WO2003065989A2 - (oxime)carbamoyl fatty acid amide hydrolase inhibitors - Google Patents

(oxime)carbamoyl fatty acid amide hydrolase inhibitors Download PDF

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WO2003065989A2
WO2003065989A2 PCT/US2003/003222 US0303222W WO03065989A2 WO 2003065989 A2 WO2003065989 A2 WO 2003065989A2 US 0303222 W US0303222 W US 0303222W WO 03065989 A2 WO03065989 A2 WO 03065989A2
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Prior art keywords
phenyl
oxime
amino
carbonyl
compound
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PCT/US2003/003222
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French (fr)
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WO2003065989A3 (en
Inventor
Sing-Yuen Sit
Kai Xie
Hongfeng Deng
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Bristol-Myers Squibb Company
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Priority to JP2003565415A priority Critical patent/JP2005516986A/en
Priority to AU2003210824A priority patent/AU2003210824A1/en
Priority to EP03737600A priority patent/EP1472215A4/en
Publication of WO2003065989A2 publication Critical patent/WO2003065989A2/en
Publication of WO2003065989A3 publication Critical patent/WO2003065989A3/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/48—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C271/60—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups having oxygen atoms of carbamate groups bound to nitrogen atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • 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

Definitions

  • the present invention Yelates to novel (oxime)carbamoyl derivatives and pharmaceutical compositions comprising said derivatives which inhibit fatty acid amide hydrolase and are useful for the treatment of conditions which can be effected by inhibiting fatty acid amide hydrolase.
  • cannabinoids The analgesic properties of cannabinoids have been known for many years and to many cultures. Cannabinoids are active in many pre-clinical models of pain, including neuropathic pain. Within the last few years, several endogenous cannabinoids, including the fatty acid amides arachidonylethanolamide (anandamid ⁇ ), and arachidonyl amino acids such as N-arachidonylglycine, homo- ⁇ -linolenyl-ethanolamide and docosatetraenyl- ethanolamide, as well as 2-arachidonyl-glycerol, have been shown to induce analgesia in laboratory animals (DeVane, W. A. et.
  • cannabinoid receptor antagonists and cannabinoid receptor antisense to induce hyperalgesia in animals suggests that endogenous cannabinoids regulate the nociceptive threshold (Hargreaves, K. M. et al., Hypoactivity of the Spinal Cannabinoid System Results in NMDA- Dependent Hyperalgesia J.
  • FAAH fatty acid amide hydrolase
  • A is dibenzofuranyl, dibenzothienyl, naphthyl, indolyl, fluorenyl, carbazolyl, or represented by Formula II:
  • R is C-i -16 alkoxy optionally substituted with phenyl, pyridyl or morpholinyl; phenyl optionally substituted with C ⁇ -4 alkyl; phenoxy; phenyl-C ⁇ - alkyloxy-; pyridyloxy; pyridyl-C ⁇ -4 alkyloxy-; -N(H)-C(0)-C 1-16 alkyl; or -C(O)-N(H)-C ⁇ . ⁇ 6 alkyl;
  • R 1 is a bond or a C 1 - 3 branched or linear aliphatic hydrocarbon
  • B is C- ⁇ - 4 alkyl, indolyl, benzofuranyl, benzothienyl, dibenzofuranyl, dibenzohienyl, fluorenyl, carbazolyl, naphthyl, quinolinyl or isoquinolinyl, wherein each is optionally substituted with one or more of the same or different substituent selected from the group consisting of C ⁇ -4 branched or linear aliphatic hydrocarbon, C 1 . 4 alkoxy, halo, haloalkyl, nitro and (C ⁇ -3 alkyl) 0-2 amino-; or represented by Formula III, or Formula IV:
  • R 2 is hydrogen, halo or C ⁇ -4 alkyl
  • R 3 is Ci- 4 alkyl, pyridyl, or phenyl optionally substituted with one or more of the same or different substituents selected from the group consisting of halo,tician C 1-4 haloalkyI and nitro
  • X is CH or nitrogen
  • R 4 is Ci- 4 branched or linear aliphatic hydrocarbon, C ⁇ - alkoxy, halo, haloalkyl, nitro or amino
  • b is 0 to 3, provided that if R 2 is halo, then R 3 is not halo; and if R 3 is halo, the R 2 is not halo.
  • A is dibenzofuranyl.
  • R is C- ⁇ - 4 alkoxy optionally substituted with phenyl, phenoxy, pyridyloxy, or amido optionally substituted with CM 6 alkyl,
  • R 1 is a bond
  • B is represented by Formula III:
  • R 2 is hydrogen
  • R 3 is methyl, pyridyl, phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • R 2 is hydrogen or methyl
  • R 3 is methyl or phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • R 2 is hydrogen or methyl; and R 3 is methyl, or phenyi optionally substituted with one or more halo, haloalkyl or nitro.
  • B is represented by Formula IV:
  • R 2 is hydrogen, or methyl
  • R 3 is Ci- 4 alkyl, pyridyl, or phenyl optionally substituted with one or more halo, haloalkyl or nitro, X is CH or nitrogen,
  • R 4 is C- ⁇ - 4 branched or linear aliphatic hydrocarbon, C1- 4 alkoxy, halo, haloalkyl or amino, and b is 0 to 3.
  • R 2 is hydrogen or methyl
  • R 3 is methyl, pyridyl, phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • compounds of Formula VI according to the first embodiment of the second aspect wherein R 2 is hydrogen and R 3 is phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • compounds of Formula VI according to the first embodiment of the second aspect wherein R 2 is methyl and R 3 is methyl.
  • compounds of Formula VI according to the first embodiment of the second aspect, a member selected from the group consisting of pyridine-3-carbaldehyde, 0-[[(4-undecyloxy-phenyl)amino]carbonyl] oxime; pyridine-3-carbaIdehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
  • 4-trifluoromethyl-benzaldehyde 0-[[(4-nonyloxy-phenyl)amino] carbonyl]oxime; benzaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(2-phenylethoxy)phenyl]amino]carbonyl]oxime;
  • 4-fluorobenzaldehyde 0-[[[4-(2-phenylethoxy)phenyl]amino] carbonyl]oxime; 2-fluoro-5-trif luoromethyl-benzaldehyde, 0-[[(4-nonyloxy-phenyl)amino] carbonyl]oxime;
  • 3-pyridinecarboxaldehyde 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime; 4-fluorobenzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl] amino]carbonyl]oxime; benzaldehyde, 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime;
  • 3-pyridinecarboxaldehyde 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl]amino]carbonyl]oxime;
  • 4-fluorobenzaldehyde 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-pentyloxy-phenyl)amino]carbonyl]oxime;
  • R is C-1-12 alkoxy; R 4 is halo;
  • X is CH or nitrogen; and b is 0 to 2, with the proviso that when X is nitrogen then b is 0.
  • R 1 is a C ⁇ - 3 branched or linear aliphatic hydrocarbon
  • R 4 is phenyl, C ⁇ -3 alkoxy or halo
  • X is CH or nitrogen; and b is 2.
  • R is C ⁇ -12 alkoxy;
  • R 1 is a C- ⁇ - 3 branched or linear aliphatic hydrocarbon;
  • X is CH or nitrogen.
  • a seventh aspect of the present invention a method of treating a condition or disorder by inhibiting fatty acid amidohydrolase in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating neuropathic pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating acute pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating chronic pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • an eleventh aspect of the present invention a method of treating emesis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating anxiety in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of altering feeding behaviors in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating movement disorders in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method treating glaucoma in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating brain injury in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a method of treating cardiovascular disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
  • a pharmaceutical composition for treating a condition or disorder requiring inhibition of a fatty acid amidohydrolase comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or diluent.
  • A is dibenzofuranyl, dibenzothienyl, naphthyl, indolyl, fluorenyl, carbazolyl, or represented by Formula II:
  • R is C ⁇ -16 alkoxy optionally substituted with phenyl, pyridyl or morpholinyl; phenyl optionally substituted with C ⁇ - alkyl; phenoxy; phenyl-C ⁇ -4 alkyloxy-; pyridyloxy; pyridyl-C ⁇ -4 alkyloxy-; -N(H)-C(0)-C ⁇ - ⁇ 6 alkyl; or -C(0)-N(H)-C ⁇ - ⁇ 6 alkyl;
  • R 1 is a bond or a C ⁇ -3 branched or linear aliphatic hydrocarbon
  • B is C- ⁇ -4 alkyl, indolyl, benzofuranyl, benzothienyl, dibenzofuranyl, dibenzothienyl, fluorenyl, carbazolyl, napthyl, quinolinyl or isoquinolinyl, wherein each is optionally substituted with one or more of the same or different substituent selected from the group consisting of Ci- 4 branched or linear aliphatic hydrocarbon, C ⁇ -4 alkoxy, halo, haloalkyl, nitro and (C ⁇ -3 alkyl) 0- 2 amino- or represented by Formula III or Formula IV:
  • R 2 is hydrogen, methyl
  • R 3 is C- ⁇ - 4 alkyl, pyridyl, or phenyl optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, C ⁇ -4 haloalkyl and nitro
  • X is CH or nitrogen
  • R 4 is C- ⁇ - 4 branched or linear aliphatic hydrocarbon, C ⁇ -4 alkoxy, halo, haloalkyl, nitro or amino
  • b is 0 to 3.
  • A is represented by Formula II:
  • R is C ⁇ - ⁇ 2 alkoxy; phenoxy; pyridyloxy; or amido optionally substituted with Ci.-i ⁇ alkyl; and R 1 is a bond.
  • R 2 is preferably hydrogen or methyl, and R 3 is preferably methyl, or phenyl optionally substituted with one or more halo, haloalkyl or nitro.
  • B is represented by Formula IV:
  • X is preferably CH, R 4 is preferably halo, and b is 1.
  • X is nitrogen, however, b is preferably 0.
  • B is represented by Formula V:
  • X is preferably nitrogen.
  • a dependnent embodiment describes a variable as being "phenyl or pyridyl", wherein said phenyl and pyridyl were described in the independent embodiment as being “optionally substituted”, then the phenyl and pyridyl of the dependent embodiment will also be optionally substituted.
  • halo or “halogen” includes fiuoro, chloro, bromo and iodo.
  • alkyl or alkylene includes straight or branched chain configurations.
  • the compounds of this invention can exist in the form of pharmaceutically acceptable salts.
  • Such salts include addition salts with inorganic acids such as, for example, hydrochloric acid and sulfuric acid, and with organic acids such as, for example, acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid.
  • the acidic group can exist in the form of alkali metal salts such as, for example, a potassium salt and a sodium salt; alkaline earth metal salts such as, for example, a magnesium salt, and a calcium salt; and salts with organic bases such as a triethylammonium salt and an arginine salt.
  • the compounds of the present invention may be hydrated or non-hydrated.
  • the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of this invention may also be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those skilled in the pharmaceutical arts.
  • the compounds can be administered alone, but generally will be administered with a pharmaceutical carrier selected upon the basis of the chosen route of administration and standard pharmaceutical practice.
  • Compounds of this invention can also be administered in intranasal form by topical use of suitable intranasal vehicles, or by transdermal routes, using transdermal skin patches. When compounds of this invention are administered transdermally the dosage will be continuous throughout the dosage regimen.
  • the dosage and dosage regimen and scheduling of a compounds of the present invention must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and extent of the disease condition. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level that will produce effective beneficial effects without causing any harmful or untoward side effects.
  • Scheme 1A Reaction conditions: (i) R-halide, NaH, DMF, room temp.; (ii) NaOH, EtOH, room temp., (iii) (a) N 3 P(O)(OPh) 2 , Et 3 N, toluene at room temp, following by 90 min. at reflux, (b) addition of oxime C at room temp, with stirring for 1 hr., heating to 85°C; n is 0 to 3; R, and R 2 are as defined above.
  • 2,4-Difluoro-benzaldehvde oxime (Scheme 1, Compound C) To a mixture of 2,4-difluorobenzaldehyde (0.80 g, 5.6 mmol) and hydroxyamine HCI salt (0.43 g, 6.2 mmol) in EtOH (5 mL) was added K 2 C0 3 (0.85 g, 6.2 mmol). The resultant mixture was stirred at rt for 24 hours. The mixture was diluted with MeOH (20 mL). The precipitates were filter off and washed with MeOH. The product from filtrate was purified by recrystalization (EtOAc/Hexanes).
  • reaction mixture was stirred at r.t. for 10 min. and then at 80 °C for 1 h.
  • the mixture was diluted with EtOAc, washed with H 2 0.
  • the residue was purified by by preparative HPLC (YMC 30X100 mm (5 uM packing), 10% MeOH/90% water/01 % TFA as mobile phase A, 90% MeOH/10%water/0.1% TFA as mobile phase B).
  • H4-FAAH cells Homogenates of crude membranes were prepared from H4 cells that express transfected human FAAH (H4-FAAH cells). Briefly, cells were grown in DMEM supplemented with 10% FBS and Geneticin at a final concentration of 500 ⁇ g/ml(Gibco BRL, Rockville, MD). Confluent cultures of H4-FAAH cells were rinsed twice with phosphate-buffered saline [138 mM NaCI, 4.1 mM KCI, 5.1 mM Na 2 P0 4 , 1.5 mM KH 2 P0 4 (pH 7.5), 37°C] and incubated for 5 to 10 minutes at 4°C in lysis buffer [1 mM sodium bicarbonate].
  • Example 5 (40 mg/kg, i.p.) suppressed the development of thermal hyperalgesia induced by paw carrageenan. Paw carrageenan injection (0, 0:45 hr, Carr) produced strong thermal hyperalgesia as evidenced by the short escape latencies seen in vehicle treated rats (0, 2:15 hr, Carr) as compared to the long baseline latencies (0:00 hr).
  • Example 5 Animals pretreated with Example 5 (#1, 0:15 hr) failed to exhibit hyperalgesic responses (compare 0 to ⁇ at 2:15 hr) and instead the latencies for drug treated animals were comparable to baseline.
  • Example 5 Inflammation-induced Edema
  • Example 5 inhibited swelling by 26% at 40 mg/kg (Ex. 5 - 40, ip administered at -30 min and +2hr relative to carrageenan) but showed no efficacy at 20 mg/kg (Ex. 5 - 20, ip).
  • the reference agent dexamethasone (Dex, 1 mg/kg, ip) inhibited swelling by 70%. Table IV, below, summarizes the data.

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Abstract

The present invention relates to novel oxime carbamoyl derivatives and pharmaceutical compositions comprising said derivatives which inhibit fatty acid amide hydrolase. These pharmaceutical compositions are useful for the treatment of conditions which can be effected by inhibiting fatty acid amide hydrolase including, but not limited to, neuropathic pain, emesis, anxiety, altering feeding behaviors, movement disorders, glaucoma, brain injury, and cardiovascular disease.

Description

(OXIME)CARBAMOYL FATTY ACID AMIDE HYDROLASE INHIBITORS
FIELD OF THE INVENTION
The present invention Yelates to novel (oxime)carbamoyl derivatives and pharmaceutical compositions comprising said derivatives which inhibit fatty acid amide hydrolase and are useful for the treatment of conditions which can be effected by inhibiting fatty acid amide hydrolase.
BACKGROUND OF THE INVENTION
Effective treatment of pain with current therapies is limited by adverse effects and a lack of efficacy against all components of pain.
Current research is aimed at understanding the molecular and physiological components of pain processing to develop more effective analgesics (Levine, J. D., New Directions in Pain Research: Meeting Report Molecules to Maladies, Neuron 20: 649-654, 1998; Pasternak, G. W., The Central Questions in Pain Perception May Be Peripheral, PNAS 95:10354- 10355, 1998).
The analgesic properties of cannabinoids have been known for many years and to many cultures. Cannabinoids are active in many pre-clinical models of pain, including neuropathic pain. Within the last few years, several endogenous cannabinoids, including the fatty acid amides arachidonylethanolamide (anandamidθ), and arachidonyl amino acids such as N-arachidonylglycine, homo-γ-linolenyl-ethanolamide and docosatetraenyl- ethanolamide, as well as 2-arachidonyl-glycerol, have been shown to induce analgesia in laboratory animals (DeVane, W. A. et. al., Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptors, Science 258: 1946-1949, 1992; Hanus, L. et. al., Two New Unsaturated Fatty Acid Ethanolamides in Brain that Bind to the Cannabinoid Receptor, J. Med. Chem. 36: 3032-3034, 1993; Machoulam, R. et. al., Identification of an Endogenous 2-Monoglyceride, Present in Canine Gut, That Binds To Cannabinoid Receptors, Biochem. Pharmacol. 50: 83-90, 1995; Vogel, Z. et. al., Cannabinomimetic Behavioral Effects of and Adenylate Cyclase Inhibition By Two New Endogenous Anandamides, Eur. J. Pharmacol. 287: 145-152, 1995; Hargreaves, K. M. et al., Cannabinoids Reduce Hyperalgesia and Inflammation Via Interaction With Peripheral CB1 Receptors, Pain 75: 11 II I 9, 1998; Rice, A. S.C., et. al., The Anti-Hyperalgesic Actions of the Cannabinoid Anandamide and the Putative CB2 Receptor Agonist
Palmitoylethanolamide in Visceral and Somatic Inflammatory Pain, Pain 76: 189-199, 1998; Huang, S.M., et al., Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain, J. Biological Chemistry, 276: 46, 42639-42644, 2001). The ability of cannabinoid receptor antagonists and cannabinoid receptor antisense to induce hyperalgesia in animals suggests that endogenous cannabinoids regulate the nociceptive threshold (Hargreaves, K. M. et al., Hypoactivity of the Spinal Cannabinoid System Results in NMDA- Dependent Hyperalgesia J. Neurosci. 18: 451-457, 1998; Piomelli, D. et. al., Control of Pain Initiation By Endogenous Cannabinoids, Nature 394: 277- 281 , 1998; Fields, H. L. et. al., An Analgesia Circuit Activated By Cannabinoids, Nature 395: 381-383, 1998). Elevation of levels of neuroactive fatty acid amides such as anandamide may provide a unique mechanism to achieve analgesia. The mechanisms by which endogenous cannabinoids are synthesized are not well understood; therefore, targets for drugs aimed at increasing the synthesis of these compounds are slow to be identified.
