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WO2009106561A1 - Composés pyrazines pour le traitement de troubles apparentés à gpr119 - Google Patents

Composés pyrazines pour le traitement de troubles apparentés à gpr119 Download PDF

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WO2009106561A1
WO2009106561A1 PCT/EP2009/052268 EP2009052268W WO2009106561A1 WO 2009106561 A1 WO2009106561 A1 WO 2009106561A1 EP 2009052268 W EP2009052268 W EP 2009052268W WO 2009106561 A1 WO2009106561 A1 WO 2009106561A1
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methyl
alkyl
phenyl
carboxylate
amino
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Gary Johansson
Lars Johansson
Tobias Koolmeister
Michael Weber
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Swedish Orphan Biovitrum AB
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Biovitrum AB
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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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present invention relates to novel pyrazine compounds, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for the prophylaxis and treatment of medical conditions relating to disorders of the G-protein- coupled receptor GPRl 19 such as diabetes, obesity and osteoporosis.
  • Diabetes mellitus is a group of disorders characterized by abnormal glucose homeostasis resulting in high levels of blood glucose.
  • Type 1 also referred to as insulin-dependent diabetes mellitus or IDDM
  • Type 2 diabetes also referred to as non- insulin-dependent diabetes mellitus or NIDDM
  • Type 2 diabetes accounts for approximately 90% of all diabetic cases.
  • Type 2 diabetes is a serious progressive disease that results in the development of microvascular complications (e.g. retinopathy, neuropathy, nephropathy) as well as macrovascular complications (e.g. accelerated atherosclerosis, coronary heart disease, stroke). More than 75% of people with Type 2 diabetes die of cardiovascular diseases.
  • Type 2 diabetes involves insulin resistance, insulin secretory dysfunction (i.e. pancreatic beta cell dysfunction) and hepatic glucose overproduction. Insulin resistance is highly correlated with obesity. Accumulating reports suggest insulin resistance to be central to a cluster of metabolic abnormalities - including dyslipidemia, hypertension, endothelial dysfunction, reduced fibrinolysis, and chronic systemic inflammation - that together are responsible for the increased cardiovascular risk. Current antidiabetic therapy is targeting the defects mentioned above. For instance, sulphonylureas increase production of endogenous insulin.
  • Obesity is linked to a wide range of medical complications, such as diabetes, cardiovascular disease and cancer In addition, being overweight can exacerbate the development of osteoporosis and asthma. Obesity is also proven to double the risk of hypertension. Obesity has only recently been regarded as a disease in the sense of being a specific target for medical therapy. Current therapies for obesity are based on diet and exercise and stomach surgery for extremely obese patients Two weight loss medications are today available for long- term use.
  • Sibutramine a serotonin- and noradrenaline-reuptake inhibitor
  • a prominent side effect is hypertension
  • Orhstat inhibits the hpase-mediated breakdown of fat in the gastrointestinal tract, thereby limiting caloric intake resulting in weight loss
  • approximately 20% of the patients using Orlistat develop faecal incontinence and urgency.
  • Osteoporosis or porus bone
  • GIP Glucose-dependent Insulmotropic Polypeptide
  • GPRl 19 is a G-protein coupled receptor identified as SNORF25 in WO 00/50562 In humans, GPRl 19 is selectively expressed m pancreas and gastrointestinal tract Activation of GPRl 19 by lysophosphatidylcholme (LPC) induces glucose-dependent insulin secretion from pancreatic beta-cells (Soga et al , Biochem Biophys Res Commun 326, 744-751, 2005). GPRl 19 agonists stimulate insulin secretion m rat islets and reduce blood glucose in diabetic Lep ⁇ mice (WO 2004/065380 and Chu et al., Endocrinology 148, 2601-9, 2007).
  • LPC lysophosphatidylcholme
  • GPRl 19 agonists enhance the release of the mcretins, GLP-I and GIP in mice models and in GLUTag cells, which is a model used to investigate the function of intestinal L-cells (Chu et al., Endocrinology Jan 17, 2008).
  • GPRl 19 Another endogenous ligand for GPRl 19, oleoylethanolamide (OEA), and a small molecule GPRl 19 agonist, PSN632408, both suppress food intake and reduce body weight gain in rat (Overton et al., Cell Metabolism 3, 167-175, 2006). Taken together, these data suggest that GPRl 19 is an interesting target for treating diabetes and/or obesity.
  • OOA oleoylethanolamide
  • PSN632408 a small molecule GPRl 19 agonist
  • WO 2004/065380 disclose compounds that are modulators of the Rup3 receptor, also referred to as SNORF25 (WO 00/50562) or as GPRl 19 (Fredriksson et al., FEBS Lett, 554, 381- 388, 2003), and which inter alia may be used for the treatment of metabolic disorders and complications thereof, such as diabetes and obesity.
  • WO 2005/061489, WO 2006/067531, WO 2006/067532 and WO 2006/070208 disclose compounds that are agonists of GPRl 16, also referred to as SNORF25 or as GPRl 19 (see Overton et al, Cell Metabolism 3, 167-175, 2006), and which inter alia may be used for the treatment of metabolic disorders and complications thereof, such as diabetes and obesity.
  • WO 2006/076231 discloses a synergistic effect of a GPRl 19 agonist in combination with a DPP-IV inhibitor, m lowering elevated glucose levels m mice.
  • WO 2007/120689 discloses a method of using GPRl 19 receptor to identify compounds useful for increasing bone mass in an individual.
  • GPRl 19 agonists are shown to enhance GIP in wildtype mice.
  • compounds of the general Formula (Ia) to (Ic) are active as agonists of GPRl 19 and are potentially useful in the treatment or prophylaxis of disorders relating to GPRl 19.
  • disorders include Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, obesity, hypertension, chronic systemic mflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis
  • the invention provides a compound of Formula (Ia),
  • A is CH 2 , O, NR 10 , C(O), S, S(O) or S(O) 2 ,
  • B is CH 2 , O, NR 10 , C(O), S, S(O) or S(O) 2 , provided that when B is O, NR 10 , C(O), S, S(O) or S(O) 2 , then A is CH 2 ,
  • D is N, C or CR 11 , provided that D must be CR 11 and said R 11 must be hydrogen or methyl when B is selected from O, NR 10 , C(O), S, S(O) and S(O) 2 ,
  • — is a single bond when D is N or CR 11 or a double bond when D is C;
  • E and G are independently Ci 3-alkylene, each optionally substituted with a substituent independently selected from the group consisting of Ci 3-alkyl, Ci 4-alkoxy, carboxy, fluoro-Ci 3-alkyl, hydroxy, hydroxymethyl, and fluoro, provided that the ring formed by D, E, N and G has not more than 7 ring atoms, and further provided that the said ring has 6 or 7 ring atoms when D is N, and yet further provided that the total number of substituents on E and G independently is not more than 2;
  • R 1 is C(O)OR 2 , C(O)R 2 , S(O) 2 R 2 , C(O)NR 2 R 3 or -CH 2 -C(O)NR 2 R 3 , or a 5- or 6-membered heteroaryl group linked via a ring carbon atom, wherein the said heteroaryl group is optionally substituted with Ci- 4 -alkyl;
  • Ar 1 is phenyl or heteroaryl, each of which is optionally independently substituted in one or more positions with a substituent selected from:
  • R 2 is selected from:
  • Ci_3-alkylaminocarbonyl-C2-6-alkyl (w) Ci_3-alkylaminocarbonyl-C2-6-alkyl, (x) di(Ci_ 3 -alkyl)aminocarbonyl-C 2 - 6 -alkyl,
  • R 3 is selected from'
  • R 4 is independently selected from:
  • Ci_ 3 -alkylaminocarbonyl-C 2 - 4 -alkyl (s) di(Ci_ 3 -alkyl)aminocarbonyl-C 2 - 4 -alkyl,
  • R 5 is each independently selected from:
  • R 6 is independently selected from:
  • R 7 is independently selected from Ci 4 -alkyl
  • R 8 is independently selected from.
  • R is each independently selected from' (a) Ci_ 4 -alkoxy-C 2 - 4 -alkyl,
  • R 10 is independently selected from.
