WO2010019828A1 - Glucagon receptor antagonists - Google Patents

Glucagon receptor antagonists Download PDF

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Publication number
WO2010019828A1
WO2010019828A1 PCT/US2009/053792 US2009053792W WO2010019828A1 WO 2010019828 A1 WO2010019828 A1 WO 2010019828A1 US 2009053792 W US2009053792 W US 2009053792W WO 2010019828 A1 WO2010019828 A1 WO 2010019828A1
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Prior art keywords
phenyl
enyl
substituted
alkyl
compound
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PCT/US2009/053792
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French (fr)
Inventor
Jorge E. Gomez-Galeno
Scott J. Hecker
Qun Dang
Matthew P. Grote
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Metabasis Therapeutics, Inc.
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Publication of WO2010019828A1 publication Critical patent/WO2010019828A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • 61/088,562 (Attorney Ref: MTI.091); 61/088,613 (Attorney Ref: MTI.083); 61/088,619 (Attorney Ref: MTI.081); 61/088,627 (Attorney Ref: MTI.089); 61/088,631
  • 61/088,643 (Attorney Ref: MTI.092); 61/088,644 (Attorney Ref: MTI.086); 61/088,646
  • compositions comprising one or more of such compounds, and methods of their use for treating, preventing, or ameliorating a glucoregulatory or glucagon receptor-mediated disease.
  • Glucagon is a 29-amino acid pancreatic hormone which is secreted from the pancreatic ⁇ cells into the portal blood supply in response to hypoglycemia and acts as a counterregulatory hormone to insulin. Most of the physiological effects of glucagon are mediated by its interaction with a glucagon receptor in the liver, followed by activation of adenylate cyclase to increase the intracellular cAMP levels. The result is an increase in glycogenosis and gluconeogenesis, while attenuating the ability of insulin to inhibit these metabolic processes (Johnson et al., J. Biol. Chem. 1972, 247, 3229-3235).
  • Diabetes is a disease characterized by elevated levels of plasma glucose. Uncontrolled hyperglycemia is associated with an increased risk for microvascular and macrovascular diseases, including nephropathy, retinopathy, hypertension, stroke, and heart disease. Control of glucose homeostasis is a major approach to the treatment of diabetes.
  • one of the potential treatments for diabetes, glucoregulatory and metabolic disorders, and glucagon receptor-mediated diseases is to block a glucagon receptor with a glucagon receptor antagonist to improve insulin responsiveness, to decrease the rate of gluconeogenesis, and/or to lower plasma glucose levels by reducing the rate of hepatic glucose output in a patient.
  • X is 1,4-phenyIene, 2-4-thienylene or 2,5-thienylene;
  • R b is selected from R a , hydroxyl, fluoro, and -(CH 2 )pOR c ;
  • R a and R c are selected from H, and d -3 -alkyl;
  • p is 0 or 1 ;
  • m is 1, 2 or 3;
  • A is selected from B a is selected from null and -CHR a ;
  • B b is selected from B a , -O-, -S-, -NR a -, -C(O)-, -S(O)-, -S(O) 2 -, and -CF 2 -;
  • E is selected from C 1- 12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 3-8 -cycloalkyl, C 4-8 - cycloalkenyl, aryl, heteroaryl, C 3-8 -cycloalkyl-substituted aryl, C 4 .8-cycloalkenyl-substituted aryl, phenyl-substituted aryl, C3-8-cycloalkyl-substituted heteroaryl, C 4-8 -cycloalkenyl- substituted heteroaryl, phenyl-substituted heteroaryl, C 3-8 -cycloalkyl-C 1-6 -
  • D is a substituted group selected from C 1-6 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-8 - cycloalkyl, C 4-8 -cycloalkenyl, aryl, C 1-8 -alkyl-aryl, heteroaryl, C 1-8 -alkyl-heteroaryl, heterocyclyl or C 1-8 -alkyl-heterocyclyl, wherein said group is substituted with L and, optionally, one or more additional groups;
  • L is a group selected from hydrogen, alkyl, aryl, aryloxy, arylalkoxy, aryl-N(R a )-, heteroaryl, heteroaryloxy-, heteroarylalkoxy, heteroaryl-N(R a )-, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy-, cycloalkyloxy-, cycloalkyl-N(R a )-, heterocyclyl, heterocyclyloxy-, heterocyclylalkoxy-, heterocyclyl-N(R a )-, alkenyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkenylalkyloxy, or alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocarbocycle or a spiroheterocyclic ring
  • Z a is selected from a bond, -CR a 2 -, -C(O)N(R a )-, -C(O)O-, -C(O)-, -C(O)C(R a ) 2 -, - C(R a ) 2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR a -, -S(O) 2 C(R a ) 2 -, and -S(O)C(R a ) 2 -, Z b is selected from Z a , -O-, -S-, -N(R a )-, -N(R a )C(R a ) 2 -, -N(R a )C(O)-, -OC(R a ) 2 -, -SC(R a ) 2 -, -C(R a )
  • R a is selected from H, and methyl
  • A is selected from , and
  • B a is selected from null and -CHR a ;
  • B b is selected from B a , -O-, and -CF 2 -;
  • E is selected from C 1- i 2 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, napthyl, thienyl, benzothienyl, quinolyl, cyclohexyl-substituted phenyl, cyclohexenyl-substituted phenyl, phenyl-substituted phenyl, cyclohexylmethyl, cyclohexenylmethyl, benzyl, phenoxy, cyclohexyl-substituted benzyl, cyclohexenyl- substituted benzyl, phenyl-substituted benzyl, each optionally substituted;
  • D is a substituted group selected from phenyl, thiazolyl, oxazolyl, indolyl, or isoxazolyl wherein said group is substituted with L and, optionally, one or more additional groups;
  • L is a group selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, phenoxy-, benzyloxy-, cyclohexyl, cyclohexylmethyl, cyclohexylmethoxy-, cyclohexyloxy-, cyclohexyl-N(R a )-, alkenyl, cyclohexenyl, alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocyclohexyl; wherein said group, excluding hydrogen, is optionally substituted;
  • Z a is selected from a bond, -CR a 2 -, -C(O)N(R 3 )-, -C(O)O-, -C(O)-, -C(O)C(R a ) 2 -, - C(R a ) 2 C(O)- and -S(O) 2 NR a -;
  • Z b is selected from Z a , -O-, -N(R a )-, -N(R a )C(R a ) 2 - -OC(R a ) 2 -, -C(R a ) 2 N(R a )-, and
  • compositions comprising a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers.
  • compounds and pharmaceutical compositions comprising compounds of Formula I or Formula I-A are provided, including pharmaceutically acceptable salts or co-crystals, and prodrugs thereof which have glucagon receptor antagonist or inverse agonist activity.
  • pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucagon receptor antagonist is indicated, including Type I and II diabetes, insulin resistance and hyperglycemia.
  • methods of making or manufacturing compounds of Formula I or Formula I-A, and pharmaceutically acceptable salts or co-crystals, and prodrugs thereof are also provided.
  • the present invention relates to compounds having glucagon receptor antagonist or inverse agonist activity, and methods for their use provided.
  • the present invention also relates to pharmaceutically acceptable salts and co-crystals, prodrugs, and pharmaceutically acceptable salts and co-crystals of these prodrugs of these compounds.
  • the invention relates to compounds and pharmaceutical compositions comprising a compounds provided herein, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers.
  • glucagon receptor antagonists include Type I and II diabetes, insulin resistance and hyperglycemia. Also provided are methods of making or manufacturing compounds provided herein, and pharmaceutically acceptable salts or co-crystals, and prodrugs thereof.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • treat means to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • prevent are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptom(s); barring a subject from acquiring a disease; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • terapéuticaally effective amount are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • pharmaceutically acceptable carrier refers to a pharmaceutical ly-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • each component is "pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • glucagon receptor refers to a glucagon receptor protein or variant thereof, which is capable of mediating a cellular response to glucagon in vitro or in vivo.
  • GCGR variants include proteins substantially homologous to a native GCGR, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions (e.g., GCGR derivatives, homologs, and fragments), as compared to the amino acid sequence of a native GCGR.
  • the amino acid sequence of a GCGR variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native GCGR.
  • the GCGR is a human glucagon receptor.
  • glucagon receptor antagonist or "GCGR antagonist” refers to a compound that, e.g., partially or completely blocks, decreases, prevents, inhibits, or downregulates GCGR activity. There terms also refer to a compound that binds to, delays the activation of, inactivates, or desensitizes GCGR. A GCGR antagonist may act by interfering with the interaction of glucagon with GCGR.
  • GCGR-mediated condition, disorder, or disease refers to a condition, disorder, or disease characterized by inappropriate, e.g., less than or greater than normal or for the physiological conditions, GCGR activity.
  • GCGR-mediated condition, disorder or disease may be completely or partially mediated by inappropriate GCGR activity.
  • a GCGR-mediated condition, disorder or disease is one in which modulation of GCGR results in some effect on the underlying symptom, condition, disorder, or disease, e.g., a GCGR antagonist results in some improvement in at least some of patients being treated.
  • alkyl and the prefix “alk” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents.
  • alkyl also encompasses linear, branched, and cyclic alkyl, unless otherwise specified.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C
  • linear C 1-6 and branched C 3-6 alkyl groups are also referred as "lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, t- butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
  • C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • Cycloalkyl also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds.
  • the alkenyl may be optionally substituted with one or more substituents.
  • alkenyl also embraces radicals having "cis” and “trans” configurations, or alternatively, "E” and “Z” configurations, as appreciated by those of ordinary skill in the art.
  • alkenyl encompasses both linear and branched alkenyl, unless otherwise specified.
  • C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C 2 -I 5 ), 2 to 12 (C2-12), 2 to 10 (C 2 .io), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3 -is), 3 to 12 (Cs -I2 ), 3 to 10 (C3-io), or 3 to 6 (C 3.$) carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, isopropenyl, pentenyl, hexenyl, heptenyl, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, 2-butenyl, 2-methyl-2-butenyl, 4-methylbutenyl, and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds. The alkynyl may be optionally substituted one or more substituents.
  • alkynyl also encompasses both linear and branched alkynyl, unless otherwise specified.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 12 (C 2 -I 2 ), 2 to 10 (C 2 -io), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3- 10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 3-methyl-1-pentynyl, 2-heptynyl, and the like.
  • C 2- 6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • cycloalkyl refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents.
  • the cycloalkyl has from 3 to 20 (C 3-20 ), from 3 to 15 (C 3-15 ), from 3 to 12 (C 3-12 ), from 3 to 10 (C 3-10 ), or from 3 to 7 (C 3-7 ) carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl.
  • cycloalkenyl refers to a cyclic unsaturated bridged and/or non-bridged monovalent hydrocarbon radical, which contains one or more double bonds in its ring.
  • the cycloalkenyl may be optionally substituted with one or more substituents.
  • the cycloalkenyl has from 3 to 20 (C 3-20 ), from 3 to 15 (C 3-12 ), from 3 to 12 (C 3-12 ), from 3 to 10 (C 3-10 ), or from 3 to 7 (C 3- 7) carbon atoms.
  • cycloalkynyl refers to a cyclic unsaturated bridged and/or non-bridged monovalent hydrocarbon radical, which contains one or more triple bonds in its ring.
  • the cycloalkynyl may be optionally substituted one or more substituents.
  • the cycloalkynyl has from 3 to 20 (C 3-20 ), from 3 to 15 (C 3-12 ), from 3 to 12 (C 3-12 ), from 3 to 10 (C 3-10 ), or from 3 to 7 (C3.7) carbon atoms.
  • aralkyl or "aryl-alkyl” refers to a monovalent alkyl group substituted with aryl. In certain embodiments, both alkyl and aryl may be optionally substituted with one or more substituents.
  • heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. In some embodiments, each ring contains 5 to 6 atoms.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyramidyl, pyridazinyl, triazolyl, tetrazolyl, and triazinyl.
  • bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzothiophenyl, fi ⁇ ro(2,3-b) pyridyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofiiranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.
  • tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl.
  • heteroaryl may also be optionally substituted with one or more substituents.
  • Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and aromatic heterocyclic groups fused to cycloalkyl rings. Heteroaryl also includes such groups in charged form, e.g., pyridinium.
  • heterocyclyl refers to a monocyclic non- aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclic radicals include, but are not limited to benzoxazinyl, benzodioxanyl, benzodioxolyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, chromanyl, chromonyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, 2,3- dihydrofuro(2,3-b)pyridyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1 ,4-dithianyl, imidazolidinyl, imida
  • Heterocyclyl/heterocyclic also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4- pyridones attached through the nitrogen or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils). Heterocyclyl/heterocyclic also includes such moieties in charged form, e.g., piperidinium. In certain embodiments, heterocyclyl/heterocyclic may also be optionally substituted with one or more substituents.
  • alkoxy refers to an -OR radical, wherein R is, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each as defined herein.
  • R is aryl, it is also known as aryloxy.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, w-propoxy, 2-propoxy, n-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzoxy, and 2-naphthyloxy.
  • alkoxy may also be optionally substituted with one or more substituents.
  • acyl refers to a -C(O)R radical, wherein R is, for example, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each as defined herein.
  • acyl groups include, but are not limited to, formyl, acetyl, propionyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, docosanoyl, myristoleoyl, palmitoleoyl, oleoyl, linoleoyl, arachidonoyl, benzoyl, pyridinylcarbonyl, and furoyl.
  • acyl may also be optionally substituted with one or more substituents.
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • the term "optionally substituted” is intended to mean that a group, including alkyl, alkoxy, acyl, alkyl-cycloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aryloxy, aralkyl, aryl-alkenyl, aryl-alkynyl, heteroaryl, heteroarylalkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, and heterocyclyl, or acyl, may be substituted with one or more substituents, in one embodiment, one, two, three, four substituents, where in some embodiments each substituent is independently selected from the group consisting of cyano, halo, oxo, nitro, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkyn
  • solvate refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • compounds are provided.
  • the compounds have glucagon receptor antagonist or inverse agonist activity.
  • the present invention also relates to pharmaceutically acceptable salts and co-crystals, prodrugs, and pharmaceutically acceptable salts and co-crystals of these prodrugs of these compounds.
  • Preferred compounds of the present invention include those of Formula I, including those of Formula I-A as shown below.
  • the compounds of Formula I or Formula I-A may be a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compounds have Formula I:
  • X is 1,4-phenyIene, 2-4-thienylene or 2,5-thienylene;
  • R b is selected from R a , hydroxyl, fluoro, and -(CH 2 ) p OR a ;
  • R a and R c are selected from H, and Cijj-alkyl; p is O or 1 ; m is 1, 2 or 3; and A is selected from , , and
  • B a is selected from null and -CHR"
  • B b is selected from B a , -O-, -S-, -NR a -, -C(O)-, -S(O)-, -S(O) 2 -, and -CF 2 -;
  • E is selected from C 2-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 3-8 -cycloalkyl, C 4-8 - cycloalkenyl, aryl, heteroaryl, C 3-8 -cycloalkyl-substituted aryl, C 4-8 -cycloalkenyl-substituted aryl, phenyl-substituted aryl, C 3-8 -cycloalkyl-substituted heteroaryl, C 4-8 -cycloalkenyl- s ⁇ bstituted heteroaryl, phenyl-substituted heteroaryl, C 3-8 -cycloalkyl
  • D is a substituted group selected from C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-8 - cycloalkyl, C 4-8 -cycloalkenyl, aryl, C 1-8 -alkyl-aryl, heteroaryl, C 1-8 -alkyl-heteroaryl, heterocyclyl or C 1-8 -alkyl-heterocyclyl, wherein said group is substituted with L and, optionally, one or more additional groups;
  • L is a group selected from hydrogen, alkyl, aryl, aryloxy, arylalkoxy, aryl-N(R a )-, heteroaryl, heteroaryloxy-, heteroarylalkoxy, heteroaryl-N(R a )-, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy-, cycloalkyloxy-, cycloalkyl-N(R a )-, heterocyclyl, heterocyclyloxy-, heterocyclylalkoxy-, heterocyclyl-N(R a )-, alkenyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkenylalkyloxy, or alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocarbocycle or a spiroheterocyclic ring
  • Z a is selected from a bond, -CR a 2 -, -C(O)N(R a )-, -C(O)O-, -C(O)-, -C(O)C(R a ) 2 -, - C(R a ) 2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR a -, -S(O) 2 C(R a ) 2 --, and -S(O)C(R a ) 2 --,
  • R a may be selected from H, and methyl.
  • R b may be H and m may be 2.
  • B B may be selected from null, -CH 2 - and -CHMe-; and B b may be selected from B a , -O-, - NH-, -NMe-, and -C(O)-.
  • B b may be selected from null, -CH 2 - and -CHMe-, -O-, -NH-, -NMe-, and -C(O)-.
  • A may be selected from the group consisting of:
  • D may be selected from the group consisting of:
  • E may be selected from the group consisting of: 3-t- butoxyphenyl, 4-t-butoxyphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 3-(3,3-dimethylbut-1- enyl)phenyl, Z-3-(3,3-dimethylbut-1-enyl)phenyl, 4-(3,3-dimethylbut-1-enyl)phenyl, Z-A- (3,3-dimethylbut-1-enyl)phenyl, 3-(4-t-butylcyclohex-1-enyl)phenyl, 4-(4-t-butylcyclohex-1- enyl)phenyl, 3-(4-t-butylcyclohexyl)phenyl, 4-(4-t-butylcyclohexyl)phenyl, 4-(4-t-butylcyclohexyl)phenyl, 4-(4-t-butylcyclohexyl)
  • L may be selected from the group consisting of: hydrogen, trifluoromethyl, trifluoromethoxy, chloro, r-butyl, 3,3-dimethylbut-1-enyl, 4,4- dimethylcyclohex- 1-enyl, t-butyl-cyclohexane, t-butyl-cyclohex-1-enyl, cyclohex-1-enyl, 2,4-bis(trifluoromethyl)-phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-chlorophenyl, 4- chlorophenyl, 4-chloro-3-cyclopropylphenyl, 4-chloro-4-ethylphenyl, 4-chloro-2- fluorophenyl, 4-chloro-2-isopropylphenyl, 2-chloro-4-methylphenyl, 4-chloro-2- methylphenyl, 2-chloro-4-trifluoromethylphenyl,
  • — may represent an optionally substituted group selected from the group consisting of:
  • Z a may be selected from a bond, — CH 2 -, -CH(Me)-, - C(O)NH-, -C(O)O-, -C(O)-, and - CH 2 C(O)-.
  • Z b may be selected from Z a , -O-, -NH-, -CH 2 O-, and -CH 2 NH-.
  • the compounds have Formula I-A
  • R a is selected from H, and methyl
  • A is selected from , and
  • B a is selected from null and -CHR a ;
  • B b is selected from B a , -O-, and -CF 2 -;
  • E is selected from C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, napthyl, thienyl, benzothienyl, quinolyl, cyclohexyl-substituted phenyl, cyclohexenyl-substituted phenyl, phenyl-substituted phenyl, cyclohexylmethyl, cyclohexenylmethyl, benzyl, phenoxy, cyclohexyl-substituted benzyl, cyclohexenyl- substituted benzyl, phenyl-substituted benzyl, each optionally substituted;
  • D is a substituted group selected from phenyl, thiazolyl, oxazolyl, indolyl, or isoxazolyl wherein said group is substituted with L and, optionally, one or more additional groups;
  • L is a group selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, phenoxy-, benzyloxy-, cyclohexyl, cyclohexylmethyl, cyclohexylmethoxy-, cyclohexyloxy-, cyclohexyl-N(R a )-, alkenyl, cyclohexenyl, alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocyclohexyl; wherein said group, excluding hydrogen, is optionally substituted;
  • Z a is selected from a bond, -CR a 2 -, -C(O)N(R a )-, -C(O)O-, -C(O)-, -C(O)C(R a ) 2 -, - C(R a ) 2 C(O)-, and -S(O) 2 NR a -;
  • Z b is selected from Z a , -O-, -N(R a )-, -N(R a )C(R a ) 2 -, -OC(R a ) 2 -, -C(R a ) 2 N(R a )-, and ⁇ C(R a ) 2 O-; represents a phenyl or an heterocycle containing 1-2 nitrogen atoms or 0-2 oxygen atoms, wherein said group is optionally substituted; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • B a may be selected from null, -CH 2 - and -CHMe-.
  • A may be selected from the group consisting of:
  • D may be selected from the group consisting of:
  • L and A represent the points of attachment to L and A moieties, respectively.
  • E may be selected from 3-t-butoxyphenyl, 4-t- butoxyphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 3-(3,3-dimethylbut-1-enyl)phenyl, Z-3-(3,3- dimethylbut- 1 -enyl)phenyl, 4-(3,3-dimethylbut- 1 -enyl)phenyl, Z-4-(3,3-dimethylbut-l - enyl)phenyl, 3-(4-t-butylcyclohex-1-enyl)phenyl, 4-(4-t-butylcyclohex-1-enyl)phenyl, 3-(4-t- butylcyclohexyl)phenyl, 4-(4-t-butylcyclohexyl)phenyl, 4-(4-t-butylphenyl)phenyl, 3-(4,4- dimethyl-cyclohex-1
  • L may be selected from hydrogen, trifluoromethyl, trifluoromethoxy, chloro, f-butyl, 3,3-dimethylbut-1-enyl, 4,4-dimethylcyclohex-1-enyl, t- butyl-cyclohexane, t-butyl-cyclohex-1-enyl, cyclohex-1-enyl, 2,4-bis(trifluoromethyl)- phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-chlorophenyl, 4-chlorophenyl, 4-chlorophenyl, 4-chloro-3- cyclopropylphenyl, 4-chloro-4-ethylphenyl, 4-chloro-2-fluorophenyl, 4-chloro-2- isopropylphenyl, 2-chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 2-chloro-4- trifluoromethylphenyl, 3
  • R a , R b , B a , B b , A, D, E, L, , Z a , and Z b may simultaneously be selected from such groupings or any selected subgrouping.
  • the compounds of Formula I or Formula I-A may be a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • Exemplary compounds include those shown in Example 1.
  • each functionality or substituent appearing at any location within the disclosed compounds may be independently selected, and as appropriate, independently substituted.
  • a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.
  • All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
  • the compounds of the present invention can have stereogenic centers. Consequently, the compounds can exist in enantiomeric or diastereomeric forms or in mixture thereof.
