • pyranyl including 1 ,2-pyranyl or 1 ,4-pyranyl
  • dihydropyranyl including 1 ,2-pyranyl or 1 ,4-pyranyl
  • dihydropyranyl including 1 ,2-pyranyl or 1
  • 1,3,5,2-oxadiazinyl 1,3,5,2-oxadiazinyl
  • morpholinyl 1,3,5,2-oxadiazinyl
  • azepinyl 1,3,5,2-oxadiazinyl
  • oxepinyl 1,3,5,2-oxadiazinyl
  • thiepinyl 1,3,5,2-oxadiazinyl
  • diazepinyl 1,3,5,2-oxadiazinyl
  • 2-fused-ring heteroaryls examples include, indolizinyl, pyrindinyl,
  • pyranopyrrolyl 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including
  • pyrido[3,4-b]-pyridinyl pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl
  • pteridinyl indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl,
  • quinazolinyl benzodiazinyl
  • benzopyranyl benzothiopyranyl
  • benzoxazolyl indoxazinyl, anthranilyl
  • benzodioxolyl benzodioxanyl
  • benzoxadiazolyl benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl,
  • benzotriazolyl benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.
  • 3-fused-ring heteroaryls or heterocycloalkyls include
  • fused-ring heteroaryls include benzo-fused heteroaryls such as indolyl, isoindolyl (also known as “isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (including quinolinyl (also known as “ 1 -benzazinyl”) or isoquinolinyl (also known as
  • 2-benzazinyl phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”) or quinazolinyl (also known as “1,3 -benzodiazinyl”)), benzopyranyl (including “chromanyl” or “isochromanyl”), benzothiopyranyl (also known as “thiochromanyl”), benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzothienyl (also known as “benzothiophenyl,” “thionaphthenyl,” or “benzothiofuranyl”), isobenzofur
  • benzimidazolyl benzotriazolyl
  • benzoxazinyl including 1 ,3,2-benzoxazinyl
  • heteroaryl also includes substituents such as pyridyl and quinolinyl that are fused to a C4-C10 carbocyclic ring, such as a C5 or a Ce carbocyclic ring, or to a 4-10- membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group.
  • the one or more substituents are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group.
  • ethylene refers to the group -CH 2 -CH 2 -
  • propylene refers to the group -CH 2 -CH 2 -CH 2 -
  • butylene refers to the group -CH 2 -CH 2 -CH 2 -CH 2 -
  • methylenoxy refers to the group -CH2-O-
  • methylenethioxy refers to the group -CH 2 -S-
  • ethylene refers to the group -CH 2 -CH 2 -
  • propylene refers to the group -CH 2 -CH 2 -CH 2 -
  • butylene refers to the group -CH 2 -CH 2 -CH 2 -CH 2 -
  • methylenoxy refers to the group -CH2-O-
  • methylenethioxy refers to the group -CH 2 -S-
  • methylenamino refers to the group -CH 2 -N(H)-
  • ethylenoxy refers to the group -CH 2 -CH 2 -0-
  • ethylenethioxy refers to the group - CH 2 -CH 2 -S-
  • ethylenamino refers to the group -CH 2 -CH 2 -N(H)-
  • a substituent is "substitutable” if it comprises at least one carbon, sulfur, oxygen or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition. If a substituent is described as being “substituted,” a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon, oxygen, sulfur or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated).
  • substituent may be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent.
  • One exemplary substituent may be depicted as -NR'R," wherein R' and R" together with the nitrogen atom to which they are attached, may form a heterocyclic ring.
  • the heterocyclic ring formed from R' and R" together with the nitrogen atom to which they are attached may be partially or fully saturated.
  • the heterocyclic ring consists of 3 to 7 atoms.
  • the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, pyridyl and thiazolyl.
  • substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions.
  • tetrazolyl which has only one
  • substitutable position would be optionally substituted with up to one non-hydrogen substituent.
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.
  • alkylcycloalkyl contains two moieties: alkyl and cycloalkyl.
  • a Ci-Ce- prefix on Ci-C6-alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C 6 - prefix does not describe the cycloalkyl moiety.
  • the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents.
  • compositions for preventing and/or treating a subject comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, and one or more pharmaceutically acceptable excipients.
  • a "pharmaceutically acceptable" excipient is one that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • the carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
  • the carrier can be a solid, a liquid, or both.
  • the disclosed compounds can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended.
  • the active compounds and compositions for example, can be administered orally, rectally, parenterally, ocularly, inhalationaly, or topically.
  • administration can be epicutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, vaginal, intravaginal, transvaginal, ocular, intraocular, transocular, enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular,
  • intracerebroventricular intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavernosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracisternal, epidural, peridural, intravitreal, etc.
  • Oral administration of a solid dose form can be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one of the disclosed compound or compositions.
  • the oral administration can be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of formula I are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets can contain a controlled-release formulation.
  • the dosage forms also can comprise buffering agents or can be prepared with enteric coatings.
  • oral administration can be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).
  • Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • compositions can comprise a parenteral dose form.
  • Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations e.g., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • an appropriate amount of a pharmaceutically acceptable carrier is used in the formulation to render the formulation isotonic.
  • the pharmaceutically acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution.
  • Other acceptable excipients include, but are not limited to, thickeners, diluents, buffers, preservatives, surface active agents and the like.
  • compositions can comprise a topical dose form.
  • Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation can include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds and compositions are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions.
  • Liposomes can also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the disclosed compound or composition is dissolved or suspended in suitable carrier.
  • a typical formulation suitable for ocular or aural administration can be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments,
  • biodegradable e.g. absorbable gel sponges, collagen
  • non-biodegradable e.g. silicone implants
  • wafers lenses
  • particulate or vesicular systems such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, can be incorporated together with a preservative, such as benzalkonium chloride.
  • Such formulations can also be delivered by iontophoresis.
  • compositions can be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3 rd Ed.), American Pharmaceutical Association, Washington, 1999.
  • the disclosed compounds can be used, alone or in combination with other therapeutic agents, in the treatment or prevention of various conditions or disease states.
  • the administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
  • the two or more compounds can be administered simultaneously, concurrently or sequentially.
  • compositions comprising an effective amount of a compound of the invention or a pharmaceutically accepted salt, solvate, clathrate, or prodrug thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions may further comprise additional agents. These compositions are useful for modulating the activity of ghrelin receptor, thus to improve the prevention and treatment of ghrelin receptor associated human diseases such as obesity and/or metabolic disorders.
  • the above-described compounds and compositions are useful for the inhibition, reduction, prevention, and/or treatment of diseases which are pathophysiologically modulated by the ghrelin receptor. Accordingly, in some forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the ghrelin receptor, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as disclosed above, or a pharmaceutically acceptable salt or adduct thereof.
  • Suitable subjects can include mammalian subjects. Mammals include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In some forms, humans are the subjects. Human subjects can be of either gender and at any stage of development.
  • Diseases modulated by the ghrelin receptor include obesity, overweight, eating disorder, diabetes, metabolic syndrome, cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, gastric disorder or substance abuse.
  • Metabolic disorders treatable by the instant methods include diabetes, Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease.
  • Gastric disorders treatable by the instant methods include post-operative ileus (POI), diabetic gastroparesis, and opioid induced bowel dysfunction.
  • Gastrointestinal diseases treatable by the instant methods include irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.
  • Substance abuse treatable by the instant methods includes alcohol and drug abuse, and said drug includes amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, and opioids.
  • the compound of Formula (I) is a ghrelin receptor modulator. In some other methods the compound of Formula (I) is a ghrelin receptor agonist. In some methods the compound of Formula (I) is a ghrelin receptor antagonist. In some methods, the compound of Formula (I) or a pharmaceutically acceptable salt or adduct thereof, is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration. In some other methods, administration is accomplished by administering an oral form of the compound of Formula (I) or a
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.01 microgram per Kg ⁇ g/Kg) body weight per day to about 100 mg/Kg body weight per day, or from about 0.1 ⁇ g /Kg/day to about 10 mg/Kg/day, or from about 1 ⁇ g /Kg /day to about 5 mg/ Kg /day, or from about 10 ⁇ /Kg/day to about 5 mg/Kg/day, or from about 100 ⁇ g /Kg/day to about 5 mg/Kg/day, or from about 500 ⁇ g /Kg/day to about 5 mg/Kg/day.
  • a ghrelin receptor agonist is any molecule that binds to and activates the Ghrelin receptor in the cells.
  • a ghrelin receptor antagonist is any molecule that binds to and inhibits the activity of Ghrelin receptor.
  • Obesity is a medic . aLconditipographn in which excess body . fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems.
  • Obesity treatment includes inducing weight loss, reducing bodyweight, reducing food intake, reducing appetite, increasing metabolic rate, reducing fat intake, reducing carbohydrate craving; or inducing satiety.
  • the obesity-related disorders herein are associated with, caused by, or result from obesity.
  • obesity-related disorders include overeating, binge eating, and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH- deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e g, children with acute lymphoblastic leukemia.
  • obesity-related disorders are metabolic syndrome, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer, nicotine addiction, substance addiction and alcoholism.
  • the compositions of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy,
  • a metabolic disorder is a disorder of metabolism, such as diabetes, Type 1 diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease.
  • Congestive heart failure is a condition in which the heart's function as a pump to deliver oxygen rich blood to the body is inadequate to meet the body's needs.
  • Congestive heart failure can be caused by diseases that weaken the heart muscle, or diseases that cause stiffening of the heart muscles, or diseases that increase oxygen demand by the body tissue beyond the capability of the heart to deliver. Many diseases can impair the pumping action of the ventricles. For example, the muscles of the ventricles can be weakened by heart attacks or infections (myocarditis). The diminished pumping ability of the ventricles due to muscle weakening is called systolic dysfunction. After each ventricular contraction (systole) the ventricle muscles need to relax to allow blood from the atria to fill the ventricles. This relaxation of the ventricles is called diastole.
  • diastolic dysfunction diseases such as hemochromatosis or amyloidosis can cause stiffening of the heart muscle and impair the ventricles' capacity to relax and fill; this is referred to as diastolic dysfunction.
  • the most common cause of this is longstanding high blood pressure resulting in a thickened (hypertrophied) heart.
  • the pumping action and filling capacity of the heart may be normal, abnormally high oxygen demand by the body's tissues (for example, with hyperthyroidism) may make it difficult for the heart to supply an adequate blood flow (called high output heart failure). In some patients one or more of these factors can be present to cause congestive heart failure.
  • Congestive heart failure can affect many organs of the body.
  • the weakened heart muscles may not be able to supply enough blood to the kidneys, which then begin to lose their normal ability to excrete salt (sodium) and water.
  • This diminished kidney function can cause to body to retain more fluid.
  • the lungs may become congested with fluid (pulmonary edema) and the person's ability to exercise is decreased. Fluid may likewise accumulate in the liver, thereby impairing its ability to rid the body of toxins and produce essential proteins.
  • the intestines may become less efficient in absorbing nutrients and medicines. Over time, untreated, worsening congestive heart failure will affect virtually every organ in the body.
  • Agonism action refers to the binding of a molecule to a receptor that leads to the activation of the receptor, thus triggering a cellular response similar to the cellular response for a known agonist for the receptor.
  • Antagonism action refers to the binding of a molecule to a receptor that leads to the inhibition of the receptor.
  • To modulate, or forms thereof, means either increasing, decreasing, or maintaining a cellular activity mediated through a cellular target. It is understood that wherever one of these words is used it is also disclosed that it could be 1%, 5%, 10%, 20%, 50%, 100%, 500%, or 1000% increased from a control, or it could be 1%, 5%, 10%, 20%, 50%, or 100% decreased from a control.
  • a “subject” is meant an individual.
  • the "subject” can include, for example, domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.) mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animal.
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, etc.
  • mammals non-human mammals
  • primates primates
  • non-human primates rodents
  • birds reptiles, amphibians, fish, and any other animal.
  • the subject can be a mammal such as a primate or a human.
  • the subject can also be a non-human.
  • treating or “treatment” is meant the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • active treatment that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder
  • causal treatment that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • reduced means relative to the state of the disease, including the molecular state of the disease, not just the physiological state of the disease.
  • a treatment can inadvertently cause harm.
  • palliative treatment that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder
  • preventative treatment that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder
  • supportive treatment that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • preventing refers to the ability of a compound or composition (such as the disclosed compounds and compositions) to prevent a disease identified herein in patients diagnosed as having the disease or who are at risk of developing such disease. In this context, preventing includes the delaying the onset of the disease relative to a control. These terms do not require that the treatment in fact be effective to produce any of the intended results. It is enough that the results are intended.
  • compositions used are of sufficient quantity to treat a subject as defined herein.
  • Toxicity is the degree to which a substance, molecule, is able to damage something, such as a cell, a tissue, an organ, or a whole organism, that has been exposed to the substance or molecule.
  • something such as a cell, a tissue, an organ, or a whole organism, that has been exposed to the substance or molecule.
  • the liver, or cells in the liver, hepatocytes can be damaged by certain substances.
  • the methods of the present invention are preferably nontoxic.
  • Step 3 132. To a mixture of lc (1.0 g, 6.1 mmol) and K 2 C0 3 (2.5 g, 18.3 mmol) in dry CH 3 CN (20 mL) was added CH 3 1 (0.95 g, 6.7 mmol) dropwise under N 2 atmosphere. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with brine, dried over anhydrous Na 2 S0 4 and concentrated. The residue was purified by column chromatography (silica, ethyl acetate/ petroleum ether 1 : 10, v:v) to provide compound Id (0.69 g, 81% yield).
