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WO2010091164A1 - Inhibiteurs de la glucosylcéramide synthase - Google Patents

Inhibiteurs de la glucosylcéramide synthase Download PDF

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Publication number
WO2010091164A1
WO2010091164A1 PCT/US2010/023168 US2010023168W WO2010091164A1 WO 2010091164 A1 WO2010091164 A1 WO 2010091164A1 US 2010023168 W US2010023168 W US 2010023168W WO 2010091164 A1 WO2010091164 A1 WO 2010091164A1
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alkyl
compound
nmr
found
formula
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PCT/US2010/023168
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English (en)
Inventor
Naing Aay
Ron G. Aoyama
Arlyn Arcalas
Wai Ki Vicky Chan
Hongwang Du
Patrick Kearney
Elena S. Koltun
Jason August Nachtigall
Michael Pack
Steven James Richards
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Exelixis, Inc.
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Priority to ARP100100327A priority Critical patent/AR075368A1/es
Priority to TW099103666A priority patent/TW201040149A/zh
Publication of WO2010091164A1 publication Critical patent/WO2010091164A1/fr

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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/58—Nitrogen atoms attached in position 4
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of cancer and metabolic diseases.
  • GCS glucosylceramide synthase
  • Glucosylceramide synthase is a pivotal enzyme which catalyzes the initial glycosylation step in the biosynthesis of glucosylceramide-based glycosphingolipids (GSLs) namely via the pivotal transfer of glucose from UDP-glucose (UDP-GIc) to ceramide to form glucosylceramide.
  • GCS is a transmembrane, type III integral protein localized in the cis/medial Golgi, Glycosphingolipids (GSLs) are believed to be integral for the dynamics of many cell membrane events, including cellular interactions, signaling, and trafficking.
  • GSL structures have been shown (see, Yamashita et al, Proc, Nail. Acad. ScL CJSA 1999, 96(16), 9142-9147) to be essential for embryonic development and for the differentiation of some tissues. Ceramide plays a central role in sphingolipid metabolism and downregulation of GCS activity has been shown to have marked effects on the sphingolipid pattern with diminished expression of glycosphingolipids. Sphingolipids (SLs) have a biomodulatory role in physiological as well as pathological cardiovascular conditions.
  • sphingolipids and Their regulating enxym.es appear to play a role in adaptive responses to chronic hypoxia in the neonatal rat heart (see, El Alwani et al, Prostaglandins & Other Lipid Mediators 2005, 78(1-4), 249-263).
  • GCS inhibitors have been proposed for the treatment of a variety of diseases (see, for example, WO2005068426), Such treatments include treatment of glycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fabry diseases), diseases associated with glycolipid accumulation (e.g., Gaucher disease; Miglustat (Zavesca), a GCS inhibitor, has been approved for therapy in type 1 Gaucher disease patients, see, Treiber et al., Xe ⁇ iobiotica 2007, 37(3), 298-314), diseases that cause renal hypertrophy or hyperplasia such as diabetic nephropathy; diseases that cause hyperglycemia or hyperinsulemia; cancers in which glycolipid synthesis is abnormal, infectious diseases caused by organisms which use cell surface glycolipids as receptors, infectious diseases in which synthesis of glucosylceramide is essential or important,
  • glycolipid storage diseases e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fab
  • SUBSTITUTE SHEET diseases in which excessive glyco lipid synthesis occurs e.g., atherosclerosis, polycystic kidney disease, and renal hypertrophy
  • neuronal disorders e.g., atherosclerosis, polycystic kidney disease, and renal hypertrophy
  • neuronal disorders e.g., neuronal injury, inflammatory diseases or disorders associated with macrophage recruitment and activation (e.g., rheumatoid arthritis, Crohn's disease, asthma and sepsis), and diabetes mellitus and obesity (see, WO 2006053043).
  • overexpression of GCS is implicated in multi-drug resistance and disrupts ceramide-induced apoptosis.
  • ceramide induces apoptosis in acute myeloid leukemia (AML) cells and that P-glycoprotein (p-gp) confers resistance to ceramide-induced apoptosis, with modulation of the ceramide-glucosylceramide pathway making a marked contribution to this resistance in TF-I cells.
  • p-gp P-glycoprotein
  • GCS inhibitors can be useful for treatment of proliferative disorders by inducing apoptosis in diseased cells.
  • the present invention comprises glucosylceramide synthase (GCS) modulators of structural formula (I),
  • R 1 , A, L, R 2 , R 3 , and m are as defined hereinbelow.
  • the invention comprises compositions comprising a GCS modulator compound of the invention and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention comprises method for the treatment of a cancer or a metabolic disease in a subject in need of such treatment comprising administering to the subject an effective amount of a GCS inhibitor of the invention or a pharmaceutical composition comprising an effective amount of a GCS inhibitor of the invention.
  • the invention comprises GCS modulators.
  • the invention comprises GCS modulators of structural formula (I),
  • R A is independently R ⁇ , Ci-C 6 alkyl, Ci-C 4 haloalkyl, aryl, aryl(Ci-C 4 )alkyl, or -Ci-C 6 alkyl-R A2 , wherein the aryl of the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three R A2 groups, wherein each R ⁇ is independently halogen, cyano, nitro, -OR A1 , -SR A
  • L is -[C(R L ) 2 ] p -L 1 -[C(R L ) 2 ] q -, wherein /? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and each R L is independently hydrogen, methyl, or halomethyl; R 1 is -N(R 10 XR 11 ) or a moiety of formula (a),
  • R , 10 is hydrogen or Ci-C 4 alkyl
  • R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -Ci-C 6 alkyl-N(R 12 ) 2 , or -Ci-C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or Ci-C 4 alkyl; and
  • R 13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three R 13A groups, wherein each R 13A group is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl(C
  • R 20 is -R B2 , hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 , wherein each R B2 is independently cyano, nitro, -OR B3 , -SR B3 , -N(R B3 ) 2 , -C(O)R B3 ,
  • each R B3 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; or two R B3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C 3 )alkyl, halogen, or Ci-C 4 haloalkyl; and each R 21 is independently halogen or -R 20 ; one R 2 is hydrogen or methyl optionally substituted with one, two or three halo groups, and the other R 2 is methyl optionally substituted with one, two or three halo groups, or both R 2 taken together with the carbon atom to which they are attached form a cyclopropyl group; m is
  • R 1 , A, L, R 2 , R 3 , and m are as defined herein.
  • the compounds of the invention, or their pharmaceutically acceptable salts may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure, and may exist as single stereoisomers, racemates, and mixtures of stereoisomers.
  • the compounds of the invention, or their pharmaceutically acceptable salts, as single stereoisomers, racemates, and mixtures of stereoisomers are all intended to be within the scope of this invention.
  • Embodiment (2) In another embodiment, the compound of Formula (I) is that where each R 2 is independently methyl optionally substituted with one, two, or three halo groups, or both R 2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (1).
  • each R 2 In subembodiment (2-a), each R 2 is methyl, or both R 2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (1).
  • subembodiment (2-b) each R 2 is methyl; and all other groups are as defined in embodiment (1).
