WO2014207508A1 - Composé pyridylique approprié pour le traitement de troubles métaboliques - Google Patents

Composé pyridylique approprié pour le traitement de troubles métaboliques Download PDF

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WO2014207508A1
WO2014207508A1 PCT/IB2013/055278 IB2013055278W WO2014207508A1 WO 2014207508 A1 WO2014207508 A1 WO 2014207508A1 IB 2013055278 W IB2013055278 W IB 2013055278W WO 2014207508 A1 WO2014207508 A1 WO 2014207508A1
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pyridin
chloro
cyano
trifluoromethyl
alkyl
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PCT/IB2013/055278
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English (en)
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Nabajyoti Deka
Rajiv Sharma
Sivaramakrishnan Hariharan
Mahesh URAVANE
Kamlesh CHAVAN
Santanu MEDHI
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Piramal Enterprises Limited
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Priority to PCT/IB2013/055278 priority Critical patent/WO2014207508A1/fr
Publication of WO2014207508A1 publication Critical patent/WO2014207508A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present description relates to a compound of Formula 1, a pharmaceutical composition comprising the same, and a process for its preparation. Although sufficient for other uses, the compound of Formula 1 and the pharmaceutical composition comprising the same are suitable for treating metabolic disorders, such as those treatable by administering an insulin sensitizer. Background
  • a metabolic disorder is a disorder or defect of metabolism that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, water or nucleic acids.
  • Diabetes is a metabolic disorder that affects the ability to produce or use insulin, in an individual. Blood glucose levels are higher than normal for individuals with diabetes.
  • type 1 diabetes the pancreas does not produce insulin.
  • Type 1 diabetes is generally diagnosed in childhood and hence, known as juvenile diabetes. This type accounts for about 5 % of people with diabetes.
  • type 2 diabetes there are two possible defects: i) pancreas does not produce enough insulin; and ii) the tissues are unable to use insulin properly, and the resulting condition is called as insulin resistance.
  • Type 2 diabetes is a chronic metabolic disease characterized by insulin resistance, hyperglycemia and hyperinsulinema. It represents about 95 % of the human population with diabetes. Diabetic patients are also at an increased risk of developing cardiovascular disease due to risk factors such as dyslipidemia, obesity, hypertension and glucose intolerance. Uncontrolled diabetes is the leading cause of blindness, renal failure, non-traumatic limb amputation and premature cardiovascular mortality.
  • A is selected from (Ci-C6)alkyl, (C3-Ce)cycloalkyl, -0(Ci-C6)alkyl, (C6-Cio)aryl, and nitrogen-heteroaryl;
  • B is O or C(O); or B is absent and X bonds to A; X is N or CR a ;
  • Ri and R 2 are hydrogen or Ri and R 2 together form a (C2-C3)alkylene bridge
  • R3 is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halogen, cyano, and amino;
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 or -C(0)NHR 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R7 is (C6-Cio)aryl or nitrogen-heteroaryl
  • R a is selected from hydrogen, hydroxyl, and cyano
  • n is the integer 1 or 2;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • -0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, and halogen, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Cr Ce)alkoxy, halogen, amino, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted; heteroaryl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound, which does not readily undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • (Ci-C6)alkyl refers to a saturated aliphatic group, including straight or branched-chain alkyl group containing from 1 to 6 carbon atoms. Suitable examples of alkyl groups containing from 1 to 6 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2- dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl or tert-butyl.
  • the "(Ci-C6)alkyl” or “alkyl” is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl.
  • the "(Ci-C6)alkyl” or “alkyl” is unsubstituted or the "(Ci-C6)alkyl” or “alkyl” is substituted by one, two, three, four, or five substituents.
  • a "(C2-C3) alkylene bridge” or an “alkylene bridge” refers to a straight or branched divalent hydrocarbon bridge linking two different carbons of the same ring structure, consisting solely of carbon and hydrogen, containing no unsaturation and having two to three carbon atoms.
  • the alkylene bridge links any two carbons within a ring structure.
  • alkylene bridge is an ethylene bridge.
  • -0(Ci-C 6 )alkyl refers to a (Ci-C 6 )alkyl or alkyl group as defined herein attached via oxygen linkage to the rest of the molecule.
  • Representative examples of "-0(Ci-C6)alkyl”, “(Ci-C6)alkoxy” or “alkoxy” include, but are not limited to, methoxy, ethoxy or propoxy.
  • the "-0(Ci-C6)alkyl", “(Ci-C6)alkoxy” or “alkoxy” is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, and halogen.
  • "-0(Ci-C6)alkyl", “(Ci-C6)alkoxy” or “alkoxy” is unsubstituted or "-0(Ci- C6)alkyl", “(Ci-C6)alkoxy” or “alkoxy” is substituted by one, two, three, four, or five substituents.
  • (C3-C6)cycloalkyl refers to a saturated mono-, or bi-cyclic ring system containing a three to six carbon atoms.
  • Examples of cycloalkyl rings containing three to six carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • (C3-C6)cycloalkyl” or “cycloalkyl” is unsubstituted or substituted by one or more identical or different substituents selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, amino, halogen, (C6-Cio)aryl, and heterocyclyl.
