WO2010128152A1 - Fused heterocyclic c-glycosides for the treatment of diabetes - Google Patents

Fused heterocyclic c-glycosides for the treatment of diabetes 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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PCT/EP2010/056286
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French (fr)
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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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    • 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

Abstract

The present invention provides compounds of Formula (IA) wherein A is selected from Formula (II) which have an inhibitory effect on the sodium dependent glucose transporter SGLT and their use in the treatment of diabetes.

Description

FUSED HETEROCYCLIC C-GLYCOSIDES FOR THE TREATMENT OF
DIABETES
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, β-cell dysfunction, and as therapeutic and/or prophylactic agents for obesity.
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), is characterized by loss of the insulin-producing β-cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. Tyρe-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 β-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. In diabetes, the resultant problems are grouped under "microvascular disease" (due to damage of small blood vessels) and "macrovascular disease" (due to damage of the arteries). Examples of microvascular disease include diabetic retinopathy, neuropathy and nephropathy, while examples of 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) is known to be one of the causative factors contributing to the development of obesity.
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. 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. Opinon in Investigational Drugs (2007): 8(4), 285-292 and references cited hereinj. Both of them are characterized by their different substrate affinity. Although both of them show 59% homology in their amino acid sequence, they are functionally different. 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. As a consequence, glucose filtered in the glomerulus is reabsorbed into the renal proximal tubular epithelial cells by SGLT2, a low-affinity/high-capacity system, residing on the surface of epithelial cell lining in S1 and S2 tubular segments. Much smaller amounts of glucose are recovered by SGLT1 , as a high-affinity/low-capacity system, on the more distal segment of the proximal tubule. In healthy human, more than 99% of plasma glucose that is filtered in the kidney glomerulus is reabsorbed, resulting in less than 1% of the total filtered glucose being excreted in urine. It is estimated that 90% of total renal glucose absorption is facilitated by SGL.T2; remaining 10% is likely mediated by SGLT1 [J. Parenter. Enteri Nυtr. 2004, 28, 364-371].
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. In addition, SGLT2 inhibitors which lead to loss of excess glucose thereby excess calorie may have additional potential for the treatment of obesity.
Indeed small molecule SGLT2 inhibitors have been discovered and antidiabetic therapeutic potential of such molecules have been reported in literature [T-1095 (Diabetes, 1999, 48, 1794-1800, Dapagliflozin (Diabetes, 2008. 57: 1723-1729)}. Various O-aryl and O-heteroaryl glycosides have been reported as SGLT-2 inhibitors in patent publications such as: WO 01/74834, WO 03/020737, US 04/0018998, WO 01/68660, WO 01/16147, WO 04/099230, WO 05/011592, US 06/0293252, WO 05/021566, Various glucopyranosyl-substituted aromatic and heteroaromatic compounds have also been reported as SGLT-2 inhibitors in patent publications such as: WO 01/27128, WO 04/080990, US 06/0025349, WO 05/085265, WO 05/085237, WO 06/054629. WO 06/011502. Glucopyranosyl-sυbstitυted 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).
For the purposes of this invention inhibition of SGLT means inhibitions exclusively of SGLT2, inhibitions exclusively of SGLT1 or inhibition of both SGLT1 and SGLT2.
Accordingly, in one aspect, the invention provides compounds of Formula (IA):
Figure imgf000006_0001
A is
Figure imgf000006_0002
A! is a heterocycyl or carbocyclyl;
Q is U-X3 or R1β;
Z' and Z" are each, independently, a bond. d.* alkylene or C2.,, alkenylene, where Z' and Zκ 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(R3)-, -C(R")(R>, -C(O)-. -C(O)NR3-, -NR3C(O)-, - N(R3JC(O)N(R5)-, -N(R3JSO2-, Or -SO2N(R3)-;
V is halogen, -ORnior hydrogen; m - 0~4; n ~ 0~4; p « 0-2; R' and R* are independently, hydrogen, halogen, Chalky!, perhaioalkyl, or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or S;
R\ Rlaand R1B are independently selected from hydrogen, C1^ alkyl. Cδ.,caryl-Ci. ,.alkyl, -C(O)Ce,,t.aryl or -C(O)Ci^alkyl;
R? and R2a are independently halogen, hydroxy, Ct^hydroxyalkyl, cyano, nitro, - NR'R5, -CH2NR4R5, C1^ alkyl, Cϊ7 cycloalkyl, C^alkoxy, C3.7 cycloalkoxy, -S(O)PR3, - S(OkNR4R6, -OS(O)2R3, -C(O)R3, -C(O)OR3, -CH2C(O)OR3, -C(O)NR4R5, - CHzC(O)NR4R6, -NR3C(O)NR4R5, -NR3C(O)OR3. Cβhaloalkyl, C1-6 perhaloalkyi, C3. vcycloalkylCi^alkyl, C«.iOaryl, Ce-ioarylCi^alkyl, Cβ-ioaryloxy, Cz-ioheterocyclyl. C?. 10heterocyclylCi.4alkyl, CMoheteroaryid^aikyl, C ieheteroaryl, d-utheteroaryloxy, or C1, 10heterocycloxy;
R3 is hydrogen, Ci.δalkyl, C3.? cycloalkyl, Cβ-ioaryl. Ci.i0heteroaryl, or C2. 1fiheterocyclyl; q = 0-3;
X is [C(R6)(R7)]t;
Y is H1 C1 4 alkyl. OR1 or NR8R9 t = 1-3;
R8 and R7 are independently hydrogen or Ci^aikyl, or Rδ and R7 form an oxo group and t-1, or when R6 and R7 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;
R4 and R* are independently hydrogen. C1^ alkyl, C3 ? cycloalkyl, C3./cycloalkylC^ ..alkyl, arylC^alkyK C^oaryl. C^oheteroaryl. Ci.ioheteroarylCi^aikyl. Cs.ioheterocyclyl, C?.ioheterocyclylC,.^alkyl or
R4 and Rs 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
R6 and R8 are independently hydrogen, Ci^ alkyl, C3.? cycloalkyl, Cv/cycloalkylCL 4a!kyl, arylC^alkyl, C,5.iOaryl, C^oheteroaryl, Ct ^heteroarylC^alkyl, C^oheterocyclyl. Cz ioheterocyclylCt^alkyl or
R8 and R9 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 S1 the said ring system may further be optionally substituted;
R10 is CM alkyl, C8.ioaryl, C..iπheteroaryl, Ca.7cycloalkyl, Cji0heterocydyl, where C1 4 alky! may be optionally substituted by one or more hydroxy or halogens, and Xa is halogen, hydroxy, cyano, nitro, -NR4R5, -CHjNR4R5. C1.* alkyl. CM hydroxylalkyl, C6 haloalkyl, Ci.operhaloalkyl, Ci.4alkoxy, C3 r cycloalkyl, tnhalo Ci 4alkoxyl, C3.-, cycloalkoxy, -C(O)RVC(O)OR3, -CH2C(O)OR3, -C(O)NR4R5, -CH2C(O)NR4R5, - NR3C(O)NR4R*. -NR5C(O)OR-*, -S(O)PR3. -S(O)?NR4RS, -OS(O)^1 C37cycloalkyl, C3 ycycloalkylC^alky!, CδiOaryl, CB.ioarylCi.4alkyl. C^^aryloxy, CMoheterocyclyl. C2.iG heterocyclylCMalkyl, Ci-i0heteroaryl, C1-10 heteroaryld^alkyl, Ci-toheteroaryloxy, or Ci- ioheterocycloxy, or a stereoisomer, enanttomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof
In another aspect, the invention provides compounds of Formula (IA)
Figure imgf000008_0001
wherein A is selected from.
Figure imgf000008_0002
provided that when A is
Figure imgf000009_0001
it is not substituted with hydroxy or methoxy;
Q is L3-Xn or R10;
I ie «,7? Y' 7V-'
T and Z" are each, independently, a bond, Ct.4 alkylene or C24 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(R3)-, -C(R1XR")-. -C(O)-. -C(O)NR3-. -NR3C(O)-, - N(RS)C(O)N(R3)-, -N(R3JSO2-, Or -SO2N(R3)-;
Y is halogen, ~ORthor hydrogen; m = 0-4; n - 0-4; p ~ 0-2;
R' and Ry are independently, hydrogen, halogen, Chalky), perhaloalkyl, or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or
S;
R1, Riaand Rib are independently selected from hydrogen, C^alkyl, Cδ.iOaryl-C,. 4alkyl, -C(0)C6.ioaryl or -C(O)C ,-6alkyl;
Rz and R23 are independently halogen, hydroxy, d-ohydroxyalkyl, cyano, nitro, • NR4R5, -CH?NR4Rδ, C^alkyl, C3.? cycloalkyl. C^alkoxy, C3.? cycloalkoxy, -S(O)PR3, - S(O)2NR4R5, -OS(O)2R3, -C(O)R3, -C(O)OR3. -CH2C(O)OR3, -C(O)NR4R3, - CHjC(O)NR4R6, -NR3C(O)NR4R5, -NR3C(O)OR3 C1 6haloalkyl, C1* perhaloalkyl, C3. vcycloalkylCs^alkyl, Cs ioaryl, Cg.ioarylCi.4alkyl, Cs,ioarytoxy. Cs.ioheterocyclyl, C2. t0heterocyclylC1.4alkyl, C^ioheteroarylC^alkyl, C1-10heteroaryl( d-^heteroaryloxy, or Cv 10heterocycloxy;
Ra is hydrogen, Cv^alkyl, C3-? cycloalkyi. C,5.iOaryl. Ci i0heteroaryl, or C?, 10heterocyclyl; q = 0-3;
X is [C(R6)(R7)](;
Y is H, CM alky!, OR1 or NR8R8 R6 and Rr are independently hydrogen or Chalky!, or R6 and R7 form an oxo group and t-1 , or when R6 and R7 are Chalky! on the same carbon they can be taken together to form a cyclic ring which may contain N. S or O atoms;
R4 and R5 are independently hydrogen, Ci 6alkyt, C^cycioalkyl. C?.?cycloalkyiC,. 4afkyl. arylCt-talkyl, C&.ioaryl, Ci.iβheteroaryl, C1-10heteroarylC^^alkyl, C^.ioheterocyclyi, C2 ,oheterocyctylCi-4alkyi or
R4 and Rs 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
R8 and R* are independently hydrogen, Ci^alkyl, C^cycloalkyl, C3 ? cycloalkylCi.. 4alkyl. arylC^aikyl, C^ary!, C,_,0heteroaryl, Ci.KiheteroarylC^alkyl, Cj-ioheterocyclyl, C2.,oheterocyclylCi.4alkyl or
R8 and R9 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;
R10 is C^ alkyl. Cβ^ary!, Ci-tβheteroaryl, Ca-ycycloalkyl, C^ioheterocyclyl, where C1-4 alky! may be optionally substituted by one or more hydroxy or halogens and C&.ioary! may be optionally substituted with one or more CMalkyl. C^alkoxy, or Cv^haloalkyl; and
Xa is halogen, hydroxy, cyano, nitro; -NR4R5, -CH2NR4R5, Chalky!. C1 4 hydroxylalkyi, d.6haloalkyl. Ci.6perhaloalkyl, C^aikoxy, trihalo Ci.4alkoxyl, an optionally substituted C^7 cycloalkoxy, -C(O)R3, -C(O)OR3, -CHsC(O)OR*, -C(O)NR4R', - CH2C(O)NR"Rδ, -NR3C(O)NR4R5, -NR3C(O)OR3, -S(Oy^. -S(O)2NR4R-, -OS(O)2R^ an optionally substituted C.v,cycloalkyl, an optionally substituted C:κ/CycloalkylC(.4alkyl. an optionally substituted C6.10aryl, an optionally substituted C^ioarylCu^alkyl, an optionally substituted C6i3aryloxy, an optionally substituted C2.)oheterocyciyl. an optionally substituted C2.10 heterocyclic Malkyl, an optionally substituted Ci toheteroaryl, an optionally substituted CM0heteroarylCi.4alkyl, an optionally substituted Ci.to heteroaryloxy, or an optionally substituted Ci.ioheterocycloxy; or a pharmaceutically acceptable salt thereof.
Definitions For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.
As used herein, the term 'alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Preferably 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. tert-butyt, 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. Unless stated otherwise specifically in the specification, 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.
As used herein, the term "haloalkyl" refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein. Preferably 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. Preferably, 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. For example, where the sυbstitυent is ffυoro. common haloalkyl groups are triffυoroalkyl, 2,2.2-triffuoroethyl or 2,2,2,1, 1-peπtaftυoroethyl groups.
"Halogen" or "halo" may be fluorine, chlorine, bromine or Iodine.
The term "alkenyl" refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon double bond. The term "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.
The term "alkynyl" refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon triple bond. The term "C2-Ce-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,
The term "aryf" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-2.0 carbon atoms in the ring portion. Preferably, the aryf is a (Cδ-Cto) 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, triflυoromethyl. trifluoromethoxy, cycloalkyl, cycloalkoxy, halogen, hydroxy, alkoxy, acyl. alkyi-C(O)-O~, aryl-O~, heteroaryi-O--, amino, thiol, alkyl-S-, aryl-S-, nitro, cyano, carboxy, alkyf-O-C(O)-, carbamoyl, alkyl-S(O)--, alkylsulfonyl, alkylsulfonamido, and heterocyclyl.
The term "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. Furthermore, the term "aryl" as used herein, 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. As used herein, the term "alkoxy* refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy. 2-propoxy, bυtoxy: tørt-butoxy, pentyloxy, hexyloxy, cyciopropyloxy-, or cyclohexyloxy-. Preferably, alkoxy groups have about 1-7; more preferably about 1-4 carbons.
As used herein, the term "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. Preferably, R in the acyl residue is alkyl, or alkoxy, or aryl, or heteroaryl. Also preferably, 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.
As used herein, the term "carbamoyl" refers to H2NC(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)-.
As used herein, the term "sulfonyf refers to R-SO2-, wherein R is hydrogen, alkyl, aryl. hereoaryl. aryl-alkyl, heteroaryl-alkyl, alkoxy, aryloxy, cycloalkyl, or heterocyclyl.
As used herein, the tent* "sulfonamido- refers to alkyl-S<O)rNH-, aryl-S(O)2-NH-, aryl- alkyl-S(O)rNH-, heteroaryl-S(O)2-NH-, heteroaryl~aikyf~S{O)rNH-, alkyl-S(O)2-N(alkyl)-. aryl-S(O)rN(alkyl)-, ary!-alkyl-S<O)rN(alkyl)-, heteroaryl-S(O)rN{alkyl)-, or heteroaryl- alkyl-S{O)rN(alkyl)~.
As used herein, the term "heterocyclyl" or "heterocyclo" 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. Examples of 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. azetidiπyl, tetrahydrofuranyl, pyrrαlidinyl, tetrahydropyranyl, piperidinyl, morpholino. thiomorpholiπyf, piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl.
The term "heterocyclyl" further refers to heterocyclic groups as defined herein substituted with 1, 2 or 3 substituents selected from the groups consisting of the following:
(a) alkyl,
(b) hydroxy (or protected hydroxy); (C) halo;
(d) OXO, i.e., =O;
(e) amino (Le. NH2), alkylamino (/.e.NH-alkyl) or dialkylamino;
(f) alkoxy;
(g) cycloalkyl; (h) carboxyf;
(i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge;
(j) alkyl-O-C{O)--;
(k) mercapto:
(I) nitro;
<m) cyano.
(n) sulfamoyl or sulfonamido;
(o) aryl,
(P) alkyl-C(O)-O~;
(q) aryl-C(0>0-;
(r) aryl-S»;
(s) aryfoxy.
(t) alkyl-S-;
(U) formyl. i.e., HC(O)-;
(v) carbamoyl;
(w) aryl-alkyl--; and (x) aryl substituted with alkyl, cycloalkyl, alkoxy. hydroxy, amino, alkyl-C(O)- NH-. alkylamino, dialkylamino or halogen.
As used herein, the term "heterocyclylalkyl" is a heterocyclyl as defined above bonded through an alkyl group, such as morpholine-CHj-
As used herein, the term "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. alkyl-C(O)--, acylamino, carbamoyl, alkyl-NH-, (alkyl)2N--, thiol, alkyt-S~, nitro, cyano, carboxy, alkyl- 0-C(O)", sulfonyl, sulfonamido, sulfamoyl, or heterocyclyl. 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|heptyl, bicyclo[2.2.1]heptenyl, 6,6- dιmethylbicyclo[3.1.1]heptyl, 2,6,6-trimethyfbicyclo{3.1.1]heptyt, or bicyclo{2.2.2]octyl. Exemplary tricyclic hydrocarbon groups include adamantyl.
As used herein, the term "sulfamoyl" refers to H2NS(O)?-, alkyl'NHS(O)2- (alkyl)2NS(O)r- , aryl-NHS(O)r, alkyl(ary!)-NS(O)r! (aryl)2NS(O)r, heteroaryl-NHS{O)r, (aryl-alkyl)- NHS(O)2-. or (heteroaryl-alkyl)-NHS(O)2-.
As used herein, the term "aryloxy" refers to both an ™O-aryl and an ~O-heteroaryl group, wherein aryl and heteroaryl are defined herein.
As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic- or bicyclic- or polycyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N1 O or S. Preferably, 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. fυranyi, pyrrofyl, pyrazolyl, imidazoyl, oxazolyi, isoxazolyl.. thiazolyl, isothiazolyl. triazolyl, oxadiazoiyl, thiadiazolyl and tetrazolyl. Examples of bicyclic heteroaryl groups include indolyl, benxofuranyl, quinolyl, isoquinolyl indazolyl, indoiinyl, isoindolyl, indolizinyl. bertzamidazolyl, and qυinolinyl. 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. 3-, 4-, or 5-isothiazolyl> 2-, 4-, or 5- oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2. 3-trjazolyl, tetrazoiyl 2- , 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-: 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5- pyrimidinyl.
The term "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-. 7-, or 8- purinyl, 1-, 2-, 3«, 4-, 6-, 7-t 8-, or 9- quinolizinyl, 2~, 3-, 4-, 5~, 6-, 7-, or 8-quinoliyl, 1-. 3-. 4-. 5-. 6-, 7-, or 8-isoqutnoliyl, 1-, 4-, 5-. 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-. 2-, 3-, 4-, 6-, 7-, S-, 9-, or 10-phenanthridinyi, 1- , 2-. 3-. 4-. 5-, 6-. 7-. 8-, or 9-acridinyl. 1-, 2-, 4-. 5-. 6-. 7-. 8-. or 9-perimidinyl, 2-. 3-. 4-. 5-. 6-. 8-, 0-, or 10- phenathrotinyl. 1~, 2- . 3-, 4-, 6-, 7-, 8-, or 9-phenazinyi, 1-, 2-, 3-. 4-. 6-. 7-. 8-. 9-. or 10- phenothiazinyJ, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or l~, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- benzisoqinolinyt, 2-; 3-. 4-. or thieno[2,3-bjfuranyl. 2-. 3-. 5-. 6-. 7-. 8-. 9-. 10 -, or 11-7H-ρyrazino(2,3-c]carbazolyt,2-! 3-, S-. S-, or 7-2H- furo[3,2-b|- pyranyi, 2-, 3~. 4-, 5-. 7-. or 8-5H-pyrido[2,3-d]-o-oxazinyl. 1-, 3-, or 5-1H-pyrazolo{4,3-d]~ oxazolyL 2-, A-, or 54H-imidazo[4,5-dj| thiazolyl: 3-, S-, or 8-pyrazinot2>3-dJpyridazinyl, 2-. 3-, 5-, or 6- imidazo[2,t~b] thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furQ[3,4-Ci|cfnnolinyi, 1-. 2-. 3-. 4', 5-, 6", 8-, 9-, 10, or 11~4H-pyrido[2.3-c}carbazolyl, 2-, 3-, 6-, or 7-imidazo[1 ,2- b][12,4}triazinyl. 7-benzo{b]thienyt, 2-, 4-, 5- , 6-, or 7-benzoxazoiyi, 2-, 4-, 5-. 6-, or 7- benzimidazoJyl, 2-, 4-, 4-. S-. 6-t or 7-benzothiazolyJ, 1-. 2-. 4», 5-, &-, 7-, 8-, or 9- benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyf, 1-, 2», Z-.. 5-, 6-, 7-, 8-, 9-, 10-, or 11- 1H-pyrrok>l1.2-b](2Jbenzazapinyi. 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-isoqυinolinyl, 2-, 3-, 4-, S-, 6-, or 7-indolyl. 2-. 3-, 4-, 5-. 6-, or 7-benzotb]thienyl. 2-, 4-, 5- , 6-, or 7- benzoxazolyi, 2-, A-, 5-, 6-, or 7-benzimidazolyi, 2-, 4-, 5-, 6-, or 7-benzothiazolyl. A heteroøryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
Unless otherwise mentioned, alkyl, alkenyl, alkoxy, cycloaJkyl, aryl, arylalkyf, heteroary), heterocycfyl, heterocyclylalkyl may be optionally substituted with one or more than one substitυents selected from hydroxyl. cyano, nitro, d-β-a'kyl, Crs-alkenyl, C?-s-alkynyl, C1- 6-alkoxy, C2-*; alkenyloxy. Crβ alkynyloxy, halogen, haloalkyl, perhaloalkyl. Cr6. alkylcarbonyl, (CH2)^COOR3, amino, Cr6.alkylamino, di-d-e a'kylamino, C,-» alkyJaminocarbonyl, di-d-β-alkyiaminocarbonyl, Crβ-alMcarbonyiamino, &->~$- alkylcarbonyI(Ci-6.alkyOamino, Crsalkylsulfonylamtno, Ci-6.alkylsulfonyl(Ci-& alkyl)amino, d^thioalkyl, Cre.alkylsυlfanyl, Cre-alkylsυlfinyl, C-e-alkylsυlfonyl, aminosυlfonyj, Cr&alMQ^ioosulfonyl and di-Crβafkylaminosulfonyl, aminocarbonyld- 6alkyl, CreaminocarbonylCrsalkyi, di-CreaminocarbonylCrsalKyl. sulfanylCr6alkyl, C1- 8alkylsυlfanylCr«alkyl, sulfinylCrβalM. Crβalkylsulfinyld-ealkyl, sulfonylCrealkyl, d- ealkylsυlfonylCi-βaikyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, where each of the aforementioned hydrocarbon groups may be optionally substituted by one or more halogen, alkyl, hydroxyl, oxo, d-e-alkoxy. amino, d-e-alkylamino, di-Cre-alkylarn'no or cyano.