  • the processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
  • THF Tetrahydrofuran
  • DME 1,2-Dimethoxyethane
  • DMF N,N- Dimethylformamide
  • DCC N, N'-Dicyclohexylcarbodiimide
  • EDCI or EDC l-(3- Di methylaminopropyl)-3 -ethyl carbodiimide hydrochloride
  • LiHMDS Lithium hexamethyldisilyl azide
  • HOBt 1-Hydroxybenzotriazole
  • EtOAc Ethyl acetate
  • EtOH Ethanol
  • IPA iso-Propanol
  • ACN Acetonitrile
  • DIPEA N,N-Diisopropyl-ethyl amine
  • MTBE Methyl-teit-butyl ether
  • the carboxylic acids 3 are converted to the corresponding amides by methods known for amide bond formation reactions.
  • generation of an acid chloride 2 from 1 takes place under standard conditions (e.g. thionyl chloride in toluene or oxalyl chloride and catalytic DMF in dichloromethane).
  • Treatment of acid chloride 2 with amines generates the amides of Formula I or I-A.
  • amines can be directly coupled with the carboxylic acid 4 by use of an activating agent (for example, DCC or EDCI with or without a catalyst such as DMAP or HOBT) to directly generate the amides of Formula I or I- A.
  • an activating agent for example, DCC or EDCI with or without a catalyst such as DMAP or HOBT
  • the amide bond in the last step can also be formed by other reported methods known for amide bond formation, for example, reaction of an N-hydroxysuccinimidyl ester of carboxylic acid 3 and an amine such as taurine gives the target taurine amide of Formula I-A.
  • Other activated esters e.g. pentafluorophenyl esters
  • compounds of the invention may be resolved to enantiomerically pure compositions or synthesized as enantiomerically pure compositions using any method known in art.
  • compounds of the invention may be resolved by direct crystallization of enantiomer mixtures, by diastereomer salt formation of enantiomers, by the formation and separation of diasteriomers or by enzymatic resolution of a racemic mixture.
  • reaction methodologies may be useful in preparing the compounds of the invention, as recognized by one of skill in the art.
  • Various modifications to the above schemes and procedures will be apparent to one of skill in the art, and the invention is not limited specifically by the method of preparing the compounds of the invention.
  • the methods of the invention comprise administering a therapeutically effective amount of at least one compound of the invention, e.g., a compound of Formula I or Formula I-A.
  • Relative activity of the compounds of the invention may be determined by any method known in the art, including the assays described herein.
  • the invention relates to methods of treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease associated with a glucagon receptor, impaired glucose tolerance, or a metabolic syndrome, comprising administering to a subject having or being suspected to have such a condition, disorder, or disease, a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • the subject is a mammal. In another embodiment, the subject is a human.
  • the invention relates to methods of treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease responsive to the modulation of a glucagon receptor, comprising administering to a subject having or being suspected to have such a condition, disorder, or disease, a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • the subject is a mammal. In another embodiment, the subject is a human.
  • Yet other aspects relate to methods of treating, preventing, or ameliorating one or more symptoms of a GCGR-mediated condition, disorder, or disease, comprising administering to a subject having or being suspected to have such a condition, disorder, or disease, a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • a compound provided herein e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • Yet other aspects relate to methods of treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease responsive to a decrease in the hepatic glucose production or in the blood glucose level of a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • a compound provided herein e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • Yet other aspects relate to methods of modulating the biological activity of a glucagon receptor, comprising contacting the receptor with one or more of the compounds provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • a compound of Formula I or Formula I-A including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • the conditions and diseases treatable with the methods provided herein include, but are not limited to, type 1 diabetes, type 2 diabetes, gestational diabetes, ketoacidosis, nonketotic hyperosmolar coma (nonketotic hyperglycaemia), impaired glucose tolerance (IGT), insulin resistance syndromes, syndrome X, low HDL levels, high LDL levels, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, dyslipidemia, arteriosclerosis, atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, vascular resenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, and lipid disorders.
  • a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, and/or topical (e.g., transdermal or local) routes of administration, and may be formulated alone or together in suitable dosage unit with a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof, appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant
  • topical e.g., transdermal or local
  • the dose may be in the form of one, two, three, four, five, six, or more sub-doses that are administered at appropriate intervals per day.
  • the dose or sub-doses can be administered in the form of dosage units containing from about 0.1 to about 1,000 mg, from about 0.1 to about 500 mg, or from 0.5 about to about 100 mg of active ingredient(s) per dosage unit, and if the condition of the patient requires, the dose can, by way of alternative, be administered as a continuous infusion.
  • an appropriate dosage level is about 0.01 to about 100 mg per kg patient body weight per day (mg/kg per day), about 0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, or about 0.05 to about 10 mg/kg per day, which may be administered in single or multiple doses.
  • a suitable dosage level may be about 0.01 to about 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about 0.1 to about 10 mg/kg per day. Within this range, the dosage may be about 0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg per day.
  • the pharmaceutical compositions can be provided in the form of tablets containing 1.0 to 1,000 mg of the active ingredient, particularly about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compositions may be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • glucagon receptor in still another embodiment, provided herein is a method of modulating the biological activity of a glucagon receptor, comprising contacting the receptor with one or more of the compounds provided herein, e.g., a compound of Formula I, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
  • the glucagon receptor is expressed by a cell.
  • a compound provided herein is able to displace radiolabeled glucagon from the human glucagon receptor by at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 8
  • the activity of a compound provided herein is described in terms of the concentrations of compound required for the displacement of 50% of the radiolabeled glucagon from the human glucagon receptor (the ICso values).
  • the IC50 value of a compound provided herein is less than ⁇ 10,000 nM, 9,000 nM, 8,000 nM, 7,000 nM, 6,000 nM, 5,000 nM, 4,000 nM, 3,000 nM, 2,000 nM, 1,000 nM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM or 5 nM.
  • the activity of a compound provided herein is described in terms of the concentrations of compounds required for functional antagonism of glucagon in hepatocytes from various species (EC 5 0).
  • the EC 5 0 value for a compound provided herein is less than ⁇ 10,000 nM, 9,000 nM, 8,000 nM, 7,000 nM, 6,000 nM, 5,000 nM, 4,000 nM, 3,000 nM, 2,000 nM, 1,000 nM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM or 5 nM.
  • a compound provided herein exhibits the ability to reduce blood glucose in an animal.
  • circulating blood glucose in fasting or non-fasting (freely-feeding) animals can be reduced between 10% and 100%.
  • a reduction of 100% refers to complete normalization of blood glucose levels, not 0% blood glucose levels.
  • Normal blood glucose in rats for example, is approximately 80 mg/dL (fasted) and approximately 120 mg/dL (fed).
  • an excessive circulating blood glucose level in a fasting or freely fed animal e.g.
  • rat is reduced, after administration of 10 mg/kg of a compound provided herein, by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,
  • the compounds provided herein may also be combined or used in combination with other therapeutic agents useful in the treatment, prevention, or amelioration of one or more symptoms of the conditions, disorders, or diseases for which the compounds provided herein are useful.
  • the methods generally comprise the step of administering to a patient in need thereof, such as an animal subject including a human subject, an effective amount of a compound of the invention.
  • compositions useful in the methods of the invention are provided.
  • the pharmaceutical compositions of the invention may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form.
  • the pharmaceutical compositions should generally be formulated to achieve a physiologically compatible pH, and may range from a pH of about 3 to a pH of about 11 , preferably about pH 3 to about pH 7, depending on the formulation and route of administration. In alternative embodiments, it may be preferred that the pH is adjusted to a range from about pH 5.0 to about pH 8.0.
  • compositions comprising a compound provided herein as an active ingredient, e.g., a compound of Formula I, I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof.
  • a pharmaceutically acceptable vehicle, carrier, diluent, excipient or a mixture thereof.
  • the pharmaceutical compositions may be formulated in various dosage forms, including, but limited to, the dosage forms for oral, parenteral, or topical administration.
  • compositions may also be formulated as modified release dosage forms, including, but not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • modified release dosage forms including, but not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modifled-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2003; Vol. 126).
  • the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, e.g., a compound of Formula I or Formula I- ⁇ , including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof.
  • a compound provided herein e.g., a compound of Formula I or Formula I- ⁇ , including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof.
  • a compound provided herein e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof.
  • a compound provided herein e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions provided herein.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents. It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
  • compositions provided herein may be administered parenteral Iy by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • the pharmaceutical compositions provided herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).
  • compositions provided herein may be administered topically to the skin, orifices, or mucosa.
  • topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
  • compositions provided herein may be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches.
  • the topical formulation of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
  • compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • modified release refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • the pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
  • the pharmaceutical compositions provided herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action. Coloring and flavoring agents can be used in all of the dosage forms described herein.
  • compositions provided herein may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those described in U.S. Pat. Nos.
  • any suitable components known in the art for the desired formulation may be used, as outlined in U.S. Provisional Application Nos. 61/088,562; 61/088,613; 61/088,619; 61/088,627; 61/088,631; 61/088,635; 61/088,638; 61/088,640; 61/088,642; 61/088,643; 61/088,644; 61/088,646; 61/088,647; 61/088,648; the contents of which are herein incorporated by reference.
  • Combination Therapy It is also possible to combine any compound of the present invention with one or more other active ingredients useful in the methods described herein, including compounds in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequential administration to a patient in need of treatment. When administered sequentially, the combination may be administered in two or more administrations. In an alternative embodiment, it is possible to administer one or more compounds of the present invention and one or more additional active ingredients by different routes.
  • a first therapeutic agent e.g., a therapeutic agent such as a compound provided herein
  • a first therapeutic agent can be administered prior to (e.g., 5 min, 15 min, 30 min, 45 min, 1 hr, 2 hrs, 4 hrs, 6 hrs, 12 hrs, 24 hrs, 48 hrs, 72 hrs, 96 hrs, 1 wk, 2 wks, 3 wks, 4 wks, 5 wks, 6 wks, 8 wks, or 12 wks before), concomitantly with, or subsequent to (e.g., 5 min, 15 min, 30 min, 45 min, 1 hr, 2 hrs, 4 hrs, 6 hrs, 12 hrs, 24 hrs, 48 hrs, 72 hrs, 96 hrs, 1 wk, 2 wks, 3 wks, 4 wks, 5 wks, 6 wks, 8 wks, or 12 wks after
  • the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
  • the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • simultaneous therapy effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • combination therapy with compounds of this invention maybe useful in reducing the dosage of the second drug or agent.
  • the compounds of the present invention can be administered in combination with anti-diabetic pharmaceutical agents.
  • Suitable antidiabetic agents include, but are not limited to, insulin sensitizers, biguanides (e.g., buformin, metformin, and phenformin), PPAR agonists (e.g., troglitazone, pioglitazone, and rosiglitazone), insulin and insulin mimetics, somatostatin, ⁇ -glucosidase inhibitors (e.g., voglibose, miglitol, and acarbose), dipeptidyl peptidase-4 inhibitors, liver X receptor modulators, insulin secretogogues (e.g., acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glybur
  • insulin sensitizers e.g
  • a cholesterol absorption inhibitor e.g., ezetimibe
  • sequestrants nicotinyl alcohol, nicotinic acid and salts thereof, PPAR ⁇ agonists, PPAR ⁇ / ⁇ dual agonists, inhibitors of cholesterol absorption, acyl CoAxholesterol acyltransferase inhibitors, antioxidants, PPAR ⁇ agonists, antiobesity compounds, ileal bile acid transporter inhibitors, anti-inflammatory agents, and protein tyrosine phosphatase- IB (PTP-IB) inhibitors.
  • PTP-IB protein tyrosine phosphatase- IB
  • the dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • the weight ratio of a compound provided herein to the second active ingredient depends upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the weight ratio of the compound provided herein to the PPAR agonist will generally range from about 1000:1 to about 1:1000 or about 200:1 to about 1:200.
  • Combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • Example 1-A Ammonium 2-(4-r2-(4'-tert-butyl-biphenyl-4-yl)-2-(4'-chloro-3'-methyl- biphenyl-4-vD-ethyl1benzoylamino>-ethanesulfonate
  • Step A 4-bromobenzaldehyde (1.0 g, 5.4 mmol) was added to a 100 mL RB flask containing 4-chloro-2-methylphenylboronic acid (2.7 g, 15.8 mmol), sodium carbonate (3.4 g, 32.07 mmol), and dichlorobis(tri-o-tolylphosphine)palladium(II) (544 mg, 0.69 mmol).
  • Step B To a 100 mL RB flask equipped with an addition funnel and a reflux condenser was added magnesium turnings (140 mg, 5.7 mmol), ether (10 mL), and a crystal of iodine. A solution of p-dibromobenzene (1.35 g, 5.7 mmol) in ether (10 mL) was added dropwise at such a rate to maintain reflux. This solution was allowed to stir for 1.5 h, at which point the crude Grignard reagent was carried to the next step without purification.
  • Step C To the crude Grignard reagent (5.7 mmol) in Ether (20 mL) at -78 °C was added 4'-Chloro-2'-methyl-biphenyl-4-carbaldehyde (1.1 g, 4.7 mmol) in Ether (10 mL) in a dropwise fashion. The reaction was stirred at -78 °C for 30 minutes, at which point the cooling bath was removed and it was allowed to warm to room temperature, where it was stirred for an additional 1 hour before being quenched with a solution of saturated aqueous ammonium chloride. The reaction mixture was diluted with Et 2 O, and the organic layer was separated, washed with brine and dried over sodium sulfate.
  • Step D (4-Bromo-phenyl)-(4'-chloro-2'-methyl-biphenyl-4-yl)-methanol (1.0 g, 2.6 mmol) was added to a 100 mL RB flask containing 4-tert-butylphenylboronic acid (1.4 g, 7.8 mmol), sodium carbonate (1.65 g, 15.6 mmol), and dichlorobis(tri-o- tolylphosphine)palladium(II) (304 mg, 0.33 mmol).
  • Step E To a solution of (4'-tert-Butyl-biphenyl-4-yl)-(4'-chloro-2'-methyl- biphenyl-4-yl)-methanol (350 mg, 0.8 mmol) in dichloromethane (10 mL) at 0 °C was added Dess-Martin periodinane (3.3 mL of a 0.48M solution, 1.6 mmol). The reaction was stirred at 0 °C for 30 minutes, at which point TLC analysis indicated it had gone to completion. The cooling bath was removed, and the reaction was warmed to room temperature.
  • Step F A solution of 4-Bromomethyl-benzoic acid ethyl ester (3.0 g, 13 mmol) in triethylphosphite (30 mL) was heated to 150 °C for 30 minutes, at which point TLC analysis indicated the reaction had gone to completion. The remaining triethylphosphite was removed by distillation at reduced pressure, and the product was cooled to room temperature. The product, 4-(diethoxy-phosphorylmethyl)-benzoic acid ethyl ester was thereby obtained as a colorless oil (3.8 g, 99%).
  • Step G To a solution of 4-(diethoxy-phosphorylmethyl)-benzoic acid ethyl ester (221 mg, 0.74 mmol) in THF (5 mL) at -78 °C was added LHMDS (0.75 mL of a IM solution in toluene, 0.75 mmol). The reaction was stirred at -78 °C for 15 minutes, then was allowed to warm to 0 °C and was stirred for an additional 15 minutes.
  • LHMDS 0.75 mL of a IM solution in toluene, 0.75 mmol
  • Step H To a solution of 4-[-2-(4'-tert-Butyl- biphenyl-4-yl)-2-(4'-chloro-2 > - methyl-biphenyl-4-yl)-vinyl]-benzoic acid ethyl ester (320 mg, 0.55 mmol) in ethyl acetate (10 mL) was added platinum dioxide. The reaction was shaken under 40 psi hydrogen gas for Ih, then passed through a 0.45 ⁇ m syringe filter.
  • Step I To a solution of 4-[2-(4'-tert-Butyl-biphenyl-4-yl)-2-(4'-chloro-2'-methyl- biphenyl-4-yl)-ethyl]-benzoic acid ethyl ester (310 mg, 0.53 mmol) in methanol (5 mL) was added NaOH (2.5 mL of a 3.5 N solution, 8.75 mmol) followed by THF (5 mL), and the reaction was stirred 14 hours. The solvents were removed by rotary evaporation, and the residue was partitioned between ethyl acetate and 0.5 N HCl.
  • Step J To a solution of EDCI (154 mg, 0.8 mmol) in DMF (8 mL) was added HOBt (123 mg, 0.8 mmol) and 4-[2-(4'-tert-Butyl-biphenyl-4-yl)-2-(4'-chloro-2'-methyl- biphenyl-4-yl)-ethyl]-benzoic acid (290 mg, 0.51 mmol). This reaction was stirred 30 minutes, at which point taurine (135 mg, 1.02 mmol) and HOnig's base (0.35 mL, 2.04 mmol) were added, and the reaction was stirred for an additional 14 hours.
  • Example 1-B Ammonium 2-[4-(((4'-tert-butyl-biphenyl-4-yl')-[4-(4'-chloro-2'-methyl- biphenyl-4-yl)-thiazol-2-yl]-amino ⁇ -methyl)-benzoylamino]-ethanesulfonate [00151]
  • Step A A mixture of 4-iodoaniline (5g), 4-t-butylphenylboronic acid (4.88g), PdCl2(P(o-tol)3) 2 (896 mg) and sodium carbonate (7.2g) in dimethoxyethane (40mL)/ethanol (20 mL)/water (10 mL) was heated at 125 °C for a 20 min period.
  • Step B A mixture of the product from Step 1 above (113 mg), 4-formylbenzoate methyl ester (82 mg), sodium cyanoborohydride (126 mg) and acetic acid (0.2 mL) in DMF (2 mL) was stirred at 110 °C for Ih. The mixture was partitioned between ether and water. The organic layer was washed (water, sat aq. sodium chloride) and dried (magnesium sulfate). Concentration under reduced pressure and chromatography on silica gel using an ethyl acetate/hexanes gradient afforded the product as a white powder.
  • Step D A mixture of the bromide from Step 3 above (100 mg), 2-methyl-4- chlorophenyl boronic acid (83 mg), PdCl 2 (P(o-tol) 3 ) 2 (13 mg) and sodium carbonate (84 mg) in dimethoxyethane (6mL)/ethanol (3 mL)/water (1.5 mL) was heated at 125 °C for a 10 min period. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate.
  • Step E A mixture of the product from step 4 above (100 mg), hydroxybenzotriazol hydrate (26 mg), EDCI (32 mg), taurine (32 mg) and N,N-diisopropyl ethyl amine (40 ⁇ L) in DMF was stirred at room temperature was stirred at room temperature for 16 h. The crude mixture was loaded on a C-18 flash chromatography column and eluted with an acetonitri Ie: water gradient.
  • the product-containing fractions were pooled and chromatographed again on a C-18 HPLC column (Phenomenex, Gemini, C 18, 5 micron, AXIA, 30mmIDxl50mmL) eluting with a gradient of aqueous ammonium bicarbonate (20 mM) and acetonitri Ie (50% to 100% acetonitrile over 20 min) at 30 mL/min to yield the compound illustrated immediately above as the ammonium salt.
  • Example 1-C 2-(4-(2-(4-tert-Butyl-phenv ⁇ -2-r4-(2'.4'-dichlorobiphenyl-4-vn-1H-imidazol- 2-yll-ethyl)benzo ⁇ lamino)-ethanesulfonic acid
  • Step A To a stirred solution of 4-[2-(4-tert-Butylphenyl)-2-carboxyethyl]-benzoic acid methyl ester (l.Og, generated as reported in Bioorg Med Chem Lett 14, 2047-2050 (2004)) in DMF added cesium carbonate (1.955g) and allowed to react for a Ih period. The solvent was removed under reduced pressure. The residue was redissolved in methanol and treated with 4-bromophenacyl bromide (0.97g). The resulting mixture was stirred at room temperature for additional 16h and concentrated under reduced pressure. The crude product in toluene (50 mL) was treated with ammonium acetate (1.5g) and heated to reflux for a 4h period.
  • Steps B-C Using the conditions described in Example 1-B, Steps D and E, the product from Step A above was converted into the title compound.
  • LCMS: [M+H] + 676.2, 678.2. Elemental Analysis: Calculated for C 36 H 35 N 3 O 4 Cl 2 S + (2.0)H 2 O+(0.7)CH 3 OH. C: 59.96, H: 5.73, N: 5.72; Found: C: 60.19, H: 6.12, N: 5.35.
  • Example 1-D 2-f 4-r2-r4-(4-Benzofuran-2-vO-l H-imidazol-2-v ⁇ -2-(4-tert-butyl-phenyn- ethyll-benzoylaminol -ethanesulfonic acid
  • Example 1 -E 2-(4- (S. ⁇ -Dichloro-S-methyl ⁇ -frEM-trifluoromethoxy-phenyliminoi ⁇ J- dihvdro-benzoim idazol- 1 -ylmethyl ⁇ -benzoy laminoVethanesulfonic acid [00159] A solution of 0.38g of 4- ⁇ 5,6-dichloro-3-methyl-2-[(E)-4-trifluoromethoxy- phenylimino]-2,3-dihydro-beiizoimidazol-1-ylmethyl ⁇ -benzoic acid (prepared as reported in WO05065680, UA20070105930, US07301036) in DMF (15 mL) was treated with taurine (286 mg), HOBt-H 2 O (0.22g), EDCI ( 0.284g) and DIPEA (0.4 mL).
  • Example 1-F 2-(4- ⁇ -[6-(4-Isobutyl-phenyl ' )-pyridin-3-yloxy1-butvU-benzoylamino ' )- ethanesulfonic acid
  • Step A In an oven dried flask, terephthaldehydic acid monomethyl ester (1.5 g, 9.1 mmol) in 20 mL THF was cooled to -50 °C in a dry ice/isopropanol bath. This solution was then charged with TiCU (1.0 mL, 9.1 mmol). The solution was allowed to warm to 0 °C, then was treated with w-propyl magnesium chloride (6.8 mL of a 2.0 M solution in diethyl ether, 13.7 mmol) and was allowed to warm to room temperature over one hour, and was then stirred at room temperature for an additional hour.