Anandamide and the other identified endogenous cannabinoids are inactivated through a cleavage mechanism by a membrane-bound enzyme, fatty acid amide hydrolase (FAAH). FAAH, therefore, provides an important target for regulating the activity of endogenous cannabinoids. The inhibition of FAAH may elevate levels of anandamide or other endogenous cannabinoids to increase the nociceptive threshold. Furthermore, the inhibition of FAAH would also extend the therapeutic benefits of other cannabinoid agonists in the treatment of emesis, anxiety, feeding behaviors, movement disorders, glaucoma, neuroprotection and cardiovascular disease. SUMMARY OF THE INVENTION
The above and other objects and advantages, which will be apparent to one of skill in the art, are achieved in the present invention which is directed to, in a first aspect, a compound of Formula I:
Figure imgf000004_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein
A is dibenzofuranyl, dibenzothienyl, naphthyl, indolyl, fluorenyl, carbazolyl, or represented by Formula II:
Figure imgf000004_0002
wherein a is 1 or 2, R is C-i-16 alkoxy optionally substituted with phenyl, pyridyl or morpholinyl; phenyl optionally substituted with Cι-4 alkyl; phenoxy; phenyl-Cι- alkyloxy-; pyridyloxy; pyridyl-Cι-4 alkyloxy-; -N(H)-C(0)-C1-16 alkyl; or -C(O)-N(H)-Cι.ι6 alkyl;
R1 is a bond or a C1-3 branched or linear aliphatic hydrocarbon; and B is C-ι-4 alkyl, indolyl, benzofuranyl, benzothienyl, dibenzofuranyl, dibenzohienyl, fluorenyl, carbazolyl, naphthyl, quinolinyl or isoquinolinyl, wherein each is optionally substituted with one or more of the same or different substituent selected from the group consisting of Cι-4 branched or linear aliphatic hydrocarbon, C1.4 alkoxy, halo, haloalkyl, nitro and (Cι-3 alkyl)0-2 amino-; or represented by Formula III, or Formula IV:
Figure imgf000004_0003
wherein R2 is hydrogen, halo or Cι-4 alkyl; R3 is Ci-4 alkyl, pyridyl, or phenyl optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, „ C1-4haloalkyI and nitro; X is CH or nitrogen; R4 is Ci-4 branched or linear aliphatic hydrocarbon, Cι- alkoxy, halo, haloalkyl, nitro or amino; and b is 0 to 3, provided that if R2 is halo, then R3 is not halo; and if R3 is halo, the R2 is not halo. According to another embodiment of the first aspect of the present invention are provided compounds of Formula I according to the first embodiment of the first aspect wherein A is dibenzofuranyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula I according to the first embodiment of the first aspect wherein A is indolyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula I according to the first embodiment of the first aspect wherein A is represented by Formula II:
Figure imgf000005_0001
wherein a is 1 ,
R is C-ι-4 alkoxy optionally substituted with phenyl, phenoxy, pyridyloxy, or amido optionally substituted with CM6 alkyl,
R1 is a bond; and B is represented by Formula III:
Figure imgf000005_0002
wherein
R2 is hydrogen, and
R3 is methyl, pyridyl, phenyl optionally substituted with one or more halo, haloalkyl or nitro. According to another embodiment of the first aspect of the present invention are provided compounds of Formula I according to the first embodiment of the first aspect wherein B is represented by Formula III:
Figure imgf000006_0001
wherein
R2 is hydrogen or methyl; and
R3 is methyl or phenyl optionally substituted with one or more halo, haloalkyl or nitro.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula I according to the first embodiment of the first aspect wherein B is represented by Formula III:
Figure imgf000006_0002
wherein R2 is hydrogen or methyl; and R3 is methyl, or phenyi optionally substituted with one or more halo, haloalkyl or nitro. According to another embodiment of the first aspect of the present invention are provided compounds of Formula I according to the first embodiment of the first aspect wherein B is represented by Formula IV:
^^ (IV) wherein X is CH; R4 is halo; and b is 1. According to another embodiment of the first aspect of the present invention are provided compounds of Formula I according to the first embodiment of the first aspect wherein B is represented by Formula IV:
^^ (IV) wherein X is nitrogen; and b is 0. According to another embodiment of the first aspect of the present invention are provided compounds of Formula I according to the first embodiment of the first aspect wherein B is represented by Formula V:
Figure imgf000007_0001
wherein X is nitrogen.
According to various embodiments of a second aspect of the present invention are provided compounds of Formula III, Formula IV or Formula V:
(V)
Figure imgf000007_0002
wherein
R2 is hydrogen, or methyl,
R3 is Ci-4 alkyl, pyridyl, or phenyl optionally substituted with one or more halo, haloalkyl or nitro, X is CH or nitrogen,
R4 is C-ι-4 branched or linear aliphatic hydrocarbon, C1-4 alkoxy, halo, haloalkyl or amino, and b is 0 to 3.
According to various embodiments of a second aspect of the present invention are provided compounds of Formula VI:
Figure imgf000007_0003
or a pharmaceutically acceptable salt or solvate thereof, wherein a is 1 ; R is C1-12 alkoxy;
R2 is hydrogen or methyl; and
R3 is methyl, pyridyl, phenyl optionally substituted with one or more halo, haloalkyl or nitro.
According to another embodiment of the second aspect of the present invention are provided compounds of Formula VI according to the first embodiment of the second aspect wherein R2 is hydrogen and R3 is phenyl optionally substituted with one or more halo, haloalkyl or nitro. According to another embodiment of the second aspect of the present invention are provided compounds of Formula VI according to the first embodiment of the second aspect wherein R2 is methyl and R3 is methyl.
According to another embodiment of the second aspect of the present invention are provided compounds of Formula VI according to the first embodiment of the second aspect, a member selected from the group consisting of pyridine-3-carbaldehyde, 0-[[(4-undecyloxy-phenyl)amino]carbonyl] oxime; pyridine-3-carbaIdehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-octyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; 3,4-dif luorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
2,6-difluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
2,4-difluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
3-fluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl] oxime; benzaldehyde, 0-[[(4-octyloxy-phenyl)amino]carbonyl]oxime; 2,3-difluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-undecyloxy-phenyl)amino]carbonyl]oxime;
2,4,5-trifluorobenzaldehyde, 0-[[(4-nonyloxy phenyl)amino]carbonyl] oxime;
4-fluorobenzaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-undecyloxy-phenyl)amino]carbonyl]oxime;
4-trifluoromethyl-benzaldehyde, 0-[[(4-nonyloxy-phenyl)amino] carbonyl]oxime; benzaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(2-phenylethoxy)phenyl]amino]carbonyl]oxime;
2-fluoro-3-trifluoromethyl-benzaldehyde, 0-[[(4-nonyloxy-phenyl)amino] carbonyI]oxime;
(4-undecyloxy-phenyl)-carbamic acid phenyl ester; propan-2-one, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(phenylmethoxy)phenyl]amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[[4-(2-phenylethoxy)phenyl]amino] carbonyl]oxime; 2-fluoro-5-trif luoromethyl-benzaldehyde, 0-[[(4-nonyloxy-phenyl)amino] carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[[4-(phenylmethoxy)phenyl]amino] carbonyl]oxime;
3-pyridinecarboxaldehyde, 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime; 4-fluorobenzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl] amino]carbonyl]oxime; benzaldehyde, 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-pentyloxy-phenyl)amino]carbonylJoxime;
4-fluorobenzaldehyde, 0-[[(4-butoxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-heptyloxy phenyl)amino]carbonyl]oxime;
3-pyridinecarboxaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl]amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-pentyloxy-phenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-pentyloxy-phenyl)amino]carbonyl]oxime;
2,4-difluorobenzaldehyde, benzaldehyde, 0-[[(4-nonanoylamino-phenyl) amino]carbonyl]oxime; 4-fluorobenzaldehyde, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-pentyloxy-phenyI)amino]carbonyl]oxime; propan-2-one, 0-[[(4-undecyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[( 4-pentyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-propoxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-butoxy-phenyl)amino]carbonyI]oxime; benzaldehyde, 0-[[(4-hexyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-hexyloxy-phenyl)amino]carbonyl]oxime; and pyridine-3-carbaldehyde, 0-[[(4-butoxy-phenyI)amino]carbonyl]oxime.
According to various embodiments of a third aspect of the present invention are provided compounds of Formula VII:
Figure imgf000010_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein a is 1 ;
R is C-1-12 alkoxy; R4 is halo;
X is CH or nitrogen; and b is 0 to 2, with the proviso that when X is nitrogen then b is 0.
According to another embodiment of the third aspect of the present invention are provided compounds of Formula VI according to the first embodiment of the third aspect wherein X is CH and is a member selected from the group consisting of:
(4-undecyloxy-phenyl)-carbamic acid phenyl ester;
(4-decyloxy-phenyl)-carbamic acid phenyl ester; (4-dodecyloxy-phenyl)-carbamic acid phenyl ester;
(4-octyloxy-phenyl)-carbamic acid 2-fluoro-phenyl ester;
(4-octyloxy-phenyl)-carbamic acid phenyl ester;
(4-heptyloxy-phenyl)-carbamic acid phenyl ester; and
(4-decyloxy-phenyl)-carbamic acid 2-fluoro-phenyl ester. According to various embodiments of a fourth aspect of the present invention are provided compounds of Formula VIII
Figure imgf000011_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein a is 1 ; R is C-1-12 alkoxy;
R1 is a Cι-3 branched or linear aliphatic hydrocarbon;
R4 is phenyl, Cι-3 alkoxy or halo;
X is CH or nitrogen; and b is 2. According to another embodiment of the fourth aspect of the present invention are provided compounds of Formula VIII according to the first embodiment of the fourth aspect wherein X is CH and is a member selected from the group consisting of:
(4-butoxy-benzyl)-carbamic acid 4-fluoro-phenyl ester; pyridine-3-carbaldehyde, 0-[[(4-butoxy-benzyl)amino]carbonyl]oxime;
(4-butoxy-benzyl)-carbamic acid phenyl ester;
[1 -(4-butoxy-phenyl)-propyl]-carbamic acid 2-fluoro-phenyl ester;
(4-butoxy-benzyI)-carbamic acid 2,4-difluoro-phenyl ester;
(4-butoxy-benzyl)-carbamic acid 4-methoxy-phenyl ester; [1 -(4-bύtoxy-phenyl)-propyl]-carbamic acid 4-fluoro-phenyl ester;
(4-butoxy-benzyl)-carbamic acid 2-fluoro-phenyl ester; and
(4-butoxy-benzyl)-carbamic acid 3-chloro-phenyl ester.
According to various embodiments of a fifth aspect of the present invention are provided compounds of Formula IX:
Figure imgf000011_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein a is 1 ;
R is Cι-12 alkoxy; R1 is a C-ι-3 branched or linear aliphatic hydrocarbon; and
X is CH or nitrogen.
According to another embodiment of the fifth aspect of the present invention are provided compounds of Formula IX according to the first embodiment of the fifth aspect wherein X is CH and is a member selected from the group consisting of:
(4-butoxy-benzyl)-carbamic acid quinoϋn-6-yl ester;
(4-butoxy-benzyl)-carbamic acid naphthaIen-2-yl ester;
[1-(4-butoxy-phenyl)-propyl]-carbamic acid quinolin-6-yl ester; and (4-butoxy-benzyl)-carbamic acid naphthalen-1-yl ester.
According to various embodiments of a sixth aspect of the present invention is provided a method of treating a condition or disorder by inhibiting fatty acid amidohydrolase in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I or a compound having the structure
Figure imgf000012_0001
According to various embodiment of a seventh aspect of the present invention is provided a method of treating a condition or disorder by inhibiting fatty acid amidohydrolase in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of a eighth aspect of the present invention is provided a method of treating neuropathic pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I. According to various embodiments of a ninth aspect of the present invention is provided a method of treating acute pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of a tenth aspect of the present invention is provided a method of treating chronic pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of an eleventh aspect of the present invention is provided a method of treating emesis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of a twelfth aspect of the present invention is provided a method of treating anxiety in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of a thirteenth aspect of the present invention is provided a method of altering feeding behaviors in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I. According to various embodiments of a fourteenth aspect of the present invention is provided a method of treating movement disorders in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of a fifteenth aspect of the present invention is provided a method treating glaucoma in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of a sixteenth aspect of the present invention is provided a method of treating brain injury in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of a seventeenth aspect of the present invention is provided a method of treating cardiovascular disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
According to various embodiments of an eighteenth aspect of the present invention is provided a pharmaceutical composition for treating a condition or disorder requiring inhibition of a fatty acid amidohydrolase comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or diluent.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel series of compounds of
Formula I, its hydrates and solvates thereof:
Figure imgf000014_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein A is dibenzofuranyl, dibenzothienyl, naphthyl, indolyl, fluorenyl, carbazolyl, or represented by Formula II:
Figure imgf000014_0002
wherein a is 1 or 2, R is Cι-16 alkoxy optionally substituted with phenyl, pyridyl or morpholinyl; phenyl optionally substituted with Cι- alkyl; phenoxy; phenyl-Cι-4 alkyloxy-; pyridyloxy; pyridyl-Cι-4 alkyloxy-; -N(H)-C(0)-Cι-ι6 alkyl; or -C(0)-N(H)-Cι-ι6 alkyl;
R1 is a bond or a Cι-3 branched or linear aliphatic hydrocarbon; and B is C-ι-4 alkyl, indolyl, benzofuranyl, benzothienyl, dibenzofuranyl, dibenzothienyl, fluorenyl, carbazolyl, napthyl, quinolinyl or isoquinolinyl, wherein each is optionally substituted with one or more of the same or different substituent selected from the group consisting of Ci-4 branched or linear aliphatic hydrocarbon, Cι-4 alkoxy, halo, haloalkyl, nitro and (Cι-3 alkyl)0-2 amino- or represented by Formula III or Formula IV:
Figure imgf000014_0003
wherein
R2 is hydrogen, methyl, R3 is C-ι-4 alkyl, pyridyl, or phenyl optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, Cι-4haloalkyl and nitro, X is CH or nitrogen, R4 is C-ι-4 branched or linear aliphatic hydrocarbon, Cι-4 alkoxy, halo, haloalkyl, nitro or amino, and b is 0 to 3.
Preferably, A is represented by Formula II:
Figure imgf000015_0001
wherein a is 1 , R is Cι-ι2 alkoxy; phenoxy; pyridyloxy; or amido optionally substituted with Ci.-iβ alkyl; and R1 is a bond. When B is represented by Formula III:
Figure imgf000015_0002
R2 is preferably hydrogen or methyl, and R3 is preferably methyl, or phenyl optionally substituted with one or more halo, haloalkyl or nitro. When B is represented by Formula IV:
Figure imgf000015_0003
X is preferably CH, R4 is preferably halo, and b is 1. When X is nitrogen, however, b is preferably 0. When B is represented by Formula V:
Figure imgf000015_0004
X is preferably nitrogen.
The description of the invention herein should be construed in congruity with the laws and principals of chemical bonding. For example, when a moiety is optionally substituted and said substitution requires the removal of a hydrogen atom from the moiety to be substituted, the description of the moiety should be read to include the moiety with or without said hydrogen atom. As another example, if a variable is defined as a particular moiety or atom and is further defined to have value of 0 or some integer, the bond(s) attaching said moiety should be suitably removed in the event the variable equals 0. An embodiment or aspect which depends from another embodiment or aspect, will describe only the variables having values and provisos that differ from the embodiment or aspect from which it depends. For example, if a dependnent embodiment describes a variable as being "phenyl or pyridyl", wherein said phenyl and pyridyl were described in the independent embodiment as being "optionally substituted", then the phenyl and pyridyl of the dependent embodiment will also be optionally substituted.
It is to be understood that the present invention may include any and all possible stereoisomers, geometric isomers, diastereoisomers, enantiomers, anomers and optical isomers, unless a particular description specifies otherwise. More particularly, the groups attached to the oxime portion of compounds of Formula (I), i.e., N=C, may assume transoid or cisoid configurations.
As used herein, "halo" or "halogen" includes fiuoro, chloro, bromo and iodo. As used herein, "alkyl" or "alkylene" includes straight or branched chain configurations.
The compounds of this invention can exist in the form of pharmaceutically acceptable salts. Such salts include addition salts with inorganic acids such as, for example, hydrochloric acid and sulfuric acid, and with organic acids such as, for example, acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid. Further, in case the compounds of this invention contain an acidic group, the acidic group can exist in the form of alkali metal salts such as, for example, a potassium salt and a sodium salt; alkaline earth metal salts such as, for example, a magnesium salt, and a calcium salt; and salts with organic bases such as a triethylammonium salt and an arginine salt. The compounds of the present invention may be hydrated or non-hydrated.
The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of this invention may also be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those skilled in the pharmaceutical arts. The compounds can be administered alone, but generally will be administered with a pharmaceutical carrier selected upon the basis of the chosen route of administration and standard pharmaceutical practice. Compounds of this invention can also be administered in intranasal form by topical use of suitable intranasal vehicles, or by transdermal routes, using transdermal skin patches. When compounds of this invention are administered transdermally the dosage will be continuous throughout the dosage regimen.
The dosage and dosage regimen and scheduling of a compounds of the present invention must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and extent of the disease condition. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level that will produce effective beneficial effects without causing any harmful or untoward side effects.
Compounds of the present invention may be synthesized according to the description provided below. Variables provided in the schema below are defined in accordance with the description of compounds of Formula (I) unless otherwise specified.
EXPERIMENTALS Scheme 1 :
Figure imgf000017_0001
Scheme 1 Reaction conditions: (i) R-halide, NaH, DMF, room temp.; (ii) NaOH, EtOH, room temp., (iii) (a) N3P(0)(OPh)2, Et3N, toluene at 105°C, (b) addition of oxime C at 80°C; n is 0 to 3; R, R2, R3, and B are as defined above.
Scheme 1A:
Figure imgf000018_0001
Scheme 1A Reaction conditions: (i) R-halide, NaH, DMF, room temp.; (ii) NaOH, EtOH, room temp., (iii) (a) N3P(O)(OPh)2, Et3N, toluene at room temp, following by 90 min. at reflux, (b) addition of oxime C at room temp, with stirring for 1 hr., heating to 85°C; n is 0 to 3; R, and R2 are as defined above.
Scheme 1B:
Figure imgf000018_0002
Scheme 1 B Reaction conditions: (iv) (a) N3P(O)(OPh)2, Et3N, toluene at 105°C, (b) B-OH at 80°C; n is 0 to 3; R and B are as defined above.
The following Intermediates 1 to 39 may be used to synthesize Examples 1 to 124 in accordance with Schemes 1 , 1A and 1 B.
INTERMEDIATE 1
Figure imgf000018_0003
4-Propoxy-benzoic acid ethyl ester: (Scheme 1 , Compound A) To a solution of ethyl 4-hydroxybenzoate (2.0 g, 12 mmol) and bromopropane (4.0 g, 32.8 mmol) in DMF (50 mL) was added NaH (60% in mineral oil, 0.80 g, 20.8 mmol). The resultant suspension was stirred at room temperature for 1.0 hour. The mixture was diluted with ethyl acetate (EtOAc) (300 mL), washed with H20, and then was dried over Na2S04. After filtration and concentration in vacuo, the residue was purified by flash chromatography (Si0 : EtOAc/Hexanes). This compound was obtained as a yellow oil (2.26 g, 10.9 mmol, 91% yield). 1H NMR (DMSO-cfe) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.24 (q, 2H, J=6.9 Hz), 3.98 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (t, 3H, J=6.6 Hz), 0.97 (t, 3H, J=7.2 Hz); Anal. Calcd for Cι2H16O3-0.47 C6H14: C, 71.54; H, 9.14; N, 0.00. Found: C, 71.57; H, 8.78, N, 0.00; Mass Spec: 209.04 (MH+).
INTERMEDIATE 2
Figure imgf000019_0001
4-Ethoxy-benzoic acid ethyl ester: (Scheme 1, Compound A)
Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 7.89 (d, 2H, J=9.0 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.24 (q, 2H, J=6.9 Hz), 4.08 (q, 2H, J=6.9 Hz), 1.31 (m, 6H); Anal. Calcd for CιιH14θ3«0.47C6Hi4: C, 70.71 ; H, 8.83; N, 0.00; Found: C, 71.10; H, 8.43, N, 0.00; Mass Spec: 194.93 (MH+).
