WO2010004343A1 - Piperidinyl gpcr agonists - Google Patents

Piperidinyl gpcr agonists Download PDF

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Publication number
WO2010004343A1
WO2010004343A1 PCT/GB2009/050825 GB2009050825W WO2010004343A1 WO 2010004343 A1 WO2010004343 A1 WO 2010004343A1 GB 2009050825 W GB2009050825 W GB 2009050825W WO 2010004343 A1 WO2010004343 A1 WO 2010004343A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
compound according
preparation
mmol
Prior art date
Application number
PCT/GB2009/050825
Other languages
French (fr)
Inventor
Lisa Sarah Bertram
Matthew Colin Thor Fyfe
Revathy Perpetua Jeevaratnam
John Keily
Thomas Martin Krulle
Chrystelle Marie Rasamison
Colin Peter Sambrook-Smith
Simon Andrew Swain
Original Assignee
Prosidion Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0812646A external-priority patent/GB0812646D0/en
Priority claimed from GB0812622A external-priority patent/GB0812622D0/en
Priority claimed from GB0902391A external-priority patent/GB0902391D0/en
Priority to MX2011000060A priority Critical patent/MX2011000060A/en
Priority to CN2009801263533A priority patent/CN102083813A/en
Priority to CA2728042A priority patent/CA2728042A1/en
Priority to AU2009269772A priority patent/AU2009269772A1/en
Priority to US13/003,546 priority patent/US20110269734A1/en
Application filed by Prosidion Limited filed Critical Prosidion Limited
Priority to EP09785303A priority patent/EP2321297A1/en
Priority to EA201170151A priority patent/EA201170151A1/en
Priority to JP2011517245A priority patent/JP2011527331A/en
Publication of WO2010004343A1 publication Critical patent/WO2010004343A1/en
Priority to IL209978A priority patent/IL209978A0/en
Priority to ZA2010/08955A priority patent/ZA201008955B/en
Priority to MA33508A priority patent/MA32467B1/en

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Classifications

    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • 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

Definitions

  • the present invention is directed to G-protein coupled receptor (GPCR) agonists.
  • GPCR G-protein coupled receptor
  • the present invention is directed to agonists of GPRl 19 that are useful for the treatment of obesity, e g as regulators of satiety, metabolic syndrome and for the treatment of diabetes.
  • Obesity is characterized by an excessive adipose tissue mass relative to body size.
  • body fat mass is estimated by the body mass index (BMI; weight(kg)/height(m) 2 ), or waist circumference
  • BMI body mass index
  • Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pam and even certain cancers
  • Hypothalamic centres are also able to sense peripheral hormones involved in the maintenance of body weight and degree of adiposity, such as insulin and leptin, and fat tissue derived peptides
  • Drugs aimed at the pathophysiology associated with insulin dependent Type I diabetes and non-insulin dependent Type II diabetes have many potential side effects and do not adequately address the dyslipidaemia and hyperglycaemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycaemic agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.
  • metabolic syndrome places people at high risk of coronary artery disease, and is characterized by a cluster of risk factors including central obesity (excessive fat tissue in the abdominal region), glucose intolerance, high triglycerides and low HDL cholesterol, and high blood pressure.
  • central obesity excessive fat tissue in the abdominal region
  • glucose intolerance high triglycerides
  • low HDL cholesterol high blood pressure
  • Myocardial ischemia and microvascular disease is an established morbidity associated with untreated or poorly controlled metabolic syndrome.
  • GPRl 19 (previously referred to as GPRl 16) is a GPCR identified as SNORF25 in WO00/50562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers. AAN95194 (human), AAN95195 (rat) and ANN95196
  • GPRl 19 is expressed in the pancreas, small intestine, colon and adipose tissue.
  • the expression profile of the human GPRl 19 receptor indicates its potential utility as a target for the treatment of obesity and diabetes.
  • International patent applications WO2005/061489, WO2006/070208 and WO2006/067532 disclose heterocyclic derivatives as GPRl 19 receptor agonists
  • International patent applications WO2006/067531, WO2007/003960, WO2007/003961, WO2007/003962 and WO2007/003964, WO2007/116230 and WO2007/116229 disclose GPRl 19 receptor agonists
  • the present invention relates to agonists of GPRl 19 which are useful for the treatment of diabetes and as peripheral regulators of satiety, e g for the treatment of obesity and metabolic syndrome
  • (I) or pharmaceutically acceptable salts thereof are agonists of GPRl 19 and are useful for the prophylactic or therapeutic treatment of diabetes and obesity.
  • the present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • R 1 is -SO 2 Me or -CONHR 6 ;
  • R 2 , R 3 and R 4 are independently selected from hydrogen and methyl, n is 0, 1 or 2,
  • R 5 is independently Ci 4 alkyl, C M alkoxy, fluoro, chloro, Ci 3 fluoroalkyl or benzyl
  • R 6 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, 3-pipendinyl or 4-piperidinyl, wherein the azetidinyl, pyrrolidinyl and pipe ⁇ dinyl rings may be optionally substituted with OH, CH 2 OH or CH 3 , Ci 3 alkyl, C 2 A alkyl substituted by -N(R 7 ) 2 and/or one or two hydroxy groups, or alkyl substituted by a 4- to 6-membered nitrogen-containing heterocyclic ring; and
  • R 7 is independently hydrogen or methyl In one embodiment of the invention, Q is CH In another Q is N. Q is preferably CH
  • R 1 is -SO 2 Me In another, R 1 is -CONHR 6
  • R 1 is preferably -CONHR 6
  • R 2 and R 3 are preferably methyl, for example R 2 is methyl and R 3 is hydrogen.
  • R 4 is hydrogen and m another R 4 is methyl
  • R 4 is preferably hydrogen.
  • the stereocenter produced preferably has the (R)- configuration.
  • n is preferably 1.
  • R 5 is preferably meta or para, more preferably para, to the point of attachment to the piperidmyl nitrogen.
  • R 5 is preferably Ci 3 alkyl, fluoro, chloro or Ci 3 fluoroalkyl, more preferably C 2 3 alkyl, chloro or Ci 3 fluoroalkyl, especially chloro, ethyl or isopropyl, more especially chloro.
  • W and X are preferably CH, for example W, X and Y may be CH Y is preferably N
  • R 6 is preferably hydrogen or C 2 3 alkyl substituted by -N(R 7 ) 2 or one or two hydroxy groups, for example hydrogen or C 2 3 alkyl substituted by one or two hydroxy groups.
  • R 6 is more preferably C 2 3 alkyl substituted by one or two hydroxy groups, e g. 2-hydroxyethyl, 2- hydroxy-1-methylethyl, 2,3-dihydroxypropyl or 2-hydroxy-l-hydroxymethylethyl.
  • R 6 is C 2 ⁇ alkyl substituted a 4- to 6-membered nitrogen-containing heterocyclic ring
  • suitable 4- to 6-membered nitrogen-containing heterocyclic rings include pyrrolidmyl and azetidinyl
  • R 7 is preferably hydrogen
  • Q is N; one of W, X and Y is N or CH and the others are CH where the H may be replaced by
  • R 1 is -SO 2 Me or -CONHR 6 ;
  • R 2 , R 3 and R 4 are independently selected from hydrogen and methyl, n is 0, 1 or 2, R 5 is Ci 4 alkyl, Ci 4 alkoxy, fluoro, chloro, Ci 3 fluoroalkyl or benzyl; and
  • R 6 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, Ci 3 alkyl, or C 2 3 alkyl substituted by amino or one or two hydroxy groups; and pharmaceutically acceptable salts thereof
  • a further group of compounds which may be mentioned are those where: Q is CH; one of W, X and Y is N or CH and the others are CH where the H may be replaced by R 5 when present;
  • R 1 is -SO 2 Me or -CONHR 6 ; when R 1 is -SO 2 Me, R 2 and R 3 are hydrogen, and when R 1 is -CONHR 6 , R 2 and R 3 are independently selected from hydrogen and methyl,
  • R 4 is hydrogen or methyl; n is 0, 1 or 2,
  • R 5 is independently Ci 4 alkyl, CM alkoxy, fluoro, chloro or Ci 3 fluoroalkyl
  • R 6 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, 4-pipendinyl, Ci 3 alkyl, or C 2 ⁇ alkyl substituted by amino and/or one or two hydroxy groups, or by a 4- or 5-membered nitrogen- containing heterocyclic ring.
  • R 5 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, Ci 3 alkyl, or C 2 3 alkyl substituted by amino or one or two hydroxy groups
  • preferred compounds of this invention include those in which several or each variable in formula (I) is selected from the preferred, more preferred or particularly listed groups for each variable Therefore, this invention is intended to include all combinations of preferred, more preferred and particularly listed groups
  • alkyl means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and fert-butyl.
  • Fluoroalkyl means alkyl groups substituted by one or more fluoro atoms, e g. CHF 2 and CF 3 .
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their raceinic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof
  • the above formula (I) is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of formula (I) and pharmaceutically acceptable salts thereof Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used
  • salts derived from bases include those derived from bases such as, for example, potassium and sodium salts and the like.
  • Salts derived from pharmaceutically acceptable non-toxic acids include those derived from inorganic and organic acids such as, for example, hydrochloric, methanesulfonic, sulfuric, p-toluenesulfonic acid and the like. Since the compounds of formula (I) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).
  • the compounds of formula (I) can be prepared as described below, wherein R 1 , R 2 , R 3 , R 4 , R 5 , Q, W, X and Y are defined as above, PG represents a protecting group, DG represents a displaceable group e g, F, Cl, Br, MeSC> 2 , and Ak is Ci 2 alkyl.
  • Unichiral building blocks for compounds of formula (I), where R 4 is Me can be readily prepared from known compounds (Scheme 1).
  • Scheme 1 the ethyl ester of compound (II) where PG is Boc has been previously reported (US Patent 6,518,423) Saponification and hydrogenation, under standard conditions, will yield the racemic compound of formula (III) Chiral reduction of the alkenoic acid (II) under suitable conditions, such as a hydrogenation in the presence of a chiral catalyst, yields compounds of formula (III) in high enantiomeric excess.
  • a suitable catalyst is [Rh(norbornadiene) 2 ]BF 4 and (S)-l-[(R)-2-(di-tert- butylphosphmo)ferrocenyl]ethylbis(2-methylphenyl)phosphine
  • compounds of formula (IV) can then be obtained by reduction of the carboxylic acids of formula (III) under standard conditions, for example employing borane in a suitable solvent such as THF.
  • Compounds of formula (I) where Q is CH and R 1 is -SO 2 Me can also be prepared from compounds of formula (VI), by reaction with the appropriate 4-methanesulfonylphenol under Mitsunobu conditions (for example using a suitable solvent such as THF, at between O 0 C and room temperature, followed by the addition of triphenylphosphme and diisopropylazo- dicarboxylate) followed by removal of the protecting group under conditions well known to those with skill in the art.
  • Mitsunobu conditions for example using a suitable solvent such as THF, at between O 0 C and room temperature, followed by the addition of triphenylphosphme and diisopropylazo- dicarboxylate
  • the compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000, compounds and more preferably 10 to 100 compounds of formula (I)
  • Compound libraries may be prepared by a combinatorial "split and mix” approach or by multiple parallel synthesis using either solution or solid phase chemistry, using procedures known to those skilled in the art.
  • labile functional groups in the intermediate compounds e.g. hydroxy, carboxy and amino groups
  • the protecting groups may be removed at any stage in the synthesis of the compounds of formula (I) or may be present on the final compound of formula (I).
  • a comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, Protective Groups in Organic Chemistry, T.W. Greene and P.G M. Wuts, (1991) Wiley-Interscience, New York, 2 nd edition.
  • the compounds of formula (I) are useful as GPRl 19 agonists, e.g. for the treatment and/or prophylaxis of obesity and diabetes.
  • the compounds of formula (I) will generally be administered in the form of a pharmaceutical composition.
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), in combination with a pharmaceutically acceptable carrier.
  • composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a pharmaceutical composition for the treatment of disease by modulating GPRl 19, resulting in the prophylactic or therapeutic treatment of obesity, e.g. by regulating satiety, or for the treatment of diabetes, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof
  • compositions may optionally comprise other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route m any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy
  • the compounds of formula (I), or pharmaceutically acceptable salts thereof can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques
  • a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration, e g oral or parenteral (including intravenous).
  • compositions can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension m an aqueous liquid, as a non-aqueous liquid, as an oil-m-water emulsion, or as a water-m-oil liquid emulsion.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices
  • the compositions may be prepared by any of the methods of pharmacy In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation
  • the compounds of formula (I), or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectm, acacia, magnesium stearate, and stearic acid
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen
  • any convenient pharmaceutical media may be employed.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystallme cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free -flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent
  • Each tablet preferably contains from about 0 05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient
  • a formulation intended for the oral administration to humans may contain from about 0 5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg
  • Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like.
  • compositions can be in a form suitable for use in transdermal devices.
  • These formulations may be prepared, using a compound of formula (I), or a pharmaceutically acceptable salt thereof, via conventional processing methods
  • a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid It is preferable that the mixture forms unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface -active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface -active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface -active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface -active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood
  • dosage levels on the order of 0.01mg/kg to about 150mg/kg of body weight per day are useful m the treatment of the above-indicated conditions, or alternatively about
  • obesity may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • the compounds of formula (I) may be used in the treatment of diseases or conditions in which GPRl 19 plays a role
  • the invention also provides a method for the treatment of a disease or condition in which GPRl 19 plays a role comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof
  • Diseases or conditions in which GPRl 19 plays a role include obesity and diabetes.
  • the treatment of obesity is intended to encompass the treatment of diseases or conditions such as obesity and other eating disorders associated with excessive food intake e.g by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound and diabetes (including Type 1 and Type 2 diabetes, impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidaemia). And the treatment of patients who have an abnormal sensitivity to ingested fats leading to functional dyspepsia
  • the compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertension.
  • the compounds of the invention may offer advantages over compounds acting via different mechanisms for the treatment of the above mentioned disorders in that they may offer beta-cell protection, increased cAMP and insulin secretion and also slow gastric emptying.
  • the compounds of the invention may also be used for treating conditions characterised by low bone mass such asosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar bone loss, osteotomy bone loss, childhood idiopathic bone loss, Paget's disease, bone loss due to metastatic cancer, osteolytic lesions, curvature of the spine and loss of height.
  • low bone mass such asosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar bone loss, osteotomy bone loss, childhood idiopathic bone loss, Paget's disease, bone loss due to metastatic cancer, osteolytic lesions, curvature of the spine and loss of height.
  • the invention also provides a method for the regulation of satiety comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method for the treatment of obesity comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method for the treatment of diabetes, including Type 1 and Type 2 diabetes, particularly type 2 diabetes, comprising a step of administering to a patient m need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof
  • the invention also provides a method for the treatment of metabolic syndrome (syndrome X), impaired glucose tolerance, hyper lipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • metabolic syndrome sekunder X
  • impaired glucose tolerance hyper lipidemia
  • hypertriglyceridemia hypercholesterolemia
  • low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition as defined above
  • treatment includes both therapeutic and prophylactic treatment
  • the compounds of formula (I) may exhibit advantageous properties compared to known
  • the compounds may exhibit improved potency or half-life, or solubility or metabolic profiles, or improved anti-obesity effects, or other advantageous properties for compounds to be used as pharmaceuticals.
  • the compounds of formula (I), or pharmaceutically acceptable salts thereof, may be administered alone or in combination with one or more other therapeutically active compounds.
  • the other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of formula (I) or a different disease or condition.
  • the therapeutically active compounds may be administered simultaneously, sequentially or separately.
  • the compounds of formula (I) may be administered with other active compounds for the treatment of obesity and/or diabetes, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides, ⁇ 2 agonists, glitazones, PPAR- ⁇ agonists, mixed PPAR- ⁇ / ⁇ agonists, RXR agonists, fatty acid oxidation inhibitors, ⁇ -glucosidase inhibitors, dipeptidyl peptidase IV inhibitors, GLP-I agonists e g GLP-I analogues and mimetics, ⁇ -agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antio
  • pancreatic lipase inhibitors MCH-I antagonists and CB-I antagonists (or inverse agonists), amylin antagonists, lipoxygenase inhibitors, somostatin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, PTPlB inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanm receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e g.
  • sibutramine CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-I inhibitors or sorbitol dehydrogenase inhibitors.
  • Combination therapy comprising the administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one other antiobesity agent represents a further aspect of the invention.
  • the present invention also provides a method for the treatment of obesity in a mammal, such as a human, which method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antiobesity agent, to a mammal in need thereof
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antiobesity agent for the treatment of obesity.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with another antiobesity agent, for the treatment of obesity.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antiobesity agent(s) may be co-administered or administered sequentially or separately.
  • Co-administration includes administration of a formulation which includes both the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antiobesity agent(s), or the simultaneous or separate administration of different formulations of each agent
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antiobesity agent in the manufacture of a medicament for the treatment of obesity.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antiobesity agent, and a pharmaceutically acceptable carrier.
  • the invention also encompasses the use of such compositions in the methods described above.
  • GPRl 19 agonists are of particular use m combination with centrally acting antiobesity agents
  • the other antiobesity agent for use in the combination therapies according to this aspect of the invention is preferably a CB-I modulator, e g. a CB-I antagonist or inverse agonist.