  • Step B 4-(l-Hydroxy-butyl)-benzoic acid methyl ester (343 mg, 1.64 mmol) and 2-chloro-5-hydroxypyridine (320 mg, 2.47 mmol) in toluene (5 mL) at 0 °C was added 1,1 '- (azodicarbonyl)dipiperidine (623 mg, 2.47 mmol) followed by tributylphosphine (0.34 mL, 2.47 mmol). THF (5 mL) was added to facilitate stirring and the reaction was allowed to warm to room temperature, where it was stirred for 2 hrs. The reaction was concentrated to dryness by rotary evaporator.
  • Step C 4-[l-(6-Chloro-pyridin-3-yloxy)-butyl]-benzoic acid methyl ester (300 mg, 0.94 mmol) in toluene (3 mL) was treated with water (3 mL), tetrakis (triphenylphosphine) palladium (108 mg, 0.1 mol%), and 4-isobutylphenylboronic acid (334 mg, 1.87 mmol). This solution was heated to reflux for S min, at which point it was allowed to cool to room temperature. Potassium fluoride (109 mg, 1.87 mmol) was added in one portion, and the reaction was then heated at 90 °C for 16 hrs.
  • reaction was evaporated to dryness by rotary evaporator and purified by column chromatography on silica gel (100 x 42 mm S1O2) eluting with 10% acetone in hexanes to yield 4- ⁇ l-[6-(4-isobutyl-phenyl)-pyridin- 3-yloxy]-butyl ⁇ -benzoic acid methyl ester as a light yellow oil (353 mg, 90%).
  • Step D To a solution of 4- ⁇ l-[6-(4-isobutyl-phenyl)-pyridin-3-yloxy]-butyl ⁇ - benzoic acid methyl ester (418 mg, 1 mmol) in 2 mL of ethanol was added 2 mL of a 3.5 N solution of aqueous sodium hydroxide. THF (2 mL) was then added to clear the resulting suspension, and the reaction was stirred for 16 hrs. After evaporation to dryness, the residue was partitioned between ethyl acetate and water and was acidified with 2.4 N hydrochloric acid.
  • Step E To a solution of 4- ⁇ l-[6-(4-isobutyl-phenyl)-pyridin-3-yloxy]-butyl ⁇ - benzoic acid (412 mg, 1.02 mmol) in THF (10 mL) was added NJT- dicyclohexylcarbodiimide (DCC, 253 mg, 1.23 mmol) and N-hydroxysuccinimide (177 mg, 1.53 mmol) followed by a catalytic amount of 4-dimethylaminopyridine (DMAP, ⁇ 10 mg). This reaction was then stirred for 16 hrs before being evaporated to dryness.
  • DCC dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • Step F To a solution of 4- ⁇ l-[6-(4-Isobutyl-phenyl)-pyridin-3-yloxy]-butyl ⁇ - b ⁇ nzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (103 mg, 0.2 mmol) in ethanol (3 niL) in a microwave vial was added water (1 mL), taurine (52 mg, 0.4 mmol), and triethylamine (0.12 mL, 0.8 mmol). The vial was then heated in the microwave reactor at 125 °C for 6 min.
  • the reaction mixture was acidified using trifluoroacetic acid (TFA, excess, 0.2 mL) and taken up in 20% v/v acetonitrile.
  • TFA trifluoroacetic acid
  • the resulting solution was purified by preparatory HPLC on a Shimadzu modular HPLC system using a Waters Atlantis dC18 30 x 75 mm preparatory column and running a gradient from 40% acetonitrile to 100% acetonitrile over 13 min. TFA was used as an ionizer and was present in 0.05% (v/v). Detection was accomplished using an in-line UV detector running at 254 nm.
  • Example 1-G 2:2-(4-
  • Example 1-H 2-(4- ⁇ l-f6-f4-Isobutyl-phenyl ' >-pyridin-3-yloxy]-3.3-dimethyl-butyl ⁇ - benzoylaminoVethanesulfonic acid
  • Example 1-1 4:2-(4-ll-[6-(4-Isobutyl-phenvD-pyridin-3-yloxy]-ethv ⁇ -benzoylaminoV ethanesulfonic acid
  • Step A Ethyl-4-acetylbenzoate (550 mg, 2.86 mmol) was dissolved in ethanol (13 mL) and treated with sodium borohydride (10% on basic alumina, 300 mg). This suspension was heated to reflux for 2 hrs, then cooled to room temperature and filtered. The ethanol was removed by rotary evaporation; the residue was taken up in ethyl acetate and washed sequentially with IN HCl and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to yield racemic 4-(l-hydroxy-ethyl)-benzoic acid methyl ester as a colorless oil, 549 mg (99%).
  • Example 1 -J 2-C4-11 -F3-( 3.5-DichlorophenvD5-(6-methoxynaphthalen-2-v ⁇ -pyrazol-l -yll- ethyl t -benzoylam inoVethanesulfonic acid
  • a microwave reaction vial was loaded with a mixture of the starting carboxylic acid (144 mg), taurine (126 mg), l-ethyl-3- (3-dimethylaminopropyl)-carbodiimide (160 mg), 1 -hydroxybenzotriazole hydrate (127 mg), and diisopropylethylamine (0.458 mL), in DMF (6 mL).
  • the vial was capped and heated at 80 °C for a 4 minute period.
  • the crude sample was then treated with an excess of IM aqueous sodium hydroxide and flash chromatographed on C18-silica gel using an acetonitrile/water gradient.
  • Example 1-K 2-(4-(2-r5-chloro-1-(3-trifluoromethyl-phenv ⁇ -1H-indole-2-carbonyl]- heptvU-benzoylaminoVethanesulfonic acid:
  • Example 1-L Preparation of Preparation of 2-(4-((((l J R.4/?)-4-tert-butylcvclohexyn(l- methyl-5-(trifluoromethoxy)-lH-benzo[dlimidazol-2-v0amino)methvDbenzamido) ethanesulfonic acid
  • Step A Preparation of 2,5-dioxopyrrolidin-1-yl 4-(((( ⁇ R,4R)-4-tert- butylcyclohexyl)(l-methyl-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2- yl)amino)methyl)benzoate.
  • Step B Preparation of 2-(4-((((l ⁇ ,4 ⁇ )-4-tert-butylcyclohexyl)(l-methyl-5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)methyl)benzamido)ethanesulfonic acid.
  • the resulting suspension was heated in a sealed flask at 125 °C for 6 min.
  • the clear solution was concentrated under reduced pressure.
  • the residue was dissolved in DMF (ca. 3 mL) and treated with water (1 mL) and trifluoroacetic acid (0.2 mL).
  • This mixture was loaded on top of a C- 18 silica flash chromatography column and eluted with a gradient of acetonitrile and water (each solvent containing 0.1% of trifluoroacetic acid).
  • the product-containing fractions were pooled and concentrated under reduced pressure to remove the acetonitrile.
  • the white precipitate obtained was filtered and dried under vacuum at 50 °C to yield the title compound as a white solid.
  • Example 1-M 2-(4-[l-(4'-te ⁇ t-Butyl-biphenyl-4-vD-3-(4-iodo-phenv ⁇ -ureidomethyll- benzoylaminol-ethanesulfonic acid
  • Step A A mixture of 4-iodoaniline (5g), 4-t-butylphenylboronic acid (4.88g), PdCb(P(o-tol)3) 2 (896 mg) and sodium carbonate (7.2g) in dimethoxyethane (40mL)/ethanol (20 mL)/water (10 mL) was heated at 125 °C for a 20 min period. The precipitate was removed by filtration and the product obtained after aqueous workup was chromatographed on silica using an ethyl acetate hexanes gradient. The product was obtained as a yellow solid.
  • Step B A mixture of the product from Step 1 above (113 mg), 4-formylbenzoate methyl ester (82 mg), sodium cyanoborohydride (126 mg) and acetic acid (0.2 mL) in DMF (2 mL) was stirred at 110 °C for Ih. The mixture was partitioned between ether and water. The organic layer was washed (water, sat aq. sodium chloride) and dried (magnesium sulfate). Concentration under reduced pressure and chromatography on silica gel using an ethyl acetate/hexanes gradient afforded the product as a white powder.
  • Step D The iodide from Step 3 above in THF (15 mL) and methanol (10 mL) was treated with an aqueous solution of IM NaOH. The reaction mixture was heated at 60 °C for a 3h period. The mixture was acidified with an excess of IM aqueous HCl, diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude product was used without further purification.
  • Step F A mixture of the iodide form Step E above (50 mg), 2-methyl-4- chlorophenyl boronic acid (36 mg), PdCl2(P(o-tol) ⁇ )2 (6 mg) and sodium carbonate (37 mg) in dimethoxyethane (2mL)/ethanol (1 mL)/water (0.5 mL) was heated at 125 °C for a 10 min period. The mixture was acidified with an excess of IM aqueous HCl. The product was extracted with ethyl acetate and the organic phase was evaporated under reduced pressure. The crude product was treated with IM aqueous sodium hydroxide and methanol and loaded on top of a C-18 silica gel flash chromatography column.
  • Example 1-N 2-(4- ⁇ r(4'-tert-Butyl-biphenyl-4-y1H4'-chloro-2'-methyl-biphenyl-4- yloxycarbonvD-aminol-methv ⁇ -benzoylaminoVethanesulfonic acid
  • Steps B-D Utilizing the methods described in Example 1-M, Steps D-F, the sodium salt of the title compound was obtained as a white solid.
  • LCMS 71 1.6 (M-H) ' , 824.1 (M+CF3CO2)-.
  • Example 2-A Human Glucagon Receptor Affinity
  • Compounds provided herein are dissolved in a suitable solvent (e.g. dimethlysulfoxide) at a concentration of 10 mM and then diluted in buffer (50 mM Hepes, pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 , 0.2% BSA) to concentrations ranging from 1 nM to 100 ⁇ M.
  • buffer 50 mM Hepes, pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 , 0.2% BSA
  • Compounds (20 ⁇ l/well) and [ l25 I]Glucagon (Perkin Elmer; final concentration: 0.125 nM;20 ⁇ l/well) are added to and mixed in wells of a 96-well plate (Costar, Corning) containing 120 ⁇ l of buffer.
  • a membrane preparation containing the human glucagon receptor isolated from human liver samples or obtained from a recombinant cell line
  • the binding mixtures are incubated for 2 hour at room temperature.
  • a MultiScreen 96-well filter plate (Millipore) is incubated with 200 ⁇ l of buffer, which is vacuumed through the filter just before the binding mixtures are transferred to the plate.
  • binding mixtures are transferred to the wells of the MultiScreen 96-well filter plate and filtered through by applying vacuum. The plate is washed once with 200 ⁇ l per well of buffer and the filters are dried and counted by means of a gamma counter.
  • Exemplified compounds displace radiolabeled glucagon from the human glucagon receptor by >15% at 1000 nM or have an IC 50 of ⁇ 10,000 nM.
  • Example 2-B Functional antagonism in hepatocvtes from various species
  • hepatocytes Primary human, monkey, dog, rat, or mouse hepatocytes are seeded onto collagen- coated 24-well plates in Williams E medium (supplemented with 10% fetal bovine serum) and incubated at 37°C overnight in M 199 medium (supplemented with 15 mM glucose and 10 nM human insulin). The following day cells are washed twice with a glucose-free Kreb- bicarbonate buffer, pH 7.4, containing 0.1% BSA. Cells are then incubated at 37° C with the aforementioned buffer containing 1 nM glucagon and varying concentrations of a glucagon antagonist (0 - 100 microM). Control wells without glucagon or antagonist are also included.
  • Example 2 -C Glucose lowering in diabetic animals
  • the effects of compounds provided herein on blood glucose levels are assessed in animal models of type 1 or 2 diabetes such as, but not limited to, the db/db mouse, the Zucker fatty (ZF) rat, the Zucker diabetic (ZDF) rat, the glucagon-challenged dog, the alloxan- or streptozotocin-treated mouse or rat, the NOD mouse or the BB rat.
  • type 1 or 2 diabetes such as, but not limited to, the db/db mouse, the Zucker fatty (ZF) rat, the Zucker diabetic (ZDF) rat, the glucagon-challenged dog, the alloxan- or streptozotocin-treated mouse or rat, the NOD mouse or the BB rat.
  • Compounds are dissolved in an appropriate vehicle such as polyethylene glycol- 400 or cyclodextrin and administered to animals at doses of 0.1 to 100 mg/kg either by intraperitoneal injection, intravenous injection, or oral gavage.
  • Animal models used in this evaluation e.g. the db/db mouse, the ZF rat, the ZDF rat, the glucagon-challenged (0.3-5 ⁇ g/kg) dog, the alloxan- or streptozotocin-treated mouse or rat, the NOD mouse, or BB rat
  • Animal models used in this evaluation e.g. the db/db mouse, the ZF rat, the ZDF rat, the glucagon-challenged (0.3-5 ⁇ g/kg) dog, the alloxan- or streptozotocin-treated mouse or rat, the NOD mouse, or BB rat
  • animals may be subjected to a glucose tolerance test following compound administration by intravenous or oral administration of up to 2g/kg of glucose.
  • Blood glucose levels are assessed in blood samples obtained by tail bleed or by sampling an appropriate blood vessel by means of a syringe or catheter.
  • Glucose is measured using a portable glucometer such as the OneTouch or HemoCue meters at regular time intervals for up to 24 hrs.
  • the extent of blood glucose lowering elicited by the compounds provided herein is determined by comparison to those in control animals administered only the vehicle.
  • the percentage of blood glucose lowering attained is calculated relative to blood glucose levels in vehicle-treated nondiabetic or non-glucagon-challenged control animals.
  • Example 2-D Glucose lowering in db/db mice
  • the percentage glucose lowering is calculated by factoring in the blood glucose levels of vehicle-treated lean db/+ (heterozygote) mice, with 100% representing the normalization of blood glucose levels from the hyperglycemic state (vehicle-treated db/db mice) to the normoglycemic state (vehicle-treated db/+ mice).
  • Example 2-E Glucose lowering in glucagon-challenged Beagle dogs

Abstract

The present invention relates to compounds of Formula I that generally bind to the glucagon receptor and act as glucagon receptor antagonists or inverse agonists. The compounds can be used to treating, preventing, or ameliorating one or more symptoms of a GCGR-mediated condition, disorder, or disease such as type I diabetes, type 2 diabetes, gestational diabetes, and related conditions and disorders.

Description

GLUCAGON RECEPTOR ANTAGONISTS
RELATED APPLICATIONS
[0001] The present application claims the benefit of the filing date of U.S. Provisional
Application Nos: 61/088,562 (Attorney Ref: MTI.091); 61/088,613 (Attorney Ref: MTI.083); 61/088,619 (Attorney Ref: MTI.081); 61/088,627 (Attorney Ref: MTI.089); 61/088,631
(Attorney Ref: MTI.084); 61/088,635 (Attorney Ref: MTI.079); 61/088,638 (Attorney Ref:
MTI.080); 61/088,640 (Attorney Ref: MTI.082); 61/088,642 (Attorney Ref: MTI.087);
61/088,643 (Attorney Ref: MTI.092); 61/088,644 (Attorney Ref: MTI.086); 61/088,646
(Attorney Ref: MT1.085); 61/088,647 (Attorney Ref: MTI.090); 61/088,648 (Attorney Ref: MTI.088); each of which was filed on August 13, 2008, and each of which is herein incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] Provided herein are compounds which are useful for modulating the activity of a glucagon receptor. Also provided herein are pharmaceutical compositions comprising one or more of such compounds, and methods of their use for treating, preventing, or ameliorating a glucoregulatory or glucagon receptor-mediated disease.
BACKGROUND OF THE INVENTION
[0003] Glucagon is a 29-amino acid pancreatic hormone which is secreted from the pancreatic α cells into the portal blood supply in response to hypoglycemia and acts as a counterregulatory hormone to insulin. Most of the physiological effects of glucagon are mediated by its interaction with a glucagon receptor in the liver, followed by activation of adenylate cyclase to increase the intracellular cAMP levels. The result is an increase in glycogenosis and gluconeogenesis, while attenuating the ability of insulin to inhibit these metabolic processes (Johnson et al., J. Biol. Chem. 1972, 247, 3229-3235). As such, the overall rates of hepatic glucose synthesis and glycogen metabolism are controlled by the systemic ratio of insulin and glucagon (Roden et al., J. Clin. Invest. 1996, 97, 642-648; Brand et al, Diabetologia 1994, 37, 985-993). [0004] Diabetes is a disease characterized by elevated levels of plasma glucose. Uncontrolled hyperglycemia is associated with an increased risk for microvascular and macrovascular diseases, including nephropathy, retinopathy, hypertension, stroke, and heart disease. Control of glucose homeostasis is a major approach to the treatment of diabetes. It has been demonstrated in healthy animals as well as in animal models of types I and II diabetes that removal of circulating glucagon with selective and specific antibodies resulted in reduction of the glycemic level (Brand et al, Diabetologia 1994, 37, 985-993; Brand et al, Diabetes 1994, 43(Suppl. 1), 172A). Therefore, one of the potential treatments for diabetes, glucoregulatory and metabolic disorders, and glucagon receptor-mediated diseases is to block a glucagon receptor with a glucagon receptor antagonist to improve insulin responsiveness, to decrease the rate of gluconeogenesis, and/or to lower plasma glucose levels by reducing the rate of hepatic glucose output in a patient.
[0005] There is still a need for novel glucagon receptor antagonists that can be used to modulate impaired glucose tolerance and glucagon receptor-mediated diseases. Accordingly, it is an object of the present invention to provide such compounds and methods of use.
[0006] All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.
SUMMARY OF THE INVENTION
[0007] In accordance with the present invention, novel compounds having glucagon receptor antagonist or inverse agonist activity have been identified, and methods for their use provided. [0008] In a first aspect of the invention, compounds of Formula I are provided:
Figure imgf000004_0001
wherein:
X is 1,4-phenyIene, 2-4-thienylene or 2,5-thienylene;
Rb is selected from Ra, hydroxyl, fluoro, and -(CH2)pORc; Ra and Rc are selected from H, and d-3-alkyl; p is 0 or 1 ; m is 1, 2 or 3; and
A is selected from
Figure imgf000005_0001
Ba is selected from null and -CHRa;
Bb is selected from Ba, -O-, -S-, -NRa-, -C(O)-, -S(O)-, -S(O)2-, and -CF2-; E is selected from C1- 12-alkyl, C2-12-alkenyl, C2-12-alkynyl, C3-8-cycloalkyl, C4-8- cycloalkenyl, aryl, heteroaryl, C3-8-cycloalkyl-substituted aryl, C4.8-cycloalkenyl-substituted aryl, phenyl-substituted aryl, C3-8-cycloalkyl-substituted heteroaryl, C4-8-cycloalkenyl- substituted heteroaryl, phenyl-substituted heteroaryl, C3-8-cycloalkyl-C1-6-alkyl, C3-8- cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8- cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, aryloxy, aryloxy-C1-6-alkyl, C3-8-cycloalkyl-substituted aryl-C1-6-alkyl, C4- 8-cycloalkenyl-substituted aryl-C1-6-alkyl, phenyl-substituted aryl-C1-6-alkyl, heteroaryl-C1-6- alkyl, C3-8-cycloalkyl-substituted heteroaryl-C1-6-alkyl, C4-8-cycloalkenyl-substituted heteroaryl-C1-6-alkyl, or phenyl-substituted heteroaryl-C1-6-alkyl, each optionally substituted;
D is a substituted group selected from C1-6-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-8- cycloalkyl, C4-8-cycloalkenyl, aryl, C1-8-alkyl-aryl, heteroaryl, C1-8-alkyl-heteroaryl, heterocyclyl or C1-8-alkyl-heterocyclyl, wherein said group is substituted with L and, optionally, one or more additional groups;
L is a group selected from hydrogen, alkyl, aryl, aryloxy, arylalkoxy, aryl-N(Ra)-, heteroaryl, heteroaryloxy-, heteroarylalkoxy, heteroaryl-N(Ra)-, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy-, cycloalkyloxy-, cycloalkyl-N(Ra)-, heterocyclyl, heterocyclyloxy-, heterocyclylalkoxy-, heterocyclyl-N(Ra)-, alkenyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkenylalkyloxy, or alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocarbocycle or a spiroheterocyclic ring containing up to three heteroatoms, 0-1 of which are selected from O and S and 0-3 of which are N; wherein said group, excluding hydrogen, is optionally substituted;
Za is selected from a bond, -CRa 2-, -C(O)N(Ra)-, -C(O)O-, -C(O)-, -C(O)C(Ra)2-, - C(Ra)2C(O)-, -S(O)-, -S(O)2-, -S(O)2NRa-, -S(O)2C(Ra)2-, and -S(O)C(Ra)2-, Zb is selected from Za, -O-, -S-, -N(Ra)-, -N(Ra)C(Ra)2-, -N(Ra)C(O)-, -OC(Ra)2 -, -SC(Ra)2-, -C(Ra)2N(Ra)-, -C(Ra)2θ-, -C(Ra)2S-, -C(=NRa)NRa-, and -C(=N-CN)NRa-;
Figure imgf000006_0001
represents an aryl or heteroaryl, wherein said group is optionally substituted; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0009] In another aspect, compounds of Formula I-A are provided:
Figure imgf000006_0002
I-A, wherein: Ra is selected from H, and methyl;
A is selected from , and
Figure imgf000006_0003
Figure imgf000006_0004
Ba is selected from null and -CHRa;
Bb is selected from Ba, -O-, and -CF2-;
E is selected from C1-i2-alkyl, C2-12-alkenyl, C2-12-alkynyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, napthyl, thienyl, benzothienyl, quinolyl, cyclohexyl-substituted phenyl, cyclohexenyl-substituted phenyl, phenyl-substituted phenyl, cyclohexylmethyl, cyclohexenylmethyl, benzyl, phenoxy, cyclohexyl-substituted benzyl, cyclohexenyl- substituted benzyl, phenyl-substituted benzyl, each optionally substituted;
D is a substituted group selected from phenyl, thiazolyl, oxazolyl, indolyl, or isoxazolyl wherein said group is substituted with L and, optionally, one or more additional groups;
L is a group selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, phenoxy-, benzyloxy-, cyclohexyl, cyclohexylmethyl, cyclohexylmethoxy-, cyclohexyloxy-, cyclohexyl-N(Ra)-, alkenyl, cyclohexenyl, alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocyclohexyl; wherein said group, excluding hydrogen, is optionally substituted;
Za is selected from a bond, -CRa 2-, -C(O)N(R3)-, -C(O)O-, -C(O)-, -C(O)C(Ra)2 -, - C(Ra)2C(O)- and -S(O)2NRa-; Zb is selected from Za, -O-, -N(Ra)-, -N(Ra)C(Ra)2- -OC(Ra)2-, -C(Ra)2N(Ra)-, and
-C(Ra)2O-;
Figure imgf000007_0001
represents a phenyl or an heterocycle containing 1-2 nitrogen atoms or 0-2 oxygen atoms, wherein said group is optionally substituted; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0010] In another aspect, pharmaceutical compositions are provided comprising a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers. [0011] In yet other aspects, compounds and pharmaceutical compositions comprising compounds of Formula I or Formula I-A are provided, including pharmaceutically acceptable salts or co-crystals, and prodrugs thereof which have glucagon receptor antagonist or inverse agonist activity. Further provided herein are pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucagon receptor antagonist is indicated, including Type I and II diabetes, insulin resistance and hyperglycemia. Also provided are methods of making or manufacturing compounds of Formula I or Formula I-A, and pharmaceutically acceptable salts or co-crystals, and prodrugs thereof. [0012] These and other aspects of the invention will be more clearly understood with reference to the following preferred embodiments and detailed description. DETAILED DESCRIPTION OF THE INVENTION
[0013] In certain aspects, the present invention relates to compounds having glucagon receptor antagonist or inverse agonist activity, and methods for their use provided. The present invention also relates to pharmaceutically acceptable salts and co-crystals, prodrugs, and pharmaceutically acceptable salts and co-crystals of these prodrugs of these compounds. [0014] In another aspects, the invention relates to compounds and pharmaceutical compositions comprising a compounds provided herein, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers. Other aspects relate to methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucagon receptor antagonist is indicated, including Type I and II diabetes, insulin resistance and hyperglycemia. Also provided are methods of making or manufacturing compounds provided herein, and pharmaceutically acceptable salts or co-crystals, and prodrugs thereof.