Ηeteroaryf and "heterocyclyl" is also intended to include oxidized S or N. such as sulfinyl, sulfonyl and N-oxide of tertiary ring nitrogen.
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. Non limitative examples of such cyclic rings are as follows:
Figure imgf000018_0001
"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. Thus, the term "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)).
A discussion of prodrugs is provided in Higuchi, T., et a/.. "Pro-drugs as Novel Delivery Systems," A C S. Symposium Series, Vol. 14. and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, Anglican Pharmaceutical Association arid Pergamon Press, 1987. "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. For example, "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. 2-oxo- glutaric acid, glycerophosphorirc acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, mafonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic aαd. 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, υndecylenic 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. trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylamtnoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine: choline, betaine, benetbamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, trometbamine, purines, piperaztne, piperidine, N- ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine. ethanolamine, trimethytamine. dicyclohexylamine, choline and caffeine.
Often crystallizations produce a solvate of the compound of the invention. As used herein, the term "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. Alternatively, the solvent may be an organic solvent. Thus, 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. Such a medium includes alt pharmaceutically acceptable carriers, diluents or excjpients thereof.
As used herein, 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. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be induded.
A "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.
Examples of isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2H and *H, carbon, such as 11C, 13C and 14C, chlorine, such as 38CI1 fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and "isi, oxygen, such as 150, 17O ar\d 18O1 phosphorus, such as 32P, and sulphur, such as 35S. Substitution with heavier isotopes such as deuterium, i.e. 2H, 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.
Embodiments of the Invention
Throughout this specification and in the claims that follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
In one embodiment of the present invention, the compounds are represented by Formula
(IA):
Figure imgf000022_0001
wherein
A iS
Figure imgf000022_0002
A' is a heterocycyl or carbocyclyl, Q is La-Xs or R10;
Z' and T are each, independently, a bond, C1^ 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(R3)-, -C(R )(R")-, -C(O)- -C(O)NR3-, -NR3C(O)-, - N(R3)C(O)N(R3)-, -N(R3)SOr> or -SO?N(R3)-;
V is halogen, -OR1&or hydrogen; m - 0-4; n = 0-4; p « 0-2;
R' and R' are independently, hydrogen, halogen, Chalky}, perhaloalkyl, or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or S;
R1, Rtaand R1I> are independently selected from hydrogen, Ci.βalkyl, Ce ,oaryl~Ci 4alkyl, -C(O)C6.,0aryl or -C(O)C1^IKyI;
R2 and R2a are independently halogen, hydroxy, Ci.«hydroxyalkyL cyano, nitro, - NR4R5, -CH?NR4R5. C,.8alkyl, Cw cycloalkyl. C^alkoxy, C3.7 cycloalkoxy, -S(O)PR3, • S(O)2NR4R5, -OS(O)?R3, -C(O)R3, -C(O)OR3, -CH2C(O)OR3, -C(O)NR4R5, - CH2C(O)NR*R5, -NR3C(O)NR4R5, -NR3C(O)OR3, Ci 6haloalkyl, C^perhaloalkyi, C3. ycycloalkylCI.4alkyl1 C&.iOaryl, Ce-iαarylCi^alkyl, C6.ioaryloxyt Ca ioheterocyclyl, C?. 10heterocydylCi.4alkyl, C1-i0heteroarylC1.4alky), Ci.i0heteroaryl, d.ioheteroaryloxy, or Ci. foheterocydoxy;
R3 is hydrogen, Ci.βalkyl, C^7 cycloalkyl. Cs.,oaryl. d.ioheteroaryl, or C?. 10heterocyclyl: q = 0-3;
X is [C(R6KR7)],;
Y is H, C, 4 aikyl. OR1 or NR8R9 t * 1-3;
R6 and R7 are independently hydrogen or Chalky!, or Rδ and R7 form an oxo group and t~1. or when R5 and R? are C1 4alkyl on the same carbon they can be taken together to form a cyclic ring which may contain N, S or O atoms;
R4 and R& are independently hydrogen, C-..6alky!, Cj..? cycloalkyl, C^?cyctoalkylC-.. 4alkyi. arylC^alkyl, C?,.,oaryl, C^oheteroaryl, C^oheteroarylCMalkyl, Cs ioheterocyclyl, C2.!oheterocydylC1.4alkyl or
R4 and R6 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 R8 and R* are independently hydrogen, C1 6 alkyl, C».y cycloalkyl, C3.ycycloalkylC,. 4afkyl, arylCi^alkyi. CVioaryl. CMoheteroaryl, Ct ^heteroaryiCi^alkyi, C2 !0heterocyclyl, CMoheterocyclylC^alkyl or
R8 and R9 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;
Ruι is Ci.« alkyl, Cβ.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. -NR4R5, -CHxNR4R6, C n alkyl, Ci.4 hydroxylalkyl, C^haloalkyl. Ci.eperhaloalkyl, Ci^alkoxy, C3./ cycloalkyl. trihalo Ci 4 alkoxyl, C3? cydoalkoxy. -C(O)R3. -C(O)OR3. -CH2C(O)OR3, -C(O)NR4R5, - CH2C(O)NR*R6, -NR3C(O)NR4R5. -NR3C(O)OR3, -S(O)PRa, -S(O)5NR4R*. -OS(O)2Rl C3. rcycloalkyl, C^rcycioalkylCi-nalkyl, C^oaryi, Cβ-ioarylC^alkyl, Ce-toaryloxy, C1.10 heterocyclyl. Ci.ioheterocyclylC?.4alkyl, Ct icheteroaryi, Ci.(oheteroarylCi./,alkyl, CM0 heteroaryloxy, or Ci.10heterocycloxy; or a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
In another embodiment, the invention provides compounds of Formula (IA):
Figure imgf000024_0001
wherein A is selected from:
Figure imgf000025_0001
provided that when A is
Figure imgf000025_0002
rt is not substituted with hydroxy or methoxy,
Q is L3-X,, or R10,
Z and T are each, independently, a bond, CM 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(R1J(R1)-, -C(O)- -C(O)NR3-, -NR3C(O)-, - N(R^)C(O)N(R5K -N(R?)SOr. or -SO^N(R')-,
V is halogen, ~ORnior hydrogen, m = 0~4, n = 0-4. p β 0-2,
R' and R' are independently, hydrogen, halogen Ci δalkyl. peihaloaikyl. or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or S
R' Ru and R1b are independently selected from hydrogen C<_.5a!kyl C8 1OaIyI-C1 4alkyl, -C^Cf^oaryi or -CtOiC^alkyl;
R'' and R*'3 are independently halogen, hydroxy. Ci Λhydroxyalkyl. cyano, nitro. - NR4R", -CH,NR4R5, C w afkyl. Cj r cycloalkyl, C, 4 alkoxy, C3 , cycloalkoxy, -S(O)0R3, - S(O^NR4R5 -OS(O)2R3 -C(O)R i -C(O)OR'4. -CH2C(O)OR5, -CpJNRW - CH2C(O)NR4R5, -NR3C(O)NR4R5. -NR3C(O)OR2, C^haloalkyl, Ct.eperhaloalkyl, C*. vcycloalkylC^alkyl, Cβ-ioaryl, C6.!oarylCMaJkyl, C6.10aryloxy, C2.,oheterocyclyl, C2.. wheterocyclyid^alkyl, C10heteroarylC^alkyL Ci.i0heteroaryl, Ci.10heteroaryloxy, or CL toheterocycloxy;
R3 is hydrogen, C^alkyl, C37 cycloalkyl, Cβ.ioaryi. d.ioheteroaryt. or Cz. toheterocyclyl; q = 0-3;
X is tC(R6)(R7)]t;
Y is H, Cw alkyl, OR1 or NR8R9 t * 1-3:
R6 and R7 are independently hydrogen or Ci 6 alkyl, or R6 and R; form an oxo group and t-1 , or when Rδ and R7 are CV4alkyl on the same carbon they can be taken together to form a cyclic ring which may contain N. S or O atoms;
R4 and Rs are independently hydrogen, C^aikyl, C^cycioalkyl. C^cycloalkylCi, 4alkyl. arylCi.4alkyi, C^^aryl, CMoheteroaryl, Ci.ioheteroarytCi^alkyi, C-Autheterocyclyl, C2.!0heterocyclylCi 4alkyi or
R4 and Rs 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
R8 and R* are independently hydrogen, C^ alkyl, C3-? cycloalkyl, Cg^cycloalkyld. 4alkyl, arylCi.4alkyl, C^ary!, C,.ioheteroaryl. Ct.ioheteroarylC1 4alkyl. Cs.Kiheterocyclyl, Cj..,oheterocyclylC1.4alkyl or
R8 and R9 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:
R10 is C1-4 alkyl, Cβ.i(taryl, Cj.icheteroaryi. Cr?cycloalkyl. Cj.^heterocyclyl, where Ct-4 alkyl may be optionally substituted by one or more hydroxy or halogens and C6.i0aryl may be optionally substituted with one or more Ci.4aikyl, C^alkoxy, or Ci.4haloalkyl; and
X3 is halogen, hydroxy, cyano, nitro, -NR4R5, -CH2NRΛRS. C1^ alkyl, CM hydroxylalkyl, Ci.ehaloalkyl, C1-6perhaloalkyl, C-^ alkoxy, trihalo C^alkoxyl, an optionally substituted C3.? cycloaikoxy, -C(O)R3, -C(O)OR3, -CH5C(O)OR3, -C(O)NR4R5, - CHjC(O)NR4R5, -NR3C(O)NR4R5. -NR3C(O)OR3, -S(O)PR3, -S(O)2NR4R5, -OS(O)2R3, an optionally substituted Cj.ycycioalkyl, an optionally substituted Ca.ycycloaikylCi.^alkyi, an optionally substituted C^ary'. an optionally substituted Cs-ioaryld^alkyl, an optionally substituted Cβ.ioaryfoxy, an optionally substituted CMoheterocyclyJ, an optionally substituted Cz føheterocyclytCi^alkyi, an optionally substituted C1^0 heteroaryt. an optionally substituted Ci.,0heteroarylCMalkyl, an optionally substituted CM0 heteroaryloxy, or an optionally substituted Ci toheterocycloxy; or a pharmaceutically acceptable salt thereof.
Various embodiments of the invention are described below. It will be appreciated that the features specified in each embodiment may be combined with other specified features, to provide further embodiments.
In one embodiment, the invention relates to compounds of Formula (IA), where A: is a CMoheterocycyl.
In another enbodiment, the invention relates to compounds of Formula (IA), wherein A is selected from.
.
Figure imgf000027_0001
or
In another embodiment of the compounds of formula (IA), A is
Figure imgf000028_0001
In embodiment of the compound of Formula (IA), Q is L3-X3, wherein L8 is a Ct 4 alkylene {e.g. methylene, ethylene or isopropylene).
In another embodiment of the compounds of formula (IA), X8 is
Figure imgf000028_0002
Each of whJch may be optionally substituted with one or more sυbstituents which may be independently selected from halogen, hydroxyl, C1^ alkyl. C3-? cycloalkyl, C^7 cycloalkoxyl, CMalkoxyl. C2.4 alkenyl: C^i0 aryl, Ci.toheteroaryl, cyano, -C(O)- C1-4 alkyl. - C(O)-N- CM alkyl. -C(O)-N-di C,.4 alkyl, -S- C4 alkyl, SOr C4 alkyl. trihalo C^alkoxyl, - o- C3.? cycloalkyl and -O- C- cylcoalkoxyl, In yet another embodiment X3 is an optionaily substituted aryl, optionally substituted with one or more independently selected halogen, Ci 4 alkyl. CM alkoxyl, C3.? cycloalkyl, -O- C57CyClOaIkIyI, -S- C1 4alkyl. -SO2- CM alkyl, trihalo C1^ alkyl, trihalo C1.* alkoxyl, Ce.,0 aryl, Ci.10heteroaryl. cyano, nitro NR4R5, -CH2NR4R5 or -C(O)- C M alky!.
In another embodiment of the invention, the compound is of Formula (IA), wherein Q is Rw and R10 is methyl, ethyl, isopropyl, isobutyl, triflouromethyl or cyclopentyl.
In another embodiment of the invention, the compound is of Formula (IA), wherein Q is R1(! and R10 is a C6-10aryf which may be optionally substituted with one or more substituents which may be independently selected from Chalky!, Ci^alkoxy, and C1. 4haloalkyi.
In another embodiment of Formula (IA) as descriibed above
X iS -CH2-;
Y is OR1;
V is OR1
R1, R1a and Rlb are hydrogen.
In another embodiment the invention provides a compound of formula (lib): 4b
Figure imgf000029_0001
wherein
Lb is a bond or an optionally substituted C1^ alkylene;
R i?b R i3i> Rnb R'st> and R^ are each, independently, hydrogen, halogen, C4 alkyl, C-..* alkoxyL Cc^cycloalkyl, O- Cs ? cycloalklyl. -S- Ct.4 alkyl. -SO2- C14 alkyl, trihalo CM alkyl, trihalo C1^aIkOXyI1 Cδ iOaryl, Ci i0heteroary!, cyano, nitro, NR4R5, -CH?NR4R5 or -C(O)- d alkyl; or a pharmaceutically acceptable salt thereof.
In an exemplary embodiment of the compounds of formula (lib) U is methylene; Rub. Ri» Riat> Risb and Riβb are each hydrogen; and RM* is Ct.Λ alkyl.
In one embodiment the invention provides a compound of formula (Mc).
Figure imgf000030_0001
wherein
L0 is a bond or an optionally substituted C M alkylene;
R12t, Rt3c, R14c, R1Sc and R'6c are each, independently, hydrogen, halogen, C4 alkyl. C1.4 alkoxyl, Ca-ycycloalkyi, -O- C3./ cycloalktyl, *S- CM alkyl. -SO2- CM alkyl, trihalo C1-, alkyl, trihalo C M alkoxyl, C6. ,0 aryls C ,. ,0 heteroaryl, cyano. nitro, NR4R6, -CH2NR4R^ or -C(O)- C1 4 alkyl; or a pharmaceutically acceptable salt thereof.
In another embodiment the invention provides a compound of formula (Hd);
Figure imgf000030_0002
wherein
Ui is a bond or an optionally substituted C1 Λ alkylene; R t« Rm R i3d R i4<s Qnd R isd are each independently. hydrogen, halogen, CMalkyl, C4 afkoxyl, Cs^cycloalkyl, -O- Cϊ7cycloalklyl, -S- CMalkyl. -SO2- C^alkyl, trihalo C,.«alkyl, trihalo d.4 alkoxyl, Cs.,oaryl, CMoheteroaryl, cyano, nitro, NR4R5, -CH3NR4R5 or -C(O)- C, .4 aikyl; or a pharmaceutically acceptable salt thereof.
In an examplary embodiment of the compounds of formula (Hd) la is methylene; R1W. Ri2d Ri4d and RMxi arø each nycjrogen; and R«3d js c^alkyl.
fn yet another examplary embodiment of the compounds of formula (Md) L<j is ethylene; Rii* Ri24 Ri4« and Rt5d are βach hydrogen; and Rm js cMalkoxyl.
In one embodiment the invention provides a compound of formula (lie);
Figure imgf000031_0001
wherein
U is a bond or an optionally substituted C1^ alkylene; Rii* R i2e R ise R i4o and R ii* are eacn independently, hydrogen, halogen, Chalky!, Ci 4 alkoxyl. C3 ?cycloalkyl. -O- Cjycycloalklyl, -S- C1^ aikyl, -SOr C^alkyl. trihaio Ct^alkyl trihalo CL4 alkoxyl, C.3.10aryl, C1-10 heteroaryl, cyano, nitro, NR4R5, -CH2NR4R5 or -C(O)- Ci 4alkyl; or a pharmaceutically acceptable salt thereof.
In an examplary embodiment of the compounds of formula (He) Le is a bond; R11". R12*, R1"* and R'Sβ are hydrogen; and Rm is C1., aikyl or C1^ aikoxyl
In yet another examplary embodiment of the compounds of formula (He) U is methylene; Rm, R1?e. R14e and RiS* are hydrogen; and R!'^ is CM alkyl or C,., alkoxyl.
In another embodiment the invention provides a compound of formula (Hf);
Figure imgf000032_0001
wherein
Lf is a bond or an optionaify substituted Cu alkylene;
R11f s R12f, R13f t R14f and R15f are each, independently, hydrogen, haiogen, CMalkyl. C1.* aikoxyl, C^cycloalkyl, -O- C37CyClOaIkIyI1 -S- CMalkyl, -SO3- CMalkyl, trihalo C^ alkyl, trihalo C1-O aikoxyl. C6-10 aryl. C1-10 heteroaryl, cyano, nitro NR4R5, -CH2NR4R5 or -C(O)- Ct^alkyi; or a pharmaceutically acceptable salt thereof.
in an exemplary embodiment of the compounds of formula (Hf) Lf is a bond; RHf, R!Jf, R14f and R15f are hydrogen; and R13f is C,.4alkyf.
In another embodiment the invention provides a compound of formula (Hg).
Figure imgf000032_0002
wherein
Lg is a bond or an optionally substituted Cj 4 alkylene;
R iia R i?9 R i3a R i*a and R iss are eacn independently, hydrogen, halogen, Ch alky!, C1^ aikoxyl, C37 cycloalky!.. -O- C^cycloalklyl, -S- Ci.Λalkyl« SO2- Ci^alkyl, trihalo C^alkyl. trihaio Ci 4alkoxyl, Ce ioaryl, CM0 heteroaryl, cyano, nitro NR4R'J, -CH2NR4R5 or -C(O)- C^^alkyl; or a pharmaceutically acceptable salt thereof. In another embodiment the invention provides a compound of formula (Hh):
Figure imgf000033_0001
wherein
Ln is a bond or an optionally substituted C1 4 alkylene;
R"h. Riah. Rκth, Rt4h and R15h are each, independently, hydrogen, halogen, CMalkyl, C1,, afkoxyl, C^cycloalkyl, -O- C3-7CyCiOaIkIyI, -S- C^ alkyl -SOr Ct^alkyl, trihalo Ci^alkyl, trihalo d^aikoxyl, Cδ.ioaryl, d-ioheteroaryl, cyano, nitro NR-1R8. -CH2NR4R5 or -C(O)-
C^alkyl; or a pharmaceutically acceptable salt thereof.
In another embodiment individual compounds according to the invention are those listed in the Examples section below.
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.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O. de.~ acetone, d6-DMSO.
Compounds of the invention, i.e. compounds of formula (I), (IA)1 (Hb). (Hc), (Hd), (He), (Hf)= (Hg) and (Uh) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co- crystals with suitable co-crystal formers. 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. Hence the invention further provides co-crystals comprising a compound of formula (I), (IA)1 (lib), (lie), (Hd), (He), (Uf)1 (Hg) and (Hh).
As used herein, 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.
The term "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. In one non-limiting embodiment, the term "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. In another non-limiting embodiment, the term "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.
As used herein, the term "patient" refers to an animal. Preferably, 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. In a preferred embodiment, the subject is a human.
As used herein, 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,
As used herein, the term "treating" or "treatment" of any disease or disorder 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). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treating" or 'treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder,
As used herein, the term "a,': "an,κ "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. Any asymmetric atom (e.g., carbon or the like) of the compoυnd(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)~, (Sy or (RS)- configuration. In certain embodiments, 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. Sυbstitυents at atoms with unsaturated bonds may, if possible, be present in as- (Z)- or trans- (E)- form.
Accordingly, as used herein 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. In particular, 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. e.g.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. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof. When both a basic group and an acid group are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules. Furthermore, 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 ,
Thus, as a further aspect, 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.
As a further aspect, 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. For example, 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. 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. inhibitors of glucose-6-phosphatase, orfructose-1 ,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate). nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (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 β3- agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor. Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-Il antagonists or ACE inhibitors. ECE inhibitors, diuretics, β- blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2- adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable. Examples of angiotensin Il receptor antagonists are candesartan cilexetti. potassium losartan. eprosartan mesylate, valsartan, telmisartan. irbesartan, EXP-3174. L-158809, EXP- 3312, olrnesartaα medoxomil. tasosartan, KT-3-671 , GA-01 13: RU-64276, EMD- 90423, BR-9701 , etc. 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 comprising a compound of formula (I). (IA), (lib), (lie), (Hd), (He), (Hf), (Hg) and (Hh) or Ks prodrug and pharmaceutically acceptable excipients.
In still another embodiment of the present invention, the prodrug is selected from a group comprising, esters and hydrates.
The term "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. Examples of 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. In still another embodiment of the present invention, 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.
In still another embodiment of the present invention, 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.
GENERAL SYNTHETIC ASPECTS
Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a "protecting group", unless the context indicates otherwise. 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. For example, 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. 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.
Mixtures of isomers obtainable according to the invention 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.
The following applies in general to ail processes mentioned herein before and hereinafter.
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. in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about -100 βC to about 190 "C, including, for example, from approximately -80 *C to approximately 150 °C, for example at from -80 to -60 °C, at room temperature, at from -20 to 400C or at reflux temperature, under atmospheric pressure or in a dosed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.
At all stages of the reactions, 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".
The 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. 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. Such 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. AIf 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 4m Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
Typically, the compounds of formula (I), (IA), (lib), (lie), (Hd), (He), (Hf), (Hg) and (Hh) can be prepared according to the Schemes provided infra.
Method of Preparation
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), In the reactions described in the schemes herein below, 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.