  • CB-I modulators include SR141716 (rimonabant) and SLV-319 ((45)-(-)-3-(4- chlorophenyl)- ⁇ -methyl-]V-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-lH-pyrazole-l- carboxamide); as well as those compounds disclosed m EP576357, EP656354, WO 03/018060, WO 03/020217, WO 03/020314, WO 03/026647, WO 03/026648, WO 03/027076, WO
  • GPRl 19 has been suggested to play a role
  • diseases or conditions in which GPRl 19 has been suggested to play a role include those described in WO 00/50562 and US 6,468,756, for example cardiovascular disorders, hypertension, respiratory disorders, gestational abnormalities, gastrointestinal disorders, immune disorders, musculoskeletal disorders, depression, phobias, anxiety, mood disorders and
  • HOBt H 2 O (77.0 mg, 660 ⁇ mol) was added to a stirred solution of 4-[3-(4-carboxy-3- methylphenoxy)propyl]piperidine-l-carboxylic acid tert-butyl ester (Preparation 7, 200 mg, 530 ⁇ mol) and EDCI (126 mg, 660 ⁇ mol) in THF (10 mL) After 1 h, 2-aminoethanol (64 ⁇ L,
  • NEt 3 (13.0 mL, 93.4 mmol) was added to a stirred solution of terf-butyl 4-((R)-3- hydroxy-l-methylpropyl)piperidme-l-carboxylate (Preparation 3, 20.0 g, 77.9 mmol) and methanesulfonyl chloride (9 80 g, 85 6 mmol) m DCM (200 mL). The reaction mixture was warmed to ambient temperature and stirred for 3 h.
  • HOBt H 2 O (771 mg, 5.71 mmol) was added to a stirred solution of 6-[3-(l-tert- butoxycarbonylpiperidin-4-yl)propoxy]-2-methylnicotinic acid (Preparation 49, 1.80 g, 4.76 mmol), EDCI (1.10 g, 5.71 mmol) and DIPEA (2.50 niL, 14.3 mmol) in THF (50 mL). After 15 min, 2-aminopropane-l,3-diol (650 mg, 7.13 mmol) was added and the resulting mixture was stirred at ambient temperature for 16 h.
  • 2,5-Dichloropyrimidine (17.4 g, 117 mmol) was added portionwise, then the reaction was heated to 110 0 C for 4 h After cooling to 2O 0 C, the reaction was poured into H 2 O (200 mL) and extracted with EtOAc (3 x 500 mL) The combined organic extracts were washed with IM HCl (2 x 200 mL), before being dried (MgSO 4 ) and concentrated.
  • Method 2 Products were purified by column chromotography (DCM-MeOH, 98 2).
  • HOBt H 2 O 50 0 mg, 370 ⁇ mol
  • EDCI 70 5 mg, 370 ⁇ mol
  • THF 7 inL
  • 2-aminoethanol 68 ⁇ L, 1.13 mmol
  • HOBt H 2 O 100 mg, 735 ⁇ mol
  • 4- ⁇ 3-[l-(5-chloro- pyrimidin-2-yl)pipendin-4-yl]propoxy ⁇ -2-methylbenzoic acid Preparation 12, 220 mg, 565 ⁇ mol
  • EDCI 141 mg, 735 ⁇ mol
  • THF 12 mL
  • DMF 600 ⁇ L
  • (2- aminoethyl)carbamic acid terf-butyl ester 268 ⁇ L, 1.694 mmol
  • Examples 110 and 111 N-(( ⁇ )-3-Amino-2-hydroxypropyl)-4- ⁇ 3-[l-(5-chloropyrimidin-2-yl)- piperidin-4-yl]propoxy ⁇ -2,6-dimethylbenzamide and N-((S)-3-Amino-2-hydroxypropyl)-4- ⁇ 3- [l-(5-chloropyrimidin-2-yl)piperidin-4-yl]propoxy ⁇ -2,6-dimethylbenzamide
  • amides listed in Table 7 were obtained in enantiomerically pure form employing procedures similar to that outlined for Examples 110 and 111, with the exception that the individual enantiomers of the Boc-protected intermediates were separated by preparative chiral HPLC using a Daicel Chiralpak IA column (250 x 20mm, 5 ⁇ m), with an eluent of IHAPrOH (7:3) at a flow rate of 15 mL/min, and UV detection at 250 nm.
  • Example 128 4-[3-(5'-Chloro-3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-4-yl)propoxy]-N-(2- hydroxyethyl)-2-methylbenzamide
  • HATU (82.0 m , 220 ⁇ mol) was added to a stirr ted sxolution of 4-[3-(5'-chloro- 3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-4-yl)propoxy]-2-methylbenzoic acid (Preparation 27, 118 mg, 180 ⁇ mol), ethanolamine (22.0 ⁇ L, 360 ⁇ mol) and DIPEA (63.0 ⁇ L, 360 ⁇ L) in THF (7 mL), and the resulting solution was stirred at ambient temperature for 16 h.
  • Example 141 4- ⁇ 3-[ 1 -(5-Fluoropyrimidin-2-yl)pipendm-4-yl]propoxy ⁇ -N-(2-hydroxyethyl)-2- methylbenzamide
  • Example 142 4- ⁇ 3-[l-(5-Chloropyrimidin-2-yl)pipendin-4-yl]propoxy ⁇ -N-((li?,2S)-2,3- dihydroxy-l-methylpropyl)-2,6-dimethylbenzamide
  • Example 146 N-(2-Hydroxy- 1 -hydroxymethylethyl)-6- ⁇ 3 -[ 1 -(5-isopropylpyrimidin-2-yl)- pipe ⁇ din-4-yl] propoxy ⁇ -2-methylnicotmamide
  • Example 148 6-[3-(5'-Chloro-3,4,5,6-tetrahydro-2H-[l,2']bipyridmyl-4-yl)propoxy]-N-(2- hydroxy- 1 -hydroxymethylethyl)-2-methylnicotinamide
  • Example 160 N-((5)-2,3-Dihydroxypropyl)-6- ⁇ 3-[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]- propoxy ⁇ -2-methylnicotinamide
  • Example 161 5'-Fluoro-4-[3-(5-methanesulfonyl-6-methylpyridin-2-yloxy)propyl]-3,4,5,6- tetrahydro-2H-[ 1 ,2']bipyridinyl
  • 2,5-Difluoropyridine (65.0 mg, 490 ⁇ mol) and DBU (72.0 ⁇ L, 490 ⁇ mol) were added to a solution of 3-methanesulfonyl-2-methyl-6-(3-piperidin-4-yl-propoxy)pyridine hydrochloride (Preparation 54, 125 mg, 330 ⁇ mol) m DMSO (500 ⁇ L) and the resulting solution stirred at 50 0 C for 72 h.
  • the biological activity of the compounds of the invention may be tested in the following assay systems-
  • yeast cell-based reporter assays have previously been described in the literature (e.g. see Miret J. J. et al, 2002, J. Biol. Chem., 277:6881-6887, Campbell R.M. et al, 1999, Bioorg. Med. Chem. Lett., 9:2413-2418; King K. et al, 1990, Science, 250: 121-123); WO 99/14344; WO 00/12704, and US 6,100,042). Briefly, yeast cells have been engineered such that the endogenous yeast G-alpha (GPAl) has been deleted and replaced with G-protein chimeras constructed using multiple techniques.
  • G-alpha G-alpha
  • yeast GPCR Ste3 has been deleted to allow for heterologous expression of a mammalian GPCR of choice
  • elements of the pheromone signaling transduction pathway which are conserved in eukaryotic cells (for example, the mitogen-activated protein kinase pathway), drive the expression of Fusl.
  • ⁇ -galactosidase LacZ
  • Fuslp Fusl promoter
  • Yeast cells were transformed by an adaptation of the lithium acetate method described by Agatep et al, (Agatep, R. et al, 1998, Transformation of Saccharomyces cerevisiae by the lithium acetate/single-stranded carrier DNA/polyethylene glycol (LiAc/ss-DNA/PEG) protocol.
  • yeast cells were grown overnight on yeast tryptone plates (YT) Carrier smgle-stranded DNA (lO ⁇ g), 2 ⁇ g of each of two Fuslp- LacZ reporter plasmids (one with URA selection marker and one with TRP), 2 ⁇ g of GPRl 19 (human or mouse receptor) in yeast expression vector (2 ⁇ g origin of replication) and a lithium acetate/ polyethylene glycol/ TE buffer was pipetted into an Eppendorf tube The yeast expression plasrmd containing the receptor/ no receptor control has a LEU marker. Yeast cells were inoculated into this mixture and the reaction proceeds at 30 0 C for 60min.
  • the yeast cells were then heat-shocked at 42 0 C for 15min The cells were then washed and spread on selection plates
  • the selection plates are synthetic defined yeast media minus LEU, URA and TRP (SD- LUT). After incubating at 30 0 C for 2-3 days, colonies that grow on the selection plates were then tested in the LacZ assay.
  • yeast cells carrying the human or mouse GPRl 19 receptor were grown overnight in liquid SD-LUT medium to an unsaturated concentration (i.e. the cells were still dividing and had not yet reached stationary phase) They were diluted m fresh medium to an optimal assay concentration and 90 ⁇ l of yeast cells added to 96-well black polystyrene plates (Costar) Compounds, dissolved in DMSO and diluted in a 10% DMSO solution to 1OX concentration, were added to the plates and the plates placed at 30 0 C for 4h.
  • Fluorescein di ⁇ -D-galactopyranoside
  • FDG Fluorescein di ( ⁇ -D-galactopyranoside)
  • a stable cell line expressing recombinant human GPRl 19 was established and this cell line may be used to investigate the effect of compounds of the invention on intracellular levels of cyclic AMP (cAMP).
  • cAMP cyclic AMP
  • the cell monolayers are washed with phosphate buffered saline and stimulated at 37 0 C for 30mm with various concentrations of compound in stimulation buffer plus 1 % DMSO. Cells are then lysed and cAMP content determined using the Perkin Elmer
  • AlphaScreenTM Analogously fluorescent Luminescent Proximity Homogeneous Assay
  • Buffers and assay conditions are as described in the manufacturer's protocol.
  • Animals are maintained on a reverse phase light-dark cycle (lights off for 8 h from 09.30-17.30 h) during which time the room was illuminated by red light Animals have free access to a standard powdered rat diet and tap water during a two week acclimatization period
  • the diet is contained in glass feeding jars with aluminum lids Each lid had a 3-4 cm hole in it to allow access to the food.
  • Animals, feeding jars and water bottles are weighed (to the nearest 0.1 g) at the onset of the dark period. The feeding jars and water bottles are subsequently measured 1 , 2, 4, 6 and 24 h after animals are dosed with a compound of the invention and any significant differences between the treatment groups at baseline compared to vehicle -treated controls.
  • HIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in RPMI1640 medium supplemented with 10% fetal calf serum and 3OnM sodium selenite All experiments were done with cells at less than passage 70, in accordance with the literature, which describes altered properties of this cell line at passage numbers above 81 (Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships Diabetes 1989 Jan;38(l) 44-8)
  • HIT-T15 cells were plated in standard culture medium in 96-well plates at 100,000 cells/ 0 1ml/ well and cultured for 24 hr and the medium was then discarded Cells were incubated for 15min at room temperature with lOO ⁇ l stimulation buffer (Hanks buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH 7 4).
  • lOO ⁇ l stimulation buffer Hormoned salt solution, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH 7 4).
  • HIT-T 15 cells were plated in standard culture medium m 12-well plates at 106 cells/ 1 ml/ well and cultured for 3 days and the medium was then discarded. Cells were washed x 2 with supplemented Krebs-Ringer buffer (KRB) containing 119 mM NaCl, 4.74 mM KCl, 2.54 inM CaCl 2 , 1.19 mM MgSO 4 , 1.19 mM KH2PO4, 25 mM NaHCO 3 , 1OmM HEPES at pH 7.4 and 0 1% bovine serum albumin Cells were incubated with ImI KRB at 37°C for 30 min which was then discarded.
  • KRB Krebs-Ringer buffer
  • Representative compounds of the invention were found to increase insulin secretion at an EC 50 of less than 10 ⁇ M Compounds showing an EC 50 of less than 1 ⁇ M in the insulin secretion assay may be preferred
  • Blood samples (20 ⁇ L) are then taken 25, 50, 80, 120, and 180 min after GIc administration.
  • the 20 ⁇ L blood samples for measurement of GIc levels are taken from the cut tip of the tail into disposable micro-pipettes (Dade Diagnostics Inc., Puerto Rico) and the sample added to 480 ⁇ L of haemolysis reagent.
  • Duplicate 20 ⁇ L aliquots of the diluted haemolysed blood are then added to 180 ⁇ L of Trinders glucose reagent (Sigma enzymatic (Trinder) colorimetric method) in a 96-well assay plate. After mixing, the samples are left at rt for 30 min before being read against GIc standards (Sigma glucose/urea nitrogen combined standard set).

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Abstract

Compounds of formula (I):or pharmaceutically acceptable salts thereof, are GPCR agonists and are useful as for the treatment of diabetes and obesity.

Description

PIPERIDINYL GPCR AGONISTS
BACKGROUND OF THE INVENTION
The present invention is directed to G-protein coupled receptor (GPCR) agonists. In particular, the present invention is directed to agonists of GPRl 19 that are useful for the treatment of obesity, e g as regulators of satiety, metabolic syndrome and for the treatment of diabetes.
Obesity is characterized by an excessive adipose tissue mass relative to body size. Clinically, body fat mass is estimated by the body mass index (BMI; weight(kg)/height(m)2), or waist circumference Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pam and even certain cancers
Pharmacological approaches to the treatment of obesity have been mainly concerned with reducing fat mass by altering the balance between energy intake and expenditure. Many studies have clearly established the link between adiposity and the brain circuitry involved in the regulation of energy homeostasis. Direct and indirect evidence suggest that serotonergic, dopaminergic, adrenergic, cholinergic, endocannabmoid, opioid, and histaminergic pathways in addition to many neuropeptide pathways (e.g. neuropeptide Y and melanocortins) are implicated in the central control of energy intake and expenditure. Hypothalamic centres are also able to sense peripheral hormones involved in the maintenance of body weight and degree of adiposity, such as insulin and leptin, and fat tissue derived peptides Drugs aimed at the pathophysiology associated with insulin dependent Type I diabetes and non-insulin dependent Type II diabetes have many potential side effects and do not adequately address the dyslipidaemia and hyperglycaemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycaemic agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.
Similarly, metabolic syndrome (syndrome X) places people at high risk of coronary artery disease, and is characterized by a cluster of risk factors including central obesity (excessive fat tissue in the abdominal region), glucose intolerance, high triglycerides and low HDL cholesterol, and high blood pressure. Myocardial ischemia and microvascular disease is an established morbidity associated with untreated or poorly controlled metabolic syndrome.
There is a continuing need for novel antiobesity and antidiabetic agents, particularly ones that are well tolerated with few adverse effects
GPRl 19 (previously referred to as GPRl 16) is a GPCR identified as SNORF25 in WO00/50562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers. AAN95194 (human), AAN95195 (rat) and ANN95196
(mouse)).
In humans, GPRl 19 is expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPRl 19 receptor indicates its potential utility as a target for the treatment of obesity and diabetes. International patent applications WO2005/061489, WO2006/070208 and WO2006/067532 disclose heterocyclic derivatives as GPRl 19 receptor agonists International patent applications WO2006/067531, WO2007/003960, WO2007/003961, WO2007/003962 and WO2007/003964, WO2007/116230 and WO2007/116229 disclose GPRl 19 receptor agonists The present invention relates to agonists of GPRl 19 which are useful for the treatment of diabetes and as peripheral regulators of satiety, e g for the treatment of obesity and metabolic syndrome
SUMMARY OF THE INVENTION Compounds of formula (I):
Figure imgf000003_0001
(I) or pharmaceutically acceptable salts thereof, are agonists of GPRl 19 and are useful for the prophylactic or therapeutic treatment of diabetes and obesity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof.
Figure imgf000003_0002
(I) wherein Q is CH or N; one of W, X and Y is N or CH and the others are CH where the H may be replaced by R5 when present,
R1 is -SO2Me or -CONHR6;
R2, R3 and R4 are independently selected from hydrogen and methyl, n is 0, 1 or 2,
R5 is independently Ci 4 alkyl, CM alkoxy, fluoro, chloro, Ci 3 fluoroalkyl or benzyl, R6 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, 3-pipendinyl or 4-piperidinyl, wherein the azetidinyl, pyrrolidinyl and pipeπdinyl rings may be optionally substituted with OH, CH2OH or CH3, Ci 3 alkyl, C2 A alkyl substituted by -N(R7)2 and/or one or two hydroxy groups, or
Figure imgf000003_0003
alkyl substituted by a 4- to 6-membered nitrogen-containing heterocyclic ring; and
R7 is independently hydrogen or methyl In one embodiment of the invention, Q is CH In another Q is N. Q is preferably CH
In one embodiment of the invention, R1 is -SO2Me In another, R1 is -CONHR6
R1 is preferably -CONHR6
One or both of R2 and R3 are preferably methyl, for example R2 is methyl and R3 is hydrogen.
In one embodiment of the invention R4 is hydrogen and m another R4 is methyl R4 is preferably hydrogen. When R4 is methyl, the stereocenter produced preferably has the (R)- configuration. n is preferably 1. When n is 1, R5 is preferably meta or para, more preferably para, to the point of attachment to the piperidmyl nitrogen.
R5 is preferably Ci 3 alkyl, fluoro, chloro or Ci 3 fluoroalkyl, more preferably C2 3 alkyl, chloro or Ci 3 fluoroalkyl, especially chloro, ethyl or isopropyl, more especially chloro.
