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WO2009150144A1 - Nouveaux modulateurs de gpr119 - Google Patents

Nouveaux modulateurs de gpr119 Download PDF

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Publication number
WO2009150144A1
WO2009150144A1 PCT/EP2009/057074 EP2009057074W WO2009150144A1 WO 2009150144 A1 WO2009150144 A1 WO 2009150144A1 EP 2009057074 W EP2009057074 W EP 2009057074W WO 2009150144 A1 WO2009150144 A1 WO 2009150144A1
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Prior art keywords
benzodioxin
alkyl
phenyl
piperidine
carboxylate
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Inventor
Tobias Koolmeister
Gary Johansson
Antti Hartikka
Wei Berts
Björn M. Nilsson
Lars Johansson
Rikard Emond
Peter Brandt
Jonas Nilsson
Bengt Lindqvist
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INOVACIA AB
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INOVACIA AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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- 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.
  • TZDs Thiazolidindiones
  • a major side effect of TZDs is weight gain due to fluid retention and increase in total body fat.
  • Current therapies have limited durability and/or significant side effects.
  • Orlistat inhibits the lipase-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
  • 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.
  • Teen can develop osteoporosis, but it is common in older women. 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. Risk factors 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 Insulinotropic Polypeptide
  • GPRl 19 is a G-protein coupled receptor identified as SNORF25 in WO 00/50562. In humans, GPRl 19 is selectively expressed in pancreas and gastrointestinal tract. Activation of GPRl 19 by lysophosphatidylcholine (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 in rat islets and reduce blood glucose in diabetic Lep ⁇ mice (WO 2004/065380 and Chu et al, Endocrinology 148, 2601- 2609, 2007).
  • LPC lysophosphatidylcholine
  • GPRl 19 agonists enhances the release of the incretins, 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 149, 2038-2047, 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 discloses 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 2008/025798, WO 2008/025799 and WO 2008/025800 disclose pyridine, pyridazine and pyrimidine compounds, respectively, as agonists of GPRl 19, which can 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, in lowering elevated glucose levels in mice. Further, a synergistic effect with the said combination is shown in increasing blood GLP-I levels after glucose challenge in 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 wild type mice. DISCLOSURE OF THE INVENTION
  • compounds of the general Formula (Ia) to (Id) 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 inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis.
  • the present invention provides a compound of Formula (Ia),
  • W, X and Y are each independently CH 2 , O, NH or N(CHs), provided that at least one of W and X is CH 2 ; m is each independently 0 or 1 ;
  • R 1 is -C(O)OR 2 , -C(O)R 2 , -C(O)NR 2 R 3 , -C(O)CH 2 NR 2 R 3 , -CH 2 C(O)NR 2 R 3 , -S(O) 2 R 2 , -C(O)C(O)R 9 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 bromine, chlorine and fluorine, (c) Ci-4-alkylsulfoximine, (d) -S(O)R 4 ,
  • N-heterocyclylcarbonylvinyl wherein N-heterocyclyl is optionally substituted with Ci- 4 -alkyl
  • R 2 is selected from:
  • R 3 is selected from: (a) hydrogen,
  • R 4 is independently selected from:
  • R 5 is each independently selected from:
  • Ci_ 4 -alkoxy-C 2 - 4 -alkyl Ci_ 4 -alkylamino-C 2 - 4 -alkyl
  • R 6 is independently selected from:
  • R 7 is independently selected from:
  • Ci-4-alkyl is independently selected from: (a) hydrogen,
  • R 9 is aryl or heteroaryl, each of which is optionally substituted in one or more positions with a substituent independently selected from the group Z 2 as defined above.
  • W, X and Y are each independently CH2, O or NH, provided that (i) at least one of W and X is CH2, and (ii) no more than one of W, X and Y is NH.
  • m is each 1. - -
  • a preferred group of compounds of the invention are compounds of Formula (Ib):
  • W and X are each independently CH 2 or O, provided that at least one of W and X is CH 2 ; Y is CH 2 , O or NH; and Ar 1 , Z 1 , Z 2 , R 1 to R 9 are as defined in Formula (Ia).
  • a further preferred group of compounds of the invention are compounds of Formula (Ic):
  • Z 1 , Z 2 , R 1 to R 6 are as defined in Formula (Ia);
  • Ar 1 is phenyl or heteroaryl, each of which is optionally substituted in one or two positions with a substituent independently selected from the group Z consisting of:
  • halogen selected from bromine, chlorine and fluorine
  • R 8 is independently selected from:
  • R 9 is phenyl which is optionally substituted in one or two positions with a substituent independently selected from the group Z 2 as defined herein for Formula (Ia).
