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WO2010128152A1 - C-glycosides hétérocycliques condensés pour le traitement du diabète - Google Patents

C-glycosides hétérocycliques condensés pour le traitement du diabète Download PDF

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Publication number
WO2010128152A1
WO2010128152A1 PCT/EP2010/056286 EP2010056286W WO2010128152A1 WO 2010128152 A1 WO2010128152 A1 WO 2010128152A1 EP 2010056286 W EP2010056286 W EP 2010056286W WO 2010128152 A1 WO2010128152 A1 WO 2010128152A1
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tetrahydro
pyran
hydroxymethyl
triol
alkyl
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Gregory Raymond Bebernitz
Sandeep Bhausaheb Bhosale
Debnath Bhuniya
Atul Kashinath Hajare
Tanaji Mengawade
Partha P. Mukhopadhyay
P. Venkata Palle
Dumbala Srinivas Reddy
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Novartis AG
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Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/06—Heterocyclic radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals

Definitions

  • the Invention relates to compounds which have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT and their use in therapy.
  • This disclosure relates to a series of novel glycoside derivatives, their polymorphs, stereoisomers, prodrugs, solvates, pharmaceutically acceptable salts and formulations thereof.
  • the disclosure also relates to the process for preparation of substituted glycoside derivatives along with their sodium-D-glucose cotransporter (SGLT) inhibition effects, which are beneficial for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the inhibition of SGLT would be beneficial, such as diabetes (including Type- 1 and Type-ll), obesity, dyslipidemia, insulin resistance, and other metabolic syndrome, and/or diabetes- related complications including retinopathy, nephropathy, neuropathy, ischemic heart disease, arteriosclerosis, ⁇ -cell dysfunction, and as therapeutic and/or prophylactic agents for obesity.
  • SGLT sodium-D-glucose cotransporter
  • Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition.
  • Glucose level abnormalities can result in serious long-term complications, which include cardiovascular disease, chronic renal failure, retinal damage, nerve damage (of several kinds), microvascular damage and obesity.
  • Type 1 diabetes also known as Insulin Dependent Diabetes Mellitus (IDDM)
  • IDDM Insulin Dependent Diabetes Mellitus
  • Ty ⁇ e-2 diabetes previously known as adult- onset diabetes, maturity-onset diabetes, or Non-Insulin Dependent Diabetes Mellitus (NIDDM) - is due to a combination of increased hepatic glucose output, defective insulin secretion, and insulin resistance or reduced insulin sensitivity (defective responsiveness of tissues to insulin).
  • Chronic hyperglycemia can also lead to onset or progression of glucose toxicity characterized by decrease in insulin secretion from ⁇ -cell. insulin sensitivity; as a result diabetes mellitus is self-exacerbated ⁇ Diabetes Care, 1990. 13, 610 ⁇ .
  • Chronic elevation of blood glucose level also leads to damage of blood vessels.
  • the resultant problems are grouped under "microvascular disease” (due to damage of small blood vessels) and "macrovascular disease” (due to damage of the arteries).
  • microvascular disease include diabetic retinopathy, neuropathy and nephropathy
  • macrovascular disease include coronary artery disease, stroke, peripheral vascular disease, and diabetic myonecrosis.
  • Diabetic retinopathy characterized by the growth of weakened blood vessels in the retina as well as macular edema (swelling of the macula), can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
  • Diabetic neuropathy is characterized by compromised nerve function in the lower extremities. When combined with damaged blood vessels, diabetic neuropathy can lead to diabetic foot. Other fornis of diabetic neuropathy may present as mononeuritis or autonomic neuropathy. Diabetic nephropathy is characterized by damage to the kidney, which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure worldwide.
  • a high glycemic diet i.e., a diet that consists of meals that give high postprandial blood sugar
  • a high glycemic diet i.e., a diet that consists of meals that give high postprandial blood
  • Type 2 diabetes is characterized by insulin resistance and/or inadequate insulin secretion in response to elevated glucose level.
  • therapies for type 2 diabetes ate targeted towards increasing insulin sensitivity (such as TZDs), hepatic glucose utilization (such as biguanides), directly modifying insulin levels (such as insulin, insulin analogs, and insulin secretagogues), increasing incretin hormone action (such as exenatide and sitagliptin), or inhibiting glucose absorption from the diet (such as alpha gfucosidase inhibitors) [Nature 2001, 414, 821-827].
  • Glucose is unable to diffuse across the cell membrane and requires transport proteins.
  • the transport of glucose into epithelial cells is mediated by a secondary active cotransport system, the sodium-D-glucose cotransporter (SGLT), driven by a sodium- gradient generated by the Na+/K+-ATPase.
  • SGLT sodium-D-glucose cotransporter
  • Glucose accumulated in the epithelial cell is further transported into the blood across the membrane by facilitated diffusion through GLUT transporters [Kidney International 2007, 72. S27-S35]
  • SGLT belongs to the sodium/glucose cotransporter family SLCA5.
  • Two different SGLT isoforms, SGLT1 and SGLT2 have been identified to mediate renal tubular glucose reabsorption in humans [Curr.
  • SGLT1 transports glucose as well as galactose, and is expressed both in the kidney and in the intestine, while SGLT2 is found exclusively in the S1 and S2 segments of the renal proximal tgbule.
  • SGLT2 a low-affinity/high-capacity system, residing on the surface of epithelial cell lining in S1 and S2 tubular segments.
  • the SGLT2 was cloned as a candidate sodium glucose cotransporter, and its tissue distribution, substrate specificity, and affinities are reportedly very similar to those of the low-affinity sodium glucose co-transporter in the renal proximal tubule.
  • a drug with a mode of action of SGLT2 inhibition will be a novel and complementary approach to existing classes of medication for diabetes and its associated diseases to meet the patient's needs for both blood glucose control, while preserving insulin secretion.
  • SGLT2 inhibitors which lead to loss of excess glucose thereby excess calorie may have additional potential for the treatment of obesity.
  • Glucopyranosyl-s ⁇ bstit ⁇ ted aromatic or heteroaromatic compounds where, in general, the sugar moiety has been modified at C4, C5, or C6 positions of pyranose have been published (US 06/0009400, US 06/0019948, US 06/0035841. US 06/0074031, US 08/0027014, WO 08/016132).
  • inhibition of SGLT means inhibitions exclusively of SGLT2, inhibitions exclusively of SGLT1 or inhibition of both SGLT1 and SGLT2.
  • the invention provides compounds of Formula (IA):
  • a ! is a heterocycyl or carbocyclyl
  • Q is U-X 3 or R 1 ⁇ ;
  • Z' and Z" are each, independently, a bond. d.* alkylene or C 2 .,, alkenylene, where Z' and Z ⁇ together make no more than a 4-carbon chain and the hydrocarbon bonds may be optionally substituted by one or more hydroxy or halogens.
  • Y' is -G-, -S(O) p - ; -N(R 3 )-, -C(R")(R>, -C(O)-. -C(O)NR 3 -, -NR 3 C(O)-, - N(R 3 JC(O)N(R 5 )-, -N(R 3 JSO 2 -, Or -SO 2 N(R 3 )-;
  • V is halogen, -OR ni or hydrogen; m - 0 ⁇ 4; n ⁇ 0 ⁇ 4; p « 0-2; R' and R * are independently, hydrogen, halogen, C h alky!, perhaioalkyl, or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or S;
  • R ⁇ R la and R 1B are independently selected from hydrogen, C 1 ⁇ alkyl. C ⁇ ., c aryl-Ci. ,.alkyl, -C(O)Ce,, t .aryl or -C(O)Ci ⁇ alkyl;
  • R ? and R 2a are independently halogen, hydroxy, C t ⁇ hydroxyalkyl, cyano, nitro, - NR'R 5 , -CH 2 NR 4 R 5 , C 1 ⁇ alkyl, C ⁇ 7 cycloalkyl, C ⁇ alkoxy, C 3 .
  • X is [C(R 6 )(R 7 )] t ;
  • Y is H 1 C 1 4 alkyl.
  • OR 1 or NR 8 R 9 t 1-3;
  • R 8 and R 7 are independently hydrogen or Ci ⁇ aikyl, or R ⁇ and R 7 form an oxo group and t-1, or when R 6 and R 7 are C ⁇ alkyl on the same carbon they can be taken together to form a cyclic ring which may contain N, S or O atoms;
  • R 4 and R* are independently hydrogen.
  • R 4 and R s taken together may form a monocyclic or a bicyclic ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O, N or S, the said ring system may further be optionally substituted; and
  • R 6 and R 8 are independently hydrogen, Ci ⁇ alkyl, C 3 . ? cycloalkyl, Cv/cycloalkylC L 4 a!kyl, arylC ⁇ alkyl, C,5.i O aryl, C ⁇ oheteroaryl, C t ⁇ heteroarylC ⁇ alkyl, C ⁇ oheterocyclyl. Cz ioheterocyclylC t ⁇ alkyl or
  • R 8 and R 9 along with the nitrogen to which they are bound form a monocyclic or a bicyclic ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O, N and S 1 the said ring system may further be optionally substituted;
  • R 10 is C M alkyl, C 8 .ioaryl, C..i ⁇ heteroaryl, Ca. 7 cycloalkyl, Cji 0 heterocydyl, where C 1 4 alky! may be optionally substituted by one or more hydroxy or halogens, and X a is halogen, hydroxy, cyano, nitro, -NR 4 R 5 , -CHjNR 4 R 5 . C 1 .* alkyl.
  • the invention provides compounds of Formula (IA)
  • A is selected from.
  • Q is L 3 -X n or R 10 ;
  • T and Z" are each, independently, a bond, Ct. 4 alkylene or C 24 alkenylene. where Z' and Z" together make no more than a 4-earbon chain and the hydrocarbon bonds may be optionally substituted by one or more hydroxy or halogens.
