Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
  • A61P9/06—Antiarrhythmics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• PYRROLOTRIAZINES AS POTASSIUM ION CHANNEL INHIBITORS
• the present invention provides for pyrrolotriazines useful as inhibitors of potassium channel function (especially inhibitors of the K v l subfamily of voltage gated K + channels, more especially inhibitors of K v 1.5 (which have been linked to the ultra- rapidly activating delayed rectifier K + current I Kur ), and/or K v 1.3 channels, and/or K v l . l channels) and to pharmaceutical compositions containing such compounds.
• the present invention further provides for methods of using such compounds in the treatment and prevention of arrhythmia, I Ku r-associated disorders, and other disorders mediated by ion channel function.
• the ultra-rapidly activating delayed rectifier K + current (IK UT ) is believed to represent the native counterpart to a cloned potassium channel designated K v 1.5 and, while present in human atrium, it appears to be absent in human ventricle. Furthermore, because of its rapidity of activation and limited slow inactivation, l Km is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of I U that is a compound which blocks K v 1.5, would overcome the short coming of other compounds by prolonging refractoriness by retarding repolarization in the human atrium without causing the delays in ventricular repolarization that underlie
• Antiarrhythmic agents of Class III are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression.
• Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves' ophthalmopathy and asthma. Although the underlying pathogenesis of each of these conditions may vary, they have in common the appearance of a variety of auto-antibodies and self-reactive lymphocytes.
• Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates.
• lymphocytes recognize the foreign tissue antigens and begin to produce immune mediators which lead to graft rejection or graft-vs-host rejection.
• autoimmune or a rejection process tissue destruction caused by inflammatory cells and the mediators they release.
• Anti-inflammatory agents such as NSAIDs act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease.
• cytotoxic agents such as cyclophosphamide, act in such a nonspecific fashion in which both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb to infection as they are to their autoimmune disease.
• Inhibitors of K v 1.5 and other K v l.x channels stimulate gastrointestinal motility.
• the compounds of the invention are believed to be useful in treating motility disorders such as reflux esophagitis. See Frey et al, "Blocking of cloned and native delayed rectifier K channels from visceral smooth muscles by phencyclidine",
• Inhibitors of K v 1.5 relax pulmonary artery smooth muscle.
• the compounds of the invention are believed to be useful in treating hypertension and otherwise improving vascular health. See Davies et al, "K v channel subunit expression in rat pulmonary arteries", Lung, 179(3): 147-161 (2001), Epub. Feb. 4, 2002; Pozeg et al, "In vivo gene transfer of the 02-sensitive potassium channel K v 1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats", Circulation, 107(15):2037-2044 (Apr. 22, 2003), Epub. Apr. 14, 2003.
• Inhibitors of K v 1.3 increase insulin sensitivity.
• the compounds of the invention are believed to be useful in treating diabetes. See Xu et al, "The voltage-gated potassium channel K v 1.3 regulates peripheral insulin sensitivity", Proc. Natl. Acad. Sci. U.S.A., 101(9):3112-3117 (Mar. 2, 2004), Epub. Feb. 23, 2004; MacDonald et al., "Members of the K v l and K v 2 voltage-dependent K(+) channel families regulate insulin secretion", Mol. Endocrinol, 15(8): 1423-1435 (Aug.
• K v l.x channels improves cognition in animal models.
• the compounds of the invention are believed to be useful in improving cognition and/or treating cognitive disorders. See Cochran et al, "Regionally selective alterations in local cerebral glucose utilization evoked by charybdotoxin, a blocker of central voltage- activated K+-channels", Eur. J. Neurosci., 14(9): 1455-1463 (Nov. 2001); Kourrich et al., "Kaliotoxin, a K v l. l and K v 1.3 channel blocker, improves associative learning in rats", Behav. Brain Res., 120(l):35-46 (Apr. 8, 2001).
• R 1 , R 3 , and R 24 are defined below.
• a respective effective amount of at least one compound described herein provided are methods of treating (including ameliorating), reducing the risk of, or preventing arrhythmias, atrial fibrillation, atrial flutter, supraventricular arrhythmias, gastrointestinal disorders (such as reflux esophagitis or a motility disorder), inflammatory or immunological disease (such as chronic obstructive pulmonary disease), diabetes, cognitive disorders, migraine, epilepsy, hypertension, or treating I Ku r-associated conditions, or controlling heart rate.
• arrhythmias such as atrial fibrillation, atrial flutter, supraventricular arrhythmias, gastrointestinal disorders (such as reflux esophagitis or a motility disorder), inflammatory or immunological disease (such as chronic obstructive pulmonary disease), diabetes, cognitive disorders, migraine, epilepsy, hypertension, or treating I Ku r-associated conditions, or controlling heart rate.
• compositions comprising a therapeutically effective amount of at least one compound described herein and a pharmaceutically acceptable vehicle or carrier thereof.
• Such compositions can further comprise one or more other agent(s).
