WO2010091104A1 - Inhibiteurs de la glucosylcéramide synthase - Google Patents

Inhibiteurs de la glucosylcéramide synthase Download PDF

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WO2010091104A1
WO2010091104A1 PCT/US2010/023080 US2010023080W WO2010091104A1 WO 2010091104 A1 WO2010091104 A1 WO 2010091104A1 US 2010023080 W US2010023080 W US 2010023080W WO 2010091104 A1 WO2010091104 A1 WO 2010091104A1
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alkyl
oxy
compound
methyl
formula
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PCT/US2010/023080
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WO2010091104A8 (fr
Inventor
Wai Ki Vicky Chan
Hongwang Du
Patrick Kearney
Elena S. Koltun
Jason August Nachtigall
Kevin Noson
Michael Pack
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Exelixis, Inc.
Richards, Steven, James
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Priority to ARP100100326A priority Critical patent/AR075367A1/es
Priority to TW099103670A priority patent/TW201040156A/zh
Publication of WO2010091104A1 publication Critical patent/WO2010091104A1/fr
Publication of WO2010091104A8 publication Critical patent/WO2010091104A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems

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 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. Natl. Acad. Sci. USA 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. Sphingo lipids (SLs) have a biomodulatory role in physiological as well as pathological cardiovascular conditions.
  • sphingolipids and their regulating enzymes 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), 249-261).
  • 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., Xenobiotica 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, diseases in which excessive glycolipid synthesis occurs (e.g., atherosclerosis, polycystic kidney disease, and renal hypertrophy
  • 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),
  • the invention comprises pharmaceutical compositions which comprise a GCS modulator compound of the invention, optionally as a pharmaceutically acceptable salt, 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 ⁇ , wherein the aryl of 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
  • E is -(CH 2 )-, -C(H)(CH 3 )-, or -C(O)-;
  • L is -[C(R L ) 2 ] p -L 1 -[C(R L ) 2 ] q -, wherein p is 1, 2, or 3;
  • q is an integer selected from 0 to (3-p);
  • L 1 is a bond, -O- or -NH-; and each R L is independently hydrogen, methyl, or halomethyl;
  • R 1 is -N(R 10 XR 11 ) or a moiety of formula,
  • R 10 is hydrogen or C 1 -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 C 1 -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
  • 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 ;
  • R 20 and R 21 when present, are not aryl(Ci-C 4 )alkyl; and provided that when L 1 is a bond, E is -C(O)-, R 1 is -N(R 10 XR 11 ), R 11 is R 13 , and R 13 is
  • R 13A when present, is not aryl(Ci-C 4 )alkyl.
  • the present invention further comprises GCS modulators of structural formula (IV),
  • R 1 , E, A, L, X 1 , Q, R 4 , R 5 , m and n as defined herein in embodiment (1).
  • 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.
  • the invention also comprises each of the following embodiments:
  • Embodiment (2) In another embodiment, the compound of Formula (I) is that where Q is -O-; and all other groups are as defined in embodiment (1). In subembodiment
  • the compound of Formula (I) is that where Q is -O-, and m is 1, 2, or 3; and all other groups are as defined in embodiment (1).
  • Embodiment (3) In another embodiment, the compound of Formula (I) is that where E is -C(O)-; and all other groups are as defined in embodiment (1) or (2).
  • Embodiment (4) In another embodiment, the compound of Formula (I) is that where E is -(CH 2 )- or -C(H)(CHs)-; and all other groups are as defined in embodiment (1) or embodiment (2). In subembodiment (4-a), the compound of Formula (I) is that where E is -CH 2 -; and all other groups are as defined in one of embodiment (1) or (2).
  • Embodiment (5) In another embodiment, the compound of Formula (I) is that where A is C 3 -Cs 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) - (4).
  • the compound of Formula (I) is that where A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, imidazolyl, oxazolyl, or pyridyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, imidazolyl, oxazolyl, and pyridyl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where 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) - (4).
  • the compound of Formula (I) is that where A is phenyl, cyclopropyl, or cyclohexyl, wherein the phenyl, cyclopropyl, and cyclohexyl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where 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) - (4).
  • the compound of Formula (I) is that where 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) - (4).
  • the compound of Formula (I) is that where A is aryl; optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where 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) - (4).
  • the compound of Formula (I) is that where 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) - (4).
  • Embodiment (6) In another embodiment, the compound of Formula (I) is that where R 20 is -R B2 , hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(d-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(Ci-C 4 )alkyl, or -Ci-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) - (5).