  • Embodiment (3) In another embodiment, the compound of Formula (I) is that where both R 2 taken together with the carbon atom to which they are attached form a cyclopropyl group; and all other groups are as defined in embodiment (2).
  • Embodiment (4) In another embodiment, the compound of Formula (I) is that were A is isopropyl, t-butyl, C 3 -Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • the compound of Formula (I) is that where A is C 3 -Cs cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is C 3 -Cs cycloalkyl optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is C 3 -Cs cycloalkyl or aryl, wherein the cycloalkyl and aryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is C 3 -Cs cycloalkyl or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3).
  • A is heteroaryl optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (3); such as, for example, A is indolyl optionally substituted by one, two, or three R A groups.
  • Embodiment (5) In another embodiment, the compound of Formula (I) is that where A is phenyl optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • A is phenyl substituted by two R A groups attached to adjacent carbon atoms, and the two R A groups taken together, form -O-(G) y _O-; wherein each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; such as, for example A is 2,3-dihydro-l,4-benzodioxin-6-yl or 2,2-difluoro-l,3-benzodioxol-5-yl.
  • each R A is independently R ⁇ , Ci-C 6 alkyl, C 1 -C 4 haloalkyl, aryl, aryl(Ci-C 4 )alkyl, or -Ci-C 6 alkyl-R A2 , wherein the aryl(Ci-C 4 )alkyl group is optionally substituted with one, two, or three R A2 groups, wherein each R A2 is independently halogen, cyano, nitro, -OR A1 , -SR A1 , -N(R A1 ) 2 , -C(O)R A1 , -S(O)R A1 , -S(O) 2 R A1 , -S(O)N(R A1 ) 2 , -S(O) 2 N(R A1 ) 2 , -C(O)OR A1 ,
  • the compound of Formula (I) is that where when R A is present, each R A is independently halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, phenyl, benzyl, -OR A1 , -N(R A1 ) 2 , or -C(O)R A1 , wherein each R A1 is independently hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; or two R A attached to adjacent carbon atoms, taken together, form -O-(G) y _O-; each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (5).
  • the compound of Formula (I) is that where R 20 is -R B2 , hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aiyl(C 1 -C 4 )alkyl, or -Ci-C 4 alkyl-R B2 , wherein each R B2 is independently cyano, nitro, -OR B3 , -SR B3 , -N(R B3 ) 2 , -C(O)R B3 , -S(O)R B3 , -S(O) 2 R 63 , -S(O)N(R B3 ) 2 , -S(O) 2 N(R B3 ) 2 , -C(O)OR B3 , -C(O)N(R B3 ) 2 , -N(R B3 )C(O)R B3
  • the compound of Formula (I) is that where R 20 is hydrogen, -OR B3 , -N(R B3 ) 2 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(C r C 4 )alkyl, or -C 1 -C 4 alkyl-R B2 ; wherein R B2 is -OR B3 or -N(R B3 ) 2 ; and when R 21 is present, each R 21 is independently halogen or -R 20 ; and all other groups are as defined in any one of embodiments (1) - (6).
  • the compound of Formula (I) is that where R 20 is hydrogen, Ci-C 4 alkyl, -OR B3 , or -N(R B3 ) 2 , wherein each R B3 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; and when R 21 is present, each R 21 is independently halogen or -R 20 ; and all other groups are as defined in any one of embodiments (1) - (6).
  • Embodiment (8) In another embodiment, the compound of Formula (I) is that where R 1 is: (i) -N(R 10 XR 11 ), wherein R 10 is hydrogen or -Ci-C 4 alkyl; and R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -C 1 -C 6 alkyl-N(R 12 ) 2 , or -C 1 -C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or Ci-C 4 alkyl; and R 13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one,
  • the compound of Formula (I) is that where R 1 is: (i) -N(R 10 XR 11 ), wherein R 10 is hydrogen or -Ci-C 4 alkyl; and R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -Ci-C 6 alkyl-N(R 12 )2, or -Ci-C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or Ci-C 4 alkyl; and R 13 is a 4 - 10 membered monocyclic, a 5 - 10 membered bridged-bicyclic, or a 5-10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annul
  • R 20 is hydrogen, -OR B3 , -N(R B3 ) 2 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 ; wherein R B2 is -OR B3 or -N(R B3 ) 2 ; and R 21 is Ci-C 4 alkyl or Ci-C 4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (7).
  • the compound of formula (I) is that of subembodiment (8), wherein w is 0, 1, or 2; and all other groups are as defined in any one of embodiments (1) - (7).
  • the compound of formula (I) is that of subembodiment (8-a), wherein w is 0, 1, or 2; and all other groups are as defined in any one of embodiments (1) - (7).
  • Embodiment (9) In another embodiment, the compound of Formula (I) is that where R 1 is:
  • ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or the moiety of formula (a) is
  • Embodiment (10) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 )(R ⁇ ) or a moiety of formula (a):
  • ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; wherein R 20 is hydrogen, -OR B3 , -N(R B3 ) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 ; wherein R B2 is -OR B3 or -N(R B3 ) 2 , and R 21 is Ci-C 4 alkyl or Ci-C 4 haloalkyl; (b) the moiety of formula (a) is , wherein t is 1 , 2, or 3, R 20 is hydrogen, Ci-C 4 alkyl, Ci-C 4
  • Embodiment (11) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a),
  • ring B is a 5-10 membered bridged-bicyclic heterocyclyl ring; and R 10 , R 11 , w, R 20 , R 21 , and all other groups are as defined in any one of embodiments (I) - (IO).
  • R 1 is -N(R 10 )(R ⁇ ) or a moiety of formula (a), wherein ring B is 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, or l-azabicyclo[2.2.2]oct-3-yl and R 10 , R 11 , w, R 20 , R 21 , and all other groups are as defined in any one of embodiments (1) - (10).
  • Embodiment (12) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a) wherein said moiety of formula (a) is
  • R 1 is -N(R 10 )(R ⁇ ) or a moiety of formula (a) wherein ring B is piperazin-1-yl or 1,4-diazepan-l-yl; and R 10 , R 11 , R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (I) - (IO).
  • R 1 is -N(R 10 XR 11 ) or 4-methylpiperazin-l-yl, 3-methylpiperazin-l-yl, 4- methyl- 1,4-diazepan-l-yl, piperazin-1-yl, 4-(l-methylethyl)-piperazin-l-yl, 4-(2- fluoroethyl)piperazin-l-yl, or 4-ethylpiperazin-l-yl; and R 10 , R 11 , and all other groups are as defined in any one of embodiments (1) - (9).
  • Embodiment (13) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 1 J ) or a moiety of formula (a),
  • R 21 , w, and all other groups are as defined in any one of embodiments (I) - (IO).
  • R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein ring B is azetidin- 1-yl, pyrrolidin-1-yl, or piperidin-1-yl and R 10 , R 11 , R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (10).
