WO2012069948A1 - 4- (5-cyano-pyrazol-1-yl) -piperidine derivatives as gpr 119 modulators - Google Patents

4- (5-cyano-pyrazol-1-yl) -piperidine derivatives as gpr 119 modulators Download PDF

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Publication number
WO2012069948A1
WO2012069948A1 PCT/IB2011/054996 IB2011054996W WO2012069948A1 WO 2012069948 A1 WO2012069948 A1 WO 2012069948A1 IB 2011054996 W IB2011054996 W IB 2011054996W WO 2012069948 A1 WO2012069948 A1 WO 2012069948A1
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Prior art keywords
methyl
carboxylate
pyrazol
cyano
piperidine
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PCT/IB2011/054996
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English (en)
French (fr)
Inventor
Vincent Mascitti
Kim Francis Mcclure
Michael John Munchhof
Ralph Pelton Robinson, Jr.
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Pfizer Inc.
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Priority to AU2011333427A priority Critical patent/AU2011333427A1/en
Priority to AP2013006809A priority patent/AP2013006809A0/xx
Priority to KR1020137013064A priority patent/KR20130083915A/ko
Priority to MX2013004083A priority patent/MX2013004083A/es
Priority to SG2013023189A priority patent/SG189830A1/en
Priority to MA35928A priority patent/MA34805B1/fr
Priority to CN2011800550665A priority patent/CN103298801A/zh
Priority to CA2814231A priority patent/CA2814231A1/en
Priority to EA201370118A priority patent/EA201370118A1/ru
Priority to JP2013540458A priority patent/JP2013543885A/ja
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to EP11802149.2A priority patent/EP2643310A1/en
Priority to BR112013011865A priority patent/BR112013011865A2/pt
Publication of WO2012069948A1 publication Critical patent/WO2012069948A1/en
Priority to ZA2013/02362A priority patent/ZA201302362B/en
Priority to TNP2013000166A priority patent/TN2013000166A1/fr
Priority to CU2013000059A priority patent/CU20130059A7/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a new class of cyanopyrazoles, pharmaceutical compositions containing these compounds, and their use to modulate the activity of the G-protein-coupled receptor, GPR1 19.
  • Diabetes mellitus are disorders in which high levels of blood glucose occur as a consequence of abnormal glucose homeostasis.
  • the most common forms of diabetes mellitus are Type I (also referred to as insulin-dependent diabetes mellitus) and Type II diabetes (also referred to as non-insulin-dependent diabetes mellitus).
  • Type II diabetes accounting for roughly 90% of all diabetic cases, is a serious progressive disease that results in microvascular complications (including retinopathy, neuropathy and
  • nephropathy as well as macrovascular complications (including accelerated
  • Sitagliptin a dipeptidyl peptidase IV inhibitor
  • Sitagliptin is a new drug that increases blood levels of incretin hormones, which can increase insulin secretion, reduce glucagon secretion and have other less well characterized effects.
  • sitagliptin and other dipeptidyl peptidases IV inhibitors may also influence the tissue levels of other hormones and peptides, and the long-term consequences of this broader effect have not been fully investigated.
  • insulin resistance may be due to reduced numbers of cellular insulin receptors, disruption of cellular signaling pathways, or both.
  • the beta cells compensate for insulin resistance by increasing insulin output.
  • the beta cells become unable to produce sufficient insulin to maintain normal glucose levels (euglycemia), indicating progression to Type I I diabetes.
  • fasting hyperglycemia occurs due to insulin resistance combined with beta cell dysfunction.
  • beta cell defect dysfunction There are two aspects of beta cell defect dysfunction: 1 ) increased basal insulin release (occurring at low, non-stimulatory glucose concentrations), which is observed in obese, insulin-resistant pre-diabetic stages as well as in Type II diabetes, and 2) in response to a hyperglycemic challenge, a failure to increase insulin release above the already elevated basal level, which does not occur in pre-diabetic stages and may signal the transition from normo-glycemic insulin-resistant states to Type II diabetes.
  • Current therapies to treat the latter aspect include inhibitors of the beta-cell ATP-sensitive potassium channel to trigger the release of endogenous insulin stores, and administration of exogenous insulin. Neither achieves accurate normalization of blood glucose levels and both carry the risk of eliciting hypoglycemia.
  • agonist modulators of novel, similarly functioning, beta-cell GPCRs would also stimulate the release of endogenous insulin and promote normalization of glucose levels in Type II diabetes patients. It has also been shown that increased cAMP, for example as a result of GLP-1 stimulation, promotes beta-cell proliferation, inhibits beta- cell death and, thus, improves islet mass. This positive effect on beta-cell mass should be beneficial in Type II diabetes where insufficient insulin is produced.
  • metabolic diseases have negative effects on other physiological systems and there is often co-occurrence of multiple disease states (e.g., Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,
  • GPR 1 19 modulators a new class of GPR 1 19 modulators. These compounds include:
  • these compounds modulate the activity of the G-protein-coupled receptor. More specifically the compounds modulate GPR1 19.
  • said compounds are useful for the treatment of diseases, such as diabetes, in which the activity of GPR119 contributes to the pathology or symptoms of the disease.
  • diseases such as diabetes, in which the activity of GPR119 contributes to the pathology or symptoms of the disease.
  • diseases such as diabetes, in which the activity of GPR119 contributes to the pathology or symptoms of the disease.
  • diseases such as diabetes
  • Type lb idiopathic Type I diabetes
  • LADA latent autoimmune diabetes in adults
  • EOD early-onset Type 2 diabetes
  • YOAD youth-onset atypical diabetes
  • MODY maturity onset diabetes of the young
  • malnutrition-related diabetes gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis),
  • dyslipidemia post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,
  • the compounds may be used to treat neurological disorders such as Alzheimer's disease, schizophrenia, and impaired cognition.
  • the compounds will also be beneficial in gastrointestinal illnesses such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, etc.
  • the compounds may also be used to stimulate weight loss in obese patients, especially those afflicted with diabetes.
  • a further embodiment of the invention is directed to pharmaceutical compositions containing a compound of this invention.
  • Such formulations will typically contain a compound of this invention in admixture with at least one pharmaceutically acceptable excipient.
  • Such formulations may also contain at least one additional pharmaceutical agent. Examples of such agents include anti-obesity agents and/or anti-diabetic agents Additional aspects of the invention relate to the use of the compounds of this invention in the preparation of medicaments for the treatment of diabetes and related conditions as described herein.
  • halogen refers to a chlorine, fluorine, iodine, or bromine atom
  • - C4 alkyl refers to a branched or straight chained alkyl group containing from 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.;
  • C.,- C 4 alkoxy refers to a straight or branched chain alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, etc.;
  • C3-C6 cycloalkyl refers to a nonaromatic ring that is fully hydrogenated and exists as a single ring. Examples of such carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
  • C.,- C 4 haloalkyl refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, substituted with one or more halogen atoms;
  • C.,- C 4 haloalkoxy refers to a straight or branched chain alkoxy group containing from 1 to 4 carbon atoms, substituted with one or more halogen atoms;
  • 5 to 10 membered heteroaryl means a carbocyclic aromatic system having a total of 5 to 10 ring atoms and containing one, two, three or four heteroatoms selected independently from oxygen, nitrogen and sulfur and having one, two or three rings wherein such rings may be fused.
  • fused means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring.
  • fused is equivalent to the term “condensed”.
  • heteroaryl embraces aromatic radicals such as pyridine, pyridazine, pyrazine, pyrimidine, imidazo[1 ,2-a]pyridine, imidazo[1 ,5-a]pyridine, [1 ,2,4]triazolo[4,3-a]pyridine, [1 ,2,4]triazolo[4,3-b]pyridazine, [1 ,2,4]triazolo[4,3- a]pyrimidine, and [1 ,2,4]triazolo[1 ,5-a]pyridine;
  • terapéuticaally effective amount means an amount of a compound of the
  • present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein;
  • patient refers to warm blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans;
  • treat embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient's disease (or condition) or any tissue damage associated with the disease;
  • modulated refers to the activation of the G-protein-coupled receptor GPR1 19 with compounds of the present invention
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • salts is intended to refer to pharmaceutically acceptable salts and to salts
  • pharmaceutically acceptable salts is intended to refer to either pharmaceutically acceptable acid addition salts" or “pharmaceutically acceptable basic addition salts” depending upon the actual structure of the compound.
  • pharmaceutically acceptable acid addition salts is intended to apply to any nontoxic organic or inorganic acid addition salt of the base compounds or any of its intermediates.
  • inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
  • organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids.
  • Such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
  • Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents.
  • non-toxic organic or inorganic basic addition salts of the compounds or any of its intermediates include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline.
  • alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides
  • ammonia and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline.
  • Stereoisomer refers to compounds that possess one or more chiral centers and each center may exist in the R or S configuration. Stereoisomers includes all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof. "Geometric isomer” refers to compounds that may exist in cis, trans, anti, syn,
  • E
  • Z
  • Certain of the compounds of this invention may exist as geometric isomers. The compounds may possess one or more asymmetric centers, thus existing as two, or more, stereoisomeric forms. The present invention includes all the individual
  • stereoisomers and geometric isomers of the compounds of this invention and mixtures thereof can be obtained by chiral separation or using the relevant enantiomer in the synthesis. As noted above, some of the compounds exist as isomers. These isomeric mixtures can be separated into their individual isomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 123 l, 125 l and 36 CI, respectively.
  • Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays.
  • Certain isotopically labeled ligands including tritium, 14 C, 35 S and 125 l could be useful in radioligand binding assays.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 0, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine receptor occupancy.
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the
  • Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and/or various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound of the present invention followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the compounds may also exist in one or more crystalline states, i.e. as co-crystals, polymorphs, or they may exist as amorphous solids. All such forms are encompassed by the invention and claims.
  • the composition further includes at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent.
  • Example anti-obesity agents include dirlotapide, mitratapide, implitapide, R56918 (CAS No. 403987), CAS No. 913541 -47-6, lorcaserin, cetilistat, PYY3-36, naltrexone, oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat, exenatide, AOD-9604 (CAS No.