• at least one other anti-arrhythmic agent such as sotalol, dofetilide, diltiazem or Verapamil
• at least one calcium channel blocker or at least one anti-platelet agent (such as clopidogrel, cangrelor, ticlopidine, CS-747, ifetroban and aspirin)
• at least one anti-hypertensive agent such as a beta adrenergic blocker, ACE inhibitor (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, or lisinopril)
• a II antagonist such as sotalol, dofeti
• Another aspect of this invention is directed to methods of treating, inhibiting, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by inhibitors of potassium channel function (especially inhibitors of the K v l subfamily of voltage gated K + channels, more especially inhibitors of K v 1.5 (which have been linked to the ultra-rapidly activating delayed rectifier K + current I Ku r), and/or K v 1.3 channels, and/or K v l . l channels), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or an individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
• inhibitors of potassium channel function especially inhibitors of the K v l subfamily of voltage gated K + channels, more especially inhibitors of K v 1.5 (which have been linked to the ultra-rapidly activating delayed rectifier K + current I Ku r), and/or K v 1.3 channels, and/or K v l . l channels
• Another aspect of this invention is directed to methods of treating, inhibiting, or ameliorating arrhythmia, or maintaining normal sinus rhythm, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or an individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
• Another aspect of this invention is directed to methods of controlling heart rate, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or an individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
• alk refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, or 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ?-butyl, pentyl, hexyl, heptyl, octyl, or any subset of the foregoing.
• substituted alkyl refers to alkyl groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing.
• groups such as by groups described above in the definition of R 10 , such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted),
• alkenyl refers to straight or branched chain hydrocarbon groups having
• substituted alkenyl refers to alkenyl groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing.
• alkynyl refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at least one triple carbon to carbon bond, such as ethynyl.
• substituted alkynyl refers to alkynyl groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing.
• aryl refers to aromatic homocyclic (i.e., hydrocarbon) mono-, bi- or tricyclic ring-containing groups such as having 6 to 12 members such as phenyl, naphthyl and biphenyl. Phenyl is an example of an aryl group.
• substituted aryl refers to aryl groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing, where optionally one or more pair of substituents together with the atoms to which they are bonded form a 3 to 7 member ring.
• groups such as by groups described above in the definition of R 10 , such as selected from alkyl, substituted alkyl,
• cycloalkyl refers to mono-, bi- or tri homocyclic ring groups of 3 to 15 carbon atoms which are, respectively, fully saturated and partially unsaturated.
• the rings of multi-ring cycloalkyl groups may be fused, bridged and/or joined through one or more spiro unions.
• substituted cycloalkyl refers to a cycloalkyl group substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing.
• groups such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alk
• halogen and “halo” refer to fluorine, chlorine, bromine and iodine.
• haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF 3 , having the specified number of carbon atoms, substituted with 1 or more halogen, up to and including perhalo alkyls (where all hydrogen atoms are replaced with a halogen).
• heterocycle refers to fully saturated or partially or completely unsaturated, including aromatic amino acids
• heteroaryl or nonaromatic cyclic groups (for example, 3 to 13 ring member monocyclic, 7 to 17 ring member bicyclic, or 10 to 20 ring member tricyclic ring systems, such as, in certain embodiments, a monocyclic or bicyclic ring containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
• Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
• the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
• heterocycles may be fused, bridged and/or joined through one or more spiro unions.
• Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyr
• bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, benzodioxolyl, dihydrobenzodioxolyl, benzodioxinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydro
• hexahydroimidazopyridinyl (such as l,5,6,7,8,8a-hexahydroimidazo[l,5-a]pyridin-3-yl),
• Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
• substituted heterocycle refers to heterocycle, heterocyclic and heterocyclo groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from alkyl, substituted alkyl, alkenyl, oxo, aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), cyano, nitro, amido, amino, substituted amino, lactam, urea, urethane, sulfonyl, or any subset of the foregoing, where optionally one or more pair of substitu
• alkanoyl refers to alkyl group (which may be optionally substituted as described above) linked to a carbonyl group (i.e., -C(O)-alkyl).
• aroyl refers to an aryl group (which may be optionally substituted as described above) linked to a carbonyl group (i.e., -C(O)-aryl). Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.
• salts may form salts or solvates which are also within the scope of this invention.
• Reference to a compound described herein is understood to include reference to salts thereof, unless otherwise indicated.
• zwitterions when a compound described herein contains both a basic moiety and an acidic moiety, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)" as used herein.
• the salts are
• Salts of the compounds described herein may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• the present invention is intended to cover the compounds in their neutral state, salts of those compounds, or mixtures of the compounds in their neutral state with one or more salt forms, or mixtures of salt forms.
• the compounds described herein which contain a basic moiety may form salts with a variety of organic and inorganic acids.
• Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates,
• camphorsulfonates cyclopentanepropionates, digluconates, dodecylsulfates,
• ethanesulfonates fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3- phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesul
• the compounds described herein which contain an acidic moiety may form salts with a variety of organic and inorganic bases.
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N- bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, ?-butyl amines, and salts with amino acids such as arginine, lysine and the like.
• organic bases for example, organic amines
• organic bases for example, organic amines
• benzathines such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N- bis(dehydroabietyl
• Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
• lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates
• any compound that can be converted in vivo to provide the bioactive agent i.e., the compound of formula (I)
• prodrugs as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula (I) with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates, and the like.
