WO2012088431A1 - Faah inhibitors - Google Patents

Faah inhibitors Download PDF

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Publication number
WO2012088431A1
WO2012088431A1 PCT/US2011/066870 US2011066870W WO2012088431A1 WO 2012088431 A1 WO2012088431 A1 WO 2012088431A1 US 2011066870 W US2011066870 W US 2011066870W WO 2012088431 A1 WO2012088431 A1 WO 2012088431A1
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Prior art keywords
alkyl
group
ring
pharmaceutically acceptable
acceptable salt
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PCT/US2011/066870
Other languages
French (fr)
Inventor
Colleen Hudson
Timothy C. Barden
James Jia
Ara Mermerian
Bo Peng
Jane Yang
Xiang Y Yu
Kevin Sprott
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Ironwood Pharmaceuticals, Inc.
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Publication of WO2012088431A1 publication Critical patent/WO2012088431A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to indole and azaindole compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH).
  • Fatty Acid Amide Hydrolase FAAH
  • compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment of various disorders.
  • eCB endocannabinoid
  • the eCB system comprises at least two receptors: the CB1 cannabinoid receptor, widely distributed in the brain and present in some peripheral organs, and the CB2 receptor, found principally in the periphery and immune systems and in some regions of the brain.
  • the endogenous agonists of these receptors are the endogenous cannabinoids (eCBs), a family of lipids comprising the fatty acid anandamide (AEA) as well as other fatty acids.
  • Endocannabinoid-degrading enzymes including fatty acid amide hydrolase (FAAH), are responsible for cleaving and deactivating eCBs in vivo.
  • FAAH is an integral membrane protein that is expressed in high levels in several brain regions, especially in the neurons of the hippocampus, cerebellum, neocortex and olfactory bulb.
  • FAAH is the principal enzyme responsible for the hydrolysis of AEA in vivo and is also capable of hydrolyzing a wide variety of other substrates. It is known that inhibiting FAAH can lead to increases in fatty acids, including AEA, which could enhance cannabinoid signals within the eCB system.
  • fatty acid amides can induce analgesia in acute and chronic animal models of pain.
  • increasing the level of AEA and other fatty acid amides e.g., N- palmitoyl ethanolamide, N-oleoylethanol amide and oleamide
  • FAAH inhibitors of FAAH are useful in the treatment of pain.
  • Inhibitors of FAAH might also be useful in the treatment of other disorders involving deregulation of the eCB system (e.g., depression, anxiety, eating disorders, gastrointestinal and cardiovascular disorders, inflammation, excitotoxic insult, brain trauma, and fibromyalgia), and may avoid some of the side effects typically associated with CB receptor agonists (e.g., catalepsy or hypothermia).
  • other disorders involving deregulation of the eCB system e.g., depression, anxiety, eating disorders, gastrointestinal and cardiovascular disorders, inflammation, excitotoxic insult, brain trauma, and fibromyalgia
  • CB receptor agonists e.g., catalepsy or hypothermia
  • FAAH inhibitors may be useful agents for treating symptoms or achieving disease modification changes in multiple sclerosis.
  • AEA acts as a substrate for COX-2, which can convert it to a prostamide.
  • certain prostamides may be elevated in the presence of an FAAH inhibitor.
  • FAAH inhibitors may also be useful agents for treating glaucoma.
  • ring A is selected from the group consisting of phenyl and a 6-membered monocyclic
  • heteroaryl ring wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms;
  • each J A is independently selected from the group consisting of halogen, -N0 2 , -CN, -R 4 , -C(0)R A , -C(S)R A , -C(0)OR A , -OC(0)R A , -N(R A )S(0) 2 R A , -N(R A )C(0)R A ,
  • each R A is independently selected from hydrogen, Ci-6 aliphatic, Ci-6 alkoxy, Ci -6 alkylthio, C 3- 6 cycloaliphatic, C 3- 6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R A is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, -0(C 1-4 alkyl), -S(C 1-4 alkyl), -N(C alkyl) 2 , C haloalkyl or C 1-4 haloalkoxy; and wherein each of said R A that is a C 1-6 aliphatic, C 1-6 alkoxy or C 1-6 alkylthio is optionally substituted by one instance of C 3-6 cyclo
  • each R 4 is independently selected from Ci -6 aliphatic, C 3-6 cycloaliphatic, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R 4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, -OCd ⁇ alkyl), -S(C 1-4 alkyl) or -N(d-4 alkyl) 2 ; and wherein each R 4 that is a C 1-6 aliphatic is optionally substituted by one instance of a C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkoxy, C 3-6
  • halocycloalkoxy phenyl, 3- to 6-membered heterocyclic or 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; or
  • heterocyclic ring contains up to two heteroatoms selected from N, O or S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, -CN, -NH 2 , -OH, C M alkyl, C haloalkyl-0(Ci-4 alkyl), -N(C 1-4 alkyl) 2 or -S(C alkyl); n is an integer selected from the group consisting of 0, 1, 2 and 3;
  • ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
  • heteroatoms selected from the group consisting of N, O and S;
  • each J B is independently selected from the group consisting of halogen, -N0 2 , -CN, -OH, Cj-6 aliphatic, C3-6 cycloaliphatic, C 1-6 haloaliphatic, Ci -6 alkoxy, Ci -6 haloalkoxy and C 3- 6 cycloalkoxy;
  • n is an integer selected from the group consisting of 0, 1, 2 and 3;
  • ring C is a 5-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
  • each J is independently selected from the group consisting of halogen, -N0 2 , -CN, -R , -C(0)R c , -C(S)R C , -C(0)OR c , -OC(0)R c , -N(R c )C(0)R c , -N(R C )C(S)R C , -OR c , -SR C , -S(0)R c , -S(0) 2 R c , -N(R c )S(0) 2 R c , -S(0) 2 N(R c ) 2 , -C(0)N(R c ) 2 and -N(R C ) 2 ; each R is independently selected from hydrogen, Ci -6 aliphatic, Ci-6 alkoxy, C 1-6 alkylthio, C 3- 6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocycl
  • each R is independently selected from C 1-6 aliphatic, C 3-6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, 3- to 6-membered heterocyclic or 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently
  • each R is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C M alkyl, -0(C alkyl), -S(C 1-4 alkyl)
  • R is a Ci -6 aliphatic, it is optionally substituted by one instance of C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkoxy or C 3-6
  • heterocyclic ring contains up to three ring heteroatoms selected from the group consisting of N, O and S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C 1-4 alkyl, Ci_ 4 alkoxy, -CN, -NH 2 , -OH, -0(Cn alkyl), - ⁇ alkyl) 2 or -S(C 1-4 alkyl);
  • p is an integer selected from the group consisting of 0, 1, 2 and 3;
  • each R 1 is independently selected from hydrogen, Q-6 aliphatic or Ci -6 haloaliphatic,
  • R 2 is selected from the group consisting of halogen, -CN or C 1,5 aliphatic; wherein said C 1-6 aliphatic is independently and optionally substituted by up to three instances of halogen,
  • ring A is selected from the group consisting of phenyl and a 6-membered monocyclic heteroaryl ring; wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms;
  • each J A is independently selected from the group consisting of-R 4 , -C(0)OR 5 , -C(S)R A , -N(R A )C(0)R A , -N(R A )C(S)R A , -SR A , -S(0)R A , -S(0) 2 R A , -N(R A )S(0) 2 R A and -S(0) 2 N(R A ) 2 ;
  • each R A is independently selected from hydrogen, Ci -6 aliphatic, C 1-6 alkoxy, C 1-6 alkylthio, C 3- 6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R A is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, -0(Ci-4 alkyl), -S(C 1-4 alkyl) or -N(C alkyl) 2 ; and wherein each R A that is a C 1-6 aliphatic, Ci-6 alkoxy or C 1-6 alkylthio is optionally substituted by one instance of C 3- cycloalkyl, C 3- 6 halocycloalkyl, pheny
  • each R 4 is independently selected from C 3-6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R 4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C 1-4 alkoxyl, -S(C 1-4 alkyl) or-NCC M alkyf ;
  • each R 5 is independently selected from Ci -6 aliphatic, C 3-6 cycloaliphatic, phenyl, 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R 5 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , Ci ⁇ alkyl, Ci ⁇ haloalkyl,-0(C 1-4 alkyl), -S(Ci-4 alkyl) or-N(Ci-4 alkyl) 2 ; and wherein each R 5 that is a Ci_6 aliphatic is optionally substituted by one instance of C 3-6 cycloalkyl, C 3-6 halocycloalkyl, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroary
  • ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
  • heteroatoms selected from the group consisting of N, O and S; m is an integer selected from the group consisting of 0, 1, 2 and 3;
  • each J B is independently selected from the group consisting of halogen, -N0 2 , -CN, -OH, Ci-6 aliphatic, C3-6 cycloaliphatic, C 1-6 haloaliphatic, Ci- alkoxy, Ci -6 haloalkoxy and C 3- 6 cycloalkoxy;
  • ring C is selected from the group consisting of phenyl, C 3- cycloalkyl, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S; each J c is independently selected from the group consisting of halogen, -N0 2 , -OH, -CN, -R 11 , -C(0)R c , -C(S)R C , -C(0)OR c , -OC(0)R c , -N(R c )C(0)R c , -N(R C )C(S)R C , -OR c , -SR C , -S(0)R c , -S(0) 2 R c , -N(R c )S(0) 2 R c , -S(0) 2 N(R c ) 2 ,
  • each R c is independently selected from hydrogen, C 1-6 aliphatic, C 1-6 alkoxy, Ci -6 alkylthio, C 3-6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R c is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C alkyl, -0(C ⁇ ⁇ alkyl), -S(C 1-4 alkyl) or -N(Ci- alkyl) 2 ; and wherein each R c that is a Q-e aliphatic, C 1-6 alkoxy or Ci -6 alkylthio is optionally substituted by one instance of C 3-6 cycloalkyl, C 3-6 halocyclo
  • p is an integer selected from the group consisting of 0, 1, 2 and 3; each R 1 is independently selected from a hydrogen, C ⁇ - aliphatic or Ci -6 haloaliphatic; and R 2 is selected from the group consisting of halogen, -N0 2 , -CN and C ⁇ aliphatic; wherein said C 1-6 aliphatic is optionally substituted by up to three instances of halogen.
  • the invention also relates to pharmaceutical compositions comprising a compound according to Formula A or Formula B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant. Also within the scope of the invention are pharmaceutical compositions, further comprising at least one additional therapeutic agent.
  • the invention also relates to methods for the treatment or prevention of pain
  • autoimmune disorders disease-states or indications that are accompanied by inflammatory processes; gastrointestinal diseases or disorders; pruritus; substance abuse-related syndromes, disorders, diseases or withdrawal symptoms; psychiatric disorders; neurological or neurodegenerative disorders; ocular disorders; appetite-related disorders; gynecological disorders, urinary system disorders and sleep disorders; by using one of the compounds or pharmaceutical composition of the invention, either alone or in combination therapy.
  • compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase "optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. If a substituent radical or structure is not identified or defined as “optionally substituted", the substituent radical or structure is not substituted.
  • groups such as -H, halogen, -N0 2 , -CN, -OH, -NH 2 or -OCF3 would not be substitutable groups.
  • the phrase "up to”, as used herein, refers to zero or any integer number that is equal to or less than the number following the phrase.
  • optionally substituted with "up to 3" means substituted with 0, 1, 2, or 3 substituents.
  • a specified number range of atoms includes any integer therein.
  • a group having from 1-4 atoms could have 1 , 2, 3 or 4 atoms. It will be understood by one of ordinary skill in the art that when a group is characterized as substituted (as opposed to optionally substituted) with, e.g., "up to 3" substituents, it can only be substituted with 1, 2 or 3 substituents.
  • stable refers to compounds that are not substantially altered when subjected to conditions that allow for their production, detection, and, in some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 25 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • a compound such as the compounds of the invention or other compounds herein disclosed may be present in its free form (e.g., an amorphous form or polymorphs). Under certain conditions, compounds may also form salts, and/or other multi-component crystalline forms (e.g., solvates, (e.g., hydrates) and co-crystals). As used herein, the term co-form is synonymous with the term multi-component crystalline form. When one of the components in the co-form has clearly transferred a proton to the other component, the resulting co-form is referred to as a "salt".
  • solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein (or its salts or co-crystals).
  • a "hydrate” is a particular type of solvate in which the solvent is water.
  • solvents that can form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, tetrahydrofuran (THF), dichloromethane (DCM), and N ⁇ V-dimethylformamide (DMF).
  • DMSO dimethyl sulfoxide
  • ethyl acetate acetic acid
  • ethanolamine tetrahydrofuran
  • DCM dichloromethane
  • structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure, for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers,
  • the present disclosure also embraces isotopically-labeled compounds that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • Certain isotopically labeled compounds of the present invention e.g., those labeled with 3 H and 1 C
  • Tritiated (i.e., H) and carbon- 14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • aliphatic or "aliphatic group”, as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms and in yet other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, .fee-butyl, tert-butyl, butenyl, propargyl, acetylene and the like.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms or 1-3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl radical includes radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • an alkenyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examples include, but are not limited to, vinyl, allyl and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms).
  • Examples include, but are not limited to, ethynyl, propynyl, and the like.
  • carbocyclic refers to a ring system formed only by carbon and hydrogen atoms. Unless otherwise specified, throughout this disclosure carbocycle is used as a synonym of "non-aromatic carbocycle” or “cycloaliphatic”. In some instances the term can be used in the phrase “aromatic carbocycle”, and in this case it refers to an "aryl group” as defined below.
  • cycloaliphatic refers to a cyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a cycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused, spiro or bridged. In one embodiment, the term “cycloaliphatic” refers to a monocyclic C3-C12 hydrocarbon or a bicyclic G7-C12
  • any individual ring in a bicyclic or tricyclic ring system has 3-7 members.
  • Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • cycloaliphatic also includes polycyclic ring systems in which the non- aromatic carbocyclic ring can be "fused" to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, as long as the radical or point of attachment is on the non-aromatic carbocyclic ring.
  • heterocycle refers to a ring system in which one or more ring members are an independently selected heteroatom, which is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule.
  • heterocycle is used as a synonym of "non-aromatic heterocycle”.
  • the term can be used in the phrase “aromatic heterocycle”, and in this case it refers to a "heteroaryl group” as defined below.
  • heterocycle also includes fused, spiro or bridged heterocyclic ring systems.
  • a heterocycle may be monocyclic, bicyclic or tricyclic.
  • the heterocycle has 3-18 ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur or nitrogen, and each ring in the system contains 3 to 7 ring members.
  • a heterocycle may be a monocycle having 3-7 ring members (2-6 carbon atoms and 1—4 heteroatoms) or a bicycle having 7-10 ring members (4-9 carbon atoms and 1-6 heteroatoms).
  • Examples of bicyclic heterocyclic ring systems include, but are not limited to: adamantanyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl.
  • heterocycle also includes polycyclic ring systems wherein the heterocyclic ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the heterocyclic ring.
  • heterocyclic rings include, but are not limited to, the following
  • aryl (as in “aryl ring” or “aryl group”), used alone or as part of a larger moiety, as in “aralkyl”, “aralkoxy”, “aryloxyalkyl”, refers to a carbocyclic ring system wherein at least one ring in the system is aromatic and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aryl group may be monocyclic, bicyclic or tricyclic and contain 6-18 ring members.
  • the term also includes polycyclic ring systems where the aryl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the aryl ring.
  • aryl rings include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl, and anthracenyl.
  • An optionally substituted "aralkyl” can be substituted on both the alkyl and the aryl portion.
  • an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion.
  • substituted aralkoxy which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion.
  • a substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom.
  • heteroaryl or “heteroaromatic” or “heteroaryl group” or “aromatic heterocycle” used alone or as part of a larger moiety as in “heteroaralkyl” or
  • heteroarylalkoxy refers to a ring system wherein at least one ring in the system is aromatic and contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and which has a single point of attachment to the rest of the molecule.
  • a heteroaryl ring system may be monocyclic, bicyclic or tricyclic and have a total of five to fourteen ring members. In one embodiment, all rings in a heteroaryl system are aromatic. Also included in this definition are heteroaryl radicals where the heteroaryl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or combinations thereof, as long as the radical or point of attachment is in the heteroaryl ring.
  • a bicyclic 6,5 heteroaromatic system, as used herein, for example, is a six-membered
  • heteroaromatic ring fused to a second five-membered ring wherein the radical or point of attachment is on the six-membered ring.
  • Heteroaryl rings include, but are not limited to the following monocycles: 2-furanyl, 3- furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3- pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2- triazolyl and 5-triazolyl), 2-
  • benzimidazolyl benzofuryl, benzothiophenyl, benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1 -isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
  • indolyl e.g., 2-indolyl
  • quinolinyl e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl
  • isoquinolinyl e.g., 1 -isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl.
  • cyclo encompasses mono-, bi- and tri-cyclic ring systems including cycloaliphatic, heterocyclic, aryl or heteroaryl, each of which has been previously defined.
  • fused bicyclic ring systems comprise two rings which share two adjoining ring atoms.
  • Bridged bicyclic ring systems comprise two rings which share three or four adjacent ring atoms.
  • bridge refers to a bond or an atom or a chain of atoms connecting two different parts of a molecule. The two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are referred to as "bridgeheads".
  • bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbomanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa- tricyclo[3.3.1.03,7]nonyl.
  • ring atom refers to an atom such as C, N, O or S that is part of the ring of an aromatic group, a cycloaliphatic group or a heteroaryl ring.
  • a “substitutable ring atom” is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group.
  • substituted ring atom does not include ring nitrogen or carbon atoms which are shared when two rings are fused.
  • substituted does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to one or more moiety other than hydrogen and no hydrogens are available for substitution.
  • Heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quatemized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic or heteroaryl ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • two independent occurrences of a variable may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered,
  • heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring Exemplary rings that are formed when two independent occurrences of a substituent are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of a substituent that are bound to the same atom and are taken together with that atom to form a ring, where both occurrences of the substituent are taken together with the atom to which they are bound to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the group is attached to the rest of the molecule by a single point of attachment; and b) two independent occurrences of a substituent that are bound to different atoms and are taken together with both of those atoms to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formed has two points of attachment with the rest of the
  • an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain can optionally be replaced with said other atom or group. Unless otherwise specified, the optional replacements form a chemically stable compound. Optional interruptions can occur both within the chain and/or at either end of the chain; i.e., both at the point of attachment(s) to the rest of the molecule and/or at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound.
  • the replacement atom is bound to an H on the terminal end.
  • the resulting compound could be -OCH 2 CH 3 , -CH 2 OCH 3 , or -CH 2 CH 2 OH.
  • the divalent linker -CH 2 CH 2 CH 2 - were optionally interrupted with -0-, the resulting compound could be -OCH 2 CH 2 -, -CH 2 OCH 2 -, or - CH 2 CH 2 0-.
  • the optional replacements can also completely replace all of the carbon atoms in a chain.
  • a C 3 aliphatic can be optionally replaced by -N(R )-, -C(O)-, and -N(R )- to form -N(R $ )C(0)N(R $ )- (a urea).
  • the term "vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
  • the term "geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
  • terminal refers to the location of a group within a substituent.
  • a group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure.
  • Carboxyalkyl i.e., R x O(0)C-alkyl is an example of a carboxy group used terminally.
  • a group is internal when the group is present in the middle of a substituent at the end of the substituent bound to the rest of the chemical structure.
  • Alkylcarboxy e.g., alkyl-C(0)0- or alkyl-O(CO)-
  • alkylcarboxyaryl e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-
  • carboxy groups used internally are examples of carboxy groups used internally.
  • a bond drawn from a substituent to the center of one ring within a multiple-ring system represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system.
  • formula D3 represents possible substitution in any of the positions shown in formula D4:
  • each substituent only represents substitution on the ring to which it is attached.
  • Y is an optional substituent for ring A only
  • X is an optional substituent for ring B only.
  • alkoxy or “alkylthio” refer to an alkyl group, as previously defined, attached to the molecule, or to another chain or ring, through an oxygen (“alkoxy”, e.g., -O-alkyl) or a sulfur (“alkylthio,” e.g., -S-alkyl) atom.
  • C n-m “alkoxyalkyl”, Cn-m “alkoxyalkenyl”, C n-m “alkoxyaliphatic”, and C n-m “alkoxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups, wherein the total number of carbons between the alky and alkoxy, alkenyl and alkoxy, aliphatic and alkoxy or alkoxy and alkoxy, as the case may be, is between the values of n and m. When these moieties are optionally substituted they can be substituted in either of the portions on both sides of the oxygen or sulfur.
  • aryloxy, “arylthio”, “benzyloxy” or “benzylthio” refer to an aryl or benzyl group attached to the molecule, or to another chain or ring, through an oxygen
  • aryloxy "benzyloxy,” e.g., -O-Ph, -OCH 2 Ph) or sulfur (“arylthio,” e.g., -S-Ph, -S- CH 2 Ph) atom.
  • aryloxyalkyl "benzyloxyalkyl” "aryloxyalkenyl” and “aryloxyaliphatic” mean alkyl, alkenyl or aliphatic, as the case may be, substituted with one or more aryloxy or benzyloxy groups, as the case may be. In this case, the number of atoms for each aryl, aryloxy, alkyl, alkenyl or aliphatic will be indicated separately.
  • a 5-6- membered aryloxyiC alkyl is a 5-6-membered aryl ring, attached via an oxygen atom to a Cj-4 alkyl chain, which, in turn, is attached to the rest of the molecule via the terminal carbon of the C alkyl chain.
  • an optionally substituted "aralkyl” can potentially be substituted on both the alkyl and the aryl portion. Unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies, for example, to a substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom.
  • an optionally substituted 6- membered aryloxy(C 3 alkyl) group could be, for instance, -(CH 3 ) 2 CH 2 - [p-(MeO)-Ph]; an optionally substituted 6-membered heteroaryloxy(C 4 alkyl) could, for instance, be
  • alkyl chain on the "aralkyl” group is also substituted that will be specifically indicated.
  • an optionally substituted 6-membered heteroaryloxy(C 4 alkyl) that is also optionally substituted on the alkyl would be referred to as "an optionally substituted 6-membered heteroaryloxy(C 4 alkyl), wherein said C 4 alkyl chain is optionally substituted”.
  • An example of this latter group could be 5, 6-dimethyl-l,3-pyrimidine-0-CF(CH 3 )-CH(OH)CH 2 -, wherein the alkyl chain is substituted with F and with -OH.
  • haloalkyl means alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • a C 1-3 haloalkyl could be -CFHCH 2 CHF 2 and a C 1-2 haloalkoxy could be -OC(Br)HCHF 2 .
  • This term includes perfluorinated alkyl groups, such as -CF 3 and -CF 2 CF 3 .
  • cyano refers to -CN or -C ⁇ N.
  • cyanoalkyl mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups.
  • amino refers to -NH 2 .
  • aminoalkyl means alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups.
  • a C 1-3 aminoalkyl could be -CH(NH 2 )CH 2 CH 2 NH 2 and a Ci -2 aminoalkoxy could be -OCH 2 CH 2 NH 2 .
  • hydroxyl or "hydroxy” refers to -OH.
  • hydroxyalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups.
  • a Ci -3 hydroxyalkyl could be -CH 2 (CH 2 OH)CH 3 and a C 4 hydroxyalkoxy could be -OCH 2 C(CH 3 )(OH)CH 3 .
  • an "aroyl” or “heteroaroyl” refers to a -C(0)-aryl or a -C(O)- heteroaryl.
  • the aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
  • a "carbonyl”, used alone or in connection with another group refers to -C(O)- or -C(0)H.
  • an "alkoxycarbonyl” refers to a group such as -C(0)0(alkyl).
  • An aliphatic chain can be optionally interrupted by a carbonyl group or can optionally be substituted by an oxo group, and both expressions refer to the same: e.g., -CH 2 - C(0)-CH 3 .
  • linker refers to a bifunctional chemical moiety attaching a compound to a solid support or soluble support.
  • a "linker”, as used herein, refers to a divalent group in which the two free valences are on different atoms (e.g., carbon or heteroatom) or are on the same atom but can be substituted by two different substituents.
  • a methylene group can be a Ci alkyl linker (-CH 2 -), which can be substituted by two different groups, one for each of the free valences (e.g., as in Ph-CH 2 -Ph, wherein methylene acts as a linker between two phenyl rings).
  • Ethylene can be a C 2 alkyl linker (-CH 2 CH 2 -) wherein the two free valences are on different atoms.
  • the amide group for example, can act as a linker when placed in an internal position of a chain (e.g., -CONH- ).
  • a linker can be the result of interrupting an aliphatic chain by certain functional groups or of replacing methylene units on said chain by said functional groups.
  • a linker can be a C 1-6 aliphatic chain in which up to two methylene units are substituted by -C(O)- or -NH- (as in -CH 2 -NH-CH 2 -C(0)-CH 2 - or - CH 2 -NH-C(0)- CH 2 -).
  • An alternative way to define the same -CH 2 -NH-CH 2 -C(0)-CH 2 - and - CH 2 -NH- C(0)-CH 2 - groups is as a C 3 alkyl chain optionally interrupted by up to two -C(O) - or -NH- moieties.
  • Cyclic groups can also form linkers: e.g., a 1,6-cyclohexanediyl can be a linker between two R groups, as in
  • protecting group refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound.
  • a protecting group has one or more, or preferably all, of the following characteristics: a) reacts selectively in good yield to give a protected substrate that is stable to the reactions occurring at one or more of the other reactive sites; and b) is selectively removable in good yield by reagents that do not attack the regenerated functional group.
  • nitrogen protecting group refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the
  • the term "displaceable moiety” or “leaving group” refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.
  • amide coupling agent or "amide coupling reagent” means a compound that reacts with the hydroxyl moiety of a carboxy moiety thereby rendering it susceptible to nucleophilic attack.
  • exemplary amide coupling agents include DIC
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • the invention relates to a compound of Formula A, or a pharmaceutically acceptable salt thereof,
  • ring A is selected from the group consisting of phenyl and a 6-membered monocyclic
  • heteroaryl ring wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms;
  • each J A is independently selected from the group consisting of halogen, -N0 2 , -CN, -R 4 , -C(0)R A , -C(S)R A , -C(0)OR A , -OC(0)R A , -N(R A )S(0) 2 R A , -N(R A )C(0)R A , -N(R A )C(S)R A , -OR A , -SR A , -S(0)R A , -S(0) 2 R A , -S(0) 2 N(R A ) 2 , -C(0)N(R A ) 2 and -N(R A ) 2 ; wherein, optionally, two R A groups attached to the same N atom, together with said N, form a 5- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from O or N;
  • each R A is independently selected from hydrogen, Ci -6 aliphatic, Ci-6 alkoxy, C 1-6 alkylthio, a C 3- 6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R A is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, -0(C 1-4 alkyl), -S(C alkyl), -N(C 1-4 alkyl) 2 , C haloalkyl or C haloalkoxy; and wherein each of said R A that is a Ci -6 aliphatic, C 1-6 alkoxy or Ci -6 alkylthio is optionally substituted by one instance of C 3-6 cycl
  • halocycloalkoxy phenyl, 3- to 6-membered heterocyclic or 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl rings contain up to 3 heteroatoms independently selected from N, O or S; or
  • heterocyclic ring contains up to two heteroatoms selected from N, O or S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, -CN, -NH 2 , -OH, CM alkyl, C 1-4 haloalkyl-0(C alkyl), -N(Ci ⁇ alkyl) 2 or -S(C 1-4 alkyl); n is an integer selected from the group consisting of 0, 1, 2 and 3;
  • ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
  • heteroatoms selected from the group consisting of N, O and S;
  • each J B is independently selected from the group consisting of halogen, -N0 2 , -CN, -OH, d-6 aliphatic, C 3 - 6 cycloaliphatic, C 1-6 haloaliphatic, C 1-6 alkoxy, Ci -6 haloalkoxy and C 3- 6 cycloalkoxy;
  • n is an integer selected from the group consisting of 0, 1, 2 and 3;
  • ring C is a 5-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
  • each J is independently selected from the group consisting of halogen, -N0 2 , -CN, -R , -C(0)R c , -C(S)R C , -C(0)OR c , -OC(0)R c , -N(R c )C(0)R c , -N(R C )C(S)R C , -OR c , -SR C , -S(0)R c , -S(0) 2 R c , -N(R c )S(0) 2 R c , -S(0) 2 N(R c ) 2 , -C(0)N(R c ) 2 and -N(R C ) 2 ; each R is independently selected from hydrogen, C 1- aliphatic, C 1-6 alkoxy, C e alkylthio,
  • each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R c is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C alkyl, -0(C alkyl) or -N(C 1- alkyl) 2 ; and wherein, when R c is a C 1-6 aliphatic, C 1-6 alkoxy or Ci-6 alkylthio, it is optionally substituted by one instance of C 3- 6 cycloalkyl, C3-6halocycloalkyl, C 3- 6 cycloalkoxy or C 3-6 halocycloalkoxy;
  • each R is independently selected from C 1-6 aliphatic, C 3- 6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, 3- to 6-membered heterocyclic or 5- to 6-memebered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, -0(C 1-4 alkyl), -S(Ci4 alkyl) or -N(Ci-4 alkyl) 2 ; and wherein, when R 8 is a Ci -6 aliphatic, it is optionally substituted by one instance of C 3- 6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkoxy or C 3-6
  • p is an integer selected from the group consisting of 0, 1, 2 and 3;
  • each R 1 is independently selected from hydrogen, C ⁇ - aliphatic or C 1-6 haloaliphatic
  • R 2 is selected from the group consisting of halogen, -CN or C 1jS aliphatic; wherein said C 1-6 aliphatic is independently and optionally substituted by up to three instances of halogen, -CN, -NH 2 ,-OH or -0(C lA alkyl).
  • ring B is a 6-membered heteroaryl or phenyl; wherein said heteroaryl contains up to two ring nitrogen atoms.
  • each J B is independently selected from the group consisting of halogen, C1-4 alkyl, cyclopropyl, cyclopropyloxy, Q-4 haloalkyl, C1-4 alkoxy and C 4 haloalkoxy.
  • each J B is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propyloxy and isopropyloxy.
  • each J is independently selected from the group consisting of bromo, chloro, fluoro, methyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy.
  • compounds of the invention are represented by Formula A-1, or are pharmaceutically acceptable salts thereof:
  • m is 0 or 1.
  • compounds of the invention are represented by Formula A-2, or are pharmaceutically acceptable salts thereof:
  • each R 1 is independently selected from the group consisting of hydrogen and C -4 alkyl. In other embodiments, each R 1 is hydrogen.
  • R 2 is selected from the group consisting of halogen, -CN, Cuhaloalkyl and CM alkyl. In other embodiments, R 2 is methyl.
  • compounds of the invention are represented by Formula A-3, or are pharmaceutically acceptable salts thereof:
  • ring A is selected from the group consisting of
  • each J A is independently selected from the group consisting of halogen, -CN, -N3 ⁇ 4, -OH, CM alkyl, C 1-4 alkenyl, -NH(Ci-4 alkyl), -N(C M alkylfe, -NHC(0)(C 1-4 alkyl), -NHS(0) 2 (C 1-4 alkyl), -C(0)0(C alkyl), -OC(0)(C alkyl), -C(0)(C alkyl), -0(C 1-4 alkyl), -C(S)(C 1-4 alkyl), -NHC(S)(C alkyl) , -S(C M alkyl), -S(0)(C 1-4 alkyl), -S(0) 2 (C M alkyl), -S(0) 2 N(C 1-4 alkyl) 2 , a 3- to 6-membered heterocyclic and
  • each J A is independently selected from the group consisting of morpholine, pyrrolidine, piperidine, thiophene, thiazole, thiadiazole,oxazole and oxadiazole. In yet further embodiments, each J A is independently selected from the group consisting of:
  • two J A groups attached to two vicinal ring A atoms, together with said ring atoms form a 5- to 6-membered heterocyclic ring, wherein said heterocyclic ring is selected from the group consisting of:
  • each R is independently selected from the group consisting of halogen and C 1-4 alkyl; and wherein the variable o is an integer selected from the group consisting of 0, 1 and 2.
  • each R 17 is independently selected from the group consisting of fluoro, chloro and methyl. In still other embodiments, the variable o is 0.
  • the compounds of the invention are represented by Formula A-4, or are pharmaceutically acceptable salts thereof:
  • each of the variables Q ls Q 2 , Q 3 and Q 4 is independently selected from C, N, O or
  • compounds of the invention are represented by Formula A-5, are pharmaceutically acceptable salts thereof:
  • compounds of Formula A-5 are represented by Formula A-6, or are pharmaceutically acceptable salts thereof:
  • the moiety -(CH 2 )-Ring C is selected from the group consisting of:
  • p is 1 or 2.
  • the compounds of Formulae A-4, A-5 and A-6 are represented by Formula A-7, or are pharmaceutically acceptable salts thereof:
  • J C is halogen, C alkyl or C ⁇ alkoxy.
  • J C is halogen, methyl, ethyl, methoxy or ethoxy.
  • J c is chloro, fluoro, methyl or methoxy.
  • the moiety represented by is selected from the group consisting of: [0087] In some embodiments, the compounds of the invention are selected from the group consisting of:
  • ring A is selected from the group consisting of phenyl and a 6-membered monocyclic
  • heteroaryl ring wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms;
  • each J A is independently selected from the group consisting of-R 4 , -C(0)OR 5 , -C(S)R A , -N(R A )C(0)R A , -N(R A )C(S)R A , -SR A , -S(0)R A , -S(0) 2 R A , -N(R A )S(0) 2 R A and -S(0) 2 N(R A ) 2 ;
  • each R A is independently selected from hydrogen, Ci -6 aliphatic, C 1-6 alkoxy, Ci -6 alkylthio, C 3-6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R A is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C M alkyl, -0(C 1-4 alkyl), -S(C 1-4 alkyl) or -N(C M alkyl) 2 ; and wherein each R A that is a C 1-6 aliphatic, Ci -6 alkoxy or C 1-6 alkylthio is optionally substituted by one instance of C 3-6 cycloalkyl, C 3- halocycloalkyl, phen
  • each R 4 is independently selected from C 3-6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R 4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , Ci ⁇ alkoxyl, -0(C alkyl), -S(C 1-4 alkyl) or-N(C 1-4 alkyl)2,;
  • each R 5 is independently selected from Ci -6 aliphatic, C 3- 6 cycloaliphatic, phenyl, 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R 5 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, C haloalkylj-OtC alkyl), -S(Ci-4 alkyl) or-N(C M alkyl) 2 ; and wherein each R 5 that is a C 1-6 aliphatic is optionally substituted by one instance of C 3-6 cycloalkyl, C 3-6 halocycloalkyl, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings
  • heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S, and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, Ci-4 alkoxy, -CN, -NH 2 ,-OH, -0(C 1-4 alkyl), -N(CM alkyl) 2 or -S(C 1-4 alkyl);
  • n is an integer selected from the group consisting of 1, 2 and 3;
  • ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
  • heteroatoms selected from the group consisting of N, O and S; m is an integer selected from the group consisting of 0, 1, 2 and 3;
  • each J B is independently selected from the group consisting of halogen, -N0 2 , -CN, -OH, Ct-6 aliphatic, C 3 - 6 cycloaliphatic, Ci- haloaliphatic, C 1-6 alkoxy, d ⁇ haloalkoxy and C 3- 6 cycloalkoxy;
  • ring C is selected from the group consisting of phenyl, C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S; each J c is independently selected from the group consisting of halogen, -N0 2 , -OH, -CN, -R 11 , -C(0)R c , -C(S)R C , -C(0)OR c , -OC(0)R c , -N(R c )C(0)R c , -N(R C )C(S)R C , -OR c , -SR C , -S(0)R c , -S(0) 2 R c , -N(R c )S(0) 2 R c , -S(0) 2 N(R c ) 2
  • each R is independently selected from hydrogen, C 1-6 aliphatic, C 1-6 alkoxy, C 1-6 alkylthio, C 3- 6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C alkyl, -0(Ci- 4 alkyl), -S(C M alkyl) or -N(C 1-4 alkyl) 2 ; and wherein each R that is a C 1-6 aliphatic, C 1-6 alkoxy or Ci -6 alkylthio is optionally substituted by one instance of C 3- cycloalkyl, C 3-6 halocycloalkyl, phenyl,
  • each R 11 is independently selected from Ci -6 aliphatic, C 3-6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, Oor S; wherein each R 11 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH 2 , C M alkyl, -0(C alkyl), -S(C alkyl) or -N(Ci-4 alkyl) 2 ; and wherein each R 11 that is a 0 1-6 aliphatic is optionally substituted by one instance of C 3-6 cycloalkyl, C 3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein said heterocyclic or hetero
  • each said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S; and wherein each of said heterocyclic rings is optionally and independently substituted by up to three instances of halogen, C 1-4 alkyl, C 1-4 alkoxy, -CN, -NH 2 ,-OH, -0(C 1-4 alkyl), -N(C M alkyl) 2 or -S(C M alkyl);
  • p is an integer selected from the group consisting of 0, 1, 2 and 3; and each R is independently selected from a hydrogen, Ci- 6 aliphatic or Ci -6 haloaliphatic; and R 2 is selected from the group consisting of halogen, -N0 2 , -CN and C ⁇ * aliphatic;
  • Ring B is a 6-membered heteroaryl or phenyl; wherein said heteroaryl contains up to two ring nitrogen atoms.
  • each J B is independently selected from the group consisting of halogen, C 1 -4 alkyl, cyclopropyl, cyclopropyloxy, Cr 4 haloalkyl, Ci- 4 alkoxy and Ci-4 haloalkoxy.
  • each J B is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,
  • J B is independently selected from the group consisting of bromo, chloro, fluoro, methyl, ethoxy, trifluoromethyl, trifluoromethoxy and methoxy.
  • the compounds of Formula B are represented by Formula B-1, or are pharmaceutically acceptable salts thereof:
  • m is 0 or 1.
  • the compounds of Formulae B and B-1 are represented by Formula B-2, or are pharmaceutically acceptable salts thereof:
  • each R 1 is independently selected from the group consisting of hydrogen and Ci- 4 alkyl. In other embodiments, each R 1 is hydrogen.
  • R is selected from the group consisting of halogen, -CN, C ⁇ haloalkyl and ⁇ alkyl. In other embodiments R is methyl.
  • ring C is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl; wherein said 5- to 6- membered heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S.
  • ring C is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiophene, thiazole, thiadiazole, oxazole, oxadiazole, pyrazole and imidazole.
  • ring C is selected from the group consisting of:
  • ring C is selected from the group consisting of:
  • p is 0, 1 or 2.
  • each group represented by is independently selected from the group consisting of:
  • each J is independently selected from the group consisting of halogen, CM haloalkyl, C alkyl and C alkoxy.
  • each J c is independently selected from the group consisting of fluoro, chloro, trifluoromethyl, methyl and methoxy.
  • the compounds of Formulae B, B-1 and B-2 are represented by Formula B-3, or are pharmaceutically acceptable salts thereof:
  • n 1 or 2.
  • each J A is independently selected from the group consisting of -C(0)0(C 1- 4 alkyl), -C(S)(Ci-4 alkyl), -NHC(0)(C alkyl), -NHC(S)(C alkyl), -S(Ci-4 alkyl), -S(0)(C alkyl),
  • -S(0) 2 (C alkyl), -NHS(0) 2 (C M alkyl), -S(0) 2 N(CM alkyl) 2 , C 3-6 cycloaliphatic, C 3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl;
  • each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms
  • each said C alkyl is optionally and
  • heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S; wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, C 1-4 alkoxy, -CN, -NH 2 ,-OH, -0(C M alkyl), -N(C 1-4 alkyl) 2 or -S(CM alkyl).
  • halogen C alkyl, C 1-4 alkoxy, -CN, -NH 2 ,-OH, -0(C M alkyl), -N(C 1-4 alkyl) 2 or -S(CM alkyl).
  • each J A is independently selected from the group consisting of -C(0)OMe, -C(S)Me, -NHC(0)Me, -NHC(S)Me, -SMe, -S(0)Me, -S(0) 2 Me, -NHS(0) 2 Me and
  • each J A is independently selected from the group consisting of-C(C-)OMe, -C(0)Me, -SMe, -S(0) 2 Me and -NHS(0) 2 Me.
  • each J A is independently selected from the group consisting of cyclopropyl, morpholine, pyrrolidine, piperidine, thiophene, thiazole and thiadiazole.
  • each J A is independently selected from the group consisting of:
  • each R is independently selected from the group consisting of halogen and C
  • variable o is an integer selected from the group consisting of 0, 1 and 2.
  • each R 17 is independently selected from the group consisting of fluoro, chloro and methyl.
  • the variable o is 0.
  • the compounds of Formulae B, B-l, B-2 and B-3 are represented by any one of Formulae B-4 to B-19, or are pharmaceutically acceptable salts thereof:
  • At least one of the variables Xi, X 3 and X4 is N and the rest are C. In still other embodiments n is 1.
  • the compounds of Formulae B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18 and B-19 are represented by any one of Formulae B-20 to B-35, or are pharmaceutically acceptable salts thereof:
  • the compounds of the invention are selected from the group consisting of:
  • the compounds of Formula A and Formula B may be prepared according to the schemes and examples depicted and described below. Unless otherwise specified, the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds or prepared using well-known synthetic methods.
  • the reaction was then poured into ice- water, extracted with dichloromethane (3x), dried (sodium sulfate), and concentrated.
  • the material was either used crude or purified using silica gel chromatography using ethyl acetate in hexanes to afford the desired N-alkylated azaindole 3-ketoester (In certain cases, the acid is the major product observed with only a trace of the ester product present).
  • a solution of tin (II) dichloride dihydrate (4.2 equiv) in concentrated hydrochloric acid ( ⁇ 6M) was added. The reaction was allowed to stir and was warmed up to room temperature, then stored at 5 °C overnight (12 hours). The resulting precipitate was filtered, washed with water (2x), then ethanol (3x) and dried thoroughly to the desired arylhydrazine hydrochloride salt.
  • reaction mixture was then cooled to room temperature, filtered through celite, diluted with ethyl acetate and successively washed with water (2 x 50 mL) and saturated sodium chloride solution (2 x 50 mL), dried (sodium sulfate), filtered and concentrated . Purification was achieved by silica gel chromatography using ethyl acetate in hexanes to afford the appropriate indole 3-thiophenyl product.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound of Formula A or Formula B.
  • the salts of the compounds of Formula A or Formula B will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of Formula A or Formula B or of their pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure.
  • a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • the salts can be prepared in situ during the final isolation and purification of the compounds.
  • the salts can be prepared from the free form of the compound in a separate synthetic step.
  • suitable pharmaceutically acceptable salts are salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine, be
  • salts may be prepared from pharmaceutically acceptable nontoxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
  • Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,r-methylene-bis-(2-hydroxy-3-n
  • compositions and methods of administration are provided.