  • Y is -O-, -S(OV. 'N(R 3 )-, -C(R 1 XR")-. -C(O)-. -C(O)NR 3 -. -NR 3 C(O)-, - N(R S )C(O)N(R 3 )-, -N(R 3 JSO 2 -, Or -SO 2 N(R 3 )-;
  • R' and R y are independently, hydrogen, halogen, C h alky), perhaloalkyl, or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or
  • R 1 , R ia and R ib are independently selected from hydrogen, C ⁇ alkyl, C ⁇ .i O aryl-C,. 4 alkyl, -C(0)C 6 .ioaryl or -C(O)C , -6 alkyl;
  • R z and R 23 are independently halogen, hydroxy, d-ohydroxyalkyl, cyano, nitro, • NR 4 R 5 , -CH ? NR 4 R ⁇ , C ⁇ alkyl, C 3 .? cycloalkyl. C ⁇ alkoxy, C 3 .? cycloalkoxy, -S(O) P R 3 , - S(O) 2 NR 4 R 5 , -OS(O) 2 R 3 , -C(O)R 3 , -C(O)OR 3 .
  • X is [C(R 6 )(R 7 )] ( ;
  • Y is H, CM alky!, OR 1 or NR 8 R 8 R 6 and R r are independently hydrogen or C h alky!, or R 6 and R 7 form an oxo group and t-1 , or when R 6 and R 7 are C h alky! on the same carbon they can be taken together to form a cyclic ring which may contain N. S or O atoms;
  • R 4 and R 5 are independently hydrogen, Ci 6 alkyt, C ⁇ cycioalkyl. C?.?cycloalkyiC,. 4 afkyl. arylC t -talkyl, C&.ioaryl, Ci.i ⁇ heteroaryl, C 1-10 heteroarylC ⁇ alkyl, C ⁇ .ioheterocyclyi, C 2 ,oheterocyctylCi- 4 alkyi or
  • R 4 and R s taken together may form a monocyclic or a bicyclic ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O, N or S, the said ring system may further be optionally substituted; and
  • R 8 and R* are independently hydrogen, Ci ⁇ alkyl, C ⁇ cycloalkyl, C 3 ? cycloalkylCi.. 4 alkyl. arylC ⁇ aikyl, C ⁇ ary!, C,_, 0 heteroaryl, Ci. K iheteroarylC ⁇ alkyl, Cj-ioheterocyclyl, C 2 .,oheterocyclylCi. 4 alkyl or
  • R 8 and R 9 along with the nitrogen to which they are bound form a monocyclic or a bicyclic ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O, N and S, the said ring system may further be optionally substituted;
  • R 10 is C ⁇ alkyl.
  • Xa is halogen, hydroxy, cyano, nitro ; -NR 4 R 5 , -CH 2 NR 4 R 5 , C h alky!. C 1 4 hydroxylalkyi, d. 6 haloalkyl. Ci. 6 perhaloalkyl, C ⁇ aikoxy, trihalo Ci.
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety.
  • the alkyl comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms.
  • Representative examples of alkyl include methyl, ethyl, ⁇ -propyl, /so- propyl, n-butyl, sec-butyl, /so-butyf.
  • n-pentyl isopentyl, neopentyl, /7-hexyl, 3- methylhexyl, 2,2- dimethylpentyl, 2,3-dimethyfpentyl, n-heptyl, n-octyl, n-nonyl, or n- decyl.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms, and linking the rest of the molecule to a radical group, e.g., methylene, ethylene, propylene. n ⁇ butylene. and the like.
  • the alkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkeylene to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • an alkylene group may be optionally substituted by one or more of the following groups. Ci 4 alkyl, trihaloC ⁇ alkyl. halogen (especially fluoro) or hydroxyl.
  • haloalkyl refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein.
  • the haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyi.
  • a monohaloalkyi can have one iodo, bromo, chloro or fluoro within the alkyl group.
  • Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyi.
  • the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
  • Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dicbloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochlorometbyL dichlorofluoromethyl, difluoroethyl. difluoropropyl, dichloroethyl and dichloropropyl.
  • a perhaloalkyi refers to an alkyl having ail hydrogen atoms replaced with halo atoms.
  • d- s haloalkyl refers to an alkyl group substituted by up to seven halogen groups, e.g. fluoro groups.
  • common haloalkyl groups are triff ⁇ oroalkyl, 2,2.2-triffuoroethyl or 2,2,2,1, 1-pe ⁇ taft ⁇ oroethyl groups.
  • Halogen or halo may be fluorine, chlorine, bromine or Iodine.
  • alkenyl refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon double bond.
  • CrCealkenyl refers to a monovalent group derived from a hydrocarbon having two to six carbon atoms and comprising at least one carbon-carbon double bond.
  • alkynyl refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon triple bond.
  • C 2 -C e -alkynyl refers to a monovalent group derived from a hydrocarbon having two to six carbon atoms and comprising at least one carbon-carbon triple bond,
  • aryf refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-2.0 carbon atoms in the ring portion.
  • the aryf is a (C ⁇ -C t o) aryl.
  • Representative examples are phenyl, biphenyl, naphthyl, anthracyi, phenanthryi ortetrahydronaphthyl.
  • An aryl group may optionally be substituted by 1-4 independently selected substituents.
  • Preferred substituents for an aryl group are alkyl, trifl ⁇ oromethyl. trifluoromethoxy, cycloalkyl, cycloalkoxy, halogen, hydroxy, alkoxy, acyl.
  • aryl also refers to a bicyclic or polycyclic group in which a monocyclic aryl ring is fused to one or more or heterocyclyl rings or carbocylic rings, where the radical or point of attachment is on the aryl ring.
  • Nonlimiting examples include bertzoxazine. quinoline, isoquinoline, indole, isoindole, chroman, quinoxaline. benzoazepine, oxa-aza- benzocyloheptene. benzofuran, tetrahydronaphthalene and indan.
  • aryl refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently. or linked to a common group such as a methylene or ethylene moiety.
  • the common linking group also can be a carbonyl as in benzophenone or oxygen as in diphenylether or nitrogen as in diphenylamine.
  • alkoxy * refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy.
  • alkoxy groups have about 1-7 ; more preferably about 1-4 carbons.
  • acyP refers to a group R-C(O)- of from 1 to 10 carbon atoms of a straight, branched, or cyclic configuration or a combination thereof, attached to the parent structure through carbonyl functionality. Such group can be saturated or unsaturated, and aliphatic or aromatic.
  • R in the acyl residue is alkyl, or alkoxy, or aryl, or heteroaryl.
  • one or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl.
  • Examples of acyl include acetyl, benzoyl, propionyl. isobutyryl, t- butoxycarbonyl, benzyloxycarbonyl and the like.
  • Lower acyl refers to acyl containing one to four carbons.
  • carbamoyl refers to H 2 NC(O)-, alkyl-NHC ⁇ O)-, (alkyl) ? NC(O)-, aryl-NHC(O)-. alkyi(aryl)-NC(O) ⁇ . heteroaryl-NHC(O)-, alkyi(heteroaryl)-NC(O)-, aryl- alkyl-NHC(O)-, or alkyl(aryl-alkyl)-NC(O)-.
  • sulfonyf refers to R-SO 2 -, wherein R is hydrogen, alkyl, aryl. hereoaryl. aryl-alkyl, heteroaryl-alkyl, alkoxy, aryloxy, cycloalkyl, or heterocyclyl.
  • tent* refers to alkyl-S ⁇ O)rNH-, aryl-S(O) 2 -NH-, aryl- alkyl-S(O) r NH-, heteroaryl-S(O) 2 -NH-, heteroaryl ⁇ aikyf ⁇ S ⁇ O) r NH-, alkyl-S(O) 2 -N(alkyl)-.
  • heterocyclyl refers to an optionally substituted, saturated or unsaturated non-aromatic ring or ring system, e.g., which is a A- , 5-, 6-, or 7-membered monocyclic. 7-. 8-. 9-, 10-. 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and H, where the N and S can also optionally be oxidized to various oxidation states.
  • the heterocyclic group can be attached at a heteroatom or a carbon atom.
  • the heterocyclyl can include fused or bridged rings as well as spirocyclic rings.
  • heterocycies indude dihydrofuranyl, [1 ,3]dioxolane. 1 , 4-dioxane, 1,4-ditNane. piperazinyl, 1 ,3-dioxolane, imidazolidinyl, imidazotinyi, pyrrolidine, dihydropyran, oxathiolane. dithiolane, 1,3-dioxane, 1,3-dithianyl, oxathtanyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl.
  • azetidi ⁇ yl tetrahydrofuranyl, pyrr ⁇ lidinyl, tetrahydropyranyl, piperidinyl, morpholino.
  • thiomorpholi ⁇ yf piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl.
  • heterocyclyl further refers to heterocyclic groups as defined herein substituted with 1, 2 or 3 substituents selected from the groups consisting of the following:
  • heterocyclooxy wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge
  • aryl-alkyl-- (w) aryl-alkyl--; and (x) aryl substituted with alkyl, cycloalkyl, alkoxy. hydroxy, amino, alkyl-C(O)- NH-. alkylamino, dialkylamino or halogen.
  • heterocyclylalkyl is a heterocyclyl as defined above bonded through an alkyl group, such as morpholine-CHj-
  • cycloalkyl or “carbocyclyP refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3- 9, or 3-7 carbon atoms, each of which can be optionally substituted by one, or two : or three, or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy.
  • exemplary monocyclic hydrocarbon groups include, but are not limited to. cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl.
  • Exemplary bicyclic hydrocarbon groups include bornyl, indyl.
  • hexahydroindyl tetrahydronaphthyl, decahydronaphthyl, b»cyclo(2.1.i)hexyl, bicyclo[2.2.1
  • Exemplary tricyclic hydrocarbon groups include adamantyl.
  • sulfamoyl refers to H 2 NS(O)?-, alkyl'NHS(O) 2 - (alkyl) 2 NS(O)r- , aryl-NHS(O) r , alkyl(ary!)-NS(O) r! (aryl) 2 NS(O) r , heteroaryl-NHS ⁇ O) r , (aryl-alkyl)- NHS(O) 2 -. or (heteroaryl-alkyl)-NHS(O) 2 -.
  • aryloxy refers to both an TMO-aryl and an ⁇ O-heteroaryl group, wherein aryl and heteroaryl are defined herein.
  • heteroaryl refers to a 5-14 membered monocyclic- or bicyclic- or polycyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N 1 O or S.
  • the heteroaryl is a S- 10 or 5-7 membered ring system.