  • 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
  • the compound of Formula (I) is that where R 1 is: (i) -N(R 10 )R ⁇ , 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) 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
  • the compound of Formula (I) is that where R 1 is -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 4 - 10 membered monocyclic, a 5 - 10 membered bridged-bicyclic, or a 5-10 membered spiro-bicyclic heterocyclyl ring, where
  • 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 methyl; or R 1 is (ii) a moiety of formula (a),
  • ring B 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 (9) 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
  • 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;
  • 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 ;
  • R B2 is -OR B3 or -N(R B3 ) 2 ;
  • R 21 when present, is Ci-C 4 alkyl or Ci-C 4 haloalkyl;
  • 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) - (8).
  • Embodiment (10) 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 (1) - (9).
  • R 1 is -N(R 10 XR 11 ) 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) - (9).
  • 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 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 (1) - (9).
  • the compound of formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein
  • R 1 is -N(R 10 XR 11 ) or 4-methylpiperazin-l-yl, 3-methylpiperazin-l-yl, 4-methyl-l,4- diazepan-1-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) - (5), (7) and (8).
  • 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),
  • R 1 is -N(R 10 )(R ⁇ ) 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) - (9).
  • R 1 is -N(R 10 XR 11 ) or 3-(dimethylamino)azetidin-l-yl, 3-(dimethylamino)pyrrolidin-l-yl, 3- aminoazetidin-1-yl, 3-aminopyrrolidin-l-yl, 4-amino-4-methylpiperidin-l-yl, 3- aminopiperidin-1-yl, 4-aminopiperidin-l-yl, 3-(methylamino)pyrrolidin-l-yl, 4- (methylamino)piperidin-l-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) - (5), (7) and (8).
  • Embodiment (13) 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, -O- or -NH-; and each R L is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (12).
  • 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) - (12).
  • the compound of Formula (I) is that where L is -[C(R L ) 2 ] p -L 1 -[C(R L ) 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 each R L is independently hydrogen or methyl; and all other groups are as defined in any one of embodiments (I) - (12).
  • the compound of Formula (I) is that where L is - [C(R L )2]p-L 1 -[C(R L )2] q -, wherein/?
  • Embodiment (14) 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) - (13).
  • Embodiment (15) 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 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) - (13).
  • the compound of Formula (I) is that where R 1 is -N(R ⁇ )R 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) - (13).
  • Embodiment (16) in another embodiment, is that where R 1 is -N(R 10 )(R ⁇ ) 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) - (13).
  • the compound of Formula (I) is that where R 1 is -N (R ⁇ )R 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, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept- 2-yl are optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (13).
  • each R 13A group is independently halogen, cyano, nitro, C1-C4 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)N
  • each R 13A group is independently halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aiyl(C 1 -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) - (12), (14), and (15).
  • Embodiment (18) 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-Ci-C 6 alkyl-N(R 12 ) 2 or -C3-C6 cycloalkyl-N(R 12 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (13).
  • 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)-l-methylethyl, 2-(ethylamino)ethyl, 2- (diethylamino)ethyl, 2-(diethylamino)- 1 -methylethyl, 3 -aminopropyl,
  • Embodiment (19) In another embodiment, the compound of Formula (I) is that where R 1 -N(R 10 )(R ⁇ ); and all other groups are as defined in any one of embodiments (1) - (8), (13), and (15) - (18).
  • Embodiment (21) in another embodiment, the compound of Formula (I) is that where R 21 is halogen or -R 20 , wherein R 20 is -R B2 , hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -Cg 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 , -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
  • the compound of Formula (I) is that where R 21 is Ci-C 4 alkyl, Ci-C 4 haloalkyl, or -N(R B3 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
  • the compound of Formula (I) is that where w is zero or 1, and R 21 is Ci-C 4 alkyl, Ci-C 4 haloalkyl, or -N(R B3 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
  • the compound of Formula (I) is that where w is zero or 1, and R 21 is Ci-C 4 alkyl or -N(R B3 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
  • the compound of Formula (I) is that where w is zero or 1, and R 21 is Ci-C 4 alkyl; and all other groups are as defined in any one of embodiments (1) - (18) and (20).
  • the compound of Formula (I) is that where w is zero or 1, and R 21 is -N(R B3 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
  • Embodiment (22) 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 -CH 2 -O-CH 2 -; and all other groups are as defined in any one of embodiments (1) - (12) and (14) - (21).