[0015] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0016] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
Definitions
[0017] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
[0018] The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
[0019] The terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptom(s); barring a subject from acquiring a disease; or reducing a subject's risk of acquiring a disorder, disease, or condition.
[0020] The term "therapeutically effective amount" are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician. [0021] The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutical ly-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.
[0022] The term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. [0023] The term "glucagon receptor" or "GCGR" refers to a glucagon receptor protein or variant thereof, which is capable of mediating a cellular response to glucagon in vitro or in vivo. GCGR variants include proteins substantially homologous to a native GCGR, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions (e.g., GCGR derivatives, homologs, and fragments), as compared to the amino acid sequence of a native GCGR. In certain embodiments, the amino acid sequence of a GCGR variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native GCGR. In certain embodiments, the GCGR is a human glucagon receptor. [0024] The term "glucagon receptor antagonist" or "GCGR antagonist" refers to a compound that, e.g., partially or completely blocks, decreases, prevents, inhibits, or downregulates GCGR activity. There terms also refer to a compound that binds to, delays the activation of, inactivates, or desensitizes GCGR. A GCGR antagonist may act by interfering with the interaction of glucagon with GCGR. [0025] The term "GCGR-mediated condition, disorder, or disease" refers to a condition, disorder, or disease characterized by inappropriate, e.g., less than or greater than normal or for the physiological conditions, GCGR activity. Inappropriate GCGR functional activity might arise as the result of an increase in glucagon concentration, GCGR expression in cells which normally do not express GCGR, increased GCGR expression or degree of intracellular activation, leading to, e.g., abnormal plasma glucose levels; or decreased GCGR expression. A GCGR-mediated condition, disorder or disease may be completely or partially mediated by inappropriate GCGR activity. In particularly, a GCGR-mediated condition, disorder or disease is one in which modulation of GCGR results in some effect on the underlying symptom, condition, disorder, or disease, e.g., a GCGR antagonist results in some improvement in at least some of patients being treated.
[0026] The term "alkyl" and the prefix "alk" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents. The term "alkyl" also encompasses linear, branched, and cyclic alkyl, unless otherwise specified. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C|.2o), 1 to 15 (CM5), 1 to 12 (CM2), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, t- butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, C1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. Cycloalkyl also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
[0027] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenyl may be optionally substituted with one or more substituents. The term "alkenyl" also embraces radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations, as appreciated by those of ordinary skill in the art. As used herein, the term "alkenyl" encompasses both linear and branched alkenyl, unless otherwise specified. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-I5), 2 to 12 (C2-12), 2 to 10 (C2.io), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-2o), 3 to 15 (C3-is), 3 to 12 (Cs-I2), 3 to 10 (C3-io), or 3 to 6 (C 3.$) carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, isopropenyl, pentenyl, hexenyl, heptenyl, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, 2-butenyl, 2-methyl-2-butenyl, 4-methylbutenyl, and the like. [0028] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds. The alkynyl may be optionally substituted one or more substituents. The term "alkynyl" also encompasses both linear and branched alkynyl, unless otherwise specified. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 12 (C2-I2), 2 to 10 (C2-io), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-2o), 3 to 15 (C3-15), 3 to 12 (C3-12), 3 to 10 (C3- 10), or 3 to 6 (C3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 3-methyl-1-pentynyl, 2-heptynyl, and the like. For example, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. [0029] The term "cycloalkyl" refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents. In certain embodiments, the cycloalkyl has from 3 to 20 (C 3-20), from 3 to 15 (C3-15), from 3 to 12 (C3-12), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl.
[0030] The term "cycloalkenyl" refers to a cyclic unsaturated bridged and/or non-bridged monovalent hydrocarbon radical, which contains one or more double bonds in its ring. The cycloalkenyl may be optionally substituted with one or more substituents. In certain embodiments, the cycloalkenyl has from 3 to 20 (C3-20), from 3 to 15 (C3-12), from 3 to 12 (C3-12), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms.
[0031] The term "cycloalkynyl" refers to a cyclic unsaturated bridged and/or non-bridged monovalent hydrocarbon radical, which contains one or more triple bonds in its ring. The cycloalkynyl may be optionally substituted one or more substituents. In certain embodiments, the cycloalkynyl has from 3 to 20 (C3-20), from 3 to 15 (C3-12), from 3 to 12 (C3-12), from 3 to 10 (C3-10), or from 3 to 7 (C3.7) carbon atoms.
[0032] The term "aralkyl" or "aryl-alkyl" refers to a monovalent alkyl group substituted with aryl. In certain embodiments, both alkyl and aryl may be optionally substituted with one or more substituents. [0033] The term "heteroaryl" (HAR) refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. In some embodiments, each ring contains 5 to 6 atoms. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. The heteroaryl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyramidyl, pyridazinyl, triazolyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzothiophenyl, fiιro(2,3-b) pyridyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofiiranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted with one or more substituents. Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and aromatic heterocyclic groups fused to cycloalkyl rings. Heteroaryl also includes such groups in charged form, e.g., pyridinium. [0034] The term "heterocyclyl" (Hetcy) or "heterocyclic" refers to a monocyclic non- aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to benzoxazinyl, benzodioxanyl, benzodioxolyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, chromanyl, chromonyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, 2,3- dihydrofuro(2,3-b)pyridyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1 ,4-dithianyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, and 1,3,5-trithianyl. Heterocyclyl/heterocyclic also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4- pyridones attached through the nitrogen or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils). Heterocyclyl/heterocyclic also includes such moieties in charged form, e.g., piperidinium. In certain embodiments, heterocyclyl/heterocyclic may also be optionally substituted with one or more substituents.
[0035] The term "alkoxy" refers to an -OR radical, wherein R is, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each as defined herein. When R is aryl, it is also known as aryloxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, w-propoxy, 2-propoxy, n-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzoxy, and 2-naphthyloxy. In certain embodiments, alkoxy may also be optionally substituted with one or more substituents.
[0036] The term "acyl" refers to a -C(O)R radical, wherein R is, for example, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each as defined herein. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, docosanoyl, myristoleoyl, palmitoleoyl, oleoyl, linoleoyl, arachidonoyl, benzoyl, pyridinylcarbonyl, and furoyl. In certain embodiments, acyl may also be optionally substituted with one or more substituents. [0037] The term "halogen", "halide" or "halo" (Halo) refers to fluorine, chlorine, bromine, and/or iodine.
[0038] The term "optionally substituted" is intended to mean that a group, including alkyl, alkoxy, acyl, alkyl-cycloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aryloxy, aralkyl, aryl-alkenyl, aryl-alkynyl, heteroaryl, heteroarylalkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, and heterocyclyl, or acyl, may be substituted with one or more substituents, in one embodiment, one, two, three, four substituents, where in some embodiments each substituent is independently selected from the group consisting of cyano, halo, oxo, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C6-H aryl, heteroaryl, heterocyclyl, -C(O)Re, -C(O)ORe, -C(O)NRfRg, - C(NRe)NRfRg, -ORe, -OC(O)RC, -OC(O)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg, - OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(=NRh)NRfRg, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NRfRg, - NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, and -S(O)2NRfRg, wherein each Re, Rf, Re, and Rh is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; or Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0039] The term "solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
Compounds of the Invention
[0040] In one aspect of the invention, compounds are provided. In certain embodiments, the compounds have glucagon receptor antagonist or inverse agonist activity. The present invention also relates to pharmaceutically acceptable salts and co-crystals, prodrugs, and pharmaceutically acceptable salts and co-crystals of these prodrugs of these compounds. [0041] Preferred compounds of the present invention include those of Formula I, including those of Formula I-A as shown below. In certain embodiments, the compounds of Formula I or Formula I-A may be a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0042] In one embodiment, the compounds have Formula I:
Figure imgf000015_0001
wherein: X is 1,4-phenyIene, 2-4-thienylene or 2,5-thienylene;
Rb is selected from Ra, hydroxyl, fluoro, and -(CH2)pORa;
Ra and Rc are selected from H, and Cijj-alkyl; p is O or 1 ; m is 1, 2 or 3; and A is selected from , , and
Figure imgf000016_0001
Figure imgf000016_0002
Ba is selected from null and -CHR";
Bb is selected from Ba, -O-, -S-, -NRa-, -C(O)-, -S(O)-, -S(O)2-, and -CF2-; E is selected from C2-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, C3-8-cycloalkyl, C4-8- cycloalkenyl, aryl, heteroaryl, C3-8-cycloalkyl-substituted aryl, C4-8-cycloalkenyl-substituted aryl, phenyl-substituted aryl, C3-8-cycloalkyl-substituted heteroaryl, C4-8-cycloalkenyl- sυbstituted heteroaryl, phenyl-substituted heteroaryl, C3-8-cycloalkyl-Ci.6-alkyl, C3-8- cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8- cycloalkenyl- C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, aryloxy, aryloxy-C1-6-alkyl, C4-8-cycloalkyl-substituted aryl-C1-6-alkyl, C4- 8-cycloalkenyl-substituted aryl-C1-6-alkyl, phenyl-substituted aryl-C1-6-alkyl, heteroaryl-C1-6- alkyl, C3-8-cycloalkyl-substituted heteroaryl-C1-6-alkyl, C4-8-cycloalkenyl-substituted heteroaryl-C1-6-alkyl, or phenyl-substituted heteroaryl-C1-6-alkyl, each optionally substituted;
D is a substituted group selected from C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-8- cycloalkyl, C4-8-cycloalkenyl, aryl, C1-8-alkyl-aryl, heteroaryl, C1-8-alkyl-heteroaryl, heterocyclyl or C1-8-alkyl-heterocyclyl, wherein said group is substituted with L and, optionally, one or more additional groups;
L is a group selected from hydrogen, alkyl, aryl, aryloxy, arylalkoxy, aryl-N(Ra)-, heteroaryl, heteroaryloxy-, heteroarylalkoxy, heteroaryl-N(Ra)-, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy-, cycloalkyloxy-, cycloalkyl-N(Ra)-, heterocyclyl, heterocyclyloxy-, heterocyclylalkoxy-, heterocyclyl-N(Ra)-, alkenyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkenylalkyloxy, or alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocarbocycle or a spiroheterocyclic ring containing up to three heteroatoms, 0-1 of which are selected from O and S and 0-3 of which are N; wherein said group, excluding hydrogen, is optionally substituted;
Za is selected from a bond, -CRa 2-, -C(O)N(Ra)-, -C(O)O-, -C(O)-, -C(O)C(Ra)2-, - C(Ra)2C(O)-, -S(O)-, -S(O)2-, -S(O)2NRa-, -S(O)2C(Ra)2--, and -S(O)C(Ra)2--,
Zb is selected from Za, -O-, -S- -N(Ra)-, -N(Ra)C(Ra)2-, -N(Ra)C(O)-, -OC(Ra)2-, -SC(Ra)2 -, -C(Ra)2N(Ra)-, -C(Ra)2O-, -C(Ra)2S-, -C(=NRa)NRa-, and -C(=N-CN)NRa-;
Figure imgf000017_0001
represents an aryl or heteroaryl, wherein said group is optionally substituted; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0043] With reference to Formula I, in certain embodiments, Ra may be selected from H, and methyl. In other embodiments, Rb may be H and m may be 2. In yet other embodiments, BB may be selected from null, -CH2- and -CHMe-; and Bb may be selected from Ba, -O-, - NH-, -NMe-, and -C(O)-. In yet other embodiments, Bb may be selected from null, -CH2- and -CHMe-, -O-, -NH-, -NMe-, and -C(O)-. [0044] In yet another embodiment, A may be selected from the group consisting of:
Figure imgf000017_0002
Figure imgf000018_0001
[0045] In yet another embodiment, D may be selected from the group consisting of:
Figure imgf000018_0002
wherein L and Zb represent the points of attachment to L and Zb moieties, respectively. [0046] In yet another embodiment, E may be selected from the group consisting of: 3-t- butoxyphenyl, 4-t-butoxyphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 3-(3,3-dimethylbut-1- enyl)phenyl, Z-3-(3,3-dimethylbut-1-enyl)phenyl, 4-(3,3-dimethylbut-1-enyl)phenyl, Z-A- (3,3-dimethylbut-1-enyl)phenyl, 3-(4-t-butylcyclohex-1-enyl)phenyl, 4-(4-t-butylcyclohex-1- enyl)phenyl, 3-(4-t-butylcyclohexyl)phenyl, 4-(4-t-butylcyclohexyl)phenyl, 4-(4-t- butylphenyl)phenyl, 3-(4,4-dimethyl-cyclohex-1,5-dienyl)phenyl, 4-(4,4-dimethyl-cyclohex- 1 ,5-dienyl)phenyl, 3 -(4,4-dimethylcyclohex- 1 -enyl)phenyl, 4-(4,4-dimethylcyclohex- 1 - enyl)phenyl, 3-(4,4-dimethylcyclohexyl)phenyl, 4-(4,4-dimethylcyclohexyl)phenyl, 3-(4,4- dipropylcyclohexyl)phenyl, 4-(4,4-dipropylcyclohexyl)phenyl, 3-(4,4-dipropylcyclohex- 1 - enyl)phenyl, 4-(4,4-dipropylcyclohex-1-enyl)phenyl, 4-(spiro[4.5]dec-8-yl)phenyl, 3-(4,4- dimethylcyclohex- 1 -enyl)benzyl, 4-(4,4-dimethylcyclohex-2-enyl)benzyl, 3-(4,4- dipropylcyclohex- 1 -enyl)benzyl, 4-(4,4-dipropylcyclohex- 1 -enyl)benzyl, 3-(cyclohex- 1 - enyl)benzyl, or 4-(cyclohex-1-enyl)benzyl, 6-methoxy-2-naphthyl, 6-trifluoromethoxy-2- naphthyl, 7-methoxy-quinol-3-yl, 7-trifluoromethoxy-quinol-3-yl. [0047] In yet another embodiment, L may be selected from the group consisting of: hydrogen, trifluoromethyl, trifluoromethoxy, chloro, r-butyl, 3,3-dimethylbut-1-enyl, 4,4- dimethylcyclohex- 1-enyl, t-butyl-cyclohexane, t-butyl-cyclohex-1-enyl, cyclohex-1-enyl, 2,4-bis(trifluoromethyl)-phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-chlorophenyl, 4- chlorophenyl, 4-chloro-3-cyclopropylphenyl, 4-chloro-4-ethylphenyl, 4-chloro-2- fluorophenyl, 4-chloro-2-isopropylphenyl, 2-chloro-4-methylphenyl, 4-chloro-2- methylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-chloro-4-trifluoromethylphenyl, 4-chloro- 2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2- fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyI, 2-fluoro-4-trifluoromethyIphenyl, 3- fluoro-4-trifluoromethyl-phenyl, 4-methylphenyl, 2-methyl- 4-trifluoromethylphenyl, 4- trifluoromethylphenyl, benzooxazol-2-yl, 2-methyl-benzooxazol-5-yl, 2-methyl-benzooxazol- 6-yl, benzofuran-2-yl , 3-chlorobenzofuran-2-yl, or 3-fluorobenzofuran-2-yl, 4-t-butyl- spirocyclohexyl;
Figure imgf000019_0001
[0048] In yet another embodiment, — may represent an optionally substituted group selected from the group consisting of:
Figure imgf000020_0001
[0049] In yet another embodiment, Za may be selected from a bond, — CH2-, -CH(Me)-, - C(O)NH-, -C(O)O-, -C(O)-, and - CH2C(O)-. In yet other embodiments, Zb may be selected from Za, -O-, -NH-, -CH2O-, and -CH2NH-. [0050] In another embodiment, the compounds have Formula I-A
Figure imgf000021_0001
wherein:
Ra is selected from H, and methyl;
A is selected from
Figure imgf000021_0003
, and
Figure imgf000021_0002
Ba is selected from null and -CHRa;
Bb is selected from Ba, -O-, and -CF2-;
E is selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, napthyl, thienyl, benzothienyl, quinolyl, cyclohexyl-substituted phenyl, cyclohexenyl-substituted phenyl, phenyl-substituted phenyl, cyclohexylmethyl, cyclohexenylmethyl, benzyl, phenoxy, cyclohexyl-substituted benzyl, cyclohexenyl- substituted benzyl, phenyl-substituted benzyl, each optionally substituted;
D is a substituted group selected from phenyl, thiazolyl, oxazolyl, indolyl, or isoxazolyl wherein said group is substituted with L and, optionally, one or more additional groups;
L is a group selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, phenoxy-, benzyloxy-, cyclohexyl, cyclohexylmethyl, cyclohexylmethoxy-, cyclohexyloxy-, cyclohexyl-N(Ra)-, alkenyl, cyclohexenyl, alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocyclohexyl; wherein said group, excluding hydrogen, is optionally substituted;
Za is selected from a bond, -CRa 2-, -C(O)N(Ra)-, -C(O)O-, -C(O)-, -C(O)C(Ra)2-, - C(Ra)2C(O)-, and -S(O)2NRa-;
Zb is selected from Za, -O-, -N(Ra)-, -N(Ra)C(Ra)2-, -OC(Ra)2-, -C(Ra)2N(Ra)-, and ^C(Ra)2O-;
Figure imgf000022_0001
represents a phenyl or an heterocycle containing 1-2 nitrogen atoms or 0-2 oxygen atoms, wherein said group is optionally substituted; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0051] With reference to the compounds of Formula I or Formula I-A, in certain embodiments, Ba may be selected from null, -CH2- and -CHMe-.
[0052] In yet other embodiments, A may be selected from the group consisting of:
Figure imgf000022_0002
[0053] In yet other embodiments, D may be selected from the group consisting of:
Figure imgf000022_0003
Figure imgf000023_0001
wherein L and A represent the points of attachment to L and A moieties, respectively.
[0054] In yet other embodiments, E may be selected from 3-t-butoxyphenyl, 4-t- butoxyphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 3-(3,3-dimethylbut-1-enyl)phenyl, Z-3-(3,3- dimethylbut- 1 -enyl)phenyl, 4-(3,3-dimethylbut- 1 -enyl)phenyl, Z-4-(3,3-dimethylbut-l - enyl)phenyl, 3-(4-t-butylcyclohex-1-enyl)phenyl, 4-(4-t-butylcyclohex-1-enyl)phenyl, 3-(4-t- butylcyclohexyl)phenyl, 4-(4-t-butylcyclohexyl)phenyl, 4-(4-t-butylphenyl)phenyl, 3-(4,4- dimethyl-cyclohex-1,5-dienyl)phenyl, 4-(4,4-dimethyl-cyclohex-1,5-dienyl)phenyl, 3-(4,4- dimethylcyclohex- 1 -enyl)phenyl, 4-(4,4-dimethylcyclohex- 1 -enyl)phenyl, 3-(4,4- dimethylcyclohexyl)phenyl, 4-(4,4-dimethylcyclohexyl)phenyl, 3-(4,4- dipropylcyclohexyl)phenyl, 4-(4,4-dipropylcyclohexyl)phenyl, 3-(4,4-dipropylcyclohex- 1 - enyl)phenyl, 4-(4,4-dipropylcyclohex-1-enyl)phenyl, 4-(spiro[4.5]dec-8-yl)phenyl, 3-(4,4- dimethylcyclohex- 1 -enyl)benzyl, 4-(4,4-dimethylcyclohex-2-enyl)benzyl, 3-(4,4- dipropylcyclohex- 1 -enyl)benzyl, 4-(4,4-dipropylcyclohex- 1 -enyl)benzyl, 3-(cyclohex- 1 - enyl)benzyl, or 4-(cyclohex-1-enyl)benzyl, 6-methoxy-2-naphthyl, 6-trifluoromethoxy-2- naphthyl, 7-methoxy-quinol-3-yl, and 7-trifluoromethoxy-quinol-3-yl.
[0055] In yet other embodiments, L may be selected from hydrogen, trifluoromethyl, trifluoromethoxy, chloro, f-butyl, 3,3-dimethylbut-1-enyl, 4,4-dimethylcyclohex-1-enyl, t- butyl-cyclohexane, t-butyl-cyclohex-1-enyl, cyclohex-1-enyl, 2,4-bis(trifluoromethyl)- phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-chlorophenyl, 4-chlorophenyl, 4-chloro-3- cyclopropylphenyl, 4-chloro-4-ethylphenyl, 4-chloro-2-fluorophenyl, 4-chloro-2- isopropylphenyl, 2-chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 2-chloro-4- trifluoromethylphenyl, 3 -chloro-4-trifluoromethylphenyl, 4-chloro-2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2-fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-trifluoromethyl- phenyl, 4-methylphenyl, 2-methyl- 4-trifluoromethylphenyl, 4-trifluoromethylphenyl, benzooxazol-2-yl, 2-methyl-benzooxazol-5-yl, 2-methyl-benzooxazol-6-yl, benzofiiran-2-yl , 3-chlorobenzofuran-2-yl, or 3-fluorobenzoftiran-2-yl, 4-t-butyl-spirocyclohexyl.