• “Pharmaceutically acceptable” refers to those compounds, materials,
• compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio or which have otherwise been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
• the various compounds described herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to isomers, such as enantiomers, diastereomers, and other stereoisomeric forms.
• Such forms may be defined, in terms of absolute stereochemistry, as (R)- or (5)-, or as (D)- or (L)- for amino acids.
• the present invention is meant to include all such possible individual stereoisomers and mixtures thereof, including their racemic and optically pure enantiomeric or diastereomeric forms.
• the compounds may be prepared as racemates and can
• (+) and (-), (R)- and (5)-, or (D)- and (L)-isomers or corresponding diastereomers may be prepared using chiral synthons or chiral reagents, or they may be resolved from racemic mixtures using conventional techniques, such as chiral chromatography or reverse phase HPLC.
• optically active (+) and (-), (R)- and (5)-, or (D)- and (L)-isomers or corresponding diastereomers may be prepared using chiral synthons or chiral reagents, or they may be resolved from racemic mixtures using conventional techniques, such as chiral chromatography or reverse phase HPLC.
• the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
• the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H or D and 3 H or T, carbon such as n C, 13 C, and 14 C, chlorine, such as 36 C1, fluorine such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as N and N, oxygen, such as O, O, and O, phosphorus, such as P, and sulfur, such as 35 S.
• Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, 3 H, and carbon- 14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• Substitution with heavier isotopes such as deuterium, 2 H or D, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Substitution with positron emitting isotopes, such as n C, 18 F, 15 0, and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• PET Positron Emission Topography
• All stereoisomers of the present compounds such as those which may exist due to asymmetric carbons on the various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms are contemplated within the scope of this invention.
• Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• the present invention is intended to cover stable compounds.
• any variable e.g., R 13
• its definition at each occurrence is independent of its definition at every other occurrence.
• R 13 at each occurrence is selected independently from the definition of R 13 .
• substituents and/or variables are permissible only if such combinations result in stable compounds.
• “Therapeutically effective amount” refers to that amount of a compound which, when administered to a subject, is sufficient to effect treatment for a disease or disorder described herein.
• the amount of a compound which constitutes a “therapeutically effective amount” will vary depending on the compound, the disorder and its severity, and the age of the subject to be treated, but can be determined routinely by one of ordinary skill in the art.
• “Treating” or “treatment” as used herein covers the treatment, prophylaxis, and/or reducing the risk, of a disease or disorder described herein, or treatment, prophylaxis, or reducing the risk of a symptom of a disease or disorder, in a subject, such as a human, and includes:
• Subject refers to a warm blooded animal such as a mammal, such as a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and disorders described herein.
• A is -(CH 2 ) m -R 2 , -CH(R 26 )-R 2 , -(CH 2 ) n . 1 -0-R 2 , -(CH 2 ) n -i-NR 25 -R 2 ,
• R 1 is Ci-io alkyl substituted with 1-2 -OH, haloCi_io alkyl, C 2 _i 2 alkenyl,
• R 2 is phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl, pyridinone, pyrrolidinyl, tetrahydropyranyl, or thiazolyl, any of which are substituted with 0-2 R 2a ;
• alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
• R 3 is phenyl, pyridinyl, pyrimidinyl, dihydropyran, or tetrahydropyran any of which may be substituted with 0-1 R 3a ;
• R 3a is halo, CN, NH 2 , -0-Ci_ 3 alkyl, or morpholinyl;
• R 13 at each occurrence, is independently H, -OH, F, CI, Br, I, CN, Ci_io alkyl,
• Ci-10 alkoxy, haloCi-10 alkyl, C3-10 cycloalkyl, C2-12 alkenyl, C2-12 alkynyl, C6-ioaryl, a 4- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, a 4- to 12-membered heteroaryl-Ci_io alkyl, -CN, -N0 2 , -(CH 2 ) m -S0 2 R 14 , -NR 14 S0 2 R 14 , 0, -CONR 14 R 14 , -(CH 2 ) m -S0 2 NR 14 R 14 , -(CH 2 ) m -NR 14 S0 2 R 14 , -(CH 2 ) n -NR 14 S0 2 NR 14 R 14 ,
• alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
• R 14 is independently selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, Ce-w aryl, or a 4- to 12-membered heteroaryl, or a 4- to 12-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be substituted with 0-3 R 14a and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O; or
• two R 14 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring may be substituted with 0-1 R 14a and optionally contain 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
• R 14a at each occurrence, is independently selected from F, CI, Br, I, C 1-10 alkyl, haloCi-ioalkyl, C6-ioaryl, C 3 _iocycloalkyl, a 4- to 12-membered heteroaryl, a 4- to
• R 24 is independently selected from hydrogen, Ci-ioalkyl, C 3 _ 6 cycloalkyl, or phenyl;
• R 25 is independently selected from hydrogen, Ci-ioalkyl, C 3 _ 6 cycloalkyl, or phenyl;
• R 26 at each occurrence, is independently selected from hydrogen, Ci-ioalkyl, C 3 _ 6 cycloalkyl, or phenyl;
• n 0 to 4.