INTERMEDIATE 3
Figure imgf000019_0002
4-Pentyloxy-benzoic acid ethyl ester: (Scheme 1, Compound A)
Prepared as described for the example above. 1H NMR (DMSO-cfe) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.24 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 7H, J=6.6 Hz), 0.97 (t, 3H, J=7.2 Hz); Anal. Calcd for Cι4H2oθ3»0.37C6H14: C, 72.63; H, 9.46; N, 0.00; Found: C, 72.69; H, 9.12, N, 0.00; Mass Spec: 237.11 (MH+). INTERMEDIATE 4
Figure imgf000020_0001
4-Butoxy-3-methoxy-benzoic acid methyl ester: (Scheme 1, Compound
A) Prepared as described for the example above. 1H NMR (DMSO- /6) δ 7.57 (dd, 1 H, J=8.4, 1.8 Hz), 7.43 (d, 1 H, J=1.8 Hz), 7.06 (d, 1 H, J=8.4 Hz), 4.02 (q, 2H, J=6.6 Hz), 3.82 (s, 3H), 3.80 (s, 3H), 1.72 (m, 2H), 1.44 (m, 2H), 0.92 (t, 3H, J=7.5 Hz); Mass Spec: 239.21 (MH+).
INTERMEDIATE 5
Figure imgf000020_0002
4-Hexyloxy-benzoic acid ethyl ester: (Scheme 1, Compound A) Prepared as described for the example above. 1H NMR (DMSO-^e) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.26 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 9H), 0.89 (t, 3H, J=7.2 Hz); Mass Spec: 251 (MH+).
INTERMEDIATE 6
Figure imgf000020_0003
4-Heptyloxy-benzoic acid ethyl ester: (Scheme 1. Compound A)
Prepared as described for the example above. 1H NMR (DMSO-αfe) 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.26 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 11 H), 0.85 (t, 3H, J=7.2 Hz); Mass Spec. 265 (MH+).
INTERMEDIATE 7
Figure imgf000021_0001
4-Octyloxy-benzoic acid ethyl ester: (Scheme 1 , Compound A) Prepared as described for the example above. 1H NMR (DMSO-cfe) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.26 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 13H), 0.84 (t, 3H, J=7.2 Hz); Mass Spec: 279.36 (MH+).
INTERMEDIATE 8
Figure imgf000021_0002
4-Nonyloxy-benzoic acid ethyl ester: (Scheme 1, Compound A) Prepared as described for the example above. 1H NMR (DMSO-Oβ) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.26 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 15H), 0.84 (t, 3H, J=7.2 Hz); Mass Spec: 293.32 (MH+).
INTERMEDIATE 9
Figure imgf000021_0003
4-Decyloxy-benzoic acid ethyl ester: (Scheme 1. Compound A) Prepared as described for the example above. 1H NMR (DMSO-Oe) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.26 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 17H), 0.83 (t, 3H, J=7.2 Hz); Mass Spec. 307.27 (MH+).
INTERMEDIATE 10
Figure imgf000022_0001
4-Undecyloxy-benzoic acid ethyl ester: (Scheme 1, Compound A)
Prepared as described for the example above. 1H NMR (DMSO-c/6) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.26 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 19H), 0.83 (t, 3H, J=7.2 Hz); Mass Spec: 321.28 (MH+).
INTERMEDIATE 11
Figure imgf000022_0002
4-Dodecyloxy-benzoic acid ethyl ester: (Scheme 1, Compound A) Prepared as described for the example above. 1H NMR (DMSO-c6) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.26 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 21 H), 0.83 (t, 3H, J=6.6 Hz); Mass Spec: 335.29 (MH+).
INTERMEDIATE 12
Figure imgf000022_0003
4-(3-Morpholin-4-yl-propoxy)-benzoic acid ethyl ester: (Scheme 1 , Compound A) Prepared as described for the example above. 1H NMR (DMSO- 6) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.26 (q, 2H, J=6.9 HZ), 4.08 (t, 2H, J=6.6 Hz), 3.56 (t, 4H, J=4.5 Hz), 2.36 (m, 6H), 1.72 (m, 2H), 1.32 (m, 2H), 1.29 (t, 3H, J=6.9 Hz); Mass Spec: 294.32 (MH+).
INTERMEDIATE 13
Figure imgf000023_0001
(4-Butoxy-phenyl)-acetic acid methyl ester: (Scheme 1, Compound A)
Prepared as described for the example above. 1H NMR (DMSO-c/6) δ 7.16 (dd, 2H, J=6.6, 1.8 Hz), 6.85 (dd, 2H, J=6.6, 1.8 Hz), 3.93 (t, 2H, J=6.3 Hz), 3.59 and 3.58 (5H, CH2, CH3), 1.67 (m, 2H), 1.40 (m, 2H) , 0.92 (t, 3H, J=7.2 Hz).
INTERMEDIATE D
Figure imgf000023_0002
3-Butoxy-benzoic acid ethyl ester: (Scheme 1. Compound A) Prepared as described for the example above. 1H NMR (DMSO-α6) δ 7.53 (dd, 1 H, J=7.8, 1.5 Hz), 7.42 (m, 2H), 7.20 (dd, 1 H, J=8.4, 1.5 Hz), 4.31 (q, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.47 (m, 2H), 1.32 (t, 3H, J=6.9 Hz), 0.93 (t, 3H, J=7.5 Hz); Mass Spec: 223.24 (MH+).
INTERMEDIATE 15
Figure imgf000023_0003
4-Butoxy-benzoic acid: (Scheme 1, Compound B) To a solution of ethyl 4-butoxybenzoate (2.0 g, 9.6 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at room temperature for 3 hours, diluted with H20 (30 mL), acidified to about pH 1.0 using HCI (6N). The precipitates were filtered off by filter paper, washed by H20 and hexanes. This compound was obtained as a white solid. (1.63 g, 9.1 mmol, 94 % yield). 1H NMR (DMSO-cfe) δ 12.59 (br. s, 1 H), 7.88 (d, 2H, J=9.5 Hz), 6.97 (d, 2H, J=9.5 Hz), 4.01 (t, 2H, J=6.5 Hz), 1.68 (m, 2H), 1.42 (m, 2H), 0.91 (t, 3H, J=6.5 Hz); 13C NMR (DMSO): 166.9, 162.2, 131.2, 122.7, 114.0, 67.3, 30.5, 18.6 and 13.5; Mass Spec: 195.17 (MH+).
INTERMEDIATE 16
Figure imgf000024_0001
4-Pentyloxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 12.59 (br, s, 1 H), 7.88 (d, 2H, J=9.6 Hz), 6.97 (d, 2H, J=9.6 Hz), 4.01 (t, 2H, J=6.9 Hz), 1.69 (m, 2H), 1.32 (m, 4H), 0.89 (t, 3H, J=6.9 Hz); Mass Spec: 209.23 (MH+).
INTERMEDIATE D
Figure imgf000024_0002
4-Propoxy-benzoic acid: (Scheme 1. Compound B) Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 12.6 (br, s, 1 H), 7.88 (d, 2H, J=9.6 Hz), 6.97 (d, 2H, J=9.6 Hz), 4.01 (t, 2H, J=6.9 Hz), 1.72 (m, 2H), 0.97 (t, 3H, J=7.5 Hz); Mass Spec: 181.18 (MH+).
INTERMEDIATE 18
Figure imgf000024_0003
4-Ethoxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 12.59 (br. s, 1 H), 7.88 (d, 2H, J=9.6 Hz), 6.97 (d, 2H, J=9.6 Hz), 4.08 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=6.9 Hz); Mass Spec: 167.13 (MH+). INTERMEDIATE 19
Figure imgf000025_0001
4-Butoxy-3-methoxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-ofe) δ 12.6 (br, s, 1 H), 7.54 (dd, 1 H, J=8.4, 1.8 Hz), 7.43 (d, 1 H, J=1.8 Hz), 7.06 (d, 1 H, J=8.4 Hz), 4.02 (q, 2H, J=6.6 Hz), 3.80 (s, 3H), 1.72 (m, 2H), 1.44 (m, 2H), 0.92 (t, 3H, J=7.5 Hz).
INTERMEDIATE 20
Figure imgf000025_0002
4-Hexyloxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-d6) δ 12.59 (s, 1 H), 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 6H), 0.89 (t, 3H, J=7.2 Hz); Mass Spec: 223 (MH+).
INTERMEDIATE 21
Figure imgf000025_0003
4-Heptyloxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 12.59 (s, 1 H), 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 8H), 0.85 (t, 3H, J=7.2 Hz); Mass Spec: 237.16 (MH+).
INTERMEDIATE 22
Figure imgf000025_0004
4-Octyloxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-cfe) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 10H), 0.84 (t, 3H, J=7.2 Hz); Mass Spec: 251.11 (MH+).
INTERMEDIATE 23
Figure imgf000026_0001
4-Nonyloxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-Oe) δ 12.58 (s, 1 H), 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 12H), 0.84 (t, 3H, J=7.2 Hz).
INTERMEDIATE 24
Figure imgf000026_0002
4-Dodecyloxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO- 6) δ 12.6 (s, 1 H), 7.86 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 18H), 0.84 (t, 3H, J=6.6 Hz).
INTERMEDIATE 25
Figure imgf000026_0003
4-Undecyloxy-benzoic acid: (Scheme 1. Compound B) Prepared as described for the example above. 1H NMR (DMSO-c/6) δ 12.6 (s, 1 H), 7.86 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 16H), 0.84 (t, 3H, J=6.6 Hz). INTERMEDIATE 26
Figure imgf000027_0001
4-Decyloxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-cfe) δ 12.6 (s, 1 H), 7.86 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (m, 14H), 0.84 (t, 3H, J=6.6 Hz).
INTERMEDIATE 27
Figure imgf000027_0002
4-(3-Morpholin-4-yl-propoxy)-benzoic acid: (Scheme 1, Compound B)
Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 7.78 (d, 2H, J=8.4 Hz), 6.79 (d, 2H, J=8.4 Hz), 4.08 (t, 2H, J=6.6 Hz), 3.56 (t, 4H, J=4.5 Hz), 2.36 (m, 6H), 1.85 (m, 2H).
INTERMEDIATE 28
Figure imgf000027_0003
(4-Butoxy-phenyl)-acetic acid: (Scheme 1. Compound B) Prepared as described for the example above. 1H NMR (DMSO-ofe) δ 12.21 (br. s, 1 H), 7.16 (dd, 2H, J=6.6, 1.8 Hz), 6.85 (dd, 2H, J=6.6, 1.8 Hz), 3.93 (t, 2H, J=6.3 Hz), 3.46 (s, 2H), 1.69 (m, 2H), 1.43 (m, 2H) , 0.92 (t, 3H, J=7.2 Hz).
INTERMEDIATE 29
Figure imgf000027_0004
3-Butoxy-benzoic acid: (Scheme 1, Compound B) Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 7.53 (dd, 1 H, J=7.8, 1.5 Hz), 7.42 (m, 2H), 7.17 (dd, 1H, J=8.4, 1.5 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.47 (m, 2H), 0.93 (t, 3H, J=7.2 Hz).
INTERMEDIATE 30
Figure imgf000028_0001
2,4-Difluoro-benzaldehvde oxime: (Scheme 1, Compound C) To a mixture of 2,4-difluorobenzaldehyde (0.80 g, 5.6 mmol) and hydroxyamine HCI salt (0.43 g, 6.2 mmol) in EtOH (5 mL) was added K2C03 (0.85 g, 6.2 mmol). The resultant mixture was stirred at rt for 24 hours. The mixture was diluted with MeOH (20 mL). The precipitates were filter off and washed with MeOH. The product from filtrate was purified by recrystalization (EtOAc/Hexanes). This compound was obtained as a white solid (0.84 g, 5.3 mmol, 94% yield). 1H NMR (DMSO-αfe) δ 12.98 (br. s, 1 H), 8.17 (s, 1 H), 7.79 (m, 1H), 7.32 (m, 1H), 7.11 (m, 1H); Analytical HPLC 1.03 min. (95%); Mass Spec: 158.06 (MH+).
INTERMEDIATE 31
Figure imgf000028_0002
2-Fluoro-6-trifluoromethyl-benzaldehvde oxime: (Scheme 1, Compound
C) Prepared as described for the example above. 1 H NMR (DMSO-ofe) δ 11.96 (br. s, 1H), 8.21 (m, 1H), 7.65 (m, 3H); Analytical HPLC 1.20 min. (96%); Mass Spec: 208.14 (MH+). INTERMEDIATE 32
Figure imgf000029_0001
3,4-Difluoro-benzaldehvde oxime: (Scheme 1, Compound C)
Prepared as described for the example above. Analytical HPLC 1.00 min. (92%); Mass Spec: 158 (MH+).
INTERMEDIATE 33
Figure imgf000029_0002
3-Fluoro-benzaldehvde oxime: (Scheme 1, Compound C) Prepared as described for the example above. Analytical HPLC 0.90 min. (95%); Mass Spec: 138 (MH-).
INTERMEDIATE 34
Figure imgf000029_0003
4-Trif luoromethyl-benzaldehyde oxime: (Scheme 1 , Compound C)
Prepared as described for the example above. Analytical HPLC 1.31 min. (95%); Mass Spec: 188.01 (MH+).
INTERMEDIATE 35
Figure imgf000029_0004
2-Fluoro-3-trifluoromethyl-benzaldehvde oxime: (Scheme 1, Compound
C) Prepared as described for the example above. Analytical HPLC 1.41 min. (90%); Mass Spec: 206.00 (MH-). INTERMEDIATE 36
Figure imgf000030_0001
2,3,5,6-Tetrafluoro-benzaldehvde oxime: (Scheme 1, Compound C)
Prepared as described for the example above. Analytical HPLC 0.83 min. (96%); Mass Spec: 191.98 (MH-).
INTERMEDIATE 37
Figure imgf000030_0002
2.6-Difluoro-benzaldehvde oxime: (Scheme 1, Compound C) Prepared as described for the example above. Analytical HPLC 0.86 min. (95%); Mass Spec: 158.05 (MH+).
INTERMEDIATE 38
Figure imgf000030_0003
2,3-Difluoro-benzaldehvde oxime: (Scheme 1, Compound C) Prepared as described for the example above. Analytical HPLC 0.83 min. (90%); Mass Spec: 156.04 (MH-).
INTERMEDIATE 39
Figure imgf000030_0004
2,4,5-Trifluoro-benzaldehvde oxime: (Scheme 1, Compound C) Prepared as described for the example above. Analytical HPLC 0.89 min. (91%); Mass Spec: 174.00 (MH-). EXAMPLE 1
Figure imgf000031_0001
3-Pyridinecarboxaldehyde, 0-[[[4-(Heptyloxy)phenyl]amino]- carbonyl]oxime (Scheme 1, Compound D) To a solution of 4- heptyloxybenzoic acid (0.20 g, 0.85 mmol) and Et3N (0.18 g, 1.8 mmol) in toluene (5 mL) was added diphenylphosphoryl azide (0.322 g, 1.2 mmol). The resultant mixture was stirred at r.t. for 10 min. and then at 105 °C under N2 for 60 min. After the mixture was cooled to r.t., 3-pyridinealdoxime (0.20 g, 1.7 mmol) was added. The reaction mixture was stirred at r.t. for 10 min. and then at 80 °C for 1 h. The product (free base) was purified by flash chromatography (Siθ2: EtOAc/Hexanes) and then was dissolved in a solution of TFA in THF (5.0 mg/mL, 17.8 mL, 0.78 mmol). Removal of solvent provided this compound (TFA salt) as a pale yellow solid (0.244 g, 0.52 mmol, 61 % yield). 1H NMR (DMSO-αfe) δ 9.72 (s, 1 H), 8.99 (s, 1 H), 8.72 (m, 2H), 8.32 (d, 1 H, J=9.0 Hz), 7.56 (m, 1 H), 7.40 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=6.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.72 (m, 2H), 1.32 (m, 8H), 0.87 (t, 3H, J=7.0 Hz); Anal. Calcd for C2oH25N303 »0.98 C2F302H!: C, 56.44; H, 5.60; N,
8.99. Found: C, 56.41 ; H, 5.64, N, 8.94. Mass Spec: 356.28 (MH+).
EXAMPLE 2
Figure imgf000031_0002
(4-Butoxyphenyl)methylcarbamic acid, 3-pyridinyl ester (Scheme 1, Compound D) Prepared as described for the example above. 1H NMR (DMSO- /β) δ 8.51 (m, 3H), 7.75 (m, 1 H), 7.55 (m, 1 H), 7.24 (d, 2H, J=9.0 Hz), 6.91 (d, 2H, J=8.7 Hz), 4.22 (d, 2H, J=6.0), 3.92 (t, 2H, J=6.6 Hz), 1.70 (m, 2H), 1.36 (m, 2H), 0.92 (t, 3H, J=7.5 Hz); Anal. Calcd for C17H20N2C I .55 C2F3O2H1: C, 50.64; H, 4.56; N, 5.88. Found: C, 50.49; H, 4.58, N, 5.73. Mass Spec: 301.17 (MH+). EXAMPLE 3
Figure imgf000032_0001
3-Pyridinecarboxaldehyde, O-[[[4-(undecyloxy)phenyl]amino]- carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. 1H NMR (DMSO-c/6) δ 9.72 (s, 1 H), 8.99 (s, 1 H), 8.72 (m, 2H), 8.32 (d, 1 H, J=9.0 Hz), 7.56 (m, 1 H), 7.40 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=6.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.72 (m, 2H), 1.32 (m, 16 H), 0.87 (t, 3H,
J=7.0 Hz). Mass Spec: 412.33 (MH+).
EXAMPLE 4
Figure imgf000032_0002
3-Pyridinecarboxaldehyde, O-[[[4-(nonyloxy)phenyl]amino]- carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. 1H NMR (DMSO-c/6) δ 9.72 (s, 1 H), 8.99 (s, 1 H), 8.72 (m, 2H), 8.32 (d, 1 H, J=9.0 Hz), 7.56 (m, 1 H), 7.40 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=6.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.72 (m, 2H), 1.32 (m, 12 H), 0.87 (t, 3H,
J=7.0 Hz). Mass Spec: 384.89 (MH+).
EXAMPLE 5
Figure imgf000032_0003
4-Fluorobenzaldehyde, 0-[[(4-butoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above in a form of free base. No trifluoroacetic acid was used. 1H NMR (DMSO- /6) δ 9.66 (s, 1 H), 8.64 (s, 1 H), 7.90 (m, 2H), 7.38 (m, 2H), 7.34 (t, 2H, J=6.0 Hz), 6.92 (d, 2H, J=4.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.72 (m, 2H), 1.40 (m, 2H), 0.92 (t, 3H, J=7.5 Hz); Anal. Calcd for
Figure imgf000033_0001
C, 65.44; H, 5.79; N, 8.48. Found: C, 65.48; H, 5.88, N, 8.46. Mass Spec: 331.14 (MH+).
EXAMPLE 6
Figure imgf000033_0002
2-Propanone, 0-[[(4-ethoxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. This compound was purified by preparative HPLC (YMC 30X100 mm (5 uM packing), 10% MeOH/90% water/01% TFA as mobile phase A, 90% MeOH/10%water/0.1 % TFA as mobile phase B). Analytical HPLC 1.10 min. (95%). Mass Spec: 237 (MH+).
EXAMPLE 7
Figure imgf000033_0003
2-Propanone, 0-[[(4-propoxyphenyl)amino]carbonyl]oxime
(Scheme 1, Compound D) Prepared as described for the example above. 1H NMR (DMSO- e) δ 9.36 (s, 1 H), 7.34 (d, 2H, J=9.0 Hz), 6.85 (dd, 2H, J=6.9, 2.1 Hz), 3.87 (t, 2H, J=6.9 Hz), 1.97 (s, 6H), 1.72 (m, 2H), 0.96 (t, 3H, J=7.5 Hz); Analytical HPLC 1.27 min. (95%). Mass Spec: 251.24 (MH+).