Scheme 1 ,
Figure imgf000043_0001
Compounds of formula (H) wherein all symbols are defined herein above may be reacted with compounds of formula (ill) wherein LG is a leaving group such as halide, tosyl or mesyl. The reaction may be carried out in the presence of a base and a solvent to provide compounds of formula (IV). Compounds of formuia (IV) may be reacted with compounds of formula (V) wherein all symbols are defined wherein above. The reaction may be carried out in presence of a reagent such as aikyl-ϋ or Mg to provide compounds of formula (I) wherein Q is attached to a nitrogen in the heterocyclic ring all other symbols are defined herein above.
Scheme 2.
Figure imgf000044_0001
Compounds of formula (II) wherein all symbols are defined herein above may be reacted with compounds of formula (V) wherein ail other symbols are defined herein above. The reaction may be carried out in presence of a reagent such as alkyi-ti or Mg to provide compounds of formula (Vl). Compounds of formula (Vl) may be reacted with compounds of formula (III) wherein LG is selected from halide, tosyi or mesyl. The reaction may be carried out in the presence of a base and a solvent or under Buchwald coupling conditions to provide compounds of formula (J) wherein Q is attached to the nitrogen of the bicyclic ring and ail other symbols are defined herein above.
Scheme 3:
Figure imgf000045_0001
Alternatively, 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.
Scheme 4:
Figure imgf000045_0002
Alternatively, 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
Scheme 5;
Figure imgf000046_0001
Carbonyl function of compounds of formula (X) wherein all symbols are defined herein above are protected to provide compounds of formula (Xl) and may be reacted with compounds of formula (V) wherein all symbols are defined wherein above to provide compounds of formula (XII). The reaction may be carried out in presence of a reagent such as alkyl-Li or Mg. Compounds of formula (XII) may be reacted with a Grignard reagent of formula (XIII) orWittig reagent of formula (XfV) followed by hydrogenation to provide compounds of formula (I) and all other symbols are defined herein above.
Scheme 6:
Figure imgf000047_0001
Carbonyl function of compounds of formula (X) wherein all symbols are defined herein above are protected to provide compounds of formula (Xi) and may be reacted with compounds of formula (V) wherein A is a bond and all other symbols are defined wherein above to provide compounds of formula (XIf). The reaction may be carried out in presence of a reagent such as alkyJ-U or Mg. Compounds of formula (XH) may be reacted with an aldehyde of formula (XV) in the presence of a base, followed by hydrogenation or compounds of formula (XH) may be reacted with alkyl halides of formυia (XVI) in the presence of a base to provide compounds of formula (I) and all other symbols are defined herein above.
Compounds of formυia (IA) where Y is NR8R8 and R3 and R9 are independently hydrogen, d,e alkyl, Ccv?cycloalkyl, Cs-ycycloalkylCi^alkyl, arylC^alkyl, C& ,oaryl, Ci.. 10heteroaryl. C^oheteroarylC^alky!. CS-IQheterocyclyl, C2-10heterocyclylCi4alkyi or R8 and R9 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)
Figure imgf000048_0001
where V. R1 . Rla. X and Q are as hereinbefore defined and LG is a suitable leaving group, with a compound of HNR8R9. Where X is an alkyjene, suitable LG include mesylate or tosylate and the transformation may be carried out with a suitable base, e.g. tήethylamine in a suitable solvent such as dimethylformamide, or similar conditions well known to those skilled in the art. Where X is carbonyl, 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.
Compounds of formula (IA') may be prepared from compounds of formula (IA")
Figure imgf000048_0002
under suitable conditions for forming a leaving group, e.g. where LG is tosyl or rnesyl, by reaction of the corresponding tosyl or mesyl halide, e.g. chloride, in a suitable solvent such as 2,6-lutidine, or under similar conditions well known to those skilled in the art.
Compounds of formula (IA) where Y is NR8R9 and Rδ and R9 along with the nitrogen to which they are bound form a monocyclic or a bicyclic ring system which is aromatic, may alternatively be prepared by reaction of compounds of formula (IA")
Figure imgf000048_0003
where V, R1 , R1a, X and Q are as hereinbefore defined and W is a suitable precursor to the formation of the desired ring. For example, where Y is a 1 ,2,3-tria2θlyl or tetrazolyl group, 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.
It will be understood that the processes detailed above and elsewhere herein are solely for the purpose of illustrating the invention and should not be construed as limiting. A process utilizing similar or analogous reagents and/or conditions known to one skilled in the art may also be used to obtain a compound of the invention.
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.
The following Examples are intended to illustrate the invention and are not to be construed as being limitations thereon. If not mentioned otherwise, all evaporations are performed under reduced pressure, between about 50 mmHg and 100 mmHg. The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis, melting point (m.p.) and spectroscopic characteristics, e.g. MS, IR and NMR. Abbreviations used are those conventional in the art.
EXAMPLES
Preparation 1. 6-Bromo-2,2-dimethyl~3,4-dihydro-2H-benzo[1 ,4]oxazine
oεt
Fe/HCI
Figure imgf000050_0001
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-bromσ isobυtyrate (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).
1H NMR (400 MHz, CDCI2): δ 1.29 (t, J - 7.2 Hz. 3H), 1.67 (s, 6H).4.28 (q, J * 7.2 Hz1 2H). 6.91 (d, J « 8.8 Hz, 1H), 7.56 (dd; J ~ 9.2.. 2.4 Hz; 1H). 7.91 (d, J * 2.4 Hz. 1H). Step II; To a stirred solution of 2-(4-bromo-2«nitro-phenoxy)~2-methyl propionic acid ethyl ester (1.0 g. 3.01 mmol) in ethanol (15 ml) was added Iron powder (837 mg, 15.06 mmol). cone, hydrochloric acid 0.3 ml was added to the reaction mixture and heated to reflux for 4 h. filtered through celite, concentrated and diluted with water (50 ml). After usual work up, compound was purified by silica gel column chromatography to furnish 6- bromo-2.2-dimethyl-4H-benzop,4]αxazin-3-one (517 mg).
1H NMR (400 MHz, CDCI3). δ 1.56 (s, 6H), 6.86 (d, J - 8.4 Hz, 1H), 6.96 (d. J = 2.4 Hz, 1H). 7.12 (dd, J = 8.4, 2.4 Hz, 1H), 8.22 (bs, 1H)
Step IM: To a stirred solution of 6-bromo-2,2-dimetbyl-4H-benzo|:1,4]oxazin-3-one (4.0g, 15.62 mmol) in THF (15 ml) was added 1.0 M Borane-tetrahydrofuran complex in THF (46.9 ml, 46.87 mmol) and refluxed for 6 h. The reaction mixture was cooled to 0 °C. quenched with methanol (30 ml) and concentrated under reduced pressure. The resulting residue was taken in ethyl acetate (100 mi), washed with aqueous saturated sodium bicarbonate solution (50 ml), water (50 ml), brine (50 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography to provide the titled compound (3.26 g).
1H NMR (400 MHz, CDCI3): δ 1.37 (s. 6H). 3.15 (s. 2H), 6.67 (d, J * 8.4 Hz, 1H), 6.82- 6.85 (mt 2H).
Preparation 2. 6-Bromo-2-methyl>3,4-dihydro-2H-benzo{1,4]oxazine
Figure imgf000051_0001
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|1,4]oxazin-3-one (3.21 g).
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. The resulting residue was taken in ethyl acetate (50 ml), washed with aqueous saturated sodium bicarbonate solution (20 mi), water (20 ml), brine (20 ml), dried over sodium sulphate and concentrated to give the titled compound (2.32 g). Preparation 3. β-Bromo^^-ethyl-benzyl^-methyl-S^-dihycfro^H- benzo[1 ,4]øxazine.
Figure imgf000052_0001
To a stirred solution of 6-bromo-2~methyl-3,4-dihydro-2H-beraro[1 ,4}oxazine (obtained in preparation 2) (500 mg, 2.19 mmol) in DMF (2.1 ml) was added 4-ethylbenzyl chloride {410 mg, 2.63 mmol), sodium iodide (21.9 mg,), potassium carbonate (605 mg, 4.39 mmol) and heated at 6O°C for 16 h, quenched with water (40 ml). After usual work up, compound was purified by silica gel column chromatography (1% ethyl acetate in hexane) to furnish the titled compound (Yield « 605 mg).
1H NMR (400 MHz. CDCI3): δ 1.26 (t, J = 7.6 Hz, 3H), 1.46 (d. J « 8.6 Hz, 3H ), 2.67 (q, J « 7.6 Hz, 2H), 3.08-3.13 (m. 1H), 3.23-3.26 (m, 1H), 4.23-4.27 (m, 1H), 4.42 (s, 2H) 6.70 (d. J = 8.4 Hz, 1H), 6.75 (d, J * 8.4, 1H), 6.84 (s, 1H), 7.20-7.23 (m, 4H); MS (El) m/z 346.0 (M+ 1)
Preparation 4. 6-Bromo-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazine
Figure imgf000052_0002
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)-proρan-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).
1H NMR (400 MHz, CDCI3): δ 1.07 (d( J * 6.4 Hz. 3H), 3.36-3.39 (m, 1H), 3.57-3.62 <m, 1H), 4.10-4.13 (m, 1H), 6.09 (s. 1H ), 6.53-6.59 (m, 2H)1 6.68 (d, J * 2.0 Hz. 1H) MS (El) m/z 226 (M+1).
Example 1. (2S,3R,4R,5S,6R)-2-[4-(4«Ethyl-benzyl)«3,4-dihydro«2H« benzo[1,4]oxazin-6-ylJ-^-hydroxymethyJ-tetrahydro-pyran-3,4>5-triol
OfMS
BF8Et2O. εtjSiH
Figure imgf000053_0001
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). The 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. The resulting residue was taken in ethyl acetate (100 ml), washed with aqueous saturated sodium bicarbonate solution (100 ml), water (100 ml), brine (100 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography (5% ethyl acetate in hexane) to provide 6-bromo-3,4-dihydro-2H- benzop^oxazine (8.5 g).
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). After usual work up, compound was purified by silica gel column chromatography (3% ethyl acetate \n hexane) to furnish 6-bromo-4- (4-ethyl-benzyl)-3)4-dihydro-2H-ben2o[1,4]oxa2:ine (2.2 g).
1H NMR (400 MHz, CDCIS): 6 1.25 (t, J * 8.0 Hz, 3H), 2.65 (q, J - 8.0 Hz1 2H), 3.35 (t, J « 4.4 Hz, 2H)t 4.24 (t, J = 4.4 Hz, 2H), 4.41 (s, 2H), 6.89 (d, J = 8.4 Hz, 1H). 6.76 (dd, J * 8.4, 2.4 Hz, 1H), 6.85 (d, J * 2.0 Hz, 1H), 7.20-7.33 (m, 4H). MS (ES) m/z 334.0 (M+2)
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. The 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. After stirring for 40 min., 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). This reaction mixture was extracted with ethyl acetate (3 X 20 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography to furnish (3R,4S.5$,6R)-2-{4-(4-Ethyl-benzyl)-3.4-dihydro-2H- benzo{1.4}oxazin-6-yl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3.4,5-triot (1.0 g). 1H NMR (400 MHz. CD3OD): δ 1.22 (t, J * 7.6 Hz. 3H). 2.63 (q. J * 7.6 Hz1 2H), 2.98 (s, 3H), 3.10 (d. J ~ 9.2 Hz, 1H), 3.35-3.40 (m. 3H). 3.56 (m, 1H)1 3.73 (t, J - 9.2 Hz, 1H). 3.79 (dd, J « 12,0, 5.6 Hz. 1H), 3.92 (dd, J « 11.6. 2.0 Hz, 1H), 4.21-4.26 (m. 2H). 4.42 (d, J = 15.6 Hz, 1H). 4.54 (d, J - 15.6 Hz. 1H). 6.71 (d, J * 8.4 Hz, 1H), 6.86 (do, J * 8.0, 1.2 Hz. 1H). 7.02 (d, J = 1.6 Hz, 1H)1 7.17 (d. J * 8.0 Hz. 2H). 7.27 (d. J = 8.0 Hx1 2H). MS (ES) m/z 446.3 (M+ 1).
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 triflυoride diethyletharate complex (0.57 mi, 4.52 mmoJ), and triethylsilane (1.3 ml. 9.04 mmol) at -5 °C. After stirring for 4 h at 0 °C, reaction was quenched with aq. saturated sodium bicarbonate solution (8 ml). The volatiles were evaporated under reduced pressure: the resulting mixture was extracted with ethyl acetate (3 X 20 ml). The organic layer was washed with brine (5 mi), dried over sodium sulphate, concentrated and purified by preparative HPLC to furnish the titled compound (180 mg) 1H NMR (400 MHz, CDjOD): δ 1.24 (t, J * 7.6 Hz. 3H). 2.64 (q, J « 7.6 Hz1 2H)1 3.29- 3.44 (m, 6H), 3.67 (dd, J = 12.0, 5.2 Hz, 1H), 3.86 (d, J * 11.6 Hz, 1H), 3.97 (d, J - 9.2 Hz. 1H). 4.20 (t. J = 4.0 Hz. 2H), 4.42 (d, J * 15.6 Hz. 1H). 4.48 (d, J = 156 Hz, 1H), 6.67 (d. J - 9.6 Hz, 1H), 6.71 <d, J * 8.0 Hz, 1H). 6.88 (s. 1H). 7.17 (d( J = 8.0 Hz, 2H), 7.26 (d, J a 8.0 Hz, 2H). MS (ES) m/z 416.1 (M+1).
Examples 2-15 were prepared in an analogoues procedure as described in example 1.
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Example 444.1 Η NMR (400 MHz, DMSO-D6). (peaks 13 correspond to major isomer) δ 1.20 (d, J - 6.8 Hz, 6H), 1.27 (d. J = 6.2 Hz. 3H). 2.86-
OH 2.94 (m. 1H). 2.96-3.12 (m, 1H), 3.15-3.23
Figure imgf000061_0001
(m, 3H), 3.28-3.44 (m, 3H), 3.67-3.70 (m,
HO Y' xf' OH OH 1H), 3.84 (d, J a 9.2 Hz. 1H), 4.19 (t, J « 6
(2R,3S.4R.5R)-2- Hz, 1H). 4.35-4.49 (m, 3H), 4.67 (d, J ~ 4.8
Hydroxymethyl-6- Hz1 1H), 4.92 (d, J « 4.4 Hz, 2H), 6.55 (d, J
(4-(4- - 7.9 Hz, 1H), 6.64 (dd, J « 7.9 Hz, 1H), isopropylbenzyi)-2- 6.81 (d, J * 5.2 Hz. 1H). 7.20-7.27 (m, 4H) methyl-3,4-dihydro~
2H- benzo[1,4]oxazin~
6-yl}~tetrahydro- pyran-3,4,5-triof
Example rH NMR (400 MHz1 CD3OD): (peaks 14 Y correspond to major isomer) δ 1.16 (d. J - 6.4 Hz, 3H). 1.26 (d, J = 6.8 Hz, 6H), 2 87- r 2,94 (m, 2H), 3.41-3.51 <m, 3H). 3.62-3.65 v- .o.τΛ f^Sr0 (m, 1H), 3.83-3.86 (m, 1H). 3.92-3.97 (m,
HO ^Y"" OH OH 1H), 4.01-4.07 (m, 2H), 4.09-4.36 (m, 1H),
(2R.3S,4R.5R)-2~ 4.37-4.65 (m, 2H), 6.66-6.68 (m, 1H), 6.72- Hydroxymethyl-6- 6.77 (m, 2H)1 7.21 (d. J = 8.2 Hz, 2H), 7.28 {4-(4-isoproρyl- (d, J = 7.7 Hz, 2H) ! benzyl)~3-metnyi- 3,4~dihydro-2H- benzo{1,4}oxazin~ 6-ylJ-tetrahydro- pyran-3A5-triol
Example 340,1 TH NMR (400 MHz, CD3OD) (peaks
LIST'S 15 OH -V'° correspond to major isomer) δ 1.17- 1.22
,'0N- J (m, 6H): 3.37-3.52 (m. 7H), 3.68-3.72 (m,
HθΥ-'O!<
OH 1H): 3.88 (d, J = 12.0 Hz. 1H). 3.91-4.03
Figure imgf000062_0002
Example 16. (23,3R,4S,5S,6R)-2-[4-{4-Ethy{-benzyl)-3>4-dihydro-2H- benzofi^Joxaiin-β-yll-β-methyl-tetrahydro-pyfan-S.^S-trJol
2 UAlHa
Figure imgf000062_0001
To a stirred solution of (2S,3R.4R,5S,6R)~2-[4-(4-Ethyl-benzyl)~3,4-dihydro-2H- benzQ[1,4|oxazin~δ~yl]-6-hydroxymethyMetrahydro-pyran-3,4,54rioi (150 mg. 0.36 mmol) in lutidine (3 ml) was added tosyl chloride at 0 °C. After stirring for overnight at ambient temperature, reaction was quenched by the addition of water (5 mi) This mixture was extracted with ethyl acetate (2 X 10 ml). Organic layer was evaporated under reduced pressure and purified by column chromatoghraphy to give toluene-4-sulfonic acid (2.R.3S,4R,5R.6S)-β-t4-(4-ethyl-benzyl)-3l4-dJhydro-2H-benzo[1.4]oxazin-6-yl3~3ι4,5- trihydroxy-tetrahydro-pyran»2-ylmethyl ester (150 mg). MS (ES) mte 570.1 (M+1). To a stirred solution of lithium aluminium hydride (35 mg, 0.92 mmol) in dry THF (4 ml) was added a solution of Toluene-4-sulfonic acid (2R,3S,4Rt5R,6S)-6-|4-(4-ethyl-benzyl) - S^-dihydro^H-benzoti^Joxaϊin-β-ylj-S^.δ-trihydroxy-tetrahydro-pyran^-ylmethyl ester (175 mg, 0 307 mmol) in THF (2 ml) at 0 °C. After stirring at ambient temperature for overnight, reaction mixture was cooled to 0 °C and quenched by the addition of aq saturated sodium sulfate solution. This was filtered through celite bed, washed with methanol, concentrated and purified to give the titled compound. (Yield - 5 mg). 1H NMR (400 MHz, CD3OD): δ 1.23-1 31 (m, 6H), 2.64 (q. J * 7,6 Hz. 2H). 3.09 (t. J « 9.2 Hz, 2H). 3.33-3.41 (m, 4H), 3.94 (d. J = 8.8 Hz. 1H). 4.21 (t, J = 3.6 Hz. 2H). 4.44 (s, 2H), 6.62 <d, J - 8.0 Hz. 1H). 6.71 (d, J * 8.4 Hz, 1H), 6.82 (s, 1H), 7.18 <d, J * 8.0 Hz. 2H). 7.26 (d, J « 8.0 Hz, 2H). MS (ES) m/z 400.3 (M+1).
Example 17. (2S,3R14R,δS,6R)-2-C4'(4.MethyI-benzyl).3,4-dihydfθ-2H« ber>zo|:1,4Joxa2in-6-yl3-6-hydroxymethyl-tetrahydro-pyran-3,4,5-trJol
HN' ~1 D tA par
DMF. KXO,
X **\Jr HJf
Figure imgf000063_0001
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). After usual work up, compound was purified by silica gel column chromatography to furnish 6- bromo-4-(4-methoxy-benzyl)-3,4-dihydro-2H-benzo(1 ,4]oxazine (2.2 g). 1H NMR (400 MHz, CDCI3): δ 3.28 (t, J = 4.4 Hz1 2H), 3-8 (s, 3H), 4.20 (t, J * 4.4 Hz. 2H), 4.34 (s, 2H), 6.64 (d, J * 8.4 Hz1 1H)1 6.70 (dds J * 8>4, 2.0 Hz1 1H), 6.80 (d, J -■ 2.0 Hz, 1H). 6.87 (d. J « 8.4 Hz, 2H). 7 17 (d, J « 8.4 Hz, 2H). MS (ES) m/z 336.1 (M+2) StepH: To a stirred solution of 6-bromo~4-(4-methoxy-benzyl)-3.4-dihydro-2H- benzo|i,4Joxazine {20.0 g. 59.8 mmol) in TΗF-toIuene (1.2 mixture, 150 ml) was added 1.6 M n-BuU in hexanes (37.4 mf, 59.8 mmol) at -78 °C, The reaction mixture was stirred for 40 min., then it was transferred to a stirred solution of 2,3,4,6-tetrakis-Q- (trimethylsilyl)-D-glucopyranone (28.0 g, 59.8 mmol) in toluene (150 ml) at -78 °C. After stirring for 40 min.. 0.6 N methanesulfonic acid in methanol (140 ml) was added and stirred for 20 h at room temperature. Reaction was quenched by the addition of aq. saturated sodium bicarbonate (30 ml). This was extracted with ethyl acetate (3 X 100 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography to furnish (3R,4S.5S,6R)-6-Hydroxymethyl-2-methoxy-2~l4-(4-methoxy- benzyt)-3,4-dihydro-2H-benzQ[1 ,41oxazin~6-ylHetrahydro-pyran-3.4,5-triol (10.2 g). 1H NMR (400 MHz. CD3OD): 6 3,02 (s, 3H), 3.11 (d, J » 9.6 Hz1 1H), 3.31-3.33 (m, 2H), 3.39 (t. J = 9.2 Hz, 1H), 3.54-3.58 (m, 1H), 3.74 (t, J * 9.2 Hz, 1H). 3.78 (s, 3H), 3.81 (t, J = 5.6 Hz, 1H), 3.93 (dd, J ~ 11.6, 1.6 Hz, 1H), 3.99-4.24 (m. 2H), 4.39 (d, J * 15,2 Hz, 1H)1 4.49 (d. J * 15.2 Hz1 1H), 6.70 {d, J « 8.0 Hz, 1H), 6.85-6.90 (m, 3H), 7.05 (s, 1H), 7.29 (d, J - 8.4 Hz, 2H). MS (ES) ιn/z 448.1 (M+ 1).
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. After stirring for 4 h at 0 °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!3R,4R15S,6R)-2-(4-(4- Methoxy-benzyl)-3,4-dihydro-2H-benzo[1)4]oxazin-6-ylJ-6-hydroxymethyl-tetrahydro- pyran-3,4,5-trtol.