  • R 11 is selected from:
  • R is each independently selected from
  • each R 5 is independently selected from the group consisting of hydrogen and C]_ 4 -alkyl, or two R 5 groups together with the nitrogen to which they are attached form a pyrrolidine or an azetidme ring,
  • Ci-3-alkyl Ci-3-alkyl
  • Ci_3-alkoxy-Ci_ 2 -alkyl Ci_3-alkoxy-Ci_ 2 -alkyl
  • a preferred group of compounds of formula (Ia) are the compounds of Formula (Ib),
  • A is CH 2 , O, NR 10 , C(O), S, S(O) or S(O) 2 ,
  • B is CH 2 , O, NR 10 , C(O), S, S(O) or S(O) 2 , provided that when B is O, NR 10 , C(O), S, S(O) or S(O) 2 , then A is CH 2 , m is each independently O or 1 , D is N or CR 11 , provided that D must be CR 11 and said R 1 1 must be hydrogen or methyl when B is selected from O, NR 10 , C(O), S, S(O) and S(O) 2 , and further provided that each m is 1 when D is N, Ar 1 , Z 1 , Z 2 , R 1 to R 9 and R 12 are as defined in Formula (Ia),
  • R is independently selected from
  • R 11 is selected from
  • A is CH 2 , O or NR 10 ;
  • B is CH 2 , O or NR 10 , provided that when B is O or NR 10 , then A is CH 2 , m is each independently 0 or 1;
  • Z 1 , Z 2 , R 1 to R 7 , R 9 and R 12 are as defined in Formula (Ia);
  • R 10 is as defined in Formula (Ib),
  • Ar 1 is phenyl or 5- or 6-membered heteroaryl, each of which is optionally substituted in one or two positions with a substituent independently selected from the group Z 3 consisting of:
  • halogen selected from bromine, chlorine and fluorine
  • R 8 is independently selected from:
  • a preferred subgroup of compounds of Formula (Ic) consists of compounds wherein:
  • A is CH 2 and B is O or NR 10 , or A is O or NR 10 and B is CH 2 , m is each 1 ,
  • Ar 1 is phenyl, pyridinyl or thienyl, each of which is optionally substituted in one or two positions with a substituent independently selected from the group Z 4 consisting of
  • R 1 is a group R 1A selected from C(O)OR 2A , C(O)R 2A , S(O) 2 R 2A , C(O)NR 2A R 3A , -CH 2 -C(O)NR 2A R 3A , or a 5- or 6-membered heteroaryl group linked via a ring carbon atom, wherein the said heteroaryl group is optionally substituted with Ci- 4 -alkyl;
  • R 2A is selected from:
  • heteroaryl-Ci_ 4 -alkyl wherein any aryl or heteroaryl residue, alone or as a part of another group, is optionally substituted in one or more positions with a substituent independently selected from the group Z 5 consisting of
  • R 3A is selected from:
  • R 5A is each independently selected from:
  • R 7A is independently selected from Ci- 4 -alkyl
  • R 10 is independently selected from'
  • R 12 is each hydrogen
  • A is CH 2 and B is O or NR 10
  • Ar 1 is selected from methylsulfonylphenyl, (ammocarbonyl)phenyl, [(methylamino)carbonyl]phenyl, [(dimethylamino)carbonyl]phenyl, [(4-methylpiperazm-l-yl)carbonyl]phenyl, [2-(hydroxy- methyl)morpholin-4-ylcarbonyl]phenyl, (methylsulfmyl)phenyl, pyridinyl, [(3-hydroxy- pyrrolidm- 1 -yl)carbonyl]phenyl, ⁇ [(2-hydroxymethyl)pyrrolidm- 1 -yl]carbonyl ⁇ phenyl, [(3-hydroxyazetidin- 1 -yl)carbonyl]phenyl, (ammocarbonyl)fluorophenyl, [(methoxy- carbonyl)amino]phenyl, [(methyl
  • Ar 1 is selected from 4-methylsulfonylphenyl, 4-(ammocarbonyl)phenyl, 4-[(methylamino)carbonyl]phenyl, 4-[(dimethylamino)carbonyl]phenyl, 4-[(4-methyl- piperazin-l-yl)carbonyl]phenyl, 4- ⁇ [2-(hydroxymethyl)morpholin-4-yl]carbonyl ⁇ phenyl, 4-(methylsulfinyl)phenyl, 4-pyridinyl, 4-[(3-hydroxypyrrolidin-l-yl)carbonyl]phenyl, 4- ⁇ [2-(hydroxymethyl)pyrrohdin- 1 -yl]carbonyl ⁇ phenyl, 4- [(3-hydroxyazetidin- 1 -yl)- carbonyl]phenyl, 4-(aminocarbonyl)-3-fluorophenyl, 4- [(methoxycarbonyl)amino]phenyl, 4-[(methoxy
  • R 1A is selected from C(O)OR 2A , C(O)R 2A or a 6-membered heteroaryl group.
  • R 1A is C(O)OR 2A , wherein R 2A is selected from tert-but ⁇ l, phenyl, benzyl, ⁇ o-butyl, ethyl, isopropyl, 2,2-dimethylpropyl, 1-cyclopropylethyl and (3- methyloxetan-3-yl)methyl
  • R 1A is C(O)R 2A , wherein R 2A is selected from phenyl, 1-methyl- lH-pyrrol-2-yl, 3,4-dichlorophenyl and 1 -ethylpropyl.
  • R is 2-pyrimidmyl.
  • R 10 is independently selected from hydrogen, methyl and cyclopropyl.
  • Particularly preferred compounds of Formula (Ia) to (Ic) are the compounds selected from the group consisting of
  • Another object of the invention is a compound of Formula (Ia) to (Ic) for use m therapy
  • the compounds can be used in the treatment or prophylaxis of disorders relating to GPRl 19.
  • disorders are Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperhpidemia, hypercholesterolemia, dyslipidemia, syndrome X, obesity, hypertension, chrome systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis.
  • Another object of the invention is the use of a compound of Formula (Ia) to (Ic) in the manufacture of a medicament for use in the treatment or prophylaxis of disorders related to GPRl 19.
  • the GPR119-related disorder is any disorder or symptom wherein GPRl 19 is involved in the process or presentation of the disorder or the symptom.
  • the GPRl 19- related disorders include, but are not limited to, Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperhpidemia, hypercholesterolemia, dyslipidemia, syndrome X, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis
  • Another object of the invention is a method for modulating the GPRl 19 receptor activity (e g , agonizing human GPRl 19), comprising administering to a subject (e g , mammal, human, or animal) in need thereof an effective amount of a compound of Formula (Ia) to (Ic) or a composition comprising such a compound
  • Yet another object of the invention is a method for the treatment or prophylaxis of disorders related to GPRl 19, said method comprising administering to a subject (e.g , mammal, human, or animal) m need of such treatment an effective amount of a compound of Formula (Ia) to (Ic)
  • the GPRl 19-related disorder is any disorder or symptom wherein GPRl 19 is involved m the process or presentation of the disorder or the symptom
  • the GPRl 19-related disorders include, but are not limited to Type 1 and Type 2 diabetes, inadequate glucose tolerance, msulm resistance, hyperglycemia, hyperhpidemia, hypercholesterolemia, dyslipidemia, syndrome X, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis
  • Methods delineated herein include those wherein the subject is identified as in need of a particular stated treatment. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e g opinion) or objective (e.g. measurable by a test or diagnostic method).
  • the methods herein include those further comprising monitoring subject response to the treatment administrations Such monitoring may include periodic sampling of subject tissue, fluids, specimens, cells, proteins, chemical markers, genetic materials, etc as markers or indicators of the treatment regimen
  • monitoring may include periodic sampling of subject tissue, fluids, specimens, cells, proteins, chemical markers, genetic materials, etc as markers or indicators of the treatment regimen
  • the subject is prescreened or identified as in need of such treatment by assessment for a relevant marker or indicator of suitability for such treatment.
  • the invention provides a method of monitoring treatment progress
  • the method includes the step of determining a level of diagnostic marker (Marker) (e.g , any target or cell type delineated herein modulated by a compound herein) or diagnostic measurement (e g., screen, assay) m a subject suffering from or susceptible to a disorder or symptoms thereof delineated herein, m which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof
  • the level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status
  • a second level of Marker m the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy
  • a pre-treatment level of Marker m the subject is determined prior to beginning treatment according to this invention, this pre-treatment level of Marker can then be compared
  • a level of Marker or Marker activity in a subject is determined at least once Comparison of Marker levels, e g , to another measurement of Marker level obtained previously or subsequently from the same patient, another patient, or a normal subject, may be useful in determining whether therapy according to the invention is having the desired effect, and thereby permitting adjustment of dosage levels as appropriate
  • Determination of Marker levels may be performed using any suitable sampling/expression assay method known m the art or described herein
  • suitable samples include blood, urine, tissue, mouth or cheek cells, and hair samples containing roots
  • suitable samples would be known to the person skilled in the art
  • Determination of protein levels and/or mRNA levels (e g , Marker levels) m the sample can be performed using any suitable technique known m the art, including, but not limited to, enzyme immunoassay, ELISA, radio labelling/assay techniques, blotting/chemilummescence methods, real-time PCR, and
  • Ci 6-alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms
  • Ci 5-alkyl Ci 4-alkyl
  • Ci 3-alkyl Ci 2-alkyl
  • Cj 6-alkyl C2 5-alkyl
  • C24-alkyl C23-alkyl
  • C3 6-alkyl C4 5-alkyl
  • examples of said Ci 6-alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, z-butyl and straight- and branched-chain pentyl and hexyl
  • cyano-Ci-6-alkyl denotes a Ci_6-alkyl group, as defined above, substituted with a cyan
  • amino-Ci_6-alkyl denotes a Ci_6-alkyl group, as defined above, substituted with an amino group.
  • exemplary amino-Ci_6-alkyl groups include 2-aminoethyl and 3-aminopropyl.
  • hydroxy-Ci_6-alkyl denotes a straight or branched alkyl group that has a hydrogen atom thereof replaced with OH.
  • examples of said hydroxy-Ci_ 6 -alkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxybutyl and 2-hydroxy-2-methylpropyl.