  • Step l
  • Step 1
  • the intracellular calcium assay was carried out in a 384- well format FLIPRTM (Molecular Device) HEK293/GHSRl a cell line. Cells were seeded 24 hr prior to the experiments at an optimal density per well. Preincubation with selected calcium dye lasted for 30-60 min at room temperature or 37 °C. Test compounds, dissolved in DMSO, were added at the appropriate time and incubated for 15 min followed by the addition of ghrelin with FlexStation or FLIPR. Relative fluorescence was monitored by the FLIPRTM Molecular Device. EC50 and IC5 values were estimated from dose-response data using GraphPad Prism software.

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Abstract

Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the ghrelin receptor. The compounds have the general formula (I).

Description

ASYMMETRIC UREAS AND MEDICAL USES THEREOF
FIELD OF THE INVENTION
1. The present invention relates to novel compounds based on asymmetric ureas, and medical uses thereof, particularly in the treatment of medical conditions modulated by the ghrelin receptor.
BACKGROUND
2. The growth hormone secretagogue receptor (GHS-R) regulates a number of physiological processes, including growth hormone (GH) release, metabolism, and appetite. Ghrelin, a circulating hormone produced predominantly by endocrine cells in the stomach, is its endogenous ligand. Ghrelin is a 28 amino acid peptide with an acyl side chain required for biological activity (Kojima et al., Nature, 402, 656-660, 1999). Ghrelin has been shown to stimulate growth hormone (GH) release and to increase food intake when administered both centrally and peripherally (Wren et al., Endocrinology, 141, 4325-4328, 2000).
3. Endogenous levels of ghrelin rise on fasting and fall on re-feeding in humans (Cummings et al., Diabetes, 50, 1714-1719, 2001). Ghrelin also appears to play a role in maintaining long term energy balance and appetite regulation. Chronic administration of ghrelin in rodents leads to hyperphagia and weight gain that are independent of growth hormone secretion (Tschop et al., Nature, 407, 908-913, 2000). Circulating ghrelin levels decrease in response to chronic overfeeding and increase in response to chronic negative energy balance associated with anorexia or exercise. Obese people generally have low plasma ghrelin levels (Tschop et al., Diabetes, 50, 707-709, 2001) accordingly to the physiological response of the body in reducing calories intake. Intravenous ghrelin is effective in
stimulating food intake in humans. A recent study showed a 28% food intake increase from a buffet meal with a ghrelin infusion compared with saline control (Wren et al., J Clin
Endocrinology and Metabolism, 86, 5992, 2001).
4. In view of the above experimental evidence, compounds that modulate ghrelin receptor activity have been proposed for preventing and/or treating disorders associated with ghrelin receptor physiology. For example, antagonists at ghrelin receptor may reduce appetite, reduce food intake, induce weight loss and treat obesity without affecting or reducing the circulating growth hormone levels. On the other hand, agonists at ghrelin receptor may _be useful in stimulating food intake and thus be useful in treating eating disorders, for example anorexia nervosa, or in treating cachexia resulting from cancer, AIDS or Chronic Obstructive Pulmonary Disease (COPD). Ghrelin agonists may also be useful as gastropfokinetic agents which can enhance gastrointestinal motility by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm.
Gastroprokinetic agents are used to relieve gastrointestinal symptoms such as abdominal discomfort, bloating, constipation, heart burn, nausea, and vomiting, and are used to treat a number of gastrointestinal disorders, including but not limiting to, irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia. Furthermore, compounds that modulate ghrelin receptor activity can also be used to prevent or treat diseases related to substance abuse, for example, alcohol or drug (e.g., amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, and opioids) abuse, which refers to a maladaptive pattern of use of a substance that is not considered dependent.
5. A number of compounds acting on the ghrelin receptor have been reported in the literature. YIL-781 , for example, is a small molecule ghrelin receptor antagonist from Bayer that reportedly improves glucose tolerance, suppress appetite and promote weigh loss (Esler et al., Endocrinology 148 (1 1): 5175-5185); LY44471 1 is an orally active ghrelin receptor agonist from Lilly that reportedly induces adiposity by stimulating food consumption and sparing fat utilization (Bioorg. & Med. Chem. Lett., 2004, 14, 5873-5876); Anamorelin is an orally available ghrelin receptor small molecule agonist from Helsinn Therapeutics that is in clinical trials for the treatment of anorexia and cachexia in cancer patients. Other small molecule ghrelin receptor modulators can be found in WO 2008/092681, US 2009/0253673, WO 2008/148853, WO 2008/148856, US 2007/0270473 and US 2009/0186870.
6. In view of the above, it is desirable to find new compounds which modulate ghrelin receptor activity with enhanced efficacy and fewer undesirable side effects.
SUMMARY
7. In view of the foregoing, the inventors have developed a novel class of compounds particularly well-suited for modulating the ghrelin receptor and having the general formula (I):
Figure imgf000004_0001
Formula (I)
with R and R1-R14 as defined herein, and pharmaceutically acceptable salts or adducts thereof.
8. Compounds of formula (I), also known as asymmetric ureas, are particularly useful for preventing and/or treating diseases that are pathophysiologically related to the ghrelin receptor in a subject. Accordingly, in another embodiment the invention provides a method of treating a disease that is mediated by the ghrelin receptor, comprising administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof.
9. Also disclosed are pharmaceutical compositions for preventing and/or treating diseases which are pathophysiologically related to ghrelin receptor in a subject, comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, and one or more pharmaceutically acceptable excipients.
DETAILED DESCRIPTION
10. Before the present compounds, compositions, articles, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods or specific treatment methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
Materials
. Compounds
1 1. Disclosed are compounds, and pharmaceutically acceptable salts or adducts thereof, represented by formula (1):
Figure imgf000005_0001
Formula (I)
wherein:
R is selected from the group consisting of aryl, arylalkyl, carbocyclic ring,
heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, optionally substituted with one or more independent R103 substituents;
12. Ri and R2 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, - C(0)R101, -C(0)OR101, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more independent R103 substituents; or Ri and R2, together with the atoms connecting the same, form a fused or non- fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R103 substituents;
13. R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R101, -C(0)OR101, -C(O)NR,01R102, -S(0)2R102 , -SR101 and -S(O)2NR101R102, optionally substituted with one or more independent R103 substituents;
14. R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -OR103,
NR101R102, -C(0)R101, -C(O)OR10], -C(O)NR101R102, -alkyl U101R102, -S(0)2R10 , -SR101 and -S(O)2NR101R102, optionally substituted with one or more independent R103 substituents; or R3 and R4, together with the atoms connecting R3 and R4, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R103 substituents;
15. R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, oxide (=0), -C(0)R101, -C(0)OR101, -C(O)NR101R102, -S(0)2R102 , -SR101 and -S(O)2NR101R102, optionally substituted with one or more independent R103 substituents;
16. R<5, R7, R8, R9, Rio, R1 1, Ri2, R13 and Ru are each independently selected from the group consisting of hydrogen, cyano, -N02, -OR101, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R101, -C(0)OR101, -C(O)NRI0 IR102, - R101R,02, - R101S(O)2R102, -NR101C(O)R102, -S(0)2R10 , -SR101 and -S(O)2NR101R102, each optionally independently substituted with one or more independent R103 substituents; or any two or more substituents selected from the group consisting of Rt, R7, R8, R9, Rio, Rn, Ri2, Ri3 and R14 together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R103 substituents; and
17. R101, R102 and R103 are each independently selected from the group consisting of hydrogen, cyano, -N02, -OR101, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R101, -C(0)OR101, -C(O) R101R102, -NR101R102, -NR101S(O)2R102, -NR101C(O)R102, - S(0)2R102 , -SR101 and -S(O)2NR101R102, each optionally independently substituted with one or more independent R103 substituents; or R101, R102, together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R103 substituents.
18. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R is aryl or heteroaryl. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R is R is selected from the group consisting of phenyl, naphthalene, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl, fluorenyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl, which is optionally independently substituted with from one to six substituents independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkyl, cyano, -N02, -OR101, hydroxy, amino, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R101, -C(0)OR101, -C(O)NR,01R102, -NR10,R102, -NR101S(O)2R102, -NR101C(O)R102, -S(0)2R102 , - SR101 and -S(O)2NR101R102.
19. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R is phenyl or naphthalene which is optionally independently substituted with from one to six substituents independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, trifluoromethyl, cyano, methoxy, ethoxy, methyl and ethyl.
20. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Ri and R2 are not both hydrogen; or R] and R2, together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Ri is selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, -OR101, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and
heteroarylalkyl. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Rj is selected from the group consisting of alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl and heteroarylalkyl. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Rj is selected from the group consisting of methyl, -CH2OH, and -CH2-0-CH2-phenyl.
21. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R2 is hydrogen, alkyl or cycloalkyl. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R3 is hydrogen, alkyl or cycloalkyl. 22. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R4 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amino, alkoxy, alkylamino, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and aminoalkyl. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R4 is methyl, ethyl, benzyl, or benzyl substituted with from one to five substituents independently selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl, methoxy, cyano and hydroxy.
23. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, oxide (=0), aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R101, -C(0)OR101 and -C(O)NR101R102 In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R5 is methyl.
24. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R6, R7, Rs, R9, Rio, R1 1, R12, R13 and RH are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, , -C(0)OR101, and -alkylOR103.. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R8 and R9 are each independently hydrogen, alkyl, cycloalkyl, -C(0)OR101, or -alkylOR103. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Rg and R9 are each independently hydrogen, methyl, ethyl, -C(=0)OEt, or -CH2OH. In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Rg and R9, together with the atom connecting them, form a cycloalkyl ring. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein said cycloalkyl ring as formed by R8 and R9 together with the atom connecting them, is cyclopropane. 25. In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein the compound of formula (I) is a compound selected from the group consisting of:
-
1■
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
- -
Figure imgf000014_0001
met ypper ne- -car oxyate,
Figure imgf000015_0001
Figure imgf000016_0001
Me^Me yl)ethyl)urea,
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Me ^^ H u ^ yl)urea,
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Me H \^ ( 1 -methylpiperidin-4-yl)urea,
Figure imgf000030_0001
Figure imgf000031_0001
OMeH U ( 1 -methylpiperidin-4-yl)urea,
Figure imgf000032_0001
^ -NAN H-V ΙΛΟ CI ΜΘ ( 1 -methylpiperidin-4-yl)urea,
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
methylpiperidin-4-yl)urea.
1. Isomers
26. When an asymmetric center is present in a compound of formula (I), hereinafter referred to as the disclosed compounds, the compound may exist in the form of optical isomers (enantiomers). In some forms, the disclosed compounds and compositions can comprise enantiomers and mixtures, including racemic mixtures of the compounds of formula (I). In some forms, for compounds of formula (I) that contain more than one asymmetric center, the disclosed compounds and compositions can comprise diastereomeric forms (individual diastereomers and mixtures thereof) of compounds. When a compound of formula (I) contains an alkenyl group or moiety, geometric isomers may arise.
2. Tautomeric Forms 27. The disclosed compositions and compounds comprise the tautomeric forms of compounds of formula (I). Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. The various ratios of the tautomers in solid and liquid form are dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound. 3. Salts
28. The disclosed compositions and compounds can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound can be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also can be used as an aid in the isolation, purification, and/or resolution of the compound.
29. Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound, such as the disclosed compounds, with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the disclosed methods because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the disclosed compounds are non-toxic "pharmaceutically acceptable salts." Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the disclosed compounds which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
30. Suitable pharmaceutically acceptable acid addition salts of the disclosed compounds, when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and
trifluoroacetic acids. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclylic, carboxylic, and sulfonic classes of organic acids.
31. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
32. Furthermore, where the disclosed compounds carry an acidic moiety, suitable pharmaceutically acceptable salts thereof can include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., copper, calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In some forms, base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine,
tromethamine and zinc salts.
33. Organic salts can be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, Ν,Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( -methylglucamine), and procaine. Basic nitrogenrcontaining groups can be quaternized with agents such as lower alkyl (C1-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others. In some forms, hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. The disclosed compounds can exist in both unsolvated and solvated forms. A "solvate" as used herein is a nonaqueous solution or dispersoid in which there is a noncovalent or easily dispersible combination between solvent and solute, or dispersion means and disperse phase.
4. Adducts
34. Also disclosed are so-called "adducts" of the disclosed compounds. An representive type of adduct can be Lewis acid adduct. Lewis acid is a molecular entity (and the corresponding chemical species) that is an electron-pair acceptor and therefore able to react with a Lewis base to form a Lewis adduct, by sharing the electron pair furnished by the Lewis base. An illustrative example is given by the reaction of trimethylboron and ammonia to give the adduct Me3BNH3. Typical Lewis acids are boron trihalides, for example, boron trifluoride. Thus, the disclosed compounds encompass boron trihalides adduct, for example, boron trifluoride adduct.
5. Isotopes
35. Also disclosed are isotopically labeled compounds, which are identical to those compounds recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, I3C, nC, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36C1, respectively. Disclosed compounds, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are contemplated. Certain isotopically labeled disclosed compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon- 14, i.e. , 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula (I) (and other disclosed compounds) and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. 6. General Synthetic Schemes
36. The compounds of the formula (I) (and other disclosed compounds), or their pharmaceutically acceptable salts or adducts, can be prepared by the methods as illustrated by examples described in the "Examples" section, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or can be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the Compendium of Organic Synthesis Methods, Vol. I-VI (published by Wiley-Interscience)). Preferred methods include, but are not limited to, those described below. During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W.
Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, and P. G. M. Wuts and T.W.Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 2006, which are hereby incorporated by reference. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.
7. Definition of Terms
37. The term "alkyl" refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; in one embodiment from one to twelve carbon atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms.
Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like.
38. The term "alkenyl" refers to a linear or branched-chain hydrocarbyl substituent containing one or more double bonds and from two to twenty carbon atoms; in another embodiment, from two to twelve carbon atoms; in another embodiment, from two to six carbon atoms; and in another embodiment, from two to four carbon atoms. Examples of alkenyl include ethenyl (also known as vinyl), allyl, propenyl (including 1-propenyl and 2- propenyl) and butenyl (including 1 -buteny], 2-butenyl and 3-butenyl). The term "alkenyl" embraces substituents having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.