W and X are preferably CH, for example W, X and Y may be CH Y is preferably N R6 is preferably hydrogen or C2 3 alkyl substituted by -N(R7)2 or one or two hydroxy groups, for example hydrogen or C2 3 alkyl substituted by one or two hydroxy groups. R6 is more preferably C2 3 alkyl substituted by one or two hydroxy groups, e g. 2-hydroxyethyl, 2- hydroxy-1-methylethyl, 2,3-dihydroxypropyl or 2-hydroxy-l-hydroxymethylethyl.
When R6 is C2^alkyl substituted a 4- to 6-membered nitrogen-containing heterocyclic ring, suitable 4- to 6-membered nitrogen-containing heterocyclic rings include pyrrolidmyl and azetidinyl
R7 is preferably hydrogen
A group of compounds which may be mentioned are those where:
Q is N; one of W, X and Y is N or CH and the others are CH where the H may be replaced by
R5 when present;
R1 is -SO2Me or -CONHR6;
R2, R3 and R4 are independently selected from hydrogen and methyl, n is 0, 1 or 2, R5 is Ci 4 alkyl, Ci 4 alkoxy, fluoro, chloro, Ci 3 fluoroalkyl or benzyl; and
R6 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, Ci 3 alkyl, or C2 3 alkyl substituted by amino or one or two hydroxy groups; and pharmaceutically acceptable salts thereof
A further group of compounds which may be mentioned are those where: Q is CH; one of W, X and Y is N or CH and the others are CH where the H may be replaced by R5 when present;
R1 is -SO2Me or -CONHR6; when R1 is -SO2Me, R2 and R3 are hydrogen, and when R1 is -CONHR6, R2 and R3 are independently selected from hydrogen and methyl,
R4 is hydrogen or methyl; n is 0, 1 or 2,
R5 is independently Ci 4 alkyl, CM alkoxy, fluoro, chloro or Ci 3 fluoroalkyl, and R6 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, 4-pipendinyl, Ci 3 alkyl, or C2^ alkyl substituted by amino and/or one or two hydroxy groups, or by a 4- or 5-membered nitrogen- containing heterocyclic ring.
In this further group of compounds, certain compounds which may be mentioned are those where R5 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, Ci 3 alkyl, or C2 3 alkyl substituted by amino or one or two hydroxy groups
While the preferred groups for each variable have generally been listed above separately for each variable, preferred compounds of this invention include those in which several or each variable in formula (I) is selected from the preferred, more preferred or particularly listed groups for each variable Therefore, this invention is intended to include all combinations of preferred, more preferred and particularly listed groups
Specific compounds of the invention which may be mentioned are those included in the Examples and pharmaceutically acceptable salts thereof.
As used herein, unless stated otherwise, "alkyl" means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and fert-butyl.
"Fluoroalkyl" means alkyl groups substituted by one or more fluoro atoms, e g. CHF2 and CF3.
Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their raceinic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof The above formula (I) is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of formula (I) and pharmaceutically acceptable salts thereof Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
When the compound of formula (I) and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. Salts derived from bases include those derived from bases such as, for example, potassium and sodium salts and the like. Salts derived from pharmaceutically acceptable non-toxic acids, include those derived from inorganic and organic acids such as, for example, hydrochloric, methanesulfonic, sulfuric, p-toluenesulfonic acid and the like. Since the compounds of formula (I) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis). The compounds of formula (I) can be prepared as described below, wherein R1, R2, R3, R4, R5, Q, W, X and Y are defined as above, PG represents a protecting group, DG represents a displaceable group e g, F, Cl, Br, MeSC>2, and Ak is Ci 2 alkyl.
Unichiral building blocks for compounds of formula (I), where R4 is Me, can be readily prepared from known compounds (Scheme 1). For example, the ethyl ester of compound (II) where PG is Boc has been previously reported (US Patent 6,518,423) Saponification and hydrogenation, under standard conditions, will yield the racemic compound of formula (III) Chiral reduction of the alkenoic acid (II) under suitable conditions, such as a hydrogenation in the presence of a chiral catalyst, yields compounds of formula (III) in high enantiomeric excess. An example of a suitable catalyst is [Rh(norbornadiene)2]BF4 and (S)-l-[(R)-2-(di-tert- butylphosphmo)ferrocenyl]ethylbis(2-methylphenyl)phosphine Compounds of formula (IV) can then be obtained by reduction of the carboxylic acids of formula (III) under standard conditions, for example employing borane in a suitable solvent such as THF.
Scheme 1
Figure imgf000006_0001
II HI IV
Compounds of formula (I) can be prepared as outlined in Scheme 2. Compounds of formula (VII) can be synthesized by reaction of a phenol of formula (V) with an alcohol of formula (VI) under, for example, Mitsunobu conditions Subsequent removal of the protecting group, using conditions well known to those with skill in the art, and reaction with an appropriate 6-membered heteroaromatic hahde, yields compounds of formula (I)
Scheme 2
Figure imgf000006_0002
VI
Compounds of formula (I) where Q is CH and R1 is -SO2Me can also be prepared from compounds of formula (VI), by reaction with the appropriate 4-methanesulfonylphenol under Mitsunobu conditions (for example using a suitable solvent such as THF, at between O0C and room temperature, followed by the addition of triphenylphosphme and diisopropylazo- dicarboxylate) followed by removal of the protecting group under conditions well known to those with skill in the art. Subsequent reaction with an appropriate 6-membered heteroaromatic halide in dimethylsulfoxide and l,8-diazabicyclo[5.4.0]undec-7-ene at 1000C, yields compounds of formula (I) (Scheme 2)
Compounds of formula (I) where Q is N and R1 is SC>2Me can also be produced as outlined in Scheme 3. For example, the compound of formula (VIII) where R2 is methyl, R3 is hydrogen and DG is fluorine is commercially available. Bromine-metal exchange using butyllithium m a suitable solvent such as toluene, m the presence of a chelating agent such as TMEDA, if required, at low temperature followed by the addition of dimethyldisulfide affords the corresponding sulfide. Subsequent oxidation of the sulfide to the sulfone, using a standard oxidizing agent such as m-CPB A, affords compounds of formula (IX) Compounds of formula (X) are then formed by displacement of the leaving group in compounds of formula (IX) with the alkoxide of a compound of formula (VI) under standard conditions. Removal of the protecting group using conditions well known to those with skill in the art, followed by reaction with an appropriate 6-membered heteroaromatic halide, under suitable conditions, such as standard displacement conditions in DMSO in the presence of l,8-diazabicyclo[5 4 0]undec-7- ene, yields compounds of formula (I) as described above
Scheme 3
Figure imgf000007_0001
Compounds of formula (I) where R1 is -CONHR6 can also be produced as outlined in Scheme 4 Reaction of compounds of formula (VI) under suitable conditions with compounds of formula (XI) yields compounds of formula (XII). An example of suitable conditions is Mitsunobu conditions using a suitable solvent such as THF, at between O0C and room temperature, followed by the addition of triphenylphosphine and diisopropylazodicarboxylate Removal of the protecting group, using conditions well known to those with skill in the art, followed by reaction with an appropriate 6-membered heteroaromatic halide, under suitable conditions, yields compounds of formula (XIII). An example of suitable conditions is standard displacement conditions in DMSO in the presence of l,8-diazabicyclo[5.4 0]undec-7-ene. Hydrolysis of the alkyl ester (XIII) under standard hydrolysis conditions, for example LiOH in MeOH and H2O, yields the carboxyhc acids (XIV). A subsequent amide bond formation, under standard conditions, well known to those with skill in the art, yields compounds of formula (I) where R1 is -CONHR6 as described above Scheme 4
Figure imgf000008_0001
Also, compounds of formula (I), where Q is CH, R1 is -CONHR6 and R2 and R3 are Me can be produced as outlined in Scheme 5. Reaction of compounds of formula (XV) with 4- bromo-3,5-dimethylphenol in sulfolane with K2CO3 at 850C, yields compounds of formula (XVI). Subsequent reaction with w-butyllithium in THF at -780C, followed by quenching with CO2, yields compounds of formula (XIV) Reaction of compounds of formula (XVII) with an appropriate 6-membered heteroaromatic hahde, under suitable conditions, yields compounds of formula (XVIII) Examples of suitable conditions are standard displacement conditions in DMSO in the presence of l,8-diazabicyclo[5.4 0]undec-7-ene, or Buchwald coupling conditions using, for example, bis(dibenzylideneacetone)palladium, NaOt-Bu, and 2,8,9-triisobutyl-2,5,8,9- tetraaza-l-phosphabicyclo[3.3.3]undecane A subsequent amide bond formation, under standard conditions, well known to those with skill in the art, yields compounds of formula (I), where Q is CH, R1 is -CONHR6 and R2 and R3 are Me as described above.
Scheme 5
Figure imgf000009_0001
The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000, compounds and more preferably 10 to 100 compounds of formula (I) Compound libraries may be prepared by a combinatorial "split and mix" approach or by multiple parallel synthesis using either solution or solid phase chemistry, using procedures known to those skilled in the art.
During the synthesis of the compounds of formula (I), labile functional groups in the intermediate compounds, e.g. hydroxy, carboxy and amino groups, may be protected. The protecting groups may be removed at any stage in the synthesis of the compounds of formula (I) or may be present on the final compound of formula (I). A comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, Protective Groups in Organic Chemistry, T.W. Greene and P.G M. Wuts, (1991) Wiley-Interscience, New York, 2nd edition.
Any novel intermediates, such as those defined above, may be of use in the synthesis of compounds of formula (I) and are therefore also included within the scope of the invention, for example compounds of any one of formulae (VII), (X), (XIII), (XIV) and (XVIII) or a salt or protected derivative thereof.
The processes for the production of compounds of formula (I) described above also represent further aspects of the invention
As indicated above the compounds of formula (I) are useful as GPRl 19 agonists, e.g. for the treatment and/or prophylaxis of obesity and diabetes. For such use the compounds of formula (I) will generally be administered in the form of a pharmaceutical composition.
The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), in combination with a pharmaceutically acceptable carrier.
Preferably the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
Moreover, the invention also provides a pharmaceutical composition for the treatment of disease by modulating GPRl 19, resulting in the prophylactic or therapeutic treatment of obesity, e.g. by regulating satiety, or for the treatment of diabetes, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof
The pharmaceutical compositions may optionally comprise other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route m any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy
In practice, the compounds of formula (I), or pharmaceutically acceptable salts thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e g oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension m an aqueous liquid, as a non-aqueous liquid, as an oil-m-water emulsion, or as a water-m-oil liquid emulsion In addition to the common dosage forms set out above, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices The compositions may be prepared by any of the methods of pharmacy In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation
The compounds of formula (I), or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectm, acacia, magnesium stearate, and stearic acid Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystallme cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free -flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent Each tablet preferably contains from about 0 05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient
For example, a formulation intended for the oral administration to humans may contain from about 0 5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like.
Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, using a compound of formula (I), or a pharmaceutically acceptable salt thereof, via conventional processing methods As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface -active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient Compositions containing a compound of formula (I), or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of 0.01mg/kg to about 150mg/kg of body weight per day are useful m the treatment of the above-indicated conditions, or alternatively about
0 5mg to about 7g per patient per day For example, obesity may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The compounds of formula (I) may be used in the treatment of diseases or conditions in which GPRl 19 plays a role Thus the invention also provides a method for the treatment of a disease or condition in which GPRl 19 plays a role comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof Diseases or conditions in which GPRl 19 plays a role include obesity and diabetes. In the context of the present application the treatment of obesity is intended to encompass the treatment of diseases or conditions such as obesity and other eating disorders associated with excessive food intake e.g by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound and diabetes (including Type 1 and Type 2 diabetes, impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidaemia). And the treatment of patients who have an abnormal sensitivity to ingested fats leading to functional dyspepsia The compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertension.
The compounds of the invention may offer advantages over compounds acting via different mechanisms for the treatment of the above mentioned disorders in that they may offer beta-cell protection, increased cAMP and insulin secretion and also slow gastric emptying.
The compounds of the invention may also be used for treating conditions characterised by low bone mass such asosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar bone loss, osteotomy bone loss, childhood idiopathic bone loss, Paget's disease, bone loss due to metastatic cancer, osteolytic lesions, curvature of the spine and loss of height.
The invention also provides a method for the regulation of satiety comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. The invention also provides a method for the treatment of obesity comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
The invention also provides a method for the treatment of diabetes, including Type 1 and Type 2 diabetes, particularly type 2 diabetes, comprising a step of administering to a patient m need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof
The invention also provides a method for the treatment of metabolic syndrome (syndrome X), impaired glucose tolerance, hyper lipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above. The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition as defined above
In the methods of the invention the term "treatment" includes both therapeutic and prophylactic treatment The compounds of formula (I) may exhibit advantageous properties compared to known
GPRl 19 agonists, for example, the compounds may exhibit improved potency or half-life, or solubility or metabolic profiles, or improved anti-obesity effects, or other advantageous properties for compounds to be used as pharmaceuticals.
The compounds of formula (I), or pharmaceutically acceptable salts thereof, may be administered alone or in combination with one or more other therapeutically active compounds.
The other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of formula (I) or a different disease or condition. The therapeutically active compounds may be administered simultaneously, sequentially or separately. The compounds of formula (I) may be administered with other active compounds for the treatment of obesity and/or diabetes, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides, α2 agonists, glitazones, PPAR-γ agonists, mixed PPAR-α/γ agonists, RXR agonists, fatty acid oxidation inhibitors, α-glucosidase inhibitors, dipeptidyl peptidase IV inhibitors, GLP-I agonists e g GLP-I analogues and mimetics, β-agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents e.g. pancreatic lipase inhibitors, MCH-I antagonists and CB-I antagonists (or inverse agonists), amylin antagonists, lipoxygenase inhibitors, somostatin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, PTPlB inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanm receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e g. sibutramine, CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-I inhibitors or sorbitol dehydrogenase inhibitors.
Combination therapy comprising the administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one other antiobesity agent represents a further aspect of the invention.
The present invention also provides a method for the treatment of obesity in a mammal, such as a human, which method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antiobesity agent, to a mammal in need thereof
The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antiobesity agent for the treatment of obesity. The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with another antiobesity agent, for the treatment of obesity.
The compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antiobesity agent(s) may be co-administered or administered sequentially or separately. Co-administration includes administration of a formulation which includes both the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antiobesity agent(s), or the simultaneous or separate administration of different formulations of each agent
Where the pharmacological profiles of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antiobesity agent(s) allow it, coadministration of the two agents may be preferred.
The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antiobesity agent in the manufacture of a medicament for the treatment of obesity.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antiobesity agent, and a pharmaceutically acceptable carrier. The invention also encompasses the use of such compositions in the methods described above.
GPRl 19 agonists are of particular use m combination with centrally acting antiobesity agents The other antiobesity agent for use in the combination therapies according to this aspect of the invention is preferably a CB-I modulator, e g. a CB-I antagonist or inverse agonist.
Examples of CB-I modulators include SR141716 (rimonabant) and SLV-319 ((45)-(-)-3-(4- chlorophenyl)-Λ^-methyl-]V-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-lH-pyrazole-l- carboxamide); as well as those compounds disclosed m EP576357, EP656354, WO 03/018060, WO 03/020217, WO 03/020314, WO 03/026647, WO 03/026648, WO 03/027076, WO
03/040105, WO 03/051850, WO 03/051851, WO 03/053431, WO 03/063781, WO 03/075660,
WO 03/077847, WO 03/078413, WO 03/082190, WO 03/082191, WO 03/082833, WO
03/084930, WO 03/084943, WO 03/086288, WO 03/087037, WO 03/088968, WO 04/012671,
WO 04/013120, WO 04/026301, WO 04/029204, WO 04/034968, WO 04/035566, WO 04/037823 WO 04/052864, WO 04/058145, WO 04/058255, WO 04/060870, WO 04/060888,
WO 04/069837, WO 04/069837, WO 04/072076, WO 04/072077, WO 04/078261 and WO
04/108728, and the references disclosed therein.
Other diseases or conditions in which GPRl 19 has been suggested to play a role include those described in WO 00/50562 and US 6,468,756, for example cardiovascular disorders, hypertension, respiratory disorders, gestational abnormalities, gastrointestinal disorders, immune disorders, musculoskeletal disorders, depression, phobias, anxiety, mood disorders and
Alzheimer's disease. All publications, including, but not limited to, patents and patent application cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as fully set forth.
The invention will now be described by reference to the following examples which are for illustrative purposes and are not to be construed as a limitation of the scope of the present invention
EXAMPLES
Materials and methods Column chromatography was carried out on SiO2 (40-63 mesh) unless specified otherwise LCMS data were obtained as follows: Method A: Atlantis 3// Ci8 column (3.0 X 20.0 mm, flow rate = 0.85 mL/min) eluting with a H2O-CH3CN solution containing 0 1% HCO2H over 6 min with UV detection at 220 nm. Gradient information. 0.0-0.3 min 100% H2O, 0 3— 4 25 min: Ramp up to 10% H2O-90% CH3CN; 4 25-4 4 mm- Ramp up to 100% CH3CN; 4 4- 4.9 mm: Hold at 100% CH3CN; 4 9-6 0 min Return to 100% H2O. The mass spectra were obtained using an electrospray ionisation source in either the positive (ES+) or negative (ES ) ion modes, Method B. Waters Xterra MS C 18, 5μm (4.6 x 50mm, flow rate 1.5mL/min) eluting with a H2O-MeCN gradient containing 0.1% v/v ammonia over 12min with UV detection at 215 and 254nm. Gradient information: 0.0 - 8.0mm: Ramp from 95% H2O-5% MeCN to 5% H2O- 95% MeCN; 8.0 - 9.9min: Hold at 5% H2O-95% MeCN; 9.9 - lO.Omin: Return to 95% H2O-5%
MeCN; 10.0 - 12.0min Hold at 95% H2O-5% MeCN. Mass spectra were obtained using an electrospray ionization source in either the positive (ES+) or negative (ES ) mode.