  • a heteroaryl group may be optionally substituted with 1-4 independently selected substituents.
  • Preferred substituents for an heteroaryf group include alkyl and halogen. Examples of monocyclic heteroaryl groups include pyridyl, thienyl. f ⁇ ranyi, pyrrofyl, pyrazolyl, imidazoyl, oxazolyi, isoxazolyl..
  • bicyclic heteroaryl groups include indolyl, benxofuranyl, quinolyl, isoquinolyl indazolyl, indoiinyl, isoindolyl, indolizinyl. bertzamidazolyl, and q ⁇ inolinyl. More specific heteroaryl groups include 2- or 3-tbienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5- imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyi.
  • heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryi, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Representative examples are 1 « , 2-, 3-, 5-, 6-, 7-, or 8- indolizinyi, 1-, 3-, 4-. 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, S-, 6-, or 7-indofyl, 2-, 3-, A- , 5-, 6-, or 7-Jndazolyl. 2-. 4-, 5-. 6-.
  • 6-, 7-, or 8-phthalazinyl 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3- , S-, 6-, 7-, or 8- quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnoMnyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, S-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2- t 3-, 4-, 5-, 6-, 7-.. or 8-carbzaotyl, 1-, 3-. 4-, 5-, 6-, 7- % 8-, or 9-carbolinyl. 1-.
  • Typical fused heteroary groups include, but are not limited to 2-, 3-. 4-, 5-. 6-. 7-, or 8-quinolinyl, 1-, 3-, A-, 5-, 6-. 7-. or 8-isoq ⁇ inolinyl, 2-, 3-, 4-, S-, 6-, or 7-indolyl. 2-. 3-, 4-, 5-.
  • a hetero ⁇ ryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • alkyl, alkenyl, alkoxy, cycloaJkyl, aryl, arylalkyf, heteroary), heterocycfyl, heterocyclylalkyl may be optionally substituted with one or more than one substit ⁇ ents selected from hydroxyl. cyano, nitro, d- ⁇ -a'kyl, Crs-alkenyl, C?-s-alkynyl, C 1 - 6 -alkoxy, C 2 -*; alkenyloxy. Cr ⁇ alkynyloxy, halogen, haloalkyl, perhaloalkyl. Cr 6 .
  • alkylcarbonyl (CH 2 ) ⁇ COOR 3 , amino, C r6 .alkylamino, di-d-e a'kylamino, C,-» alkyJaminocarbonyl, di-d- ⁇ -alkyiaminocarbonyl, Cr ⁇ -alM c arbonyiamino, &-> ⁇ $- alkylcarbonyI(Ci-6.alkyOamino, Crsalkylsulfonylamtno, Ci-6.alkylsulfonyl(Ci-& alkyl)amino, d ⁇ thioalkyl, Cr e .alkyls ⁇ lfanyl, Cre-alkyls ⁇ lfinyl, C-e-alkyls ⁇ lfonyl, aminos ⁇ lfonyj, Cr & alMQ ⁇ ioosulfonyl and di-Cr ⁇ afkylaminosulfonyl, aminocarbonyld
  • sulfanylCr 6 alkyl C 1 - 8 alkyls ⁇ lfanylCr «alkyl, sulfinylCr ⁇ alM.
  • ⁇ eteroaryf and "heterocyclyl” is also intended to include oxidized S or N. such as sulfinyl, sulfonyl and N-oxide of tertiary ring nitrogen.
  • cyclic rings Two substituents on the same carbon may be taken together can form a cyclic ring, which may optionally have heteroatoms selected from O, N or S.
  • cyclic rings are as follows:
  • Prodrugs is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood or conversion in the gut or liver.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier. Amsterdam)).
  • prodrugs as Novel Delivery Systems
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Daig Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, nydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid.
  • 2.2-dichloroacetic acid adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid.
  • 2-hydroxyethanesulfonic acid formic acid, fumaric acid, galactaric acid, genttsic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutartc acid.
  • naphthalene-2- sulfonic acid 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, ⁇ ndecylenic acid, and the like.
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic 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, such as ammonia, isopropylamine.
  • Particularly preferred organic bases are isopropylamine, diethylamine. ethanolamine, trimethytamine. dicyclohexylamine, choline and caffeine.
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as a hydrate, including a monohydrate. dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • a "pbamiaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes alt pharmaceutically acceptable carriers, diluents or excjpients thereof.
  • the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomers forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”. which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of Formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2 H and *H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 38 CI 1 fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and "isi, oxygen, such as 15 0, 17 O ar ⁇ d 18 O 1 phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations Sections using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • A' is a heterocycyl or carbocyclyl, Q is L a -X s or R 10 ;
  • Z' and T are each, independently, a bond, C 1 ⁇ alkylene or C ⁇ 4 alkenylene. where Z' and X together make no more than a 4-carbon chain and the hydrocarbon bonds may be optionally substituted by one or more hydroxy or halogens.
  • Y' is -CK -S(OV, -N(R 3 )-, -C(R )(R")-, -C(O)- -C(O)NR 3 -, -NR 3 C(O)-, - N(R 3 )C(O)N(R 3 )-, -N(R 3 )SO r> or -SO ? N(R 3 )-;
  • R' and R' are independently, hydrogen, halogen, C h alky ⁇ , perhaloalkyl, or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or S;
  • R 1 , R ta and R 1I> are independently selected from hydrogen, Ci. ⁇ alkyl, Ce ,oaryl ⁇ Ci 4 alkyl, -C(O)C 6 ., 0 aryl or -C(O)C 1 ⁇ IKyI;
  • R 2 and R 2a are independently halogen, hydroxy, Ci. «hydroxyalkyL cyano, nitro, - NR 4 R 5 , -CH ? NR 4 R 5 . C,. 8 alkyl, C w cycloalkyl. C ⁇ alkoxy, C 3 . 7 cycloalkoxy, -S(O) P R 3 , • S(O) 2 NR 4 R 5 , -OS(O) ?
  • X is [C(R 6 KR 7 )],
  • Y is H, C, 4 aikyl. OR 1 or NR 8 R 9 t * 1-3;
  • R 6 and R 7 are independently hydrogen or C h alky!, or R ⁇ and R 7 form an oxo group and t ⁇ 1. or when R 5 and R ? are C 1 4 alkyl on the same carbon they can be taken together to form a cyclic ring which may contain N, S or O atoms;
  • R 4 and R & are independently hydrogen, C-.. 6 alky!, Cj..? cycloalkyl, C ⁇ ?cyctoalkylC-.. 4 alkyi. arylC ⁇ alkyl, C ? ,., o aryl, C ⁇ oheteroaryl, C ⁇ oheteroarylC M alkyl, Cs ioheterocyclyl, C 2 . ! oheterocydylC 1 .4alkyl or
  • R 4 and R 6 taken together may form a monocyclic or a bicycitc ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O. N or S. the said ring system may further be optionally substituted; and R 8 and R* are independently hydrogen, C 1 6 alkyl, C».y cycloalkyl, C 3 .ycycloalkylC,. 4 afkyl, arylCi ⁇ alkyi. CVioaryl. C M oheteroaryl, C t ⁇ heteroaryiCi ⁇ alkyi, C 2 !0 heterocyclyl, C M oheterocyclylC ⁇ alkyl or
  • R 8 and R 9 along with the nitrogen to which they are bound form a monocyclic or a bicyclic ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O. N and S, the said ring system may further be optionally substituted;
  • R u ⁇ is Ci. « alkyl, C ⁇ .ioaryl, Cvioheteroaryl, Cvjcycloalkyl, d-ioheterocycloalkyl, where C ⁇ alkyl may be optionally substituted by one or more hydroxy or halogens; and
  • Xa is halogen, hydroxy, cyano, nitro. -NR 4 R 5 , -CH x NR 4 R 6 , C n alkyl, Ci. 4 hydroxylalkyl, C ⁇ haloalkyl. Ci.eperhaloalkyl, Ci ⁇ alkoxy, C 3 ./ cycloalkyl. trihalo Ci 4 alkoxyl, C 3? cydoalkoxy. -C(O)R 3 . -C(O)OR 3 . -CH 2 C(O)OR 3 , -C(O)NR 4 R 5 , - CH 2 C(O)NR*R 6 , -NR 3 C(O)NR 4 R 5 .
  • the invention provides compounds of Formula (IA):
  • A is selected from:
  • Q is L 3 -X,, or R 10 ,
  • Z and T are each, independently, a bond, C M alkylene or C?. 4 alkenyfene, where Z' and Z" together make no more than a 4-carbon chain and the hydrocarbon bonds may be optionally substituted by one or more hydroxy or halogens
  • Y is -O-, -S(OV, -N(R ? K -C(R 1 J(R 1 )-, -C(O)- -C(O)NR 3 -, -NR 3 C(O)-, - N(R ⁇ )C(O)N(R 5 K -N(R ? )SO r . or -SO ⁇ N(R')-,
  • R' and R' are independently, hydrogen, halogen Ci ⁇ alkyl. peihaloaikyl. or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or S
  • R' R u and R 1b are independently selected from hydrogen C ⁇ _. 5 a!kyl C 8 1 OaIyI-C 1 4 alkyl, -C ⁇ C f ⁇ oaryi or -CtOiC ⁇ alkyl;
  • R'' and R * ' 3 are independently halogen, hydroxy. Ci ⁇ hydroxyalkyl. cyano, nitro. - NR 4 R", -CH,NR 4 R 5 , C w afkyl. Cj r cycloalkyl, C, 4 alkoxy, C 3 , cycloalkoxy, -S(O) 0 R 3 , - S(O ⁇ NR 4 R 5 -OS(O) 2 R 3 -C(O)R i -C(O)OR' 4 . -CH 2 C(O)OR 5 , -CpJNRW - CH 2 C(O)NR 4 R 5 , -NR 3 C(O)NR 4 R 5 .