  • the invention comprises a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as discussed above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant.
  • the pharmaceutical composition further comprises at least one additional therapeutic agent.
  • the pharmaceutical composition further comprises an additional therapeutic agent which is chosen from the group consisting of painkillers, non-steroidal anti-inflammatory drugs (NSAIDs), cannabinoid receptor agonists, opiate receptor agonists, anti-infective agents, sodium channel blockers, N-type calcium channel blockers, local anesthetics, VRl agonists and antagonists, agents used for migraines, topical agents used in the treatment of localized pruritus, anti-inflammatory and/or immunosuppressive agents, agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists and nicotine replacement therapies), ADD/ ADHD agents, agents to treat alcoholism, such as opioid antagonists, agents for reducing alcohol withdrawal symptoms such as benzodiazepines and beta-blockers, antihypertensive agents such as ACE inhibitors and Angiotensin II Receptor blockers, Renin inhibitors, vasodilators, agents used to treat glaucoma such as direct-acting Miotics (cholinergic agonists), indirect
  • Miotics (cholinesterase inhibitors), Carbonic anhydrase inhibitors, selective adrenergic agonists, Osmotic diuretics, antidepressants such as SSRIs, tricyclic antidepressants, and dopaminergic antidepressants, cognitive improvement agents, acetylcholinesterase inhibitors, anti-emetic agents (e.g., 5HT3 antagonists), neuroprotective agents, neuroprotective agents currently under investigation, antipsychotic medications, agents used for multiple sclerosis, disease-modifying anti-rheumatic drugs (DMARDS), biological response modifiers (BRMs),
  • DARDS disease-modifying anti-rheumatic drugs
  • BRMs biological response modifiers
  • COX-2 selective inhibitors COX-1 inhibitors, immunosuppressives, PDE4 inhibitors, corticosteroids, histamine HI receptor antagonists, histamine H2 receptor antagonists, proton pump inhibitors, leukotriene antagonists, 5-lipoxygenase inhibitors, nicotinic acetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonists and antagonists, NK1 and NK2 antagonists, NMDA antagonists, potassium channel modulators, GABA modulators, anticancer agents such as tyrosine kinase inhibitors, anti-hyperlipidemia drugs, appetite
  • suppressing agents such as insulin, GI (gastrointestinal) agents, and serotonergic and noradrenergic modulators.
  • a typical formulation is prepared by mixing a compound of Formula A or Formula B, or a pharmaceutically acceptable salt thereof, and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of Formula A or Formula B is being formulated.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (e.g., GRAS— Generally Regarded as Safe) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc., and mixtures thereof.
  • the formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of Formula A or Formula B or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance e.g., a compound of Formula A or Formula B, a pharmaceutically acceptable salt thereof
  • a suitable solvent in the presence of one or more of the excipients described above.
  • a compound having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution.
  • Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
  • the compound of Formula A or Formula B or a pharmaceutically acceptable salt thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
  • Pharmaceutical formulations of compounds of Formula A or Formula B, or a pharmaceutically acceptable salt thereof may be prepared for various routes and types of administration.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition (weigh weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • the initial pharmaceutically effective amount of the inhibitor administered will be in the range of about 0.01-100 mg/kg per dose, namely about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • the term "therapeutically effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutically or pharmaceutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms.
  • the pharmaceutical compositions of Formula A or Formula B will be formulated, dosed, and administered in a fashion, i.e., in amounts, concentrations, schedules, courses, vehicles, and route(s) of administration consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular human or other mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.
  • prophylactically effective amount refers to an amount effective in preventing or substantially lessening the chances of acquiring a disease or disorder or in reducing the severity of the disease or disorder or one or more of its symptoms before it is acquired or before the symptoms develop. Roughly, prophylactic measures are divided between primary prophylaxis (to prevent the development of a disease) and secondary prophylaxis (whereby the disease has already developed and the patient is protected against worsening of its severity).
  • Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and
  • preservatives such as octadecyldimethylbenzyl ammonium chloride
  • hexamethonium chloride benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;
  • proteins such as serum albumin, gelatin, or immunoglobulins
  • hydrophilic polymers such as polyvinylpyrrolidone
  • amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine
  • chelating agents such as EDTA
  • sugars such as sucrose, mannitol, trehalose or sorbitol
  • salt-forming counter-ions such as sodium
  • metal complexes e.g., Zn-protein complexes
  • non-ionic surfactants such as TWEENTM, PLURONICSTM or polyethylene glycol (PEG).
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules
  • Remington's The Science and Practice of Pharmacy, 21 st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter "Remington's”).
  • Controlled drug delivery systems supply the drug to the body in a manner precisely controlled to suit the drug and the conditions being treated.
  • the primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time.
  • controlled release is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release”, “delayed release”, “modified release” or “sustained release”.
  • sustained-release preparations are the most common applications of controlled release. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, wherein the matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • immediate-release preparations may also be prepared.
  • the objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • the compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot", thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.
  • Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled-release characteristics in the composition.
  • formulations include those suitable for the administration routes detailed herein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and
  • formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • administer in reference to a compound, composition or formulation of the invention mean introducing the compound into the system of the animal in need of treatment.
  • administration and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.
  • compositions described herein may be administered systemically or locally, e.g.: orally (e.g., using capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like), by inhalation (e.g., with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g., using ear drops), topically (e.g., using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc), ophthalmically (e.g., with eye drops, ophthalmic gels, ophthalmic ointments), rectally (e.g., using enemas or suppositories), nasally, buccally, vaginally (e.g., using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.), via an implanted reservoir or the like, or parenterally depending on the severity and type
  • compositions are administered orally, intraperitoneally or intravenously.
  • compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution-retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetylene glycol, g
  • Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time-delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • a water soluble taste-masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.
  • Formulations of a compound of Formula A or Formula B or a pharmaceutically acceptable salt thereof that are suitable for oral administration may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs.
  • Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • a water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • aqueous suspensions When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain one or more demulcents, preservatives, flavoring and coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain one or more demulcents, preservatives, flavoring and coloring agents and antioxidants.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.
  • Oily suspensions may be formulated by suspending the compound of Formula A or Formula B in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated
  • Aqueous suspensions of compounds of Formula A or Formula B contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium
  • heptadecaethyleneoxycetanol a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • the injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • the injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Other formulations suitable for vaginal administration may be presented as pess
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
  • Topically transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol,
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • an ointment such as petrolatum.
  • the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w.
  • the active ingredients may be employed with either an oil- based, paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil- in-water cream base.
  • the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • the oily phase of emulsions prepared using compounds of Formula A or Formula B may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier otherwise known as an emulgent
  • hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer.
  • the emulsifier includes both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of compounds of Formula A or Formula B include TweenTM-60, SpanTM-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • compositions may also be administered by nasal aerosol or by inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Formulations suitable for intrapulmonary or nasal administration have a mean particle size, for example, in the range of 0.1 to 500 microns (including particles with a mean particle size in a range between 0.1 and 500 microns in micron increments such as 0.5, 1, 30, 35 microns, etc.) and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • the pharmaceutical composition may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited herein above, or an appropriate fraction thereof, of the active ingredient.
  • veterinary composition comprising a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • disease disease
  • disorder condition
  • condition may be used interchangeably here to refer to a condition where an increase in the concentration of an endogenous cannabinoid (eCB) might be beneficial or a condition that can be treated by a FAAH inhibitor.
  • eCB cannabinoid
  • the terms “subject” and “patient” are used interchangeably.
  • the terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a "mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human.
  • a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
  • a primate e.g., a monkey, chimpanzee and a human
  • the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit).
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit
  • the subject is a "human”.
  • biological sample includes, without limitation, in vivo or ex vivo cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous humor or other body fluids or extracts thereof.
  • Treating refers to alleviating or abrogating the cause and/or the effects of the disorder or disease.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a condition wherein an increase in the concentration of eCB might be beneficial or that can be treated with a FAAH inhibitor, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of said condition, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the invention).
  • therapies e.g., one or more therapeutic agents such as a compound or composition of the invention.
  • the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of condition wherein an increase in the concentration of eCB might be beneficial or a condition that can be treated with a FAAH inhibitor.
  • the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of said condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
  • the terms “prevent”, “preventing” and “prevention” with regard to a disorder or disease refer to averting the cause and/or effects of a disease or disorder prior to the disease or disorder manifesting itself.
  • the terms “prophylaxis” or “prophylactic use”, as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease.
  • preventing refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill, but who has been or may be near a person with the disease.
  • chemotherapy refers to the use of medications, e.g., small molecule drugs (rather than e.g., “vaccines”) for treating a disorder or disease.
  • chemoprophylaxis refers to the use of medications, e.g., small molecule drugs (rather than e.g.,” vaccines) for the prevention of a disorder or disease.
  • the methods of the invention are a preventative or "pre ⁇ emptive" measure to a patient, preferably a human, having a predisposition to developing a condition or symptom that can be improved by an increase in the concentration of an eCB or treated with a FAAH inhibitor.
  • pain e.g., acute pain, chronic pain, neurogenic pain, dental pain, menstrual pain, dysmenorrheal pain, visceral pain, abdominal pain, pelvic pain, abdominal discomfort, neuropathic pain, headache, migraines, allodynia, hyperalgesia, post operative pain (e.g., associated with orthopedic surgery, gynecological surgery, abdominal surgery, incisions, oral surgery), back pain, pain caused by inflammation (e.g., arthritis, osteoarthritis, spondylitis, rheumatoid arthritis, Crohn's disease, irritable bowel syndrome, pain associated with injury, burns or trauma, and pain associated with fibromyalgia);
  • inflammation e.g., arthritis, osteoarthritis, spondylitis, rheumatoid arthritis, Crohn's disease, irritable bowel syndrome, pain associated with injury, burns or trauma, and pain associated with fibromyalgia
  • inflammation e.g., arthritis, osteo
  • an impulse control disorder e.g., pathological gambling, compulsive shopping, hypersexuality
  • a compulsion disorder e.g., a dopamine dysregulation syndrome
  • an eating disorder e.g., anorexia and bulimia
  • obesity e.g., by appetite suppression
  • elevated intraocular pressure e.g., glaucoma
  • a cardiovascular disorder e.g., hypertension
  • an inflammatory disorder e.g., allergy (e.g., food allergy, respiratory inflammation, inflammation of the skin and gastrointestinal inflammation), asthma, Crohn's disease);
  • allergy e.g., food allergy, respiratory inflammation, inflammation of the skin and gastrointestinal inflammation
  • asthma Crohn's disease
  • emesis e.g., as a side effect of chemotherapy
  • some cancers excitotoxic insult (e.g., in cerebral ischemia, seizure and edema due to traumatic brain injury), asphyxia;
  • gastrointestinal disorders e.g., attenuation of cholera induced fluid accumulation, nausea, vomiting, gastric ulcers, diarrhea, paralytic ileus, IBS, IBD, colitis, and gastroesophageal reflux conditions);
  • urinary system disorders e.g. overactive bladder and interstitial cystitis
  • autoimmune disorders e.g., multiple sclerosis.
  • the compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of pain.
  • the pain can be chronic pain, acute pain, perioperative pain (e.g., associated with surgery), postoperative pain, visceral pain, abdominal pain, abdominal discomfort, pelvic pain, inflammatory pain, cancer pain, headache pain, pain associated with cough, neuropathic pain, deafferentation pain, chronic nociceptive pain, dental pain (such as odontalgia), bone pain, joint pain (e.g., osteoarthritis or rheumatoid arthritis), myofascial pain (e.g., muscular injury, fibromyalgia), labor pain, pain associated with injuries, trauma, allergies, dermatitis, immunodeficiency, Hodgkin's disease, Myasthenia gravis, nephrotic syndrome, scleroderma, or thyroiditis, central and peripheral pathway mediated pain, pain associated with fibromyalgia, or pain associated with or the result of injury
  • Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous systems. It can occur in the peripheral nerves, dorsal roots, spinal cord and certain regions of the brain. It can also result from a peripheral nerve disorder such as neuroma, nerve compression, nerve crush, nerve stretch or incomplete nerve transsection. It can be associated with neuronal lesions, such as those induced by diabetes, HIV, herpes infection, nutritional deficiencies or a stroke. Chronic neuropathic pain can result from injury and/or inflammation such as chronic lower back pain. Acute neuropathic pain includes, for example, traumatic pain (e.g., bone fracture pain, sprains, strains and soft tissue damage), muscle pain, burn pain, and sun burn pain.
  • traumatic pain e.g., bone fracture pain, sprains, strains and soft tissue damage
  • Neuropathic pain can also be associated with, for example, nerve injury, head trauma, hyperalgesia, allodynia, dysesthesias, sciatica, amputation (e.g., phantom limb syndrome, stump pain), fibromyalgia, chemotherapeutic neuropathy, cancer pain (e.g., tumors of the brainstem, thalamus or cortex), AIDS-related neuropathy, painful traumatic mononeuropathy, painful polyneuropathy, multiple sclerosis, root avulsions, post-thoracotomy syndrome. It can be the result of a central nervous system injury (such as pain in stroke or spinal cord injury patients).
  • amputation e.g., phantom limb syndrome, stump pain
  • fibromyalgia chemotherapeutic neuropathy
  • cancer pain e.g., tumors of the brainstem, thalamus or cortex
  • AIDS-related neuropathy painful traumatic mononeuropathy
  • painful polyneuropathy painful polyneuropathy
  • Neuropathic pain also includes lower back pain, toxin induced pain, neurogenic pain, thalamic pain syndrome, repetitive motion pain (e.g., carpal tunnel syndrome) or pain induced by post-mastectomy syndrome, by surgery or by radiation.
  • Neuralgia is a type of neuropathic pain that is thought to be linked to four possible mechanisms: ion gate malfunctions; a nerve becoming mechanically sensitive and creating an ectopic signal; cross signals between large and small fibers; and malfunction due to damage in the central processor.
  • TN trigeminal neuralgia
  • ATN atypical trigeminal neuralgia
  • post-herpetic neuralgia caused by shingles or herpes.
  • Neuralgia is also involved in disorders such as sciatica and brachial plexopathy with neuropathia. Neuralgias that do not involve the trigeminal nerve are occipital neuralgia and glossopharyngeal neuralgia. Neuropathic pain also includes referred pain.
  • Visceral, abdominal or pelvic pain or discomfort includes, for example, pancreas pain (e.g. pain associated with pancreatitis) urological pain (e.g., associated with interstitial cystitis, urinary bladder pain, prostate pain), renal pain (e.g. renal colic, pain caused by kidney stones), gynecological pain (e.g. dysmenorrhea, menstrual cramps, menstruation,
  • pancreas pain e.g. pain associated with pancreatitis
  • urological pain e.g., associated with interstitial cystitis, urinary bladder pain, prostate pain
  • renal pain e.g. renal colic, pain caused by kidney stones
  • gynecological pain e.g. dysmenorrhea, menstrual cramps, menstruation
  • gastrointestinal pain e.g., pain associated with irritable bowel syndrome (IBS with all its variants), Crohn's disease, celiac disease, ulcerative colitis, peptic ulcers, stomach pain, rectal pain, bowel pain, intestinal pain, intestinal cramps, gastritis and non-ulcer dyspepsia
  • IBS irritable bowel syndrome
  • Visceral pain also includes non-cardiac chest pain and referred pain.
  • abdominal, visceral or pelvic pain caused by cancer, bacterial infections, parasitic infections, surgery, trauma, medications, gallstones, diverticulitis or digestive disorders.
  • Inflammatory pain includes both inflammatory pain that is a significant component of a disorder or disease and that that is considered a minor component or symptom.
  • inflammatory pain induced by or associated with disorders such as osteoarthritis, rheumatic fever, rheumatoid arthritis, rheumatic disease, tendonitis, juvenile arthritis, spondylitis, gouty arthritis, psoriatic arthritis, interstitial cystitis, peripheral neuritis, mucositis, fibromyalgia, pancreatitis, enteritis, diverticulitis, cellulites, bone fractures, postoperative ileus, Crohn's Disease, ulcerative colitis, cholecystitis, teno-synovitis, gout, vulvodynia, fibromyalgia, sprains and strains, systemic lupus erythematosus, myositis, bronchitis and influenza and other viral infections such as the common cold
  • autoimmune disorders (muscular injury, fibromyalgia), muscoskeletal pain, and pain due to inflammatory bowel diseases.
  • inflammatory pain disorders that can be treated are included some autoimmune disorders or diseases.
  • Cancer pain can be induced by or associated with tumors such as lymphatic leukemia, Hodgkin's disease, malignant lymphoma, osteosarcoma, bone cancer,
  • Chemotherapy pain is a side effect of chemotherapy treatments.
  • Headache pain includes cluster headache, migraines with and without aura, tension type headache, headaches caused by injury or infection, hangovers, and headaches with unknown origins.
  • the compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of inflammatory disorders, including, for example, chronic and acute inflammatory disorders.
  • disorders with inflammatory components include asthma, atopic allergy, allergy, atherosclerosis, bronchial asthma, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemia, osteoarthritis, sepsis, septic shock (e.g., as antihypovolemic and/or antihypotensive agents), systemic lupus erythematosus, stroke, transplantation of tissue and organs, vasculitis, interstitial cystitis, diabetic retinopathy and ventilator induced lung injury.
  • the compounds and pharmaceutical compositions described herein can also be used alone or in combination therapy for the treatment or prevention of disease-states or indications that are accompanied by inflammatory processes such as:
  • Lung diseases e.g., asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non- atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "whez-infant syndrome",
  • asthma e.g., asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non- atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "whez
  • pneumoconiosis including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis;
  • Rheumatic diseases or autoimmune diseases or musculoskeletal diseases e.g., all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, and polymyalgia rheumatica; reactive arthritis; rheumatic soft tissue diseases; inflammatory soft tissue diseases of other genesis; arthritic symptoms in degenerative joint diseases (arthroses); tendinitis, bursitis, osteoarthritis, traumatic arthritis, gout (metabolic arthritis); collagenoses of any genesis, e.g., systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still disease, Felty syndrome; and osteoporosis and other bone resorption diseases;
  • rheumatic diseases or autoimmune diseases or musculoskeletal diseases e.g., all forms of rheumatic diseases, especially rheumatoid arthritis,
  • Allergic diseases including all forms of allergic reactions, e.g., allergic rhinitis, allergic conjunctivitis, infectious parasitic, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, delayed or immediate hypersensitivity, and contact dermatitis;
  • allergic reactions e.g., allergic rhinitis, allergic conjunctivitis, infectious parasitic, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, delayed or immediate hypersensitivity, and contact dermatitis;
  • Vascular diseases e.g., panarteritis nodosa, polyarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis, atherosclerosis, reperfusion injury and erythema nodosum, myocardial ischemia, thrombosis.
  • Dermatological diseases e.g., dermatitis, psoriasis, sunburn, burns, and eczema;
  • Renal, urinary and pancreatic diseases e.g., nephrotic syndrome and all types of nephritis (such as glomerulonephritis); pancreatitis; bladder hyperrelexia following bladder inflammation; other renal diseases that can be treated by the compounds and compositions herein described include urinary incontinence or vesicle inflammation, uresesthesia urgency, overactive bladder, urinary frequency, interstitial cystitis or chronic prostatitis.
  • Hepatic diseases e.g., acute liver cell disintegration; acute hepatitis of various genesis (such as viral, toxic, drug-induced) and chronically aggressive and/or chronically intermittent hepatitis, liver fibrosis associated with liver injury or disease, including fibrosis caused or exacerbated by alcoholic liver cirrhosis, chronic viral hepatitis, non alcoholic steatohepatitis and primary liver cancer;
  • acute liver cell disintegration e.g., acute liver cell disintegration
  • acute hepatitis of various genesis such as viral, toxic, drug-induced
  • chronically aggressive and/or chronically intermittent hepatitis liver fibrosis associated with liver injury or disease, including fibrosis caused or exacerbated by alcoholic liver cirrhosis, chronic viral hepatitis, non alcoholic steatohepatitis and primary liver cancer
  • Gastrointestinal diseases e.g., ulcers, inflammatory bowel diseases, regional enteritis (Crohn's disease), ulcerative colitis, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, esophagitis, NSAID-induced ulcer, non-ulcerative dyspepsia and gastroesophageal reflux disease;
  • Neurodegenerative diseases e.g., treatment/reduction of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, edema, spinal cord injury, cerebral ischemia, seizures, neurodegeneration associated with multiple sclerosis, or the like, neuroprotection, neurogenesis;
  • Eye diseases e.g., allergic keratitis, uveitis, or ulcerative colitis, rhinitis, or rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, glaucoma and sympathetic ophthalmia;
  • Progressive central nervous system or neurological diseases e.g., brain edema, particularly tumor-related brain edema, multiple sclerosis, spasticity associated with multiple sclerosis, acute encephalomyelitis, meningitis, acute spinal cord injury, trauma;
  • dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Parkinson's disease and Creutzfeldt- Jacob disease, Huntington's chorea, Pick's disease, amyotrophic lateral sclerosis (ALS)), vascular dementia (including multi-infarct dementia and dementia associated with intracranial space occupying lesions, infections and related conditions such as HIV infection); Guillain-Barre syndrome, myasthenia gravis, stroke, and various forms of seizures (such as nodding spasms), hyperactivity, dyskinesias;
  • Blood diseases e.g., acquired hemolytic anemia, aplastic anemia, and idiopathic thrombocytopenia;
  • Tumor diseases e.g., acute lymphatic leukemia, Hodgkin's disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, and extensive metastases; other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration).
  • Endocrine diseases e.g., endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de Quervain, Hashimoto thyroiditis, Morbus Basedow, granulomatous thyroiditis, struma lymphomatosa, Graves disease, type I diabetes (such as insulin-dependent diabetes); organ and tissue transplantations and graft vs. host diseases;
  • endocrine diseases e.g., endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de Quervain, Hashimoto thyroiditis, Morbus Basedow, granulomatous thyroiditis, struma lymphomatosa, Graves disease, type I diabetes (such as insulin-dependent diabetes); organ and tissue transplantations and graft vs. host diseases;
  • Severe states of shock e.g., septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS);
  • Viral or bacterial parasitic infectious disease for example AIDS and meningitis;
  • angioedema and diabetes (such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and diabetic symptoms associated with insulitis (e.g., hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion)).
  • diabetes such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and diabetic symptoms associated with insulitis (e.g., hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion)).
  • GI diseases or disorders e.g., functional gastrointestinal disorders, ulcers, inflammatory bowel diseases (IBD), colitis, regional enteritis (Crohn's disease), ulcerative colitis, diarrhea, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, functional dyspepsia, diverticulitis, gastrointestinal bleeding, irritable bowel syndrome (IBS), non-ulcerative dyspepsia and gastroesophageal reflux disease.
  • IBD inflammatory bowel diseases
  • colitis e.g., colitis, regional enteritis (Crohn's disease), ulcerative colitis, diarrhea, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, functional dyspepsia, diverticulitis, gastrointestinal bleeding, irritable bowel syndrome (IBS), non-ulcerative dyspepsia and gastroesophageal reflux disease.
  • IBS irritable bowel
  • the compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of pruritus (itch).
  • pruritus originated in the skin (dermal pruritus), neuropathic pruritus, neurogenic or
  • Pruritus can be a symptom of primary skin diseases or of systemic disease. Skin diseases notorious for causing intense pruritus include scabies, pediculosis, insect bites, urticaria, atopic and contact dermatitis, lichen planus, miliaria, and dermatitis ⁇ ⁇ . In other cases pruritus is prominent without any identifiable skin lesions: e.g., dry skin (especially in elderly people), systemic disease, and use of certain drugs can generate pruritus.
  • Systemic diseases that cause generalized pruritus include cholestatic diseases, uremia, polycythemia vera, and hematologic malignancies.
  • Pruritus may also occur during the later months of pregnancy. Barbiturates, salicylates, morphine and cocaine can cause pruritus. Less well-defined causes of pruritus include hyper- and hypothyroidism, diabetes, iron deficiency, and internal cancers of many types.
  • the compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of substance abuse related syndromes, disorders or diseases include, including, for example, drug abuse and drug withdrawal.
  • Abused substances can include alcohol, amphetamines, amphetamine-like substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing.
  • the compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance-induced anxiety or mood disorder. In addition, they can be used to reduce tobacco craving; treat nicotine dependency, addiction, or withdrawal; or aid in the cessation or lessening of tobacco in a subject in need thereof.
  • the compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of psychiatric disorders, such as depressions (including major depressive disorder, bipolar depression, unipolar depression, single or recurrent major depressive episodes (e.g., with or without psychotic features, catatonic features, and/or melancholic features), postpartum onset, seasonal affective disorder, dysthymic disorders (e.g., with early or late onset and with or without atypical features), neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders); manic-depressive psychoses; bipolar disorders; extreme psychotic states (such as mania, schizophrenia, and excessive mood swings where behavioral stabilization is desired); post-traumatic stress disorder; panic disorder; compulsive disorders (e.g., obsessive compulsive disorder, stereotypic, self-injurious and repetitive behaviors, trichtillomania), psychiatric tremors such as dys
  • alopecia areata also known as systemic sclerosis (SS)
  • amyloses amyotrophic lateral sclerosis
  • ankylosing spondylarthritis ankylosing spondylitis
  • antiphospholipid syndrome autoimmune Addison's disease
  • autoimmune hemolytic anemia autoimmune hepatitis
  • autoimmune inner ear disease AIED
  • autoimmune lymphoproliferative syndrome ALPS
  • autoimmune thrombocytopenic purpura ATP
  • Behcet's disease cardiomyopathy, celiac sprue-dermatitis hepetiformis
  • chronic fatigue immune dysfunction syndrome CIDS
  • chronic inflammatory demyelinating polyneuropathy cicatricial pemphigoid
  • cold agglutinin disease connective
  • neurodegenerative disorders include dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt- Jakob disease, motor neuron disease; vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Age- Associated Memory Impairment.
  • dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt- Jakob disease, motor neuron disease; vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins
  • neurological disorders include amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, ischemia, traumatic head or brain injury, brain inflammation, eye injury, stroke and neuroinflammation.
  • ALS amyotrophic lateral sclerosis
  • multiple sclerosis epilepsy
  • ischemia traumatic head or brain injury
  • brain inflammation eye injury
  • stroke and neuroinflammation neuroinflammation.
  • the compounds and compositions here described can also be used for the treatment/reduction of
  • the compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of ocular disorders including, for example, glaucoma (such as normal tension glaucoma), glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, and acute injury to the eye tissue (e.g., conjunctivitis).
  • Ocular disorders also include neurodegenerative disease conditions of the retina and the optic nerve, for example, in patients presenting risk factors for glaucoma, such as high intraocular pressure, family history of glaucoma, glaucoma in the contralateral eye and high myopia.
  • the compounds and compositions described herein can also be used, alone or in combination therapy, to treat or prevent appetite related disorders such as emesis, vomiting and nausea, food behavioral problems or feeding disorders (e.g., anorexias, cachexias, wasting conditions and bulimia) and obesity or obesity-related disorders (e.g., diabetes type II, hyperlipidemia).
  • appetite related disorders such as emesis, vomiting and nausea, food behavioral problems or feeding disorders (e.g., anorexias, cachexias, wasting conditions and bulimia) and obesity or obesity-related disorders (e.g., diabetes type II, hyperlipidemia).
  • Certain gynecological disorders can be treated by inhibition of uterus contraction caused by hormones and prostanoid-induced muscle contraction using compounds or compositions described herein, for example, premature labor, menstrual cramps, menstrual irregularity, dysmenorrhea.
  • Some sleep disorders can be treated with compounds or compositions described herein, for example insomnia, night terrors, nightmares, vivid dreaming, restlessness, bruxism, somnambulism, narcolepsy, circadian rhythm adjustment disorders, and the like. Also contemplated are sleep disorders associated with neurological or mental disorders or with pain.
  • Cardiovascular diseases that can be treated with the compounds and compositions of the invention described herein include myocardial ischemia, thrombosis, hypertension or cardiac arrhythmias.
  • Compounds and compositions of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.
  • the invention provides a method of inhibiting FAAH in a biological sample, comprising contacting said biological sample with a compound or composition of the invention.
  • a FAAH inhibitor in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, without limitation, biological assays and biological specimen storage.
  • the compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents.
  • the active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
  • an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed.
  • compounds described herein can be administered to a subject in a dosage range from between about 0.001 to about 100 mg/kg body weight/day, from about 0.001 to about 50 mg/kg body weight/day, from about 0.001 to about 30 mg/kg body weight/day, from about 0.001 to about 10 mg/kg body weight/day.
  • an effective amount can be achieved using a first amount of a compound of Formula A or Formula B or a pharmaceutically acceptable salt thereof and a second amount of an additional suitable therapeutic agent (e.g., an agent to treat pain).
  • an additional suitable therapeutic agent e.g., an agent to treat pain
  • the compound of Formula A or Formula B and the additional therapeutic agent are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone).
  • the compound of Structural Formula A or Formula B and the additional therapeutic agent are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose).
  • the compound of Structural Formula A or Formula B can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose.
  • the compound of Structural Formula A or Formula B can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer- therapeutic agent is administered in an effective amount.
  • the terms “in combination” or “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents).
  • therapy e.g., one or more prophylactic and/or therapeutic agents.
  • the use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.
  • Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, a capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each.
  • coadministration also encompasses use of each compound in a sequential manner in either order.
  • coadministration involves the separate administration of a first amount of a compound of Formula A or B and a second amount of an additional therapeutic agent, the compounds are
  • the period of time between each administration that can result in the desired therapeutic effect can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile.
  • a compound of Formula A or Formula B and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound described herein
  • a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anticancer agent) to a subject.
  • a second therapy e.g., a prophylactic or therapeutic agent such as an anticancer agent
  • Additional therapeutic agents that can be combined with compounds described herein include, without limitation:
  • FAAH inhibitors e.g., OL-135, LY2183240, URB-597, CAY-10402, PF-750, BMS-469908, SSR-411298, TK-25, PF-04457845, PF-3845, SA-47, JNJ-245, JNJ-28833155 and JNJ-1661010;
  • painkillers such as acetaminophen or paracetamol
  • non-steroidal anti-inflammatory drugs such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives
  • propionic acid derivatives alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprof
  • fenamic acid derivatives meclofenamic acid, mefe-namic acid, and tolfenamic acid
  • oxicams isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican
  • salicylates acetyl salicylic acid, sulfasalazine
  • pyrazolones azolones
  • opiate receptor agonists such as morphine, propoxyphene (DarvonTM), tramadol, buprenorphin;
  • cannabinoid receptor agonists such as dronabinol, A9-THC, CP-55940, WIN- 55212-2, HU-210;
  • sodium channel blockers such as carbamazepine, mexiletine, lamotrigine, pregabalin, tectin, NW-1029, CGX-1002;
  • N-type calcium channel blockers such as ziconotide, NMED-160, SPI-860; serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram;
  • VR1 agonists and antagonists such as NGX-4010, WL-1002, ALGRX-4975, WL-10001, AMG-517;
  • agents used for migraines such as sumatriptan, zolmitriptan, naratriptan, eletriptan, rauwolscine, yohimbine, metoclopramide;
  • topical agents used in the treatment of localized pruritus e.g., camphor/menthol lotions or creams containing 0.125 to 0.25% menthol, doxepin (e.g., Sinequan , Zonalon ), phenol (e.g., Cepastat®, Chloraseptic® gargle, Ulcerease), 0.5 to 2%, pramoxine (e.g., AnusolTM ointment, Proctofoam-NS, TronolaneTM Cream, TucksTM Hemorrhoidal), eutectic mixture of local anesthetics (EMLA), and corticosteroids;
  • camphor/menthol lotions or creams containing 0.125 to 0.25% menthol doxepin (e.g., Sinequan , Zonalon ), phenol (e.g., Cepastat®, Chloraseptic® gargle, Ulcerease), 0.5 to 2%
  • pramoxine e.g
  • anti-inflammatory and/or immunosuppressive agents such as methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus,
  • corticosteroids corticosteroids, statins, interferon beta, RemicadeTM (infliximab), EnbrelTM (etanercept) and HumiraTM (adalimumab);
  • agents designed to treat tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename ZybanTM) and nicotine replacement therapies;
  • ADD/ADHD agents e.g., RitalinTM (methylphenidate hydrochloride),
  • AdderallTM amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate
  • agents to treat alcoholism such as opioid antagonists (e.g., naltrexone (also known under the tradename Re Via M) and nalmefene), disulfiram (also known under the tradename AntabuseTM), and acamprosate (also known under the tradename CampralTM));
  • opioid antagonists e.g., naltrexone (also known under the tradename Re Via M) and nalmefene)
  • disulfiram also known under the tradename AntabuseTM
  • acamprosate also known under the tradename CampralTM
  • agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NeurontinTM);
  • antihypertensive agents e.g., ACE inhibitors and Angiotensin II Receptor blockers such as benazepril , captopril , enalapril , fosinopril , lisinopril, candesartan , eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, renin inhibitors such as aliskiren, vasodilators such as minoxidil;
  • Angiotensin II Receptor blockers such as benazepril , captopril , enalapril , fosinopril , lisinopril, candesartan , eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, renin inhibitors such as aliskiren, vasodilators
  • agents used to treat glaucoma e.g., direct-acting miotics (cholinergic agonists), indirect acting miotics (cholinesterase inhibitors), carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide, brinzolamide, dorzolamide), selective adrenergic agonists (e.g., apraclonidine, brimonidine), beta-blockers (bimolol, betaxolol, carteolol, levobetaxolol, levobunolol, metipranolol), osmotic diuretics (e.g., glycerin, mannitol);
  • antidepressants e.g., SSRIs (e.g., fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine), tricyclic antidepressants (e.g., imipramine, amitriptiline, chlomipramine and nortriptiline), dopaminergic antidepressants (e.g., bupropion and amineptine), SNRIs (e.g., venlafaxine and reboxetine);
  • SSRIs e.g., fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine
  • tricyclic antidepressants e.g., imipramine, amitriptiline, chlomipramine and nortriptiline
  • dopaminergic antidepressants e.g., bupropion and
  • cognitive improvement agents e.g., donepezil hydrochloride (AriceptTM) and other acetylcholinesterase inhibitors;
  • anti-emetic agents e.g., 5HT3 antagonists such as ondansetron, granisetron, metoclopramide;
  • neuroprotective agents e.g., memantine, L-dopa, bromocriptine, pergolide, talipexol, pramipexol, cabergoline, neuroprotective agents currently under investigation including anti-apoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetics,
  • neuroprotective agents are, e.g., the monoamine oxidase B inhibitors selegiline and rasagiline, dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10; [00252] antipsychotic medications: e.g., ziprasidone (GeodonTM), risperidone
  • agents used for multiple sclerosis such as beta-interferon (e.g., AvonexTM, BetaseronTM) baclofen and CopaxoneTM;
  • DARDS disease-modifying anti-rheumatic drugs
  • methotrexate azathioptrine
  • leflunomide azathioptrine
  • pencillinamine gold salts
  • mycophenolate mofetil mycophenolate mofetil
  • BRMs biological response modifiers
  • NSAIDS such as piroxicam, naproxen, indomethacin, ibuprofen and the like
  • COX-2 selective inhibitors such as CelebrexTM
  • COX-1 inhibitors such as
  • FeldeneTM immunosuppressives such as steroids, cyclosporine, tacrolimus, rapamycin and the like;
  • PDE4 inhibitors such as theophylline, drotaverine hydrochloride, cilomilast, roflumilast, denbufylline, rolipram, tetomilast, enprofylline, arofylline, cipamfylline, tofimilast, filaminast, piclamilast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2- phenylethyljpyridine, mesopram, N-(3,5-dichloro-4-pyridinyl)-2-[ 1 -(4-fiuorobenzyl)-5- hydroxy-lH- -indol-3-yl]-2-oxoacetamide, CDC-801 (Celgene), CC-1088 (Celgene),
  • corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
  • histamine HI receptor antagonists such as bromopheniramine,
  • histamine H2 receptor antagonists such as cimetidine, famotidine and ranitidine;
  • proton pump inhibitors such as omeprazole, pantoprazole and esomeprazole;
  • leukotriene antagonists and 5-lipoxygenase inhibitors such as zafirlukast, montelukast, pranlukast and zileuton;
  • nicotinic acetylcholine receptor agonists such as ABT-202, A-366833, ABT- 594; BTG-102, A-85380, CGX1204;
  • P2X3 receptor antagonists such as A-317491, ISIS-13920, AZD-9056;
  • NGF agonists and antagonists such as RI-724, RI- 1024, AMG-819, AMG-403, PPH 207;
  • NK1 and NK2 antagonists such as DA-5018, R-l 16301; CP-728663, ZD-2249;
  • NMDA antagonist such as NER-MD-11, CNS-5161, EAA-090, AZ-756, CNP- 3381; potassium channel modulators such as CL-888, ICA-69673, retigabine;
  • GABA modulators such as lacosamide and propofol
  • anti-cancer agents such as tyrosine kinase inhibitors imatinib (Gleevec/Glivec) and gefitinib (Iressa);
  • anti hyperlipidemia drugs such as statins, ezetimibe, niacin and bile acid sequestrants;
  • appetite suppressing agents e.g., sibutramine, taranabant, rimobamant;
  • anti-diabetic medications such as insulin, tolbutamide (OrinaseTM),
  • acetohexamide (DymelorTM), tolazamide (TolinaseTM), chlo ropamide (DiabineseTM), glipizide (GlucotrolTM), glyburide (DiabetaTM, MicronaseTM, GlynaseTM), glimepiride
  • serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram, flibanserin; and
  • GI agents e.g., laxatives (e.g., lubiprostone (AmitizaTM), Fybogel®, Regulan®, Normacol® and the like), a gastrointestinal agent used for the treatment of idiopathic chronic constipation and constipation-predominant IBS, GI motility stimulants (e.g., domperidone, metoclopramide, mosapride, itopride), antispasmodic drugs (e.g., anticholinergics such as hyoscyamine or dicyclomine); anti-diarrheal medicines such loperamide (ImodiumTM) and bismuth subsalicylate (as found in Pepto Bismol and Kaopectate ), GCC (Guanylate Cyclase C) agonists (e.g., Linaclotide), 5HT4 agonists (e.g., Tegasarod), 5HT3 antagonists (e
  • LC/MS was run on a Waters Acquity system using a Polar CI 8 column, and 5 to 60% acetonitrile/water over 5 min.
  • the ionization method for the MS was electrospray.
  • Microwave reactions were run on a Personal Chemistry Optimizer, at 0-240 °C, a power of 0-300 W and a pressure of 0-21 bar.
  • Solvent A 0.1% Trifluoroacetic acid in water
  • Solvent B 0.1% Trifluoroacetic acid in acetonitrile
  • reaction mixture was then concentrated to a residue, reconstituted in water (50 mL), and washed with ethyl acetate (2 x 50 mL).
  • the aqueous layer was acidified with 3M hydrochloric acid solution (0.95 mL) and back-extracted with ethyl acetate (2 x 50 mL), dried (sodium sulfate), filtered and concentrated to afford a yellow solid.
  • dichloromethane (7 mL) was added a solution of 5-chloro-2-((2,5-dimethyl-lH-pyrrolo[2,3- b]pyridin-l-yl)methyl)thiazole (400 mg, 1.44 mmol) in dichloromethane (2 mL).
  • the reaction mixture was stirred at 0 °C for 30 minutes then warmed to room temperature and stirred at that temperature for 5 minutes, then cooled again to 0 °C.
  • Methyl oxalyl chloride (0.401 mL, 4.32 mmol) was added to the reaction mixture, resulting in the formation of a suspension.
  • the reaction was concentrated to a dark brown residue, and was reconstituted in dichloromethane (20 mL). This mixture was cooled to 0 °C, after which 2-methoxypyridin-4-amine (218 mg, 1.76 mmol), followed by triethylarnine (0.245 mL, 1.76 mmol) was added. After 30 minutes, the reaction was complete. The reaction was diluted in water and extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to a gold-colored solid. Purification was achieved by silica gel chromatography (Luknova 120g, 20 mL/min) using 10 to 50% ethyl acetate in hexanes over 50 minutes.
  • Example 4b (see general route 4, step H, M and K):
  • reaction mixture was stirred at 80 °C for 24 hours, after which it was diluted with water, extracted with ethyl acetate (3 x 50 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 40g) using 0 to 80% ethyl acetate in hexanes to afford 5-methoxy-2- methyl-l-(pyridin-2-ylmethyl)-l H-indole as a yellow-brown solid in 8% yield.
  • reaction mixture was stirred at -78 °C for an additional 30 minutes, after it was warmed to room temperature, quenched by the addition of saturated ammonium chloride solution (500 mL) extracted with diethyl ether (2 x 500 mL), dried (sodium sulfate), filtered and carefully concentrated to a residue (during the solvent removal process, the temperature of the rotovap bath must be carefully monitored and kept below 30 °C to minimize product loss due to volatility). Purification was achieved by silica gel chromatography (300g silica) using 0 to 15% diethyl ether in pentane to afford 5-chloro-2-methylthiazole (13.3 g, 100 mmol, 65% yield) as a dark brown liquid.
  • reaction mixture was then quenched by the addition of water (5 mL), concentrated to a residue, reconstituted in water (40 mL) and extracted with ethyl acetate (2 x 60 mL), (magnesium sulfate), filtered and concentrated to afford (4-methyl-l,3-thiazol-2-yl)methanol (1.70 g, 13.2 mmol, 84% yield) as viscous oil. This material was used in the subsequent step without any purification.
  • reaction was refluxed at 95 °C for 24 hours, after which the reaction was cooled to room temperature, filtered through a pad of celite, extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to an orange residue.
  • LCMS analysis indicated about 60% conversion to the desired product, after which additional 25% sodium methoxide solution (282 iL) was added.
  • the reaction was then heated for 24 hours, after which it was cooled to room temperature, concentrated to a residue, diluted in water, extracted with ethyl acetate (3 x 50 mL), dried (sodium sulfate), filtered and concentrated.
  • First pass purification was achieved by silica gel chromatography (Luknova 40 g, 20 mL/min) using 10 to 50% ethyl acetate in hexanes over 60 minutes.
  • reaction mixture was poured into saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (3 x 50 mL), washed with saturated sodium bicarbonate solution (2 x 50 mL), dried (sodium sulfate), filtered, and concentrated to an off-white solid.
  • Methyl 1 -(4-chlorobenzyl)-3-(2-(2-methoxypyridin-4-ylamino)-2-oxoacetyl)-2- methyl-lH-indole-5-carboxylate was synthesized as a white solid in 56% yield starting from methyl l-(4-chlorobenzyl)-2 -methyl- lH-indole-5-carboxylate using general procedure G.