  • Example anti-diabetic agents include metformin, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide, tendamistat, trestatin, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone, exendin-3, exendin-4, trodusquemine, reservatrol, hyrtiosal extract, sitaglip
  • the compounds or compositions of this invention may be administered in an effective amount for treating a condition selected from the group consisting of hyperlipidemia, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g.
  • ITT impaired glucose tolerance
  • conditions of impaired fasting plasma glucose metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance,
  • the method further includes administering a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient.
  • This method may be used for admistering the compositions simultaneously or sequentially and in any order.
  • the compounds of this invention are useful in the manufacture of a medicament for treating a disease, condition or disorder that modulates the activity of G-protein-coupled receptor GPR1 19. Furthermore, the compounds are useful in the preparation of a medicament for the treatment of diabetes or a morbidity associated with said diabetes.
  • reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
  • Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds.
  • specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • Compounds of the invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1 -19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).
  • the compounds of this invention can be prepared using methods analogously known in the art for the production of ethers.
  • the reader's attention is directed to texts such as: 1 ) Hughes, D. L; Organic Reactions 1992, 42 Hoboken, NJ, United States; 2) Tikad, A.; Routier, S.; Akssira, M.; Leger, J. -M.I; Jarry, C; Nicolast, G. Synlett 2006, 12, 1938-42; and 3) Loksha, Y. M.; Globisch, D.; Pedersen, E. B.; La Colla, P.; Collu, G.; Loddo, R. J. Het. Chem. 2008, 45, 1 161 -6 which describe such reactions in greater detail.
  • Z is -C(0)-0-R 6 or pyrimidine substituted with d-C 4 alkyl, CF 3 , halogen, cyano, C3-C6 cycloalkyi or C3-C6 cycloalkyi wherein one carbon atom of said cycloalkyi moiety may optionally be substituted with methyl or ethyl;
  • n 1 , 2, or 3;
  • n 0, 1 or 2;
  • R 1 is hydrogen, Ci-C 4 alkyl, or C3-C6 cycloalkyi
  • R 2a is hydrogen, fluoro or Ci-C 4 alkyl
  • each R 3 is individually selected from the group consisting of: hydroxy, halogen, cyano, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, C-i-C 4 haloalkoxy, -SO2-R 7 , -
  • R 4a is hydrogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, CrC 4 haloalkyl, or halogen, wherein said alkyl is optionally substituted with hydroxyl or C C 4 alkoxy;
  • R 4b is hydrogen, C C 4 alkyl, -CH 2 -Ci-C 3 haloalkyl, -C 2 -C 4 alkyl-OH or -CH 2 -C C 4 alkoxy;
  • R 5 is hydrogen or when R 1 is hydrogen then R 5 is hydrogen or C C 4 alkyl
  • R 6 is Ci-C 4 alkyl or C3-C6 cycloalkyi wherein one carbon atom of said cycloalkyi moiety may optionally be substituted with methyl or ethyl;
  • R 7 is represented by C C 4 alkyl, C 3 -C 6 cycloalkyi, NH 2 , or -(CH 2 ) 2 -OH;
  • R 8 is represented by hydrogen or Ci-C 4 alkyl
  • R 9 is represented by hydrogen, Ci-C 4 alkyl, C3-C6 cycloalkyi, -(CH 2 ) 2 -OH, - (CH 2 ) 2 -0-CH 3 , -(CH 2 ) 3 -OH, -(CH 2 ) 3 -0-CH 3 , 3-oxetanyl, or 3-hydroxycyclobutyl;
  • compounds of Formula C can be prepared via a condensation reaction of compounds of Formula A and the commercial compound B (Sigma-Aldrich) in a diverse array of solvents including but not limited to ethanol, toluene and acetonitrile at temperatures ranging from 22°C to 130°C depending upon the solvent utilized for a period of 1 to 72 hours.
  • base modifiers such as sodium acetate or sodium
  • bicarbonate may be added in one to three equivalents to neutralize the salts.
  • the reaction may be conducted in polar protic solvents such as methanol and ethanol at temperatures ranging from 22°C to 85°C. Typical conditions for this transformation include the use of 3 equivalents of sodium acetate in ethanol heated at 85°C for 3 hours.
  • Compounds of Formula A can be prepared via a four-step procedure starting with substituted or unsubstituted 4-piperidinone hydrochloride salts (J. Med. Chem. 2004, 47, 2180). First these salts are treated with an appropriate alkyl chloroformate or bis(alkyl) dicarbonate in the presence of excess base to form the corresponding alkyl carbamate. The ketone group is then condensed with ferf-butoxycarbonyl hydrazide to form the corresponding /V-(ferf-butoxy)carbonyl (BOC) protected hydrazone derivative. This is subsequently reduced to the corresponding BOC protected hydrazine derivative using reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride.
  • reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride.
  • A/-(ferf-butoxy)carbonyl group is cleaved under acidic conditions such as trifluoroacetic acid or hydrochloric acid to give compounds of Formula A, which are typically isolated and used as the corresponding salts (e.g., dihydrochloride salt).
  • compounds of Formula D may be prepared from compounds of Formula C via the formation of intermediate diazonium salts via the Sandmeyer reaction (Comp. Org. Synth., 1991 , 6, 203) These salts may be prepared via diazotization of compounds of Formula C with sodium nitrite and aqueous acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and acetic alone or in combinations. This reaction is typically carried out in water at 0°C to 100°C. Alternatively, anhydrous conditions using alkyl nitrites such as ferf-butylnitrite with solvents such as acetonitrile may be utilized (J. Med. Chem.
  • Formula D via the use of reducing agents such as lithium aluminum hydride, sodium borohydride, lithium borohydride, borane-dimethylsulfide, borane-tetrahydrofuran in polar aprotic solvents such as tetrahydrofuran, diethyl ether, 1 ,4-dioxane or 1 ,2- dimethoxyethane at temperatures ranging from 0°C to 1 10°C for 1 to 24 hours.
  • Typical conditions include the use of borane-dimethylsulfide in tetrahydrofuran at 70°C for 14 hours.
  • a cyano group In order to prepare compounds of Formula F from compounds of Formula E, a cyano group must be introduced (Step 4) This may be achieved via a range of conditions.
  • One method of cyano group introduction may be the use of a copper salt such as copper cyanide in a polar aprotic solvent such as /V,/V-dimethylformamide (DMF), /V-methylpyrrolidinone (NMP), A/,/ ⁇ /-dimethylacetamide (DMA) at temperatures ranging from 22°C to 200°C for 1 to 24 hours. Copper cyanide in N,N- dimethylformamide heated at 165°C for 5 hours is a typical protocol for this
  • alkali cyanide salts such as potassium or sodium cyanide may be used in conjunction with catalysts such as 18-crown-6 (US2005020564) and or tetrabutylammonium bromide (J. Med. Chem. 2003, 46, 1 144) in polar aprotic solvents such acetonitrile and dimethylsulfoxide at temperatures ranging from 22°C to 100°C for the addition of a cyano group to this template.
  • cyanide salts used in catalytic procedures include zinc cyanide, copper cyanide, sodium cyanide, and potassium hexacyanoferrate (I I).
  • the metal catalysts can be copper catalysts such as copper iodide and or palladium catalysts such as tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), palladium tetrakis- triphenylphosphine (Pd(PPh 3 ) 4 ), or dichloro(diphenyl-phosphinoferrocene)-palladium (Pd(dppf)C ).
  • These catalysts may be used alone or in any combination with any of the above cyanide salts.
  • ligands such as 1 , 1 '- bis(diphenylphosphino)-ferrocene (dppf) or metal additives such as zinc or copper metal.
  • the reactions are carried out in polar aprotic solvents such as NMP, DMF, DMA with or without water as an additive.
  • the reactions are carried out at temperatures ranging from 22°C to 150°C via conventional or microwave heating for 1 to 48 hours and may be conducted in a sealed or non-sealed reaction vessel.
  • Typical conditions for Step 4 include the use of zinc cyanide, Pd 2 (dba)3, dppf, and zinc dust in DMA heated at 120°C in a microwave for 1 hour (J. Med. Chem. 2005, 48, 1 132).
  • Step 5 compounds of Formula G, can be synthesized from compounds of Formula F via the Mitsunobu reaction.
  • the Mitusunobu reaction has been reviewed in the synthetic literature (e.g., Chem. Asian. J. 2007, 2, 1340; Eur. J. Org. Chem. 2004, 2763; S. Chem. Eur. J. 2004, 10, 3130), and many of the synthetic protocols listed in these reviews may be used.
  • the use of Mitsunobu reaction protocols utilizing azodicarboxylates such as diethyl azodicarboxylate (DEAD), di-ferf-butyl
  • azodicarboxylate TAD
  • diisopropyl azodicarboxylate DID
  • a phosphine reagent such as triphenylphosphine (PPh 3 ), tributylphoshine (PBU3) and polymer supported triphenylphosphine (PS-PP i3) are combined with compounds of Formula F and a compound of general structure X-OH.
  • Solvents utilized in this reaction may include aprotic solvents such as toluene, benzene, THF, 1 ,4-dioxane and acetonitrile at temperatures ranging from 0°C to 130°C depending on the solvent and
  • azodicarboxylates utilized. Typical conditions for this transformation are the use of DEAD with PS-PPh 3 in 1 ,4-dioxane at 22°C for 15 hours.
  • An alternative to the Mitsunobu reaction for preparing compounds of Formula G is to convert the compounds of Formula F to the corresponding methanesulfonate or para-toluenesulphonate derivatives using methanesulfonyl chloride or para- toluenesulfonyl chloride, respectively, in the presence of a base such as triethylamine or pyridine.
  • the intermediate sulfonate ester is then combined with a compound of general X-OH, in the presence of a base such as potassium carbonate, sodium hydride, or potassium ferf-butoxide to yield compounds of Formula G.
  • Compounds of Formula K may be prepared from compounds of Formula F in three Steps: 1 ) oxidation of the primary alcohol to the corresponding aldehyde of Formula H (Step 6, Scheme 1 ), 2) reaction of the aldehyde intermediate of Formula H with an organometallic reagent of the Formula R 1 M, wherein M is lithium (Li) or magnesium halide (MgCI, MgBr or Mgl) to provide a secondary alcohol of Formula J, wherein R 1 is d-C 4 alkyl or C3-C6 cycloalkyl (Step 7), and 3) reaction of the secondary alcohol of Formula J with a phenol of the Formula X- OH under Mitsunobu reaction conditions (Step 8).
