WO2010022055A2 - Inhibiteurs de canaux sodiques sensibles au potentiel - Google Patents

Inhibiteurs de canaux sodiques sensibles au potentiel Download PDF

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WO2010022055A2
WO2010022055A2 PCT/US2009/054169 US2009054169W WO2010022055A2 WO 2010022055 A2 WO2010022055 A2 WO 2010022055A2 US 2009054169 W US2009054169 W US 2009054169W WO 2010022055 A2 WO2010022055 A2 WO 2010022055A2
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amino
triazin
phenyl
acetamide
piperidin
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WO2010022055A3 (fr
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John L. Buchanan
Howard Bregman
Nagasree Chakka
Erin F. Dimauro
Bingfan Du
Hanh Nho Nguyen
Xiao Mei Zheng
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Amgen Inc
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Amgen Inc
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    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 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 invention provides compounds that are inhibitors of voltage-gated sodium channel (Nav), in particular Nav 1.7 and are therefore useful for the treatment of diseases treatable by inhibition of these channels, in particular, chronic pain disorders. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
  • Nav voltage-gated sodium channel
  • Chronic pain by definition involves abnormal electrical spiking of neurons in the pain pathways: peripheral sensory neurons, spinal cord neurons, neurons in the pain matrix of the brain (e.g., somatosensory cortex, insular cortex, anterior cingular cortex), and / or neurons in brainstem.
  • peripheral sensory neurons e.g., somatosensory cortex, insular cortex, anterior cingular cortex
  • neurons in the pain matrix of the brain e.g., somatosensory cortex, insular cortex, anterior cingular cortex
  • neurons in brainstem e.g., somatosensory cortex, insular cortex, anterior cingular cortex
  • firing of these neurons is modulated and governed by many different receptors, enzymes, and growth factors, in most neurons the fast upstroke of the electrical spike is produced by entry of sodium ions through voltage-gated sodium channels (Hille B, Ion Channels of Excitable Membranes. Sinauer Associates, Inc.: Sunderland MA, 3 rd Ed. 2001).
  • Nonselective sodium channel inhibitors such as lidocaine, mexiletine, and carbamazepine show clinical efficacy in chronic pain, including neuropathic pain, but they are limited in dose and in use, likely due to effects on sodium channels outside the pain pathway.
  • Navl .7 governs one or more control points critical for pain perception. Accordingly, a drug that inhibits Navl .7 should effectively treat chronic pain in humans.
  • the present invention fulfils this and related needs.
  • X is -NH-, -0-, -S-, or -SO 2 -;
  • Y is O, S, or N-CN A is aryl or heteroaryl;
  • R 1 is alkyl, haloalkyl, substituted alkyl, acyloxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl wherein the ring in cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl is optionally substituted with one to three substitutents independently selected from alkyl, halo, haloalkyl, alkoxy, hydroxyl, or haloalkoxy;
  • R 2 is hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, amino, monosubstituted or disubstitued amino, sulfonyl, or alkoxyalkyl;
  • R 3 is hydrogen, halo, alkyl, alkoxy, cyano, or haloalkyl;
  • R 4 is hydrogen, alkyl, substituted alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cyano, amino, monoalkylamino, or dialkylamino;
  • R 5 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl; and R 6 is aryl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or aralkyl wherein one or two carbon atoms in the alkyl chain in aralkyl are optionally replaced by -N-, -O-, or -CO- provided that -N-, -O-, or -CO- are not on adjacent atoms; or
  • R 5 and R 6 together with the nitrogen atom to which they are attached form ring B having the formula: wherein ring B is a heteroaryl, four membered heterocyclyl, heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl ring, and wherein each aforementioned ring in R 5 , R 6 and ring B is substituted with R a , R b or R c where R a is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, thio, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl
  • X is -NH-, -O-, -S-, or -SO 2 -; Y is O, S, or N-CN A is aryl or heteroaryl;
  • R 1 is alkyl, haloalkyl, substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl wherein the ring in cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl is optionally substituted with one to three substitutents independently selected from alkyl, halo, haloalkyl, alkoxy, hydroxyl, or haloalkoxy;
  • R 2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, amino, monosubstituted or disubstitued amino, sulfonyl, or alkoxyalkyl;
  • R 3 is hydrogen
  • R 4 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, amino, monoalkylamino, or dialkylamino; and ring B is a heteroaryl, heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl ring, each ring substituted with R a , R b or R c where R a is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, thio, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxy, aminoalkoxy,
  • the compound of Formula (II) has the structure (IF):
  • a pharmaceutical composition comprising a compound of Formula (I), (II) or (IF),or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method of treating a disease by inhibition of voltage- gated sodium channel in a patient comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), (II) or (IF) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the disease is chronic pain.
  • the embodiment is chronic pain associated with, but are not limited to, post-herpetic neuralgia (shingles), osteoarthritis, painful diabetic neuropathy, complex regional pain syndrome (CRPS), cancer- or chemotherapy-induced pain, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorders, and migraine, Primary Erythromelalgia, and Paroxysmal Extreme Pain Disorder.
  • shingles post-herpetic neuralgia
  • osteoarthritis painful diabetic neuropathy
  • CRPS complex regional pain syndrome
  • cancer- or chemotherapy-induced pain chronic back pain
  • phantom limb pain trigeminal neuralgia
  • HIV-induced neuropathy cluster headache disorders
  • migraine Primary Erythromelalgia
  • Paroxysmal Extreme Pain Disorder Paroxysmal Extreme Pain Disorder.
  • Navl .7 inhibitors include but are not limited to depression (Morinville et al., J Comp Neurol., 504:680-689 (2007)), bipolar and other CNS disorders (Ettinger and Argoff, Neurotherapeutics, 4:75-83 (2007)), epilepsy: ibid., and Gonzalez, Termin, Wilson, Methods and Principles in Medicinal Chemistry, 29:168-192 (2006)), multiple sclerosis (Waxman, Nature Neurosci. 7 :932-941 (2006)), Parkinson's (Do and Bean, Neuron 39 : 109-120 (2003); Puopolo et al., J. Neurosci.