  • the compound of Formula (I) is that where L is -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) - (12) and (14) - (21).
  • the compound of Formula (I) is that where L is Ci-Csalkylene; and all other groups are as defined in any one of embodiments (1) - (12) and (14) - (21).
  • Embodiment (23) In another embodiment, the compound of Formula (I) is that where L is -CH 2 -O-CH 2 -; and all other groups are as defined in any one of embodiments (I) - (12) and (14) - (21).
  • each R A is independently R A2 , Ci-C 6 alkyl, C 1 -C 4 haloalkyl, aryl, aryl(Ci-C4)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 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, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, aryl(C 1 -C 4 )alkyl, -OR A1 , -N(R A1 ) 2 , or -C(O)R A1 , wherein each R A1 is independently hydrogen or Ci-C 4 alkyl; 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) - (23).
  • the compound of Formula (I) is that where when R A is present, each R A is independently halogen, cyano, Ci-C 4 alkyl, Ci-C 4 haloalkyl, phenyl, benzyl, -OR A1 , -N(R A1 ) 2 , or -C(O)R 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) - (23).
  • Embodiment (25) In another embodiment, the compound of Formula (I) is that where each R 4 , when present, is independently halo, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkoxy, or benzyl; and all other groups are as defined in any one of embodiments (1) - (24). In subembodiment (25-a), the compound of Formula (I) is that where each R 4 , when present, is independently chloro, fluro, bromo, methyl, trihalomethyl, methoxy, or benzyl; and all other groups are as defined in any one of embodiments (1) - (24). [0037] Embodiment (26): In another embodiment, the compound of Formula (I) which is a compound of formula (Ia):
  • Embodiment (27) In another embodiment, the compound of Formula (I) which is a compound of formula (Ib):
  • Embodiment (28) In another embodiment, the compound of Formula (I) is that which is a compound of Table 1.
  • Embodiment (29) 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) and (6) - (27). In subembodiment (29-a), the compound of Formula (I) is that where A is phenyl substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4) and (6) - (27).
  • the compound of Formula (I) is that where A is phenyl; and all other groups are as defined in any one of embodiments (1) - (4) and (6) - (27).
  • the compound of Formula (I) is that where 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; and all other groups are as defined in any one of embodiments (1) - (4), (6) - (23), and (25) - (27); for example, A is 2,3-dihydro-l,4-benzodioxin-6-yl or 2,2-difluoro-l,3-benzodioxol-5- yi.
  • Embodiment (31) In another embodiment, the compound of Formula (I) is a compound of formula (III):
  • 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.
  • ring B is, for example, piperazinyl
  • the moiety of formula (a) is a piperazinyl ring substituted with R 20 and (R 21 ) w , wherein R 20 , R 21 , and w are as defined herein.
  • ring B is a 4 - 10 membered monocyclic heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms
  • the moiety of formula (a) is, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or 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 (32) 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, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.
  • R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • 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 R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • ring B is a 7 - 10 membered bridged-bicyclic heterocyclyl ring, optionally comprising one or two additional nitrogen atoms within the heterocyclyl ring; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (10), (13) - (18), (20) - (27), and (29)
  • ring B is a 7 - 10 membered spiro-bicyclic heterocyclyl ring, optionally comprising one additional nitrogen atom within the heterocyclyl ring; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • ring B is a 5 or 6 membered heteroaryl; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1)
  • ring B is an 8 - 10 membered fused-bicyclic heteroaryl; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or diazepanyl; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • Embodiment (33) In another embodiment, the compound of Formula (I) is that where n is 0, 1, 2, or 3; and all other groups are as defined in any one of embodiments (I) - (27) and (29) - (32). In subembodiment (33-a), the compound of Formula (I) is that where n is 0 or 1; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (32). In subembodiment (33-b), the compound of Formula (I) is that where n is 0; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (32).
  • Embodiment (34) In another embodiment, the compound of Formula (I) is that where m is 0, 1, 2, or 3; Q is -O-; and all other groups are as defined in any one of embodiments (1), (3) - (27), and (29) - (33). In subembodiment (34-a), 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), (3) - (27), and (29) - (33).
  • Embodiment (35) In another embodiment, the compound of Formula (I) is that where when present, R 5 is independently halogen or C 1 -C 4 alkyl, wherein the alkyl group is optionally substituted with one, two, or three R 51 groups wherein each R 51 is independently hydroxy or halogen; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (34).