  • reaction mixture was stirred at room temperature for 30 minutes after which it was acidified with aqueous 1M hydrochloric acid solution (lOmL), extracted with dichloromethane (3 x 50 mL) dried (sodium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography using 10 to 50% ethyl acetate in hexanes to afford 2-(l-(4- chlorobenzyl)-2-methyl-5-(methylsulfonamido)- 1 H-indol-3 -yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide as a solid in a 15% yield.
  • reaction mixture was diluted with saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3 x 100 mL), washed with saturated sodium chloride solution (50mL), dried (sodium sulfate) and concentrated to a residue. Purification was achieved by silica gel chromatography using 0 to 70% ethyl acetate in hexanes to afford 2-methyl-5-(pyrrolidin-l-yl)-lH-indole (0.600 g, 3.00 mmol, 32% yield) as a crude solid. This material was used in the subsequent step without any purification.
  • reaction mixture was heated to 65 °C for 16 hours, after which it was cooled, quenched with water (50 mL), extracted with dichloromethane (3 x 100 mL), washed with water (1 x 100 mL), dried (sodium sulfate), filtered and concentrated to afford l-(4-chlorobenzyl)-2-methyl-5- (pyrrolidin-l-yl)-lH-indole (0.192 g, 0.591 mmol, 43 % yield) as a solid. This material was used in the subsequent step without any purification.
  • re-suspension buffer 50 mM Tris-HCl buffer, pH 7.4, containing 1 raM EDTA and 3 mM MgCl 2 .
  • a Bradford Protein assay was performed to determine protein concentration. The protein was aliquotted into screw cap Cryo tubes each containing ⁇ 400 ⁇ , flash frozen in liquid nitrogen and stored at -80 °C until used for the assay. A similar protocol was used to obtain brain membrane homogenates from mice.
  • Brain cerebral cortex tissue (ABS, Inc.) from 3 human donors (2 females, 1 male; 63-85 years old) was collected previously and flash-frozen in liquid nitrogen within 4 hours post-mortem interval. Tissue was stored at -80 °C. Serology was negative for a defined list of infectious agents. Brain cortex samples (equal amounts from 3 donors pooled as 10 g total) were homogenized as described below.AU tissue samples were handled following Centers for Disease Control Biosafety Level 2 (BL-2) procedures for working with bio-hazardous materials by trained personnel in BL-2 certified laboratories. Brain tissue was thawed in ice- cold homogenization buffer 20 mM HEPES (pH 7.0), 1 mM MgCl 2 .
  • Protein concentrations of the brain microsome suspensions were determined using BioRad protein assay kit (BioRad). The protein was aliquotted and flash frozen as 0.2 mL aliquots in liquid nitrogen and stored at -80 °C until use.
  • RBM homogenates (7 ⁇ g protein in 20 sL final volume of 10 mM Tris pH 6.5) were mixed with 180 ⁇ . of a mixture of the following: 2.0 ⁇ unlabelled anandamide, 0.03 ⁇ radio labeled anandamide [ethanolamine 1- H] (40-60 Ci/mmol, product number ART-626,
  • Bovine Serum Albumin fatty acid-free BSA, electrophoresis grade, Sigma, St. Louis, MO
  • 10 mM Tris-HCl pH 6.5
  • 1 mM EDTA in the presence and absence of test compounds (vehicle was DMSO at a final concentration of 1%) and incubated for 10 minutes at 37 °C. Samples were placed on ice to terminate the reactions.
  • 3 H-ethanolamine product and un-reacted 3 H-anandamide substrate were then separated either: (1) by using chloroform/ methanol extraction or (2) by passing the reaction mixture through a glass fiber filter containing activated charcoal. Samples were extracted with chloroform/methanol by adding 0.4 mL of chloroform/methanol (1:1 v/v), vigorously mixing the samples, and separating the aqueous and organic phases by centrifugation. Radioactivity
  • IC50 values were determined as described by Jonsson et al. (2001 Br J Pharmacol. 133:1263).
  • reactions were purified using a modification of the solid-phase extraction method described by Wilson et al (2003 Anal. Biochem. 318 : 270). This method was modified as follows: after reactions were incubated at 37 °C for 10 minutes and chilled on ice, the reaction mixtures were acidified by adding 10 of sodium phosphate solution [0.5M (pH 2.0)]. Next,
  • Table 1 provides activity data for certain compounds tested for inhibition of FAAH using the FAAH rat, mouse and human brain homogenate assays.
  • the known FAAH inhibitors 3'-(aminocarbonyl)biphenyl-3-yl cyclohexylcarbamate (URB597), [l-(4- chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]acetic acid (indomethacin) and 5-benzoyl- 2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (Ketorolac) were used as controls in these assays.
  • A Less than 100 nM
  • B between 100 nM and 1 ⁇
  • C between 1 ⁇ and 10 ⁇
  • D greater than 10 ⁇ .
  • Example 6 Whole cell anandamide hydrolysis assay:
  • cDNA expression clone for human FAAH-1 (in pcDNA3 vector) (Genbank Accession U82535; obtained from Benjamin Cravatt, Scripps Research Institute, La Jolla, California) was linearized by digestion with Bglll (New England Biolabs) and transfected by calcium phosphate into human HeLa cells (ATCC catalog #CCL-2).
  • the HeLa cell line was selected as a host because it does not express FAAH or exhibit FAAH activity such that all subsequent activity can be attributed to the transfected gene.
  • a stable HeLa-derived clone designated 5c5
  • MEM modified Eagles medium
  • FBS fetal bovine serum
  • G-418 0.5 mg/mL G-418
  • Clone 5c5 (50,000 cells in 150 was seeded into 96-well plates and incubated overnight (5% C0 2 , 37 °C). Media was carefully replaced with 180 ⁇ , DMEM/F12 medium (VWR catalog # 45000-350) containing 15 mM HEPES, pH 7.4 and 0.1% fatty acid free BSA (Sigma catalog # A0281). Then, 2 yL of lOOx desired final concentrations of certain exemplary compounds described herein were made up in DMSO, added to wells containing cells, and plates were incubated at 37 °C for 10 min.
  • anandamide (Cayman catalog # 90050) spiked with 8 ⁇ of anandamide-(ethanolamine-l-[ 3 H]) (American Radiolabeled Chemicals, Inc., catalog #ART 626) was added to the cells and the plates were incubated for an additional 15 min at 37 °C. The reactions were terminated by chilling the plates on ice and adding 20 ⁇ , of 0.5 M of potassium phosphate buffer (adjusted to pH 2.1 with phosphoric acid).
  • the charcoal glass fiber filter plates were pre- washed with methanol by centrifugation 650 x g for 10 min). Next, 80 ⁇ , of water was added to the wells of the pre-washed 96-well charcoal filter plate. Then, 90 ⁇ , of the acidified reaction mixture was added to the water in the wells of the charcoal plate. The samples were centrifuged as above. The substrate remained bound to the charcoal, whereas the [ 3 H]- ethanolamine product formed flowed through and was transferred to the microplates containing scintillation cocktail and quantified in a micro-plate scintillation counter (Perkin-Elmer Microbeta). Control reactions with either no cells or cells treated with DMSO alone were performed in triplicate and used to define background (no cells) and 100% activity (DMSO alone).
  • Table 2 FAAH human whole cell assay.
  • a - Less than 100 nM, B between 100 nM and 1 ⁇ , C - between 1 ⁇
  • Binding assays can be used to characterize potential CB1 receptor binding affinity for the disclosed compounds and compositions.
  • cDNA expression clones for human CB1 (hCBl, Genbank Accession No. AY225225) expressed in vector pcDNA3.1+ can be purchased from UMR cDNA Resource Center, Rolla, MO (Clone ID CNR01L000 for hCBl).
  • HEK-293-derived cell lines that recombinantly express hCBl can be established.
  • the clone hCBl (CNR1L) is transfected into human embryonic kidney cells (HEK-293) using Lipofectamine 2000 (Gibco, Cat# 11668-019) according to the manufacturer's protocol.
  • Transfected clones are isolated by single colony purification and clones are screened for receptor expression using a whole cell, 3 H-CP 55,940 radioligand binding assay.
  • HEK-293 stable cells are maintained in Dulbecco's modified Eagles medium (DMEM) containing 10% fetal bovine serum, 2 mM L-glutamine and 0.5mg/mL G-418.
  • DMEM Dulbecco's modified Eagles medium
  • Membranes are isolated from transfected cells as follows. Monolayers of cultured cells are washed twice with phosphate-buffered saline (PBS). Cells are scraped into 20 mM HEPES, pH 7.4, 10 mM EDTA containing complete cocktail protease inhibitors (Roche, Catalog # 11 697 498 001) and are homogenized by an electric-powered mechanical probe homogenizer (Omni GLH; probe G7-195S) for 40 seconds at 7000 rpm. Homogenates are centrifuged 10 minutes at 1000 x g at 4°C. The supernatant is collected and is centrifuged for 1 hour at 40,000 x g.
  • PBS phosphate-buffered saline
  • Radioligand binding assays can be performed by incubating membranes (2- 10 ug protein) prepared from HEK-293 cells expressing recombinant human cannabinoid receptor, CBl, at room temperature with 0.5 nM cannabinoid receptor agonist, [ 3 H]-CP 55,940 (Perkin Elmer, catalog # NET1051) in 0.2 mL of binding buffer (50 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 , 2.5 mM EDTA) and 0.1 % fatty acid free bovine serum albumin (Sigma Cat. # A0821) for 90 minutes.
  • a rapid filtration technique using Millipore FB filter plates Catalog #
  • compounds of the invention display a decreased affinity for binding to the CBl receptor. In some embodiments, compounds of the invention displayed a decreased affinity for binding to the CBl receptor when compared to other known FAAH inhibitors.
  • compounds of the invention show increased selectivity for binding to FAAH relative to their binding to the CBl receptor.
  • the safety profile of the compounds can be evaluated in nonclinical toxicology studies in rodents and non-rodents.
  • Male and female animals are administered test compound in a vehicle by an appropriate route (e.g., oral, intramuscular, intravenous) once daily for, e.g., 14 or 28 consecutive days. Additional animals receive the vehicle only and serve as the vehicle control group.
  • Clinical observations, changes in body weights and feed consumption, ophthalmic and clinical pathology (hematology, clinical chemistry, coagulation) parameters are evaluated in each animal during the in life portion of the study.
  • toxicokinetic evaluations for systemic exposure determinations are conducted on separate groups of animals at each dose level of the test compound.
  • results are compared to vehicle control values using statistical analyses where appropriate. Results are used to determine the no-observed-adverse- effect-level (NOAEL) and toxicity profile in the test species.
  • NOAEL no-observed-adverse- effect-level
  • Human ether-a-gogo-related (hERG) ion channel encodes the inward rectifying voltage gated potassium channel in the heart and has a major role during the repolarization of the cardiac action potential. It is well established that blockade of this ion channel can lead to potentially lethal arrhythmias. hERG pre-clinical safety data is often used by regulatory agencies in elucidate the toxicity profile of certain compositions. The disclosed compounds of the invention can be tested for their ability to inhibit hERG ion channels.
  • Media components include F 12 Nutrient Mixture (Ham) with GlutaMAXTM (Invitrogen, Cat# 31765), Fetal Bovine Serum, Certified (Invitrogen, Cat# 16000-044 - not heat activated), and Geneticin® Selective Antibiotic (Invitrogen, Cat# 10131-027).
  • GlutaMAXTM Invitrogen, Cat# 31755
  • Fetal Bovine Serum Certified
  • Geneticin® Selective Antibiotic Invitrogen, Cat# 10131-027.
  • One vial of frozen cells, at 1.62xl0 6 cells are thawed into a T150 flask (BD Falcon 355001) with 40 mL of pre-warmed complete media. Cells are cultured at 37 °C, 5% C0 2 for four hours prior to gently changing media. 99% of cells appear attached at this time point.
  • the flask is media changed at 24 hours post-thaw, the cells are imaged, media changed, and returned to the incubator. At this point, the cells appear healthy and about 25% confluent in the flask. Cells are typically passed 24-48 hours after thaw according to the following intervals and densities below. Cells are incubated at 30 °C for 48 hours prior to assay. Incubation Interval Cells/T150 to Passage Total CeU Yield/T150
  • a three pulse protocol can be applied by stepping from a holding potential of -80mV to +40mM for 2s, to activate hERG channels. The membrane voltage is then stepped back to -50mV for 2s to evoke a tail current prior to returning to the holding potential for Is. This sequence can be repeated a further two times. This voltage protocol is applied prior to drug (Pre compound) and after 600s in the presence of drug (Post compound).
  • the amplitude of the hERG tail current is calculated by measuring the difference between the maximum current on stepping to -50mV of the third pulse (i.e. peak of the outward hERG tail current) and the current measured immediately prior to activation of any hERG current. This parameter is assessed before (pre tail current amplitude) and after 600 s incubation (post tail current amplitude) in drug. In order to assess the amount of block produced by test compounds, the data is first filtered using the IonWorksTM software to exclude any cells where the seal resistance is less than 50MOhm. The remaining data is then exported to an excel compatible data file and only currents with tail currents greater than 250pA are analyzed. The post/pre tail current amplitude ratio for the third pulse is calculated for each drug and control, and presented as percent inhibition.
  • the compounds of the invention displayed decreased inhibition of the hERG channel. In some embodiments, the compounds of the invention displayed a decreased inhibition of the hERG channel when compared to other known F AAH inhibitors.
  • Compounds are formulated in a 1 % DMA / 99% Vitamin E TPGS vehicle. Prepared compounds are dosed via oral gavage (PO). Following the appropriate pretreatment time of 2 hours, rats are anesthetized with isoflurane gas. Blood is collected into tubes containing EDTA via retro-orbital eye bleed. Whole blood is spun in a micro-centrifuge at approximately 13,000 rpm for 5 minutes at room temperature. Separated plasma is
  • Plasma samples are thawed and the required amount of plasma for standards, blanks and dilutions are made.
  • the dilutions are prepared before plating.
  • Preparation of crash solution included cold acetonitrile + 0.1% formic acid and 25 ng/mL of a FAAH inhibitor used as internal standard, solvent standards of the FAAH inhibitor being studied were prepared at 10, 30, 100, 300, 1000, 3000, 10000, 30000, 100000, and 300000 ng/mL in DMSO. Then a plasma standard curve is generated from the solvent standards (final concentrations of standards in plasma are: 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000 ng/mL).
  • each plasma sample/dilution, standard, or blank is transferred into 96-well plates.
  • 200 of cold crash solution was added.
  • the plate is covered and gently vortexed.
  • the plate is centrifuged at 3500 rpm, 4°C for 10 min.
  • 200 of each supernatant was transferred into new plates.
  • the plates are dried under nitrogen in a Turbo Vap at 55°C.
  • the sample in each well is re-suspended with 100 of 30% acetonitrile, covered and vortexed gently.
  • the well solutions are analyzed by the LC/MS/MS conditions and specifications below.
  • HPLC column is a Clipeus C8, 2.1 30 mm, 5 ⁇ , with Basic 8 guard column using 20 ⁇ , injections.
  • Mobile phase used is mobile phase A: 0.1% Formic Acid in water and mobile phase B: 0.1% Formic Acid in 85:10:5
  • the flow rate for the run is 0.5 mL/min and the gradient for the 4 minute total run time was: 0.0 minutes 35% B; 0.5 minutes 35% B; 1.5 minutes 95% B; 2.3 minutes 95% B; and 2.4 minutes 35% B.
  • Example 11 Reduction of Spasticity in a Mouse Model of Multiple Sclerosis
  • CREAE chronic relapsing experimental autoimmune encephalomyelitis
  • Spasticity is assessed by measuring the force required to bend individual hind limbs to full flexion against a strain gauge.
  • selected doses are administered to spastic CREAE mice by an appropriate route (e.g., oral, intraperitoneal, or intravenous).
  • Spasticity is measured pre-dose and at various times after compound administration (for example 1, 2, 4 and 24 hours post-dose).
  • the mean force of resistance to hindlimb flexion at each post-dose timepoint is compared to the mean pre-dose force using an appropriate statistical test (e.g. analysis of variance or paired t-tests.).
  • FAAH inhibitors and their elevation of endo-cannabinoids would be expected to control spasticity in this animal disease model see, for example, Baker et al. 2001 supra) and Ligresti et al. 2006 Br. J. Pharmacol. 147(1): 83).
  • CREAE chronic relapsing experimental autoimmune encephalomyelitis
  • test agent or negative control agent e.g., a vehicle control
  • an appropriate route e.g., oral, intraperitoneal, or intravenous
  • Clinical and neurological symptoms can be scored daily (e.g., starting at Day 11), and motor coordination can be assessed using the RotoRod test.
  • animals are killed and their spinal cords are rapidly removed. Nerve content of the spinal cords is determined, for example, using a neurofilament enzyme-linked immunosorbant assay (Pryce et al. 2003 supra). Results for animals treated with the test agent are compared to those for animals treated with the negative control agent. Based on previous investigations, FAAH inhibitors would be expected to inhibit neurodegeneration in this animal model (Pryce et al. 2003 supra).
  • Compounds can be tested for their ability to inhibit pain and depression in a putative animal model of fibromyalgia (Nagakura et al. 2009 Pain 146:26). Rats are administered a subcutaneous injection of reserpine (1 mg/kg) once daily for 3 consecutive days to deplete biogenic amines. Treated rats manifest symptoms of pain and depression. Muscle pain can be assessed by applying increasing pressure to a hindlimb muscle until a withdrawal response is elicited. Tactile allodynia can be assessed by measuring the hindlimb withdrawal threshold following application of Von Frey filaments of incrementally increasing weights to the plantar surface of the hind paw. Depression can be assessed by immobility time in the forced swim test.
  • a test compound in the model is administered to the rats by an appropriate route (e.g., oral, intraperitoneal, or intravenous) approximately 5 days after reserpine treatment.
  • Muscle pressure threshold, tactile response threshold, and immobility time in the forced swim test are measured at appropriate times after compound administration (for example 0.5, 1, 2, and 4 hours post-dose). Results are compared to pre-dose values using an appropriate statistical test.
  • Example 14 Behavioral effect of FAAH inhibitors alone or in combination with L-DOPA in MPTP-lesioned marmosets
  • FAAH inhibitors can be tested for their ability to reduce hyperactivity or dyskinesia in stable L-DOPA induced MPTP-lesioned marmosets.
  • L-DOPA dopamine precursor 3,4-dihydroxyphenylalanine; levodopa
  • levodopa has been previously demonstrated to induce a stable marmoset model with dyskinesia and hyperactivity, see for example, Gomez-Ramirez et al. (2006) Mov. Disord. 21:839-846; Visanji et al. (2008) Mov. Disord. 23:1922-1925; and Visanji et al (2009) Neurobiol Dis. 35: 184-192).
  • L-DOPA 20 mg kg
  • benserazide 5 mg kg
  • the effect of FAAH inhibitor alone and on L-DOPA response can be assessed.
  • L- DOPA can be administered s.c. at a dose volume of 1 ml/kg, as L-DOPA methyl ester (Sigma, Canada) in combination with benserazide (Sigma, Canada).
  • a dose of 10 mg/kg FAAH inhibitor may be employed for all behavioral observations and administered orally at a dose volume of 5 ml/kg.
  • animals are fed normally and receive a maintenance oral L-DOPA dose at 9:00 a.m. At 4:00 p.m. animals are administered either vehicle (p.o.) or FAAH inhibitor (10 mg/kg, p.o.).
  • animals are fed their normal diet between 7:00-7:30 a.m. after which time all food is removed from their cages. Water is available ad libitum.
  • each animal receives either vehicle (p.o.) or FAAH inhibitor (p.o.).
  • Two hours after this, at approximately 11 :00 a.m. animals receive either vehicle or L-DOPA (s.c.) treatment.
  • Behavioral assessment commences directly following this second treatment.
  • 0 absent
  • 1 mild, fleeting, rare, present less than 30% of the observation period
  • 2 moderate, not interfering with normal activity, present more than 30% of the observation period
  • 3 marked, at times interfering with normal activity, present less than 70% of the observation period
  • 4 severe, continuous, replacing normal activity, present more than 70% of the observation period.
  • chorea and dystonia can be graded separately and the score given to represent the most disabling dyskinesia observed, whether chorea or dystonia, in any 10-minute period of assessment.
  • a quantitative assessment of marmoset activity can be made using computer-operated passive infra-red sensors, essentially as described previously in Maccarrone et al. 2003 J. Neurochem. 85:1018; and Visanji et al. 2009 J Pharm Exp Ther 328: 276.
  • a single sensor containing a hemispherical lens (Guardall, Mississauga, ON, Canada) is mounted 1.5 m above the top of each the observation cage. The sensor is positioned so that motion was detected throughout the entirety of the cage below. The signal is fed via an RS-232 input to a computer.
  • Proprietary Motion Detector software (Research Electronics, Toronto Western Hospital, Toronto, ON, Canada) is utilized that displayed within Microsoft Excel (Microsoft, Redmond, WA). Activity counts are logged in 1-min epochs for the entire 6 h duration of the experiment and cumulated over the peak dose period of 2-4 h.
  • Assessment of marmoset hyperactivity is further assessed over time by quantifying the average activity of counts per minute of the same animals obtained prior to administration of MPTP (i.e., in the normal state). Activity over the same period of 2-4 h is calculated and used to identify minutes of high activity (a minute when activity was above the average per minute of the animal prior to MPTP). High activity counts (the total counts obtained in high activity minutes) are cumulated. High activity time (the number of high activity minutes) is also calculated.
  • mice are injected intraperitoneally (IP) with cortagine (10 ⁇ g/kg, 0.8 ml/kg in DMSO/cremophor/ isotonic saline (1:1:8 v:v:v).
  • cortagine a selective corticotropin releasing factor receptor 1 (CRFi) agonist, prepared as described previously (Rivier et al. 2007 J. Med. Chem. 50:1668), can be stored in a powder form at -80 ° C and prepared in sterile water (12.5 g/ml) immediately before use.
  • CRFi corticotropin releasing factor receptor 1
  • FAAH inhibitors can be formulated as suspensions in DMSO/cremophor/ isotonic saline (1:1:8 v:v:v).
  • concentrations of FAAH inhibitors compound suspensions can be 6 mg/ml for 30 mg/kg dose; 2 mg/ml for the 10 mg/kg dose; or 1.5 mg/ml for the 3 mg/kg dose.
  • Vehicle treatment can be administered to rats by per os (PO) route at dose- volume of 5 ml/kg.
  • FAAH inhibitor treatment can be administered to rats by subcutaneous (SC) route at dose volume of 2 ml/kg.
  • the vehicle for the PO route was DMSO/cremophor/ isotonic saline (1:1:8 v:v:v).
  • Test agents can be administered to non-fasted rats which are restrained by hand.
  • the regimen of administration of FAAH inhibitors can involve one delivery (PO or SC) performed 120 min before IP injection of cortagine.
  • Visceral pain is assessed using a non-invasive pressure transducer system referred to as "sensor balloon” as previously described (Larauche et al. 2009 supra; Ness et al. 1988 Brain Res. 450:153).
  • Sensor balloon a non-invasive pressure transducer system referred to as "sensor balloon” as previously described (Larauche et al. 2009 supra; Ness et al. 1988 Brain Res. 450:153).
  • Adult non-fasted SD rats, a 4-5 cm “sensor balloon” lubricated with surgical lubricant (Surgilube, Fougera, Melville) is inserted intra-anally under brief isoflurane anesthesia.
  • the "sensor balloon” can be positioned such that its distal end is 1 cm proximal to the anal verge and secured in place by tapping the balloon catheter to the tail. Rats are placed individually in Boolman's cage and allowed to recover from anesthesia and habituation.
  • the colorectal procedure can be performed using the Distender Series Ilir dual barostat (G&J Electronics Inc, Toronto, Ontario).
  • CRD colorectal distension
  • the colorectal distension ("CRD") protocol consists of 2 CRD at 60 mmHg to unfold the balloon followed by 2 sets of CRD at 10, 20, 40 and 60 mmHg, 20 s duration, 4-min inter-stimulus interval.
  • the intra-luminal colonic pressure (ICP) can be recorded for 20 s before, during and after termination of CRD.
  • the AUC of ICP during CRD over non-distended ICP can be recorded as the VRM (visceromotor response, see Larauche et al. 2009 supra.
  • ICP amplitudes can be normalized as percent of the VRM response to the highest (60 mmHg) in the 1 st set of CRD for each rat.
  • VRM to the 1 st set of CRD before treatment represents baseline VRM at different pressures of distention and is averaged for each group of rats. Rats can also be visually observed for any other behavioral responses.
  • Rats are habituated to oral gavage (once/day) and to Bollman's cages (4h/day) for 3 consecutive days preceding the treatment. They are placed in a quiet rat room 48 h before the experimental day and are not disturbed outside of the training/gavage sessions.
  • animals can be equipped with distension balloons and placed in Bollman's cages before being brought to the experimental room, where they are left 20 min to recover from anesthesia.
  • a baseline CRD (CRD#1) of 40 min is performed at 10, 20, 40, 60 mmHg and the visceromotor response (VMR) assessed.
  • VMR visceromotor response
  • DMSO/cremophor/ isotonic saline (1:1:8 v:v:v), 1.5 ml), or FAAH inhibitor in vehicle Two hours after, cortagine (10 ⁇ g/kg in vehicle, IP) can be injected. Fifteen minutes after cortagine injection, a second CRD (CRD#2) of 40 min can be performed. At the end of the distension, the balloons are removed prior to placing the rats back into their home cages ( ⁇ 15 min).
  • Example 16 Reduction of Scratching in a Mouse Model of an Acute Allergenic Response
  • mice e.g., C57B16/J strain weighing approximately 20-25 g
  • a vehicle control agent administered by an appropriate route (e.g., oral, intraperitoneal, or intravenous).
  • mice marble burying assay can be used to assess the potential effects of compounds on compulsive, anxiety-like behavior, and is considered a model of obsessive compulsive disorder (Deacon 2006 Nat Protoc. 1: 122; Kinsey et al. 2011 Pharmacol Biochem Behav. 98: 21).
  • Groups of mice e.g., C57B16/J strain weighing approximately 20-25 g
  • a test compound or a vehicle control agent administered by an appropriate route (e.g., oral, intraperitoneal, or intravenous).
  • each mouse is placed in a cage filled to a depth of about 5 cm with bedding, in which approximately 20 marbles (approximately 10 mm in diameter) are arranged in a grid-like fashion across the surface of the bedding. After an appropriate time (e.g., approximately 20 min), the mouse is carefully removed from the cage and the number of buried marbles is determined. The mean and standard error of the mean for each group of mice is calculated. Differences between means can be analyzed by an appropriate statistical test (e.g. analysis of variance or paired t-tests.)
  • Example 18 Reduction of Bladder Hypersenstivity in a Rat Modell of Overactive Bladder
  • the potential effects of compounds on urinary bladder overactivity can be assessed using the acetic acid-induced bladder hypersensitivity model in the rat.
  • Groups of female rats e.g., Sprague-Dawley rats weighing approximately 200-250 grams
  • a vehicle control agent administered by an appropriate route (e.g., oral, intraperitoneal, or intravenous).
  • Cystometrograms are measured under continuous anesthesia during intravesical infusion of saline or dilute acetic acid (e.g, at a flow rate of 0.1 ml/min for 60 min) to induce repetitive micturitions.
  • Urological parameters such as micturition reflex frequency and amplitude can be determined from the cystometrograms measured at baseline and after compound treatment. The mean and standard error of the mean for each group is calculated. Differences between group means can be analyzed by an appropriate statistical test (e.g. analysis of variance or paired t-tests.).

Abstract

The present disclosure relates to compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment or prevention of various disorders. Compounds of the invention are represtented by one of Formula A or Formula B:

Description

FAAH INHIBITORS
PRIORITY CLAIM
[0001] This application claims priority to United States Provisional Application Serial Nos. 61/426,663, filed on December 23, 2010 and 61/446,826, filed on February 25, 2011. The entire contents of the aforementioned applications are herein incorporated by reference.
TECHNICAL FIELD
[0001] The present disclosure relates to indole and azaindole compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides
pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment of various disorders.
BACKGROUND
[0002] The endocannabinoid (eCB) system has been implicated in a variety of processes including cell signaling, memory encoding, compensatory mechanisms, and
immunosuppressant and anti-inflammatory responses. The eCB system comprises at least two receptors: the CB1 cannabinoid receptor, widely distributed in the brain and present in some peripheral organs, and the CB2 receptor, found principally in the periphery and immune systems and in some regions of the brain. The endogenous agonists of these receptors are the endogenous cannabinoids (eCBs), a family of lipids comprising the fatty acid anandamide (AEA) as well as other fatty acids.
[0003] Endocannabinoid-degrading enzymes, including fatty acid amide hydrolase (FAAH), are responsible for cleaving and deactivating eCBs in vivo. FAAH is an integral membrane protein that is expressed in high levels in several brain regions, especially in the neurons of the hippocampus, cerebellum, neocortex and olfactory bulb. FAAH is the principal enzyme responsible for the hydrolysis of AEA in vivo and is also capable of hydrolyzing a wide variety of other substrates. It is known that inhibiting FAAH can lead to increases in fatty acids, including AEA, which could enhance cannabinoid signals within the eCB system. It has also been demonstrated that a number of fatty acid amides can induce analgesia in acute and chronic animal models of pain. Thus, increasing the level of AEA and other fatty acid amides (e.g., N- palmitoyl ethanolamide, N-oleoylethanol amide and oleamide) by inhibiting FAAH may lead to an increase in the nociceptive threshold. For these reasons, inhibitors of FAAH are useful in the treatment of pain. Inhibitors of FAAH might also be useful in the treatment of other disorders involving deregulation of the eCB system (e.g., depression, anxiety, eating disorders, gastrointestinal and cardiovascular disorders, inflammation, excitotoxic insult, brain trauma, and fibromyalgia), and may avoid some of the side effects typically associated with CB receptor agonists (e.g., catalepsy or hypothermia).
[0004] In addition, previous studies have demonstrated that eCBs can control spasticity and provide neuroprotection in multiple sclerosis rodent models. Thus, certain FAAH inhibitors may be useful agents for treating symptoms or achieving disease modification changes in multiple sclerosis. There is also evidence that when FAAH activity is reduced or absent, AEA acts as a substrate for COX-2, which can convert it to a prostamide. Thus, certain prostamides may be elevated in the presence of an FAAH inhibitor. Given that certain prostamides are associated with reduced intraocular pressure and ocular hypotensivity, FAAH inhibitors may also be useful agents for treating glaucoma.
SUMMARY
[0005] The compounds of the instant disclosure, and their pharmaceutically acceptable salts thereof, are useful as FAAH inhibitors. In one aspect, compounds of the present disclosure are represented by Formula A,
Figure imgf000003_0001
Formula A wherein:
ring A is selected from the group consisting of phenyl and a 6-membered monocyclic
heteroaryl ring; wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms;
each JA is independently selected from the group consisting of halogen, -N02, -CN, -R4, -C(0)RA, -C(S)RA, -C(0)ORA , -OC(0)RA, -N(RA)S(0)2RA, -N(RA)C(0)RA,
-N(RA)C(S)RA, -ORA, -SRA, -S(0)RA, -S(0)2RA , -S(0)2N(RA)2 , -C(0)N(RA)2 and -N(RA)2 ; wherein, optionally, two RA groups attached to the same N atom, together with said N, form a 5- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from O or N;
each RA is independently selected from hydrogen, Ci-6 aliphatic, Ci-6 alkoxy, Ci-6 alkylthio, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each RA is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4alkyl, -0(C1-4alkyl), -S(C1-4 alkyl), -N(C alkyl)2, C haloalkyl or C1-4 haloalkoxy; and wherein each of said RA that is a C1-6 aliphatic, C1-6 alkoxy or C1-6 alkylthio is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heterocyclic; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S;
each R4 is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4 alkyl, -OCd^ alkyl), -S(C1-4alkyl) or -N(d-4 alkyl)2; and wherein each R4 that is a C1-6 aliphatic is optionally substituted by one instance of a C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy, C3-6
halocycloalkoxy, phenyl, 3- to 6-membered heterocyclic or 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; or
alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring
atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two heteroatoms selected from N, O or S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, -CN, -NH2, -OH, CM alkyl, C haloalkyl-0(Ci-4 alkyl), -N(C1-4alkyl)2 or -S(C alkyl); n is an integer selected from the group consisting of 0, 1, 2 and 3;
ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
heteroatoms selected from the group consisting of N, O and S;
each JB is independently selected from the group consisting of halogen, -N02, -CN, -OH, Cj-6 aliphatic, C3-6 cycloaliphatic, C1-6 haloaliphatic, Ci-6 alkoxy, Ci-6haloalkoxy and C3- 6 cycloalkoxy;
m is an integer selected from the group consisting of 0, 1, 2 and 3;
ring C is a 5-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
each J is independently selected from the group consisting of halogen, -N02, -CN, -R , -C(0)Rc, -C(S)RC, -C(0)ORc , -OC(0)Rc, -N(Rc)C(0)Rc, -N(RC)C(S)RC, -ORc, -SRC, -S(0)Rc, -S(0)2Rc , -N(Rc)S(0)2Rc, -S(0)2N(Rc)2 , -C(0)N(Rc)2 and -N(RC)2; each R is independently selected from hydrogen, Ci-6 aliphatic, Ci-6 alkoxy, C1-6 alkylthio, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each Rc is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C alkyl, -0(Ci-4 alkyl) or -N(C alkyl)2; and wherein, when Rc is a C1-6 aliphatic, C1- alkoxy or C1-6 alkylthio, it is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy or C3-6 halocycloalkoxy;
each R is independently selected from C1-6 aliphatic, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, 3- to 6-membered heterocyclic or 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently
Q
selected from N, O or S; wherein each R is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, CM alkyl, -0(C alkyl), -S(C1-4 alkyl)
o
or -N(Ci-4 alkyl)2; and wherein, when R is a Ci-6 aliphatic, it is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy or C3-6
halocycloalkoxy; or
alternatively, two J groups attached to two vicinal ring C atoms, together with said ring
atoms, form a 5-to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to three ring heteroatoms selected from the group consisting of N, O and S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C1-4 alkyl, Ci_4 alkoxy, -CN, -NH2, -OH, -0(Cn alkyl), -Ν^μ alkyl)2 or -S(C1-4 alkyl);
p is an integer selected from the group consisting of 0, 1, 2 and 3;
each R1 is independently selected from hydrogen, Q-6 aliphatic or Ci-6 haloaliphatic,
R2 is selected from the group consisting of halogen, -CN or C 1,5 aliphatic; wherein said C1-6 aliphatic is independently and optionally substituted by up to three instances of halogen,
-CN, -NH2,-OH or -Ο(0 alkyl).
[0006] In a second aspect, compounds of the present disclosure are represented by Formula B,
Figure imgf000006_0001
Formula B
wherein:
ring A is selected from the group consisting of phenyl and a 6-membered monocyclic heteroaryl ring; wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms;
each JA is independently selected from the group consisting of-R4, -C(0)OR5, -C(S)RA, -N(RA)C(0)RA, -N(RA)C(S)RA, -SRA, -S(0)RA, -S(0)2RA , -N(RA)S(0)2RA and -S(0)2N(RA)2;
each RA is independently selected from hydrogen, Ci-6 aliphatic, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each RA is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4 alkyl, -0(Ci-4 alkyl), -S(C1-4 alkyl) or -N(C alkyl)2; and wherein each RA that is a C 1-6 aliphatic, Ci-6 alkoxy or C1-6 alkylthio is optionally substituted by one instance of C3- cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S;
each R4 is independently selected from C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4alkoxyl,
Figure imgf000007_0001
-S(C1-4 alkyl) or-NCCM alkyf ;
each R5 is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, phenyl, 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R5 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, Ci^ alkyl, Ci^haloalkyl,-0(C1-4 alkyl), -S(Ci-4 alkyl) or-N(Ci-4 alkyl)2; and wherein each R5 that is a Ci_6 aliphatic is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; or alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S, and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, Ci^ alkoxy, -CN, -NH2,-OH, -C C^ a-kyl), -N(C1-4 alkyl)2 or -S(C1-4 alkyl); n is an integer selected from the group consisting of 1, 2 and 3;
ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
heteroatoms selected from the group consisting of N, O and S; m is an integer selected from the group consisting of 0, 1, 2 and 3;
each JB is independently selected from the group consisting of halogen, -N02, -CN, -OH, Ci-6 aliphatic, C3-6 cycloaliphatic, C1-6 haloaliphatic, Ci- alkoxy, Ci-6haloalkoxy and C3- 6 cycloalkoxy;
ring C is selected from the group consisting of phenyl, C3- cycloalkyl, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S; each Jc is independently selected from the group consisting of halogen, -N02, -OH, -CN, -R11, -C(0)Rc, -C(S)RC, -C(0)ORc , -OC(0)Rc, -N(Rc)C(0)Rc, -N(RC)C(S)RC, -ORc, -SRC, -S(0)Rc, -S(0)2Rc , -N(Rc)S(0)2Rc, -S(0)2N(Rc)2 , -C(0)N(Rc)2 and -N(RC)2 ;
each Rc is independently selected from hydrogen, C1-6 aliphatic, C1-6 alkoxy, Ci-6 alkylthio, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each Rc is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C alkyl, -0(C\^ alkyl), -S(C1-4 alkyl) or -N(Ci- alkyl)2; and wherein each Rc that is a Q-e aliphatic, C1-6 alkoxy or Ci-6 alkylthio is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6- membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; each R11 is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each Rn is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4 alkyl, -0(C1-4 alkyl), -S(C1-4 alkyl) or -N(Ci-4 alkyl)2; and wherein each R1 1 that is a Ci-6 aliphatic is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; or alternatively, two J groups attached to two vicinal ring C atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein each said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S; and wherein each of said heterocyclic rings is optionally and independently substituted by up to three instances of halogen, C^ alkyl, Ci_4 alkoxy, -CN, -NH2i-OH, -0(CM alkyl), -N(CM alkyl)2 or -S(C1-4 alkyl);
p is an integer selected from the group consisting of 0, 1, 2 and 3; each R1 is independently selected from a hydrogen, C\- aliphatic or Ci-6 haloaliphatic; and R2 is selected from the group consisting of halogen, -N02, -CN and C^ aliphatic; wherein said C1-6 aliphatic is optionally substituted by up to three instances of halogen.
[0007] The invention also relates to pharmaceutical compositions comprising a compound according to Formula A or Formula B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant. Also within the scope of the invention are pharmaceutical compositions, further comprising at least one additional therapeutic agent.
[0008] The invention also relates to methods for the treatment or prevention of pain;
autoimmune disorders; disease-states or indications that are accompanied by inflammatory processes; gastrointestinal diseases or disorders; pruritus; substance abuse-related syndromes, disorders, diseases or withdrawal symptoms; psychiatric disorders; neurological or neurodegenerative disorders; ocular disorders; appetite-related disorders; gynecological disorders, urinary system disorders and sleep disorders; by using one of the compounds or pharmaceutical composition of the invention, either alone or in combination therapy.
DETAILED DESCRIPTION
[0009] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulae. While the invention will be described in conjunction with the disclosed embodiments, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein but include any methods and materials similar or equivalent to those described herein that could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques or the like, this application controls.
Description of Exemplary Compounds:
Definitions and general terminology
[0010] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March 's Advanced Organic Chemistry, 5th Ed., Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, which are herein incorporated by reference in their entirety.
[0011] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term
"substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. If a substituent radical or structure is not identified or defined as "optionally substituted", the substituent radical or structure is not substituted. As it will be apparent to one of ordinary skill in the art, groups such as -H, halogen, -N02, -CN, -OH, -NH2 or -OCF3 would not be substitutable groups.
[0012] The phrase "up to", as used herein, refers to zero or any integer number that is equal to or less than the number following the phrase. For example, optionally substituted with "up to 3" means substituted with 0, 1, 2, or 3 substituents. As described herein, a specified number range of atoms includes any integer therein. For example, a group having from 1-4 atoms could have 1 , 2, 3 or 4 atoms. It will be understood by one of ordinary skill in the art that when a group is characterized as substituted (as opposed to optionally substituted) with, e.g., "up to 3" substituents, it can only be substituted with 1, 2 or 3 substituents.
[0013] When any variable occurs more than one time at any position, its definition on each occurrence is independent from every other occurrence.
[0014] Selection of substituents and combinations envisioned by this disclosure are only those that result in the formation of stable or chemically feasible compounds. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions that allow for their production, detection, and, in some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 25 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
[0015] A compound, such as the compounds of the invention or other compounds herein disclosed may be present in its free form (e.g., an amorphous form or polymorphs). Under certain conditions, compounds may also form salts, and/or other multi-component crystalline forms (e.g., solvates, (e.g., hydrates) and co-crystals). As used herein, the term co-form is synonymous with the term multi-component crystalline form. When one of the components in the co-form has clearly transferred a proton to the other component, the resulting co-form is referred to as a "salt". When both compounds in a multi-component crystalline form are independently solids at room temperature, the resulting co-form is referred to as a "co-crystal". In co-crystals, no proton transfer takes place between the different components of the co-form. The formation of a salt or a co-crystal is determined by how large is the difference in the pKas between the partners that form the mixture. As used herein, a "solvate" refers to an association or complex of one or more solvent molecules and a compound disclosed herein (or its salts or co-crystals). A "hydrate" is a particular type of solvate in which the solvent is water.
Examples of solvents that can form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, tetrahydrofuran (THF), dichloromethane (DCM), and N^V-dimethylformamide (DMF).
[0016] Unless only one of the isomers is drawn or named specifically, structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure, for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers,
diastereomers, and cis-trans isomers (double bond or conformational) of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the disclosure.
[0017] The present disclosure also embraces isotopically-labeled compounds that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, nC, 13C, 14C, 13N, 15N, 150, 170, 180, 32P, 33P, 35S, 18F, 36C1, 123I, and 125I, respectively. Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3H and 1 C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., H) and carbon- 14 (i.e., 14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron-emitting isotopes such as 150, 13N, nC, and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
[0018] The terms "aliphatic" or "aliphatic group", as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms and in yet other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, .fee-butyl, tert-butyl, butenyl, propargyl, acetylene and the like.
[0019] The term "alkyl", as used herein, refers to a saturated linear or branched-chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms or 1-3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.
[0020] The term "alkenyl" refers to a linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond, wherein the alkenyl radical includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Unless otherwise specified, an alkenyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examples include, but are not limited to, vinyl, allyl and the like. [0021] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms).
Examples include, but are not limited to, ethynyl, propynyl, and the like.
[0022] The term "carbocyclic" refers to a ring system formed only by carbon and hydrogen atoms. Unless otherwise specified, throughout this disclosure carbocycle is used as a synonym of "non-aromatic carbocycle" or "cycloaliphatic". In some instances the term can be used in the phrase "aromatic carbocycle", and in this case it refers to an "aryl group" as defined below.