  • a preferred subgroup of compounds of Formula (Ic) consists of compounds wherein:
  • Ar 1 is phenyl, quinolinyl, pyridinyl, thiazolyl, thienyl, furyl or isoxazolyl, each of which is optionally substituted in one or two positions with a substituent independently selected from the group Z 4 consisting of: (a) halogen selected from chlorine and fluorine,
  • R 1 is a group R 1A , which is selected from -C(O)OR 2A , -C(O)R 2A , -C(O)NR 2A R 3A , -CH 2 C(O)NR 2A R 3A , -C(O)C(O)-phenyl or a 6-membered heteroaryl group linked via a ring carbon atom, wherein the said heteroaryl group is optionally substituted with methyl;
  • R 2A is selected from:
  • R 3A is selected from:
  • heterocyclic ring may be optionally substituted with: i) one hydroxy, amino or methyl 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;
  • R 5A is each independently selected from: (a) hydrogen,
  • Ar 1 is selected from [(dimethylamino)carbonyl]phenyl, (methylsulfonyl)phenyl, quinolinyl, [(diethylamino)- carbonyljphenyl, [(4-methylpiperidin- 1 -yl)carbonyl]phenyl, [(4-oxopiperidin- 1 -yl)- carbonyljphenyl, (methylsulfonyl)pyridinyl, [(methylsulfonyl)amino]phenyl, ⁇ [(2- morpholin-4-ylethyl)amino]sulfonyl ⁇ phenyl, (methylsulfonyl)nitrophenyl, (methyl- sulfonyl)aminophenyl, ⁇ [2-(dimethylamino)ethyl] amino ⁇ (methylsulfonyl)phenyl, ⁇ [2-(dimethylamino)ethyl] amino
  • Ar 1 is selected from 4-[(dimethylamino)carbonyl]phenyl, 4-(methyl- sulfonyl)phenyl, quinolin-5-yl, 4-[(diethylamino)carbonyl]phenyl, 4-[(4-methylpiperidin- l-yl)carbonyl]phenyl, 4-[(4-oxopiperidin-l-yl)carbonyl]phenyl, 5-(methylsulfonyl)pyridin- 2-yl, 4-[(methylsulfonyl)amino]phenyl, (4- ⁇ [(2-morpholin-4-ylethyl)amino]sulfonyl ⁇ - phenyl, 4-(methylsulfonyl)-2-nitrophenyl, 2-amino-4-(methylsulfonyl)phenyl, 2- ⁇ [2- (dimethylamino)ethyl] amino ⁇ -4-(methylsulfonyl)
  • R 1A is selected from C(O)OR 2A , C(O)R 2A , -CH 2 -C(O)NR 2A R 3A , -C(O)C(O)-phenyl or a 6-membered heteroaryl group linked via a ring carbon atom.
  • R 1A is C(O)OR 2A , wherein R 2A is selected from benzyl, tert-butyl, ethyl, (l-methylcyclopropyl)methyl and isopropyl.
  • R 1A is C(O)R 2A , wherein R 2A is selected from 4-cyanobenzyl, 3,4- dichlorophenyl, 2,4-difluorobenzyl, 3-(trifluoromethyl)benzyl, 4-methoxybenzyl, (IH- indol-3-yl)methyl, (1 -methyl- IH- indol-3-yl)methyl, cyclohexylmethyl, 2-methyl-2-phenyl- n-propyl, 2-(4-methoxyphenyl)ethyl, 2-(3-chloro-4-methoxyphenyl)ethyl, 2-(4- hydroxyphenyl)ethyl, 2-(lH-indol-3-yl)ethyl, 2-cyclohexylethyl, 3-(4-fluorophenyl)propyl,
  • R 1A is -C ⁇ 2 -C(O)NR 2A R 3A , wherein R 2A and R 3A are both ethyl.
  • R 1A is -C(O)C(O)-phenyl.
  • R 1A is 2-pyrimidinyl.
  • Particularly preferred compounds of Formula (Ic) are the compounds selected from the group consisting of:
  • a further preferred group of compounds of the invention are compounds of Formula (Id):
  • Z 1 , Z 2 , R 1 to R 6 are as defined in Formula (Ia);
  • R 8 and R 9 are as defined in Formula (Ic);
  • Ar 1 is phenyl which is optionally substituted in one or two positions with a substituent independently selected from the group Z 3 as defined in Formula (Ic).