  • Ci _ ⁇ -alkyl group is attached to the remainder of the molecule through an oxygen, sulfur or nitrogen atom, respectively.
  • Ci 6-alkoxy all subgroups thereof are contemplated such as Ci 5-alkoxy, Ci 4 -alkoxy, Ci 3-alkoxy, Ci_ 2 -alkoxy, C 2 -6-alkoxy, C 2 -5-alkoxy, C 2 - 4 -alkoxy, C 2 -3-alkoxy, C3_6-alkoxy, C 4 -S- alkoxy, etc.
  • Ci_6-alkoxy examples include methoxy, ethoxy, n-propoxy, isopropoxy, «-butoxy, isobutoxy, sec-butoxy, ?-butoxy and straight- and branched-chain pentoxy and hexoxy etc
  • Subgroups of "Ci- ⁇ -alkylthio” and “Ci_6-alkylammo” are to be construed accordingly.
  • the term "Ci_4-alkylsulfmyl” denotes a group C1-4- alkyl-S(O)— .
  • Ci_ 4 -alkylsulfinyl groups include methylsulf ⁇ nyl and ethylsulfmyl.
  • dihydroxy-C2_6-alkyl denotes a C2_6-alkyl group which is disubstituted with hydroxy and wherein said hydroxy groups are attached to different carbon atoms.
  • Exemplary dihydroxy-C 2 - 6 -alkyl groups include 2,3-dihydroxy- propyl and 2,4-dihydroxybutyl.
  • di(Ci_ 4 -alkyl)amino denotes a group (Ci_ 4 -alkyl) 2 N— , wherein the two alkyl portions may be the same or different.
  • Exemplary di(Ci_4-alkyl)amino groups include N,N-dimethylamino, N-ethyl-N-methylamino and N,N- diethylamino.
  • di(Ci_4-alkyl)ammo-C2-4-alkyl denotes a group as defined above, attached to a C24-alkyl group
  • Exemplary di(Ci_ 4 -alkyl)amino-C 2 - 4 -alkyl groups include 2-(dimethylamino)ethyl and 3-(diethyl- amino)propyl.
  • fluoro-Ci_6-alkyl denotes a Ci_6-alkyl group substituted by one or more fluorine atoms.
  • fluoro-Ci_6-alkyl examples include 2-fluoroethyl, fluoromethyl, 2-fluoro-l-(fluoromethyl)ethyl, trifluoromethyl, 3,3,3- trifluoropropyl and 2,2,2-trifluoroethyl.
  • aryl-Ci_6-alkyl means a Ci_6-alkyl group substituted by an aryl group.
  • aryl-Ci_5-alkyl include benzyl, 2- phenylethyl, 1-phenylethyl and 2-methyl-2-phenylpropyl.
  • arylcarbonyl-Ci_ 4 -alkyl denotes an arylcarbonyl group (e.g., benzoyl) that is attached through a Q ⁇ -alkyl group.
  • arylcarbonyl-Ci_ 4 -alkyl examples include 3-oxo-3-phenylpropyl, 2-oxo-2-phenylethyl and l-methyl-3-oxo-3-phenylpropyl.
  • heteroarylcarbonyl-Ci_4-alkyl denotes a heteroarylcarbonyl group (e.g., 3-pyridinylcarbonyl) that is attached through a Ci-4-alkyl group.
  • heteroarylcarbonyl-Ci 4 -alkyl examples include 3-oxo-3-(3-pyridinyl)- propyl, 2-oxo-2-(3-py ⁇ dmyl)ethyl and l-methyl-3-oxo-3-(3-pyridinyl)propyl.
  • Ci_6-alkoxy-C2-6-alkyl denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms connected to an alkyl group having from from 2 to 6 carbon atoms.
  • Examples of said Ci_6-alkoxy-C 2 -6-alkyl include methoxyethyl, ethoxyethyl, isopropoxyethyl, n-butoxyethyl, ?-butoxyethyl and straight- and branched-chain pentoxyethyl.
  • Ci_6-alkoxy-C2-6-alkyl all subgroups thereof are contemplated such as Ci_5-alkoxy-C 2 -6-alkyl, Ci_ 4 -alkoxy-C 2 -6-alkyl, Ci_3-alkoxy-C2-6-alkyl, Ci_2-alkoxy-C2-6-alkyl, C2-6-alkoxy-C2_6-alkyl, C2-5-alkoxy-C2-6- alkyl, C 2 - 4 -alkoxy-C 2 - 6 -alkyl, C 2 - 3 -alkoxy-C 2 - 6 -alkyl, C 3 _ 6 -alkoxy-C 2 - 6 -alkyl, C 4 _ 5 -alkoxy- C 2 - 6 -alkyl, Ci_ 6 -alkoxy-C 2 - 5 -alkyl, Ci_ 6 -alkoxy-C 2 - 4 -alkoxy-C
  • C2-6-alkenyl denotes a straight or branched hydrocarbon chain radical containing one carbon-carbon double bond and having from 2 to 6 carbon atoms.
  • Examples of said C 2 -6-alkenyl include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl, 1-pentenyl, and 1-hexenyl.
  • C 2 -6-alkenyl all subgroups thereof are contemplated such as C 2 -5-alkenyl, C 2 - 4 -alkenyl, C 2 -3-alkenyl, C3_6-alkenyl, C 4 _5- alkenyl, etc.
  • aryl-C 2 -6-alkenyl means a C 2 -6-alkenyl group substituted by an aryl group
  • aryl-C2 6-alkenyl include styryl and cinnamyl.
  • C 2 -6-alkynyl denotes a straight or branched hydrocarbon chain radical containing one carbon-carbon triple bond and having from 2 to 6 carbon atoms.
  • Examples of said C 2 -6-alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-biitynyl, 2-butynyl, and l-methylprop-2-yn-l-yl.
  • aryl-C2-6-alkynyl means a C2- ⁇ -alkynyl group substituted by an aryl group.
  • aryl-C2-6-alkynyl include phenylethynyl, 3-phenyl-l-propyn-l-yl, 3-phenyl-2-propyn- 1 -yl and 4-phenyl-2-butyn- 1 -yl.
  • C 3 _7-cycloalkyl denotes a cyclic alkyl group having a ring size from 3 to 7 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • C3_7-cycloalkyl For parts of the range "C3_7-cycloalkyl” all subgroups thereof are contemplated such as C3_6-cycloalkyl, C3_5-cycloalkyl, C3_4- cycloalkyl, C4 7-cycloalkyl, C4 6-cycloalkyl, C45-cycloalkyl, C5 7-cycloalkyl, Ce 7- cycloalkyl.
  • C3-7-cycloalkyl-Ci_ 4 -alkyl denotes a C3-7- cycloalkyl group attached to a Ci- 4 -alkyl group.
  • Exemplary C3-7-cycloalkyl-Ci_ 4 -alkyl groups include cyclopropylmethyl, 1-cyclopropylethyl, cyclohexylmethyl and 2-cyclo- hexylethyl.
  • cycloalkyl portion as part of the group C 3 _ 7 -cycloalkyl-Ci_ 4 -alkyl is substituted with methyl
  • examples of such groups include (l-methylcyclopropyl)methyl and 2-(4-methylcyclohexyl)ethyl.
  • C7_8-bicyclyl denotes a carbobicyclic saturated aliphatic ring system in which two non-adjacent carbon atoms of a monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms.
  • Examples of said C7_s-bicyclyl include radicals obtainable from bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane (norbornane) and bicyclo[2.2.2]octane.
  • C7_8-bicyclylalkyl means a Ci_6-alkyl group substituted by a C 7 _ 8 -bicyclyl group as defined above.
  • An exemplary C 7 _ 8 -bicyclylalkyl group is bicyclo[2.2.1 ]hept-2-ylmethyl (2-norbonylmethyl).
  • Cs_8-cycloalkenyl denotes a monocyclic or bicyclic alkenyl group of 5 to 8 carbon atoms having one carbon-carbon double bond.
  • Examples of monocyclic cycloalkenyl groups are cyclopent-3-en-l-yl and cyclohexen-1- yl
  • An exemplary bicyclic cycloalkenyl group is bicyclo[2.2.1]hept-5-en-2-yl (norbornen-
  • oxo-C4_6-cycloalkyl refers to a C4_6- cycloalkyl wherein one of the ring carbons is a carbonyl.
  • oxo-C 4 _ ⁇ - cycloalkyl include 2-oxocyclobutyl, 3-oxocyclobutyl, 2-oxocyclopentyl and 4-oxo- cyclohexyl
  • fluoro-C36-cycloalkyl denotes a C3 6- cycloalkyl group substituted by one or two fluorine atoms.
  • fluoro-C3 6- cycloalkyl examples include 2,2-difluorocyclopropyl and 4-fluorocyclohexyl
  • Ci 3 -alkoxy-C 4 6-cycloalkyl denotes a C 4 6- cycloalkyl group substituted by a Ci 3 -alkoxy group.
  • examples of said "Ci 3 -alkoxy-C4 ⁇ - cycloalkyl” include 4-methoxycyclohexyl and 2-ethoxycyclopentyl.