[0023] The term "cycloaliphatic" (or "non-aromatic carbocycle", "non-aromatic carbocyclyl", "non-aromatic carbocyclic") refers to a cyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a cycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused, spiro or bridged. In one embodiment, the term "cycloaliphatic" refers to a monocyclic C3-C12 hydrocarbon or a bicyclic G7-C12
hydrocarbon. In some embodiments, any individual ring in a bicyclic or tricyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
[0024] The term "cycloaliphatic" also includes polycyclic ring systems in which the non- aromatic carbocyclic ring can be "fused" to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, as long as the radical or point of attachment is on the non-aromatic carbocyclic ring.
[0025] The term "heterocycle" (or "heterocyclyl" or "heterocyclic"), as used herein, refers to a ring system in which one or more ring members are an independently selected heteroatom, which is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, through this disclosure, heterocycle is used as a synonym of "non-aromatic heterocycle". In some instances the term can be used in the phrase "aromatic heterocycle", and in this case it refers to a "heteroaryl group" as defined below. The term heterocycle also includes fused, spiro or bridged heterocyclic ring systems. Unless otherwise specified, a heterocycle may be monocyclic, bicyclic or tricyclic. In some embodiments, the heterocycle has 3-18 ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur or nitrogen, and each ring in the system contains 3 to 7 ring members. In other embodiments, a heterocycle may be a monocycle having 3-7 ring members (2-6 carbon atoms and 1—4 heteroatoms) or a bicycle having 7-10 ring members (4-9 carbon atoms and 1-6 heteroatoms). Examples of bicyclic heterocyclic ring systems include, but are not limited to: adamantanyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl.
[0026] As used herein, the term "heterocycle" also includes polycyclic ring systems wherein the heterocyclic ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the heterocyclic ring.
[0027] Examples of heterocyclic rings include, but are not limited to, the following
monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3- thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1- tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4- thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the following bicycles: 3-lH-benzimidazol-2-one, 3-(l-alkyl)-benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro- imidazol-2-one.
[0028] As used herein, the term "aryl" (as in "aryl ring" or "aryl group"), used alone or as part of a larger moiety, as in "aralkyl", "aralkoxy", "aryloxyalkyl", refers to a carbocyclic ring system wherein at least one ring in the system is aromatic and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aryl group may be monocyclic, bicyclic or tricyclic and contain 6-18 ring members. The term also includes polycyclic ring systems where the aryl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the aryl ring. Examples of aryl rings include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl, and anthracenyl. An optionally substituted "aralkyl" can be substituted on both the alkyl and the aryl portion. For instance, unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies, for example, to substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom.
[0029] The term "heteroaryl" (or "heteroaromatic" or "heteroaryl group" or "aromatic heterocycle") used alone or as part of a larger moiety as in "heteroaralkyl" or
"heteroarylalkoxy" refers to a ring system wherein at least one ring in the system is aromatic and contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a heteroaryl ring system may be monocyclic, bicyclic or tricyclic and have a total of five to fourteen ring members. In one embodiment, all rings in a heteroaryl system are aromatic. Also included in this definition are heteroaryl radicals where the heteroaryl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or combinations thereof, as long as the radical or point of attachment is in the heteroaryl ring. A bicyclic 6,5 heteroaromatic system, as used herein, for example, is a six-membered
heteroaromatic ring fused to a second five-membered ring wherein the radical or point of attachment is on the six-membered ring.
[0030] Heteroaryl rings include, but are not limited to the following monocycles: 2-furanyl, 3- furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3- pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2- triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3- oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles:
benzimidazolyl, benzofuryl, benzothiophenyl, benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1 -isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
[0031] As used herein, "cyclo" (or "cyclic", or "cyclic moiety") encompasses mono-, bi- and tri-cyclic ring systems including cycloaliphatic, heterocyclic, aryl or heteroaryl, each of which has been previously defined.
[0032] "Fused" bicyclic ring systems comprise two rings which share two adjoining ring atoms.
[0033] "Bridged" bicyclic ring systems comprise two rings which share three or four adjacent ring atoms. As used herein, the term "bridge" refers to a bond or an atom or a chain of atoms connecting two different parts of a molecule. The two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are referred to as "bridgeheads". Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbomanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa- tricyclo[3.3.1.03,7]nonyl.
[0034] "Spiro" bicyclic ring systems share only one ring atom (usually a quaternary carbon atom).
[0035] The term "ring atom" refers to an atom such as C, N, O or S that is part of the ring of an aromatic group, a cycloaliphatic group or a heteroaryl ring. A "substitutable ring atom" is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term "substitutable ring atom" does not include ring nitrogen or carbon atoms which are shared when two rings are fused. In addition, "substitutable ring atom" does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to one or more moiety other than hydrogen and no hydrogens are available for substitution.
[0036] "Heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quatemized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic or heteroaryl ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl). [0037] In some embodiments, two independent occurrences of a variable may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered,
heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring. Exemplary rings that are formed when two independent occurrences of a substituent are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of a substituent that are bound to the same atom and are taken together with that atom to form a ring, where both occurrences of the substituent are taken together with the atom to which they are bound to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the group is attached to the rest of the molecule by a single point of attachment; and b) two independent occurrences of a substituent that are bound to different atoms and are taken together with both of those atoms to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formed has two points of attachment with the rest of the molecule.
[0038] For example, where a phenyl group is substituted with two occurrences of Ro as in Formula Dl:
Figure imgf000018_0001
Di these two occurrences of Ro are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring as in Formula D2:
Figure imgf000018_0002
D2
[0039] It will be appreciated that a variety of other rings can be formed when two independent occurrences of a substituent are taken together with the atom(s) to which each substituent is bound and that the examples detailed above are not intended to be limiting.
[0040] In some embodiments, an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain can optionally be replaced with said other atom or group. Unless otherwise specified, the optional replacements form a chemically stable compound. Optional interruptions can occur both within the chain and/or at either end of the chain; i.e., both at the point of attachment(s) to the rest of the molecule and/or at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound. Unless otherwise specified, if the replacement or interruption occurs at a terminal end of the chain, the replacement atom is bound to an H on the terminal end. For example, if -CH2CH2CH3 were optionally interrupted with -0-, the resulting compound could be -OCH2CH3, -CH2OCH3, or -CH2CH2OH. In another example, if the divalent linker -CH2CH2CH2- were optionally interrupted with -0-, the resulting compound could be -OCH2CH2-, -CH2OCH2-, or - CH2CH20-. The optional replacements can also completely replace all of the carbon atoms in a chain. For example, a C3 aliphatic can be optionally replaced by -N(R )-, -C(O)-, and -N(R )- to form -N(R$)C(0)N(R$)- (a urea).
[0041] In general, the term "vicinal" refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
[0042] In general, the term "geminal" refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
[0043] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., RxO(0)C-alkyl is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent at the end of the substituent bound to the rest of the chemical structure. Alkylcarboxy (e.g., alkyl-C(0)0- or alkyl-O(CO)-) and alkylcarboxyaryl (e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.
[0044] As described herein, a bond drawn from a substituent to the center of one ring within a multiple-ring system (as shown below), represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system. For example, formula D3 represents possible substitution in any of the positions shown in formula D4:
Figure imgf000020_0001
[0045] This also applies to multiple ring systems fused to optional ring systems (which would be represented by dotted lines). For example, in Formula D5, X is an optional substituent both for ring A and ring B.
Figure imgf000020_0002
[0046] If, however, two rings in a multiple ring system each have different substituents drawn from the center of each ring, then, unless otherwise specified, each substituent only represents substitution on the ring to which it is attached. For example, in Formula D6, Y is an optional substituent for ring A only, and X is an optional substituent for ring B only.
Figure imgf000020_0003
D6
[0047] As used herein, the terms "alkoxy" or "alkylthio" refer to an alkyl group, as previously defined, attached to the molecule, or to another chain or ring, through an oxygen ("alkoxy", e.g., -O-alkyl) or a sulfur ("alkylthio," e.g., -S-alkyl) atom. The terms Cn-m "alkoxyalkyl", Cn-m "alkoxyalkenyl", Cn-m "alkoxyaliphatic", and Cn-m "alkoxyalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups, wherein the total number of carbons between the alky and alkoxy, alkenyl and alkoxy, aliphatic and alkoxy or alkoxy and alkoxy, as the case may be, is between the values of n and m. When these moieties are optionally substituted they can be substituted in either of the portions on both sides of the oxygen or sulfur. For example, an optionally substituted C4 alkoxyalkyl could be, for instance, -CH2CH2OCH2(Me)CH3 or -CH2(OH)0 CH2CH2CH3; a C5 alkoxyalkenyl could be, for instance, =CHCH20 CH2CH2CH3 or =CHCH2 CH2 O CH2CH3. [0048] The terms "aryloxy", "arylthio", "benzyloxy" or "benzylthio", refer to an aryl or benzyl group attached to the molecule, or to another chain or ring, through an oxygen
("aryloxy", "benzyloxy," e.g., -O-Ph, -OCH2Ph) or sulfur ("arylthio," e.g., -S-Ph, -S- CH2Ph) atom. For instance, the terms "aryloxyalkyl", "benzyloxyalkyl" "aryloxyalkenyl" and "aryloxyaliphatic" mean alkyl, alkenyl or aliphatic, as the case may be, substituted with one or more aryloxy or benzyloxy groups, as the case may be. In this case, the number of atoms for each aryl, aryloxy, alkyl, alkenyl or aliphatic will be indicated separately. Thus, a 5-6- membered aryloxyiC alkyl) is a 5-6-membered aryl ring, attached via an oxygen atom to a Cj-4 alkyl chain, which, in turn, is attached to the rest of the molecule via the terminal carbon of the C alkyl chain.
[0049] An optionally substituted "aralkyl" can potentially be substituted on both the alkyl and the aryl portion. Unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies, for example, to a substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom. For example, an optionally substituted 6- membered aryloxy(C3alkyl) group could be, for instance, -(CH3)2CH2- [p-(MeO)-Ph]; an optionally substituted 6-membered heteroaryloxy(C4alkyl) could, for instance, be
-CH2CH2CH2-0-(3-F-2-pyrydyl) or -CH(CH3)-0-CH2CH2-(5,6-dimethyl-l,3-pyrimidine). If the alkyl chain on the "aralkyl" group is also substituted that will be specifically indicated. For instance an optionally substituted 6-membered heteroaryloxy(C4alkyl) that is also optionally substituted on the alkyl, would be referred to as "an optionally substituted 6-membered heteroaryloxy(C4alkyl), wherein said C4 alkyl chain is optionally substituted". An example of this latter group could be 5, 6-dimethyl-l,3-pyrimidine-0-CF(CH3)-CH(OH)CH2-, wherein the alkyl chain is substituted with F and with -OH.
[0050] As used herein, the terms "halogen" or "halo" mean F, CI, Br, or I.
[0051] The terms "haloalkyl", "haloalkenyl", "haloaliphatic", and "haloalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms.
For example, a C1-3 haloalkyl could be -CFHCH2CHF2 and a C1-2 haloalkoxy could be -OC(Br)HCHF2. This term includes perfluorinated alkyl groups, such as -CF3 and -CF2CF3. [0052] As used herein, the term "cyano" refers to -CN or -C≡N.
[0053] The terms "cyanoalkyl", "cyanoalkenyl", "cyanoaliphatic", and "cyanoalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups. For example a C1-3 cyanoalkyl could be -C(CN)2CH2CH3 and a Ci-2 cyanoalkenyl could be =CHC(CN)H2.
[0054] As used herein, an "amino" group refers to -NH2.
[0055] The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic", and "aminoalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups. For example, a C1-3 aminoalkyl could be -CH(NH2)CH2CH2NH2 and a Ci-2 aminoalkoxy could be -OCH2CH2NH2.
[0056] The term "hydroxyl"or "hydroxy" refers to -OH.
[0057] The terms "hydroxyalkyl", "hydroxyalkenyl", "hydroxyaliphatic", and
"hydroxyalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups. For example, a Ci-3 hydroxyalkyl could be -CH2(CH2OH)CH3 and a C4 hydroxyalkoxy could be -OCH2C(CH3)(OH)CH3.
[0058] As used herein, an "aroyl" or "heteroaroyl" refers to a -C(0)-aryl or a -C(O)- heteroaryl. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
[0059] As used herein, a "carbonyl", used alone or in connection with another group refers to -C(O)- or -C(0)H. For example, as used herein, an "alkoxycarbonyl," refers to a group such as -C(0)0(alkyl).
[0060] As used herein, an "oxo" refers to =0, wherein oxo is usually, but not always, attached to a carbon atom. An aliphatic chain can be optionally interrupted by a carbonyl group or can optionally be substituted by an oxo group, and both expressions refer to the same: e.g., -CH2- C(0)-CH3.
[0061] As used herein, in the context of resin chemistry (e.g., using solid resins or soluble resins or beads), the term "linker" refers to a bifunctional chemical moiety attaching a compound to a solid support or soluble support.
[0062] In all other situations, a "linker", as used herein, refers to a divalent group in which the two free valences are on different atoms (e.g., carbon or heteroatom) or are on the same atom but can be substituted by two different substituents. For example, a methylene group can be a Ci alkyl linker (-CH2-), which can be substituted by two different groups, one for each of the free valences (e.g., as in Ph-CH2-Ph, wherein methylene acts as a linker between two phenyl rings). Ethylene can be a C2 alkyl linker (-CH2CH2-) wherein the two free valences are on different atoms. The amide group, for example, can act as a linker when placed in an internal position of a chain (e.g., -CONH- ). A linker can be the result of interrupting an aliphatic chain by certain functional groups or of replacing methylene units on said chain by said functional groups. E.g., a linker can be a C1-6 aliphatic chain in which up to two methylene units are substituted by -C(O)- or -NH- (as in -CH2-NH-CH2-C(0)-CH2- or - CH2-NH-C(0)- CH2-). An alternative way to define the same -CH2-NH-CH2-C(0)-CH2- and - CH2-NH- C(0)-CH2- groups is as a C3 alkyl chain optionally interrupted by up to two -C(O) - or -NH- moieties. Cyclic groups can also form linkers: e.g., a 1,6-cyclohexanediyl can be a linker between two R groups, as in
Figure imgf000023_0001
[0063] Divalent groups of the type =CH-R or =C-R2, wherein both free valences are in the same atom and are attached the same substituent, are also possible. In this case, they will be referred to by their IUPAC accepted names. For instance, an alkylidene (such as, for example, a methylidene (=CH2) or an ethylidene (=CH-CH3)) would not be encompassed by the definition of a linker in this disclosure.
[0064] The term "protecting group", as used herein, refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In certain
embodiments, a protecting group has one or more, or preferably all, of the following characteristics: a) reacts selectively in good yield to give a protected substrate that is stable to the reactions occurring at one or more of the other reactive sites; and b) is selectively removable in good yield by reagents that do not attack the regenerated functional group.
Exemplary protecting groups are detailed in Greene, T. W., Wuts, P. G in Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference. The term "nitrogen protecting group", as used herein, refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the
characteristics exemplified above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
[0065] As used herein, the term "displaceable moiety" or "leaving group" refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.
[0066] As used herein, "amide coupling agent" or "amide coupling reagent" means a compound that reacts with the hydroxyl moiety of a carboxy moiety thereby rendering it susceptible to nucleophilic attack. Exemplary amide coupling agents include DIC
(diisopropylcarbodiimide), EDCI (l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (dicyclohexylcarbodiimide), BOP (Benzotriazol- 1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate), pyBOP ((Benzotriazol- 1 -yloxy)tripyrrolidinophosphonium
Hexafiuorophosphate), etc.
[0067] The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
Compound embodiments:
[0068] In one aspect, the invention relates to a compound of Formula A, or a pharmaceutically acceptable salt thereof,
Figure imgf000025_0001
Formula A
wherein:
ring A is selected from the group consisting of phenyl and a 6-membered monocyclic
heteroaryl ring; wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms;
each JA is independently selected from the group consisting of halogen, -N02, -CN, -R4, -C(0)RA, -C(S)RA, -C(0)ORA , -OC(0)RA, -N(RA)S(0)2RA, -N(RA)C(0)RA, -N(RA)C(S)RA, -ORA, -SRA, -S(0)RA, -S(0)2RA , -S(0)2N(RA)2 , -C(0)N(RA)2 and -N(RA)2 ; wherein, optionally, two RA groups attached to the same N atom, together with said N, form a 5- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from O or N;
each RA is independently selected from hydrogen, Ci-6 aliphatic, Ci-6 alkoxy, C1-6 alkylthio, a C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each RA is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4alkyl, -0(C1-4alkyl), -S(C alkyl), -N(C1-4alkyl)2, C haloalkyl or C haloalkoxy; and wherein each of said RA that is a Ci-6 aliphatic, C1-6 alkoxy or Ci-6 alkylthio is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heterocyclic; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; each R is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C alkyl, -0(Ci-4 alkyl), -S(C1-4 alkyl) or -N(C!-4 alkyl)2; and wherein each R4 that is a Ci-6 aliphatic is optionally substituted by one instance of a C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy, C3-6
halocycloalkoxy, phenyl, 3- to 6-membered heterocyclic or 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl rings contain up to 3 heteroatoms independently selected from N, O or S; or
alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring
atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two heteroatoms selected from N, O or S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, -CN, -NH2, -OH, CM alkyl, C1-4haloalkyl-0(C alkyl), -N(Ci^ alkyl)2 or -S(C1-4 alkyl); n is an integer selected from the group consisting of 0, 1, 2 and 3;
ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
heteroatoms selected from the group consisting of N, O and S;
each JB is independently selected from the group consisting of halogen, -N02, -CN, -OH, d-6 aliphatic, C3-6 cycloaliphatic, C1-6 haloaliphatic, C1-6 alkoxy, Ci-6haloalkoxy and C3- 6 cycloalkoxy;
m is an integer selected from the group consisting of 0, 1, 2 and 3;
ring C is a 5-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
each J is independently selected from the group consisting of halogen, -N02, -CN, -R , -C(0)Rc, -C(S)RC, -C(0)ORc , -OC(0)Rc, -N(Rc)C(0)Rc, -N(RC)C(S)RC, -ORc, -SRC, -S(0)Rc, -S(0)2Rc , -N(Rc)S(0)2Rc, -S(0)2N(Rc)2 , -C(0)N(Rc)2 and -N(RC)2; each R is independently selected from hydrogen, C1- aliphatic, C1-6 alkoxy, C e alkylthio,
C3-6 cycloaliphatic, C3- cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each Rc is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C alkyl, -0(C alkyl) or -N(C1- alkyl)2; and wherein, when Rc is a C1-6 aliphatic, C1-6 alkoxy or Ci-6 alkylthio, it is optionally substituted by one instance of C3-6 cycloalkyl, C3-6halocycloalkyl, C3-6 cycloalkoxy or C3-6 halocycloalkoxy;
each R is independently selected from C1-6 aliphatic, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, 3- to 6-membered heterocyclic or 5- to 6-memebered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4 alkyl, -0(C1-4 alkyl), -S(Ci4 alkyl) or -N(Ci-4 alkyl)2; and wherein, when R8 is a Ci-6 aliphatic, it is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy or C3-6
halocycloalkoxy; or
alternatively, two Jc groups attached to two vicinal ring C atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to three ring heteroatoms selected from the group consisting of N, O and S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, C alkoxy, -CN, -NH2, -OH, -0(C1-4 alkyl), -N(CM alkyl)2 or -S(CM alkyl);
p is an integer selected from the group consisting of 0, 1, 2 and 3;
each R1 is independently selected from hydrogen, C\- aliphatic or C1-6 haloaliphatic; and
R2 is selected from the group consisting of halogen, -CN or C1jS aliphatic; wherein said C1-6 aliphatic is independently and optionally substituted by up to three instances of halogen, -CN, -NH2,-OH or -0(ClA alkyl).
[0069] In some embodiments of Formula A, ring B is a 6-membered heteroaryl or phenyl; wherein said heteroaryl contains up to two ring nitrogen atoms.
[0070] In some embodiments of Formula A, each JB is independently selected from the group consisting of halogen, C1-4 alkyl, cyclopropyl, cyclopropyloxy, Q-4 haloalkyl, C1-4 alkoxy and C 4 haloalkoxy. In other embodiments, each JB is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propyloxy and isopropyloxy. In still other embodiments, each J is independently selected from the group consisting of bromo, chloro, fluoro, methyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy.
[0071] In some embodiments, compounds of the invention are represented by Formula A-1, or are pharmaceutically acceptable salts thereof:
Figure imgf000028_0001
Formula A-1
wherein m is 0 or 1.
[0072] In some embodiments, compounds of the invention are represented by Formula A-2, or are pharmaceutically acceptable salts thereof:
Figure imgf000028_0002
[0073] In some embodiments of compounds of Formulae A, A-1 and A-2, each R1 is independently selected from the group consisting of hydrogen and C -4 alkyl. In other embodiments, each R1 is hydrogen.
[0074] In some embodiments of compounds of Formulae A, A-1 and A-2, R2 is selected from the group consisting of halogen, -CN, Cuhaloalkyl and CM alkyl. In other embodiments, R2 is methyl.
[0075] In some embodiments, compounds of the invention are represented by Formula A-3, or are pharmaceutically acceptable salts thereof:
Figure imgf000029_0001
Formula A-3
wherein up to two of variables X\, X2, X3 and X4 in ring A are N and the remaining variables are C; and wherein n is 0, 1 or 2.
[0076] In some embodiments of Formula A-3, ring A is selected from the group consisting of
Figure imgf000029_0002
[0077] In some embodiments of the compounds of Formulae A, A-l, A-2 and A-3, each JA is independently selected from the group consisting of halogen, -CN, -N¾, -OH, CM alkyl, C1-4 alkenyl, -NH(Ci-4 alkyl), -N(CM alkylfe, -NHC(0)(C1-4 alkyl), -NHS(0)2(C1-4 alkyl), -C(0)0(C alkyl), -OC(0)(C alkyl), -C(0)(C alkyl), -0(C1-4 alkyl), -C(S)(C1-4 alkyl), -NHC(S)(C alkyl) , -S(CM alkyl), -S(0)(C1-4 alkyl), -S(0)2(CM alkyl), -S(0)2N(C1-4 alkyl)2, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each said C alkyl is independently and optionally substituted by up to three instances of halogen, hydroxy or C1-4 alkoxy; or, alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two heteroatoms selected from N or O; wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen or C1-4 alkyl. In other embodiments, each JA is independently selected from the group consisting of halogen, -CN, -NH2, -OH, methyl, ethyl, isopropyl, -CH=CH2, -OCF3, -CF3, -C(0)OMe, -C(0)Me, -OCH3, -CH2OH, -CH2OMe, -OC(0)Me, -NHC(0)Me, -NHC(S)Me, -SMe, -S(0)2Me, -NHS(0)2Me and -S(0)2N(Me)2. In still other embodiments, each JA is independently selected from the group consisting of bromo, chloro, fluoro, -CN, -NH2, -OH, methyl, ethyl, -CH=CH2, -C(0)OMe, -C(0)Me, -OCH3, -CH2OH, -CH2OMe, -OC(0)Me, -NHC(0)Me, -SMe, -NHS(0)2Me and -S(0)2N(Me)2. In further embodiments, each JA is independently selected from the group consisting of morpholine, pyrrolidine, piperidine, thiophene, thiazole, thiadiazole,oxazole and oxadiazole. In yet further embodiments, each JA is independently selected from the group consisting of:
Figure imgf000030_0001
[0078] Alternatively in other embodiments of Formulae A, A-l, A-2 and A-3, two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two ring oxygen atoms, and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen or C alkyl. In further embodiments, two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring, wherein said heterocyclic ring is selected from the group consisting of:
Figure imgf000030_0002
wherein each R is independently selected from the group consisting of halogen and C1-4 alkyl; and wherein the variable o is an integer selected from the group consisting of 0, 1 and 2. In other embodiments, each R17 is independently selected from the group consisting of fluoro, chloro and methyl. In still other embodiments, the variable o is 0.
[0079] In other embodiments, the compounds of the invention are represented by Formula A-4, or are pharmaceutically acceptable salts thereof:
Figure imgf000031_0001
Formula A-4
wherein each of the variables Qls Q2, Q3 and Q4 is independently selected from C, N, O or
[0080] In other embodiments, compounds of the invention are represented by Formula A-5, are pharmaceutically acceptable salts thereof:
Figure imgf000031_0002
Formula A-:
wherein up to two of the variables Qi, Q2 and Q3 are N and the rest are C.
[0081] In still other embodiments, compounds of Formula A-5 are represented by Formula A-6, or are pharmaceutically acceptable salts thereof:
Figure imgf000031_0003
(JC)p-1
Formula A-6
wherein up to two of Q2 and Q3 are N and the rest are C. [0082] In some embodiments of Formula A-6, the moiety -(CH2)-Ring C is selected from the group consisting of:
Figure imgf000032_0001
[0083] In some embodiments of the compounds of Formulae A-4, A-5 and A-6, p is 1 or 2.
[0084] In some embodiments, the compounds of Formulae A-4, A-5 and A-6 are represented by Formula A-7, or are pharmaceutically acceptable salts thereof:
Figure imgf000032_0002
Formula A-7
[0085] In some embodiments of the compounds of Formulae A, A-1, A-2, A-3, A-4, A-5, A-6 and A-7, JC is halogen, C alkyl or C^ alkoxy. In other embodiments, JC is halogen, methyl, ethyl, methoxy or ethoxy. In still other embodiments, Jc is chloro, fluoro, methyl or methoxy.
[0086] In further embodiments, the moiety represented by
Figure imgf000032_0003
is selected from the group consisting of:
Figure imgf000032_0004
Figure imgf000032_0005
[0087] In some embodiments, the compounds of the invention are selected from the group consisting of:
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Formula B
wherein:
ring A is selected from the group consisting of phenyl and a 6-membered monocyclic
heteroaryl ring; wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms;
each JA is independently selected from the group consisting of-R4, -C(0)OR5, -C(S)RA, -N(RA)C(0)RA, -N(RA)C(S)RA, -SRA, -S(0)RA, -S(0)2RA , -N(RA)S(0)2RA and -S(0)2N(RA)2;
each RA is independently selected from hydrogen, Ci-6 aliphatic, C1-6 alkoxy, Ci-6 alkylthio, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each RA is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, CM alkyl, -0(C1-4 alkyl), -S(C1-4 alkyl) or -N(CM alkyl)2; and wherein each RA that is a C1-6 aliphatic, Ci-6 alkoxy or C1-6 alkylthio is optionally substituted by one instance of C3-6 cycloalkyl, C3- halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S;
each R4 is independently selected from C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, Ci^ alkoxyl, -0(C alkyl), -S(C1-4 alkyl) or-N(C1-4 alkyl)2,;
each R5 is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, phenyl, 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R5 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4 alkyl, C haloalkylj-OtC alkyl), -S(Ci-4 alkyl) or-N(CM alkyl)2; and wherein each R5 that is a C1-6 aliphatic is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; or
alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring
atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S, and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, Ci-4 alkoxy, -CN, -NH2,-OH, -0(C1-4 alkyl), -N(CM alkyl)2 or -S(C1-4 alkyl);
n is an integer selected from the group consisting of 1, 2 and 3;
ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
heteroatoms selected from the group consisting of N, O and S; m is an integer selected from the group consisting of 0, 1, 2 and 3;
each JB is independently selected from the group consisting of halogen, -N02, -CN, -OH, Ct-6 aliphatic, C3-6 cycloaliphatic, Ci- haloaliphatic, C1-6 alkoxy, d^ haloalkoxy and C3- 6 cycloalkoxy;
ring C is selected from the group consisting of phenyl, C3-6 cycloalkyl, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S; each Jc is independently selected from the group consisting of halogen, -N02, -OH, -CN, -R11, -C(0)Rc, -C(S)RC, -C(0)ORc , -OC(0)Rc, -N(Rc)C(0)Rc, -N(RC)C(S)RC, -ORc, -SRC, -S(0)Rc, -S(0)2Rc , -N(Rc)S(0)2Rc, -S(0)2N(Rc)2 , -C(0)N(Rc)2 and -N(RC)2 ;
each R is independently selected from hydrogen, C1-6 aliphatic, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C alkyl, -0(Ci-4 alkyl), -S(CM alkyl) or -N(C1-4 alkyl)2; and wherein each R that is a C1-6 aliphatic, C1-6 alkoxy or Ci-6 alkylthio is optionally substituted by one instance of C3- cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6- membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S;
each R11 is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, Oor S; wherein each R11 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, CM alkyl, -0(C alkyl), -S(C alkyl) or -N(Ci-4 alkyl)2; and wherein each R11 that is a 01-6 aliphatic is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; or
alternatively, two Jc groups attached to two vicinal ring C atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein each said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S; and wherein each of said heterocyclic rings is optionally and independently substituted by up to three instances of halogen, C1-4 alkyl, C1-4 alkoxy, -CN, -NH2,-OH, -0(C1-4alkyl), -N(CM alkyl)2 or -S(CM alkyl);
p is an integer selected from the group consisting of 0, 1, 2 and 3; and each R is independently selected from a hydrogen, Ci-6 aliphatic or Ci-6 haloaliphatic; and R2 is selected from the group consisting of halogen, -N02, -CN and C\* aliphatic;
wherein said C1-6 aliphatic is optionally substituted by up to three instances of halogen.
[0089] In some embodiments of Formula B, Ring B is a 6-membered heteroaryl or phenyl; wherein said heteroaryl contains up to two ring nitrogen atoms.
[0090] In some embodiments of Formula B, each JB is independently selected from the group consisting of halogen, C1-4 alkyl, cyclopropyl, cyclopropyloxy, Cr4 haloalkyl, Ci-4 alkoxy and Ci-4 haloalkoxy. In other embodiments, each JB is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,
fluoromethoxyl, difluoromethoxy, trifluoromethoxy, ethoxy, propyloxy and isopropyloxy. In still other embodiments, JB is independently selected from the group consisting of bromo, chloro, fluoro, methyl, ethoxy, trifluoromethyl, trifluoromethoxy and methoxy.
[0091] In one embodiment, the compounds of Formula B are represented by Formula B-1, or are pharmaceutically acceptable salts thereof:
Figure imgf000038_0001
Formula B-1
wherein m is 0 or 1.
[0092] In some embodiments, the compounds of Formulae B and B-1 are represented by Formula B-2, or are pharmaceutically acceptable salts thereof:
Figure imgf000039_0001
Formula B-2
[0093] In some embodiments of Formulae B, B-1 and B-2, each R1 is independently selected from the group consisting of hydrogen and Ci-4 alkyl. In other embodiments, each R1 is hydrogen.
[0094] In some embodiments of Formulae B, B-1 and B-2, R is selected from the group consisting of halogen, -CN, C^haloalkyl and Ο alkyl. In other embodiments R is methyl.
[0095] In some embodiments of compounds of Formulae B, B-1 and B-2, ring C is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl; wherein said 5- to 6- membered heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S. In other embodiments, ring C is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiophene, thiazole, thiadiazole, oxazole, oxadiazole, pyrazole and imidazole. In still other embodiments, ring C is selected from the group consisting of:
Figure imgf000039_0002
[0096] In further embodiments, ring C is selected from the group consisting of:
Figure imgf000039_0003
[0097] In yet further embodiments, p is 0, 1 or 2.
e embodiments of Formulae B, B-1 or B-2, each group represented by
Figure imgf000040_0001
is independently selected from the group consisting of:
Figure imgf000040_0002
[0099] In some embodiments, each J is independently selected from the group consisting of halogen, CM haloalkyl, C alkyl and C alkoxy. In other embodiments, each Jc is independently selected from the group consisting of fluoro, chloro, trifluoromethyl, methyl and methoxy.
[00100] In some embodiments, the compounds of Formulae B, B-1 and B-2 are represented by Formula B-3, or are pharmaceutically acceptable salts thereof:
Figure imgf000040_0003
Formula B-3
wherein up to two of the variables Xl5 X2, X3 and X4 are N and the rest are C. [00101] In some embodiments of the compounds of Formulae B, B-l , B-2 and B-3, n is 1 or 2.
[00102] In some embodiments of the compounds of Formulae B, B-l, B-2 and B-3, each JA is independently selected from the group consisting of -C(0)0(C1-4 alkyl), -C(S)(Ci-4 alkyl), -NHC(0)(C alkyl), -NHC(S)(C alkyl), -S(Ci-4 alkyl), -S(0)(C alkyl),
-S(0)2(C alkyl), -NHS(0)2(CM alkyl), -S(0)2N(CM alkyl)2, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl;
wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms
independently selected from N, O or S; wherein each said C alkyl is optionally and
independently substituted by up to three instances of halogen, hydroxy or C alkoxy; or, alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S; wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, C1-4 alkoxy, -CN, -NH2,-OH, -0(CM alkyl), -N(C1-4 alkyl)2 or -S(CM alkyl). In other
embodiments, each JA is independently selected from the group consisting of -C(0)OMe, -C(S)Me, -NHC(0)Me, -NHC(S)Me, -SMe, -S(0)Me, -S(0)2Me, -NHS(0)2Me and
-S(0)2N(Me)2. In still other embodiments, each JA is independently selected from the group consisting of-C(C-)OMe, -C(0)Me, -SMe, -S(0)2Me and -NHS(0)2Me. In further embodiments each JA is independently selected from the group consisting of cyclopropyl, morpholine, pyrrolidine, piperidine, thiophene, thiazole and thiadiazole. In yet further embodiments each JA is independently selected from the group consisting of:
Figure imgf000041_0001
[00103] Alternatively, in other embodiments, two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two oxygen atoms, and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, CM alkoxy, -CN, -NH2,-OH, -0(C1-4 alkyl), -N(C1-4 alkyl)2 or -S(CM alkyl). In still other embodiments, two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring, wherein said heterocyclic ring is selected from the group consisting of:
Figure imgf000042_0001
wherein each R is independently selected from the group consisting of halogen and C
alkyl; and wherein the variable o is an integer selected from the group consisting of 0, 1 and 2. In further embodiments each R17 is independently selected from the group consisting of fluoro, chloro and methyl. In yet further embodiments, the variable o is 0.
[00104] In some embodiments, the compounds of Formulae B, B-l, B-2 and B-3 are represented by any one of Formulae B-4 to B-19, or are pharmaceutically acceptable salts thereof:
Figure imgf000043_0001
42
Figure imgf000044_0001
Formula B-16 Formula B-17 Formula B-18
Figure imgf000044_0002
Formula B-19.
[00105] In other embodiments, at least one of the variables Xi, X3 and X4 is N and the rest are C. In still other embodiments n is 1.
[00106] In some embodiments, the compounds of Formulae B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18 and B-19 are represented by any one of Formulae B-20 to B-35, or are pharmaceutically acceptable salts thereof:
Figure imgf000045_0001
Formula B-20 Formula B-21 Formula B-22
Figure imgf000045_0002
Formula B-30 Formula B-31
Formula B-29
Figure imgf000046_0001
Formula B-32 Formula B-33 Formula B-34
Figure imgf000046_0002
Formula B-35.
[00107] In some embodiments, the compounds of the invention are selected from the group consisting of:
Figure imgf000047_0001
Methods of preparing the compounds:
[00108] The compounds of Formula A and Formula B may be prepared according to the schemes and examples depicted and described below. Unless otherwise specified, the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds or prepared using well-known synthetic methods.
General Synthetic methods and General Synthetic Schemes
[00109] General synthetic procedures for the compounds of this invention are described below. The synthetic schemes are presented as examples and do not limit the scope of the invention in any way. GENERAL SYNTHETIC ROUTES AND PROCEDURES General Route 1 (contains general procedures A, B, C and D)
Figure imgf000048_0001
Formation of indole 3-ketoester (General Procedure A)
[00110] To a 0 °C solution of the appropriate indole (1.0 equiv) in dichloromethane (0.1M) was added neat oxalyl dichloride (2.0 equiv). The reaction was stirred at 0 °C for 20 minutes, after which LCMS of the methanolysis product indicated complete conversion to the acid chloride (by presence of methyl ketoester). The reaction was concentrated to dryness, reconstituted in dichloromethane (0.1M), cooled to 0 °C and then treated with excess methanol (10-30 equiv). The product was isolated via filtration of the observed precipitate or extracted with ethyl acetate (3x), dried (sodium sulfate), filtered and concentrated to afford the corresponding ketoester as a solid.
N-alkylation of indole 3-ketoester (General Procedure B)
[00111] A slurry of the indole 3-ketoester (1.0 equiv), appropriate benzyl bromide or chloride (1.1 equiv), potassium iodide (0.05 equiv) and potassium carbonate (1.3 equiv) was heated at 65 °C in either NN-dimethylformamide or acetonitrile (0.1-0.2M) until LCMS analysis indicated completion of the reaction (2-5 hours). The reaction mixture was cooled to room temperature, diluted in water, extracted with ethyl acetate (3x), dried (sodium sulfate), filtered and concentrated to a residue. Purification was achieved by silica gel chromatography using ethyl acetate in hexanes to afford the desired alkylation product.
Saponification of indole 3- ketoester (General Procedure C)
[00112] To a 0 °C solution of the N-alkylated indole 3-ketoester in 3 : 1 : 1
THF:methanol: water (0.1M) was added solid lithium hydroxide monohydrate (1.5 equiv). The reaction was monitored by LCMS analysis until completion (0.2-3 hours) after which the solvent was removed in vacuo and the resulting residue was diluted in water. This solution was washed with ethyl acetate (l-3x), and the aqueous layer was acidified with 3M aqueous hydrochloric acid solution (1.5 equiv), back-extracted with ethyl acetate (3x), dried (sodium sulfate), filtered and concentrated to afford desired N-alkylated ketoacid as a solid. This material was used in the next step without further purification.
1-propanephosphonic acid anhydride cyclic trimer (T3P)-mediated ketoamide coupling (General Procedure D)
[00113] To a room temperature solution of N-alkylated indole-3 -ketoacid (1.0 equiv) in acetonitrile or DMF (0.1-0.2 M) was successively added triethylamine (5.0 equiv), 2- methoxypyridin-4-amine (1.2 equiv), and a 50% ethyl acetate solution of 1-propanephosphonic acid anhydride cyclic trimer (T3P) (3.0 equiv). The reaction was stirred at room temperature or heated to 60 °C while monitoring the reaction for completeness (1-12 hours). The reaction was diluted in brine, extracted with ethyl acetate (3x), dried (sodium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography using ethyl acetate in hexanes or a 7:1 solution of acetonitrile/methanol in dichloromethane. The desired N- alkylated 3 -ketoamide was isolated as a solid.
General Route 2 (contains general procedures E, F, C and D)
Figure imgf000050_0001
N-Alkylation of azaindole core (General Procedure £)
[00114] To a 0 °C solution of the appropriate azaindole (1.0 equiv) in DMSO or DMF (0.2-0.3 M) was added powdered potassium hydroxide (2.0 equiv). The reaction was warmed to room temperature and stirred for one hour after which the appropriate benzyl bromide or chloride (1.1 equiv) was added. The mixture was monitored by LCMS analysis until completion (1-4 hours), after which the reaction mixture was diluted in water, extracted with ethyl acetate (3x), dried (sodium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography using ethyl acetate in hexanes to afford the desired N-alkylated azaindole.
Friedel-Crafts Acylation of N-alkylated azaindole (General Procedure F)
[00115] To a stirred suspension of aluminum trichloride (3.0 equiv) in dichloromethane (0.1M) at 0 °C was added a solution of N-alkylated azaindole (1.0 equiv) in dichloromethane (0.1M). The reaction mixture was warmed to room temperature and stirred for one hour, after which methyl 2-chloro-2-oxoacetate (3.0 equiv) was added. The resulting solution or suspension (for cases of non-homogeneous reactions, 1-2 mL of acetonitrile was added to solubilize the reaction mixture) was stirred at room temperature with LCMS monitoring until completion or the reaction was achieved (1-12 hours). The reaction was then poured into ice- water, extracted with dichloromethane (3x), dried (sodium sulfate), and concentrated. The material was either used crude or purified using silica gel chromatography using ethyl acetate in hexanes to afford the desired N-alkylated azaindole 3-ketoester (In certain cases, the acid is the major product observed with only a trace of the ester product present).
General Route 3 (contains general procedures E and G)
Figure imgf000051_0001
Direct formation of N-alkylated indole-3 ketoamide (General Procedure G):
[00116] To a cooled (-78 °C or 0 °C) solution of the appropriate indole (1.0 equiv) in dichloromethane (0.05-0.1 M) was added oxalyl chloride (1-2 equiv). The reaction progress was monitored by LCMS (methanol as solvent for aliquot) indicating the presence of a ketoacid chloride intermediate. The reaction was concentrated to dryness, reconstituted in
dichloromethane (0.05-0.1 M), and cooled to 0 °C. To this cooled mixture was successively added 2-methoxypyridin-4-amine (1.0 equiv), followed by triethylamine (2.0 equiv). The reaction progress was monitored by LCMS for completion (30-60 minutes), after which the reaction was diluted in water and extracted with dichloromethane (3x), dried (sodium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography using ethyl acetate in hexanes to afford the desired N-alkylated indole-3 -ketoamide product as a solid. General Route 4, Indole/ Azaindole core constructions (contains general procedures and M):
Figure imgf000052_0001
Aryl hydrazine formation (General Procedure H)
[00117] A solution of the aniline (1.0 equiv) in concentrated hydrochloric acid (2.0- 3.0M) was stirred at room temperature for 2 hours, after which the mixture was cooled to 0 °C. A solution of sodium nitrite (1.1-1.2 equiv) in water (4M) was added dropwise over 45 minutes, while maintaining an internal temperature of <5 °C. After an additional hour of stirring at 0 °C, a solution of tin (II) dichloride dihydrate (4.2 equiv) in concentrated hydrochloric acid (~6M) was added. The reaction was allowed to stir and was warmed up to room temperature, then stored at 5 °C overnight (12 hours). The resulting precipitate was filtered, washed with water (2x), then ethanol (3x) and dried thoroughly to the desired arylhydrazine hydrochloride salt.
Indole cyclization (General Procedure M)
[00118] A suspension of the arylhydrazine hydchloride (1.4 equiv) and thiophenyl acetone (1.0 equiv) in tert-butanol or isobutyl alcohol (0.5M) was heated to 90 °C for 1 hour.
The reaction mixture was then cooled to room temperature, filtered through celite, diluted with ethyl acetate and successively washed with water (2 x 50 mL) and saturated sodium chloride solution (2 x 50 mL), dried (sodium sulfate), filtered and concentrated . Purification was achieved by silica gel chromatography using ethyl acetate in hexanes to afford the appropriate indole 3-thiophenyl product.