[0056] In yet other embodiments
Figure imgf000024_0001
represents an optionally substituted group selected from the group consisting of:
Figure imgf000024_0003
Figure imgf000024_0002
Figure imgf000025_0001
[0057] In certain embodiments, Ra, Rb, Ba, Bb, A, D, E, L,
Figure imgf000025_0002
, Za, and Zb may simultaneously be selected from such groupings or any selected subgrouping. Again, the compounds of Formula I or Formula I-A may be a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0058] Exemplary compounds include those shown in Example 1.
[0059] For the purposes of this invention, where one or more functionalities or substituents are incorporated into a compound of the invention, including preferred embodiments, each functionality or substituent appearing at any location within the disclosed compounds may be independently selected, and as appropriate, independently substituted. Further, where a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.
[0060] The above compounds are listed only to provide examples that may be used in the methods of the invention. Based upon the instant disclosure, the skilled artisan would recognize other compounds intended to be included within the scope of the presently claimed invention that would be useful in the methods recited herein. Preparation of Compounds of the Invention
[0061] The compounds in this invention may be prepared by the processes described herein in the following general schemes and examples, as well as relevant published literature procedures that are used by those skilled in the art. It should be understood that the following schemes are provided solely for the purpose of illustration and do not limit the invention which is defined by the claims.
[0062] All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have stereogenic centers. Consequently, the compounds can exist in enantiomeric or diastereomeric forms or in mixture thereof. The processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization. [0063] Compounds of Formula I and Formula I-A can be prepared according to the methodology outlined in the following general synthetic schemes or with modifications of these schemes that will be evident to persons skilled in the art, or by other methods readily known to those of skill in the art. Exemplary synthesis methods are illustrated in Example 1 herein. [0064] As will be recognized by those of skill in the art, the following abbreviations have the following meanings: THF: Tetrahydrofuran; DME: 1,2-Dimethoxyethane; DMF: N,N- Dimethylformamide; DCC: N, N'-Dicyclohexylcarbodiimide; EDCI or EDC: l-(3- Di methylaminopropyl)-3 -ethyl carbodiimide hydrochloride; LiHMDS: Lithium hexamethyldisilyl azide; HOBt: 1-Hydroxybenzotriazole; EtOAc: Ethyl acetate; EtOH: Ethanol; IPA: iso-Propanol; ACN: Acetonitrile; DIPEA: N,N-Diisopropyl-ethyl amine; MTBE: Methyl-teit-butyl ether
Figure imgf000026_0001
Scheme 1 [0065] With reference to Scheme 1, synthesis of carboxylic acids of Formula 3 can be accomplished by linking the precursor carboxylic acid 1 to a resin or using a suitable protecting group such as t-butyl and elaborating the functional group Fg into the A group as exemplified in the following disclosures, each of which is herein incorporated by reference.
[0066] Where *ϊinn A Δ i ics see US 2007/0249688, WO 2007/120270.
[0067] Wherein A is , see US 2008/0125468.
[0068] Wherein A is , see US2008/0280982.
[0069] Wherein A is , see US 2008/0300289, WO 2007/120284.
[0070] Wherein A is
Figure imgf000027_0001
, see US 2008/0300308.
[0071] Wherein A is
Figure imgf000027_0003
, see WO 2007/114855.
[0072] Wherein A is
Figure imgf000027_0002
, see US 2007/0088071.
[0073] Wherein A is
Figure imgf000027_0004
see US 2007/0093544.
[0074] Wherein A is see US 2008/0085926, US 6,881,746, WO
2004/002480, WO 2006/102067, WO 2008/098244.
[0075] Wherein A is
Figure imgf000027_0006
see WO 2007/136577, WO 2006/102067. [0076J Wherein A is see us 2003/0236292, US 6,762,318, WO
2003/048109.
[0077] Wherein A is
Figure imgf000028_0001
R ° , see US 2003/0236292, US 6,762,318, WO
2003/048109, WO 2008/098244.
[0078] Wherein A is
Figure imgf000028_0002
, see WO 2004/100875, WO 2004/0014789, US
6,881,746, WO 2004/002480.
[0079] Wherein A is
Figure imgf000028_0003
, see US 6,881,746, WO 2004/002480.
[0080] Wherein A is
Figure imgf000028_0004
, see US 6,875,760, US 6,953,812, WO
2000/69810, WO 2002/40444, J. Med. Chem. 2007, 50, 113-128.
[0081] Wherein A is
Figure imgf000028_0005
, see US 6,875,760, US 6,953,812, US
2004/0152750, WO 2004/056763.
[0082] Wherein A is
Figure imgf000028_0006
, see US 6,875,760, WO 2000/69810.
[0083] Wherein A is
Figure imgf000028_0007
, see US 6,875,760, WO 2000/69810.
[0084] Wherein A is
Figure imgf000028_0008
, see US 6,875,760, WO 2000/69810. [0085] Wherein A is
Figure imgf000029_0004
, see US 2004/0152750, WO 2004/056763.
[0086] Wherein A is
Figure imgf000029_0005
, see US 2004/0152750, WO 2004/056763.
[0087] Wherein A is
Figure imgf000029_0006
, see US 2004/0152750, WO 2004/056763.
[0088] Wherein A is
Figure imgf000029_0001
, see US 7,301,036, US 2007/0105930.
[0089] Wherein A is
Figure imgf000029_0007
Figure imgf000029_0002
see US 7,301,036, WO 2005/058845.
[0090] Wherein A is
Figure imgf000029_0008
, see US 2006/0116366, WO
2004/050039.
[0091] Wherein A is
Figure imgf000029_0009
see US 2004/0209928.
[0092] Wherein A is , see WO 2006/102067.
Figure imgf000029_0003
[0093] Wherein A is
Figure imgf000030_0002
see US 2006/0084681, US 2007/0203186, US
2008/0108620, WO 2007/015999, 2005/121097.
[00941 An alternative method for synthesizing compounds of the invention is exemplified with reference to Scheme II.
Compound I, Il
Figure imgf000030_0001
Scheme II
[0095J The carboxylic acids 3 are converted to the corresponding amides by methods known for amide bond formation reactions. As an example, generation of an acid chloride 2 from 1 takes place under standard conditions (e.g. thionyl chloride in toluene or oxalyl chloride and catalytic DMF in dichloromethane). Treatment of acid chloride 2 with amines generates the amides of Formula I or I-A. Alternatively, amines can be directly coupled with the carboxylic acid 4 by use of an activating agent (for example, DCC or EDCI with or without a catalyst such as DMAP or HOBT) to directly generate the amides of Formula I or I- A. The amide bond in the last step can also be formed by other reported methods known for amide bond formation, for example, reaction of an N-hydroxysuccinimidyl ester of carboxylic acid 3 and an amine such as taurine gives the target taurine amide of Formula I-A. Other activated esters (e.g. pentafluorophenyl esters) can also be used to effect the amide bond formation. [0096] In certain preferred embodiments, compounds of the invention may be resolved to enantiomerically pure compositions or synthesized as enantiomerically pure compositions using any method known in art. By way of example, compounds of the invention may be resolved by direct crystallization of enantiomer mixtures, by diastereomer salt formation of enantiomers, by the formation and separation of diasteriomers or by enzymatic resolution of a racemic mixture. [0097] These and other reaction methodologies may be useful in preparing the compounds of the invention, as recognized by one of skill in the art. Various modifications to the above schemes and procedures will be apparent to one of skill in the art, and the invention is not limited specifically by the method of preparing the compounds of the invention.
Methods of the Invention
[0098] In another aspect of the invention, methods are provided. In preferred embodiments, the methods of the invention comprise administering a therapeutically effective amount of at least one compound of the invention, e.g., a compound of Formula I or Formula I-A. Relative activity of the compounds of the invention may be determined by any method known in the art, including the assays described herein.
[0099] In one embodiment, the invention relates to methods of treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease associated with a glucagon receptor, impaired glucose tolerance, or a metabolic syndrome, comprising administering to a subject having or being suspected to have such a condition, disorder, or disease, a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.
[00100] In another embodiment, the invention relates to methods of treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease responsive to the modulation of a glucagon receptor, comprising administering to a subject having or being suspected to have such a condition, disorder, or disease, a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. [00101] Yet other aspects relate to methods of treating, preventing, or ameliorating one or more symptoms of a GCGR-mediated condition, disorder, or disease, comprising administering to a subject having or being suspected to have such a condition, disorder, or disease, a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
[00102] Yet other aspects relate to methods of treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease responsive to a decrease in the hepatic glucose production or in the blood glucose level of a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
[00103] Yet other aspects relate to methods of modulating the biological activity of a glucagon receptor, comprising contacting the receptor with one or more of the compounds provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof. [00104] The conditions and diseases treatable with the methods provided herein include, but are not limited to, type 1 diabetes, type 2 diabetes, gestational diabetes, ketoacidosis, nonketotic hyperosmolar coma (nonketotic hyperglycaemia), impaired glucose tolerance (IGT), insulin resistance syndromes, syndrome X, low HDL levels, high LDL levels, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, dyslipidemia, arteriosclerosis, atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, vascular resenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, and lipid disorders.
[00105] Depending on the condition, disorder, or disease to be treated and the subject's condition, a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, and/or topical (e.g., transdermal or local) routes of administration, and may be formulated alone or together in suitable dosage unit with a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof, appropriate for each route of administration. [00106] The dose may be in the form of one, two, three, four, five, six, or more sub-doses that are administered at appropriate intervals per day. The dose or sub-doses can be administered in the form of dosage units containing from about 0.1 to about 1,000 mg, from about 0.1 to about 500 mg, or from 0.5 about to about 100 mg of active ingredient(s) per dosage unit, and if the condition of the patient requires, the dose can, by way of alternative, be administered as a continuous infusion. [00107] In certain embodiments, an appropriate dosage level is about 0.01 to about 100 mg per kg patient body weight per day (mg/kg per day), about 0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, or about 0.05 to about 10 mg/kg per day, which may be administered in single or multiple doses. A suitable dosage level may be about 0.01 to about 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about 0.1 to about 10 mg/kg per day. Within this range, the dosage may be about 0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg per day.
[00108] For oral administration, the pharmaceutical compositions can be provided in the form of tablets containing 1.0 to 1,000 mg of the active ingredient, particularly about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compositions may be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
[00109] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [00110] In still another embodiment, provided herein is a method of modulating the biological activity of a glucagon receptor, comprising contacting the receptor with one or more of the compounds provided herein, e.g., a compound of Formula I, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof. In one embodiment, the glucagon receptor is expressed by a cell. [00111] In certain embodiments, a compound provided herein is able to displace radiolabeled glucagon from the human glucagon receptor by at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of radiolabeled glucagon from the human glucagon receptor at the compound concentration of 1 ,000 nM.
[00112] In certain embodiments, the activity of a compound provided herein is described in terms of the concentrations of compound required for the displacement of 50% of the radiolabeled glucagon from the human glucagon receptor (the ICso values). In certain embodiments, the IC50 value of a compound provided herein is less than < 10,000 nM, 9,000 nM, 8,000 nM, 7,000 nM, 6,000 nM, 5,000 nM, 4,000 nM, 3,000 nM, 2,000 nM, 1,000 nM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM or 5 nM. [00113] In certain embodiments, the activity of a compound provided herein is described in terms of the concentrations of compounds required for functional antagonism of glucagon in hepatocytes from various species (EC50). In certain embodiments, the EC50 value for a compound provided herein is less than < 10,000 nM, 9,000 nM, 8,000 nM, 7,000 nM, 6,000 nM, 5,000 nM, 4,000 nM, 3,000 nM, 2,000 nM, 1,000 nM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM or 5 nM.
[00114] In certain embodiments, a compound provided herein exhibits the ability to reduce blood glucose in an animal. In certain embodiments, circulating blood glucose in fasting or non-fasting (freely-feeding) animals can be reduced between 10% and 100%. A reduction of 100% refers to complete normalization of blood glucose levels, not 0% blood glucose levels. Normal blood glucose in rats, for example, is approximately 80 mg/dL (fasted) and approximately 120 mg/dL (fed). In certain embodiments, an excessive circulating blood glucose level in a fasting or freely fed animal (e.g. rat) is reduced, after administration of 10 mg/kg of a compound provided herein, by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%
[00115] As described further herein, the compounds provided herein may also be combined or used in combination with other therapeutic agents useful in the treatment, prevention, or amelioration of one or more symptoms of the conditions, disorders, or diseases for which the compounds provided herein are useful.
[00116] In all methods described above, in certain embodiments, the methods generally comprise the step of administering to a patient in need thereof, such as an animal subject including a human subject, an effective amount of a compound of the invention. Pharmaceutical Compositions of the Invention
[00117] While it is possible for the compounds of the present invention to be administered neat, it may be preferable to formulate the compounds as pharmaceutical compositions. As such, in yet another aspect of the invention, pharmaceutical compositions useful in the methods of the invention are provided. The pharmaceutical compositions of the invention may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form. The pharmaceutical compositions should generally be formulated to achieve a physiologically compatible pH, and may range from a pH of about 3 to a pH of about 11 , preferably about pH 3 to about pH 7, depending on the formulation and route of administration. In alternative embodiments, it may be preferred that the pH is adjusted to a range from about pH 5.0 to about pH 8.0.
[00118] More particularly, in certain embodiments, pharmaceutical compositions comprising a compound provided herein as an active ingredient, e.g., a compound of Formula I, I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof. [00119] The pharmaceutical compositions may be formulated in various dosage forms, including, but limited to, the dosage forms for oral, parenteral, or topical administration. The pharmaceutical compositions may also be formulated as modified release dosage forms, including, but not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modifled-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2003; Vol. 126). [00120] In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, e.g., a compound of Formula I or Formula I-Λ, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof.
[00121] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof.
[00122] In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, e.g., a compound of Formula I or Formula I-A, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or a mixture thereof.
[00123] The pharmaceutical compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions provided herein.
[00124] The pharmaceutical compositions provided herein may be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents. It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
[00125] The pharmaceutical compositions provided herein may be administered parenteral Iy by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. The pharmaceutical compositions provided herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).
[00126] The pharmaceutical compositions provided herein may be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration. The pharmaceutical compositions provided herein may be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulation of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof. [00127] The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. As used herein, the term "modified release" refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
[00128] The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s). [00129] The pharmaceutical compositions provided herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action. Coloring and flavoring agents can be used in all of the dosage forms described herein. [00130] The pharmaceutical compositions provided herein may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those described in U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.
[00131] Any suitable components known in the art for the desired formulation may be used, as outlined in U.S. Provisional Application Nos. 61/088,562; 61/088,613; 61/088,619; 61/088,627; 61/088,631; 61/088,635; 61/088,638; 61/088,640; 61/088,642; 61/088,643; 61/088,644; 61/088,646; 61/088,647; 61/088,648; the contents of which are herein incorporated by reference.
Combination Therapy [00132] It is also possible to combine any compound of the present invention with one or more other active ingredients useful in the methods described herein, including compounds in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequential administration to a patient in need of treatment. When administered sequentially, the combination may be administered in two or more administrations. In an alternative embodiment, it is possible to administer one or more compounds of the present invention and one or more additional active ingredients by different routes. By way of example, a first therapeutic agent (e.g., a therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 min, 15 min, 30 min, 45 min, 1 hr, 2 hrs, 4 hrs, 6 hrs, 12 hrs, 24 hrs, 48 hrs, 72 hrs, 96 hrs, 1 wk, 2 wks, 3 wks, 4 wks, 5 wks, 6 wks, 8 wks, or 12 wks before), concomitantly with, or subsequent to (e.g., 5 min, 15 min, 30 min, 45 min, 1 hr, 2 hrs, 4 hrs, 6 hrs, 12 hrs, 24 hrs, 48 hrs, 72 hrs, 96 hrs, 1 wk, 2 wks, 3 wks, 4 wks, 5 wks, 6 wks, 8 wks, or 12 wks after) the administration of a second therapeutic agent to a subject to be treated. [00133] The skilled artisan will recognize that a variety of active ingredients may be administered in combination with the compounds of the present invention that may act to augment or synergistically enhance the activity of the compounds of the invention.
[00134] According to the methods of the invention, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used. [00135] In addition to being useful in treating or preventing certain diseases and disorders, combination therapy with compounds of this invention maybe useful in reducing the dosage of the second drug or agent.
[00136] By way of example, in certain embodiments, the compounds of the present invention can be administered in combination with anti-diabetic pharmaceutical agents. Suitable antidiabetic agents include, but are not limited to, insulin sensitizers, biguanides (e.g., buformin, metformin, and phenformin), PPAR agonists (e.g., troglitazone, pioglitazone, and rosiglitazone), insulin and insulin mimetics, somatostatin, α-glucosidase inhibitors (e.g., voglibose, miglitol, and acarbose), dipeptidyl peptidase-4 inhibitors, liver X receptor modulators, insulin secretogogues (e.g., acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide, sulfonylureas, tolazamide, tolbutamide, tolcyclamide, nateglinide, and repaglinide), other glucagon receptor antagonists, GLP-I, GLP-I mimetics, GLP-I receptor agonists, GIP, GIP mimetics, GIP receptor agonists, PACAP, PACAP mimetics, PACAP receptor 3 agonists, cholesterol lowering agents, HMG- CoA reductase inhibitors (e.g., statins, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, rivastatin, NK- 104 (a.k.a. itavastatin, nisvastatin, and nisbastatin), and ZD-4522 (also known as rosuvastatin, atavastatin, and visastatin)), a cholesterol absorption inhibitor (e.g., ezetimibe), sequestrants, nicotinyl alcohol, nicotinic acid and salts thereof, PPAR α agonists, PPAR α/γ dual agonists, inhibitors of cholesterol absorption, acyl CoAxholesterol acyltransferase inhibitors, antioxidants, PPAR δ agonists, antiobesity compounds, ileal bile acid transporter inhibitors, anti-inflammatory agents, and protein tyrosine phosphatase- IB (PTP-IB) inhibitors. [00137] The dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. [00138] The weight ratio of a compound provided herein to the second active ingredient depends upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with a PPAR agonist the weight ratio of the compound provided herein to the PPAR agonist will generally range from about 1000:1 to about 1:1000 or about 200:1 to about 1:200. Combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
[00139] To assist in understanding the present invention, the following Examples are included. The experiments relating to this invention should not, of course, be construed as specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the invention as described herein and hereinafter claimed.
EXAMPLES
[00140] The present invention is described in more detail with reference to the following non-limiting examples, which are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof. The examples illustrate the preparation of certain compounds of the invention, and the testing of these compounds in vitro and/or in vivo. Those of skill in the art will understand that the techniques described in these examples represent techniques described by the inventors to function well in the practice of the invention, and as such constitute preferred modes for the practice thereof. However, it should be appreciated that those of skill in the art should in light of the present disclosure, appreciate that many changes can be made in the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Example 1: PREPARATION OF COMPOUNDS OF THE INVENTION
Example 1-A: Ammonium 2-(4-r2-(4'-tert-butyl-biphenyl-4-yl)-2-(4'-chloro-3'-methyl- biphenyl-4-vD-ethyl1benzoylamino>-ethanesulfonate [00141] Step A: 4-bromobenzaldehyde (1.0 g, 5.4 mmol) was added to a 100 mL RB flask containing 4-chloro-2-methylphenylboronic acid (2.7 g, 15.8 mmol), sodium carbonate (3.4 g, 32.07 mmol), and dichlorobis(tri-o-tolylphosphine)palladium(II) (544 mg, 0.69 mmol). Dimethoxyethane (20 mL), ethanol (10 mL), and water (5 mL) were added, and the reaction was stirred at 120 °C for 1 hour at which point TLC analysis indicated that the reaction had gone to completion. The reaction was filtered hot through celite and concentrated to dryness. Purification by flash column chromatography was performed on an ISCO Sg-IOOc system, using a 40 gram pre-packed column and eluting with a linear gradient of ethyl acetate in hexanes starting at 1% EtOAc and ending at 10% EtOAc over 20 minutes. This afforded the desired product, 4'-Chloro-2'-methyl-biphenyl-4-carbaldehyde as a colorless solid, 1.1 g, 92%. LC-MS m/z = 231 [Ci4H1 iOCl + H]+.
Figure imgf000042_0001
[00142] Step B: To a 100 mL RB flask equipped with an addition funnel and a reflux condenser was added magnesium turnings (140 mg, 5.7 mmol), ether (10 mL), and a crystal of iodine. A solution of p-dibromobenzene (1.35 g, 5.7 mmol) in ether (10 mL) was added dropwise at such a rate to maintain reflux. This solution was allowed to stir for 1.5 h, at which point the crude Grignard reagent was carried to the next step without purification.
Figure imgf000042_0002
[00143] Step C: To the crude Grignard reagent (5.7 mmol) in Ether (20 mL) at -78 °C was added 4'-Chloro-2'-methyl-biphenyl-4-carbaldehyde (1.1 g, 4.7 mmol) in Ether (10 mL) in a dropwise fashion. The reaction was stirred at -78 °C for 30 minutes, at which point the cooling bath was removed and it was allowed to warm to room temperature, where it was stirred for an additional 1 hour before being quenched with a solution of saturated aqueous ammonium chloride. The reaction mixture was diluted with Et2O, and the organic layer was separated, washed with brine and dried over sodium sulfate. Purification was performed on an ISCO Sg-IOOc system, using a 40 gram pre-packed column and eluting with a linear gradient of ethyl acetate in hexanes starting at 10% EtOAc and ending at 20% EtOAc over 25 minutes, thereby affording the desired product, (4-Bromo-phenyl)-(4'-chloro-2'-methyl- biphenyl-4-yl)-methanol (1.03 g, 56%) as a pale yellow oil. 1H NMR (300 MHz, CDC13): δ 7.5-7.1 (m, 11 H), 5.84 (d, J = 3.3 Hz, 2 H), 2.28 (d, J = 3.6 Hz, 1 H), 2.22 (s, 3 H). LC-MS m/z = 388 [C20Hi6OBrCl+ H]+.