1H NMR (400 MHz, CD3OD): δ 3.28 (t, J * 4.4 Hz1 2H), 3.33-3.46 (m, 4H). 3.68 (dd, J * 11.6. 4.8 Hz, 1H), 3.79 (s, 3H), 3.86 (d, J * 11.6 Hz. 1H). 3.97 (d, J * 9.2 Hz, 1H), 4.19 (t, J = 4.0 Hz, 2H), 4.39 (d. J ~ 15.6 H2, 1H), 4.44 (d, J - 15.6 Hz, 1H). 6.67 (d, J ~ 8 0 Hz. 1H). 6.70 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 3H), 7.27 (d, J - 8.4 Hz, 2H). MS (ES) m& 418.2 (M-M).
Step IV: To a stirred solution of (2S,3R,4R!5S,6R)-2-[4-(4-Wethoxy-benzyl)-3.4"dihydro- 2H-benzol1)4i|oxazfn-6-yl}-6«hydroxymethyl-tetrahydro-pyrafv3,4,5-tήol (140 mg, 0.33 mmof) in methanol ( 5 ml) was added 10% palladium on charcoal (25 mg), 0.05 ml cone. HCI and stirred under hydrogen balloon pressure for 18 h. Reaction mixture was filtered through celite bed, washed with methaol and concentrated. The resulting residue was titurated in n-hexanes and dried under vacuum to furnish (2S,3R,4R,5$.6R)-2-(3.4- Dihydro-2H-benzo[1 ,4]oxazin-6-yl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (90 mg). 1H NMR (400 MHz, CD3OD): δ 3.29-3,44 (m, 4H)1 3.70-3.72 (m, 3H), 3.91 (d, J * 11.2 Hz, 1H), 4.15 (d, J = 9.6 Hz, 1H), 4.45 (t. J * 4.4 Hz, 2H), 7.04 (d, J « 8.4 Hz. 1H). 7.34 (S, 1H), 7.42 (d, J = 8.4 Hz, 1H). MS (ES) m/z 298.3 (M+1),
Step V: To a stirred solution of (2S,3R.4R,5S.6R)-2-(3..4-dihydro~2H-benzo[1,4;|oxazin-6- yl)~6-hydtOxymethyMetrahydro-pyran-3,4,5-triol (70 mg, 0.23 mmoi) in DMF (2 ml), was added potassium carbonate (65 mg, 0.47 mmoi) and 4-methylbenzyl bromide (65 mg, 0.33 mmoi). Reaction mixture was heated at 50 °C for 2h, queched by the addition of water (3 ml). After usual work up product was purified by column chromatoghraphy to give the titled compound (20 mg).
1H NMR (400 MHz1 CD3OD): δ 2.33 (s, 3H), 3.29*3.46 <n% 6H), 3.67 (dd, J * 12.0« 5.2 Hz. 1H), 3.86 (d, J * 12.0 Hz. 1H). 3.97 (d. J * 9.6 Hz1 1H), 4.20 (L J = 4.4 Hz, 2H), 4.42 (d, J * 15.6 Hz, 1H), 4.48 (d, J - 15.6 Hz, 1H), 6.67 (d, J * 9.6 Hz, 1H), 6,71 (d, J * 8.0 Hz, 1H)1 6.87 (S, 1H). 7.15 (d. J » 8.0 Hz, 2H)1 7.23 (d, J « 8.0 Hz1 2H). MS (ES) m/z 402.3 (M+1).
Examples 18-56 were prepared in an analogoυes procedure as described in example
17.
Example # Structure IWS 1H NMR (M+1)
Example 438,0 1H NMR (400 MHz, CD3OD). δ 3.31-3.44 (m, 18 6H)1 3.63 (dd, J * 11.6, 4.8 Hz1 1H), 3.84 (d, J « 11.2 Hz, 1H)1 3 96 (d, J ~ 9.2 Hz. 1H), 4.26
OH r:#'Y -ό (t. J - 4.0 Hz. 2H). 4.64 (d: J * 15.6 Hz, 1H), k,..oNJ^.J
,.-\ A. 4.69 (d, J * 15.6 Hz.. 1H)1 6.70 (dd. J - 8.O1 1.2 no γ OH
QH Hz. 1H). 6.74 (d, J - 8.0 Hz1 1H), 6.93 (d, J -
(2R,3S,4R,5R.6S)-2- 1.2 Hz1 1H). 7.46-7.87 (m, 7H). Hydroxymethyl-6-(4- rtaphthaien-2~yimethyt-
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
- -
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0002
Example 57. {2R,3S,4R,SR)-2-Hydroxymethyl-6-[4-(4-isopropoxy-benxyl)-3,4- dihydro-2H-benzo[1,4]oxazin-6-yJJ-tetrahydro-pyran-3,4,δ-triol
Figure imgf000080_0001
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 bσrøntribromide 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). After usual work up, compound was purified by silica gel column chromatography (8% ethyl acetate in hexane) to furnish 4-(6-bromo-2.3-dihydro- benzoji ,4]oxazin-4-ylmethyl)-phenQl (1.12 g).
1H NMR (400 MHz, CDCI3): δ 3.31 (t, J * 4.4 H2. 2H), 4.22 (1 J * 4.4 Hz, 2H). 4.35 (S, 2H), 4.91 (S, 1H), 6.67 (d, J = 8.4 Hz1 1H)1 6.75 (dd, J = 8.4, 2.0 H2, 1H), 6.80-6.82 (m, 3H), 7.15 (d J * 6.4 Hz, 2H). MS (ES) rn/z 322.0 (M+2)
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). After usual work up product was purified by silica gel column chromatography (3% ethyl acetate in hexane) to furnish 6-bromo-4-(4-isopropoxy-benzyl)-3,4-dihydrθ'2H-benzo(;i ,4]oxazine (1.4 g). 1H NMR (400 MHz. CDCI3): δ 1.33 (d, J = 6.0 Hz, 6H), 3.29 (t, J - 4.4 Hz, 2H)5 4.21 (t, 4.4 Hz. 2H). 4.34 (s. 2H). 4.53 (q, J = 6.0 Hz1 1H), 6.65 (d. J » 8.4 Hz. 1H). 6.70 (dd, J - 8.4, 2.0 Hz, 1H), 6.81 (d, J « 1.6 Hz, 1H). 6.85 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H).
Step III: To a stirred solution of 6-bromo-4-(4-isopropoxy-benzyl)-3,4~dihydro-2H- benzoπ.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. The reaction mixture was stirred for 40 min., then ft was transferred to a stirred solution of 2,3,4,6~tetrakis-Q~(trimethylsiiyl)- D-giucopyranone (1.67 g, 3.59 mmαi) in toluene (9 ml) at -78°C. After the reaction mixture was stirred for 40 min., quenched by the addition of water (9 ml). This was extracted with ethyl acetate (3 X 10 ml), washed with brine (1 X 5 ml), dried over sodium sulphate and concentrated. The resulting residue was taken in methanol (10 ml), and added triflic acid (150 μL), heated to 40 °C for 30 min. Reaction mixture was cooled to 30 °C, volatiles were removed under reduced pressure. The resulting residue was taken in aq. saturated sodium bicarbonate (6 ml) extracted with ethy! acetate (3 X 10 ml), washed with brine (5 ml), dried over sodium sulphate, concentrated and purified by silica gei column chromatography (4% methanol in dichloromethane) to furnish (3R.4S,5S,6R)-8- Hydroxymethyl-2-[4-(4-isopropoxy-benzyl)-3:4-dihydro-2H-benzo[1.4]oxaztπ-6-yl]-2- methoxy-tetrahydro-pyran-3A5-triol (950 mg).
1H NMR (400 MHz. CD3OD): δ 1.28 (dd, J = 6.0, 1.6 Hz, 6H), 2 99 (s, 3H), 3.09 (d: J - 9.6 Hz1 1H), 3.37-3.52 (m, 3H), 3.52-3.56 (m, 1H), 3.72 (t, J « 9.2 H2, 1H), 3.78 (dd, J - 12.0, 5.6 Hz, 1H), 3.90 (dd, J = 11.6, 2.0 Hz1 1H), 4.10-4.38 (m, 2H), 4.36 (d, J * 15.2 Hz. 1H). 4.46 (d, J * 15.6 Hz, 1H), 4.52-4.61 (m. 1H). 6.68 (d, J * 8.0 Hz, 1H), 6.82-6.86 (m, 3H), 7.03 (d, J = 1.6 Hz, 1H), 7.24 (d. J = 8.8 Hz, 2H). MS (ES) m/z 476.3 (M+1). Step IV. To a stirred solution of (3R,4S,5S,6R)-6-Hydroxymethyl-2-[4-(4-isopropoxy- benzyO-3,4-dihydro-2H-benzo[1,4)oxaztn-6-yl]-2-methoxy-tetrahydro-pyran-3,4,5-triol (560 mg, 1.15 mmol) in aeetonitrile-dichloromethane (2:1 mixture. 7 ml) was added boron triflυoride diethyletharate complex (0.23 ml, 2.314 mmol) and triethylsilane (0.73 ml, 4.628 mmol) at -20 °C. After stirring for 4 h at 0 °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).
1H NMR (400 MHz, CD3OD):(peaks correspond to major isomer) δ 0.88 (dd, J « 6.0, 1.6 Hz, 6H), 2.85-3.04 (m, 6H), 3.25 (dd, J * 11.6, 2.4 Hz, 1H), 3.44 (d. J= 11.6, 1H)S 3.56 (d; J * 9.2 Hz, 1H), 3.77 (bs, 2H), 3.94-4.19 (m, 3H), 6.24 (d, J ~ 8.0 Hz, 1H), 6.28 (d. J - 8.0 Hz, 1H), 6.44 (d. J « 6.8 Hz, 2H), 6.48 (s, 1H), 6.82 (d, J « 7.2 Hz, 2H). MS (El) m/z 446.3 (M+1).
Example 58 was prepared in an analogoues procedure as described in example 57.
Figure imgf000082_0001
Figure imgf000083_0002
Example 59. {2S,3R,4R,5S<6R)*2-[4»(4.Ethyl-pheny0-3,4-cHhydro-2H- benzot1,4]oxazm-6-ylJ-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
Figure imgf000083_0001
Step I: To a stirred solution of (2R,3S,4R(5R,6S)-2-hydroxymethyl-6-H-(4-methoxy- benzyl)-3l4-dihydro-2H"ben2θ[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 was quenched by the addition of water {5 ml). Organic layer was diluted with dichloromethane (30 mi), washed with 1N HC! (15 mi), water (10 ml), bπne (10 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography (20% ethyl acetate in hexane) to furnish {(2R.3R,4R:5S)-3,4,5- triacetoxy-6-{4-[(4-methoxyphenyl)methyl)-2,3-dihydro-1,4-benzoxa2in-6- yl)tetrahydropyran-2-yl]methyl acetate (617 mg).
!H NMR (400 MHz, CDCIj): (peaks coirespond to major isomer) 6 1.80 (s, 3H), 1.99 (s,
3H), 2.04 (S1 3H), 2.05 (S, 3H), 3.28 (t, J = 4.0 Hz, 2H), 3.80 (S1 3H)1 4.10-4.27 (mt 6H):
4.39 (s; 2H). 5.12 (t J = 9.6 Hz, 1H)( 5.19 (t J - 9.6 Hz. 1H), 5.28 (t, J = 9.6 Hz, 1H),
6.66 (d, J * 8.4 Hz1 1H)1 6.76 (d, J - 8.0 Hz, 1H), 6.79 (s, 1H), 6.87 (d. J - 8.4 Hz, 2H),
7.23 (d, J « 8.4 Hz. 2H). MS (ES) m/z 586.4 (M+1).
Step If: To a stirred solution of ((2R,3R>4R!5S)-314,5-trfacetoxy-6»[4-[(4~ methoxyphenyl)methyl]-2, 3-dihydro- 1 ,4-benzoxazin-6-yl]tetrahydropyran-2-yl]methyl acetate(610 mg, 1.0 mmol) in methanol-dichloromethane (1:1 mixture, 8 ml) was added
10% palladium on charcoal {90 mg). The 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
[(2R.3Rl4R,5S)-3!4(5-triacetoxy-6-(3.4-dihydro-2H-1,4-benzoxazin-6-yl)tetrahydropyran-
2-yljmethyl acetate (430 mg).
MS (ES) m/z 466.3 (M+1).
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-δ-yiHetrahydro-pyran-2-ylmethyl ester (320 mg, 0.7 mmol), in dichloromethane (4 ml) was added copper (II) acetate (250 mgt 1.4 mrnoJ), triethylamine (0.2 ml, 1.4 mmol), molecular sieves (300 mg), 4-ethylphenyl boronic acid
(206 mg, 1.4 mmol). After 8 h, additional amonut of 4-ethylphenyl boronic acid (206 mg) was added in portions. The reaction was stirred for 60 h, filtered through ceiite bed. filtrate was concentrated and purified by preparative HPLC to furnish [(2R,3R,4R.5S)-
3,4,5-triacetoxy-6-[4-(4-ethylphenyl)-2,3-dihydro-1,4-benzoxazfπ-6-ylJtetrahydropyran-2- yljmethy! acetate (110 mg).
1H NMR (400 MHz, CDCI3): (peaks correspond to major isomer) δ 1.25 (t, J - 7.6 Hz,
3H), 1.78 (S1 3H), 1.94 (s, 3H). 1.97 (s, 3H). 2.00 (S. 3H). 2.65 (q, J = 7.6 Hz, 2H), 3.65
(t, J = 4.0 Hz. 2H). 3.85-3.89 <m, 1H)1 4.09-4.305 (m, 5H), 4.95 (t, J = 9.6 Hz, 1H), 502
{t. J - 9.6 Hz, 1H), 5.27 (t, J - 96 Hz, 1H). 6.67 (dd; J * 8.0, 1.6 Hz; 1H), 6.75 (d, J * 8.4
Hz. 1H). 6.78 (d, J - 1.6 Hz, 1H)1 7.14 (d, J ~ 8.4 Hz, 2H), 7.23 (d, J « 8.4 Hz. 2H). MS
(ES) tn/z 570.4 (M-«-1).
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
(120 mg. 0,21 mmol) in methanol (3 ml) was added sodium methoxide (2 mg). The reaction mixture was stirred for 20 h at 20 °C1 concentrated and purified by preparative HPLC to furnish the titled compound. (Yield » 75 mg).
1H NMR <400 MHz, CD3OD): (peaks correspond to major isomer) δ 1.21 (t, J » 7.6 Hz, 3H), 2.60 (q, J - 7.6 Hz, 2H), 3.23-3.36 (m.4H)1 3.59 (dd, J ~ 11.2, 4.0 Hz, 1H), 3.63 (t, J * 4.4 Hz, 2H), 3.80 (d, J * 12.0 Hz. 1H). 3.86 (d, J « 9.2 Hz, 1H), 4.21 (t, J * 3.6 Hz, 2H), 6.76 (S, 2H), 6.84 (s, 1H). 7.14 (d, J = 8.8 Hz, 2H)t 7.17 (d, J = 8.8 Hz. 2H). MS (El) mfz 402.3 (M+1).
Example 60. (2R,3S,4R,5R)-24lydroxyfnethyl-6-{4«[2-<4-methoxy-phenyl)-ethyl|-3,4- dihydro-H-benzot1,4)oxazm-6-yl}-tetrahydro-pyran-3,4,5-triol
Figure imgf000085_0001
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) at 0 °C After 15 rnin, reaction mixture was heated to 70 °C for 15 h. quenched by the addition of water. After usual work up, the compound was purified by silica gel column chromatography (10% ethyl acetate in hexane) to furnish 1-(6-bromo-2,3-dihydro-benzo[1.4]oxazin-4-yl)- 2-(4-methoxy-phenyl)-ethanone (1.8 g).
1H NMR (400 MHz, CDCI3): δ 3.79 (s, 3H), 3.86 (bs, 4H), 4.14 (bs. 2H): 6.76 (ds J * 8.4 Hz, 1H), 6.86 (d. J « 8.8 Hz. 2H)1 7,16 (d, J * 8.4 Hz: 4H). MS (ES) iWz 364.0 (M+2). 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- tetrahydrofuraπ complex solution in THF (8.3 ml, 8.3 mmol) at room temperature. The reaction mixture was reffυxed for 15 h. Reaction was cooled to 25 °C1 quenched by the addition of methanol; volatiles were removed under reduced pressure. The resulting residue was taken in ethyl acetate (30 ml) and washed with aqueous saturated sodium bicarbonate solution (20 ml) , water (20 ml), brine (20 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography (4% ethyl acetate in hexane) to furnish 6-bromo-4-[2-(4-methoxy-phenyl)-ethyl3-3.4~dihydro-2H- benzo[1 ,4]oxazine (624 mg).
1H NMR (400 MHz, CDCI3): δ 2.81 (t. J - 7.2 Hz, 2H), 3.18 (d, J - 4.4 Hz, 2H). 3.43 (d( J * 7.2 Hz. 2H), 3.79 (s. 3H), 4.08 (t, J = 4.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 1H), 6.67 (ύ<i, J = 8.4, 2.0 Hz, 1H), 6.74 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H)1 7.12 (d, J = 8.4 Hz, 2H). MS (ES) m/z 3500 (M+2),
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. Then il was transferred to a stirred solution of 2,3,4,6-tetrakis- 0-(trimethylsilyl)-D-glucopyranone (820 mg, 1.75 mmol) in toluene (9 ml) at -78°C. After the reaction mixture was stirred for 30 min.. quenched by the addition of water (10 ml), extracted with ethyl acetate (3 X 10 ml), washed with water (5 ml), brine (5 mi), dried over sodium sulphate and concentrated. The resulting residue was taken in methanol (8 ml), and added triflic acid (50 μl), heated to 40 °C for 40 min. Reaction mixture was cooled, quenched with aq. saturated sodium bicarbonate (3 mi), extracted with ethyl acetate (3 X 10 ml), washed with brine (5 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography (4% methanol in dichloromethane) to furnish the desired product (245 mg).
The above intermediate (220 mg, 0.48 mmol) was taken in acetonitrile-dichloromethane mixture (2.5:1 mixture. 3.5 ml) and cooled to -20 °C. To it was added boron trifluonde diethyletharate complex (0.09 ml, 0.72 mmol) and tnethylsilane (0.11 ml, 0.95 mmol) and stirred for 45 min at 0 °C. Reaction was quenched with aq. saturated sodium bicarbonate solution (4 ml). The volatiles were evaporated under reduced pressure and the resulting was extracted with ethyl acetate (3 X 10 ml). The ethyl acetate layers were mixed and washed with brine (1 X 5 ml), dried over sodium sulphate, concentrated and purffied by preparative HPLC chromatography to furnish the titled compound (52 mg). 1H NMR (400 MHz, CDCt3): (peaks correspond to major Isomer) δ 1.64 ( br s. 1H). 2.38 (bs, 2H), 2.79 (t, J a 7.2 Hz, 2H), 3.22 (t, J - 4.0 Hz, 2H)1 3.40-3.49 (m, 5H), 3.65 (t. J « 6.0 Hz. 2H). 3.77 (s, 3H). 3.78 (d, J - 11.2 Hz, 1H), 3.90 (d. J * 11.2 Hz, 1H), 4.04 (d, J « 9.2 Hz, 1H), 4.12 (t, J ~ 4.0 Hz, 2H), 6.59 <d, J * 9.6 Hz, 2H), 6.75 (d, J * 8.0 Hz, 1H), 6.83 (d. J * 8.4 Hz, 2H), 7.10 (d, J * 8.4 Hz1 2H). MS (ES) m/z 432.1 (M-H).
Examples 61-62 were prepared in an analøgoues procedure as described in example 60.
Figure imgf000087_0001
Figure imgf000088_0002
Example 63. (2S,3R,4R,5S,6R)-2~[1 -<4-Ethyl~benzyl)-1 ,2,3,4-tetrahydro-qυ lnolin-7- yl]-6-hydroxymethyl-tetrahydro^>yran-3,4,δ-trlof
Of J
BFjEt2O. EUSiH
Figure imgf000088_0001
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). All organic layers were mixed and washed with water (50 ml), brine (50 mi), dried over sodium sulfate, concentrated and purified by silica gel coulmn chromatography to furnish 7-bromo-1-(4-ethyJ-benzyl)-1,2,3,4-tetrahydro-quino{ine (3.0 g). 1H NMR (400 MHz, CDCI3): δ 1.25 (t, J - 7.6 Hz, 3H). 1.98 (m. 2H). 2.66 (q, J « 7.6 Hz; 2H), 2.75 (t, J ~ 6.4 Hz. 2H). 3.34 (t, J * 5.6 Hz, 2H). 4.44 (s. 2H). 6.68 (d, J = 7.2 Hz, 2H), 6.82 (d, J « 8.0 Hz. 1H). 7.17 (s. 4H). MS (ES) m/z 332.0 (M+2) 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. The 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. saturated sodium bicarbonate (20 ml), extracted with ethyl acetate (3 X 50 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography to furnish (3R,4S,5S.6R)- 2-[1-(4-ethyl-benzyl)-1 ,2,3,4-tetrahydro-quinolin-7-yl}-6-hydroxymethy}-2-methoxy- tetrahydro-pyran-3,4,5-triol (2.0 g).
1H NMR (400 MHz, CD2OD): δ 1.21 (t, J « 7.6 Hz, 3H). 1.97-2.02 (m, 2H), 2.62 (q. J ~ 7.6 Hz, 2H), 2,78-2.80 (m: 2H): 2.93 (s: 3H): 3.09 (d, J * 9.6 Hz. 1H). 3.37-3.42 (m, 3H), 3.52-3.56 (m, 1H), 3.71 (t, J = 8.8 Hz, 1H), 3.78 (dd, J = 12.0, 6.0 Hz, 1H), 3.90 (dd, J * 11.6, 1.6 Hz, 1H), 4.41 (d. J - 16.8 Hz, 1H), 4.61 (d, J = 16.4 Hz, 1H), 6.79 (d, J « 7.6 Hz. 1H). 6.81 (s, 1H), 6.92 (d, J - 7.6 Hz. 1H), 7.14 (d, J * 8.0 Hz, 2H), 7.22 (d. J - 8.0 Hz1 2H)
MS (ES) mte 444.1 (M+1).