• n 0 to 4.
• n-1 2 to 4.
• the present invention provides compound of formula (I), enantiomers, diastereomers, tautomers, prodrugs or salts thereof wherein:
• A is -(CH 2 ) m -R 2 , -CH(R 26 )-R 2 , -(CH ⁇ -O-R 2 , -(CH ⁇ -NR ⁇ -R 2 ,
• R 1 is Ci-io alkyl substituted with 1-2 -OH, haloCi_io alkyl, C 2-12 alkenyl,
• R 2 is phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl, pyridinone, pyrrolidinyl, tetrahydropyranyl, or thiazolyl, any of which are substituted with 0-2 R 2a ;
• alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1 , 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
• R 3 is phenyl, pyridinyl, pyrimidinyl, dihydropyran, or tetrahydropyran any of which may be substituted with 0-1 R 3a ;
• R 3a is halo, CN, NH 2 , -0-C 1-3 alkyl, or morpholinyl;
• alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
• R 14 is independently selected from hydrogen, d_io alkyl, C3-10 cycloalkyl, C6-10 aryl, a 4- to 12-membered heteroaryl or a 4- to 12-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be substituted with 0-3 R 14a and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O; or
• two R 14 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring may be substituted with 0- 1 R 14a and optionally contain 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
• R 14a at each occurrence, is independently selected from F, CI, Br, I, d_io alkyl, haloCi-ioalkyl, C6-ioaryl, C 3 -iocycloalkyl, a 4- to 12-membered heteroaryl, a 4- to
• R 24 is independently selected from hydrogen, Ci-ioalkyl, C 3 _ 6 cycloalkyl, or phenyl;
• R 25 is independently selected from hydrogen, Ci-ioalkyl, C 3 _ 6 cycloalkyl, or phenyl;
• R 26 is independently selected from hydrogen, Ci-ioalkyl,
• n 0 to 4.
• n-1 2 to 4.
• the present invention provides compound of formula (I), or enantiomers, diastereomers, tautomers, prodrugs or salts thereof wherein:
• A is -(CH 2 ) m -R 2 , -CH(R 26 )-R 2 , -(CH 2 ) n . 1 -0-R 2 , -(CH 2 ) n -i-NR 25 -R 2 ,
• R 1 is Ci-io alkyl substituted with 1-2 -OH, haloCi_io alkyl, C 2 _i 2 alkenyl, or C3-10
• R 1 is -C(0)-R la ;
• R la is -NH-phenyl, -NH-Ci_ 6 alkyl-phenyl, -NH-C 3 - 6 cycloalkyl, -piperidinyl, piperazinyl, or -NH-pyrimidinyl, wherein the phenyl, alkyl, cycloalkyl, piperidinyl, piperazinyl, or pyrimidinyl may be substituted with 0-2 R 13 ;
• R 2 is phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl, pyridinone, pyrrolidinyl, tetrahydropyranyl, thiazolyl, imidazolyl, isoxazolyl, oxazolyl, morpholinyl, benzothiazolyl, or tetrahydronaphthalenyl, any of which are substituted with 0-2 R 2a ;
• R 2a at each occurrence, is independently H, -OH, F, CI, Br, I, d_io alkyl, Ci_io alkoxy, haloCi_io alkyl, C3-10 cycloalkyl, C2-12 alkenyl, C2-12 alkynyl, C6-ioaryl, a 4- to 12-membered heteroaryl,
• R 3 is phenyl, pyridinyl, pyrimidinyl, dihydropyran, or tetrahydropyran any of which may be substituted with 0-1 R 3a ;
• R 3a is halo, CN, NH 2 , -0-Ci_ 3 alkyl, or morpholinyl;
• R 13 at each occurrence, is independently H, -OH, F, CI, Br, I, CN, Ci_io alkyl,
• Ci-10 alkoxy, haloCi-10 alkyl, C3-10 cycloalkyl, C 2 _i 2 alkenyl, C 2 _i 2 alkynyl, C6-ioaryl, a 4- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, a 4- to 12-membered heteroaryl-Ci_io alkyl, -CN, -N0 2 , -(CH 2 ) m -S0 2 R 14 , -NR 14 S0 2 R 14 , 0, CONR 14 R 14 , (CH 2 ) m -S0 2 NR 14 R 14 , -(CH 2 ) m -NR 14 S0 2 R 14 , -(CH 2 ) n -NR 14 S0 2 NR 14 R 14 , NR 14 S0 2 NR 14 R 14 , NR 14 S0 2 NR 14 R 14 , -C0 2 NR 14 R 14 , -
• R 13 is S0 2 NHP(0)(OH) 2 ;
• R 14 at each occurrence, is independently selected from hydrogen, d_io alkyl, C 3 -1 0 cycloalkyl, C6-1 0 aryl, a 4- to 12-membered heteroaryl or a 4- to 12-membered
• heterocyclyl wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be substituted with 0-3 R 14a and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O; or alternatively, two R 14 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring may be substituted with 0- 1 R 14a and optionally contain 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
• R 24 is independently selected from hydrogen, Ci-ioalkyl, C 36 cycloalkyl, or phenyl;
• R 25 is independently selected from hydrogen, Ci-ioalkyl, C 36 cycloalkyl, or phenyl;
• R 26 is independently selected from hydrogen, Ci-ioalkyl, Ciioalkyl-OH, C 3 _ 6 cycloalkyl, or phenyl;
• n 0 to 4.
