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WO2009106565A1 - Agonistes du gpr119 - Google Patents

Agonistes du gpr119 Download PDF

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Publication number
WO2009106565A1
WO2009106565A1 PCT/EP2009/052281 EP2009052281W WO2009106565A1 WO 2009106565 A1 WO2009106565 A1 WO 2009106565A1 EP 2009052281 W EP2009052281 W EP 2009052281W WO 2009106565 A1 WO2009106565 A1 WO 2009106565A1
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Prior art keywords
alkyl
methyl
hydroxy
cycloalkyl
heterocyclyl
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PCT/EP2009/052281
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English (en)
Inventor
Ulf Bremberg
Gary Johansson
Tobias Koolmeister
Michael Weber
Antti Hartikka
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Swedish Orphan Biovitrum AB
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Biovitrum AB
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Publication of WO2009106565A1 publication Critical patent/WO2009106565A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

Definitions

  • the present invention relates to certain novel compounds, to pharmaceutical compositions comprising these novel 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-msulm-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 dyshpidemia, 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.
  • sulphonylureas increase production of endogenous insulin
  • Metformin lowers hepatic glucose output.
  • Thiazolidindiones (TZDs) reduce insulin resistance in muscle and liver and suppress inflammatory responses.
  • a major side effect of TZDs is weight gam due to fluid retention and increase in total body fat.
  • An earlier drug in this class, troglitazone was withdrawn due to rare but serious cases of hepatotoxicity.
  • Current therapies have limited durability and/or significant side effects.
  • Orlistat inhibits the lipase-mediated breakdown of fat m 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
  • Osteoporosis is a disabling disease characterized by low bone mass and structural deterioration of bone tissue, leading to compromised bone strength and an increased risk of fractures of the hip, spine and wrist
  • As many as half of all women and a quarter of men older than 50 will have an osteopeorosis-related fracture in their life-time Riskfactors include getting older, gender, family history, body size, ethnicity (higher risk for Caucasians and Asians), inactive lifestyle, smoking and overconsumption of alcohol.
  • 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 msulm secretion from pancreatic beta-cells (Soga et al., Biochem. Biophys. Res Commun. 326, 744-751, 2005).
  • LPC lysophosphatidylcholme
  • 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) GPRl 19 agonists enhance the release of the lncretins, 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 gam 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 mter 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, hyperhpidemia, hypercholesterolemia, dyshpidemia, syndrome X, obesity, hypertension, chronic systemic mflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis
  • the present 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 (i) when B is O, C(O), S, S(O) or S(O) 2 , then A is CH 2 , and (ii) when B is NR 10 , then A is CH 2 or CO; 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 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:
  • halogen selected from chlorine, bromine and fluorine
  • R 2 is selected from:
  • R 3 is selected from
  • Ci_ 6 -alkylsulfonyl-C 2 - 6 -alkyl 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 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 12 is selected from
  • a preferred group of compounds of the invention are compounds of Formula (Ib),
  • 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 ,
  • D is N or CR 11 , provided that D must be CR 11 and said R 11 must be hydrogen or methyl when B is O or NR 10 , and further provided that each m is 1 when D is N,
  • Ar 1 , Z ⁇ Z ⁇ R 1 to R y and R IZ are as defined in Formula (Ia),
  • R , 10 is selected from (a) hydrogen
  • R is selected from:
  • a further preferred group of compounds of the invention are compounds of Formula (Ic),
  • A is O and B is CH 2 , or A is CH 2 and B is O;
  • Z 1 , Z 2 , R 1 to R , R 9 and R 12 are as defined in Formula (Ia),
  • Ar 1 is phenyl or pyridinyl, each of which is optionally substituted m 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 O and B is CH 2 ,
  • Ar 1 is phenyl or pyridmyl, each of which is optionally substituted in one or two positions with a substituent independently selected from the group Z 4 consisting of
  • Ci_4-alkylsulfonamido Ci_4-alkylsulfonamido
  • 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 , -CH2-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
  • NR 9A R 9A provided that R 1A is not selected from C(O)OR 2A , C(O)NR 2A R 3A and -CH 2 -C(O)NR 2A R 3A ,
  • R 3A is selected from
  • R 5A is each independently selected from:
  • heterocyclic ring (0 di(Ci 2-alkyl)amino-C23-alkyl; or two R 5A groups together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with: i) a substituent selected from: (aa) hydroxy, (bb) amino, (cc) methylammo,
  • R 7A is independently selected from Ci- 4 -alkyl;
  • Two groups R 9A together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with: i) one hydroxy or amino group, ii) one or two fluorine atoms, or iii) one or two oxo groups, provided that when the substituent is selected from fluorine, hydroxy and amino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R 9A groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with methyl,
  • R 12 is selected from:
  • Ar 1 is selected from (ammocarbonyl)phenyl, fluoro(aminocarbonyl)phenyl, fluoro[(propylamino)carbonyl]- phenyl, [(dimethylammo)carbonyl]phenyl, (methylsulfmyl)phenyl, fluoro(methyl- sulfonyl)phenyl, (methylsulfonyl)pyridmyl, ⁇ [[2-(dimethylamino)ethyl](methyl)amino]- carbonyljpyridinyl, (aminocarbonyl)pyridinyl and (4-methylpiperazin-l-yl)carbonyl- pyridinyl.