EXAMPLE 8
Figure imgf000033_0004
2-Propanone, 0-[[(4-pentyloxyphenyl)amino]carbonyI]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.67 min. (95%). Mass Spec: 279.18 (MH+). EXAMPLE 9
Figure imgf000034_0001
Benzaldehyde, O-[[(4-ethoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.41 min. (85%). Mass Spec: 285.21 (MH+).
EXAMPLE 10
Figure imgf000034_0002
Benzaldehyde, O-[[(4-propoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.64 min. (85%). Mass Spec: 299.15 (MH+).
EXAMPLE 11
Figure imgf000034_0003
Benzaldehyde, O-[[(4-pentyIoxyphenyl)amino]carbonyl]oxime
(Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.85 min. (95%). Mass Spec: 327.20 (MH+).
EXAMPLE 12
Figure imgf000034_0004
4-Fluorobenzaldehyde, 0-[[(4-ethoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. 1H NMR (DMSO- e) δ 9.66 (s, 1 H), 8.64 (s, 1 H), 7.90 (m, 2H), 7.38 (m, 4H), 6.90 (d, 2H, J=4.5 Hz), 3.92 (q, 2H, J=6.5 Hz), 1.31 (t, 3H, J=7.2 Hz). Analytical HPLC 1.46 min. (95%). Mass Spec: 303 (MH+).
EXAMPLE 13
Figure imgf000035_0001
4-Fluorobenzaldehyde, O-[[(4-propoxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 1.67 min. (94%). Mass Spec: 317 (MH+).
EXAMPLE 14
Figure imgf000035_0002
4-Fluorobenzaldehyde, 0-[[(4-pentyloxyphenyl)amino]carbonyl]oxime
(Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 1.76 min. (97%). Mass Spec: 345.24 (MH+).
EXAMPLE 15
Figure imgf000035_0003
3-Pyridinecarboxaldehyde, 0-[[(4-ethoxyphenyl)amino]carbonyl]-oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC0.99 min. (95%). Mass Spec: 286.24 (MH+). EXAMPLE 16
Figure imgf000036_0001
3-Pyridinecarboxaldehyde, 0-[[(4-propoxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.28 min. (95%). Mass Spec: 300.15 (MH+).
EXAMPLE 17
Figure imgf000036_0002
3-Pyridinecarboxaldehyde, 0-[[(4-pentyloxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.50 min. (95%). Mass Spec: 328.27 (MH+).
EXAMPLE 18
Figure imgf000036_0003
2-Propanone, 0-[[(4-butoxy-3-methoxyphenyl)amino]carbonyl]oxime
(Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.35 min. (98%). Mass Spec: 295.27 (MH+).
EXAMPLE 19
Figure imgf000036_0004
Benzaldehyde, 0-[[(4-butoxy-3-methoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.59 min. (99%). Mass Spec: 343 (MH+). EXAMPLE 20
Figure imgf000037_0001
4-Fluorobenzaldehyde, O-[[(4-butoxy-3-methoxyphenyl)amino]- carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.61 min. (95%). Mass Spec: 361.24 (MH+).
EXAMPLE 21
Figure imgf000037_0002
3-Pyridinecarboxaldehyde, 0-[[(4-butoxy-3-methoxyphenyl)amino]- carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.27 min. (99%). Mass Spec: 344.30 (MH+).
EXAMPLE 22
Figure imgf000037_0003
2-Propanone, O-[[(4-hexyloxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above.- Analytical HPLC 1.70 min. (94%). Mass Spec: 293 (MH+).
EXAMPLE 23
Figure imgf000037_0004
Benzaldehyde, 0-[[(4-hexyloxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 1.84 min. (99%). Mass Spec: 341.26 (MH+).
EXAMPLE 24
Figure imgf000038_0001
4-Fluorobenzaldehyde, 0-[[(4-hexyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.86 min. (99%). Mass Spec: 359.22 (MH+).
EXAMPLE 25
Figure imgf000038_0002
3-Pyridinecarboxaldehyde, O-[[(4-hexyloxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.64 min. (90%). Mass Spec: 342.30 (MH+).
EXAMPLE 26
Figure imgf000038_0003
2-Propanone, 0-[[(4-heptyloxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 1.98 min. (91%). Mass Spec: 307.19 (MH+). EXAMPLE 27
Figure imgf000039_0001
Benzaldehyde, 0-[[(4-heptyloxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 2.11 min. (93%). Mass Spec: 355.18 (MH+).
EXAMPLE 28
Figure imgf000039_0002
4-Fluorobenzaldehyde, 0-[[(4-heptyloxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 2.10 min. (90%). Mass Spec: 373.11 (MH+).
EXAMPLE 29
Figure imgf000039_0003
2-Propanone, 0-[[(4-octyloxyphenyl)amino]carbonyl]oxime
(Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 1.89 min. (87%). Mass Spec: 321 (MH+).
EXAMPLE 30
Figure imgf000039_0004
3-Pyridinecarboxaldehyde, O-[[(4-octyloxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.0 min. (85%). Mass Spec:370.13 (MH+).
EXAMPLE 31
Figure imgf000040_0001
2-Propanone, O-[[(4-nonyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.64 min. (97%). Mass Spec: 335.31 (MH+).
EXAMPLE 32
Figure imgf000040_0002
2-Propanone, O-[[(4-decyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.03 min. (99%). Mass Spec: 349.35 (MH+).
EXAMPLE 33
Figure imgf000040_0003
Benzaldehyde, 0-[[(4-decyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.10 min. (99%). Mass Spec: 397.38 (MH+).
EXAMPLE 34
Figure imgf000040_0004
4-Fluorobenzaldehyde, 0-[[(4-decyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.11 min. (97%). Mass Spec: 415.34 (MH+).
EXAMPLE 35
Figure imgf000041_0001
3-Pyridinecarboxaldehyde, 0-[[(4-decyIoxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.01 min. (85%). Mass Spec: 398.34 (MH+).
EXAMPLE 36
Figure imgf000041_0002
2-Propanone, 0-[[(4-undecyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.25 min. (90%). Mass Spec: 363.26 (MH+).
EXAMPLE 37
Figure imgf000041_0003
Benzaldehyde, 0-[[(4-undecyloxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 2.36 min. (96%). Mass Spec: 411.28 (MH+). EXAMPLE 38
Figure imgf000042_0001
4-FIuorobenzaldehyde, 0-[[(4-undecyloxyphenyl)amino]carbonyl]-oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 2.37 min. (97%). Mass Spec: 429.30 (MH+).
EXAMPLE 39
Figure imgf000042_0002
Benzaldehyde, O-[[(4-butoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. 1H NMR (DMSO-cfe) δ 9.66 (s, 1 H), 8.62 (s, 1 H), 7.82 (m, 2H), 7.52 (m, 3H), 7.40 (d, 2H, J=8.5 Hz), 6.90 (d, 2H, J=9.0 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.72 (m, 2H), 1.40 (m, 2H), 0.92 (t, 3H, J=7.5 Hz);Analytical HPLC 1.67 min. (90%). Mass Spec: 313.15 (MH+).
EXAMPLE 40
Figure imgf000042_0003
2-Propanone, O-[[(4-dodecyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.15 min. (99%). Mass Spec: 377.43 (MH+).
EXAMPLE 41
Figure imgf000042_0004
Benzaldehyde, 0-[[(4-dodecyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.20 min. (99%). Mass Spec: 425.41 (MH+).
EXAMPLE 42
Figure imgf000043_0001
4-Fluorobenzaldehyde, O-[[(4-dodecyloxyphenyl)amino]carbonyl]-oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.21 min. (99%). Mass Spec: 443.37 (MH+).
EXAMPLE 43
Figure imgf000043_0002
3-Pyridinecarboxaldehyde, O-[[(4-dodecyloxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.27 min. (85%). Mass Spec: 426.32 (MH+).
EXAMPLE 44
Figure imgf000043_0003
3-Pyridinecarboxaldehyde, O-[[(4-butoxyphenyl)amino]carbonyl]-oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.48 min. (95%). Mass Spec: 314.20 (MH+). EXAMPLE 45
Figure imgf000044_0001
Benzaldehyde, O-[[(4-octyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.99 min. (99%). Mass Spec: 369.27 (MH+).
EXAMPLE 46
Figure imgf000044_0002
4-Fluorobenzaldehyde, 0-[[(4-octyloxyphenyl)amino]carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 1.99 min. (96%). Mass Spec: 387.39 (MH+).
EXAMPLE 47
Figure imgf000044_0003
Benzaldehyde, 0-[[(4-nonyloxyphenyl)amino]carbonyl]oxime
(Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.04 min. (95%). Mass Spec: 383.30 (MH+).
EXAMPLE 48
Figure imgf000044_0004
4-Fluorobenzaldehyde, 0-[[(4-nonyloxyphenyl)amino]carbonyl]oxime
(Scheme 1, Compound D) Prepared as described for the example above.
Analytical HPLC 2.0 min. (95%). Mass Spec: 401.30 (MH+). EXAMPLE 49
Figure imgf000045_0001
3,4-Dif luorobenzaldehyde, 0-[[(4-nonyloxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. 1H NMR (DMSO-d6) δ 9.66 (s, 1 H), 8.62 (s, 1 H), 7.90 (m, 1 H), 7.65 (m, 2H), 7.40 (d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=9.0 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.72 (m, 2H), 1.25 (m, 12H), 0.85 (t, 3H, J=7.5 Hz). Analytical HPLC 2.03 min. (95%). Mass Spec: 419.20 (MH+).
EXAMPLE 50
Figure imgf000045_0002
2,6-Difluorobenzaldehyde, 0-[[(4-nonyloxyphenyl)amino]carbonyl]- oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 2.05 min. (85%). Mass Spec: 419 (MH+).
EXAMPLE 51
Figure imgf000045_0003
2,4-Difluorobenzaldehyde, 0-[[(4-nonyloxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.07 min. (99%). Mass Spec: 419.31 (MH+). EXAMPLE 52
Figure imgf000046_0001
3-Fluorobenzaldehyde, O-[[(4-nonyloxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.05 min. (95%). Mass Spec: 401.33 (MH+).
EXAMPLE 53
Figure imgf000046_0002
4-(Trifluoromethyl)benzaldehyde, O-[[(4-nonyloxyphenyl)amino]- carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 1.64 min. (99%). Mass Spec: 451.25 (MH+).
EXAMPLE 54
Figure imgf000046_0003
2-Fluoro-3-(trifluoromethyl)benzaldehyde, 0-[[(4-nonyloxyphenyl)- amino]carbonyI]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.11 min. (85%). Mass Spec: 469.07 (MH+). EXAMPLE 55
Figure imgf000047_0001
2,3-Difluorobenzaldehyde, 0-[[(4-nonyloxyphenyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.08 min. (90%). Mass Spec: 419.17 (MH+).
EXAMPLE 56
Figure imgf000047_0002
2,4,5-Trif luorobenzaldehyde, 0-[[(4-nonyloxyphenyl)amino]carbonyl]- oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 2.01 min. (95%). Mass Spec: 437 (MH+).
EXAMPLE 57
Figure imgf000047_0003
2-Fluoro-5-(trif luoromethyl)benzaldehyde, 0-[[(4-nonyloxyphenyl)- amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.11 min. (95%). Mass Spec: 469.13 (MH+). EXAMPLE 58
Figure imgf000048_0001
4-Fluorobenzaldehyde, 0-[[4-[3-(4-morpholinyl)propoxyphenyl]amino]- carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 2.68 min. (85%). Mass Spec: 402.30 (MH+).
EXAMPLE 59
Figure imgf000048_0002
4-Nitrobenzaldehyde, 0-[[(4-butoxyphenyl)amino]carbonyl]oxime
(Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.83 min. (85%). Mass Spec: 358.17 (MH+).
EXAMPLE 60
Figure imgf000048_0003
2-Propanone, 0-[[(4-butoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. 1H NMR (DMSO-cfe) δ 9.39 (br. s, 1 H), 7.36 (d, 2H, J=8.1 Hz), 6.90 (dd, 2H, J=7.0, 2.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.97 (s, 6H), 1.67 (m, 2H), 1.42 (m, 2H), 0.91 (t, 3H, J=7.0 Hz). Analytical HPLC 1.59 min. (95%). Mass Spec: 265.16 (MH+).
EXAMPLE 61
Figure imgf000048_0004
2-Propanone, 0-[[(4-butoxyphenylmethyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.44 min. (95%). Mass Spec: 279.32 (MH+).
EXAMPLE 62
Figure imgf000049_0001
Benzaldehyde, O-[[(4-butoxyphenylmethyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.66 min. (95%). Mass Spec: 327.31 (MH+).
EXAMPLE 63
Figure imgf000049_0002
4-FIuorobenzaldehyde, O-[[(4-butoxyphenylmethyl)amino]carbonyl]- oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.66 min. (85%). Mass Spec: 345.28 (MH+).
EXAMPLE 64
Figure imgf000049_0003
3-Pyridinecarboxaldehyde, O-[[(4-butoxyphenylmethyl)amino]- carbonyl]oxime (Scheme 1 , Compound D) Prepared as described for the example above. Analytical HPLC 1.55 min. (95%). Mass Spec: 328.29 (MH+). EXAMPLE 65
Figure imgf000050_0001
3-Pyridinecarboxaldehyde, 0-[[(3-butoxyphenyl)amino]carbonyl]-oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.39 min. (95%). Mass Spec: 314.28 (MH+).
EXAMPLE 66
Figure imgf000050_0002
2-Propanone, 0-[[(3-butoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.47 min. (97%). Mass Spec: 265.32 (MH+).
EXAMPLE 67
Figure imgf000050_0003
Benzaldehyde, 0-[[(3-butoxyphenyl)amino]carbonyl]oxime
(Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.69 min. (92%). Mass Spec: 313.27 (MH+).
Figure imgf000050_0004
4-Fluorobenzaldehyde, 0-[[(3-butoxyphenyl)amino]carbonyl]oxime (Scheme 1, Compound D) Prepared as described for the example above. Analytical HPLC 1.71 min. (92%). Mass Spec: 331.30 (MH+). EXAMPLE 69
Figure imgf000051_0001
3-Pyridinecarboxaldehyde, O-[[([1 ,1 '-biphenyl]-4- yl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method A: filtration of the reaction mixture, and the solid was recrystallized from EtOAc/hexanes, provided the title compound as light yellow solid in 38% yield. 1H NMR (DMSO, 400 MHz) δ 10.06 (s, 1 H), 8.96 (d, J = 2.0 Hz, 1 H), 8.74 (s, 1 H), 8.72 (dd, J = 1.6 Hz, J = 4.8 Hz, 1 H), 8.25 (dt, J = 1.8 Hz, J = 6.2 Hz 1 H), 7.68- 7.63 (m, 6H), 7.67-7.64 (dd, J = 4.8 Hz, J = 8.4 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1 H); 13C NMR (DMSO, 400 MHz) δ 152.7, 152.0, 151.5, 149.3, 139.5, 137.5, 135.0, 134.6, 128.8, 127.0, 126.5, 126.2, 124.0, 119.5; Mass spec: 318.0 (MH+); Anal. Calcd. for Ci9H14N302: C = 72.14 %, H = 4.46 %, N = 13.28 %; found: C = 72.09 %, H = 4.68 %, N = 13.14 %.
EXAMPLE 70
Figure imgf000051_0002
3-Pyridinecarboxaldehyde, O-[[(4'-ethyl-[1 ,1 '-biphenyl]-4- yl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. 1H NMR (DMSO, 400 MHz) δ 10.03 (s, 1 H), 8.97 (d, J = 1.7 Hz, 1 H), 8.74 (s, 1 H), 8.72 (dd, J = 1.7 Hz, J = 4.8 Hz, 1 H), 8.25 (dt, J = 1.6 Hz, J = 8.0 Hz 1 H), 7.63 (m, 4H), 7.57-7.54 (m, 3H), 7.28 (d, J = 8.3 Hz, 2H), 2.63 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); 13C NMR (DMSO, 400 MHz) δ 152.6, 151.9, 151.5, 149.3, 142.6, 137.2, 136.9, 135.0, 134.6, 128.2, 126.7, 126.5, 126.1 , 124.0, 119.5, 27.7, 15.5; Mass spec: 346.1 (MH+); Anal. Calcd. for C2iH18N3θ2: C = 73.24 %, H = 5.26 %, N = 12.20; found: C = 73.10 %, H = 5.46 %, H = 12.25 %.
EXAMPLE 71
Figure imgf000052_0001
3-Pyridinecarboxaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method A provided the title compound as white need like crystal in 24% yield. 1H NMR (DMSO, 400 MHz) δ 9.94, (s, 1 H), 8.96 (d, J = 1.7 Hz, 1 H), 8.72 (s, 1 H), 8.71 (dd, J = 1.8 Hz, J = 4.9 Hz, 1 H), 8.25 (dt, J = 1.9 Hz, J = 8.0 Hz, 1 H), 7.56-7.53 (m 3H), 7.37 (t, J = 7.4 Hz, 2H), 7.11 (t, J = 8.4 Hz, 1 H), 7.03 (d, J = 6.8 Hz, 2H), 6.98 (d, 8.2 Hz, 2H); 13C NMR (DMSO, 400 MHz) δ 157.2, 152.5, 151.9, 151.7, 149.3, 134.6, 133.8, 129.9, 126.5, 124.0, 122.9, 121.1 , 119.5, 117.8; Mass spec: 334.0 (MH+); Anal. Calcd. for C19H14N3O3: C = 68.66 %, H = 4.24 %, N = 12.64 %; found: C = 68.50 %, H = 4.49 %, N = 12.57 %.
EXAMPLE 72
Figure imgf000052_0002
Benzaldehyde, O-[[([1,1'-biphenyl]-4-yl)amino]carbonyl]oxime
(Scheme 1B, Compound D') Prepared as described for the example above. Using work-up method B: after removal of the solvent, the residue was chromatographed by silica gel column packed with EtOAc/hexanes or EtOAc/dichloromethane, to provide the title compound as white solid in 25% yield. 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1 H), 8.18 (br, 1 H), 7.75-7.73 (m 2H), 7.61 -7.58 (m, 6H), 7.54-7.42 (m, 5H), 7.34 (tt, J = 1.2 Hz, J = 7.4 Hz, 1 H). Anal. Calcd. for C20H15N2θ2-0.198H2θ: C = 75.32 %, H = 4.87 %, N = 8.78 %; found: C = 75.33 %, H = 5.16 %, N = 8.66 %. EXAMPLE 73
Figure imgf000053_0001
Benzaldehyde, O-[[([1 ,1 '-biphenyl]-4-yl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method B provided the title compound as white solid in 14% yield. 1H NMR (CDCI3, 400 MHz) δ 8.40 (s, 1 H), 8.09 (br, 1 H), 7.77-7.73 (m 2H), 7.60-7.58 (m, 6H), 7.44 (t, J = 7.3 Hz, 2H), 7.34 (tt, J = 1.2 Hz, J = 7.4 Hz, 1 H), 7.18 (t, J = 8.56 Hz, 2H); 166.6, 164.0, 1.52.7, 151.7, 140.4, 137.4, 136.1 , 130.4, 130.3, 128.8, 127.8, 127.2, 126.9, 126.0, 120.0, 116.6, 116.4.