  • the "(C3-C6)cycloalkyl” or “cycloalkyl” is unsubstituted or the "(C3-C6)cycloalkyl” or “cycloalkyl” is substituted by one, two, three, four, or five substituents.
  • (C6-Ci 0 )aryl refers to a monocyclic or polycyclic hydrocarbon group having from six to ten ring members, the ring members being carbon atoms, in which at least one carbocyclic ring is present which has an aromatic conjugated ⁇ electron system.
  • aryl residues include phenyl and naphthyl.
  • (C6-Cio)aryl or "aryl”, for example phenyl or naphthyl, is unsubstituted or substituted by one or more of the same or different substituents selected from halogen, (Ci- Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, cyano, amino, (C 6 - Cio)aryl, heterocyclyl and C(0)OH.
  • the "(C6-Cio)aryl" or “aryl” is unsubstituted or the "(C6-Cio)aryl” or “aryl” is substituted by one, two, three, four, or five substituents.
  • heteroatom refers to nitrogen (N), oxygen (O) and sulfur (S). It should be noted that any heteroatom with unsatisfied valences is assumed to have a hydrogen atom to satisfy the valency.
  • heterocyclyl refers to a saturated, partially unsaturated or aromatic, monocyclic or polycyclic ring system containing three to ten ring atoms, of which one or two are identical or different heteroatoms selected from nitrogen, oxygen and sulfur and the remaining ring atoms are carbon atoms.
  • the nitrogen or sulfur atom(s) are independently oxidized or the nitrogen atom(s) is independently quaternized.
  • the ring heteroatoms are present in any desired number and in any position with respect to each other provided that the resulting heterocyclic system is stable.
  • the heterocyclyl group may, for example, have one or two oxygen atoms and/or one or two sulfur atoms and/or one or two nitrogen atoms in the ring.
  • Suitable examples of monocyclic heterocyclyl groups are pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, azepinyl, and diazepinyl.
  • Polycyclic heterocyclyl groups can include two fused rings (bicyclic), at least one of the rings has at least one heteroatom.
  • Exemplary bicyclic heterocyclic groups include benzoxazolyl, quinolyl, isoquinolyl, indolyl, isoindolyl, and benzofurazanyl.
  • Polycyclic heterocyclyl groups can include two fused rings which contain one or two bridgehead carbon atoms.
  • the bicyclic heterocyclic groups containing two bridgehead carbon atoms include 2,6-diaza-bicyclo[2.2.2]octane, 3,8- diazabicyclo[3.2.1]octane, and 3,6-diaza-bicyclo[3.2.2] nonane.
  • Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bonds within the rings, as well as unsaturated heterocyclic ring systems which contain from one to six double bonds within the rings provided that the resulting ring system is stable.
  • Unsaturated rings may be non-aromatic or aromatic.
  • Aromatic heterocyclyl groups are also be referred to as "heteroaryls.”
  • the term “heteroaryl” refers to a "nitrogen-heteroaryl” herein but is broader.
  • Heteroaryl refers to an unsaturated monocyclic or bicyclic heterocyclic ring system having from five to ten ring member atoms, in which at least one ring is present which has an aromatic conjugated ⁇ electron system; the ring member atoms include one or two heteroatoms selected from nitrogen, oxygen, and sulfur and the remaining ring members are carbon atoms, wherein the sulfur or nitrogen heteroatom(s) are independently optionally oxidized, and the nitrogen heteroatom(s) are independently optionally quaternized.
  • heteroaryl examples include furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzoxazole, quinoline, isoquinoline, indole, isoindole and benzofuran.
  • the heterocyclyl group is unsubstituted or substituted with from one to five, identical or different, substituents for the ring carbon and ring nitrogen atoms selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, amino, (C6-Cio)aryl, heterocyclyl, and C(0)OH.
  • the substituents can be present at one or more positions provided that a stable molecule results.
  • the heterocyclyl is unsubstituted or the heterocyclyl is substituted by one, two, three, four, or five substituents.
  • nitrogen-heteroaryl refers to an unsaturated monocyclic or bicyclic heterocyclic ring system having from five to ten ring member atoms, in which at least one ring is present which has an aromatic conjugated ⁇ electron system; the ring member atoms include one or two nitrogen heteroatoms and the remaining ring members are carbon atoms, wherein the nitrogen heteroatom(s) are independently optionally oxidized, and the nitrogen heteroatom(s) are independently optionally quaternized.
  • the ring member atoms include from four to nine carbon atoms. Any suitable ring position of the nitrogen-heteroaryl moiety can be covalently linked to the defined chemical structure. Examples of nitrogen- heteroaryl include pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, and pyridazine, quinoline and isoquinoline.
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different substituents selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (Cs-Cio)aryl, heterocyclyl, and C(0)OH.
  • substituents selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (Cs-Cio)aryl, heterocyclyl, and C(0)OH.
  • the "nitrogen-heteroaryl” is unsubstituted or the "nitrogen- heteroaryl” is substituted by one, two, three, four or five substituents.
  • halogen or "halo” unless otherwise stated refers to fluorine, chlorine, bromine, and iodine atoms. Two or more atoms of "halogen” or “halo” can be the same or different.