  • the compound of Formula (I) is that where when present, R 5 is independently halogen or Ci-C 4 alkyl; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (34).
  • the invention also comprises as another embodiment, a pharmaceutical composition which comprises a GCS modulator compound, optionally as a pharmaceutically acceptable salt thereof, according to any one of the embodiments herein, together with a pharmaceutically acceptable diluent, excipient, and/or carrier.
  • a pharmaceutical composition which comprises a GCS modulator compound, optionally as a pharmaceutically acceptable salt thereof, according to any one of the embodiments herein, together with a pharmaceutically acceptable diluent, excipient, and/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, metabolic disorders, and lysosomal storage diseases.
  • cancers which may be modulated by a compound or composition of the invention include, but are not limited to, cancers in which glycolipid synthesis is abnormal, for example, breast cancer, renal adenocarcinoma, brain cancer, neuroblastoma, lung cancer, intestinal cancer, pancreas and prostrate cancer.
  • 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.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • 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.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles 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.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of 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. [0062] 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.
  • compositions can 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 75% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • 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, however, can vary.
  • 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.
  • 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. [0074] If a group "R” is depicted as floating on a heterocyclic ring system, as for example
  • the "R” group can reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • 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.
  • Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,
  • 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_4)alkyl means a group selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and tert-butyi.
  • Alkylamino means an alkyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e., substituents of the form -N(H)R 0 , where R 0 is an alkyl group).
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, hexylamino, and the like.
  • 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 (including, for example, 2,3-dihydro-lH-indol-2-yl, 2,3-dihydro-lH-indol-5-yl, and the like), isoindolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-6-yl, and the like), phthalimidyl, and the like.
  • Aryl(Ci-C 4 )alkyl means 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 heteroaromatic rings in its core structure (but may have aromatic
  • 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, 1- 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.
  • the polycyclic heteoaryl radical includes fused, bridged and spiro ring systems.
  • the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting.
  • 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 fused-bicyclic, bridged-bicyclic, and spiro 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,
  • 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.
  • Stepreoisomer 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 includes 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.
  • 3-benzyloxy-2-aminopropanyl amide (3) is coupled with a suitably functionalized carboxylic acid, wherein X 1 , Q, R 4 , R 5 , m and n are as defined herein, such as, for example, 2-phenyloxy benzoic or 2-phenyloxy-nicotinic acid.
  • the coupling reaction is typically carried out in the presence of l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC, Novabiochem) and 1-Hydroxybenzotriazole (HOBt, Novabiochem) to give 3-benzyloxy(2-phenyloxyarylamido)propanyl amide (4).
  • the Boc protected amino acid (5) is coupled with a suitably functionalized amine, 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),
  • the coupling reaction is typically carried out in the presence EDC and HOBt to give a 3-hydroxy propanyl amide (6).
  • the resulting alcohol (6) may then be alkylated by treatment with sodium hydride and a suitably functionalized electrophile (where A, R L , and q are as defined herein, and LG 1 is a leaving group, such as halo), such as, for example, benzyl bromide, followed by the de-protection reaction performed under acidic conditions to provide a suitably functionalized amine (8).
  • a suitably functionalized electrophile where A, R L , and q are as defined herein, and LG 1 is a leaving group, such as halo
  • amine (8) is coupled with a suitably functionalized carboxylic acid, wherein X 1 , Q, R 4 , R 5 , m and n are as defined herein, such as, for example, 2-phenyloxy benzoic or 2-phenyloxy-nicotinic acid.
  • the coupling reaction is typically carried out in the presence of EDC and HOBt to afford (9), a compound of formula (I), where E is -C(O)-, L is -[C(R L ) 2 ] q -O-(CH 2 ) p -, A, X 1 , R 4 , R 5 , m and n are as defined herein, and -N(R X )(R Y ) is R 1 , wherein one of R x and R Y is R 10 and the other of R and R is R , or R and R and the nitrogen atom to which they are attached form a moiety of formula (a).
  • the invention further comprises a method of preparing a compound of formula (I), the method comprising: (i) coupling a compound of formula (14),
  • A, L, and E are as defined herein, * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -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),
  • A, L, X 1 , Q, R 4 , R 5 , m and n are as defined herein, and * indicates optional (R) or (S) chirality of the adjacent carbon atom; with a compound of formula (17) 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 (II); 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.