Abbreviations and acronyms Ac Acetyl; t-Bu: tert-Butyl; Boc: tert-butyloxycarbonyl, DBU: l,8-Diazabicyclo[5.4.0]undec-7-ene; DCM: Dichloromethane; DEAD: Diethyl azodicarboxylate; DIAD- Diisopropyl azodicarboxylate, DIPEA Λ^Λf-Diisopropylethylarmne;
DMF Dimethylformamide, DMSO: Dimethylsulfoxide; EDCI: l-(3-Dimefhylaminopropyl)-3- ethylcarbodiimide hydrochloride; Et: Ethyl; HATU: 0-(7-Azabenzotnazol-l-yl)-N,N,N,N'- tetramethyluronium hexafluorophosphate; HOAt: l-Hydroxy-7-azabenzotriazole; HOBt: 1- Hydroxybenzotriazole; HPLC- High performance liquid chromatography; h- hour(s); IH- Isohexane; ϊPr: Isopropyl; Me: Methyl; mm: minute/s; MP: Macroporous polystyrene; PE-AX column silica based quaternary amine column; Ph: Phenyl, RP-HPLC: Reverse phase-high performance liquid chromatography; RT: Retention time, SCX column: strong cation exchange column (silica bound tosic acid column), THF- Tetrahydrofuran
The syntheses of the following compounds have been described elsewhere: tert-butyl 4- ((iζt^-ethoxycarbonyl-l-methylvinyOpipendine-l-carboxylate: US Patent 6,518,423, tert-butyl
4-(3-hydroxypropyl)piperidine-l-carboxylate. Tetrahedron 1999, 55, 11619-11639, 2-chloro-5- lsopropylpyrimidme: WO03/074495; (+)-(45,l'i?)-2,2-dimethyl-4-(l '-aminoethyl)-l,3- dioxolane: Liebigs Ann./Recueύ, 1997, 1089-1100; 5-ethyl-2-fluoropyndme: US2005/277681; 4-(3-methanesulfonyloxypropyl)piperidine-l-carboxyhc acid tert-butyl ester: WO98/07703, 6- hydroxy-2,4-dimethylnicotinic acid ethyl ester. Tetrahedron 1970, 26, 4641-4648, 6-hydroxy-2- mefhylnicotmic acid ethyl ester Tetrahedron, 1974, 30, 623-32; 3-piperidm-4-yl-propan-l-ol: Tetrahedron 1999, 55, 11619-11639. All other compounds were available from commercial sources Preparation 1: tert-Butyl 4-((£)-2-carboxy-l-methylvinyl)piperidine-l-carboxylate
Figure imgf000016_0001
A solution of tert-butyl 4-((£)-2-ethoxycarbonyl-l -methyl vinyl)piperidme-l- carboxylate (18.7 g, 62.9 inmol) in MeOH (90 mL) and H2O (25 mL) was treated with 2M NaOH (94.5 mL, 189 mmol). The reaction was stirred for 16 h, the MeOH was removed under reduced pressure, then the remainder was partitioned between EtOAc and H2O. The aqueous layer was separated and acidified to pH 2 with 12M HCl, before being extracted with EtOAc (2x) The organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated, then the remainder was recrystallised from EtOAc-IH to provide the title compound: m/z (ES ) = 268.3 [M - H] (Method A).
Preparation 2: tert-Butyl 4-((i?)-2-carboxy-l-methylethyl)piperidine-l -carboxylate
Figure imgf000016_0002
ferf-Butyl 4-((£)-2-carboxy-l -methyl vmyl)pipeπdine-l -carboxylate (Preparation 1, 13O g, 0.483 mol) was placed in a hydrogenation flask under an Ar atmosphere, then degassed
MeOH (400 mL) was added [Rh(norbornadiene)2]BF4 (1.80 g, 4.81 mmol) and (S)-l-[(R)-2-(di- fer?-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine (2.90 g, 5.08 mmol) were placed in a separate Schlenk flask under Ar, before being treated with degassed MeOH (200 mL) This catalyst mixture was stirred for 15 mm at ambient temperature, before being transferred via cannula into the hydrogenation flask. The Schlenk flask was rinsed with more degassed MeOH (100 mL). These washings were transferred to the hydrogenation flask, then more degassed MeOH (300 mL) was added The hydrogenation flask was sealed, the Ar replaced by H2, and the pressure set to 1.05 bar. The reaction mixture was heated to 350C, and stirring/shaking was started. After 48 h, the reaction was stopped and a representative sample of the reaction mixture was analysed by HPLC and 1H NMR. The conversion was 100% and the enantiomeric purity of the crude (i?)-acid was 98 2%, as ascertained by the following HPLC method Column: CHIRALPAK AD-H (previously used with CF3CO2H-contammg solvents) 4.6 x 250 mm, Solvent: C6H14-(PrOH (97:3 isocratic); Temperature: 2O0C; Flow rate: 1 mL/min, UV -detection (210, 230 nm), Sample. 100 μL reaction solution dissolved with 1 mL MeOH. Retention times (S)-acid: 19 3 mm, (i?)-acid: 20 6 mm, starting enoic acid: 22.1 min.
Isolation procedure: The MeOH was evaporated, then the crude hydrogenation product was dissolved in ^-BuOMe and extracted with aqueous NaOH. The aqueous phase was added to a mixture of IM HCl and EtOAc. The aqueous phase was extracted further with EtOAc, then the combined organic extracts were washed with brine and dried (MgSO4). The title compound was isolated following filtration and complete removal of the solvent.
Preparation 3: tort-Butyl 4-((.R)-3 -hydroxy- l-methylpropyl)pipeπdine-l -carboxylate
Figure imgf000017_0001
BH3 THF (IM, 15.7 mL, 15.7 mmol) was added dropwise over 5 min to a stirred solution of tert-butyl 4-((R)-2-carboxy-l-methylethyl)piperidine-l-carboxylate (Preparation 2, 1.70 g, 6 30 mmol) in anhydrous THF at 00C. After 1 h, the reaction was treated with Et2O, then with 2M HCl. The organic layer was washed with brine, before being dried (Na2SO4). Filtration, solvent evaporation, and column chromatography (EtOAc-CH2Cl2, 1:3) provided the title compound. RT = 3.17 min, m/z (ES+) = 258.1 [M + H]+ (Method A).
Preparation 4: 4-[(R)-3-(4-Methanesulfonylphenoxy)-l-methylpropyl]piperidme-l-carboxylic acid tert-butyl ester
Figure imgf000017_0002
DEAD (10.8 mL, 68.4 mmol) was added to a stirred solution of tert-butyl 4-((/?)-3- hydroxy-l-methylpropyl)piperidme-l-carboxylate (Preparation 3, 8.00 g, 31.1 mmol), 4- methanesulfonylphenol (5 63 g, 32 7 mmol) and PPh3 (10 60 g, 40 4 mmol) in anhydrous THF (300 mL) at 00C. After stirring at ambient temperature for 0 5 h, the solvent was removed in vacuo, and the remainder was dissolved in EtOAc to give a solution that was washed with 2M NaOH (2x) and brine. The organic layer was dried (MgSO^, concentrated under reduced pressure and the remainder was triturated with IH-Et2O The solid produced was filtered and washed with Et2O. The combined washings and filtrate were concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc-IH, 3:7) to afford the title compound- RT = 4 09 min; m/z (ES+) = 412 00 [M + H]+ (Method A)
Preparation 5: 4-[(R)-3-(4-Methanesulfonylphenoxy)-l-methylpropyl]piperidine hydrochloride
Figure imgf000017_0003
A mixture of 4-[(R)-3-(4-methanesulfonylphenoxy)-l-methylpropyl]piperidine-l- carboxyhc acid tert-butyl ester (Preparation 4, 15.50 g, 37.7 mmol) and 4M HCl in dioxane (150 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo, azeotropmg with toluene (2x), to afford the title compound: RT = 2 19 min, m/z (ES+) = 311.93 [M + H]+ (Method A).
Preparation 6: 4-[3-(4-Methoxycarbonyl-3-methylphenoxy)propyl]piperidine-l-carboxyhc acid tert-butyl ester
DIAD (8.00 mL, 40.9 mmol) was added to a stirred solution of 4-hydroxy-2-mefhyl- benzoic acid methyl ester (6 00 g, 37 4 mmol), tert-butyl 4-(3-hydroxypropyl)prperidine-l- carboxylate (8.25 g, 34.0 mmol) and PPh3 (10.71 g, 40.9 mmol) in anhydrous THF (60 mL) at ambient temperature After stirring for 7 5 h, the solvent was removed in vacuo, and the remainder was dissolved in EtOAc and washed with 2M NaOH (2x) and brine The organic layer was dried (MgSO4), concentrated under reduced pressure and the remainder was triturated with IH-Et2O. The solid produced was filtered and washed with Et2O. The combined washings and filtrate were concentrated under reduced pressure and purified by column chromatography (EtOAc-IH, 1 9) to afford the title compound: RT = 4.48 min; mlz (ES+) = 392.3 [M + H]+
(Method A)
Preparation 7- 4-[3-(4-Carboxy-3-methylphenoxy)propyl]piperidme-l-carboxylic acid tert- butyl ester
Figure imgf000018_0002
To a solution of 4-[3-(4-methoxycarbonyl-3-methylphenoxy)propyl]piperidme-l- carboxyhc acid tert-butyl ester (Preparation 6, 6.00 g, 15.3 mmol) in MeOH (200 mL) and H2O (20 mL) was added LiOH H2O (6.43 g, 153.3 mmol) and the resulting mixture was stirred at 4O0C for 16 h. The MeOH was evaporated off under reduced pressure, then the remainder was dissolved in H2O (200 mL), washed with EtOAc and acidified to pH 4 with 2M HCl, before being extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to yield the title compound RT = 4.06 min; mlz (ES+) = 378 22 [M + H]+ (Method A).
Preparation 8: 4-{3-[4-(2-Hydroxyethylcarbamoyl)-3-methylphenoxy]propyl}pipeπdine-l- carboxyhc acid
Figure imgf000018_0003
ester
Figure imgf000018_0004
HOBt H2O (77.0 mg, 660 μmol) was added to a stirred solution of 4-[3-(4-carboxy-3- methylphenoxy)propyl]piperidine-l-carboxylic acid tert-butyl ester (Preparation 7, 200 mg, 530 μmol) and EDCI (126 mg, 660 μmol) in THF (10 mL) After 1 h, 2-aminoethanol (64 μL,
1 06 mmol) was added and the resulting mixture was stirred at ambient temperature for 16 h The reaction mixture was diluted with DCM, washed with IM NaOH, dried through a hydrophobic frit and concentrated in vacuo. Purification by column chromatography (EtOAc- IH, 4-1) afforded the title compound- RT = 3 54 min; mlz (ES+) = 421 14 [M + H]+ (Method A)
Preparation 9: N-(2-Hydroxyethyl)-2-methyl-4-(3-piperidin-4-ylpropoxy)benzamide hydrochloride
Figure imgf000019_0001
This compound was prepared from 4-{3-[4-(2-hydroxyethylcarbamoyl)-3-methyl- phenoxy]propyl}piperidine-l-carboxylic acid tert-butyl ester (Preparation 8, 710 mg, 1.69 mmol) using a procedure similar to that outlined m Preparation 5: RT = 2.02 mm; mlz (ES+) : 321.10 [M + H]+ (Method A).
Preparation 10: 2-Methyl-4-(3-pipendin-4-yl-propoxy)benzoic acid hydrochloride
Figure imgf000019_0002
This compound was prepared from 4-[3-(4-carboxy-3-methylphenoxy)propyl]- piperidine-1-carboxylic acid tert-butyl ester (Preparation 7, 126 mg, 340 μmol) using a procedure similar to that outlined in Preparation 5: RT = 2 37 min, mlz (ES+) = 278 17 [M + H]+ (Method A).
Preparation 11 : 4- { 3 - [ 1 -(5 -Chloropyrimidm-2-yl)piperidin-4-yl]propoxy } -2-methylbenzoic acid methyl ester
Figure imgf000019_0003
4M HCl in dioxane (7.7 mL) was added to a stirred solution of 4-[3-(4- methoxycarbonyl-3-methylphenoxy)propyl]piperidme-l-carboxyhc acid terf -butyl ester (Preparation 6, 4.00 g, 10.2 mmol) in dioxane (10 mL) at ambient temperature After 3 h, the mixture was diluted with Et2O and the solid product formed was collected by filtration and washed with Et2O to afford the hydrochloride salt of 2-methyl-4-(3-piperidin-4-ylpropoxy)- benzoic acid methyl ester: RT = 2.65 mm; mlz (ES+) = 292 4 [M + H]+ (Method A) To a stirred solution of this compound (1.27 g, 3.89 mmol) in DMSO (12 mL) was added 2,5-dichloro- pyrimidine (580 mg, 3 89 mmol) and DBU (1 25 mL, 8 54 mmol) and the resulting solution was stirred at 1000C for 16 h. The reaction mixture was diluted with H2O and extracted with EtOAc
(2x), then the combined organic extracts were washed with brine, before being dried (MgSO4). Filtration, removal of solvent under reduced pressure and purification by column chromatography (EtOAc-IH, 1 :19) afforded the title compound: RT = 4.80 min; mlz (ES+) = 404.15 [M + H]+ (Method A).
Preparation 12: 4-{3-[l-(5-Chloropyrimidin-2-yl)piperidin-4-yl]propoxy}-2-methylbenzoic acid
Figure imgf000020_0001
A mixture Of LiOH-H2O (308 mg, 7.33 mmol) and 4-{3-[l-(5-chloropyrimidin-2-yl)- piperidin-4-yl]propoxy}-2-methylbenzoic acid methyl ester (Preparation 11, 1.41 g, 3.49 mmol) in THF (48 mL) and H2O (4.8 niL) was heated at 650C for 96 h. The THF was removed under reduced pressure, then the remainder was partitioned between 2M NaOH and EtOAc. The aqueous phase was acidified to pH 1 with 12M HCl, before being extracted with EtOAc (2x).
The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound: RT = 4.27 min; mlz (ES+) = 390.15 [M + H]+
(Method A).
Preparation 13 : 4- [3 -(5'-Ethyl-3 ,4,5 ,6-tetrahydro-2H-[ 1 ,2']bipyridinyl-4-yl)propoxy] -2-methyl- benzoic acid methyl ester
Figure imgf000020_0002
The title compound was synthesized from 4-[3-(4-methoxycarbonyl-3-methyl- phenoxy)propyl]piperidine-l-carboxylic acid fert-butyl ester (Preparation 6) and 5-ethyl-2- fluoropyridine employing the procedures outlined in Preparation 11: RT = 3.18 min; mlz (ES+) = 397.20 [M + H]+ (Method A).
Preparation 14 : 4- [3 -(5'-Ethyl-3 ,4,5 ,6-tetrahydro-2H-[ 1 ,2']bipyridinyl-4-yl)propoxy] -2- methylbenzoic acid
Figure imgf000020_0003
2M NaOH (18.9 mL, 37.9 mmol) was added to a solution of 4-[3-(5'-ethyl-3,4,5,6- tetrahydro-2H-[l,2']bipyridinyl-4-yl)propoxy]-2-methylbenzoic acid methyl ester (Preparation 13, 1.50 g, 3.79 mmol) in MeOH (30 mL) and the resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was acidified to pH 6 with 2M HCl and concentrated in vacuo to afford the title compound- RT = 2 90 min, mlz (ES+) = 383 18 [M + H]+ (Method A)
Preparation 15: 4-{3-[l-(5-Ethylpyrimidin-2-yl)piperidm-4-yl]propoxy}-2-methylbenzoic acid methyl ester
Figure imgf000021_0001
The title compound was synthesized from 4-[3-(4-methoxycarbonyl-3-methyl- phenoxy)propyl]piperidme-l-carboxylic acid tert-butyl ester (Preparation 6) and 5-ethyl-2- chloropynmidine employing the procedures outlined in Preparation 11: RT = 4.51 mm; mlz (ES+) = 398 83 [M + H]+ (Method A).