Figure imgf000043_0001
[00144] Step D: (4-Bromo-phenyl)-(4'-chloro-2'-methyl-biphenyl-4-yl)-methanol (1.0 g, 2.6 mmol) was added to a 100 mL RB flask containing 4-tert-butylphenylboronic acid (1.4 g, 7.8 mmol), sodium carbonate (1.65 g, 15.6 mmol), and dichlorobis(tri-o- tolylphosphine)palladium(II) (304 mg, 0.33 mmol). Dimethoxyethane (16 mL), ethanol (8 mL), and water (4 mL) were added, and the reaction was stirred at 120 °C for 1 hour at which point TLC analysis indicated that the reaction had gone to completion. The reaction was filtered hot through celite and concentrated to dryness. Purification by flash column chromatography was performed on an ISCO Sg-IOOc system, using a 40 gram pre-packed column and eluting with a linear gradient of ethyl acetate in hexanes starting at 5% EtOAc and ending at 20% EtOAc over 27 minutes. This afforded the desired product, (4'-tert-Butyl- biphenyl-4-yl)-(4'-chloro-2'-methyl-biphenyl-4-yl)-methanol as a colorless solid, 1.05 g, 93%. 1H NMR (300 MHz, CDC13): δ 7.6-7.4 (m, 9 H), 7.3-7.1 (m, 6 H), 5.84 (d, J = 3.3 Hz, 2 H), 2.28 (d, J= 3.6 Hz, 1 H), 2.22 (s, 3 H), 1.39 (s, 9H). LC-MS m/z = 442 [C30H29OCl + H]+.
Figure imgf000043_0002
[00145] Step E: To a solution of (4'-tert-Butyl-biphenyl-4-yl)-(4'-chloro-2'-methyl- biphenyl-4-yl)-methanol (350 mg, 0.8 mmol) in dichloromethane (10 mL) at 0 °C was added Dess-Martin periodinane (3.3 mL of a 0.48M solution, 1.6 mmol). The reaction was stirred at 0 °C for 30 minutes, at which point TLC analysis indicated it had gone to completion. The cooling bath was removed, and the reaction was warmed to room temperature. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography performed on an ISCO Sg-IOOc system, using a 40 gram pre-packed column and eluting with a linear gradient of ethyl acetate in hexanes starting at 0% EtOAc and ending at 20% EtOAc over 22 minutes to afford the product, (4'-tert-Butyl-biphenyl-4-yl)-(4'-chloro- 2'-methyl-biphenyl-4-yl)-methanone, as a colorless solid, 295 mg (85%). 1H NMR (300 MHz, CDC13): δ 7.9 (m, 4 H), 7.7 (d, J = 8.7 Hz, 2 H), 7.6 (d, J = 8.7 Hz, 2 H), 7.5 (d, J = 8.7 Hz, 2 H), 7.4 (d, J= 8.7 Hz, 2 H), 7.3-7.1 (m, 3H), 2.29 (s, 3 H), 1.38 (s, 9H). LC-MS m/z = 440 [C30H27OCl+ H]+.
Figure imgf000044_0001
[00146] Step F: A solution of 4-Bromomethyl-benzoic acid ethyl ester (3.0 g, 13 mmol) in triethylphosphite (30 mL) was heated to 150 °C for 30 minutes, at which point TLC analysis indicated the reaction had gone to completion. The remaining triethylphosphite was removed by distillation at reduced pressure, and the product was cooled to room temperature. The product, 4-(diethoxy-phosphorylmethyl)-benzoic acid ethyl ester was thereby obtained as a colorless oil (3.8 g, 99%). 1H NMR (300 MHz, CDC13): δ 7.9 (m, 2 H), 7.3 (m, 2 H), 4.3 (q, J= 6.9 Hz, 2H), 4.0 (m, 4H), 3.2 (d, J= 22.2 Hz, 2H), 1.3 (t, 3H), 1.2 (t, 6H). 31P NMR (300 MHz, CDC13): δ 26.2 ppm.
Figure imgf000044_0002
[00147] Step G: To a solution of 4-(diethoxy-phosphorylmethyl)-benzoic acid ethyl ester (221 mg, 0.74 mmol) in THF (5 mL) at -78 °C was added LHMDS (0.75 mL of a IM solution in toluene, 0.75 mmol). The reaction was stirred at -78 °C for 15 minutes, then was allowed to warm to 0 °C and was stirred for an additional 15 minutes. The reaction was then recooled to -78 °C and was treated with (4'-tert-Butyl-biphenyl-4-yl)-(4l-chloro-2'-methyl-biphenyl-4- yl)-methanone (295 mg, 0.67 mmol) in THF (5 mL). The reaction was allowed to warm to room temperature and was stirred 14 hours. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography performed on an ISCO Sg- 100c system, using a 40 gram pre-packed column and eluting with a linear gradient of ethyl acetate in hexanes starting at 0% EtOAc and ending at 20% EtOAc over 25 minutes to afford the product, 4-[-2-(4'-tert-Butyl-biphenyl-4-yl)-2-(4'-chloro-2'-methyl-biphenyl-4-yl)-vinyl]- bβnzoic acid ethyl ester (320 mg, 81%) as a mixture of £ and Z isomers. LC-MS m/z = 586 [C40H37O2Cl+ H]+.
Figure imgf000045_0001
[00148] Step H: To a solution of 4-[-2-(4'-tert-Butyl- biphenyl-4-yl)-2-(4'-chloro-2>- methyl-biphenyl-4-yl)-vinyl]-benzoic acid ethyl ester (320 mg, 0.55 mmol) in ethyl acetate (10 mL) was added platinum dioxide. The reaction was shaken under 40 psi hydrogen gas for Ih, then passed through a 0.45 μm syringe filter. The solvent was removed by rotary evaporation to afford the product, 4-[2-(4'-tert-Butyl-biphenyl-4-yl)-2-(4'-chloro-2'-methyl- biphenyl-4-yl)-ethyl] -benzoic acid ethyl ester (310 mg, 97%) as a colorless solid. LC-MS m/z = 588 [C40H39O2Cl+ H]+.
Figure imgf000045_0002
[00149] Step I: To a solution of 4-[2-(4'-tert-Butyl-biphenyl-4-yl)-2-(4'-chloro-2'-methyl- biphenyl-4-yl)-ethyl]-benzoic acid ethyl ester (310 mg, 0.53 mmol) in methanol (5 mL) was added NaOH (2.5 mL of a 3.5 N solution, 8.75 mmol) followed by THF (5 mL), and the reaction was stirred 14 hours. The solvents were removed by rotary evaporation, and the residue was partitioned between ethyl acetate and 0.5 N HCl. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed by rotary evaporation to furnish the product, 4-[2-(4'-tert-Butyl-biphenyl-4-yl)-2-(4'-chloro-2'- methyl-biphenyl-4-yl)-ethyl]-benzoic acid (290 mg, 98%), as a colorless foam. LC-MS m/z = 560 [C38H35O2Cl+ H]+.
Figure imgf000046_0001
[00150] Step J: To a solution of EDCI (154 mg, 0.8 mmol) in DMF (8 mL) was added HOBt (123 mg, 0.8 mmol) and 4-[2-(4'-tert-Butyl-biphenyl-4-yl)-2-(4'-chloro-2'-methyl- biphenyl-4-yl)-ethyl]-benzoic acid (290 mg, 0.51 mmol). This reaction was stirred 30 minutes, at which point taurine (135 mg, 1.02 mmol) and HOnig's base (0.35 mL, 2.04 mmol) were added, and the reaction was stirred for an additional 14 hours. The title compound, ammonium 2-{4-[2-(4l-tert-Butyl-biphenyl-4-yl)-2-(4'-chloro-2'-methyl-biphenyl-4-yl)- ethyl]-benzoylamino}-ethanesulfonate, was isolated by preparatory HPLC on a Shimadzu modular HPLC system using a Waters Atlantis Cl 8 30x75 mm preparatory column, a 5 mM aqueous ammonium carbonate buffer, and running a gradient from 40% acetonitrile to 100% acetonitrile over 13 minutes. Detection was accomplished using an in-line UV detector running at 254 nm. Lyophilization of the fractions containing product provided the title compound as a colorless solid (100 mg, 28%). 1H NMR (300 MHz, DMSO-^6): δ 8.4 (t, 1H), 7.6-7.1 (m, 19H), 7.1-7.0 (s, 4H), 4.5 (t, H), 3.4 (m, 4H), 2.6 (t, 2H), 2.2 (s, 3H), 1.3 (s, 9H). LC-MS m/z = 666 [C40H40O4CIS+ H]+. Anal. Calcd for (C40H43CIN2O4S + 1.8 H2O + 0.2 NH4HCO3): C, 66.00; H, 6.56; N, 4.21. Found: C, 65.83; H, 6.75; N, 4.53.
Figure imgf000046_0002
Example 1-B: Ammonium 2-[4-(((4'-tert-butyl-biphenyl-4-yl')-[4-(4'-chloro-2'-methyl- biphenyl-4-yl)-thiazol-2-yl]-amino}-methyl)-benzoylamino]-ethanesulfonate [00151] Step A: A mixture of 4-iodoaniline (5g), 4-t-butylphenylboronic acid (4.88g), PdCl2(P(o-tol)3)2 (896 mg) and sodium carbonate (7.2g) in dimethoxyethane (40mL)/ethanol (20 mL)/water (10 mL) was heated at 125 °C for a 20 min period. The precipitate was removed by filtration and the product obtained after aqueous workup was chromatographed on silica using an ethyl acetate hexanes gradient. The product was obtained as a yellow solid. 1H NMR (CDCI3): δ 7.45 - 7.47 (2H, m), 7.38 - 7.41 (4H, m), 6.72 - 6.74 (2H, m), 3.68 (2H, broad s), 1.33 (9H, s).
Figure imgf000047_0001
[00152] Step B: A mixture of the product from Step 1 above (113 mg), 4-formylbenzoate methyl ester (82 mg), sodium cyanoborohydride (126 mg) and acetic acid (0.2 mL) in DMF (2 mL) was stirred at 110 °C for Ih. The mixture was partitioned between ether and water. The organic layer was washed (water, sat aq. sodium chloride) and dried (magnesium sulfate). Concentration under reduced pressure and chromatography on silica gel using an ethyl acetate/hexanes gradient afforded the product as a white powder. 1H NMR (CDCb): δ 8.00 - 8.01 (2H, d, J= 8.3 Hz), 7.38 - 7.45 (8H, m), 6.64 - 6.66 (2H, m), 4.42 - 4.43 (2H, d, J= 4.9 Hz), 4.19 (1H, m), 3.90 (3H, s), 1.33 (9H, s).
Figure imgf000047_0002
[00153] Step C: A mixture of 500 me of the product from Step 2 above. 377 me of Fmoc- isothiocyanate and 442 μL of N,N-diisopropyl ethyl amine in dichloromethane was stirred at room temperature for 16h. The crude product [(M+H)+ = 655.9] obtained after evaporation was dissolved in dichloromethane and treated with piperidine (2 mL). After stirring at room temperature for 2h, the reaction mixture was concentrated under reduced pressure to give an intermediate thiourea [(M+H)+ = 433.6]. The crude was dissolved in dichloromethane, treated with 2'-bromo-4-bromoacetophenone (372 mg) and acetic acid (0.3 mL). After 3h, aqueous workup and chromatography afforded the product as a yellow solid [(M+H)+ = 611.6].
Figure imgf000048_0001
[00154] Step D: A mixture of the bromide from Step 3 above (100 mg), 2-methyl-4- chlorophenyl boronic acid (83 mg), PdCl2(P(o-tol)3)2 (13 mg) and sodium carbonate (84 mg) in dimethoxyethane (6mL)/ethanol (3 mL)/water (1.5 mL) was heated at 125 °C for a 10 min period. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. The crude product [(M+H)+ =657.6] was dissolved in THF/methanol (15 iτiL/10 mL) and treated with IM aqueous sodium hydroxide (5 mL). The mixture was heated at 65 °C for 3h, allowed to cool to room temperature and acidified with an excess of IM aqueous HCl. The product was extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure and used without further purification.
Figure imgf000048_0002
[001S5] Step E: A mixture of the product from step 4 above (100 mg), hydroxybenzotriazol hydrate (26 mg), EDCI (32 mg), taurine (32 mg) and N,N-diisopropyl ethyl amine (40 μL) in DMF was stirred at room temperature was stirred at room temperature for 16 h. The crude mixture was loaded on a C-18 flash chromatography column and eluted with an acetonitri Ie: water gradient. The product-containing fractions were pooled and chromatographed again on a C-18 HPLC column (Phenomenex, Gemini, C 18, 5 micron, AXIA, 30mmIDxl50mmL) eluting with a gradient of aqueous ammonium bicarbonate (20 mM) and acetonitri Ie (50% to 100% acetonitrile over 20 min) at 30 mL/min to yield the compound illustrated immediately above as the ammonium salt. NMR: 1H NMR (CDCb): δ 7.92 - 7.94 (2H, m), 7.77 - 7.78 (2H, d, J= 8.3 Hz), 7.67 - 7.68 (2H, m), 7.46 - 7.58 (8H, m), 7.31 - 7.33 (3H, m), 7.20 - 7.25 (2H, m), 7.00 (1H, s), 5.40 (2H, m), 3.77 - 3.79 (2H, m), 3.05 - 3.08 (2H, m), 2.28 (3H, s), 1.36 (9H, s). LC-MS: (+) 750.6.
Figure imgf000049_0001
Example 1-C: 2-(4-(2-(4-tert-Butyl-phenvπ-2-r4-(2'.4'-dichlorobiphenyl-4-vn-1H-imidazol- 2-yll-ethyl)benzoγlamino)-ethanesulfonic acid
[00156] Step A: To a stirred solution of 4-[2-(4-tert-Butylphenyl)-2-carboxyethyl]-benzoic acid methyl ester (l.Og, generated as reported in Bioorg Med Chem Lett 14, 2047-2050 (2004)) in DMF added cesium carbonate (1.955g) and allowed to react for a Ih period. The solvent was removed under reduced pressure. The residue was redissolved in methanol and treated with 4-bromophenacyl bromide (0.97g). The resulting mixture was stirred at room temperature for additional 16h and concentrated under reduced pressure. The crude product in toluene (50 mL) was treated with ammonium acetate (1.5g) and heated to reflux for a 4h period. The toluene was removed under reduced pressure and the residue was partitioned (ethyl acetate/water). The organic phase was washed (water, saturated aqueous sodium chloride solution), dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using an ethyl acetate/hexanes gradient, to afford the product with LCMS [M+H]+: 520.0.
Figure imgf000050_0001
[00157] Steps B-C: Using the conditions described in Example 1-B, Steps D and E, the product from Step A above was converted into the title compound. LCMS: [M+H]+ = 676.2, 678.2. Elemental Analysis: Calculated for C36H35N3O4Cl2S + (2.0)H2O+(0.7)CH3OH. C: 59.96, H: 5.73, N: 5.72; Found: C: 60.19, H: 6.12, N: 5.35.
Figure imgf000050_0002
Example 1-D: 2-f 4-r2-r4-(4-Benzofuran-2-vO-l H-imidazol-2-vπ-2-(4-tert-butyl-phenyn- ethyll-benzoylaminol -ethanesulfonic acid
[00158] This compound was prepared in a similar manner as described for the synthesis of Example 1-B. LCMS: [M+H]+ = 676.2, 678.2. Elemental Analysis: Calculated for C38H37N3O5S + (2.5)H2O+(1.1)CF3CO2H. C: 59.01, H: 5.31, N: 5.14; Found: C: 59.21, H: 5.62, N: 4.78.
Figure imgf000051_0001
Example 1 -E: 2-(4- (S.ό-Dichloro-S-methyl^-frEM-trifluoromethoxy-phenyliminoi^J- dihvdro-benzoim idazol- 1 -ylmethyl } -benzoy laminoVethanesulfonic acid [00159] A solution of 0.38g of 4-{5,6-dichloro-3-methyl-2-[(E)-4-trifluoromethoxy- phenylimino]-2,3-dihydro-beiizoimidazol-1-ylmethyl}-benzoic acid (prepared as reported in WO05065680, UA20070105930, US07301036) in DMF (15 mL) was treated with taurine (286 mg), HOBt-H2O (0.22g), EDCI ( 0.284g) and DIPEA (0.4 mL). The reaction mixture was stirred at room temperature for 16h. The entire mixture was then loaded on top of a reverse phase silica column and the column eluted with an acetonitrile/water gradient. The product-containing fractions were pooled, concentrated and the residue was purified one more time on a Shimadzu modular HPLC system using a Waters Atlantis dC18 30x150 mm column and running a gradient from 40% to 100% acetonitrile over 13 minutes. TFA was used as an ionizer and was present in 0.05% (v/v). Detection was accomplished using an inline UV detector running at 254 nm. LCMS m/z: 617.0 (C25H2I N4O5 SC 12F3+H)+. Elemental Analysis Calculated for C25H21N4O5SCl2F3 + 1.7 H2O: C: 46.33%, H: 3.79%, N: 8.65%. Found: C: 46.14%, H: 3.63%, N: 8.44%.
Figure imgf000051_0002
Example 1-F: 2-(4-π-[6-(4-Isobutyl-phenyl')-pyridin-3-yloxy1-butvU-benzoylamino')- ethanesulfonic acid
[00160] Step A: In an oven dried flask, terephthaldehydic acid monomethyl ester (1.5 g, 9.1 mmol) in 20 mL THF was cooled to -50 °C in a dry ice/isopropanol bath. This solution was then charged with TiCU (1.0 mL, 9.1 mmol). The solution was allowed to warm to 0 °C, then was treated with w-propyl magnesium chloride (6.8 mL of a 2.0 M solution in diethyl ether, 13.7 mmol) and was allowed to warm to room temperature over one hour, and was then stirred at room temperature for an additional hour. Saturated ammonium chloride was added to quench any remaining Grignard, and the solution was diluted with ethyl acetate and filtered through celite. The compound was purified by chromatography on silica gel column (130 x 42 mm SiO2), eluting with 10% ethyl acetate in dichloromethane to furnish 833 mg (44 %) of racemic 4-(l-hydroxy-butyl)-benzoic acid methyl ester as a faint yellow oil. 1H NMR (300 MHz, CDCl3): 58.02 (d, J= 8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 4.78 (dd, J, = 6.0 Hz, J2 = 1.8 Hz, 1 H), 3.94 (s, 3 H), 1.62-1.88 (m, 2 H), 1.23-1.53 (m, 2 H), 0.96 (t, J = 7.3 Hz, 3 H). LC-MS m/z = 209 [C12H16O3 + H]+.
Figure imgf000052_0001
[00161] Step B: 4-(l-Hydroxy-butyl)-benzoic acid methyl ester (343 mg, 1.64 mmol) and 2-chloro-5-hydroxypyridine (320 mg, 2.47 mmol) in toluene (5 mL) at 0 °C was added 1,1 '- (azodicarbonyl)dipiperidine (623 mg, 2.47 mmol) followed by tributylphosphine (0.34 mL, 2.47 mmol). THF (5 mL) was added to facilitate stirring and the reaction was allowed to warm to room temperature, where it was stirred for 2 hrs. The reaction was concentrated to dryness by rotary evaporator. The residue was then taken up in ethyl acetate and filtered through celite, followed by purification by chromatography on silica gel (ISCO cartridge, 40 g), eluting with a gradient of zero to 10% ethyl acetate in dichloromethane over 20 min to afford the desired product, 4-[l-(6-chloro-pyridin-3-yloxy)-butyl]-benzoic acid methyl ester, as a colorless oil, 300 mg (57%). 1H NMR (300 MHz, CDCl3): δ 8.03 (d, J = 8.0 Hz, 2 H), 8.00 (d, J= 2.94 Hz, 1 H), 7.42 (d, J= 8.0 Hz, 2 H), 7.05-7.17 (m, 2 H), 5.13 (dd, J, = 6.0 Hz, J2 = 1.8 Hz, 1 H), 3.94 (s, 3 H), 1.62-1.88 (m, 2 H), 1.23-1.53 (m, 2 H), 0.96 (t, J= 7.3 Hz, 3 H). LC-MS m/z = 320 [C17H18ClNO3 + H]+.
Figure imgf000053_0001
[00162] Step C: 4-[l-(6-Chloro-pyridin-3-yloxy)-butyl]-benzoic acid methyl ester (300 mg, 0.94 mmol) in toluene (3 mL) was treated with water (3 mL), tetrakis (triphenylphosphine) palladium (108 mg, 0.1 mol%), and 4-isobutylphenylboronic acid (334 mg, 1.87 mmol). This solution was heated to reflux for S min, at which point it was allowed to cool to room temperature. Potassium fluoride (109 mg, 1.87 mmol) was added in one portion, and the reaction was then heated at 90 °C for 16 hrs. The reaction was evaporated to dryness by rotary evaporator and purified by column chromatography on silica gel (100 x 42 mm S1O2) eluting with 10% acetone in hexanes to yield 4-{l-[6-(4-isobutyl-phenyl)-pyridin- 3-yloxy]-butyl} -benzoic acid methyl ester as a light yellow oil (353 mg, 90%). 1H NMR (300 MHz, CDCl3): 58.33 (d, J = 2.9 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.55 (d, J= 8.5 Hz, 1 H), 7.46 (d, J= 8.2 Hz, 2 H), 7.05-7.17 (m, 3 H), 5.13 (dd, J1 = 6.0 Hz, J2 = 1.8 Hz, 1 H), 3.94 (s, 3 H), 2.51 (d, J = 7.0 Hz, 2 H), 1.88-2.20 (m, 4 H), 1.40- 1.63 (m, 2 H), 0.96 (t, J = 7.3 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 6 H). LC-MS m/z = 418 [C27H3INO3 + H]+.