  • Ar is selected from 4-(aminocarbonyl)phenyl, 3-fluoro-4- (ammocarbonyl)phenyl, 3-fluoro-4-[(propylammo)carbonyl]phenyl, 4-[(drmethylamino)- carbonyl]phenyl, 2-fluoro-4-(methylsulfonyl)phenyl, 4-(methylsulfmyl)phenyl, 5-(methyl- sulfonyl)pyridin-2-yl, 6- ⁇ [ [2-(dimethylamino)ethyl](methyl)ammo] carbonyl ⁇ pyridin-3 -yl, 5-(ammocarbonyl)pyridm-2-yl, 6-(methylsulfonyl)py ⁇ dm-3-yl, 6-[(4-methylpiperazm-l- yl)carbonyl]pyridm-3 -yl and 5 -[(4-methylpiperazin- 1 -
  • 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-butyl, ethyl and isopropyl.
  • R 1A is C(O)R 2A , wherein R 2A is 1 -ethylpropyl.
  • R 1A is 2-pyrimidinyl
  • R 12 is selected from hydrogen and methyl.
  • 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 m 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, dyshpidemia, 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 m 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, dyshpidemia, syndrome X, obesity, hypertension, chrome 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) rn need thereof
  • 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, insulin 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 m 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 m 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 m 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, blottmg/chemilummescence methods, real-
  • Ci 6 -alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms
  • Ci 4 -alkyl Ci 3-alkyl
  • Ci 2 -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, ⁇ -propyl, isopropyl, w-butyl, isobutyl, sec-butyl, f-butyl and straight- and branched-cham pentyl and hexyl
  • cyano-Ci-6-alkyl denotes a Ci_6-alkyl group, as defined above, substituted
  • 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-6-alkyl group is attached to the remainder of the molecule through an oxygen, sulfur or nitrogen atom, respectively.
  • Ci 6-alkoxy For parts of the range "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, C 3 _6-alkoxy, C 4 _ 5 - alkoxy, etc.
  • Examples of said "Ci_6-alkoxy” include methoxy, ethoxy, n-propoxy, isopropoxy, «-butoxy, isobutoxy, sec-butoxy, ?-butoxy and straight- and branched-chain pentoxy and hexoxy etc.
  • Ci_ 4 -alkylsulfmyl denotes a group C 1 ⁇ - alkyl-S(O)— .
  • Exemplary Ci_ 4 -alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
  • dihydroxy-C 2 _6-alkyl denotes a C 2 _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-C 2 _4-alkyl denotes a group as defined above, attached to a C 2 _4-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.
  • examples of said fluoro-Ci_6-alkyl 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. Examples 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-pyridinyl)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_e-alkoxy-C 2 -6-alkyl For parts of the range "Ci_e-alkoxy-C 2 -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, C2 4-alkoxy-C26-alkyl, C2 3-alkoxy-C2-6-alkyl, C3 6-alkoxy-C2 6-alkyl, C4 5 -alkoxy- C 2 - 6 -alkyl, Ci_ 6 -alkoxy-C 2 - 5 -alkyl, Ci.