Desulfurization of 3-thiophenyl indole derivatives (General Procedure J)
[00119] A slurry of the 3-thiophenyl indole (1.0 equiv)and 2-mercaptobenzoic acid (2.0 equiv) and in trifluoroacetic acid (0.1-0.2 M) was stirred at room temperature for 30 minutes, after which the trifluoroacetic acid was removed by rotary evaporation. The remaining residue was taken up in ethyl acetate and washed with IN sodium hydroxide solution (2x), washed with water (3x), dried (sodium sulfate), filtered and concentrated. Purification was achieved by silica gel column chromatography using ethyl acetate in hexanes to afford the desired indole as a solid.
Desulfurization of 3-thiophenyl indole derivatives (General Procedure K)
[00120] To a solution of the 3-thiophenyl indole (1.0 equiv) in ethanol (0.1M) was added a suspension of Raney Nickel in water (20-30 equiv). The suspension was heated to 90 °C while monitoring by LCMS for completion of reaction (1-5 hours), after which the reaction was cooled to room temperature, filtered through celite, washed with ethyl acetate (3 x 50 mL), and concentrated. Purification was achieved by silica gel chromatography using ethyl acetate in hexanes to afford the desired indole as a solid.
Pharmaceutically acceptable salts:
[00121] The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of Formula A or Formula B. For use in medicine, the salts of the compounds of Formula A or Formula B will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of Formula A or Formula B or of their pharmaceutically acceptable salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure.
Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
[00122] Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments the salts can be prepared from the free form of the compound in a separate synthetic step.
[00123] When the compound of Formula A or Formula B is acidic or contains a sufficiently acidic bioisostere, suitable pharmaceutically acceptable salts are salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
[00124] When the compound of Formula A or Formula B is basic or contains a sufficiently basic bioisostere, salts may be prepared from pharmaceutically acceptable nontoxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,r-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
[00125] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al.,
"Pharmaceutical Salts," J. Pharm. Sc , 1977:66:1-19, incorporated herein by reference in its entirety.
Pharmaceutical compositions and methods of administration:
[00126] The compounds disclosed herein, and their pharmaceutically acceptable salts thereof, may be formulated as pharmaceutical compositions or "formulations".
[00127] In another aspect, the invention comprises a pharmaceutical composition comprising a compound as discussed above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant. In a further embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent. In other embodiments, the pharmaceutical composition further comprises an additional therapeutic agent which is chosen from the group consisting of painkillers, non-steroidal anti-inflammatory drugs (NSAIDs), cannabinoid receptor agonists, opiate receptor agonists, anti-infective agents, sodium channel blockers, N-type calcium channel blockers, local anesthetics, VRl agonists and antagonists, agents used for migraines, topical agents used in the treatment of localized pruritus, anti-inflammatory and/or immunosuppressive agents, agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists and nicotine replacement therapies), ADD/ ADHD agents, agents to treat alcoholism, such as opioid antagonists, agents for reducing alcohol withdrawal symptoms such as benzodiazepines and beta-blockers, antihypertensive agents such as ACE inhibitors and Angiotensin II Receptor blockers, Renin inhibitors, vasodilators, agents used to treat glaucoma such as direct-acting Miotics (cholinergic agonists), indirect-acting
Miotics (cholinesterase inhibitors), Carbonic anhydrase inhibitors, selective adrenergic agonists, Osmotic diuretics, antidepressants such as SSRIs, tricyclic antidepressants, and dopaminergic antidepressants, cognitive improvement agents, acetylcholinesterase inhibitors, anti-emetic agents (e.g., 5HT3 antagonists), neuroprotective agents, neuroprotective agents currently under investigation, antipsychotic medications, agents used for multiple sclerosis, disease-modifying anti-rheumatic drugs (DMARDS), biological response modifiers (BRMs),
COX-2 selective inhibitors, COX-1 inhibitors, immunosuppressives, PDE4 inhibitors, corticosteroids, histamine HI receptor antagonists, histamine H2 receptor antagonists, proton pump inhibitors, leukotriene antagonists, 5-lipoxygenase inhibitors, nicotinic acetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonists and antagonists, NK1 and NK2 antagonists, NMDA antagonists, potassium channel modulators, GABA modulators, anticancer agents such as tyrosine kinase inhibitors, anti-hyperlipidemia drugs, appetite
suppressing agents, anti-diabetic medications such as insulin, GI (gastrointestinal) agents, and serotonergic and noradrenergic modulators.
[00128] A typical formulation is prepared by mixing a compound of Formula A or Formula B, or a pharmaceutically acceptable salt thereof, and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of Formula A or Formula B is being formulated. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (e.g., GRAS— Generally Regarded as Safe) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc., and mixtures thereof. The formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of Formula A or Formula B or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
[00129] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (e.g., a compound of Formula A or Formula B, a pharmaceutically acceptable salt thereof) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. A compound having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
[00130] The compound of Formula A or Formula B or a pharmaceutically acceptable salt thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen. Pharmaceutical formulations of compounds of Formula A or Formula B, or a pharmaceutically acceptable salt thereof, may be prepared for various routes and types of administration.
Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition (weigh weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur. As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered will be in the range of about 0.01-100 mg/kg per dose, namely about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
[00131] The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The therapeutically or pharmaceutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms. [00132] The pharmaceutical compositions of Formula A or Formula B will be formulated, dosed, and administered in a fashion, i.e., in amounts, concentrations, schedules, courses, vehicles, and route(s) of administration consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular human or other mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.
[00133] The term "prophylactically effective amount" refers to an amount effective in preventing or substantially lessening the chances of acquiring a disease or disorder or in reducing the severity of the disease or disorder or one or more of its symptoms before it is acquired or before the symptoms develop. Roughly, prophylactic measures are divided between primary prophylaxis (to prevent the development of a disease) and secondary prophylaxis (whereby the disease has already developed and the patient is protected against worsening of its severity).
[00134] Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and
methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;
cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in
Remington's: The Science and Practice of Pharmacy, 21st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter "Remington's").
[00135] "Controlled drug delivery systems" supply the drug to the body in a manner precisely controlled to suit the drug and the conditions being treated. The primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time. The term "controlled release" is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release", "delayed release", "modified release" or "sustained release".
[00136] "Sustained-release preparations" are the most common applications of controlled release. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, wherein the matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid- glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.
[00137] "Immediate-release preparations" may also be prepared. The objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.
[00138] Implantable devices coated with a compound of this invention are another embodiment of the present invention. The compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot", thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled-release characteristics in the composition.
[00139] The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and
formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
[00140] The terms "administer", "administering" or "administration" in reference to a compound, composition or formulation of the invention mean introducing the compound into the system of the animal in need of treatment. When a compound of the invention is provided in combination with one or more other active agents, "administration" and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.
[00141] The compositions described herein may be administered systemically or locally, e.g.: orally (e.g., using capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like), by inhalation (e.g., with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g., using ear drops), topically (e.g., using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc), ophthalmically (e.g., with eye drops, ophthalmic gels, ophthalmic ointments), rectally (e.g., using enemas or suppositories), nasally, buccally, vaginally (e.g., using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.), via an implanted reservoir or the like, or parenterally depending on the severity and type of the disease being treated. The term "parenteral" as used herein includes, but is not limited to,
subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally, intraperitoneally or intravenously.
[00142] The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00143] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution-retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. A water soluble taste-masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.
[00144] Formulations of a compound of Formula A or Formula B or a pharmaceutically acceptable salt thereof that are suitable for oral administration may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs.
Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
[00145] Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
[00146] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[00147] The active compounds can also be in microencapsulated form with one or more excipients as noted above.
[00148] When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain one or more demulcents, preservatives, flavoring and coloring agents and antioxidants.
[00149] Sterile injectable forms of the compositions described herein (e.g., for parenteral administration) may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.
[00150] Oily suspensions may be formulated by suspending the compound of Formula A or Formula B in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated
hydroxyanisol or alpha-tocopherol.
[00151] Aqueous suspensions of compounds of Formula A or Formula B contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium
carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
[00152] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[00153] In order to prolong the effect of a compound described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsuled matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[00154] The injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.
[00155] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays.
[00156] The pharmaceutical compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[00157] Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used.
[00158] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
[00159] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as
benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredients may be employed with either an oil- based, paraffinic or a water-miscible ointment base.
[00160] Alternatively, the active ingredients may be formulated in a cream with an oil- in-water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
[00161] The oily phase of emulsions prepared using compounds of Formula A or Formula B may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A
hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilizers suitable for use in the formulation of compounds of Formula A or Formula B include Tween™-60, Span™-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
[00162] The pharmaceutical compositions may also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. Formulations suitable for intrapulmonary or nasal administration have a mean particle size, for example, in the range of 0.1 to 500 microns (including particles with a mean particle size in a range between 0.1 and 500 microns in micron increments such as 0.5, 1, 30, 35 microns, etc.) and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
[00163] For use, the pharmaceutical composition (or formulation) may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
[00164] The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited herein above, or an appropriate fraction thereof, of the active ingredient.
[00165] In another aspect, a compound of Formula A or Formula B or a
pharmaceutically acceptable salt thereof may be formulated in a veterinary composition comprising a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
Therapeutic Methods:
[00166] The terms, "disease", "disorder", and "condition" may be used interchangeably here to refer to a condition where an increase in the concentration of an endogenous cannabinoid (eCB) might be beneficial or a condition that can be treated by a FAAH inhibitor.
[00167] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a "mammal" including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a "human".
[00168] The term "biological sample", as used herein, includes, without limitation, in vivo or ex vivo cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous humor or other body fluids or extracts thereof.
[00169] "Treat", "treating" or "treatment" with regard to a disorder or disease refers to alleviating or abrogating the cause and/or the effects of the disorder or disease. As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a condition wherein an increase in the concentration of eCB might be beneficial or that can be treated with a FAAH inhibitor, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of said condition, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the invention). In specific embodiments, the terms "treat", "treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of condition wherein an increase in the concentration of eCB might be beneficial or a condition that can be treated with a FAAH inhibitor. In other embodiments the terms "treat", "treatment" and "treating" refer to the inhibition of the progression of said condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
[00170] As used herein, the terms "prevent", "preventing" and "prevention" with regard to a disorder or disease refer to averting the cause and/or effects of a disease or disorder prior to the disease or disorder manifesting itself. The terms "prophylaxis" or "prophylactic use", as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. As used herein, the terms "prevent", "prevention" and
"preventing" refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill, but who has been or may be near a person with the disease.
[00171] The term "chemotherapy" refers to the use of medications, e.g., small molecule drugs (rather than e.g., "vaccines") for treating a disorder or disease. [00172] The term "chemoprophylaxis" refers to the use of medications, e.g., small molecule drugs (rather than e.g.," vaccines") for the prevention of a disorder or disease.
[00173] In one embodiment, the methods of the invention are a preventative or "pre¬ emptive" measure to a patient, preferably a human, having a predisposition to developing a condition or symptom that can be improved by an increase in the concentration of an eCB or treated with a FAAH inhibitor.
[00174] Also described are methods for treating or preventing various disorders with a composition that includes any of the various embodiments of the compound of Formula A or Formula B or pharmaceutically acceptable salts thereof. Among the disorders or symptoms that can be treated or prevented are: pain (e.g., acute pain, chronic pain, neurogenic pain, dental pain, menstrual pain, dysmenorrheal pain, visceral pain, abdominal pain, pelvic pain, abdominal discomfort, neuropathic pain, headache, migraines, allodynia, hyperalgesia, post operative pain (e.g., associated with orthopedic surgery, gynecological surgery, abdominal surgery, incisions, oral surgery), back pain, pain caused by inflammation (e.g., arthritis, osteoarthritis, spondylitis, rheumatoid arthritis, Crohn's disease, irritable bowel syndrome, pain associated with injury, burns or trauma, and pain associated with fibromyalgia);
[00175] anxiety, depression, an impulse control disorder (e.g., pathological gambling, compulsive shopping, hypersexuality), a compulsion disorder, a dopamine dysregulation syndrome, an eating disorder (e.g., anorexia and bulimia);
[00176] obesity (e.g., by appetite suppression), elevated intraocular pressure (e.g., glaucoma), a cardiovascular disorder (e.g., hypertension);
[00177] an inflammatory disorder (e.g., allergy (e.g., food allergy, respiratory inflammation, inflammation of the skin and gastrointestinal inflammation), asthma, Crohn's disease);
[00178] emesis (e.g., as a side effect of chemotherapy), some cancers, excitotoxic insult (e.g., in cerebral ischemia, seizure and edema due to traumatic brain injury), asphyxia;
[00179] addictive behaviors, sleep disorders, epilepsy, epileptiform-induced damage, progressive CNS diseases (e.g., Parkinson's, motor neuron disorders, amyotrophic lateral sclerosis (ALS), Huntington's and motor dysfunction, dyskinesia); hyperactivity disorders, restless leg syndrome, periodic limb movement disorder; [00180] gastrointestinal disorders (e.g., attenuation of cholera induced fluid accumulation, nausea, vomiting, gastric ulcers, diarrhea, paralytic ileus, IBS, IBD, colitis, and gastroesophageal reflux conditions);
[00181] urinary system disorders (e.g. overactive bladder and interstitial cystitis);
[00182] and autoimmune disorders (e.g., multiple sclerosis).
[00183] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of pain. The pain can be chronic pain, acute pain, perioperative pain (e.g., associated with surgery), postoperative pain, visceral pain, abdominal pain, abdominal discomfort, pelvic pain, inflammatory pain, cancer pain, headache pain, pain associated with cough, neuropathic pain, deafferentation pain, chronic nociceptive pain, dental pain (such as odontalgia), bone pain, joint pain (e.g., osteoarthritis or rheumatoid arthritis), myofascial pain (e.g., muscular injury, fibromyalgia), labor pain, pain associated with injuries, trauma, allergies, dermatitis, immunodeficiency, Hodgkin's disease, Myasthenia gravis, nephrotic syndrome, scleroderma, or thyroiditis, central and peripheral pathway mediated pain, pain associated with fibromyalgia, or pain associated with or the result of injury or age.
[00184] Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous systems. It can occur in the peripheral nerves, dorsal roots, spinal cord and certain regions of the brain. It can also result from a peripheral nerve disorder such as neuroma, nerve compression, nerve crush, nerve stretch or incomplete nerve transsection. It can be associated with neuronal lesions, such as those induced by diabetes, HIV, herpes infection, nutritional deficiencies or a stroke. Chronic neuropathic pain can result from injury and/or inflammation such as chronic lower back pain. Acute neuropathic pain includes, for example, traumatic pain (e.g., bone fracture pain, sprains, strains and soft tissue damage), muscle pain, burn pain, and sun burn pain. Neuropathic pain can also be associated with, for example, nerve injury, head trauma, hyperalgesia, allodynia, dysesthesias, sciatica, amputation (e.g., phantom limb syndrome, stump pain), fibromyalgia, chemotherapeutic neuropathy, cancer pain (e.g., tumors of the brainstem, thalamus or cortex), AIDS-related neuropathy, painful traumatic mononeuropathy, painful polyneuropathy, multiple sclerosis, root avulsions, post-thoracotomy syndrome. It can be the result of a central nervous system injury (such as pain in stroke or spinal cord injury patients). Neuropathic pain also includes lower back pain, toxin induced pain, neurogenic pain, thalamic pain syndrome, repetitive motion pain (e.g., carpal tunnel syndrome) or pain induced by post-mastectomy syndrome, by surgery or by radiation. Neuralgia is a type of neuropathic pain that is thought to be linked to four possible mechanisms: ion gate malfunctions; a nerve becoming mechanically sensitive and creating an ectopic signal; cross signals between large and small fibers; and malfunction due to damage in the central processor. Under the general heading of neuralgia are trigeminal neuralgia (TN), atypical trigeminal neuralgia (ATN), and post-herpetic neuralgia (caused by shingles or herpes). Neuralgia is also involved in disorders such as sciatica and brachial plexopathy with neuropathia. Neuralgias that do not involve the trigeminal nerve are occipital neuralgia and glossopharyngeal neuralgia. Neuropathic pain also includes referred pain.
[00185] Visceral, abdominal or pelvic pain or discomfort includes, for example, pancreas pain (e.g. pain associated with pancreatitis) urological pain (e.g., associated with interstitial cystitis, urinary bladder pain, prostate pain), renal pain (e.g. renal colic, pain caused by kidney stones), gynecological pain (e.g. dysmenorrhea, menstrual cramps, menstruation,
endometriosis, ovarian pain), gastrointestinal pain (e.g., pain associated with irritable bowel syndrome (IBS with all its variants), Crohn's disease, celiac disease, ulcerative colitis, peptic ulcers, stomach pain, rectal pain, bowel pain, intestinal pain, intestinal cramps, gastritis and non-ulcer dyspepsia), angina, myocardial ischemia. Visceral pain also includes non-cardiac chest pain and referred pain. Also included is abdominal, visceral or pelvic pain caused by cancer, bacterial infections, parasitic infections, surgery, trauma, medications, gallstones, diverticulitis or digestive disorders. Inflammatory pain includes both inflammatory pain that is a significant component of a disorder or disease and that that is considered a minor component or symptom. For example, inflammatory pain induced by or associated with disorders such as osteoarthritis, rheumatic fever, rheumatoid arthritis, rheumatic disease, tendonitis, juvenile arthritis, spondylitis, gouty arthritis, psoriatic arthritis, interstitial cystitis, peripheral neuritis, mucositis, fibromyalgia, pancreatitis, enteritis, diverticulitis, cellulites, bone fractures, postoperative ileus, Crohn's Disease, ulcerative colitis, cholecystitis, teno-synovitis, gout, vulvodynia, fibromyalgia, sprains and strains, systemic lupus erythematosus, myositis, bronchitis and influenza and other viral infections such as the common cold. Inflammatory pain also includes sympathetically maintained pain, pain due to venomous and non- venomous snake bite, spider bite or insect sting, sports injury pain, sprain pain, joint pain, myofascial pain
(muscular injury, fibromyalgia), muscoskeletal pain, and pain due to inflammatory bowel diseases. Among the inflammatory pain disorders that can be treated are included some autoimmune disorders or diseases.
[00186] Cancer pain can be induced by or associated with tumors such as lymphatic leukemia, Hodgkin's disease, malignant lymphoma, osteosarcoma, bone cancer,
lymphogranulomatoses, lymphosarcoma, solid malignant tumors, and extensive metastases. Chemotherapy pain is a side effect of chemotherapy treatments.
[00187] Headache pain includes cluster headache, migraines with and without aura, tension type headache, headaches caused by injury or infection, hangovers, and headaches with unknown origins.
[00188] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of inflammatory disorders, including, for example, chronic and acute inflammatory disorders. Examples of disorders with inflammatory components include asthma, atopic allergy, allergy, atherosclerosis, bronchial asthma, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemia, osteoarthritis, sepsis, septic shock (e.g., as antihypovolemic and/or antihypotensive agents), systemic lupus erythematosus, stroke, transplantation of tissue and organs, vasculitis, interstitial cystitis, diabetic retinopathy and ventilator induced lung injury. The compounds and pharmaceutical compositions described herein can also be used alone or in combination therapy for the treatment or prevention of disease-states or indications that are accompanied by inflammatory processes such as:
[00189] (1) Lung diseases: e.g., asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non- atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy-infant syndrome",
pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis;
[00190] (2) Rheumatic diseases or autoimmune diseases or musculoskeletal diseases: e.g., all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, and polymyalgia rheumatica; reactive arthritis; rheumatic soft tissue diseases; inflammatory soft tissue diseases of other genesis; arthritic symptoms in degenerative joint diseases (arthroses); tendinitis, bursitis, osteoarthritis, traumatic arthritis, gout (metabolic arthritis); collagenoses of any genesis, e.g., systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still disease, Felty syndrome; and osteoporosis and other bone resorption diseases;
[00191] (3) Allergic diseases including all forms of allergic reactions, e.g., allergic rhinitis, allergic conjunctivitis, infectious parasitic, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, delayed or immediate hypersensitivity, and contact dermatitis;
[00192] (4) Vascular diseases: e.g., panarteritis nodosa, polyarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis, atherosclerosis, reperfusion injury and erythema nodosum, myocardial ischemia, thrombosis.
[00193] (5) Dermatological diseases: e.g., dermatitis, psoriasis, sunburn, burns, and eczema;
[00194] (6) Renal, urinary and pancreatic diseases: e.g., nephrotic syndrome and all types of nephritis (such as glomerulonephritis); pancreatitis; bladder hyperrelexia following bladder inflammation; other renal diseases that can be treated by the compounds and compositions herein described include urinary incontinence or vesicle inflammation, uresesthesia urgency, overactive bladder, urinary frequency, interstitial cystitis or chronic prostatitis.
[00195] (7) Hepatic diseases: e.g., acute liver cell disintegration; acute hepatitis of various genesis (such as viral, toxic, drug-induced) and chronically aggressive and/or chronically intermittent hepatitis, liver fibrosis associated with liver injury or disease, including fibrosis caused or exacerbated by alcoholic liver cirrhosis, chronic viral hepatitis, non alcoholic steatohepatitis and primary liver cancer;
[00196] (8) Gastrointestinal diseases: e.g., ulcers, inflammatory bowel diseases, regional enteritis (Crohn's disease), ulcerative colitis, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, esophagitis, NSAID-induced ulcer, non-ulcerative dyspepsia and gastroesophageal reflux disease; [00197] (9) Neurodegenerative diseases: e.g., treatment/reduction of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, edema, spinal cord injury, cerebral ischemia, seizures, neurodegeneration associated with multiple sclerosis, or the like, neuroprotection, neurogenesis;
[00198] (10) Eye diseases: e.g., allergic keratitis, uveitis, or iritis, conjunctivitis, blepharitis, neuritis nervi optici, choroiditis, glaucoma and sympathetic ophthalmia;
[00199] (11) Diseases of the ear, nose, and throat (ENT) area: e.g., tinnitus, allergic rhinitis or hay fever, gingivitis, otitis externa, caused by contact eczema, infection, etc., and otitis media;
[00200] (12) Progressive central nervous system or neurological diseases: e.g., brain edema, particularly tumor-related brain edema, multiple sclerosis, spasticity associated with multiple sclerosis, acute encephalomyelitis, meningitis, acute spinal cord injury, trauma;
cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Parkinson's disease and Creutzfeldt- Jacob disease, Huntington's chorea, Pick's disease, amyotrophic lateral sclerosis (ALS)), vascular dementia (including multi-infarct dementia and dementia associated with intracranial space occupying lesions, infections and related conditions such as HIV infection); Guillain-Barre syndrome, myasthenia gravis, stroke, and various forms of seizures (such as nodding spasms), hyperactivity, dyskinesias;
[00201] (13) Blood diseases: e.g., acquired hemolytic anemia, aplastic anemia, and idiopathic thrombocytopenia;
[00202] (14) Tumor diseases: e.g., acute lymphatic leukemia, Hodgkin's disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, and extensive metastases; other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration).
[00203] (15) Endocrine diseases: e.g., endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de Quervain, Hashimoto thyroiditis, Morbus Basedow, granulomatous thyroiditis, struma lymphomatosa, Graves disease, type I diabetes (such as insulin-dependent diabetes); organ and tissue transplantations and graft vs. host diseases;
[00204] (16) Severe states of shock: e.g., septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS);
[00205] (17) Viral or bacterial parasitic infectious disease: for example AIDS and meningitis; and
[00206] (18) Various other disease-states or conditions including, restenosis following percutaneous transluminal coronary angioplasty, acute and chronic pain, atherosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, granulocyte transfusion, sarcoidosis, gingivitis, pyrexia; edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and
angioedema, and diabetes (such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and diabetic symptoms associated with insulitis (e.g., hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion)).
[00207] The compounds and compositions herein described can be used alone or in combination therapy for the treatment of gastrointestinal (GI) diseases or disorders: e.g., functional gastrointestinal disorders, ulcers, inflammatory bowel diseases (IBD), colitis, regional enteritis (Crohn's disease), ulcerative colitis, diarrhea, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, functional dyspepsia, diverticulitis, gastrointestinal bleeding, irritable bowel syndrome (IBS), non-ulcerative dyspepsia and gastroesophageal reflux disease.
[00208] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of pruritus (itch). For example, pruritus originated in the skin (dermal pruritus), neuropathic pruritus, neurogenic or
psychogenic pruritus would all be included. Pruritus (itching) can be a symptom of primary skin diseases or of systemic disease. Skin diseases notorious for causing intense pruritus include scabies, pediculosis, insect bites, urticaria, atopic and contact dermatitis, lichen planus, miliaria, and dermatitis ηβ εύίοιτηϊβ. In other cases pruritus is prominent without any identifiable skin lesions: e.g., dry skin (especially in elderly people), systemic disease, and use of certain drugs can generate pruritus. Systemic diseases that cause generalized pruritus include cholestatic diseases, uremia, polycythemia vera, and hematologic malignancies.
Pruritus may also occur during the later months of pregnancy. Barbiturates, salicylates, morphine and cocaine can cause pruritus. Less well-defined causes of pruritus include hyper- and hypothyroidism, diabetes, iron deficiency, and internal cancers of many types. [00209] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of substance abuse related syndromes, disorders or diseases include, including, for example, drug abuse and drug withdrawal. Abused substances can include alcohol, amphetamines, amphetamine-like substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing. The compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance-induced anxiety or mood disorder. In addition, they can be used to reduce tobacco craving; treat nicotine dependency, addiction, or withdrawal; or aid in the cessation or lessening of tobacco in a subject in need thereof.
[00210] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of psychiatric disorders, such as depressions (including major depressive disorder, bipolar depression, unipolar depression, single or recurrent major depressive episodes (e.g., with or without psychotic features, catatonic features, and/or melancholic features), postpartum onset, seasonal affective disorder, dysthymic disorders (e.g., with early or late onset and with or without atypical features), neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders); manic-depressive psychoses; bipolar disorders; extreme psychotic states (such as mania, schizophrenia, and excessive mood swings where behavioral stabilization is desired); post-traumatic stress disorder; panic disorder; compulsive disorders (e.g., obsessive compulsive disorder, stereotypic, self-injurious and repetitive behaviors, trichtillomania), psychiatric tremors such as dyskinesia, dyskinesia associated with Parkinson's disease, dystonia or spasticity, dystonia or spasticity associated with multiple sclerosis, attention disorders such as ADHD (attention deficit hyperactivity disorders), hyperactivity, hyperactivity disorders, restless leg syndrome, periodic limb movement disorder, autism, anxiety states, generalized anxiety, an impulse control disorder (e.g., pathological gambling, compulsive shopping, hypersexuality), a compulsion disorder, a dopamine dysregulation syndrome, agoraphobia, as well as those behavioral states characterized by social withdrawal.
[00211] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of an autoimmune disease or disorder or at least one symptom associated with said disease or disorder, including, for example, alopecia areata (also known as systemic sclerosis (SS)), amyloses, amyotrophic lateral sclerosis, ankylosing spondylarthritis, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue-dermatitis hepetiformis; chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, connective tissue diseases, crest syndrome, Crohn's disease, Degos' disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia- fibromyositis, graft vs. host disease, transplantation rejection, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, lupus erythematosus, Meniere's disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomena, reactional arthritis, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS), Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, undifferentiated spondylarthritis, uveitis, vitiligo, and Wegener's granulomatosis. The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for neuroprotection in individuals suffereing from multiple sclerosis or other autoimmune diseases.
[00212] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of neurological or
neurodegenerative disorders. Examples of neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt- Jakob disease, motor neuron disease; vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Age- Associated Memory Impairment. Examples of neurological disorders include amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, ischemia, traumatic head or brain injury, brain inflammation, eye injury, stroke and neuroinflammation. The compounds and compositions here described can also be used for the treatment/reduction of
neurodegeneration or decreased brain activity associated with stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, hypoxia, hypoglycemia, gas poisoning, drug intoxication, diabetes mellitus, edema, spinal cord injury, cerebral ischemia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, seizures, neurodegeneration associated with multiple sclerosis, or the like.
[00213] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of ocular disorders including, for example, glaucoma (such as normal tension glaucoma), glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, and acute injury to the eye tissue (e.g., conjunctivitis). Ocular disorders also include neurodegenerative disease conditions of the retina and the optic nerve, for example, in patients presenting risk factors for glaucoma, such as high intraocular pressure, family history of glaucoma, glaucoma in the contralateral eye and high myopia.
[00214] The compounds and compositions described herein can also be used, alone or in combination therapy, to treat or prevent appetite related disorders such as emesis, vomiting and nausea, food behavioral problems or feeding disorders (e.g., anorexias, cachexias, wasting conditions and bulimia) and obesity or obesity-related disorders (e.g., diabetes type II, hyperlipidemia).
[00215] Certain gynecological disorders can be treated by inhibition of uterus contraction caused by hormones and prostanoid-induced muscle contraction using compounds or compositions described herein, for example, premature labor, menstrual cramps, menstrual irregularity, dysmenorrhea.
[00216] Some sleep disorders can be treated with compounds or compositions described herein, for example insomnia, night terrors, nightmares, vivid dreaming, restlessness, bruxism, somnambulism, narcolepsy, circadian rhythm adjustment disorders, and the like. Also contemplated are sleep disorders associated with neurological or mental disorders or with pain. [00217] Cardiovascular diseases that can be treated with the compounds and compositions of the invention described herein include myocardial ischemia, thrombosis, hypertension or cardiac arrhythmias.
[00218] Compounds and compositions of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.
[00219] In another embodiment, the invention provides a method of inhibiting FAAH in a biological sample, comprising contacting said biological sample with a compound or composition of the invention. Use of a FAAH inhibitor in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, without limitation, biological assays and biological specimen storage.
Combination Therapies:
[00220] The compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents. For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
[00221] When co-administered with other agents, e.g., when co-administered with another pain medication, an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. For example, compounds described herein can be administered to a subject in a dosage range from between about 0.001 to about 100 mg/kg body weight/day, from about 0.001 to about 50 mg/kg body weight/day, from about 0.001 to about 30 mg/kg body weight/day, from about 0.001 to about 10 mg/kg body weight/day.
[00222] When combination therapy is employed, an effective amount can be achieved using a first amount of a compound of Formula A or Formula B or a pharmaceutically acceptable salt thereof and a second amount of an additional suitable therapeutic agent (e.g., an agent to treat pain).
[00223] In one embodiment of this invention, the compound of Formula A or Formula B and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, the compound of Structural Formula A or Formula B and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose). In yet another embodiment, the compound of Structural Formula A or Formula B can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, the compound of Structural Formula A or Formula B can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer- therapeutic agent is administered in an effective amount.
[00224] As used herein, the terms "in combination" or "co-administration" can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.
[00225] Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, a capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequential manner in either order. When coadministration involves the separate administration of a first amount of a compound of Formula A or B and a second amount of an additional therapeutic agent, the compounds are
administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration that can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, a compound of Formula A or Formula B and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other. [00226] More specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound described herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anticancer agent) to a subject.
[00227] Additional therapeutic agents that can be combined with compounds described herein include, without limitation:
[00228] FAAH inhibitors: e.g., OL-135, LY2183240, URB-597, CAY-10402, PF-750, BMS-469908, SSR-411298, TK-25, PF-04457845, PF-3845, SA-47, JNJ-245, JNJ-28833155 and JNJ-1661010;
[00229] painkillers such as acetaminophen or paracetamol;
[00230] non-steroidal anti-inflammatory drugs (NS AIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives
(indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (meclofenamic acid, mefe-namic acid, and tolfenamic acid), biphenyl-carboxylic acid derivatives, oxicams (isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone), and COX-2 inhibitors, such as the coxibs (celecoxib, deracoxib, valdecoxib, rofecoxib, parecoxib and etoricoxib);
[00231] other pain relieving agents such as gabapentin, topical capsaicin, tanezumab, esreboxetine;
[00232] opiate receptor agonists such as morphine, propoxyphene (Darvon™), tramadol, buprenorphin;
[00233] cannabinoid receptor agonists such as dronabinol, A9-THC, CP-55940, WIN- 55212-2, HU-210;
[00234] anti-infective agents;
[00235] sodium channel blockers such as carbamazepine, mexiletine, lamotrigine, pregabalin, tectin, NW-1029, CGX-1002;
[00236] N-type calcium channel blockers such as ziconotide, NMED-160, SPI-860; serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram;
[00237] local anesthetics such as ambroxol, lidocaine;
[00238] VR1 agonists and antagonists such as NGX-4010, WL-1002, ALGRX-4975, WL-10001, AMG-517;
[00239] agents used for migraines, such as sumatriptan, zolmitriptan, naratriptan, eletriptan, rauwolscine, yohimbine, metoclopramide;
[00240] topical agents used in the treatment of localized pruritus: e.g., camphor/menthol lotions or creams containing 0.125 to 0.25% menthol, doxepin (e.g., Sinequan , Zonalon ), phenol (e.g., Cepastat®, Chloraseptic® gargle, Ulcerease), 0.5 to 2%, pramoxine (e.g., Anusol™ ointment, Proctofoam-NS, Tronolane™ Cream, Tucks™ Hemorrhoidal), eutectic mixture of local anesthetics (EMLA), and corticosteroids;
[00241] anti-inflammatory and/or immunosuppressive agents such as methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus,
corticosteroids, statins, interferon beta, Remicade™ (infliximab), Enbrel™ (etanercept) and Humira™ (adalimumab);
[00242] agents designed to treat tobacco abuse: e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban™) and nicotine replacement therapies;
[00243] ADD/ADHD agents: e.g., Ritalin™ (methylphenidate hydrochloride),
Strattera™ (atomoxetine hydrochloride), Concerta™ (methylphenidate hydrochloride) and
Adderall™ (amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate);
[00244] agents to treat alcoholism, such as opioid antagonists (e.g., naltrexone (also known under the tradename Re Via M) and nalmefene), disulfiram (also known under the tradename Antabuse™), and acamprosate (also known under the tradename Campral™));
[00245] agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin™);
[00246] antihypertensive agents: e.g., ACE inhibitors and Angiotensin II Receptor blockers such as benazepril , captopril , enalapril , fosinopril , lisinopril, candesartan , eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, renin inhibitors such as aliskiren, vasodilators such as minoxidil;
[00247] agents used to treat glaucoma: e.g., direct-acting miotics (cholinergic agonists), indirect acting miotics (cholinesterase inhibitors), carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide, brinzolamide, dorzolamide), selective adrenergic agonists (e.g., apraclonidine, brimonidine), beta-blockers (bimolol, betaxolol, carteolol, levobetaxolol, levobunolol, metipranolol), osmotic diuretics (e.g., glycerin, mannitol);
[00248] antidepressants: e.g., SSRIs (e.g., fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine), tricyclic antidepressants (e.g., imipramine, amitriptiline, chlomipramine and nortriptiline), dopaminergic antidepressants (e.g., bupropion and amineptine), SNRIs (e.g., venlafaxine and reboxetine);
[00249] cognitive improvement agents: e.g., donepezil hydrochloride (Aricept™) and other acetylcholinesterase inhibitors;
[00250] anti-emetic agents: e.g., 5HT3 antagonists such as ondansetron, granisetron, metoclopramide;
[00251] neuroprotective agents: e.g., memantine, L-dopa, bromocriptine, pergolide, talipexol, pramipexol, cabergoline, neuroprotective agents currently under investigation including anti-apoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetics,
antiglutamatergic agents and dopamine receptors. Other clinically evaluated neuroprotective agents are, e.g., the monoamine oxidase B inhibitors selegiline and rasagiline, dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10; [00252] antipsychotic medications: e.g., ziprasidone (Geodon™), risperidone
(Risperdal™), and olanzapine (Zyprexa™);
[00253] agents used for multiple sclerosis such as beta-interferon (e.g., Avonex™, Betaseron™) baclofen and Copaxone™;
[00254] disease-modifying anti-rheumatic drugs (DMARDS) such as methotrexate, azathioptrine, leflunomide, pencillinamine, gold salts, mycophenolate mofetil,
cyclophosphamide, CP-690,550; biological response modifiers (BRMs) such as Enbrel™, Remicade™, IL-1 antagonists; NSAIDS such as piroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2 selective inhibitors such as Celebrex™; COX-1 inhibitors such as
Feldene™; immunosuppressives such as steroids, cyclosporine, tacrolimus, rapamycin and the like;
[00255] PDE4 inhibitors such as theophylline, drotaverine hydrochloride, cilomilast, roflumilast, denbufylline, rolipram, tetomilast, enprofylline, arofylline, cipamfylline, tofimilast, filaminast, piclamilast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2- phenylethyljpyridine, mesopram, N-(3,5-dichloro-4-pyridinyl)-2-[ 1 -(4-fiuorobenzyl)-5- hydroxy-lH- -indol-3-yl]-2-oxoacetamide, CDC-801 (Celgene), CC-1088 (Celgene),
Lirimilast, ONO-6126 (Ono), CC- 10004 (Celgene) and MN-001 (Kyorin), ibudilast and pentoxifylline, for use in treating inflammation, lung disorders and as bronchodilators;
[00256] corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
[00257] histamine HI receptor antagonists such as bromopheniramine,
οΜθ ηβιώβτηιηβ, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdiazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine;
[00258] histamine H2 receptor antagonists such as cimetidine, famotidine and ranitidine;
[00259] proton pump inhibitors such as omeprazole, pantoprazole and esomeprazole;
[00260] leukotriene antagonists and 5-lipoxygenase inhibitors such as zafirlukast, montelukast, pranlukast and zileuton; [00261] nicotinic acetylcholine receptor agonists such as ABT-202, A-366833, ABT- 594; BTG-102, A-85380, CGX1204;
[00262] P2X3 receptor antagonists such as A-317491, ISIS-13920, AZD-9056;
[00263] NGF agonists and antagonists such as RI-724, RI- 1024, AMG-819, AMG-403, PPH 207;
[00264] NK1 and NK2 antagonists such as DA-5018, R-l 16301; CP-728663, ZD-2249;
[00265] NMDA antagonist such as NER-MD-11, CNS-5161, EAA-090, AZ-756, CNP- 3381; potassium channel modulators such as CL-888, ICA-69673, retigabine;
[00266] GABA modulators such as lacosamide and propofol;
[00267] anti-cancer agents such as tyrosine kinase inhibitors imatinib (Gleevec/Glivec) and gefitinib (Iressa);
[00268] anti hyperlipidemia drugs such as statins, ezetimibe, niacin and bile acid sequestrants;
[00269] appetite suppressing agents: e.g., sibutramine, taranabant, rimobamant;
[00270] anti-diabetic medications such as insulin, tolbutamide (Orinase™),
acetohexamide (Dymelor™), tolazamide (Tolinase™), chlo ropamide (Diabinese™), glipizide (Glucotrol™), glyburide (Diabeta™, Micronase™, Glynase™), glimepiride
(Amaryl™), gliclazide (Diamicron™), repaglinide (Prandin™), nateglinide (Starlix™), pramlintide (Symlin™) and exenatide (Byetta™);
[00271] serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram, flibanserin; and
[00272] GI agents: e.g., laxatives (e.g., lubiprostone (Amitiza™), Fybogel®, Regulan®, Normacol® and the like), a gastrointestinal agent used for the treatment of idiopathic chronic constipation and constipation-predominant IBS, GI motility stimulants (e.g., domperidone, metoclopramide, mosapride, itopride), antispasmodic drugs (e.g., anticholinergics such as hyoscyamine or dicyclomine); anti-diarrheal medicines such loperamide (Imodium™) and bismuth subsalicylate (as found in Pepto Bismol and Kaopectate ), GCC (Guanylate Cyclase C) agonists (e.g., Linaclotide), 5HT4 agonists (e.g., Tegasarod), 5HT3 antagonists (e.g., alosetron, ramosetron, ondansetron). EXAMPLES
General analytical techniques
[00273] LC/MS was run on a Waters Acquity system using a Polar CI 8 column, and 5 to 60% acetonitrile/water over 5 min. The ionization method for the MS was electrospray.
[00274] Automated column chromatography was run using an ISCO system. One of the Companion, Combifiash, or Combiflash Rf was used in each case.
[00275] Microwave reactions were run on a Personal Chemistry Optimizer, at 0-240 °C, a power of 0-300 W and a pressure of 0-21 bar.
[00276] HPLC for purification was run on a Varian Prepstar instrument using the following conditions:
Solvent A: 0.1% Trifluoroacetic acid in water
Solvent B: 0.1% Trifluoroacetic acid in acetonitrile
Figure imgf000086_0001
[00277] All references provided in the Examples are herein incorporated by reference in their entirety. As used herein, all abbreviations, symbols and conventions are consistent with those used in the contemporary scientific literature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2 Ed., Washington, D.C.: American
Chemical Society, 1997, herein incorporated by reference in its entirety.
Synthetic procedures:
Example 1 (see general route 1, procedure A, B, C and D):
methyl 2-(5-methoxy-2-methyl-lH-indol-3-yl)-2-oxoacetate
Figure imgf000087_0001
[00278] To a solution of 5-methoxy-2-methyl- 1 H-indole (3.45 g, 21.4 mmol) in dichloromethane (100 mL) at 0 °C was added oxalyl chloride (2.06 mL, 23.5 mmol). After 30 minutes, the reaction was warmed to room temperature, and LCMS analysis indicated the presence of the ketoacid chloride (via analysis of the methanolysis product). The reaction mixture was concentrated to dryness and then reconstituted in dichloromethane (100 mL) and cooled to 0 °C. Methanol (8.00 mL, 198 mmol) was added after which the reaction mixture was warmed to room temperature, resulting in the formation of a solid precipitate, which was filtered and washed with hexanes and dried to afford methyl 2-(5-methoxy-2-methyl-lH-indol- 3-yl)-2-oxoacetate (4.08 g, 16.5 mmol, 77 % yield) as a light pink solid. No further purification of this material was necessary. Ή NMR (400 MHz, CDC13) δ (ppm): 8.49 (br. s, 1H), 7.59 (d, 1H), 7.22 (d, 1H), 6.88 (dd, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 2.45 (s, 3H). methyl 2-(l-((2-chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-2- oxoacetate
Figure imgf000088_0001
[00279] A slurry of 2-chloro-5-(chloromethyl)thiazole (530 mg, 3.15 mmol), methyl 2- (5-methoxy-2-methyl-lH-indol-3-yl)-2-oxoacetate (600 mg, 2.43 mmol), potassium iodide (20.1 mg, 0.121 mmol) and potassium carbonate (402 mg, 2.91 mmol) in N,N- dimethylformamide (13.5 mL) was heated at 65 °C for 2 hours, after which the reaction was cooled to room temperature, diluted in water (100 mL), extracted with ethyl acetate (3 x 100 mL), dried (sodium sulfate), filtered and concentrated to a brown residue. Purification was achieved by silica gel chromatography (Luknova 80g, 20 mL/min) using 30 to 100% ethyl acetate in hexanes over 60 minutes to afford methyl 2-(l-((2-chlorothiazol-5-yl)methyl)-5- methoxy-2-methyl-lH-indol-3-yl)-2-oxoacetate (798 mg, 2.11 mmol, 87 % yield) as a yellow foam. 1H NMR (400 MHz, CDC13) δ (ppm): 7.51 (d, 1H), 7.39 (d, 1H), 7.21 (d, 1H), 6.93 (dd, 1H), 5.39 (s, 2H), 3.98 (s, 3H), 3.86 (s, 3H), 2.65 (s, 3H). LCMS: [ES]' found 377.20.