  • compounds of Formula H can are formed via oxidation procedures including the use of 1 to 20 equivalents of activated manganese dioxide in solvents including but not limited to dichloromethane, acetonitrile, hexane or acetone alone or in combinations for 1 to 72 hours at 22°C to 80°C.
  • this oxidation can be conducted with 1 to 3 equivalents of trichloroisocyanuric acid in the presence of 0.1 to 1 equivalents of 2,2,6, 6-tetramethylpiperidine-1 -oxyl (TEMPO) in dichloromethane or chloroform at temperatures ranging from 0°C to 22°C for 0.1 to 12 hours.
  • TEMPO 2,2,6, 6-tetramethylpiperidine-1 -oxyl
  • Typical conditions for this transformation are the use of trichloroisocyanuric acid in the presence of 0.1 equivalent of TEMPO in dichloromethane at 22°C for 1 hour.
  • compounds of Formula N wherein R 1 is Ci-C 4 alkyl or C3-C6 cycloalkyl may be prepared in two steps from the intermediate of Formula J wherein R 1 is CrC 4 alkyl or C3-C6 cycloalkyl, by 1 ) oxidation to the corresponding ketone of Formula M (Step 10), and 2) reaction of the ketone of Formula M with an amino compound of the Formula X-NH-R 5 under reductive amination conditions (Step 1 1 ).
  • compounds of Formula L and Formula N, wherein R 5 is Ci-C 4 alkyl may be prepared from the corresponding compounds of Formula L, wherein R 5 is H, or the corresponding compounds of Formula N, wherein R 5 is H, by alkylation with an alkyl halide of Formula (CrC 4 )-CI, (C-i-C 4 )-Br or (d-C 4 )-l in the presence of a base.
  • (diazomethyl)phosphonate or dimethyl-1 -diazo-2-oxopropylphosphonate and bases such as potassium carbonate or potassium ferf-butoxide in solvents including methanol, ethanol or tetrahydrofuran at temperatures ranging from -78°C to 22°C for 0.1 to 24 hours.
  • solvents including methanol, ethanol or tetrahydrofuran at temperatures ranging from -78°C to 22°C for 0.1 to 24 hours.
  • Typical conditions for this transformation include the use of dimethyl-1 -diazo-2- oxopropylphosphonate and 2 equivalents of potassium carbonate in methanol at 22°C for 0.75 hour.
  • metal catalysts in this reaction can be copper catalysts such as copper iodide and or palladium catalysts such as Pd 2 (dba)3, Pd(PPh 3 ) 4 , Pd(dppf)Cl2 or Pd(PPh3)2Cl2. These catalysts may be used alone or in any combination.
  • Base additives are typically used in this reaction and may include amine bases such as diethylamine, triethylamine, diisopropylethylamine or pyrrolidine or inorganic bases such as potassium carbonate or potassium fluoride.
  • the reactions are carried out in solvents such as dichloromethane, chloroform, acetonitrile, DMF, toluene or 1 ,4-dioxane with or without water as an additive.
  • solvents such as dichloromethane, chloroform, acetonitrile, DMF, toluene or 1 ,4-dioxane with or without water as an additive.
  • the reactions are carried out at temperatures ranging from 0°C to 150°C depending on the solvent for times ranging from 0.1 to 48 hours. Typical conditions for this transformation include the use of Cul and Pd(PPh 3 ) 2 Cl2 in DMF at 90°C for 2 hours.
  • Scheme 3 shows methods for the preparation of compounds of Formula W.
  • Step 1 of Scheme 3 compounds of Formula F (see also Scheme 2) can be treated with reagents such as phosphorus tribromide or carbon tetrabromide and triphenylphosphine to give compounds of Formula S.
  • compounds of Formula S are then allowed to react with triphenylphosphine in solvents such as
  • Step 4 compounds of Formula W are formed from compounds of Formula V via hydrogenation in the presence of transition metal catalysts.
  • transition metal catalysts include the use of 5 - 20% palladium on carbon or 5 - 20% palladium hydroxide on carbon.
  • compounds of Formula W may be prepared from aldehydes of Formula H via Wittig reaction with triphenylphosphonium salts of Formula AA (Step 5, Scheme 3).
  • this reaction produces alkene compounds of Formula V, which again are typically isolated as mixtures of E and Z geometric isomers, and may be converted to compounds of Formula W by hydrogenation.
  • the salts of Formula AA are obtained in a similar manner to that used for preparing salts of Formula T via conversion of the corresponding alcohol to the bromide and subsequent reaction with triphenylphosphine.
  • substituents R 3 on the group X later in the synthesis even as the last step.
  • R 3 is S0 2 R 7
  • the S0 2 R 7 group may be in formed in the last step by oxidation of the corresponding compound bearing a substituent of general formula S-R 7 .
  • Compounds of this invention may be prepared according to sequences analogous to those shown in Schemes 1 , 2 and 3 starting with 3,3-difluoro-4,4- dihydroxy 1 -piperidine carboxylic acid 1 , 1 -dimethylethyl ester (WO 2008121687). In a manner similar to that described for the preparation of intermediates of formula A in Scheme 1 , this material may be converted to hydrazine dervatives of formula DD, which are then used similarly to the intermediates of formula A in Scheme 1.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethyleneoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxyl-protecting groups include for example, allyl, acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 .
  • some of the compounds of this invention are acidic and they form salts with pharmaceutically acceptable cations.
  • Some of the compounds of this invention are basic and form salts with pharmaceutically acceptable anions. All such salts are within the scope of this invention and they can be prepared by conventional methods such as combining the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate.
  • the salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
  • the compounds are obtained in crystalline form according to procedures known in the art, such as by dissolution in an appropriate solvent(s) such as ethanol, hexanes or water/ethanol mixtures.
  • Compounds of the present invention modulate the activity of G-protein-coupled receptor GPR1 19.
  • said compounds are useful for the prophylaxis and treatment of diseases, such as diabetes, in which the activity of GPR119 contributes to the pathology or symptoms of the disease.
  • another aspect of the present invention includes a method for the treatment of a metabolic disease and/or a metabolic-related disorder in an individual which comprises administering to the individual in need of such treatment a therapeutically effective amount of a compound of the invention, a salt of said compound or a pharmaceutical composition containing such compound.
  • the metabolic diseases and metabolism-related disorders are selected from, but not limited to, hyperlipidemia, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis),
  • dyslipidemia post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, endothelial dysfunction, hyper apo B lipoproteinemia and impaired vascular compliance.
  • ITT impaired glucose tolerance
  • the compounds may be used to treat neurological disorders such as Alzheimer's disease, schizophrenia, and impaired cognition.
  • the compounds will also be beneficial in gastrointestinal illnesses such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, etc.
  • the compounds may also be used to stimulate weight loss in obese patients, especially those afflicted with diabetes.
  • the present invention further provides a method for preventing or ameliorating the symptoms of any of the diseases or disorders described above in a subject in need thereof, which method comprises administering to a subject a therapeutically effective amount of a compound of the present invention.
  • Further aspects of the invention include the preparation of medicaments for the treating diabetes and its related co-morbidities.
  • the compounds need to be administered in a quantity sufficient to modulate activation of the G-protein- coupled receptor GPR1 19. This amount can vary depending upon the particular disease/condition being treated, the severity of the patient's disease/condition, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc.
  • the compounds When administered systemically, the compounds typically exhibit their effect at a dosage range of from about 0.1 mg/kg/day to about 100 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.
  • the compounds of the present invention may be administered by a variety of routes. They may be administered orally. The compounds may also be administered parenterally (i.e., subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally), rectally, or topically.
  • the compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided.
  • Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.
  • Suitable anti-diabetic agents include an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, a diacylglycerol O-acyltransferase 1 (DGAT-1 ) inhibitor, a phosphodiesterase (PDE)-10 inhibitor, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an oamylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an oglucoside hydrolase inhibitor (e.g., acarbose), an oglucosidase inhibitor (e.g., adiposine, camiglibose, emig
  • Suitable anti-obesity agents include 1 1 ⁇ -hydroxy steroid dehydrogenase-1 (1 1 ⁇ -
  • HSD type 1 inhibitors, stearoyl-CoA desaturase-1 (SCD-1 ) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e.
  • anorectic agents such as a bombesin agonist
  • neuropeptide-Y antagonists e.g., NPY Y5 antagonists
  • PYY3-36 including analogs thereof
  • thyromimetic agents dehydroepiandrosterone or an analog thereof
  • glucocorticoid agonists or antagonists orexin antagonists
  • glucagon-like peptide-1 agonists ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter s Gamble Company, Cincinnati, OH)
  • human agouti-related protein (AGRP) inhibitors ghrelin antagonists, histamine 3 antagonists or inverse agonists
  • neuromedin U agonists e.g., MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide), opioid antagonist, orexin antagonist, and the like.
  • Preferred anti-obesity agents for use in the combination aspects of the present invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541 -47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6, 10b- tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide described in PCT Publication No. WO 2005/1 16034 or US Publication No.
  • CCKa agonists e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6, 10b- t
  • PYY 3 - 3 6 includes analogs, such as peglated PYY 3-36 e.g., those described in US Publication 2006/0178501 ), opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (NS2330), leptin, liraglutide,
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • compositions which comprise a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
  • compositions include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of diabetes and related conditions as described above.
  • compositions can be formulated for administration by any route known in the art, such as subdermal, inhalation, oral, topical, parenteral, etc.
  • the compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats,
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils, for example almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • agents such as local anesthetics, preservatives and buffering agents etc. can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain, for example, from about 0.1 % to about 99 by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will contain, for example, from about 0.1 to 900 mg of the active ingredient, more typically from 1 mg to 250mg.
  • starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England), Mallinckrodt Baker (Phillipsburg NJ); EMD
  • NMR spectra were recorded on a Varian UnityTM 400 (DG400-5 probe) or 500 (DG500-5 probe - both available from Varian Inc., Palo Alto, CA) at room temperature at 400 MHz or 500 MHz respectively for proton analysis. Chemical shifts are expressed in parts per million (delta) relative to residual solvent as an internal reference.