  • methyl-C3 e-cycloalkyl denotes a C3 ⁇ - cycloalkyl group substituted by one or two methyl groups
  • Examples of said "methyl-C3 6- cycloalkyl” include 4-methylcyclohexyl and 3,3-dimethylcyclopentyl.
  • acyl which may be straight or branched, denotes a carbonyl group that is attached through its carbon atom to a hydrogen atom to form a Ci -acyl group (i e , a formyl group) or to an alkyl group, where alkyl is defined as above
  • Ci 6-acyl all subgroups thereof are contemplated such as Ci 5-acyl, Ci 3-acyl, Ci 2-acyl, C 2 e-acyl, C 2 5-acyl, C 2 4 -acyl, C 2 3-acyl, C 3 e-acyl, C 4 5-acyl, etc
  • Exemplary acyl groups include formyl, acetyl (i.e , C 2 -acyl), propanoyl, butanoyl, pentanoyl, hexanoyl
  • C 2 6-acyl-Ci_6-alkyl refers to a group Ci 5-alky
  • Ci 6-alkylsulfonyl which may be straight or branched, denotes a hydrocarbon having from 1 to 6 carbon atoms with a sulfonyl group
  • Ci 5-alkylsulfonyl Ci 4 -alkylsulfonyl
  • Ci 3-alkylsulfonyl Ci 2 -alkylsulfonyl, C 2 6- alkylsulfonyl, C 2 5 -alkylsulfonyl, C 2 4 -alkylsulfonyl, C 2 3 -alkylsulfonyl, C 3 6 -alkylsulfonyl, C 4 5 -alkylsulfonyl, etc.
  • Ci 6 -alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, «-butylsulfonyl, sec-butylsulfonyl, te/t-butylsulfonyl, pentylsulfonyl and hexylsulfonyl Unless otherwise stated or indicated, the term "hydroxy-C 2 4-alkylsulfonyl” denotes a C 2 4- alkylsulfonyl group as defined above substituted with a hydroxy group Examples of said hydroxy-C 2 4 -alkylsulfonyl include hydroxymethylsulfonyl and 2-hydroxyethylsulfonyl Unless otherwise stated or indicated, the term "Ci_4-alkylsulfonamido" denotes a group d_ 4 -alkyl-S0 2 NH—
  • Ci-4-alkylsulfoximine refers to a group with the following chemical structure.
  • R a is Ci- 4 -alkyl.
  • Ci_3-alkylene refers to the diradicals methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -) and propylene (-CH 2 -CH 2 -CH 2 -).
  • halogen shall mean fluorine, chlorine, bromine or iodine
  • aryl refers to a hydrocarbon ring system having at least one aromatic ring, preferably mono- or bicyclic.
  • aryls are phenyl, indenyl, 2,3-dihydroindenyl (indanyl), 1-naphthyl, 2-naphthyl or 1,2,3,4- tetrahydronaphthyl.
  • heteroaryl refers to a mono- or bicyclic heteroaromatic ring system having 5 to 10 ring atoms in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur or oxygen.
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, quinazolinyl, indolyl, isomdolyl, 1,3-dihydro-isomdolyl, pyrazolyl, pyridazmyl, quinolmyl, quinoxalinyl, thiadiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4- benzodioxinyl, 2,3-dihydro-l,4-benzodioxinyl, benzothiazolyl, benzimidazo
  • heterocyclyl refers to a non-aromatic fully saturated or partially unsaturated monocyclic ring system having 4 to 7 ring atoms with at least one heteroatom such as O, N, or S, and the remaining ring atoms are carbon
  • heterocyclic groups include piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, azepinyl, azetidinyl, pyrrolidinyl, morpholinyl, imidazolinyl, lmidazohdinyl, thiomorpholinyl, pyranyl, dioxanyl, piperazinyl and 5,6-dihydro-4H-l,3- oxazin-2-yl.
  • exemplary heterocyclic groups containing sulfur in oxidized form are 1,1- dioxido-thiomorpholmyl and 1,1-dioxido-isothiazolidinyl.
  • heterocyclic ring When two groups R 5 , two groups R 5A , two groups R 9 or two groups R 9A described herein form a heterocyclic ring and said heterocyclic ring is substituted with one or two oxo groups, examples of such groups include 2-pyrrolidon-l-yl, 2-piperidon- 1 -yl, 2-azetidinon- 1-yl, 2,5-dioxopyrrolidm-l-yl and hydantom- 1 -yl (i.e , 2,5-dioxoimidazolidin-l-yl).
  • heterocyclic ring When two groups R 5 , two groups R 5A , two groups R 9 or two groups R 9A described herein form a heterocyclic ring and said heterocyclic ring is substituted with one or two fluoro atoms, examples of such groups include 4-fluoropiperidm-l-yl, 4,4-difluoropiperidin- 1 -yl, 3-fluoropyrrolidin-l-yl and 3,3-difluoropyrrolm-l-yl.
  • examples of such groups include 4-hydroxypiperidin-l-yl, 3-hydroxypiperidin-l-yl, 3-hydroxy- pyrrolidin- 1 -yl and 3-hydroxyazetidin-l-yl
  • examples of such groups include 4-ammopiperidin-l-yl, 3-aminopiperidm-l-yl, and 3-aminopyrrolidin- 1-yl
  • heteroaryl-Ci 4 -alkyl denotes a heteroaryl group that is attached through a Ci_ 4 -alkyl group.
  • heteroaryl-Ci_ 4 -alkyl examples include 2-(pyridin-2-yl)ethyl and 1,3 benzodioxol-5-ylmethyl.
  • C-heterocyclyl indicates bonding via a carbon atom of said heterocyclyl, for example piperidin-4-yl, tetrahydrofuran-2-yl, oxetan-3-yl, tetrahydrofuran-3-yl and 5,6-dihydro-4H- l,3-oxazin-2-yl, while "N-heterocyclyl” indicates bonding through nitrogen in a nitrogen- containing heterocyclyl group, for example piperidin- 1 -yl and piperazm-1-yl.
  • Ci-4-alkyl When C-heterocyclyl is substituted by Ci-4-alkyl, said Ci-4-alkyl is attached to a ring nitrogen atom or a ring carbon atom thereof
  • Exemplary C-heterocyclyl groups substituted by Ci -4- alkyl include l-methylpiperidin-4-yl and 3-methyloxetan-3-yl
  • N-heterocyclyl-C2 4-alkyl refers to a nitrogen-containing heterocyclyl group that is directly linked to a C24-alkyl group via a nitrogen atom of said heterocyclyl
  • Exemplary N-heterocyclyl-C 2 4 -alkyl groups include 2-(pyrrolidm-l-yl)ethyl, 3-(4-morpholmyl)propyl, 2-(piperazm- 1 -yl)ethyl and 2-(4- morpholinyl)ethyl.
  • heterocyclyl as part of the group N-heterocyclyl-C 2 4 -alkyl is substituted by methyl
  • said heterocyclyl is selected from 1 -piperazmyl or 1-homopiperazinyl and said methyl is attached to the 4-position of the piperazme or homopiperazme ring
  • Exemplary N-heterocyclyl-C 2 - 4 -alkyl groups wherein heterocyclyl is substituted with methyl are 2-(4-methylpiperazm-l-yl)ethyl, 2-(4-methylhomopiperazin-l-yl)ethyl.
  • C-heterocyclyl-Ci 4-alkyl refers to a heterocyclyl group that is directly linked to a Ci 4 -alkyl group via a carbon atom of said heterocyclyl
  • Exemplary C-heterocyc IyI-C 1 4 -alkyl groups include tetrahydropyran-4- ylmethyl, piperidin-4-ylmethyl, tetrahydrofuran-2-ylmethyl, oxetan-3-ylmethyl and 2-(pipe ⁇ dmyl-4-yl)ethyl.
  • heterocyclyl as part of the group C-heterocyclyl-Ci 4 -alkyl is substituted by methyl, said methyl is attached to a ring nitrogen atom or ring carbon atom thereof
  • Exemplary C-heterocyclyl-Ci- 4 -alkyl groups wherein heterocyclyl is substituted with methyl are 2-(l-methylpipendm-4-yl)ethyl and 3-methyloxetan-3-ylmethyl
  • oxo-N-heterocyclyl denotes a nitrogen- containing heterocyclyl group that is substituted with one or two oxo groups
  • oxo-N-heterocyclyl-C 2 4 -alkyl refers to an oxo-N-heterocyclyl group that is directly linked to a C24-alkyl group through a nitrogen atom of its heterocyclyl portion and where oxo-N-heterocyclyl is as defined above
  • Exemplary oxo- ⁇ L heterocyclyl-C 2 4 -alkyl groups include 2-(2-pyrrolidon-l-yl)ethyl, 3-(2-pyrrohdon-l-yl)propyl and 2-(2,5-dioxoimidazohdm-l-yl)ethyl.