39. The term "benzyl" refers to methyl radical substituted with phenyl, i.e., the
following structure:
Figure imgf000040_0001
40. The term "carbocyclic ring" refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to form the ring). A carbocyclic ring typically contains from 3 to 10 carbon ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A "carbocyclic ring system" alternatively may be 2 or 3 rings fused together, such as naphthalenyl,
tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl, indanyl,
bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as "phenalenyl"), fluorenyl, and decalinyl.
41. The term "heterocyclic ring" refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 ring atoms ("ring atoms" are the atoms bound together to form the ring), in which at least one of the ring atoms is a heteroatom that is oxygen, nitrogen, or sulfur, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
42. The term "cycloalkyl" refers to a saturated carbocyclic substituent having three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
43. The term "cycloalkyl" also includes substituents that are fused to a C6-C10 aromatic ring or to a 5- 10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group. When such a fused cycloalkyl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a carbon atom of the cycloalkyl group. The fused C6-CJO aromatic ring or to a 5- 10-membered heteroaromatic ring may be optionally substituted with halogen, C1-C6 alkyl, C3-C10 cycloalkyl, or =0.
44. The term "cycloalkenyl" refers to a partially unsaturated carbocyclic substituent having three to fourteen carbon atoms, typically three to ten carbon atoms. Examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
45. A cycloalkyl or cycloalkenyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. Alternatively, 2 or 3 rings may be fused together, such as bicyclodecanyl and decalinyl.
46. The term "aryl" refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms. The term "aryl" may refer to substituents such as phenyl, naphthyl and anthracenyl. The term "aryl" also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C4-C10 carbocyclic ring, such as a C5 or a C6 carbocyclic ring, or to a 4- 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group. The fused C4-C10 carbocyclic or 4- 10-membered heterocyclic ring may be optionally substituted with halogen, C)-C6 alkyl, C3-C10 cycloalkyl, or =0. Examples of aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as "phenalenyl"), and fluorenyl.
47. In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix "Cx-Cy-," wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Ci-Ce-alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C3-C6-cycloalkyl refers to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.
48. In some instances, the number of atoms in a cyclic substituent containing one or more heteroatoms (e.g., heteroaryl or heterocycloalkyl) is indicated by the prefix "X-Y- membered", wherein wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent. Thus, for example, 5-8-membered
heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one ore more heteroatoms, in the cyclic moiety of the heterocycloalkyl.
49. The term "hydrogen" refers to hydrogen substituent, and may be depicted as -H.
50. The term "hydroxy" refers to -OH. When used in combination with another term(s), the prefix "hydroxy" indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phenol.
51. The term "hydroxyalkyl" refers to an alkyl that is substituted with at least one hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
52. The term "nitro" means -N02.
53. The term "cyano" (also referred to as "nitrile") -CN, which also may be
N
C depicted:
54. The term "carbonyl" means -C(0)-, which also may be depicted as:
Figure imgf000042_0001
55. The term "amino" refers to -ΝΉ2.
56. The term "alkylamino" refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom. Examples of alkylamino substituents include monoalkylamino such as methylamino (exemplified by the
formula -NH(CH3)), which may also be depicted:
Figure imgf000042_0002
and dialkylamino dimeth lamino, (exemplified by the formula -N(CH3)2), which may also be depicted.
Figure imgf000042_0003
57. The term "aminocarbonyl" means -C(0)-NH2, which also may be depicted
Figure imgf000043_0001
58. The term "halogen" refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -CI), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is a fluorine.
59. The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents. For example, haloalkyl refers to an alkyl that is substituted with at least one halogen substituent. Where more than one hydrogen is replaced with halogens, the halogens may be the identical or different. Examples of haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl. Illustrating further, "haloalkoxy" refers to an alkoxy that is substituted with at least one halogen substituent. Examples of haloalkoxy substituents include chloromethoxy, 1 -bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 2,2,2-trifluoroethoxy. It should be recognized that if a substituent is substituted by more than one halogen substituent, those halogen substituents may be identical or different (unless otherwise stated).
60. The prefix "perhalo" indicates that each hydrogen substituent on the substituent to which the prefix is attached is replaced with an independently selected halogen substituent. If all the halogen substituents are identical, the prefix may identify the halogen substituent. Thus, for example, the term "perfluoro" means that every hydrogen substituent on the substituent to which the prefix is attached is replaced with a fluorine substituent. To illustrate, the term "perfluoroalkyl" refers to an alkyl substituent wherein a fluorine substituent is in the place of each hydrogen substituent. Examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl. To illustrate further, the term "perfluoroalkoxy" refers to an alkoxy substituent wherein each hydrogen substituent is replaced with a fluorine substituent. Examples of perfluoroalkoxy substituents include trifluoromethoxy (-O-CF3), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy.
61. The term "oxo" refers to =0.
62. The term "oxy" refers to an ether substituent, and may be depicted as -0-.
63. The term "alkoxy" refers to an alkyl linked to an oxygen, which may also be represented as -O-R, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
64. The term "alkylthio" means -S-alkyl. For example, "methylthio" is -S-CH3. Other examples of alkylthio include ethylthio, propylthio, butylthio, and hexylthio.
65. The term "alkylcarbonyl" means -C(0)-alkyl. For example, "ethylcarbonyl" may
be depicted as:
Figure imgf000044_0001
. Examples of other alkylcarbonyl include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcabonyl, and hexylcarbonyl.
66. The term "aminoalkylcarbonyl" means -C(0)-alkyl-NH2. For example,
"aminomethylcarbonyl" may be depicted as:
Figure imgf000044_0002
67. The term "alkoxycarbonyl" means -C(0)-0-alkyl. For example, "ethoxycarbonyl"
may be depicted as:
Figure imgf000044_0003
. Examples of other alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl. In another embodiment, where the carbon atom of the carbonyl is attached to a carbon atom of a second alkyl, the resulting functional group is an ester.
68. The terms "thio" and "thia" mean a divalent sulfur atom and such a substituent may be depicted as -S-. For example, a thioether is represented as "alkyl-thio-alkyl" or, alternatively, alkyl-S-alkyl.
69. The term "thiol" refers to a sulfhydryl substituent, and may be depicted as -SH.
70. The term "thione" refers to =S. 71. The term "sulfonyl" refers to -S(0)2-, which also may be depicted as
Figure imgf000045_0001
Thus, for example, "alkyl-sulfonyl-alkyl" refers to alkyl-S(0)2-alkyl. Examples of
alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
erm "aminosulfonyl" means -S(0)2-NH2, which also may be depicted
Figure imgf000045_0002
73. The term "sulfmyl" or "su!foxido" means -S(O)-, which also may be depicted as:
Figure imgf000045_0003
74. Thus, for example, "alkylsulfinylalkyl" or "alkylsulfoxidoalkyl" refers to alkyl-S(0)-alkyl. Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.
75. The term "heterocycloalkyl" refers to a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being
independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (e.g., nitrogen, oxygen, or sulfur). In a group that has a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heterocycloalkyl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. 76. The term "heterocycloalkyl" also includes substituents that are fused to a Ce-Cio aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bound to a heteroatom of the
heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one more substituents, the one or more substituents, unless otherwise specified, are each bound to a heteroatom of the
heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group. The fused C6-C 10 aromatic ring or to a 5-10-membered heteroaromatic ring may be optionally substituted with halogen, Ci-Ce alkyl, C3-C 10 cycloalkyl, or =0.
77. The term "heteroaryl" refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothioiuranyl, isobenzothioiuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl. In a group that has a heteroaryl substituent, the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. The term "heteroaryl" also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.
78. Examples of single-ring heteroaryls include furanyl, dihydrofuranyl,
tetradydrofuranyl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiaediazolyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl,
1.2.4- oxadiazolyl (also known as "azoximyl"), 1 ,2,5-oxadiazolyl (also known as "furazanyl"), or 1 ,3,4-oxadiazolyl), oxatriazolyl (including 1 ,2,3,4-oxatriazolyl or 1 ,2,3,5-oxatriazolyl), dioxazolyl (including 1 ,2,3-dioxazolyl, 1 ,2,4-dioxazolyl, 1 ,3,2-dioxazolyl, or 1 ,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1 ,2-pyranyl or 1 ,4-pyranyl), dihydropyranyl, pyridinyl (also known as "azinyl"), piperidinyl, diazinyl (including pyridazinyl (also known as " 1 ,2-diazinyl"), pyrimidinyl (also known as " 1 ,3 -diazinyl" or "pyrimidyl"), or pyrazinyl (also known as " 1 ,4-diazinyl")), piperazinyl, triazinyl (including s-triazinyl (also known as " 1 ,3, 5 -triazinyl"), as-triazinyl (also known 1 ,2,4-triazinyl), and v-triazinyl (also known as " 1 ,2, 3-triazinyl")), oxazinyl (including 1 ,2,3-oxazinyl, 1 ,3,2-oxazinyl, 1 ,3,6-oxazinyl (also known as "pentoxazolyl"), 1 ,2,6-oxazinyl, or 1 ,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including
1.2.5- oxathiazinyl or 1 ,2,6-oxathiazinyl), oxadiazinyl (including 1 ,4,2-oxadiazinyl or
1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
79. Examples of 2-fused-ring heteroaryls include, indolizinyl, pyrindinyl,
pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including
pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl,
quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl,
benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.
80. Examples of 3-fused-ring heteroaryls or heterocycloalkyls include
5,6-dihydro-4H-imidazo[4,5, l -ij]quinoline, 4,5-dihydroimidazo[4,5, l -hi]indole,
4,5,6,7-tetrahydroimidazo[4,5, l -jk][ l ]benzazepine, and dibenzofuranyl.
81. Other examples of fused-ring heteroaryls include benzo-fused heteroaryls such as indolyl, isoindolyl (also known as "isobenzazolyl" or "pseudoisoindolyl"), indoleninyl (also known as "pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl"), benzazinyl (including quinolinyl (also known as " 1 -benzazinyl") or isoquinolinyl (also known as
"2-benzazinyl")), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as "1,2-benzodiazinyl") or quinazolinyl (also known as "1,3 -benzodiazinyl")), benzopyranyl (including "chromanyl" or "isochromanyl"), benzothiopyranyl (also known as "thiochromanyl"), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl," "thionaphthenyl," or "benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl,"
"isothionaphthenyl," or "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl,
benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1 ,3,2-benzoxazinyl ,
1 ,4,2-benzoxazinyl , 2,3, 1 -benzoxazinyl , or 3, 1,4-benzoxazinyl ), benzisoxazinyl (including 1,2-benzisoxazinyl or 1 ,4-benzisoxazinyl), tetrahydroisoquinolinyl , carbazolyl, xanthenyl, and acridinyl.
82. The term "heteroaryl" also includes substituents such as pyridyl and quinolinyl that are fused to a C4-C10 carbocyclic ring, such as a C5 or a Ce carbocyclic ring, or to a 4-10- membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. When such a fused heteroaryl group is substituted with one more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. The fused C4-C10 carbocyclic or 4- 10-membered heterocyclic ring may be optionally substituted with halogen, Ci-Ce alkyl, C3- C10 cycloalkyl, or =0.
83. The term "ethylene" refers to the group -CH2-CH2- The term "ethynelene" refers to the group -CH=CH- The term "propylene" refers to the group -CH2-CH2-CH2- The term "butylene" refers to the group -CH2-CH2-CH2-CH2- The term "methylenoxy" refers to the group -CH2-O- The term "methylenethioxy" refers to the group -CH2-S- The term
"methylenamino" refers to the group -CH2-N(H)- The term "ethylenoxy" refers to the group -CH2-CH2-0- The term "ethylenethioxy" refers to the group - CH2-CH2-S- The term "ethylenamino" refers to the group -CH2-CH2-N(H)-
84. A substituent is "substitutable" if it comprises at least one carbon, sulfur, oxygen or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition. If a substituent is described as being "substituted," a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon, oxygen, sulfur or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated).
85. If a substituent is described as being "optionally substituted," the substituent may be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent. One exemplary substituent may be depicted as -NR'R," wherein R' and R" together with the nitrogen atom to which they are attached, may form a heterocyclic ring. The heterocyclic ring formed from R' and R" together with the nitrogen atom to which they are attached may be partially or fully saturated. In one embodiment, the heterocyclic ring consists of 3 to 7 atoms. In another embodiment, the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, pyridyl and thiazolyl.
86. This specification uses the terms "substituent," "radical," and "group"
interchangeably. If a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one
substitutable position) would be optionally substituted with up to one non-hydrogen substituent. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.
87. A prefix attached to a multi-moiety substituent only applies to the first moiety. To illustrate, the term "alkylcycloalkyl" contains two moieties: alkyl and cycloalkyl. Thus, a Ci-Ce- prefix on Ci-C6-alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C6- prefix does not describe the cycloalkyl moiety. To illustrate further, the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents. If the halogen substitution may only occur on the alkyl moiety, the substituent would be described as "alkoxyhaloalkyl." If the halogen substitution may occur on both the alkyl moiety and the alkoxy moeity, the substituent would be described as "haloalkoxyhaloalkyl."
88. When a substituent is comprised of multiple moieties, unless otherwise indicated, it is the intention for the final moiety to serve as the point of attachment to the remainder of the molecule. For example, in a substituent A-B-C, moiety C is attached to the remainder of the molecule. In a substituent A-B-C-D, moiety D is attached to the remainder of the molecule. Similarly, in a substituent aminocarbonylmethyl, the methyl moiety is attached to the remainder of the molecule, where the substituent may also be be depicted as
Figure imgf000050_0001
In a substituent trifluoromethylaminocarbonyl, the carbonyl moiety is attached to the remainder of the molecule, where the substituent may also be depicted as
Figure imgf000051_0001
89. If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
. Pharmaceutical Compositions
90. Pharmaceutical compositions for preventing and/or treating a subject are further provided comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, and one or more pharmaceutically acceptable excipients.