Preparation 16: 4-{3-[l-(5-Ethylpyrimidin-2-yl)piperidm-4-yl]propoxy}-2-methylbenzoic acid
Figure imgf000021_0002
A mixture Of LiOH-H2O (63.3 mg, 1 51 mmol) and 4-{3-[l-(5-ethylpyrimidin-2-yl)- piperidin-4-yl]propoxy}-2-methylbenzoic acid methyl ester (Preparation 15, 60.0 mg, 1.51 mmol) in MeOH (2 inL) and H2O (200 μL) was heated at 5O0C for 5 h. The MeOH was removed under reduced pressure, then the remainder was partitioned between H2O and EtOAc The aqueous phase was acidified to pH 4 with 2M HCl, before being extracted with EtOAc (2x). The combined organic extracts were washed with brme, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound. RT = 3.80 min, mlz (ES+) = 384 34 [M + H]+
(Method A)
Preparation 17: 4-[3-(4-Bromo-3,5-dimethylphenoxy)propyl]piperidine-l-carboxylic acid tert- butyl ester
Figure imgf000021_0003
4-Bromo-3,5-dimethylphenol (13.75 g, 68.4 mmol) and K2CO3 (18 9Og, 136.8 mmol) were added to a solution of 4-(3-methanesulfonyloxypropyl)piperidme-l-carboxylic acid tert- butyl ester (21.98 g, 68.4 mmol) in sulfolane (260 mL) and the resulting solution was heated at 85°C for 4 h. The reaction mixture was diluted with Et2O (500 mL) and H2O (500 mL) and the organic layer was washed with H2O (4x), 2M NaOH (2x) and brine, before being dried (MgSO4). Filtration, solvent removal and purification by column chromotagraphy (DCM) furnished the title compound- RT = 4 94 min; mlz (ES+) = 426 20 [M + H]+ (Method A)
Preparation 18: 4-[3-(4-Carboxy-3,5-dimethylphenoxy)propyl]piperidine-l-carboxylic acid tert-buty\ ester
Figure imgf000022_0001
To a solution of 1.6 M n-butyllithium in hexane (20 64 mL, 51 6 mmol) m anhydrous THF (23 mL) at -780C under argon, was added a solution of 4-[3-(4-bromo-3,5-dimethyl- phenoxy)propyl]piperidme- 1 -carboxylic acid fert-butyl ester (Preparation 17, 11 00 g, 25 8 mmol) in anhydrous THF (34 mL). The reaction mixture was stirred at -78°C for 50 min, then
CO2 gas was bubbled through the reaction mixture as it warmed to ambient temperature (-0.5 h) The reaction mixture was quenched with H2O and diluted with EtOAc. The organic layer was extracted with 2M NaOH (2x) and the combined basic extracts were combined with the aqueous layer. The aqueous was acidified to pH 1 with 2M HCl and extracted with EtOAc (3x), then the combined organic extracts were washed with brine and dried (MgSO4). Filtration, solvent removal and purification by column chromatography ((EtOAc-IH, 3.7)) furnished the title compound- RT = 3 93 min; mlz (ES+) = 392 23 [M + H]+ (Method A)
Preparation 19: 2,6-Dimethyl-4-(3-piperidin-4-ylpropoxy)benzoic acid hydrochloride
Figure imgf000022_0002
4M HCl in dioxane (21 95 mL) was added to a stirred solution of 4-[3-(4-carboxy-3,5- dimethylphenoxy)propyl]piperidine-l -carboxylic acid tert-butyl ester (Preparation 18, 4 91 g, 12.5 mmol) in dioxane (20 mL) at ambient temperature. After 2.5 h, the solid product that had formed was collected by filtration and washed with Et2O to afford the title compound: RT =
2.50 min; mlz (ES+) = 291 40 [M + H]+ (Method A).
Preparation 20: 4-{3-[l-(5-Chloropyrimidin-2-yl)piperidm-4-yl]propoxy}-2,6-dimethyl- benzoic acid
Figure imgf000022_0003
To 2,6-dimethyl-4-(3-pipeπdm-4-ylpropoxy)benzoic acid hydrochloride (Preparation 19, 600 mg, 1.83 mmol) in DMSO (850 μL) was added 2,5-dichloropyrimidme (327 mg, 2.20 mmol), DBU (960 μL, 6.41 mmol) and H2O (6 drops). The resulting suspension was heated in a sealed tube in the microwave at 13O0C for 3 h The reaction mixture was diluted with H2O, acidified to pH 5 with 2M HCl and extracted with EtOAc (3x), then the combined organic extracts were washed with brine, before being dried (MgSO,*). Filtration, removal of solvent under reduced pressure and purification by column chromatography (EtOAc-IH, 2 3 to 3:2) afforded the title compound: RT = 4.20 min; mlz (ES+) = 404.16 [M + H]+ (Method A).
The benzoic acids listed in Table 1 were synthesised from 2,6-dimethyl-4-(3-piperidm- 4-ylpropoxy)benzoic acid hydrochloride (Preparation 19) and either 5-chloro-2-fluoropyridme or the appropriate 2-chloropyrimidme employing a procedure similar to that outlined in Preparation 20
=
=
=
=
Figure imgf000023_0001
Preparation 25 : 4- [3 -(5'-Isopropyl-3,4,5 ,6-tetrahydro-2H-[ 1 ,2']bipyridinyl-4-yl)propoxy] -2,6- dimethylbenzoic acid
Figure imgf000023_0002
9? To a solution of 2,6-dimethyl-4-(3-piperidin-4-ylpropoxy)benzoic acid hydrochloride (Preparation 19, 280 mg, 853 μmol) in dioxane (4 inL) was added 2-chloro-5-isopropyl- pyridme (1.59g, 1.02 mmol), bis(dibenzylideneacetone)palladium (78 1 mg, 85.0 μmol), NaOt- Bu (287 mg, 2.99 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-l-phosphabicyclo[3 3.3]undecane (29 2 mg, 85.0 μmol). Argon was bubbled through the reaction mixture for 0.5 h, then the reaction mixture was heated in a sealed tube in the microwave at 115°C for 1 5 h The reaction was diluted with methanol, filtered through celite and concentrated in vacuo The remainder was diluted with H2O, acidified to pH 5 with 2M HCl and extracted with EtOAc (2x) The combined organics were washed with brine, dried (MgSO4), concentrated in vacuo and purified by column chromatography (EtOAc-IH, 3:2) to afford the title compound: RT = 2 98 min; mlz (ES+) = 411.21 [M + H]+ (Method A).
Preparation 26. 4- [3 -(5'-Isopropyl-3,4,5 ,6-tetrahydro-2H-[ 1 ,2']bipyridinyl-4-yl)propoxy] -2- methylbenzoic acid
Figure imgf000024_0001
The title compound was synthesized from 2-methyl-4-(3-pipeπdin-4-ylpropoxy)- benzoic acid hydrochloride (Preparation 10, 100 mg, 320 μmol) employing a procedure similar to that outlined in Preparation 25: RT = 3.05 min; mlz (ES+) = 397.22 [M + H]+ (Method A).
The benzoic acids listed in Table 2 were synthesized from 2-inethyl-4-(3-piperidm-4- ylpropoxy)benzoic acid hydrochloride (Preparation 10), and the appropriate 5-fluoropyridine, 5-chloropyridine or 5-ethylpyrimidine employing a procedure similar to that outlined in Preparation 20.
Table 2
Figure imgf000024_0002
Figure imgf000025_0004
Preparation 30: 4-((R)-3-Methanesulfonyloxy-l-methylpropyl)piperidine-l-carboxylic acid fert-butyl ester
Figure imgf000025_0001
NEt3 (13.0 mL, 93.4 mmol) was added to a stirred solution of terf-butyl 4-((R)-3- hydroxy-l-methylpropyl)piperidme-l-carboxylate (Preparation 3, 20.0 g, 77.9 mmol) and methanesulfonyl chloride (9 80 g, 85 6 mmol) m DCM (200 mL). The reaction mixture was warmed to ambient temperature and stirred for 3 h. Further methanesulfonyl chloride (5.00 g, 43.7 mmol) and NEt3 (6 90 mL, 49.5 mmol) were added and stirring at ambient temperature was continued for 1O h The reaction mixture was partitioned between DCM and H2O, then the organic phase was washed with IM HCl, IM NaOH and brine, dried (MgSO4), filtered and concentrated in vacuo Purification by column chromotography (EtOAc-DCM, I- 19) afforded the title compound: RT = 3 65 min, mlz (ES+) = 336.19 [M + H]+ (Method A)
Preparation 31: 4-[(R)-3-(4-Methoxycarbonyl-3-methylphenoxy)-l-methylpropyl]piperidine-l- carboxyhc acid rerf-butyl ester
Figure imgf000025_0002
The title compound was synthesied from 4-hydroxy-2-methylbenzoic acid methyl ester (8 10 g, 48 7 mmol) and 4-((#)-3-methanesulfonyloxy-l-methylpropyl)piperidine-l-carboxylic acid tert-b\xty\ ester (Preparation 30, 16.3 g, 48.7 mmol) employing a procedure similar to that outlined in Preparation 17. RT = 4 55 min, mlz (ES+) = 406.30 [M + H]+ (Method A)
Preparation 32: 2-Methyl-4-((R)-3-pipeπdm-4-yl-butoxy)benzoic acid hydrochloride
Figure imgf000025_0003
To a solution of 4-[(Λ)-3-(4-methoxycarbonyl-3-methylphenoxy)-l-methylpropyl]- pipeπdine-1-carboxylic acid tert-butyl ester (Preparation 31, 10.0g, 24 7 mmol) in MeOH (100 mL) and H2O (10 mL) was added LiOH-H2O (10 4 g, 246 9 mmol) and the resulting mixture was stirred at 5O0C for 16 h The MeOH was evaporated off under reduced pressure, then the remainder was dissolved in H2O and acidified to pH 1 with IM HCl, before being extracted with DCM (2x). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to yield 4-[(i?)-3-(4-carboxy-3-methylphenoxy)-l-methylpropyl]piperidme-l-carboxylic acid tert-butyl ester RT = 4.10 mm; mlz (ES+) = 392.30 [M + H]+ (Method A). This compound was stirred with 4M HCl in dioxane for 2 h. Removal of the solvent in vacuo afforded the title compound: RT = 2.43 min; mlz (ES+) = 292.18 [M + H]+ (Method A).
Preparation 33 : 4- { (R) -3 - [ 1 -(5 -Chloropyrimidin-2-yl)piperidm-4-yl]butoxy } -2-methylbenzoic acid
Figure imgf000026_0001
The title compound was synthesized from 2-methyl-4-((.R)-3-piperidin-4-ylbutoxy)- benzoic acid hydrochloride (Preparation 32, 500 mg, 1.53 mmol) and 2,5-dichloropyrimidme (270 mg, 1 84 mmol) employing a procedure similar to that outlined in Preparation 20: RT = 4.39 min; mlz (ES+) = 404 14 [M + H]+ (Method A).
Preparation 34: 4-{(i?)-3-[l-(5-Ethylpynmidin-2-yl)piperidin-4-yl]butoxy}-2-methylbenzoic acid
Figure imgf000026_0002
The title compound was synthesized from 2-methyl-4-((.R)-3-piperidin-4-ylbutoxy)- benzoic acid hydrochloride (Preparation 32, 500 mg, 1 53 mmol) and 2-chloro-5-ethyl- pyrimidme (260 mg, 1.84 mmol) employing a procedure similar to that outlined in Preparation
20: RT = 3 92 min; mlz (ES+) = 398 21 [M + H]+ (Method A).
Preparation 35: 5-ferz-Butyl-2-chloropyridine
Figure imgf000026_0003
3,3-Dimethylbutyraldehyde (6.30 mL, 50.0 mmol) was added dropwise over 20 min to a stirring solution of inorpholine (4.00 mL, 46.0 mmol) in anhydrous cyclohexane (40 mL) under argon The resulting solution was heated at 800C for 16 h, before cooling to ambient temperature and adding EtOAc (40 mL), hydroqumone (20.0 mg) and acetic acid (0.3 mL). The reaction mixture was heated to 780C and 2-chloroacrylnitrile (5.54 mL, 69.0 mmol) was added dropwise over 20 min Hetaing at 780C was continued for 1 h, then HCl gas was bubbled through the reaction mixture for 15 min, before cooling to ambient temperature Saturated aqueous NaHCO3 was added to adjust the reaction mixture to pH 8, then the organic phase was separated and the aqueous extracted with EtOAc (2x). The combined organics were washed with brme, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc- IH, 1 -9) afforded the title compound- RT = 3 42 min; mlz (ES+) = 170 06 [M + H]+ (Method A)
Preparation 36: 4-[3-(5'-tert-Butyl-3,4,5,6-tetrahydro-2H-[l,2']bipyndinyl-4-yl)propoxy]-2- methylbenzoic acid
Figure imgf000027_0001
The title compound was synthesized from 2-methyl-4-(3-piperidin-4-ylpropoxy)- benzoic acid hydrochloride (Preparation 10, 400 mg, 1.28 mmol) and 5-terf-butyl-2-chloro- pyridme (Preparation 35, 302 mg, 1 79 mmol) employing a procedure similar to that outlined m Preparation 25: RT = 3.07 nun; mlz (ES+) = 411.16 [M + H]+ (Method A)
Preparation 37. 4- { 3- [ 1 -(5-Isopropylpyrimidin-2-yl)piperidin-4-yl]propoxy } -2-methylbenzoic acid methyl ester
Figure imgf000027_0002
The title compound was synthesized from 4-[3-(4-methoxycarbonyl-3-methyl- phenoxy)propyl]piperidme-l-carboxyhc acid tert-butyl ester (Preparation 6) and 2-chloro-5- isopropylpyrimidme employing the procedures outlined in Preparation 11 RT = 4.44 min; mlz (ES+) = 412 22 [M + H]+ (Method A).
Preparation 38: 4-{3-[l-(5-Isopropylpyrimidm-2-yl)pipendin-4-yl]propoxy}-2-methylbenzoic acid
Figure imgf000027_0003
To a solution of 4-{3-[l-(5-isopropylpyπmidm-2-yl)piperidm-4-yl]propoxy}-2-methyl- benzoic acid methyl ester (Preparation 37, 726 mg, 1.76 mmol) in MeOH (17 inL) and H2O (3 mL) was added NaOH (704 mg, 17 6 mmol) and the resulting mixture was stirred at 5O0C for 16 h. THF (5 mL) was added to the reaction mixture and heating was continued for 72 h The reaction mixture was cooled to ambient temperature, acidified to pH 1 with 2M HCl and extracted with DCM and EtOAc. The combined organic extracts were concentrated in vacuo to yield the title compound- RT = 3 90 min; mlz (ES+) = 398 19 [M + H]+ (Method A) Preparation 39: 4-[(R)-3-(4-Bromo-3,5-dimethylphenoxy)-l-methylpropyl]piperidine-l - carboxylic acid tert-butyl ester
Figure imgf000028_0001
Reaction of 4-bromo-3,5-dimethylphenol with 4-((7?)-3-methanesulfonyloxy-l- methylpropyl)piperidine-l -carboxylic acid tert -butyl ester (Preparation 30) employing a procedure similar to that utilized in Preparation 17 furnished the title compound: RT = 5.40 min; mlz (ES+) = 440 18 [M + H]+ (Method A).
Preparation 40: 4-[(7?)-3-(4-Carboxy-3,5-dimethylphenoxy)-l-methylpropyl]piperidine-l- carboxylic acid tert-butyl ester
Figure imgf000028_0002
Using a procedure similar to that employed in Preparation 18, 4-[(R)-3-(4-bromo-3,5- dimethylphenoxy)-l-methylpropyl]piperidine-l-carboxylic acid tert-butyl ester (Preparation 39) was transformed into the corresponding arylhthium, which was then reacted with CO2 to furnish the title compound: RT = 4.28 min; mlz (ES ) = 404.45 [M - H] (Method A)
Preparation 41: 2,6-Dimethyl-4-((R)-3-piperidm-4-ylbutoxy)benzoic acid hydrochloride
Figure imgf000028_0003
A stirred solution of 4-[(i?)-3-(4-carboxy-3,5-dimethylphenoxy)-l-methylpropyl]- piperidine-1 -carboxylic acid tert-butyl ester (Preparation 40, 200 mg, 0.49 mmol) in CH2Cl2 (3 mL) at O0C was treated with a solution of TFA (2 mL) in CH2Cl2 (3 inL). After 2 h, the reaction mixture was concentrated under reduced pressure, before being stirred with CH2Cl2 (3 mL) and
IM HCl (2 mL) After 1 h, the mixture was concentrated in vacuo to afford the title compound" RT = 2.13 min; mlz (ES+) = 306.15 [M + H]+ (Method A).
Preparation 42: 4-{(R)-3-[l-(5-Chloropyrimidin-2-yl)piperidin-4-yl]butoxy}-2,6-dimethyl- benzoic acid
Figure imgf000029_0001
Reaction of 2,6-dimethyl-4-((R)-3-piperidm-4-ylbutoxy)benzoic acid hydrochloride (Preparation 41) with 2,5-dichloropyrimidme, utilizing a procedure similar to that outlined m Preparation 11, yielded the title compound: RT = 4.24 min; mlz (ES+) = 418 22 [M + H]+ (Method A)
Preparation 43' 6-[(7?)-3-(l-terf-Butoxycarbonylpiperidin-4-yl)butoxy]-2-methylnicotinic acid ethyl ester
Figure imgf000029_0002
DIAD (5.20 mL, 20.6 mmol) was added to a stirred solution of fe?t-butyl 4-((/?)-3- hydroxy-l-methylpropyl)piperidme-l-carboxylate (Preparation 3, 4 56 g, 17 7 mmol), 6- hydroxy-2-methylnicotmic acid ethyl ester (4.44 g, 26.6 mmol) and PPh3 (6.97 g, 26.6 mmol) in anhydrous THF (50 mL) at ambient temperature. After stirring for 30 mm, the solvent was removed in vacuo, and the remainder was dissolved in EtOAc and washed with 2M NaOH (2x) and brine. The organic layer was dried (MgSO4), concentrated under reduced pressure to approximately one fifth of the original volume and IH was added. The solid produced was removed by filtration and the filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc-IH, 3.17) to afford the title compound. RT = 4.75 mm, mlz (ES+) = 421 28 [M + H]+ (Method A).