  • C ⁇ - ⁇ -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 For parts of the range "C 2 -6-alkenyl", all subgroups thereof are contemplated such as C 2 - 5 -alkenyl, C 2 - 4 -alkenyl, C 2 - 3 -alkenyl, C 3 _ 6 -alkenyl, C 4 _ 5 - alkenyl, etc.
  • aryl-C 2 -6-alkenyl means a C 2 -6-alkenyl group substituted by an aryl group. Examples of said 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.
  • C3_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, C46-cycloalkyl, C45-cycloalkyl, C5 7-cycloalkyl, Ce 7- cycloalkyl.
  • C 3 -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_g-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-s-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_e- cycloalkyl wherein one of the ring carbons is a carbonyl
  • Examples of "0X0-C 4 -6- cycloalkyl” include 2-oxocyclobutyl, 3-oxocyclobutyl, 2-oxocyclopentyl and 4-oxo- cyclohexyl.
  • fluoro-C3_6-cycloalkyl denotes a C3_ ⁇ - 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/ ⁇ _6- cycloalkyl group substituted by a Ci-3-alkoxy group.
  • Examples of said "Ci_3-alkoxy-C4-6- cycloalkyl” include 4-methoxycyclohexyl and 2-ethoxycyclopentyl.
  • methyl-C3_e-cycloalkyl denotes a C3-6- cycloalkyl group substituted by one or two methyl groups.
  • methyl-C3_6- cycloalkyl examples 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 For parts of the range "Ci_6-acyl" all subgroups thereof are contemplated such as Ci-5-acyl, Ci-4-acyl, Ci -3 -acyl, Ci -2 -acyl, C 2 -6-acyl, C 2 - 5 -acyl, C 2 . 4 -acyl, C 2- 3-acyl, C 3 -6-acyl, C 4 _5-acyl, etc.
  • exemplary acyl groups include formyl, acetyl (i.e., C 2 -acyl), propanoyl, butanoyl, pentanoyl, hexanoyl.
  • Exemplary C 2 - 6 -acyl-Ci_ 6 -alkyl groups include 2-acetylethyl and 3-acetylpropyl.
  • Ci_6-alkylsulfonyl which may be straight or branched, denotes a hydrocarbon having from 1 to 6 carbon atoms with a sulfonyl group.
  • Ci_ 4 -alkylsulfonyl Cu-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, seobutylsulfonyl, ter?-butylsulfonyl, pentylsulfonyl and hexylsulfonyl.
  • hydroxy-C 2 _4-alkylsulfonyl denotes a C 2 _4- alkylsulfonyl group as defined above substituted with a hydroxy group.
  • hydroxy-C 2 4 -alkylsulfonyl examples include hydroxymethylsulfonyl and 2-hydroxy ethylsulfonyl.
  • Ci 4-alkylsulfonamido denotes a group C] 4 -alkyl-S ⁇ 2 NH—
  • Ci 4 -alkylsulfonamido groups include methylsulfonyl- ammo and ethylsulfonylammo.