  • Example 1
  • Step 1 (R)-tert-butyl 3-(benzyloxy)-l-(4-methylpiperazin-l-yl)-l-oxopropan- 2-yl(methyl)carbamate: To a solution of (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)- propanoic acid ( 2.95 g, 10 mmol) in dichloromethane (250 niL) were added N- methylpiperazine (1.11 g, 10 mmol) , 1-hydroxybenzotriazole (1.53 g, 10 mmol), diisopropylethylamine (3.4 mL, 20 mmol), and l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide methiodide (2.11 g, 11 mmol).
  • the reaction was stirred at room temperature for 8 hours.
  • the organic solution was extracted with water (2 X 250 mL) and 2N aqueous sodium hydroxide solution (2 X 250 mL) and then dried with magnesium sulfate.
  • the dichloromethane was removed via rotary evaporation and the residual oil treated with a solution of hexane/ethyl acetate (4:1) to yield the desired product as a white crystalline solid that was collected by filtration (1.68 g, 4.45 mmol).
  • Step 2 (R)-2-amino-3-(benzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one: To a solution of (R)-tert-butyl 3-(benzyloxy)-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- yl(methyl)-carbamate (1.68 g, 4.45 mmol) in methanol (20 mL) was added 4N solution of hydrochloric acid in dioxane (4.4 mL, 17.6 mmol). The solution was heated at 55 0 C for three hours then cooled to room temperature. LCMS analysis indicated complete Boc- deprotection of the starting material.
  • Step 3 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- ⁇ [(phenylmethyl)oxy] methyl ⁇ ethyl] pyridine-3-carboxamide: The (R)-2-amino-3 - (benzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one from step 2 (4.44 mmol assumed) was dissolved into dry acetonitrile (50 mL).
  • Step 1 (R)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 niL) was added N-methylmorpholine (16 mL, 146.2 mmol), 1-methylpiperazine (1.78 mL, 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 (R)-2-amino-3-(3-methylbenzyloxy)-l-(4-methylpiperazin-l- yl)propan-l-one: To a solution of (R)-tert-butyl 3 -hydroxy- l-(4-methy lpiperazin-1 -yl)-l- oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in tetrahydrofuran (4 mL) at 0 0 C was added sodium hydride (18 mg, 0.77 mmol).
  • reaction mixture was stirred at 0 0 C for 5 minutes followed by the addition of 3-methylbenzyl bromide (103 ⁇ L, 0.77 mmol) in tetrahydrofuran (1 mL). The reaction was stirred at 0 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 mL) followed by the addition of 4N HCl in dioxane (3 mL). The reaction was heated to 65 0 C for 1 h.
  • Step 3 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-( ⁇ [(3-methylphenyl)methyl]oxy ⁇ - methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: To a solution of (R)-2-amino-3-(3-methylbenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one (0.7 mmol) in dichloromethane (4 rnL) was added N-methylmorpholine (0.77 rnL, 7 mmol), 2-(4- chlorophenoxy)nicotinic acid (203 mg, 0.77mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (148 mg, 0.77 mmol), and 1-Hydroxybenzotriazole (
  • Step 1 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine: To a solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methanol (1.0 g, 6.0 mmol) in dichloromethane (25 mL) was added carbontetrabromide (3.0 g, 9 mmol), and triphenylphosphine (2.35 g, 9.0 mmol).
  • Step 2 2- ⁇ [2-chloro-4-(trifiuoromethyl)phenyl]oxy ⁇ -N-[(lR)-l- ⁇ [(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)oxy]methyl ⁇ -2-(4-methylpiperazin- 1 -yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 6-(bromomethyl)- 2,3-dihydrobenzo[b][l,4]dioxine was substituted for 3-methylbenzyl bromide, and 2-(2- chloro-4-fluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid.
  • the aqueous layer was collected, acidified with IM HCl to pH 3, and extracted with ethyl acetate (3 X 100 mL) with addition of saturated aqueous lithium chloride (100 mL). The organic layer was dried over magnesium sulfate. The ethyl acetate was concentrated in vacuo to give 630 mg (55%) of 2-(2-chloro-6-methylphenoxy)nicotinic acid which was used without further purification.