Preparation 44: 6-[(R)-3-(l-ter?-Butoxycarbonylpiperidin-4-yl) butoxy]-2-methylmcotinic acid
Figure imgf000029_0003
LiOH H2O (3 00 g, 71 4 mmol) was added to a stirred solution of 6-[(R)-3-(l-tert- butoxycarbonylpiperidm-4-yl)butoxy]-2-methylnicotinic acid ethyl ester (Preparation 43, 3 00 g, 7.14 mmol) in MeOH (40 mL) and H2O (4 mL) and the resulting suspension was stirred at 600C for 16 h The solvent was removed in vacuo, then the remainder was dissolved in H2O, acidified to pH 1 with 2M HCl and extracted with DCM (3x). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound: RT = 4 02 min; mlz (ES+) = 393.28 [M + H]+ (Method A). Preparation 45 : 6- { (R) -3 - [ 1 -(5 -Chloropyrimidin-2-yl)piperidm-4-yl]butoxy } -2-methylnicotinic acid
Figure imgf000030_0001
4M HCl in dioxane (100 inL) was added to 6-[(R)-3-(l-fe?t-butoxycarbonyrpiperidin-4- yl)butoxy]-2-methylnicotinic acid (Preparation 44, 2 70 g, 6 89 mmol) and the resulting solution was stored at ambient temperature for 2 h. The resulting solid was collected by filtration and washed with Et 2O to afford the hydrochloride salt of 2-methyl-6-((R)-3-piperidm- 4-ylbutoxy)mcotinic acid. RT = 2 43 min, mlz (ES+) = 292 18 [M + H]+ To a stirred solution of this compound (500 mg, 1 37 mmol) in DMSO (1 inL) was added 2,5-dichloropyrimidine (410 mg, 2.74 mmol) and DBU (814 μL, 5.48 mmol) and the resulting solution was heated at 1000C in a sealed tube in the microwave for 1.5 h. The reaction mixture was diluted with 10% aqueous citric acid and EtOAc, then the organic phase was separated and washed with H2O (3x) and brine (3x), before being dried (MgSOzi). Filtration, removal of solvent under reduced pressure and purification by recrystallisation (EtOAc) afforded the title compound: RT = 4 63 min, mlz (ES+) = 405 12 [M + H]+ (Method A).
Preparation 46: δ-JS-fl-^-Isopropylpyrirrridin^-y^piperidm^-yllpropoxyJ^-methylnicotinic acid ethyl ester
Figure imgf000030_0002
4M HCl in dioxane (10 niL) was added to 6-[(R)-3-(l-ferf-butoxycarbonylpiperidin-4- yl)butoxy]-2-methylnicotmic acid ethyl ester (Preparation 43, 2.00 g, 4.80 mmol) and the resulting solution was stirred at ambient temperature for 4 h The solvent was removed in vacuo to afford the hydrochloride salt of 2-methyl-6-(3-piperidin-4-ylpropoxy)nicotmic acid ethyl ester To a stirred solution of this compound in DMSO (20 mL) was added 2-chloro-5- lsopropyl-pyrimidme (357 mg, 2 29 mmol) and DBU (1.52 g, 11.0 mmol) and the resulting solution was heated at 1000C for 16 h. The solvent was removed in vacuo at 8O0C and the remainder was dissolved in DCM and washed with saturated NaHCO3 solution and brine, before being dried (MgSO^, filtered and concentrated in vacuo. Purification by column chromatography (EtOAc-IH, 1 :4) afforded the title compound: RT = 4 64 min, mlz (ES+) =
427.23 [M + H]+ (Method A).
Preparation 47 : 6- { 3- [ 1 -(5-Isopropylpyrimidin-2-yl)pipendin-4-yl]propoxy } -2-methyl- nicotimc acid
Figure imgf000031_0001
To a solution of 6-{3-[l-(5-isopropylpyrhnidm-2-yl)piperidin-4-yl]propoxy}-2-methyl- nicotinic acid ethyl ester (Preparation 46, 137 mg, 322 μmol) m MeOH (4 2 mL) and H2O (0 8 mL) was added NaOH (133 mg, 3.22 mmol) and the resulting mixture was stirred at 5O0C for 18 h. The reaction mixture was cooled to ambient temperature, acidified to pH 1 with 2M HCl and extracted with DCM and EtOAc. The combined organic extracts were concentrated in vacuo to yield the title compound: RT = 3 54 min; mlz (ES+) = 399 21 [M + H]+ (Method A)
Preparation 48: 6-[3-(l-tert-Butoxycarbonylpiperidin-4-yl)propoxy]-2-methylmcotinic acid ethyl ester
Figure imgf000031_0002
The title compound was synthesized from tert -butyl 4-(3-hydroxypropyl)prperidine-l- carboxylate (5.00 g, 2 05 mmol) and 6-hydroxy-2-methylnicotinic acid ethyl ester (4.47 g, 2.47 mmol) employing a procedure similar to that outlined in Preparation 43 RT = 4.60 min; mlz (ES+) = 407 24 [M + H]+ (Method A).
Preparation 49: 6-[3-(l-tert-Butoxycarbonylpiperidin-4-yl)propoxy]-2-methylmcotinic acid
Figure imgf000031_0003
The title compound was synthesized from 6-[3-(l-terZ-butoxycarbonylpipeπdin-4-yl)- propoxy]-2-methylnicotmic acid ethyl ester (Preparation 48, 7.07 g, 1.74 mmol) employing a procedure similar to that employed in Preparation 44. RT = 3.96 min, mlz (ES+) = 379.16 [M + H]+ (Method A)
Preparation 50 : N-(2-Hydroxy- 1 -hydroxymethylethyl)-2-methyl-6-(3 -piperidin-4-ylpropoxy)- nicotinamide hydrochloride
Figure imgf000031_0004
HOBt H2O (771 mg, 5.71 mmol) was added to a stirred solution of 6-[3-(l-tert- butoxycarbonylpiperidin-4-yl)propoxy]-2-methylnicotinic acid (Preparation 49, 1.80 g, 4.76 mmol), EDCI (1.10 g, 5.71 mmol) and DIPEA (2.50 niL, 14.3 mmol) in THF (50 mL). After 15 min, 2-aminopropane-l,3-diol (650 mg, 7.13 mmol) was added and the resulting mixture was stirred at ambient temperature for 16 h. The THF was removed in vacuo and the residue dissolved in DCM (200 mL) and washed with IM NaOH, H2O and brine, before being dried (MgSO4). Filtration, solvent evaporation, and purification by column chromatography (EtOAc- MeOH, 25: 1) afforded 4-{3-[5-(2-hydroxy-l-hydroxymethylethylcarbamoyl)-6-methylpyridin- 2-yloxy]propyl}piperidine-l-carboxylic acid terf-butyl ester: RT = 3.28 min; mlz (ES+) = 452.29 [M + H]+. To this compound was added 4M HCl in dioxane (2.8 mL) and the resulting solution was stirred at ambient temperature for 2 h. Removal of the solvent in vacuo afforded the title compound: RT = 1.88 min; mlz (ES+) = 352.15 [M + H]+ (Method A).
Preparation 51 : N-((S)-2,3-Dihydroxypropyl)-2-methyl-6-(3-piperidin-4-ylpropoxy)- nicotinamide
Figure imgf000032_0001
The title compound was synthesized from 6-[3-(l-tert-butoxycarbonylpiperidin-4-yl)- propoxy]-2-methylnicotinic acid (Preparation 49, 290 mg, 766 μmol) and (S)-3-amino- propane-l,2-diol (104.7 mg, 1.15 mmol) employing procedures similar to those outlined in Preparation 50: RT = 1.89 min; mlz (ES ) = 350.34 [M - H] (Method A).
Preparation 52: 6-{3-[l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl]propoxy}-2-methylnicotinic acid
Figure imgf000032_0002
4M HCl in dioxane was added to 6-[3-(l-ter?-butoxycarbonylpiperidin-4-yl)propoxy]-2- methylnicotinic acid (Preparation 49, 250 mg, 6.61 mmol) and the resulting solution stirred at ambient temperature for 2 h. Removal of the solvent in vacuo afforded 2-methyl-6-(3-piperidin- 4-ylpropoxy)nicotinic acid hydrochloride. To a solution of this compound in DMSO (5 mL) was added 2-chloro-5-ethylpyrimidine (222 mg, 1.56 mmol) and DBU (750 μL, 4.67 mmol) and the resulting solution was stirred at 7O0C for 72 h and at 1000C for 3 h. The reaction mixture was diluted with MeOH (10 mL) and purified using a PE-AX column (MeOH-DCM, 1: 1) to afford the title compound: RT = 3.66 min; mlz (ES+) = 385.28 [M + H]+ (Method A).
Preparation 53: 6-Fluoro-3-methanesulfonyl-2-methylpyridine
Figure imgf000032_0003
To a solution of 3-bromo-6-fluoro-2-methylpyndine (3 25 g, 17 1 mmol) and TMEDA (3 35 mL, 22 2 mmol) in toluene (200 mL) at -75°C under argon was added 1 6 M n- butyllithium in hexane (12.8 mL, 20.5 mmol) over 10 min, and the mixture stirred for 50 min before dimethyldisulfide (1 84 mL, 20.5 mmol) was added. The reaction was stirred for Ih at 750C then warmed to 20C and quenched with saturated NH4CI solution (40 mL). The organic phase was collected, washed with brine, dried (MgSO4) and the solvent was removed under vacuum to give a residue which was purified by column chromatography (IH-EtOAc, 39:1) to furnish 6-fruoro-2-methyl-3-methylsulfanyrpyridme. To a solution of this compound (330 mg, 2.10 mmol) in DCM (7 mL) at O0C was added 77% 3-chloroperbenzoic acid (970 mg, 4.30 mmol) over 15 min A further aliquot of DCM (5 mL) was added and the mixture stirred for 1 h
The reaction mixture was diluted with DCM (25 mL), washed with Na2Cθ3 (15 mL) and the organic phase was collected through a hydrophobic frit. The solvent was removed under vacuum to furnish the title compound. RT = 2.13 min, mlz (ES+) = 189.89 [M + H]+ (Method A).
Preparation 54: 3-Methanesulfonyl-2-methyl-6-(3-piperidin-4-ylpropoxy)pyndme hydrochloride
Figure imgf000033_0001
NaH (197 mg, 4.93 mmol) was added portionwise to a solution of terf-butyl 4-(3- hydroxypropyl)piperidme-l-carboxylate (1.00 g, 4.11 mmol) in THF (10 mL) and the resulting reaction mixture stirred at ambient temperature for 1 h 6-Fluoro-3-methanesulfonyl-2- methylpyridme (Preparation 53, 778 mg, 4.11 mmol) was added to the reaction mixture and the resulting solution stirred at 7O0C for 2.5 h before quenching with H2O The reaction mixture was extracted with EtOAc (3 X 100 mL) and the combined organic extracts washed with brine, dried (MgSO4), filtered and concentrated in vacuo Purification by column chromatography (IH- EtOAc, 3:7) afforded 4-[3-(5-methanesulfonyl-6-methylpyridin-2-yloxy)propyl]piperidme-l- carboxylic acid tert-butyl ester: RT = 4 17 min, mlz (ES+) = 413.18 [M + H]+. To this compound (740 mg, 1 79 mmol) was added 4M HCl in dioxane (10 mL) and the resulting solution stirred at ambient temperature for 2 h. The solvent was removed in vacuo to afford the title compound RT = 2.21 mm; mlz (ES+) = 313.23 [M + H]+ (Method A).
Preparation 55 : 3- [ 1 -(5-Chloropyrimidin-2-yl)piperidin-4-yl]propan- 1 -ol
Figure imgf000033_0002
A stirred solution of 3-piperidin-4-ylpropan-l-ol hydrochloride (15.0 g, 84 mmol) in DMSO (120 mL) was cooled to O0C, before being treated dropwise with DBU (30.0 mL, 201 mmol) over 5 min. 2,5-Dichloropyrimidine (17.4 g, 117 mmol) was added portionwise, then the reaction was heated to 1100C for 4 h After cooling to 2O0C, the reaction was poured into H2O (200 mL) and extracted with EtOAc (3 x 500 mL) The combined organic extracts were washed with IM HCl (2 x 200 mL), before being dried (MgSO4) and concentrated. The residue was purified by column chromatography (EtOAc-IH, 4.6) to provide the title compound 1H NMR (CDCl3) δ \ 10-1.23 (m, 2H), 1.30-1.38 (m, 2H), 1.48-1.57 (m, IH), 1.58-1.66 (m, 2H), 1.78 (d, 2H), 2 86 (m, 2H), 3 66 (t, 2H), 4 67 (d, 2H), 8 20 (s, 2H)
Preparation 56 : 6- { 3- [ 1 -(5-Chloropyrimidin-2-yl)piperidin-4-yl]propoxy } -2-methylnicotinic acid ethyl ester
Figure imgf000034_0001
DIAD (2.88 mL, 14.7 mmol) was added dropwise over 10 min to a stirred solution of 3- [l-(5-chloropyrimidin-2-yl)piperidin-4-yl]propan-l-ol (Preparation 55, 2.50 g, 9 8 mmol), 6- hydroxy -2-methylnicotinic acid ethyl ester (1 95 g, 10 8 mmol), and PPh3 (3 85 g, 14 7 mmol) m anhydrous THF (40 mL). After 16 h, the THF was removed under reduced pressure, then the residue was partitioned between EtOAc (200 mL) and IM NaOH (100 mL). The organic layer was washed with brine, before being dried (MgSO4), filtered and concentrated. The remainder was triturated with EtOAc-IH, then the filtrate was collected and purified by flash chromatography (EtOAc-IH, 1 :9) to furnish the title compound: mlz (ES+) = 419.16 [M -I- H]+ (Method A)
Preparation 57 : 6- { 3- [ 1 -(5-Chloropyrimidin-2-yl)piperidin-4-yl]propoxy } -2-methylnicotinic acid
Figure imgf000034_0002
6-{3-[l-(5-Chloropyrimidin-2-yl)piperidm-4-yl]propoxy }-2-methylnicotimc acid ethyl ester (Preparation 56, 2.65 g, 6.33 mmol) was saponified, using a procedure similar to that outlined in Preparation 44, to furnish the title compound mlz (ES+) = 391.13 [M + H]+ (Method A)
Preparation 58: 6-{3-[l-(5-Chloropyrimidin-2-yl)piperidin-4-yl]propoxy}-2,4-dimethyl- nicotinic acid ethyl ester
Figure imgf000034_0003
3-[l-(5-Chloropyrimidin-2-yl)piperidm-4-yl]propan-l-ol (Preparation 55, 1 55 g, 6 05 mmol) was condensed with 6-hydroxy-2,4-dimethylmcotinic acid ethyl ester (1.30 g, 6.66 mmol), employing a protocol similar to that outlined in Preparation 56, to furnish the title compound: mlz (ES+) = 433.17 [M + H]+ (Method A). Preparation 59' 6-{3-[l-(5-Chloropyriimdin-2-yl)piperidin-4-yl]propoxy}-2,4-dimethyl- nicotinic acid
Figure imgf000035_0001
6- { 3 -[ 1 -(5 -Chloropyrimidin-2-yl)piperidm-4-yl]propoxy } -2,4-dimethylnicotinic acid ethyl ester (Preparation 58, 0.50 g, 1.15 mmol) was saponified, using a procedure similar to that outlined in Preparation 44, to furnish the title compound mlz (ES+) = 405.15 [M + H]+ (Method A)
Examples
The Examples in Table 3 were synthesised using the following general procedure: To a solution of 4-[(R)-3-(4-methanesulfonylphenoxy)-l-methyrpropyl]piperidine hydrochloride (Preparation 5, 50.0 mg, 160 μmol) in DMSO (1 inL) was added DBU (36.0 μL, 240 μmol) and the appropriate aryl hahde (240 μmol) The reaction mixture was heated overnight at 1000C then loaded on to an SCX cartridge (2 g). The SCX cartridge was washed with MeOH, then the product was eluted with 1% NH3 in MeOH. Evaporation of the solvent afforded the crude product that was purified using one or more of the following purification methods:
Method 1 : Products were triturated with Et2O then filtered
Method 2: Products were purified by column chromotography (DCM-MeOH, 98 2).
Method 3" Products were dissolved in MeOH and shaken with MP-Isocyanate at ambient temperature for 1 h. Purified products were obtained upon filtration and evaporation of the solvent
Table 3
Figure imgf000035_0002
= B)
= B)
= B)
= B)
= B)
= B)
= B)
= B)
Figure imgf000036_0001
Figure imgf000037_0001
Example 18: 4- { 3- [ 1 -(5-Chloropyrimidin-2-yl)piperidin-4-yl]propoxy } -N-(2-hydroxyethyl)-2- methylbenzamide
Figure imgf000038_0001
HOBt H2O (50 0 mg, 370 μmol) was added to a stirred solution of 4-{3-[l-(5-chloro- pyrimidin-2-yl)pipendin-4-yl]propoxy}-2-methylbenzoic acid (Preparation 12, 110 mg, 283 μmol) and EDCI (70 5 mg, 370 μmol) in THF (7 inL). After 20 min, 2-aminoethanol (68 μL, 1.13 mmol) was added and the resulting mixture was heated at 4O0C for 16 h. The THF was removed in vacuo and the residue partitioned between EtOAc and 2M NaOH. The organic phase was separated and washed with 2M NaOH, IM HCl and brine, before being dried (MgSO4) Filtration, solvent evaporation, and purification by column chromatography (EtOAc) afforded the title compound: RT = 3 79 min, mlz (ES+) = 433.24 [M + U]+ (Method A)
The amides listed in Table 4 were synthesised by condensing the appropriate acid with the appropriate amine, employing a procedure similar to that outlined in Example 18.