  • halo(Ci-C 6 )alkyl refers to a "(Ci-C 6 )alkyl” or “alkyl” as defined herein in which one or more of the hydrogen atoms of the alkyl group are substituted with one or more of the same or different halogen atoms.
  • a monohaloalkyl for example, has a chlorine, bromine, iodine or fluorine atom.
  • Dihaloalkyls and polyhaloalkyls have two or more of the same or different halogen atoms.
  • halo(Ci-C6)alkyl or haloalkyl examples include but are not limited to chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl and the like.
  • halo(Ci-C6)alkoxy refers to a (Ci-C6)alkoxy or alkoxy as defined herein wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more same or different halogen atoms.
  • Representative examples of haloalkoxy groups include but not limited to difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ) or trifluorethoxy (OCH 2 CF 3 ).
  • amino refers to the group NR x R y in which R x and R y are independently selected from hydrogen, (Ci-C6)alkyl, t-butoxy carbonyl, and (C6-Cio)aryl.
  • N-oxide refers to the oxide of the nitrogen atom of a nitrogen-heteroaryl or heterocycle. N-oxide can be formed in presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or hydrogen peroxide.
  • stereoisomer is a general term used for all isomers of individual compounds that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • tautomer refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
  • pharmaceutically acceptable salt refers to a product obtained by reaction of the compound of Formula 1 with a suitable acid or a base.
  • solvate or “pharmaceutically acceptable solvate” describes a complex wherein the compound is coordinated with a proportional amount of a solvent molecule.
  • Specific solvates, wherein the solvent is water, are referred to as hydrates.
  • the "pharmaceutically acceptable solvate” is a pharmaceutically acceptable hydrate.
  • isosteres refer to the molecules or ions with the same number of atoms and/or the same number of valence electrons. This definition also includes groups that produce compounds that can sometimes have similar biological activities. Some evidence for the validity of this notion was the observation that some pairs, such as benzene and thiophene, thiophene and furan, and even benzene and pyridine, exhibited similarities in many physical and chemical properties.
  • prodrugs includes simple prodrugs of the compounds of Formula 1 , for example esters, amides and other simple derivatives.
  • prodrug refers to compounds that are drug precursors, which following administration, release the drug in vivo via a chemical or physiological process e.g., a prodrug on being brought to the physiological pH or through an enzyme action is converted to the desired drug form.
  • the compounds can be crystallized in different forms.
  • polymorph refers to a specific crystalline form of a compound which differs only in the arrangement and/or conformation of the molecule in the crystal lattice. Polymorphs of a compound have different physical and chemical properties
  • isotopic forms refers to all isotopically labeled forms of compounds of Formula 1, wherein one or more atoms of compounds of Formula 1 are enriched by their respective isotopes.
  • isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2 H and 3 H, carbon such as U C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 0, 17 0 and
  • therapeutically effective amount refers to an amount of compound or composition comprising, e.g., a compound of Formula 1, sufficient to significantly induce a positive modification in the condition to be regulated or treated, but low enough to avoid undue or severe side effects within the scope of sound medical judgment.
  • the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated/prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized.
  • treatment refers to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g., diabetes). Treatment also includes treating the symptoms of the disease or condition.
  • Prevent refers to delaying, slowing, inhibiting, reducing or ameliorating the onset of diabetes.
  • pharmaceutically acceptable means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • pharmaceutically acceptable medium refers to a composition comprising at least one ingredient selected from carriers, diluents, and excipients, wherein the “pharmaceutically acceptable medium” is pharmaceutically acceptable.
  • metabolic disorder refers to a disease, disorder or a condition characterized by an alteration in the normal metabolism of carbohydrates, lipids, proteins, water or nucleic acids.
  • mammal refers to warm-blooded vertebrate animals of the class Mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human.
  • the compound is a compound of Formula 1, wherein,
  • A is selected from (Ci-C6)alkyl, (C 3 -C6)cycloalkyl, -0(Ci-C6)alkyl, (X C ⁇ aryl, and nitrogen-heteroaryl;
  • B is O or C(O); or B is absent and X bonds to A;
  • X is N or CR a ;
  • Ri and R 2 are hydrogen or optionally Ri and R 2 together form a (C 2 -C3)alkylene bridge;
  • R3 is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halogen, cyano, and amino;
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 or -C(0)NHR 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R7 is (C6-Cio)aryl or nitrogen-heteroaryl
  • R a is selected from hydrogen, hydroxy or cyano
  • n is the integer 1 or 2;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • -0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, and halogen, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Ci 0 )aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted; or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.