  • fluoro-N-heterocyclyl denotes a nitrogen- containing heterocyclyl group that is substituted at a position other than alpha to a ring heteroatom with one or two fluorine atoms
  • fluoro-N-heterocyclyl-C 2 4 -alkyl refers to a fluoro-N-heterocyclyl group that is directly linked to a C 2 4 -alkyl group through a nitrogen atom of its heterocyclyl portion and where fluoro-N-heterocyclyl is as defined above
  • Exemplary fiuoro-N-heterocyclyl ⁇ vi-alkyl groups include 2-(3-fluoropyrrolidin-l-yl)- ethyl and 3-(3-fluoropyrrolidm-l-yl)propyl.
  • hydroxy-N-heterocyclyl denotes a nitrogen-contammg heterocyclyl group that is substituted at a position other than alpha to a ring heteroatom with a hydroxy group
  • hydroxy-N-heterocyclyl-C 2 4 -alkyL refers to a hydroxy-N-heterocyclyl group that is directly linked to a C24-alkyl group through a nitrogen atom of its heterocyclyl portion and where hydroxy-N-heterocyclyl is as defined above
  • Exemplary hydro xy-N-heterocyclyl-C 2 4 -alkyl groups include 2-(4-hydroxy- pipe ⁇ dm- 1 -yl)ethyl and 3-(3-hydroxypipendm- 1 -yl)propyl
  • the term “ammo-N-heterocyclyl” denotes a nitrogen- containing heterocyclyl group that is substituted at a position other than alpha to a ring heteroatom with an ammo group.
  • the term “amino-JV-heterocycryl-C 2 4 -alkyl” refers to a ammo-N-heterocyclyl group that is directly linked to a C 2 4 -alkyl group through a nitrogen atom of its heterocyclyl portion and where amino-N-heterocyclyl is as defined above Exemplary amino-N-heterocyclyl-C 2 4 -alkyl groups include 2-(4-aminopipe ⁇ din-l- yl)ethyl and 3-(3-ammopipe ⁇ dm-l-yl)propyl Unless otherwise stated or indicated, the term “azabicyclyl” denotes a bicyclic heterocyclyl group
  • C-heterocyclylsulfonyl When C-heterocyclylsulfonyl is substituted by Ci 4-alkyl, said heterocyclyl is selected from a nitrogen-containing heterocyclyl, and said Ci 4 -alkyl is attached to a ring nitrogen atom thereof.
  • An exemplary C-heterocyclylsulfonyl group substituted by Ci 4 -alkyl includes 1 -methylpiperidm-4-ylsulfonyl
  • Exemplary C 2 4 -acylammo groups include acetylammo and propionylammo
  • C 2 4-acylammo-Ci 4-alkyl denotes a C24 acylammo group, as defined above, attached to a Ci 4 -alkyl group
  • Examplary C 2 4 - groups include (acetylammo)methyl and 2-(acetylammo)ethyl.
  • the term "ammocarbonyl-Ci 4 -alkyl” denotes a Ci 4 - alkyl group, as defined above, substituted with an aminocarbonyl group.
  • exemplary aminocarbonyl-Ci 4 -alkyl groups include 2-(aminocarbonyl)ethyl and 3-(ammocarbonyl)- propyl.
  • carboxy denotes a group -C(O)OH
  • carboxy-Ci 3 -alkyl refers to a carboxy group, as defined above, attached to a Ci 3-alkyl group
  • Exemplary carboxy-Ci 3-alkyl groups include 2-carboxyethyl and 3-carboxypropyl
  • carboxy-Ci 3-alkylcarbonylamino refers to a carboxy-Ci 3-alkyl groups, as defined above, attached to the carbonyl carbon of carbonylammo (i e , -C(O)NH-)
  • Exemplary carboxy-Ci 3-alkylcarbonylamino groups include (2-carboxyethyl)carbonylammo and (3-carboxypropyl)carbonylamino
  • C-heterocyclylcarbonyl refers to a heterocyclyl group that is directly bonded to a carbonyl group via a carbon atom while “N-heterocyclylcarbonyl” refers to
  • C-heterocyclylcarbonyl is substituted by Ci 4-alkyl
  • said heterocyclyl is selected from a nitrogen-containing heterocyclyl, and said Ci 4 -alkyl is attached to a ring nitrogen atom thereof.
  • An exemplary C-heterocyclylcarbonyl group substituted by Ci 4 -alkyl includes 1 -methylpipe ⁇ dm-4-ylcarbonyl.
  • N-heterocyclylcarbonyl ⁇ 4-alkyl refers to a N-heterocyclylcarbonyl group that is directly linked to a C 2 4 -alkyl group through its carbonyl carbon atom and where N- heterocyclylcarbonyl is as defined above
  • Exemplary N-heterocyclylcarbonyl-C 2 4 -alkyl groups include 2-(pyrrolidm-l-ylcarbonyl)ethyl, 2-(piperazin-l-ylcarbonyl)ethyl and 2- (pipe ⁇ dm- 1 -ylcarbonyl)ethyl
  • heterocyclyl as part of the group N-heterocyclylcarbonyl-C2 4-alkyl is substituted by methyl, said heterocyclyl is selected from 1-piperazmyl or 1 -homopiperazmyl and said methyl is attached to the 4-position of the piperazme or homopiperazme ring.
  • Exemplary jV-heterocyclylcarbonyl-C2 ⁇ -alkyl groups wherein heterocyclyl is substituted with methyl are 2-(4-methylpiperazm-l-ylcarbonyl)ethyl, 2-(4-methylhomopiperazin-l-ylcarbonyl)- ethyl
  • C-heterocyclylcarbonyl-C2 4-alkyl refers to a C-heterocyclylcarbonyl group that is directly linked to a C 2 4 -alkyl group through its carbonyl carbon atom and where C- heterocyclylcarbonyl is as defined above.
  • Exemplary C-heterocyclylcarbonyl-C 2 4 -alkyl groups include 2-(tetrahydropyran-4-ylcarbonyl)ethyl, 2-(pipe ⁇ din-3-ylcarbonyl)ethyl and 2-(pipe ⁇ dm-4-ylcarbonyl)ethyl
  • heterocyclyl as part of the group C-heterocyclylcarbonyl-C2 4-alkyl is substituted by methyl
  • said heterocyclyl is selected from a nitrogen-containing heterocyclyl and said methyl is attached to a ring nitrogen atom thereof
  • An exemplary C-heterocyclylcarbonyl- C 2 4 -alkyl group wherein heterocyclyl is substituted with methyl is 2-(l-methylpipe ⁇ dm-4- ylcarbonyl)ethyl.
  • C-heterocyclyloxy refers to a heterocyclic group that is directly bonded to an oxygen atom via a carbon atom.
  • Examples of C-heterocyclyloxy groups include 3-piperidmyloxy, 4-piperidmyloxy, 3-tetrahydrofuranyloxy, and 4-tetrahydropyranyloxy
  • Ci 4-alkyl When C-heterocyclyloxy is substituted by Ci 4-alkyl, said heterocyclyl is selected from a nitrogen-contammg heterocyclyl, and said Ci 4 -alkyl is attached to a ring nitrogen atom thereof
  • An exemplary C-heterocyclyloxy group substituted by Ci 4-alkyl includes 1 -methylpiperidin-4-ylo xy
  • hydroxy ⁇ 4 -alkoxy-Ci 4 -alkyl refers to a hydroxy ⁇ 4 -alkoxy group that is directly attached to a Ci 4-alkyl group Representative examples of such groups include.
  • [CF 3 CH 3 (OH)C]-C 1 6 -alkyl refers to a CF 3 CH 3 (OH)C- group that is directly attached to a Ci 6 -alkyl group.
  • Representative examples of such groups include
  • the carbon-carbon double or triple bonds present in the groups C 3 e-alkenyl, C 3 6 -alkynyl, aryl-C 3 6 -alkenyl and aryl-C 3 6 -alkynyl as values for R 2 are meant to be located at positions other than conjugated with a carbonyl group or adjacent to a nitrogen, oxygen or sulfur atom
  • Coupled agent refers to a substance capable of catalyzing a coupling reaction, such as amidation or estenfication
  • Examples of coupling agents include, but are not limited to, carbonyldiimidazole, dicyclohexylcarbodiimide, pyridine, 4-dimethylamino- pyridme, and tnphenylphosphme
  • Another example of a coupling agent is l-ethyl-3-(3- dimethylammopropyl)carbodnmide hydrochloride (EDC), which is used in the presence of 1-hydroxybenzotriazole (HOBT) and a base such as triethylarmne
  • exo and endo are stereochemical prefixes that describe the relative configuration of a substituent on a bridge (not a bridgehead) of a bicyclic system such as l-azabicyclo[2 2 l]heptane and bicyclo[2.2 l]heptane If a substituent is oriented toward the larger of the other bridges, it is endo. If a substituent is oriented toward the smaller bridge it is exo Both exo and endo forms and their mixtures are part of the present invention
  • Syndrome X also called metabolic syndrome refers to a syndrome comprising some or all of the following diseases 1) dyshpoprotememia (combined hypercholesterolemia-hypertriglyceridemia, low HDL-cholesterol), 2) obesity (in particular upper body obesity), 3) impaired glucose tolerance (IGT) leading to noninsulin-dependent diabetes mellitus (NIDDM), 4) essential hypertension and (5) thrombogemc/fibrmolytic defects
  • “Pharmaceutically acceptable” means being useful m preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • Treatment as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established
  • An effective amount refers to an amount of a compound that confers a therapeutic effect (e g , treats, controls, ameliorates, prevents, delays the onset of, or reduces the risk of developing a disease, disorder, or condition or symptoms thereof) on the treated subject
  • the therapeutic effect may be objective (i e , measurable by some test or marker) or subjective (i.e , subject gives an indication of or feels an effect).