  • this invention is directed to use of the compounds of Formula (I), (II) and (IF) as a medicament.
  • the medicament is used in the treatment of chronic pain.
  • the embodiment is chronic pain associated with, but are not limited to, post-herpetic neuralgia (shingles), osteoarthritis, painful diabetic neuropathy, complex regional pain syndrome (CRPS), cancer- or chemotherapy-induced pain, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorders, and migraine, Primary Erythromelalgia, and Paroxysmal Extreme Pain Disorder.
  • Other potential indications include but are not limited to depression, bipolar and other CNS disorders, multiple sclerosis, Parkinson's disease, restless legs syndrome, ataxia, tremor, muscle weakness, dystonia, tetanus, anxiety, depression, learning and memory, cognition, cardiac arrhythmia and fibrillation, contractility, congestive heart failure, sick sinus syndrome, schizophrenia, neuroprotection after stroke, drug and alcohol abuse, Alzheimer's, and cancer.
  • this invention is directed compounds of Formula (I), (II) and (IF) for use in the treatment of chronic pain.
  • the embodiment is chronic pain associated with, but are not limited to, post-herpetic neuralgia (shingles), osteoarthritis, painful diabetic neuropathy, complex regional pain syndrome (CRPS), cancer- or chemotherapy- induced pain, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorders, and migraine, Primary Erythromelalgia, and Paroxysmal Extreme Pain Disorder.
  • Other potential indications include but are not limited to depression, bipolar and other CNS disorders, multiple sclerosis, Parkinson's disease, restless legs syndrome, ataxia, tremor, muscle weakness, dystonia, tetanus, anxiety, depression, learning and memory, cognition, cardiac arrhythmia and fibrillation, contractility, congestive heart failure, sick sinus syndrome, schizophrenia, neuroprotection after stroke, drug and alcohol abuse, Alzheimer's, and cancer.
  • X is -NH-, -0-, -S-, or -SO 2 -;
  • A is aryl or heteroaryl
  • R 2 is hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, amino, monosubstituted or disubstitued amino, sulfonyl, or alkoxyalkyl
  • R 3 is hydrogen, halo, alkyl, alkoxy, cyano, or haloalkyl
  • R 4 is hydrogen, alkyl, substituted alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cyano, amino, monoalkylamino, or dialkylamino;
  • R 5 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl; and R 6 is aryl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or aralkyl wherein one or two carbon atoms in the alkyl chain in aralkyl are optionally replaced by -N-, -O-, or -CO- provided that -N-, -O-, or -CO- are not on adjacent atoms; or
  • ring B is a heteroaryl, four membered heterocyclyl, heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl ring, and wherein each aforementioned ring in R 5 , R 6 and ring B is substituted with R a , R b or R c where R a is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, thio, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino and R b and R c are independently selected from hydrogen, alkoxycarbony
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • Alicyclic means a non-aromatic ring e.g., cycloalkyl or heterocyclyl ring.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkylthio means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.
  • Alkylsulfonyl means a -SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkylamino means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.
  • Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkoxycarbonyl means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, e.g., 2- methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
  • alkoxyalkyloxy or “alkoxyalkoxy” means a -OR radical where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, 2-ethoxyethoxy, and the like.
  • Aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -NRR' where R is hydrogen, alkyl, or -COR a where R a is alkyl, each as defined above, and R is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl, each as defined herein, e.g., aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like.
  • Aminoalkoxy means a -OR radical where R is aminoalkyl as defined above, e.g., 2- aminoethoxy, 2-dimethylaminopropoxy, and the like.
  • Aminocarbonyl means a -CONRR' radical where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl , each as defined herein and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined herein, e.g., - CONH 2 , methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like.
  • Aminosulfonyl means a -SO 2 NRR' radical where R is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined herein and R' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined herein, e.g., - SO 2 NH 2 , methylaminosulfonyl, 2-dimethylaminosulfonyl, and the like.
  • Acyl means a -COR radical where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined herein, e.g., acetyl, propionyl, benzoyl, pyridinylcarbonyl, and the like.
  • R is alkyl
  • the radical is also referred to herein as alkylcarbonyl.
  • Acyloxyalkyl means a -alkyleneOCOR radical where R is alkyl as defined above.
  • Acylamino means a -NHCOR radical where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined herein, e.g., acetylamino, propionylamino, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Alkyl means a -(alkylene)-R radical where R is aryl as defined above.
  • Aryloxy means a -OR radical where R is aryl as defined above, e.g., phenoxy, naphthyloxy.
  • Aryloxyalkyl means a -alkylene-OR radical where R is aryl as defined above, e.g., phenoxymethyl, phenoxyethyl, and the like.
  • Alkyloxy means a -OR radical where R is aralkyl as defined above.
  • Alkylthio means a -SR radical where R is aralkyl as defined above.
  • Bridged heterocyclyl means a saturated or unsaturated monovalent bicyclic group of
  • ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, where some of the rings are created by one or more bridges.
  • Representative examples include but are not limited to:
  • Cycloalkyl means a cyclic, saturated, monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
  • the cycloalkyl ring can optionally be fused to phenyl or monocyclic heteroaryl ring as defined herein.
  • fused cycloalkyl it means that the cycloalkyl ring is fused to phenyl or monocyclic heteroaryl ring.
  • the cycloalkyl ring is referred to herein as "monocyclic cycloalkyl” it means that the cycloalkyl ring is not fused to phenyl or monocyclic heteroaryl ring.