  • the compound is a compound of Formula 1, wherein,
  • A is selected from (C3-C6)cycloalkyl, (C6-Cio)aryl, and nitrogen-heteroaryl;
  • X is N
  • Ri and R 2 are hydrogen;
  • R3 is selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, and cyano;
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R 7 is (C6-Cio)aryl
  • n is the integer 1 ;
  • (Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci-
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1, wherein,
  • A is selected from (C 3 -C6)cycloalkyl, (C6-Ci 0 )aryl, and nitrogen-heteroaryl;
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, and cyano;
  • R 4 is hydrogen or methyl;
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R7 is selected from 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-2- methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 3-chlor
  • n is the integer 1 ;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1, wherein,
  • A is 3-methoxyphenyl
  • X is N
  • Ri and R 2 are hydrogen; R 3 is chlorine;
  • R 4 is hydrogen
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen
  • R7 is selected from 3-fluoro-4-methylphenyl, 4-trifluoromethylphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-chloro- 4-fluorophenyl, 2-chloro-4-triflurormethyl, 3-chloro-4-fluorophenyl, phenyl-4-carboxylic acid [phenyl-4-C(0)OH] , and biphenyl [phenyl-4-phenyl] ;
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is 3-trifluoromethylphenyl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is cyano
  • R 4 is hydrogen
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen
  • R 7 is selected from 4-trifluoromethylphenyl, 2,4-difluorophenyl, 3,4-dimethoxyphenyl, and 2,4-dichlorophenyl; n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is 3-chlorophenyl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is (Ci-Ce)alkyl or cyano
  • R 4 is hydrogen or methyl
  • R5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl;
  • R 7 is selected from 3-trifluoromethylphenyl, 2,5- dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, and 3- chloro-4-fluorophenyl;
  • n is the integer 1 ;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1, wherein,
  • A is 4-methoxyphenyl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R 6 is hydrogen or methyl
  • R 7 is selected from 4-fluoro-2-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoro methyl phenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-trifluoro methoxy phenyl, and biphenyl [phenyl-4-phenyl] ;
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is 2,4-dimethoxyphenyl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is chlorine
  • R 4 is hydrogen
  • R 5 is -S(0) 2 R 7 ;
  • R 6 is hydrogen
  • R 7 is selected from 3-trifluoromethylphenyl, 2,5-dimethoxyphenyl, 2,4-difluorophenyl, and 2,4-dichlorophenyl; n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is unsubstituted phenyl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is chlorine
  • R 4 is hydrogen
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen
  • R 7 is selected from 2,4-difluorophenyl, 3-chloro-4-fluorophenyl, and 3,4-dimethoxyphenyl; n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is a (C3-C6)cycloalkyl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is cyano
  • R 4 is hydrogen
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen
  • R7 is 3-chloro-4-fluorophenyl
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is nitrogen-heteroaryl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, and cyano;
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R7 is selected from 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-2- methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-methoxyphenyl, 4-methoxy phenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-di methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-fluorophenyl, 3-fluoro phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2- chlorophenyl, 3-
  • n is the integer 1;
  • (Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (Cs-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1, wherein, A is pyridin-2-yl; B is absent and X bonds to A;
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is trifluoromethyl or chlorine
  • R 4 is hydrogen or methyl
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is 4-(trifluoromethyl)pyridin-2-yl; B is absent and X bonds to A;
  • X is N
  • Ri and R 2 are hydrogen;
  • R3 is cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R 7 is 2,4-difluorophenyl
  • n is the integer 1;
  • the compound is a compound of Formula 1, wherein,
  • A is 6-mo holino-4-(trifluoromethyl)pyridin-2-yl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is cyano
  • R 4 is methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is methyl
  • R 7 is 2,4-difluorophenyl or 3,4-dimethoxyphenyl
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is pyrimidin-2-yl
  • X is N; Ri and R 2 are hydrogen;
  • R3 is cyano or chlorine
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R7 is selected from 4-cyanophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, and biphenyl [phenyl-4- phenyl];
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is (C 6 -Cio)aryl
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R 3 is halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R7 IS (C6-Cio)aryl or nitrogen-heteroaryl;
  • R a is hydroxy or cyano
  • n is the integer 1 ;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1, wherein,
  • A is phenyl
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R3 is chlorine or cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R 7 is selected from 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-2- methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-methoxyphenyl, 4-methoxy phenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-di methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4- difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4- chlorophen
  • R a is hydroxy
  • n is the integer 1 ;
  • phenyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1, wherein,
  • A is 4-chlorophenyl
  • B is absent and X bonds to A;
  • X is CR a ;
  • Ri and R2 are hydrogen
  • R 3 is chlorine or cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R 7 is selected from 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-chloro-4- trifluoromethylphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-chlorophenyl, 3-fluoro- 4-methoxyphenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4- fluorophenyl, and 2,4-dichlorophenyl;
  • R a is hydroxy
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is 4-chloro-3-trifluoromethylphenyl
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R3 is chlorine or cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R 7 is selected from 3-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 3- chloro-4-fluorophenyl, and 2,4-dichlorophenyl;
  • R a is hydroxy