  • Prodrugs refers to compounds that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, e g by hydrolysis m the blood.
  • the prodrug compound usually offers advantages of solubility, tissue compatibility or delayed release m a mammalian organism (see Silverman, R.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups, such as a hydroxy, amino or mercapto groups, present in a compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • prodrugs include, but are not limited to, acetate, formate and succinate derivatives of hydroxy functional groups or phenyl carbamate derivatives of amino functional groups Throughout the specification and the appended claims, a given chemical formula or name shall also encompass all salts, hydrates, solvates, N-oxides and prodrug forms thereof Further, a given chemical formula or name shall encompass all tautomeric and stereoisomeric forms thereof Stereoisomers include enantiomers and diastereomers Enantiomers can be present in their pure forms, or as racemic (equal) or unequal mixtures of two enantiomers. Diastereomers can be present in their pure forms, or as mixtures of diastereomers. Diastereomers also include geometrical isomers, which can be present in their pure cis or trans forms or as mixtures of those.
  • the compounds of the Formula (Ia) to (Ic) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof.
  • pharmacologically acceptable addition salts mentioned below are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form.
  • acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, ⁇ -aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like.
  • inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid
  • organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid
  • Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and ammo acids, such as, e.g. argimne and lysine.
  • the term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
  • excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
  • Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsif ⁇ ers, flavouring agents, buffers, and the like.
  • the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and more preferably between 1-50% by weight in preparations for oral administration.
  • the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply m doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles Tablets and granules may be coated in a conventional manner.
  • the compounds of Formula (Ia) to (Ic) may be administered with other active compounds for the treatment of diabetes and/or obesity, for example insulin and insulin analogs, DPP- IV inhibitors, sulfonyl ureas, biguanides, ⁇ 2 agonists, glitazones, PPAR- ⁇ agonists, mixed PPAR- ⁇ / ⁇ agonists, RXR agonists, ⁇ -glucosidase inhibitors, PTPlB inhibitors, 11- ⁇ - hydroxy steroid dehydrogenase Type 1 inhibitors, phosphodiesterase inhibitors, glycogen phosphorylase inhibitors, MCH-I antagonists, CB-I antagonists (or inverse agonists), amylm antagonists, CCK receptor agonists, p3-agonists, leptm and leptin mimetics, serotonergic/dopaminergic antiobesity drugs, gastric lipase inhibitors, pancreatic lipase inhibitors, fatty acid
  • DPP-IV inhibitor means a compound which inhibits, antagonizes or decreases the activity of dipeptidyl peptidase IV (EC 3.4.14.5).
  • the said DPP-IV inhibitor can e.g. be a compound as disclosed in WO 2005/056003; WO 2005/056013; WO 2005/095343, WO 2005/113510; WO 2005/120494, WO 2005/121131; WO 2005/121089; WO 2006/013104; or WO 2006/076231, including references therein.
  • the compounds of the Formula (Ia) to (Ic) above may be prepared by, or in analogy with, conventional methods.
  • the preparation of intermediates and compounds according to the examples of the present invention may in particular be illuminated by the following Schemes 1-6
  • suitable deprotecting agent such as TFA, HCl (g) or aqueous concentrated HCl, m a suitable solvent, such as DCM, dioxane or ethanol, at ambient or elevated temperature,
  • suitable deprotecting agent such as TFA, HCl (g) or aqueous concentrated HCl, m a suitable solvent, such as DCM, dioxane or ethanol, at ambient or elevated temperature,
  • HOBT/EDC propylphosphomc anhydride, HBTU or TBTU; at ambient temperature;
  • Reagents and conditions (a) appropriate acid chloride or chloroformate, suitable base, such as triethylamine; in a suitable solvent, such as THF or DMF, at ambient temperature,
  • suitable coupling reagent such as I,l'-carbonylbis(li7- lmidazole), m a suitable solvent, such as DCM, acetomt ⁇
  • suitable deprotectmg agent such as TFA, HCl (g) or aqueous HCl, m a suitable solvent, such as DCM, dioxane or ethanol, at ambient or elevated temperature,
  • aryl- or heteroarylboronic acid (i) appropriate aryl- or heteroarylboronic acid; appropnate catalyst, such as Pd(PPh 3 ) 4 , a suitable base, such as K 2 CO 3 or NaHCO 3 , in a suitable solvent mixture such as 1 ,4- dioxane/water or toluene/isopropyl alcohol/water, at elevated temperature, for example 90 0 C,
  • HOBT/EDC propylphosphonic anhydride, HBTU or TBTU; at ambient temperature;
  • a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above
  • the compounds of Formula (Ia) to (Ic) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers
  • optical isomers e.g as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers
  • the separation of mixtures of optical isomers to obtain pure enantiomers is well known m the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns
  • the chemicals used in the synthetic routes delineated herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents
  • the methods desc ⁇ bed above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R Larock, Comprehensive Organic
  • any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups.
  • the recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
  • LRESIMS Low-resolution electrospray ionization mass spectra
  • HRESIMS High-resolution electrospray ionization mass spectra
  • System D X-b ⁇ dge C18 5 ⁇ m (250 x 4.6 mm), gradient 10-100% MeOH in H 2 O, flow rate 1 mL/min, with a gradient time of 20 min; or System E. Zorbax C18 5 ⁇ m (150 x 4 6 mm), gradient 10-100% MeOH m H 2 O (+ 0.1% TFA), flow rate 1 mL/min, with a gradient time of 26 min,
  • Analytical LCMS data were obtained on an Agilent 1100 system equipped with System F ACE 3 C8 column (50 x 3 0 mm), gradient 10-97% H 2 O (+ 0 1% TFA) in CH 3 CN, flow rate 1 mL/mm, with a gradient time of 3 0 mm, or
  • the title compound was prepared from tert-butyl 4- ⁇ [(5-bromopyrazin-2-yl)amino]- methyljpiperidine- 1-carboxylate (2.0 g, 0.0053 mol; Intermediate 1) and 4-carboxy- benzeneboronic acid (0.98 g, 0.0059 mol) in accordance with the procedure described for Example 1.
  • the reaction was monitored by TLC using DCM .MeOH (8 2) as a mobile phase.
  • the title compound was prepared from 5-[4-(methylsulfonyl)phenyl]-N-(pipe ⁇ din-4- ylmethyl)pyrazin-2-amine (90 mg, 0.26 mmol, Intermediate 2) and phenyl chloroformate (0.036 mL, 0.28 mmol) in accordance with the procedure described for Example 2.
  • the reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative TLC on silica using EtOAc. acetone (8.2) as mobile phase. Yield 32 mg (26%); Analytical HPLC purity 95.1% (System A); HRESIMS (ESI + ) calcd for C 24 H 26 N 4 O 4 S- 466 1675, found 466.1692.
  • the title compound was prepared from 5-[4-(methylsulfonyl)phenyl]-N-(piperidin-4- ylmethyl)pyrazin-2-amine (90 mg, 0.26 mmol; Intermediate 2) and neopentyl chloroformate (0.04 mL, 0.28 mmol) m accordance with the procedure described for Example 2.
  • the reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative TLC on silica using EtOAc as mobile phase. Yield 32 mg (27%); Analytical HPLC: purity 99.4% (System A), HRESIMS (ESI + ) calcd for C 23 H 32 N 4 O 4 S: 460.2144, found 460.2163.
  • the title compound was prepared from tert-but ⁇ 4- ⁇ [(5-bromopyrazm-2- yl)ammo]methyl ⁇ piperidme-l-carboxylate (100 mg, 0.26 mmol, Intermediate 1) and A- methylsulf ⁇ nylphenyl boromc acid (55 0 mg, 0 29 mmol) in accordance with the procedure described for Example 1.
  • the reaction was monitored by TLC using DCM:MeOH (9 5 0 5) as a mobile phase
  • the crude product was purified by preparative TLC on silica using DCM:MeOH (9 5 0 5) as eluent to give the title compound. Yield 42 mg (36%), Analytical HPLC: purity 98 1% (System D); HRESIMS (ESI + ) calcd for C 22 H 30 N 4 O 3 S 430.2039, found 430 2051
  • the title compound was prepared from tert-butyl 4- ⁇ [(5-bromopyrazin-2- yl)amino]methyl ⁇ piperidine-l-carboxylate (100 mg, 0.26 mmol; Intermediate 1) and ⁇ 4- [(4-methylpiperazm- 1 -yl)carbonyl]phenyl ⁇ boronic acid (83.9 mg, 0 29 mmol) in accordance with the procedure described Example 1.
  • the reaction was monitored by TLC using DCMMeOH (9.5:0.5) as a mobile phase.