  • Cycloalkylalkyl means a -(alkylene)-R radical where R is cycloalkyl as defined above; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
  • Cycloalkoxy means a -OR radical where R is cycloalkyl as defined above, e.g., cyclopropoxy, cyclobutoxy, and the like.
  • Cycloalkylalkyloxy means a -OR radical where R is cycloalkylalkyl as defined above.
  • Cycloalkenyl means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms containing one or two double bond(s), e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and the like.
  • Carboxy means -COOH.
  • Disubstituted amino means a -NRR' radical where R and R' are independently alkyl, cycloalkyl, cycloalkylalkyl, acyl, sulfonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined herein, e.g., dimethylamino, phenylmethylamino, and the like.
  • R and R' are alkyl, the group is referred to herein as dialkylamino
  • Frour-membered heterocyclyl means saturated monovalent monocyclic group of 4 ring atoms in which one ring atom is N, the remaining ring atoms being C.
  • Halo means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , - CF 2 CF 3 , -CF(CH 3 ) 2 , and the like.
  • fluoroalkyl When the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkyl.
  • Haloalkoxy means a -OR radical where R is haloalkyl as defined above e.g., -OCF 3 , -
  • R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.
  • Hydroalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy ethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-
  • Hydroxyalkoxy or "hydroxyalkyloxy” means a -OR radical where R is hydroxyalkyl as defined above.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic group of 5 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C.
  • the heterocyclyl ring is optionally fused to a (one) aryl or heteroaryl ring as defined herein provided the aryl and heteroaryl rings are monocyclic.
  • the heterocyclyl ring fused to monocyclic aryl or heteroaryl ring is also referred to in this Application as "bicyclic heterocyclyl" ring.
  • heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, tetrahydroisoquinolinyl, and the like.
  • heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • heterocyclyl group contains at least one nitrogen atom
  • it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.
  • heterocyclyl group is a saturated ring and is not fused to aryl or heteroaryl ring as stated above, it is also referred to herein as saturated monocyclic heterocyclyl. It will be apparent to a person skilled in the art, that when ring B in Formula (I) is heterocyclyl, there is at least one nitrogen atom present in the heterocyclyl ring.
  • Heterocyclylalkyl means a -(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heterocyclylalkyloxy means a -OR radical where R is heterocyclylalkyl as defined above.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. It will be apparent to a person skilled in the art, that when ring B in Formula (I) is heteroaryl, there is at least one nitrogen atom present in the heteroaryl ring.
  • Heteroaralkyl means a -(alkylene)-R radical where R is heteroaryl as defined above.
  • Heteraryloxy means a -OR radical where R is heteroaryl as defined above, e.g., pyridinyloxy, thiophenyloxy, and the like.
  • Heteroaralkyloxy means a -OR radical where R is heteroaralkyl as defined above.
  • “Monosubstituted amino” means a -NHR radical where R is alkyl, cycloalkyl, cycloalkylalkyl, acyl, sulfonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl, each as defined herein, e.g., methylamino, 2-phenylamino, hydroxyethylamino, and the like.
  • R is alkyl, the group is referred to herein as monoalkylamino.
  • the present invention also includes the prodrugs of compounds of Formula (I).
  • the term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups in vivo or by routine manipulation.
  • Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., JV, ⁇ /-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., JV, ⁇ /-dimethylaminocarbonyl
  • amides e.g., trifluoroacetylamino, acetylamino, and the like
  • Prodrugs of compounds of Formula (I) are also within the scope of this invention.
  • the present invention also includes protected derivatives of compounds of Formula (I).
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups.
  • a comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999) , the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of Formula (I) can be prepared by methods well known in the art.
  • a "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenes
  • the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.
  • the compounds of the present invention may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated.
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • “Sulfonyl” means a -SO 2 R radical where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, each as defined herein, e.g., methylsulfonyl, phenylsulfonyl, benzylsulfonyl, pyridinylsulfonyl, and the like.
  • R is alkyl, it is also referred to herein as alkylsulfonyl.
  • “Sulfonylamino” means a -NHSO 2 R radical where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, each as defined herein.
  • “Spiroheterocyclyl” means a bicyclic compound ring of 6 to 14, preferably 6 to 12 carbon ring atoms where the rings are connected through one carbon atom and in which one or two ring atoms are heteroatom selected from N, O, or S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C.
  • the spiroheterocyclyl ring optionally contains one or two oxo group within the ring and is optionally substituted with phenyl or monocyclic heteroaryl ring. Representative examples include, but are not limited to,
  • Substituted alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms where one or two hydrogen atoms in the alkyl chain are independently replaced by hydroxyl, alkoxy, amino, monosubstituted amino, disubstituted amino, cyano, sulfonyl, aminocarbonyl, aminosulfonyl, -NHCONH 2 , carboxy, acyl, acylamino, or alkoxycarbonyl, each group as defined herein.
  • Substituted alkynyl means a linear saturated monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a triple bond where one or two hydrogen atoms in the alkynyl chain are independently replaced by phenyl, hydroxyl, alkoxy, amino, monosubstituted amino, disubstituted amino, cyano, sulfonyl, aminocarbonyl, aminosulfonyl, -NHCONH 2 , carboxy, acyl, acylamino, or alkoxycarbonyl, each group as defined herein.
  • Thio means a -SR radical where R is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, each as defined herein, e.g., methylthio, phenylthio, benzylthio, pyridinylthio, and the like.
  • R is alkyl, it is also referred to herein as alkylthio.
  • ring B in the claims and in the specification of this Application "....ring B is a heteroaryl, heterocyclyl, bridged heterocylcyl, or spiroheterocyclyl ring, each ring substituted with R a , R b or R c " and similar phrases used for others groups in the claims and in the specification with respect to the compound of Formula (I) means that the rings can be mono-, di-, or trisubstituted unless indicated otherwise.