  • Step 1 Ethyl S-bromo-l-chloronicotinate: To a solution of 5-bromo-2- chloronicotinic acid (1.00 g, 4.23 mmol) in ethanol (8.5 mL) was added concentrated H 2 SO 4 (1.40 mL, 25.38 mmol) drop wise over a minute. The reaction was heated to reflux for 2 hours. All solvent was removed in vacuo and the residue was taken up in ethyl acetate (20 mL) and washed once with 1 M NaOH (20 mL) and then dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the ethyl acetate was removed in vacuo. The remaining oil was used in the next step without further purification. MS (EI) for C 8 H 7 BrClNO 2 found 263.90 (MH + ).
  • Step 2 Ethyl 5-bromo-2-(4-chlorophenoxy)nicotinate: A solution of ethyl 5- bromo-2-chloronicotinate (939.00 mg, 3.55 mmol), 4-chlorophenol (547.68, 4.26 mmol), and cesium carbonate (1735.04 mg, 5.33 mmol) in dimethylacetamide (35 mL) was heated to 130 0 C for 16 hours.
  • Step 3 5-bromo-2-(4-chlorophenoxy)nicotinic acid: Ethyl 5-bromo-2-(4- chlorophenoxy)nicotinate (1120.00 mg, 3.14 mmol) was dissolved in tetrahydrofuran (15 mL) and 12.5 mL (12.5 mmol) of a 1 M LiOH solution was added and this was heated to 70 0 C for 6 hours. After cooling to room temperature, the reaction was washed with diethyl ether (20 mL) and the water layer was acidified to pH 2 and extracted with ethyl acetate (2 X 20 mL).
  • 2-(2-benzyl-4-chlorophenoxy)nicotinic acid was (prepared in the manner of Example 4) wherein 2-chloronicotinic acid was substituted for 5- bromo-2-chloronicotinic acid and 2-benzylphenol was substituted for 4-chlorophenol.
  • 1 H NMR 400 MHz DMSO-J 6 ): ⁇ 8.87 (d, IH), 8.21 (m, IH), 8.09 (m, IH), 7.32 (s, 2H), 7.21 (m, 7H), 7.07 (m, 5H), 5.21 (q, IH), 4.45 (q, 2H), 3.83 (s, 2H), 3.66 (m, 2H), 3.46 (m, 4H),
  • Step 1 (R)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate: To a solution of (R)-methyl aziridine-2-carboxylate [prepared according to Tetrahedron: Asymmetry (2002), 13(11), 1129-1134] (1000.00 mg, 9.89 mmol) in acetonitrile (20 mL) was added Boc anhydride (2374.63mg, 10.88 mmol). The reaction was stirred at room temperature for two hours after which all solvent was removed on the rotary evaporator. The remaining oil was utilized without further purification for the next step.
  • 1 H NMR 400 MHz, DMSO-J 6 ): ⁇ 3.70 (s, 3H), 3.14 (q, IH), 2.46 (m, IH), 2.39 (m, IH), 1.38 (s, 9H).
  • Step 2 (R)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)- methoxy)propanoate: (R)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate (1200.00 mg, 5.96 mmol) was dissolved in anhydrous chloroform (20 mL) followed by (1- methylcyclopropyl)methanol (1540.94 mg, 17.89 mmol) and 0.04 mL (0.28 mmol) of a 7 M boron trifluoride diethyl etherate solution. The reaction was stirred at room temperature for 24 hours and quenched with a few drops of methanol.
  • Step 3 (R)-2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)methoxy)- propanoic acid: (R)-methyl 2-(tert-butoxycarbonylamino)-3-((l- methylcyclopropyl)methoxy)-propanoate (1150.00 mg, 4.00 mmol) was dissolved in tetrahydrofuran (20 mL) and 6 mL (6.00 mmol) of a 1 M LiOH solution was added and this was heated to 70 0 C for 4 hours.
  • Step 1 (2R)-methyl 2-amino-3-(l-phenylethoxy)propanoate: (2R)-methyl 2- (tert-butoxycarbonylamino)-3-(l-phenylethoxy)propanoate was prepared as described in Example 4 (steps 1 and 2) wherein alpha methyl benzyl alcohol was substituted for (1- methylcyclopropyl)methanol.
  • This Boc-ester (880 mg, 2.72 mmol) was suspended in ether (2.7 mL) and treated with 4M solution of HCl in dioxane (13.6 mL, 54.4 mmol) and stirred at room temperature for 2h. The solvents were removed in vacuo and the residue was used directly in the next step.