  • the peak shapes are denoted as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; 2s, two singlets.
  • Atmospheric pressure chemical ionization mass spectra were obtained on a WatersTM Spectrometer (Micromass ZMD, carrier gas: nitrogen) (available from Waters Corp., Milford, MA, USA) with a flow rate of 0.3 mL/minute and utilizing a 50:50 water/acetonitrile eluent system.
  • Electrospray ionization mass spectra were obtained on a liquid chromatography mass spectrometer from WatersTM (Micromass ZQ or ZMD instrument (carrier gas: nitrogen) (Waters Corp., Milford, MA, USA) utilizing a gradient of 95:5 - 0:100 water in acetonitrile with 0.01% formic acid added to each solvent.
  • These instruments utilized a Varian Polaris 5 C18-A20x2.0mm column (Varian Inc., Palo Alto, CA) at flow rates of 1 ml_/minute for 3.75 minutes or 2 mL/minute for 1.95 minutes.
  • Concentration in vacuo refers to evaporation of solvent under reduced pressure using a rotary evaporator.
  • the assay for GPR1 19 agonists utilizes a cell-based (hGPR119 HEK293-CRE beta-lactamase) reporter construct where agonist activation of human GPR1 19 is coupled to beta-lactamase production via a cyclic AMP response element
  • CRE CRE-enabled beta-lactamase substrate
  • CCF4-AM Live Blazer FRET-B/G Loading kit, Invitrogen cat #
  • hGPR119-HEK-CRE- beta-lactamase cells (Invitrogen 2.5 x 10 7 /mL) were removed from liquid nitrogen storage, and diluted in plating medium (Dulbecco's modified Eagle medium high glucose (DMEM; Gibco Cat # 1 1995-065), 10% heat inactivated fetal bovine serum (HIFBS; Sigma Cat # F4135), 1X MEM
  • plating medium Dulbecco's modified Eagle medium high glucose (DMEM; Gibco Cat # 1 1995-065), 10% heat inactivated fetal bovine serum (HIFBS; Sigma Cat # F4135), 1X MEM
  • Nonessential amino acids (Gibco Cat # 15630-080), 25 mM HEPES pH 7.0 (Gibco Cat # 15630-080), 200 nM potassium clavulanate (Sigma Cat # P3494).
  • the cell concentration was adjusted using cell plating medium and 50 microL of this cell suspension (12.5 x 10 4 viable cells) was added into each well of a black, clear bottom, poly-d-lysine coated 384-well plate (Greiner Bio-One cat# 781946) and incubated at 37 degrees Celsius in a humidified environment containing 5% carbon dioxide. After 4 hours the plating medium was removed and replaced with 40 microL of assay medium (Assay medium is plating medium without potassium clavulanate and HIFBS).
  • Varying concentrations of each compound to be tested was then added in a volume of 10 microL (final DMSO ⁇ 0.5%) and the cells were incubated for 16 hours at 37 degrees Celsius in a humidified environment containing 5% carbon dioxide. Plates were removed from the incubator and allowed to equilibrate to room temperature for approximately 15 minutes. 10 microL of 6 X CCF4/AM working dye solution (prepared according to instructions in the Live Blazer FRET-B/G Loading kit, Invitrogen cat #
  • GPR1 19 agonist activity was also determined with a cell-based assay utilizing an HTRF (Homogeneous Time-Resolved Fluorescence) cAMP detection kit (cAMP dynamic 2 Assay Kit; Cis Bio cat # 62AM4PEC) that measures cAMP levels in the cell.
  • the method is a competitive immunoassay between native cAMP produced by the cells and the cAMP labeled with the dye d2.
  • the tracer binding is visualized by a Mab anti- cAMP labeled with Cryptate.
  • the specific signal i.e. energy transfer
  • hGPR1 19 HEK-CRE beta-lactamase cells (Invitrogen 2.5 x 10 7 /ml_; the same cell line used in the beta-lactamase assay described above) were removed from cryopreservation and diluted in growth medium (Dulbecco's modified Eagle medium high glucose (DMEM; Gibco Cat # 1 1995-065), 1 % charcoal dextran treated fetal bovine serum (CD serum; HyClone Cat # SH30068.03), 1x MEM Nonessential amino acids (Gibco Cat # 15630-080) and 25 mM HEPES pH 7.0 (Gibco Cat # 15630- 080)).
  • growth medium Dulbecco's modified Eagle medium high glucose (DMEM; Gibco Cat # 1 1995-065), 1 % charcoal dextran treated fetal bovine serum (CD serum; HyClone Cat # SH30068.03), 1x MEM Nonessential amino acids (Gibco Cat # 15630-080) and 25
  • the cell concentration was adjusted to 1.5 x 10 5 cells/mL and 30 ml_s of this suspension was added to a T-175 flask and incubated at 37 degrees Celsius in a humidified environment in 5% carbon dioxide. After 16 hours (overnight), the cells were removed from the T-175 flask (by rapping the side of the flask), centrifuged at 800 x g and then re-suspended in assay medium (1x HBSS +CaCI 2 + MgCI 2 (Gibco Cat # 14025-092) and 25 mM HEPES pH 7.0 (Gibco Cat # 15630-080)).
  • the cell concentration was adjusted to 6.25 x 10 5 cells/mL with assay medium and 8 ⁇ of this cell suspension (5000 cells) was added to each well of a white Greiner 384-well, low- volume assay plate (VWR cat # 82051-458).
  • Varying concentrations of each compound to be tested were diluted in assay buffer containing 3-isobutyl-1-methylxanthin (IBMX; Sigma cat # I5879) and added to the assay plate wells in a volume of 2 microL (final IBMX concentration was 400 microM and final DMSO concentration was 0.58%). Following 30 minutes incubation at room temperature, 5 microL of labeled d2 cAMP and 5 microL of anti-cAMP antibody (both diluted 1 :20 in cell lysis buffer; as described in the manufacturers assay protocol) were added to each well of the assay plate.
  • IBMX 3-isobutyl-1-methylxanthin
  • GPR1 19 agonist activity was also determined with a cell-based assay utilizing
  • U20S hGPR1 19 ⁇ -arrestin cells were removed from cryopreservation and diluted in growth medium (Minimum essential medium (MEM; Gibco Cat # 1 1095-080), 10% heat inactivated fetal bovine serum (HI FBS; Sigma Cat # F4135-100), 100 mM sodium pyruvate (Sigma Cat # S8636), 500 microg/mL G418 (Sigma Cat # G8168) and 250 microg/mL Hygromycin B (Invitrogen Cat # 10687-010).
  • MEM Minimum essential medium
  • HI FBS 10% heat inactivated fetal bovine serum
  • 100 mM sodium pyruvate Sigma Cat # S8636
  • 500 microg/mL G418 Sigma Cat # G8168
  • 250 microg/mL Hygromycin B Invitrogen Cat # 10687-010.
  • the cell concentration was adjusted to 1 .66 x 10 5 cells/mL and 30 mLs of this suspension was added to a T-175 flask and incubated at 37 degrees Celsius in a humidified environment in 5% carbon dioxide. After 48 hours, the cells were removed from the T-175 flask with enzyme-free cell dissociation buffer (Gibco cat # 13151 -014), centrifuged at 800 x g and then re-suspended in plating medium (Opti- MEM I (Invitrogen/BRL Cat # 31985-070) and 2 % charcoal dextran treated fetal bovine serum (CD serum; HyClone Cat # SH30068.03).
  • enzyme-free cell dissociation buffer Gibco cat # 13151 -014
  • Opti- MEM I Invitrogen/BRL Cat # 31985-070
  • CD serum HyClone Cat # SH30068.03
  • the cell concentration was adjusted to 2.5 x 10 5 cells/mL with plating medium and 10 microL of this cell suspension (2500 cells) was added to each well of a white Greiner 384-well low volume assay plate (VWR cat # 82051 -458) and the plates were incubated at 37 degrees Celsius in a humidified environment in 5% carbon dioxide.
  • PCR polymerase chain reaction
  • the amplified product was purified (Qiaquick Kit, Qiagen, Valencia, CA) and digested with BamHI and EcoRI (New England BioLabs, Ipswich, MA) according to the manufacturer's protocols.
  • the vector pFB-VSVG-CMV-poly (published in PCT patent publication no. 2010/106457) was digested with BamHI and EcoRI (New England BioLabs, Ipswich, MA).
  • the digested DNA was separated by electrophoresis on a 1 % agarose gel; the fragments were excised from the gel and purified (Qiaquick Kit, Qiagen, Valencia, CA).
  • the vector and gene fragments were ligated (Rapid Ligase Kit, Roche, Pleasanton, CA) and transformed into OneShot DH5alpha T1 R cells (Invitrogen, Carlsbad, CA). Eight ampicillin-resistant colonies (“clones 1-8") were grown for miniprep (Qiagen Miniprep Kit, Qiagen, Valencia, CA) and sequenced to confirm identity and correct insert orientation.
  • the pFB-VSVG-CMV-poly-hGPR1 19 construct (clone #1 ) was transformed into OneShot DH I OBac cells (Invitrogen, Carlsbad, CA) according to manufacturers' protocols. Eight positive (i.e.
  • hGPR1 19 bacmid was isolated via a modified Alkaline Lysis procedure using the buffers from a Qiagen Miniprep Kit (Qiagen, Valencia, CA). Briefly, pelleted cells were lysed in buffer P1 , neutralized in buffer P2, and precipitated with buffer N3. Precipitate was pelleted via centrifugation (17,900xg for 10 minutes) and the supernatant was combined with isopropanol to precipitate the DNA.
  • Suspension adapted Sf9 cells grown in Sf900ll medium were transfected with 10 microL hGPR1 19 bacmid DNA according to the manufacturer's protocol (Cellfectin, Invitrogen, Carlsbad, CA). After five days of incubation, the conditioned medium (i.e. "P0" virus stock) was centrifuged and filtered through a 0.22 ⁇ filter (Steriflip, Millipore, Billerica, MA).