  • Treating" or “treatment” of a disease includes: preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound of Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • Table I shows representative compounds of Formula (I) where A is phenyl, R 3 and R 4 are hydrogen, Y is -O- and other groups are as listed below . Note, the carbon atom in the phenyl ring to which -NHCOR 1 group is attached is postion 1
  • Table II shows representative compounds of Formula (I) where A is phenyl, R is hydrogen, Y is -O- and other groups are as listed below. Note, the carbon atom in the phenyl ring to which -NHCOR 1 group is attached is postion 1
  • Table III shows representative compounds of Formula (I) where A is phenyl, R 4 is hydrogen, Y is -O- and other groups are as listed below. Note, the carbon atom in the phenyl ring to which -NHCOR 1 group is attached is postion 1
  • Table IV shows representative compounds of Formula (I) where A is phenyl, R 3 and R 4 are hydrogen, Y is -O- and other groups are as listed below. Note, the carbon atom in the phenyl ring to which -NHCOR 1 group is attached is postion 1
  • Table V shows representative compounds of Formula (I) where A is phenyl, X is -NH-, R 3 is hydrogen, and other groups are as listed below. Note, the carbon atom in the phenyl ring to which -NHCYR 1 group is attached is postion 1
  • X is -NH-.
  • X is -O-. III. In yet another embodiment, X is -S- or -SO 2 -.
  • X is -NH- and Y is O or S.
  • Y is O.
  • Y is S.
  • Y is N-CN.
  • X is -NH-. IF . In another embodiment, X is -O- . HF . In yet another embodiment, X is -S- or -SO 2 -. IV. In yet another embodiment, X is -NH- and Y is O or S. Within this embodiment IV, in one group of compounds Y is O. Within this embodiment IV, in another group of compounds Y is S.
  • A is aryl.
  • in one group of compounds A is phenyl.
  • R 4 is hydrogen, and R 2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, or .
  • R 4 is hydrogen, and R 2 is hydrogen, methyl, ethyl, propyl fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl.
  • R 4 is hydrogen
  • R 2 is hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably hydrogen, methyl, chloro or fluoro and the R 1 CONH- group is meta to the triazinylamino group.
  • R 4 is hydrogen
  • R 2 is hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably hydrogen, methyl, chloro or fluoro
  • the R 2 group is ortho to R ⁇ ONH-and the R 1 CONH- group is meta to the triazinylamino group.
  • R 4 and R 2 are hydrogen.
  • R 4 is hydrogen
  • R 2 is alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxyl, preferably alkyl or halo, preferably methyl, chloro, or fluoro and the R 2 group is ortho to R ⁇ ONH-and the R 1 CONH- group is meta to the triazinylamino (X is NH) group.
  • R 4 and R 2 are independently alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • R 4 and R 2 are independently methyl, ethyl, propyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxy.
  • R 4 and R 2 are independently methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably methyl, chloro or fluoro and the R 1 CONH- group is meta to the triazinylamino group.
  • R 4 and R 2 are independently methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably methyl, chloro or fluoro, and the R 2 and R 4 groups are ortho to R 1 CONH- and the R 1 CONH- group is meta to the triazinylamino (X is NH) group.
  • A is heteroaryl.
  • one group of compounds A is monocyclic heteroaryl, preferably pyridinyl or thiophenyl, R 4 is hydrogen, and R 2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • R 4 and R 2 are independently alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • *® ⁇ - ⁇ is heterocyclyl substituted as defined in
  • group of compounds ⁇ - ⁇ is pyrrolidin- 1 -yl, piperidin- 1 -yl or piperazin- 1 -yl substituted as defined in the Summary, preferably substituted at the 4-position with phenyl or monocyclic heteroaryl wherein phenyl and monocyclic heteroaryl ring is optionally substituted with R d and R e as defined in the Summary.
  • unsaturated monocyclic heterocyclyl preferably 1,2,5,6-tetrahydropiperidin-l-yl, substituted as defined in the Summary, preferably substituted at the 4-position with phenyl or monocyclic heteroaryl wherein phenyl and monocyclic heteroaryl ring is optionally substituted with R d and R e as defined in the Summary .
  • *@ ⁇ - ⁇ is piperidin- 1-yl substituted at the 4-position with phenyl which is optionally substituted with R d and R e where R d and R e are independently cyano, alkyl, haloalkyl, halo, alkoxy, hydroxyl, phenyl, or heteroaralkyl, preferably phenyl.
  • ⁇ - ⁇ is piperazin-1-yl substituted at the 4-position with phenyl which is optionally substituted with R d and R e where R d and R e are independently cyano, alkyl,
  • B haloalkyl, halo, alkoxy, hydroxyl, phenyl, or heteroaralkyl.
  • ⁇ - ⁇ is piperazin- 1-yl substituted at the 4-position with phenyl wherein the phenyl ring is optionally substituted at the 3-position with R d where R d is alkyl, haloalkyl, halo, or alkoxy and optionally substituted at the 2-position with R e where R e is alkyl, halo, alkoxy, haloalkyl or phenyl.
  • ⁇ — ⁇ is piperazin-1-yl substituted at the 4-position with 2,3-dichlorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl, 2-fluorophenyl, 3- trifluoromethylphenyl, or 2-biphenyl.
  • ⁇ - ⁇ is 4-(4-cyanophenyl)piperidin-l-yl, 4-(5-chloro-2-methoxyphenyl)- piperazin-1-yl, 4-(3,4-dichlorophenyl)piperazin-l-yl, 4-(2-l .2.3-triazol-2-ylphenyl)piperazin- 1-yl, 4-(4-fluorophenyl)piperazin-l-yl, 4-(2,5-dimethylphenyl)piperazin-l-yl, 4-(3,4- dimethylphenyl)piperazin-l-yl, 4-phenylpiperazin-l-yl, 4-(2-chlorophenyl)piperazin-l-yl, 4- (2-methoxyphenyl)piperazin-l-yl, 4-(4-methoxyphenyl)piperazin-l-yl, or 4-(2-methyl- phenyl)piperazin-l-yl.