2-(l-((2-chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-2-oxoacetic acid
Figure imgf000088_0002
[00280] To a 0 °C solution of methyl 2-(l-((2-chlorothiazol-5-yl)methyl)-5-methoxy-2- methyl-lH-indol-3-yl)-2-oxoacetate (798 mg, 2.16 mmol) in tetrahydrofuran (20 mL) and water (5 mL) was added solid lithium hydroxide hydrate (88.0 mg, 2.11 mmol). The reaction mixture was stirred at 0 °C for one hour, after which it was warmed to room temperature and stirred at that temperature for two hours.
[00281] The reaction mixture was then concentrated to a residue, reconstituted in water (50 mL), and washed with ethyl acetate (2 x 50 mL). The aqueous layer was acidified with 3M hydrochloric acid solution (0.95 mL) and back-extracted with ethyl acetate (2 x 50 mL), dried (sodium sulfate), filtered and concentrated to afford a yellow solid. The product 2-(l-((2- chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-2-oxoacetic acid (630 mg, 1.73 mmol, 82 % yield) was used without any purification in the next step. (This reaction proceeds in a THF/methanol/water solvent system, but methanol was excluded in this case to minimize methanolysis of 2-chlorothiazole moiety to a 2-methoxythiazole moiety). 1H NMR (400 MHz, CDC13) δ (ppm): 7.84 (d, 1H), 7.42 (s, 1H), 7.23 (d, 1H), 6.96 (dd, 1H), 5.44 (s, 2H), 3.89 (s, 3H), 2.80 (s, 3H).
2-(l-((2-chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypy ridin-4-yl)-2-oxoacetamide (AO 1)
Figure imgf000089_0001
[00282] A solution of 2-( 1 -((2-chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl- 1 H- indol-3-yl)-2-oxoacetic acid (630 mg, 1.73 mmol), triethylamine (1.20 ml, 8.63 mmol), 2- methoxypyridin-4-amine (257 mg, 2.07 mmol), and 50% in ethyl acetate solution of T3P (1.54 ml, 5.18 mmol) in acetonitrile (8 mL) was stirred at room temperature, resulting in an orange reaction color. The reaction mixture was stirred for 12 hours, after which there was about 50% conversion by LCMS analysis. Additional triethylamine (1.20 mL, 8.63 mmol), T3P (1.54 ml, 5.18 mmol), and 2-methoxypyridin-4-amine (30 mg) was added, and the reaction was heated for at 60 °C for 4 hours, after which it was diluted in saturated sodium chloride solution (100 mL), extracted with ethyl acetate (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to a orange-brown residue. Purification was achieved by silica gel chromatography (Luknova 80g, 20 mL/min) using 30 to 100% ethyl acetate in hexanes over 60 minutes. 2-(l-((2- chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl- 1 H-indol-3 -yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide (320 mg, 0.680 mmol, 39% yield) was isolated as a gold solid. lH NMR (400 MHz, CDC13) δ (ppm): 9.03 (br. s, IH), 8.13 (d, IH), 7.74 (d, IH), 7.41 (s, IH), 7.24 (d, IH), 7.20 (d, IH), 7.15 (dd, IH), 6.94 (dd, IH), 5.42 (s, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 2.75 (s, 3H).
Example 2 (see general route 2, procedure E, F, C and D):
5-chloro-2-((2,5-dimethyl-lH-pyrrolo[2,3-b]pyridin-l-yl)methyl)thiazole
Figure imgf000090_0001
[00283] To a solution of 2,5-dimethyl-lH-pyrrolo[2,3-b]pyridine (300 mg, 2.05 mmol, Adesis) and 2-(bromomethyl)-5-chlorothiazole (480 mg, 2.26 mmol) was added powdered potassium hydroxide (230 mg, 4.10 mmol). The reaction mixture was stirred at room temperature for 30 minutes, after which it was diluted in ethyl acetate (60 mL), washed successively with water (3 x 15 mL) and saturated sodium chloride solution (3 x 15 mL), dried (sodium sulfate), filtered and concentrated to a solid. Purification was achieved by silica gel chromatography (ISCO 24g, 35 mL/min) using 5 to 40% ethyl acetate in hexanes over 35 minutes to afford 5-cmoro-2-((2,5-dimethyl-lH-pyrrolo[2,3-b]pyridin-l-yl)methyl)thiazole (400 mg, 1.44 mmol, 70% yield) as a yellow solid. 1H NMR (400 MHz, CDC13) δ (ppm): 8.09 (d, IH), 7.60 (d, IH), 7.47 (s, IH), 6.18 (s, IH), 5.63 (s, 2H), 2.44 (s, 3H), 2.42 (s, 3H). methyl 2-(l-((5-cWorothiazol-2-yl)methyl)-2,5^
oxoacetate
Figure imgf000091_0001
[00284] To a 0 °C slurry of aluminum trichloride (576 mg, 4.32 mmol) in
dichloromethane (7 mL) was added a solution of 5-chloro-2-((2,5-dimethyl-lH-pyrrolo[2,3- b]pyridin-l-yl)methyl)thiazole (400 mg, 1.44 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at 0 °C for 30 minutes then warmed to room temperature and stirred at that temperature for 5 minutes, then cooled again to 0 °C. Methyl oxalyl chloride (0.401 mL, 4.32 mmol) was added to the reaction mixture, resulting in the formation of a suspension.
Acetonitrile (1 mL) was added, which completely solubilized the reaction mixture, after which it was allowed to warm to room temperature and stir for one hour, then stored in the freezer for 12 hours. The reaction mixture was poured onto ice (20 g), extracted with dichloromethane (3 x 25 mL), and washed with saturated sodium bicarbonate solution (2 x 20 mL). The initial aqueous layer was then basified with saturated sodium carbonate solution and extracted with ethyl acetate (2 x 20 mL). This organic layer was successively washed with water (2 x 10 mL) and saturated sodium chloride solution (2 x 20 mL), then combined with the previous dichloromethane extracts. The combined organic layers were dried (sodium sulfate), filtered and concentrated to a solid. Purification was achieved by silica gel chromatography (ISCO 24g, 30 mL/min) using 5 to 20% ethyl acetate in hexanes over 15 minutes then a second gradient from 20 to 50% ethyl acetate in hexanes over 15 minutes to afford methyl 2-(l-((5- chlorothiazol-2-yl)methyl)-2,5-dimethyl- 1 H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetate ( 169 mg, 0.461 mmol, 32% yield) as a light yellow oil that solidified upon standing. LCMS: [ES]+ found 364.1. 2-(l-((5-chlorothiazol-2-yl)methyl)-2,5-dimethyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-2- oxoacetic acid
Figure imgf000092_0001
[00285] To a room temperature solution of methyl 2-( 1 -((5-chlorothiazol-2-yl)methyl)- 2,5-dimethyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetate (169 mg, 0.461 mmol) in
tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL), was added lithium hydroxide monohydrate (58.0 mg, 1.39 mmol), after which the reaction mixture was stirred for 30 minutes. The reaction mixture was then concentrated to a residue, reconstituted in water (3 mL), and acidified with 1M hydrochloric acid solution (3 mL) which resulted in the formation of a precipitate. This solid was filtered, washed with water (2 x 5 mL), and dried to afford 2- (l-((5-c orotluazol-2-yl)methyl)-2,5-dimethyl-lH-pyn-olo[2,3-b]pyridin-3-yl)-2-oxoacetic acid (114 mg, 0.326 mmol, 70% yield) as a white solid. 1H NMR (400 MHz, CDC13) δ (ppm): 8.41 (s, 1H), 8.23 (s, 1H), 7.50 (s, 1H), 5.78 (s, 2H), 2.89 (s, 3H), 2.48 (s, 3H).
2-(l-((5-chlorothiazol-2-yI)methyl)-2,5-d^
methoxypyridin-4-yl)-2-oxoacetamide (A09)
Figure imgf000092_0002
A solution of 2-(l-((5-chlorothiazol-2-yl)memyl)-2,5-dimethyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-
2-oxoacetic acid (114 mg, 0.326 mmol), triethylamine (0.227 mL, 1.63 mmol), 2- methoxypyridin-4-amine (53.0 mg, 0.424 mmol), and a 50% in ethyl acetate solution of T3P (0.582 mL, 0.978 mmol) in acetonitrile (5 mL) was stirred at room temperature for one hour. The reaction was then diluted in water (15 mL), extracted with ethyl acetate (2 x 40 mL), washed successively with water (3 x 10 mL) and saturated sodium chloride solution (3 x 10 mL), dried (sodium sulfate), filtered and concentrated to afford a residue. Purification was achieved by silica gel chromatography (Luknova 40g, 20 mL/min) using 10 to 60% ethyl acetate in hexanes over 20 minutes to afford 2-(l-((5-chlorothiazol-2-yl)methyl)-2,5-dimethyl- lH-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide (132 mg, 1.45 mmol, 89% yield) as a white solid. Ή NMR (400 MHz, CDC13) δ (ppm): 9.07 (br. s, IH), 8.33 (d, IH), 8.21 (d, IH), 8.15 (d, IH), 7.50 (s, IH), 7.26 (d, IH), 7.15 (dd, IH), 5.76 (s, 2H), 3.97 (s, 3H), 2.87 (s, 3H), 2.49 (s, 3H). LCMS. [ES]+ found 456.0.
Example 3 (see general route 3, procedure E and G):
2-(l-(4-chlorobenzyl)-2-methyl-5-(methylthio)-lH-mdol -yl)-N-(2-methoxvpyridin-4- yl)-2-oxoacetamide (B01)
Figure imgf000093_0001
[00286] To a solution of 2-methyl-5-(methylthio)- 1 H-indole (540 mg, 3.05 mmol) and 4- chlorobenzyl chloride (515 mg, 3.20 mmol, Aldrich) in DMSO (15 mL) was added crushed solid potassium hydroxide (513 mg, 9.14 mmol) resulting in a dark brown solution. The reaction was stirred at room temperature for 24 hours, after which the reaction was diluted in water, extracted with dichloromethane (3 x 40 mL), washed with water (4 x 50 mL), dried (sodium sulfate), filtered and concentrated to a dark brown residue. Purification was achieved by silica gel chromatography (Luknova 40 g, 20 mL/min) using 5 to 40% ethyl acetate in hexanes over 35 minutes. l-(4-chlorobenzyl)-2-methyl-5-(methylthio)-l H-indole (640 mg, 2.12 mmol, 70 % yield) was isolated as a 5.2:1 mixture of l-(4-chlorobenzyl)-2-methyl-5- (methylthio)-l H-indole and 1, 3 -bis(4-chlorobenzyl)-2-methyl-5-(methylthio)-l H-indole (yield determined by 1H NMR) and was used in the next step as a mixture. 1H NMR (400 MHz, CDClj) δ (ppm): 7.56 (d, IH), 7.23 (m, 2H), 7.07-7.14 (m, 2H), 6.87 (d, 2H), 6.27 (s, IH), 5.24 (s, 2H), 2.50 (s, 3H), 2.34 (s, 3H).
[00287] To a 0 °C solution of a 5.2/1 mixture of 1 -(4-chlorobenzyl)-2-methyl-5- (methylthio)-lH-indole and l,3-bis(4-chlorobenzyl)-2-methyl-5-(methylthio)-lH-indole (530 mg, 1.76 mmol) in dichloromethane (20 mL) was added oxalyl chloride (0.164 mL, 1.88 mmol), resulting in a dark brown reaction color. After 10 minutes of stirring at 0 °C, the reaction was complete (by LCMS analysis of the methanolysis product). The reaction was concentrated to a dark brown residue, and was reconstituted in dichloromethane (20 mL). This mixture was cooled to 0 °C, after which 2-methoxypyridin-4-amine (218 mg, 1.76 mmol), followed by triethylarnine (0.245 mL, 1.76 mmol) was added. After 30 minutes, the reaction was complete. The reaction was diluted in water and extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to a gold-colored solid. Purification was achieved by silica gel chromatography (Luknova 120g, 20 mL/min) using 10 to 50% ethyl acetate in hexanes over 50 minutes. The product, 2-(l-(4-chlorobenzyl)-2-methyl-5- (methylthio)-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide (618 mg, 1.24 mmol, 70 % yield) was isolated as a yellow solid (l,3-bis(4-chlorobenzyl)-2-methyl-5-(methylthio)- lH-indole does not react in this step and is easily separated from the reaction mixture). 1H NMR (400 MHz, CDC13) δ (ppm): 9.02 (br. s, IH), 8.18 (d, IH), 8.15 (d, IH), 7.28 (m, 2H), 7.19-7.25 (m, 2H), 7.13-7.17 (m, 2H), 6.94 (d, 2H), 5.34 (s, 2H), 3.96 (s, 3H), 2.68 (s, 3H), 2.54 (s, 3H).
Example 4a (see general route 4, procedure H, M and J):
2-methyl-5-(methylthio)-lH-indole
Figure imgf000094_0001
[00288] A slurry of l-(phenylthio)propan-2-one (638 mg, 3.83 mmol, Matrix Scientific) and (4-(methylthio)phenyl)hydrazine hydrochloride (841 mg, 4.41 mmol, Matrix Scientific) was heated in t-Butanol (18 mL) for 45 minutes at 100 °C resulting in an orange reaction color.
After cooling to room temperature, the reaction was diluted in water (50 mL), extracted with ethyl acetate (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to afford 2-methyl- 5-(methylthio)-3-(phenylthio)-lH-indole (948 mg, 3.32 mmol, 87 % yield) as a tan solid. 1H NMR (400 MHz, CDC13) δ (ppm): 8.23 (br. s, 1H), 7.50 (m, 1H), 7.28 (d, 1H), 7.13-7.20 (m, 3H), 7.02-7.07 (m, 3H), 2.51 (s, 3H), 2.47 (s, 3H). LCMS: 4.02 min, [ES]- found 284.10.
[00289] A slurry of 2-mercaptobenzoic acid (1.02 g, 6.64 mmol) and 2-methyl-5- (methylthio)-3-(phenylthio)-lH-indole (0.948 g, 3.32 mmol) in trifluoroacetic acid (20 mL) was stirred at room temperature for 30 minutes, after which the trifluoroacetic acid was removed in vacuo. The remaining dark orange-red residue was reconstituted in ethyl acetate and washed with 1M aqueous sodium hydroxide (2 x 50 mL), then with water (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to a dark orange residue. Purification was achieved by column chromatography using silica gel (ISCO 120g, 20 mL/min) using 5 to 30% ethyl acetate in hexanes over 60 minutes to afford 2-methyl-5-(methylthio)-lH-indole (540 mg, 3.05 mmol, 92 % yield) as an orange oil. Ή NMR (400 MHz, CDC13) δ (ppm): 7.86 (br. s, 1H), 7.52 (d, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 6.16 (s, 1H), 2.50 (s, 3H), 2.44 (s, 3H). LCMS: 3.39 min, [ES]+ found 178.00.
Example 4b (see general route 4, step H, M and K):
6-methyl-5H-[l,3]dioxolo[4,5-f| indole
Figure imgf000095_0001
[00290] A room temperature solution of benzo[d][l,3]dioxol-5-amine hydrochloride
(25.0 g, 144 mmol) in concentrated 12M aqueous hydrochloric acid solution (60 mL) was stirred for two hours, after which, it was cooled to 0 °C to which a solution of sodium nitrite
(11.5 g, 167 mmol), in water (50 mL), was added, dropwise over 45 minutes, with internal temperature monitoring such that the reaction temperature does not warm above 5 °C. After stirring for one hour at 0 °C, the reaction mixture was poured slowly into a 0 °C pre-made solution of tin(II) chloride dihydrate (136 g, 605 mmol) in concentrated 12M aqueous hydrochloric acid solution (125 mL). The reaction mixture was allowed to warm up to room temperature, after which it was stored in the freezer overnight (12 hours), leading to the formation of a precipitate. This dark brown solid was successively washed with water (2 x 100 mL) and diethyl ether (3 x 100 mL), and dried to afford benzo[d][l,3]dioxol-5-ylhydrazine hydrochloride (8.60 g, 46.1 mmol, 32% yield) as a dark brown solid. 1H NMR (400 MHz, CD3OD) δ (ppm): 6.79 (d, 1H), 6.63 (d, 1H), 6.50 (dd, 1H), 6.06 (s, 1H), 5.94 (s, 2H).
[00291] A slurry of l-(phenylthio)propan-2-one (1.30 g, 7.82 mmol, Matrix Scientific) and benzo[d][l,3]dioxol-5-ylhydrazine hydrochloride (2.10 g, 11.1 mmol) was heated in isobutyl alcohol (15 mL) for 60 minutes at 90 °C. After cooling to room temperature, the reaction was filtered through celite, diluted in ethyl acetate (100 mL), washed successively with water (2 x 30 mL) and saturated sodium chloride solution (2 x 30 mL), dried (sodium sulfate), filtered and concentrated to a residue. Purification was achieved by silica gel chromatography (ISCO 24g, 35 mL/min) using 5 to 50% ethyl acetate in hexanes over 30 minutes to afford 6- methyl-7-(phenylthio)-5H-[l,3]dioxolo[4,5-fJindole (1.23 g, 4.34 mmol, 55 % yield) as a solid. 1H NMR (400 MHz, CDC13) δ (ppm): 8.09 (br. s, 1H), 7.14-7.18 (m, 2H), 7.01-7.06 (m, 3H), 6.92 (s, 1H), 6.81 (s, 1H), 5.91 (s, 2H), 2.46 (s, 3H). LCMS: 1.89 min, [ES]" found 282.20.
[00292] To a slurry of Raney nickel (7.00 g, 119 mmol, 50% solution in water) in absolute ethanol (50 mL) was added solid 6-methyl-7-(phenylthio)-5H-[l,3]dioxolo[4,5- fjindole (1.23 g, 4.34 mmol). The reaction suspension was heated to 90 °C for five hours, after which it was cooled too room temperature, filtered through celite, washed with ethyl acetate (3 x 20 mL), and concentrated to a solid. Purification was achieved by silica gel chromatography (ISCO 40g, 40 mL/min) using 5 to 30% ethyl acetate in hexanes over 30 minutes to afford 6- methyl-5H-[l,3]dioxolo[4,5-fJindole (0.760 g, 3.48 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, CDC13) 5 (ppm): 7.70 (br. s, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 6.09 (s, 1H), 6.81 (s, 1H), 5.90 (s, 2H), 2.39 (s, 3H). LCMS: 1.27 min, [ES]- found 174.00.
The following compounds were prepared according to general route 1:
2-(l-((5-chlorothiazol-2-yl)methyl)-6-fluoro-5-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A03)
Figure imgf000097_0001
[00293] 2-(l-((5-chlorothiazol-2-yl)memyl)-6-fluoro-5-memoxy-2-methyl-lH-indol-3- yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid using general route 1. Purification was achieved by silica gel chromatography (Luknova 40g, 20 mL/min ) using 2 to 9% of a 7:1 solution of acetonitrile/methanol in dichloromethane over 55 minutes. Ή NMR (400 MHz, CDC13) δ (ppm): 9.02 (br. s, 1H), 8.15 (d, 1H), 7.86 (d, 1H), 7.55 (s, 1H), 7.24 (d, 1H), 7.12-7.15 (m, 2H), 5.48 (s, 2H), 3.96 (s, 6H, two shifts isochronous), 2.73 (s, 3H).
2-(5-methoxy-l-((5-methoxy-l,2,4-thiadiazol-3-yl)methyl)-2-methyl-lH-mdol-3-yl)-N-(2 methoxypyridin-4-yl)-2-oxoacetamide (A16)
Figure imgf000097_0002
[00294] 2-(5-methoxy- 1 -((5-methoxy- 1 ,2,4-thiadiazol-3-yl)methyl)-2-methyl- 1 H-indol- 3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a solid using general route 1. 1H NMR (400 MHz, CDC13) δ (ppm): 9.09 (s, 1H), 8.13 (s, 1H), 7.69 (s, 1H), 7.34 (s, 1H), 7.26 (s, 1H, isochronous with CDC13), 7.15 (d, 1H), 6.89 (d, 1H), 5.30 (s, 2H), 4.10 (s, 3H), 4.04 (s, 3H), 3.83 (s, 3H), 2.81 (s, 3H). 2-(5-chloro-l-((5-chlorothiazol-2-yl)methyl)-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yI)-2-oxoacetamide (A05)
Figure imgf000098_0001
[00295] 2-(5-chloro-l-((5-chlorothiazol-2-yl)methyl)-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a solid using general route 1. Ή NMR (400 MHz, CDC13) δ (ppm): 9.03 (s, IH), 8.19 (d, IH), 8.15 (d, IH), 7.54 (s, IH), 7.25- 7.32 (m, 3H), 7.16 (dd, IH), 5.54 (s, 2H), 3.97 (s, 3H), 2.81 (s, 3H).
2-(l-((5-chlorothiazol-2-yl)methyl)-2-methy^^
2-oxoacetamide (A04)
Figure imgf000098_0002
[00296] 2-(l-((5-chlorothiazol-2-yl)methyl)-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a solid using general route 1. 1H NMR (400 MHz, CDC13) δ (ppm): 9.02 (s, IH), 8.14-8.17 (m, 2H), 7.54 (s, IH), 7.37-7.40 (m, IH), 7.30-7.34 (m, 2H), 7.26-7.27 (m, IH), 7.17 (dd, IH), 5.57 (s, 2H), 3.97 (s, 3H), 2.82 (s, 3H). 2-(5-chloro-l-((5-chlorothiazol-2-yl)methyl)-6-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A10)
Figure imgf000099_0001
[00297] 2-(5-chloro-l-((5-chlorothiazol-2-yl)methyl)-6-methoxy-2-methyl-lH-indol-3- yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid using general route 1. 1H NMR (400 MHz, CDC13) δ (ppm): 9.06 (br. s, IH), 8.17 (s, IH), 8.14 (d, IH), 7.54 (s, IH), 7.24 (d, IH), 7.16 (dd, IH), 6.83 (s, IH), 5.49 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 2.77 (s, 3H). LCMS [ES]+ found 506.0.
2-(l-((2-chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A01)
Figure imgf000099_0002
[00298] 2-(l-((2-chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a gold solid in 39% yield using general route 1. Purification was achieved by silica gel chromatography (Luknova 80g, 20 mL/min) using 30 to 100% ethyl acetate in hexanes over 60 minutes. 1H NMR (400 MHz, CDC13) δ (ppm): 9.03 (br. s, IH), 8.13 (d, IH), 7.74 (d, IH), 7.41 (s, IH), 7.24 (d, IH), 7.20 (d, IH), 7.15 (dd, IH), 6.94 (dd, IH), 5.42 (s, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 2.75 (s, 3H). 2-(6-chloro-l-((5-chIorothiazol-2-yl)methyl)-2,5-dimethyl-lH-indol-3-yl)-N^ methoxypyridin-4-yl)-2-oxoacetamide (A19)
Figure imgf000100_0001
[00299] 2-(6-cWoro-l-((5-cMorothiazol-2-yl)methyl)-2,5-dimethyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid using general procedure 1. Purification was achieved by silica gel chromatography using 0 to 70% ethyl acetate in hexanes over 30 minutes. 1H NMR (400 MHz, CDC13) δ (ppm): 1H NMR (400 MHz, CDC13) δ (ppm): 9.01 (s, IH), 8.15 (d, IH), 8.03 (s, IH), 7.55 (s, IH), 7.38 (s, IH), 7.25 (d, IH), 7.15 (dd, IH), 5.49 (s, IH), 3.96 (s, 3H), 2.78 (s, 3H), 2.47 (s, 3H).
2-(l-((5-chlorothiazol-2-yl)methyl)-5-methoxy-2,6-dimethyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A20)
Figure imgf000100_0002
[00300] 2-(l-((5-cWorotliiazol-2-yl)methyl)-5-methoxy-2,6-dimethyl-lH-indol-3-yl)-N- (2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid using general route 1. Purification was achieved by silica gel chromatography using 10% to 70% ethyl acetate in hexanes over 35 minutes. Ή NMR (400 MHz, CDC13) δ (ppm): 9.11 (br s, IH), 8.10 (d, IH), 7.63 (s, IH), 7.51 (s, IH), 7.23 (s, IH), 7.13 (d, IH), 7.06 (s, IH), 5.42 (s, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 2.70 (s, 3H), 2.29 (s, 3H)., LCMS: [M+H]+ , found 485.0. 2-(l-((5-chlorothiazol-2-yl)methyI)-6-fluoro-2,5-dimethyl-lH-indoI-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A 18)
Figure imgf000101_0001
[00301] 2-(l (5-chlorotmazol-2-yl)methyl)-6-fluoro-2,5-dimethyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized using general route 1. Purification was achieved by silica gel chromatography using 5 to 80% ethyl acetate in hexanes over 35 minutes. Ή NMR (400 MHz, CDC13) δ (ppm): 8.78 (s, IH), 7.86 (d, IH), 7.68 (d, IH), 7.26 (s, IH, isochronous with CDC13), 6.98 (d, IH), 6.88 (d, IH), 6.75 (d, IH), 5.17 (s, 2H), 3.68 (s, 3H), 2.48 (s, 3H), 2.08 (s, 3H).
The following compound was sysnthesized by general route 2.
2-(l-((5-chlorothiazol-2-yl)methyl)-5-methoxy-2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)- N-(2-methoxypyridin-4-yl)-2-oxoacetamide (A17)
Figure imgf000101_0002
[00302] 2-( 1 -((5,-chlorothiazol-2-yl)methyl)-5-methoxy-2-methyl- 1 H-pyrrolo[2,3 - b]pyridin-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized using general route 2. Purification was achieved by silica gel chromatography using 5 to 50% ethyl acetate in hexanes over 40 minutes. 1H NMR (400 MHz, CDC13) δ (ppm): 9.13 (br. s, IH), 8.10 (m, 3H), 7.47 (s, IH), 7.23 (d, IH), 7.1 l(d, IH), 5.70 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.82 (s, 3H). The following compounds were prepared according to general route 3:
2-(l-(4-chlorobenzyl)-2-methyl-5-(thiazol-2-yl)-lH-mdol-3-yl)-N-(2-methoxypyridm-4 yl)-2-oxoacetamide (B03)
Figure imgf000102_0001
[00303] 2-( 1 -(4-chlorobenzyl)-2-methyl- 1 H-indol-5-yl)thiazole was synthesized as a 15:1 mixture of 2-(l -(4-chlorobenzyl)-2 -methyl- lH-indol-5-yl)thiazole and 2-(l,3-bis(4- chlorobenzyl)-2-methyl-lH-indol-5-yl)thiazole starting from 2-(2 -methyl- lH-indol-5- yl)thiazole, 4-chlorobenzyl chloride and DMSO as solvent using general procedure E. A 71% yield of 2-(l-(4-chlorobenzyl)-2-methyl-lH-indol-5-yl)thiazole was determined by 1H NMR.
[00304] 2-(l-(4-chlorobenzyl)-2-methyl-5-(thiazol-2-yl)-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid in 65% yield starting from a 15:1 mixture of 2-(l-(4-chlorobenzyl)-2-methyl-lH-indol-5-yl)thiazole and 2-(l,3- bis(4-chlorobenzyl)-2-methyl-lH-indol-5-yl)thiazole using general procedure G. Purification was achieved by silica gel chromatography (ISCO 120g, 20 mL/min) using 10 to 75% ethyl acetate in hexanes over 60 minutes, followed by a repurification on silica gel (Luknova 40g, 20 mL/min) using an isocratic 12% solution of a 7:1 acetonitrile/methanol mixture in
dichloromethane. 1H NMR (400 MHz, CDC13) δ (ppm): 9.11 (s, 1H), 8.79 (d, 1H), 8.16 (d, 1H), 7.95 (dd, 1H), 7.85 (d, 1H), 7.26-7.31 (m, 5H), 7.19 (dd, 1H), 6.96 (d, 2H), 5.38 (s, 2H), 3.97 (s, 3H), 2.45 (s, 3H). 2-(l-((5-chlorothiophen-2-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yI)-2-oxoacetamide (Al 1)
Figure imgf000103_0001
[00305] To a solution of 5-methoxy-2-methyl- 1 H-indole ( 1.50 g, 9.31 mmol) in N,N- dimethylformamide (10 mL) at 0 °C was added sodium hydride (0.558 g, 14.0 mmol). The reaction was stirred at room temperature for 20 minutes, after which 2-chloro-5- (chloromethyl)thiophene (1.87 g, 11.2 mmol) was added. The reaction mixture was stirred at 80 °C for 24 hours, after which it was diluted with water, extracted with ethyl acetate (3 x 50 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 40g) using 0 to 80% ethyl acetate in hexanes to afford 5-methoxy-2- methyl-l-(pyridin-2-ylmethyl)-l H-indole as a yellow-brown solid in 8% yield.
[00306] 2-(l-((5-chlorothiophen-2-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid in 24% yield starting from l-((5-chlorothiophen-2-yl)methyl)-5-methoxy-2-methyl-l H-indole using general procedure G. Ή NMR (400 MHz, CDC13) δ (ppm): 9.11 (s, 1H), 8.13 (d, 1H), 7.71 (s, 1H), 7.26 (d, 1H, isochronous with CDC13), 7.15 (d, 2H), 6.91 (d, 1H), 6.73 (d, 1H), 6.62 (d, 1H), 5.30 (s, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 2.70 (s, 3H). 2-(5-methoxy-2-methyl-l-(oxazol-2-ylmethyl)-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)- 2-oxoacetamide (A12)
Figure imgf000104_0001
[00307] 2-(5-methoxy-2-methyl- 1 -(oxazol-2-ylmethyl)- 1 H-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid using general route 3. 1H NMR (400 MHz, CDC13) δ (ppm): 9.03 (s, 1H), 8.14 (d, 1H), 7.70 (s, 1H), 7.38 (d, 1H), 7.26 (d, 2H, isochronous with CDCI3), 7.15 (d, 1H), 7.09 (d, 1H), 6.93 (d, 1H), 5.38 (s, 2H), 3.96 (s, 3H), 3.84 (s, 3H), 2.83 (s, 3H).
2-(5-methoxy-2-methyl-l-(pyrimidin-2-ylmethyl)-lH-indol-3-yl)-N-(2-methoxypyridin-4- yl)-2-oxoacetamide (A13)
Figure imgf000104_0002
[00308] 2-(5-methoxy-2-methyl- 1 -(pyrimidin-2-ylmethyl)- 1 H-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid using general route 3. 1H NMR (400 MHz, CD3OD) 6 (ppm): 8.06 (d, 1H), 7.53 (s, 1H), 7.30 (m, 2H), 7.22 (d, 1H), 7.09 (s, 1H), 6.86 (m, 2H), 5.58 (s, 2H), 3.91 (s, 3H), 3.73 (s, 3H), 3.63 (s, 3H), 2.65 (s, 3H). 2-(l-((5-chlorothiazol-2-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A07)
Figure imgf000105_0001
[00309] 2-(l-((5-chlorothiazol-2-yl)methyl)-5-methoxy-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid using general route 3. Ή NMR (400 MHz, CDC13) δ (ppm): 9.21 (s, IH), 8.10 (d, IH), 7.66 (s, IH), 7.50 (s, IH), 7.24 (d, IH), 7.20 (d, IH), 7.15 (d, IH), 6.89 (d, IH), 5.39 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 2.68 (s, 3H).
2-(5-methoxy-2-methyl-l-((5-methylthiazol-2-yl)methyl)-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A06)
Figure imgf000105_0002
[00310] 2-(5-methoxy-2-methyl-l-((5-methylthiazol-2-yl)methyl)-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid starting from 2- (chloromethyl)-4-methyl-l,3-thiazole using general route 3. Ή NMR (400 MHz, CDC13) δ (ppm): 9.13 (s, IH), 8.12 (d, IH), 7.70 (s, IH), 7.36 (s, IH), 7.26 (m, 2H, isochronous with CDC13), 7.16 (d, IH), 6.91 (d, IH), 5.46 (s, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 2.74 (s, 3H), 2.36 (s, 3H). 2-(l-(4-chlorobenzyl)-2-methyl-5-morpholino-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl 2-oxoacetamide (B06)
Figure imgf000106_0001
2-(l-(4-cWorobenzyl)-2-methyl-5-mo holino-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl^ oxoacetamide was synthesized as an orange solid using general route 3. Ή NMR (400 MHz, CDC13) δ (ppm): 9.02 (s, IH), 8.14 (d, IH), 7.81 (s, IH), 7.24-7.29 (m, 6H), 6.94-6.96 (m, 2H), 5.33 (s, 2H), 3.96 (s, 3H), 3.90 (s, 4H), 3.19 (s, 4H), 2.68 (s, 3H).
2-(l-((5-chlorothiazol-2-yl)methyl)-2,5-dimethyl-lH-indol-3-yl)-N-(2-methoxypyrW
yl)-2-oxoacetamide (A14)
Figure imgf000106_0002
[00311] 2-( 1 -((5-chlorothiazol-2-yl)methyl)-2,5-dimethyl- 1 H-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid in 17% yield using general route 3. 1H NMR (400 MHz, CDC13) δ (ppm): 9.04 (br. s, IH), 8.14 (d, IH), 7.95 (s, IH), 7.52 (s, IH), 7.26 (d, 2H), 7.16 (d, IH), 7.13 (d, IH), 5.51 (s, 2H), 3.96 (s, 3H), 2.77 (s, 3H), 2.46 (s, 3H). LCMS: 1.77 min, [ES]+ found 454.93. 2-(6-chloro-l-((5-chlorothiazol-2-yl)m^
methoxypyridin-4-yl)-2-oxoacetamide (A08)
Figure imgf000107_0001
[00312] 2-(6-cMoro-l-((5-chlorothiazol-2-yl)methyl)-5-methoxy-2-methyl-lH-indol-3- yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid using general route 3. 1H NMR (400 MHz, CDC13) δ (ppm): 9.09 (br. s, IH), 8.13 (d, IH), 7.79 (s, IH), 7.54 (s, IH), 7.37 (s, IH), 7.23 (d, IH), 7.14 (d, IH), 5.45 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 2.75 (s, 3H). LCMS: 1.78 min, [ES]+ found 505.37.
2-(5-methoxy-2-methyl-l-((4-methylthiazol-2-yl)methyl)-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A15)
Figure imgf000107_0002
[00313] 2-(5-methoxy-2-methyl- 1 -((4-methylthiazol-2-yl)methyl)- 1 H-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a gold solid using general procedure G. 1H NMR (400 MHz, CDC13) δ (ppm): 9.01 (s, IH), 8.13 (d,lH), 7.75 (d, IH), 7.24 - 7.29 (m, 2H), 7.15 (dd, IH), 6.91 (dd, IH), 6.80 (s, IH), 5.56 (s, 2H), 3.87 (s, 3H), 3.56 (s,3H), 2.80 (s, 3H), 2.44 (s, 3H). 2-(5-(4-chlorobeiizyl)-6-methyl-5H-[l,3]dioxolo[4,5-fJindoI-7-yl)-N-(2-methoxypyrW yl)-2-oxoacetamide (B08)
Figure imgf000108_0001
[00314] 6-methyl-5H-[l,3]dioxolo[4,5-fjindole was synthesized according to general route 4. 2-(5-(4-chlorobenzyl)-6-methyl-5H-[ 1 ,3]dioxolo[4,5-fJindol-7-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid in using general route 3. Ή NMR (400 MHz, CDC13) δ (ppm): 9.00 (br. s, 1H), 8.13 (d, 1H), 7.65 (s, 1H), 7.28 (d, 2H), 7.23 (d, 1H), 7.15 (dd, 1H), 6.94 (d, 2H), 6.65 (s, 1H), 5.96 (s, 2H), 5.26, (s, 2H), 3.96 (s, 3H), 2.64 (s, 3H). LCMS: [ES]+ found 478.0.
The following compounds or precursors of compounds were not prepared
according to any of the general routes:
2-(bromomethyl)-5-chlorothiazole
Figure imgf000108_0002
[00315] To a -78 °C solution of 2-methylthiazole (15.0 g, 152 mmol) in tetrahydrofuran (500 mL) was added a 2.5M in hexanes solution of n-butyllithium (73.0 mL, 182 mmol) over 30 minutes with internal temperature monitoring such that the internal temperature did not rise above -65 °C. This anion solution was stirred at -78 °C for an addition 30 minutes, after which hexachloroethane (43.1 g, 182 mmol) was added portionwise over 30 minutes with internal temperature monitoring such that the internal temperature did not rise above -65 °C. The reaction mixture was stirred at -78 °C for an additional 30 minutes, after it was warmed to room temperature, quenched by the addition of saturated ammonium chloride solution (500 mL) extracted with diethyl ether (2 x 500 mL), dried (sodium sulfate), filtered and carefully concentrated to a residue (during the solvent removal process, the temperature of the rotovap bath must be carefully monitored and kept below 30 °C to minimize product loss due to volatility). Purification was achieved by silica gel chromatography (300g silica) using 0 to 15% diethyl ether in pentane to afford 5-chloro-2-methylthiazole (13.3 g, 100 mmol, 65% yield) as a dark brown liquid.
[00316] A solution of 5-Chloro-2-methylthiazole (7.00 g, 52.2 mmol), N- Bromosuccinimide (11.6 g, 65.3 mmol) and azobisisobutyronitrile (0.860 g, 5.20 mmol) in carbon tetrachloride (75 mL) was refluxed for three hours after which additional N- Bromosuccinimide (2.00 g, 1 1.2 mmol) and azobisisobutyronitrile (0.100 g, 0.600 mmol) were added. The reaction was refluxed an additional three hours, after which the reaction mixture was cooled to room temperature and allowed to stir at that temperature for 12 hours. The reaction mixture was then filtered and carefully to a residue (during the solvent removal process, the temperature of the rotovap bath must be carefully monitored and kept below 30 °C to minimize product loss due to volatility). Purification was achieved by silica gel
chromatography (300g silica) using 0 to 10% diethyl ether in pentane to afford 2- (bromomethyl)-5-chlorothiazole (3.60 g, 16.9 mmol, 32% yield) as an amber liquid. This compound should be kept cold to enhance its stability.
2-(chloromethyl)-4-methyl-l,3-thiazole
Figure imgf000109_0001
[00317] To a 0 °C solution of 4-methyl-l,3-thiazole-2-carbaldehyde (2.00 g, 15.7 mmol) in methanol (20 mL) was added sodium borohydride (0.700 g, 18.9 mmol) portionwise, after which the reaction was warmed to room temperature and stirred at that temperature for two hours. The reaction mixture was then quenched by the addition of water (5 mL), concentrated to a residue, reconstituted in water (40 mL) and extracted with ethyl acetate (2 x 60 mL), (magnesium sulfate), filtered and concentrated to afford (4-methyl-l,3-thiazol-2-yl)methanol (1.70 g, 13.2 mmol, 84% yield) as viscous oil. This material was used in the subsequent step without any purification. [00318] To a 0 °C solution of (4-methyl-l,3-thiazol-2-yl)methanol (1.70 g, 14.4 mmol) in dichloromethane (25 mL) was added thionyl chloride (2.55 g, 21.6 mmol) dropwise, after which the reaction mixture was allowed to warm up to room temperature and stirred at that temperature for two hours. The reaction mixture was washed by the addition of saturated sodium bicarbonate solution (1 x 40 mL), and the organic layer was separated, dried (sodium sulfate), filtered and concentrated to a residue. Purification was achieved by silica gel chromatography using 20% ethyl acetate in hexanes to afford 2-(chloromethyl)-4-methyl-l,3- thiazole (1.20 g, 8.12 mmol, 56% yield) as pale yellow viscous oil. 1H NMR (300 MHz, CDC13) δ (ppm): 6.87 (s, 1H), 4.76 (s, 2H), 2.40 (s, 3H).
2-(2-methyl-lH-indol-5-yl)thiazole
Figure imgf000110_0001
[00319] To a slurry of zinc dust (1.21 g, 18.6 mmol) in tetrahydrofuran (5 mL) was added 1,2-dibromoethane (0.144 mL, 1.67 mmol). This slurry was heated to a rapid boil with a heat gun twice (to incite evolution of ethylene). To this resulting slurry was added
chlorotrimethylsilane (0.0950 mL, 0.743 mmol) followed by a solution of 2-bromothiazole (1.02 g, 6.19 mmol) in tetrahydrofuran (3 mL). The reaction was stirred for 15 minutes, after which a solution of Pd(Ph3P)4 (0.143 g, 0.124 mmol) and 5-bromo-2-methyl-lH-indole (1.30 g, 6.19 mmol) was added. The reaction was refluxed at 95 °C for 24 hours, after which the reaction was cooled to room temperature, filtered through a pad of celite, extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to an orange residue. Purification of the reaction mixture by silica gel chromatography (Luknova 120g, 20 mL/min) using 10 to 50% ethyl acetate in hexanes over 60 minutes afforded 2-(2-methyl-lH- indol-5-yl)thiazole (640 mg, 2.99 mmol, 48 % yield) as a yellow foam. 1H NMR (400 MHz, CDCI3) 6 (ppm): 8.12 (s, 1H), 8.08 (br. s, 1H), 7.82 (d, 1H), 7.76 (dd, 1H), 7.31 (dd, 1H), 7.24 (d, 1H), 6.28 (s, 1H), 2.45 (s, 3H). 2-(5-methoxy-l-((2-methoxythiazol-5-yl)methyl)-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (A02)
Figure imgf000111_0001
[00320] To a 0 °C solution of 2-( 1 -((2-chlorothiazol-5-yl)methyl)-5-methoxy-2-methyl- lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide (145 mg, 0.308 mmol) in methanol (15 mL) was added a 25% wt. solution of sodium methoxide (0.282 mL, 1.23 mmol). The reaction was warmed to room temperature and stirred for 2 hours, after which the reaction was then heated to 50 °C for 12 hours. LCMS analysis indicated about 60% conversion to the desired product, after which additional 25% sodium methoxide solution (282 iL) was added. The reaction was then heated for 24 hours, after which it was cooled to room temperature, concentrated to a residue, diluted in water, extracted with ethyl acetate (3 x 50 mL), dried (sodium sulfate), filtered and concentrated. First pass purification was achieved by silica gel chromatography (Luknova 40 g, 20 mL/min) using 10 to 50% ethyl acetate in hexanes over 60 minutes. Repurification by silica gel chromatography (Luknova 40 g, 20 mL/min) was necessary using 2 to 9% of a 7:1 acetonitrile/methanol mixture in dichloromethane over 60 minutes to afford pure 2-(5-memoxy-l-((2-metnoxythiazol-5-yl)methyl)-2-methyl-lH-indol-3- yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide (52.0 mg, 0.111 mmol, 36 % yield) as a tan solid. 1H NMR (400 MHz, CDC13) δ (ppm): 9.00 (br. s, IH), 8.14 (d, IH), 7.74 (d, IH), 7.24- 7.27 (m, 2H), 7.15 (dd, IH), 7.02 (s, IH), 6.93 (dd, IH), 5.33 (s, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.87 (s, 3H), 2.77 (s, 3H). 2-(l-(4-chlorobenzyl)-2-methyl-5-(methylsu
4-yl)-2-oxoacetamide (B04)
Figure imgf000112_0001
[00321] 2-(l-(4-chlorobenzyl)-2-methyl-5-(methylsulfonyl)-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was prepared according to general route 3 with the addition of the following step.