  • X is tC(R 6 )(R 7 )]t
  • Y is H, Cw alkyl, OR 1 or NR 8 R 9 t * 1-3:
  • R 6 and R 7 are independently hydrogen or Ci 6 alkyl, or R 6 and R ; form an oxo group and t-1 , or when R ⁇ and R 7 are C V4 alkyl on the same carbon they can be taken together to form a cyclic ring which may contain N. S or O atoms;
  • R 4 and R s are independently hydrogen, C ⁇ aikyl, C ⁇ cycioalkyl. C ⁇ cycloalkylCi, 4 alkyl. arylCi. 4 alkyi, C ⁇ aryl, C M oheteroaryl, Ci.ioheteroarytCi ⁇ alkyi, C- A utheterocyclyl, C 2 . !0 heterocyclylCi 4 alkyi or
  • R 4 and R s taken together may fon-n a monocyclic or a bicyclic ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O, N or S, the said ring system may further be optionally substituted; and
  • R 8 and R* are independently hydrogen, C ⁇ alkyl, C 3 - ? cycloalkyl, Cg ⁇ cycloalkyld. 4 alkyl, arylCi. 4 alkyl, C ⁇ ary!, C,.ioheteroaryl. C t .ioheteroarylC 1 4 alkyl. Cs. K iheterocyclyl, Cj..,oheterocyclylC 1 . 4 alkyl or
  • R 8 and R 9 along with the nitrogen to which they are bound form a monocyclic or a bicyclic ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O, N and S, the said ring system may further be optionally substituted:
  • R 10 is C 1-4 alkyl, C ⁇ . i( taryl, Cj.icheteroaryi. Cr?cycloalkyl. Cj. ⁇ heterocyclyl, where Ct-4 alkyl may be optionally substituted by one or more hydroxy or halogens and C 6 .i 0 aryl may be optionally substituted with one or more Ci. 4 aikyl, C ⁇ alkoxy, or Ci. 4 haloalkyl; and
  • X 3 is halogen, hydroxy, cyano, nitro, -NR 4 R 5 , -CH 2 NR ⁇ R S .
  • the invention relates to compounds of Formula (IA), where A : is a C M oheterocycyl.
  • the invention relates to compounds of Formula (IA), wherein A is selected from.
  • Q is L 3 -X 3 , wherein L 8 is a C t 4 alkylene ⁇ e.g. methylene, ethylene or isopropylene).
  • Each of whJch may be optionally substituted with one or more s ⁇ bstituents which may be independently selected from halogen, hydroxyl, C 1 ⁇ alkyl. C 3 -? cycloalkyl, C ⁇ 7 cycloalkoxyl, C M alkoxyl. C 2 . 4 alkenyl : C ⁇ i 0 aryl, Ci.toheteroaryl, cyano, -C(O)- C 1-4 alkyl. - C(O)-N- C M alkyl. -C(O)-N-di C,. 4 alkyl, -S- C 4 alkyl, SO r C 4 alkyl.
  • X 3 is an optionaily substituted aryl, optionally substituted with one or more independently selected halogen, Ci 4 alkyl. C M alkoxyl, C 3 .? cycloalkyl, -O- C 57 CyClOaIkIyI, -S- C 1 4 alkyl. -SO 2 - C M alkyl, trihalo C 1 ⁇ alkyl, trihalo C 1 .* alkoxyl, C e ., 0 aryl, Ci. 10 heteroaryl. cyano, nitro NR 4 R 5 , -CH 2 NR 4 R 5 or -C(O)- C M alky!.
  • the compound is of Formula (IA), wherein Q is R w and R 10 is methyl, ethyl, isopropyl, isobutyl, triflouromethyl or cyclopentyl.
  • the compound is of Formula (IA), wherein Q is R 1(! and R 10 is a C6-10aryf which may be optionally substituted with one or more substituents which may be independently selected from C h alky!, Ci ⁇ alkoxy, and C 1 . 4 haloalkyi.
  • Y is OR 1 ;
  • R 1 , R 1a and R lb are hydrogen.
  • the invention provides a compound of formula (lib): 4b
  • L b is a bond or an optionally substituted C 1 ⁇ alkylene
  • R i?b R i3i> R n b R 'st > and R ⁇ are each, independently, hydrogen, halogen, C 4 alkyl, C-..* alkoxyL Cc ⁇ cycloalkyl, O- C s ? cycloalklyl. -S- C t . 4 alkyl. -SO 2 - C 14 alkyl, trihalo CM alkyl, trihalo C 1 ⁇ aIkOXyI 1 C ⁇ i O aryl, Ci i 0 heteroary!, cyano, nitro, NR 4 R 5 , -CH ? NR 4 R 5 or -C(O)- d alkyl; or a pharmaceutically acceptable salt thereof.
  • U is methylene; R ub .
  • R i R iat> R isb and R i ⁇ b are each hydrogen; and
  • R M* is Ct . ⁇ alkyl.
  • the invention provides a compound of formula (Mc).
  • L 0 is a bond or an optionally substituted C M alkylene
  • R 12t , R t3c , R 14c , R 1Sc and R' 6c are each, independently, hydrogen, halogen, C 4 alkyl. C 1 .4 alkoxyl, Ca-ycycloalkyi, -O- C 3 ./ cycloalktyl, *S- C M alkyl. -SO 2 - C M alkyl, trihalo C 1 -, alkyl, trihalo C M alkoxyl, C 6 . , 0 aryl s C ,. , 0 heteroaryl, cyano. nitro, NR 4 R 6 , -CH 2 NR 4 R ⁇ or -C(O)- C 1 4 alkyl; or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of formula (Hd);
  • Ui is a bond or an optionally substituted C 1 ⁇ alkylene;
  • R t « R m R i3d R i4 ⁇ s Qnd R i s d are each independently. hydrogen, halogen, C M alkyl, C 4 afkoxyl, Cs ⁇ cycloalkyl, -O- C ⁇ 7 cycloalklyl, -S- C M alkyl. -SO 2 - C ⁇ alkyl, trihalo C,. «alkyl, trihalo d.
  • l a is methylene; R 1W .
  • L ⁇ j is ethylene; R ii* R i24 R i4 « and R t5d are ⁇ ach hydrogen; and R m j s c M alkoxyl.
  • the invention provides a compound of formula (lie);
  • U is a bond or an optionally substituted C 1 ⁇ alkylene;
  • R ii * R i2 e R i se R i4 o and R ii * are eacn independently, hydrogen, halogen, C h alky!, C i 4 alkoxyl. C 3 ? cycloalkyl. -O- Cjycycloalklyl, -S- C 1 ⁇ aikyl, -SO r C ⁇ alkyl. trihaio Ct ⁇ alkyl trihalo C L4 alkoxyl, C.3. 10 aryl, C 1-10 heteroaryl, cyano, nitro, NR 4 R 5 , -CH 2 NR 4 R 5 or -C(O)- Ci 4 alkyl; or a pharmaceutically acceptable salt thereof.
  • L e is a bond;
  • R 12 *, R 1 "* and R' S ⁇ are hydrogen; and
  • R m is C 1 ., aikyl or C 1 ⁇ aikoxyl
  • U is methylene; R m , R 1?e . R 14e and R iS * are hydrogen; and R !' ⁇ is C M alkyl or C,., alkoxyl.
  • the invention provides a compound of formula (Hf); wherein
  • L f is a bond or an optionaify substituted Cu alkylene
  • R 11f s R 12f , R 13f t R 14f and R 15f are each, independently, hydrogen, haiogen, C M alkyl.
  • L f is a bond; R Hf , R !Jf , R 14f and R 15f are hydrogen; and R 13f is C,. 4 alkyf.
  • the invention provides a compound of formula (Hg).
  • Lg is a bond or an optionally substituted Cj 4 alkylene
  • R ii a R i? 9 R i3 a R i *a and R i ss are eacn independently , hydrogen, halogen , C h alky!, C 1 ⁇ aikoxyl, C 37 cycloalky!.. -O- C ⁇ cycloalklyl, -S- Ci. ⁇ alkyl « SO 2 - Ci ⁇ alkyl, trihalo C ⁇ alkyl. trihaio Ci 4 alkoxyl, Ce ioaryl, C M0 heteroaryl, cyano, nitro NR 4 R' J , -CH 2 NR 4 R 5 or -C(O)- C ⁇ alkyl; or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of formula (Hh):
  • L n is a bond or an optionally substituted C 1 4 alkylene
  • R ⁇ th , R t4h and R 15h are each, independently, hydrogen, halogen, C M alkyl, C 1 ,, afkoxyl, C ⁇ cycloalkyl, -O- C 3-7 CyCiOaIkIyI, -S- C ⁇ alkyl -SO r Ct ⁇ alkyl, trihalo Ci ⁇ alkyl, trihalo d ⁇ aikoxyl, C ⁇ .ioaryl, d-ioheteroaryl, cyano, nitro NR -1 R 8 . -CH 2 NR 4 R 5 or -C(O)-
  • Isotopically-labeled compounds of formula (I), (IA). (lib), (lie), (Hd) 1 (lie), (lit), (Hg) and (Hh) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopicaily-labeled reagents in place of the non- labeied reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O. d e . ⁇ acetone, d 6 -DMSO.
  • These co-crystals may be prepared from compounds of formula (I), (IA), (lib), (lie), (Wd), (He), (Hf) 1 (Mg) and (Hh) by known co-crystal forming procedures.
  • Such procedures include grinding, heating, co-subliming, co ⁇ melting, or contacting in solution compounds of formula (I) 1 (IA) 1 (lib), (lie), (ltd), (He), (Iff), (Hg) and (Hh) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co- crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound of formula (I), (IA) 1 (lib), (lie), (Hd), (He), (Uf) 1 (Hg) and (Hh).
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients. disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see. for example. Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that wiii elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions., slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by SGLT-2 and SGLT-1 , or (ii) associated with SGLT-2 and SGLT-1 activity, or (iii) characterized by abnormal activity of SGLT-2 and SGLT-1; or (2) reducing or inhibiting the activity of SGLT-2 and SGLT-1 or (3) reducing or inhibiting the expression of SGLT-2 and SGLT-1.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of SGLT-2 and SGLT-1; or at least partially reducing or inhibiting the expression of SGLT-2 and SGLT- 1.
  • the term "patient” refers to an animal.
  • the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a human.