=
:
:
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0002
Example 71 : N-((i?)-2-Hydroxy- 1 -methylethyl)-4- { 3- [ 1 -(5-isopropyrpyrimidin-2-yl)piperidin- 4-yl]propoxy}-2,6-dimethylbenzamide
Figure imgf000047_0001
HOAt (70.0 mg, 504 μmol) was added to a stirred solution of 4-{3-[l-(5-isopropyl- pyrimidin-2-yl)pipendin-4-yl]propoxy}-2,6-dimethylbenzoic acid (Preparation 22, 150 mg, 360 μmol), EDCI (70.5 mg, 370 μmol) and NEt3 (150 μL, 1.08 mmol) in THF (5 mL). After 20 min, (R)-2-aminopropan-l-ol (85.0 μL, 1.08 mmol) was added and the resulting mixture was heated at 550C for 19 h. The THF was removed in vacuo and the residue partitioned between EtOAc and 2M NaOH. The organic phase was separated and washed with 2M NaOH, IM HCl and brine, before being dried (MgSO/t). Filtration, solvent evaporation, and trituration with EtOAc afforded the title compound: RT = 3.48 min; mlz (ES+) = 469.22 [M + H]+ (Method A).
The amides listed in Table 5 were synthesised by condensing the appropriate acid with the appropriate amine, employing a procedure similar to that outlined in Example 71.
Table 5
Figure imgf000047_0003
Figure imgf000048_0002
Example 75 : N-(2- Aminoethyl)-4- { 3 - [ 1 -(5 -chloropyrimidm-2-yl)pipendin-4-yl]propoxy } -2- methylbenzamide
Figure imgf000048_0001
HOBt H2O (100 mg, 735 μmol) was added to a stirred solution of 4-{3-[l-(5-chloro- pyrimidin-2-yl)pipendin-4-yl]propoxy}-2-methylbenzoic acid (Preparation 12, 220 mg, 565 μmol) and EDCI (141 mg, 735 μmol) in THF (12 mL) and DMF (600 μL). After 15 mm, (2- aminoethyl)carbamic acid terf-butyl ester (268 μL, 1.694 mmol) was added and the resulting mixture was stirred at ambient temperature for 96 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and 2M NaOH. The organic phase was separated and washed with 2M NaOH, 2M HCl and brme, before being dried (MgSO4). Filtration, solvent evaporation, and purification by column chromatography (EtOAc-IH, 1 1 to 1 0) afforded [2-(4- { 3-[ 1 -(5-chloropyrimidin-2-yl)piperidin-4-yl]propoxy } -2-methylbenzoylamino)ethyl]carbamic acid tert-butyl ester RT = 4.26 mm; mlz (ES+) = 532.32 [M + H]+. To a stirred suspension of this compound in dioxane (7 mL) was added 4M HCl in dioxane (1.75 mL, 7.0 mmol) and the resulting solution was stirred at ambient temperature for 3 h The solvent was removed in vacuo and the remainder was dissolved EtOAc and 2M HCl The acidic layer was basified to pH 10 with 2M NaOH and extracted with EtOAc (3x). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound: RT = 3.13 mm; mlz (ES+) = 432 21 [M + H]+ (Method A).
The amino-containmg amides listed in Table 6 were synthesised by condensing the appropriate acid with the appropriate Boc-amino-containing amine, followed by Boc deprotection, employing procedures similar to those outlined in Example 75.
Table 6
Figure imgf000048_0003
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
=
=
=
Figure imgf000055_0001
Examples 110 and 111: N-((^)-3-Amino-2-hydroxypropyl)-4-{3-[l-(5-chloropyrimidin-2-yl)- piperidin-4-yl]propoxy}-2,6-dimethylbenzamide and N-((S)-3-Amino-2-hydroxypropyl)-4-{3- [l-(5-chloropyrimidin-2-yl)piperidin-4-yl]propoxy}-2,6-dimethylbenzamide
Figure imgf000055_0002
To a solution of 4-{3-[l-(5-chloropynmidin-2-yl)piperidin-4-yl]propoxy}-2,6- dimethylbenzoic acid (Preparation 20, 602 mg, 1 49 mmol) and (3-amino-2- hydroxypropyl)carbamic acid tert-butyl ester (425 mg, 2 23 mmol) in DMF (15 inL) was added HOBt (245 mg, 1 60 mmol), DIPEA (0 57 mL, 3 27 mmol) and EDCI (350 mg, 1 83 mmol) After stirring at 500C for 18 h, the reaction mixture was partitioned between EtOAc (50 mL) and water/brine (150 mL, 1: 1). The layers were separated and the aqueous phase extracted with EtOAc (3 x 50 mL), then the combined organics were washed with IM HCl (50 mL), IM NaOH (50 mL) and brine (50 mL). The organic phase was dried (MgSO4), filtered and concentrated to a residue which was purified by column chromatography (IH:EtOAc, 1:4) to give [3-(4-{3-[l- (5-chloropyrimidin-2-yl)piperidin-4-yl]propoxy}-2,6-dimethylbenzoylamino)-2-hydroxy- propyl] carbamic acid tert-butyl ester as a racemic mixture: RT = 4.40 min; mlz (ES+) = 576.31 [M + H]+ (Method A). The individual enantiomers of this compound were separated by preparative chiral HPLC using a Daicel Chiralpak IA column (250 x 20mm, 5μm), with an eluent of MeCN//PrOH (9:1), at a flow rate of 13 mL/min, and UV detection at 250 nm. To a solution of enantiomer 1 (RT = 16.17 min, Daicel Chiralpak IA, 308 mg, 0.535 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL) and the solution was stirred at ambient temperature for 3 h. The solvent was removed and the residue was partitioned between EtOAc (200 mL) and IM
NaOH (100 mL). The layers were separated and the aqueous phase extracted with EtOAc (2 x 50 mL), then the combined organics were washed with brine (100 mL) and dried (MgSO4). Filtration and removal of the solvent in vacuo provided the free amine, which was redissolved in MeOH (100 mL) and IM HCl (5 mL). Concentration followed by several co-evaporations with MeOH afforded one of the title compounds as its hydrochloride salt: RT = 2.92 min; mlz (ES+) =
476.21 [M + H]+ (Method A). Deprotection of the other enantiomeric Boc -protected intermediate under similar conditions afforded the enantiomeric title compound, which displayed spectroscopic data identical to that described above.
The amides listed in Table 7 were obtained in enantiomerically pure form employing procedures similar to that outlined for Examples 110 and 111, with the exception that the individual enantiomers of the Boc-protected intermediates were separated by preparative chiral HPLC using a Daicel Chiralpak IA column (250 x 20mm, 5μm), with an eluent of IHAPrOH (7:3) at a flow rate of 15 mL/min, and UV detection at 250 nm.
Table 7
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
=
:
Figure imgf000060_0001
Example 128: 4-[3-(5'-Chloro-3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-4-yl)propoxy]-N-(2- hydroxyethyl)-2-methylbenzamide
Figure imgf000061_0001
HATU (82.0 m , 220 μmol) was added to a stirr ted sxolution of 4-[3-(5'-chloro- 3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-4-yl)propoxy]-2-methylbenzoic acid (Preparation 27, 118 mg, 180 μmol), ethanolamine (22.0 μL, 360 μmol) and DIPEA (63.0 μL, 360 μL) in THF (7 mL), and the resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DCM (150 mL), washed with H2O, saturated aqueous NaHCO3 solution, dried (MgSO4), filtered and concentrated in vacuo. Purification by RP-HPLC afforded the title compound: RT = 3.40 min; mlz (ES+) = 432.25 [M + H]+ (Method A).
The amides listed in Table 8 were synthesised by condensing the appropriate acid with the appropriate amine, employing a procedure similar to that outlined in Example 128.
=
=
:
:
Figure imgf000061_0002
Figure imgf000062_0002
Example 137: N-(2-Hydroxyethyl)-4-[3-(5'-isopropyl-3,4,5,6-tetrahydro-2H-[l ,2']bipyridinyl-4- yl)propoxy] -2-methylbenzamide
Figure imgf000062_0001
2-Chloro-5-isopropy pyridine (65.0 mg, 420 μmol) w tas added to a stirred solution of N- (2-hydroxyethyl)-2-methyl-4-(3-piperidin-4-ylpropoxy)benzamide hydrochloride (Preparation 9, 100 mg, 280 μmol) and DBU (63.0 μL, 420 μmol) in DMSO (0.5 mL). The reaction mixture was heated at 1250C for 60 h, before being poured into H2O (50 mL) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc) afforded the title compound: RT = 2.73 min; mlz (ES+) = 440.28 [M + H]+ (Method A).
The compounds listed in Table 9 were synthesized from N-(2-hydroxyefhyl)-2-methyl- 4-(3-piperidin-4-ylpropoxy)benzamide hydrochloride (Preparation 9) and 2,5-difluoropyridine or 3,6-dichloropyridazine, employing a procedure similar to that outlined in Example 137.
Table 9
Figure imgf000063_0003
Example 14O- N-(2-Hydroxyethyl)-4-{3-[l-(6-isopropoxypyπdazin-3-yl)piperidin-4-yl]- propoxy } -2-methylbenzamide
Figure imgf000063_0001
To a solution of N-(2-hydroxyethyl)-2-methyl-4-(3-piperidin-4-ylpropoxy)benzamide hydrochloride (Preparation 9, 50.0 mg, 140 μmol) in dioxane (1 5 mL) was added 3-chloro-6- lsopropoxypyridazine (36 0 mg, 210 μmol), NaOt-Bu (27 0 mg, 280 μmol) and 2,8,9- triisobutyl^^.S^-tetraaza-l-phosphabicyclop.SJJundecane (5.0 mg, 14.0 μmol). Argon was bubbled through the reaction mixture for 20 min, then palladium acetate (11.0 mg, 49.0 μmol) was added. Argon was bubbled through the reaction mixture for 10 min, then the reaction mixture was heated in a sealed tube in the microwave at 1200C for 2 h The reaction mixture was diluted with methanol, filtered through celite and concentrated in vacuo Purification by column chromatography (EtOAc) afforded the title compound: RT = 2.67 min; mlz (ES+) = 457.28 [M + H]+ (Method A).
Example 141 : 4-{ 3-[ 1 -(5-Fluoropyrimidin-2-yl)pipendm-4-yl]propoxy } -N-(2-hydroxyethyl)-2- methylbenzamide
Figure imgf000063_0002
To a solution of N-(2-hydroxyethyl)-2-methyl-4-(3-piperidin-4-ylpropoxy)benzamide hydrochloride (Preparation 9, 68.0 mg, 191 μmol) in toluene (1.5 mL) was added 2-chloro-5- fluoropyrimidme (27 8 mg, 210 μmol), NaOt-Bu (45 9 mg, 478 μmol) and 2,8,9-triisobutyl- 2,5,8,9-tetraaza-l-phosphabicyclo[3.3 3]undecane (7.0 mg, 19.1 μmol). Argon was bubbled through the reaction mixture for 15 min, then bis(dibenzlideneacetone)palladium (17.5 mg, 19.1 μmol) was added Argon was bubbled through the reaction mixture for 15 min, then the reaction mixture was heated in a sealed tube in the microwave at 10O0C for 1 h. The reaction mixture was diluted with methanol, filtered through celite and concentrated in vacuo The remainder was dissolved in EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated in vacuo. Purification by RP-HPLC afforded the title compound: RT = 3.53 min; mlz (ES+) = 417.20 [M + H]+ (Method A).
Example 142: 4-{3-[l-(5-Chloropyrimidin-2-yl)pipendin-4-yl]propoxy}-N-((li?,2S)-2,3- dihydroxy-l-methylpropyl)-2,6-dimethylbenzamide
Figure imgf000064_0001
To a solution of 4-{3-[l-(5-chloropynmidin-2-yl)piperidin-4-yl]propoxy}-2,6- dimethylbenzoic acid (Preparation 20, 168 mg, 0 416 mmol) and (+)-(4S,17?)-2,2-dimethyl-4- (l'-ammoethyl)-l,3-dioxolane (70 mg, 0.484 mmol) in DMF (10 inL) was added HOBt (65 mg, 0.424 mmol), DIPEA (0.16 mL, 0.92 mmol) and EDCI (98 mg, 0 511 mmol). After stirring at 5O0C for 18 h, the reaction mixture was partitioned between EtOAc (50 mL) and water/brme
(150 mL, 1: 1). The layers were separated and the aqueous phase extracted with EtOAc (3 x 50 mL), then the combined organics were washed with IM NaOH solution (50 mL) and brine (50 mL) The organic phase was dried (MgSO4), filtered and concentrated to a residue before being redissolved in IM HCl solution (in MeOH, 50 mL) After removal of the solvent in vacuo the crude material was purified by column chromatography (DCM-MeOH, 10 1) to give the title compound: RT = 3.82 min; mlz (ES+) = 491.18 [M + H]+ (Method A).
Example 143: 6-{(R)-3-[l-(5-Chloropyrimidin-2-yl)piperidm-4-yl]butoxy}-N-((S)-2,3- dihydroxypropyl)-2-methylnicotinamide
Figure imgf000064_0002
HATU (113 mg, 298 μmol) was added to a stirred solution of 6-{(i?)-3-[l-(5-chloro- pyrimidin-2-yl)pipendin-4-yl]butoxy}-2-methylnicotmic acid (Preparation 45, 100 mg, 248 μmol), (5)-3-aminoρroρane-l,2-diol (34 0 mg, 372 μmol) and DIPEA (65.0 μL, 372 μL) in THF (7 mL), and the resulting solution was stirred at ambient temperature for 72 h The reaction mixture was diluted with EtOAc and washed with 10% aqeous citric acid, H2O (3x) and brine, dried (MgSO4), filtered and concentrated in vacuo Purification by recrystallisation (EtOAc) afforded the title compound. SR (CDCl3) 0.94 (d, 3H), 1.20-1.40 (m, 2H), 1.48-1.67 (m, 3H), 1 68-1 78 (m, 2H), 1 85-1 98 (m, IH), 2 61 (s, 3H), 2 75-2 98 (m, 4H), 3 52-3 72 (m, 4H), 3.84-3.94 (m, IH), 4.30-4.45 (m, 2H), 4.70-4.80 (m, 2H), 6.17-6 28 (m, IH), 6 54 (d, IH), 7.62 (d, IH), 8 21 (s, 2H); RT = 3.61 min; mlz (ES+) = 478.15 [M + H]+ (Method A). Example 144- 6-{(i?)-3-[l-(5-Chloropyrimidin-2-yl)piperidm-4-yl]butoxy}-N-(2-hydroxy-l- hydroxymethylethyl)-2-methylnicotmamide
Figure imgf000065_0001
The title compound was synthesized from 6- { (/?)-3-[ 1 -(5-chloropyrimidin-2-yl)- piperidin-4-yl]butoxy}-2-methylnicotinic acid (Preparation 45, 100 mg, 248 μmol) and 2- aminopropane-l,3-diol (34 mg, 372 μmol) emplying a procedure similar to that outlined in Example 143: RT = 3.51 mm; mlz (ES+) = 478.14 [M + H]+ (Method A).
Example 145: N-((R)-2-Hydroxy-l-methylethyl)-6-{3-[l-(5-isopropylpyπinidin-2-yl)piperidin-
4-yl]propoxy } -2-methylnicotinamide
Figure imgf000065_0002
HOBt H2O (36.0 mg, 270 μmol) was added to a stirred solution of 6-{3-[l-(5-isopropyl- pyrimidin-2-yl)pipendin-4-yl]propoxy}-2-methylnicotinic acid (Preparation 47, 100 mg, 250 μmol) and EDCI (51 5 mg, 270 μmol) in THF (7 mL). After 20 mm, (i?)-2-aminopropan-l-ol
(20 0 mg, 270 μmol) was added and the resulting mixture was stirred at ambient temperature for 16 h The THF was removed in vacuo and the residue partitioned between EtOAc and 2M NaOH The organic phase was separated and washed with 2M NaOH, IM HCl and brine, before being dried (MgSO4). Filtration, solvent evaporation, and purification by recrystallisation afforded the title compound: RT = 3.79 min; mlz (ES+) = 433.24 [M + H]+ (Method A).
Example 146 : N-(2-Hydroxy- 1 -hydroxymethylethyl)-6- { 3 -[ 1 -(5-isopropylpyrimidin-2-yl)- pipeπdin-4-yl] propoxy } -2-methylnicotmamide
Figure imgf000065_0003
The title compound was synthesized from 6-{3-[l-(5-isopropylpyrirmdin-2-yl)- piperidin-4-yl] propoxy }-2-methylnicotmic acid (Preparation 47, 100 mg, 250 μmol) and 2- aminopropane-l,3-diol (25.0 mg, 270 μmol) employing a procedure similar to that outlined in Example 145: RT = 2.98 min; mlz (ES+) = 472.22 [M + H]+ (Method A). Example 147" 6-{ 3-[ 1 -(5-Chloropyrimidin-2-yl)piperidin-4-yl]propoxy } -N-(2-hydroxy-l - hydroxymethylethyl)-2-methylnicotmamide
Figure imgf000066_0001
To a solution of N-(2-hydroxy-l-hydroxymethylethyl)-2-methyl-6-(3-piperidm-4-yl- propoxy)nicotmamide hydrochloride (Preparation 50, 125 mg, 320 μmol) in DMSO (5 mL) was added 2,5-dichloropyrimidine (72.0 mg, 490 μmol) and DBU (119 μL, 800 μmol) and the resulting solution was stirred at 1000C for 16 h The reaction mixture was diluted with EtOAc (100 mL) then washed with H2O and brme, before being dried (MgSO4), filtered and concentrated in vacuo. Purification by recrystallisation (EtOAc) and RP-HPLC afforded the title compound. RT = 3.48 min, m/z (ES+) = 464.16 [M + H]+ (Method A).