[00322] To a solution of 2-(l-(4-chlorobenzyl)-2-methyl-5-(methylthio)-lH-indol-3-yl)- N-(2-methoxypyridin-4-yl)-2-oxoacetamide (80.8 mg, 0.168 mmol) in dichloromethane (4 mL) was added m-chloroperoxybenzoic acid (75.0 mg, 0.337 mmol) at room temperature. After two hours, the reaction was complete by LCMS analysis. The reaction mixture was poured into saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (3 x 50 mL), washed with saturated sodium bicarbonate solution (2 x 50 mL), dried (sodium sulfate), filtered, and concentrated to an off-white solid. Purification was achieved by column chromatography (Luknova 25g, 20 mL/min) using 10 to 100% ethyl acetate over 70 minutes affording 2-(l-(4-chlorobenzyl)-2-methyl-5-(methylsulfonyl)-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (72.1 mg, 0.141 mmol, 84 % yield) as a pale-yellow solid. Ή NMR (400 MHz, CDC13) δ (ppm): 9.10 (br. s, IH), 8.82 (d, IH), 8.16 (d, IH), 7.81 (dd, IH), 7.37 (d, IH), 7.31 (m, 2H) 7.24-7.27 (m, 2H), 6.93 (d, 2H), 5.43 (s, 2H), 3.97 (s, 3H), 3.13 (s, 3H), 2.74 (s, 3H).
I l l methyl l-(4-chlorobenzyl)-3-(2-(2-methoxypyridm-4-ylamino)-2-oxoacetyl)-2-methyl- lH-indole-5-car boxy late (B02)
Figure imgf000113_0001
[00323] To a slurry of 1 -(4-chlorobenzyl)-2-methyl- 1 H-indole-5-carboxylic acid (350 mg, 1.17 mmol) in diethyl ether (50 mL) and methanol (50.0 mL) was added a 2M solution in diethyl ether of trimethylsilyldiazomethane (2.92 mL, 5.84 mmol). The reaction was stirred at room temperature for 30 minutes, after which the slurry became homogeneous and gold in color. The reaction mixture was concentrated to afford the product, methyl l-(4-chlorobenzyl)- 2-methyl-lH-indole-5-carboxylate (350 mg, 1.12 mmol, 96 % yield) as a tan solid, which was used in the subsequent step without any purification. Ή NMR (400 MHz, CDC13) δ (ppm): 8.16 (d, IH), 7.66 (dd, IH), 7.07-7.10 (m, 2H), 7.01 (d, IH), 6.71 (d, 2H), 6.27 (s, IH), 5.12 (s, 2H), 3.76 (s, 3H), 2.20 (s, 3H).
[00324] Methyl 1 -(4-chlorobenzyl)-3-(2-(2-methoxypyridin-4-ylamino)-2-oxoacetyl)-2- methyl-lH-indole-5-carboxylate was synthesized as a white solid in 56% yield starting from methyl l-(4-chlorobenzyl)-2 -methyl- lH-indole-5-carboxylate using general procedure G. 1H NMR (400 MHz, CDC13) δ (ppm): 9.06 (s, IH), 8.90 (s, IH), 8.16 (d, IH), 7.97 (dd, IH), 7.24-7.30 (m, 4H), 7.19 (dd, IH), 6.95 (d, 2H), 5.40 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 2.71 (s, 3H).
2-(l-(4-chlorobenzyl)-2-methyl-5-(methylsulfonamido)-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (B05)
Figure imgf000114_0001
[00325] To a solution of 2-methyl-5-nitro-lH-indole (1.00 g, 5.68 mmol) in acetonitrile (11.4 mL) was added potassium carbonate (1.57 g, 11.4 mmol), and 4-chlorobenzyl chloride (0.914 g, 5.68 mmol). The reaction mixture was heated to 70 °C for 16 hours after which it was complete by LCMS analysis. The reaction was cooled to room temperature, diluted with water, then concentrated to remove the acetonitrile, leading to the formation of a precipitate. This solid was filtered and dried to afford l-(4-chlorobenzyl)-2-methyl-5-nitro-lH-indole as a solid (1.50 g, 4.99 mmol, 88 % yield).
[00326] 2-(l-(4-chlorober^yl)-2-methyl-5-nitro-lH-indol-3-yl)-N-(2-methoxypyridin-4- yl)-2-oxoacetamide was synthesized using l-(4-chlorobenzyl)-2-methyl-5-nitro-lH-indole following general procedure G to yield 2-(l-(4-chlorobenzyl)-2-methyl-5-nitro-lH-indol-3-yl)- N-(2-methoxypyridin-4-yl)-2-oxoacetamide as a solid in 44% yield. 1H NMR (400 MHz, CDC13) δ (ppm): 9.17 (d, 1H), 9.12 (s, 1H), 8.15-8.18 (m, 2H), 7.30-7.33 (m, 3H), 7.25-7.27 (m, 1H), 7.20 (dd, 1H), 6.94 (d, 2H), 5.43 (s, 2H), 3.99 (s, 3H), 2.75 (s, 3H).
[00327] To a solution of 2-(l-(4-chlorobenzyl)-2-methyl-5-nitro-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (0.182 g, 0.380 mmol) in tetrahydrofuran (1.9 mL) absolute ethanol (3.8 mL) and saturated ammonium chloride solution (1.9 mL) was added iron powder (0.127 g, 2.28 mmol). The reaction mixture was heated to 70 °C for 2 hours, after which it was cooled to room temperature and filtered through a pad of celite using ethyl acetate as the solvent (150 mL). The filtrate was dried (sodium sulfate), and concentrated to afford a residue. Purification was achieved by silica gel chromatography using 0 to 80% ethyl acetate in hexanes to afford 2-(5-amino-l-(4-chlorobenzyl)-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide as a yellow solid in 49% yield. 1H NMR (400 MHz, CD3OD) 5 (ppm): 8.04 (d, 1H), 7.44 (d, 1H), 7.27-7.30 (m, 3H), 7.20-7.22 (m, 1H), 7.14 (d, 1H), 7.00 (d, 2H), 6.70-6.73 (m, 1H), 5.38 (s, 2H), 3.90 (s, 3H), 2.57 (s, 3H).
[00328] To a solution of 2-(5-amino-l-(4-chlorobenzyl)-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (0.139 g, 0.310 mmol) in dichloromethane (3.1 mL) was added pyridine (0.122 g, 1.55 mmol) followed by methanesulfonyl chloride (0.035 g, 0.310 mmol). The reaction mixture was stirred at room temperature for 30 minutes after which it was acidified with aqueous 1M hydrochloric acid solution (lOmL), extracted with dichloromethane (3 x 50 mL) dried (sodium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography using 10 to 50% ethyl acetate in hexanes to afford 2-(l-(4- chlorobenzyl)-2-methyl-5-(methylsulfonamido)- 1 H-indol-3 -yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide as a solid in a 15% yield. Ή NMR (400 MHz, CDC13) δ (ppm): 9.36 (s, 1H), 8.14 (d, 2H), 7.20-7.37 (m, 6H), 6.97 (d, 2H), 5.36 (s, 2H), 3.96 (s, 3H), 2.97 (s, 3H), 2.68 (s, 3H) [N-H sulfonamide proton not observed].
2-(l-(4-chlorobeiizyI)-2-methyl-5-^yrroUdin-l-yl)-lH-indol -yl)-N-(2-methoxypyridin- 4-yl)-2-oxoacetamide (B07)
Figure imgf000115_0001
[00329] To an oven-dried, nitrogen-purged vial was added 5-bromo-l-(4-chlorobenzyl)- 2-methyl-lH-indole (2.00 g, 9.52 mmol), Pd2(dba)3 (0.087 g, 0.095 mmol) and
dicyclohexyl(2',4',6l-triisopropylbiphenyl-2-yl)phosphine (0.182 g, 0.381 mmol) after which the vial containing this mixture of solids was again evacuated and back-filled with nitrogen. Pyrrolidine (0.787 mL, 9.52 mmol) was then added followed by a 1M in tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (21.0 mL, 21.0 mmol). The reaction mixture was heated to 65 °C for 16 hours, after which it was cooled to room temperature and quenched by the addition of 1M hydrochloric acid solution (2 mL) and stirred for 30 minutes. The reaction mixture was diluted with saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3 x 100 mL), washed with saturated sodium chloride solution (50mL), dried (sodium sulfate) and concentrated to a residue. Purification was achieved by silica gel chromatography using 0 to 70% ethyl acetate in hexanes to afford 2-methyl-5-(pyrrolidin-l-yl)-lH-indole (0.600 g, 3.00 mmol, 32% yield) as a crude solid. This material was used in the subsequent step without any purification.
[00330] To a solution of 2-methyl-5-(pyrrolidin-l-yl)-lH-indole (0.275 g, 1.37 mmol) in NN-dimethylformamide (2.8 mL) was added l-(bromomethyl)-4-chlorobenzene (0.282 g, 1.37 mmol) followed by a 60% dispersion in mineral oil of sodium hydride (0.0660 g, 1.65 mmol). The reaction mixture was heated to 65 °C for 16 hours, after which it was cooled, quenched with water (50 mL), extracted with dichloromethane (3 x 100 mL), washed with water (1 x 100 mL), dried (sodium sulfate), filtered and concentrated to afford l-(4-chlorobenzyl)-2-methyl-5- (pyrrolidin-l-yl)-lH-indole (0.192 g, 0.591 mmol, 43 % yield) as a solid. This material was used in the subsequent step without any purification.
[00331] 2-(l-(4-chlorobenzyl)-2-methyl-5-(pyrrolidin-l-yl)-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a solid in 32% yield starting fromo 1 -(4-chlorobenzyl)-2-methyl-5-(pyrrolidin- 1 -yl)- 1 H-indole using general procedure G. 1 H NMR (400 MHz, CDC13) δ (ppm): 9.00 (s,lH), 8.13 (d, IH), 7.43 (d, IH), 7.25-7.27 (m, 3H), 7.13-7.15 (m, IH), 7.07 (d, IH), 6.94-6.96 (d, 2H), 6.57-6.60 (m, IH), 5.30 (s, 2H), 3.96 (s, 3H), 3.34 (t, 4H) 2.65 (s, 3H), 2.02 (m, 4H).
Biological Assays:
Example 5: FAAH Inhibition Using Rat and Human Brain Homogenate Assays:
[00332] The ability of compounds to inhibit FAAH was measured in human whole cell and human and rodent brain homogenates as described herein.
A. FAAH Rat Brain Membrane (RBM) Homogenate Preparation
[00333] Adult rats (Charles River CD strain, female, 200 g) were anaesthetized with isofluorane and rapidly decapitated. Each brain was quickly removed and chilled in tubes (3 brains per tube) on ice. About 25 mL of "homogenization buffer" (20 mM HEPES buffer, pH
7.0, with 1 mM MgCl2) was added to 15 to 20 g of brain. The brains were homogenized on ice for 1 minute using an Omni GLH homogenizer (Omni International, Marietta, Georgia). The homogenates were then transferred to three centrifuge tubes and centrifuged at 36,500g for 20 minutes at 4 °C. The supernatant was discarded and each pellet was re-suspended in 25 mL homogenization buffer. The re-suspended material was again centrifuged (36,500g, 20 minutes at 4 °C). Pellets were combined by re-suspension in 10 mL of homogenization buffer and incubated in a 37 °C water bath for 15 minutes. The tubes were then placed on ice for 5 minutes followed by centrifugation at 36,500 g for 20 minutes at 4 °C. The supernatant was discarded and the membrane pellets were then re-suspended in 40 mL of "re-suspension buffer" (50 mM Tris-HCl buffer, pH 7.4, containing 1 raM EDTA and 3 mM MgCl2). A Bradford Protein assay was performed to determine protein concentration. The protein was aliquotted into screw cap Cryo tubes each containing ~ 400 μί, flash frozen in liquid nitrogen and stored at -80 °C until used for the assay. A similar protocol was used to obtain brain membrane homogenates from mice.
B. FAAH Human Brain Membrane (HBM) Homogenate Preparation.
[00334] Brain cerebral cortex tissue (ABS, Inc.) from 3 human donors (2 females, 1 male; 63-85 years old) was collected previously and flash-frozen in liquid nitrogen within 4 hours post-mortem interval. Tissue was stored at -80 °C. Serology was negative for a defined list of infectious agents. Brain cortex samples (equal amounts from 3 donors pooled as 10 g total) were homogenized as described below.AU tissue samples were handled following Centers for Disease Control Biosafety Level 2 (BL-2) procedures for working with bio-hazardous materials by trained personnel in BL-2 certified laboratories. Brain tissue was thawed in ice- cold homogenization buffer 20 mM HEPES (pH 7.0), 1 mM MgCl2. Approximately 4 mL of buffer was used per gram of tissue. Human brain tissue was homogenized in buffer in an ice- cold mortar with a pestle. Homogenates were centrifuged at 36,500 x g for 20 minutes at 4 °C. Supernatants were discarded. Pellets were re-suspended and homogenized in ice-cold homogenization buffer as before. The tubes were capped and incubated upright in a 37 °C water bath for 15 minutes followed by incubation on ice for 5 min. The tubes were centrifuged as before. The brain membrane microsome pellets were re-suspended using ice-cold re- suspension buffer (50 mM Tris-HCl buffer, pH 7.4, containing 1 mM EDTA and 3 mM
MgCl2). Protein concentrations of the brain microsome suspensions were determined using BioRad protein assay kit (BioRad). The protein was aliquotted and flash frozen as 0.2 mL aliquots in liquid nitrogen and stored at -80 °C until use.
Determination of FAAH Activity
[00335] FAAH activity was assayed in the respective homogenates described herein
(Rat brain, Mouse brain or Human brain) for certain exemplary compounds using a
modification of the method of Omeir et al. (1995 Life Sci. 56:1999) and Fowler et al. (1997 J. Pharmacol. Exp. Ther. 283:729).
[00336] For the assay of FAAH activity in rat brain membrane (RBM) homogenates, RBM homogenates (7 μg protein in 20 sL final volume of 10 mM Tris pH 6.5) were mixed with 180 μΐ. of a mixture of the following: 2.0 μΜ unlabelled anandamide, 0.03 μϋί radio labeled anandamide [ethanolamine 1- H] (40-60 Ci/mmol, product number ART-626,
American Radiolabeled Chemicals, St. Louis, MO), 1 mg mL Bovine Serum Albumin (fatty acid-free BSA, electrophoresis grade, Sigma, St. Louis, MO), 10 mM Tris-HCl (pH 6.5), and 1 mM EDTA in the presence and absence of test compounds (vehicle was DMSO at a final concentration of 1%) and incubated for 10 minutes at 37 °C. Samples were placed on ice to terminate the reactions.
[00337] 3H-ethanolamine product and un-reacted 3H-anandamide substrate were then separated either: (1) by using chloroform/ methanol extraction or (2) by passing the reaction mixture through a glass fiber filter containing activated charcoal. Samples were extracted with chloroform/methanol by adding 0.4 mL of chloroform/methanol (1:1 v/v), vigorously mixing the samples, and separating the aqueous and organic phases by centrifugation. Radioactivity
(corresponding to FAAH-catalyzed breakdown of 3H-anandamide) found in aliquots (0.2 mL) of the aqueous phase was determined by liquid scintillation counting with quench correction.
IC50 values were determined as described by Jonsson et al. (2001 Br J Pharmacol. 133:1263).
Alternatively, reactions were purified using a modification of the solid-phase extraction method described by Wilson et al (2003 Anal. Biochem. 318 : 270). This method was modified as follows: after reactions were incubated at 37 °C for 10 minutes and chilled on ice, the reaction mixtures were acidified by adding 10 of sodium phosphate solution [0.5M (pH 2.0)]. Next,
90 μΐ, aliquots of the acidified reaction mixtures were applied to activated charcoal (that had been previously washed with methanol as described by Wilson et al. (supra)) containing 80 μ]., of water on top of a glass fiber filter, centrifuged, and the radioactivity in the eluate was counted as described previously by Wilson et al. (supra). [00338] FAAH activity using human homogenates was assayed based on methods adapted from Omeir et al 1995 (supra) with modifications by Fowler et al 1997 (supra).
Separation of H-product and [ H]-ethanolamine product was based on modifications of Wilson et al 2003 (supra). FAAH assays were conducted in 0.2 mL (volume final) of reaction buffer per well [10 mM Tris (pH 7), 1 mM EDTA, 0.1% fatty acid free BSA (Sigma catalog #
A0281), 0.5 μΜ anandamide (Cayman catalog # 90050), 70,000 dpm of anandamide- (ethanolamine-l-[3H]) (60 Ci/mmol, radiochemical purity >99%, American Radiolabeled Chemicals, Inc., catalog # ART 626)] in the presence and absence of test compounds (vehicle is DMSO at a final concentration of 1%). Reactions were initiated by adding 12.5 μg of brain microsome. Reactions were conducted at 37 °C for 10 min. The reactions were terminated by chilling the plates on ice and adding 20 μΐ, of 0.5 M of potassium phosphate buffer (adjusted to pH 2.1 with phosphoric acid). [ H]-ethanolamine product and un-reacted [ H]-anandamide substrate were separated by passing the reaction mixture through a glass fiber filter containing activated charcoal, and the radioactivity in the eluate was counted as described previously by Wilson et al. (supra).
[00339] Table 1 provides activity data for certain compounds tested for inhibition of FAAH using the FAAH rat, mouse and human brain homogenate assays. The known FAAH inhibitors, 3'-(aminocarbonyl)biphenyl-3-yl cyclohexylcarbamate (URB597), [l-(4- chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]acetic acid (indomethacin) and 5-benzoyl- 2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (Ketorolac) were used as controls in these assays.
Table 1: Average activity of the compounds of this invention, expressed as IC50 (the
concentration of the agent needed to induce 50% inhibition of the enzyme) of FAAH extracted from human and rat brain homogenates. A = Less than 100 nM, B = between 100 nM and 1 Μ, C = between 1 μΜ and 10 μΜ, D = greater than 10 μΜ.
Figure imgf000119_0001
A06 B B
A07 A A
A08 A A
A09 A A
A10 A A
Al l A A
A12 B C
A13 C C
A14 A A
A15 A A
A16 B A
B01 A A
B02 A A
B03 A A
B04 A A
B05 A B
B06 B B
B07 C B
B08 A A
A17 A A
A18 A A
A19 A A
A20 A A
Example 6: Whole cell anandamide hydrolysis assay:
[00340] FAAH activity was assayed in whole cells using methods disclosed previously (Maccarone et al. 1998 J Biol. Chem. 273:32332 and Bisogno et al. 1997 J Biol. Chem.
272::3315). In addition to the cell lines described in Maccarone et al. and Bisogno et al., MCF7 (ATCC designation HTB-22) and T84 (ATCC designation CCL-248) cell lines were also used in these assays.
A. HeLa cell transfection with human FAAH-1
[00341] cDNA expression clone for human FAAH-1 (in pcDNA3 vector) (Genbank Accession U82535; obtained from Benjamin Cravatt, Scripps Research Institute, La Jolla, California) was linearized by digestion with Bglll (New England Biolabs) and transfected by calcium phosphate into human HeLa cells (ATCC catalog #CCL-2). The HeLa cell line was selected as a host because it does not express FAAH or exhibit FAAH activity such that all subsequent activity can be attributed to the transfected gene. Following transfection, a stable HeLa-derived clone, designated 5c5, was isolated by single colony purification and expanded and maintained in modified Eagles medium (MEM; VWR catalog # 45000-300) containing 10% fetal bovine serum (FBS), 2 mM L-glutamine, and 0.5 mg/mL G-418 (Sigma catalog # G5013).
B. FAAH whole cell activity assay
[00342] Clone 5c5 (50,000 cells in 150
Figure imgf000121_0001
was seeded into 96-well plates and incubated overnight (5% C02, 37 °C). Media was carefully replaced with 180 μΐ, DMEM/F12 medium (VWR catalog # 45000-350) containing 15 mM HEPES, pH 7.4 and 0.1% fatty acid free BSA (Sigma catalog # A0281). Then, 2 yL of lOOx desired final concentrations of certain exemplary compounds described herein were made up in DMSO, added to wells containing cells, and plates were incubated at 37 °C for 10 min. Next, 20 iL of 5 μΜ anandamide (Cayman catalog # 90050) spiked with 8 μθί of anandamide-(ethanolamine-l-[3H]) (American Radiolabeled Chemicals, Inc., catalog #ART 626) was added to the cells and the plates were incubated for an additional 15 min at 37 °C. The reactions were terminated by chilling the plates on ice and adding 20 μί, of 0.5 M of potassium phosphate buffer (adjusted to pH 2.1 with phosphoric acid).
[00343] The acidified reactions were transferred to 96-well filter plates (0.25 mL capacity/well, 1.2 micron glass fiber pre-filter packed above 0.65 micron pore-size PVDF membrane, Millipore catalog MSFCN6B50) containing 25 i charcoal (neutral activated carbon, Fisher Scientific catalog CI 70-500) per well. Prior to the assay, charcoal was measured and loaded onto the plate using an aluminum 96-well column loading device (Millipore catalog MACL09625). The filter plate was assembled over an empty 96-well plate (Costar) using a centrifuge alignment frame (Millipore catalog MACF09604) to allow for collection of the filtrate in the receiver plate. The charcoal glass fiber filter plates were pre- washed with methanol by centrifugation 650 x g for 10 min). Next, 80 μΐ, of water was added to the wells of the pre-washed 96-well charcoal filter plate. Then, 90 μΐ, of the acidified reaction mixture was added to the water in the wells of the charcoal plate. The samples were centrifuged as above. The substrate remained bound to the charcoal, whereas the [3H]- ethanolamine product formed flowed through and was transferred to the microplates containing scintillation cocktail and quantified in a micro-plate scintillation counter (Perkin-Elmer Microbeta). Control reactions with either no cells or cells treated with DMSO alone were performed in triplicate and used to define background (no cells) and 100% activity (DMSO alone).
[00344] Following subtraction of background radioactivity, data were expressed as percent inhibition relative to 100% activity and fit with a nonlinear regression curve using GraphPad Prism Software (GraphPad Software Inc). IC50 values were calculated from the resulting dose-response curves constrained at top and bottom to 100% and 0%, respectively and are summarized in Table 2.
Table 2: FAAH human whole cell assay.
A - Less than 100 nM, B = between 100 nM and 1 μΜ, C - between 1 μΜ
and 10 μΜ, D= greater than 10 μΜ.
Figure imgf000122_0001
Example 7. Human CB1 Cannabinoid Receptor Assay
[00345] Binding assays can be used to characterize potential CB1 receptor binding affinity for the disclosed compounds and compositions.
A. CB1 Clones
[00346] cDNA expression clones for human CB1 (hCBl, Genbank Accession No. AY225225) expressed in vector pcDNA3.1+ can be purchased from UMR cDNA Resource Center, Rolla, MO (Clone ID CNR01L000 for hCBl).
B. Stable and Transient Transfection
[00347] Stable, HEK-293-derived cell lines that recombinantly express hCBl can be established. In brief, the clone hCBl (CNR1L) is transfected into human embryonic kidney cells (HEK-293) using Lipofectamine 2000 (Gibco, Cat# 11668-019) according to the manufacturer's protocol. Transfected clones are isolated by single colony purification and clones are screened for receptor expression using a whole cell, 3H-CP 55,940 radioligand binding assay. HEK-293 stable cells are maintained in Dulbecco's modified Eagles medium (DMEM) containing 10% fetal bovine serum, 2 mM L-glutamine and 0.5mg/mL G-418.
C. Human CB1 Cannabinoid Receptor Radioligand Binding Assay
[00348] Membranes are isolated from transfected cells as follows. Monolayers of cultured cells are washed twice with phosphate-buffered saline (PBS). Cells are scraped into 20 mM HEPES, pH 7.4, 10 mM EDTA containing complete cocktail protease inhibitors (Roche, Catalog # 11 697 498 001) and are homogenized by an electric-powered mechanical probe homogenizer (Omni GLH; probe G7-195S) for 40 seconds at 7000 rpm. Homogenates are centrifuged 10 minutes at 1000 x g at 4°C. The supernatant is collected and is centrifuged for 1 hour at 40,000 x g. The supernatant is then decanted and the resulting pellet is resuspended in 20 mM HEPES, pH 7.4, 5 mM MgCl2, 1 mM EDTA, 10% sucrose with complete cocktail protease inhibitors. Protein concentration of membrane suspensions are measured by Bradford Protein Assay using bovine serum albumin as the standard (BioRad catalog #500-0006). Protein concentrations of membrane suspensions are adjusted with the final buffer in the range of 5 to 10 mg/mL and are stored at -80°C until further use. D. Cannabinoid receptor radioligand binding assay
[00349] Radioligand binding assays can be performed by incubating membranes (2- 10 ug protein) prepared from HEK-293 cells expressing recombinant human cannabinoid receptor, CBl, at room temperature with 0.5 nM cannabinoid receptor agonist, [3H]-CP 55,940 (Perkin Elmer, catalog # NET1051) in 0.2 mL of binding buffer (50 mM Tris-HCl, pH 7.5, 5 mM MgCl2, 2.5 mM EDTA) and 0.1 % fatty acid free bovine serum albumin (Sigma Cat. # A0821) for 90 minutes. A rapid filtration technique using Millipore FB filter plates (Catalog #
MADVNOB) and filtration apparatus (Millipore system Catalog MAVM0960R) with vacuum aspiration is used to harvest and rinse labeled membranes (8 times with 0.2 mL of chilled binding buffer). The radioactivity bound to the filters is counted with 0.05 mL of liquid scintillant (UltraGold MV, PerkinElmer catalog # 6013159) in a scintillation counter (Perkin Elmer Microbeta instrument). Nonspecific binding was determined in the presence of unlabeled 1 uM CP 55,940 (Sigma Aldrich, catalog # CI 112). Binding data are analyzed using GraphPad Prism (GraphPad Software, Inc. San Diego, CA).
[00350] In some embodiments, compounds of the invention display a decreased affinity for binding to the CBl receptor. In some embodiments, compounds of the invention displayed a decreased affinity for binding to the CBl receptor when compared to other known FAAH inhibitors.
[00351] In some embodiments, compounds of the invention show increased selectivity for binding to FAAH relative to their binding to the CBl receptor.
Example 8. Nonclinical Safety Profile Determination
[00352] The safety profile of the compounds can be evaluated in nonclinical toxicology studies in rodents and non-rodents. Male and female animals are administered test compound in a vehicle by an appropriate route (e.g., oral, intramuscular, intravenous) once daily for, e.g., 14 or 28 consecutive days. Additional animals receive the vehicle only and serve as the vehicle control group. Clinical observations, changes in body weights and feed consumption, ophthalmic and clinical pathology (hematology, clinical chemistry, coagulation) parameters are evaluated in each animal during the in life portion of the study. In rodents, toxicokinetic evaluations for systemic exposure determinations are conducted on separate groups of animals at each dose level of the test compound. In non-rodents, toxicokinetic evaluations are conducted on the same animals used for toxicity evaluations. Additional groups of animals can be included to assess recovery from any findings. At the end of the dosing and recovery periods, necropsy examinations are performed and organ weights, macroscopic and
microscopic evaluations are conducted. Results are compared to vehicle control values using statistical analyses where appropriate. Results are used to determine the no-observed-adverse- effect-level (NOAEL) and toxicity profile in the test species.
Example 9. hERG-related compound toxicity
[00353] Human ether-a-gogo-related (hERG) ion channel encodes the inward rectifying voltage gated potassium channel in the heart and has a major role during the repolarization of the cardiac action potential. It is well established that blockade of this ion channel can lead to potentially lethal arrhythmias. hERG pre-clinical safety data is often used by regulatory agencies in elucidate the toxicity profile of certain compositions. The disclosed compounds of the invention can be tested for their ability to inhibit hERG ion channels.
hERG Testing Methods
hERG-CHO Culture Conditions
[00354] Media components include F 12 Nutrient Mixture (Ham) with GlutaMAX™ (Invitrogen, Cat# 31765), Fetal Bovine Serum, Certified (Invitrogen, Cat# 16000-044 - not heat activated), and Geneticin® Selective Antibiotic (Invitrogen, Cat# 10131-027). One vial of frozen cells, at 1.62xl06 cells are thawed into a T150 flask (BD Falcon 355001) with 40 mL of pre-warmed complete media. Cells are cultured at 37 °C, 5% C02 for four hours prior to gently changing media. 99% of cells appear attached at this time point. The flask is media changed at 24 hours post-thaw, the cells are imaged, media changed, and returned to the incubator. At this point, the cells appear healthy and about 25% confluent in the flask. Cells are typically passed 24-48 hours after thaw according to the following intervals and densities below. Cells are incubated at 30 °C for 48 hours prior to assay. Incubation Interval Cells/T150 to Passage Total CeU Yield/T150
48 hours 1.4xl06 10.6xl06
72 hours 0.4x106 9.7xl06 hERG Voltage testing conditions
[00355] Using an automated patch clamp apparatus (IonWorks ), a three pulse protocol can be applied by stepping from a holding potential of -80mV to +40mM for 2s, to activate hERG channels. The membrane voltage is then stepped back to -50mV for 2s to evoke a tail current prior to returning to the holding potential for Is. This sequence can be repeated a further two times. This voltage protocol is applied prior to drug (Pre compound) and after 600s in the presence of drug (Post compound).
[00356] The amplitude of the hERG tail current is calculated by measuring the difference between the maximum current on stepping to -50mV of the third pulse (i.e. peak of the outward hERG tail current) and the current measured immediately prior to activation of any hERG current. This parameter is assessed before (pre tail current amplitude) and after 600 s incubation (post tail current amplitude) in drug. In order to assess the amount of block produced by test compounds, the data is first filtered using the IonWorks™ software to exclude any cells where the seal resistance is less than 50MOhm. The remaining data is then exported to an excel compatible data file and only currents with tail currents greater than 250pA are analyzed. The post/pre tail current amplitude ratio for the third pulse is calculated for each drug and control, and presented as percent inhibition.
[00357] In some embodiments, the compounds of the invention displayed decreased inhibition of the hERG channel. In some embodiments, the compounds of the invention displayed a decreased inhibition of the hERG channel when compared to other known F AAH inhibitors.
Example 10. Pharmacokinetic studies
[00358] Pharmacokinetic studies can be conducted to determine absorption and distribution profiles of the disclosed compounds which are orally administered to rats. a. Compound administration and blood preparation
[00359] Compounds are formulated in a 1 % DMA / 99% Vitamin E TPGS vehicle. Prepared compounds are dosed via oral gavage (PO). Following the appropriate pretreatment time of 2 hours, rats are anesthetized with isoflurane gas. Blood is collected into tubes containing EDTA via retro-orbital eye bleed. Whole blood is spun in a micro-centrifuge at approximately 13,000 rpm for 5 minutes at room temperature. Separated plasma is
subsequently aliquoted into eppendorf tubes. Samples are stored at -80 °C until prepped for analysis.
b. FAAH Plasma Sample Preparation (KS Method)
[00360] Plasma samples are thawed and the required amount of plasma for standards, blanks and dilutions are made. The dilutions are prepared before plating. Preparation of crash solution included cold acetonitrile + 0.1% formic acid and 25 ng/mL of a FAAH inhibitor used as internal standard, solvent standards of the FAAH inhibitor being studied were prepared at 10, 30, 100, 300, 1000, 3000, 10000, 30000, 100000, and 300000 ng/mL in DMSO. Then a plasma standard curve is generated from the solvent standards (final concentrations of standards in plasma are: 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000 ng/mL). 50 μL· of each plasma sample/dilution, standard, or blank is transferred into 96-well plates. To each well, 200 of cold crash solution was added. The plate is covered and gently vortexed. The plate is centrifuged at 3500 rpm, 4°C for 10 min. 200 of each supernatant was transferred into new plates. The plates are dried under nitrogen in a Turbo Vap at 55°C. The sample in each well is re-suspended with 100 of 30% acetonitrile, covered and vortexed gently. The well solutions are analyzed by the LC/MS/MS conditions and specifications below.
c. LC/MS/MS Conditions:
[00361] HPLC column is a Clipeus C8, 2.1 30 mm, 5 μπι, with Basic 8 guard column using 20 μΐ, injections. Mobile phase used is mobile phase A: 0.1% Formic Acid in water and mobile phase B: 0.1% Formic Acid in 85:10:5 ACN: IPA: H20. The flow rate for the run is 0.5 mL/min and the gradient for the 4 minute total run time was: 0.0 minutes 35% B; 0.5 minutes 35% B; 1.5 minutes 95% B; 2.3 minutes 95% B; and 2.4 minutes 35% B. Example 11. Reduction of Spasticity in a Mouse Model of Multiple Sclerosis
[00362] The anti-spastic effect of compounds can be assessed in the mouse chronic relapsing experimental autoimmune encephalomyelitis (CREAE) model of multiple sclerosis as previously described in Baker et al, 1990 J. Neuroimmunol. 28: 261 ; Baker et al. 2000 Nature 404: 84; and Baker et al., 2001 FASEB J. 15: 300. CREAE is induced in Biozzi ABH mice by subcutaneous injection of syngeneic spinal cord homogenate in Freund's complete adjuvant on Day 0 and Day 7. A proportion of the inoculated mice (approximately 50-60%) develop hindlimb spasticity between 60 and 80 days post-inoculation. Spasticity is assessed by measuring the force required to bend individual hind limbs to full flexion against a strain gauge. To assess the effect of a compound on spasticity, selected doses are administered to spastic CREAE mice by an appropriate route (e.g., oral, intraperitoneal, or intravenous).
Spasticity is measured pre-dose and at various times after compound administration (for example 1, 2, 4 and 24 hours post-dose). The mean force of resistance to hindlimb flexion at each post-dose timepoint is compared to the mean pre-dose force using an appropriate statistical test (e.g. analysis of variance or paired t-tests.). FAAH inhibitors and their elevation of endo-cannabinoids would be expected to control spasticity in this animal disease model see, for example, Baker et al. 2001 supra) and Ligresti et al. 2006 Br. J. Pharmacol. 147(1): 83).
Example 12. Neuroprotection in a Mouse Model of Multiple Sclerosis
[00363] Agents can be tested for their ability to inhibit neurodegeneration in the mouse chronic relapsing experimental autoimmune encephalomyelitis (CREAE) model of multiple sclerosis as described in Baker et al. 1990 supra; Pryce et al. 2003 Brain 126:2191; and Al-Izki et al. 2011 J. Mult. Scler. Epub. 1 Apr. CREAE is induced in Biozzi ABH mice by
subcutaneous injection of syngeneic spinal cord homogenate in Freund's complete adjuvant on
Day 0 and Day 7. An additional injection of spinal cord homogenate is administered on Day 28 during the post-acute remission period to induce a paralytic relapse, which leads to the accumulation of nerve damage. Selected doses of test agent or negative control agent (e.g., a vehicle control) are administered by an appropriate route (e.g., oral, intraperitoneal, or intravenous) starting around Day 28, and continuing for a suitable period thereafter (e.g., 14 or
28 days). Clinical and neurological symptoms can be scored daily (e.g., starting at Day 11), and motor coordination can be assessed using the RotoRod test. At the end of the dose administration period, animals are killed and their spinal cords are rapidly removed. Nerve content of the spinal cords is determined, for example, using a neurofilament enzyme-linked immunosorbant assay (Pryce et al. 2003 supra). Results for animals treated with the test agent are compared to those for animals treated with the negative control agent. Based on previous investigations, FAAH inhibitors would be expected to inhibit neurodegeneration in this animal model (Pryce et al. 2003 supra).
Example 13. Reduction of Pain and Depression in an Animal Model of Fibromyalgia
[00364] Compounds can be tested for their ability to inhibit pain and depression in a putative animal model of fibromyalgia (Nagakura et al. 2009 Pain 146:26). Rats are administered a subcutaneous injection of reserpine (1 mg/kg) once daily for 3 consecutive days to deplete biogenic amines. Treated rats manifest symptoms of pain and depression. Muscle pain can be assessed by applying increasing pressure to a hindlimb muscle until a withdrawal response is elicited. Tactile allodynia can be assessed by measuring the hindlimb withdrawal threshold following application of Von Frey filaments of incrementally increasing weights to the plantar surface of the hind paw. Depression can be assessed by immobility time in the forced swim test. To assess the effect of a test compound in the model, selected doses are administered to the rats by an appropriate route (e.g., oral, intraperitoneal, or intravenous) approximately 5 days after reserpine treatment. Muscle pressure threshold, tactile response threshold, and immobility time in the forced swim test are measured at appropriate times after compound administration (for example 0.5, 1, 2, and 4 hours post-dose). Results are compared to pre-dose values using an appropriate statistical test.
Example 14: Behavioral effect of FAAH inhibitors alone or in combination with L-DOPA in MPTP-lesioned marmosets
[00365] FAAH inhibitors can be tested for their ability to reduce hyperactivity or dyskinesia in stable L-DOPA induced MPTP-lesioned marmosets. L-DOPA (dopamine precursor 3,4-dihydroxyphenylalanine; levodopa) has been previously demonstrated to induce a stable marmoset model with dyskinesia and hyperactivity, see for example, Gomez-Ramirez et al. (2006) Mov. Disord. 21:839-846; Visanji et al. (2008) Mov. Disord. 23:1922-1925; and Visanji et al (2009) Neurobiol Dis. 35: 184-192). The effects of FAAH inhibitors on motor activity, parkinsonian disability, dyskinesia and psychosis can be assessed through the monitoring of behavioral responses in the group of MPTP-lesioned marmosets with stable L- DOPA-induced dyskinesia and hyperactivity.
[00366] Based on previous dose-finding studies in these animals, a dose of L-DOPA (20 mg kg) / benserazide (5 mg kg), can be used to elicit hyperactivity, dyskinesia and psychosis that was stable and reproducible on successive L-DOPA administrations. The effect of FAAH inhibitor alone and on L-DOPA response can be assessed. For behavioral observations, L- DOPA can be administered s.c. at a dose volume of 1 ml/kg, as L-DOPA methyl ester (Sigma, Canada) in combination with benserazide (Sigma, Canada). Based on its ability to maximally elevate plasma levels of AEA, PEA and OEA in MPTP-lesioned marmosets, a dose of 10 mg/kg FAAH inhibitor may be employed for all behavioral observations and administered orally at a dose volume of 5 ml/kg.
Treatments
[00367] On days prior to behavioral assessment, animals are fed normally and receive a maintenance oral L-DOPA dose at 9:00 a.m. At 4:00 p.m. animals are administered either vehicle (p.o.) or FAAH inhibitor (10 mg/kg, p.o.). On days of behavioral assessment, animals are fed their normal diet between 7:00-7:30 a.m. after which time all food is removed from their cages. Water is available ad libitum. At approximately 9:00 a.m., each animal receives either vehicle (p.o.) or FAAH inhibitor (p.o.). Two hours after this, at approximately 11 :00 a.m., animals receive either vehicle or L-DOPA (s.c.) treatment. Behavioral assessment, as described below commences directly following this second treatment.
[00368] To prevent any confounding effects of prior treatment with oral FAAH inhibitor on the assessment of response to vehicle treatment, the order of these treatments are randomized in each animal. A minimum of 48 h is left between behavioral observations in the same animal.
Behavioral assessment of marmoset behavior
[00369] After administration of final treatment (L-DOPA, s.c), animals can be placed immediately into observation cages (0.8 x 0.8 x 0.7 m) containing food, water and a wooden perch and left undisturbed for the 6 h duration of the experiment. Behavior can be monitored via recorded DVD footage and analyzed post hoc by a movement disorder neurologist blinded to the treatment. Methods for assessment of behavior are essentially as described previously in Fox et al. 2006 Arch. Neurol. 63:134; and Gomez-Ramirez et al. 2006 Mov Disord. 21 :839. L- DOP A-induced dyskinesia and psychosis can be independently assessed after 2—4 hours after injection with L-DOPA. During this period, for each 10 min epoch, dyskinesia and psychosis can be rated from 0 to 4: 0 = absent; 1 = mild, fleeting, rare, present less than 30% of the observation period; 2 = moderate, not interfering with normal activity, present more than 30% of the observation period; 3 = marked, at times interfering with normal activity, present less than 70% of the observation period; 4 = severe, continuous, replacing normal activity, present more than 70% of the observation period. For dyskinesia, chorea and dystonia can be graded separately and the score given to represent the most disabling dyskinesia observed, whether chorea or dystonia, in any 10-minute period of assessment. For psychosis, hyperkinesia, response to non-apparent stimuli (hallucinatory behavior), repetitive grooming and stereotypies can be graded separately. For this measure, the score given represented the most disabling of any of the four sub-score levels observed, in any 10 min period of assessment.
[00370] In addition, a quantitative assessment of marmoset activity can be made using computer-operated passive infra-red sensors, essentially as described previously in Maccarrone et al. 2003 J. Neurochem. 85:1018; and Visanji et al. 2009 J Pharm Exp Ther 328: 276. A single sensor containing a hemispherical lens (Guardall, Mississauga, ON, Canada) is mounted 1.5 m above the top of each the observation cage. The sensor is positioned so that motion was detected throughout the entirety of the cage below. The signal is fed via an RS-232 input to a computer. Proprietary Motion Detector software (Research Electronics, Toronto Western Hospital, Toronto, ON, Canada) is utilized that displayed within Microsoft Excel (Microsoft, Redmond, WA). Activity counts are logged in 1-min epochs for the entire 6 h duration of the experiment and cumulated over the peak dose period of 2-4 h.
[00371] Assessment of marmoset hyperactivity is further assessed over time by quantifying the average activity of counts per minute of the same animals obtained prior to administration of MPTP (i.e., in the normal state). Activity over the same period of 2-4 h is calculated and used to identify minutes of high activity (a minute when activity was above the average per minute of the animal prior to MPTP). High activity counts (the total counts obtained in high activity minutes) are cumulated. High activity time (the number of high activity minutes) is also calculated.