  • Step 2 (2R)-methyl 2-(2-(4-chlorophenoxy)benzamido)-3-(l-phenylethoxy)- propanoate: (2R)-methyl 2-amino-3-(l-phenylethoxy)propanoate (706 mg, 2.72 mmol) was suspended in dichloroethane (9.1 mL). To the suspension was added 2-(4- chlorophenoxy)nicotinic acid (1019 mg, 4.08 mmol), prepared as described in Example 4, HATU (1550 mg, 4.08 mmol) and diisopropylethyl amine (0.71 mL, 4.08 mmol). The reaction mixture was stirred overnight at room temperature.
  • Step 3 (2R)-2-(2-(4-chlorophenoxy)benzamido)-3-(l-phenylethoxy)propanoic acid: (R)-methyl 2-(2-(4-chlorophenoxy)nicotinamido)-3-(l-phenylethoxy)propanoate (800 mg, 1.76 mmol) was dissolved in THF (8.8 mL). To that solution was added IM LiOH (7.0 mL). After stirring at room temperature for Ih, the organic solvent was removed in vacuo. The aqueous solvent was washed with diethyl ether, diluted with ethyl acetate and washed with IM HCl. The organic layer was separated and dried with MgSO 4 . The crude semi-solid was used without further purification.
  • Step 4 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- ⁇ [(l-phenylethyl)oxy]methyl ⁇ ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - ⁇ [( 1 -phenylethyl)oxy]methyl ⁇ -ethyl]pyridine-3 - carboxamide.
  • Step 1 (R)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 mL) was added N-methylmorpholine (16 mL, 146.2 mmol), 1-methylpiperazine (1.78 mL, 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 (R)-2-(tert-butoxycarbonylamino)-3-(4-methylpiperazin-l-yl)-3- oxopropyl methanesulfonate: To a solution of (R)-tert-butyl 3 -hydroxy- 1 -(4- methylpiperazin-l-yl)-l-oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in dichloromethane (5 rnL) and triethylamine (0.3 rnL) at 0 0 C was added methanesulfonyl chloride (0.06 rnL, 0.77 mmol) and N'N'-Dimethyaminopyridine (10 mg, 0.08 mmol).
  • Step 3 (R)-2-amino-3-(benzylamino)-l-(4-methylpiperazin-l-yl)propan-l- one: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-(4-methylpiperazin-l-yl)-3- oxopropyl methanesulfonate (100 mg, 0.27 mmol) in acetonitrile (5 mL) was added benzyl amino (0.5 mL, 4.2 mmol). The reaction mixture was heated to 65 0 C for 16 h, and concentrated in vacuo.
  • Step 4 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- ⁇ [(phenylmethyl)amino]methyl ⁇ ethyl]pyridine-3-carboxamide: To a solution of (R)-2- amino-3-(benzylamino)-l-(4-methylpiperazin-l-yl)propan-l-one (150 mg, 0.43 mmol) in dichloromethane (10 mL) was added N-methylmorpholine (0.23 mL, 2.15 mmol), 2-(4- chlorophenoxy)nicotinic acid (203 mg, 0.77mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (148 mg, 0.77 mmol), and 1-Hydroxybenzotriazole (HOBt) (
  • Step 1 (R)-ethyl 2-amino-3-(benzyloxy)propanoate: To a solution of (R)-3- (benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (10 g, 33.8 mmol, Acros) in dichloromethane (120 niL) were added 1-hydroxybenzotriazole (6.8 g, 50.8 mmol), N- methylmorpholine (7.4 mL, 67.8 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (9.7 g, 50.8 mmol), and Ethyl alcohol (40 mL, 676 mmol).
  • Step 2 (R)-ethyl 3-(benzyloxy)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)- nicotinamido)propanoate: To a solution of (R)-ethyl 2-amino-3-(benzyloxy)propanoate (750 mg, 3.36 mmol) in dichloromethane (20 mL) were added 1-hydroxybenzotriazole (500 mg, 3.70 mmol), N-methylmorpholine (3.0 mL, 26.88 mmol), l-[3-(dimethylamino)propyl]- 3-ethylcarbodiimide hydrochloride (700 mg, 3.70 mmol), and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid (1.0 g, 3.36 mmol).