  • R 1 is -N(R 10 )(R ⁇ ) or 3 -(dimethylamino)azetidin- 1 -yl, 3 -(dimethylamino)pyrrolidin- 1 -yl, 3 -aminoazetidin- 1 -yl, 3-aminopyrrolidin-l-yl, 4-amino-4-methylpiperidin-l-yl, 3-aminopiperidin-l-yl, 4- aminopiperidin- 1 -yl, 3 -(methylamino)pyrrolidin- 1 -yl, 4-(methylamino)piperidin- 1 -yl, (l-methylethyl)amino-piperidinyl, or 4-hydroxypiperidin-l-yl, and R 10 , R 11 , and all other groups are as defined in any one of embodiments (1) - (9).
  • Embodiment (14) In another embodiment, the compound of Formula (I) is that where L is -[C(R L )2] p -L 1 -[C(R L )2] q -, wherein /? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and each R L is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (13).
  • the compound of Formula (I) is that where L is -[C(R L )2] p -L 1 -[C(R L )2] q -,wherein/? is 1 or 2; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and each R L is independently hydrogen or methyl; and all other groups are as defined in any one of embodiments (1) - (13). [0026] Embodiment (15): In another embodiment, the compound of Formula (I) is that
  • R 1 is a moiety of formula (a) , (a); and ring B, R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (14).
  • Embodiment (16) in another embodiment, is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is a 4 - 10 membered monocyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (14).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is azetidinyl, pyrrolidinyl, or piperidinyl, wherein said azetidinyl, pyrrolidinyl, and piperidinyl are optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (14).
  • Embodiment (17) in another embodiment, is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is a 5 - 10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (14).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, or 2,5-diazabicyclo[2.2.1]hept-2-yl, wherein 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8- yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl,
  • Embodiment (18) in another embodiment, the compound of Formula (I) is that where when R 13A is present, each R 13A group is independently halogen, cyano, nitro, C 1 -C 4 alkyl, Ci-C 4 haloalkyl, aryl(Ci-C 4 )alkyl, -OR B1 , -SR B1 , -N(R B1 ) 2 , -C(O)R B1 , -S(O)R B1 , -S(O) 2 R B1 , -S(O)N(R B1 ) 2 , -S(O) 2 N(R B1 ) 2 , -C(O)OR B1 , -C(O)N(R B1 ) 2 , -N(R B1 )C(O)R B1 , -N(R B1 )C(O)OR B1 , -N(R B1 )C(O)OR B1
  • the compound of Formula (I) is that where when R 13A is present, each R 13A group is independently halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl(Ci-C 4 )alkyl, -OR B1 , -SR B1 , or -N(R B1 ) 2 , wherein each R B1 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; and all other groups are as defined in any one of embodiments (1) - (14), (16), and (17).
  • Embodiment (19) in another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 1 J ) or a moiety of formula (a), wherein R 11 is -C 1 -C 6 alkyl-N(R 12 ) 2 or -C3-C6 CyClOaUCyI-N(R 12 ) 2 ; and all other groups are as defined in any one of embodiments (I) - (14).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is -Ci-C 3 alkyl-N(R 12 ) 2 or -C 3 -C 6 cycloalkyl-N(R 12 ) 2 ; each R 12 is independently hydrogen or -C 1 -C 3 alkyl; and all other groups are as defined in any one of embodiments (1) - (14).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is 2-aminoethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)- 1 -methylethyl,
  • Embodiment (20) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ); and R 10 , R 11 , and all other groups are as defined in any one of embodiments (1) - (6), (9), (14), and (16) - (19).
  • Embodiment (21) In another subembodiment, the compound of Formula (I) is that where each R 3 is independently halogen, cyano, nitro, Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 6 cycloalkyl, -OR C1 , -N(R C1 ) 2 , -C(O)R C1 , -S(O)R C1 , -S(O) 2 R 01 , -S(O)N(R C1 ) 2 , -S(O) 2 N(R C1 ) 2 , -C(O)OR C1 , -C(O)N(R C1 ) 2 , -N(R C1 )C(O)R C1 , -N(R C1 )C(O)OR C1 , -N(R C1 )C(O)N(R C1 ) 2 , or -N(R
  • the compound of Formula (I) is that where each R is halogen, C 1 -C 4 alkyl, Ci-C 4 haloalkyl, or -OR , wherein each R is independently hydrogen, Ci-C 4 alkyl, or
  • Ci-C 4 haloalkyl and all other groups are as defined in any one of embodiments (1) - (20).
  • the compound of Formula (I) is that where m is 1, 2, or 3; and R 3 is halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, or -OR C1 , wherein each R C1 is independently hydrogen,
  • Ci-C 4 alkyl, or Ci-C 4 haloalkyl; and all other groups are as defined in any one of embodiments
  • Embodiment (22) In another embodiment, the compound of Formula (I) is that where w is zero or 1, and R 21 , when present, is Ci-C 4 alkyl or Ci-C 4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (15) and (21).
  • Embodiment (23) In another embodiment, the compound of Formula (I) is that where L is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 -O-, -CH 2 CH 2 -O-, or
  • Embodiment (24) In another embodiment, the compound of Formula (I) is that where L is Ci -C 3 alkylene; and all other groups are as defined in any one of embodiments (1) -
  • Embodiment (25) In another embodiment, the compound of Formula (I) is that
  • Embodiment (26) In another embodiment, the compound of Formula (I) is that
  • Embodiment (27) In another embodiment, the compound of Formula (I) is that which is a compound listed in Table 1.
  • Embodiment (29) In another embodiment, the compound of Formula (I) is that where m is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (28). [0041] Embodiment (30): In another embodiment, the compound of Formula (I) is that where L is -CH 2 -; and all other groups are as defined in any one of embodiments (1) - (29). [0042] When R 1 is a moiety of formula (a),
  • ring B in the definition of R 1 is (i) a heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or (ii) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl.
  • Ring B refers to the annular atoms which together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring.
  • R 1 is a piperazinyl ring substituted with R 20 and (R 21 ) w , wherein R 20 , R 21 , and w are as defined herein.
  • R 1 is, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl and the like, wherein the 4 - 10 membered monocyclic heterocyclyl ring is substituted with R 20 and (R 21 ) w , wherein R 20 , R 21 , and w are as defined herein.
  • Embodiment (31) In another embodiment, the compound of Formula (I) is that where when R 1 is a moiety of formula (a), ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, 8-azabicyclo[3.2.1]octyl, l-azabicyclo[2.2.2]oct-3-yl,
  • ring B is a 7 - 10 membered fused-bicyclic heterocyclyl ring, optionally comprising one, two, or three additional nitrogen atoms within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is a 7 - 10 membered bridged-bicyclic heterocyclyl ring, optionally comprising one or two additional nitrogen atoms within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is a 7 - 10 membered spiro-bicyclic heterocyclyl ring, optionally comprising one additional nitrogen atom within the heterocyclyl ring; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is a 5 or 6 membered heteroaryl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is an 8 - 10 membered fused-bicyclic heteroaryl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or diazepanyl; and all other groups are as defined in any one of embodiments (1) - (19) and (21) - (30).
  • Embodiment (32) In another embodiment, the compound of Formula (I) is that where L is -(CH 2 ) p -L 1 -(CH 2 ) q - , wherein p is 1 or 2; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and all other groups are as defined in any one of embodiments (1) - (22), and (24) - (31). In subembodiment (32-a), L is -CH 2 O(CH2) q -.