91. A "pharmaceutically acceptable" excipient is one that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. The carrier can be a solid, a liquid, or both.
92. The disclosed compounds can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended. The active compounds and compositions, for example, can be administered orally, rectally, parenterally, ocularly, inhalationaly, or topically. In particular, administration can be epicutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, vaginal, intravaginal, transvaginal, ocular, intraocular, transocular, enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular,
intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavernosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracisternal, epidural, peridural, intravitreal, etc.
93. Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA, 1995. Oral administration of a solid dose form can be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one of the disclosed compound or compositions. In some forms, the oral administration can be in a powder or granule form. In some forms, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of formula I are ordinarily combined with one or more adjuvants. Such capsules or tablets can contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents or can be prepared with enteric coatings.
94. In some forms, oral administration can be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
95. In some forms, the disclosed compositions can comprise a parenteral dose form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. . Typically, an appropriate amount of a pharmaceutically acceptable carrier is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. Other acceptable excipients include, but are not limited to, thickeners, diluents, buffers, preservatives, surface active agents and the like.
96. In some forms, the disclosed compositions can comprise a topical dose form. "Topical administration" includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation can include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds and compositions are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan
(October 1999).
97. Formulations suitable for topical administration to the eye include, for example, eye drops wherein the disclosed compound or composition is dissolved or suspended in suitable carrier. A typical formulation suitable for ocular or aural administration can be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments,
biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, can be incorporated together with a preservative, such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.
98. Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The disclosed pharmaceutical compositions can be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.
99. The disclosed compounds can be used, alone or in combination with other therapeutic agents, in the treatment or prevention of various conditions or disease states. The administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds can be administered simultaneously, concurrently or sequentially.
100. Disclosed are pharmaceutical compositions comprising an effective amount of a compound of the invention or a pharmaceutically accepted salt, solvate, clathrate, or prodrug thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions may further comprise additional agents. These compositions are useful for modulating the activity of ghrelin receptor, thus to improve the prevention and treatment of ghrelin receptor associated human diseases such as obesity and/or metabolic disorders.
Methods
101. All of the methods of the invention may be practiced with a compound of the invention alone, or in combination with other agents.
. Treating
102. The above-described compounds and compositions are useful for the inhibition, reduction, prevention, and/or treatment of diseases which are pathophysiologically modulated by the ghrelin receptor. Accordingly, in some forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the ghrelin receptor, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as disclosed above, or a pharmaceutically acceptable salt or adduct thereof.
103. Suitable subjects can include mammalian subjects. Mammals include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In some forms, humans are the subjects. Human subjects can be of either gender and at any stage of development.
104. Diseases modulated by the ghrelin receptor, and treatable by the methods disclosed herein, include obesity, overweight, eating disorder, diabetes, metabolic syndrome, cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, gastric disorder or substance abuse. Metabolic disorders treatable by the instant methods include diabetes, Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease. Gastric disorders treatable by the instant methods include post-operative ileus (POI), diabetic gastroparesis, and opioid induced bowel dysfunction. Gastrointestinal diseases treatable by the instant methods include irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia. Substance abuse treatable by the instant methods includes alcohol and drug abuse, and said drug includes amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, and opioids.
105. In some methods the compound of Formula (I) is a ghrelin receptor modulator. In some other methods the compound of Formula (I) is a ghrelin receptor agonist. In some methods the compound of Formula (I) is a ghrelin receptor antagonist. In some methods, the compound of Formula (I) or a pharmaceutically acceptable salt or adduct thereof, is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration. In some other methods, administration is accomplished by administering an oral form of the compound of Formula (I) or a
pharmaceutically acceptable salt or adduct thereof.
106. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.01 microgram per Kg ^g/Kg) body weight per day to about 100 mg/Kg body weight per day, or from about 0.1 μg /Kg/day to about 10 mg/Kg/day, or from about 1 μg /Kg /day to about 5 mg/ Kg /day, or from about 10 § /Kg/day to about 5 mg/Kg/day, or from about 100 μg /Kg/day to about 5 mg/Kg/day, or from about 500 μg /Kg/day to about 5 mg/Kg/day.
107. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of a compound of Formula I for a given disease. In some other forms, disclosed are methods of preventing and/or treating a subject, further comprising one or more therapeutic agents.
. More Definitions of Terms
108. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.
1. A, an, the
109. As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.
2. Abbreviations
1 10. Abbreviations, which are well known to one of ordinary skill in the art, may be used (e.g., "h" or "hr" for hour or hours, "g" or "gm" for gram(s), "mL" for milliliters, and "rt" for room temperature, "nm" for nanometers, "M" for molar, and like abbreviations).
3. About
1 1 1. The term "about," when used to modify the quantity of an ingredient in a composition, concentrations, volumes, process temperature, process time, yields, flow rates, pressures, and like values, and ranges thereof, employed in describing the embodiments of the disclosure, refers to variation in the numerical quantity that can occur, for example, through typical measuring and handling procedures used for making compounds, compositions, concentrates or use formulations; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of starting materials or ingredients used to carry out the methods; and like considerations. The term "about" also encompasses amounts that differ due to aging of a composition or formulation with a particular initial concentration or mixture, and amounts that differ due to mixing or processing a composition or formulation with a particular initial concentration or mixture. Whether modified by the term "about" the claims appended hereto include equivalents to these quantities. 4. Comprise
1 12. Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises," means "including but not limited to," and is not intended to exclude, for example, other additives, components, integers or steps.
5. Ghrelin receptor agonist
A ghrelin receptor agonist is any molecule that binds to and activates the Ghrelin receptor in the cells.
6. Ghrelin receptor antagonist
1 13. A ghrelin receptor antagonist is any molecule that binds to and inhibits the activity of Ghrelin receptor.
7. pathophysiological!) mediated to ghrelin receptor
1 14. Something is "pathophysiologically mediated by the ghrelin receptor" if the ghrelin receptor is involved in the functional changes in body associated with or resulting from disease or injury.
8. Obesity
1 15. Obesity is a medic.aLconditip„n in which excess body. fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Obesity treatment includes inducing weight loss, reducing bodyweight, reducing food intake, reducing appetite, increasing metabolic rate, reducing fat intake, reducing carbohydrate craving; or inducing satiety. The obesity-related disorders herein are associated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating, binge eating, and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH- deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer, nicotine addiction, substance addiction and alcoholism. The compositions of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy,
9. metabolic disorder
1 16. A metabolic disorder is a disorder of metabolism, such as diabetes, Type 1 diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease.
10. congestive heart failure
1 17. Congestive heart failure (CHF) is a condition in which the heart's function as a pump to deliver oxygen rich blood to the body is inadequate to meet the body's needs.
Congestive heart failure can be caused by diseases that weaken the heart muscle, or diseases that cause stiffening of the heart muscles, or diseases that increase oxygen demand by the body tissue beyond the capability of the heart to deliver. Many diseases can impair the pumping action of the ventricles. For example, the muscles of the ventricles can be weakened by heart attacks or infections (myocarditis). The diminished pumping ability of the ventricles due to muscle weakening is called systolic dysfunction. After each ventricular contraction (systole) the ventricle muscles need to relax to allow blood from the atria to fill the ventricles. This relaxation of the ventricles is called diastole. Diseases such as hemochromatosis or amyloidosis can cause stiffening of the heart muscle and impair the ventricles' capacity to relax and fill; this is referred to as diastolic dysfunction. The most common cause of this is longstanding high blood pressure resulting in a thickened (hypertrophied) heart. Additionally, in some patients, although the pumping action and filling capacity of the heart may be normal, abnormally high oxygen demand by the body's tissues (for example, with hyperthyroidism) may make it difficult for the heart to supply an adequate blood flow (called high output heart failure). In some patients one or more of these factors can be present to cause congestive heart failure. Congestive heart failure can affect many organs of the body. For example, the weakened heart muscles may not be able to supply enough blood to the kidneys, which then begin to lose their normal ability to excrete salt (sodium) and water. This diminished kidney function can cause to body to retain more fluid. The lungs may become congested with fluid (pulmonary edema) and the person's ability to exercise is decreased. Fluid may likewise accumulate in the liver, thereby impairing its ability to rid the body of toxins and produce essential proteins. The intestines may become less efficient in absorbing nutrients and medicines. Over time, untreated, worsening congestive heart failure will affect virtually every organ in the body.
11. agonism action
1 18. Agonism action refers to the binding of a molecule to a receptor that leads to the activation of the receptor, thus triggering a cellular response similar to the cellular response for a known agonist for the receptor.
12. antagonism action
1 19. Antagonism action refers to the binding of a molecule to a receptor that leads to the inhibition of the receptor.
13. Modulate
120. To modulate, or forms thereof, means either increasing, decreasing, or maintaining a cellular activity mediated through a cellular target. It is understood that wherever one of these words is used it is also disclosed that it could be 1%, 5%, 10%, 20%, 50%, 100%, 500%, or 1000% increased from a control, or it could be 1%, 5%, 10%, 20%, 50%, or 100% decreased from a control.
14. Optional
121. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
15. Or
122. The word "or" or like terms as used herein means any one member of a particular list and also includes any combination of members of that list. 16. Publications
123. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.
17. Subject
124. As used throughout, by a "subject" is meant an individual. Thus, the "subject" can include, for example, domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.) mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animal. The subject can be a mammal such as a primate or a human. The subject can also be a non-human.
18. Treating
125. By "treating" or "treatment" is meant the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. These terms include active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. These terms can mean that the symptoms of the underlying disease are reduced, and/or that one or more of the underlying cellular,
physiological, or biochemical causes or mechanisms causing the symptoms are reduced. It is understood that reduced, as used in this context, means relative to the state of the disease, including the molecular state of the disease, not just the physiological state of the disease. In certain situations a treatment can inadvertently cause harm. In addition, these terms include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. These terms mean both treatment having a curing or alleviating purpose and treatment having a preventive purpose. The treatment can be made either acutely or chronically. It is understood that treatment can mean a reduction or one or more symptoms or characteristics by at least 5% 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, 99.99%, 100%, relative to a control. In the context of these terms, preventing refers to the ability of a compound or composition (such as the disclosed compounds and compositions) to prevent a disease identified herein in patients diagnosed as having the disease or who are at risk of developing such disease. In this context, preventing includes the delaying the onset of the disease relative to a control. These terms do not require that the treatment in fact be effective to produce any of the intended results. It is enough that the results are intended.
19. Therapeutically effective
126. The term "therapeutically effective" means that the amount of the composition used is of sufficient quantity to treat a subject as defined herein.
20. Toxicity
127. Toxicity is the degree to which a substance, molecule, is able to damage something, such as a cell, a tissue, an organ, or a whole organism, that has been exposed to the substance or molecule. For example, the liver, or cells in the liver, hepatocytes, can be damaged by certain substances. The methods of the present invention are preferably nontoxic.
Examples
128. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. A. Example 1
1. Preparation of compounds of formula (I)
129. The following are examples of preparation of compounds of formula (I). This example is intended to be purely exemplary and is not intended to limit the disclosure.
Synthesis of Compound 1 (an intermediate compound)
Figure imgf000062_0001
1a 1 b 1c
Figure imgf000062_0002
1d Compound 1
Step 1:
130. A solution of la (5g, 25 mmol) in dry THF (10 mL) was cooled to 5 °C under nitrogen atmosphere. 60% NaH (2.4 g, 60 mmol) was added and the resulting mixture was stirred for 30 min. CH31 (8.5 g, 60 mmol) was then added to the mixture and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate/petroleum ether 1 : 15, v:v) to provide compound lb (2.9 g, 51% yield). 1H-NMR (CDC13, 300 MHz): 5=3.74 (t, 2H), 3.41 (s, 2H), 2.50 (t, 2H), 1.44 (s, 9H), 1.06 (s, 6H). LC-MS 228 [M+l ]+ .
Step 2:
131. A solution of 1 b (2.0 g, 8.8 mmol) in THF (30 mL) was treated with 1.5 mL of cone. HCl at room temperature. The resulting mixture was heated at 60 °C for 3h, then cooled to room temperature. A white precipitate resulted and was collected by filtration and dried to obtain compound lc (1.1 g, 78% yield) as HCl salt. This product was used in the next step without further purification.
Step 3: 132. To a mixture of lc (1.0 g, 6.1 mmol) and K2C03 (2.5 g, 18.3 mmol) in dry CH3CN (20 mL) was added CH31 (0.95 g, 6.7 mmol) dropwise under N2 atmosphere. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography (silica, ethyl acetate/ petroleum ether 1 : 10, v:v) to provide compound Id (0.69 g, 81% yield). Ή-NMR (CDC13, 300 MHz): «5=2.65 (t, 2H), 2.50 (t, 2H), 2.38 (s, 2H), 2.32 (s, 3H), 1.14 (s, 6H). LC- MS: 142 [M+l]+ .
Step 4:
133. A mixture of Id (0.5 g, 3.5 mmol) and methyl amine (30% in MeOH, 5 mL) was hydrogenated (50 psi, 60 °C) in the presence of 5% Pd/C (50 mg) in MeOH (5 mL). After cooling, the reaction mixture was filtered, the solvent evaporated under reduced pressure and the residue purified by column chromatography (silica, MeOH/CH2Cl2 1 : 15, v:v) to provide Compound 1 (0.21 g, 39 % yield). Ή-NMR (CDC13, 300 MHz): (5=2.65 (t, 2H), 2.56 (d, 3H), 2.51 (t, 2H), 2.38 (s, 2H), 2.32 (s, 3H), 1 .14 (s, 6H). LC-MS: 157 [M+l]+ .