  • Step 4 N-[(lR)-2-[(3R)-3-aminopyrrolidin-l-yl]-2-oxo-l-
  • Step 5 2- ⁇ [2-chloro-4-(trifluoromethyl)phenyl]oxy ⁇ -N-[(lR)-2-oxo-2- ⁇ (3R)-3- [(phenylmethyl)amino]pyrrolidin-l-yl ⁇ -l- ⁇ [(phenylmethyl)oxy]methyl ⁇ ethyl]pyridine-3- carboxamide: To a solution of N-((R)-l-((R)-3-aminopyrrolidin-l-yl)-3-(benzyloxy)-l- oxopropan-2-yl)-2-(2-chloro-4-(trifluoromethyl)phenoxy)nicotinamide (50 mg, 0.08 mmol) in dichloromethane (3 rnL) were added benzaldehyde (0.08 rnL, 0.08 mmol) and glacial acetic acid (1 drop).
  • 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 inhibiteurs de la glucosylcéramide synthase (GCS) de formule structurale (I) et sur les sels pharmaceutiquement acceptables de ceux-ci, formule dans laquelle R1, E, A, L, X1, Q, R4, R5, m et n sont tels que définis ici, ainsi que sur les N-oxydes de ceux-ci et sur leurs sels pharmaceutiquement acceptables. L'invention porte en outre sur une composition comprenant les composés, les N-oxydes et/ou les 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 aussi 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.
PCT/US2010/023080 2009-02-06 2010-02-03 Inhibiteurs de la glucosylcéramide synthase WO2010091104A1 (fr)

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WO2014043068A1 (fr) * 2012-09-11 2014-03-20 Genzyme Corporation Inhibiteurs de synthase de glucosylcéramide
WO2012129084A3 (fr) * 2011-03-18 2014-04-24 Genzyme Corporation Inhibiteurs de la glucosylcéramide synthase
CN105189490A (zh) * 2013-03-15 2015-12-23 建新公司 (s)-(2-(2-(4-氟苯基)噻唑-4-基)丙-2-基)氨基甲酸奎宁环-3-基酯的盐形式
EP3318277A1 (fr) 2016-11-04 2018-05-09 Institut du Cerveau et de la Moelle Epiniere-ICM Inhibiteurs de la synthase de glucosylcéramide pour le traitement de maladies du motoneurone
WO2021221953A1 (fr) 2020-04-28 2021-11-04 The Regents Of The University Of Michigan Inhibiteurs pyridine de la glucosylcéramide synthase et procédés thérapeutiques les utilisant
EP4041734A4 (fr) * 2019-11-15 2023-08-30 Yuhan Corporation Nouveaux dérivés ayant une fraction 1,2,3,4-tétrahydronaphtalène ou un sel pharmaceutiquement acceptable de ceux-ci et compositions pharmaceutiques les comprenant
EP4041733A4 (fr) * 2019-11-15 2023-08-30 Yuhan Corporation Nouveaux dérivés ayant une fraction 2,3-dihydro-1h-indène ou 2,3-dihydrobenzofurane ou un sel pharmaceutiquement acceptable de ceux-ci et compositions pharmaceutiques les comprenant
WO2023172475A3 (fr) * 2022-03-11 2023-10-26 Merck Sharp & Dohme Llc Analogues de pyrimidine cycliques non aromatiques utilisés en tant qu'inhibiteurs de glucosylcéramide synthase
WO2023177563A3 (fr) * 2022-03-14 2023-10-26 Merck Sharp & Dohme Llc Analogues de pyrazole amide fusionnés utilisés en tant qu'inhibiteurs de glucosylcéramide synthase
US11857512B2 (en) 2020-07-24 2024-01-02 Genzyme Corporation Pharmaceutical compositions comprising venglustat

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WO2012129084A3 (fr) * 2011-03-18 2014-04-24 Genzyme Corporation Inhibiteurs de la glucosylcéramide synthase
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KR20140092239A (ko) * 2011-03-18 2014-07-23 젠자임 코포레이션 글루코실세라마이드 합성효소 억제제
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EP4098654A1 (fr) * 2012-09-11 2022-12-07 Genzyme Corporation Inhibiteurs de synthase de glucosylcéramide
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US11857512B2 (en) 2020-07-24 2024-01-02 Genzyme Corporation Pharmaceutical compositions comprising venglustat
WO2023172475A3 (fr) * 2022-03-11 2023-10-26 Merck Sharp & Dohme Llc Analogues de pyrimidine cycliques non aromatiques utilisés en tant qu'inhibiteurs de glucosylcéramide synthase
WO2023177563A3 (fr) * 2022-03-14 2023-10-26 Merck Sharp & Dohme Llc Analogues de pyrazole amide fusionnés utilisés en tant qu'inhibiteurs de glucosylcéramide synthase

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