Figure imgf000053_0002
[00163] Step D: To a solution of 4-{l-[6-(4-isobutyl-phenyl)-pyridin-3-yloxy]-butyl}- benzoic acid methyl ester (418 mg, 1 mmol) in 2 mL of ethanol was added 2 mL of a 3.5 N solution of aqueous sodium hydroxide. THF (2 mL) was then added to clear the resulting suspension, and the reaction was stirred for 16 hrs. After evaporation to dryness, the residue was partitioned between ethyl acetate and water and was acidified with 2.4 N hydrochloric acid. The layers were separated, and the organic layer was washed with brine, dried with sodium sulfate, and finally evaporated to dryness. The product, 4-{l-[6-(4-isobutyl-phenyl)- pyridin-3-yloxy]-butyl}-benzoic acid was thereby obtained as a colorless foam (412 mg, 101%). 1H NMR (300 MHz, CDCl3): 58.33 (d, J = 2.9 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 2 H), 7.79 (d, J= 8.0 Hz, 2 H), 7.55 (d, J= 8.5 Hz, 1 H), 7.46 (d, J= 8.2 Hz, 2 H), 7.05-7.17 (m, 3 H), 5.13 (dd, J/ = 6.0 Hz, J2 = 1.8 Hz, 1 H), 2.51 (d, J = 7.0 Hz, 2 H), 1.88-2.20 (m, 4 H), 1.40-1.63 (m, 2 H), 0.96 (t, J= 7.3 Hz, 3 H), 0.92 (d, J= 6.7 Hz, 6 H). LC-MS m/z = 404 [C26H29NO3 H- H]+.
Figure imgf000054_0001
[00164] Step E: To a solution of 4-{l-[6-(4-isobutyl-phenyl)-pyridin-3-yloxy]-butyl}- benzoic acid (412 mg, 1.02 mmol) in THF (10 mL) was added NJT- dicyclohexylcarbodiimide (DCC, 253 mg, 1.23 mmol) and N-hydroxysuccinimide (177 mg, 1.53 mmol) followed by a catalytic amount of 4-dimethylaminopyridine (DMAP, ~10 mg). This reaction was then stirred for 16 hrs before being evaporated to dryness. The residue was then taken up in dichloromethane and filtered before being preloaded on silica and purified by column chromatography (ISCO cartridge, 4Og) eluting with a gradient of 10% to 50% ethyl acetate in hexanes. The resultant product, 4-{l-[6-(4-isobutyl-phenyl)-pyridin-3- yloxy] -butyl} -benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester, was thereby obtained in 81% yield (424 mg) as a colorless solid. 1H NMR (300 MHz, CD3OD): 58.26 (d, J= 2.3 Hz, 1 H), 8.15 (d, J= 8.5 Hz, 2 H), 7.73 (d, J = 8.5 Hz, 2 H), 7.66 (d, J= 8.5 Hz, 1 H), 7.37 (m, 1 H), 7.23 (d, J= 8.5 Hz, 2 H), 5.50 (dd, J1 = 6.0 Hz, J2 = 1.8 Hz, 1 H), 2.93 (s, 4H), 2.51 (d, J = 7.0 Hz, 2 H), 1.88-2.20 (m, 4 H), 1.40-1.63 (m, 2 H), 1.02 (t, J= 7.3 Hz, 3 H), 0.95 (d, J = 6.7 Hz, 6 H). LC-MS m/z = 501 [C30H32N2O5 + H]+.
Figure imgf000054_0002
[00165] Step F: To a solution of 4-{l-[6-(4-Isobutyl-phenyl)-pyridin-3-yloxy]-butyl}- bβnzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (103 mg, 0.2 mmol) in ethanol (3 niL) in a microwave vial was added water (1 mL), taurine (52 mg, 0.4 mmol), and triethylamine (0.12 mL, 0.8 mmol). The vial was then heated in the microwave reactor at 125 °C for 6 min. The reaction mixture was acidified using trifluoroacetic acid (TFA, excess, 0.2 mL) and taken up in 20% v/v acetonitrile. The resulting solution was purified by preparatory HPLC on a Shimadzu modular HPLC system using a Waters Atlantis dC18 30 x 75 mm preparatory column and running a gradient from 40% acetonitrile to 100% acetonitrile over 13 min. TFA was used as an ionizer and was present in 0.05% (v/v). Detection was accomplished using an in-line UV detector running at 254 nm. Rotary evaporation of the solvated compound provided the title compound, 2-(4-{l-[6-(4-isobutyl-phenyl)-pyridin-3-yloxy]-butyl}- benzoylamino)-ethanesulfonic acid, complexed with TFA, as a colorless solid in 40% isolated yield (42 mg).
Figure imgf000055_0001
[00166] 1H NMR (300 MHz, CD3OD): 58.37 (m, 1 H), 8.19 (m, 2 H), 7.86 (d, J = 8.5 Hz, 2 H), 7.73 (d, J= 8.5 Hz, 2 H), 7.57 (d, J= 8.5 Hz, 2 H), 7.42 (d, J= 8.5 Hz, 2 H), 5.70 (dd, J, = 6.0 Hz, J2 = 1.8 Hz, 1 H), 3.81 (t, J= 6.45 Hz, 2 H), 3.07 (t, J= 6.45 Hz, 2 H), 2.60 (d, J = 7.0 Hz, 2 H), 1.88-2.20 (m, 4 H), 1.40-1.63 (m, 2 H), 1.02 (t, J= 7.3 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 6 H). LC-MS m/z = 511 [C28H34N2OsS + H]+. Anal. Calcd for (C28H34N2OsS+ 1.3 TFA): C, 55.78; H, 5.40; N, 4.25. Found: C, 55.80; H, 5.45; N, 4.46. HPLC conditions: Column = Waters Atlantis; dC18-150 x 4.6 mm; Mobile phase = Solvent A: H2O/0.05% TFA; Solvent B: ACN/0.05% TFA. Flow rate = 2.0 mL/min; UV@ 254 nm. Retention time in minutes, (rt = 6.83/20.00, 99% purity). Melting Point (uncorrected) 78-80 °C.
Figure imgf000056_0001
Example 1-G: 2:2-(4-|'l-f6-p-Tolyl-pyridin-3-yloxy')-butyl]-benzoylamino}-ethanesulfonic acid
[00167] The title compound was prepared from terephthaldehydic acid monomethyl ester according to the procedure described for the synthesis of Example 1-F, steps A through F, substituting 4-methylphenylboronic acid for 4-isobutylphenylboronic acid in step C. 1H NMR (300 MHz, CD3OD): 58.37 (d, J = 2.6 Hz, 1 H), 8.16 (m, 2 H), 7.86 (d, J = 8.5 Hz, 2 H), 7.68 (d, J= 8.5 Hz, 2 H), 7.56 (d, J= 8.5 Hz, 2 H), 7.44 (d, J = 8.5 Hz, 2 H), 5.68 (dd, J, = 6.0 Hz, J2 = 1.8 Hz, 1 H), 3.81 (t, J= 6.45 Hz, 2 H), 3.06 (t, J= 6.45 Hz, 2 H), 2.47 (s, 3 H), 1.88-2.28 (m, 4 H), 1.40-1.63 (m, 2 H), 1.02 (t, J = 7.3 Hz, 3 H). LC-MS m/z = 511 [C28H34N2O5S + H]+. Anal. Calcd for (C28H34N2O5S+ 1.3 TFA): C, 55.78; H, 5.40; N, 4.25. Found: C, 55.80; H, 5.45; N, 4.46. HPLC conditions: Column = Waters Atlantis; dC18-150 x 4.6 mm; Mobile phase = Solvent A: H2O/0.05% TFA; Solvent B: ACN/0.05% TFA. Flow rate = 2.0 mL/min; UV@ 254 nm. Retention time in minutes, (rt = 6.83/20.00, 99% purity). Melting Point (uncorrected) 78-80 °C.
Figure imgf000056_0002
Example 1-H: 2-(4-{ l-f6-f4-Isobutyl-phenyl'>-pyridin-3-yloxy]-3.3-dimethyl-butyl}- benzoylaminoVethanesulfonic acid
[00168] The title compound was prepared from terephthaldehydic acid monomethyl ester according to the procedure described for the synthesis of Example 1-F, steps A through F, substituting neopentyl magnesium chloride for n-propyl magnesium chloride in step A. 1H NMR (300 MHz, CD3OD): 58.37 (d, J= 2.6 Hz, 1 H), 8.16 (m, 2 H), 7.86 (d, J= 8.5 Hz, 2 H), 7.72 (d, J= 8.5 Hz, 2 H), 7.57 (d, J= 8.5 Hz, 2 H), 7.42 (d, J= 8.5 Hz, 2 H), 5.79 (dd, J1 = 6.0 Hz, J2 = 1.8 Hz, 1 H), 3.78 (t, J= 6.45 Hz, 2 H), 3.05 (t, J= 6.45 Hz, 2 H), 2.60 (d, J= 7.0 Hz, 2 H), 2.47 (s, 3 H), 2.19 (m, 1H), 1.58-2.02 (m, 4 H), 1.29 (m, 1H), 1.12 (s, 9 H), 0.92 (d, J = 6.7 Hz, 6 H). LC-MS m/z = 539 [C30H38N2O5S + H]+. Anal. Calcd for (C28H34N2O5S +0.5 TFA +1.9 H2O): C, 59.11; H, 6.77; N, 4.45. Found: C, 58.72; H, 6.56; N, 4.87. HPLC conditions: Column = Waters Atlantis; dC18-150 x 4.6 mm; Mobile phase = Solvent A: H2O/0.05% TFA; Solvent B: ACN/0.05% TFA. Flow rate = 2.0 mlJmin; UV@ 254 nm. Retention time in minutes, (it = 5.96/20.00, 99% purity). Melting Point (uncorrected) 87-89 °C.
Figure imgf000057_0001
Example 1-1: 4:2-(4-ll-[6-(4-Isobutyl-phenvD-pyridin-3-yloxy]-ethvπ-benzoylaminoV ethanesulfonic acid
[00169] Step A: Ethyl-4-acetylbenzoate (550 mg, 2.86 mmol) was dissolved in ethanol (13 mL) and treated with sodium borohydride (10% on basic alumina, 300 mg). This suspension was heated to reflux for 2 hrs, then cooled to room temperature and filtered. The ethanol was removed by rotary evaporation; the residue was taken up in ethyl acetate and washed sequentially with IN HCl and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to yield racemic 4-(l-hydroxy-ethyl)-benzoic acid methyl ester as a colorless oil, 549 mg (99%). 1H NMR (300 MHz, CDCl3): 58.02 (d, J= 8.0 Hz, 2 H), 7.42 (d, J= 8.0 Hz, 2 H), 4.94 (q, J= 6.5 Hz, 1 H), 4.36 (q, J= 6.5 Hz, 2 H), 1.51 (d, J = 8.5 Hz, 3 H), 1.37 (t, J= 7.3 Hz, 3 H). LC-MS m/z = 195 [C10H12O3 + H]+.
[00170] The title compound was prepared from 4-(l-hydroxy-ethyl)-benzoic acid methyl ester according to the procedure described for the synthesis of Example 1-F, steps B through F. 1H NMR (300 MHz, CD3OD): 58.37 (s, 1 H), 8.18 (s, 2 H), 7.86 (d, J= 8.5 Hz, 2 H), 7.72 (d, J= 8.5 Hz, 2 H), 7.57 (d, J= 8.5 Hz, 2 H), 7.42 (d, J= 8.5 Hz, 2 H), 5.82 (m, 1 H), 3.78 (t, J = 6.45 Hz, 2 H), 3.05 (t, J = 6.45 Hz, 2 H), 2.59 (d, J = 7.0 Hz, 2 H), 1.88 (m, 1 H), 1.76 (d, J= 7.0 Hz, 2 H), 0.92 (d, J= 6.7 Hz, 6 H). LC-MS m/z = 483 [C26H30N2O5S + H]+. Anal. Calcd for (C26H30N2O5S +0.3 TFA +1.5 H2O + 0.1 EtOH): C, 58.69; H, 6.23; N, 5.11. Found: C, 58.32; H, 6.36; N, 5.50. HPLC conditions: Column = Waters Atlantis; dC18-150 x 4.6 mm; Mobile phase = Solvent A: H2O/0.05% TFA; Solvent B: ACN/0.05% TFA. Flow rate = 2.0 mL/min; UV@ 254 nm. Retention time in minutes, (rt = 3.64/20.00, 99% purity). Melting Point (uncorrected) 108-110 °C.
Figure imgf000058_0001
Example 1 -J: 2-C4-11 -F3-( 3.5-DichlorophenvD5-(6-methoxynaphthalen-2-vπ-pyrazol-l -yll- ethyl t -benzoylam inoVethanesulfonic acid
[00171] A microwave reaction vial was loaded with a mixture of the starting carboxylic acid (144 mg), taurine (126 mg), l-ethyl-3- (3-dimethylaminopropyl)-carbodiimide (160 mg), 1 -hydroxybenzotriazole hydrate (127 mg), and diisopropylethylamine (0.458 mL), in DMF (6 mL). The vial was capped and heated at 80 °C for a 4 minute period. The crude sample was then treated with an excess of IM aqueous sodium hydroxide and flash chromatographed on C18-silica gel using an acetonitrile/water gradient. The product-containing fractions were pooled, concentrated and acidified, the title compound was obtained after purification by preparative HPLC using a Waters Atlantis dC18 30x75 mm preparatory column and running a gradient from 60/40 to 0:100 water: acetonitrile (with both solvents containing 0.05% trifluoroacetic acid). Detection was accomplished using an in-line UV detector running at 254 nm. Molecular ion at [M-H]- = 622.4 and 626.4. Elemental analysis for C3IH27N3O5Cl2S + 2.5H2O: Calculated: C: 55.61%, H: 4.82%, N: 6.28% Found: C: 55.60%, H: 5.06%, N: 5.97%
Figure imgf000058_0002
Example 1-K: 2-(4-(2-r5-chloro-1-(3-trifluoromethyl-phenvπ-1H-indole-2-carbonyl]- heptvU-benzoylaminoVethanesulfonic acid:
[00172] To a mixture 2.Og of 4-{2-[5-chloro-1-(3-trifluoromethyl-phenyl)-1H-iπdole-2- carbonyl]-heptyl}-benzoic acid (Prepared as described in UA20070088071), HOBt-hydrate (0.94 g), EDCI (1.17g) and taurine (1.02 g) in DMF (15 mL) added diisopropyl ethyl amine (2.02 mL). The resulting reaction mixture was stirred at room temperature for 16h. The solvent was removed under reduced pressure. The residue was treated with an excess of 1 M sodium hydroxide and loaded on a C- 18 reverse phase flash chromatography column. The column was eluted with an acetonitrile/water gradient. The product-containing fractions were concentrated to remove the acetonitrile and then lyophilized to give the sodium salt of the title compound as a white solid. LCMS [M-H]-: 647.6. Elemental Analysis: Calculated for C32H3IN2O5F3ClSNa: C: 57.27, H: 4.66, N: 4.17. Found: C: 57.41, H: 4.95, N: 4.22
Figure imgf000059_0001
Example 1-L: Preparation of Preparation of 2-(4-((((lJR.4/?)-4-tert-butylcvclohexyn(l- methyl-5-(trifluoromethoxy)-lH-benzo[dlimidazol-2-v0amino)methvDbenzamido) ethanesulfonic acid
[00173] Step A: Preparation of 2,5-dioxopyrrolidin-1-yl 4-((((\R,4R)-4-tert- butylcyclohexyl)(l-methyl-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2- yl)amino)methyl)benzoate. A solution of 4-{[(4-^rørø-te/?-butyl-cyclohexyl)-(l-methyl-5- trifluoromethoxy-1H-benzoimidazol-2-yl)-amino]-methyl}-benzoic acid (370 mg), which was as described in WO2004/100875, in TΗF (10 mL) was treated with JV- hydroxysuccinimide (119 mg) and DCC (179 mg). The resulting mixture was stirred at room temperature for 16 hrs. The white precipitate formed was removed by filtration and the filtrate was concentrated under reduced pressure. Chromatography on silica gel using an ethyl acetate/hexanes gradient yielded the desired succinyl ester (234 mg). [00174] Step B: Preparation of 2-(4-((((lΛ,4Λ)-4-tert-butylcyclohexyl)(l-methyl-5- (trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)amino)methyl)benzamido)ethanesulfonic acid. To a solution of the desired succinyl ester (234 mg) in 6 mL of ethanol and 2 mL of water was added 97 mg of taurine and 0.215 mL of triethyl amine. The resulting suspension was heated in a sealed flask at 125 °C for 6 min. The clear solution was concentrated under reduced pressure. The residue was dissolved in DMF (ca. 3 mL) and treated with water (1 mL) and trifluoroacetic acid (0.2 mL). This mixture was loaded on top of a C- 18 silica flash chromatography column and eluted with a gradient of acetonitrile and water (each solvent containing 0.1% of trifluoroacetic acid). The product-containing fractions were pooled and concentrated under reduced pressure to remove the acetonitrile. The white precipitate obtained was filtered and dried under vacuum at 50 °C to yield the title compound as a white solid. LCMS: m/z = 611.6 (MH+). Elemental Analysis: Calculated for C29H37N4O5SF3 + (0.5) H2O: C: 56.21, H: 6.18, N: 9.04. Found: C: 55.99, H: 5.80, N: 8.98.
Figure imgf000060_0001
Example 1-M: 2-(4-[l-(4'-teιt-Butyl-biphenyl-4-vD-3-(4-iodo-phenvπ-ureidomethyll- benzoylaminol-ethanesulfonic acid
[00175] Step A: A mixture of 4-iodoaniline (5g), 4-t-butylphenylboronic acid (4.88g), PdCb(P(o-tol)3)2 (896 mg) and sodium carbonate (7.2g) in dimethoxyethane (40mL)/ethanol (20 mL)/water (10 mL) was heated at 125 °C for a 20 min period. The precipitate was removed by filtration and the product obtained after aqueous workup was chromatographed on silica using an ethyl acetate hexanes gradient. The product was obtained as a yellow solid. 1H NMR (CDCI3): δ 7.45 - 7.47 (2H, m), 7.38 - 7.41 (4H, m), 6.72 - 6.74 (2H, m), 3.68 (2H, broad s), 1.33 (9H, s).
Figure imgf000061_0001
[00176] Step B: A mixture of the product from Step 1 above (113 mg), 4-formylbenzoate methyl ester (82 mg), sodium cyanoborohydride (126 mg) and acetic acid (0.2 mL) in DMF (2 mL) was stirred at 110 °C for Ih. The mixture was partitioned between ether and water. The organic layer was washed (water, sat aq. sodium chloride) and dried (magnesium sulfate). Concentration under reduced pressure and chromatography on silica gel using an ethyl acetate/hexanes gradient afforded the product as a white powder. 1H NMR (CDCb): δ 8.00 - 8.01 (2H, d, J = 8.3 Hz), 7.38 - 7.45 (8H, m), 6.64 - 6.66 (2H, m), 4.42 - 4.43 (2H, d, J= 4.9 Hz), 4.19 (1H, m), 3.90 (3H, s), 1.33 (9H, s).
Figure imgf000061_0002
[00177] Step C: A mixture of 500 mg of the product from Step 2 above, 656 mg of 4- iodophenylisocyanate and 1.33 mL of N,N-diisopropyl ethyl amine in dichloromethane was stirred at room temperature for 16h. Aqueous workup left a crude product [(M-I-H)+ = 619.4] that was used directly in Step D below.
Figure imgf000061_0003
[00178] Step D: The iodide from Step 3 above in THF (15 mL) and methanol (10 mL) was treated with an aqueous solution of IM NaOH. The reaction mixture was heated at 60 °C for a 3h period. The mixture was acidified with an excess of IM aqueous HCl, diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude product was used without further purification.
Figure imgf000062_0001
[00179] Step E: A mixture of the product from step 4 above (500 mg), hydroxybenzotriazol hydrate (139 mg), EDCI (174 mg), taurine (166 mg) and N,N- diisopropyl ethyl amine (206 μL) in DMF was stirred at room temperature was stirred at room temperature for 16 h. The crude mixture was loaded on a C-18 flash chromatography column and eluted with an acetonitrile:water gradient. The white solid obtained ([M-H]- = 711.6)was used in the following step.
Figure imgf000062_0002
[00180] Step F: A mixture of the iodide form Step E above (50 mg), 2-methyl-4- chlorophenyl boronic acid (36 mg), PdCl2(P(o-tol)ϊ)2 (6 mg) and sodium carbonate (37 mg) in dimethoxyethane (2mL)/ethanol (1 mL)/water (0.5 mL) was heated at 125 °C for a 10 min period. The mixture was acidified with an excess of IM aqueous HCl. The product was extracted with ethyl acetate and the organic phase was evaporated under reduced pressure. The crude product was treated with IM aqueous sodium hydroxide and methanol and loaded on top of a C-18 silica gel flash chromatography column. The column was eluted with a gradient of acetonitrile-water gradient. The sodium salt of the title compound was obtained as white solid. LCMS: 708.9 (M-H)-, 823.1 (M+CF3CO2). HNMR (500 MHz, CD3OD, partial): 5.06 (2H, broad s), 3.79 (2H, t, J = 6.8 Hz), 3.08 (2H, t, J = 6.6 Hz), 2.24 (3H, s), 1.35 (9H, s).
Figure imgf000063_0001
Example 1-N: 2-(4-{r(4'-tert-Butyl-biphenyl-4-y1H4'-chloro-2'-methyl-biphenyl-4- yloxycarbonvD-aminol-methvπ -benzoylaminoVethanesulfonic acid
[00181] Step A: A mixture of 500 mg of the product from Step 2, Example 1 above, 265 mg of triphosgene, and 1.35 mL of N,N-diisopropyl ethyl amine in dichloromethane was stirred at room temperature for Ih. The solvent was evaporated under reduced pressure. The residue was dissolved in DMF and treated with 4-iodophenol (295 mg) and DABCO (300 mg). The reaction mixture was stirred at room temperature for about 16h. After aqueous workup, the crude product obtained [(M+H)+ = 620.4] was used directly.
Figure imgf000063_0002
[00182] Steps B-D: Utilizing the methods described in Example 1-M, Steps D-F, the sodium salt of the title compound was obtained as a white solid. LCMS: 71 1.6 (M-H)', 824.1 (M+CF3CO2)-. 1HNMR (500 MHz, CD3OD, partial): 5.10 (2H, broad s), 3.80 (2H, t, J = 6.4 Hz), 3.17 (2H, broad t), 2.24 (3H, s), 1.35 (9H, s).