EXAMPLE 74
Figure imgf000053_0002
Benzaldehyde, O-[[(4'-ethyl-[1 ,1 '-biphenyl]-4-yl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method C: after removal of solvent, the residue was dissolved in methanol and filtrated, the filtrate was purified by preparative HPLC with methanol:H20 (30:70 to about 100:0 v/v, containing 1% TFA) as a mobile phase to provide the title compound as white solid in 11% yield. 1H NMR (DMSO, 500 MHz) δ 9.99 (s, 1 H), 8.66 (s, 1 H), 7.84 (d, J = 8.1 Hz, 2H), 7.66-7.60 (m, 4H), 7.57-7.50 (m, 5H), 7.28 (d, J = 88.11 Hz, 2H), 2.63 (q, J = 7.5 Hz, 2H), 1.21 (m, 3H); 13C NMR (DMSO, 500 MHz) δ 154.8, 151.7, 142.5, 137.4, 136.9, 131.4, 130.3, 128.9, 128.2, 128.0, 126.7, 126.1 , 119.4, 27.7, 15.5; Mass spec: 345.1 (MH+); Anal. Calcd. for C22H20N2O2: C = 76.72 %, H = 5.85 %, N = 8.13 %; found: C = 76.67 %, H = 5.91 %, N = 8.02 %. EXAMPLE 75
Figure imgf000054_0001
4-Fluorobenzaldehyde, 0-[[(4'-ethyl-[1 ,1 '-biphenyl]-4- yl)amino]carbonyl]oxime (Scheme 1B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 10% yield. 1H NMR (CDCI3, 400 MHz) δ 8.40 (s, 1 H), 8.06 (s, 1 H), 7.76-7.73 (m, 2H), 7.59 (m, 4H), 7.52-7.50 (m, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 8.6 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); 13C NMR (CDCI3, 400 MHz) δ 166.0, 164.0, 152.7, 151.7, 143.4, 137.8, 137.4, 135.8, 130.4, 130.3, 128.3, 127.6, 126.8, 120.0, 116.5, 116.4, 28.5, 15.6; Anal. Calcd. for C22H19FN2O2: C = 72.91 %, H = 5.28 %, N = 7.73 %; found: C = 72.51 %, H = 5.40 %, N = 7.63 %.
EXAMPLE 76
Figure imgf000054_0002
Benzaldehyde, O-[[(4-phenoxyphenyl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method B provided the title compound as white solid in 28% yield. 1H NMR (CDClg, 500 MHz) δ 8.35 (s, 1 H), 8.03 (br, 1 H), 7.66 (d, J= 8.5 2H), 7.47-7.39 (m, 5H), 7.28-7.25 (m, 2H), 7.02 (t, J = 7.4 Hz, 1 H), 6.98-6.92 (m, 4H); Mass spec: 333.1 (MH+); Anal. Calcd. for C20H16N2O3: C = 72.28 %, H = 4.85 %, N = 8.43 %; found: C = 72.12 %, H = 4.80 %, N = 8.39 %.
EXAMPLE 77
H
OuOrT 4-Fluorobenzaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method B provided the title compound as white solid in 26% yield. 1H NMR (CDCI3, 400 MHz) δ 8.39 (s, 1 H), 7.99 (br, 1 H), 7.75-7.71 (m, 2H), 7.48 (m, 2H), 7.33 (m, 2H), 7.19-7.15 (m, 2H), 7.09 (t, J = 7.4 Hz, 1 H), 7.05-6.98 (m, 4H); Anal. Calcd. for C2oHi5FN2θ3-0.185H2θ: C = 68.11 %, H = 4.11 %, N = 7.94 %; found: C = 68.11 %, H = 4.36 %, N = 7.88 %.
EXAMPLE 78
Figure imgf000055_0001
3-Pyridinecarboxaldehyde, O-[[[4- (phenylmethoxy)phenyl]amino]carbonyl]oxime (Scheme 1 B, Compound
D') Prepared as described for the example above. Using work-up method A provided the title compound as white solid in 50% yield. 1H NMR (CDCI3, 500 MHz) δ 8.90 (br, 1 H), 8.75 (br, 1 H), 8.43 (s, 1 H), 8.09 (d, J = 7.9 Hz, 1 H), 7.84 (br, 1 H), 7.44-7.31 (m, 8H), 6.98 (d, J = 8.9 Hz, 2H), 5.07 (s, 2H); 13C NMR (CDCI3, 500 MHz) δ 155.9, 152.6, 151.8, 151.1 , 149.7, 136.9, 134.5, 129.9, 128.6, 128.0, 127.5, 123.9, 121.8, 115.5, 70.3; Mass spec: 348.1 (MH+); Anal. Calcd. for C2oHι7N303: C = 69.15%, H = 4.93%, N = 12.10%; found: C = 68.90 %, H = 5.05 %, N = 12.10 %.
EXAMPLE 79
Figure imgf000055_0002
3-Pyridinecarboxaldehyde, O-[[[4-(2- phenylethoxy)phenyl]amino]carbonyl]oxime (Scheme 1 B, Compound
D') Prepared as described for the example above. Using work-up method A provided the title compound as white solid in 21% yield. 1H NMR (CDCI3, 500 MHz) δ 8.92 (br, 1 H), 8.77 (br, 1 H), 8.44 (s, 1 H), 8.11 (d, J = 7.9 Hz, 1 H), 7.81 (br, 1 H), 7.44 (br, 1 H), 7.39 (d, J = 8.9 Hz, 2H), 7.34-7.28 (m, 4H), 7.26- 7.22 (m, 1 H), 6.90 (dt, J = 3.4 Hz, J= 8.9 Hz, 2H), 4.17 (q, J = 7.15 Hz, 2H), 3.10 (t, J = 7.1 Hz, 3H); 13C NMR (CDCI3, 500 MHz) δ 152.4, 151.8, 151.0, 149.5, 180.0, 136.5, 134.6, 129.0, 128.5, 126.5, 122.0, 115, 69.0, 35.8; Mass spec: 362.0 (MH+); Anal. Calcd. for C21H19N3O3: C = 69.79%, H = 5.30%, N = 11.63%; found: C = 69.42%, H = 5.26%, N = 11.65%.
EXAMPLE 80
Figure imgf000056_0001
3-Pyridinecarboxaldehyde, 0-[[[4-(3- phenylpropoxy)phenyl]amino]carbonyl]oxime (Scheme 1 B, Compound
D') Prepared as described for the example above. Using work-up method A provided the title compound as white solid in 26% yield. 1H NMR (CDCI3, 500 MHz) δ 8.94 (br, 1 H), 8.79 (br, 1 H), 8.44 (s, 1 H), 8.10 (d, J = 7.9 Hz, 1 H), 7.82 (br, 1 H), 7.45 (br, 1 H), 7.40 (d, J = 8.9 Hz, 2H), 7.30-7.28 (m, 2H), 7.22- 7.18 (m, 3H), 6.90 (dt, J = 3.4 Hz, J= 8.9 Hz, 2H), 3.96 (t, J = 6.3 Hz, 2H), 2.82 (t, J = 7.35 Hz, 2H), 2.11 (m, 2H); 13C NMR (CDCI3, 500 MHz) δ 161.5, 152.0, 150.5, 141.5, 134.5, 129.5, 128.5, 128.4, 125.9, 121.8, 115.1 , 67.2, 32.1 , 30.8; Mass spec: 376.1 (MH+); Anal. Calcd. for C22H21N3O3: C = 70.38%, H = 5.64%, N = 11.19%; found: C = 69.96%, H = 5.59%, N = 11.03%.
EXAMPLE 81
Figure imgf000056_0002
4-Fluorobenzaldehyde, 0-[[[4-
(phenylmethoxy)phenyl]amino]carbonyl]oxime (Scheme 1 B, Compound
D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 10% yield. 1H NMR (CDCI3, 500 MHz) δ 8.31 (s, 1 H), 7.86 (br, 1 H), 7.65 (dd, J = 5.3 Hz, J = 8.7 Hz, 2H), 7.37- 7.30 (m, 6H), 7.27-7.24 (t, J =7.2 Hz, 1 H), 7.09 (t, J = 8.6 Hz, 2H), 6.91 (dt, J = 3.4 Hz, J = 8.9 Hz, 2H), 4.99 (s, 2H); Mass spec: 365.1 (MH+); Anal. Calcd. for C2ιH17FN203: C = 69.22%, H = 4.70%, N = 7.69%; found: C = 69.44%, H = 4.84%, N = 7.54%.
EXAMPLE 82
Figure imgf000057_0001
4-Fluorobenzaldehyde, 0-[[[4-(2- phenylethoxy)phenyl]amino]carbonyl]oxime
(Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 48% yield. 1H NMR (CDCI3, 500 MHz) δ 8.31 (s, 1 H), 7.85 (br, 1 H), 7.67-7.63 (m, 2H), 7.32 (d, J = 8.9 Hz, 2H), 7.27-7.21 (m, 4H), 7.18 (t, J = 7.0 Hz, 1 H), 6.83 (dt, J = 3.4 Hz, J = 8.9 Hz, 2H), 4.10 (t, J = 7.2 Hz, 2H), 3.03 (t, J = 7.1 Hz, 2H); Mass spec: 379.1 (MH+); Anal. Calcd. for C22H19FN2θ3: C = 69.83%, H = 5.06%, N = 7.40%; found: C = 69.71 %, H = 5.05%, N = 7.21%.
EXAMPLE 83
Figure imgf000057_0002
4-Fluorobenzaldehyde, 0-[[[4-(3- phenylpropoxy)phenyl]amino]carbonyl]oxime (Scheme 1 B, Compound
D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 32% yield. 1H NMR (CDCI3, 500 MHz) δ 8.30 (s, 1 H), 7.85 (br, 1 H), 7.67-7.63 (m, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.22 (t, J = 6.0 Hz, 2H), 7.15-7.01 (m, 5H), 6.82 (dt, J = 3.4 Hz, J = 8.9 Hz, 2H), 3.88 (t, J = 6.3 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.03 (m, 2H); 13C NMR (CDCI3, 500 MHz) δ 156.2, 152.5, 141.5, 130.3, 130.3, 129.7, 128.5, 128.4, 125.9, 121.8, 116.5, 116.3, 115.0, 67.2, 32.1 , 30.8; Mass spec: 393.0 (MH+); Anal. Calcd. for C23H21FN2O3O.I H2O: C = 70.07%, H = 5.42%, N = 7.10%; found: C = 70.09%, H = 5.46%, N = 6.71%.
EXAMPLE 84
Figure imgf000058_0001
Benzaldehyde, 0-[[[4-(phenylmethoxy)phenyl]amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 33% yield. 1H NMR (CDClg, 500 MHz) δ 8.41 (s, 1 H), 8.02 (br, 1 H), 7.72-7.70 (m, 2H), 7.54-7.37 (m, 9H), 7.34-7.31 (m, 1 H), 6.98 (dt, J = 3.4 Hz, J = 6.9 Hz, 2H), 5.07 (s, 2H); 13C NMR (CDCI3, 500 MHz) δ 155.7, 153.6, 136.9, 131.9, 130.1 , 129.8, 129.1 , 128.6, 128.2, 128.0, 127.5, 121.8, 115.4; Mass spec: 347.0 (MH+); Anal. Calcd. for C21H18N2O3: C = 72.82%, H = 5.24%, N = 8.09%; found: C = 72.69%, H = 5.28%, N = 8.00%.
EXAMPLE 85
Figure imgf000058_0002
Benzaldehyde, 0-[[[4-(2-phenylethoxy)phenyl]amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 23% yield. 1H NMR (CDCI3, 500 MHz) δ 8.41 (s, 1 H), 8.01 (br, 1 H), 7.72-7.70 (m, 2H), 7.54-7.45 (m, 3H), 7.41 (d, J = 8.9 Hz, 2H), 7.34-7.28 (m, 4H), 7.26-7.23 (m, 2H), 6.90 (dt, J = 3.3 Hz, J = 9.0 Hz, 2H), 4.17 (t, J = 7.2 Hz, 2H), 3.10 (t, J = 7.1 Hz, 2H); 13C NMR (CDCI3, 500 MHz) δ 153.6, 152.3, 138.2, 136.2, 131.9, 129.9, 129.8, 129.1 , 129.0, 128.5, 128.2, 126.5, 121.8, 115.1 , 69.0, 35.8; Mass spec: 361.0 (MH+); Anal. Calcd. for C22H20N2O3: C = 73.32%, H = 5.59%, N = 7.77%; found: C = 73.34%, H = 5.82%, N = 7.73%. EXAMPLE 86
Figure imgf000059_0001
Benzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl]amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 25% yield. 1H NMR (CDCI3, 500 MHz) δ 8.41 (s, 1 H), 8.02 (br, 1 H), 7.72-7.71 (m, 2H), 7.54-7.46 (m, 3H), 7.41 (d, J = 8.9 Hz, 2H), 7.30 (t, J = 6.85 Hz, 2H), 7.23-7.19 (m, 3H), 6.90 (dt, J = 3.4 Hz, J = 9.0 Hz, 2H), 3.96 (t, J = 6.3 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.12 (m, 2H); 13C NMR (CDCI3, 500 MHz) δ 156.1 , 153,6, 152.4, 141.5, 136.2, 131.9, 129.85, 129.80, 128.5, 128.4,
128.2, 126.0, 121.8, 115.0, 67.2, 32.1 , 30.8; Mass spec: 375.0 (MH+); Anal. Calcd. for C23H22N2θ3: C = 73.78%, H = 5.92%, N = 7.48%; found: C = 73.82%, H = 6.02%, N = 7.35%.
EXAMPLE 87
Figure imgf000059_0002
3-Pyridinecarboxaldehyde, O-[[(3-phenoxyphenyl)amino]carbonyl]oxime (Scheme 1B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 34% yield. 1H NMR (DMSO, 400 MHz) δ 10.06 (s, 1 H), 8.93 (d, J = 1.6 Hz, 1 H), 8.70 (d, J = 1.6 Hz, 1 H), 8.69 (s, 1 H), 8.21 (dt, J = 2.0 Hz, J = 8.1 Hz, 1 H), 7.54 (dd, J = 4.9 Hz, J = 7.8 Hz, 1 H), 7.40 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 8.1 Hz, 1 H), 7.29-7.26 (m, 2H), 7/16 (t, J = 7.4 Hz, 1 H), 7.03 (dd, J = 1.1 Hz, J = 8.7 Hz, 2H), 6.71 (m, 1 H); 13C NMR (DMSO, 400 MHz) δ 158.1 , 152.6, 151.3, 149.7, 138.1 , 134.6, 130.3, 129.8, 123.6, 119.2, 114.7, 114.3, 110.2; Mass spec: 334.0 (MH+); Anal. Calcd. for C19H14N3O3: C = 68.46%, H = 4.54%, N = 12.61%; found: C = 68.42%, H = 4.42%, N = 12.62%. EXAMPLE 88
Figure imgf000060_0001
4-Fluorobenzaldehyde, 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime (Scheme 1B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 34% yield. 1H NMR (CDCI3, 500 MHz) δ 8.36 (s, 1 H), 8.00 (br, 1 H), 7.12 (m, 2H), 7.37-7.27 (m, 4H), 7.22 (t, J = 2.1 Hz, 1 H), 7.17-7.10 (m, 3H), 7.04 (dt, J = 1.1 Hz, J = 7.6 Hz, 2H), 6.78 (dt, J = 2.1 Hz, J = 7.1 Hz, 1 H); 13C NMR (CDCI3, 500 MHz) δ 165.9, 163.9, 158.0, 156.9, 152.8, 151.6, 138.3, 130.4, 130.3, 130.2, 129.8, 126.0, 125.9, 123.5, 119.1 , 116.5, 116.4, 114.6, 114.4, 110.3; Mass spec: 350.9 (MH+); Anal. Calcd. for C2oH 5FN2θ3: C = 68.57%, H = 4.32%, N = 8.00%; found: C = 68.77%, H = 4.48%, N = 7.76%.
EXAMPLE 89
Figure imgf000060_0002
4-Fluorobenzaldehyde, 0-[[(2-phenoxyphenyl)amino]carbonyl]oxime
(Scheme 1 B, Compound D') Prepared as described for the example above.
Using work-up method C provided the title compound as white solid in 16% yield, mp 141.5-142.0 °C. 1H NMR (CDCI3, 500 MHz) δ 8.73 (br, 1 H), 8.32 (dd, J = 1.3 Hz, J = 8.2 Hz, 1 H), 8.30 (s, 1 H), 7.55-7.51 (m, 2H), 7.36 (t, J = 8.7 Hz, 2H), 7.21 (t, J = 7.8 Hz, 1 H), 7.12 (t, J = 7.4 Hz, 1 H), 7.11-7.08 (m, 3H), 7.03 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 1.4 Hz, J = 8.1 , 1 H); 13C NMR (CDCI3, 500 MHz) δ 156.8, 152.2, 145.0, 130.2, 130.1 , 129.9, 129.4, 124.8, 124.1 , 123.5, 119.9, 119.1 , 117.4, 116.3, 116.2; Mass spec: 351.0 (MH+); Anal. Calcd. for C2oHι5FN2θ3-0.41 H20: C = 67.15%, H = 4.46 %, N = 7.83 %; found: C = 67.13%, H = 4.39 %, N = 7.76 %. EXAMPLE 90
Figure imgf000061_0001
Benzaldehyde, O-[[(2-phenoxyphenyl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 16% yield, mp 141.5-142.0 °C. 1H NMR (CDCl3, 500 MHz) δ 8.73 (br, 1 H), 8.32 (dd, J = 1.3 Hz, J = 8.2 Hz, 1 H), 8.30 (s, 1 H), 7.55-7.51 (m, 2H), 7.36 (t, J = 8.7 Hz, 2H), 7.21 (t, J = 7.8 Hz, 1 H), 7.12 (t, J = 7.4 Hz, 1 H), 7.11 -7.08 (m, 3H), 7.03 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 1.4 Hz, J = 8.1 , 1 H); 13C NMR (CDCI3, 500 MHz) δ 156.8, 152.2, 145.0, 130.2, 130.1 , 129.9, 129.4, 124.8, 124.1 , 123.5, 119.9, 119.1 , 117.4, 116.3, 116.2; Mass spec: 351.0 (MH+); Anal. Calcd. for C2oHi5FN2θ3-0.41 H20: C = 67.15%, H = 4.46 %, N = 7.83 %; found: C = 67.13%, H = 4.39 %, N = 7.76 %.
EXAMPLE 91
Figure imgf000061_0002
Benzaldehyde, 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime (Scheme 1B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as gel-like material in 50% yield. 1H NMR (CDCl3, 500 MHz) δ 8.39 (s, 1 H), 8.11 (br, 1 H), 7.70 (d, J = 5.1 Hz, 2H), 7.53-7.45 (m, 3H), 7.37-7.28 (m, 4H), 7.24-7.23 (m 1 H), 7.12 (t, J = 7.4 Hz, 1 H), 7.04 (m, J = 7.7 Hz, 2H), 6.79-6.76 (m, 1 H); 13C NMR (CDCI3, 500 MHz) δ 158.0, 156.9, 153.9, 151.7, 138.3, 132.0, 130.2, 129.8, 129.6, 129.1 , 128.9, 128.2, 123.5, 119.2, 119.1 , 114.6, 114.4, 110.4; Mass spec: 333.0 (MH+); Anal. Calcd. for C20H16N2O3: C = 72.28%, H = 4.85%, N = 8.43%; found: C = 72.10%, H = 4.72%, N = 8.40%.