  • the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process
  • treating refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treating or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder
  • Any asymmetric atom (e.g., carbon or the like) of the compo ⁇ nd(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R) ⁇ , (Sy or (RS)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • S ⁇ bstit ⁇ ents at atoms with unsaturated bonds may, if possible, be present in as- (Z)- or trans- (E)- form.
  • a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cts or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid.
  • t tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O, O' ⁇ p-toJuoyl tartaric acid, mandehc acid, malic acid or camphor-10- sulfonic acid can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof.
  • the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
  • the compounds of the present invention, including their salts can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the present invention are useful as both prophylactic and therapeutic treatments for diseases or conditions related to the inhibition of SGLT-2 and SGLT-1 ,
  • the invention relates to a method for treating a disease or condition related to the inhibition of SGLT-2, comprising administration of an effective therapeutic amount of a compound of formula (I), (IA), (lib), (lie), (Hd), (He), (lit), (Hg) and (Mh) or a pharmaceutically acceptable salt thereof.
  • Compounds of formula (I), (IA). (lib), (lie), (Hd), (He), (Hf), (Hg) and (Hh) may be useful in the treatment of metabolic disorders, or conditions such as (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia. hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema and hyperuricaemia.
  • Compounds of formula (I), (IA), (lib), (lie), (Hd), (He), (Hf). (Hg) and (Hh) may be also suitable for preventing beta-cell degeneration such as apoptosis or necrosis of pancreatic beta cells, for improving or restoring the functionality of pancreatic ceils, increasing the number and size of pancreatic beta cells, for use as diuretics in treating edema or for use as antihypertensives and for the prevention and treatment of acute renal failure.
  • the invention relates to a method for treating a disorder selected from type 1 and type 2 diabetes mellitus. complications of diabetes, comprising administration of an effective amount of a compound of formula (I), (IA), (Hb), (lie), (Hd). (He), (Hf): (Hg) and (Hh) or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I), (IA), (Hb), (Hc), (lid), (He), (Hf), (Hg) and (Hh) of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, for use in therapy.
  • a compound of the formula (I), (IA), (lib), (lie), (lid), (He), (Uf), (Hg) and (Hh), or a pharmaceutically acceptable salt thereof, as defined above may be administered simultaneously, sequentially or separately in combination with one or more agents for the treatment of disorders previously listed.
  • Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamide, tolbutamide, gfimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosigiitazone. pioglitazone), PPAR-gamma-agonists (e.g. Gl 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha- glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors (e.g.
  • antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamide, tolbutamide, gfimepiride), nateglinide, repaglinide, thia
  • IAF237, MK-431 alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.
  • the list also includes inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g.
  • avasimibe or cholesterol absorption inhibitors such as. for example, ezetimibe
  • bile acid-binding substances such as. for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or A8C1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfiuramine.
  • axokine antagonists of the cannabinoidi receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or ⁇ 3- agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
  • angiotensin Il receptor antagonists are candesartan cilexetti. potassium losartan. eprosartan mesylate, valsartan, telmisartan. irbesartan, EXP-3174.
  • Angiotensin tl receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
  • a combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.
  • a combination with GABA-receptor antagonists, Na-channel blockers, topirarnat. protein- kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes. Such combinations may offer significant advantages, including synergistic activity, in therapy.
  • the present invention is also in relation to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I).
  • IA formula (IA), (lib), (lie), (Hd), (He), (Hf), (Hg) and (Hh) or Ks prodrug and pharmaceutically acceptable excipients.
  • the prodrug is selected from a group comprising, esters and hydrates.
  • prodrug is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or rnercapto or acid group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto or acid group, respectively.
  • prodrugs include, but are not limited to, acetate., formate and benzoate derivatives of alcohol or amides of amine functional groups in the compounds of the invention and the like.
  • the excipients are selected from a group comprising, binders, anti-adherents, disintegrants, fillers, diluents, flavors, colors, glidants, lubricants, preservatives, sorbents and sweeteners or combination(s) thereof.
  • the composition is formulated into various dosage forms selected from a group comprising tablet, troches, lozenges, aqueous or oily suspensions, ointment, patch, gel, lotion, dentifrice, capsule, emulsion, creams, spray, drops, dtspersible powders or granules, emulsion in hard or soft gel capsules, syrups and elixirs.
  • Dosages of agents of the invention employed in practicing the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for oral administration are of the order of 0.1 to 10 mg/kg.
  • protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J F. W. McOrnie, "Protective Groups in Organic Chemistry", Plenum Press. London and New York 1973.
  • Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se.
  • salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e g. the sodium salt of 2-ethylhexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium
  • Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal saits of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
  • Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereoisomers can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gei or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
  • Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
  • All the above-mentioned process steps can be carried out under reaction conditions that are known per se, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them., in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g.
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers. for example analogously to the methods described under "Additional process steps”.
  • solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane.
  • esters such as lower alkyl-lower alkanoates, for example ethyl acetate
  • ethers such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane.
  • liquid aromatic hydrocarbons such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide : bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methycyclohexane. or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes.
  • solvent mixtures may also be used in working up, for example by chromatography or partitioning.
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the invention relates also to those forms of the process in which a compound obtainable as Bn intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyi 4 m Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
  • the compounds of formula (I), (IA), (lib), (lie), (Hd), (He), (Hf), (Hg) and (Hh) can be prepared according to the Schemes provided infra.
  • the invention provides, in another aspect, a process for preparing a compound of formula (I).
  • the schemes detailed below show general schemes for synthesizing compounds of formula (I),
  • any reactive group present such as hydroxyl, amino, carbonyl or imino groups may be protected during the reaction by conventional protecting groups such as trimethylsilyf, tert-butyldimethylsilyi, benzyl, acetal, ketal etc., which are cleaved again after the reaction.
  • compounds of formula (Vl) may be coupled with compounds of formula (VII) under peptide coupling conditions or compounds of formula (ViII) in the presence of a base, followed by reduction of resulting amides to provide compounds of formula (I) wherein Q attaches to a nitrogen via an amide bond and all other symbols are defined herein above.
  • compounds of formula (Vl) may be coupled with aldehydes of formula (IX) under reductive amination conditions to provide compounds of formula (I) wherein Q attaches to a nitrogen atom and ail symbols are defined herein above
  • CS-IQheterocyclyl, C2-10heterocyclylCi 4 alkyi or R 8 and R 9 along with the nitrogen to which they are bound form a monocyclic or a bicyclic ring system which may be saturated, partially saturated or aromatic and may optionally have additional heteroatoms selected from O, N and S, the said ring system may further be optionally substituted may be prepared by reaction of compounds of formula (IV)
  • LG is a suitable leaving group, with a compound of HNR 8 R 9 .
  • suitable LG include mesylate or tosylate and the transformation may be carried out with a suitable base, e.g. t ⁇ ethylamine in a suitable solvent such as dimethylformamide, or similar conditions well known to those skilled in the art.
  • suitable LG include halide and the transformation may be carried out with a suitable base in a suitable solvent under conditions well known to those skilled in the art.
  • LG is tosyl or rnesyl
  • W is a suitable precursor to the formation of the desired ring.
  • W represents azide and the ring may be formed by reaction with a suitable reagent, e.g. for 1,2,3 triazole with a suitable alkynyl group or for a tetrazolyl with a suitable cyano-derivative under conditions well-known to those skilled in the art.
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
  • Step I To a stirred solution of 4-bromo-2-nitro phenol (2.0 g, 9.17 mmol) in acetonitrile (18 ml) was added ethyl 2-brom ⁇ isob ⁇ tyrate (2.15 g, 11.01 mmol), sodium iodide (138 mg, 0.91 mmol), cesium carbonate (3.59 g, 11.01 mmol) and heated at 60 "C for 18 h. Usual work up after quenching the reaction with water (50 ml) gave us the crude product which was purified by silica gel column chromatography to furnish 2 ⁇ (4-bromo-2-nitro ⁇ phenoxy)-2-methyl propionic acid ethyl ester (2.73 g).
  • Step IM To a stirred solution of 6-bromo-2,2-dimetbyl-4H-benzo
  • Step I To a stirred solution of 4-bromo-2-nitro phenol (5.0 g, 22.93 mmol) in DMF (23 ml) was added ethyl 2-bromo propionate (6.22 g. 34.40 mmol). cesium carbonate (11.20 g, 34.40 mmol) and heated at 60°C for 18 h. quenched with water (50 ml). Usual work up provided crude 2-(4-bromo-2-nitro-phenoxy)-propionic acid ethyl ester (5.07 g), which was taken for next reaction.
  • Step Ii To a stirred solution of 2-(4 ⁇ bromo-2-nitro ⁇ phenoxy) ⁇ propionic acid ethyl ester (5.0 g. 15.72 mmol) in ethanol (78.0 ml) was added Iron powder (4.40 g. 78.61 mmol), cone, hydrochloric acid (1.5 ml) was added and heated to reflux for 4 h, filtered through celite, concentrated and quenched with water (50 ml). After usual work up, crude material obtained was purified by silica gel column chromatography to furnish the 6 ⁇ bromo-2-methyl-4H-benzo
  • Step III To a stirred solution of 6"brorno-2-methyl-4H ⁇ benzop.4]oxazin-3-one (3.0 g. 12.39 mmol) in THF (12.3 ml) was added 1.0 M borane-tetrahydrofuran complex in THF (37.2 ml, 37.19 mmol) and refluxed for 16 h. The reaction mixture was cooled to 0 °C, quenched with methanol (30 ml) and concentrated under reduced pressure.
  • Step I To a stirred solution of 4-bromo-2-nitro phenol (5.0 g, 22.93 mmol) in acetone (44 ml) was added 2-chJoroacetone (3.21 g, 34.40 mmol), sodium carbonate (4.86 g, 45.87 mmol), sodium iodide (3.48 g, 22.93 mmol) and heated at 4O°C for 24 h. The reaction mixture was filtered through celite, concentrated, and quenched with water (50 ml). After usual work up, compound was precipitated with diisopropyl ether to furnish 1-(4-bromo- 2-nitro-phenoxy)-propan-2 ⁇ one (3.61 g).