  • B compounds ⁇ — ⁇ is piperidin-1-yl substituted at the 4-position with benzyloxy, 4- chlorophenyl, or 4-fluorophenyl.
  • ⁇ - ⁇ is piperidin-1-yl substituted at the 4-position with l,3-thiazol-2-yl or 1,2-pyrazol-l-yl, each substituted at the 4-position with phenyl, thiophen-3-yl or cyclohex-1-enyl.
  • ⁇ - ⁇ is bicyclic heterocyclyl, bridged heterocylcyl, or spiroheterocyclyl ring substituted as defined in the Summary.
  • one group of compounds v - ⁇ is 1,2, 3,4-tetrahydroisoquinolin-2-yl, 5,6,7, 8-tetrahydro-l,6-
  • B another group of compounds ⁇ is 1, 2, 3, 4-tetrahydroisoquinolin-2-yl substituted as defined in the Summary, preferably substituted at 5- or 6-position of the 1,2,3,4- tetrahydroisoquinolin-2-yl ring.
  • ⁇ is 1, 2, 3, 4-tetrahydroisoquinolin-2-yl substituted as defined in the Summary, preferably substituted at 5- or 6-position of the 1,2,3,4- tetrahydroisoquinolin-2-yl ring.
  • phenyl within this embodiment, in another group of compounds x - ⁇ is 1,2,3,4- tetrahydroisoquinolin-2-yl substituted with at 5-position with R a where R a is halo, alkoxycarbonyl, alkoxy, or cyano.
  • ⁇ - ⁇ is l,2,3,4-tetrahydroisoquinolin-2-yl, 6- bromo- 1 ,2,3 ,4-tetrahydroisoquinolin-2-yl, 5-methoxycarbonyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 2-yl, 6-trifluoromethoxy- 1 ,2,3 ,4-tetrahydroisoquinolin-2-yl, 5-methoxy- 1 ,2,3 ,A- tetrahydroisoquinolin-2-yl, 5-cyano-l,2,3,4-tetrahydroisoquinolin-2-yl, 5-chloro-l,2,3,4- tetrahydroisoquinolin-2-yl, 7-chloro- 1 ,2,3 ,4-tetrahydroisoquinolin-2-yl, 7-bromo- 1 ,2,3 ,A
  • XI(a) is heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl.
  • B in one group of compounds ⁇ — ⁇ is heterocyclyl.
  • R 1 is alkyl, preferably methyl.
  • R 1 is haloalkyl, preferably trifluoromethyl.
  • R 1 is substituted alkyl. Within this embodiment, in one group of compounds R 1 is alkyl substituted with alkoxy or cyano. Within this embodiment, in one group of compounds R 1 is methoxymethyl. Within this embodiment, in one group of compounds R 1 is cyanomethyl.
  • R 1 is cycloalkylalkyl. Within this embodiment, in one group of compounds R 1 is monocyclic cycloalkylalkyl. Within this embodiment, in one group of compounds R 1 is cyclopropylmethyl.
  • — is spirocarbocyclic substituted as defined in the Summary.
  • XVII is spirocarbocyclic substituted as defined in the Summary.
  • v - ⁇ is heterospirocyclic substituted as defined in the Summary.
  • ⁇ - ⁇ is bridged heterocyclyl, preferably
  • R b is as defined in the Summary.
  • R 1 is cycloalkylalkyl or heterocyclylalkyl substituted as defined in the Summary.
  • one group of compounds A is phenyl.
  • R 4 is hydrogen
  • R 2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • R 4 is hydrogen
  • R 2 is hydrogen, methyl, ethyl, propyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, or hydroxy,.
  • R 4 is hydrogen
  • R 2 is hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably hydrogen, methyl, chloro or fluoro and the R 1 CONH- group is meta to the triazinylamino group.
  • R 4 is hydrogen
  • R 2 is hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably hydrogen, methyl, chloro or fluoro
  • the R 2 group is ortho to R ⁇ ONH-and the R 1 CONH- group is meta to the triazinylamino group.
  • R 4 and R 2 are hydrogen.
  • R 4 is hydrogen
  • R 2 is alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxyl, preferably alkyl or halo, preferably methyl, chloro, or fluoro and the R 2 group is ortho to R ⁇ ONH-and the R 1 CONH- group is meta to the triazinylamino group.
  • R 4 and R 2 are independently alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • R 4 and R 2 are independently methyl, ethyl, propyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxy.
  • R 4 and R 2 are independently methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably methyl, chloro or fluoro and the R 1 CONH- group is meta to the triazinylamino group.
  • R 4 and R 2 are independently methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably methyl, chloro or fluoro, and the R 2 and R 4 groups are ortho to R 1 CONH- and the R 1 CONH- group is meta to the triazinylamino group.
  • R 4 and R 2 are independently methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably methyl, chloro or fluoro
  • the R 2 and R 4 groups are ortho to R 1 CONH- and the R 1 CONH- group is meta to the triazinylamino group.
  • B Within independent groups I, II, III, IV, V, F, IF, HF, IV, XII, XIII, XIV, and
  • A is heteroaryl.
  • A is monocyclic heteroaryl, preferably pyridinyl or thiophenyl, R 4 is hydrogen, and R 2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • R 4 and R 2 are independently alkyl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • ⁇ - is heterocyclyl substituted as defined in the Summary.
  • one group of compounds is monocyclic heterocyclyl substituted as defined in the
  • ⁇ - is unsaturated monocyclic heterocyclyl, preferably 1,2,5,6-tetrahydropiperidin-l-yl, substituted as defined in the Summary, preferably substituted at the 4-position with phenyl or monocyclic heteroaryl wherein phenyl and monocyclic heteroaryl ring is optionally substituted with R d and R e as defined in the Summary .