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is an unsubstituted phenyl
  • X is CR a ;
  • Ri and R 2 are hydrogen; R 3 is chlorine or cyano;
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R7 is selected from 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-chloro-4- trifluoromethylphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2- chloro-4-fluorophenyl, 3-chloro-4-fluorophenyl, 2,4-dichlorophenyl, and 3,4-dichlorophenyl; R a is hydroxy;
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is an unsubstituted phenyl; B is absent and X bonds to A;
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R 3 is chlorine or cyano
  • R 4 is hydrogen or methyl
  • R5 is -S(0)2R?;R6 is hydrogen or methyl;
  • R 7 is selected from quinolin-8-yl, phenyl, 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4- methylphenyl, 4-fluoro-2-methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl,
  • R a is hydroxy or cyano
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is an unsubstituted phenyl; B is absent and X bonds to A;
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R3 is chlorine
  • R 4 is hydrogen
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen
  • R7 is selected from 4-isopropylphenyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3- chloro-4-fluorophenyl, and 2,4-dichlorophenyl;
  • R a is cyano
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is an unsubstituted phenyl
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R 3 is cyano
  • R 4 is methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is methyl
  • R 7 is selected from 3-trifluoromethylphenyl, 2,4-difluorophenyl, 3,4-dimethoxyphenyl, 2- chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluoro-phenyl, and 2,4- dichlorophenyl;
  • R a is cyano
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is an unsubstituted phenyl
  • X is CR a ;
  • Ri and R 2 are hydrogen; R 3 is chlorine or cyano;
  • R4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R7 is nitrogen-heteroaryl
  • R a is hydroxy or cyano
  • n is the integer 1 ;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1, wherein,
  • A is an unsubstituted phenyl
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R3 is chlorine or cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R 7 is quinolin-8-yl
  • R a is cyano
  • n is the integer 1 ;
  • the compound is a compound of Formula 1,
  • A is selected from (C3-C6)cycloalkyl, -0(Ci-C6)alkyl, (C6-Cio)aryl, and nitrogen-heteroaryl;
  • B is C(O); or B is absent and X bonds to A;
  • X is N or CR a ;
  • Ri and R 2 are hydrogen or optionally Ri and R 2 together form a. (C 2 -C3)alkylene bridge;
  • R 3 is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halogen, cyano, and amino;
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -C(0)NHR 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R 7 is (C6-Cio)aryl
  • R a is hydroxy
  • n is the integer 1 ;
  • (Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • -0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, and halogen, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is (C 6 -Cio)aryl
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R 3 is halogen or cyano
  • R 4 is hydrogen or methyl;
  • R 5 is -C(0)NHR 7 ;
  • R6 is hydrogen or methyl
  • R 7 is (C 6 -Cio)aryl
  • R a is hydroxy
  • n is the integer 1 ;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is selected from cyclohexyl, phenyl or pyrimidin-2-yl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is cyano
  • R 4 is hydrogen or methyl
  • R 5 is -C(0)NHR 7 ;
  • R6 is hydrogen or methyl
  • R 7 is selected from 2,4-difluorophenyl, 3-chlorophenyl, 2-chlorophenyl, and 2, 4- dimethoxyphenyl;
  • n is the integer 1 ;
  • the compound is a compound of Formula 1,
  • A is pyrimidin-2-yl
  • B is absent or X bonds to A
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is cyano;
  • R 4 is hydrogen or methyl;
  • R 5 is -C(0)NHR 7 ;
  • R6 is hydrogen or methyl
  • R7 is 2,4-difluorophenyl
  • n is the integer 1 ;
  • the compound is a compound of Formula 1,
  • A is -0(Ci-C 6 )alkyl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is cyano
  • R 4 is hydrogen or methyl
  • R 5 is -C(0)NHR 7 ;
  • R 6 is hydrogen or methyl
  • R 7 is (C 6 -Cio)aryl
  • n is the integer 1 ;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • -0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, and halogen, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is (Ci-C 6 )alkyl
  • X is N; Ri and R 2 together form an alkylene bridge containing two bridgehead carbon atoms;
  • R 3 is cyano
  • R 4 is hydrogen or methyl
  • R 5 is -C(0)NHR 7 ;
  • R6 is hydrogen or methyl
  • R 7 is (C6-Cio)aryl
  • n is the integer 1 ;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, amino, t- butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Ci 0 )aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is nitrogen-heteroaryl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R7 is (C6-Cio)aryl or nitrogen-heteroaryl
  • n is the integer 2;
  • (Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is nitrogen-heteroaryl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R 7 is selected from quinolin-8-yl, 4-methylphenyl, 4-isopropylphenyl, 3-fluoro-4- methylphenyl, 4-fluoro-2-methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 3-chlorophen
  • n is the integer 2;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is 5-trifluoromethyl-pyridin-2-yl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R 7 is selected from 3-chloro-4-methylphenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 2-fluoromethyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-chloro-4- fluoromethylphenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 2,4- dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chlorophenyl, and 4- chlorophenyl; n is the integer 2;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is 4-trifluoromethylpyrimidin-2-yl
  • X is N
  • Ri and R 2 are hydrogen;
  • R3 is halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R 7 is 4-isopropylphenyl, 4-fluoro-2-methylphenyl, 3-chloro-4-methylphenyl, 2-trifluoro methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,4-difluorophenyl, 2,3,4- trifluorophenyl, 2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-4-methoxy phenyl, 3-methoxyphenyl, 2,5-dimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4- chlorophenyl, 4-fluoro-3-chlorophenyl, 2,4-dichlorophenyl, and 3,4-dichlorophenyl;
  • n is the integer 2;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, halogen, alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1, wherein,
  • A is nitrogen-heteroaryl
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-Ce)alkyl
  • R 7 is nitrogen-heteroaryl
  • n is the integer 2;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted; or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N-oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.