  • Step II To a stirred solution of 1-(4-bromo-2-nitro-phenoxy)-pro ⁇ an-2-one (500 mg. 1.82 mmol) m methanol (18 ml) was added Raney-Nickef (100 mg, 20% w/w) and stirred under hydrogen pressure (balloon) for 16 h, filtered through celite : concentrated. After usual work up. compound was purified by silica gel coiumn chromatography to furnish the titled compound (213 mg).
  • Step I To an tee-cold stirred solution of D-glucorto-1,5-lactone (5 g. 28.1 mmof) and N- methylmorpholine (22.7 ml. 230.2 mmol) in THF (50 ml) under argon was added trimethyfsilyl chloride (21.4 ml, 168.4 mmol) via a dropping funnel and maintaing the temperature below 5°C. After 1 h, the reaction was heated to 35 °C for 5 h. Then it was allowed to cool to 20 °C as the reaction stirred overnight. Reaction mixture was cooled to O°C and quenched by the addition of water (50 ml).
  • reaction mixture was diluted with toluene (50 ml) and the organic layer was separated and washed with sodium dihydogen phosphate monobasic solution in water (50 ml), brine (50 ml), dried over anhydrous sodium sulphate, filtered, and concentrated to provide 2,3,4,6-tetrakis-O- (trimethylsilyl)-D-glucopyranone (11.5 g).
  • Step II To a stirred solution of 6-bromo-2H-1,4-benzoxazin-3(4H)-one (10 g, 43.85 mmol) in THF (25 ml) was added 1.0 M borane-tetrahydrofuran complex in THF (153.5 ml, 153.48 mmol) and refluxed for 14 h. The reaction mixture was cooled to room temperature, quenched with methanol (50 ml) and concentrated under reduced pressure.
  • Step III To a stirred solution of 6-bromo-3,4-dihydro ⁇ 2H-benzo ⁇ 1,4]oxazine (2.0 g, 9.34 mmol) in DMF (10 ml) was added 4-ethylbenzyl chloride (2.0 ml, 14,01 mmol), sodium iodide (250 mg, 0.93 mmol), potassium carbonate (2.58 g, 18.68 mmol) and heated at 6O°C for 20 h, quenched with water (40 ml).
  • Step IV To a stirred solution of 6-bromo-4-(4-ethyl-benzyl)-3,4-dihydro-2H- benzo[1 ,4]oxazine (2.1 9, 6.32 mmol) in THF-toluene (30 ml of 1.2 mixture) was added 1.6 M solution of n-BuLi in hexanes (3.95 ml, 6.32 mmol) at -78 °C.
  • reaction mixture was stirred for 30 min , then it was transferred to a stirred solution of 2,3,4.6-tetrakis O- (tnmethylsilyl)-D-glucopyranone (2.94 g, 6.32 mmol) in toluene (20 ml) at -78 °C.
  • 0.6 N methanesulfonic acid in methanol 15 ml was added and stirred for 20 h at room temperature. Reaction was quenched by the addition of aq. saturated sodium bicarbonate (10 ml).
  • Step V To a stirred solution of (3R.4S,5S.6R)-2-f4-(4-ethyl-benzyl)-3,4-dihydro-2H- benzop ,4]oxazin-6-yl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran ⁇ 3,4,5'triol (1.0 g, 2.26 mmol) in acetonitrile-dichlorometbane mixture (1.1 mixture, 10 ml) was added boron trifl ⁇ oride diethyletharate complex (0.57 mi, 4.52 mmoJ), and triethylsilane (1.3 ml. 9.04 mmol) at -5 °C.
  • Examples 2-15 were prepared in an analogoues procedure as described in example 1.
  • Step I To a stirred solution of 6-bromo-3,4-dthydro-2H-benzo(1,4 ⁇ oxa2tne (1.5 g, 7.0 mmol) in DMF (10 ml) was added 4-methoxybenzyl chloride (1.43 ml, 10.5 mmol), sodium iodide (105 mg, 0.7 mmol), and potassium carbonate (1.93 g. 14.0 mmol). The reaction mixture was heated at 60 °C for 20 h, quenched with water (40 ml).
  • Step HI To a stirred solution of (3R,4S.5S,6R)-6-hydroxymethyl-2-methoxy-2-[4'(4- methoxy-benzyl)-3,4-dihydro-2H-benzo(1,4]oxazin-6-yl]-tetrahydro-pyran-3.4.5-triol. (10.0 g, 22.3 mmol) in acetonitrile-dichloromethane mixture (1:1. 100 ml) was added boron trifluoride diethyletharate complex (5.7 ml, 44.7 mmol) and triethylsilane (14.3 ml, 89.4 mmoi) at -10 °C.
  • reaction was quenched with aq. saturated sodium bicarbonate solution (30 ml). The volatiles were evaporated under reduced pressure, the resulting was extracted with ethyl acetate (3 X 70 ml). The ethyl acetate layers were mixed, washed with brine (1 X 15 ml), dried over sodium sulphate, concentrated and purified by preparative HPLC to furnish (2S !
  • Step IV To a stirred solution of (2S,3R,4R ! 5S,6R)-2-[4-(4-Wethoxy-benzyl)-3.4"dihydro- 2H-benzol1 ) 4 i
  • Step V To a stirred solution of (2S,3R.4R,5S.6R)-2-(3..4-dihydro ⁇ 2H-benzo[1,4;
  • Step I To a stirred solution of 4-benzyl»6-bromo-4(4-Methoxy-benzyl)-3.4-dihydro-2H- benzo[1 ,4Joxazine (1.8 g. 5.4 mmol) in dichloromethane (10 mi) was added 1.0 M b ⁇ r ⁇ ntribromide solution in dichtoromethane (27.0 ml, 27,0 mmol) at »78 °C. The reaction mixture was stirred for 3 h. quenched by the addition of aq. saturated sodium bicarbonate solution (15 ml).
  • Step II To a stirred solution of 4-(6-bromo-2,3-dihydro-benzoi1,4 ⁇ oxazin-4-ylmethyl)- phenol (1.5 g. 4.68 mmol) in DMF (10 ml) was added cesium carbonate (3.0 g, 9.36 mmol). isopropyl bromide (0.9 ml, 9.36 mmol) and sodium iodide (70 mg, 0.47 mmol). The reaction mixture was heated to 60 °C for 20 h. Reaction mixture was cooled to room temperature and quenched by the addition of water (50 ml).
  • Step III To a stirred solution of 6-bromo-4-(4-isopropoxy-benzyl)-3,4 ⁇ dihydro-2H- benzo ⁇ .43oxazine (1.3 g, 3,59 mmol) in THF-toluene (1 :2,mixture. 9 ml) was added 2.5 M n-BuLi in hexanes (1.6 ml, 3.92 mmof) at -78 °C.
  • reaction was quenched with aq. saturated sodium bicarbonate solution (4 ml). The volatiles were evaporated under reduced pressure, extracted with ethyl acetate (3 X 7 ml). The ethyl acetate layers were mixed, washed with brine (4 ml), dried over sodium sulphate, concentrated and purified by preparative HPLC to furnish the titled compound (55 mg).
  • Example 58 was prepared in an analogoues procedure as described in example 57.
  • Step I To a stirred solution of (2R,3S,4R ( 5R,6S)-2-hydroxymethyl-6-H-(4-methoxy- benzyl)-3 l 4-dihydro-2H"ben2 ⁇ [1 ( 4]oxazin-6»yiHetrahydro ⁇ pyran-3 > 4.5-triof (590 mg, 1 41 mmol) in dichloromethane (10 ml) was added N.N'-dimethylaminopyridine (9 mg : 0.07 mmoj), acetic anhydride (1.2 ml, 12.3 mmol) and pyridine (0.95 ml, 11.7 mmol) at 20 °C. After stirring for 20 h.
  • reaction mixture was stirred under hydrogen atmosphere in balloon pressure for 20 h at 2O°C. Reaction mixture was filtered through celite bed, concentrated and purified by silica gel column chromatography to furnish
  • Step III To a stirred solution of acetic acid (2R ! 3R,4R.5S,6S)-3,4,5-triacetoxy-6-(3,4- dihydro-2H-benzop,4Joxazin- ⁇ -yiHetrahydro-pyran-2-ylmethyl ester (320 mg, 0.7 mmol), in dichloromethane (4 ml) was added copper (II) acetate (250 mg t 1.4 mrnoJ), triethylamine (0.2 ml, 1.4 mmol), molecular sieves (300 mg), 4-ethylphenyl boronic acid
  • Step IV To a stirred solution of acetic acid (2R,3R,4R ! 5S,6S)-3.4 ! 54riacetoxy-6-[4-(4- ethyl-phenyl)-3.4-dihydro- 2H- benzo[1 ,4]oxazin-6-yl]-tetrahydro-pyran-2-ylmethyl ester
  • Step I To a stirred solution of 6-bromo-3,4-dihydro-2H-benzo(1,4Joxazine (1.5 g, 7.0 mmol) in dichloromethane - dimethylforrnamide (1:1 mixture. 40 ml) was added 4- methoxyphenyl acetic acid (1.8 g, 10.5 mmol), HOBt (2.4 g, 17.5 mmol), diisopropyiethylamine (4.8 ml, 28 mmol ).
  • EDCI.HCI 3.4 g . 17.5 mmol
  • reaction mixture was heated to 70 °C for 15 h. quenched by the addition of water.
  • Step II To a stirred solution of 1 -(6-bromo-2.3-dihydro-benzo[1,4 ⁇ oxa2Jn ⁇ 4-yi)-2-(4- methoxy-phenyl)- «thanone (1.0 g, 2.8 mmol) in THP (10 ml) was added 1.0M borane- tetrahydrofura ⁇ complex solution in THF (8.3 ml, 8.3 mmol) at room temperature. The reaction mixture was reff ⁇ xed for 15 h. Reaction was cooled to 25 °C 1 quenched by the addition of methanol; volatiles were removed under reduced pressure.
  • Step III To a stirred solution of 6-bromo-4-[2-(4-methoxy-phenyi)-ethyl]-3.4-dihydro ⁇ 2H ⁇ benzo[1 ,4 ⁇ oxazine (610 mg, 1.75 mmol) in THF-toluene (1 :2 mixture, 9 ml) was added 2.5 M solution of n-BuLi in hexanes (0.77 ml, 1.92 mmol) at -78°C. The reaction mixture was stirred for the 30 min.