  • a preferred subgroup of compounds of the general Formula (Id) consists of compounds wherein:
  • Ar 1 is phenyl, which is optionally substituted in one or two positions with a substituent independently selected from the group Z 4 as defined in Formula (Ic); R 1 is a group R 1A , wherein R 1A is as defined in Formula (Ic); R 2A , R 3A , and R 5A are as defined in Formula (Ic).
  • Ar 1 is methylsulfonylphenyl.
  • R IA is selected from C(O)OR 2A and C(O)R 2A
  • R 1A is C(O)OR 2A , wherein R 2A is Ci- 6 alkyl.
  • R 2A is tert- butyl.
  • R 1A is C(O)R 2A , wherein R 2A is selected from C 3 - 6 -cycloalkyl- Ci- 3 -alkyl and phenyl. Preferably R 2A is selected from cyclohexylmethyl and phenyl.
  • Particularly preferred compounds of Formula (Id) are the compounds selected from the group consisting of:
  • Another object of the invention is a compound of Formula (Ia) to (Id) for use in therapy.
  • the compounds can be used in the treatment or prophylaxis of disorders relating to GPRl 19. Examples of such disorders are Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, 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 the use of a compound of Formula (Ia) to (Id) 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, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis.
  • the method for preparation of a pharmaceutical composition comprises combining a compound according to any of the formulae herein with a pharmaceutically acceptable carrier.
  • the method further comprises combining a compound according to any of the formulae herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the additional therapeutic agent can be, for example, a DPP-IV inhibitor.
  • 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 (Id) or a composition comprising such a compound.
  • a subject e.g., mammal, human, or animal
  • an effective amount of a compound of Formula (Ia) to (Id) or a composition comprising such a compound e.g., agonizing human GPRl 19
  • 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) in need of such treatment an effective amount of a compound of Formula (Ia) to (Id).
  • a subject e.g., mammal, human, or animal
  • 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 GPR119-related disorders include, but are not limited to Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, 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.
  • 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) in a subject suffering from or susceptible to a disorder or symptoms thereof delineated herein, in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof.
  • a level of diagnostic marker e.g., any target or cell type delineated herein modulated by a compound herein
  • diagnostic measurement e.g., screen, assay
  • a second level of Marker in 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 in the subject is determined prior to beginning treatment according to this invention; this pre-treatment level of Marker can then be compared to the level of Marker in the subject after the treatment commences, to determine the efficacy of the treatment.
  • a level of Marker or Marker activity in a subject is determined at least once.
  • Comparison of Marker levels 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 in the art or described herein.
  • a tissue or fluid sample is first removed from a subject.
  • suitable samples include blood, urine, tissue, mouth or cheek cells, and hair samples containing roots. Other suitable samples would be known to the person skilled in the art.
  • Determination of protein levels and/or mRNA levels (e.g., Marker levels) in the sample can be performed using any suitable technique known in the art, including, but not limited to, enzyme immunoassay, ELISA, radio labelling/assay techniques, blotting/chemiluminescence methods, real-time PCR, and the like.
  • enzyme immunoassay ELISA
  • radio labelling/assay techniques blotting/chemiluminescence methods
  • real-time PCR real-time PCR
  • 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
  • Ci_ 2 -alkyl Ci_ 5 -alkyl
  • Ci_ 4 -alkyl Ci_ 3 -alkyl
  • Ci_ 2 -alkyl Ci_ 5 -alkyl
  • Ci_ 4 -alkyl Ci_ 3 -alkyl
  • Ci_ 2 -alkyl Ci_ 5 -alkyl
  • Ci_ 4 -alkyl Ci_ 3 -alkyl
  • Ci_ 2 -alkyl Ci_ 5 -alkyl
  • Ci_ 4 -alkyl Ci_ 3 -alkyl
  • Ci_ 2 -alkyl Ci_ 5 -alkyl
  • Ci_ 4 -alkyl Ci_ 3 -alkyl
  • Ci_ 6 -alkyl examples include methyl, ethyl, /? -propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-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 cyano group.
  • exemplary cyano-Ci_6-alkyl groups include 2-cyanoethyl and 3-cyanopropyl.
  • 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-hydroxy ethyl, 2-hydroxy-l,l- dimethylethyl, 2-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxybutyl and 2- hydroxy-2-methylpropyl.