  • L is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 -O-, -CH 2 CH 2 -O-, or -CH 2 -O-CH 2 -; and all other groups are as defined in any one of embodiments (1) - (22), and (24) - (31).
  • Embodiment (33) In another embodiment, the compound of Formula (I) is that where A is
  • each R A is independently halogen, Ci -C 4 alkyl, Ci-C 4 haloalkyl, or -OR A1 , wherein each R A1 is independently hydrogen, Ci-C 4 alkyl, or Ci-C 4 haloalkyl, or two R A attached to adjacent carbon atoms, taken together, form -O-(G) y _O-; wherein each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) -(3), (5) - (27), and (29) - (32).
  • the invention also comprises as another embodiment, a pharmaceutical composition
  • a pharmaceutical composition comprising a GCS modulator compound according to any one of the preceding embodiments and a pharmaceutically acceptable excipient, diluent, or carrier.
  • Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application.
  • the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention also comprises as another embodiment a method for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention (supra).
  • Diseases and disorders mediated by GCS or implicated by GCS include, but are not limited to cancers, and metabolic disorders.
  • the invention also comprises as another embodiment a method for treating cancer, comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention.
  • Examples of metabolic diseases and disorders mediated by GCS or implicated by GCS include but are not limited to, Tay Sachs, Sandhoffs, GMl gangliosidosis, atherosclerosis, polycystic kidney disease, renal hypertrophy, rheumatoid arthritis, Crohn's disease, asthma, sepsis, diabetes mellitus, and obesity; and lysosomal storage diseases such as, for example Fabry diseases, and Gaucher disease.
  • the invention further comprises as another embodiment a method for treating metabolic disorders, comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention.
  • the invention also comprises as another embodiment a method for inducing decreased GCS catalytic activity in a cell, in vitro, comprising contacting the cell with an effective amount of a compound according to any of the preceding embodiments.
  • the invention also comprises as another embodiment, use of a GCS modulator of any of the preceding embodiments of the invention for the preparation of a medicament for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment.
  • Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • formulations depend 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 suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example,
  • Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [0061] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution
  • Suspensions in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.
  • Compressed gases can be used to disperse a compound of this disclosure in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
  • the compounds of this disclosure are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and, in addition, can include other medicinal agents and pharmaceutical agents.
  • Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s).
  • Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents.
  • combination products employ the compounds of this disclosure within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of this disclosure can alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • a substituent "R” can reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group can reside on either the 5-membered or the 6- membered ring of the fused ring system.
  • the two "R's" can reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
  • L is a divalent moiety linking A to the parent structure.
  • particular members defining L may be written, for example, in the form -X-Y- or -Y-X-. Such members are intended to replace the term being defined, in this case L, as written, such that the leading (left) bond is attached to the parent moiety and the ending (right) bond is attached to A.
  • L is of the form -X-Y-
  • the X is bonded to the parent moiety and Y is bonded to A.
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound of the invention into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkoxy means the group -OR 0 wherein R 0 is alkyl, as defined herein.
  • alkyl means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined.
  • Representative examples for alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like.
  • (Ci_C 4 )alkyl means a group selected from methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, isobutyl and tert-butyl.
  • Aryl means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms.
  • the monocyclic aryl radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic.
  • the valency may be located on any atom of any ring of the aryl group, valency rules permitting.
  • Representative examples include phenyl, naphthyl, indanyl, benzodioxolyl, benzodioxanyl, benzopyranyl, 2,3-dihydro-lH-indolyl
  • (Ci-C 4 )alkyl an aryl moiety attached to a parent structure via a one-to-four carbon alkylene group. Examples include benzyl, phenethyl, and the like.
  • “Bridged-bicyclic heterocyclyl ring” refers to a heterocyclyl ring system in which a valence bond, an atom, or a chain of atoms connects two or more non-adjacent positions of a heterocyclyl ring system. Such a system may contain isolated or conjugated unsaturation, but not aromatic or hetero aromatic rings in its core structure (but may have aromatic substitution
  • Examples of 5 - 10 membered bridged-bicyclic heterocylyl rings include 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3- yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept- 2-yl, and the like.
  • Cycloalkyl means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms.
  • the cycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the cycloalkyl radical includes fused bicyclic, bridged bicyclic and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, and bicyclo[2.2.2]octanyl.
  • fused-bicyclic refers to a bicyclic ring system where two rings have more than one shared atom in their ring structures, where each bond is part of a ring, where each ring is ortho- fused to the other ring; and where no bond is common to more than two rings.
  • a spiro ring system is not a fused-bicyclic by this definition, but fused bicyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms.
  • Halo and halogen mean a fluoro, chloro, bromo or iodo group.
  • Haloalkyl means an alkyl radical, as defined herein, substituted with one or more halo atoms.
  • halo-substituted (Ci_ 4 )alkyl includes trifluoromethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, perchloroethyl, 2-bromopropyl, and the like.
  • Haloalkyl includes, for example, halomethyl which means a methyl group substituted by one, two, or three halogen atoms, where each halogen is independently selected.
  • Halomethyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, chlorofluoromethyl, and the like.
  • Heteroaryl means a monovalent monocyclic or polycyclic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms.
  • the monocyclic heteroaryl radical is aromatic and whereas the polycyclic heteroaryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic, where the aromatic ring contains at least one heteroatom.
  • heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, isoindolyl, benzimidazolyl, benzo furanyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyrrolo[3,2-c]pyr
  • Heterocyclyl means a monovalent, monocyclic or polycyclic hydrocarbon radical having 3 to 13 ring atoms of which one or more of the ring atoms, for example, 1, 2, 3 or 4 ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon.
  • the heterocyclyl group may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the heterocyclyl radical includes monocyclic, fused-bicyclic, bridged-bicyclic, and spiro-bicyclic ring systems. Unless otherwise stated, the heterocyclyl may be attached at any annular or bridge carbon or heteroatom which results in the creation of a stable structure.
  • heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, 1
  • substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not.
  • substituents only sterically practical and/or synthetically feasible compounds are meant to be included.
  • Spiro ring refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below:
  • a ring atom of a saturated bridged ring system (rings C and C), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spiro ring (ring D) attached thereto.
  • a representative example of a spiro ring system is 2,3-dioxa-8-azaspiro[4.5]decan-8-yl.
  • Stepoisomer means any of two or more isomers containing the same atoms bonded to each other in an identical manner but differing from each other in the spatial arrangement of the atoms or groups of atoms.
  • Stepoisomer includes, for example, an enantiomer, a geometric isomer, a diastereomer, a rotamer, cis-isomer, trans-isomer, and conformational isomer.
  • the names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to encompass all possible stereoisomers and any mixture, racemic or otherwise, thereof.
  • the present invention also includes N-oxidc derivatives of the compounds of the invention. JV-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e., N ⁇ O), e.g., pyridine iV-oxide, and which possess the desired pharmacological activity.
  • Patient and “subject” for the purposes of the present invention include humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
  • 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. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977;66:1-19 both of which are incorporated herein by reference. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 2-
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • a metal ion such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • organic bases examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, JV-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Effective amount is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease.