  • Examples 61-62 were prepared in an anal ⁇ goues procedure as described in example 60.
  • Step I To a stirred solution of 7-bromo-1,2.3 > 4-tetrahydroquino ⁇ ine hydrochloride (2.5 g, 10.05 mmol) in DMF (10 ml) was added potassium carbonate ⁇ 2.76 g, 20.1 mmo!), sodium iodide (150 mg « 1 mmol), 4-ethylbenzyi chloride (2.24 ml. 15.08 mmol) and heated to 6O°C for overnight. Reaction mixture was cooied to room temperature, quenched with addition of water (50 ml), extracted with ethyl acetate (3 X 30 ml).
  • Step Jl To a stirred solution of 7 ⁇ Bromo-1-(4-ethyl-benzyl) ⁇ 1 ,2,3,4 ⁇ tetrahydro-quinoline (2.8 g, 8.78 mmol) in THF4oluene (1.2 mixture, 30 ml) was added 1 6 M n-8uLi in hexanes ⁇ 5.48 ml, 8.78 mmol) at -78 °C.
  • reaction mixture was stirred for 40 min., then it was transferred to a stirred solution of 2,3,4,6 ⁇ tetrakis-O ⁇ (trimethylsilyl)-D- glucopyranone (4.0 g, 8.78 mmol) in toluene (30 ml) at -78 °C. After stirring it for 40 min., 0-6 N methanesulfonic acid in methanol (30 ml) was added and stirred for 20 h at room temperature. Reaction was quenched by the addition of aq.
  • Step III To a stirred solution of (3R,4S ! 5S,6R)-2-t1-(4-ethyl-benzyl)-1,2..3,4-tetrahydro- qutnolin ⁇ -yll- ⁇ -hydroxymethyl ⁇ -methoxy-tetrahydro-pyran-S ⁇ . ⁇ -trioi (2.0 g, 4.51 mmol) in acetonitrile-dichloromethane (1 :1 mixture,30 ml) was added boron trifluoride diethyletharate complex (1.14 ml, 9.02 mmol) and triethylsilane (2.68 ml, 18.04 mmol) at •10 °C.
  • reaction was quenched with aq, saturated sodium bicarbonate solution (10 ml). The volatiles were evaporated under reduced pressure, extracted with ethyf acetate (3 X 20 ml). The ethyl acetate layers were mixed, washed with brine (5 ml), dried over sodium sulphate, concentrated and purified by preparative HPLC to furnish the titled compound (270 mg) .
  • Examples 64-71 were prepared in an analogoues procedure as described in example 63.
  • Step I To a stirred solution of 7 ⁇ bromo-1.2,3,4-tetrahydroquinoline hydrochloride (5.0 g, 20.11 mmol) in DMF (20 ml) was added potassium carbonate (5.55 g, 40.2 mmol), sodium iodide (301 mg. 2.01 mmol). 4-methGxybenzyl chloride (4.1 ml, 30 17 mmoi) and heated to 60 °C for overnight. Reaction mixture was cooled to room temperature, quenched by the addition of water (100 ml), extracted with ethyl aceiate (3 X 70 ml).
  • Step Ii To a stirred solution of 7-bromo-1 ⁇ (4 ⁇ methoxy-benzyr)-1.2,3,4-tetrahydro ⁇ quinoline (2.97 g, 8.9 mmol) in THF-toluene (1:2 mixture , 30 ml) was added 1.6 M n ⁇ BuLi in hexanes (5.58 ml, 8.9 mmol) at -78 °C. The reaction mixture was stirred for 40 min.
  • Step III To a stirred solution of (3R,4S,5S,6R)-6-Hydroxymethyl-2-methoxy-2-
  • Step IV To a stirred solution of (2R l 3S,4R l 5R,6S)-2-hydroxymethyl ⁇ 6-[1-(4 ⁇ methoxy- benzyl)-1 ) 2,3 N 4-tetrahydro « quinofin-7-yl ⁇ -tetrahydro-pyran-3 l 4 : 5-triol (1.04 g, 2.5 mmol) in methanol (15ml) was added 10% palladium on charcoal (100 mg), 0.05 mi of cone. HCI and stirred under hydrogen ballon pressure for 18 h. Reaction mixture was filtered through celite bed, washed with methanol and concentrated.
  • Step V To a stirred solution of (2R,3S,4R,5R,6S)-2 ⁇ hydroxymethyl-6-(1 ,2,3 ⁇ 4-tetrahydro- quino ⁇ fn ⁇ 7-yl)-tetrahydro-pyran ⁇ 3,4.S-triol (50 mg, 0.16 mmof) in DMF (1 ml), was added potassium carbonate (47 mg, 0.33 mrnol) and 4 ⁇ methylbenzy! bromide (34 ⁇ l, 0.25 mmol). Reaction mixture was heated at 50 °C for 2 h, queened by the addition of water (1 ml). After usual work up product was purified by column chromatoghraphy to furnish the titled compound ( Yield ⁇ 27 mg).
  • Examples 73-91 were prepared in an analogoues procedure as described in example 72.
  • Step I To a stirred solution of S-bromo-indofine (SOQ mg, 2.5 mmol) in DMF (4 ml) was added potassium carbonate (700 mg : 5.0 mmol), 4-isopropyibenz.yl bromide (0.63 ml, 3.8 mmof) and heated to 60 °C for 3 h. Reaction mixture was cooled to room temperature, quenched by the addition of water (15 mf). extracted with ethyl acetate (3 X 10 ml).
  • Step Ii To a stirred solution of 5-brom ⁇ "1-(4-tsopropyJ-benzyi)-2,3-dihydro-1H-indoie (740 mg, 2.24 mmol) in THF-t ⁇ luene (1:2 mixture, 15 ml) was added 1.6 M n-Bu ⁇ in hexanes (1.4 ml, 2.24 mmol) at -78 °C. The reaction mixture was stirred for 40 mm., then it was transferred to a stirred solution of 2 !
  • Examples 93-95 were prepared in an anaiogoues procedure as described in example
  • Step I To an ice-cold solution of 6-bromotndole (800 mg. 4.1 mmol) in DMF (8 ml) under argon was added sodium hydride (60% in mineral oil, 277 mg, 6.9 mmol) and stirred for 30 min followed by the addition of 4-ethylbenzyl chloride (2.2 ml. 14.7 mmol) and stirred further for 2h at room temperature. The reaction was quenched by the addition of water (20 ml). Crude product obtained after usual work up was purified by silica gel column chromatography to furnish 6-bromo-1-(4-ethyl-benzyl)-1H-indole (1.25 g). 1H NMR (400 MHz.
  • Step II To an ice cold solution of 6-bromo-1-(4-ethyl-benzyl)-1H-indole (1.24 g, 3.95 mmol) in trifluoroacetic acid (15 ml) was added 1.0 M bora ⁇ e-tetrahydrofuran complex in THF (7.9 ml, 7.9 mmol) and stirred for 3 h. The reaction was quenched by the addition of water and the mixture was concentrated under reduced pressure. The resulting residue was taken in SN sodium hydroxide solution (15 ml) and extracted with ethyl acetate (2 X 10 ml).
  • Step III To a stirred solution of 6-bromo-1-(4-ethyl-benzyl)-2,3-dihydr ⁇ -1H-indole (700 mg. 2.21 mmol) m THF-toluene (9 ml of 1:2 mixture) was added 1.6 M solution of n-Bu ⁇ in nexanes (1.4 ml, 2.21 mmoi) at «78 °C. The reaction mixture was stirred for 30 min and was then transferred to a stirred solution of 2,3,4 ,6-tetrakis-0-(trimethylsilyi)-D- glucopyranone (1.03 g, 2.21 mmol) in toluene (9 ml) at -78 °C.
  • Step I To a stirred solution of 6-bromoxindole (5.0 g, 23.6 mmol) in THF (25 ml) was added 1.0 M bora ⁇ e-tetrahydrofuran complex in THF (82.5 ml, 82.5 mmol) at room temperature After complete addition, the reaction mixture was refluxed for 18 h. Reaction mixture was cooled to room temperature, quenched by the addition of methanol and solvents were evaporated under reduced pressure.
  • Step H To a stirred solution of 6-bromo-indoline (3.7 g, 18.7 mmol) in DMF (30 ml) was added potassium carbonate (5.2 g, 37.4 mmol). 4-methoxybenzyl chloride (3.8 ml, 28.0 mmol), sodium iodide (1.4 g. 9.3 mmol) and heated to 50 ⁇ C for 3 h. Reaction mixture was cooled to room temperature, quenched by the addition of water (50 ml), extracted with ethyl acetate (3 X 20 ml).
  • Step III To a stirred solution of 6-bromo-1-(4-methoxy-benzyl)-2,3 dihydro-1H indole (2.7 g, 8.5 mmol) in THF-toluene (1:2 mixture, 30 ml) was added 1.6 M n-Bu ⁇ in hexanes (5.3 ml, 8.5 mmol) at -78 °C. The reaction mixture was stirred for 40 rnin., and then transferred to a stirred solution of 2.3,4,6-tetrakis-0-(trimethylsflyl)-D-glucopyranone (4.0 g. 8.5 mmol) in toluene (30 ml) at -78 °C.
  • Example 100 (2S,3R,4R,5S,6R)-2-[1-(4-Ethoxy «ben2yl) «2,3-dihydro-1H-lndol.$.yl]-6- hydroxymethyl-tetrahydro-pyra ⁇ -3,4,5-triof.
  • Step I To a stirred solution of (2R,3S l 4R,5R.6S)-2-hydroxymethyl-6-[1-(4-methoxy- benzyO ⁇ .S-dihydro-1H-indol- ⁇ -ylJ-tetrahydro-pyran-S ⁇ . ⁇ -tfiol in methanol (4 ml) was added 10% palladium on charcoal (10 mg). 0.1 ml of cone, hydrochloric acid. Reaction mixture was stirred under hydrogen atmosphere (balloon pressure) for 18 h.