  • the compound is a compound of Formula 1,
  • A is (Ci-C 6 )alkyl
  • X is N
  • Ri and R 2 together form an alkylene bridge containing two bridgehead carbon atoms
  • R 3 is halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R7 is (C6-Cio)aryl or nitrogen-heteroaryl
  • n is the integer 1 ;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Ci 0 )aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is methyl
  • X is N
  • Ri and R2 together form an alkylene bridge containing two bridgehead carbon atoms
  • R 3 is halogen or cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R 7 is selected from 4-isopropylphenyl, 4-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, and
  • n is the integer 1 ;
  • the compound is a compound of Formula 1, wherein,
  • A is selected from (Ci-C6)alkyl, (C3-C6)cycloalkyl, and (C6-Cio)aryl;
  • X is N
  • Ri and R 2 are hydrogen;
  • R3 is selected from (Ci-C6)alkyl, halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R7 IS (C6-Cio)aryl or nitrogen-heteroaryl ;
  • n is the integer 1 ;
  • (Ci-Ce)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is compound of Formula 1,
  • A is selected from (Ci-C6)alkyl, (C 3 -C6)cycloalkyl, and (C6-Ci 0 )aryl;
  • X is N
  • Ri and R 2 are hydrogen;
  • R 3 is selected from (Ci-C6)alkyl, halogen or cyano
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or (Ci-C6)alkyl
  • R 7 is selected from 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, and 3-trifluoromethylphenyl; n is the integer 1 ;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Ci 0 )aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted; or an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, N- oxide, a pharmaceutically acceptable solvate, a polymorph, isostere or a prodrugs thereof.
  • the compound is a compound of Formula 1,
  • A is (C 6 -Cio)aryl
  • X is CR a ;
  • Ri and R2 are hydrogen
  • R 3 is cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R6 is hydrogen or methyl
  • R 7 is (C 6 -Cio)aryl
  • R a is hydrogen
  • n is the integer 1;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound is a compound of Formula 1,
  • A is (C 6 -Cio)aryl
  • X is CR a ;
  • Ri and R 2 are hydrogen;
  • R 3 is cyano
  • R 4 is hydrogen or methyl
  • R 5 is -S(0) 2 R 7 ;
  • R 6 is hydrogen or methyl
  • R 7 is (C 6 -Cio)aryl
  • R a is hydrogen; n is the integer 2;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • Representative compounds of Formula 1 encompassed in accordance with the present invention include but not limited to:
  • the compounds of the present invention also include all their isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs and N-oxides, isosteres and prodrugs thereof.
  • A is selected from (Ci-C6)alkyl, (C3-C6)cycloalkyl, -0(Ci-C6)alkyl, (C6-Cio)aryl, and nitrogen-heteroaryl ;
  • B is O or C(O); or B is absent and X bonds to A;
  • X is N or CR a ;
  • Ri and R 2 are hydrogen or optionally Ri and R 2 together form a (C2-C3)alkylene bridge;
  • R 3 is selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halogen, cyano, and amino;
  • R 4 is hydrogen or (Ci-C6)alkyl
  • R 5 is -S(0) 2 R 7 or -C(0)NHR 7 ;
  • R6 is hydrogen or (Ci-Ce)alkyl
  • R7 is (C6-Cio)aryl or nitrogen-heteroaryl ;
  • R a is selected from hydrogen, hydroxyl, and cyano
  • n is the integer 1 or 2;
  • (Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, halogen, hydroxy, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, amino, t-butoxy carbonyl amino, (C6-Cio)aryl, and heterocyclyl, wherein the substituents are not further substituted;
  • -0(Ci-C6)alkyl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-Ce)alkyl, halo(Ci-C6)alkyl, and halogen, wherein the substituents are not further substituted;
  • (C6-Cio)aryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci- Ce)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • nitrogen-heteroaryl is unsubstituted or substituted by one or more of the same or different groups selected from (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, halogen, cyano, (C6-Cio)aryl, heterocyclyl, and C(0)OH, wherein the substituents are not further substituted;
  • the compound of Formula 1 is preparable in a number of different ways including using methods well known to those of ordinary skill in the art.
  • a method to prepare the compounds of Formula 1 is illustratable in Scheme 1, but is not limited thereto. It will be appreciated by those of ordinary skill in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent to be used in the synthetic steps.
  • One or more of the reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard literature procedures known in the art.
  • the starting compounds and the intermediates used for the synthesis of the compounds and the final compounds of the present invention are referred to by the symbols (a), (b), (c), (d), (e), and (f) in Scheme 1 below.
  • compound of formula (c), wherein A, B, X, Ri, R2, R3, R 4 , R6, and n are as defined above can be prepared by reacting compound of formula (a), (wherein R 3 , R 4 , and R6 are as defined above), with a compound of formula (b) (wherein A, B, X, Ri, R 2 and n are as defined above), in the presence of a solvent such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence of a base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or potassium fluoride (reaction step la).