  • Ci-4-alkylsulfoximine refers to a group with the following chemical structure O
  • 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 iodme
  • 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 m which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur or oxygen Only one ring need be aromatic and said heteroaryl moiety can be linked to the remainder of the molecule via a carbon or nitrogen atom m any ring
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, lmidazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidmyl, quinazolmyl, mdolyl, lsomdolyl, 1,3-dihydro-isomdolyl, pyrazolyl, pyndazmyl, qumolmyl, quinoxalinyl, thiadiazolyl, benzofuranyl,
  • 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 pipe ⁇ dmyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, azepmyl, azetidinyl, pyrrolidmyl, morpholmyl, imidazolmyl, lmidazohdmyl, thiomorpholmyl, 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
  • examples of such groups include 4-hydroxypiperidin-l-yl, 3-hydroxypiperidin-l-yl, 3-hydroxy- pyrrolidm- 1 -yl and 3-hydroxyazetidin-l-yl
  • examples of such groups include 4-ammopiperidin-l-yl, 3-aminopiperidm-l-yl, and 3-ammopyrrolidin- 1-yl
  • examples of such groups include 4-ammopiperidin-l-yl, 3-aminopiperidm-l-yl, and 3-ammopyrrolidin- 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 pipe ⁇ dm-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 m a nitrogen- contammg heterocyclyl group, for example pipe ⁇ dm- 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 and 2-(4-methylhomopiperazm- 1 -yl)ethyl Unless otherwise stated or indicated, the term "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-methylpiperidm-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-iV-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-C 2 4 -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 hydroxy-N-heterocyclyl-C 2 4 -alkyl groups include 2-(4-hydroxy- pipendm- 1 -yl)ethyl and 3-(3-hydroxypipe ⁇ dm- 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-N-heterocyclyl-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-aminopiperidin-l- yl)ethyl and 3-(3-ammopipe ⁇ dm-l-yl)propyl
  • the term “azabicyclyl” denotes a bicyclic heterocyclyl group with seven or
  • 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 24-acylarmno-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
  • N-heterocyclylcarbonyl refers to a mtrogen- containing heterocyclyl group that is directly bonded to a carbonyl group via a nitrogen atom
  • Examples of N-heterocyclylcarbonyl groups include 1-pipe ⁇ dmylcarbonyl, 1-piperazinylcarbonyl and 1-pyrrolidmcarbonyl
  • Exemplary C-heterocyclylcarbonyl groups include 3-pipe ⁇ dinylcarbonyl, 4-piperidmylcarbonyl and tetrahydropyranyl-4- ylcarbonyl When C-heterocyclylcarbonyl is substituted by Ci
  • An exemplary C-heterocyclylcarbonyl group substituted by Ci 4 -alkyl includes 1 -methylpiperidin-4-ylcarbonyl.
  • the term "N-heterocyclylcarbonyl-C 2 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-C24-alkyl groups include 2-(pyrrolidm-l-ylcarbonyl)ethyl, 2-(piperazin-l-ylcarbonyl)ethyl and 2- (pipe ⁇ dm- 1 -ylcarbonyl)ethyl When heterocyclyl as part of the group N-heterocyclylcarbonyl-C24-alkyl is substituted by methyl, said heterocyclyl is selected from 1-piperazmy
  • 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-C24-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-C24-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 esterif ⁇ cation
  • Examples of coupling agents include, but are not limited to, carbonyldiimidazole, dicyclohexylcarbodiimide, pyridine, 4-dimethylamino- pyridine, and triphenylphosphme
  • Another example of a coupling agent is l-ethyl-3-(3- dimethylammopropyl)carbodumide hydrochloride, which is used in the presence of 1-hydroxybenzotriazole and a base such as tnethylamine
  • exo and end ⁇ 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 ljheptane 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 melhtus (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 comp ⁇ se the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form.
  • Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
  • Exemplary 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
  • Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylammes, benzathine, and ammo acids, such as, e.g. arginme and
  • 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, biguamdes, ⁇ 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-agomsts, leptm and leptm mimetics, serotonergic/dopaminergic antiobesity drugs, gastric lipase inhibitors, pancreatic lipase inhibitors
  • 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 m 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 PREPARATION OF COMPOUNDS OF THE INVENTION
  • 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 invention may in particular be illuminated by the following Schemes 1-3
  • suitable reducing agent such as NaBH.4, in a suitable solvent, such as ethanol or methanol; at r t.