EXAMPLE 92
Figure imgf000062_0001
3-Pyridinecarboxaldehyde, O-[[(2-phenoxyphenyl)amino]carbonyl]oxime (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 42% yield. 1H NMR (CDCI3, 500 MHz) δ 13.26 (br, 1 H), 8.91 (d, J = 1.6 Hz, 1 H), 8.81 (dd, J = 1.4 Hz, J = 5.2 Hz, 1 H), 8.45 (s, 1 H), 8.38 (br, 1 H), 8.29-8.27 (m, 2H), 7.66 (dd, J = 5.2 Hz, J = 8.0 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1 H), 7.15 (t, J = 7.4 Hz, 1H), 7.08 (td, J = 1.5 Hz, J = 8.1 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 6.95 (dd, J = 1.3 Hz, J = 8.1 Hz, 1 H); 13C NMR (CDCI3, 500 MHz) δ 16101 , 160.7, 156.5, 150.6, 149.2, 147.9, 145.5, 145.3, 138.3, 130.1 , 128.8, 128.5, 125.6, 124.7, 124.5, 123.8, 119.8, 118.7, 117.8, 116.7, 114.4; Mass spec: 334.0 (MH+); Anal. Calcd. for C19H15N3O3O.I 85H2O: C = 67.78%, H = 4.60%, N = 12.48%; found: C = 67.74%, H = 4.46%, N = 12.47%.
EXAMPLE 93
Figure imgf000062_0002
4-Hexyloxyphenylcarbamic acid, phenyl ester (Scheme 1 B, Compound
D") Prepared as described for the example above. Analytical HPLC 1.81 min. (99%). Mass Spec: 314 (MH+). EXAMPLE 94
Figure imgf000063_0001
4-Hexyloxyphenylcarbamic acid, 2-f luorophenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 1.80 min. (97%). Mass Spec: 331.39 (MH+).
EXAMPLE 95
Figure imgf000063_0002
4-Butoxyphenylcarbamic acid, methyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 9.40 (br. s, 1 H), 7.32 (d, 2H, J=8.0 Hz), 6.83 (dd, 2H, J=7.5, 2.5 Hz), 3.89 (t, 2H, J=6.5 Hz), 1.65 (m, 2H), 1.40 (m, 2H), 0.92 (t, 3H, J=7.5 Hz). Analytical HPLC 1.51 min. (95%). Mass Spec: 224.15 (MH+).
EXAMPLE 96
Figure imgf000063_0003
4-Heptyloxyphenylcarbamic acid, phenyl ester (Scheme 1 B, Compound
D") Prepared as described for the example above. Analytical HPLC 2.08 min. (91%). Mass Spec: 328.18 (MH+).
EXAMPLE 97
Figure imgf000063_0004
4-Heptyloxyphenylcarbamic acid, 2-f luorophenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 2.06 min. (99%). Mass Spec: 346.17 (MH+). EXAMPLE 98
Figure imgf000064_0001
4-Octyloxyphenylcarbamic acid, phenyl ester (Scheme 1 B, Compound
D") Prepared as described for the example above. Analytical HPLC 1.97 min. (85%). Mass Spec: 342.29 (MH+).
EXAMPLE 99
Figure imgf000064_0002
4-Octyloxyphenylcarbamic acid, 2-f luorophenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 1.64 min. (90%). Mass Spec: 360.26 (MH+).
EXAMPLE 100
Figure imgf000064_0003
4-Butyloxyphenylcarbamic acid, 4-f luorophenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. 1H NMR (DMSO-Gfe) δ 7.47 (d, 2H, J=7.0 Hz), 7.38 (d, 2H, J=4.0 Hz), 7.25 (d, 2H, J=7.0 Hz), 6.90 (dd, 2H, J=6.0, 2.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.72 (m, 2H), 1.40 (m, 2H), 0.92 (t, 3H, J=7.5 Hz); Analytical HPLC 1.90 min. (95%). Mass Spec: 320 (MH+). EXAMPLE 101
Figure imgf000065_0001
4-Decyloxyphenylcarbamic acid, phenyl ester (Scheme 1 B, Compound
D") Prepared as described for the example above. Analytical HPLC 2.09 min. (97%). Mass Spec: 370.38 (MH+).
EXAMPLE 102
Figure imgf000065_0002
4-Decyloxyphenylcarbamic acid, 2-fluorophenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 2.07 min. (98%). Mass Spec: 388.43 (MH+).
EXAMPLE 103
Figure imgf000065_0003
4-Undecyloxyphenylcarbamic acid, phenyl ester (Scheme 1 B,
Compound D") Prepared as described for the example above. Analytical HPLC 2.33 min. (93%). Mass Spec: 384.26 (MH+).
EXAMPLE 104
Figure imgf000065_0004
4-Undecyloxyphenylcarbamic acid, 2-fluorophenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 2.31 min. (96%). Mass Spec: 402.25 (MH+). EXAMPLE 105
Figure imgf000066_0001
4-Dodecyloxyphenylcarbamic acid, phenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 2.18 min. (85%). Mass Spec: 398.36 (MH+).
EXAMPLE 106
Figure imgf000066_0002
4-Dodecyloxyphenylcarbamic acid, 2-fluorophenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 2.18 min. (95%). Mass Spec: 416.38 (MH+).
EXAMPLE 107
Figure imgf000066_0003
4-Butoxyphenylcarbamic acid, 2-fluorophenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 1.61 min. (97%). Mass Spec: 304.18 (MH+).
EXAMPLE 108
Figure imgf000066_0004
4-Butoxyphenylcarbamic acid, 4-f luorophenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. 1H NMR (DMSO-c/e) δ 7.33 (d, 2H, J=8.1 Hz), 7.23 (m, 4H), 6.90 (dd, 2H, J=7.0, 2.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.72 (m, 2H), 1.42 (m, 2H), 0.91 (t, 3H, J=7.0 Hz). Analytical HPLC 1.65 min. (95%). Mass Spec: 304.18 (MH+). EXAMPLE 109
Figure imgf000067_0001
4-Butoxyphenylcarbamic acid, 3,4-dif luorophenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 1.71 min. (97%). Mass Spec: 322 (MH+).
EXAMPLE 110
Figure imgf000067_0002
4-Butoxyphenylcarbamic acid, 2-methoxyphenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 1.57 min. (97%). Mass Spec: 316.18 (MH+).
EXAMPLE 111
Figure imgf000067_0003
4-(Butoxyphenylmethyl)carbamic acid, phenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 1.59 min. (95%). Mass Spec: 300.0 (MH+).
EXAMPLE 112
Figure imgf000067_0004
4-(Butoxyphenylmethyl)carbamic acid, 2-fluorophenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. 1H NMR (DMSO- e) δ 9.40 (br. s, 1 H), 7.26 (m, 6H), 6.90 (d, 2H, J=8.4 Hz), 4.19 (d, 2H, J=6.0 Hz), 3.92 (t, 2H, J=6.5 Hz), 1.67 (m, 2H), 1.42 (m, 2H), 0.91 (t, 3H, J=7.0 Hz). Analytical HPLC 1.59 min. (95%). Mass Spec: 318 (MH+).
EXAMPLE 113
Figure imgf000068_0001
4-(Butoxyphenylmethyl)carbamic acid, 4-methoxyphenyl ester
(Scheme 1B, Compound D") Prepared as described for the example above.
Analytical HPLC 1.60 min. (95%). Mass Spec: 330.25 (MH+).
EXAMPLE 114
Figure imgf000068_0002
4-(Butoxyphenylmethyl)carbamic acid, 6-quinolϊnyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 1.30 min. (95%). Mass Spec: 351.25 (MH+).
EXAMPLE 115
Figure imgf000068_0003
4-(Butoxyphenylmethyl)carbamic acid, 1-naphthalenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 1.77 min. (95%). Mass Spec: 350 (MH+).
EXAMPLE 116
Figure imgf000068_0004
4-(Butoxyphenylmethyl)carbamic acid, 2-naphthalenyl ester
(Scheme 1B, Compound D") Prepared as described for the example above.
Analytical HPLC 1.80 min. (98%). Mass Spec: 350.26 (MH+).
EXAMPLE 117
Figure imgf000069_0001
4-(Butoxyphenylmethyl)carbamic acid, 4-(1-methylethyl)phenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 1.82 min. (95%). Mass Spec: 342 (MH+).
EXAMPLE 118
Figure imgf000069_0002
4-(Butoxyphenylmethyl)carbamic acid, 3-(dimethylamino)phenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 1.32 min. (90%). Mass Spec: 343.29 (MH+).
EXAMPLE 119
Figure imgf000069_0003
4-(Butoxyphenylmethyl)carbamic acid, 4-(trifluoromethyl)phenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 1.77 min. (99%). Mass Spec: 368.14 (MH+). EXAMPLE 120
Figure imgf000070_0001
4-(Butoxyphenylmethyl)carbamic acid, 2,4-difluorophenyl ester (Scheme 1B, Compound D") Prepared as described for the example above. Analytical HPLC 1.66 min. (99%). Mass Spec: 336.14 (MH+).
EXAMPLE 121
Figure imgf000070_0002
4-(Butoxyphenylmethyl)carbamic acid, 4-fluorophenyl ester (Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 1.61 min. (85%). Mass Spec: 318.15 (MH+).
EXAMPLE 122
Figure imgf000070_0003
4-(Butoxyphenylmethyl)carbamic acid, 3-chlorophenyl ester
(Scheme 1 B, Compound D") Prepared as described for the example above. Analytical HPLC 1.72 min. (86%). Mass Spec: 334.12 (MH+).
EXAMPLE 123
Figure imgf000070_0004
4-Phenoxyphenylcarbamic acid, 2-fluorophenyl ester (Scheme 1B, Compound D') Prepared as described for the example above. Using work-up method C provided the title compound as white solid in 11% yield. 1H NMR (CDCI3, 400 MHz) δ 7.43 (br, 1 H), 7.41 (br, 1H), 7.35-7.30 (m, 2H), 7.28-7.13 (m, 4H), 7.09 (dt, J = 0.9 Hz, J = 7.4 Hz, 1 H), 7.03-6.97 (m, 5H); (s, 1 H), 8.06 (s, 1 H), 7.76-7.73 (m, 2H), 7.59 (m, 4H), 7.52-7.50 (m, 2H),
7.27 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 8.6 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H),
1.28 (t, J = 7.6 Hz, 3H); 13C NMR (CDCI3, 400 MHz) δ 153.6, 129.8, 129.7, 127.0, 126.9, 124.4, 124.1 , 123.1 , 120.5, 119.8, 119.6, 118.6, 118.5, 116.8, 116.7; Anal. Calcd. for C19Hι4FN03: C = 70.58 %, H = 4.36 %, N = 4.33 %; found: C = 70.54 %, H = 4.31 %, N = 4.21 %.
EXAMPLE 124
Figure imgf000071_0001
4'-Ethyl-[1,1 '-biphenyl]-4-yIcarbamic acid, 2-fluorophenyl ester (Scheme 1 B, Compound D') Prepared as described for the example above. Using work-up method B provided the title compound as white solid in 30% yield. 1H NMR (CDCI3, 400 MHz) δ 7.57-7.55 (m, 2H), 7.52-7.49 (m, 4H), 7.36-7.33 (m, 1 H), 7.30-7.27 (m, 2H), 7.25-7.14 (m, 3H), 7.05 (br, 1 H), 2.70 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); Anal. Calcd. for C2ιH18FN02: C = 75.21 %, H = 5.41 %, N = 4.18 %; found: C = 75.27 %, H = 5.40 %, N = 4.25
%,
Scheme 2:
Figure imgf000071_0002
Scheme 2 Reaction conditions: (i) R1- alide, NaH, DMF, 50°C; (ii) NaOH, EtOH, room temp.; (iii) (a) N3P(0)(OPh)2, Et3N, toluene at 105°C, (b) B-OH at 80°C; Ft, R and B are as defined above. The following Intermediates 40 to 41 may be used to synthesize Examples 125 to 135.
INTERMEDIATE 40
Figure imgf000072_0001
2-(4-Butoxy-phenyl)-butyric acid methyl ester: (Scheme 2, Compound
E) The mixture of methyl 4-butoxyphenylacetate (1.20 g, 5.4 mmol) and NaH (60% in mineral oil, 0.50 g, 12.5 mmol) in DMF (25.0 mL) was stirred at 50 °C for 40 min. Bromoethane (2.0 g, 18.3 mmol) was added and the stirring continued at rt for one hour. The reaction mixture was diluted with EtOAc (300 mL), washed with H20, and then was dried over Na2S04. After filtration and concentration in vacuo, the residue was purified by flash chromatography (Si02: EtOAc/Hexanes). This compound was obtained as a yellow oil (0.85 g, 3.4 mmol, 63% yield). 1H NMR (DMSO-d6) δ 7.16 (d, 2H, J=7.0 Hz), 6.87 (d, 2H, J=8.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 3.55 (s, 3H), 3.45 (t, 1 H, J=9.0), 1.93 (m, 1 H), 1.63 (m, 3H), 1.42 (m, 2H), 0.97 (t, 3H, J=7.2 Hz), 0.79 (t, 3H, J=4.0 Hz).
INTERMEDIATE 41
Figure imgf000072_0002
2-(4-Butoxy-phenvO-butyric acid: (Scheme 2, Compound F) To a solution of 2-(4-butoxy-phenyl)-butyric acid methyl ester (2.0 g, 8.0 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with H20 (30 mL), acidified to pH ~ 1.0 using HCI (6N). The precipitates were filtered off by filter paper, washed by H20 and hexanes. This compound was obtained as a white solid. (1.4 g, 5.9 mmol, 74 % yield). 1H NMR (DMSO-c/6) δ 12.20 (br. s, 1 H), 7.16 (d, 2H, J=7.0 Hz), 6.87 (d, 2H, J=8.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 3.31 (t, 2H, J=6.9 Hz), 1.93 (m, 1 H), 1.63 (m, 3H), 1.42 (m, 2H), 0.97 (t, 3H, J=7.2 Hz), 0.79 (t, 3H, J=4.0 Hz).
EXAMPLE 125
Figure imgf000073_0001
[1-(4-Butoxy-phenyl)-propyl]-carbamic acid quinolin-6-yl ester (Scheme 2, Compound G) To a solution of 2-(4-butoxy-phenyl)-butyhc acid (0.050 g, 0.23 mmol) and Et3N (0.053 g, 0.53 mmol) in toluene (2 mL) was added diphenylphosphoryl azide (0.096 g, 0.35 mmol). The resultant mixture was stirred at r.t. for 10 min. and then at 107 °C under N2 for 60 min. After the mixture was cooled to r.t., quinolin-6-ol (0.050 g, 0.34 mmol) was added. The reaction mixture was stirred at r.t. for 10 min. and then at 80 °C for 1 h. The mixture was diluted with EtOAc, washed with H20. After filtration and concentration in vacuo, the residue was purified by by preparative HPLC (YMC 30X100 mm (5 uM packing), 10% MeOH/90% water/01 % TFA as mobile phase A, 90% MeOH/10%water/0.1% TFA as mobile phase B).. This compound was obtained as a pale yellow solid (0.040 g, 0.11 mmol, 46% yield): mp 115-118 °C; 1H NMR (DMSO-ofe) δ 8.93 (m, 1 H), 8.45 (d, 1 H, J=9.0Hz), 8.40 (d, 1 H, J=8.5), 8.02 (d, 1 H, J=9.0 Hz), 7.77 (s, 1 H), 7.62 (dd, 1 H, J=8.5, 4.5 Hz), 7.55 (dd, 1 H, J=9.0, 2.5 Hz), 7.25 (d, 2H, J=8.5 Hz), 6.98 (d, 2H, J=8.5 Hz), 4.43 (m, 1 H), 3.95 (t, 2H, J=6.5 Hz), 1.75 (m, 1 H), 1.65 (m,
3H), 1.42 (m, 2H), 0.90 (m, 6H). Mass Spec: 379.33 (MH+).
EXAMPLE 126
Figure imgf000073_0002
[1-(4-Butoxy-phenyl)-propyl]-carbamic acid 4-methoxy-phenyl ester (Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.73 min. (88%). Mass Spec: 358.25 (MH+). EXAMPLE 127
Figure imgf000074_0001
[1-(4-Butoxy-phenyl)-propyl]-carbamic acid naphthalen-1-yl ester (Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.86 min. (98%). Mass Spec: 378.25 (MH+).
EXAMPLE 128
Figure imgf000074_0002
[1-(4-Butoxy-phenyl)-propyl]-carbamic acid naphthalen-2-yl ester
(Scheme 2, Compound G) Prepared as described for the example above. 1H NMR (DMSO-cfe) δ 8.30 (d, 1 H, J=9.0Hz), 7.90 (m, 3H), 7.60 (s, 1H), 7.45 (m, 2H), 7.25 (m, 3H), 6.90 (d, 2H, J=8.5 Hz), 4.43 (m, 1 H), 3.95 (t, 2H, J=6.5 Hz), 1.75 (m, 1H), 1.65 (m, 3H), 1.42 (m, 2H), 0.90 (m, 6H). Analytical HPLC 1.87 min. (99%). Mass Spec: 378.12 (MH+).
EXAMPLE 129
Figure imgf000074_0003
[1-(4-Butoxy-phenyl)-propyl]-carbamic acid 4-isopropyl-phenyl ester (Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.91 min. (96%). Mass Spec: 370.31 (MH+). EXAMPLE 130
Figure imgf000075_0001
[1 -(4-Butoxy-phenyl)-propyl]-carbamic acid 3-trif luoromethyl-phenyl ester (Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.84 min. (96%). Mass Spec: 396.18 (MH+).
EXAMPLE 131
Figure imgf000075_0002
[1-(4-Butoxy-phenyl)-propyl]-carbamic acid 2,4-difluoro-phenyl ester (Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.77 min. (89%). Mass Spec: 364.17 (MH+).
EXAMPLE 132
Figure imgf000075_0003
[1 -(4-Butoxy-phenyl)-propyl]-carbamic acid 4-fluoro-phenyl ester
(Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.72 min. (89%). Mass Spec: 346.18 (MH+).
EXAMPLE 133
Figure imgf000075_0004
[1 -(4-Butoxy-phenyl)-propyl]-carbamic acid 4-dimethylamino-phenyl ester (Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.53 min. (96%). Mass Spec: 371 (MH+). EXAMPLE 134
Figure imgf000076_0001
[1-(4-Butoxy-phenyl)-propyl]-carbamic acid phenyl ester (Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.70 min. (88%). Mass Spec : 328.19 (MH+).
EXAMPLE 135
Figure imgf000076_0002
[1 -(4-Butoxy-phenyl)-propyl]-carbamic acid 2-fluoro-phenyl ester
(Scheme 2, Compound G) Prepared as described for the example above. Analytical HPLC 1.70 min. (89%). Mass Spec: 346.18 (MH+).
Scheme 3:
Figure imgf000076_0003
Scheme 3 Reaction conditions: (i) W-acid chloride, Et3N, dichloroethane, room temp.; (ii) NaOH, EtOH, room temp.; (iii) (a) N3P(0)(OPh)2, Et3N, toluene at 105°C, (b) B-OH at 80°C; W is Cι-12 alkyl and B is as defined above.
The following Intermediates 42 and 43 may be used to synthesize
Examples 136 to 140. INTERMEDIATE 42
Figure imgf000077_0001
4-Decanoylamino-benzoic acid ethyl ester: (Scheme 3, Compound H)
To a solution of 4-amino-benzoic acid ethyl ester (2.0 g, 12.1 mmol) and decanoyl chloride (2.35 g, 13.3 mmol) in methylene chloride (20 mL) was added Et3N (1.34 g, 13.3 mmol). The resultant mixture was stirred at room temperature for one hour and then was diluted with EtOAc, washed by H20, dried over MgS0 . After filtration and concentration in vacuo, the product was directly used in the next step.