  • Ci_6-alkoxy a group which 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, C2-6-alkoxy, C2-5-alkoxy, C2-4-alkoxy, C2-3-alkoxy, C3_6-alkoxy, C4_5- alkoxy, etc.
  • Ci_6-alkoxy examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy etc.
  • Subgroups of "Ci_6-alkylthio” and “Ci_6-alkylamino” are to be construed accordingly.
  • Ci_4-alkylsulfinyl denotes a group Ci_4- alkyl-S(O)— .
  • Exemplary Ci_ 4 -alkylsulfmyl groups include methylsulfinyl and ethylsulfinyl.
  • 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)2N— , 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 5 N- diethylamino.
  • di(Ci_4-alkyl)amino-C2-4-alkyl denotes a group di(Ci_4-alkyl)amino, as defined above, attached to a C2-4-alkyl group.
  • Exemplary di(Ci_ 4 -alkyl)amino-C 2 - 4 -alkyl groups include 2-(dimethylamino)ethyl and 3-(diethyl- amino)propyl.
  • di(Ci-2-alkyl)amino-C2-3-alkoxy denotes a group di(Ci_2-alkyl)amino, as defined above, attached to a C2-3-alkoxy group.
  • Exemplary di(Ci-2-alkyl)amino-C2-3-alkoxy groups include 2-(dimethylamino)ethoxy and 3-(diethyl- amino)propoxy.
  • 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. 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 Ci_4-alkyl group.
  • arylcarbonyl-Ci_ 4 -alkyl examples include 3-oxo-3-phenylpropyl, 2-oxo-2-phenylethyl and 1 -methyl-S-oxo-S-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.
  • aryloxymethyl denotes a group aryl-O- CH 2 — .
  • An exemplary aryloxymethyl group is phenoxymethyl.
  • Ci_6-alkoxy-Ci_6-alkyl denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms connected to an alkyl group having from from 1 to 6 carbon atoms.
  • Examples of said Ci_ 6 -alkoxy-Ci_ 6 -alkyl include — o —
  • Ci_6-alkoxy-Ci_6- alkyl For parts of the range "Ci_6-alkoxy-Ci_6- alkyl" all subgroups thereof are contemplated such as Ci_5-alkoxy-Ci_6-alkyl, Ci_4-alkoxy- d- 6 -alkyl, Ci_ 3 -alkoxy-Ci_ 6 -alkyl, Ci_ 2 -alkoxy-Ci_ 6 -alkyl, C 2 - 6 -alkoxy-Ci_ 6 -alkyl, C 2-5 - alkoxy-Ci_ 6 -alkyl, C 2 - 4 -alkoxy-Ci_ 6 -alkyl, C 2 - 3 -alkoxy-Ci_ 6 -alkyl, C 3 - 6 -alkoxy-Ci_ 6 -alkyl, C 4 _ 5 -alkoxy-Ci_ 6 -alkyl, Ci_ 6 -al
  • 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-methylallyl, 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-C2-6-alkenyl means a C2-6-alkenyl group substituted by an aryl group.
  • aryl-C2-6-alkenyl include styryl and cinnamyl.
  • C2-6-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-butynyl, 2-butynyl, and l-methylprop-2-yn-l-yl.
  • aryl-C 2 - 6 -alkynyl means a C 2 - 6 -alkynyl group substituted by an aryl group.
  • aryl-C2-6-alkynyl examples include phenyl- ethynyl, 3 -phenyl- 1-propyn-l-yl, 3-phenyl-2-propyn-l-yl and 4-phenyl-2-butyn-l-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.
  • C 3 _ 7 -cycloalkyl For parts of the range "C 3 _ 7 -cycloalkyl" all subgroups thereof are contemplated such as C3-6-cycloalkyl, C3-5-cycloalkyl, C 3-4 - cycloalkyl, C 4 _ 7 -cycloalkyl, C 4 _ 6 -cycloalkyl, C 4 _ 5 -cycloalkyl, Cs_ 7 -cycloalkyl and C 6-7 - cycloalkyl. Unless otherwise stated or indicated, the term "C3_7-cycloalkyl-Ci_4-alkyl" denotes a C3-7- cycloalkyl group attached to a Ci_ 4 -alkyl group.
  • Exemplary C 3 _ 7 -cycloalkyl-Ci_ 4 -alkyl groups include cyclopropylmethyl, 1-cyclopropylethyl, cyclohexylmethyl and 2-cyclo- hexylethyl.