  • a solvent such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, or acetonitrile
  • a base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium
  • the nitro group of compound of formula (c) is reduced to the corresponding amino group to obtain compound of formula (d), wherein A, B, X, Ri, R 2 , R 3, R 4 , R6, and n are as defined above.
  • Reduction of the nitro group may be carried out by using reducing agent such as SnCl 2 in a solvent such as ethyl acetate; or by using Fe/HCl; or in presence of gaseous hydrogen and a catalyst such as Pd-C, Rh-C, Pt-C; or any suitable method known in the art (reaction step lb).
  • the compound of formula (d) is further converted to the desired compound of formula (e), which corresponds to Formula 1, wherein R5 is SO 2 R 7 , A, B, X, Ri, R 2 , R 3, R 4 , R6, R 7 and n are as defined above, by reacting with R 7 S0 2 -halide wherein halide is represented by fluorine, chlorine, bromine or iodine and R 7 is as defined above, in the presence of pyridine or triethyl amine as a base and a solvent selected from acetonitrile, dichlorome thane, chloroform, carbon tetrachloride, tetrahydrofuran or dioxane (reaction step lc).
  • the compound of formula (d) may also be converted to the desired compound of formula (f), which corresponds to Formula 1, wherein R5 is C(0)NHR 7 , A, B, X, Ri, R 2 , R 3, R 4 , R6, R7 and n are as defined above, by reaction with [R 7 NC(0)], wherein R 7 is as defined above, in the presence a solvent selected from benzene, toluene, tetrahydrofuran or dioxane (reaction step Id).
  • the compound of Formula 1 is in an isotopically labeled form of compounds of Formula 1 , wherein one or more atoms of compounds of Formula 1 are enriched in one or more of their respective isotopes.
  • isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2 H and 3 H, carbon such as U C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 O, 17 O and 18 O, chlorine such as 36 CI, fluorine such as 18 F and sulphur such as 35 S.
  • Substitution with heavier isotopes, for example, replacing one or more key carbon- hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, for example, longer metabolism cycles, improved safety or greater effectiveness.
  • Isotopically labeled forms of compounds of Formula 1 can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described above and in the subsequent section on examples by using an appropriate isotopically labeled reagent instead of non-labeled reagent.
  • the compound of Formula 1 is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is selected from salts of acidic or basic groups present in compounds of Formula 1.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, or p-toluene sulfonate salts.
  • the compound of Formula 1 is in the form of a pharmaceutically acceptable salt with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.
  • Suitable base salts also include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.
  • a method for the treatment of metabolic disorders related to insulin resistance or hyperglycemia including administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1.
  • the mammal is a human.
  • the method for the treatment of metabolic disorders is related to insulin resistance or hyperglycemia, including type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, and nonalcoholic fatty liver disease, including administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1.
  • the mammal is a human.
  • a method for the treatment of dyslipidemia including administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1.
  • the mammal is a human.
  • a method for the treatment of type 2 diabetes and disorders related thereto including administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1.
  • the mammal is a human.
  • the compound of Formula 1 when administered to a mammal in need thereof, is useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.
  • the mammal is a human.
  • the compound of Formula 1 when administered to a mammal in need thereof, is useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia, including type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, and nonalcoholic fatty liver disease.
  • the mammal is a human.
  • the compound of Formula 1 when administered to a mammal in need thereof, is useful for the treatment of type 2 diabetes.
  • the mammal is a human.
  • the compound of Formula 1 when administered to a mammal in need thereof, is useful for the treatment of dyslipidemia.
  • the mammal is a human.
  • Administering is by any suitable method. In some embodiments, administering is an oral route. In some embodiments, administering is via injection.
  • the mammal is human.
  • the compound of Formula 1 is useful for the manufacture of a medicament for the treatment of a metabolic disorder related to insulin resistance or hyperglycemia in a mammal.
  • the pharmaceutical composition comprises, in pharmaceutically acceptable medium, a compound of Formula 1.
  • the pharmaceutical composition comprises a compound of Formula 1 or a pharmaceutically acceptable salt or solvate or a prodrug thereof, for example, together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, lozenges, capsules, powders, syrups, solutions, suspensions and the like specially formulated for oral, buccal, parenteral, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration, however oral administration is preferred.
  • buccal administration the formulation may take the form of tablets or lozenges formulated in conventional manner.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycolate) or wetting agents, such as sodium lauryl sulfate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone
  • fillers for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol
  • lubricants for
  • the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs.
  • formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydro genated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid.
  • suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydro genated edible fats
  • emulsifying agents such as lecithin, sorbitan mono-oleate or acacia
  • Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
  • the formulations according to the invention may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins or as sparingly soluble derivatives as a sparingly soluble salt, for example.
  • a method for manufacture of a medicament comprising a compound of Formula 1, which are useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.
  • treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.
  • amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02 mg - 5000 mg per day or 1 mg -1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the formulations according to the invention may contain between 0.1-99 % of the compound of Formula 1 active ingredient, conveniently from 30-95 % for tablets and capsules and 3-50 % for liquid preparations.
  • the pharmaceutical compositions may also contain one or more other therapeutically active ingredients, which differ from the compound of Formula 1.