  • the crude product was purified by preparative TLC on silica using DCM MeOH (9.5 0 5) as eluent to give the title compound. Yield 24 mg (18%); Analytical HPLC: purity 99.1% (System D); HRESIMS (ESI + ) calcd for C 27 H 3 SN 6 O 3 : 494.3005, found 494.3004.
  • the title compound was prepared from tert-bx ⁇ 4- ⁇ [(5-bromopyrazin-2- yl)amino]methyl ⁇ piperidme-l-carboxylate (100 mg, 0.26 mmol; Intermediate 1) and [4- (ammocarbonyl)phenyl]boronic acid (47.8 mg, 0.29 mmol) m accordance with the procedure described for Example 1.
  • the reaction was monitored by TLC using DCM:MeOH (9.5:0.5) as a mobile phase.
  • the crude product was purified by preparative TLC on silica using DCM:MeOH (9.5:0.5) as eluent to give the title compound. Yield 42 mg (37%); Analytical HPLC- purity 99.7% (System D); HRESIMS (ESI + ) calcd for C 22 H 29 N 5 O 3 : 411.2270, found 411.2268.
  • the title compound was prepared from tert-butyl 4- ⁇ [(5-bromopyrazm-2-yl)ammo]- methyl ⁇ piperidine-l-carboxylate (100 mg, 0.26 mmol, Intermediate 1) and ⁇ 4-[(methyl- amino)carbonyl]phenyl ⁇ boromc acid (51 8 mg, 0.29 mmol) in accordance with the procedure described for Example 1
  • the reaction was monitored by TLC using DCM MeOH (9 5 0 5) as a mobile phase
  • the crude product was purified by preparative TLC on silica using DCM-MeOH (9 5O 5) as eluent to give the title compound Yield 50 mg (43%), Analytical HPLC purity 99.1% (System D), HRESIMS (ESI + ) calcd for C 23 H 3I N 5 O 3 : 425.2427, found 425.2422
  • the title compound was prepared from tert-butyl 4- ⁇ [(5-bromopyrazm-2-yl)amino]- methyl ⁇ pipe ⁇ dine-l-carboxylate (100 mg, 0.26 mmol, Intermediate 1) and 4-pyridyl- boronic acid (35 6 mg, 0.29 mmol) in accordance with the procedure described for Example 1
  • the reaction was monitored by TLC using DCM. MeOH (9.5 0.5) as a mobile phase.
  • the title compound was prepared from 4-[5-( ⁇ [l-(t ⁇ /t-butoxycarbonyl)piperidin-4-yl]- methyl ⁇ ammo)pyrazm-2-yl]benzoic acid (100 mg, 0.24 mmol; Intermediate 3) and morpholin-2-ylmethanol (0 03 mL, 0 26 mmol) in accordance with the procedure described for Example 16.
  • the crude product was purified by preparative TLC on silica using DCM:MeOH (9 5 0 5) as eluent to give the title compound. Yield 29 mg (23%), Analytical HPLC purity 94 0% (System D), HRESIMS (ESI + ) calcd for C 27 H 37 N 5 O 511 2795, found 511 2793
  • the title compound was prepared from 4-[5-( ⁇ [l-(t ⁇ /t-butoxycarbonyl)piperidm-4-yl]- methyl ⁇ ammo)pyrazm-2-yl]benzoic acid (100 mg, 0.24 mmol; Intermediate 3) and (2R)- pyrrolidm-2-ylmethanol (0 026 mL, 0 26 mmol) m accordance with the procedure described for Example 16.
  • the crude product was purified by preparative TLC on silica using DCM:MeOH (9 5:0.5) as eluent to give the title compound.
  • the title compound was prepared from 4-[5-( ⁇ [l-(fer?-butoxycarbonyl)piperidin-4- yl]methyl ⁇ amino)pyrazin-2-yl]benzoic acid (100 mg, 0.24 mmol, Intermediate 3) and (2S)- pyrrolidin-2-ylmethanol (0.026 mL, 0.26 mmol) in accordance with the procedure described for Example 16.
  • the crude product was purified by preparative TLC on silica using DCM:MeOH (9 5:0.5) as eluent to give the title compound. Yield 24 mg (20%), Analytical HPLC: purity 85.2% (System D); HRESIMS (ESI + ) calcd for C 27 H 37 N 5 O 4 : 495.2846, found 495 2846.
  • the title compound was prepared from 4-[5-( ⁇ [l-(fer£-butoxycarbonyl)piperidin-4-yl]- methyl ⁇ amino)pyrazm-2-yl]benzoic acid (100 mg, 0.24 mmol; Intermediate 3) and azetidin-3-ol (19 mg, 0.26 mmol) in accordance with the procedure described for Example 16.
  • the crude product was purified by preparative TLC on silica using DCM MeOH (9.5 0.5) as eluent to give the title compound. Yield 24 mg (19%); Analytical HPLC: purity 94.7% (System D); HRESIMS (ESI + ) calcd for C 25 H 33 N 5 O 4 : 467.2532, found 467.2531.
  • the title compound was prepared from 2-[4-(methylsulfonyl)phenyl]-5-(piperidm-4-yl- methoxy)pyrazine (200 mg, 0.57 mmol; Intermediate 5) and phenyl chloro formate (0.08 mL, 0.63 mmol) m accordance with the procedure described for Example 22.
  • the crude product was purified by preparative TLC using EtOAc: acetone (8:2) as mobile phase to give the title compound Yield 70 mg (26%).
  • the title compound was prepared from 2-[4-(methylsulfonyl)phenyl]-5-(pipe ⁇ dm-4-yl- methoxy)pyrazine (200 mg, 0.57 mmol; Intermediate 5) and benzyl chloroformate (50% in toluene; 0.21 mL, 0.63 mmol) in accordance with the procedure described for Example 22.
  • the crude product was purified by preparative TLC using EtOAc as mobile phase to give the title compound. Yield 75 mg (27%).
  • Analytical HPLC purity 99.7% (System B), HRESIMS (ESI + ) calcd for C 25 H 27 N 3 O 5 S: 481.1671, found 481.1668.
  • the title compound was prepared from 4-(5- ⁇ [l-(t ⁇ /t-butoxycarbonyl)piperidin-4-yTJ- methoxy ⁇ pyrazm-2-yl)benzoic acid (100 mg, 0.24 mmol; Intermediate 6) and (2R)- pyrrolidm-2-ylmethanol (0 026 mL, 0 26 mmol) in accordance with the procedure described for Example 33.
  • the crude product was purified by preparative TLC using EtOAc acetone (8:2) as mobile phase to give the title compound. Yield 65 mg (54%) Analytical HPLC purity 97 4% (System B), HRESIMS (ESI + ) calcd for C 27 H 36 N 4 O 5 496 2686, found 496 2694
  • the title compound was prepared from 4-(5- ⁇ [l-(t ⁇ /t-butoxycarbonyl)piperidm-4-yl]- methoxy ⁇ pyrazm-2-yl)benzoic acid (100 mg, 0 24 mmol; Intermediate 6) and (2S)- pyrrolidm-2-ylmethanol (0 026 mL, 0 26 mmol) in accordance with the procedure described for Example 33.
  • the crude product was purified by preparative TLC using EtOAc acetone (8:2) as mobile phase to give the title compound.
  • the title compound was prepared from tert-butyl 4- ⁇ [(5-bromopyrazm-2-yl)oxy]methyl ⁇ - pipe ⁇ dme-1-carboxylate (100 mg, 0 26 mmol, Intermediate 4) and 4-methylsulfmyl- phenylboronic acid (55 mg, 0 29 mmol) in accordance with the procedure described for Example 21
  • the crude product was purified by preparative TLC using EtOAc 'hexane (8 2) as mobile phase to give the title compound Yield 50 mg (43%) Analytical HPLC purity 97.6% (System B); HRESIMS (ESI + ) calcd for C 22 H 29 N 3 O 4 S: 431.1879, found 431.1884.
  • the title compound was prepared from tert-buiy ⁇ 4- ⁇ [(5-bromopyrazm-2-yl)oxy]methyl ⁇ - piperidme-1-carboxylate (100 mg, 0.26 mmol, Intermediate 4) and ⁇ 4-[(4-methylpiperazin- l-yl)carbonyl]phenyl ⁇ boromc acid (83 9 mg, 0 29 mmol) in accordance with the procedure described for Example 21
  • the crude product was purified by preparative TLC using DCM:MeOH (9.5:0.5) as mobile phase to give the title compound Yield 60 mg (45%) Analytical HPLC purity 99.4% (System B); HRESIMS (ESI + ) calcd for C 27 H 37 N 5 O 4 495.2846, found 495 2850.
  • the title compound was prepared from fert-butyl 4- ⁇ [(5-bromopyrazm-2-yl)oxy]methyl ⁇ - piperidme-1-carboxylate (100 mg, 0 26 mmol, Intermediate 4) and ⁇ 4-[(methylamino)- carbonyl]phenyl ⁇ boromc acid (51.8 mg, 0.29 mmol) in accordance with the procedure for Example 21.
  • the crude product was purified by preparative TLC using DCM MeOH (9.5 0 5) to give the title compound. Yield 50 mg (43%).