Synthesis of Compound 2 (an intermediate compound)
Figure imgf000063_0001
2d Compound 2
Step 1:
134. To a solution of A1C13 (800 mg, 6 mmol) in dry CH2C12 (12 mL) was added acyl chloride (236 mg, 3 mmol) at 0 °C under N2. The mixture was stirred for 10 min at room temperature, then compound 2a was added (474 mg, 3 mmol) and the resulting mixture stirred at room temperature overnight. Following water quench, the organic phase was separated, dried with anhydrous Na2S04 and concentrated. The residue was purified by column chromatography (silica, ethyl acetate/petroleum ether 1 : 15, v:v) to provide compound 2b (338 mg, 56% yield) as a white solid. 1H-NMR (CDC13, 300 MHz): 3= 9.01-9.96 (m, lH), 8.32-8.35 (m, 1 H), 8.03 (d, 1 H), 7.63-7.65 (m, 1H), 7.53-7.58 (m, 1H), 6.79 (d, 1H), 4.07 (s, 3H), 2.72 (s, 3H). LC-MS: 201 [M+l ]+.
Step 2:
135. To a solution of compound 2b (167 mg, 0.84 mmol) in MeOH (5 mL) at 0 °C was added NaBH4 (127 mg, 3.34 mmol). The mixture was stirred at room temperature for 2h then the reaction was quenched with water. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic phase was separated, dried with anhydrous Na2S04 and concentrated under reduce pressure to give 2c (170 mg, 100% yield) which was used in the next step without further purification. Ή-NMR (CDC13, 300 MHz): 3= 8.30-8.33 (m, 1H). 8. 12-8. 16 (m, 1 H), 7.52-7.58 (m, 3H), 6.80 (d, 1H), 5.59 (q, 1H), 4.00 (s, 3H), 1.66 (d, 3H). LC-MS: 203 [M+l ]+.
Step 3:
136. To a mixture of 2c (170 mg, 0.84 mmol), phtalimide (186 mg, 1.26 mmol) and PPh3 (441 mg, 1.68 mmol) in dry THF (12 mL) was added DIAD (340 mg, 1.68 mmol) at room temperature under N2. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by column chromatography (silica, ethyl
acetate/petroleum ether 1 : 15, v:v) to provide compound 2d (1 13 mg, 41 % yield). Ή-NMR (CDC13, 300 MHz): 3= 8.28-8.30 (m, 1 H),. 8.12 (d, 1 H), 7.92 (d, 1H), 7.74-7.76 (m, 2H), 7.65-7.68 (m, 2H), 7 '.52-7 '.56 (m, 1H), 7.43-7.45(m, 1H), 6.87 (d, 1H), 6.24 (q, 1H), 4.01 (s, 3H), 2.01 (d, 3H).
Step 4:
137. A solution of compound 2d (1 13 mg, 0.34 mmol) in MeOH (4 mL) was treated with hydrazine hydrate (98%, 68 mg, 1.36 mmol) under reflux for 2h. The mixture was then cooled and concentrated. The residue was partitioned between CH2C12 and water. The organic phase was separated, dried with anhydrous Na2S04 and concentrated to give Compound 2 (65 mg, 95% yield) as a yellow oil. Ή-NMR (CDC13) 300 MHz): 3= 8.32 (d, 1H), 8.08 (d, 1H), 7.46-7.56 (m, 3H), 6.79 (d, 1 H), 4.86 (q, 1H), 3.96 (s, 3H), 1.64 (s, 2H), 1.52 (d, 3H). LC-MS: 202 [M+l ]+. Synthesis of Compound 3 (an intermediate compound)
Figure imgf000065_0001
3d
Compound 3
138. Compound 3 was prepared using a synthetic procedure analogous to that of Compound 2 to yield the target compound as a light-yellow oil (8.6 g, 55% yield). Ή NMR (CDC13, 300 MHz,): ό= 7.42 (d, 1H), 6.87 (d, 1H), 4.52 (q, 1H), 3.90 (s, 3H), 1.66 (s, 2H); 1.36 (d, 3H). LC-MS: 220 [M+l]+.
Synthesis of Compound 4
Figure imgf000065_0002
4b
Compound 2
Figure imgf000065_0003
Compound 4
4c
Step l :
139. To a solution of 4a (1 g, 5 mmol) in MeOH (50 mL) was added acetic acid (0.5 mL, 8.7 mmol), sodium acetate (0.5 g, 6 mmol) and hydroxylamine hydrochloride (340 mg, 5 mmol), followed by NaBH3CN (640 mg, 10 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue washed with aqueous NaHC03 solution and the mixture extracted with CH2C12 (3 χ30). The combined organic phases were dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate/petroleum ether 1 : 1 , v:v) to provide compound 4b (650 mg, 60% yield). Ή-NM (CDC13, 300 MHz): S= 4.03-4.07 (m, 2H), 2.91 -3.01 (m, 1 H), 2.76-2.84 (m, 2H), 1.83-1.88 (m, 2H), 1.41 (s, 9H), 1.23-1.35 (m,2H). LC-MS: 217 [M+l ]+.
Step 2:
140. To a solution of compound 2 (45 mg, 0.72 mmol) in CH2C12 (30 mL) at 0 °C was added TEA (1.5 mL, 10.4 mmol) and triphosgene (210 mg, 0.72 mmol). The mixture was stirred for 15 min, then 4b (155 mg, 0.72 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 30 min. Following concentration, the residue was washed with an aqueous solution of NaHC03 and extracted with CH2C12. The combined organic phases were dried with Na2S04 and concentrated to provide crude urea 4c, which was used in the next step without further purification. LC-MS: 444 [M+l]+.
Step 3:
141. To a solution of 4c (300 mg 0.92 mmol) in MeOH (20 mL) at 0 °C was added anhydrous HC1 in MeOH (2N, 10 mL). The mixture was stirred at room temperature for 2 h. After concentration, the residue was dissolved in MeOH (30 mL) and sodium acetate (0.5 g, 6 mmol), acetic acid (0.5 mL, 8.7 mmol) and 38% formaldehyde solution (2 mL, 25 mmol) were added, followed by NaBH3CN (87 mg, 1.3 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was washed with saturated aqueous NaHC03 (40 mL) solution, and extracted with CH2C12 (3 χ 50 mL). The combined organic phases were dried with anhydrous Na2S04 and concentrated under reduced pressure to yield a residue that was purified by column chromatography (silica, MeOH/CH2Cl2 1 :20, v:v) to provide Compound 4 (130 mg, 50% yield) as a white solid. Ή- M (300 MHz, CDC13): S= 8.26-8.29 (m, 1H); 8.03-8.06 (m, 1 H), 7.36-7.52 (m, 3H), 6.72-6.74 (d, 1H), 6.26-6.29 (d, 1H), 5.64-5.69 (m, 1H), 4.06-4.08 (m, 1H), 3.98 (s, 3H), 2.89-2.93 (m, 2H), 1.93-2.20 (m, 4H), 2.08 (s, 3H) 1.53-1.68 (m, 2H), 1.57 (d, 3H). LC-MS: 358 [M+lf
Synthesis of Compound 5
Figure imgf000067_0001
Step 1:
142. To a solution of 5a (5.65 g, 50 mmol) and methoxyamine (5 g, 60 mmol) in MeOH (150 mL) was added acetic acid (5 mL, 87.5 mmol), sodium acetate (5.0 g, 60 mmol), followed by NaBH3CN (640 mg, 10 mmol). The mixture was stirred at room temperature for 48 h, then quenched with aqueous sat. NaHC03 (add volume). The aqueous layer was extracted with CH2C12 (3 * 160 mL). The combined organic phase was dried over anhydrous Na2S04 and evaporated to provide product 5b (21% crude yield) as a colorless oil, which was used in the next step without further purification. LC-MS: 145 [M+l]+.
Step 2:
143. To a solution of Compound 3 (250 mg, 1.14 mmol) in CH2C12 (60 mL) at 0 °C was added TEA (3.5 ml, 25.21 mmol) and triphosgene (203 mg, 0.68 mmol). The mixture was stirred for 15 min, then crude 5b (329 mg, 2.28 mmol) was added. The resulting mixture was stirred for 30 min and evaporated. The residue was purified by column chromatography (silica, MeOH/CH2Cl2 1 :20, v:v) to afford Compound 5 (100 mg, 22% yield) as a white solid . Ή-NMR (CDC13, 300 MHz): δ= 7.17 (d, 1H); 6.84 (d, 1H), 6.21-6.30 (m, 1H), 5.16- 5.24 (m, 1H), 4.00-4.16 (m, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.18-3.29 (m, 2H), 2.53 (s, 3H), 2.21-2.50 (m, 4H), 1.69-1.90 (m, 2H), 1.50 (d, 3H). LC-MS: 390 [M+l]+.
Synthesis of Compound 6
Figure imgf000067_0002
144. An analogous procedure to the last step of the synthesis of Compound 5 provided the target Compound 6 (120 mg, 61% yield) as a yellow solid. Ή-NMR (CDC13, 300 MHz): S= 8.14 (d, 1H); 7.91 (t, 1H), 7.78 (d, 1H), 7.47-7.56 (m, 4H), 6.57 (d, 1H), 5.63-5.72 (m, 1H), 3.83-3.97 (m, 1H), 3.16 (q, 2H), 2.75 (d, 2H), 2.12 (s, 3H), 1.84-1.91 (m, 2H), 1.55-1.66 (m, 2H), 1.49 (d, 3H), 1.40-1.48 (m, 2H), 0.99 (t, 3H). LC-MS: 340 [M+l]+.
Synthesis of Compound 7
Figure imgf000068_0001
7a 7b Compound 7
145. Following an analogous synthetic procedure to the last step in the preparation of Compound 5, compound 7 (140 mg, 91% yield) was obtained as a yellow solid. Ή-NMR (300 MHz, CDC13): S= 7.32-7.35 (m, 1H); 7.16-7.23 (m, 2H), 5.22-5.36 (m, 1H), 4.82 (d, IH), 4.04-4.17 (m, 1H), 2.82-2.92 (m, 2H), 2.77 (s, 3H), 2.25 (s, 3H), 1.96-2.03 (m, 2H), 1.61-1.74 (m,4H), 1.46 (d, 3H). LC-MS: 344 [M+l]+.
Synthesis of Compound 8
Figure imgf000068_0002
Compound 2 Compound 8
146. Following an analogous synthetic procedure to the last step in the preparation of Compound 5, compound 8 (101 mg, 28% yield) was obtained as a yellow solid. Ή- MR (CDCI3, 300 MHz): δ= 8.30-8.32 (m, IH), 8.09 (t, IH), 7.43-7.48 (m, 3H), 6.77 (d, IH), 5.72-5.76 (m, IH), 4.56 (t, IH), 4.36-4.38 (m, IH), 4.00 (s, 3H), 3.12-3.15 (m, 2H), 2.64 (s, 3H), 2.36-2.39 (m, 5H), 2.00-2.03 (m, 2H), 1.60-1.66 (m, 5H); LC-MS: 356 [M+l]+.
Synthesis of Compound 9
Figure imgf000068_0003
147. Following an analogous synthetic procedure to the last step in the preparation of Compound 5, compound 9 (100 mg, 64% yield) was obtained as a white solid. 1H- NMR (CDC13, 300 MHz): (5=7.40-7.25 (m, 6H); 7.06-7.01 (t, IH), 6.75-6.72 (m, IH), 5.28-5.23 (m, IH), 4.70-4.68 (d, IH), 4.40-4.38 (m, 3H), 2.87-2.83 (m, 2H), 2.23 (s, 3H), 2.05-2.01 (m, 2H), 1.74-1.61 (m, 4H) , 1.22-1 .19 (d, 3H). LC-MS: 420 [M+l ]+.
Synthesis of Compound 10
Figure imgf000069_0001
148. Following an analogous synthetic procedure to the last step in the preparation of Compound 5, compound 10 ( 176 mg, 76% yield) was obtained as a white solid. Ή-NMR (CDCI3, 300 MHz): <5= 7.28-7.37 (m, 2H); 6.97-7.1 1 (m, 4H), 6.81 -6.85 (m, IH), 5.24-5.29 (m, IH), 4.67-4.70 (m, IH), 4.30-4.47 (m, 3H), 2.90-2.98 (m, 2H), 2.16 (s, 3H), 2.10-2.21 (m, 2H), 1.31 -1.98 (m, 4H), 1.22 (d, 3H). LC-MS: 438 [M+l]+ .
Synthesis of Compound 11
Figure imgf000069_0002
149. Following an analogous synthetic procedure to the last step in the preparation of Compound 5, compound 11 (105 mg, 35% yield) was obtained as a white solid. Ή -NMR (CDCI3, 300 MHz): 0= 7.40-7.42 (m, IH), 7.29-7.31 (m, IH), 7.25-7.27 (m, 3H), 7.05-7.10 (m, IH), 6.89-6.92 (m, IH), 5.29-5.20 (m, IH), 4.64 (d, IH), 4.37-4.44 (m, 3H), 2.91-3.01 (m, 2H), 2.32 (s, 3H), 2. 17-2.23 (m, 2H), 1.65-1.82 (m, 4H), 1.33 (d, 3H). LC-MS: 454
[M+l]+ .
Synthesis of Compound 12
Figure imgf000070_0001
Compound 1 7b Compound 12
150. Following an analogous synthetic procedure to the last step of the preparation of Compound 5, compound 12 (120 mg, 46% yield) was obtained as a white solid. Ή-NMR (CDC13, 300 MHz): δ= Ί .32-1 6 (m, 1H); 7.13-7.25 (m, 2H), 5.28-5.35 (m, 1H), 4.82-4.92 (m, 1H), 4.07-4. 12 (m, 1 H), 2.94-3.00 (m, 1H), 2.85 (s, 3H), 2.40-2.47 (m, 1H), 2.22 (s, 3H), 2.02-2.12 (m, 2H), 1 .86-1 .91 (m, 1 H), 1.41 -1.49 (m, 3H), 1.33-1.37 (m, 1H), 1.07 (s, 3H), 0.82 (d, 3H). LC-MS: 372.1 [M+l ]+.