Step III: To a stirred solution of (3R,4S!5S,6R)-2-t1-(4-ethyl-benzyl)-1,2..3,4-tetrahydro- qutnolin^-yll-δ-hydroxymethyl^-methoxy-tetrahydro-pyran-S^.δ-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. After stirring for 4 h at 0 °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) .
1H NMR (400 MHz, CD3OD): δ 1.22 (t. J « 7.6 Hz, 3H). 1.93-198 (m, 2H). 2.63 (q, J « 7.6 Hz. 2H). 2.76 (t, J * 6.4 Hz. 2H), 3.32-3.41 (m, 6H), 3.63 (dd, J « 11.6, 4.4 Hz, 1H), 3.83 (d, J - 11.6 Hz, 1H), 3.92 (d, J - 9.2 Hz. 1H), 4.43 (d, J - 16.8 Hz, 1H), 4.52 (d, J * 16.4 Hz, 1H), 6.60 (d, J * 7.6 Hz. 1H). 6.66 (s. 1H). 6.90 (d, J - 7.6 Hz, 1H), 7.13 (d, J ~ 8.0 Hz, 2H), 7.19 (d, J * 8.0 Hz, 2H). MS (El) mfz 414.1 (M+1).
Examples 64-71 were prepared in an analogoues procedure as described in example 63.
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Example 72. (2R,3S,4R,5R,6S)-2'.Hydroκymethy{-6-j;i-(4-mβthyl-benzyl)-1 ,2,3,4- tetrahydro-quinolin-7>yl]-tetrahydro-pyran-3,4,5-triof
10% Pd/C DMF, K,C0.<
H-, XT*
Figure imgf000093_0001
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). All organic layers were mixed and washed with water (150 ml), brine (50 ml), dried over sodium sulfate, concentrated and purified by silica gel coulmn chromatography to furnish 7-bromo-1-(4-methoxy-benzyl)~1,2.3,4-tetrahydro-quinoline (6.68 g). 1H NMR (400MHz1 CDCI3): δ 2.00 (t, J- 6.0 Hz, 2H), 2.77 (L J- 6.0 Hz1 2H), 3.35 (t. J- 6.0 Hz, 2H), 3.83 ( s, 3H), 4.43 (s, 2H). 6.81~6.86(m, 2H), 6.90 (d, J * 8.4 Hz. 2H). 7.22 (d, J- 8.4 Hz, 2H), 7.29 (br s, 1H). MS (ES) m/z 334.0 (M+2). 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.: then it was transferred to a stirred solution of 2,3<4:6-tetrakis-O-(trimethylsi!yf)-D- glucopyranone (4.16 g, 8.9 mmol) in toluene (20 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. saturated sodium bicarbonate (20 ml). This mixture was extracted with ethyl acetate (3 X 50 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography (4% methanol in dichloromethane) to furnish (3R.4S15S,6R)-6-hydroxymethyl-2-methoxy~2- [1-(4-methoxy-benzyl)~1 ,2.3,4-tetrahydro-quinolJn-7-yl}-tetrahydro-pytan-3,4t5-triol (4.1 β).
1H NMR (400MHz. CD3OD): 62.00 (t, J= 6.0 Hz1 2H), 2.78 (t, J= 6.0 Hz1 2H), 2.98 ( s,
3H), 3.09 (d, J= 9.2 Hz1 1H), 3.35-3.42 (m, 4H)1 3.53-3.58 (m: 1H), 3.70-3.78 (m, 5H), 3.92{dd, J= 11.6. 2.0 Hz, 1H), 4.38 {d, J= 16.0 Hz, 1H), 4.56 (d, J= 16.0 Hz, 1H), 6.79 (d, J= 7.6 Hz. 1H). 6.85 (br s, 1H)1 6.86 (d. J= 8.4 Hz, 2H)1 6.91 (d. J= 7.6 Hz1 1H)1 7.24 (d. J- 8.4 Hz, 1H). MS(ES) m/z 414 (M+1)
Step III. To a stirred solution of (3R,4S,5S,6R)-6-Hydroxymethyl-2-methoxy-2-|;i-(4- methoxy-benzyO-I^.S^-tetrahydro-quinolin^-ylJ-tetrahydro-pyran-S^.S-triol (4.1 g, 9.2 mmol) in acetonitrile-dichtoromethane mixture (1:1 mixture, 40 ml) was added boron tήfluoride diethyletharate complex (2.33 ml. 18.4 mmol) and triethylsilane (5.86 ml, 36.8 mmol) at -10 °C and stirred for 4 h at 0 °C. Reaction was quenched with aq. saturated sodium bicarbonate solution (20 ml). The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with ethyl acetate (3 X 30 ml). The ethyl acetate layers were mixed, washed with brine (5 ml), dried over sodium sulphate, concentrated and purified by preparative HPLC to furnish (2R,3S.4R15R,6S)-2- Hydroxymethyl-6~[1 -{4-methoxy- benzyl)- 112,3,4-tetrahydro-quinolin-7-yl]-tetrahydro- pyran-3A5-triol (1.04 g).
1H NMR (400MHz1 CD3OD): δ 1.96 (t, J= 6.0 Hz, 2H), 2.77 (t. J= 6.0 Hz, 2H), 3.31- 3.3.37 (m, SH), 3.42 (br d( J= 8.8 Hz1 1H), 3.64 (d, J= 12.4 Hz, 1H)1 3.67 (d. J= 5.0 Hz1 1H)1 3.79 ( s, 3H), 3.85 (d. J= 12.0 Hz1 1H), 3.94 (d. J= 9.2 Hz1 1H)1 4.40 (d. J= 16.4 Hz, 1H), 4.50 (d, J= 16.4 Hz1 1H)1 6.62 (d, J= 7.6 Hz1 1H)1 6.70 (br s, 1H), 6.87 (d, J= 8.4 Hz1 1H). 6.91 (d, J- 76 Hz, 1H), 7.22 (d, J= 8.4 Hz. 2H). MS(ES) m/z 416.2 (M+1). Step IV: To a stirred solution of (2Rl3S,4Rl5R,6S)-2-hydroxymethyl~6-[1-(4~methoxy- benzyl)-1)2,3N4-tetrahydro«quinofin-7-yl}-tetrahydro-pyran-3l4:5-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. The resulting residue was titurated in n-hexanes and dried under vacuum to furnish (2R.3S.4R.5R,6S)-2- Hydroxymethyl-6 (1 <213:4-tetrahydro-quinolin-7-yl)~tetrahydro-pyran-3,4,54riol (710 mg). 'H NMR (400MHZ1 CD3OD): δ 1.89 (t, J= 6.0 Hz, 2H), 2.73 (t, J- 6 0 Hz, 2H), 3,24 (t, J= 6.0 Hz, 2H), 3.35-3.45 (m, 4H), 362 (d, J= 12.0. 5.2 Hz, 1H). 3.86 (d, J- 11.2 Hz, 1H). 3.96 (d, J= 9.2 Hz. 1H), 6.59 <br s, 1H), 6.62 (d. J= 7.6 Hz1 1H), 6.87 (d, J= 7.6 Hz, 1H). MS(ES) m/z 296.3 (M+1).
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 μl, 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).
1H NMR (400MHz1 CD3OD). δ 1.96 (t, J= β.O Hz, 2H), 2.31 ( s, 3H), 276 <t, J= 6.0 Hz, 2H). 3.22-3.41 (m, 6H), 364 (dd, J- 12.4, 5.2 Hz, 1H), 3.84 (d, J= 12.0 Hz, 1H), 3.92(d, J= 9.6 Hz, 1H), 4.42. (d, J= 16.4 Hz, 1H), 4.52 (d. J= 16.4 Hz, 1H)1 6.60 (d. J= 7.2 Hz, 1H)t 6.66 (br s, 1H). 6.90 (d, J= 8.0 Hz, 1H). 7.11 (d. J= 7.6 Hz, 2H), 7.17 (d. J= 8.0 Hz, 2H). MS(ES) m/z 400.4 (M+1)
Examples 73-91 were prepared in an analogoues procedure as described in example 72.
Figure imgf000095_0001
Figure imgf000096_0001
i
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Example 92. (2R,3S,4R,5R,6S)-2-Hydroxymethyf -6-[1 »(4-isopropyl-benzyf )-2,3- dihydro-1H-indol-5-yl]-tetrahydro-pyran-3,4,5-triol OTMS SOjH in MsOH
Figure imgf000103_0001
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). All organic layers were mixed and washed with water (20 ml), brine (20 ml), dried over sodium sulfate, concentrated and purified by silica gel coulmn chromatography to furnish 5-bτomo-1-(4-isopropyl-ben2yl)-2,3-dihydro-1H-Jndole (750 mg). 1H NMR (400MHE1 CDCI3): δ 1.27 (d, <i* 8.0 Hz, mi 2.91-2.99 (m. 3H). 3.47 (t, J= 8.0 Hz. 2H), 4.28 (s, 2H), 7.25-7.33 (m, 7H). MS(HS) mfe 330,2 (M+2). Step Ii: To a stirred solution of 5-bromθ"1-(4-tsopropyJ-benzyi)-2,3-dihydro-1H-indoie (740 mg, 2.24 mmol) in THF-tøluene (1:2 mixture, 15 ml) was added 1.6 M n-Buϋ 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!3,4.6~tetrakis-O-(trimethylsi!yi)-D- giucopyranone (1.05 g, 2.24 mmol) in toluene (10 ml) at -78 '^C. After stirring it for 40 mm., 06 N methanesulfonic aαd in methanol (10 ml) was added and stirred for 20 h at room temperature. Reaction was quenched by the addition of aq. saturated sodium bicarbonate (5 ml). Usual work up and purification by silica gel column chromatography resulted in (3R.4S(5S,6R)-6-hydroxymethyl-2-[1-(4-isopropyl-benϊr.yl)~2,3-dihydro-1 H- indol-5-ylJ-2-methoxy-te{rahydro-pyran-3,4s5-tnol (SOO mg)
To a stirred solution of (aR^S.SS.δRV-e-hydroxymethyl-a-ii- ^isopropyi-benzyO-a^- d!hydro-1H-(ndo!-5-yl}-2"methoxy-tetrahydro-pyran-3<4,54rsoi (500 mg, 1.12 mmoi) in acetonitrile-dichloromethane (1:1 mixture, 10 ml) was added boron trifluoride diethyletharate complex (0.28 ml, 2.25 mmol) and triethylsilane (0.72 ml. 4.50 mmol) at -
10 °C and stirred for 4 h at 0 °C. Reaction was quenched with aq. saturated sodium bicarbonate solution (5 mi), extracted with ethyl acetate (3 X 10 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 (45 mg).
1H NMR (400 MHz. CD3OD): δ 1.24 (t, J « 6.8 Hz, 6H)1 2.87-2.94 (m, 3H), 3 26 (t. J - 8.4
Hz1 2H), 3.38-3.44 (m, 4H). 3.68 (dd, J * 11.2, 5.2. 1H), 3.87 (d, J « 11.2 Hz, 1H), 4.02
(d, J = 9.2 Hz, 1H). 4.22 (S1 2H), 6.54 (d, J = 8.0 Hz. 1H)t 7.07 (d, J = ao Hz1 1H), 7.14
(s, 1H), 7.19 (d. J - 7.6 Hz, 2H), 7.26 (d, J ~ 8.0 Hz, 2H).
MS (El) m/z 414.4 (M+1).
Examples 93-95 were prepared in an anaiogoues procedure as described in example
92.
Figure imgf000104_0001
Figure imgf000105_0001
Example 97: (2S,3R,4R,5S,6R)-2-[1-(4<Ethyl-benzy!)-2,3«c«hydro.1H.«ndol-6.yll.6' hydroxymethyl-tetrahydro-pyran-3,4,5-trioi
Figure imgf000106_0001
2 MeSO8H
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. CDCI3): δ 1.21 (t, J « 7.2 Hz, 3H), 2.62 (q, J « 7.2 Hz, 2H): 5.24 (s, 2H), 6.50-7.50 (m. 9H). MS (ES) m/z 315.9 (M+2)
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 boraπe-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). Combined organic layer was washed with water (15 ml), brine (15 ml), dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-bromo-1-(4-ethyl-benzyl)~2,3-dihydfo-1H-indoie (780 mg). MS (ES) m/z 318.0 (M+2)
Step III: To a stirred solution of 6-bromo-1-(4-ethyl-benzyl)-2,3-dihydrø-1H-indole (700 mg. 2.21 mmol) m THF-toluene (9 ml of 1:2 mixture) was added 1.6 M solution of n-Buϋ 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. After stirring for 40 min., 0.6 N methanesυlfonic acid in methanol (10 ml) was added and stirred for 20 h at room temperature. Reaction was quenched fay the addition of aq. saturated sodium bicarbonate solution (5 ml) and extracted with ethyl acetate (3 X 10 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish (SR^S^S.eRj^-JI^-ethyl-benzyO-a.a-dihydro-1H-indol-β-ylJ-β-hydrøxymethyl^- methoxy-tetrahydro-ρyran-3,4,5-triol (765 mg).
1H NMR (400 MHz, CD3OD): δ 1.11(t, J = 7.2 Hz, 3H). 2.52 (q, J = 7.2 Hz, 2H)1 2.78 (t, J « 8.0 Hz, 2H), 3.04 (s, 3H), 3.05-3.06 (m, 1H)1 3.11 (t. J = 7.6 Hz, 2H)1 3.31 (t, J = 9.2 Hz. 1H). 3.45-3.46 (m, 1H), 3.64 (t, J = 8.8 Hz, 1H), 3.70 (Ud, J ~ 12.0. 5.6 Hz, 1H), 3.82 (d, J - 12.0 Hz. 1H), 4.14 (s, 2H), 6.79-6.82 (m, 2H), 6.93 (d, J = 7.6 Hz, 1H), 7.06 <d, J = 8.0 Hz. 2H), 7.18 (d, J « 8.0 Hz, 2H). MS (ES) m/z 430.0 (M+1). Step IV: To a stirred solution of (3R,4S!5S,6R)-2-[1-(4-ethyl-benzyi)-2,3-dihydro-1H- indol-6-yl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (49O g. 0.931 mmol) in acetonitrite-dichloromethane mixture (1:1 mixture, 8 ml) was added boron trifluoride diethyletharate complex (0.24 ml. 1.86 mmol), and triethytsilane (0.59 ml, 3.72 mot) at -5 "C. After stirring for 4 h at 0 °C, reaction was quenched with aq. saturated sodium bicarbonate solution (4 ml). The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with ethyl acetate (3 X 8 ml). The organic layer was washed with brine (3 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish (2S!3R.4R,5S,6R)-2-{1-<4-ethyl-benzyl)-2>3-dihydro-1H- indol-6-yl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (60 mg). 1H NMR (400 MHz, CD3OD): 6 1.22 (t, J - 7.6 Hz, 3H), 2.63 (q, J * 7.6 Hz. 2H). 2.90 (t J - 8.0 Hz, 2H). 3.23 (t, J « 8.0, Hz, 2H)1 3.34-3.48 (m, 4H). 3.69 (dd. J * 12.0, 5.2 Hz, 1H)1 3.86 (dd. J - 12.0. 2.0 Hz, 1H), 4.04 (d, J « 9.2 Hz1 1H), 4.22 (s, 2H)1 6.70-6.72 (m. 2H). 7.02 (d, J - 8.0 Hz1 1H), 7.16 (d, J * 8.0 Hz, 2H), 7.27 (d. J « 8.0 Hz, 2H). MS (ES) m/z 400.2 (M+1).
Following example was prepared using the procedures described above.
Figure imgf000108_0002
Example 99: (2S,3R,4R,5S,6R)-2-[1 -(4»Methoxy4>enzyl)-2,3«d»hydro»1 H«indol-6«yl]- 6-hydroxymethyJ-tetrahydro-pyran«3,4,δ-fiol.
Figure imgf000108_0001
Step I: To a stirred solution of 6-bromoxindole (5.0 g, 23.6 mmol) in THF (25 ml) was added 1.0 M boraπe-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. The resulting residue was taken \n ethyl acetate (70 mi) and washed with aqueous sodium bicarbonate solution (50 mi) followed by water (50 ml) brine (50 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-bromo- indoline. (3.72 g). 1H NMR (400 MHz, CDCI3): δ 2.96 (t, J * 8.4 Hz1 2H): 3.57 (t J * 8.4 Hz, 2H), 3.80 (bs, 1H). 6.74 (s, 1H). 6.78-6.95 (m, 2H). MS (El) m/z 200.1 (M+2). 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 αC 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). The organic layer was washed with water (50 ml), brine (50 ml), dried over sodium sulfate, concentrated and purified by silica gel couimn chromatoghraphy to furnish 6-bromo-1-(4-mehoxy-benzyf)-2,3-dihydro-1H-indole (2.71 g). 1H NMR (400 MHz. CDCI3): δ 2.89 (t, J - 8.4 Hz1 2H), 3.31 (t, J - 8.0 Hz, 2H)t 3.81 (S. 3H), 4.16 (s, 2H), 6.61 (s, 1H), 6.74 (d, J = 7.6 Hx, 1H), 6.86-7.25 (m. 5H). MS (El) m/z 320.1 (M+2).
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-Buϋ 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. After stirring the reaction 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. saturated sodium bicarbonate solution (15 ml) and was extracted with ethyl acetate (3 X 20 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish (SR^S.SS.eR^e-hydroxymethyl-a-methoxy^-fi^-methoxy-benzyO^^dihydro-1H- indol-6-ylHetrahydro-pyran-3,4,5-triol (1.0 g). MS (El) m/z 432.2 (M+1). Step (V : To a stirred solution of (3R.4S,5S,6R)-6-hydroxymethyl-2-methoxy-2-|1-(4- methoxy-benzylJ^^-dihydro-1H-indol-e-ylJ-tetrahydro-pyran-S^.S-triol (550 mg, 1.27 mmoi) in acetonitrile-dichloromethane (1:1 mixture, 10 ml) was added boron trifluoride diethyletharate complex (0.33 ml, 2.55 mmol) and triethylsilane (0.81 ml, 5.09 mmol) at - 10 °C and stirred for 4 h at 0 °C. Reaction was quenched wrth aq. saturated sodium bicarbonate solution (5 ml), extracted with ethyl acetate (3 X 10 ml). The organic layer was washed with brine (5 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish (2R,3S,4R,5R,6S)-24iydroxymethyl^-l1-(4-methoxy~ benzy!)-2,3-dihydro-1 H-indol-6~ylKetrahydro-ρyran-3A5~triol (70 mg). 1H NMR (400 MHz, CD3OD): δ 2.84 (t. J * 8.0 Hz, 2H), 3.17 (t. J = 8 Hz, 2H)1 3.28-3.42 (m, 4H)1 3.54 (dd, J * 12.O1 5.2 Hz. 1H), 3.76 (s, 3H), 3.86 (d. J - 11.2 Hz. 1H)1 4.02 (d, J = 9.2 Hz, 1H)1 4.17 (s, 2H), 6.68-6.69 (m. 2H),6.83 (d, J « 8.8 Hz. 2H). 6.99 (d. J * 7.6 Hz. 1H), 7.26 (d, J * 8.8 Hz, 2H) MS (Ei) mfr 402.1 (M+1).
Example 100: (2S,3R,4R,5S,6R)-2-[1-(4-Ethoxy«ben2yl)«2,3-dihydro-1H-lndol.$.yl]-6- hydroxymethyl-tetrahydro-pyraπ-3,4,5-triof.
Figure imgf000110_0001
Step I : To a stirred solution of (2R,3Sl4R,5R.6S)-2-hydroxymethyl-6-[1-(4-methoxy- benzyO^.S-dihydro-1H-indol-β-ylJ-tetrahydro-pyran-S^.δ-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. Reaction mixture was filtered through celite bed, solvent was evaporated under reduced pressure to get (2S,3R.4R,5S.6R)-2-(2.3-dihydro-1 H-indol-6-yl)-6-hydroxymethyl4etrahydro- pyran-3A5-triol (30 mg). MS (El) mfz 282.0 (M+1).
Step H: To a stirred sofution of (2S.3R.4R15S.6R)-2-(213-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). The organic layer was washed with brine (5 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish (2S,3R,4Rl5S>6R)-2-|1-(4» ethoxy-beπzyl)-2,3-dihydro-1H-}ndol-6-yf)-6-hydroxymethyl-tetrahydro-pyran-3.4,5-triol
(10 mg).
1H NMR (400 MHz, CD;,OD): δ 1.35 (t, J * 6.8 Hz, 3H)1 2.84 (t, J * 8.0 Hz, 2H), 3.1? (t, J
* 8 Hz, 2H), 3.28-3.42 (m, 4H), 3.67 (dd, J * 12.0, 5.6 Hz, 1H), 3.85 (dd. J - 12.0, 2.0
Hz, 1H), 3.97-4.02 (s, 3H), 4.17 <s, 2H), 6.67-6.69 (m, 2H),6.84 {d, J * 8.8 Hz. 2H). 6.99
<d, J « 7.6 Hz. 1H). 7.24 (d, J * 8.8 Hz1 2H).
MS (El) m/z 416.1 (M+1).
Example 101. (2S,3R,4R,δS,6R)-2-l4-benzyl-chroman-6-yl3-6-hydroxymethyf- tetrahydro»pyran-3,4,5-triol
TMSOTf EtSiH
OBn
Figure imgf000111_0001
Step I: To a st»rred solution of 6-bromo-chrorna-4-one (5.0 g, 22.03 mmof) in benzene
(110 ml) was added ethylene glycol (2.73 g, 44.05 mmol), triethylorthoformate (6.52 g,
44.05 mmol). para-tolυenesυlfonic acid monohydrate (83 mg, 4,41 mmol) and azeotrope for 2h at 80°C, quenched with saturated NaHCO3 (50 ml). After usual work up. compound was purified by silica ge! column chromatography to furnish 6'- bromospiroti.S-dioxolane-Z^'-chromane] (4.83 g).