  • (d) (1) bis(neopentylglycolato)diboron; suitable base, such as KOAc, approp ⁇ ate catalyst, such as PdCi 2 (dppf)-DCM, m a suitable solvent, such as DME, at elevated temperature, for example 120 0 C (microwaves), (u) appropriate aryl hahde, suitable base, such as NaHC ⁇ 3 , appropriate catalyst, such as Pd(PPh 3 ) 4 ; m a suitable solvent mixture, such as water and DME, at elevated temperature, for example 120 0 C
  • suitable deprotecting agent such as TFA, HCl (g) or aqueous 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 HCl, m a suitable solvent, such as DCM, dioxane or ethanol, at ambient or elevated temperature
  • suitable carboxylic acid, suitable base such as t ⁇ ethylamine
  • suitable solvent such as THF, dioxane or DMF
  • coupling reagent such as
  • HOBT/EDC propylphosphomc anhydride, HBTU or TBTU; at ambient temperature;
  • appropriate acid chloride or chloroformate, suitable base such as triethylamme, in a suitable solvent, such as THF or DMF; at ambient temperature;
  • suitable coupling reagent such as l,l'-carbonylbis(lH- lmidazole), m a suitable solvent, such as DCM, acetomtrile or DCM/THF, at elevated temperature
  • suitable halogenated heteroaromatic ring such as 2-bromopy ⁇ midine
  • m a suitable solvent such as DMSO or acetomtrile
  • a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base Ui a suitable organic solvent and treating the solution with an acid, m 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 in 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 described 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 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 Transformations, VCH Publishers (1989); T. W. Greene and P.G.M.
  • LRESIMS Low-resolution electrospray ionization mass spectra
  • HRESIMS High-resolution electrospray ionization mass spectra
  • the title compound was prepared by addition of ethyl chloro formate (6 mg, 5 9 ⁇ L, 0 027 mmol) to a mixture containing l-( ⁇ 5-[3-(methoxymethyl)-4-(piperidin-4-ylmethoxy)- phenyl]pyridm-2-yl ⁇ carbonyl)-4-methylpiperazine (10 mg, 0 0288 mmol, Intermediate 5) and pyridine (5 mg, 5.1 ⁇ L, 0.0632 mmol) in DCM (0.5 mL). The resulting mixture was stirred for 10 h at r.t. and concentrated under reduced pressure. The residue was purified by preparative HPLC (System E) to give the title compound as a solid.
  • the title compound was prepared by adding a IM solution of isopropyl chloroformate in toluene (33 ⁇ L, 0.027 mmol) to a mixture containing l-( ⁇ 5-[3-(methoxymethyl)-4- (pipe ⁇ din-4-ylmethoxy)phenyl]pyridin-2-yl ⁇ carbonyl)-4-methylpiperazine (10 mg, 0.0288 mmol, Intermediate 5) and pyridine (5 mg, 5.1 ⁇ L, 0.0632 mmol) in DCM (0.5 mL). The resulting mixture was stirred for 10 h at r.t The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (System E) to give the title compound as a solid.
  • the title compound was prepared by adding a IM solution of isopropyl chloroformate in toluene (33 ⁇ L, 0.027 mmol) to a mixture containing l-( ⁇ 6-[3-(methoxymethyl)-4- (pipe ⁇ dm-4-ylmethoxy)phenyl]pyridin-3-yl ⁇ carbonyl)-4-methylpiperazine (10 mg, 0.0288 mmol, Intermediate 6) and pyridine (5 mg, 5.1 ⁇ L, 0.0632 mmol) in DCM (0.5 mL). The resulting mixture was stirred for 10 h at r.t. and concentrated under reduced pressure. The residue was purified by preparative HPLC (System E) to give the title compound as a solid. Yield 7.3 mg (61%). Analytical HPLC: purity 99% (System B), 99% (System A); HRESIMS (ESI + ) calcd for C 29 H 40 N 4 O 5 524.2999, found 524.3010.
  • Agonists to the human GPRl 19 receptor were characterized by measuring human GPRl 19 receptor-mediated stimulation of cyclic AMP (cAMP) in HEK 293 cells expressing the human GPRl 19 receptor.
  • cAMP cyclic AMP
  • cAMP content was determined using a cAMP kit based on HTRF technology (Homogeneous Time-Resolved Fluorescence, Cisbio Cat. no. 62AM2PEC).
  • HEK293 cells stably expressing the human GPRl 19 receptor (HEK293-hGPRl 19 cells) were cultured in DMEM (Gibco # 31966-021) supplemented with 10% Bovine Calf Serum (Hyclone # SH30072.03), and 500 ⁇ g/mL Hygromycin B (Roche Diagnostics 843555).
  • HEK293-hGPR119 cells were thawn and diluted to 0.4xl0 6 cells/mL in assay buffer (Ix HBSS (Gibco Cat. no. 14025-049), 20 mM Hepes (Gibco Cat. no.15630-056), 0.1% BSA, pH 7.4) and incubated with test substances for 20 min at room temperature.