Synthesis of Compound 13
Figure imgf000070_0002
151. Following an analogous synthetic procedure to the last step of the preparation of Compound 5, compound 13 (70 mg, 36%> yield) was obtained as a light yellow solid. Ή NMR (CDC13, 300 MHz): S= 8.28-8.31 (m, 1H), 8.09 (d, 1 H), 7.26-7.54 (m, 3H), 6.77 (d, 1H), 5.70-5.79 (m, 1H), 4.56 (q, 1H), 4.16-4.28 (m, 1H), 4.00 (d, 3H), 2.96-3.00 (m, 1H), 2.67 (d, 3H), 2.45 (d, 1 H), 2.25-2.26 (m, 3H), 1 .92-2.1 1 (m, 3H), 1.63 -1.67 (m, 3H), 1.40- 1.48 (m, 1H), 1.05 (d, 3H), 0.90 (d, 3H); LC-MS: 384 [M+l]+
Synthesis of Compound 14
Figure imgf000070_0003
Step 1:
152. A mixture of Id (0.5 g, 3.5 mmol) and benzyl amine (0.34 g, 3.19 mmol) in MeOH (30 mL) as stirred at room temperature for 3 h. Then NaBH3CN (0.45 g, 7.0 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduce pressure and the residue was dissolved in CH2C12 (50 mL). The mixture was washed with 100 mL of brine (100 mL) and the organic phases dried over Na2SC>4 and concentrated. The residue was purified by column chromatograph (silica, MeOH:CH2Cl2 1 :20 to 1 : 10) to provide intermediate 11a (0.2 g, 27% yield) as a light yellow oil. LC-MS: 234 [M+l f.
Step 2:
153. This procedure is analogous to the final step of the synthesis of Compound 5 and provided Compound 14 (80 mg, 20% yield) as a white solid. Ή-NMR (CDC13, 300 MHz,): (5=8.05-8. 10 (m, 1 H); 7.76-7.85 (m, 2H), 7.64-7.66 (m, 2H), 6.33-7.79 (m, 7H), 5.73-5.79 (m, 1H), 4.3 1 -4.67 (m, 4H), 3.00-3.05 (m, 1 H), 2.51-2.55 (m, 1 H), 1.97-2.30 (m, 6H), 1.59-1.69 (m, 1H), 1 .29- 1 .33 (m, 3H), 0.95-1. 15 (m, 6H). LC-MS: 430 [M+l]+.
Synthesis of Compound 15
Figure imgf000071_0001
Step 1 :
154. Analogous to the preparation of 11a, compound 12b was obtained (2.1 g, 63% yield) and used without further purification in the following step. LC-MS: 263 [M+l ]+. Step 2:
155. This step is analogous to the final step in the synthesis of Compound 5 and provided Compound 15 (140 mg, 57% yield) as a white solid. Ή-NMR (CDC13, 300 MHz): S= 7.22-7.31 (m, 2H); 7.09 (t, 1H), 6.79-6.95 (m, 4H), 5.15-5.30 (m, 1H), 4.64-4.78 (m, 1H), 4.36-4.46 (m, 3H), 3.76-3.79 (d, 3H), 3.94-3.96 (m, 1H), 2.39-2.42 (m, 1H), 2.19 (s, 3H), 1.98-2.05 (m, 2H), 1.20-1.25 (m, 2H), 1.07-1.09 (m, 6H), 0.86-0.97 (m, 3H). LC-MS: 378 [M+l]+.
Synthesis of Compound 16
Figure imgf000072_0001
Step 1:
156. The synthesis is similar to that of lib and provided 13b (l.Og, 46% yield) which was used in the following step without further purification . LC-MS: 251 [M+l]+.
Step 2:
157. Compound 16 was synthesized using a procedure similar to the final step in the preparation of Compound 5. Compound 16 was obtained as a white solid (195 mg, 49% yield). 'HNMR (CDC13, 300 MHz): δ= 7.25-7.40 (m, 6H); 7.01-7.06 (m, 3H), 6.72-6.75 (m, 1H), 5.25-5.28 (m, 1H), 4.70 (d, 1H), 4.38-4.40 (m, 3H), 2.83-2.87 (m, 2H), 2.24 (s, 3H), 2.01-2.05 (m, 2H), 1.67-1.74 (m, 4H), 1.21 (d, 3H). LC-MS: 466 [M+l]+.
Synthesis of Compound 17
Figure imgf000073_0001
a Compound 3
Figure imgf000073_0002
Step 1:
158. A mixture of lb (2 g, 8.8 mmol) and methyl amine (30% in MeOH, 4 mL) was hydrogenated (50 psi, 60 °C) in the presence of 5% Pd/C (2000 mg) in MeOH (25 mL) overnight. After cooling the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate/petroleum ether 1 : 10, v:v) to provide compound 14a (1 .0 g, 48% yield) as a light yellow oil. 'H-NTV!R (CDCI3, 300 MHz): δ= 4.07-4.09 (m, 1H), 2.65 (t, 2H), 2.51 (t, 2H), 2.43 (s, 3H), 2.38 (s, 2H), 1 .41 (s, 9H), 1. 14 (s, 6H). LC-MS: 243 [M+l]+.
Step 2:
159. To a solution of Compound 3 (382 mg, 1.74 mmol) in CH2C12 (50 mL) was added TEA (351 mg) and triphosgene (309 mg, 1.04 mmol). The mixture was stirred for 15 min at 0 °C, then 14a (407 mg, 1 .92 mmol) was added. The resulting mixture was stirred for 30 min at 0 °C and then concentrated under reduced pressure. The residue was purified by column chromatography (silica, MeOH/CH2Cl2 1 :20, v:v) to afford 14b (701 mg, 82% yield). LC-MS: 488 [M+l ]+.
Step 3:
160. To a solution of 14b (701 mg, 1.44 mmol) in THF (20 mL) was added cone. HC1 (2 mL). The mixture was heated at 75 0 C for 2h, then the solvent was evaporated to obtain crude 14c (580 mg) , which was used in next step without further purification.
Step 4:
161. To the solution of crude 14c (580 mg) in MeOH (15 mL) was added aqueous formaldehyde (38%, 4 mL, 24 mmol,), sodium acetate (200 mg, 2.4 mmol) and acetic acid (2 mL, 26 mmol), followed by NaBH3CN (135 mg, 2.9 mmol). The mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The residue was purified by column chromatography (silica, MeOH/CH2Cl2 1 :20, v:v) to afford Compound 17 (262 mg, 38% yield) as a white solid. Ή- MR (CDC13, 300 MHz): δ= 7.17-7.22 (m, 1H); 6.81-6.84 (m, 1H), 5.21-5.26 (m, 1 H), 4.81 -4.92 (m, 1H), 4.07-4.10 (m, 1H), 3.88-3.91 (m, 3H), 2.90- 2.93 (m, 1H), 2.81-2.82 (m, 3H), 2.38-2.42 (m, 1H), 2.21-2.22 (m, 3H), 1.85-2.05 (m, 4H), 1.42-1.50 (m, 3H), 1 .06-1.07 (m, 3H) , 0.77-0.87 (m, 3H). LC-MS: 402 [M+l]+:
Synthesis of Compound 18
Figure imgf000074_0001
Compound 18
Step 1:
162. To a solution of 15a (5.04 g, 26.8 mmol) in CH2C12 (80 mL) at 0 ° C was added dropwise a solution of Br2 (3.8 ] g, 24.1 mmol) in CH2C12. The solution was stirred at room temperature overnight. The reaction mixture was washed with aqueous Na2SC>3 solution, NaHC03 solution and water successively. The organic phase was dried with anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by silica column chromatography (silica, ethyl acetate/petroleum ether 1 :60, v:v) to provide compound 15b (7.1 g, quantitative yield).
Step 2:
163. To a solution of compound 15b (3 g, 1 1.2 mmol) in MeOH (90 mL) at -20 ° C to -10 ° C was added NaBIL; (936 mg, 24.5 mmol). The reaction mixture was warmed up to room temperature and stirred for 1.5h, then the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried with anhydrous a2S04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate/petroleum ether 1 :30, v:v) to provide compound 15c (2.2 g, 73% yield). Ή-NMR. (CDC13, 300 MHz): ,5=7.54-7.57 (m, 1H), 7.42-7.46 (m, IH), 7.24-7.29 (m, IH), 5.29-5.34 (m, IH), 3.81 (dd, 1H), 3.43 (dd, 1H), 2.84 (d, 1H).
Step 3:
164. To a solution of compound 15c (1.0 g, 3.72 mmol) in THF (100 mL) was added IN KOH (5.6 mL, 5.58 mmol). The reaction was stirred at room temperature overnight. Ethyl acetate (100 mL) was added and the organic phase was washed with brine, dried with anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether) to provide compound 15d (432 mg, 62% yield). Ή-NMR (CDC13, 300 MHz): ^=7.38-7.42 (m, IH), 7. 16-7.23 (m, 2H), 4.19-5.21 (m, IH), 3.20 (dd, IH), 2.63 (dd, I H).
Step 4:
165. Metallic sodium (1 1 mg, 0.53 mmol) was added to benzyl alcohol (2 mL) at room temperature under N2 and the mixture was stirred until sodium was completely dissolved. Compound 15d (100 mg, 0.53 mmol) was then added to the solution, which was then stirred at 70 0 C overnight. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica, ethyl acetate/petroleum ether 1 :4, v:v) to provide compound 15e (44 mg, 28% yield). Ή-NMR (CDC13, 300 MHz): δ= 7.53-7.56 (m, IH), 7.30-7.35 (m, 6H), 7.24-7.26 (m, IH), 5.35 (q, IH), 4.61 (q, 2H), 3.78 (q, IH), 3.38 (q, IH), 3.00 (s, IH).
Step 5:
166. To a solution of compound 15e (480 mg, 1.6 mmol), phtalimide (286 mg, 1.9 mmol) and PPh3 (629 mg, 2.4 mmol) in dry THF (20 mL) at room temperature under N2, was added DIAD (485 mg, 2.4 mmol). The mixture was stirred at room temperature overnight and
. then concentrated under reduced pressure. The residue was purified by column
chromatography (silica, ethyl acetate/petroleum ether 1 :30, v:v) to provide 15f (570 mg, 83% yield). Ή-NMR (CDC13, 300 MHz): <S= 7.79-7.85 (m, 2H), 7.70-7.74 (m, 2H), 7.58 (dd, IH), 7.40 (dd, IH), 7.24-7.27 (m, 5H), 7.19 (t, IH), 6.07 (dd, IH), 4.59 (d, 2H), 4.46 (t, IH), 4.00 (dd, IH). Step 6:
167. A solution of compound 15h (570 mg, 1.34 mmol) and hydrazine hydrate (98%) (270 mg, 5.36 mmol) in MeOH (10 mL) was heated under reflux for 2h. The mixture was then concentrated under reduced pressure, the residue was dissolved in CH2CI2 and washed with water. The aqueous phase was back extracted with CH2C12 (3 x 30 mL) and the combined organic phases were dried with anhydrous Na2S04 and concentrated to give 15g (350 mg, 88% yield). LC-MS: 296 [M+l ]+.
Step 7:
168. To a solution of 15g (350 mg, 1.19 mmol) in dry CH2C12 (10 mL) at room temperature under nitrogen was added triphosgene (353 mg, 1.19 mmol). The reaction was stirred at room temperature for 10 min, followed by the addition of 7a (235 mg, 1.43 mmol). The reaction mixture was stirred at room temperature for l h, then concentrated under reduced pressure. The residue was purified by column chromatography (silica, MeOH/CH2Cl2 1 :20, v;v) to provide compound Compound 18 (450 mg, 84% yield) as a white solid. Ή- NMR (CDCI3, 300 MHz): δ= 7.28-7.36 (m, 8H), 5.43-5.48 (m, 2H), 4.50 (q, 2H), 4.26-4.30 (m, 1H), 3.79 (q, 1H), 3.62 (q, 1H), 3. 10 (t, 2H), 2.81 (s, 3H), 2.43 (s, 3H), 2.30-2.36 (m, 2H), 2.10-2.17 (m, 2H), 1 .65-1 .70 (m, 2H). LC-MS: 450 [M+l ]+.
Synthesis of Compound 19
Figure imgf000076_0001
Compound 19
169. A solution of 5a (1 15mg, 0.584mmol), 5b (98mg, 0.596mmol) and TEA (0.5mL) in dry DCM (20mL) was stirred at room temperature under N2 for 30min. After the reaction was complete, water (l OmL) was added. The organic phase was separated, dried with
Na2S04 and concentrated. The residue was purified by column chromatography (silica, MeOH:DCM=l :20) to afford Compound 19 (108 mg, 57% yield). Ή NMR (300 MHz,
DMSO-fl/tf): 5=8. 14 (d, 1H), 7.92 (t, 1H), 7.78 (d, 1H), 7.57-7.45 (m, 4H), 6.71 (d, 1H), 5.71 -5.60 (m, 1H), 4. 1 6-4.08 (m, 1 H), 3. 17 (br, 2H); 2.72-2.61 (m, 5H), 2.50 (s, 3H), 1.93- 1.87 (m, 2H), 1 .58- 1 .5 1 (m, 5H). LC-MS : 326 [M+l ] +
Synthesis of Compound 20
Figure imgf000077_0001
170. To a solution of 6a (100 mg, 0.584mmol), TEA (1.5mL) in dry DCM (20 mL) was added triphosgene (104 mg, 0.350 mmol) at room temperature under N2. The mixture was stirred at room temperature for 30 min, then 5b (98mg, 0.596mmol) was added. The resulted mixture was stirred at room temperature for 30min. Water (l OmL) was added and the organic phase was separated, dried with Na2S04 and concentrated. The residue was purified by column chromatography (silica, MeOH:DCM=l :20) to provide Compound 20 (109 mg, 57% yield). Ή NMR (300 MHz, OMSO-d6): (5=8. 13 (d, 1 H), 7.95 (t, 1 H), 7.78 (d, 1 H), 7.56-7.45 (m, 4H), 6.70-6.68 (d, 1 H), 5.70-5.61 (m, 1H), 4.02-3.94 (m, 1H), 2.93 (br, 2H), 2.70 (s, 3H), 2.27 (s, 3H), 2. 16 (br, 2H), 1.76-1 .63 (m, 2H), 1.50-1 .35 (m, 5H). LC-MS: 326 [M+l f.