• n 0 to 4.
• n-1 2 to 4.
• the present invention provides compound of formula (la) or enantiomers, diastereomers, tautomers, prodrugs or salts thereof, wherein:
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs or salts thereof, wherein:
• A is -(CH 2 ) m -R 2 , -CH(R 26 )-R 2 , or -(CH ⁇ -O-R 2 ;
• R 1 is Ci-6 alkyl substituted with 1-2 -OH, C2-6 alkenyl, or C3-6 cycloalkyl, wherein
• R 2 is phenyl, cyclohexyl, pyridinyl, pyridazinyl, or tetrahydropyran, any of which are substituted with 0-2 R 2a ;
• R 2a at each occurrence, is independently H, -OH, F, CI, Br, I, or SO2NH2;
• R 3 is phenyl, or pyridinyl, either of which may be substituted with 0-1 R 3a ;
• R 3a is halo, CN, NH 2 , -0-Ci_ 3 alkyl, or morpholinyl;
• R 13 at each occurrence, is independently H, -OH, F, CI, Br, I, CN, Ci_6 alkyl, Ci_6 alkoxy, haloCi_6 alkyl, C2-12 alkenyl, a 4- to 6-membered heteroaryl, a 4- to 6-membered heterocyclyl, -NR 14 S0 2 R 14 , -CONR 14 R 14 , -S0 2 NR 14 R 14 , -C0 2 NR 14 R 14 ,
• R 14 is independently selected from hydrogen, Ci_6 alkyl, C 3 -6 cycloalkyl, phenyl, or a 4- to 6-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be substituted with 0-3 R 14a and the heterocyclyl is pyrrolidinyl, or dioxanyl; or
• two R 14 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring may be substituted with 0- 1 R 14a they cyclic ring is selected from morpholinyl, piperidinyl, or piperazinyl;
• R 14a is independently selected from F, CI, Br, I, Ci_6 alkyl, phenyl, C 3 - 6 cycloalkyl, -C0 2 R 26 , -C0 2 NR 24 R 24 -OR 25 -COR 24 , -NR 24 R 24 , or -NR 24 C0 2 R 24 ;
• R 24 is independently selected from hydrogen, Ci-ioalkyl, C 3 _ 6 cycloalkyl, or phenyl; R , at each occurrence, is independently selected from hydrogen, Ci-ioalkyl, C3_ 6 cycloalkyl, or phenyl;
• R 26 is independently selected from hydrogen, Ci-ioalkyl,
• n 0 to 4.
• n 0 to 4.
• n-1 2 to 4.
• the present invention provides compound of formula (I) or (I or enantiomers, diastereomers, tautomers, prodrugs or salts thereof, wherein:
• R 1 is Ci-io alkyl substituted with 1-2 -OH, haloCi_io alkyl, or C3-10 cycloalkyl, wherein the cycloalkyl may be substituted with 0-2 R 13 ; or
• the present invention provides compound of formula (I) or (I or enantiomers, diastereomers, tautomers, prodrugs or salts thereof, wherein:
• R 1 is Ci-1 0 alkyl substituted with 1-2 -OH, haloCi-1 0 alkyl, or C3-1 0 cycloalkyl, wherein the cycloalkyl may be substituted with 0-1 R 13 ; or
• the present invention provides compound of formula (I) or (I or enantiomers, diastereomers, tautomers, prodrugs or salts thereof, wherein:
• R 1 is Ci-1 0 alkyl substituted with 1-2 -OH, haloCi-1 0 alkyl, or C3-1 0 cycloalkyl, wherein the cycloalkyl may be substituted with 0-1 R 13 ; or , any of which may be substituted with 0-2 R
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs or salts thereof, wherein:
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs or salts thereof, wherein:
• R 13 at each occurrence, is independently H, -OH, F, CI, Br, I, Ci_6 alkyl, Ci_6 alkoxy, haloCi_6 alkyl, C 3 -6 cycloalkyl, phenyl, or a 4- to 12-membered heteroaryl, wherein the heteroaryl is selected from tetrazolyl, -CN, -N0 2 , -(CH 2 ) m -S0 2 R 14 ,
• R 14 is independently selected from hydrogen, Ci_6 alkyl, C 3 -6 cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substituted with 0-3 R 14a ; or
• two R 14b 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring is morpholinyl, piperidinyl, or piperazinyl, and may be substituted with 0-1 Ci- 6 alkyl; and
• R 14a at each occurrence, is independently selected from F, CI, Br, I, Ci-6 alkyl, haloCi- 6 alkyl, phenyl, or C 3 _ 6 cycloalkyl.