  • the amount of a compound of the invention which constitutes an “effective amount” will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought.
  • the effective amount for a given circumstance can be determined without undue experimentation.
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • Boc protected amino acid (1) was coupled with a suitably functionalized amine.
  • the coupling reaction was typically carried out in the presence l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC, Novabiochem) and 1-Hydroxybenzotriazole (HOBt, Novabiochem) to give an amide (2).
  • EDC 3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide
  • HOBt 1-Hydroxybenzotriazole
  • 2-amino-amide (3) was coupled with a suitably functionalized 1-phenylcyclopropanecarboxylic acid or 1 -phenyl- 1,1- dimethylcarboxylic acid.
  • the coupling reaction was typically carried out in the presence of EDC and HOBt to afford 2-(2-arylcarboxamide)-3-aryl-propanylamide (4); a compound of formula (I)-
  • R 20 , R 21 , and w are as defined herein.
  • R 20 , R 21 , and w are as defined herein.
  • the resulting carboxylic acid (7) was then coupled with suitably functionalized amines in the presence of 2- (lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU, Applied Biosystems), to afford 2-(2-arylcarboxamide)-3-aryl-propanylamide (8), a compound of formula (I). In certain examples, it was followed by the de -protection reaction performed under acidic conditions.
  • R 20 , R 21 , and w are as defined herein.
  • amine (11) was coupled with a suitably functionalized 1-phenylcyclopropanecarboxylic acid or 1 -phenyl- 1,1-dimethylcarboxylic acid.
  • the coupling reaction was typically carried out in the presence of O-(7-Azabenzotriazole-l-yl)-N, N,N'N'- tetramethyluronium hexafluorophosphate (HATU, Novabiochem) to give 2-(2-Aryl carboxamide)-3-Aryl-propanylamide (12), a compound of formula (I).
  • the invention further comprises a method of preparing a compound of formula (I), the method comprising:
  • R 20 , R 21 , and w are as defined herein; with a compound of formula (14), wherein R 2 , R 3 and m are as defined herein, to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R 20 and R 21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof; or (ii) coupling a compound of formula (15),
  • A, L, R 2 , R 3 and m are as defined herein, and * indicates optional (R) or (S) chirality of the adjacent carbon atom; with a compound of formula (16) wherein -N(R X )(R Y ) is R 1 , wherein one of R x and R Y is R 10 and the other of R x and R Y is R 11 , or R x and R Y and the nitrogen atom to which they are attached form a moiety of formula (a) ,
  • R 20 , R 21 , and w are as defined herein; to provide a compound of formula (I); and optionally separating individual isomers; and optionally modifying any of the R 20 and R 21 groups to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R 20 and R 21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof.
  • Step 1 (S)-2-amino-3-(lH-indol-3-yl)-l-(4-methylpiperazin-l-yl)propan-l-one:
  • Step 2 (l-(2,4-dichlorophenyl)-N-[(2S)-3-(lH-indol-3-yl)-l-(4-methylpiperazin- l-yl)-l-oxopropan-2-yl]cyclopropanecarboxamide: To a solution of (S)-2-amino-3-(lH- indol-3-yl)-l-(4-methylpiperazin-l-yl)propan-l-one dihydrochloride (690 mg, 1.92 mmol) and Hunig's base (1.64 mL, 9.6 mmol) in dry acetonitrile (10 mL) was added l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (Acros, 443 mg, 1.92 mmol).
  • Step 1 l-(4-(trifluoromethyl)phenyl)cyclopropanecarbonitrile: To a solution of 2-(4-(trifluoromethyl)phenyl)acetonitrile (1 g, 5.4 mmol, AK Scientific) in tetrahydrofuran (10 rnL) at O 0 C was added sodium hydride ( 0.4 g, 16.6 mmol). The reaction mixture was stirred at O 0 C for 5 minutes followed by the addition of 1 ,2-dibromoethane ( 2.6 g, 14.1 mmol) in tetrahydrofuran (1 mL).
  • Step 2 l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid: To l-(4- (trifluoromethyl)phenyl)cyclopropanecarbonitrile (600 mg, 2.8 mmol) was added 20 mL of 3 N NaOH solution and the reaction mixture was heated to reflux for 18 h, then cooled down to room temperature. The resulting solution was acidified with 1 N HCl to pH3, and extracted with 50 mL of EtOAc. The organic layer was dried over magnesium sulfate.
  • Step 3 (S)-2-amino-3-(2,4-dichlorophenyl)-l-(4-methylpiperazin-l-yl)propan-l- one: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid (10 g, 29 mmol, Aldrich) in dichloromethane (100 mL) were added N-methylpiperazine ( 1O g, 100 mmol), 1-hydroxybenzotriazole ( 5 g, 33 mmol), N-methylmorpholine ( 20 mL, 182 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.3g, 38 mmol).
  • N-methylpiperazine 1O g, 100 mmol
  • 1-hydroxybenzotriazole 5 g, 33 mmol
  • N-methylmorpholine 20 m
  • Step 4 N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2- oxoethyl]-l-[4-(trifluoromethyl)phenyl]cyclopropanecarboxamide: To a solution of (S)-2- amino-3-(2,4-dichlorophenyl)-l-(4-methylpiperazin-l-yl)propan-l-one ( 200 mg, 0.63 mmol) in dichloromethane (5 mL) were added l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid (200 mg, 0.86 mmol), 1-hydroxybenzotriazole ( 250 mg, 1.85 mmol), N-methylmorpholine (1 mL, 9.1 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydro
  • N-[(2S)-3-(3-chlorophenyl)-l-(4-methylpiperazin-l-yl)-l-oxopropan-2-yl]-l-(2,4- dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(3-chlorophenyl)propanoic acid (PepTech Corp) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid.
  • l-(2,4-dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid.
  • N-[(lS)-l-[(4-bromophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-bromophenyl)propanoic acid (SyntheTech) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4- dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid.
  • S -2-(tert-butoxycarbonylamino)-3-(4-brom
  • N-[(lS)-l-[(4-chlorophenyl)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-l- (2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 2, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (Fluka) was substituted for (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid, and l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) was substituted for l-(4- (trifluoromethyl)phenyl)cyclopropanecarboxylic acid.
  • Fluka was substituted for (S)-2-(tert-butoxycarbonyla
  • Step 1 (S)-ethyl 2-amino-3-(2,4-dichlorophenyl)propanoate: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid (5 g, 15 mmol, Fluka) in dichloromethane (100 mL) were added 1-hydroxybenzotriazole ( 3 g, 22.5 mmol), N-methylmorpholine ( 16.5 mL, 150 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride ( 4.3g, 22.8 mmol), and Ethyl alcohol ( 13.8 mL, 300 mmol).