2. Materials and methods
i. Calcium FLIPR assay
171 . The intracellular calcium assay was carried out in a 384- well format FLIPR™ (Molecular Device) HEK293/GHSRl a cell line. Cells were seeded 24 hr prior to the experiments at an optimal density per well. Preincubation with selected calcium dye lasted for 30-60 min at room temperature or 37 °C. Test compounds, dissolved in DMSO, were added at the appropriate time and incubated for 15 min followed by the addition of ghrelin with FlexStation or FLIPR. Relative fluorescence was monitored by the FLIPR™ Molecular Device. EC50 and IC5 values were estimated from dose-response data using GraphPad Prism software. To check for GHSR- 1 a agonism the compound was added at t=20 sec. and the calcium response was followed for 2 minutes. To check forGHSR- l a antagonism the compound and Ghrelin (10 nM) were added to the cells at t=20 sec. and the calcium response was measured for 2 minutes. The potency of the antagonist was calculated by its ability to reduce the ghrelin response. Dose-response curves were made for relevant antagonists,
ii. Evaluation of GHSRla antagonists on food intake test in mouse
172. Male C57BL/6J mice, 18-22 g body weight, were fasted overnight (16h before compound administration) and placed in a regular light dark cycle (6:00-18:00 light/18:00- 6:00 dark). After 1 wk acclimation, animals were sorted into two groups (n=6 each, 2 per cage) based on body weight. Animals in group one were be treated with vehicle and animals in group 2 were treated with the test agent (n=6 for each group). The cumulative food intake was evaluated at 1 , 2, 4, 8 and 24 hrs after drug or vehicle treatment. Food intake was measured by subtracting uneaten food from the initial premeasured food.
3. Results
173. The following table presents representative compounds of formula (I) with biological data including the ghrelin antagonist/agonist activity in vitro and mouse food intake results. The data clearly demonstrates that compounds of formula (I) are ghrelin receptor modulators and are useful in preventing and/or treating diseases associated with ghrelin receptor, for example, obesity.
Table 1.
Mouse Food
ICso FLIPR EC50 FLIPR
Intake
antagonist agonist
Structure (% inhibition.
Activity Activity
Doses as mg/kg
(μΜ) (μΜ/Emax)
p.
4 h,
8 hrs kg) n at 1 hr, 24 hrs kg)
Figure imgf000078_0001
Mouse Food
ICso FLIPR EC50 FLIPR Intake antagonist agonist
Structure (% inhibition.
Activity Activity
Doses as mg/kg (μΜ) (μΜ/Emax)
i.p.
,
Figure imgf000079_0001
A. 47% inhibition at 1 hr
0.066 0.020/3945 (10mg/kg)
44% inhibition at 1 hr
0.065 30/NA (10mg/kg) r
Figure imgf000079_0002
hrs, activity up to 2 hrs(30mg/kg)
39% inhibition at 1 hr, no activity up to follow hrs.(3mg/kg), 95% inhibition at 1 hr,
0.038 30/NA activity up to 24
hrs(10mg/kg), 70% inhibition at 2 hr, activity up to 24 hrs (30mg/kg) Mouse Food
IC50 FLIPR EC50 FLIPR
Intake antagonist agonist
Structure (% inhibition.
Activity Activity
Doses as mg/kg
(μΜ) (μΜ/Emax)
i.p.
0.005 30/NA NSE (10 mg/kg)
0.012 0.010/3208 NSE (10 mg/kg)
0.003 0.010/2921 NSE (10 mg/kg)
Figure imgf000080_0001
0.007 30/NA NSE (10 mg/kg)
Figure imgf000080_0002
ΛΑ- -ει 0.004 0.0082/4239 N/A
Figure imgf000080_0003
* NSE: not significant effect.

Claims

CLAIMS What is claimed is:
1. A compound of formula I), or a pharmaceutically acceptable salt or adduct thereof,
Figure imgf000081_0001
Formula (I)
wherein:
R is selected from the group consisting of aryl, arylalkyl, carbocyclic ring,
heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, optionally substituted with one or more independent R103 substituents;
Ri and R2 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -C(0)R101, - C(0)OR101, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and
heteroarylalkyl, each optionally independently substituted with one or more independent R103 substituents; or Ri and R2, together with the atoms connecting the same, form a fused or non- fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally
independently substituted with one or more R103 substituents;
R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R101, -
C(0)OR101, -C(O)NR,01R102, -S(0)2R102 , -SR101 and -S(O)2NR101R102, optionally substituted with one or more independent R103 substituents;
R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -OR103, NR101R102, - C(0)R101, -C(0)OR10', -C(O)NR101R102, -alkylNR101R102, -S(0)2R102 , -SR101 and - S(O)2NR101R102, optionally substituted with one or more independent R103 substituents; or R3 and R4, together with the atoms connecting R3 and R4, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R103 substituents; '·
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyi, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, oxide (=0), - C(0)R101, -C(0)OR101 , -C(O)NR101R102, -S(0)2R102 , -SR101 and -S(O)2NR101R102, optionally substituted with one or more independent R103 substituents;
R6, R7, Rs, R9, Rio, Ri i, R12, Ri3 and R]4 are each independently selected from the group consisting of hydrogen, cyano, -N02, -OR101, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyi, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R101 , -C(0)ORU)1, -C(O)NR101R'02, -NR101R102, -NR101 S(O)2R102, - NR101C(O)R102, -S(0)2R10 , -SR101 and -S(O)2NR101R102, each optionally independently substituted with one or more independent R103 substituents; or any two or more substituents selected from the group consisting of Re, R7, Rg, R9, Rio, R11, Ri2, Rn and R]4 together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R103
substituents; and
R101, R102 and R103 are each independently selected from the group consisting of hydrogen, cyano, -N02, -OR101 , hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyi, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, - C(0)R101, -C(0)OR101, -C(O)NR,01R102, -NRI01R102, - R^'Si ^R10 , -NR101C(O)R102, - S(0)2R102 , -SR10! and -S(O)2NR10 , R102, each optionally independently substituted with one or more independent R substituents; or R101, R102, together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R103 substituents.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or adduct thereof, wherein R is aryl or heteroaryl.
3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or adduct thereof, wherein R is selected from the group consisting of phenyl, naphthalene,
tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl,
benzonaphthenyl, fluorenyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and
tetrahydroisoquinolinyl, which is optionally independently substituted with from one to six substituents independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkyl, cyano, -N02, -OR101, hydroxy, amino, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R101, -C(0)OR101, - C(O) R101R102, -NR101R102, -NR^' S^R102, -N ,01C(O)R102, -S(0)2R10 , -SR'01 and - S(O)2NR101R102. ■
4. The compound of any of one of claims 1 to 3, or a pharmaceutically acceptable salt or adduct thereof, wherein R is phenyl or naphthalene which is optionally independently substituted with from one to six substituents independently selected from the group consisting of hydrogen, chloro, fiuoro, bromo, trifluoromethyl, cyano, methoxy, ethoxy, methyl and ethyl.
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or adduct thereof, wherein R, and R2 are not both hydrogen; or Ri and R2, together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring.
6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or adduct thereof, wherein R\ is selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, -OR101, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or adduct thereof, wherein R] is selected from the group consisting of alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl and heteroarylalkyl.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt or adduct thereof, wherein Ri is selected from the group consisting of methyl, -CH2OH, and -CH2- 0-CH2-phenyl.
9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or adduct thereof, wherein R2 is hydrogen, alkyl or cycloalkyl.
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or adduct thereof, wherein R3 is hydrogen, alkyl or cycloalkyl.
1 1. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or adduct thereof, wherein R4 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amino, alkoxy, alkylamino, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and aminoalkyl.
12. The compound of any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt or adduct thereof, wherein R4 is methyl, ethyl, benzyl, or benzyl substituted with from one to five substituents independently selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl, methoxy, cyano and hydroxy.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt or adduct thereof, wherein R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, oxide (=0), aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, - C(0)R101, -C(0)OR101 and -C(O) 101R102.
14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or adduct thereof, wherein R5 is methyl.
15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or adduct thereof, wherein Re, R7, R8, R9, Rio, Ru, R12, Rn and RM are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, , -C(0)OR101, and -alkylOR103.
16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or adduct thereof, wherein R8 and R9 are each independently hydrogen, alkyl, cycloalkyl, - C(0)OR101, or -alkylOR103,.
17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or adduct thereof, wherein R8 and R9 are each independently hydrogen, methyl, ethyl, -C(=0)OEt, or -CH2OH.
18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt or adduct thereof, wherein R8 and R9, together with the atom connecting them, form a cycloalkyl ring.
19. The compound of claim 18, or a pharmaceutically acceptable salt or adduct thereof, wherein said cycloalkyl ring is cyclopropane.
20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or adduct thereof, selected from the group consisting of:
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
methylurea,
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
yl)urea,
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Μβ H ^ NHAc yl)ureido)ethyl)phenyl)acetamide,
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
1 -(1 -methy!piperidin-4-yl)urea,
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
methy!piperidin-4-yl)urea.
21. A method of preventing and/or treating a subject, comprising administering to said subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-20, or a pharmaceutically acceptable salt or adduct thereof, wherein the subject has a disease which is pathophysiological^ mediated by the ghrelin receptor.
22. The method of claim 21 , wherein said disease is obesity, overweight, eating disorder, diabete, metabolic syndrome, cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease,
gastrointestinal disease, gastric disorder or substance abuse.
23. The method of claim 22, wherein said metabolic disorder is selected from the group consisting of diabetes, Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease.
24. The method of claim 22, wherein said gastric disorder is selected from the group consisting of Post-operative ileus (POI), diabetic gastroparesis, and opioid induced bowel dysfunction. wu υι /iiJiuj PCT/CN2011/000298
25. The method of claim 22, wherein said gastrointestinal disease is selected from the group consisting of irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.
26. The method of claim 22, wherein said substance abuse is alcohol or drug abuse.
27. The method of claim 26, wherein said drug is selected from the group consisting of amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, and opioids.
28. The method of any one of claims 21 to 27, wherein said compound or a
pharmaceutically acceptable salt or adduct thereof, is a ghrelin receptor modulator.
29. The method of any one of claims 21 to 28, wherein said compound or a
pharmaceutically acceptable salt or adduct thereof, is a ghrelin receptor agonist.
30. The method of any one of claims 21 to 29, wherein said compound or a
pharmaceutically acceptable salt or adduct thereof, is a ghrelin receptor antagonist.
3 1. The method of any one of claims 21 to 30, wherein said compound or a
pharmaceutically acceptable salt or adduct thereof, is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration.
32. The method of any one of claims 21 to 31, wherein said administration is
accomplished by administering an oral form of said compound or a pharmaceutically acceptable salt or adduct thereof.
33. The method of any one of claims 21 to 32, wherein said compound or a
pharmaceutically acceptable salt or adduct thereof, is administered in an amount of from about 0.01 microgram per Kg ^g/Kg) body weight per day to about 100 mg Kg body weight per day, from about 0.1 μg /Kg/day to about 10 mg Kg/day, from about 1 μg /Kg /day to about 5 mg/ Kg /day, from about 10 μg /Kg/day to about 5 mg/Kg/day, from about 100 μg /Kg/day to about 5 mg/Kg/day, or from about 500 μg /Kg/day to about 5 mg/Kg/day.
34. The method of any one of claims 21 to 33, further comprising administering one or more therapeutic agents.
35. The method of any one of claims 21 to 34, wherein the subject is a human.
— I l l—
36. The method of any one of claims 21 to 35, wherein the subject has been identified as needing treatment for the disease or the administration.
37. A pharmaceutical composition for preventing and/or treating a subject comprising a therapeutically effective amount of a compound according to any one of claims 1-20, and one or more pharmaceutically acceptable excipients.
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SG2013056775A SG192138A1 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
MEP-2017-123A ME02845B (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
BR112013021566-6A BR112013021566B1 (en) 2011-02-25 2012-02-23 compound, pharmaceutical composition and use of a compound of formula (i)
MA36252A MA34968B1 (en) 2011-02-25 2012-02-23 ASYMMETRIC UREA AND MEDICAL USES THEREOF
PT127493831T PT2678017T (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
AP2013007123A AP3768A (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
DK12749383.1T DK2678017T3 (en) 2011-02-25 2012-02-23 ASYMMETRIC WATER AND MEDICAL USE THEREOF
HUE12749383A HUE035039T2 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
EA201300946A EA027374B1 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
JP2013555559A JP6077468B2 (en) 2011-02-25 2012-02-23 Asymmetric urea and its medical use
PL12749383T PL2678017T3 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
MX2013006974A MX347587B (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof.