Example 148: 6-[3-(5'-Chloro-3,4,5,6-tetrahydro-2H-[l,2']bipyridmyl-4-yl)propoxy]-N-(2- hydroxy- 1 -hydroxymethylethyl)-2-methylnicotinamide
Figure imgf000066_0002
To a solution of N-(2-hydroxy-l-hydroxymethylethyl)-2-methyl-6-(3-prperidin-4-yl- propoxy)nicotmamide hydrochloride (Preparation 50, 125 mg, 320 μmol) in DMSO (5 mL) was added 5-chloro-2-fluoropyridine (70.2 mg, 533 μmol) and DBU (133 μL, 889 μmol) and the resulting solution was stirred at 1000C for 16 h. Further 5-chloro-2-fluoropyndine (93.7 mg,
712 μmol) was added to the reaction mixture and heating at 7O0C was continued for 72 h The reaction mixture was diluted with EtOAc, then washed with H2O and brme, before being dried (MgSO4), filtered and concentrated in vacuo to afford the title compound: RT = 2.90 mm; mlz (ES+) = 463 22 [M + U]+ (Method A).
Example 149: 6-{3-[l-(5-Ethylpyrimidm-2-yl)piperidm-4-yl]propoxy}-2-methylnicotmamide
Figure imgf000066_0003
The title compound was synthesized from 6-{3-[l-(5-ethylpyrimidin-2-yl)piperidin-4- yl]propoxy}-2-methylnicotmic acid (Preparation 52, 240 mg, 624 μmol) and 0 5M NH3 in dioxane (6.24 mL, 3.12 mmol) employing a procedure similar to that outlined m Example 145 RT = 3.11 min; m/z (ES+) = 384.21 [M + H]+ (Method A).
The amides listed in Table 10 were synthesised by condensing the appropriate acid with the appropriate amine, employing procedures similar to those outlined in Examples 145 and 149.
Table 10
Figure imgf000067_0001
Figure imgf000068_0001
The amino-containmg amides listed m Table 11 were synthesised by a two-step process (i) 6-{3-[l-(5-chloropyrimidin-2-yl)pipendm-4-yl]propoxy}-2,4-dimethylnicotinic acid (Preparation 59) was condensed with the appropriate Boc-amino-containmg amine, employing procedures similar to that outlined in Example 145, (ii) the Boc group was removed with 4M HCl in dioxane, utilizing a protocol similar to that outlined in Preparation 50. Table 11
Figure imgf000069_0003
Example 160: N-((5)-2,3-Dihydroxypropyl)-6-{3-[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]- propoxy } -2-methylnicotinamide
Figure imgf000069_0001
The title compound was synthesized from N-((5)-2,3-dihydroxypropyl)-2-methyl-6-(3- piperidin-4-ylpropoxy)nicotinamide (Preparation 51, 341 mg, 881 μmol) and 2-chloro-5- ethylpyrimidine (189 mg, 1.32 mmol) employing a procedure similar to that outlined in Example 147: RT = 3.08 min; mlz (ES+) = 458.38 [M + H]+ (Method A).
Example 161: 5'-Fluoro-4-[3-(5-methanesulfonyl-6-methylpyridin-2-yloxy)propyl]-3,4,5,6- tetrahydro-2H-[ 1 ,2']bipyridinyl
Figure imgf000069_0002
2,5-Difluoropyridine (65.0 mg, 490 μmol) and DBU (72.0 μL, 490 μmol) were added to a solution of 3-methanesulfonyl-2-methyl-6-(3-piperidin-4-yl-propoxy)pyridine hydrochloride (Preparation 54, 125 mg, 330 μmol) m DMSO (500 μL) and the resulting solution stirred at 500C for 72 h. The reaction mixture was poured into H2O (50 mL), extracted with EtOAc (2 X 75 mL) and the combined organic extracts washed with brine, dried (MgS O4), filtered and concentrated in vacuo Purification by column chromatography (IH-EtOAc; Tl) afforded the title compound: RT = 3.67 mm; mlz (ES+) = 408.11[M + H]+ (Method A).
Example 162: 5-Fluoro-2-{4-[3-(5-methanesulfonyl-6-methylpyridin-2-yloxy)propyl]piperidin- l-yl}pyrimidine
Figure imgf000070_0001
The title compound was synthesized from 3-methanesulfonyl-2-methyl-6-(3-piperidin- 4-ylpropoxypyridine hydrochloride (Preparation 54, 125 mg, 330 μmol) and 2-chloro-5- fluoropyrimidme (65 0 mg, 490 mmol) employing a procedure similar to that outlined in Example 161: RT = 4.24 mm; mlz (ES+) = 409.12 [M + H]+ (Method A).
The following compound may be prepared by methods analogous to those described above:
2-{4-[(/?)-3-(4-Methanesulfonylphenoxy)-l-mefhylpropyl]piperidin-l-yl}-5- trifluoromethylpyrimidine
Figure imgf000070_0002
The biological activity of the compounds of the invention may be tested in the following assay systems-
Yeast Reporter Assay
The yeast cell-based reporter assays have previously been described in the literature (e.g. see Miret J. J. et al, 2002, J. Biol. Chem., 277:6881-6887, Campbell R.M. et al, 1999, Bioorg. Med. Chem. Lett., 9:2413-2418; King K. et al, 1990, Science, 250: 121-123); WO 99/14344; WO 00/12704, and US 6,100,042). Briefly, yeast cells have been engineered such that the endogenous yeast G-alpha (GPAl) has been deleted and replaced with G-protein chimeras constructed using multiple techniques. Additionally, the endogenous yeast GPCR, Ste3 has been deleted to allow for heterologous expression of a mammalian GPCR of choice In the yeast, elements of the pheromone signaling transduction pathway, which are conserved in eukaryotic cells (for example, the mitogen-activated protein kinase pathway), drive the expression of Fusl. By placing β-galactosidase (LacZ) under the control of the Fusl promoter (Fuslp), a system has been developed whereby receptor activation leads to an enzymatic readout
Yeast cells were transformed by an adaptation of the lithium acetate method described by Agatep et al, (Agatep, R. et al, 1998, Transformation of Saccharomyces cerevisiae by the lithium acetate/single-stranded carrier DNA/polyethylene glycol (LiAc/ss-DNA/PEG) protocol.
Technical Tips Online, Trends Journals, Elsevier) Briefly, yeast cells were grown overnight on yeast tryptone plates (YT) Carrier smgle-stranded DNA (lOμg), 2μg of each of two Fuslp- LacZ reporter plasmids (one with URA selection marker and one with TRP), 2μg of GPRl 19 (human or mouse receptor) in yeast expression vector (2μg origin of replication) and a lithium acetate/ polyethylene glycol/ TE buffer was pipetted into an Eppendorf tube The yeast expression plasrmd containing the receptor/ no receptor control has a LEU marker. Yeast cells were inoculated into this mixture and the reaction proceeds at 300C for 60min. The yeast cells were then heat-shocked at 420C for 15min The cells were then washed and spread on selection plates The selection plates are synthetic defined yeast media minus LEU, URA and TRP (SD- LUT). After incubating at 300C for 2-3 days, colonies that grow on the selection plates were then tested in the LacZ assay.
In order to perform fluorimetric enzyme assays for β-galactosidase, yeast cells carrying the human or mouse GPRl 19 receptor were grown overnight in liquid SD-LUT medium to an unsaturated concentration (i.e. the cells were still dividing and had not yet reached stationary phase) They were diluted m fresh medium to an optimal assay concentration and 90μl of yeast cells added to 96-well black polystyrene plates (Costar) Compounds, dissolved in DMSO and diluted in a 10% DMSO solution to 1OX concentration, were added to the plates and the plates placed at 300C for 4h. After 4h, the substrate for the β-galactosidase was added to each well In these experiments, Fluorescein di (β-D-galactopyranoside) was used (FDG), a substrate for the enzyme that releases fluorescein, allowing a fluorimetric read-out 20μl per well of 500μM
FDG/2.5% Triton XlOO was added (the detergent was necessary to render the cells permeable). After incubation of the cells with the substrate for 60min, 20μl per well of IM sodium carbonate was added to terminate the reaction and enhance the fluorescent signal. The plates were then read in a fluoπmeter at 485/535nm The compounds of the invention give an increase in fluorescent signal of at least ~ 1.5- fold that of the background signal (i e. the signal obtained in the presence of 1% DMSO without compound). Compounds of the invention which give an increase of at least 5 -fold may be preferred
cAMP Assay
A stable cell line expressing recombinant human GPRl 19 was established and this cell line may be used to investigate the effect of compounds of the invention on intracellular levels of cyclic AMP (cAMP). The cell monolayers are washed with phosphate buffered saline and stimulated at 370C for 30mm with various concentrations of compound in stimulation buffer plus 1 % DMSO. Cells are then lysed and cAMP content determined using the Perkin Elmer
AlphaScreen™ (Amplified Luminescent Proximity Homogeneous Assay) cAMP kit. Buffers and assay conditions are as described in the manufacturer's protocol.
In vivo feeding study The effect of compounds of the invention on body weight and food and water intake may be examined m freely-feeding male Sprague-Dawley rats maintained on reverse-phase lighting Test compounds and reference compounds are dosed by appropriate routes of administration (e.g mtrapentoneally or orally) and measurements made over the following 24 h. Rats are individually housed in polypropylene cages with metal grid floors at a temperature of 21+40C and 55±20% humidity Polypropylene trays with cage pads are placed beneath each cage to detect any food spillage. Animals are maintained on a reverse phase light-dark cycle (lights off for 8 h from 09.30-17.30 h) during which time the room was illuminated by red light Animals have free access to a standard powdered rat diet and tap water during a two week acclimatization period The diet is contained in glass feeding jars with aluminum lids Each lid had a 3-4 cm hole in it to allow access to the food. Animals, feeding jars and water bottles are weighed (to the nearest 0.1 g) at the onset of the dark period. The feeding jars and water bottles are subsequently measured 1 , 2, 4, 6 and 24 h after animals are dosed with a compound of the invention and any significant differences between the treatment groups at baseline compared to vehicle -treated controls.
Anti-diabetic effects of compounds of the invention in an in-vitro model of pancreatic beta cells (HIT-T15)
Cell Culture HIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in RPMI1640 medium supplemented with 10% fetal calf serum and 3OnM sodium selenite All experiments were done with cells at less than passage 70, in accordance with the literature, which describes altered properties of this cell line at passage numbers above 81 (Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships Diabetes 1989 Jan;38(l) 44-8)
cAMP assay
HIT-T15 cells were plated in standard culture medium in 96-well plates at 100,000 cells/ 0 1ml/ well and cultured for 24 hr and the medium was then discarded Cells were incubated for 15min at room temperature with lOOμl stimulation buffer (Hanks buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH 7 4). This was discarded and replaced with compound dilutions over the range 0.001, 0.003, 0 01, 0.03, 0.1, 0.3, 1, 3, 10, 30 μM in stimulation buffer in the presence of 0 5% DMSO Cells were incubated at room temperature for 30min Then 75ul lysis buffer (5mM HEPES, 0.3% Tween-20, 0.1% BSA, pH 7.4) was added per well and the plate was shaken at 900 rpm for 20 min. Particulate matter was removed by centrifugation at 3000rpm for 5min, then the samples were transferred in duplicate to 384-well plates, and processed following the Perkin Elmer AlphaScreen cAMP assay kit instructions Briefly 25μl reactions were set up containing 8μl sample, 5μl acceptor bead mix and 12μl detection mix, such that the concentration of the final reaction components is the same as stated in the kit instructions. Reactions were incubated at room temperature for 150min, and the plate was read using a Packard Fusion instrument. Measurements for cAMP were compared to a standard curve of known cAMP amounts (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000 nM) to convert the readings to absolute cAMP amounts. Data was analysed using XLfit 3 software Representative compounds of the invention were found to increase cAMP at an ECs0 of less than 10 μM Compounds showing an EC50 of less than 1 μM in the cAMP assay may be preferred.
Insulin secretion assay
HIT-T 15 cells were plated in standard culture medium m 12-well plates at 106 cells/ 1 ml/ well and cultured for 3 days and the medium was then discarded. Cells were washed x 2 with supplemented Krebs-Ringer buffer (KRB) containing 119 mM NaCl, 4.74 mM KCl, 2.54 inM CaCl2, 1.19 mM MgSO4, 1.19 mM KH2PO4, 25 mM NaHCO3, 1OmM HEPES at pH 7.4 and 0 1% bovine serum albumin Cells were incubated with ImI KRB at 37°C for 30 min which was then discarded. This was followed by a second incubation with KRB for 30 min, which was collected and used to measure basal insulin secretion levels for each well Compound dilutions (0, 0.1, 0.3, 1, 3, 10 uM) were then added to duplicate wells in ImI KRB, supplemented with 5 6 mM glucose After 30 min incubation at 37°C samples were removed for determination of insulin levels. Measurement of insulin was done using the Mercodia Rat insulin ELISA kit, following the manufacturers instructions, with a standard curve of known insulin concentrations. For each well insulin levels were corrected by subtraction of the basal secretion level from the pre -incubation in the absence of glucose Data was analysed using XLfit 3 software.
Representative compounds of the invention were found to increase insulin secretion at an EC50 of less than 10 μM Compounds showing an EC50 of less than 1 μM in the insulin secretion assay may be preferred
Oral Glucose Tolerance Tests
The effects of compounds of the invention on oral glucose (GIc) tolerance were evaluated in male Sprague-Dawley rats Food was withdrawn 16 h before administration of GIc and remained withdrawn throughout the study. Rats had free access to water during the study A cut was made to the animals' tails, then blood (1 drop) was removed for measurement of basal GIc levels 60 min before administration of the GIc load. Then, the rats were weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl-^-cyclodextrin) 45 min before the removal of an additional blood sample and treatment with the GIc load (2 g kg : p.o ). Blood samples were then taken from the cut tip of the tail 5, 15, 30, 60, 120, and 180 min after GIc administration Blood glucose levels were measured just after collection using a commercially available glucose-meter (OneTouch® UltraTM from Lifescan) Representative compounds of the invention statistically reduced the GIc excursion at doses of <10 mg kg \ The effects of compounds of the invention on oral glucose (GIc) tolerance may also evaluated in male C57B1/6 or male oblob mice Food is withdrawn 5 h before administration of GIc and remained withdrawn throughout the study Mice have free access to water during the study A cut is made to the animals' tails, then blood (20 μL) is removed for measurement of basal GIc levels 45 min before administration of the GIc load Then, the mice are weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl-jS-cyclodextrin or 25% aqueous Gelucire 44/14) 30 min before the removal of an additional blood sample (20 μL) and treatment with the GIc load (2-5 g kg : p.o.). Blood samples (20 μL) are then taken 25, 50, 80, 120, and 180 min after GIc administration. The 20 μL blood samples for measurement of GIc levels are taken from the cut tip of the tail into disposable micro-pipettes (Dade Diagnostics Inc., Puerto Rico) and the sample added to 480 μL of haemolysis reagent. Duplicate 20 μL aliquots of the diluted haemolysed blood are then added to 180 μL of Trinders glucose reagent (Sigma enzymatic (Trinder) colorimetric method) in a 96-well assay plate. After mixing, the samples are left at rt for 30 min before being read against GIc standards (Sigma glucose/urea nitrogen combined standard set).

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000075_0001
(I) wherein Q is CH or N; one of W, X and Y is N or CH and the others are CH where the H may be replaced by R5 when present; R1 is -SO2Me or -CONHR6;
R2, R3 and R4 are independently selected from hydrogen and methyl, n is 0, 1 or 2,
R5 is independently Ci 4 alkyl, CM alkoxy, fluoro, chloro, Ci 3 fluoroalkyl or benzyl; R6 is hydrogen, 3-azetidinyl, 3-pyrrolidinyl, 3-pipendinyl or 4-piperidinyl, wherein the azetidinyl, pyrrolidinyl and piperidinyl rings may be optionally substituted with OH, CH2OH or
CH3, Ci 3 alkyl, C2 4 alkyl substituted by -N(R7)2 and/or one or two hydroxy groups, or Ci^ alkyl substituted by a 4- to 6-membered nitrogen-containing heterocyclic ring; and R7 is independently hydrogen or methyl
2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is CH.
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is N
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein W and X are CH.
5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein W, X and Y are CH.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1 is -SO2Me.
7 A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1 is -CONHR6.
8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein one or both of R2 and R3 are methyl
9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1
10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R5 is meta or para to the point of attachment to the piperidinyl nitrogen
11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R5 is para to the point of attachment to the piperidinyl nitrogen.
12 A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen
13. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R4 is methyl
14. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R4 is methyl and the stereocenter produced has the (R) -configuration
15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5 is Ci 3 alkyl, fluoro, chloro or Ci 3 fluoroalkyl.
16. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen or C2 3 alkyl substituted by -N(R7)2 or one or two hydroxy groups.
17. A compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R6 is 2-hydroxyethyl, 2-hydroxy-l-methylethyl, 2,3-dihydroxypropyl or 2-hydroxy-l- hydroxy me thy lethy 1.
18. A compound of formula (I) as defined in any one of Examples 1 to 162, or a pharmaceutically acceptable salt thereof
19 A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier
20. A method for the treatment of a disease or condition in which GPRl 19 plays a role comprising a step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.
21. A method for the regulation of satiety comprising a step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof
22. A method for the treatment of obesity comprising a step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof
23. A method for the treatment of diabetes comprising a step of administering to a subject m need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof
24. A method for the treatment of metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.
25. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use as a medicament.
26. The use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition as defined in any one of claims 20 to 24.
27. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition as defined in any one of claims 20 to 24.
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