  • ⁇ - ⁇ is piperidin-1-yl or piperazin-1-yl, each ring substituted at the 3 or 4-position, preferably A- position, with R b where R b is phenyl optionally substituted with R d , R e , or R f as defined in the Summary, and R a where R a is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, hydroxy,
  • ⁇ — ⁇ is piperidin-1-yl substituted at the 4-position with phenyl which is optionally substituted with R d and R e where R d and R e are independently cyano, alkyl, haloalkyl, halo, alkoxy, hydroxyl, phenyl, or heteroaralkyl, preferably phenyl.
  • ⁇ - ⁇ is piperazin-1-yl substituted at the 4-position with phenyl which is optionally substituted with R d and R e where R d and R e are independently cyano, alkyl,
  • haloalkyl halo, alkoxy, hydroxyl, phenyl, or heteroaralkyl.
  • *@ ⁇ - ⁇ is piperazin- 1-yl substituted at the 4-position with phenyl wherein the phenyl rng is optionally substituted at the 3-position with R d where R d is alkyl, haloalkyl, halo, or alkoxy and optionally substituted at the 2-position with R e where R e is alkyl, halo, alkoxy, haloalkyl or phenyl.
  • ⁇ — ⁇ is piperazin-1-yl substituted at the 4-position with 2,3-dichlorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl, 2-fluorophenyl, 3- trifluoromethylphenyl, or 2-biphenyl.
  • R a is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, hydroxy, or alkoxy, preferably hydrogen and R b where R b is aryloxy, heteroaryloxy, cycloalkoxy, aralkyloxy, aralkylthio, heteroaralkyloxy, heterocyclylalkyloxy, or cycloalkylalkyloxy, preferably R b is aryloxy, aralkyloxy, or aralkylthio, where the aromatic ring in R b is optionally substituted with R d , R e , or R f as defined in the Summary, preferably optionally substituted with R d and
  • ⁇ - ⁇ is piperidin-1-yl or piperazin-1-yl, each ring substituted at the 3 or 4-position (preferably 4-position) with R b where R b is heteroaryl, preferably five or six membered heteroaryl ring, even more preferably oxazolyl, thiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzisoxazolyl, benzoxazolyl, benzimidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyrazolyl, each ring optionally substituted with R d , R e , or R f as defined in the Summary, and R a where R a is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, hydroxy, or alkoxy.
  • each of above heteroaryl ring is substituted with alkyl, halo, five membered heteroaryl, unsaturated 5 or 6-membered cycloalkyl, or phenyl optionally substituted as defined in the Summary.
  • ⁇ - is bicyclic heterocyclyl, bridged heterocylcyl, or spiroheterocyclyl ring substituted as defined in the
  • ⁇ — ⁇ is 1,2,3,4- tetrahydroisoquinolin-2-yl, 5 ,6,7,8-tetrahydro- 1 ,6-naphthyridin-6-yl, 5 ,6,7,8-tetrahydro- 1 ,7-
  • ⁇ - is 1,2,3,4- tetrahydroisoquinolin-2-yl substituted as defined in the Summary, preferably substituted at 5- or 6-position of the l,2,3,4-tetrahydroisoquinolin-2-yl ring.
  • ⁇ - is 1,2,3,4- tetrahydroisoquinolin-2-yl substituted as defined in the Summary, preferably substituted at 5- or 6-position of the l,2,3,4-tetrahydroisoquinolin-2-yl ring.
  • R a is hydrogen, halo, alkoxycarbonyl, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxyalkyl, hydroxyl, aminosulfonyl, aryl, amino, acetylamino, or carboxy and R b is hydrogen, halo, or alkyl.
  • ⁇ — ⁇ is l,2,3,4-tetrahydroisoquinolin-2-yl substituted with at 5-position with R a where R a is halo, alkoxycarbonyl, alkoxy, or cyano.
  • x ⁇ is 1,2,3,4- tetrahydroisoquinolin-2-yl, 6-bromo-l,2,3,4-tetrahydroisoquinolin-2-yl, 5-methoxycarbonyl- 1 ,2,3 ,4-tetrahydroisoquinolin-2-yl, 6-trifluoromethoxy- 1 ,2,3 ,4-tetrahydroisoquinolin-2-yl, 5- methoxy-l,2,3,4-tetrahydroisoquinolin-2-yl, 5-cyano-l,2,3,4-tetrahydroisoquinolin-2-yl, 5- chloro-1 ,2,3,4-tetrahydroisoquinolin-2-yl, 7-chloro-l ,2,3,4-tetrahydroisoquinolin-2-yl, 7- bromo- 1 ,2,3 ,4-tetrahydroisoquinoquinol,
  • l,2,3,4-tetrahydroisoquinolin-2-yl 6-bromo-l,2,3,4-tetrahydroisoquinolin-2-yl, or 7-methoxycarbonyl- 1 ,2,3 ,4-tetrahydroisoquinolin-2-yl.
  • R 1 is substituted alkyl.
  • R 1 is alkyl substituted with alkoxy or cyano.
  • R 1 is methoxymethyl.
  • in one group of compounds R 1 is cyanomethyl.
  • R 1 is cycloalkylalkyl.
  • R 1 is monocyclic cycloalkylalkyl.
  • R 1 is cyclopropylmethyl.
  • X is -NH- or -O- preferably -NH-.
  • X is -O- .
  • X is -S- or -SO 2 -.
  • X is -NH- and Y is O or N-CN.
  • Y is O.
  • Y is N-CN.
  • Y is N-CN.
  • A is aryl.
  • R 4 is hydrogen
  • R 2 is hydrogen, alkyl, cycloalkyl, aryl, halo, haloalkyl, haloalkoxy, alkoxy, or hydroxyl.