KR1020187017910A KR101907573B1 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
CN201611088800.9A CN106995403B (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
GEAP201213239A GEP20156319B (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
MYPI2013003013A MY164354A (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
CA2820767A CA2820767C (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
SI201230981A SI2678017T1 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
AU2012220531A AU2012220531B2 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
NZ615283A NZ615283B2 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
UAA201311289A UA113510C2 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
CN201280008805.XA CN103874492B (en) 2011-02-25 2012-02-23 Unsymmetrical urea and medical application thereof
KR1020137025184A KR20140014186A (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
EP12749383.1A EP2678017B1 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
PE2013001934A PE20141000A1 (en) 2011-02-25 2012-02-23 ASYMMETRIC UREAS AND THE MEDICAL USES OF THEM
RS20170546A RS56033B1 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
ES12749383.1T ES2628386T3 (en) 2011-02-25 2012-02-23 Asymmetric areas and medical uses thereof
PCT/US2012/026315 WO2012116176A2 (en) 2011-02-25 2012-02-23 Asymmetric ureas and medical uses thereof
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TW101106171A TWI579273B (en) 2011-02-25 2012-02-24 Asymmetric ureas and medical uses thereof
US13/404,165 US8658797B2 (en) 2011-02-25 2012-02-24 Asymmetric ureas and medical uses thereof
ARP120100611A AR085398A1 (en) 2011-02-25 2012-02-24 ASYMMETRIC UREAS AND MEDICAL USES OF THE SAME
IL227941A IL227941A (en) 2011-02-25 2013-08-13 Asymmetric ureas and medical uses thereof
NI201300070A NI201300070A (en) 2011-02-25 2013-08-15 ASYMMETRIC UREAS AND THE MEDICAL USES OF THEM
TNP2013000346A TN2013000346A1 (en) 2011-02-25 2013-08-16 Asymmetric ureas and medical uses thereof
CL2013002412A CL2013002412A1 (en) 2011-02-25 2013-08-21 Compounds derived from (piperidin-4-yl) -ureas; pharmaceutical composition; and use as antagonists of the ghrelin receptor in the treatment of obesity, eating disorders, diabetes, cachexia caused by cancer, congestive heart failure, among others.
DO2013000195A DOP2013000195A (en) 2011-02-25 2013-08-23 NEW COMPOUNDS BASED ON ASYMMETRIC UREAS, AND MEDICAL USES OF THE SAME
ZA2013/07071A ZA201307071B (en) 2011-02-25 2013-09-19 Asymmetric ureas and medical uses thereof
EC2013012893A ECSP13012893A (en) 2011-02-25 2013-09-24 ASYMMETRIC UREAS AND MEDICAL USES OF THE SAME
CO13226995A CO6771450A2 (en) 2011-02-25 2013-09-24 Asymmetric areas and medical uses thereof
US14/150,360 US9751836B2 (en) 2011-02-25 2014-01-08 Asymmetric ureas and medical uses thereof
CY20171100635T CY1118947T1 (en) 2011-02-25 2017-06-19 ASymmetric NUTS AND MEDICAL USES OF THESE
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014100689A1 (en) 2012-12-21 2014-06-26 Aveo Pharmaceuticals, Inc. Anti-gdf15 antibodies
WO2015134839A1 (en) * 2014-03-07 2015-09-11 Helsinn Healthcare Sa P-substituted asymmetric ureas and medical uses thereof
RU2686317C2 (en) * 2015-04-24 2019-04-25 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Substituted 1,2,5-trimethyl- and 2,2,6,6-tetramethyl-4-aminopiperidines, having anti-ischemic activity
US10501479B2 (en) 2016-03-22 2019-12-10 Helsinn Healthcare Sa Benzenesulfonyl-asymmetric ureas and medical uses thereof
US11299472B2 (en) 2017-12-11 2022-04-12 Helsinn Healthcare Sa Fumarate salt of (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2- trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl) urea, methods of preparation, and uses thereof

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012113103A1 (en) * 2011-02-25 2012-08-30 Helsinn Healthcare S.A. Asymmetric ureas and medical uses thereof
EP3679930A4 (en) * 2017-08-07 2021-11-17 Hiroshima University Therapeutic agent for fatty liver diseases and therapeutic agent for adiposity
CN117466803A (en) 2017-08-21 2024-01-30 阿卡蒂亚药品公司 Compounds, salts thereof and methods for treating diseases
EP3672960A2 (en) 2017-08-21 2020-07-01 Acadia Pharmaceuticals Inc. Compounds, salts thereof and their use for the treatment of diseases
EP3542799A1 (en) 2018-03-22 2019-09-25 Helsinn Healthcare SA New centrally-active ghrelin agonist and medical uses thereof
MX2023014204A (en) 2021-06-02 2024-01-18 Helsinn Healthcare Sa Piperidine urea derivatives for use as inotropic agents.
WO2024158862A1 (en) * 2023-01-25 2024-08-02 University Of North Texas Health Science Center Thiourea antioxcompounds with neuroprotective activity

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1993325A (en) * 2004-08-02 2007-07-04 阿斯利康(瑞典)有限公司 Piperidine derivatives as histamine h3 receptor ligands

Family Cites Families (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5285174A (en) * 1976-01-05 1977-07-15 Yoshitomi Pharmaceut Ind Ltd Novel urea or thiourea derivatives
AU7545894A (en) 1993-09-02 1995-03-22 Yamanouchi Pharmaceutical Co., Ltd. Carbamate derivative and medicine containing the same
AU3785597A (en) 1996-08-14 1998-03-06 Takeda Chemical Industries Ltd. Cyclic urea compounds, their production and use as herbicides
US6399619B1 (en) 1999-04-06 2002-06-04 Merck & Co., Inc. Pyrrolidine modulators of chemokine receptor activity
IL151164A0 (en) * 2000-03-06 2003-04-10 Acadia Pharm Inc Azacyclic compounds for use in the treatment of serotonin related diseases
GB0011838D0 (en) 2000-05-17 2000-07-05 Astrazeneca Ab Chemical compounds
US20030022891A1 (en) * 2000-12-01 2003-01-30 Anandan Palani MCH antagonists and their use in the treatment of obesity
EP1368314A1 (en) 2001-03-01 2003-12-10 AstraZeneca AB N-4-piperidinyl compounds as ccr5 modulators
GB0107228D0 (en) 2001-03-22 2001-05-16 Astrazeneca Ab Chemical compounds
US6673829B2 (en) * 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
SE0103818D0 (en) 2001-11-15 2001-11-15 Astrazeneca Ab Chemical compounds
SE0200919D0 (en) 2002-03-25 2002-03-25 Astrazeneca Ab Chemical compounds
US7414057B2 (en) * 2002-09-11 2008-08-19 Merck & Co., Inc. Piperazine urea derivatives as melanocortin-4 receptor agonists
JPWO2004046110A1 (en) 2002-11-15 2006-03-16 アステラス製薬株式会社 Melanin-concentrating hormone receptor antagonist
IN2006CH00378A (en) * 2003-06-30 2007-05-11 Sumitomo Chemical Co Asymmetric urea compound and process for producing asymmetric compound by asymmetric conjugate addition reaction with the same as catalyst
US7115767B2 (en) * 2003-07-18 2006-10-03 Abbott Laboratories Tetraline derivatives as ghrelin receptor modulators
AR047537A1 (en) * 2004-02-10 2006-01-25 Janssen Pharmaceutica Nv PIRIDAZINONAUREAS AS INTEGRINE ANTAGONISTS
US20050261278A1 (en) * 2004-05-21 2005-11-24 Weiner David M Selective serotonin receptor inverse agonists as therapeutics for disease
GB0412865D0 (en) 2004-06-09 2004-07-14 Glaxo Group Ltd Chemical compounds
SE0401657D0 (en) 2004-06-24 2004-06-24 Astrazeneca Ab Chemical compounds
US7572783B2 (en) * 2004-08-13 2009-08-11 Amgen Inc. Substituted benzofused heterocycles
CA2575764A1 (en) * 2004-10-27 2006-05-11 Neurogen Corporation Diaryl ureas as cb1 antagonists
JP2008524325A (en) 2004-12-21 2008-07-10 アストラゼネカ アクチボラグ Heterocyclic MCHr1 antagonists and their use in therapy
US7829589B2 (en) 2005-06-10 2010-11-09 Elixir Pharmaceuticals, Inc. Sulfonamide compounds and uses thereof
US20080300251A1 (en) * 2005-09-05 2008-12-04 Sattigeri Jitendra A Derivatives of 3-Azabicyclo[3.1.0] Hexane as Dipeptidyl Peptidase-IV Inhibitors
EP1948190A2 (en) * 2005-11-01 2008-07-30 Transtech Pharma Pharmaceutical use of substituted amides
AR058277A1 (en) * 2005-12-09 2008-01-30 Solvay Pharm Gmbh N- SULFAMOIL - PIPERIDIN - AMIDAS, PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND AND PROCEDURE FOR PREPARATION
US20090253673A1 (en) 2006-07-12 2009-10-08 Min Ge Substituted Pyrazoles as Ghrelin Receptor Antagonists
JP2008042298A (en) 2006-08-02 2008-02-21 Olympus Corp Solid-state image pickup device
GB0701992D0 (en) 2007-02-02 2007-03-14 7Tm Pharma As Grehlin Receptor Modulators
US20080280886A1 (en) * 2007-05-08 2008-11-13 Auspex Pharmaceuticals, Inc. Substituted ureas
GB0710863D0 (en) * 2007-06-06 2007-07-18 Glaxo Group Ltd Novel compounds
GB0710865D0 (en) 2007-06-06 2007-07-18 Glaxo Group Ltd Novel compounds
WO2009020960A1 (en) 2007-08-06 2009-02-12 The Regents Of The University Of California Preparation of novel 1,3-substituted ureas as inhibitors of soluble epoxide hydrolase
WO2009039460A2 (en) * 2007-09-21 2009-03-26 Acadia Pharmaceuticals, Inc. Co-administration of pimavanserin with other agents
UA100527C2 (en) 2007-10-10 2013-01-10 Астразенека Аб Benzothiazoles as ghrelin receptor modulators
WO2009092293A1 (en) 2008-01-18 2009-07-30 Shanghai Targetdrug Co., Ltd. Pyrollidine-based compounds
WO2009089659A1 (en) 2008-01-18 2009-07-23 Shanghai Targetdrug Co., Ltd. Pyrollidine-based compounds
USRE48334E1 (en) * 2008-09-19 2020-12-01 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound and use of same
WO2010111353A1 (en) * 2009-03-25 2010-09-30 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
WO2011060397A1 (en) * 2009-11-16 2011-05-19 Schering Corporation Substituted amino heterocycles useful as hiv antagonists
WO2012113103A1 (en) * 2011-02-25 2012-08-30 Helsinn Healthcare S.A. Asymmetric ureas and medical uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1993325A (en) * 2004-08-02 2007-07-04 阿斯利康(瑞典)有限公司 Piperidine derivatives as histamine h3 receptor ligands

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9725505B2 (en) 2012-12-21 2017-08-08 Aveo Pharmaceuticals, Inc. Methods of treatment using anti-GDF15 antibodies
US11725047B2 (en) 2012-12-21 2023-08-15 Aveo Pharmaceuticals, Inc. Anti-GDF-15 antibodies
US9175076B2 (en) 2012-12-21 2015-11-03 Aveo Pharmaceuticals, Inc. Anti-GDF15 antibodies
EP3689370A1 (en) 2012-12-21 2020-08-05 Aveo Pharmaceuticals Inc. Anti-gdf15 antibodies
US10597444B2 (en) 2012-12-21 2020-03-24 Aveo Pharmaceuticals, Inc. Anti-GDF15 antibodies
WO2014100689A1 (en) 2012-12-21 2014-06-26 Aveo Pharmaceuticals, Inc. Anti-gdf15 antibodies
US9546157B2 (en) 2014-03-07 2017-01-17 Helsinn Healthcare Sa Asymmetric piperidinyl-substituted ureas as medicines
KR20160130218A (en) * 2014-03-07 2016-11-10 헬신 헬쓰케어 에스.에이. P-substituted asymmetric ureas and medical uses thereof
US9926337B2 (en) 2014-03-07 2018-03-27 Helsinn Healthcare Sa Substituted asymmetric ureas as modulators of ghrelin receptor activity
WO2015134839A1 (en) * 2014-03-07 2015-09-11 Helsinn Healthcare Sa P-substituted asymmetric ureas and medical uses thereof
AU2015227011B2 (en) * 2014-03-07 2019-05-02 Helsinn Healthcare Sa P-substituted asymmetric ureas and medical uses thereof
EA032847B1 (en) * 2014-03-07 2019-07-31 Хелсинн Хелскеа Са P-substituted asymmetric ureas and medical uses thereof
KR102354790B1 (en) * 2014-03-07 2022-01-21 헬신 헬쓰케어 에스.에이. P-substituted asymmetric ureas and medical uses thereof
US10577384B2 (en) 2014-03-07 2020-03-03 Helsinn Healthcare Sa Substituted asymmetric ureas as modulators of ghrelin receptor activity
CN106170485A (en) * 2014-03-07 2016-11-30 赫尔辛医疗股份公司 The unsymmetrical urea of para-orientation and medical application thereof
JP2017507116A (en) * 2014-03-07 2017-03-16 ヘルシン ヘルスケア ソシエテ アノニム p-Substituted asymmetric urea and its pharmaceutical use
TWI703130B (en) * 2014-03-07 2020-09-01 瑞士商赫爾辛保健股份有限公司 P-substituted asymmetric ureas and medical uses thereof
CN106170485B (en) * 2014-03-07 2021-09-03 赫尔森保健股份公司 Para-substituted asymmetric ureas and medical uses thereof
CN113527259A (en) * 2014-03-07 2021-10-22 赫尔森保健股份公司 Para-substituted asymmetric ureas and medical uses thereof
RU2686317C2 (en) * 2015-04-24 2019-04-25 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Substituted 1,2,5-trimethyl- and 2,2,6,6-tetramethyl-4-aminopiperidines, having anti-ischemic activity
US10501479B2 (en) 2016-03-22 2019-12-10 Helsinn Healthcare Sa Benzenesulfonyl-asymmetric ureas and medical uses thereof
US11299472B2 (en) 2017-12-11 2022-04-12 Helsinn Healthcare Sa Fumarate salt of (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2- trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl) urea, methods of preparation, and uses thereof
US11884646B2 (en) 2017-12-11 2024-01-30 Helsinn Healthcare Sa Fumarate salt of (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, methods of preparation, and uses thereof

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