  • HTRF reagents diluted in lysis buffer
  • Test substances was diluted in compound buffer (Ix HBSS (Gibco Cat. no. 14025-049), 20 mM Hepes (Gibco Cat. no.15630-056), 0.1% BSA, 2mM IBMX (Sigma-Aldrich Cat No. 17018, pH 7.4).
  • the potency of the agonist was quantified by determine the concentration that cause 50% activation of hGPRl 19 evoked increase in cAMP, EC50.
  • Compounds of the invention showed a concentration-dependant increase in intracellular cAMP level and generally had an EC50 value of ⁇ 10 ⁇ M.
  • HIT-T 15 cells Hamster beta-cell line, American Type Culture Collection
  • HIT-T15 cells are grown in suitable media (typically F12 Kaighn's Nutrient Mixture Kaighn's modification supplemented with 10% Horse serum, 1.5 g/L sodium bicarbonate, 2.5% dialyzed and heat-mactivated Fetal Bovme Serum) as recommended by the provider.
  • Cells are trypsmated, resuspended in growth media supplemented with 10 % DMSO, aliquoted and frozen as ready-to-use vials.
  • HTRF assay buffer For potency analyses, frozen cells are thawed, spun and resuspended in HTRF assay buffer at a suitable cell density. Cells are treated with various concentrations of test compounds, a reference compound to define 100% response, forskolin or buffer containing the same DMSO concentration as the compound solutions to define base line. Typically, stimulation proceeds for 15 to 30 minutes and thereafter the cAMP levels are determined using the HTRF® kit (Homogenous Time-Resolved FRET, CisBio).
  • pancreatic islets from Wistar rats and diabetic rat models, e.g GK rat. Briefly, islets are isolated from the rats by digestion with collagenase according to standard protocol.
  • the islets are cultured for 24 h in RPMI- 1640 medium supplemented with 11.1 mM glucose and 10 % (vol/vol) fetal calf serum
  • batches of three islets are premcubated in KRB (Krebs-Ringer bicarbonate) buffer and 3.3 mM glucose for 30 min, 37 °C
  • the batches with islets are incubated in 16.7 mM glucose and KRB buffer supplemented with vehicle or test compounds for 60 mm at 37 0 C Aliquots of the medium will be frozen for measurement of insulin using a radioimmunoassay with rabbit ant-porcine insulin antibodies.
  • mice models eg Lep ob/ob or diet-induced obese (DIO) mice
  • DIO diet-induced obese mice
  • Plasma glucose and insulin levels are determined at desired time points over a 2 hour period using blood collection from tail nick
  • Plasma glucose is determined using a Glucometer and plasma insulin is determined using an insulin ELISA following blood collection in hepa ⁇ nated tubes and centrifugation.
  • GPRl 19 modulators on body weight is determined m diabetic and obese mice models, eg Lep ob/ob or diet-induced obese (DIO) mice
  • the food intake and body weight gain is measured during subchromc treatment with vehicle or test compound via oral gavage
  • vena cava blood is collected and e.g HbAIc, GLP-I, insulin, ALAT, ASAT are measured

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (Ia) et des sels, solvates, hydrates, isomères géométriques, tautomères, isomères optiques et N-oxydes pharmaceutiquement acceptables de ceux-ci. La présente invention concerne en outre des compositions pharmaceutiques comprenant ces composés et l'utilisation de ces composés pour la prophylaxie et le traitement de pathologies médicales associées à des troubles du récepteur GPR119 couplé à la protéine G, tels que le diabète, l'obésité et l'ostéoporose.