  • frozen BI IC Bactet Cells
  • Sf900ll medium Invitrogen, Carlsbad, CA
  • hGPR1 19 P0 virus stock After 24 hours of growth, the infected cells were gently centrifuged (approximately 100 x g), resuspended in Freezing Medium (10% DMSO, 1 % Albumin in Sf900l l medium) to a final density of 1 x 10 7 cells/mL and frozen according to standard freezing protocols in 1 ml. aliquots. Creation of Working (" ⁇ 1 ⁇ Virus Stock
  • Suspension adapted Sf9 cells grown in Sf900ll medium were infected with a 1 : 100 dilution of a thawed hGPR1 19 BMC stock and incubated for several days (27 degrees Celsius with shaking). When the viability of the cells reached 70%, the conditioned medium was harvested by centrifugation and the virus titer determined by ELISA (BaculoElisa Kit, Clontech, Mountain View, CA)
  • HEK 293FT cells (Invitrogen, Carlsbad, CA) were grown in a shake flask in
  • MOI multiplicity of infection
  • the frozen cells were thawed on ice and centrifuged at 700 x g (1400 rpm) for 10 minutes at 4 degrees Celsius.
  • the cell pellet was resuspended in 20 ml. phosphate- buffered saline, and centrifuged at 1400 rpm for 10 minutes.
  • the cell pellet was then resuspended in homogenization buffer (10 mM H EPES (Gibco #15630), pH 7.5, 1 mM EDTA (BioSolutions, #BIO260-15), 1 mM EGTA (Sigma, #E-4378), 0.01 mg/mL benzamidine (Sigma #B 6506), 0.01 mg/mL bacitracin (Sigma #B 0125), 0.005 mg/mL leupeptin (Sigma #L 851 1 ), 0.005 mg/mL aprotinin (Sigma #A 1 153)) and incubated on ice for 10 minutes. Cells were then lysed with 15 gentle strokes of a tight-fitting glass Dounce homogenizer.
  • homogenization buffer 10 mM H EPES (Gibco #15630), pH 7.5, 1 mM EDTA (BioSolutions, #BIO260-15), 1 mM EGTA (Sigma, #E-4378),
  • the homogenate was centrifuged at 1000 x g (2200 rpm) for 10 minutes at 4 degrees Celsius. The supernatant was transferred into fresh centrifuge tubes on ice. The cell pellet was resuspended in homogenization buffer, and centrifuged again at 1000 x g (2200 rpm) for 10 minutes at 4 degrees Celsius after which the supernatant was removed and the pellet resuspended in homogenization buffer. This process was repeated a third time, after which the supernatants were combined, Benzonase (Novagen # 71206) and MgCI 2 (Fluka #63020) were added to final concentrations of 1 U/mL and 6 mM, respectively, and incubated on ice for one hour.
  • Benzonase Novagen # 71206
  • MgCI 2 Fruka #63020
  • the specific activity of purified [ H]-Compound A was determined by mass to be 70 Ci/mmol.
  • the binding assay can be performed with [ 3 H]-Compound B.
  • Test compounds were serially diluted in 100% DMSO (J.T. Baker #922401 ). 2 microL of each dilution was added to appropriate wells of a 96-well plate (each concentration in triplicate). Unlabeled Compound A (or Compound B), at a final concentration of 10 microM, was used to determine non-specific binding.
  • [ 3 H]-Compound A (or [ 3 H]-Compound B) was diluted in binding buffer (50 mM Tris-HCI, pH 7.5, (Sigma #T7443), 10 mM MgCI 2 (Fluka 63020), 1 mM EDTA (BioSolutions #BIO260-15), 0.15% bovine serum albumin (Sigma #A751 1 ), 0.01 mg/mL
  • binding buffer 50 mM Tris-HCI, pH 7.5, (Sigma #T7443), 10 mM MgCI 2 (Fluka 63020), 1 mM EDTA (BioSolutions #BIO260-15), 0.15% bovine serum albumin (Sigma #A751 1 ), 0.01 mg/mL
  • benzamidine (Sigma #B 6506), 0.01 mg/mL bacitracin (Sigma #B 0125), 0.005 mg/mL leupeptin (Sigma #L 851 1 ), 0.005 mg/mL aprotinin (Sigma #A 1 153)) to a concentration of 60 nM, and 100 microL added to all wells of 96-well plate (Nalge Nunc # 267245).
  • Membranes expressing GPR1 19 were thawed and diluted to a final concentration of 20 ⁇ g/100 microL per well in Binding Buffer, and 100 microL of diluted membranes were added to each well of 96-well plate.
  • the plate was incubated for 60 minutes w/shaking at room temperature (approximately 25 degrees Celsius).
  • the assay was terminated by vacuum filtration onto GF/C filter plates (Packard # 6005174) presoaked in 0.3% polyethylenamine, using a Packard harvester. Filters were then washed six times using washing buffer (50 mM Tris-HCI, pH 7.5 kept at 4 degrees Celsius). The filter plates were then air-dyed at room temperature overnight. 30 ⁇ of scintillation fluid (Ready Safe, Beckman Coulter #141349) was added to each well, plates were sealed, and radioactivity associated with each filter was measured using a Wallac Trilux MicroBeta, plate-based scintillation counter.
  • the Kd for [ 3 H]-Compound A was determined by carrying out saturation binding, with data analysis by non-linear regression, fit to a one-site hyperbola (Graph Pad Prism).
  • IC50 determinations were made from competition curves, analyzed with a proprietary curve fitting program (SIGHTS) and a 4-parameter logistic dose response equation. Ki values were calculated from IC50 values, using the Cheng- Prusoff equation.
  • the intrinsic activity is the percent of maximal activity of the test compound, relative to the activity of a standard GPR1 19 agonist, 4-[[6-[(2-fluoro-4
  • Naive male Wistar rats 200-250 g body weight on receipt
  • Harlan Laboratories Indianapolis, I N
  • the rats were housed under a controlled light cycle (light from 6 am to 6 pm) at controlled temperature and humidity conditions. Rats were acclimated to the facility for at least 1 week prior to study.
  • Example 50 was formulated as a 10% SDD in the vehicle 20 mM Tris Buffer at pH 7.4 with 0.5% methylcellulose and 0.5% HPMCAS-HF.
  • the dose (75 mg/kg) was formulated at 15 mg/mL for administration at 5 mL/kg, the required bulk was added to a mortar and ground with a small amount of vehicle to a smooth paste with a pestle, additional vehicle was added until the mixture flowed, when it was transferred to a stirred container, the mortar was rinsed several times with remaining quantity of vehicle and capped to prevent evaporation.
  • the compound was formulated on the day of doing and was stirred continuously with a magnetic stir bar prior to, and during the dosing procedure.
  • HPMCAS- HF Hydroxypropyl methylcellulose acetate succinate- high grade, fine particle
  • Blood samples were collected via the tail vein from all rats prior to dosing with vehicle or test compound via oral gavage (5 mL/kg). Ninety or thirty minutes later rats were bled and immediately dose with an oral dose of glucose (2 g/kg). The rats were re-bled at 15, 30, 60 and 120 minutes post-glucose load. Blood samples (-250 microliter/time point) were collected into EDTA tubes with aprotinin/DPPIVi (0.6 TIU/20 microliter per ml. whole blood).
  • Plasma samples were inverted several times immediately following collection and placed on ice, then spun at 14,000 rpm in a refrigerated centrifuge for 5 minutes. Plasma samples were analyzed for glucose levels using a Roche c31 1 clinical chemistry analyzer, plasma insulin concentrations were determined using the Alpco Ultra-Sensitive Insulin Rat ELISA, and total amide GLP-1 concentrations were determined using MSD ELISA kit.
  • Neat ferf-butyl nitrite (4.8 ml_, 39.3 mmol) was added slowly to a stirred mixture of isopropyl 4-[5-amino-4-(ethoxycarbonyl)-1 H-pyrazol-1 -yl]-piperidine-1 -carboxylate (Preparation 2) (8.5 g, 26.2 mmol) and copper (I I) bromide (3.7 g, 16 mmol) in acetonitrile (100 ml.) at room temperature. A significant exothermic effect was observed with the mixture warming to about 50 °C. After continued heating at 65 °C for 30 minutes, the reaction was cooled to room temperature, and then concentrated under vacuum.
  • the vial was flushed with nitrogen, sealed and heated at 120 °C for 1 hour in a microwave reactor (Biotage Initiator 2.2).
  • the reaction mixture was passed through a pad of FlorisilTM, diluted with ethyl acetate and then water was added.
  • the aqueous phase was extracted 3 times with ethyl acetate and the combined organic layers were dried over magnesium sulfate.
  • the mixture was filtered, and the filtrate evaporated under vacuum. Chromatography on silica gel eluting with 55% to 70% ethyl acetate in heptane gave the title compound as a green oil that solidified upon standing (1.06 g, 88 %).
  • the aqueous layer was extracted with ethyl acetate, and the combined organics layers were washed with brine, dried over magnesium sulfate, and the solvent removed under reduced pressure.
  • the resulting residue was purified by filtration through a short plug of silica gel eluting with 30% ethyl acetate in heptane to reveal the title compound as an colorless solid (61 .4 g, 50%). Impure material from this purification was further purified via the above chromatographic procedure to provide a second batch of the title compound (22 g, 18%) as a colorless solid.
  • Triethylamine (0.36 ml.) was then added slowly, followed by tetrabutylammonium chloride (37.4 mg, 0.12 mmol) and sodium azide (61 1 mg, 1 .82 mmol).
  • the resulting yellow suspension was vigorously stirred for 70 hours at room temperature under a nitrogen atmosphere.
  • the mixture was diluted with water and ethyl acetate.
  • the organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo.
  • a 1 L flask was charged with titanium methoxide (100 g), cyclohexanol (232 g), and toluene (461 mL). The flask was equipped with a Dean-Stark trap and condenser. The mixture was heated at 140 degrees Celsius until the methanol was removed. The toluene was removed at 180 degrees Celsius. More toluene was added and this process was repeated twice. After all the toluene was removed the flask was dried under high vacuum. Diethyl ether (580 mL) was added to the flask to prepare a 1 M solution in diethyl ether.
  • a 5 L, 3-neck flask was equipped with an overhead stirrer, inert gas inlet and a pressure-equalizing addition funnel.