  • 1-hydroxybenzotriazole 3 g, 22.5 mmol
  • N-methylmorpholine 16.5 mL, 150 mmol
  • Step 2 (S)-ethyl 3-(2,4-dichlorophenyl)-2-(l-(2,4-dichlorophenyl)cyclopropane- carboxamido) propanoate: To a solution of (S)-ethyl 2-amino-3-(2,4-dichlorophenyl)- propanoate ( 3 g, 11.5 mmol) in dichloromethane (100 niL) were added 1-hydroxybenzotriazole (1.8 g, 13.7 mmol), N-methylmorpholine ( 12.6 mL, 115 mmol), l-[3-(dimethylamino)propyl]- 3-ethylcarbodiimide hydrochloride ( 2.6g, 13.7 mmol), and l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid ( 2.7 g, 11.5 mmol, Acros ).
  • Step 3 (S)-3-(2,4-dichlorophenyl)-2-(l-(2,4-dichlorophenyl)cyclopropane- carboxamido)-propanoic acid: To a solution of (S)-ethyl 3-(2,4-dichlorophenyl)-2-(l-(2,4- dichlorophenyl)-cyclopropanecarboxamido) propanoate ( 1.5 g, 3.2 mmol) in 10 mL of MeOH was added 20 mL of 2 N NaOH solution and the reaction mixture stirred at room temperature for 18 hours.
  • Step 4 2,4-dichloro-N-alpha- ⁇ [l-(2,4-dichlorophenyl)cyclopropyl]carbonyl ⁇ -N- [2-(dimethylamino)ethyl]-L-phenylalaninamide: To a solution of (S)-3-(2,4-dichlorophenyl)- 2-(l-(2,4-dichlorophenyl)cyclopropane-carboxamido)propanoic acid (70 g, 29 mmol) in dichloromethane (5 mL) were added 1-hydroxybenzotriazole ( 25 mg, 0.19 mmol), N-methylmorpholine ( 0.172 mL, 1.57 mmol), l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride ( 36 mg, 0.19 mmol), and N ⁇ N ⁇ dimethylethane-l ⁇ -diamine (16 mg, 0.
  • Step 1 (S)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 niL) was added N-methylmorpholine (16 niL, 146.2 mmol), 1-methylpiperazine (1.78 niL, 16.08 mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (3.0 g, 16 mmol), and 1-Hydroxybenzotriazole (HOBt) (2.1 g, 16 mmol).
  • Step 2 (S)-2-amino-3-(4-chlorobenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l- one hydrochloride: To a solution of (S)-tert-butyl 3 -hydroxy- l-(4-methylpiperazin-l-yl)-l- oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in tetrahydrofuran (4 mL) at O 0 C was added sodium hydride (18 mg, 0.77 mmol).
  • reaction mixture was stirred at O 0 C for 5 minutes followed by the addition of 4-chlorobenzyl bromide (157 mg, 0.77 mmol) in tetrahydrofuran (1 mL).
  • the reaction was stirred at O 0 C for 2 h.
  • the reaction was quenched with 5 drops of water and concentrated in vacuo.
  • the concentrated reaction mixture was dissolved in methanol (5 niL), followed by the addition of 4 N HCl in dioxane (3 mL), and the resulting mixture was heated to 65°C for 1 h. Upon cooling the mixture was concentrated in vacuo to give the title compound which was used in the next step without further purification.
  • Step 3 N-[(lS)-l-( ⁇ [(4-chlorophenyl)methyl]oxy ⁇ methyl)-2-(4-methylpiperazin- l-yl)-2-oxoethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide: To a solution of (S)-2- amino-3-(4-chlorobenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one hydrochloride (0.7 mmol) in dichloromethane (4 mL) was added N-methylmorpholine (0.77 mL, 7 mmol), l-(2,4- dichlorophenyl)cyclopropanecarboxylic acid (177 mg, 0.77mmol), l-[3-
  • Step 1 Diethyl 2-acetamido-2-((2,3-dihydrobenzo[6][l,4]dioxin-6-yl)methyl)- malonate: To a freshly prepared solution of sodium ethoxide (sodium 0.6 g, 26 mmol, ethanol 50 mL ) were added 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (2 g, 8.73 mmol) and 2-acetamide-diethylmalonate (1.9 g, 8.75 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2h, and concentrated in vacuo to give the title compound that was submitted to the next step without further purification.
  • sodium ethoxide sodium 0.6 g, 26 mmol, ethanol 50 mL
  • 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (2 g, 8.73
  • Step 2 2-Acetamido-3-(2,3-dihydrobenzo[ ⁇ ] [l,4]dioxin-6-yl)propanoic acid: A solution of diethyl 2-acetamido-2-((2,3-dihydrobenzo[ ⁇ ][l,4]dioxin-6-yl)methyl)malonate (3.17 g, 8.7 mmol) and potassium hydroxide (1.11 g, 27.7 mmol) in water (35 mL) and ethanol (35 mL) was heated to reflux for 2h. The reaction mixture was concentrated in vacuo and the product was submitted to the next step without further purification.
  • Step 3 (S)-2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoic acid: 2-Acetamido-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoic acid (8.7 mmol) was dissolved in a solution of sodium hydroxide (0.42g of NaOH, 50 mL H 2 O) at 37 0 C (39 0 C bath temperature), and the pH was adjusted to 7.5 with the addition of 2N HCl.
  • sodium hydroxide (0.42g of NaOH, 50 mL H 2 O
  • Step 4 (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoate: To a solution of (S)-2-amino-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoic acid (8.7 mmol) in ethanol (25mL) was added thionyl chloride (2.0 mL, 27.4 mmol). The reaction mixture was stirred under reflux conditions (9O 0 C bath temperature) for 2 hours. The resulting solution was concentrated in vacuo and the product was submitted to the next step without further purification.
  • Step 5 (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)propanoate: To a solution of (S)-ethyl 2-amino-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)propanoate (300 mg, 1.3 mmol) in acetonitrile (15.0 mL) were added l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (250 mg, 1.1 mmol), N,N-diisopropylethylamine (1.5 mL, 9.12 mmol), and HATU ( 400 mg, 1.1 mmol).
  • the reaction mixture was stirred at room temperature for 1 hour.
  • the resulting solution was concentrated in vacuo, dissolved in dichloromethane (35 mL), and extracted with water (10 mL) 2 times. The layers were separated and the organic layer was concentrated in vacuo.
  • the product was purified by column chromatography (silica-gel, EtOAc, Hexanes), resulting in 350 mg (68.8%) of the title compound.
  • Step 6 (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(2,3-dihydro- benzo[b] [l,4]dioxin-6-yl)propanoic acid: To a solution of (S)-ethyl 2-amino-3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)propanoate (350 mg, 0.75 mmol) in 15 mL of MeOH was added 15 mL of 2 N NaOH solution and the reaction mixture was stirred at room temperature for 18 hours.
  • Step 7 N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-N'2'- ⁇ [l-(2,4-dichlorophenyl)- cyclopropyl]-carbonyl ⁇ -3-(2,3-dihydro-l,4-benzodioxin-6-yl)-L-alaninamide: To a solution of (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(2,3-dihydrobenzo[b][l,4]dioxin- 6-yl)-propanoic acid (320 mg, 0.73 mmol) in acetonitrile (15.0 mL) were added (S)-quinuclidin- 3-amine (250 mg, 1.9 mmol), N,N-diisopropylethylamine (1.0 mL, 6.0 mmol), and HATU ( 400 mg
  • Step 1 l-(4-(trifluoromethoxy)phenyl)cyclopropanecarbonitrile: To a solution of 2-(4-(trifluoromethoxy)phenyl)acetonitrile (15g, 74.6 mmol) in THF (450 mL) was added NaH (100%, 9.0 g, 375 mmol) at 0 0 C. The reaction was stirred at room temperature for 30 min and 15 mL of dibromoethane (15 mL, 174 mmol) was added. The reaction was stirred at room temperature for 48 h and quenched by addition of 10OmL of water.