  • Step H To a stirred sofution of (2S.3R.4R 1 5S.6R)-2-(2 1 3-dihydrc»imndol ⁇ 6-yl)-6- hydroxymethyl-tetrahydro-pyran-S ⁇ .S-triol (30 mg. 0.107 mmol) in DMF (1 ml) was added potassium carbonate (0.03 mg : 0.213 mmol), 4-ethoxybenzyl bromide (0.034 g, 0.16 mmol) and heated to 6O°C for 3 h. Reaction mixture was cooled to room temperature, quenched by the addition of water (5 ml), extracted with ethyl acetate (2 X 8 ml).
  • Step I To a st»rred solution of 6-bromo-chrorna-4-one (5.0 g, 22.03 mmof) in benzene
  • Step II To a stirred solution of 8.2 (2.0 g ; 7.38 mmol) in THF (8 ml) at -78 8 C was added rvButyl lithium (470 mg, 7.38 mmol) and stirred for 1h. Mean while tetra-O-Benzyl- gl ⁇ cara ⁇ olactone (3.97 g, 738 mmol) in THF (6 ml) was cooled to -78 3 C and Ithi ⁇ m salt prepared above was added to this at -78 * C. This reaction mixture was stirred for 1 h, quenched with saturated NH 4 CI (10 ml). After usual work up, compound was purified by silica gel column chromatography to furnish sugar derivaive (3.41 g).
  • Benzyl bromide (380 mg, 2.24 mmol) was added through syringe (initially 20 % of total amount was added for initiation) then slowly remaining amount was added and stirred for 1h, 6-((2S,3S,4R,5R.6R)-3,4.5-Tri$ ⁇ Denzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-chroman-4- ⁇ ne (300 mg. 0.45 mmol) was dissolved in THF (2 ml) and it was added to above prepared Grignard reagent stirred for 3h. quenched with saturated NH 4 CI (20 ml).
  • Examples 102-107 were prepared in an analogoues procedure as described in example
  • Step I To a stirred solution of 6-((2S,3S ) 4R ) 5R ⁇ 6R)-3.4.S-Tris ber»2yloxy-6- benzyloxymethyl-tetrahydro-pyran ⁇ 2-yl) chroman-4-one ⁇ 300 mg. 0.45 mmoi) in THF (2 ml) and methanol (5 ml) was added 4-ethylbenzaldehyde (66 mg, 0.49 mmol) followed by pyrrolidine (95 mg, 1.34 mmol) and stirred for 16h. Concentrated on rotavap then usual work up resulted in crude compound which was taken for hydrogenation step using the procedure described for above example to furnish the title compound (93 mg).
  • ⁇ 2S,3R,4R > 5S ⁇ 6R)-243-(3-Ethyl-benzyi)-chroman-?-yl ⁇ -6-hydroxymethyl-tetrahydro- pyratv3 t 4.5-triot.
  • a test set- up in which a CHO-K1 cell line (ATCC No. CCL 6 1) or alternatively an HEK293 cell line (ATCC No. CRL-1573). which is stably transfected with an expression vector pZeoSV (Invitrogen, EMBL accession number L36849) , which contains the cDNA for the coding sequence of the human sodium glucose cotransporter 2 (Genbank Ace No.NMJX>3G41 ) (CHO hSGLT2 or HEK-hSGLT2).
  • pZeoSV Invitrogen, EMBL accession number L36849
  • the SGLT-2 assay is carried out as follows CHO-hSGLT2 cells are cultivated in Ham ' s F12 Medium (BioWhittaker) with 10% foetal calf serum and 250 ⁇ g/rnL 2eoctn (Invitrogen).. and HEK293-hSGLT2 cells are cultivated in DMEM medium with 10% foetal calf serum and 250 ⁇ g/mL zeocin (Invitrogen). The cells are detached from the culture flasks by washing twice with PBS and subsequently treating with trypsin/EDTA. After the addition of cell culture medium the cells are centrifuged, resuspended in culture medium and counted in a Casy cell counter.
  • the reaction is started by adding 5 ⁇ t of 14 C- AMG (0.05 ⁇ Ci) to each welt. After 2 hours' incubation at 37 * C. 5% CO2 , the cells are washed again with 250 ⁇ l of PBS (200C) and then lysed by the addition of 25 ⁇ l of 0.1 N NaOH (5 min. at 37 * C). 200 ⁇ f of MicroScint20 (Packard) are added to each well and incubation »s continued for a further 20 min at 37 * C. After this incubation the radioactivity of the 14 C-AMG absorbed is measured in a Topcount (Packard) using a 14 C scintillation program.
  • Topcount Packard
  • the compounds according to the invention may for example have EC50 values below 1000 nM, particularly below 100 nM, most preferably below 10 nM.
  • the title compounds of the above Examples were evaluated in the above described assay and the results of which are collated in Table 1. TABLE 1

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Abstract

La présente invention concerne des composés de formule (IA) dans lesquels A est choisi parmi la formule (II) qui ont un effet inhibiteur sur le transporteur de glucose sodium-dépendant SGLT et leur utilisation dans le traitement du diabète.
PCT/EP2010/056286 2009-05-07 2010-05-07 C-glycosides hétérocycliques condensés pour le traitement du diabète Ceased WO2010128152A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) * 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
JP2014511874A (ja) * 2011-04-14 2014-05-19 ノバルティス アーゲー グリコシド誘導体および糖尿病の処置のためのその使用
AU2010309833B2 (en) * 2009-10-20 2014-06-12 Novartis Ag Glycoside derivatives and uses thereof
EP2714032A4 (fr) * 2011-06-01 2015-05-06 Green Cross Corp Nouveaux dérivés de diphénylméthane en tant qu'inhibiteurs de sglt2
CN105085494A (zh) * 2014-05-22 2015-11-25 中国医学科学院药物研究所 钠糖共转运体2抑制剂、其制法和其药物组合物与用途
WO2015138280A3 (fr) * 2014-03-10 2015-11-26 Innov17 Llc Modulateurs des récepteurs orphelins associés au récepteur de l'acide rétinoïque et leurs utilisations
WO2020021447A1 (fr) 2018-07-25 2020-01-30 Novartis Ag Inhibiteurs d'inflammasome nlrp3
WO2020234715A1 (fr) 2019-05-17 2020-11-26 Novartis Ag Inhibiteurs d'inflammasome nlrp3
JP2023104784A (ja) * 2022-01-18 2023-07-28 Dic株式会社 ５員環縮合環化合物及びその製造方法、硬化性組成物、硬化物、プリプレグ、回路基板、ビルドアップフィルム、半導体封止材並びに半導体装置
WO2024028782A1 (fr) 2022-08-03 2024-02-08 Novartis Ag Inhibiteurs de l'inflammasome nlrp3

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WO2005012318A2 (fr) * 2003-08-01 2005-02-10 Janssen Pharmaceutica Nv C-glycosides heterocycliques fusionnes substitues
EP1609798A1 (fr) * 2003-03-31 2005-12-28 Kissei Pharmaceutical Co., Ltd. Derive heterocyclique fusionne, composition medicale le contenant et utilisation medicale associee
EP1803721A1 (fr) * 2004-07-27 2007-07-04 Chugai Seiyaku Kabushiki Kaisha Dérivé novateur de glucitol, précurseur de ce médicament et sel de celui-ci, ainsi qu'un agent thérapeutique pour diabètes contenant celui-ci
WO2009124638A1 (fr) * 2008-04-07 2009-10-15 Merck Patent Gmbh Dérivés de glucopyranoside

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EP1609798A1 (fr) * 2003-03-31 2005-12-28 Kissei Pharmaceutical Co., Ltd. Derive heterocyclique fusionne, composition medicale le contenant et utilisation medicale associee
WO2005012318A2 (fr) * 2003-08-01 2005-02-10 Janssen Pharmaceutica Nv C-glycosides heterocycliques fusionnes substitues
EP1803721A1 (fr) * 2004-07-27 2007-07-04 Chugai Seiyaku Kabushiki Kaisha Dérivé novateur de glucitol, précurseur de ce médicament et sel de celui-ci, ainsi qu'un agent thérapeutique pour diabètes contenant celui-ci
WO2009124638A1 (fr) * 2008-04-07 2009-10-15 Merck Patent Gmbh Dérivés de glucopyranoside

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9895389B2 (en) 2009-10-20 2018-02-20 Novartis Ag Glycoside derivatives and uses thereof
AU2010309833B2 (en) * 2009-10-20 2014-06-12 Novartis Ag Glycoside derivatives and uses thereof
US8828951B2 (en) 2009-10-20 2014-09-09 Novartis Ag Glycoside derivatives and uses thereof
USRE49080E1 (en) 2009-10-20 2022-05-24 Novartis Ag Glycoside derivatives and uses thereof
WO2011107494A1 (fr) * 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
JP2014511874A (ja) * 2011-04-14 2014-05-19 ノバルティス アーゲー グリコシド誘導体および糖尿病の処置のためのその使用
EP2714032A4 (fr) * 2011-06-01 2015-05-06 Green Cross Corp Nouveaux dérivés de diphénylméthane en tant qu'inhibiteurs de sglt2
WO2015138280A3 (fr) * 2014-03-10 2015-11-26 Innov17 Llc Modulateurs des récepteurs orphelins associés au récepteur de l'acide rétinoïque et leurs utilisations
CN105085494B (zh) * 2014-05-22 2019-07-02 中国医学科学院药物研究所 钠糖共转运体2抑制剂、其制法和其药物组合物与用途
CN105085494A (zh) * 2014-05-22 2015-11-25 中国医学科学院药物研究所 钠糖共转运体2抑制剂、其制法和其药物组合物与用途
WO2020021447A1 (fr) 2018-07-25 2020-01-30 Novartis Ag Inhibiteurs d'inflammasome nlrp3
WO2020234715A1 (fr) 2019-05-17 2020-11-26 Novartis Ag Inhibiteurs d'inflammasome nlrp3
JP2023104784A (ja) * 2022-01-18 2023-07-28 Dic株式会社 ５員環縮合環化合物及びその製造方法、硬化性組成物、硬化物、プリプレグ、回路基板、ビルドアップフィルム、半導体封止材並びに半導体装置
WO2024028782A1 (fr) 2022-08-03 2024-02-08 Novartis Ag Inhibiteurs de l'inflammasome nlrp3

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