INTERMEDIATE 43
Figure imgf000077_0002
4-Decanoylamino-benzoic acid: (Scheme 3, Compound I) To a solution of 4-decanoylamino-benzoic acid ethyl ester (2.0 g, 6.6 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with H20 (30 mL), acidified to pH ~ 1.0 using HCI (6N). The precipitates were filtered off by filter paper, washed by H2O and hexanes. This compound was obtained as a white solid. (1.8 g, 6.5 mmol, 98 % yield). 1H NMR (DMSO-d6) δ 9.91 (br. s, 1 H), 7.76 (d, 2H, J=8.7 Hz), 6.50 (d, 2H, J=8.7 Hz), 2.29 (t, 2H, J=7.5 Hz), 1.57 (m, 2H), 1.25 (m, 12H),
0.85 (t, 3H, J=6.9 Hz). Mass Spec: 278.21 (MH+).
EXAMPLE 136
Figure imgf000077_0003
Benzaldehyde, 0-[[(4-Nonanoylamino-phenyl) amino]carbonyl]oxime (Scheme 3, Compound J) To a solution of 4-decanoylamino-benzoic acid (0.050 g, 0.18 mmol) and EtβN (0.053 g, 0.53 mmol) in toluene (2 mL) was added diphenylphosphoryl azide (0.096 g, 0.35 mmol). The resultant mixture was stirred at r.t. for 10 min. and then at 107 °C under N2 for 60 min. After the mixture was cooled to r.t., benzaldehyde oxime (0.050 g, 0.41 mmol) was added. The reaction mixture was stirred at r.t. for 10 min. and then at 80 °C for 30 min. The mixture was diluted with EtOAc, washed with H20. After filtration and concentration in vacuo, the residue was purified by preparative HPLC (YMC 30X100 mm (5 uM packing), 10% MeOH/90% water/01% TFA as mobile phase A, 90% MeOH/10%water/0.1% TFA as mobile phase B).. This compound was obtained as a pale yellow solid (0.038 g, 0.10 mmol, 53% yield): 1H NMR (DMSO-cfe) δ 9.78 (d, 2H, J=9.0 Hz), 8.63 (s, 1 H), 7.82 (dd, 2H, J=7.7, 2.4 Hz), 7.52 (m, 5H), 7.44 (d, 2H, J=9.0 Hz), 2.27 (t, 2H, J=9.0 Hz), 1.55 (m, 2H), 1.26 (m, 10H), 0.85 (t, 3H, J=6.6 Hz). Mass Spec:
396.22 (MH+).
EXAMPLE 137
Figure imgf000078_0001
4-Fluorobenzaldehyde, O-[[(4-Nonanoylamino-phenyl) amino]carbonyl]oxime (Scheme 3, (Compound J) Prepared as described for the example above. 1H NMR (DMSO-c/6) δ 9.78 (d, 2H, J=9.0 Hz), 8.63 (s, 1H), 7.82 (dd, 2H, J=8.7, 5.4 Hz), 7.52 (d, 2H, J=9.0 Hz), 7.32 (m, 4H), 2.27 (t, 2H, J=9.0 Hz), 1.55 (m, 2H), 1.26 (m, 10H), 0.85 (t, 3H, J=6.6 Hz). Anal. Calcd for C23H28FN3O3: C, 66.81 ; H, 6.82; N, 10.16. Found: C, 67.07, H, 6.82, N, 10.09. Mass Spec: 414.21 (MH+).
EXAMPLE 138
Figure imgf000078_0002
3-Trifluoromethylbenzaldehyde, 0-[[(4-Nonanoylamino-phenyl) amino]carbonyl]oxime (Scheme 3, Compound J) Prepared as described for the example above. 1H NMR (DMSO-αfe) δ 9.78 (d, 2H, J=9.0 Hz), 8.63 (s, 1 H), 8.15 (m, 2H), 7.92 (d, 1 H, J=9.0 Hz), 7.80 (t, 1 H, J=7.5 Hz), 7.52 (d, 2H, J=9.0 Hz), 7.32 (d, 2H, J=9.0 Hz)2.27 (t, 2H, J=9.0 Hz), 1.55 (m, 2H), 1.26 (m, 10H), 0.85 (t, 3H, J=6.6 Hz). Anal. Calcd for C24H28F3N3O3: C, 62.19; H, 6.08; N, 9.06. Found: C, 62.45, H, 6.12, N, 8.99. Mass Spec: 464.21 (MH+).
EXAMPLE 139
Figure imgf000079_0001
2,4-Difluorobenzaldehyde, 0-[[(4-Nonanoylamino-phenyl) amino]carbonyl]oxime (Scheme 3, Compound J) Prepared as described for the example above. 1H NMR (DMSO-d6) δ 9.78 (s, 2H), 8.63 (s, 1 H), 8.05 (m, 1 H), 7.52 (m, 4H), 7.22 (m, 1 H), 2.27 (t, 2H, J=9.0 Hz), 1.55 (m, 2H), 1.26 (m, 10H), 0.85 (t, 3H, J=6.6 Hz). Mass Spec: 432.20 (MH+).
EXAMPLE 140
Figure imgf000079_0002
3,4-Dif luorobenzaldehyde, 0-[[(4-Nonanoylamino-phenyl) amino]carbonyl]oxime (Scheme 3, Compound J) Prepared as described for the example above. 1H NMR (DMSO-ofe) δ 9.78 (d, 2H, J=8.1 Hz), 8.63 (s, 1 H), 8.00 (m, 1 H), 7.72-7.42 (m, 6H), 2.27 (t, 2H, J=9.0 Hz), 1.55 (m, 2H), 1.26 (m, 10H), 0.85 (t, 3H, J=6.6 Hz). Mass Spec: 432.20 (MH+). Scheme 4:
Figure imgf000080_0001
Scheme 4 Reaction conditions: (i) (a) Et3N, DPPA/toluene, room temp, to 120°C, (b) oxime, room temp, to 85°C; A is indolyl wherein K is the corresponding indole carboxylic acid, pyridyl wherein K is the corresponding pyridyl carboxylic acid, or benzofuranyl wherein K is the dibenzofurancarboxylic acid.
Examples 141 to 145 were made accordingly.
EXAMPLE 141
Figure imgf000080_0002
3-Pyridinecarboxaldehyde, 0-[[(1H-indol-5-yl)amino]carbonyl]oxime (Scheme 4, Compound L) To a suspension of indole-5-carboxylic acid (commercially available) (1 mmol) in toluene was added triethylamine (4.0 mmol) and diphenylphosphoryl azide (DPPA) (1.2 mmol) subsequently at room temperature under nitrogen atmosphere. The resultant was stirred for 15 minutes at room temperature followed by 90 minutes at reflux. The reaction mixture was cooled down to room temperature followed by the addition of the corresponding oxime, 3-pyridinealdoxime, (1 mmol). The resultant was stirred for 1 hour at room temperature or followed by heating up to 85°C. Using work-up method A: filtration of the reaction mixture, and the solid was recrystallized from EtOAc/hexanes, provided the title compound as a white solid in 57% yield. 1H NMR (DMSO, 500 MHz) δ 10.99 (s, 1 H), 9.68 (s, 1 H), 8.94 (d, J = 1.7 Hz, 1 H), 8.68-8.66 (m, 2H), 8.25 (dt, J = 7.9 Hz, J = 1.8 Hz, 1 H), 7.66 (br, 1 H), 7.53 (dd, J = 4.8 Hz, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.31 (t, J = 2.8 Hz, 1 H), 7.16 (dd, J = 1.8 Hz, J = 8.6 Hz, 1 H), 6.40 (s, 1 H); Mass spec: 281.1 (MH+); Anal. Calcd. for C15H12N4O2: C = 64.28%, H = 4.32%, N = 19.99%; found: C = 64.09%, H = 4.45%, N = 19.759%. EXAMPLE 142
Figure imgf000081_0001
4-Fluorobenzaldehyde, 0-[[(1 H-indol-5-yl)amino]carbonyl]oxime (Scheme 4, Compound L) Prepared as described above. Using work-up method C: after removal of solvent, the residue was dissolved in methanol and filtrated, the filtrate was purified by preparative HPLC with methanol:H20 (30:70 to about 100:0 v/v, containing 1% TFA) as a mobile phase to provide the title compound as white solid in 19% yield. 1H NMR (DMSO, 500 MHz) δ 11.03 (s, 1 H), 9.59 (s, 1 H), 8.64 (s, 1 H), 7.93 (dd, J = 5.6 Hz, J = 8.8 Hz, 2H), 7.69 (br, 1 H), 7.38-7.32 (m, 3H), 7.20 (dd, J = 1.8 Hz, J = 8.7 Hz, 1 H), 6.39 (t, J = 2.0 Hz, 1 H); Mass spec: 298.0 (MH+); Anal. Calcd. for C16H12N3θ2F-0.51 H2θ: C = 62.713%, H = 4.28%, N = 13.71%; found: C = 62.73%, H = 4.13%, N = 14.02%.
EXAMPLE 143
Figure imgf000081_0002
Benzaldehyde, 0-[[(1H-indol-5-yl)amino]carbonyl]oxime (Scheme 4, Compound L) Prepared as described above. Using work-up method C provided the title compound as white solid in 20% yield. 1H NMR (CDCI3, 500 MHz) δ 8.43 (s, 1 H), 8.19 (br, 1 H), 8.15 (br, 1 H), 7.82 (br, 1 H), 7.74 (d, J = 6.8 Hz, 2H), 7.54-7.46 (m, 3H), 7.38 (d, J = 8.6 Hz, 1 H), 7.29 (dd, J = 1.8 Hz, J = 8.7 Hz, 1 H), 7.24 (t, J = 2.7 Hz, 1 H), 6.55 (t, J = 2.2 Hz, 1 H); Mass spec: 280.0 (MH+); Anal. Calcd. for C16H13N3O2O.I6H2O: C = 68.11%, H = 4.76 %, N = 14.89%; found: C = 68.15%, H = 4.77 %, N = 14.75%.
EXAMPLE 144
Figure imgf000081_0003
4-Fluorobenzaldehyde, 0-[[(1 H-indol-3-yl)amino]carbonyl]oxime (Scheme 4, Compound L) Prepared as described above. Using workup method C and then B provided the title compound as light blue solid in 20% yield. 1H NMR (DMSO, 500 MHz) δ 10.91 (s, 1 H), 9.59 (s, 1 H), 8.66 (s, 1 H), 7.93 (t, J = 5.7 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.44 (m, 1 H), 7.36 (t, J = 8.1 Hz, 2H), 7.25 (m, 1 H), 7.10 (t, J = 8.1 Hz, 1 H), 7.0 (t, J = 7.7 Hz, 1 H).
EXAMPLE 145
Figure imgf000082_0001
Benzaldehyde, 0-[[(1 H-indol-3-yl)amino]carbonyl]oxime (Scheme 4,
Compound L) Prepared as described above. Using work-up method C and then B (after removal of the solvent, the residue was chromatographed by silica gel column packed with EtOAc/hexanes or EtOAc/dichloromethane) provided the title compound as a light blue solid in 11% yield. 1H NMR (CDCI3, 500 MHz) δ 8.45 (s, 1 H), 8.15 (br, 1 H), 8.05 (br, 1 H), 7.75 (d, J = 6.9 Hz, 2H), 7.62 (d, J = 1.5 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.55-7.48 (m, 3H), 7.39 (d, J = 8.2 Hz, 1 H), 7.25 (t, J = 8.0 Hz, 1 H), 7.18 (t, J = 7.9 Hz, 1 H); Mass spec: 280.0 (MH+). Anal. Calcd. for Ci6H13N3θ2-0.21 H2θ: C = 67.89%, H = 4.78%, N = 14.84%; found: C = 67.91%, H = 4.94%, N = 14.17%.
EXAMPLE 146
Figure imgf000083_0001
4-Fluorobenzaldehyde, 0-[[[4-[(4- pyridinyl)oxy]phenyl]amino]carbonyl]oxime (Scheme 4, Compound L)
Prepared as described above. Using work-up method B provided the title compound as light blue solid in 29% yield. 1H NMR (CDCI3, 500 MHz) δ 8.47 (d, J = 6.0 Hz, 2H), 8.40 (s, 1 H), 8.15 (br, 1 H), 7.74 (dd, J = 8.05 Hz, J = 11.55 Hz, 2H) 7.6 (d, J = 8.9 Hz, 2H), 7.17 (t, J = 8.55 Hz, 2H), 7.11 (d, J = 8.9 Hz, 2H), 6.86 (dd, J = 1.5 Hz, J = 4.8 Hz, 2H); Mass spec: 352.34 (MH+).
EXAMPLE 147
Figure imgf000083_0002
3-Pyridinecarboxaldehyde, O-[[[4-[(2- pyridinyl)oxy]phenyl]amino]carbonyl]oxime (Scheme 4, Compound L) Prepared as described above. Using work-up method B provided the title compound as white solid in 30% yield. 1H NMR (DMSO, 300 MHz) δ 9.96 (s, 1 H), 8.97 (d, J = 1.8 Hz, 1 H), 8.73 (s, 1 H), 8.72 (dd, J = 1.8 Hz, J = 4.9 Hz, 1 H), 8.25 (dt, J = 8.0 Hz, J = 2.0 Hz, 1 H), 8.14 (dd, J = 2.1 Hz, J = 5.2 Hz, 1H), 7.84 (td, J = 1.9 Hz, J = 7.1 Hz, 1 H), 7.57-7.53 (m, 3H), 7.13-7.09 (m, 3H), 7.01 (d, J = 8.4 Hz, 1 H); Mass spec: 335.11 (MH+). Anal. Calcd. for Ci8H14N4θ3: C = 64.67%, H = 4.22%, N = 16.76%; found: C = 64.41 %, H = 4.16%, N = 16.50%.
EXAMPLE 148
Figure imgf000083_0003
4-Fluorobenzaldehyde, 0-[[[4-[(2- pyridinyl)oxy]phenyl]amino]carbonyl]oxime (Scheme 4, Compound L)
Prepared as described above. Using workup method B provided the title compound as white solid in 22% yield. 1H NMR (CDCI3, 500 MHz) δ 8.39 (s, 1 H), 8.20 (dd, J = 4.9 Hz, J = 1.4 Hz, 1 H), 8.05 (br, 1 H), 7.75-7.68 (m, 3H), 7.55 (d, J = 8.85 Hz, 2H), 7.19-7.14 (m, 4H), 7.00 (dd, J = 5.1 Hz, J = 7.2 Hz, 1 H), 6.91 (d, J = 8.30 Hz, 1 H); 13C NMR (CDCI3, 500 MHz) δ 165.9, 163.9, 163.7, 152.7, 151.9, 150.5, 147.5, 139.7, 133.5, 130.4, 130.3, 126.03,
126.00, 121.9, 121.2, 118.5, 116.5, 116.4, 111.4; Mass spec: 352.25 (MH+). Anal. Calcd. for C19HHN3O3FO.36H2O: C = 63.78%, H = 4.15%, N = 11.74%; found: C = 63.74%, H = 3.79%, N = 11.77%.
Figure imgf000084_0001
Benzaldehyde, O-[[[4-[(2-pyridinyl)oxy]phenyl]amino]carbonyl]oxime (Scheme 4, Compound L) Prepared as described above. Using workup method C provided the title compound as white solid in 76% yield. 1H NMR (CDCI3, 500 MHz) δ 8.42 (s, 1 H), 8.27 (dd, J = 5.05 Hz, J = 1.55 Hz, 1 H), 8.17 (br, 1 H), 7.76 (td, J = 8.65 Hz, J = 1.95 Hz, 1 H, ), 7.72 (d, J = 7.05 Hz, 2H), 7.58 (d, J = 8.85 Hz, 2H), 7.53 (tt, J = 7.25 Hz, J = 1.35 Hz, 1 H), 7.48 (t, J = 6.25 Hz, 2H), 7.15 (dt, J = 8.85 Hz, J = 3.2 Hz, 2H), 7.07 (dd, J = 5.6 Hz, J = 6.5 Hz, 1 H), 6.89 (d, J = 8.35 Hz, 1 H); 13C NMR (CDCI3, 500 MHz) δ 163.5, 153.9, 152.0, 150.2, 146.7, 140.7, 134.0, 132.0, 129.7, 129.1 , 128.2, 121.9, 121.4, 118.7, 111.3; Mass spec: 334.27 (MH+). Anal. Calcd. for C19H15N3O3O.I 85H2O: C = 67.78%, H = 4.60%, N = 12.48%; found: C = 67.79%, H = 4.29%, N = 12.55%.
EXAMPLE 150
Figure imgf000084_0002
4-Fluorobenzaldehyde, 0-[[[4-[(3- pyridinyl)oxy]phenyl]amino]carbonyl]oxime (Scheme 4, Compound L)
Prepared as described above. Using workup method B provided the title compound as white solid in 93.5% yield. 1H NMR (CDCI3, 500 MHz) δ 8.39 (s, 1 H), 8.38 (d, J = 12.5 Hz, 2H), 8.08 (br, 1 H), 7.75-7.72 (m, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.34-7.29 (m, 2H), 7.19-7.15 (t, J = 8.45 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H); Mass spec: 352.09 (MH+). Anal. Calcd. for C19H14FN3θ3-1.38H20: C = 60.66%, H = 4.49%, N = 11.17%; found: C = 60.62%, H = 4.24%, N = 11.30%.
EXAMPLE 151
Figure imgf000085_0001
Benzaldehyde, 0-[[[4-[(3-pyridinyl)oxy]phenyl]amino]carbonyl]oxime (Scheme 4, Compound L) This material was prepared by the general method where R = 4-(3-pyridoxy)benzoic acid, R' = benzaldehyde oxime.
Using workup method C and then B provided the title compound as white solid in 7% yield. 1H NMR (CDCI3, 500 MHz) δ 8.43 (s, 1 H), 8.38 (d, J = 20.0
Hz, 2H), 8.17 (br, 1 H), 7.12 (d, J = 7.0 Hz, 2H), 7.56-7.46 (m, 5H), 7.32 (m, 2H), 7.05 (d, J = 6.9 Hz, 2H); Mass spec: 334.12 (MH+). Anal. Calcd. for
C19H15N3θ3-0.21 H2θ: C = 67.69%, H =4.61%, N = 12.46%; found: C =
67.75%, H = 4.81%, N = 12.22%.
EXAMPLE 152
Figure imgf000085_0002
3-Pyridinecarboxaldehyde, 0-[[(2-dibenzofuranyl)amino]carbonyl]oxime (Scheme 4, Compound L) Prepared as described above. Using work-up method A provided the title compound as white solid in 25% yield. 1H NMR (CDCI3, 500 MHz) δ 8.94 (br, 1 H), 8.77 (d, J = 3.0 Hz, 1H), 8.49 (s, 1H), 8.25 (s, 1 H), 8.14 (d, J = 6.75 Hz, 1 H), 8.09 (br, 1 H), 7.97 (d, J = 7.6 Hz, 1 H), 7.57 (t, J = 7.3 Hz, 2H), 7.50-7.46 (m, 3H), 7.36 (t, J = 7.8 Hz, 1 H); Mass spec: 332.24 (MH+). Anal. Calcd. for C19H13N3O3O.I9H2O: C = 68.19%, H = 4.03%, N = 12.56%; found: C = 68.18%, H = 3.99%, N = 12.49. EXAMPLE 153
Figure imgf000086_0001
4-Fluorobenzaldehyde, 0-[[(2-dibenzofuranyl)amino]carbonyl]oxime (Scheme 4, Compound L) Prepared as described above. Using workup method C provided the title compound as white solid in 8% yield. 1H NMR (CDCI3, 500 MHz) δ 8.43 (s, 1 H), 8.25 (s, 1 H), 8.20 (br, 1 H), 7.97 (dd, J = 7.7 Hz, J = 0.45 Hz, 1 H), 7.76 (m, 2H), 7.56 (t, J = 9.75 Hz, 2H), 7.48 (t, J = 7.3 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1 H), 7.19 (t, J = 8.65 Hz, 2H); 13C NMR (CDCI3, 500 MHz) δ 156.9, 152.7, 152.3, 130.4, 130.3, 127,5, 122.8, 120.9, 116.5, 116.4, 111.9, 111.7; Mass spec: 349.10 (MH+). Anal. Calcd. for
C20H13FN2O3: C = 68.96%, H = 3.76%, N = 8.04%; found: C = 68.82%, H = 3.77%, N = 7.77%.