  • Step 2 l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid: To a solution of NaOH (35 g, 795 mmol) in 400 mL of water was added l-(4-(trifluoromethoxy)- phenyl)cyclopropanecarbonitrile (14.9 g, 65.0 mmol). The reaction mixture was heated to 12O 0 C for 48 h. The resulting solution was cooled down to 0 0 C and acidified to pH 3 via addition of concentrated HCl. The resulting precipitate was filtered, washed with water, and dried.
  • Step 3 (S)-ethyl 2-amino-3-(4-bromophenyl)propanoate: To a solution of Boc-L- 4-bromophenylalanine (30.Og, 87.16 mmol, Chem-Impex) in ethanol (450 mL) were added thionyl chloride (8.0 mL, 109.67 mmol).
  • Step 4 (S)-ethyl 3-(4-bromophenyl)-2-(l-(4-(trifluoromethoxy)phenyl)- cyclopropanecarboxamido)propanoate: To a solution of (S)-ethyl 2-amino-3-(4- bromophenyl)propanoate (11.5 g, 42.26 mmol) in acetonitrile (150.0 mL) were added l-(4- (trifluoromethoxy)phenyl)cyclopropanecarboxylic acid (10.4 g, 42.26 mmol), N 5 N- diisopropylethylamine (13.9 mL, 84.52 mmol), and HATU ( 19.3 g, 50.71 mmol).
  • Step 5 (S)-3-(4-bromophenyl)-2-(l-(4-(trifluoromethoxy)phenyl)cyclopropane- carboxamido)propanoic acid: To a solution of (S)-ethyl 3-(4-bromophenyl)-2-(l-(4- (trifluoromethoxy)phenyl)cyclopropanecarboxamido)propanoate (17.4 g, 34.8 mmol) in 300 mL of MeOH was added 100 mL of 2 N NaOH solution and the reaction mixture stirred at room temperature for 18 hours.
  • Step 6 N-(azetidin-3-ylmethyl)-4-bromo-Nalpha-[(l- ⁇ 4-[(trifluoromethyl)oxy]- phenyl ⁇ cyclopropyl)carbonyl]-L-phenylalaninamide: To a solution of (S)-3-(4- bromophenyl)-2-( 1 -(4-(trifluoromethoxy)phenyl)cyclopropane-carboxamido)propanoic acid (100 mg, 0.2 mmol) in acetonitrile (5.0 mL) were added tert-butyl 3-(aminomethyl)azetidine-l- carboxylate (Oakwood, 40.0 mg, 0.2 mmol), N,N-diisopropyl-ethylamine (1.1 niL, 6.1 mmol), and HATU ( 76 mg, 0.2 mmol).
  • N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2- oxoethyl]-l-[4-[(trifluoromethyl)oxy]phenyl]cyclopropanecarboxamide was synthesized in a manner similar to Example 6, wherein tert-butyl 8-azabicyclo[3.2.1]octan-3-ylcarbamate was substituted for tert-butyl 3-(aminomethyl)azetidine-l -carboxylate (Oakwood).
  • N- ⁇ (lS)-2-(4-amino-4-methylpiperidin-l-yl)-l-[(2,4-dichlorophenyl)methyl]-2- oxoethyl ⁇ -l-(2,4-dichlorophenyl)cyclopropanecarboxamide 1 H NMR (400MHz, CD 3 OD): 8.50 (s, IH), 7.50-7.38 (m, 3H), 7.28-7.23 (m, IH), 7.17-7.08 (m, IH), 5.20-5.10 (m, IH), 4.10- 3.80 (m, 2H), 4.60-3.45 (m, IH), 3.18-3.02 (m, 2H), 2.98-2.83 (s, IH), 1.85-1.60 (m, 4H), 1.55- 1.37 (m, 5H), 1.13-1.00 (m, 2H).
  • N'2'- ⁇ [l-(2,4-dichlorophenyl)cyclopropyl]carbonyl ⁇ -N-[2-(dimethylamino)ethyl]- N-methyl-5-phenyl-L-norvalinamide 1 H NMR (400MHz, CD 3 OD): 8.41 (s, IH), 7.56 (s, IH), 7.43 (d, IH), 7.39 (d, IH), 7.27-7.14 (m, 5H), 4.68 (dd, IH), 3.85-3.80 (m, IH), 3.45-3.38 (m, IH), 3.17-3.11 (m, IH), 3.05 (s, 3H), 2.78 (s, 6H), 2.63-2.55 (m, 3H), 1.75-1.43 (m, 6H), 1.22- 1.05 (m, 2H).
  • N-(3-aminocyclohexyl)-2,4-dichloro-Nalpha- ⁇ [l-(2,4-dichlorophenyl)- cyclopropyl]carbonyl ⁇ -L-phenylalaninamide 1 H NMR (400MHz, CD 3 OD): 8.52 (s, IH), 7.50-7.38 (m, 4H), 7.23-7.15 (m, 2H), 4.82-4.75 (m, IH), 3.67-3.58 (m, IH), 2.20-2.13 (m, IH), 2.02-1.83 (m, 3H), 1.77-1.40 (m, 5H), 1.25-1.00 (m, 3H).
  • N'2'- ⁇ [l-(2,4-dichlorophenyl)cyclopropyl]carbonyl ⁇ -5-phenyl-N-[(3R)-piperidin- 3-yl]-L-norvalinamide 1 H NMR (400MHz, CD 3 OD): 8.45 (s, IH), 7.55-7.38 (m, 3H), 7.28- 7.20 (m, 2H), 7.17-7.08 (m, 3H), 4.37-4.32 (t, IH), 3.93-3.84 (m, IH), 3.30-3.25 (m, IH), 2.97- 2.93 (m, IH), 2.78-2.73 (m, IH), 2.62-2.47 (m, 2H), 2.02-1.85 (m, 2H), 1.80-1.62 (m, 3H), 1.58- 1.42 (m, 6H), 1.19-1.04 (m, 2H).
  • N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l- ⁇ [4-(trifluoromethyl)- phenyl]methyl ⁇ ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 6 wherein Boc-L-4-trifluoromethylphenylalanine was substituted for Boc-L-4-bromophenylalanine, l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid was substituted for l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid, and tert-butyl 8-azabicyclo[3.2.1]octan-3-ylcarbamate was substituted for l-Boc-3-(aminomethyl)azetidine .