  • in yet another group of compounds A is phenyl, R 4 is hydrogen, and R 2 is hydrogen, methyl, ethyl, propyl, cyclopropyl, phenyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl.
  • R 4 is hydrogen
  • R 2 is hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy, cyclopropyl, hydroxyl or phenyl and the R 1 CONH- group is meta to the triazinyl-X- group.
  • R 4 is hydrogen
  • R 2 is methyl, ethyl, cyclopropyl, phenyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably hydrogen, methyl, chloro or fluoro
  • the R 2 group is ortho to R 1 CONH- and the R 1 CONH- group is meta to the triazinyl-X- group.
  • R 4 and R 2 are hydrogen and R 1 CONH- group is meta to the triazinyl-X- group.
  • R 4 is hydrogen
  • R 2 is alkyl, cycloalkyl, aryl, or halo , preferably alkyl or halo, preferably methyl, chloro, or fluoro and the R 2 group is ortho to R 1 CONH- and the R 1 CONH- group is meta to the triazinyl-X- group.
  • R 4 and R 2 are independently alkyl, cycloalkyl, aryl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • R 4 and R 2 are independently methyl, ethyl, propyl, cyclopropyl, phenyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxy.
  • R 4 and R 2 are independently methyl, ethyl, cyclopropyl, phenyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy or hydroxyl, preferably methyl, chloro or fluoro and the R 1 CONH- group is meta to the triazinyl-X- group.
  • R 4 and R 2 are independently methyl, chloro, or fluoro and the R 2 and R 4 groups are ortho to R 1 CONH- and the R 1 CONH- group is meta to the triazinyl-X- group.
  • A is heteroaryl.
  • R 4 is hydrogen
  • R 2 is hydrogen, alkyl, cycloalkyl, aryl, halo, haloalkyl, haloalkoxy, alkoxy or hydroxy.
  • R 4 and R 2 are independently hydrogen, methyl, fluoro or chloro.
  • heteroaryl preferably pyrrol-
  • ring B is a four membered heterocyclyl, heterocyclyl, bridged heterocyclyl or spiroheterocyclyl ring, preferably ring B is azetidin-1-yl, piperidin-1-yl, piperazin-1-yl, 8-azabicyclo[3.2.1]oct-8-yl, 2,4-dioxo-l,3,8- triazaspior[4.5]dec-8-yl, 3,4-dihydro-l(H)-isoquinolin-2-yl, 1,4-diazepan-l-yl, or 3,6-dihydro- 2(H)pyridin-l-yl, more preferably azetidin-1-yl, piperidin-1-yl, piperazin-1-yl, 3,4-dihydro- l(H)-isoquinolin-2-yl, or 3,6-
  • R a is hydrogen and R b and R c are as defined in the Summary. More preferably, R a is hydrogen, R b is hydrogen, alkoxy, halo, or alkyl, preferably hydrogen, methoxy, fluoro, chloro, or methyl, more preferably R b is hydrogen; and R c is alkyl, substituted alkyl, substituted alkynyl, halo, haloalkyl, haloalkoxy, alkoxy, acyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, aryloxy, heteroaryloxy, aryloxyalkyl, or aralkyloxy, where the aromatic or alicyclic ring in R a , R b and R c is optionally substituted with R d , R e or R f which are independently selected from alkyl, halo, haloalkyl, haloalkyl, haloal
  • ring B is 4-(benzyloxy)piperidin-l-yl; 4-(4-phenyl- l,3-thiazol-2-yl)piperidin-l-yl; 4-(4-chlorophenoxy)piperidin-l-yl; 4-phenylpiperidin-l-yl; A- (4-cyanophenyl)piperidin- 1 -yl; 4-(3 -phenyl- 1 ,2,4-oxadiazol-5-yl)piperidin-l -yl; A- (benzylsulfanyl)piperidin-l-yl; 4-(4-(3-thiophenyl)-lH-pyrazol-l-yl)piperidin-l-yl; 4-(3- propyl- 1 ,2,4-oxadiazol-5 -yl)piperidin- 1 -yl; 4-(4-( 1 -cyclohexen- 1 -yl)- 1
  • ring B is 4-(benzyloxy)piperidin-l-yl; 4-(4- phenyl- 1 ,3-thiazol-2-yl)piperidin- 1 -yl; 4-(4-chlorophenoxy)piperidin- 1 -yl; 4-phenylpiperidin- 1-yl; 4-(4-cyanophenyl)piperidin-l-yl; 4-(3-phenyl-l,2,4-oxadiazol-5-yl)piperidin-l-yl; 4- (benzylsulfanyl)piperidin- 1 -yl; 4-(4-(3-thiophenyl)- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl; 4-(3- propyl- 1 ,2,4-oxadiazol-5 -yl)piperidin- 1 -yl; 4-(4-( 1 -cyclohexen- 1 -yl)- 1
  • ring B is 4-(benzyloxy)piperidin-l-yl; 4-(4-phenyl-l,3-thiazol-2- yl)piperidin-l-yl; 4-(4-chlorophenoxy)piperidin-l-yl; 4-phenylpiperidin-l-yl; 4-(4- cyanophenyl)piperidin-l-yl; 4-(3-phenyl-l,2,4-oxadiazol-5-yl)piperidin-l-yl; A- (benzylsulfanyl)piperidin- 1 -yl; 4-(4-(3-thiophenyl)- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl; 4-(3- propyl- 1 ,2,4-oxadiazol-5 -yl)piperidin- 1 -yl; 4-(4-( 1 -cyclohexen- 1 -yl)- 1 H-
  • B is 5-(difluoromethoxy)-3,4-dihydro-(lH)-isoquinolin-2-yl
  • R 5 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl
  • R 6 is aryl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or aralkyl wherein one or two carbon atoms in the alkyl chain in aralkyl are optionally replaced by -N-, -O-, or -CO- provided that -N-, -O-, or -CO- are not on adjacent atoms, preferably 3-(4-(trifluoromethoxy)phenoxy)propyl)amino, 3-(4-(l- methylethyl)phenyl)propyl)amino, 3-(2-(benzyloxy)phenyl)propyl)amino
  • R 1 is alkyl, preferably methyl, ethyl, propy, isopropyl, isobutyl, or t-butyl, more preferably methyl.