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• R 13 at each occurrence, is independently H, C e alkyl, or a 4- to 12-membered heteroaryl, wherein the heteroaryl is selected from tetrazolyl, -CN, - R 14 S0 2 14 , -CONR 14 R 14 , -S0 2 NR 14 R 14 , -NR 14 C0 2 NR 14 R 14 , -NR 14 C0 2 NR 14b R 14b , -NR 14 COR 14 ,
• R 14 is independently selected from hydrogen, Ci_6 alkyl, C3-6 cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substituted with 0-3 R 14a ; or
• R 14b 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring is morpholinyl, and may be substituted with 0-1 Ci- 6 alkyl;
• R 14a at each occurrence, is independently selected from F, CI, Br, I, Ci_6 alkyl, haloCi- 6 alkyl, phenyl, or C 3 _ 6 cycloalkyl.
• the present invention provides compound of formula (I) or (la), wherein:
• R 13 at each occurrence, is independently H, -OH, F, CI, Br, I, Ci_6 alkyl, Ci_6 alkoxy, haloCi_6 alkyl, C 3 -6 cycloalkyl, phenyl, or a 4- to 12-membered heteroaryl, wherein the heteroaryl is selected from tetrazolyl, -CN, -N0 2 , -(CH 2 ) m -S0 2 R 14 ,
• R 14 is independently selected from hydrogen, Ci_6 alkyl, C 3 -6 cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substituted with 0-3 R 14a ; or
• R 14 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring is morpholinyl, piperidinyl, or piperazinyl, and may be substituted with 0-1 Ci- 6 alkyl; and R a , at each occurrence, is independently selected from F, CI, Br, I, Ci_6 alkyl, haloCi_ 6 alkyl, phenyl, or C3_ 6 cycloalkyl.
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• R 13 at each occurrence, is independently H, -CN, -NHS0 2 R 14 , -CONH 2 , -S0 2 NR 14 R 14 , -NHC0 2 NR 14b R 14b , -NHCOR 14 , or -NH 2 ;
• R 14 at each occurrence, is independently selected from hydrogen or methyl.
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• R 13 at each occurrence, is -S0 2 NH 2 .
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• A is -(CH 2 ) m -R 2 , -CH(R 26 )-R 2 , -(CH 2 ) n _!-0-R 2 , -(CH ⁇ - R ⁇ -R,,
• R 2 is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, or pyridinone, any of which are substituted with 0-2 R 2a ;
• R 2a at each occurrence, is independently H, -OH, F, Ci_6 alkyl, Ci_6 alkoxy, or 6-S0 2 NR 14 R 14 .
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• A is-(CH 2 )-R 2
• R 2 is phenyl, any of which are substituted with 0-1 R a ;
• R 2a at each occurrence, is independently H, -OH, F, Ci_6 alkyl, Ci_6 alkoxy, Ci_6 haloalkoxy, or S0 2 NR 14 R 14 .
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• A is-(CH 2 )- 2 or -CH(R 26 )-R 2 ;
• R z is phenyl, or Ci- 6 alkyl, any of which are substituted with 0-1 R 2a ;
• R 2a at each occurrence, is independently H or F.
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• R 3 is phenyl
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• R 24 is independently selected from hydrogen, Ci_ 6 alkyl, C3_ 6 cycloalkyl, or phenyl;
• R 25 is independently selected from hydrogen, Ci_ 6 alkyl, C3_ 6 cycloalkyl, or phenyl;
• R 2 6, at each occurrence, is independently selected from hydrogen, Ci- 6 alkyl,
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• R 24 at each occurrence, is independently selected from hydrogen, methyl or ethyl
• R 25 at each occurrence, is independently selected from hydrogen methyl or ethyl
• R 26 at each occurrence, is independently selected from hydrogen, methyl or ethyl.
• R 26 at each occurrence, is independently selected from hydrogen, methyl or ethyl.
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• n 0-2;
• n-1 1-2.
• the present invention provides compound of formula (I) or (la), or enantiomers, diastereomers, tautomers, prodrugs, or salts thereof, wherein:
• n 1 or 2;
• n-1 2;
• n i.
• the present invention provides compound of formula (I) or (la), or salts thereof, wherein:
• R 13 is S0 2 NHP(0)(OH) 2 .
• the present invention provides compound of formula (I) or (la), or salts thereof, wherein:
• R 1 pyridinyl, substituted with 1 R 13 ;
• R 13 is S0 2 NHP(0)(OH) 2 .
• the present invention provides compound of formula (I) or (la), or salts
• the present invention provides compound of formula (I) or (la), or salts
• compounds, enantiomers, diastereomers, tautomers, or salt thereof, of the present invention are selected from the compounds exemplified in the examples.
• compositions comprising a therapeutically effective amount of at least one compound of formula (I), (la), and/or compounds exemplified in the examples.
• compositions comprising a
• At least one compound of formula (I), (la), and/or compounds exemplified in the examples, and at least one other therapeutic agent for example, anti-arrhythmic agents, calcium channel blockers, anti-platelet agents, antihypertensive agents, anti thrombotic/anti thrombolytic agents, anti coagulants, HMG- CoA reductase inhibitors, anti diabetic agents, thyroid mimetics, mineralocorticoid receptor antagonists, and cardiac glycosides, are provided.