1H NMR (400 MHz. DMSO D6): δ 2.07 (t. J = 5.5 Hz, 2H)( 4.04-4.08 (m, 2H)1 4.16-4.20
(m, 2H); 4.26 (t, J = 5.5 Hz, 2H), 6.79 (d, J * 8.6 Hz, 1H)5 7.40 (dd. J * 8.6 Hz, 2.4 Hz:
1H), 7.48 (d, J = 2.4 Hz. 1H).
Step II: To a stirred solution of 8.2 (2.0 g; 7.38 mmol) in THF (8 ml) at -788C was added rvButyl lithium (470 mg, 7.38 mmol) and stirred for 1h. Mean while tetra-O-Benzyl- glυcaraπolactone (3.97 g, 738 mmol) in THF (6 ml) was cooled to -78 3C and Ithiυm salt prepared above was added to this at -78 *C. This reaction mixture was stirred for 1 h, quenched with saturated NH4CI (10 ml). After usual work up, compound was purified by silica gel column chromatography to furnish sugar derivaive (3.41 g). To a stirred solution of above intermediate (1.0 g. 1.37 mmol) in DCM (15 ml) at -78 °C was added triethylsilane (175 mg, 1.51 mmol) followed by trimethylsilyl trifluoromethaπesulfonate (335 mg, 1.51 mmol) and stirred for 1h, quenched with saturated NaHCO3 (20 ml). After usual work up. compound was purified by silica gel column chromatography to furnish the e-^S.SS^R.SR.βR^SAδ Tris-benzyloxy-β- benzyloxymethyl-tetrahydro-pyran-2-yl)-chroman-4-one (Yield = 0.45 g). 1H NMR (400 MHz. DMSO-D6): δ 2.83 (t, J = 6.2 Hz. 2H). 3.46 (t, J = 9.3 Hz. 1H): 3.63- 3.68 (m. 4H); 3.79 (t. J ~ 8 2 Hz1 1H), 3.89 (d, J * 11.0 Hz, 1H); 4.35 (d. J * 9.5 Hz1 1H); 4.43 (d. J = 11.0 Hz, 1H); 4.49-4.61 (m, 5 H); 4.78 (d, J « 10 8 Hz, 1H). 4.84 (s. 2H); 6.89-6.91 (m, 2H); 7.05 (d, J « 8.6 Hz1 1H); 7.19-7.23 (m, 5H); 7.29-7.36 (m, 13H); 7.60 iύd, J * 8.6 Hz. 1.5 Hz. 1H). 7.79 (d, J = 1.5 Hz, 1H). MS (ES) mfz 688.5 (M-M 8). Step Mf. To a stirred suspention of magnesium (53 mg, 2.24 mmol) in THF (2.4 ml) was added one small crystal of iodine. 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$~ Denzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-chroman-4-αne (300 mg. 0.45 mmol) was dissolved in THF (2 ml) and it was added to above prepared Grignard reagent stirred for 3h. quenched with saturated NH4CI (20 ml). Crude compound (4- Benzyl-6-((2S.3S,4R,5R,6R)-3.4.5-tιis-ben2yloxy-6-benzyloxymethyl-tetrahydro-pyfan-2- yl)-chroman-4-ol. ~520 mg) obtained after usual work up was taken for next reaction Step IV: To a stirred solution of crude 4-benzyl-6-{{2S,3S<4R,5R.6R)-3.4,5-trj$- benzyioxy-6-benzyloxymethyf-tetrahydro-pyran-2-yl)-chroman-4-ol (400 mg. 0.52 mmol) in 1,4-dioxane (5 ml) was added palladium on C 10 % w/w (80 mg, 20 % w/w) followed by methanol (5 ml) and one drop of cone. HCI was added. After stirring the reaction mixture for 18 h under hydrogen atmosphere (balloon pressure), filtered through celite and concentrated. The crude product was purified by preparative HPLC to furnish title compound (41 mg).
1H NMR (400 MHz, DMSO-O6). (peaks correspond to major isomer) 6 1.52-1.61 (m, 1H), 1.65-1.75 (m, 1H); 2.65 (t. J « 12.8 Hz, 1H), 2.88-3.11 (m. 1H). 3,21-3.48 (m, 6H); 3.69 (d. J * 12.0 Hz. 1H); 3.93 (t, J - 9.0 Hz1 1H); 4.10-4 18 (m, 2H}, 4.22 (bs, 1H); 4.71 (bs, 1H); 4.93 <bs, 2H); 6.68 (d, J - 8.1 Hz, 1H); 7.05 (d, J ~ 7.8 Hz: 1H): 7.23 {s: 1H); 7.31
<bs, 5H) . MS (ES) m/z 404.4 (M+18)
Examples 102-107 were prepared in an analogoues procedure as described in example
101.
Figure imgf000113_0001
Figure imgf000114_0001
M2
Figure imgf000115_0002
Example 108. {2S,3R,4R,SS,6R)-2-t3-f(4-ethylphenyl)methylJchroman-6-yl3-6- (hydroxymethyl)tetrahydropyran-3,4,5-triol
Figure imgf000115_0001
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). 1H NMR (400 MHz, C0?OD) • (peaks correspond to major isomer) δ 1.20 (t. J - 7.28 Hz1 3H); 2.18-2.28 (m, 1H); 2.53-2.80 (n% 5H). 3.12-3.29 (m, 4H); 3.41-3.48 (m. 2H). 367- 3.81 (m, 2H); 3.90 (d. J - 9.3 Hz, 1H); 4.12 (d, J « 10.4 Hz.. 1H); 4.27-4.47 (m. 1H): 4.70 (d, J « 5,5 Hz. 1H); 4 92 (d. J = 44 Hz, 2H), 6.69 (d. J ~ 8.2 Hz, 1H). 7.00-7 04 (m. 2H); 7.17 (bs, 4H). MS (E!) m/z 432.4 (M+18)
Figure imgf000116_0001
1H NMR (400 MHz, CD3OD) : (peaks correspond to major isomer) δ 2.33 (s. 3H); 2.70- 2.75 (m. 1H); 2.81-2.97 <m, 1H), 3.15-3.18 (m, 1H); 3.43-3.50 (m, 4H), 3.72-3.75 (d, J - 11.9 Hz1 1H): 3.91 (d, J = 11.7 Hz, 1H); 4.16-4.21 (m, 2H); 4.36-4.40 (m, 1H); 7.00 (d, J ~ 8.6 Hz, 1H); 7.15 (bs, 4H); 7.63 (d, J * 8.4 Hz, 1H); 7.94 (s, 1H). MS (ES) m/z432.4 (M+18)
Following examples were prepared using an analogous procedure as described in example 1.
Figure imgf000116_0002
Figure imgf000117_0002
Following example was prepared using an analogous procedure as described in example 59.
Figure imgf000117_0001
Following examples were prepared in an analogous procedure as described in example 101.
Figure imgf000117_0003
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
The below list of examples, but not limited to these, can also be synthesized following the general synthesis described hertn above:
(2R,3S.4R.5R,6S)-2-Hydroxymethyl-6-[4-{4-methyl-3l4-dihydro-2H-berizo[1,43oxazin-7- ylmethyl)-3:4-dJhydro-2H-benzot1.4]oxa?in-6-yl]-tetrahydro-pyran'3,4.5 triol.
(2R)3S>4R!5R,6S)-2-Hydroxymethyl-6-[4-(4-methyl-3.4-dihydro-2H-benzo[1.4]oxazin-6- ylmethyl)-3,4-dihydro-2H-benzoπ<4]oxaztn-6-yl)-tetrahydro-pyran-3,4!5-trioi.
(2S«3R.4R,5S.6R)-2-H-(2<3-Dihydro-benzofυran-6-ylmethyl)-3(4-dihydro-2H- benzo[1,4}oxazin-6-yl]-6-hydroxymethyl-tetr3hydfO~pyran-3t4,5-trtol.
(2S<3R,4R,5S,6R)-2-[4-(2,3-Dihydro-benzofυran-5-ylmethyl)-3>4-dihydro-2H- benzo{1,4}oxazin-δ-yl]-6-hydroxymethyl-tetrahydro-pyran -3,4,5-triol.
(2S;3R!4R,5St6R)-2-[4-(1-Ethyt-2.3-dihydro-1H-indol-5-ylmethyl)-3.4-dthydro-2H- benzo[1,4]oxazin-6-yl3"6 hydroxymethyl-tetrahydro-pyran-3!4,5-trioK
{2S!3R,4R,5S,6R)-2-(4-Chroman-7-yl>3,4-dihydro-2H-ben2o(1,43oxazin-6-yl)-6- hydroxymethyl-tetrahydro-pyran-S^.S-triol.
{2Sl3R.4Rl5S.6R)~2-[4-(4-Dimethylamino-benzyl)«3(4-dihydro-2H-benzo{1 l4}oxazfn-6~yl] δ-hydroxymethyl-tetrahydro-pyran-S^.δ-triol.
(2R>3S.4R15R<6S)-2-Hydroxymethyl-6'{4"[4»(tetrahydro-furan-3-yloxy)-benzyl)-3,4- dihydfO-2H-benzo[1!4]oxazin-6-yf)-tetrahydro-pyian-3,4,5-triol. (2S<3R,4R,5S!6R)-2-H-(4-Ethyl-ben2yl)-7-hydroxymethyl-3(4-dihydro-2H- benzoli^Joxazin-β-ylJ-β-hydroxymethyl-tetrahydtO-pyran-a^^-triot.
(aS.SR^R.SS.eRJ^-HKδ-Ethyl-pyridtπ^-yimethyO-a^-clihydfO-aH-benzoii^joxazin-e- yl]-6-hydroxymethyl-tetrahydro-pyran-3.4,5-triol.
(2S!3Rl4R<5S,6R)-2-[4-{3-Ethyl-benzyl)-3)4-<lihydro-2H.benzo[1.4}oxa2in-8-yi]-6- hydroxymethyMetrahydro-pyran-3,4,5-triol.
(aS^R^R^S.δRJ^-K-O-Ethyl-benzyD-S^-dihydro^H-benzofi^joxaztn-y-yil-β- hydroxymethyl-tetrahydro-pyran-3,4,5-trio).
(2S,3R.4R!5S>6R)-2-[1-(4-Ethyl-benzyl)-2.3-dihydfo-1H'indof-6»y!]-6'hydroxymethy(- tetrahydro-pyran-3,4,5-triol.
(^R.SS^R.δR.βSJ^-Hydroxymethyl-β^i-CS-methoxy-benzyfJ^.S-dihydro-1H-indol-δ-yl]- tetrahydro-pyran-3,4,5-triol.
(2S,3Rt4R,5S,6R)-2-[1-{3-Ethyl-5-methoxy-benzyl)-2t3-dJhydro-1H-fndot-6-yl]-6- hydroxymethyl-tetrahydro-pyran-3,4,S-triol.
(2S,3R,4R.5S!6R)-2-[2-(3-Ethyl-benzy})-2,3-dihydro-1H-isoir)dol-5-yl]-6-hydroxymethyl~ tetrahydro-pyraπ-3,4,5-triol .
(2S>3R.4R,5S.6R)-2-[2-{3-Ethyl-phenyl)-6-hydroxymethy!-2,3-dihydro-1H-isoindol-5-yll-6- hydroxymethyl-tetrahydro-ρyran-3,4,5-tήol.
{2S,3R>4R<5S)6R)-2-[1-{3l4-Dimethyl-benzyi)-2,3-dihydro-1H-indoi-5-yl]-β- hydroxymethyt-tetrahydrO'pyran-SΛ^triol.
(2S.3R,4R,5S,6R)-2-π -(3.5-Diethyl-benzyl)-2.3-dihydro -1 H-«ndol-5-y!] -6- hydroxymethyf- tetrahydro-pyran- 3 :4,5-triol .
(2S.3Rl4R,5Sl6R)-2-π-(3-Ethyf-5-methoxy-benzyl}-2(3-dihydro-1H-tndol-5-yl}-6- hydroxymethyl-tetrahydro-pyraπ-3.4,5-trioI.
(2S.3R,4R.5St6R)-2-[1-{3-Ethyl-4-flυoro-beπzy!)-2,3-dihydro-1H4ndol-δ-yl3-6- hydroxymethyl-tetrahydro-pyran-3,4,5-trio).
(2S.3R,4R;5S.6R)-2-(1 -(3-Ethoxy-benzyf)-2,3-dthydro- 1 H-mdol-5-yl]-θ-hydroxymethyl- tetrahydro-pyran-S^.δ-triol.
{2R!3S.4R,5R.6S)'2'Hydfoxymethyl-6-n-(2-methyl-2t3-dihydro-1H-isofndoi-S-y}methyt)-
2.3-dihydfo-1 H-»ndol-5-ylJ-tettahydro-pyran-3,4 ,5-triol.
(2S<3R!4R,5S,6R)-2-[1-(5-Ethyl-ihiophen-2-y1metbyi)-2.3-dihydro-1H-Jndol-5-yl|-6- hydroxyfmethyl-tetrahydro-pyran-3,4,5-triol.
(2R,3Sl4R>5R!6S)-2-Hydroxymethyl-6-f1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxa2:fn-6- y{methyl)-2,3-dihydro~1H-indol-5-yl]-tetrahydro-pyran-3,4)5-triol. i^β-IS^taS.SR^R.δS.eRj-S^.δ-Trihydroxy-e-hydroxymethyWetrahydro-pyran-a-yD-a.S- dihydro-indoM-yimethyf}-2,3-dihydro-benzo[1,4]oxazin-4-yf}-ethanone.
{2S>3R,4R>5S(6R)-2-[1-(3-Ethy»-phenyl)»2)3-dihydro-1H-indol-5-yl]-e-hydroxymethyl- tetrahydro-pyran-3,4,5-triol.
(2S,3R>4R!5Sl6R)-2-[1-{4-Ethyl-benzyl)-2,3-dihydro-1H-ifκlol-6-yll-6-hydrøxymethy!- tetrahydro-pyran-3,4,5-triol.
(^S.SRΛR.SS.eRJ^-π-CS-Chloro-^fluoro-benzyO^.S-dihydro-1H-indoi-S-yll-ø- hydroxymethyMetrahydro-pyran-3,4,5~triol.
<2R,3S,4R,5R.6S)-2-Hydroxymethyl-6-[1 -{5-methyl-pyridin-2-ylmethyl)-2,3-dihydro- 1 H- indof~5~yiBetrahydrα~pyran~3(4.5-triol (2S.3R,4R,5S,6R)-2-{1-CycfohexyJmethyl-2,3- dihydro-1H-indol-S-yO-δ-hydroxymethyMetrahydro-pyran-S^.δ-tno!.
(2S.3R,4R,5S>6R)-2-[1 l4-Bis-(4-ethyl-ben2yO-1,2,3>4-tetrahydro-qυinoxalin-6-yl}-6- hydroxymethyt-tetrahydro-pyran-S^.δ-triol.
(2S.3Rl4R(5S,6R)-2-{1-(3-Ethyf-benzyi)-2.3!4.5-tβtrahydro-1H-benzo[b]azepin-7-yl]-6- hydroxymethyl~tetrahydro-pyran-3.4,5-trioI.
{2S.3R,4R>5S16R)-2-[9-(3-Ethyl-befuyl)-6t7,8!9-tetrahydro~5»oxa-9-aza- benzocyclohepten-S-ylj-β-hydfOxymβthyMetrahydro-pyran-S^.S-trioi.
{2S!3R<4R,5S,6R)-2-[9-(4-Ethyl-pheπyf)-6,7t8>9-tetrahydro-5Oxa-9-aza- benzocyclohepten-S-ylj-β-hydroxymethyl-tetrahydro-pyran-S^^-triol.
{2St3R.4R!5S.6R)-2-(1-Benzo(b3thiophen-2-ylmethyl-2.3-dihydro-1H-indol-5-yt)-6- hydroxymethyl-tetrahydro-pyran-3,4.5-tnol
{2R>3S.4R,5R,6S)-2-Hydroxymethy)-6-[4-(3-methoxy-phenyi)-chroman-?-yl]-tetrahydro- pyran-3.4,5-triol.
(2S(3R!4R.5S!6R)-2-[4~(4-Ethyl-ben2y{)-chroman-7-yf]-6 hydroxymethy{-tetrahydrθ" pyran-S^.S-triol.
{2S>3R,4R.5S,6R)-2-H-(4-Ethyl-phenoxy)~chroman-7-yl]-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol.
{2S,3R,4R>5S<6R)-243-(3-Ethyl-benzyi)-chroman-?-yl}-6-hydroxymethyl-tetrahydro- pyratv3t4.5-triot.
(2S,3R.4R!5S,6R)'2~[2-(3-Ethyl-phenyt)-cbroman-6-y}]-6-hydroxymβthyJ-tetrahydro« pyran-3,4,5-trioi.
(2S,3R14R,5S>6R)-2-[4-(3-Ethoxy-phenyl)-chroman-6-yi]-6-hydroxymethyl4etrahydro- pyran-3,4,5-triol. (aS^R^R.δS.eRJ-a-H-C^Ethoxy-phenylJ-chromaπ-e-yil-β-hydroxymethyl-tetrabycIro- ρyran-3,4.5-trioi.
(2St3R,4R.5S,6R)-2-{4-<5-Ethyl-furan-2-ylmethyJ)~chroman-6-ylJ-6-hydroxymethyl- tetrahydro-pyran-3,4..5-triol.
(aR.SS^R^R.eSJ-a'Hydroxymethyl-e^Φta-CS methoxyψhenylJ^thylJ-chronian-e-yl}- tetfahydro-pyran-3,4,5-triol.
(2S,3Rt4R.5S,6R)-2-H-(3-Ethoxy-5-ethyl-phenyl)-chroman-6-yf]-6-hydfoxymethyl- tetrahydro-pyran-3,4,5-triol.
(2S)3R,4R>SS,6R)-2-[8-(3-ethyl-phenyl)-5>6J,θ-tetrahydro-naphthalen-2-yl}-6- hydroxymethyf-tetrahydro-pyran-3,4,5-triol.
(2S!3R,4R>5S,6R)-2-[3~(3-Ethyl-benzyl)-2!3~dihydrobenzofuran-5-yl]"6-hydroxymethyf' tetrahydro-pyran-3,4,5-triol
{aS^R^R.SS.βRJ^-IS-CS-Ethyl-phenyO-a.S-dihydro-benzofυraπ-S-ylj-β-hydroxymethyl- tetrahydro-pyran-3,4 ,5-triot.
(2S.3R,4R,5S,6R)-2-i4-(4-Ethyf-phenyl)-3-methyl-chroman-6-yl]-6-hydroxymethyl- tetrahydro-pyran-3!4,5-triol.
(2R,3S,4R<5R>6S)-2~Hydroxymethyl-€-[1-{4-methyl-ben2yl)'indan-5-yl]-tetrahydro-pyran-
3.4,5-triol.
(2R<3S,4R,5R>6S)-2-Hydroxymethyl-6-(1-(3-methyl-benzyl)-indan-5-yl]-tetrahydro-pyran-
3,4,5-ttiol.
(2S.3Rl4R.5S)6R)-2-[1-(3-Ethyl-4-flυoro-ben?yf)-iπdan-5-yl}-6-hydroxymethyl4etrahydro- pyran-3A5-triol,
{2R>3S.4R!5Rl6S)-2Ηydroxymethy!-6-π-(4-methyl-3.4-dihydrø-2H-benzo(1.4]oxazin-6- yfnieihyl)-indan-S-yl]-tefrahydfo-pyran-3,4.5-triol.
(2S,3R.4R!5S.6R)-2-{2-(3-Ethyl phenyl)-indan-5-yl]-6-hydroxymethyl-tetrahydrO-pyran-
3.4,5-triol.
(2R,3S.4R,5R.6S)-2-Hydroxymethyl-6-[1-{2-methyl-2:3-dihydro-1H-fSOfndol-5-yImethy{)- indan-S-ylJ-tetrahydro-pyran-S^^trioi.
(2S,3R!4R>5Sl6R)-2-[1-{S~Ethyl-thtophen-2-yJmethyf)-indarv5-yl}-6-hydroxymethyl- tetrahydro-pyran-3.4>5 triol.
{2S,3R,4Rl5S,6R)-2-{1H1"(3-Ethyl-phenyl)-ethyl)-indan-5-yl}'6-hydroxymethyl- tetrahydro- pyran-3.4 ,5-tr ioi .
(2SI3R<4R,5S.6R}-2~[3-(3-Fluofo-4-methyl-t>en2yl} mdan-5-yπ-6-hydroxymethyl- tetrahydro-pyran-3.4,5-triol. (aS.aR^R.SS.β^^-ia^a.S-Dihydro-benzofuran-δ-ylmethylJ-lndan-δ-yij-β- hydroxymethyl- tetrahydro-pyran~3.4,5~triol .
(aS.aR^R.SS.eSJ^-CI-C^Ethyt-benzyO-a^-dihydro-1H-indol-S-yij-e-fiuoromethyl- tetrahydro-pyran~3,4,5-triol. {2S!3R,4R,5R!6R)-2-t1-(4-Ethyl-pheny))-2,3-dihydro-1H*indol-5-yl]-6-hydroxymethyl- tetrahydro-pyran-3A5~tfiol. {aS.aR^S.δS^RJ^-II^Ethyl-benzyO-i .a.a^-tetrahydro-quinolin-Z-ylj-β-methyf- tetrahydro-pyran-3.4,5-triol.
The inhibitory effect on the sodium-dependent glucose cotransporter SGLT, SGtT 1 and SGLT2, of compounds of formula I may be demonstrated using the following test procedures
The ability of the substances to inhibit the SGLT-2 activity may be demonstrated in 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). These cell lines transport 14 C- labelled alpha-methyl-glucopyranoside (14 C-AMG, Amersham) into the interior of the cell in sodium-dependent manner.