  • the title compound was prepared from crude N-methyl- ⁇ / -( ⁇ 5-[4-(methylsulfonyl)phenyl]- pyrazin-2-yl ⁇ methyl)piperidin-4-amine, hydrochloride (200 mg, 0.55 mmol; Intermediate 9) and ethyl chloroformate (0.06 mL, 0.66 mmol) in accordance with the procedure described for Example 43.
  • the title compound was prepared from crude N-methyl-N-( ⁇ 5-[4-(methylsulfonyl)phenyl]- pyrazm-2-yl ⁇ methyl)piperidm-4-amme, hydrochloride (200 mg, 0.55 mmol; Intermediate 9) and isopropyl chloroformate (0 88 mL, 0 66 mmol) in accordance with the procedure described for Example 43.
  • the crude product was purified by preparative TLC using DCM MeOH (95 5) as mobile phase to give the title compound Yield 70 mg (28%) Analytical HPLC purity 99% (System B), HRESIMS (ESI + ) calcd for C 22 H 30 N 4 O 4 S 446.1988, found 446 1986.
  • the title compound was prepared from crude N-methyl- ⁇ / -( ⁇ 5-[4-(methylsulfonyl)phenyl]- pyrazin-2-yl ⁇ methyl)piperidin-4-amine, hydrochloride (180 mg, 0.50 mmol; Intermediate 9) and phenyl chloroformate (0 07 mL, 0 60 mmol) m accordance with the procedure described for Example 43.
  • the crude product was purified by preparative TLC using DCMMeOH (95:5) as mobile phase to give the title compound Yield 72 mg (30%) Analytical HPLC punty 99.2% (System B), HRESIMS (ESI + ) calcd for C 25 H 28 N 4 O 4 S 480 1831, found 480 1851
  • the title compound was prepared from crude N-methyl- ⁇ / -( ⁇ 5-[4-(methylsulfonyl)phenyl]- pyrazin-2-yl ⁇ methyl)piperidin-4-amine hydrochloride (150 mg, 0 40 mmol; Intermediate 9) and benzyl chloro formate (0 08 mL, 0.50 mmol) m accordance with the procedure for Example 43.
  • the crude product was purified by preparative TLC using DCM MeOH (95 5) to give the title compound Yield 62 mg (30%) Analytical HPLC purity 99 5% (System E); HRESIMS (ESI + ) calcd for C 26 H 30 N 4 O 4 S 494 1988, found 494 1999
  • the title compound was prepared from crude N-methyl-N-( ⁇ 5-[4-(methylsulfonyl)phenyl]- pyrazm-2-yl ⁇ methyl)piperidm-4-amme hydrochloride (180 mg, 0 50 mmol; Intermediate 9) and benzoyl chloride (0.07 mL, 0 60 mmol) in accordance with the procedure described for Example 43
  • the crude product was purified by preparative TLC using DCM MeOH (95:5) as mobile phase to give the title compound. Yield 55 mg (24%) Analytical HPLC purity 99 5% (System E), HRESIMS (ESI + ) calcd for C 25 H 28 N 4 O 3 S 464 1882, found 464 1902
  • the title compound was prepared from 4-(5- ⁇ [[l-(ter?-butoxycarbonyl)piperidin-4-yl]- (methyl)ammo]methyl ⁇ pyrazm-2-yl)benzoic acid (O 2 g, O 46 mmol; Intermediate 8) and morpholin-2-ylmethanol (0.06 mL, 0.51 mmol) in accordance with the procedure described for Example 51.
  • the crude product was purified by preparative HPLC (System J). Yield 40 mg (16.7%), Analytical HPLC: purity 96.7% (System D), HRESIMS (ESI + ) calcd for C 28 H 39 N 5 O 5 : 525.2951, found 525.2971.
  • the title compound was prepared from 4-(5- ⁇ [[l-(?erf-butoxycarbonyl)piperidin-4-yl]- (methyl)ammo]methyl ⁇ pyrazin-2-yl)benzoic acid (0.2 g, 0.46 mmol; Intermediate 8) and (2 ⁇ )-pyrrolidin-2-ylmethanol (0.05 mL, 0.51 mmol) in accordance with the procedure described for Example 51.
  • the crude product was purified by preparative HPLC (System I). Yield 26 mg (11.3%); Analytical HPLC: purity 95.7% (System D); HRESIMS (ESI + ) calcd for C 28 H 39 N 5 O 4 : 509.3002, found 509.3014.
  • the title compound was prepared from tert-butyl 4-[[(5-chloropyrazin-2-yl)methyl]- (methyl)amino]piperidine- 1 -carboxylate (0.2 g, 0 58 mmol; Intermediate 7) and [4-[(4- methyl-l-piperazinyl)carbonyl]phenyl]-boromc acid (0 2 g, 0 70 mmol) in accordance with the procedure described for Example 42 to give the title compound.
  • the crude product was purified by preparative TLC using DCM:MeOH (95:5) as mobile phase. Yield 75 mg (25 9%), Analytical HPLC purity 99 7% (System B), HRESIMS (ESI + ) calcd for C 28 H 40 N 6 O 3 . 508.3162, found 508.3164
  • the title compound was prepared from tert-butyl 4-[[(5-chloropyrazin-2-yl)methyl]- (methyl)ammo]pipe ⁇ dme- 1 -carboxylate (0 15 g, 0 44 mmol, Intermediate 7) and 4- aminocarbonylphenylboronic acid (0 087 g, 0 53 mmol) in accordance with the procedure described for Example 42 to give the title compound
  • the crude product was purified by preparative TLC using DCM MeOH (95:5) as mobile phase. Yield 32 mg (17 1%), Analytical HPLC purity 98 2% (System B), HRESIMS (ESI + ) calcd for C 23 H 3I N 5 O 3 425.2427, found 425 2439.
  • the title compound was prepared from tert-butyl 4-[[(5-chloropyrazin-2-yl)methyl]- (methyl)amino]pipe ⁇ dme- 1 -carboxylate (0 15 g, 0 44 mmol; Intermediate 7) and 4-(N- methylammocarbonyl)phenylboromc acid (0.094 g, 0.53 mmol) in accordance with the procedure described for Example 42 to give the title compound.
  • the crude product was purified by preparative TLC using DCM:MeOH (95:5) as mobile phase. Yield 64 mg (33.2%), Analytical HPLC purity 98.8% (System B), HRESIMS (ESI + ) calcd for C 24 H 33 N 5 O 3 439 2583, found 439 2604
  • GENERAL PROCEDURE G2 FOR SUZUKI-TYPE CROSS-COUPLING REACTIONS Methyl ⁇ 4-[5-( ⁇ cyclopropyl[l-(2-ethylbutanoyl)piperidin-4-yl]amino ⁇ methyl)pyrazin- 2-yl] phenyl ⁇ carbamate, trifluoroacetate

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Abstract

La présente invention porte sur des composés de Formule (Ia) et sur des sels, solvates, hydrates, isomères géométriques, tautomères, isomères optiques et oxydes IV pharmaceutiquement acceptables de ces composés. La présente invention porte également sur des compositions pharmaceutiques comprenant ces composés et sur l'utilisation de ces composés pour la prophylaxie et le traitement d'états médicaux se rapportant aux troubles du récepteur GPR1 19 couplé aux protéines G, tels que le diabète, l'obésité et l'ostéoporose.
PCT/EP2009/052268 2008-02-27 2009-02-26 Composés pyrazines pour le traitement de troubles apparentés à gpr119 Ceased WO2009106561A1 (fr)

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WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012046249A1 (fr) 2010-10-08 2012-04-12 Cadila Healthcare Limited Nouveaux agonistes de gpr119
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WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
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JP2015522633A (ja) * 2012-07-24 2015-08-06 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｎ−シクロプロピル−ｎ−ピペリジニル−アミド誘導体、およびｇｐｒ１１９モジュレーターとしてのそれらの使用
JP2015523404A (ja) * 2012-08-02 2015-08-13 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｎ−シクロプロピル−ｎ−ピペリジニル−アミド、これらを含有する医薬組成物およびその使用
CN105829304A (zh) * 2013-12-20 2016-08-03 中国人民解放军军事医学科学院毒物药物研究所 N,n’取代哌啶胺类化合物、其制备方法及用途
JP2016540824A (ja) * 2013-12-20 2016-12-28 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 新規ピペリジンカルボキサミド化合物、その調製方法及び使用
CN112074513A (zh) * 2018-06-27 2020-12-11 豪夫迈·罗氏有限公司 作为优先大麻素2激动剂的吡啶和吡嗪衍生物
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US8293729B2 (en) 2009-06-24 2012-10-23 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012046249A1 (fr) 2010-10-08 2012-04-12 Cadila Healthcare Limited Nouveaux agonistes de gpr119
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
EP2858986A4 (fr) * 2012-06-12 2015-11-11 Chong Kun Dang Pharm Corp Dérivés de pipéridine agonistes de gpr119
JP2017105785A (ja) * 2012-06-12 2017-06-15 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのピペリジン誘導体
JP2015522559A (ja) * 2012-06-12 2015-08-06 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのピペリジン誘導体
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