  • the flask was flushed with nitrogen gas and charged with methyl acetate (60.1 mL, 756 mmol), titanium cyclohexyloxide (1 M solution in ether 75.6 mL), and diethyl ether (1500 mL).
  • the solution was stirred while keeping the reaction flask in a room temperature water bath.
  • the addition funnel was charged with the 3 M ethylmagnesium bromide solution (554 mL, 1 .66 moles).
  • the Grignard reagent was added drop-wise over 3 hours at room temperature.
  • the reaction flask was cooled in an ice water bath to keep the internal temperature at 10 degrees Celsius or below. Forty milliliters of the methyl acetate solution was added to the flask.
  • the Grignard reagent was then added drop-wise from the addition funnel at a rate of about 2 drops every second, and no faster than 2 mL per minute. After the first 40 mL of Grignard reagent had been added, another 20 mL portion of methyl acetate in ether solution was added. After the second 40 mL of Grignard reagent had been added, another 20 mL portion of methyl acetate in diethyl ether solution was added.
  • the mixture was stirred for an additional 15 minutes following the completion of the addition of Grignard reagent.
  • the mixture was then poured into a mixture of 660 g of ice and 60 mL of concentrated sulfuric acid with rapid stirring to dissolve all solids.
  • the phases were separated and the aqueous phase was extracted again with 50 mL of diethyl ether.
  • the combined ether extracts were washed with 15 mL of 10% aqueous sodium carbonate, 15 mL of brine, and dried over 30 grams magnesium sulfate for 1 hour with stirring.
  • the ether solution was then filtered. Tri-n-butylamine (14.3 mL, 60 mmol) and mesitylene (10 mL were added.
  • 2-Fluoro-4-bromo anisole (0.216 mL, 1.63 mmol), tri(2-furyl)phosphine (25.9 mg, 0.108 mmol), and potassium carbonate (300 mg, 2.17 mmol) were placed in a microwave vial and dissolved in anhydrous /V,/V-dimethylformamide (4.8 mL).
  • the mixture was degassed with a stream of nitrogen gas for 10 minutes, 1-methylimidazole (0.087 mL, 1.1 mmol) and palladium(ll) acetate (12.4 mg, 0.054 mmol) were added, and the mixture was degassed for another 10 minutes.
  • the vessel was placed in a microwave reactor at 140 degrees Celsius for 2 hours.
  • 2-Fluoro-4-bromoanisole (0.256 mL, 1 .93 mmol) and copper(l) iodide (375 mg, 1 .93 mmol) were placed in a microwave vial and dissolved in /V,/V-dimethylformamide (4.8 mL).
  • the mixture was degassed for 10 minutes with a stream of nitrogen gas, 1 - methylimidazole (0.078 mL, 0.96 mmol) and palladium(l l) acetate (1 1 mg, 0.048 mmol) were added, and the mixture was degassed for another 10 minutes.
  • the vessel was placed in a microwave reactor at 140 degrees Celsius for 2 hours.
  • Proton NMR indicates desired imidazole isomer as compared to the proton NMR of 5-(3-fluoro-4-methoxyphenyl)-1 -methyl-1 H Imidazole (preparation 27) and the literature Eur. J. Org. c em., 2008, 5436 and Eur. J. Org., 2006, 1379).
  • ferf-Butyl 4-oxo-1 -piperidinecarboxylate (2.00 g, 10 mmol) was dissolved in methanol (20 ml.) and cooled to 0 degrees Celsius. Powdered potassium hydroxide (1 .26 g, 22.1 mmol) was added. Iodine (2.8 g, 1 1 mmol) was dissolved in methanol (25 ml.) and was added drop wise to the reaction over 45 minutes. The reaction was then slowly warmed up to room temperature and stirred for 16 hours. The reaction was concentrated and toluene (50 ml.) was added. The resulting solids were filtered off and washed with toluene.
  • ferf-Butyl 4-[5-amino-4-(ethoxycarbonyl)-1 H-pyrazol-1-yl]-3-hydroxypiperidine-1- carboxylate (1.71 g, 4.82 mmol) was dissolved in dichloromethane (50 mL) and cooled to -78 degrees Celsius. Diethylaminosulfur trifluoride (0.710 mL, 0.58 mmol) was added drop wise, and then warmed up to 0 degrees Celsius for 25 minutes. The reaction solution was cooled to -78 degrees Celsius and methanol (10 mL) carefully added.
  • the reaction mixture was cooled to room temperature and diluted with ethyl acetate.
  • the reaction was filtered through a pad of Celite® and the filtrate was diluted with water and extracted with ethyl acetate (2x).
  • the combined organic extracts were washed with water then brine and dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • the crude residue was purified by flash chromatography eluting with a gradient from 10% to 100% ethyl acetate in heptanes to give ethyl 5-cyano-1-(3-fluoropiperidin-4-yl)-1 H-pyrazole-4- carboxylate (80 mg, 98%).
  • the combined aqueous extracts were acidified with 1 N aqueous sodium bisulfate to pH 2.
  • the acidic solution was extracted with ethyl acetate (3x) and the extracts were washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 1 -[1 -(ferf-butoxycarbonyl)-3-fluoropiperidin-4-yl]-5-cyano-1 H-pyrazole- 4-carboxylic acid as a white solid.
  • the filtrate was cooled to 0 degrees Celsius and a solution of sodium borohydride (17 mg, 0.474 mmol) dissolved in water (0.4 mL) was added very slowly (drop wise). Once addition was complete, the reaction was allowed to warm up to room temperature for 2.5 hours. The reaction solution was further diluted with water and acidified to pH 2.5 using ⁇ ⁇ sodium bisulfate. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • Triethylamine (0.036 ml_, 0.258 mmol) was added and the mixture was cooled to 0 degrees Celsius.
  • Methanesulfonic anhydride (20 mg, 0.1 12 mmol) was added drop wise and slowly allowed to warm up to room temperature over 2 hours.
  • the aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined and washed sequentially with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. The mixture was filtered, and the filtrate was
  • Step B can be performed as follows, isolating the hydrate of the ketone.
  • ferf-butyl-4-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1 (2H)- carboxylate (41.3 g, 0.15 mol) in acetonitrile (500 mL) at room temperature was added SelectfluorTM (56.9 g, 0.16 mol).
  • SelectfluorTM 56.9 g, 0.16 mol
  • the aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined and washed sequentially with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. The mixture was filtered, and the filtrate was
  • Step C can be performed starting with the hydrate tert-butyl 3-fluoro- 4,4-dihydroxypiperidine-1-carboxylate (Step 2) as follows.
  • pH 7 phosphate buffer 150 mL
  • a 35% aqueous hydrogen peroxide solution 150 mL
  • the resulting mixture was stirred for 30 minutes and diluted with ethyl acetate.
  • the organic layer was separated and sequentially with water, saturated aqueous sodium thiosulfate and brine.
  • Step D Enantiomers of terf-butyl-(3,4-c/s)-3-fluoro-4-hvdroxy-piperidine-1 -carboxylate
  • a 1 gram sample of racemic ferf-butyl-(3,4-c/s)-3-fluoro-4-hydroxy-piperidine-1- carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 90: 10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute.
  • the wavelength for monitoring the separation was 210 nM.
  • the analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralpak AD-H (4.6 mm x 25 cm) column with an isocratic mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute.
  • the wavelength for monitoring the peaks was 210 nm.
  • the following two isomers were obtained:
  • the crude sample (9.5 mg) was dissolved in dimethyl sulfoxide (1 mL) and purified by preparative reverse phase HPLC on a Waters XBridge C-m 19 x 100 mm, 0.005 mm column, eluting with a linear gradient of 80% water/acetonitrile (0.03% ammonium hydroxide modifier) to 0% water/acetonitrile in 8.5 minutes, followed by a 1.5 minute period at 0% water/acetonitrile; flow rate: 25mL/minute.
  • the title compound (5 mg) was thus obtained.
  • Analytical LCMS retention time 2.81 minutes (Waters XBridge C-ie 4.6 x 50 mm, 0.005 mm column; 90% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, followed by a 1 minute period at 5% water/acetonitrile; 0.03% ammonium hydroxide modifier; flow rate: 2.0 mL/minute); LCMS (ES+) 433.2 (M+1 ).
  • the mixture was extracted with dichloromethane (10 x 30 mL).
  • the aqueous layer was then brought to pH 12 by the addition of 1 N aqueous sodium hydroxide solution (20 mL) and was extracted three times with dichloromethane (40 mL).
  • the combined organic extracts were washed with brine, dried over sodium sulfate and filtered.
  • Example number begins at 1 1 .
  • Example 1 Isopropyl 4- ⁇ 5-cvano-4-r(2,4-difluorophenoxy)methyll-1 H-pyrazol-1 - yl ⁇ piperidine-1 -carboxylate
  • Analytical LCMS retention time: 3.62 minutes (Waters Atlantis d 8 4.6 x 50 mm, 0.005 mm; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0min; 0.05 %
  • Example 12 Isopropyl 4- ⁇ 5-cyano-4-[(2-methylphenoxy)methyll-1 H-pyrazol-1 - yl ⁇ piperidine-1 -carboxylate
  • Example 13 1-Methylcvclopropyl 4- ⁇ 5-cvano-4-[(2,5-difluorophenoxy)methyll-1 H- pyrazol-1-yl ⁇ piperidine-1-carboxylate
  • reaction mixture was diluted with dichloromethane and water. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium
  • Example 14 1-Methylcvclopropyl 4- ⁇ 5-cvano-4-[(2,3-difluorophenoxy)methyll-1 H- pyrazol-1-yl ⁇ piperidine-1 -carboxylate
  • the title compound was prepared using commercially available 2,3-diflurophenol, following procedures analogous to Example 13.
  • the crude material (49 mg) was dissolved in dimethyl sulfoxide (0.9 mL) and purified by preparative reverse-phase HPLC on a Waters XBridge C-ie column 19 x 100 mm, 0.005 column eluting with a gradient of water in acetonitrile (0.03% ammonium hydroxide modifier).