Figure imgf000086_0002
Benzaldehyde, 0-[[(2-dibenzofuranyl)amino]carbonyl]oxime (Scheme 4, Compound L) Prepared as described above. Using work-up method C provided the title compound as white solid in 21% yield. 1H NMR (CDCI3, 500 MHz) δ 8.46 (s, 1 H), (8.29 (br, 1 H), 8.26 (d, J = 1.95 Hz, 1 H), 7.97 (d, J = 7.5 Hz, 1 H), 7.75 (dd, J = 8.5 Hz, J = 1.5 Hz, 2H), 7.58-7.46 (m, 7H), 7.36 (t, J = 7.7 Hz, J = 1 H); 13C NMR (CDCI3, 500 MHz) δ 156.9, 153.8, 153.2, 152.4, 132.1 , 132.0, 129.7, 129.1 , 128.3, 127.5, 124.9, 124.1 , 122.8, 121.0, 120.0, 112.6, 111.9, 111.8; Mass spec: 331.12 (MH+). Anal. Calcd. for C2oHi4N2θ3-0.135H20: C = 72.19%, H = 4.07 %, N = 8.42%; found: C = 72.20%, H = 4.07%, N = 8.33. EXAMPLE 155
Figure imgf000087_0001
(1Z)-N-[[[(4-butoxyphenyl)amino]carbonyl]oxy]ethanimidoyl chloride
This compound was synthesized in accordance with the following literature references: Ivanov, Y. et al., Anticholinesterase activity of O-carbamoylated acylhydroxymoyl chlorides, Khim-Farm Zh.. 26:5, 62-63, 1992; and Sakamoto, T. et al., A new synthesis of nitriles from N-alkoxyimidoyl halides with zinc, Synthesis, 9: 750-752, 1991.
Biological Data:
Homogenates of crude membranes were prepared from H4 cells that express transfected human FAAH (H4-FAAH cells). Briefly, cells were grown in DMEM supplemented with 10% FBS and Geneticin at a final concentration of 500 μg/ml(Gibco BRL, Rockville, MD). Confluent cultures of H4-FAAH cells were rinsed twice with phosphate-buffered saline [138 mM NaCI, 4.1 mM KCI, 5.1 mM Na2P04, 1.5 mM KH2P04 (pH 7.5), 37°C] and incubated for 5 to 10 minutes at 4°C in lysis buffer [1 mM sodium bicarbonate]. Cells were transferred from plates to polypropylene tubes (16 x 100 mm), homogenized and centrifuged at 32,000 x g for 30 minutes. Pellets were resuspended by homogenization in lysis buffer and centrifuged at 32,000 x g for 30 minutes. Pellets were resuspended in lysis buffer (15-20 μg protein/ml) then stored at - 80°C until needed. On the day of an experiment, membranes were diluted to 2.67 μg protein/ml in 125 mM Tris-CI, pH 9.0.
Activity of FAAH was measured using a modification of the method described by Omeir et al., 1995 (Life Sci 56:1999, 1995). Membrane homogenates (240 ng protein) were incubated at room temperature for one hour with 1.67 nM anandamide [ethanolamine 1-3H] (available from American Radiolabeled Chemical Inc., St Louis, MO) and 10 μM anandamide (available from Sigma/RBI, St. Louis, MO) in the absence and presence of inhibitors. The reaction was stopped by the addition of 1 volume of a solution of 1 :1 methanol and dichloroethane. The mixture was shaken and then centrifuged at 1000 x g for 15 minutes to separate the aqueous and organic phases. An aliquot of the aqueous phase, containing [3H]-ethanolamine was withdrawn and counted by scintillation spectroscopy. Data were expressed as the percentage of [3H]-ethanolamine formed versus vehicle, after subtraction of the background radioactivity determined in the presence of 10 μM arachidonyl trifluoromethyl ketone (ATFMK), an inhibitor of FAAH. IC5o values were determined using a four-parameter logistic equation for dose- response curves. Compounds for which IC50 values are not provided herein showed no FAAH inhibition or marginal FAAH inhibition in preliminary tests.
Table I
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
++++ = <10 nM; +++ = >10-100 nM; ++ = ≥101-500 nM; + = > 500 nM The following in vivo pain models below utilized Example 5. CARRAGEENAN-INDUCED THERMAL HYPERALGESIA (Chronic Inflammatory Pain): Example 5 (40 mg/kg, i.p.) suppressed the development of thermal hyperalgesia induced by paw carrageenan. Paw carrageenan injection (0, 0:45 hr, Carr) produced strong thermal hyperalgesia as evidenced by the short escape latencies seen in vehicle treated rats (0, 2:15 hr, Carr) as compared to the long baseline latencies (0:00 hr). Animals pretreated with Example 5 (#1, 0:15 hr) failed to exhibit hyperalgesic responses (compare 0 to ■ at 2:15 hr) and instead the latencies for drug treated animals were comparable to baseline. By 120 min post-carrageenan (2:45 hr), partial development of hyperalgesia was observed, that was reversed by a second injection of Example 5 (#2, 3:00 hr) which maintained thermal escape responses at basal levels for another hour (3:00-4:00 hr). No side effects were observed at 40 mg/kg, i.p. in drug (■) or vehicle (0) treated controls (CEW = Cremophor:Ethanol:Water 10:10:80, 2 ml/kg). Data are mean +/- s.e.m. (n= 8 per group). * p < .05, ** p < .01 Tukey's HSD, compared to vehicle. The results are shown in Table II below.
Table II
Carrageenan Induced Thermal Hyperalgesia Response
Figure imgf000092_0001
Time (hr)
HARGREAVES TEST (Acute Thermal Pain) Example 5 (10 & 30 mg/kg; 2 ml/kg; i.v. hand infusion) produced a significant reversal of acute thermal pain behavior at 15 min post injection, which did not persist beyond this time. No significant side effects were observed at 10 mg/kg. However, at 30 mg/kg side effects included strong sedation, reduced activity and splayed hindlimbs. Data are mean +/- s.e.m. (n= 8 per group). ** p < .01 Dunnett's Test, compared to vehicle control. The results are shown in Table III below.
Table III Hargreaves Test for Acute Thermal Pain Response
. . .4>. . - CEW(10: 10:80)
• ■ -A- - - morphhe, 3 rrg/kg
M. example o, ιτ /κg
- Example 5, 10 mg/kg
— β- - Example 5, 3D mg/kg
Figure imgf000093_0001
0 30 60 90 120
Time (min)
PAW EDEMA MODEL (Inflammation-induced Edema) The effects of Example 5 on carrageenan-induced edema were examined in a quantitative manner (plethysmometry). Injections of carrageenan (2% lambda) into the plantar aspect of both hind paws, resulted in an increase in combined total paw volume (swelling) measured 3 hours post-injection. Example 5 inhibited swelling by 26% at 40 mg/kg (Ex. 5 - 40, ip administered at -30 min and +2hr relative to carrageenan) but showed no efficacy at 20 mg/kg (Ex. 5 - 20, ip). The reference agent dexamethasone (Dex, 1 mg/kg, ip) inhibited swelling by 70%. Table IV, below, summarizes the data.
Table IV Paw Edema Response with Carrageenan
Figure imgf000094_0001

Claims

CLAIMSWhat is claimed is:
1. A compound of Formula I:
Figure imgf000095_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein
A is dibenzofuranyl, dibenzothienyl, naphthyl, indolyl, fluorenyl, carbazolyl, or represented by Formula II:
Figure imgf000095_0002
wherein a is 1 or 2;
R is C-ι-16 alkoxy optionally substituted with phenyl, pyridyl or morpholinyl; phenyl optionally substituted with Ci-4 alkyl; phenoxy; phenyl-Cι-4 alkyloxy-; pyridyloxy; pyhdyl-Cι-4 alkyloxy-; -N(H)-C(0)-Cι-16 alkyl; or -C(0)-N(H)-C1-ι6 alkyl;
R1 is a bond or a Cι-3 branched or linear aliphatic hydrocarbon; and
B is Cι- alkyl, indolyl, benzofuranyl, benzothienyl, dibenzofuranyl; dibenzothienyl, fluorenyl, carbazolyl, naphthyl, quinolinyl or isoquinolinyl, wherein each is optionally substituted with one or more of the same or different substituent selected from the group consisting of Cι- branched or linear aliphatic hydrocarbon, Cι-4 alkoxy, halo, haloalkyl, nitro and (Cι-3 alkyl)0-2 amino-; or represented by Formula III or Formula IV:
wherein
R2 is hydrogen, halo or C-ι-4 alkyl;
R3 is C-ι-4 alkyl, pyridyl, halo, or phenyl optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, Cι-4haloalkyl and nitro; X is CH or nitrogen;
R4 is C-ι-4 branched or linear aliphatic hydrocarbon, C1-4 alkoxy, halo, haloalkyl, nitro or amino; and b is 0 to 3, provided that if R2 is halo, then R3 is not halo; and if R3 is halo, then R2 is not halo.
2. The compound of claim 1 wherein A is dibenzofuranyl.
3. The compound of claim 1 wherein A is indolyl.
4. The compound of claim 1 wherein A is represented by Formula II:
Figure imgf000096_0001
wherein a is l ,
R is C1-4 alkoxy optionally substituted with phenyl, phenoxy, pyridyloxy, or amido optionally substituted with Cι-ι6 alkyl,
R1 is a bond; and
B is represented by Formula III:
Figure imgf000096_0002
wherein
R2 is hydrogen, and
R3 is methyl, pyridyl, phenyl optionally substituted with one or more halo, haloalkyl or nitro.
5. The compound of claim 1 wherein B is represented by Formula III:
Figure imgf000096_0003
wherein
R2 is hydrogen or methyl; and R3 is methyl, or phenyl optionally substituted with one or more halo, haloalkyl or nitro.
6. The compound of claim 1 wherein B is represented by Formula IV:
Figure imgf000097_0001
wherein X is CH; R4 is halo; and b is 1.
7. The compound of claim 1 wherein B is represented by Formula IV:
^^ (IV) wherein
X is nitrogen; and b is O.
8. The compound of claim 1 wherein B is represented by Formula V:
Figure imgf000097_0002
wherein X is nitrogen.
9. The compound of claim 1 wherein B is represented by Formula III, Formula IV or Formula V:
Figure imgf000097_0003
wherein R2 is hydrogen, or methyl,
R3 is C-ι-4 alkyl, pyridyl, or phenyl optionally substituted with one or more halo, haloalkyl or nitro, X is CH or nitrogen,
R4 is C-ι-4 branched or linear aliphatic hydrocarbon, C1-4 alkoxy, halo, haloalkyl or amino, and b is 0 to 3.
10. A compound of Formula VI:
Figure imgf000098_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein a is l ;
R is Cι-12 alkoxy;
R2 is hydrogen or methyl; and
R3 is methyl, pyridyl, phenyl optionally substituted with one or more halo, haloalkyl or nitro.
11. The compound of claim 10 wherein R2 is hydrogen and R3 is phenyl optionally substituted with one or more halo, haloalkyl or nitro.
12. The compound of claim 10 wherein R2 is methyl and R3 is methyl.
13. The compound of claim 10 selected from the group consisting of: pyridine-3-carbaldehyde, 0-[[(4-undecyloxy-phenyl)amino]carbonyI]oxime; pyridine-3-carbaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; 4-fluorobenzaldehyde, 0-[[(4-octyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
3,4-difluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
2,6-difluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; 2,4-difluorobenzaldehyde, 0-[[(4-nonyloxy-phenyI)amino]carbonyl]oxime;
3-fluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-octyloxy-phenyl)amino]carbonyl]oxime;
2,3-difluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-undecyloxy-phenyl)amino]carbonyl]oxime;
2,4,5-trifluorobenzaldehyde, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-undecyloxy-phenyl)amino]carbonyl]oxime;
4-trifluoromethyl-benzaldehyde, 0-[[(4-nonyloxy- phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(2-phenylethoxy)phenyl]amino]carbonyl]oxime;
2-fluoro-3-trifluoromethyl-benzaldehyde, 0-[[(4-nonyloxy- phenyl)amino]carbonyl]oxime;
(4-undecyloxy-phenyl)-carbamic acid phenyl ester; propan-2-one, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-nonyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(phenylmethoxy)phenyl]amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[[4-(2-phenylethoxy)phenyl]amino]carbonyl]oxime;
2-fluoro-5-trifluoromethyl-benzaldehyde, 0-[[(4-nonyloxy- phenyl)amino]carbonyl]oxime; 4-fluorobenzaldehyde, 0-[[[4-(phenylmethoxy)phenyl]amino]carbonyl]oxime;
3-pyridinecarboxaldehyde, 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl]amino]carbonyl]oxime; benzaldehyde, 0-[[(3-phenoxyphenyl)amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-pentyloxy-phenyl)amino]carbonyl]oxime; 4-fluorobenzaldehyde, 0-[[(4-butoxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-heptyloxy phenyl)amino]carbonyl]oxime;
3-pyridinecarboxaldehyde, 0-[[(4-phenoxyphenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[[4-(3-phenylpropoxy)phenyl]amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-pentyloxy-phenyl)amino]carbonyl]oxime; 4-fluorobenzaldehyde, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-decyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-pentyloxy-phenyI)amino]carbonyl]oxime; 2,4-difluorobenzaldehyde, benzaldehyde, 0-[[(4-nonanoylamino-phenyl) amino]carbonyl]oxime;
4-fluorobenzaldehyde, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-pentyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-undecyIoxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-dodecyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[( 4-pentyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-propoxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-butoxy-phenyl)amino]carbonyl]oxime; benzaldehyde, 0-[[(4-hexyloxy-phenyl)amino]carbonyl]oxime; propan-2-one, 0-[[(4-heptyloxy-phenyl)amino]carbonyl]oxime; pyridine-3-carbaldehyde, 0-[[(4-hexyloxy-phenyl)amino]carbonyl]oxime; and pyridine-3-carbaldehyde, 0-[[(4-butoxy-phenyI)amino]carbonyl]oxime.
14. A compound of Formula VII:
Figure imgf000100_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein a is 1 ;
R is C-ι-12 alkoxy;
R4 is halo;
X is CH or nitrogen; and b is 0 to 2, with the proviso that when X is nitrogen then b is 0.
15. The compound of claim 14 wherein X is CH selected from the group consisting of: (4-undecyloxy-phenyl)-carbamic acid phenyl ester; (4-decyloxy-phenyl)-carbamic acid phenyl ester; (4-dodecyloxy-phenyl)-carbamic acid phenyl ester; (4-octyloxy-phenyl)-carbamic acid 2-fluoro-phenyl ester; (4-octyloxy-phenyl)-carbamic acid phenyl ester;
(4-heptyloxy-phenyl)-carbamic acid phenyl ester; and (4-decyloxy-phenyl)-carbamic acid 2-fluoro-phenyl ester;
16. A compound of Formula VIII
Figure imgf000101_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein a is 1 ;
R is Cι-12 alkoxy; R1 is a Cι-3 branched or linear aliphatic hydrocarbon;
R4 is phenyl, Cι-3 alkoxy or halo;
X is CH or nitrogen; and b is 2.
17. The compound of claim 16 wherein X is CH selected from the group consisting of:
(4-butoxy-benzyl)-carbamic acid 4-fluoro-phenyl ester; pyridine-3-carbaldehyde, 0-[[(4-butoxy-benzyl)amino]carbonyl]oxime;
(4-butoxy-benzyl)-carbamic acid phenyl ester; [1-(4-butoxy-phenyl)-propyl]-carbamic acid 2-fluoro-phenyl ester;
(4-butoxy-benzyl)-carbamic acid 2,4-difluoro-phenyl ester;
(4-butoxy-benzyl)-carbamic acid 4-methoxy-phenyl ester;
[1-(4-butoxy-phenyl)-propyl]-carbamic acid 4-fluoro-phenyl ester;
(4-butoxy-benzyl)-carbamic acid 2-fluoro-phenyl ester; and (4-butoxy-benzyl)-carbamic acid 3-chloro-phenyl ester.
18. A compound of Formula IX:
Figure imgf000102_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein a is 1 ;
R is Cι-12 alkoxy;
R1 is a Ci-3 branched or linear aliphatic hydrocarbon; and
X is CH or nitrogen.
19. The compound of claim 18 selected from the group consisting of: (4-butoxy-benzyl)-carbamic acid quinolin-6-yl ester; (4-butoxy-benzyl)-carbamic acid naphthalen-2-yl ester; [1-(4-butoxy-phenyl)-propyl]-carbamic acid quinolin-6-yl ester; and (4-butoxy-benzyl)-carbamic acid naphthalen-1-yl ester.
20. A method of treating a condition or disorder by inhibiting fatty acid amidohydrolase in a mammal comprising administering to the mammal a therapeutically effective amount of a represented by the formula:
Figure imgf000102_0002
21. A method of treating a condition or disorder by inhibiting fatty acid amidohydrolase in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
22. A method of treating neuropathic pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
23. A method of treating acute pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
24. A method of treating chronic pain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
25. A method of treating emesis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
26. A method of treating anxiety in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
27. A method of altering feeding behaviors in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
28. A method of treating movement disorders in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
29. A method treating glaucoma in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
30. A method of treating brain injury in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
31. A method of treating cardiovascular disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in claim 1.
32. A pharmaceutical composition for treating a condition or disorder requiring inhibition of a fatty acid amidohydrolase comprising a therapeutically effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier, adjuvant or diluent.
PCT/US2003/003222 2002-02-08 2003-02-04 (oxime)carbamoyl fatty acid amide hydrolase inhibitors WO2003065989A2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2003565415A JP2005516986A (en) 2002-02-08 2003-02-04 (Oxime) carbamoyl fatty acid amide hydrolase inhibitor
AU2003210824A AU2003210824A1 (en) 2002-02-08 2003-02-04 (oxime)carbamoyl fatty acid amide hydrolase inhibitors
EP03737600A EP1472215A4 (en) 2002-02-08 2003-02-04 (oxime)carbamoyl fatty acid amide hydrolase inhibitors

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US7919494B2 (en) 2005-02-17 2011-04-05 Astellas Pharma, Inc. Pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound
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US8207226B1 (en) 2008-06-03 2012-06-26 Alcon Research, Ltd. Use of FAAH antagonists for treating dry eye and ocular pain
US8207199B2 (en) 2008-07-14 2012-06-26 Astellas Pharma Inc. Azole compound
WO2010007966A1 (en) 2008-07-14 2010-01-21 アステラス製薬株式会社 Azole compound
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EP1472215A2 (en) 2004-11-03
US20030195226A1 (en) 2003-10-16
AU2003210824A8 (en) 2003-09-02
PL373970A1 (en) 2005-09-19
EP1472215A4 (en) 2007-05-09
AU2003210824A1 (en) 2003-09-02
JP2005516986A (en) 2005-06-09
US20050131032A1 (en) 2005-06-16
US6949574B2 (en) 2005-09-27
WO2003065989A3 (en) 2004-02-19

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