PCT/EP2009/052281 2008-02-27 2009-02-26 Agonistes du gpr119 Ceased WO2009106565A1 (fr)

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Cited By (23)

* Cited by examiner, † Cited by third party
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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
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production 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
EP2399914A4 (fr) * 2009-02-18 2012-08-29 Takeda Pharmaceutical Composé à noyau hétérocyclique fusionné
US8293729B2 (en) 2009-06-24 2012-10-23 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US20120322784A1 (en) * 2010-12-17 2012-12-20 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical compositions and uses thereof
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
WO2015167309A1 (fr) * 2014-05-02 2015-11-05 현대약품 주식회사 Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies métaboliques, contenant celui-ci comme principe actif
KR20150126564A (ko) * 2014-05-02 2015-11-12 현대약품 주식회사 싸이클로 헥센 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 대사성 질환의 예방 또는 치료용 약학적 조성물
RU2603346C2 (ru) * 2012-06-12 2016-11-27 Чхон Кхун Дан Фармасьютикал Корп. Производные пиперидина в качестве агонистов gpr119
WO2017078352A1 (fr) * 2015-11-04 2017-05-11 Hyundai Pharm Co., Ltd. Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter une maladie métabolique, contenant ledit dérivé comme principe actif
US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
WO2018160024A1 (fr) * 2017-02-28 2018-09-07 한국화학연구원 Dérivé de pipéridine-aryle ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et composition pharmaceutique contenant celui-ci en tant que principe actif
WO2021071837A1 (fr) * 2019-10-07 2021-04-15 Kallyope, Inc. Agonistes de gpr119
WO2021174048A1 (fr) 2020-02-28 2021-09-02 Kallyope, Inc. Agonistes de gpr40
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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US8410089B2 (en) 2009-02-18 2013-04-02 Takeda Pharmaceutical Company Limited Fused heterocyclic ring compound
EP2399914A4 (fr) * 2009-02-18 2012-08-29 Takeda Pharmaceutical Composé à noyau hétérocyclique fusionné
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
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, 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
US20120322784A1 (en) * 2010-12-17 2012-12-20 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical compositions and uses thereof
US8669271B2 (en) * 2010-12-17 2014-03-11 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical compositions and uses thereof
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
RU2603346C2 (ru) * 2012-06-12 2016-11-27 Чхон Кхун Дан Фармасьютикал Корп. Производные пиперидина в качестве агонистов gpr119
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
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
US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
KR20150126564A (ko) * 2014-05-02 2015-11-12 현대약품 주식회사 싸이클로 헥센 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 대사성 질환의 예방 또는 치료용 약학적 조성물
CN106660955A (zh) * 2014-05-02 2017-05-10 现代药品株式会社 环己烯衍生物、其制备方法及包含其作为活性成分的用于预防或治疗代谢疾病的药物组合物
US9758527B2 (en) 2014-05-02 2017-09-12 Hyundai Pharm Co., Ltd. Cyclohexene derivative, preparation method therefor, and pharmaceutical composition for preventing or treating metabolic diseases, containing same as active ingredient
KR101651505B1 (ko) 2014-05-02 2016-08-29 현대약품 주식회사 싸이클로 헥센 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 대사성 질환의 예방 또는 치료용 약학적 조성물
WO2015167309A1 (fr) * 2014-05-02 2015-11-05 현대약품 주식회사 Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies métaboliques, contenant celui-ci comme principe actif
CN106660955B (zh) * 2014-05-02 2019-08-23 现代药品株式会社 环己烯衍生物、其制备方法及包含其作为活性成分的用于预防或治疗代谢疾病的药物组合物
WO2017078352A1 (fr) * 2015-11-04 2017-05-11 Hyundai Pharm Co., Ltd. Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter une maladie métabolique, contenant ledit dérivé comme principe actif
US10723699B2 (en) 2015-11-04 2020-07-28 Hyundai Pharm Co., Ltd. Cyclohexene derivative, preparation method thereof, and pharmaceutical composition for preventing or treating metabolic disease comprising the same as active ingredient
WO2018160024A1 (fr) * 2017-02-28 2018-09-07 한국화학연구원 Dérivé de pipéridine-aryle ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et composition pharmaceutique contenant celui-ci en tant que principe actif
WO2021071837A1 (fr) * 2019-10-07 2021-04-15 Kallyope, Inc. Agonistes de gpr119
CN114945560A (zh) * 2019-10-07 2022-08-26 卡尔优普公司 Gpr119激动剂
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
WO2021174048A1 (fr) 2020-02-28 2021-09-02 Kallyope, Inc. Agonistes de gpr40
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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