• compositions comprising a therapeutically effective amount of at least one compound of formula (I), (la), or compounds exemplified in the examples, and at least one other therapeutic agent, for example, sotalol, dofetilide, diltiazem, verapamil, clopidogrel, cangrelor, ticlopidine, CS- 747, ifetroban, aspirin, a beta adrenergic blocker, an ACE inhibitor, an A II antagonist, an ET antagonist, a dual ET/A II antagonist, a vasopepsidase inhibitor, tPA, recombinant tPA, TNK, nPA, a factor Vila inhibitor, a factor Xa inhibitor, a factor XIa inhibitor, a thrombin inhibitor, warfarin, a heparin, pravastatin, lovastatin, atorvastatin, simvastatin, NK-104, ZD-4522, a big
• compositions comprising a therapeutically effective amount of at least one compound of formula (I), (la), or compounds exemplified in the examples, and at least one other therapeutic agent, for example, captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril, omapatrilat, gemopatrilat, and apixaban, are provided.
• methods of treating or preventing arrhythmia comprising administering to a patient in need thereof an effective amount of at least one compound of formula (I), (la), or compounds exemplified in the examples, are provided.
• methods of treating or preventing supraventricular arrhythmia comprising administering to a patient in need thereof an effective amount of at least one compound of formula (I), (la), or compounds exemplified in the examples, are provided.
• a method of controlling heart rate comprising administering to a patient in need thereof an effective amount of at least one compound of formula (I), (la), or compounds exemplified in the examples, is provided.
• methods of treating an iKur-associated conditions for example, gastrointestinal disorders, such as reflux esophagitis and a motility disorder; inflammatory and/or immunological diseases, such as chronic obstructive pulmonary disease; diabetes; cognitive disorders; migraines; epilepsy; and hypertension, comprising administering to a patient in need thereof an effective amount of at least one compound of formula (I), (la), or compounds exemplified in the examples, are provided.
• gastrointestinal disorders such as reflux esophagitis and a motility disorder
• inflammatory and/or immunological diseases such as chronic obstructive pulmonary disease
• diabetes cognitive disorders
• migraines migraines
• epilepsy epilepsy
• hypertension comprising administering to a patient in need thereof an effective amount of at least one compound of formula (I), (la), or compounds exemplified in the examples.
• compositions comprising a compound of the invention together with a pharmaceutically acceptable carrier, diluent, or excipient.
• a pharmaceutically acceptable carrier diluent, or excipient.
• the composition optionally further comprises another pharmaceutically acceptable carrier or diluent and/or a
• compositions for pharmaceutical use are such compositions for pharmaceutical use.
• compositions comprising a compound of the invention together with a pharmaceutically acceptable carrier, diluent, or excipient.
• a pharmaceutically acceptable carrier diluent, or excipient.
• the composition optionally further comprises another pharmaceutically acceptable carrier or diluent and/or a
• compositions for pharmaceutical use are such compositions for pharmaceutical use.
• Another aspect of this invention is directed to treatment of diseases or disorders associated with inhibition of potassium channel function, wherein the disease or disorder is atrial fibrillation, controlling heart rate, and/or prophylactically treating arrhythmia, comprising administering a therapeutically effective amount of a compound of the present invention or an individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
• the compounds of the invention may be useful in therapy.
• the compounds of the invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of diseases or disorders associated with inhibition of potassium channel function, of the K v l subfamily of voltage gated K + channels, of K v 1.5 (which have been linked to the ultra-rapidly activating delayed rectifier K + current I Ku r, and/or K v 1.3 channels, and/or K v l . l channels.
• the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).
• the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis.
• the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
• the reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
• novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
• the compounds of the present invention may be prepared by the exemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples.
• novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
• methyl pyrrolidine-2-carboxylate 1 was protected using a protecting group, for example, Boc and 2 was converted to 1-tert-butyl 2-methyl 3- bromo-lH-pyrrole-l,2-dicarboxylate 3 using NBS which acts as a brominating as well as oxidizing agent (Aust. J. Chem., 62(7):683-691 (2009)).
• Palladium mediated Suzuki cross-coupling with boronic acids or esters (R is optionally substituted aryl, heteroaryl, alkyl or cycloalkyl) followed by deprotection gave the aryl pyrrole derivative 5.
• N- amination of 5 gave compounds of general formula 6 which on acylation gave corresponding compounds 7.
• 7 undergoes cyclization to form the pyrrolotriazine core 8.
• BOP reagent yield compounds of general formula (I).
• compounds of formula (I) can be synthesized by the general sequence shown in Scheme 3.
• Commercially available 5-methyl-3,4-dihydro-2H-pyrrole 13 was treated with N-chlorosuccinimide followed by sodium methoxide to generate methyl 3- chloro-lH-pyrrole-2-carboxylate 14.
• Compound 14 was N-aminated and the product 15 was acylated to yield methyl 3-chloro-l-(methoxycarbonylamino)-lH-pyrrole-2- carboxylate 16.
• Compound 16 was treated with ammonia to yield 5-chloropyrrolo[l,2- f][l,2,4]triazine-2,4-diol 17.