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 μg/rnL 2eoctn (Invitrogen).. and HEK293-hSGLT2 cells are cultivated in DMEM medium with 10% foetal calf serum and 250 μg/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. Then 40.000 cells per well are seeded into a white.. 96-well plate coated with poly-D-lysine and incubated overnight at 37X, 5% CO? The cells are washed twice with 250 μl of assay buffer (Hanks Balanced Salt Solution. 137 niM NaCI, 5.4 mM KCI. 2.8 mM CaCI2 , 1.2 mM MgSO4 and 10 mM HEPES (pH 7.4), 50 μg/mL of gentamycin). 250 μl of assay buffer and 5 μl of test compound are then added to each well and the plate is incubated for a further 15 minutes in the incubator. 5 μl of 10% DMSO are used as the negative control. The reaction is started by adding 5 μt of 14 C- AMG (0.05 μCi) to each welt. After 2 hours' incubation at 37*C. 5% CO2 , the cells are washed again with 250 μl of PBS (200C) and then lysed by the addition of 25 μl of 0.1 N NaOH (5 min. at 37*C). 200 μf 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.
To determine the selectivity with respect to human SGLT1 an analogous test is set up in which the cDNA for hSGLTI (Genbank Ace. No. NM000343) instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293 cells.
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
Figure imgf000126_0001
It can be seen that the compounds of the invention are useful as inhibitors of SGLT and therefore useful in the treatment of diseases and conditions mediated by SGLT such as the metabolic disorders disclosed herein. It will be understood that the invention has been described by way of example only and modifications may be made whilst remaining within the scope and spirit of the invention.

Claims

We Claim
1 A compound represented by Formula (IA)
Figure imgf000128_0001
( ) wherein A is selected from
H i t
Figure imgf000128_0002
provided that when A is . it is not substituted with hydroxy or
Figure imgf000128_0003
methoxy,
Q is La-Xa or R<0.
I *»3 i IQe _ ^^7Cm ' ^Y 1 & 7." j
Z' and Z" are each, independently, a bond, C,.« alkylene or C/.« 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 mote hydroxy or halogens
Y' ts -O-. -S(OV, -N(R3)-. -C(Rl(R")-, -C(O)- -C(Q)NR^ -NR2C(O)-, - N(R^)C(O)N(R3)- -N(R^)SOr. or -SO^N(R?')-;
V is halogen, -OR1bor hydrogen, m = 0-4. n « 0-4; p a 0-2;
R" and R" are independently, hydrogen, halogen, C1.* alkyl. perhaloalkyi, or taken together form a cyclic ring which may optionally have heteroatoms selected from O, N or S;
R1, R"aand Rn' are independently selected from hydrogen, Chalky!, C^^aryl-d. 4alkyl, -C(O)C6.f0aryl or -C(O)C1-6aikyl;
R? and R28 are independently halogen, hydroxy, C^hydroxyalkyl, cyano, nitro. - NR4R5, -CH2NR4R*. C1^ alkyl, C3-7 cycloalkyi, C,.4alkoxy, C:« cycloalkoxy, -S(O)pR3, - S(O)2NR4R5, -OS(O)?R3, -C(O)R3, -C(O)OR3. -CH2C(O)OR3. -C(O)NR4R0. - CH2C(O)NR4R5. -NR3C(O)NR4R*. -NR3C(O)OR3, C,.6haloaikyf, C,.θpemaloa!kyl, C8. rcycioaikylCLialkyl, C&(Oaryl, Ce-ioarylC^afkyl, C6.ioaryloxy, C^io^eterocyclyl, C?. loheterocydyiCL^alkyl, C.ioheteroarylCi^alkyi, d.^heteroaryj, Ci.i0heteroaryloxy, or Ci- loheterocycloxy;
RJ is hydrogen, Ci.βalkyl( C3.-/ cycloalkyl, C& i9aryl, C.ioheteroaryl, or C2. -.oheterocyclyl; q - O3;
X is rC(R$)(R7)),;
Y is H. C1 4 alkyi, OR1 or NR8R3 t = 1-3;
Re and R' are independently hydrogen or Ci..δ alkyl. or Rs and Rr form an oxo group and t~1, or when Rs and R? are C,4alkyl on the same carbon they can be taken together to form a cyclic ring which may contain N, S or O atoms,
R4 and R5 are independently hydrogen, Ci.δ alkyl, C3.?cycloalkyi, C3-? cycloalkylCi, 4alkyl, aryld^alkyl. C5.10aryl, Ct-ioheteroaryl, Ci-wheteroarylC^alkyl, C^i^heterocyclyl. Cs^oheterocyclylCi^alkyl or
R4 and R* taken together may form a monocyclic or a bicycϋc 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
R6 and Rδ are independently hydrogen, C6 alkyl, C5.,- cycloalkyl, C^vcycfoalkylC? Λaikyj, arylC^alkyl, Cδ 18aryl, Ct.^heieroaryf, C,.!δheteroarylCi.4alkyl, C?. , oheterocyclyl. C2 ioheterocyclylCt.4alkyl or Rδ and Rθ along with the nitrogen to which they are bound form a monocyclic or a bicyctic 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;
R10 is CL4 alkyl, Cs-toaryi, Ci.10heteroaryl, C3.7cyc!oalkyl, C2.1C heterocyclyl, where C1.4 alkyl may be optionally substituted by one or more hydroxy or halogens and C^ary! may be optionally substituted with one or more C^alkyl, C1^aIkOXy, or C^haloalkyl; and
Xa is halogen, hydroxy, cyano, nitro. -NR*RS, -CH2NR4R5, d.4 alkyl, C1.,, hydroxylalkyl, C,.6haloalkyl, C1^ perhaloalkyi, C1^aIkOXy, trihaio C1^ alkoxyl, an optionally substituted C3.? cycloalkoxy, -C(O)R3, -C(O)OR3, -CH2C(O)OR3, -C(O)NRV, - CH2C(O)NR4R8. -NR3C(O)NR4R5, -NR3C(O)OR3, -S(O)pRa. -S(O)2NR4R5; -OS(O)3R*, an optionally substituted Cv-cycloalkyl, an optionally substituted C3.?cycloalkylCi.4alkyl. an optionally substituted C6.,oaryl, an optionally substituted CenoarylCMalkyL an optionally substituted Cβ.ioaryloxy, an optionally substituted C2.iδ heterocyclyi. an optionally substituted C2.ioheterocyclylCj.4alkyl, an optionally substituted Ci icheteroaryl.. an optionally substituted C1.10 heteroarylCi^alkyl, an optionally substituted Ci.10 heteroaryloxy, or an optionally substituted Ci.ioheterocycloxy; or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
Figure imgf000130_0001
3. The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is L3-X8, wherein Ls is a Cu* alkylene.
4. Th compound according to any one Claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Xa is
Figure imgf000131_0001
each of which may be optionally substituted with one or more substituent which are independently selected from halogen, hydroxyl, CM alkyi, Cs ycycloalkyl, C3.? cycloalkoxyl, CM alkoxyl, C^ alkenyl, C6.i0aryl. C<.i0heteroaryl, cyano, -C(O)- C^alkyl, - C(O)-N- CM alkyl, -C(O)-N~di CMalkyl, -S- CM alkyl, SO2- CMalkyl, trihalo C^ alkoxyL • o- C3.? cycloalkyl and -O- C3.? cylcoalkoxyl.
5. The compound according to any one Claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X8 is an Cδ.ioaryl which is optionally substituted wrth one or more substituent which are independently selected from halogen, C^ alkyl, C1-4 alkoxyl, Ca.;< cycloalkyl, -O- C37CyClOaIkIyI, -S- CMalkyl, -SOr C1.., alkyi, trihalo CM alkyl, trihalo C Malkoxyl, Ce.10aryi, C,,i0 heteroaryl. cyano, nitro, NR4R5. -CH2NR4R^ and - C(O)- CM alkyl.
6. The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof wherein Q is R10.
7. The compound according to Claim 6, or a pharmaceutically acceptable salt thereof, wherein R10 is methyl ethyl, isopropyl, isobυtyl. triflouromethyl or cyciopentyl.
8. The compound according to any one of Claims 1-7, or a pharmaceutically acceptable salt thereof, wherein
X iS -CH2-;
Y is OR1;
V is OR1; and
R', Rr* and R1!> are hydrogen.
9. The compound according to Claim 1. wherein the compound is of formula (lib).
Figure imgf000132_0001
(Kb) wherein
Lb is a bond or an optionally substituted CM alkylene;
RtΛ, Rnt>, R"* R!t* and R16b are each, independently, hydrogen, halogen, Chalky!, CM alkoxyl, C^cycloalkyl, -O- C37CyClOaIkIyI. -S- Chalky!. -SOr C^ alkyl, trihalo Chalky!, trihalo C M alkoxyl, C«.iearyJ, Ci i0heteroaryl. cyano, nitro NR4R5, -CHjNR4R5 or -C(O)- C1.^ alkyi; or a pharmaceutically acceptable salt thereof.
10. The compound according to Claim 9, or a pharmaceutically acceptable salt thereof, wherein U is methylene; R11h, RrAh, R13b, R1Sb and Rm> are each hydrogen; and RMβ is CM aikyl.
11. The compound according to Claim 1. wherein the compound is of formula (lie):
Figure imgf000133_0001
wherein
Lc is a bond or an optionally substituted C14 alkylene;
R12C, R1ic. R14c. Rm and R'δc are each, independently, hydrogen, halogen, Ci.4afkyl, C1^ alkoxyl. C^cycloalkyf, -O- C3--/ cycloalklyl, -S- C^afkyl, -SO2- C^ alkyl, trihalo CV! alkyl: trihalo Ci 4 alkoxyl, C«.ioaryi. CI 1δheteroaryl, cyano. nitro NR4R5, -CHjNR4R5 or -C(O)-
Ci 4 alkyl; or a pharmaceutically acceptable salt thereof.
12. The compound according to Claim 1. or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (lid):
Figure imgf000133_0002
(Md) wherein
Ld is a bond or an optionally substituted C4 alkylene;
R"d. Rnύ, Rm. RMo and RlSd are each, independently, hydrogen, halogen, CM alkyl, CM alkoxyl, C^-cycloalkyl, -O- C3 7 cycloalklyl, -S- Chalky!. -SOr Chalky!, trihalo C^alkyl. trihalo C1.4 alkoxyl, C6-To arylt Ct.mheteroaryl, cyano, nitro, NR4R5, -CHjNR4R5 or -C(O)- C .4 alkyl; or a pharmaceutically acceptable salt thereof.
13. The compound according to Cfaim 12, or a pharmaceutically acceptable salt thereof, wherein L3 is methylene; R11<J, R12d ; R14d and R14β are each hydrogen; and R13d is C»..4alkyl.
14. The compound according to Claim 12, or a pharmaceutically acceptable salt thereof, wherein U is ethylene; R1W, Rm, Ri4ti and R1δlJ are each hydrogen; and Hm is C alkoxyi.
15. The compound according to Claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (He):
Figure imgf000134_0001
(He) wherein
U is a bond or an optionally substituted C M alkylene: Rii e R ia»t R i* R«« an<} Ris* afβ each incjepen(tentjy) hydrogen, halogen, C^alkyL C4 alkoxyi. C3.7cycloalkyl. -O- C47 cycloalkJyl, -S- CM aikyl, -SO?- Ci.4alkyl. tήhalo C^alkyl. trihalo d.4 alkoxyi, Cs.10aryl, Coheteroaryi, cyano, nitro, NR4R6, -CHaNR4R5 or -C(O)- CL4 alkyl; or a pharmaceutically acceptable salt thereof.
16. The compound according to Claim 15, or a pharmaceutically acceptable salt thereof, wherein U is a bond. R11e, R12β ; R14* and R1Sβ are hydrogen; and Rm is C4 alkyl or C A alkoxyi.
17. The compound according to claim 15, wherein U is methylene; R1 **, Rt?Λ, RW|S and R1Sβ are hydrogen; and Rlϊe is C* alkyl or C4 alkoxyi.
18. The compound according to Claim 1 , wherein the compound is of formula (Hf).
Figure imgf000135_0001
(Hf) wherein
Lf is a bond or an optionally substituted C1 4 aikylene;
R1", R12f, R13', R14f and R1st are each, independently, hydrogen, halogen. C,.4alkyi, C,.-, alkoxyl. C».?cycloalkyl. -O- C57 cycioalklyl, -S- C1.* alkyl, -SO2- CM alkyl: trihalo CM alkyl, trihalo C1^aIkOXyI, C6.!0aryl, C^oheteroaryi, cyano. nitro NR4R5, -CH2NR4R5 or -C(O)- Ci.4alkyl; or a pharmaceutically acceptable salt thereof.
19, The compound according to claim 18, or a pharmaceutically acceptable sail thereof, wherein Lf is a bond; R'!f, R'*, Rul and R1Sf are hydrogen; and R13f is Chalky!.
20. The compound according to Claim 1. wherein the compound is of formula (Hg):
Figure imgf000135_0002
wherein
L8 is a bond or an optionally substituted Ci^ alkyfene;
R«a Rug R IΪ 8 R»s and Ru.g arø each independently, hydrogen, halogen. Ci.4alkyl. C1.,, alkoxyl, Ca.?cycloalkyl, -O- C5-; cycloaiklyl. -S- C,.4alkyl, -SO2- C1 4 alkyl. trihalo C1 4 alkyl, trihalo C ! Λ alkoxyl, C6.,oaryl, C1 10heteroaryl, cyano, nitro NR4RS : -CH?NR4RS or -C(O)-
Ci. Λ alkyl; or a pharmaceutically acceptable salt thereof.
21. The compound according to Claim 1. wherein the compound is of formula (Hh):
Figure imgf000136_0001
(Hh) wherein
Lh is a bond or an optionally substituted C1^ alkylene; Ri,h R i2h Rnh R i4h and R ish are each independently, hydrogen, halogen, C^ alkyl, C4 alkoxyl, C:J.> cycloafkyl, -O- C3-V cycloalklyl, -S- CMalkyl, -SO2- Ci^ alkyl, tπhalo C^ alkyl. trihalo Ci.4alkoxyl. Cβ.10ary1, C.^heteroaryl, cyano, nitro NR4R5, -CH?NR4RS or -C(O)- Ci.4alkyl. or a pharmaceutically acceptable salt thereof.
22. The compound according to Claim 1 , wherein the compound is selected from the group consisting of:
(2S<3R.4R,5S.6R)^2-[4-(4-Ethyl-benzyl)'3,4-dihydro-2H-benzo[1,4|oxazin-6-yl|-6- hydroxymethy!-tetrahydro-pyran~3A5-triol;
(aR^R.SS^RJ^-H-tS^-Dfchloro-benzyO-a^-dihydro^H-benzoti^Joxazin-β- y(}~6-hydroxymethyl~tetrahydro-pyran-3.4,5-triσ!.
(2R<3St4R.5R)-2-Hydroxymethyl-6-|4-(4-methylsulfany}-benzy!)-3.4-dihydro-2H- benzoπ ,4]oxazin-6-yl3-tetrahydro-pyran-3,4,5-triol;
{2R>3S,4R.5R,6S)-2-Hydrøxymethyl-^[4-(4'tsoptOpyl-benzyl)-3,4-dihydro-2H- benzo[1,43oxazin-6-yf)-tetrahydro-pyran-3,4t5-triol:
(2S:3R(4R>5S,6R)-2-[4-{2.4-Dichloro-benzyl)-3l4-dihydro-2H-ben2θ{1.4]oxaxin- 6«ylJ-6-hydroxymethyl-tetrahydro~pyran-3,4;5-triol;
(2S,3R,4R,5S,6Rh2-t4-{2-Chloro-5-fluorc-benzyf)-3.4-dihydro-2H- ben2θ(1,4Joxaz«n-6~yl]-6-hydroxytτtethyl-tetrahydro-pyran-3:4,5-triol; (2S!3R,4R,5S,6R)-2-{4-8iphenyl-4-ylmethyt-3,4-dihydro-2H-benzo[1,4]oxa»n-6- yl)-6-hydroxymethyf-tetrahydro-pyrarr-3,4, 5-triol ;
{2S,3R,4R,5S,6R)-2-[4-{4-E^yl-benzyl)-3,4-dihyclro-2H-benzo[1.4]oxazin-8-yfJ- frhydroxymethyJ-tetrahydro-pyran-SAS-triof.