  • 1 H NMR indicated the presence of less than 10% of what is believed to be the
  • Example 16 1 -Methylcvclopropyl 4- ⁇ 4-[(4-carbamoylphenoxy)methyll-5-cvano-1 H- pyrazol-1 -yl ⁇ piperidine-1 -carboxylate
  • the title compound was prepared using commercially available 4-hydroxybenzonitrile, following procedures analogous to Example 15.
  • the purification of the crude reaction mixture was performed by flash chromatography, eluting with a gradient mixture of ethyl acetate in heptane (0 to 100% ethyl acetate).
  • Example 18 Isopropyl 4-(4-((4-(1 H-pyrazol-1 -yl)phenoxy)methyl)-5-cvano-1 H-pyrazol-1 - yl)piperidine-1 -carboxylate
  • the title compound was prepared using 4-(1 H-pyrazol-1 -yl)phenol (WO 2003072547 ), following a procedure analogous to Example 12.
  • the purification of the crude reaction mixture was performed by flash chromatography, eluting with a gradient mixture of ethyl acetate in heptane (0 to 100% ethyl acetate).
  • Example 19 Isopropyl 4-(5-cvano-4-((2-fluoro-4-(1 H-tetrazol-5-yl)phenoxy)methyl)-1 H- pyrazol-1 -yl)piperidine-1 -carboxylate and Isopropyl 4-(5-cvano-4-((2-fluoro-4-(2H- tetrazol-5-yl)phenoxy)methyl)-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate
  • Example 21 Isopropyl 4-(5-cvano-4-((2-fluoro-4-(2-methyl-2H-tetrazol-5- yl)phenoxy)methyl)-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate
  • the reaction was quenched by addition of water and the mixture was diluted with ethyl acetate.
  • the organic phase was separated and the aqueous phase was extracted twice with ethyl acetate.
  • the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo.
  • Example 22 Isopropyl 4-(5-cvano-4-((2-fluoro-4-(2-(2-hvdroxyethyl)-2H-tetrazol-5- yl)phenoxy)methyl)-1 -pyrazol-1 -yl)piperidine-1 -carboxylate
  • Example 23 Isopropyl 4-(5-cvano-4-((2-fluoro-4-(1-(2-hvdroxyethyl)-1 H-tetrazol-5- yl)phenoxy)methyl)-1 H-pyrazol-1-yl)piperidine-1 -carboxylate
  • Example 25 1 -Methylcvclopropyl 4-(5-cvano-4- ⁇ [4-(1 -methyl-1 H-tetrazol-5- vDphenoxylmethylH H-pyrazol-1 -yl)piperidine-1-carboxylate
  • Example 26 1 -Methylcvclopropyl 4-(4-((4-carbamoyl-3-fluorophenoxy)methyl)-5-cvano-
  • Example 27 Isopropyl 4-(5-cvano-4- ⁇ 1 -[2-fluoro-4-(methylsulfonyl)phenoxylethyl ⁇ -1 H- pyrazol-1 -yl)piperidine-1 -carboxylate
  • the sample was purified by reversed-phase HPLC (Column: Waters XBridge C18 19x100, 5 micrometer; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 80%water/20%acetonitrile linear to 0%water/100%acetonitrile in 8.5 minutes, hold at 0%water / 100%acetonitrile to 10.0 minutes. Flow: 25ml_/minute. LCMS ( ES+): 479.2 M+1 ).
  • Example 28 Isopropyl 4-(5-cvano-4- ⁇ 1 -[(2-methylpyridin-3-yl)oxylethyl ⁇ -1 H-pyrazol-1 - yl)piperidine-1 -carboxylate
  • the title compound was prepared using 2-methylpyridin-3-ol and isopropyl 4-(5-cyano- 4-(1 -hydroxyethyl)-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate (Preparation 25) , following procedures analogous to Example 15.
  • the sample was purified by reversed-phase HPLC (Column: Waters XBridge C18 19x100, 5 micrometer; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 85%water/15%acetonitrile linear to
  • Example 30 1-Methylcvclopropyl 4-(5-cvano-4- ⁇ r(2-methylpyridin-3-yl)oxylmethyl ⁇ -1 H- pyrazol-1-yl)piperidine-1 -carboxylate
  • the title compound was prepared using 2-methylpyridin-3-ol, following procedures analogous to Example 13.
  • the crude material was purified by flash chromatography, eluting with a gradient mixture of ethyl acetate in heptane (60 to 100% ethyl acetate) to give 77 mg of the title compound as a white solid.
  • Example 31 1-Methylcvclopropyl 4- ⁇ 5-cvano-4-r(2,3,6-trifluorophenoxy)methyll-1 H- pyrazol-1-yl ⁇ piperidine-1 -carboxylate
  • Example 32 Isopropyl 4- ⁇ 5-cvano-4-r(2,3,6-trifluorophenoxy)methyll-1 H-pyrazol-1 - yl ⁇ piperidine-1 -carboxylate
  • the title compound was prepared using commercially available 2,3,6-trifulorophenol following procedures analogous to Example 1 1 .
  • the crude material was purified by column chromatography eluting with a 0 to 25% ethyl acetate in heptane gradient to give isopropyl 4- ⁇ 5-cyano-4-[(2,3,6-trifluorophenoxy)methyl]-1 H-pyrazol-1 -yl ⁇ piperidine- 1 -carboxylate as a clear oil.
  • the title compound was prepared from 2-fluoro-4-(1-methyl-1 H-imidazol-2-yl)phenol (Preparation 28) and isopropyl 4-(5-cyano-4-((methylsulfonyloxy)methyl)-1 H-pyrazol-1 - yl)piperidine-1 -carboxylate (Preparation 10) following procedures analogous to Example 1 1 .
  • the crude material was purified by preparative reverse-phase HPLC on a Sepax Silica 250 x 21 .2mm, 0.005 mm, eluting with a gradient of ethanol in heptane.
  • the title compound was prepared from 2-fluoro-4-(1-methyl-1 H-imidazol-5-yl)phenol (Preparation 27) and Isopropyl 4-(5-cyano-4-((methylsulfonyloxy)methyl)-1 H-pyrazol-1 - yl)piperidine-1 -carboxylate (Preparation 10) following procedures analogous to Example 1 1 .
  • the crude material was purified by preparative reverse-phase HPLC on a Sepax Silica 250 x 21 .2mm, 0.005 eluting with a gradient of ethanol in heptane.
  • Example 35 Isopropyl 4-[5-cvano-4-( ⁇ [2-methyl-6-(1 H-1 ,2,4-triazol-1-yl)pyridin-3- ylloxy ⁇ methyl)-1 H-pyrazol-1-yllpiperidine-1-carboxylate
  • the title compound was prepared using 2-methyl-6-(1 H-1 ,2,4-triazol-1-yl)pyridin-3-ol following procedures analogous to Example 12.
  • the sample was purified by reversed- phase HPLC (Column: Waters XBridge C18 19x100, 5 micrometer; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hyrdroxide in acetonitrile (v/v); Gradient: 80%water/20%acetonitrile linear to
  • Example 37 Isopropyl 4-r5-cvano-4-( ⁇ r2-methyl-6-(methylsulfonyl)pyridin-3- yllamino ⁇ methyl)-1 H-pyrazol-1-yllpiperidine-1 -carboxylate
  • the title compound was prepared using 2-methyl-6-(methylsulfonyl)pyridin-3-amine following procedures analogous to Example 36.
  • the sample was purified by reversed- phase HPLC (Column: Waters XBridge C18 19x100, 5 micrometer; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hyrdroxide in acetonitrile (v/v); Gradient: 85%water/15%acetonitrile linear to
  • Example 40 Isopropyl 4- ⁇ 5-cvano-4-r(3-cvanophenoxy)methyll-1 H-pyrazol-1- yl ⁇ piperidine-1 -carboxylat
  • Example 42 Isopropyl 4- ⁇ 5-cvano-4-[(4-cvanophenoxy)methyll-1 H-pyrazol-1- yl ⁇ piperidine-1 -carboxyla
  • Example 43 4-r(4-Cvano-2-fluorophenoxy)methyll-1 - ⁇ 1 -(5-ethylpyrimidin-2-yl)piperidin- 4-yll-1 H-pyrazole-5-carbonitrile
  • the title compound was prepared using commercially available 4-cyano-2-fluorophenol, following procedures analogous to Example 39.
  • the crude material was purified by flash chromatography eluting with a gradient from 0% to 1.5% methanol in
  • the title compound was prepared using commercially available 4-cyano-2-fluorophenol, following procedures analogous to Example 15. The crude material was purified by flash chromatography eluting with a gradient from 10% to 40% ethyl acetate in heptanes to give the title compound (21 g, 100%).
  • Example 45 Isopropyl 4- ⁇ 5-cvano-4-[(2-cvano-4-fluorophenoxy)methyll-1 H-pyrazol-1- yl ⁇ piperidine-1 -carboxylate
  • the title compound was prepared using commercially available 2-cyano-4-fluorophenol, following procedures analogous to Example 15.
  • the crude material was purified by HPLC (Column Waters Atlantis dC18 4.6x50mm, 5 micrometer; Modifier: 0.05% trifluoroacetic acid; Gradient: 95% water / 5% acetonitrile linear to 5% water / 95% acetonitrile over 4.0 min, HOLD at 5% water / 95% acetonitrile to 5.0 min; Flow: 2.0 mL/min) to give 35.8 mg (73%) of the title compound.
  • Example 50 1-Methylcvclopropyl 4- ⁇ 5-cvano-4-r(4-cvano-2-fluorophenoxy)methyll-1 H- pyrazol-1-yl ⁇ piperidine-1-carboxylate
  • Ethyl 5-cyano-1 H-pyrazole-4-carboxylate (Jubilant Chemsys Ltd. D-12, Sector-59, 201 301 , noisyda, U.P. India) (50 g, 300 mmol), ferf-butyl 4-hydroxypiperidine-1-carboxylate (67 g, 333 mmol), and triphenylphosphine (1 1 1 g, 420 mmol) were dissolved in 2-methyl tetrahydrofuran (200 mL) and cooled to 0 degrees Celsius. A 40% solution of diethyl azodicarboxylate in toluene (76.5 mL, 420 mmol) was added drop wise.