  • R 1 is haloalkyl, preferably trifluoromethyl or 1-fluoroethyl.
  • R 1 is substituted alkyl.
  • R 1 is alkyl substituted with alkoxy or cyano.
  • R 1 is methoxymethyl or methoxyethyl.
  • R 1 is cyanomethyl.
  • R 1 is cycloalkylalkyl.
  • R 1 is monocyclic cycloalkylalkyl.
  • R 1 is cyclopropylmethyl. 4H.
  • R 1 is cycloalkylalkyl, heterocyclyl or heterocyclylalkyl substituted as defined in the Summary, preferably tetrahydrofuryl.
  • Y is O or N-CN.
  • Y is O.
  • Y is -N-CN.
  • R 2 , R 3 , R 4 , R 5 and R 6 are those as described for compound of Formula (I) in 4 above.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 0 C to about 150 0 C, more preferably from about 0 0 C to about 125 0 C and most preferably at about room (or ambient) temperature, e.g., about 20 0 C.
  • Suitable solvents include DMF, DME, THF and alcohols such as ethanol, isopropanol, butanol and the like.
  • Suitable bases include amine bases such as Et 3 N and DIEA and the like, as well as bases such as K2CO3 and NaH and the like.
  • Compounds of formula 1 are either commercially available or they can be prepared by methods well known in the art. For example, N-(3-aminophenyl)- acetamide is commercially available.
  • Compound of formula 2 can then be reacted with an amine of formula 3 in the presence of an acid or a base to give a compound of Formula (I).
  • Suitable solvents include alcohols such as ethanol, isopropanol, butanol and the like, as well as solvents such as THF and DMF and the like.
  • Suitable acids include HCl and TFA and the like.
  • Suitable bases include amine bases such as Et 3 N and DIEA and the like, as well as bases such as K 2 CO 3 and NaH and the like.
  • Compounds of formula 3 are either commercially available or they can be prepared by methods well known in the art.
  • Compounds of Formula (I) can be converted to other compounds of Formula (I) by methods well known in the art.
  • compounds of Formula (I) where ring B is substituted with aryloxy, heteroaryloxy, cycloalkoxy, aralkyloxy, heteroaralkyloxy, heterocyclylalkyloxy, or cycloalkylalkyloxy can be prepared by reacting the corresponding compound of Formula (I) where ring B is substituted with a hydroxy group with aromatic or alicyclic halide, under nucleophilic aromatic/aliphatic substitution reaction conditions well known in the art.
  • Preferable solvents include DMF and the like and bases include potassium tert-butoxide and the like.
  • Compounds of Formula (I) where ring B is substituted with amino, mono or disubstituted amino can be prepared by first preparing a compound of Formula (I) wherein ring B carries an oxo group and then reacting it with an amine under reductive amination reaction conditions.
  • Treatment of compound 4 with a diamino compound of formula 6 provides a compound of formula 7 which upon reaction with an acid of formula R 1 CO 2 H or its corresponding acid halide under standing coupling conditions known in the art provides a compound of Formula (I).
  • the coupling reaction can be carried out with coupling agents such as EDCI/HOBt, O-(7-azabenzotriazole-l-yl)-N, N,N'N'- tetramethyluronium hexafluorophosphate (HATU) and chlorodipyrrolidinocarbenium hexafluorophosphate (PyCIU) (see for example, Han, S-Y.; Kim, Y-A.
  • coupling agents such as EDCI/HOBt, O-(7-azabenzotriazole-l-yl)-N, N,N'N'- tetramethyluronium hexafluorophosphate (HATU) and chlorodipyrrolidinoca
  • the compounds of the invention are Navl.7 inhibitors and hence are useful in the treatment of diseases such as chronic pain associated with, but are not limited to, post-herpetic neuralgia (shingles), osteoarthritis, painful diabetic neuropathy, complex regional pain syndrome (CRPS), cancer- or chemotherapy-induced pain, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorders, migraine, Primary Erythromelalgia, and Paroxysmal Extreme Pain Disorder.
  • diseases such as chronic pain associated with, but are not limited to, post-herpetic neuralgia (shingles), osteoarthritis, painful diabetic neuropathy, complex regional pain syndrome (CRPS), cancer- or chemotherapy-induced pain, chronic back pain, phantom limb pain, trigeminal neuralgia, HIV-induced neuropathy, cluster headache disorders, migraine, Primary Erythromelalgia, and Paroxysmal Extreme Pain Disorder.
  • Other potential indications for Navl .7 inhibitors include but are not
  • Navl.7 inhibitory activity of the compounds of the present invention can be tested using the in vitro and in vivo assays described in working Biological Examples below.
  • the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound of this invention, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • compositions are comprised of in general, a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of formula (I).
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the level of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.

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Abstract

La présente invention porte sur des composés qui sont des inhibiteurs de canal sodique sensible au potentiel (Nav), en particulier Nav 1.7 et sont particulièrement utiles pour le traitement de maladies pouvant être traitées par l'inhibition de ces canaux, en particulier, des troubles de douleur chronique. L'invention porte également sur des compositions pharmaceutiques contenant de tels composés et sur des procédés pour préparer de tels composés.
PCT/US2009/054169 2008-08-20 2009-08-18 Inhibiteurs de canaux sodiques sensibles au potentiel Ceased WO2010022055A2 (fr)

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