  • N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-l- ⁇ [4-(trifluoromethyl)- phenyl]methyl ⁇ ethyl]-l-(2,4-dichlorophenyl)cyclopropanecarboxamide was synthesized in a manner similar to Example 6 wherein Boc-L-4-trifluoromethylphenylalanine was substituted for
  • Boc-L-4-bromophenylalanine, l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid was substituted for l-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid, and tert-butyl
  • N-piperidin-4-yl-l-(biphenyl-4-ylmethyl)-2-oxoethyl]-l-(2,4-dichlorophenyl)- cyclopropane carboxamide 1 H NMR (400MHz, CD 3 OD): 8.57 (s, IH), 7.60 (d, 2H), 7.52 (d,
  • N-piperidin-4-yl-Nalpha- [(1- ⁇ 4- [(trifluoromethyl)oxy] phenyl ⁇ cyclopropyl)- carbonyl]-L-phenylalaninamide 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 8.07 (d, IH), 7.41 - 7.25
  • N-piperidin-4-yl-4-(trifluoromethyl)-Nalpha-[(l- ⁇ 4-[(trifluoromethyl)oxy]- phenylJcyclopropyOcarbonylj-L-phenylalaninamide 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 8.13
  • Step 1 (S)-l-tert-buty ⁇ 2-methyl aziridine-l,2-dicarboxylate: To a solution of (S)-methyl aziridine-2-carboxylate (prepared according to Tetrahedron Asymmetry, 2002, 13(11), 1129-1134) (1.0 g, 9.89 mmol) in acetonitrile (20 mL) was added boc-anhydride (2.37 g, 10.88 mmol). The reaction mixture was stirred at room temperature for 2 h after which solvent was removed under reduced pressure, resulting in 1.86 g of the title compound that was used in the next step without further purification.
  • 1 H NMR 400MHz, DMSO-d 6 ): ⁇ 3.70 (s, 3H), 3.14 (q, IH), 2.46 (m, IH), 2.39 (m, IH), 1.38 (s, 9H).
  • Step 2 (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)- methoxy)propanoate: (S)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate (1.0 g, 5.0 mmol) was dissolved in anhydrous chloroform (16 mL), followed by addition of (l-methylcyclopropyl)methanol (1.2, 14.9 mmol) and 0.04 mL (0.25 mmol) of a 7 M boron trifluoride diethyl etherate (Aldrich). The reaction mixture was stirred at room temperature for 24 hours and quenched with a few drops of methanol.
  • Step 3 (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methyl-cyclopropyl)- methoxy)propanoate: (S)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methyl-cyclopropyl)- methoxy)propanoate (800 mg, 2.8 mmol) was dissolved in anhydrous diethyl ether (6 mL) and 4 M HCl/dioxane (14mL, 55.7 mmol, Aldrich) was added. The reaction mixture was stirred for 4 hours at room temperature and the solvent was removed in vacuo.
  • Step 5 (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-((l- methyl-cyclopropyl)methoxy)propanoic acid: To a solution of (S)-methyl 2-(l-(2,4- dichlorophenyl)cyclopropanecarboxamido)-3-((l-methylcyclopropyl)methoxy)propanoate (850 mg, 2.1 mmol) in 10 mL of THF was added 8.5 mL of IN LiOH solution (8.5 mmol), and the reaction mixture was stirred at room temperature for 2 hours.
  • Step 1 (S)-methyl 2-(f ⁇ rt-butoxycarbonylamino)-4-methylpent-4-enoate: To a solution of (S)-2-(tert-butoxycarbonylamino)-4-methylpent-4-enoic acid (Alfa Aesar, 1.0 g, 4.4 mmol) in anhydrous acetonitrile (20 mL) was added potassium carbonate (1.8 g, 13.1 mmol) and methyl iodide (0.81 mL, 13.1 mmol).
  • Step 2 (S)-methyl 2-amino-3-(l-methylcyclopropyl)propanoate: To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-4-methylpent-4-enoate (300 mg, 1.2 mmol) in anhydrous dichloromethane (12 mL) under nitrogen atmosphere was added dimethylzinc (3 mL of a 2 M toluene solution, 6.2 mmol), followed by addition of diiodomethane (0.5 mL, 6.2 mmol). The reaction mixture was stirred overnight at room temperature. The resulting solution was extracted with saturated ammonium chloride (30 mL), and water (10 mL).
  • Step 3 (S)-methyl 2-(l-(2,4-dichlorophenyl)cyclopropanecarboxamido)-3-(l- methyl-cyclopropyl)propanoate: To a solution of (S)-methyl 2-amino-3-(l- methylcyclopropyl)propanoate (187 mg, 1.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 5.5 mmol) in dry acetonitrile (5 mL) was added l-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Acros, 250 mg, 1.1 mmol), followed by HATU (Applied Biosystems, 450 mg, 1.2 mmol).
  • Step 4 (S)-2-(l-(2,4-dichlorophenyl)cyclopropanecarboxyamido)-3-(l- methylcyclopropyl)propanoic acid: To a solution of (S)-methyl 2-(l-(2,4- dichlorophenyl)cyclopropane-carboxamido)-3-(l-methylcyclopropyl)propanoate (350 mg, 0.9 mmol) in 5 mL of THF was added 1.9 mL of IN LiOH solution (1.9 mmol), and the reaction mixture was stirred at room temperature for 2 hours.
  • Step 5 N-l-azabicyclo[2.2.2]oct-3-yl-N'2'- ⁇ [l-(2,4-dichlorophenyl)cyclopropyl]- carbonyl ⁇ -3-(l-methylcyclopropyl)-L-alaninamide: To a solution of (S)-2-(l-(2,4- dichlorophenyl)-cyclopropanecarboxyamido)-3-(l-methylcyclopropyl)propanoic acid (300 mg, 0.8 mmol) and N,N-diisopropylethylamine (00.4 mL, 2.6 mmol) in acetonitrile (4 mL) was added quinuclidin-3 -amine (Sigma-Aldrich, 117 mg, 0.9 mmol), followed by HATU (Applied Biosystems, 350 mg, 0.9 mmol).
  • Glucosylceramide synthase (GCS) activity was measured as the amount of UDP-glucose consumed during the synthase-catalyzed reaction by using the enzyme UDP-glucose dehydrogenase to create NADH from UDP-glucose and then quantitatively converting low fluorescence resazurin to high fluorescence resorufm with diaphorase and the NADH that is formed by the dehydrogenase.
  • the synthase-catalyzed reaction transferred glucose from UDP-glucose to C6-ceramide to give UDP and glucosylceramide as products; the assay measured the disappearance of the UDP-glucose substrate.

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Abstract

La présente invention porte sur des modulateurs de la glucosylcéramide synthase (GCS) de la formule structurale suivante (I) ; dans laquelle R1, A, L, R2, R3 et m sont définis présentement, ainsi que sur leurs N-oxydes et sur les sels pharmaceutiquement acceptables de ceux-ci, et sur des procédés de fabrication desdits composés. L'invention porte en outre sur des compositions comprenant les composés, les N-oxydes et/ou leurs sels pharmaceutiquement acceptables. L'invention porte également sur l'utilisation des composés et des compositions pour traiter des maladies dans lesquelles la GCS est un médiateur ou est impliquée. L'invention porte également sur l'utilisation des composés dans et pour la fabrication de médicaments, en particulier pour traiter des maladies dans lesquelles la GCS est un médiateur ou est impliquée.
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