• Compound 10 can be obtained from 17 by transition metal mediated Suzuki cross-coupling reactions with boronic acids or esters.
• Compound 17 gave 2,4,5-trichloropyrrolo[l,2-fJ[l,2,4]triazine 18 on treatment with chlorinating agents for example, POCI 3 and then displacement of the C4 chloro with amines gave regioselectively 19.
• chlorinating agents for example, POCI 3
• displacement of the C4 chloro with amines gave regioselectively 19.
• Using different palladium reagent/ ligand combinations we could achieve regioselective Suzuki cross-couplings at C2 and C5 to generate compounds of general formula (I).
• Preparative HPLC was carried on AGILENT® 1200 series, Shimadzu prominence or Waters systems. Preparative SFC was performed on Thar instrument. Reverse phase analytical HPLC/MS was performed on AGILENT® 1200 systems coupled with Mass Spectrometers. LCMS was performed on AGILENT® 1200 or Waters AQUITY® system coupled with Mass Spectrometer. Chiral analytical LC was performed on a Thar
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Buffer 0.05% TFA in H 2 0 (pH 2.5, adjusted with dilute ammonia)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Buffer 0.05% TFA in H 2 0 (pH 2.5, adjusted with dilute ammonia)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent B CH 3 CN (90%) + 20 mM NH 4 OAc in H 2 0 (10%)
• Solvent A CH 3 CN (2%) + 10 mM NH 4 COOH in H 2 0 (98%)
• Solvent B CH 3 CN (98%) + 10 mM NH 4 COOH in H 2 0 (2%)
• Solvent A CH 3 CN ( 10%) + 10 mM NH 4 COOH in H 2 0 (90%)
• Solvent B CH 3 CN (90%) + 10 mM NH 4 COOH in H 2 0 (10%)
• Solvent A CH 3 CN (2%) + 10 mM NH 4 COOH in H 2 0 (98%)
• Solvent A CH 3 CN (5%) + 5 mM NH 4 OAc in H 2 0 (95%)
• Solvent B CH 3 CN (98%) + 10 mM NH 4 COOH in H 2 0 (2%)
• Solvent A CH 3 CN (5%) + 10 mM NH 4 OAc in H 2 0 (95%)
• Solvent B CH 3 CN (95%) + 10 mM NH 4 COOH in H 2 0 (5%)
• Solvent A CH 3 CN (2%) + 10 mM NH 4 COOH in H 2 0 (98%)
• Solvent A CH 3 CN ( 10%) + 20 mM NH 4 OAc in H 2 0 (90%)
• Solvent A CH 3 CN (2%) + 10 mM NH 4 COOH in H 2 0 (98%)
• Solvent A CH 3 CN (2%) + 10 mM NH 4 COOH in H 2 0 (98%)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent A CH 3 CN (2%) + 0.1% NH 4 COOH in H 2 0 (98%)
• Solvent B CH 3 CN (98%) + 0.1% NH 4 COOH in H 2 0 (2%)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Buffer 0.05% TFA in H 2 0 (pH 2.5, adjusted with dilute ammonia)
• Solvent A CH 3 CN (10%) + 20 mM NH 4 OAc in H 2 0 (90%)
• Solvent A CH 3 CN (2%) + 10 mM NH 4 COOH in H 2 0 (98%)
• Solvent A CH 3 CN (2%) + 10 mM NH 4 COOH in H 2 0 (98%)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B 0.1% TFA in CH 3 CN
• Solvent B CH 3 CN (98%) + 0.1%TFA in H 2 0 (2%)
• Solvent A Buffer: CH 3 CN (90: 10)
• Solvent B Buffer: CH 3 CN (10:90)
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.6, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.6, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.6, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.5, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.5, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.6, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A 10 mM NH 4 HC0 3 (pH 9.5, adjusted with dilute NH 3 )
• Solvent B Methanol
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.5, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.5, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A 10 mM ammonium acetate (pH 4.6 adjusted by acetic acid)
• Solvent B CH 3 CN
• Solvent A Buffer: CH 3 CN (90: 10)
• Solvent A lOmM ammonium acetate in water
• Solvent A 5% CH 3 CN - 95% H 2 0 lOmM NH 4 OAc
• Solvent B 95% CH 3 CN - 5% H 2 0 lOmM NH 4 OAc
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.5, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent B CH 3 CN (98%) + 10 mM NH 4 COOH in H 2 0 (2%)
• Solvent A CH 3 CN (5%) + 10 mM NH 4 OAc in H 2 0 (95%)
• Solvent B CH 3 CN (98%) + 10 mM NH 4 COOH in H 2 0 (2%)
• Solvent A CH 3 CN (5%) + 0.1%TFA in H 2 0 (95%)
• Solvent B CH 3 CN (95%) + 0.1%TFA in H 2 0 (5%)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)
• Solvent A 10 mM NH 4 OAc in H 2 0 (pH 4.5, adjusted with AcOH)
• Solvent B CH 3 CN
• Solvent A Buffer: CH 3 CN (95:5)
• Solvent B Buffer: CH 3 CN (5:95)

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• 2014
  • 2014-03-07 US US14/200,055 patent/US9050345B2/en active Active
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