Figure imgf000064_0001
Example 2: Activity Assays:
Example 2-A: Human Glucagon Receptor Affinity
[00183] Compounds provided herein are dissolved in a suitable solvent (e.g. dimethlysulfoxide) at a concentration of 10 mM and then diluted in buffer (50 mM Hepes, pH 7.4, 5 mM MgCl2, 1 mM CaCl2, 0.2% BSA) to concentrations ranging from 1 nM to 100 μM. Compounds (20 μl/well) and [l25I]Glucagon (Perkin Elmer; final concentration: 0.125 nM;20 μl/well) are added to and mixed in wells of a 96-well plate (Costar, Corning) containing 120 μl of buffer. Next, an appropriate aliquot of a membrane preparation containing the human glucagon receptor (isolated from human liver samples or obtained from a recombinant cell line) is added to the wells. The binding mixtures are incubated for 2 hour at room temperature. In the meantime, a MultiScreen 96-well filter plate (Millipore) is incubated with 200 μl of buffer, which is vacuumed through the filter just before the binding mixtures are transferred to the plate. At the end of incubation, binding mixtures are transferred to the wells of the MultiScreen 96-well filter plate and filtered through by applying vacuum. The plate is washed once with 200 μl per well of buffer and the filters are dried and counted by means of a gamma counter.
[00184] Exemplified compounds displace radiolabeled glucagon from the human glucagon receptor by >15% at 1000 nM or have an IC50 of < 10,000 nM. Example 2-B: Functional antagonism in hepatocvtes from various species
[00185] Primary human, monkey, dog, rat, or mouse hepatocytes are seeded onto collagen- coated 24-well plates in Williams E medium (supplemented with 10% fetal bovine serum) and incubated at 37°C overnight in M 199 medium (supplemented with 15 mM glucose and 10 nM human insulin). The following day cells are washed twice with a glucose-free Kreb- bicarbonate buffer, pH 7.4, containing 0.1% BSA. Cells are then incubated at 37° C with the aforementioned buffer containing 1 nM glucagon and varying concentrations of a glucagon antagonist (0 - 100 microM). Control wells without glucagon or antagonist are also included. After 1 hour, an aliquot of the medium is removed and analyzed for glucose content by means of the glucose oxidase method. The background glucose levels observed in the control wells are subtracted from the glucagon and antagonist containing wells. A graph of % glucose concentration vs drug concentration is plotted and an EC50 value for inhibition of glucose production generated using Sigmaplot software (SAS, Cary, North Carolina). Alternatively, intracellular cAMP levels are measured using standard kits and ECSO values determined by plotting these levels against drug concentration. Antagonists of the glucagon receptor inhibit glucagon-induced cAMP production.
Example 2 -C: Glucose lowering in diabetic animals
[00186] The effects of compounds provided herein on blood glucose levels are assessed in animal models of type 1 or 2 diabetes such as, but not limited to, the db/db mouse, the Zucker fatty (ZF) rat, the Zucker diabetic (ZDF) rat, the glucagon-challenged dog, the alloxan- or streptozotocin-treated mouse or rat, the NOD mouse or the BB rat.
[00187] Compounds are dissolved in an appropriate vehicle such as polyethylene glycol- 400 or cyclodextrin and administered to animals at doses of 0.1 to 100 mg/kg either by intraperitoneal injection, intravenous injection, or oral gavage. Animal models used in this evaluation (e.g. the db/db mouse, the ZF rat, the ZDF rat, the glucagon-challenged (0.3-5 μg/kg) dog, the alloxan- or streptozotocin-treated mouse or rat, the NOD mouse, or BB rat) are either freely-feeding or fasted from 3 to 24 hrs prior to compound administration. In some instances, animals may be subjected to a glucose tolerance test following compound administration by intravenous or oral administration of up to 2g/kg of glucose. Blood glucose levels are assessed in blood samples obtained by tail bleed or by sampling an appropriate blood vessel by means of a syringe or catheter. Glucose is measured using a portable glucometer such as the OneTouch or HemoCue meters at regular time intervals for up to 24 hrs. The extent of blood glucose lowering elicited by the compounds provided herein is determined by comparison to those in control animals administered only the vehicle. The percentage of blood glucose lowering attained is calculated relative to blood glucose levels in vehicle-treated nondiabetic or non-glucagon-challenged control animals. Example 2-D: Glucose lowering in db/db mice
[00188] To assess the effects of compounds provided herein on blood glucose levels in the db/db mouse, an animal model of type 2 diabetes, compounds are dissolved in polyethylene glycol-400 and administered by oral gavage to db/db mice in the freely-feeding state at doses of 30 and/or 100 mg/kg. Blood glucose levels are assessed in blood samples obtained by tail bleed at baseline (prior to drug administration) and at regular time intervals over 24 hrs using a portable glucometer such as the OneTouch or HemoCue meters. The magnitude of blood glucose lowering elicited by the compounds provided herein is determined by comparison to those in db/db mice administered only the vehicle. The percentage glucose lowering is calculated by factoring in the blood glucose levels of vehicle-treated lean db/+ (heterozygote) mice, with 100% representing the normalization of blood glucose levels from the hyperglycemic state (vehicle-treated db/db mice) to the normoglycemic state (vehicle-treated db/+ mice).
Example 2-E: Glucose lowering in glucagon-challenged Beagle dogs [00189] To assess the effects of compounds provided herein on blood glucose levels in glucagon-challenged Beagle dogs, beagle dogs (n=3) are treated with vehicle (polyethylenelglycol-400) by oral gavage. After 1.5 hrs, glucagon (20 μg) is administered subcutaneously. Blood glucose levels are measured prior to glucagon administration and at 10-minute intervals thereafter for up to an hour. Blood samples for these determinations are obtained from a superficial ear vein and are measured using a OneTouch glucometer. After a 1-week washout, the animals are treated by oral gavage with compounds provided herein at a dose of 40 mg/kg (polyethylenelglycol-400 formulation). The glucagon challenge and blood sampling are then performed as before. [00190] All publications and patent applications cited herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
[00191] Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. AU such modifications are intended to be encompassed within the claims of the invention.

Claims

WHAT IS CLAIMED:
1. A compound of Formula I:
Figure imgf000067_0002
wherein:
X is 1,4-phenylene, 2-4-thienylene or 2,5-thienylene; Rb is selected from Ra, hydroxyl, fluoro, and -(CH2)PORC; Ra and Rc are selected from H, and Cu-alkyl; p is O or 1 ; m is 1, 2 or 3; and
A is selected from
Figure imgf000067_0003
and
Figure imgf000067_0001
Ba is selected from null and -CHRa;
Bb is selected from Ba, -O-, -S-, -NRa-, -C(O)-, -S(O)-, -S(O)2-, and -CF2-;
E is optionally substituted Ci.^-alkyl, C2-12-alkenyl, C2-12-alkynyl, Cj-g-cycloalkyl, C4- 8-cycloalkenyl, aryl, heteroaryl, Cs-g-cycloalkyl-substituted aryl, C^β-cycloalkenyl-substituted aryl, phenyl-substituted aryl, Ca-s-cycloalkyl-substituted heteroaryl, C4-8-cycloalkenyl- substituted heteroaryl, phenyl-substituted heteroaryl, Cs-g-cycloalkyl-C1-6-alkyl, C3-8- cycloalkyl-C2-6-alkenyl, C3-g-cycloalkyl-C2-6-alkynyl, C^g-cycloalkenyl-C1-6-alkyl, C4-8- cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, aryloxy, aryloxy-C|.6-alkyl, Ca-g-cycloalkyl-substituted aryl-C1-6-alkyl, C4.
8-cycloalkenyl-substituted aryl-Cuβ-alkyl, phenyl-substituted aryl-C1-6-alkyl, heteroaryl-C1-6- alkyl, Cs-g-cycloalkyl-substituted heteroaryl-C1-6-alkyl, C4-g-cycloalkenyl-substituted heteroaryl-C1-6-alkyl, or phenyl-substituted heteroaryl-C1-6-alkyl, each optionally substituted;
D is a substituted group selected from Ci.g-alk.yl, C2-s-alkenyl, C2-8-alkynyl, C3-8- cycloalkyl, C-μg-cycloalkenyl, aryl, C1-g-alkyl-aryl, heteroaryl, C1-g-alkyl-heteroaryl, heterocyclyl or C1-β-alkyl-heterocyclyl, wherein said group is substituted with L and, optionally, one or more additional groups;
L is a group selected from hydrogen, alkyl, aryl, aryloxy, arylalkoxy, aryl-N(Ra)-, heteroaryl, heteroaryloxy-, heteroarylalkoxy, heteroaryl-N(Ra)-, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy-, cycloalkyloxy-, cycloalkyl-N(Ra)-, heterocyclyl, heterocyclyloxy-, heterocyclylalkoxy-, heterocyclyl-N(Ra)-, alkenyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkenylalkyloxy, or alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocarbocycle or a spiroheterocyclic ring containing up to three heteroatoms, 0-1 of which are selected from O and S and 0-3 of which are N; wherein said group, excluding hydrogen, is optionally substituted;
Za is selected from a bond, -CRV, -C(O)N(Ra)-, -C(O)O-, -C(O)-, -C(O)C(R1V, - C(Ra)2C(OK -S(O)-, -S(O)2-, -S(O)2NRS -S(O)2C(Ra)2- and -S(O)C(Ra)r-,
Zb is selected from Za, -O-, -S-, -N(Ra)-, -N(Ra)C(Ra)2- -N(Ra)C(O)-, -OC(Ra)2-, -SC(Ra)2-, -C(Ra)2N(RaH -C(Ra)2O-, -C(Ra)2S-, -C(=NRa)NR% and -C(=N-CN)NRa-;
Figure imgf000068_0001
represents an aryl or heteroaryl, wherein said group is optionally substituted; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
2. A compound of claim 1, wherein X is 1-4-phenylene.
3. A compound of claim 1 or 2, wherein Rb is H, and m is 2.
4. A compound of any of the preceding claims, wherein Ba is selected from null, and - CHRa.
5. A compound of any of the preceding claims, wherein Bb is selected from null, — CHRa, -O-, and -CF2-.
6. A compound of any of the preceding claims, wherein E is selected from Ci.i2-alkyl, C2-12-alkenyl, C2-12-alkynyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, napthyl, thienyl, benzothienyl, quinolyl, cyclohexyl-substituted phenyl, cyclohexenyl-substituted phenyl, phenyl-substituted phenyl, cyclohexylmethyl, cyclohexenylmethyl, benzyl, phenoxy, cyclohexyl-substituted benzyl, cyclohexenyl-substituted benzyl, phenyl-substituted benzyl, each optionally substituted.
7. A compound of any of the preceding claims, wherein D is a substituted group selected from phenyl, thiazolyl, oxazolyl, indolyl, or isoxazolyl wherein said group is substituted with L and, optionally, one or more additional groups.
8. A compound of any of the preceding claims, wherein L is selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, phenoxy-, benzyloxy-, cyclohexyl, cyclohexylmethyl, cyclohexylmethoxy-, cyclohexyloxy-, cyclohexyl-N(Ra)-, alkenyl, cyclohexenyl, alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocyclohexyl; wherein said group, excluding hydrogen, is optionally substituted.
9. A compound of any of the preceding claims, wherein Za is selected from a bond, - CRV, -C(O)N(Ra)-, -C(O)O-, -C(O)-, -C(O)C(Ra)2-, -C(Ra)2C(O)-, and -S(O)2NRa-.
10. A compound of any of the preceding claims, wherein Zb is selected from a bond, - CRV, -C(O)N(Ra)-, -C(O)O-, -C(O)-, -C(O)C(Ra)2- -C(Ra)2C(O)-, -S(O)2NR3-, -O-, - N(RV, -N(Ra)C(Ra)2-, -OC(Ra)2- -C(Ra)2N(RaK and -C(Ra)2O-.
11. A compound of any of the preceding claims, wherein
Figure imgf000069_0001
represents an optionally substituted phenyl or an heterocycle group containing 1-2 nitrogen atoms or 0-2 oxygen atoms.
12. A compound of Formula I-A:
Figure imgf000069_0002
wherein:
Ra is selected from H, and methyl;
A is selected from
Figure imgf000069_0004
, and
Figure imgf000069_0003
Ba is selected from null and -CHRa; Bb is selected from Ba, -O-, and -CF2-; E is selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, napthyl, thienyl, benzothienyl, quinolyl, cyclohexyl-substituted phenyl, cyclohexenyl-substituted phenyl, phenyl-substituted phenyl, cyclohexylmethyl, cyclohexenylmethyl, benzyl, phenoxy, cyclohexyl-substituted benzyl, cyclohexenyl- substituted benzyl, phenyl-substituted benzyl, each optionally substituted;
D is a substituted group selected from phenyl, thiazolyl, oxazolyl, indolyl or isoxazolyl wherein said group is substituted with L and, optionally, one or more additional groups;
L is a group selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, phenoxy-, benzyloxy-, cyclohexyl, cyclohexylmethyl, cyclohexylmethoxy-, cyclohexyloxy-, cyclohexyl-N(Ra)-, alkenyl, cyclohexenyl, alkynyl, or when attached to a saturated carbon belonging to a ring, a spirocyclohexyl; wherein said group, excluding hydrogen, is optionally substituted;
Za is selected from a bond, -CRV, -C(O)N(R3)-, -C(O)O-, -C(O)-, -C(O)C(Ra)2- - C(Ra)2C(O)-, and -S(O)2NRa-;
Zb is selected from Za, -O-, -N(Ra)-, -N(Ra)C(Ra)2- -OC(R8V, -C(Ra)2N(Ra)-, and -C(Ra)2O-;
Figure imgf000070_0001
represents an optionally substituted phenyl or an heterocycle containing 1-2 nitrogen atoms or 0-2 oxygen atoms; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
13. A compound of claim 12, wherein A is selected from the group consisting of:
Figure imgf000070_0002
Figure imgf000071_0001
A compound of claim 12 or 13, wherein D is selected from the group consisting of:
Figure imgf000071_0002
Figure imgf000072_0001
wherein L and Z represent the points of attachment to L and Z moieties, respectively;
15. A compound of any of claims 12 to 14, wherein E is selected from 3-t-butoxyphenyl, 4-t-butoxyphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 3-(3,3-dimethylbut-1-enyl)phenyl, Z-3- (3,3-dimethylbut-1-enyl)phenyl, 4-(3,3-dimethylbut-1-enyl)phenyl, Z-4-(3,3-dimethylbut-1- enyOphenyl, 3-(4-t-butylcyclohex-1-enyl)phenyl, 4-(4-t-butylcyclohex-1-enyl)phenyl, 3-(4-t- butylcyclohexyl)phenyl, 4-(4-t-butylcyclohexyl)phenyl, 4-(4-t-butylphenyl)phenyl, 3-(4,4- dimethyl-cyclohex- 1 ,5-dienyl)phenyl, 4-(4,4-dimethyl-cyclohex- 1 ,5-dienyl)phenyl, 3-(4,4- dimethylcyclohex- 1 -enyl)phenyl, 4-(4,4-dimethylcyclohex- 1 -enyl)phenyl, 3-(4,4- dimethylcyclohexyl)phenyl, 4-(4,4-dimethylcyclohexyl)phenyl, 3-(4,4- dipropylcyclohexyl)phenyl, 4-(4,4-dipropylcyclohexyl)phenyl, 3-(4,4-dipropylcyclohex-l - enyOphenyl, 4-(4,4-dipropylcyclohex-1-enyl)phenyl, 4-(spiro[4.5]dec-8-yl)phenyl, 3-(4,4- dimethylcyclohex- 1 -enyl)benzyl, 4-(4,4-dimethylcyclohex-2-enyl)benzyl, 3-(4,4- dipropylcyclohex- 1 -enyl)benzyl, 4-(4,4-dipropylcyc lohex- 1 -enyl)benzyl, 3 -(eye lohex- 1 - enyl)benzyl, or 4-(cyclohex-1-enyl)benzyl, 6-methoxy-2-naphthyl, 6-trifluoromethoxy-2- naphthyl, 7-methoxy-quinol-3-yl, and 7-trifluoromethoxy-quinol-3-yl.
16. A compound of any of claims 12 to 15, wherein L is hydrogen, trifluoromethyl, trifluoromethoxy, chloro, f-butyl, 3,3-dimethylbut-1-enyl, 4,4-dimethylcyclohex-1-enyl, t- butyl-cyclohexane, t-butyl-cyclohex-1-enyl, cyclohex-1-enyl, 2,4-bis(trifluoromethyl)- phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-chlorophenyl, 4-chlorophenyl, 4-chloro-3- cyclopropylphenyl, 4-chloro-4-ethylphenyl, 4-chloro-2-fluorophenyl, 4-chloro-2- isopropylphenyl, 2-chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 2-chloro-4- trifluoromethylphenyl, 3-chloro-4-trifluoromethylphenyl, 4-chloro-2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2-fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-trifluoromethyl- phenyl, 4-methylphenyl, 2-methyl- 4-trifluoromethylphenyl, 4-trifluoromethylphenyl, benzooxazol-2-yl, 2-methyl-benzooxazol-5-yl, 2-methyl-benzooxazol-6-yl, benzofuran-2-yl , 3-chlorobenzoftiran-2-yl, or 3-fluorobenzofiiran-2-yl, 4-t-butyl-spirocyclohexyl;
17. A compound of any of claims 12 to 16, wherein: represents an optionally substituted group selected from:
Figure imgf000073_0001
Figure imgf000073_0002
18. A compound of any of claims 12 to 17, wherein Za is selected from a bond, -CH2-, CH(Me)-, -C(O)NH-, -C(O)O-, -C(O)-, and - CH2C(O)-.
19. A compound of any of claims 12 to 18, wherein Zb is selected from bond, — CH2-, CH(Me)-, -C(O)NH-, -C(O)O-, -C(O)-, and - CH2C(O)-, -O-, -NH-, -CH2O-, and - CH2NH-.
20. A compound of any of claims 12 to 19, wherein: Ra is selected from H, and methyl;
Ba is selected from null, -CH2- and -CHMe-; A is selected from the group consisting of:
Figure imgf000074_0001
D is selected from the group consisting of:
Figure imgf000074_0002
Figure imgf000075_0001
wherein L and A represent the points of attachment to L and A moieties, respectively;
E is selected from 3-t-butoxyphenyl, 4-t-butoxyphenyl, 3-t-butylphenyl, Λ-t- butylphenyl, 3-(3,3-dimethylbut-1-enyl)phenyl, Z-3-(3,3-dimethylbut-1-enyl)phenyl, 4-(3,3- dimethylbut- 1 -enyl)phenyl, Z-4-(3,3-dimethylbut- 1 -enyl)phenyl, 3-(4-t-butylcyclohex- 1 - enyl)phenyl, 4-(4-t-butylcyclohex-1-enyl)phenyl, 3-(4-t-butylcyclohexyl)phenyl, 4-(4-t- butylcyclohexyl)phenyl, 4-(4-t-butylphenyl)phenyl, 3-(4,4-dimethyl-cyclohex-l ,5- dieny Ophenyl, 4-(4,4-dimethyl-cyclohex- 1 ,5-dienyl)phenyl, 3-(4,4-dimethylcyclohex- 1 - enyl)phenyl, 4-(4,4-dimethylcyclohex-1-enyl)phenyl, 3-(4,4-dimethylcyclohexyl)phenyl, 4- (4,4-dimethylcyclohexyl)phenyl, 3-(4,4-dipropylcyclohexyl)phenyl, 4-(4,4- dipropylcyclohexyl)phenyl, 3-(4,4-dipropylcyclohex- 1 -enyl)phenyl, 4-(4,4-dipropylcyclohex- l-enyl)phenyl, 4-(spiro[4.5]dec-8-yl)phenyl, 3-(4,4-dimethylcyclohex-1-enyl)benzyl, 4-(4,4- dimethylcyclohex-2-enyl)benzyl, 3-(4,4-dipropylcyclohex- 1 -enyl)benzyl, 4-(4,4- dipropylcyclohex-1-enyl)benzyl, 3-(cyclohex-1-enyl)benzyl, or 4-(cyclohex-1-enyl)benzyl, 6-methoxy-2-naphthyl, 6-trifluoromethoxy-2-naphthyl, 7-methoxy-quinol-3-yl, and 7- trifluoromethoxy-quinol-3-yl;
L is hydrogen, trifluoromethyl, trifluoromethoxy, chloro, /-butyl, 3,3-dimethylbut-1- enyl, 4,4-dimethylcyclohex-1-enyl, t-butyl-cyclohexane, t-butyl-cyclohex-1-enyl, cyclohex- 1-enyl, 2,4-bis(trifluoromethyl)-phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-chlorophenyl, 4- chlorophenyl, 4-chloro-3-cyclopropylphenyl, 4-chloro-4-ethylphenyl, 4-chloro-2- fluorophenyl, 4-chloro-2-isopropylphenyl, 2-chloro-4-methylphenyl, 4-chloro-2- methylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-chloro-4-trifluoromethylphenyl, 4-chloro- 2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2- fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3- fluoro-4-trifluoromethyl-phenyl, 4-methylphenyl, 2-methyl- 4-trifluoromethylphenyl, 4- trifluoromethylphenyl, benzooxazol-2-yl, 2-methyl-benzooxazol-5-yl, 2-methyl-benzooxazol- 6-yl, benzofuran-2-yl , 3-chlorobenzofiiran-2-yl, or 3-fluorobenzofuran-2-yl, 4-t-butyl- spirocyclohexyl;
Figure imgf000076_0001
represents an optionally substituted group selected from:
Figure imgf000076_0003
Figure imgf000076_0002
Figure imgf000077_0001
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
21. A pharmaceutical composition comprising a compound of any of claims 1 to 20; a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers.
22. A method for treating, preventing, or ameliorating one or more symptoms of a GCGR-mediated condition, disorder, or disease, comprising administering to a subject having or being suspected to have such a condition, disorder, or disease, a therapeutically effective amount of a compound of any of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition thereof.
23. The method of claim 22, wherein said GCGR-mediated condition, disorder, or disease is selected from type 1 diabetes, type 2 diabetes, gestational diabetes, ketoacidosis, nonketotic hyperosmolar coma (nonketotic hyperglycaemia), impaired glucose tolerance (IGT), insulin resistance syndromes, syndrome X, low HDL levels, high LDL levels, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, dyslipidemia, arteriosclerosis, atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, vascular resenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, and lipid disorders.
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