  • the further therapeutically active ingredient that can be used in combination with one or more compounds of Formula 1 is selected from one or more of the agents including, but not limited to, insulin, rosiglitazone, pioglitazone, rivoglitazone, simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, tolbutamide, glibenclamide, glipizide, glimepiride, repaglinide, nateglinide, mitiglinide, exenatide, liraglutide, taspoglutide albiglutide, lixisenatide, alogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin and the like.
  • the agents including, but not limited to, insulin, rosiglitazone, pioglitazone, riv
  • the compounds of Formula 1 can be prepared as illustrated by the accompanying working examples.
  • the following examples are set forth to illustrate the synthesis and biological activity of some particular compounds of the present invention and to exemplify general processes. Accordingly, the following Examples section is in no way intended to limit the scope of the invention contemplated herein.
  • Phosphorus oxychloride 64 mL, 689 mmol was added to 6-dimethyl-5-nitro-2-oxo- l,2-dihydropyridine-3-carbonitrile (19.5 g, 107 mmol).
  • phosphorus pentachloride (20.81 g, 100 mmol) was added and reaction mixture was heated to 100 °C for 20 h. Reaction mixture was cooled and poured in ice-water mixture. The precipitate obtained was filtered washed with water and dried to obtain 2-chloro-6-methyl-5-nitronicotinonitrile.
  • Step a Synthesis of 4,6-dimethyl-5-nitro-2-oxo-l,2-dihydropyridine-3-carbonitrile
  • Phosphorus oxychloride 64 mL, 689 mmol was added to 4,6-dimethyl-5-nitro-2- oxo-l,2-dihydropyridine-3-carbonitrile (19.3 g, 100 mmol).
  • phosphorus pentachloride (20.81 g, 100 mmol) was added and reaction mixture was heated to 100 °C for 20 h. Reaction mixture was cooled and poured in ice-water mixture. The precipitate obtained was filtered washed with water and dried to obtain 2-chloro-4,6-dimethyl-5- nitronicotinonitrile. Yield: 80 %; *H NMR (300 MHz, DMSO-d 6 ): ⁇ 2.61 (s, 3H), 2.56 (s, 3H); MS (ES): m/z 211.6.
  • a substituted amine (compound of formula (b); 1 mmol), was dissoved in dimethylformamide (10 mL). To it, cesium carbonate (1 mmol) was added at room temperature (25 °C). After 30 min, the nitro compound (compound of formula (a); 1 mmol), was added and the stirring was continued further for 18 h. Reaction mixture was concentrated and diluted with water (20 mL). Reaction mixture was extracted with ethyl acetate, dried over sodium sulfate and was concentrated to obtain crude product which was purified by column chromatography (silica gel, ethyl acetate in pet ether) to obtain the nitro compound of formula (c).
  • Representative compounds of formula (d) prepared by using these procedures (C) and (D), include but are not limited to:
  • substituted benzenesulfonylchlorides used herein are commercially available (Sigma Aldrich, India) .
  • substituted isocynatobenzenes used herein are commercially available (Sigma Aldrich, India) .

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé pyridylique de formule 1, dans laquelle A, B, X, R, R2, R3, R4, R, R6, et n sont tels que définis dans la description, sous toutes leurs formes isotopiques, leurs formes stéréoisomères et tautomères et leurs mélanges selon tous les rapports, leurs sels pharmaceutiquement acceptables, leurs N-oxydes, leurs solvates pharmaceutiquement acceptables, leurs isostères et promédicaments, qui sont utiles dans le traitement de troubles métaboliques se rapportant à une résistance à l'insuline ou à une hyperglycémie. L'invention concerne également un procédé de fabrication du composé pyridylique et une composition pharmaceutique contenant le composé pyridylique.
PCT/IB2013/055278 2013-06-27 2013-06-27 Composé pyridylique approprié pour le traitement de troubles métaboliques WO2014207508A1 (fr)

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PCT/IB2013/055278 WO2014207508A1 (fr) 2013-06-27 2013-06-27 Composé pyridylique approprié pour le traitement de troubles métaboliques

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018005713A1 (fr) * 2016-06-29 2018-01-04 Congxin Liang Dérivés de pipérazine en tant que modulateurs de trpml
US11541132B2 (en) * 2017-12-21 2023-01-03 Hoffmann-La Roche Inc. Radiolabeled compounds

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2008035305A2 (fr) * 2006-09-21 2008-03-27 Piramal Life Sciences Limited Composés pour le traitement de troubles du métabolisme

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WO2008035305A2 (fr) * 2006-09-21 2008-03-27 Piramal Life Sciences Limited Composés pour le traitement de troubles du métabolisme
WO2008035306A1 (fr) * 2006-09-21 2008-03-27 Piramal Life Sciences Limited Composés pour le traitement de troubles du métabolisme

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018005713A1 (fr) * 2016-06-29 2018-01-04 Congxin Liang Dérivés de pipérazine en tant que modulateurs de trpml
US11541132B2 (en) * 2017-12-21 2023-01-03 Hoffmann-La Roche Inc. Radiolabeled compounds

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