(2S,3R.4R,5S.6R)»2.(4.(4-εmyl-benzyl)-3,4-dJhydro-2H-ben2oπ,4]oxa»n-8-yt]- 6-hydroxymethyl-tetrahydro-pyran~3,4.5-trioi;
(3R,4R,5S,6R)-2-[4-(4-Ethyl-benzyl)-2.2-dJmethyl-3.4-dihydro-2H- benzo[1,4Joxa2irv-6-yi]-6-hydroxymethyl4etrahydro-pyran~3,4,5-triol;
(2R.3S,4R,5R)-2-Hydroxymethyl~6-i4-(4-isopiOpyl-benzl)-2,2-dirmthyl-3,4- dihydro-2H-benzo[1,4)oxazJn-6-yl]-tetrahydro-pyran-3;4t5-trioi;
(2S>3R14R.5Si6R)-2-H-(4-εthyl-beπzy!)-2-methyl-3)4-dihydro-2H- benzo[1,4]oxazin-6-yl]-6-hydroxymethyJ-tetrahydro-pyran-3.4,5-trJol;
{2R;3S,4R.5R)-2-Hydroxymethyl-6-[4-<4-isopropylbenzyl)-2-methyl-3.4-dihydro 2H-benzo[1,4]oxazJn-6~ylj-tetrahydro-pyran-3,4.δ-trtol;
(2R,3S,4Rt5R)-2-HydroxymethyJ-β-[4-{4-isopropyl-besnzyl)-3-tnethyl-3;4-dihydro- 2H'benzo[1.4]oxazin-δ-yt}-tetrahydro-ρyran-3>4;5-triol;
(3R,4R<5S>6R)-2-(4-Ethyl-3-methyl-3>4-dihydrθ'2H-benzoπ.4]oxaziπ^yl)-6- hydroxymethyl-tetrahydro-pyran-S^.S-trtol;
(2S,3R!4S,5Sl6R)-2-H'(4-Ethyl-benzyl)-3.4-dihydro«2H~benzo[1<4]oxazirv6-yl]«6- methy}-tetrahydro-pyran-3,4 , 5-triol ;
(2S,3Rt4R.5S.6R)-2-[4-(4-Methyl-benzyl)-3,4-dihydrø-2H-benzo[1 ι4]oxazin-6-yl)- 6-hydroxymethyl-tetrahydro-pyran-3.4.δ-trtol;
(2R.3St4R)5R>6S)-2 Hydroxymethyl-β-{4~naphthafen-2-ylmethyl-3,4-dihydro-2H~ benzofi^Joxazin-β-yO-tetrahydro-pyfan-SΛ^-triol;
(2R,3S,4R(5R,6S)-2-Hydroxymβthyl-6-|4-(4-methanesulfony!-b€{τzyl)-3,4-dlhydro-2H- benzo(1,43oxazin-6-y[J-tetrahydtO-pyran-3,4.5-trtol;
{2S,3R,4R,5S,6R)-2-[4-(5-Chtoro-thiophen-2-ylmethyt)-3;4-dihydro-2H-benzoπ,4]oxa2in- 6~yl}-6-hydroxymethyl-tetrabydro-pyran-3,4 , S-trioi;
{2Sl3R,4R,5S,6R)~2-{4-Benzyl-3(4-dihydro-2H"benzo|1 :43oxazin-6-yl)-6-hydroxymethyt- tetrahydfo-pyran-3,4, 5-triol;
(2S.3R14R,5S,6R)-2-H-(4-Ethoxy-benzy))-3>4-dihydro-2H-betizoπ)4Joxa2in-6-y{]-6- hydroxymethyl-tetrahydrO-pyran-3,4,.5-triol;
(2St3R.4R,5S.6R)-2-H-{3-Ethoxy"benzyl)-3,4"dihydro-2H-benzo{1,4joxazin-6-yj]-6- hydrøxymethyl-tetrahydro-pyran-3(4;5-triol; (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-(4-trifluoromethoxy-benzyl)-3,4-dihydro-2H- benzo[1,4]oxazin-6-yf}-tetrahydro-pyran-3,4,5-triol;
(2R,3S.4R,5R(6S)-2-Hydroxymethyl-6-H-(3-methyl-benzyi)-3.4-dihydro-2H- benzo[1.43oxazin-6-yl}-tetrahydro-pyran-3.4,5-triol;
(ΣS.SR^R.SS.δRJ^^-Ca-Ethyl-bβnzyJJ-S^-dihydro-aH-benzoii^Joxazin-e-ylJ-e- hydroxymethyl-tetrahydro-pyran-3,4,5-triol;
(2R<3S:4R.SR,6S)-2-Hydroxymethyl-6-l4-(44rifluofomethyf-ber«ryl)~3,4-dihydro-2H- benzo(1,43øxazJn-6~yl]-tetrahydro-pyran-3A5-triol;
(2R.3S,4R.5R,6S)-2-Hydroxymβthyl-6 {4 {3-trifluoromethyl-benzyl)~3.4-dihydro-2H- benzoJI^Joxazln-e-ylJ-tetrahydro-pyran-S^.S-triol;
(2R,3S(4R!5Rl6S)-2-Hydroxymettiyl-6-[4-(2~trifIuoromethyf-benzyl)-3.4-dihydro-2H- benzo[1,4]oxazin-6-ylJ-tetrahydro-pyran-3,4,5-triol;
(2S,3R.4Rl5S,6R)'2-<4-Benzofυrarv5-ylmethyl-3,4-dihydro-2H-benzo[1,4]oxazifv6-y!)-δ- hydroxymethyl-tetrahydfo-pyran-3.4,5-triol;
(2S,3R,4R,5S!6R)-2-<4-Ethyl-3(4-d»hydro-2H-benzo[1,4]oxazin-6-yl)-6-hydroxymethyl- tetrahydro-pyran-^^-triol;
(2R.3S,4R1SR,6S)-2-Hydroxymethyl-6-[4-{3-methoxy-benzyl).3,4-dihydro-2H' benzo(1 ,4}oxazin-6-ylJ-tetrahydro-pyran-3,4,5-triol;
(2R.3S,4R.5R,6S)-2-Hydroxymethyf-6-t4-(1-p-tolyf-ethyl)-3>4-dihydro-2H- benzoli^loxazin-β-yll-tetrahydro-pyran'S^.S-triol;
(2S>3R,4R.5S,6R)-2-{4-[1-(4-εthyl-phenyf)-ethy)3-3.4-dihydro-2H-benzoC1,4]oxazJn-6-yf}- 6-hydroxymeihyf4etrahydrø-pyran-3.4,5-triol;
(2S,3R>4Rt5S,6R)-2-[4-(3-Chtoro-benzyl)-3l4-dihydro-2H-benzol1,4]oxazin-6-yl]-6- hydroxymethyt-tetrahydro-pyran-3,4,5-triol;
{2S.3R,4R,5S,6R)-2-i4-(4-tert-Butyl-benzyf)-3.4-dihydro-2H-benzo(1!4]oxaxin-6-yi3-6- hydroxymethyl4etrahydro-pyran«3,4.5-triol;
^^-{(^S.SR^R.δS.δRJ^^.δ-Trihydroxy-e-hydfoxymethyl-tetrahydro-pyran^-yl)^^- dihydro-benzoJ1,4}oxazin-4-ylmethyl]-benzon»trile;
(2S.4R,6R)-2-(4~Beitzyf-3,4-dihydro-2H-benzo[1.4]oxazin-7-yl)-6-hydroxymethyl- tetrahydro-pyran-3,4,5-tno);
(2S!4R,6R)-2-H-(4-Ethyl-benzyl)-3,4-dihydro-2H-benzoi1.4]oxazin-7-yl]-6- hydroxymethyl-tβtrahydro-pyran-3,4(5-triol;
(2R,4R,6S)-2-Hydroxymethy!-6-[4-(4-isopropy{-benzyl)-3.4-dihydro-2H-benzo|1t43oxazfn- 7-yi)-tetrahydro-pyran-3,4.δ-tfiol; (2S14R,6R)-2-[4-{4-Ethoxy-benzyl)-3,4-dihydro-2H-ben2:o|1I4}oxa2in-7-ylJ-6- hydroxymethyl-tetfahydro-pyran-3,4(5-triol;
(2R,4R<6S)-2-Hydroxymethyl-6-f4-(4-methyl-benzyf)-3<4-dihydro-2H-benzo{1,4]oxazin-7- yl]-tetrahydro-ρyran-3A5-triol;
(2SI4R>6R)-2-H-(3-Ethoxy-benzyl)'3,4-dihydro-2H-benzo[1,4]oxazin-7'yl3-6- hydroxymethyMetrahydro~pyran-3,4,5-triol;
(2R>3S,4R>5R!βS)-2-Hydroxymethyl-6'[4-{4-triffυoromethoxy-benzyl)-3,4-dihydro-2H- ben2θ(1,43oxaztn-7-ylJ-tetrahydro-pyran-3,4,5-triol;
(2R>3S,4R.5R,6S)-2-Hydroxymethyf-6-[4-(3-methyl-ben2yl)-3,4-dihydro-2H» benzof1(4]oxaz»v7~ylJ-tetrahydro-pyran-3,4,5-triol;
(aS.SR^R.SS.eRJ^^-O-εthyl-benzyO-S^-dihydro^H-benzoπ^joxazirv?^!]^. hydroxymethyt-tetrahydro-pyran-S^.S-triol;
(2R!3S,4R!5R.6S)-2-Hydroxymethyl-6-[4'(4-triflυoromethyl-benzyl)-3,4-dihydro-2H- benzo[1.4]oxazin-7-yl3 tetrahydro-pyfan-3,4.5-triol;
(2R,3St4R,5R,6S)-2-Hydroxymethyl-6-(4-{3-triflυoromethyl-benz:y})-3,4-dihydro-2H- ber>zo[1.4]oxaz}n-7-yl3~tetrahydro-pyran-3,4;5-trtol;
(2R,3St4R,5R<6S)-2-Hydroxymethyl-6-|:4-{2-triflυoromethyl-beπzyl)-3,4-dihydro-2H- benzo[1.4}oxazin-7-yi34etrahydro-pyran-3.4,5-trtol:
(2S,3R.4R,5S!6R)-2-{4-Benzofuran-5-ylmethyl-3(4-dihydro-2H-benzo(1:4]oxazin-7-yl)-6- hydroxymethyl-tetrahydro~pyran-3,4.5-triol;
(2S,3R:4Rl5S!6R)-2-{4-Ethyl-3,4-dihydro-2H~beπzo[1143oxa2iπ-7-yl)-6-hydroxymethyl- tetrahydro-pyran-,4.5-tr io) :
{2Sl3R,4R.5S)6R)»2-[4-(3-Chloro-benzyl)-3>4-dihydrO'2H'benzo[1.4]oxa2in-7.yi3-6- hydroxymethyl-tetrahydro-pyran-S^^-triol:
(2R,3S,4R.5R16S)-2-Hydroxymethyl-6-[4-(3-methoxy-benzyl)-3.4-dihydro-2H- benzo[1,4}oxazJn-7-yl)-etrahydro-pyran-3,4,5-triol:
(2R,4R,6S)-2-Hydroxymethyl-6-[4~(1-p-tolyl-ethyl)-3l4-dthydro-2H-benzo[1,4]oxazin-7- yl]-tetrahydro-pyrafτ-3,4,5-triof;
(2R!3S>4R:5R.6S)-2-Hydroxyniethy}-6-{4-[2-(4 methoxy-phenyl)-ethy!]-3!4~dihydro-2H- benzo[1.4j|oxazin-7-yJ}-tetrabydro«pyran-3,4»5-triol;
(2S,4Rt6R)-2-{4-f2-(4-Ethoxy-pheπyl)-ethylJ-3.4-dihydro-2H-benzo[1(4}oxazfn-7-yf}-6- hydroxymethyt-tetrahydro-pyran-3,4.5-trioI;
(2R,3S,4R.5R)-2-Hydroxymethyl-6-{4-(4-isopropoxy-benzyl)-3!4-dihydro-2H- benzo{1.4]oxazJn-6-y)]-tetrahydro-pyran'3;4.5-triol; (SR^R.δS.δRJ^-^-t^Cyclopentyloxy-benzyO-S^-dihydro-aH-benzoπ^loxazJn- 6-yl]-6-hydroxymethy!-tetrahydro-pyran-3,4,5-triol;
{2S,3R,4R,5S<6R)-2-[4-(4- Ethyl-phenyl)-3,4-dthydro- 2H-benzo[1.4]oxazin-6-ylj-6- hydroxymethyl-tetrahydro-pyran~3,4(5-triol;
(2R!3S,4Rt5R)-2-Hydroxymethyl-6-{4-(2-{4-methoxy-phenyl)-ethyl]-3!4~dihydro-H- benzoli^Joxazin-θ-yll-tetrahydro-pyran-SΛ.δ-trioi;
{3R,4R<5S,6R)-2-{4'i;2-(4-Ethoxy-pheny0-ethyl3-3>4-dthydro-2H-benzoπ,4]oxazifv6-yl}- 6-hydroxymethyl-tetrahydrα-pyran-3,4,5~triol;
(2R,3S,4R,5R)-2-Hydrøxymethyl-6-(4-(2-thiophen.3-y{-ethyO-3,4-dihydro-2H- benzof 1 ^Joxazin-β-ylj-tetrahydro-pyran-S^ ,5-triol;
(2S,3R,4R,5S,6R)-2-[1-(4-Ethyl-benzyl)-1,2>3,4-tetrahydro-quinolin-7-yl]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-trioi;
{2R,3S(4R>δR,6S)-2-Hydroxymethyl-6"|1-(4-rsopropyl-benzyl)-1.2,3,4-tetfahydro- quinolin-T-ylj-tetrahydro-pyran-S^.S-triol;
(3R,4R,5S,6R)-2-f1-(2l4-Dichloro-benzyl)-1.2,3,4-tetrahydro-quinolin-7«yt}-6- hydroxymethyl-tetrahydro-pyran-S^.δ-triol;
(2S.3R,4R,5S,6R)~2-(1-(2-Chloro-5-ffuoro~beπzyf)-1.2t3,4-tetrahydro-qυinolJn-7-yl]-6- hydroxymethyl-tetrahydro-pyran-S^.δ-triol;
(2R,3S>4R,5R)-2-Hydroxymethyl-6-[1-(3-methoxy-benzy0-1.2!3,4-tetrahydro-qυinofin-7- yl}~tetrahydro*pyran-3.4,5-trioi;
(3Rl4R.5S,6R)-2-[2-{4-Ethyl-benzyf)-1l2,3.44etrahydro-isoquinolin-7-ylJ-6- hydroxymethyl-tetrahydro~pyran-3.4 , 5-triol;
(2R(3S.4R,5R!δS)-2-Hydroxymethyl-6-l2-{4-methoxy-beπzyl)-1,2,3>4-tetrahydro- isoqυiπoitn-7-yt]-tetrabydfθ-pyran-3,4.S-triol;
(2S:3R.4R,5S.6R)-2-{2-{4-εthyl-benzyl)'1!2,3)4-tetrahydro-isoqυinoiin-6-ylJ-6- hydroxymethyl-tetrahydro-pyran-S^.S-triol;
(2S,3R.4R,5S.6R>2-{2-{4-Ethoxy-benzyl)-1.2,3,4-tetrahydro-isoqυinofJn-6-yl]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol;
(2R,3S.4R,5R<6S)-2-Hydroxymethyt-6-{1-(4-methyl-benzyl)-1:2(3>4-tetrahydro- quino(in~7-yi}-tetrahydro-pyran-3A5-trioi;
(2S>3R!4R.SS:6R)-2-(1-Benzyl-l2l3<4-tetrahydro-qυinoiin-7"yl)-e-hydroxymethyl- tetfabydro-pyran-S^.S-triol:
(2S,3R,4R.5S<6R)-2-[1-(4-Ethoxy-benzyi)-1,2>3,4-tetrahydro-qυinolin-7-yl)-6- hydroxymethyl-tetrahydro-pyran-3.4,S-trJol. {aS^R^R^S^R^-π^S-Ethoxy-benzyO-i.a^^-tetrahydro-quinolin-y-ylJ-β- hydroxymethyl-tetrahydro-pyran-3:4,S-triøl;
(2R>3S.4RI5R<6S)-2-Hydroxymethyl-6-[1-(44riflυoromethoxy-benzyl)-1<2!3,4-tetrahydro- quinolin-7-yl]-tetrahydro-pyran-3,4,54riot;
(ΣR.SS^R.δR.βS^a-Hydroxymethyl-β-ti^S-methyl-benzyfJ-i.a.SΛ-tetrahydro-qυinolin- 7-yl]-tetrahydro-pyran-3,4.5-triol;
(2S>3Rt4R.5S,6R)-2-π-(3-Ethy!-benzyl)-1,2>3.4-tetrahydro-qυinolin-7-ylJ-6- hydroxymethyMetrahydro-pyran-SAδ-tπol;
{aR^SΛR.δR.βSj-a-Hydroxymethyl-e-ti-ø-triflυoromethyf-benzyO-i^^^-tetrahydro- quinolin-7-yl]-tetrahydfo-pyran-3,4«5-triol;
{2R>3St4R!5R,6S)-2-Hydroxymethyl-6-{1-{3-triflυoromethyt-benzyl)-1l2.3.4-tetrahydro- quinolin-7-yl]-tetrahydro-pyran-3,4,5-tfio{;
{2R,3S,4Rt5R<6S)-2~Hydroxymethyl-6-n-(2-trifluoromethyl-benzyJ)-1,2,3!4-tetrahydro- qulnolin-7-yl]-tetrahydro-pyran-3,4,5-trio{;
(2S,3R!4R,5S!6R)-2-(1-Benzofuran-5-ylmethyl-1l2!3l4-tetrahydro-quinolin-7-yl)-6- hydroxymethyl-tetrahydro-pyratv3,4.5-triol;
(2S,3Rt4R,5S!6R)-2-(1-Ethyf-1,2,3<4-tetrahydro-qυinoiin-7-yi)-β-hydroxymethyl- tetrahydro-pyran~3A5-trioi;
(2Sl3Rt4R,5S,6R)-2-[1-(3-Chloro-benzyl)-1!2!3.4-tetrahydro-quinolin-7-yi]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-trioi:
(2R.3S(4Rl5R(6S)-2-Hydroxymethyl-6-{1-{2-{4-methoxy-phenyl)-ethytM2(3,4- tetrahydro-quJnolin^-yiHetrahydro-pyran-S^^-triol;
(2S,3R<4R!5S,6R)~2'{1-[2-(4-Ethoxy-phenyl)-ethyl]-1,2,3t4-te{rahydfo-qυino!in-7-yl}-6- hydroxymethyf-tetrahydro-pyran-3,4,5-triol;
(2R:3S>4R,SR.6S)-2-Hydroxymethyl-6-[1-(δ-methyl-isoxa2θl-3-yfmethyl)-1>2:3,4- tetrahydro-quinoliπ^-ylJ-tetrahydro-pyfan-SΛδ-triol;
(2S.3R>4R,5S,6R)-2-[1-(4-Ethyl-benzyl)-1<2,3!4-tetfahydro-qυiπolin-6-yl]-6- hydroκymethyl-tetrahydro-yran-3,4,S~triol;
(2R<3S,4R<5R!6S)-2-HydroxymethyKH1-(4-tsopropy»-benzy{)-l.2,3t4~tetrahydro- qυinolin-6-yl)-tetrahydro-pyran-3:4,5-triol;
(2R!3St4R,5R!δS)-2-Hydroxymethyl-6-|1-(4-methoxy-beπzyl)"1,2:3>4-tetfahydro- quinolin-6-yf]-tetrahydro-pyran-3:4,5-triol;
{2S,3R<4R,5S.6R)~2-[1-{3-εthyl-benzyl)-1l2,3!4-etrahydro-qυinotin-6-ylJ-δ- hydroxymethyl-tetrahydro-yran-S^.S-triol; (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[1-(4-isoproρyl-benzyl)-2,3-dihydro-1H~ indol-δ-ylJ-tetrahydro-pyrafvS^.δ-triol;
(2S:3R.4R,5S,6R)-2-[1-(4-Ethoxy-benzyl)-2,3-dihydro-1H-indof-5-yl]-6-hydroxymethyl- tetrahydro-pyran-3.4,5-iriof;
(2S,3R.4R,5S.6R)'2-[1-{4-Ethy}-benzyO-2!3-dihydro-1H-indo}-5-ylJ-6-hydroxymethyl- tetrahydro-pyran-3,4 ,5-triol;
(2S>3R14R.5S!6R)-2-i4-(4-Ethyl-phenyl)-chroman-6-yi]-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol;
(2S,3R,4R.5S!6R)-2-[1-(3.EthyJ-benzyl).2.3-dihydro-1H-indol-5-yl]-6-hydroxymethy|. tetrahydro-pyran-3,4,5-triol;
(2S,3R,4R,5S!6R)-2-[1-(4-Ethyl-benzyl)-2.3-dihydro-1H-indol-6-yl]-6' hydroxymethyl-tetrahydro-pyran-3,4,5-trJol;
(2R)3S,4R,5R,6S)-2-HydrOxymethyl-6-t1-(4-methyl-benzyl)-2(3-dihydro-1H-indol- β-ylJ-tetrahydro-pyraπ-S^.S-triot;
(2S(3R.4R(5S.6R)-2-(1-(4-Methoxy-benzyl)-2.3-dihydro-1H-Jndof-6-yl}-6- hydroxymethyl-tetrahydro-pyran~3,4,5-triol;
(2S,3R.4R,5S,6R)-2-{1-(4-Ethoxy-beπzyl)-2.3-dihydtO-1H-indol-6-yl]-6- hydroxymethyf-tetrahydro-pyran-SΛS-triol;
(2S,3R.4R,5S,6R)-2-l4-benzyl-chroman-6-yl]-6-hydroxymethyl-tetrahydrø-pyran- 3,4,5-trioi;
{2S>3R:4R.5S,6R)-2-{4-[(4-ethyfphenyl)methyl]chroman-6-yl]-6- (hydroxymethyl)tetrahydropyran-3,4,5-trJof:
(2R.3S!4R.5R,6S)-2-(hydroxymethyl)-δ-H-[{4-methoxyphenyl)methyt]chromarv6- yl]tetrahydropyran-3.4,5-triol;
(2R,3S,4R!5R,6S)-2-(hydroxymethy!)-6-[4-|{4-isopropylphenyl)methytjchroman-6- yl]tetrahydroρyran-3.4,5-triol:
(2R:3S)4R,5R.6S)-2-(hydroxymethyl)-6 [4-{4-methoxyphenyi}chroman-6- yl]tetrahydropyran~3,4.5-triol;
(2S.3R,4R,5S,6R)-2-(4-(4-ethylphenyl)chroman-6-y!]-6- (hydroxymethyJ)tetrahydropyran-3,4,5-triol;
(2R,3S,4R,5R!6S)-2-{hydroxymethy{)-6-(4-phenylchroman-6-yf)tetrahydroρyfan-3.4>5~ triol;
{2S,3R.4R,5S.6R)-2-[3-|(4-ethylphenyl)methyl]chroman-6~yl)-6- (hydroxymethyl)tetrahydropyran-3,4t5-triol. (2S,3R,4R.5S:6R)-2-(4-(3-Ethyl-benzyl)-3.4-clihyclro-2H-ben2o[1,4]oxazin-8-yl)-6- hydroxymethyl-tetrahydro-pyran-SAδ-triol;
{2S,3R,4R.5S,6R)-2-[4-(4-Ethoxyl-benzyl)-3,4-dihydro-2H-benzo[1l4]oxazm-8-yI}- 6-hydroxymethyl-tetrahydro-pyran-3,4,5-tfiol
(2R,3S>4R!5R,6S)-2-Hydroxymethyl-6-{4-(4-methoxy-phenyl)-3>4-dihydro-2H- benzoyl .4Joxa2in-6-yi]-tetrahydro-pyran-3,4,5-trioi;
{2R,3S.4R,5R,6S)-2-Hydroxymethyl-6-{4-[2-{4 methoxy-phenyl)-ethyl)-chrornan-6- yl}-tetrahydro-pyran~3,4,5-triol;
(2S13R,4R.5S,6R)-2-[4-(3-Ethyl-phenyl)-chroman-6-yl]-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol;
(2S,3R!4R)5S,6R)-2-{4-(4-Ethoxy-phenyl)-chroman-6-yi)-6-hydroxymethyl- tetrahydro-pyraπ-3,4.5-trtol;
(2S,3R<4R.5S<6R)-2-[4-(3-Ethoxy-phenyt)-chroman-6-yl]-6-hydroxymethyl- te{rahydro-pyfan-3.4,5-trtol;
{2R,3S,4R!δR<6S)-2-Hydroxymethyl-6-[4-(4-triflυoromeihyt-phenyl)-chroman-6-yi]- tetrahydro-pyran-3,4, δ-triol ;
(2R!3S>4R,5R,6S)-2-Hydroxymethyl-6-H-(3-triflυoromethyl-phenyl)-chroman~6-yl]- tetrahydro-pyran-3 A, 5-tπol :
(aR.SS^R.SR.eSJ^-Hydroxymethyl-δ-μ^S-mβthoxy-phenyO-chroman-θ-yi}- tetrahydro-pyran-3,4,5-triol:
(2R,3S14R>5R.6S)-2-Hydroxymethyl-6-(4-m-toiyl-chfOman-6-yl)-tetrahydro-pyran- 3,4.δ-triol;
(2R,3S,4R,5R;6S)-2-Hydroxymethyl-6-[3-{4-isopropyl'benzyl)-chfornan-6-yl]" tetrahydro-pyran-3,4,5-trioi;
(2S,3R>4R!5S>6R)-2-[3-{3,4-Dimethoxy-benzyl)-chroman-6-yl]-6-hydroxymethyl- tetrahydro-pyran-3,4.5-triof;
3-{3,4-DJfrtethoxy-ben2yl)-6-({2S,3R>4R:5S>6R)-3<4,5-tήhydroxy-β-hydfθxymethyl- tetrahydro-pyran-2-yl)-chroman-4-one; or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition, comprising: a compound according to any one of Claim 1-22. or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers and exαpients.
24. A method of treating a disease or condition related to the inhibition of SGLT, comprising: administering an effective amount of the compound according to any one of Claim 1-22. or a pharmaceutically acceptable salt thereof.
25. The method of claim 24, wherein the disease or condition related to the inhibition of SGLT is metabolic disorders or conditions, metabolic acidosis or ketosis, reactive hypoglycaemia, hypennsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis, obesity, high blood pressure, chronic heart failure, edema or hyperuricaemia.
26. The method of Claim 24, wherein the disease or condition related to the inhibition of SGLT is pancreatic beta cell degeneration, hypertension, edema, or acute renal failure.
27. The method of Claim 24, wherein the disease or condition related to the inhibition of SGLT is type 1 , type 2 diabetes mellKυs or complications of diabetes.
28. A combination, comprising. the compound according to any one of Claims 1-22. or a pharmaceutically acceptable salt thereof; and one or more additional pharmacologically active compounds selected from antidiabetic agents; uric acid synthesis inhibitors; drugs for influencing high blood pressure, chronic heart failure or atherosclerosis; GABA-receptor antagonists; Na- channel blockers; topiramat; protein- kinase C inhibitors; advanced glycaUon end product inhibitors; and aldose reductase inhibitors.
29. A compound according to any one of Claims 1 -22, or a pharmaceutically acceptable salt thereof, for use as a medicament.
30. A compound according to any one of Claims 1-22. or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition mediated by the inhibition of SGLT.
31. The compound of claim 30, wherein the disease or condition related to the inhibition of SGLT is metabolic disorders, metabolic acidosis or ketosis. reactive hypoglycemia, byperinsulinaemia. glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis, obesity, high blood pressure, chronic heart failure, edema or hyperuricaemia.
32. The compound of Claim 30, wherein the disease or condition related to the inhibition of SGLT is pancreatic beta cell degeneration, hypertension, edema, or acute renal failure.
33. The compound of Claim 30, wherein the disorder or diseas related to the inhibition of SGLT is type 1 , type 2 diabetes mellitυs or complications of diabetes.
34. A pharmaceutical composition according to Claim 23 for use as a medicament.
PCT/EP2010/056286 2009-05-07 2010-05-07 Fused heterocyclic c-glycosides for the treatment of diabetes WO2010128152A1 (en)

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