Example 15: Effect of FAAH inhibitors on cortagine-induced visceral hypersensitivity in rats
[00372] The cortagine-induced visceral hypersensitivity rodent model has been developed to investigate the effect of compounds on visceral pain. For this experiment, male Sprague Dawley (SD) rats (250-275g, Harlan Labs, Indianapolis, IN) are kept under standard conditions of humidity and temperature and a 12-hour light/dark cycle (lights on 6.00 a.m.). Animals can be group housed and have access to food ad libitum. Prior to the start of studies, animals are acclimatized to handling and administration of treatments (oral syringe feeding and subcutaneous injection). At the end of the experiments, animals are sacrificed by C02 gas inhalation followed by thoracotomy or isoflurane anesthesia followed by decapitation with appropriate approved animal protocols.
A. Rodent Model
[00373] On the day of the experiments, rats are injected intraperitoneally (IP) with cortagine (10 μg/kg, 0.8 ml/kg in DMSO/cremophor/ isotonic saline (1:1:8 v:v:v). Cortagine, a selective corticotropin releasing factor receptor 1 (CRFi) agonist, prepared as described previously (Rivier et al. 2007 J. Med. Chem. 50:1668), can be stored in a powder form at -80 °C and prepared in sterile water (12.5 g/ml) immediately before use. This dose had previously been established to show a significant increase in defecation, induction of diarrhea and increase in colonic motility, permeability and visceral pain in rats. (Larauche et al. 2009 Am. J. Physiol. Gastrointest. Liver Physiol. 297:G215)
B. Test Compounds
[00374] FAAH inhibitors can be formulated as suspensions in DMSO/cremophor/ isotonic saline (1:1:8 v:v:v). The concentrations of FAAH inhibitors compound suspensions can be 6 mg/ml for 30 mg/kg dose; 2 mg/ml for the 10 mg/kg dose; or 1.5 mg/ml for the 3 mg/kg dose.. Vehicle treatment can be administered to rats by per os (PO) route at dose- volume of 5 ml/kg. FAAH inhibitor treatment can be administered to rats by subcutaneous (SC) route at dose volume of 2 ml/kg. The vehicle for the PO route was DMSO/cremophor/ isotonic saline (1:1:8 v:v:v). Test agents can be administered to non-fasted rats which are restrained by hand. The regimen of administration of FAAH inhibitors can involve one delivery (PO or SC) performed 120 min before IP injection of cortagine.
C. Measurement of visceral pain
[00375] Visceral pain is assessed using a non-invasive pressure transducer system referred to as "sensor balloon" as previously described (Larauche et al. 2009 supra; Ness et al. 1988 Brain Res. 450:153). Adult non-fasted SD rats, a 4-5 cm "sensor balloon" lubricated with surgical lubricant (Surgilube, Fougera, Melville) is inserted intra-anally under brief isoflurane anesthesia. The "sensor balloon" can be positioned such that its distal end is 1 cm proximal to the anal verge and secured in place by tapping the balloon catheter to the tail. Rats are placed individually in Boolman's cage and allowed to recover from anesthesia and habituation. The colorectal procedure can be performed using the Distender Series Ilir dual barostat (G&J Electronics Inc, Toronto, Ontario). The colorectal distension ("CRD") protocol consists of 2 CRD at 60 mmHg to unfold the balloon followed by 2 sets of CRD at 10, 20, 40 and 60 mmHg, 20 s duration, 4-min inter-stimulus interval. The intra-luminal colonic pressure (ICP) can be recorded for 20 s before, during and after termination of CRD. The AUC of ICP during CRD over non-distended ICP (before CRD) can be recorded as the VRM (visceromotor response, see Larauche et al. 2009 supra. To examine the pressure-response relationship and adjust for inter- individual variation of the signal, ICP amplitudes can be normalized as percent of the VRM response to the highest (60 mmHg) in the 1st set of CRD for each rat. VRM to the 1st set of CRD before treatment represents baseline VRM at different pressures of distention and is averaged for each group of rats. Rats can also be visually observed for any other behavioral responses.
D. Experimental Protocol
[00376] All the experiments can be performed on conscious male non-fasted SD rats and at the same time in the morning to avoid circadian variations that may influence experimental results.
[00377] Rats are habituated to oral gavage (once/day) and to Bollman's cages (4h/day) for 3 consecutive days preceding the treatment. They are placed in a quiet rat room 48 h before the experimental day and are not disturbed outside of the training/gavage sessions. On the day of the experiment, at 6:30 am, animals can be equipped with distension balloons and placed in Bollman's cages before being brought to the experimental room, where they are left 20 min to recover from anesthesia. At the end of the 20 min recovery period, a baseline CRD (CRD#1) of 40 min is performed at 10, 20, 40, 60 mmHg and the visceromotor response (VMR) assessed. Immediately after the end of the first CRD, rats receive an oral gavage of vehicle
(DMSO/cremophor/ isotonic saline (1:1:8 v:v:v), 1.5 ml), or FAAH inhibitor in vehicle. Two hours after, cortagine (10 μg/kg in vehicle, IP) can be injected. Fifteen minutes after cortagine injection, a second CRD (CRD#2) of 40 min can be performed. At the end of the distension, the balloons are removed prior to placing the rats back into their home cages (~15 min).
[00378] SD rats with cortagine injected IP would be expected to experience visceral hypersensitivity to colorectal distension and visceral pain demonstrated through higher responses over baseline. Effective FAAH inhibitors would prevent or reduce the visceral hypersensitivity induced by IP injection of cortagine.
Example 16: Reduction of Scratching in a Mouse Model of an Acute Allergenic Response
[00379] The potential effects of compounds on pruritus (itch) can be assessed using a mouse model of an acute allergenic response (Sugimoto et al. 1998 Eur J Pharmacol. 351 : 1-5; Schlosburg et al. 2009 J Pharmacol Exp Ther. 329:314). Groups of mice (e.g., C57B16/J strain weighing approximately 20-25 g) are pretreated with selected doses of test compound or a vehicle control agent administered by an appropriate route (e.g., oral, intraperitoneal, or intravenous). Each mouse is then given an injection of compound 48/80 (a mast cell degranulating compound) under the scruff at the most dorsal point of the back just beneath the head in order to elicit short-term scratching behavior in the affected area. Behavior is then recorded and analyzed. The scratching response is tracked as hind leg scratching of the injection site and surrounding areas. Inactivity can also be monitored. The total number of seconds of a specific behavior (e.g., hind leg scratching) over a total observation period is scored, and the mean and standard error of the mean for each group is calculated. Differences between means can be analyzed by an appropriate statistical test (e.g. analysis of variance or paired t-tests). Example 17: Reduction of anxiety-like behavior in the Mouse Marble Burying Assay
[00380] The mouse marble burying assay can be used to assess the potential effects of compounds on compulsive, anxiety-like behavior, and is considered a model of obsessive compulsive disorder (Deacon 2006 Nat Protoc. 1: 122; Kinsey et al. 2011 Pharmacol Biochem Behav. 98: 21). Groups of mice (e.g., C57B16/J strain weighing approximately 20-25 g) are pretreated with selected doses of a test compound or a vehicle control agent administered by an appropriate route (e.g., oral, intraperitoneal, or intravenous). To assess marble burying behavior, each mouse is placed in a cage filled to a depth of about 5 cm with bedding, in which approximately 20 marbles (approximately 10 mm in diameter) are arranged in a grid-like fashion across the surface of the bedding. After an appropriate time (e.g., approximately 20 min), the mouse is carefully removed from the cage and the number of buried marbles is determined. The mean and standard error of the mean for each group of mice is calculated. Differences between means can be analyzed by an appropriate statistical test (e.g. analysis of variance or paired t-tests.)
Example 18. Reduction of Bladder Hypersenstivity in a Rat Modell of Overactive Bladder
[00381] The potential effects of compounds on urinary bladder overactivity can be assessed using the acetic acid-induced bladder hypersensitivity model in the rat. Groups of female rats (e.g., Sprague-Dawley rats weighing approximately 200-250 grams) are pretreated with selected doses of test compound or a vehicle control agent administered by an appropriate route (e.g., oral, intraperitoneal, or intravenous). Cystometrograms are measured under continuous anesthesia during intravesical infusion of saline or dilute acetic acid (e.g, at a flow rate of 0.1 ml/min for 60 min) to induce repetitive micturitions. Urological parameters such as micturition reflex frequency and amplitude can be determined from the cystometrograms measured at baseline and after compound treatment. The mean and standard error of the mean for each group is calculated. Differences between group means can be analyzed by an appropriate statistical test (e.g. analysis of variance or paired t-tests.).
OTHER EMBODIMENTS
[00382] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims

We claim:
1. A compound represented by Structural Formula A, or a pharmaceutically acceptable salt thereof;
Figure imgf000137_0001
wherein: ring A is selected from the group consisting of phenyl and a 6-membered monocyclic
heteroaryl ring; wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms; each JA is independently selected from the group consisting of halogen, -N02, -CN, -R4, -C(0)RA, -C(S)RA, -C(0)ORA , -OC(0)RA, -N(RA)S(0)2RA, -N(RA)C(0)RA, -N(RA)C(S)RA, -ORA, -SRA, -S(0)RA, -S(0)2RA , -S(0)2N(RA)2 , -C(0)N(RA)2 and -N(RA)2 ; wherein, optionally, two RA groups attached to the same N atom, together with said N, form a 5- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from O or N; each RA is independently selected from hydrogen, C1-6 aliphatic, C1-6 alkoxy, C1-6 alkylthio, a C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6 -membered heterocyclic or a 5- to- 6 -membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each RA is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH2, CM alkyl, , -0(Cl alkyl), -S(C alkyl), -N(CM alkyl)2, C haloalkyl or C1-4 haloalkoxy; and wherein each of said RA that is a C1-6 aliphatic, alkoxy or Ci-6 alkylthio is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy, C3-6halocycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heterocyclic; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S;
each R4 is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C alkyl, -0(d.4 alkyl), -S(CW alkyl) or -N(Ci-4 alkyl)2; and wherein each R4 that is a C1-6 aliphatic is optionally substituted by one instance of a C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy, C3- halocycloalkoxy, phenyl, 3- to 6-membered heterocyclic or 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; or
alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring
atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two heteroatoms selected from N, O or S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, -CN, -NH2, -OH, CM alkyl, C1-4 haloalkyl-OCd^ alkyl), -N(C alkyl)2 or -S(C alkyl); n is an integer selected from the group consisting of 0, 1, 2 and 3;
ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
heteroatoms selected from the group consisting of N, O and S;
each JB is independently selected from the group consisting of halogen, -N02, -CN, -OH, Ci-6 aliphatic, C3-6 cycloaliphatic, Ci-6 haloaliphatic, C1-6 alkoxy, Ci- haloalkoxy and C3- 6 cycloalkoxy; m is an integer selected from the group consisting of 0, 1, 2 and 3;
ring C is a 5-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S; each J is independently selected from the group consisting of halogen, -N02, -CN, -R , -C(0)Rc, -C(S)RC, -C(0)ORc , -OC(0)Rc, -N(Rc)C(0)Rc, -N(RC)C(S)RC, -ORc, -SRC, -S(0)Rc, -S(0)2Rc , -N(Rc)S(0)2Rc, -S(0)2N(Rc)2 , -C(0)N(Rc)2 and -N(RC)2; each Rc is independently selected from hydrogen, C1-6 aliphatic, Ci-6 alkoxy, Ci-6 alkylthio, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each Rc is independently and optionally substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C1-4 alkyl, -0(C\.4 alkyl) or -N(d-4 alkyl)2; and wherein, when Rc is a C1-6 aliphatic, C1- alkoxy or C1-6 alkylthio, it is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy or C3-6 halocycloalkoxy;
each R8 is independently selected from Ci- aliphatic, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, 3- to 6-membered heterocyclic or 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C^ alkyl, -0(C1-4 alkyl), -S(Ci-4 alkyl) or -N(CM alkyl)2; and wherein, when R is a Ci-6 aliphatic, it is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkoxy or C3-6
halocycloalkoxy; or
alternatively, two J groups attached to two vicinal ring C atoms, together with said ring
atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to three ring heteroatoms selected from the group consisting of N, O and S; and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, C alkoxy, -CN, -NH2, -OH, -0(CM alkyl), -N(C1-4 alkyl)2 or -S(CM alkyl);
p is an integer selected from the group consisting of 0, 1, 2 and 3; each R1 is independently selected from hydrogen, C[-6 aliphatic or C1-6 haloaliphatic,
R is selected from the group consisting of halogen, -CN or C^ aliphatic; wherein said C1-6 aliphatic is independently and optionally substituted by up to three instances of halogen, -CN, -NH2,-OH and -0(CM alkyl). The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 6-membered heteroaryl or phenyl; wherein said heteroaryl contains up to two ring nitrogen atoms.
The compound according to either claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein each JB is independently selected from the group consisting of halogen, C1-4 alkyl, cyclopropyl, cyclopropyloxy, C1-4 haloalkyl, Q-4 alkoxy and C1-4 haloalkoxy.
The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein each J is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difiuoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propyloxy and isopropyloxy. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein each J is independently selected from the group consisting of bromo, chloro, fluoro, methyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy.
The compound of claim 5 having Formula A-l, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1
Figure imgf000140_0001
Formula A-l.
7. The compound of claim 6 having Formula A-2, or a pharmaceutically acceptable salt thereof
Figure imgf000140_0002
Formula A-2.
8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from the group consisting of hydrogen and d-4 alkyl.
9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof,
wherein each R1 is hydrogen.
10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of halogen, -CN, CM
haloalkyl and C alkyl.
1 1. The compound according to claim 10, or a pharmaceutically acceptable salt thereof,
wherein R is methyl.
12. The compound of any one of claims 1 to 1 1 , having Formula A-3, or a pharmaceutically acceptable salt thereof; wherein up to two of variables Xi, X2, X3 and X4 in ring A are N and the remaining variables are C; wherein n is 0, 1 or 2
Figure imgf000141_0001
Formula A-3.
13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof,
wherein ring A is selected from the group consisting of:
Figure imgf000141_0002
14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each JA is independently selected from the group consisting of halogen, -CN, -NH2, -OH, CM alkyl, C1 -4 alkenyl, -NH(C1-4 alkyl), -N(CM alkyl)2,
-NHC(0)(C alkyl), -NHS(0)2(C1-4 alkyl), -C(0)0(CM alkyl), -OC(0)(C1 -4 alkyl),
-C(0)(C alkyl), -0(C alkyl), -C(S)(CM alkyl), -NHC(S)(C1 -4 alkyl) , -S(C1-4 alkyl),
-S(0)(C alkyl), -S(0)2(C1.4 alkyl), -S(0)2N(C1-4 alkyl)2, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and said heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each said C^ alkyl is independently and optionally substituted by up to three instances of halogen, hydroxy or alkoxy; or, alternatively two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two heteroatoms selected from N or O; wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen or C alkyl.
15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof,
wherein each JA is independently selected from the group consisting of halogen, -CN, -NH2, -OH, methyl, ethyl, isopropyl, -CH=CH2, -OCF3, -CF3, -C(0)OMe, -C(0)Me, -OCH3, -CH2OH, -CH2OMe, -OC(0)Me, -NHC(0)Me, -NHC(S)Me, -SMe,
-S(0)2Me, -NHS(0)2Me and -S(0)2N(Me)2.
16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof,
wherein each JA is independently selected from the group consisting of bromo, chloro, fluoro, -CN, -NH2, -OH, methyl, ethyl, -CH=CH2, -C(0)OMe, -C(0)Me, -OCH3, -CH2OH, -CH2OMe, -OC(0)Me, -NHC(0)Me, -SMe, -NHS(0)2Me and
-S(0)2N(Me)2.
17. The compound according to claim 14, or a pharmaceutically acceptable salt thereof,
wherein each JA is independently selected from the group consisting of morpholine, pyrrolidine, piperidine, thiophene, thiazole, thiadiazole,oxazole and oxadiazole.
18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof,
wherein each A is independentl selected from the roup consistin
Figure imgf000142_0001
19. The compound according to claim 14, or a pharmaceutically acceptable salt thereof,
wherein two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two ring oxygen atoms, and wherein said heterocyclic ring is optionally and
independently substituted by up to three instances of halogen or C alkyl.
20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof,
wherein two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring, wherein said heterocyclic ring is selected from the group consistin of:
Figure imgf000143_0001
wherein each R is independently selected from the group consisting of halogen and C alkyl; wherein o is an integer selected from the group consisting of 0, 1 and 2.
21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from the group consisting of fluoro, chloro and methyl.
22. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein o is 0.
23. The compound according to any one of claims 1 to 22, having Formula A-4, or a
pharmaceutically acceptable salt thereof, wherein each of the variables Qi, Q2, Q3 and Q4 is independently selected fr
Figure imgf000143_0002
Formula A-4.
24. The compound of claim 23 having Formula A-5, or a pharmaceutically acceptable
thereof, wherein up to two of the variables Qi, Q2 and Q3 are N and the rest are C
Figure imgf000143_0003
Formula A-5.
25. The compound according to claim 24 having Formula A-6, or a pharmaceutically acceptable salt thereof, N and the rest are C
Figure imgf000144_0001
Formula A-6.
26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein the moiety -(CH2)-Ring C is selected from the group consisting of:
Figure imgf000144_0002
27. The compound according to any one of claims 23 to 26, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.
28. The compound according to any one of claims 23 to 27 having Formula A-7, or a
pharmaceutically acceptable salt thereof
Figure imgf000144_0003
Formula A-7.
29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt
thereof, wherein Jc is halogen, C alkyl or C alkoxy.
30. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein J is halogen, methyl, ethyl, methoxy or ethoxy.
31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein J is chloro, fluoro, methyl or methoxy.
32. The compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein the moiet represented by Q3 2 is selected from the group consisting of:
Figure imgf000145_0001
Figure imgf000145_0002
33. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000147_0002
Figure imgf000147_0003
Figure imgf000147_0004
wherein: ring A is selected from the group consisting of phenyl and a 6-membered monocyclic
heteroaryl ring; wherein said monocyclic heteroaryl ring contains up to 3 ring nitrogen atoms; each JA is independently selected from the group consisting of-R4, -C(0)OR5, -C(S)RA, -N(RA)C(0)RA, -N(RA)C(S)RA, -SRA, -S(0)RA, -S(0)2RA , -N(RA)S(0)2RA and -S(0)2N(RA)2; each RA is independently selected from hydrogen, C1-6 aliphatic, Ci-6 alkoxy, C1-6 alkylthio, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each RA is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C alkyl, -Ο(0Μ alkyl), -S(CM alkyl) or -N(CW alkyl)2; and wherein each RA that is a Ci-6 aliphatic, C1-6 alkoxy or Ci-6 alkylthio is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S;
each R4 is independently selected from C3- cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R4 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, Ci^ alkoxyl, -0(Ci-4 alkyl), -S(Ci-4 alkyl) or-N(C alkyl)2>;
each R5 is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, phenyl, 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each R5 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, CM alkyl, C bidoalkyl,-0(CM alkyl), -S(CM alkyl) ΟΓ-Ν(ΟΜ alkyl)2; and wherein each R5 that is a Cl-6 aliphatic is optionally substituted by one instance ofC3-6 cycloalkyl, C3- halocycloalkyl, phenyl, a 3- to 6- membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; or alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring
atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S, and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, CM alkyl, C alkoxy, -CN, -NH2,-OH, -0(C1-4 alkyl), -N(CM alkyl)2 or -S(CM alkyl);
n is an integer selected from the group consisting of 1, 2 and 3;
ring B is selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring
heteroatoms selected from the group consisting of N, O and S;
m is an integer selected from the group consisting of 0, 1, 2 and 3;
each JB is independently selected from the group consisting of halogen, -N02, -CN, -OH, Ci-6 aliphatic, C3-6 cycloaliphatic, C1-6 haloaliphatic, Ci-6 alkoxy, C1-6haloalkoxy and C3- 6 cycloalkoxy;
ring C is selected from the group consisting of phenyl, C3-6 cycloalkyl, a 3- to 6-membered heterocyclic and a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S; each J is independently selected from the group consisting of halogen, -N02, -OH, -CN, -R11, -C(0)Rc, -C(S)RC, -C(0)ORc , -OC(0)Rc, -N(Rc)C(0)Rc, -N(RC)C(S)RC, -ORc, -SRC, -S(0)Rc, -S(0)2Rc , -N(Rc)S(0)2Rc, -S(0)2N(Rc)2 , -C(0)N(Rc)2 and -N(RC)2 ;
each R is independently selected from hydrogen, Ci-6 aliphatic, C1-6 alkoxy, C1-6 alkylthio,
C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to
6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each Rc is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, C alkyl, -0(CM alkyl), -S(CM alkyl) or -N(C1-4 alkyl)2; and wherein each Rc that is a Ci-6 aliphatic, C1-6 alkoxy or C1-6 alkylthio is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6- membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S;
each R11 is independently selected from Ci-6 aliphatic, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, Oor S; wherein each R11 is optionally and independently substituted by up to 3 instances of halogen, -CN, -OH, -NH2, CM alkyl, -0(C alkyl), -S(C^ alkyl) or -N(C!.4 alkyl)2; and wherein each R11 that is a C1-6 aliphatic is optionally substituted by one instance of C3-6 cycloalkyl, C3-6 halocycloalkyl, phenyl, a 3- to 6-membered heterocyclic or a 5- to 6-membered heteroaryl; wherein said heterocyclic or heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; or
alternatively, two Jc groups attached to two vicinal ring C atoms, together with said ring
atoms, form a 5- to 6-membered heterocyclic ring; wherein each said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S; and wherein each of said heterocyclic rings is optionally and independently substituted by up to three instances of halogen, CM alkyl, C1-4 alkoxy, -CN, -NH2)-OH, -O(Ci-) alkyl), -N(CM alkyl)2 or -S(C alkyl);
p is an integer selected from the group consisting of 0, 1, 2 and 3;
each R1 is independently selected from a hydrogen, d-6 aliphatic orC1-6 haloaliphatic;
and R2 is selected from the group consisting of halogen, -N02, -CN and Ci-e aliphatic;
wherein said C1-6 aliphatic is optionally substituted by up to three instances of halogen.
35. The compound according to claim 34, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 6-membered heteroaryl or phenyl; wherein said heteroaryl contains up to two ring nitrogen atoms.
36. The compound according to either claim 34 or claim 35, or a pharmaceutically acceptable salt thereof, wherein each JB is independently selected from the group consisting of halogen, Q-4 alkyl, cyclopropyl, cyclopropyloxy, C 1-4 haloalkyl, C 1-4 alkoxy and d-4 haloalkoxy.
37. The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein each JB is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxyl, difluoromethoxy, trifluoromethoxy, ethoxy, propyloxy and
isopropyloxy.
38. The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein each JB is independently selected from the group consisting of bromo, chloro, fluoro, methyl, ethoxy, trifluoromethyl, trifluoromethoxy and methoxy.
39. The compound according to claim 38 having Formula B-l, or a pharmaceutically
acceptable salt thereof, wherein m is 0 or 1
Figure imgf000151_0001
Formula B-l.
40. The compound according to claim 39 having Formula B-2, or a pharmaceutically
acceptable salt thereof
Figure imgf000151_0002
Formula B-2.
41. The compound according to any one of claims 34 to 40, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from the group consisting of hydrogen and C1-4 alkyl.
42. The compound according to claim 41, or a pharmaceutically acceptable salt thereof, wherein each R1 is hydrogen.
43. The compound according to any one of claims 34 to 42, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of halogen, -CN, C1 haloalkyl and Q alkyl.
44. The compound according to claim 43, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
45. The compound according to any one of claims 34 to 44, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from the group consisting of phenyl and 5- to 6- membered heteroaryl; wherein said 5- to 6-membered heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
46. The compound according to claim 45, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, thiophene, thiazole, thiadiazole, oxazole, oxadiazole, pyrazole and imidazole.
47. The compound according to claim 46, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from the group consisting of:
Figure imgf000152_0001
48. The compound according to claim 47, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from the group consisting of:
Figure imgf000152_0002
Figure imgf000152_0003
49. The compound according to any one of claims 34 to 48, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.
50. The compound according to claim 49, or a pharmaceutically acceptable salt thereof,
Figure imgf000152_0004
wherein each moiety represented by is independently selected from the group consisting of:
Figure imgf000153_0001
51. The compound according to any one of claims 34 to 50, or a pharmaceutically acceptable salt thereof, wherein each Jc is independently selected from the group consisting of halogen, C haloalkyl, C alkyl and C1-4 alkoxy.
52. The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein each Jc is independently selected from the group consisting of fluoro, chloro, trifluoromethyl, methyl and methoxy.
53. The compound of any one of claims 34 to 52 having Formula B-3, or a pharmaceutically acceptable salt thereof, wherein up to two of the variables Xls X2, X3 and X4 are N and the rest are C
Figure imgf000153_0002
Formula B-3.
54. The compound according to any one of claims 34 to 53, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
55. The compound according to any one of claims 34 to 54, or a pharmaceutically acceptable salt thereof, wherein each JA is independently selected from the group consisting of -C(0)0(Ci-4 alkyl) , -C(S)(C alkyl), -NHC(0)(C1-4 alkyl), -NHC(S)(C alkyl), -S(CM alkyl), -S(0)(CM alkyl), -S(0)2(Cu alkyl), -NHS(0)2(Ci-4 alkyl), -SiOkNCC 4 alkyl)2, C3-6 cycloaliphatic, C3-6 cycloalkoxy, phenyl, a 3- to 6-membered heterocyclic a a 5- to 6-membered heteroaryl; wherein each of said heterocyclic and heteroaryl rings contains up to 3 heteroatoms independently selected from N, O or S; wherein each said C alkyl is optionally and independently substituted by up to three instances of halogen, hydroxy or C alkoxy; or, alternatively, two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to three heteroatoms selected from the group consisting of N, O and S; wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C alkyl, C1-4 alkoxy, -CN, -NH2,-OH, -0(Ci-4 alkyl), -N(C1-4 alkyl)2 or -S(C1-4 alkyl).
56. The compound according to claim 55, or a pharmaceutically acceptable salt thereof,
wherein each JA is independently selected from the group consisting of-C(0)OMe, -C(S)Me, -NHC(0)Me, -NHC(S)Me, -SMe, -S(0)Me, -S(0)2Me, -NHS(0)2Me and -S(0)2N(Me)2.
57. The compound according to claim 56, or a pharmaceutically acceptable salt thereof,
wherein each JA is independently selected from the group consisting of -C(0)OMe, -C(0)Me, -SMe, -S(0)2Me and -NHS(0)2Me.
58. The compound according to claim 55, or a pharmaceutically acceptable salt thereof,
wherein each JA is independently selected from the group consisting of cyclopropyl, morpholine, pyrrolidine, piperidine, thiophene, thiazole and thiadiazole.
59. The compound according to claim 58, or a pharmaceutically acceptable salt thereof,
ting
Figure imgf000154_0001
60. The compound according to claim 55, or a pharmaceutically acceptable salt thereof,
wherein two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring; wherein said heterocyclic ring contains up to two oxygen atoms, and wherein said heterocyclic ring is optionally and independently substituted by up to three instances of halogen, C1-4 alkyl, C1-4 alkoxy, -CN, -NH2,-OH, -0(C alkyl), -N(C1-4alkyl)2 or -S(C1-4 alkyl).
61. The compound according to claim 60, or a pharmaceutically acceptable salt thereof, wherein two JA groups attached to two vicinal ring A atoms, together with said ring atoms, form a 5- to 6-membered heterocyclic ring, wherein said heterocyclic ring is selected from the group consistin of:
Figure imgf000155_0001
wherein each R is independently selected from the group consisting of halogen and C1-4 alkyl; and wherein o is an integer selected from the group consisting of 0, 1 and 2.
62. The compound according to claim 61, or a pharmaceutically acceptable salt thereof,
wherein each R17 is independently selected from the group consisting of fluoro, chloro and methyl.
63. The compound according to claim 62, or a pharmaceutically acceptable salt thereof,
wherein o is 0.
64. The compound of any one of claims 34 to 63 having the formula selected from any one of Formulae B-4 to B-19, or a pharmaceutically acceptable salt thereof
Figure imgf000156_0001
Formula B-4 Formula B-5 Formula B-6
Figure imgf000156_0002
Formula B-14 Formula B-15
Formula B-13
Figure imgf000157_0001
Figure imgf000157_0002
Formula B-19.
65. The compound of claim 64, or a pharmaceutically acceptable salt thereof, wherein at least one of the variables Xi, X3 and X4 is N and the rest are C.
66. The compound of claim 65, or a pharmaceutically acceptable salt thereof, wherein n is 1.
67. The compound of claim 64, or a pharmaceutically acceptable salt thereof, having a
formula selected from any one of Formulae B-20 to B-35.
Figure imgf000158_0001
Formula B-20 Formula B-21 Formula B-22
Figure imgf000158_0002
Formula B-26 Formula B-27 Formula B-28
Figure imgf000158_0003
Formula B-30 Formula B-31
Formula B-29
Figure imgf000159_0001
Figure imgf000159_0002
Formula B-35.
The compound according to claim 34, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure imgf000160_0001
69. A pharmaceutical composition comprising a compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant.
70. The pharmaceutical composition of claim 69, further comprising at least one additional therapeutic agent.
71. The pharmaceutical composition of claim 70, wherein the additional therapeutic agent is chosen from the group consisting of painkillers, non-steroidal anti-inflammatory drugs (NSAIDs), cannabinoid receptor agonists, opiate receptor agonists, anti-infective agents, sodium channel blockers, N-type calcium channel blockers, local anesthetics, VR1 agonists and antagonists, agents used for migraines, topical agents used in the treatment of localized pruritus, anti-inflammatory and/or immunosuppressive agents, agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists and nicotine replacement therapies), ADD/ ADHD agents, agents to treat alcoholism, such as opioid antagonists, agents for reducing alcohol withdrawal symptoms such as benzodiazepines and beta-blockers, antihypertensive agents such as ACE inhibitors and Angiotensin II Receptor blockers, Renin inhibitors, vasodilators, agents used to treat glaucoma such as direct-acting Miotics (cholinergic agonists), indirect acting Miotics (cholinesterase inhibitors) or Carbonic anhydrase inhibitors, selective adrenergic agonists, Osmotic diuretics, antidepressants such as SSRIs, tricyclic antidepressants, dopaminergic antidepressants, cognitive improvement agents, acetylcholinesterase inhibitors, antiemetic agents (e.g., 5HT3 antagonists), neuroprotective agents, neuroprotective agents currently under investigation, antipsychotic medications, agents used for multiple sclerosis, disease-modifying anti-rheumatic drugs (DMARDS), biological response modifiers (BRMs), COX-2 selective inhibitors, COX-1 inhibitors, immunosuppressives, PDE4 inhibitors, corticosteroids, histamine HI receptor antagonists, histamine H2 receptor antagonists, proton pump inhibitors, leukotriene antagonists, 5-lipoxygenase inhibitors, nicotinic acetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonists and antagonists, NK1 and NK2 antagonists, NMD A antagonist, potassium channel modulators, GABA modulators, anti-cancer agents such as tyrosine kinase inhibitors, anti-hyperlipidemia drugs, appetite suppressing agents, anti-diabetic medications such as insulin, GI (gastrointestinal) agents, and serotonergic and noradrenergic modulators.
72. A method for the treatment or prevention of pain comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
73. The method according to claim 72, wherein the pain is chronic pain, acute pain,
perioperative pain (e.g., associated with surgery), postoperative pain (e.g., associated with orthopedic surgery, gynecological surgery, abdominal surgery, incisions, oral surgery, visceral pain, abdominal pain, pelvic pain abdominal discomfort, inflammatory pain, cancer pain, headache pain, pain associated with a cough, neuropathic pain, deafferentation pain, chronic nociceptive pain, dental pain (such as odontalgia), bone pain, joint pain, myofascial pain (e.g., muscular injury, fibromyalgia), labor pain, pain associated with injuries or age, pain resulting from trauma, pain resulting from allergies, pain resulting from dermatitis, pain resulting from immunodeficiency, pain resulting from Hodgkin's disease, pain resulting from Myasthenia gravis, pain resulting from nephrotic syndrome, pain resulting from scleroderma, pain resulting from thyroiditis, central and peripheral pathway mediated pain, menstrual pain, neurogenic pain, dysmenorrheal pain, migraines, allodynia, hyperalgesia, back pain, pain caused by inflammation (e.g., arthritis, osteoarthritis, spondylitis, rheumatoid arthritis, Crohn's disease and irritable bowel syndrome), pain associated with burns, and pain associated with fibromyalgia.
74. A method for the treatment or prevention of autoimmune disorders comprising
administering, alone or in combination therapy, to a patient in need thereof a
therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
75. The method according to claim 74, wherein the autoimmune disorder is selected from the group consisting of alopecia areata (also known as systemic sclerosis (SS)), amyloses, amyotrophic lateral sclerosis, ankylosing spondylarthritis, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue-dermatitis hepetiformis; chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating
polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, connective tissue diseases, crest syndrome, Crohn's disease, Degos' disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, graft vs. host disease, transplantation rejection, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, lupus erythematosus, Meniere's disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomena, reactional arthritis, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS), Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, undifferentiated spondylarthritis, uveitis, vitiligo, and Wegener's granulomatosis.
76. A method for the treatment or prevention of disease-states or indications that is
accompanied by inflammatory processes comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
77. The method according to claim 76, wherein the disease-states or indications that are accompanied by inflammatory processes are chosen from the group consisting of:
lung diseases such as asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory
distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy-infant syndrome", pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis;
rheumatic diseases, autoimmune diseases, musculoskeletal diseases such as all forms of
rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, reactive arthritis; rheumatic soft tissue diseases, inflammatory soft tissue diseases of other genesis, arthritic symptoms in degenerative joint diseases (arthroses), tendinitis, bursitis, osteoarthritis, traumatic arthritis, gout (metabolic arthritis), collagenoses of any genesis, (e.g., systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still disease, Felty syndrome), osteoporosis and other bone resorption diseases;
allergic diseases including all forms of allergic reactions, (e.g., allergic rhinitis, allergic
conjunctivitis infectious parasitic, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc.), anaphylactic shock
(anaphylaxis), urticaria, angioneurotic edema, delayed or immediate hypersensitivity, and contact dermatitis; vascular diseases such as panarteritis nodosa, polyarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis, atherosclerosis, reperfusion injury, myocardial ischemia, thrombosis and erythema nodosum;
dermatological diseases such as dermatitis, psoriasis, sunburn, burns, and eczema;
renal, urinary and pancreatic diseases such as nephrotic syndrome and all types of nephritis (such as glomerulonephritis), pancreatitis, bladder hyperrelexia following bladder inflammation, urinary incontinence or vesicle inflammation, uresesthesia urgency, overactive bladder, urinary frequency, interstitial cystitis and or chronic prostatitis;
hepatic diseases such as acute liver cell disintegration; acute hepatitis of various genesis (such as viral, toxic, drug-induced) and chronically aggressive and/or chronically intermittent hepatitis, liver fibrosis associated with liver injury or disease, including fibrosis caused or exacerbated by alcoholic liver cirrhosis, chronic viral hepatitis, non-alcoholic
steatohepatitis and primary liver cancer;
gastrointestinal diseases such as ulcers, inflammatory bowel diseases, regional enteritis
(Crohn's disease), ulcerated colitis, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, esophagitis, NSAID-induced ulcer, non-ulcerative dyspepsia and
gastroesophageal reflux disease;
neurodegenerative diseases such as the neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, cerebral ischemia, seizures, spinal cord injury, associated with multiple sclerosis, or the like, neuroprotection and neurogenesis;
eye diseases such as allergic keratitis, uveitis, or iritis, conjunctivitis, blepharitis, neuritis nervi optici, choroiditis, glaucoma and sympathetic ophthalmia;
diseases of the ear, nose, and throat (ENT) area such as tinnitus, allergic rhinitis, hay fever, gingivitis, otitis externa, caused by contact eczema, infection, and otitis media;
progressive central nervous system or neurological diseases such as brain edema, particularly tumor-related brain edema, multiple sclerosis, spasticity associated with multiple sclerosis, acute encephalomyelitis, meningitis, acute spinal cord injury, trauma, dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease,
Parkinson's disease and Creutzfeldt- Jacob disease, Huntington's chorea, Pick's disease, amyotrophic lateral sclerosis (ALS)), vascular dementia (including multi-infarct dementia, dementia associated with intracranial space occupying lesions, infections, related conditions such as HIV infection, Guillain-Barre syndrome, myasthenia gravis, stroke, various forms of seizures (such as nodding spasms), and hyperactivity, dyskinesias;
blood diseases such as acquired hemolytic anemia, aplastic anemia, and idiopathic
thrombocytopenia;
tumor diseases such as acute lymphatic leukemia, Hodgkin's disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, extensive metastases, other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration);
endocrine diseases such as endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de Quervain, Hashimoto thyroiditis, Morbus Basedow, granulomatous thyroiditis, struma lymphomatosa, Graves disease, type I diabetes (such as insulin- dependent diabetes); organ and tissue transplantations and graft-versus-host diseases; severe states of shock such as septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS);
viral or bacterial parasitic infectious disease: for example AIDS and meningitis; and various other disease-states or conditions including, restenosis following percutaneous
transluminal coronary angioplasty, acute and chronic pain, atherosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, granulocyte transfusion, sarcoidosis, gingivitis, pyrexia, edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema, and diabetes (such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and diabetic symptoms associated with insulitis (e.g., Hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion)).
78. A method for the treatment or prevention of gastrointestinal diseases or disorders
comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
79. The method of claim 78, wherein the gastrointestinal diseases or disorders are chosen from the group consisting of: functional gastrointestinal disorders, ulcers, inflammatory bowel diseases (IBD), regional enteritis (Crohn's disease), ulcerative colitis, diarrhea, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, functional dyspepsia, diverticulitis, gastrointestinal bleeding, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, non-ulcerative dyspepsia and gastroesophageal reflux disease.
80. A method for the treatment or prevention of pruritus, comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or
prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
81. The method according to claim 80, wherein the pruritus is dermal pruritus, neuropathic pruritus, neurogenic pruritus or psychogenic pruritus.
82. A method for the treatment or prevention of substance abuse-related syndromes,
disorders, diseases or withdrawal symptoms comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
83. The method according to claim 82, wherein the substance abuse-related syndromes, disorders, diseases or withdrawal symptoms are chosen from the group consisting of: drug abuse and drug withdrawal, wherein the abused substances include alcohol, amphetamines, amphetamine like substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or
combinations of any of the foregoing; and the withdrawal symptoms include tobacco craving or nicotine dependency, addiction, or withdrawal.
84. A method for the treatment or prevention of psychiatric disorders comprising
administering, alone or in combination therapy, to a patient in need thereof a
therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
85. The method according to claim 84, wherein the psychiatric disorders are chosen from the group consisting of depressions (including major depressive disorder, bipolar depression, unipolar depression, single or recurrent major depressive episodes (e.g., with or without psychotic features, catatonic features, and/or melancholic features), postpartum onset, seasonal affective disorder, dysthymic disorders (e.g., with early or late onset and with or without atypical features), neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders), manic-depressive psychoses, bipolar disorders, extreme psychotic states (such as mania, schizophrenia, and excessive mood swings where behavioral stabilization is desired), post-traumatic stress disorder, panic disorder, compulsive disorders, obsessive compulsive disorder, stereotypic, self-injurious and repetitive behaviors, trichtillomania, psychiatric tremors such as dyskinesia, dyskinesia associated with Parkinson's disease, dystonia or spasticity, dystonia or spasticity associated with multiple sclerosis, attention disorders such as ADHD (attention deficit hyperactivity disorders), hyperactivity, hyperactivity disorders, restless leg syndrome, periodic limb movement disorder, autism, anxiety states, generalized anxiety, an impulse control disorder (e.g., pathological gambling, compulsive shopping, hypersexuality), a compulsion disorder, a dopamine dysregulation syndrome, agoraphobia, as well as those behavioral states characterized by social withdrawal.
86. A method for the treatment or prevention of neurological or neurodegenerative
disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
87. The method according to claim 86, wherein the neurological or neurodegenerative
disorders are chosen from the group consisting of dementia, particularly degenerative dementia including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt- Jakob disease and motor neuron disease, vascular dementia (including multi-infarct dementia), dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), dementia in Parkinson's disease, metabolism, toxins, anoxia and vitamin deficiency, and mild cognitive impairment associated with aging, particularly Age- Associated Memory Impairment, amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, ischemia, traumatic head, brain injury, brain inflammation, eye injury, stroke, neuroinflammation, neurodegeneration or decreased brain activity associated with stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, hypoxia, hypoglycemia, gas poisoning, drug intoxication, diabetes mellitus, edema, spinal cord injury, cerebral ischemia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, seizures or the like, neurodegeneration associated multiple sclerosis.
88. A method for the treatment or prevention of ocular disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
89. The method according to claim 88, wherein the ocular disorders are chosen from the group consisting of glaucoma (such as normal tension glaucoma), glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, acute injury to the eye tissue (e.g., conjunctivitis), high intraocular pressure, family history of glaucoma, glaucoma in the contralateral eye and high myopia.
90. A method for the treatment or prevention of appetite-related disorders comprising
administering, alone or in combination therapy, to a patient in need thereof a
therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
91. The method of claim 90, wherein the appetite-related disorder is chosen from the group consisting of: emesis, vomiting and nausea, food behavioral problems feeding disorders such as anorexias, cachexias, wasting conditions, bulimia, obesity, obesity-related disorders such as diabetes type II or hyperlipidemia.
92. A method for the treatment or prevention of gynecological disorders comprising
administering, alone or in combination, a therapeutically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
93. The method of claim 92, wherein the gynecological disorder is uterus contraction
caused by hormones, prostanoid-induced muscle contraction such as premature labor, menstrual cramps, menstrual irregularity or dysmenorrhea.
94. A method for the treatment or prevention of sleep disorders comprising administering, alone or in combination, a pharmaceutically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
95. The method of claim 94, wherein the sleep disorder is chosen from the group consisting of: insomnia, night terrors, nightmares, vivid dreaming, restlessness, bruxism, somnambulism, narcolepsy, circadian rhythm adjustment disorders, sleep disorders associated with neurological or mental disorders or with pain.
96. A method for the treatment of prevention of a urinary system disorder comprising administering, alone or in combination, a pharmaceutically acceptable dose of a compound according to any one of claims 1-68 or pharmaceutical composition according to any of claims 69 to 71.
97. The method of claim 96, wherein the urinary system disorder is chosen from the group consisting of overactive bladder and interstitial cystitis.
98. The method according to any of claims 72 to 97, wherein the patient is a human.
99. The method according to any of claims 72 to 97, wherein the patient is a companion animal, exotic animal or a farm animal such as a dog, cat, mouse, rat, hamster, gerbil, guinea pig, rabbit, horse, pig or cow.
100. A method of inhibiting FAAH in a biological sample, comprising contacting said
biological sample with a compound according to any one of claims 1-68 or
pharmaceutical composition according to any of claims 69 to 71.
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