  • ferf-Butyl 4-[5-cyano-4-(ethoxycarbonyl)-1 H-pyrazol-1 -yl]piperidine-1 -carboxylate (45.5 g, 131 mmol) was dissolved in tetrahydrofuran (350 ml.) and cooled to -78 degrees Celsius.
  • a 1 .5M solution of diisobutylaluminum hydride in toluene (50 g, 350 mmol) was added drop wise over 75 minutes maintaining the internal temperature between -65 degrees Celsius and -60 degrees Celsius. Once the addition was complete, the reaction mixture was warmed to -10 degrees Celsius for 90 minutes.
  • Example 53 1 -Methylcvclopropyl (3S,4S)-4-(5-cyano-4- ⁇ r2-fluoro-4- (methylcarbamoyl)phenoxylmethyl ⁇ -1 H-pyrazol-1 -yl)-3-fluoropiperidine-1 -carboxylate
  • the title compound was prepared using 3-fluoro-4-hydroxy-N-methylbenzamide (Preparation 31 A), following procedures analogous to Examples 50 and 51 .
  • the crude material was purified via HPLC (Column: Princeton 2-ethyl pyridine 250 x 21 .2 mm 5 micrometer; Gradient: 95% heptane / 5% ethanol for 1 .5 minutes, linear to 0% heptane / 100% ethanol over 10 min, HOLD at 0% heptane / 100% ethanol to 5.0 minfor 1 minute and linear to 95% heptane / 5% ethanol ; Flow: 28 mL/min) to give the desired product.
  • Example 54 1 -Methylcvclopropyl (3R,4R)-4-(5-cvano-4- ⁇ r2-fluoro-4-
  • the title compound was prepared using 3-fluoro-4-hydroxy-N-methylbenzamide (Preparation 31 A), following procedures analogous to Examples 50 and 51 .
  • the crude material was purified via HPLC (Column: Princeton 2-ethyl pyridine 250 x 21 .2mm, 5 micrometer; Gradient: 95% heptane / 5% ethanol for 1 .5 minutes, linear to 0% heptane / 100% ethanol over 10min, Hold at 0% heptane / 100% ethanol to 5.0 minfor 1 minute and linear to 95% heptane / 5% ethanol ; Flow: 28 mL/min) to give the desired product.
  • Example 55 terf-Butyl (3S,4S)-4-(5-cvano-4- ⁇ r(2-methylpyridin-3-yl)oxylmethyl ⁇ -1 H- pyrazol-1 -yl)-3-fluoropiperidine-1 -carboxylate
  • the reaction mixture was heated to 80 degrees Celsius for 1.5 hour.
  • the reaction was cooled to room temperature and concentrated under reduced pressure.
  • the crude residue was diluted with water and extracted with ethyl acetate (3x).
  • the combined organic extracts were washed with aqueous 0.5N sodium hydroxide, water and brine and dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • the crude residue was purified by flash chromatography eluting with a gradient from 30% to 100% ethyl acetate in heptanes to give the racemic product as an amber oil (30 mg, 70%).
  • Example 58 1-Methylcvclopropyl (3S,4R)-4-(5-cyano-4- ⁇ [(2-methylpyridin-3- yl)oxylmethyl ⁇ -1 H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate
  • the title compound was prepared using commercially available 3-hydroxy-2- methylpyridine, following procedures analogous to Example 55.
  • the crude material was purified by flash chromatography eluting with a gradient of 40% to 100% ethyl acetate in heptanes to give the racemic product which was further purified by chiral HPLC with the following conditions: Column: chiralcel OJ-H 4.6mm x 25cm; Mobile Phase: 85/15 carbon dioxide/methanol, Modifier: 0.2% isopropylamine; Flow Rate: 2.5ml_/minute to give the title compound.
  • Example 59 1 -Methylcvclopropyl (3R,4S)-4-(5-cvano-4- ⁇ r(2-methylpyridin-3- yl)oxylmethyl ⁇ -1 H-pyrazol-1 -yl)-3-fluoropiperidine-1 -carboxylate
  • the title compound was prepared using commercially available 3-hydroxy-2- methylpyridine, following procedures analogous to Example 55.
  • the crude material was purified by flash chromatography eluting with a gradient from 40% to 100% ethyl acetate in heptanes to give the racemic product which was further purified by chiral HPLC with the following conditions: Column: chiralcel OJ-H 4.6mm x 25cm; Mobile Phase: 85/15 carbon dioxide/methanol, Modifier: 0.2% isopropylamine; Flow Rate: 2.5ml_/minute to give the title compound.
  • the title compound was prepared using 4-(1 H-1 ,2,3-triazol-1 -yl)phenol (US Patent Application No. PCT/US2009/038315, Publication No. WO 2009/129036 A1 ) following procedures analogous to Example 15.
  • the crude material was purified by HPLC (Column: Phenomenex Gemini C18 250x21 .2 mm, 8 micrometer; Mobile Phase: from 50% acetonitrile (ammonia pH 10) in water (ammonia pH 10) to 55% acetonitrile (ammonia pH 10) in water (ammonia pH 10); Flow Rate: 25mL/minute; wavelength: 220 nm) to give the title compound.
  • the title compound was prepared using 4-(2H-1 ,2,3-triazol-2-yl)phenol (US Patent Application No. PCT/US2009/038315, Publication No. WO 2009/129036 A1 ) following procedures analogous to Example 15.
  • the crude material was purified by HPLC (Column: Phenomenex Gemini C18 250x21 .2 mm, 8 micrometer; Mobile Phase: 63% acetonitrile (ammonia pH 10) in water (ammonia pH 10); Flow Rate: 25ml_/minute; wavelength: 220 nm) to give the title compound.
  • Example 62 1 -Methylcvclopropyl 4-(4-((4-(1 H-1 ,2,3-triazol-1 -yl)phenoxy)methyl)-5- cvano-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate
  • Example 60 The title compound was prepared in a manner analogous to Example 60 starting with Example 60.
  • the crude material was purified by reverse phase HPLC:
  • Example 63 1-Methylcvclopropyl 4-(4-((4-(2H-1 ,2,3-triazol-2-yl)phenoxy)methyl)-5- cvano-1 H-pyrazol-1-yl)piperidine-1-carboxylate
  • Example 61 The title compound was prepared in a manner analogous to Example 61 starting with Example 61.
  • the crude residue was purified by preparative HPLC to yield 50 mg (39%) of the title compound as a white solid:
  • Example 64 terf-Butyl 4-r5-cvano-4-( ⁇ ri-(methylsulfonyl)piperidin-4-ylloxy ⁇ methyl)-1 H- pyrazol-1-yllpiperidine-1-carboxylate
  • the title compound was prepared in a manner analogous to Example 13.
  • the crude compound was purified by silica gel chromatography using an 1 :4 mixture of petroleum ether and ethyl acetate.
  • Example 65 ferf-Butyl 4-r5-cvano-4-( ⁇ 2-fluoro-4-r(2- hvdroxyethyl)(methyl)carbamoyllphenoxy ⁇ methyl)-1 H-pyrazol-1 -yllpiperidine-1 - carboxylate
  • Example 66 terf-Butyl 4-r5-cvano-4-( ⁇ 2-fluoro-4-r(3-hvdroxypyrrolidin-1- yl)carbonyllphenoxy ⁇ methyl)-1 H-pyrazol-1-yllpiperidine-1-carboxylate
  • Mobile phase from 40% acetonitrile (ammonia pH 10) in water (ammonia pH 10) to 60% acetonitrile (ammonia pH 10) in water (ammonia pH 10)
  • Mobile phase from 40% acetonitrile (ammonia pH 10) in water (ammonia pH 10) to 60% acetonitrile (ammonia pH 10) in water (ammonia pH 10)
  • Example 68 1 -Methylcvclopropyl 4-r5-cvano-4-( ⁇ ri-(methylsulfonyl)piperidin-4-
  • Example 64 The title compound was prepared in a manner analogous to Example 64.
  • the crude material was purified by reverse phase HPLC: Column: Phenomenex Synergi C18 150x30 mm x 4 micrometer

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BR112013011865A BR112013011865A2 (pt) 2010-11-23 2011-11-09 moduladores de gpr119
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AP2013006809A AP2013006809A0 (en) 2010-11-23 2011-11-09 4-(5-cyano-pyrazol-1-YL)-piperidine derivatives asGPR 119 modulators
MA35928A MA34805B1 (fr) 2010-11-23 2011-11-09 Dérivés de 4-(5-cyano-pyrazole-1-yl)-pipéridine en tant que modulateurs du gpr119
CN2011800550665A CN103298801A (zh) 2010-11-23 2011-11-09 作为gpr 119 调节剂的4-（5-氰基-吡唑-1-基）哌啶衍生物
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WO2012170867A1 (en) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Novel compounds as modulators of gpr-119
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
WO2017140771A1 (en) 2016-02-18 2017-08-24 Syngenta Participations Ag Pesticidally active pyrazole derivatives

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JP2017119628A (ja) * 2014-05-09 2017-07-06 日産化学工業株式会社 置換アゾール化合物及び糖尿病治療薬
CN104592120A (zh) * 2015-02-13 2015-05-06 佛山市赛维斯医药科技有限公司 一种环丙基酰肼和甲氧苯类gpr119激动剂、制备方法及其用途
CN104610151A (zh) * 2015-02-13 2015-05-13 佛山市赛维斯医药科技有限公司 含酰肼和烷氧苯类结构的化合物、其制备方法及用途
CN104892517A (zh) * 2015-02-13 2015-09-09 佛山市赛维斯医药科技有限公司 酰肼类化合物、其制备方法及用途
CN106631992B (zh) * 2017-01-05 2019-01-18 桑迪亚医药技术（上海）有限责任公司 一种4-氧-3,4-二氢-2h-吡啶-1-甲酸叔丁酯的合成方法

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WO2010140092A1 (en) * 2009-06-05 2010-12-09 Pfizer Inc. L- ( piperidin-4-yl) -pyrazole derivatives as gpr 119 modulators

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WO2012170867A1 (en) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Novel compounds as modulators of gpr-119
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
WO2017140771A1 (en) 2016-02-18 2017-08-24 Syngenta Participations Ag Pesticidally active pyrazole derivatives

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