  • examples of such groups include (l-methylcyclopropyl)methyl and 2-(4-methylcyclohexyl)ethyl.
  • cycloalkyl portion as part of the group C 3 - 6 -cycloalkyl-Ci_ 4 -alkyl is substituted with hydroxy
  • examples of such groups include (1 -hydroxy cyclopropyl)methyl and A- hydroxycyclohexylmethyl.
  • C7_8-bicyclyl denotes a bicyclic saturated hydrocarbon ring system having 7 or 8 carbon atoms, 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_8-bicyclyl include radicals obtainable from bicyclo[3.1.1]heptane, bicyclo [2.2.1] heptane (norbornane) and bicyclo[2.2.2]octane.
  • C 7 _ 8 -bicyclyl-Ci_ 6 -alkyl means a Ci_ 6 -alkyl group substituted by a C7-8-bicyclyl group as defined above.
  • An exemplary C7-8-bicyclyl- Ci_ 6 -alkyl 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- 2-yl).
  • oxo-C4_6-cycloalkyl refers to a C 4-6 - cycloalkyl wherein two hydrogens on a cycloalkyl carbon atom are replaced by an oxo group as defined herein.
  • Examples of "oxo-C 4 - 6 -cycloalkyl” include 2-oxocyclobutyl, 3- oxocyclobutyl, 2-oxocyclopentyl and 4-oxocyclohexyl.
  • fluoro-C3_6-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-C4_6-cycloalkyl denotes a C4_ 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_6-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 - -
  • Ci_6-acyl all subgroups thereof are contemplated such as Ci_5-acyl, C 1-4 -acyl, C 1-3 -acyl, C 1-2 -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 attached to a sulfonyl group.
  • Ci_5-alkylsulfonyl C 1-4 -alkylsulfonyl, C 1-3 -alkylsulfonyl, C 1-2 -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, n-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl and hexylsulfonyl.
  • hydroxy-C2-4-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 3-hydroxypropylsulfonyl and 2-hydroxyethylsulfonyl.
  • amino-C2-4-alkylsulfonyl denotes a C2-4- alkylsulfonyl group as defined above substituted with a amino group.
  • Examples of said amino-C 2 - 4 -alkylsulfonyl include 3-aminopropylsulfonyl and 2-aminoethylsulfonyl.
  • the term "Ci_4-alkylsulfonamido” denotes a group Ci_ 4 -alkyl-SO 2 NH— .
  • Exemplary Ci_ 4 -alkylsulfonamido groups include methylsulfonyl- amino and ethylsulfonylamino.
  • Ci-4-alkylsulfoximine refers to a group with the following chemical structure: , where R a is Ci-4-alkyl.
  • 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- tetrahydronaphthy 1. - -
  • 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. 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 in any ring.
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrimidinyl, quinazolinyl, indolyl, isoindolyl, 1,3-dihydro-isoindolyl, pyrazolyl, pyridazinyl, quinolinyl, quinoxalinyl, thiadiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1 ,4-benzodioxinyl, 2,3-dihydro-l,4-benzodioxinyl, benzothiazolyl, benzimidazolyl, benzothiadiazolyl, benzotriazolyl, indolinyl, iso
  • heterocyclyl or “heterocyclic ring” refers to a non-aromatic, fully saturated or partially unsaturated, preferably fully saturated, 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, imidazolidinyl, thiomorpholinyl, pyranyl, dioxanyl, piperazinyl, homopiperazinyl and 5,6-dihydro-4H-l,3-oxazin-2-yl.
  • Exemplary heterocyclic groups containing sulfur in oxidized form are 1,1-dioxido-thiomorpholinyl and 1 , 1 -dioxido-isothiazolidinyl.
  • 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, 1,3 benzodioxol-5-ylmethyl and 2-(2-furyl)ethyl.
  • 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 "JV-heterocyclyl” indicates bonding through nitrogen in a nitrogen- containing heterocyclyl group, for example piperidin-1-yl and piperazin-1-yl.
  • 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 C 1-4- alkyl include l-methylpiperidin-4-yl and 3-methyloxetan-3-yl.
  • N-heterocyclyl When N-heterocyclyl is substituted by methyl, said methyl is attached to a ring nitrogen atom or a ring carbon atom thereof.
  • Exemplary N-heterocyclyl groups substituted by methyl include 4-methyl- piperidin- 1 -yl and 4-methylpiperazin- 1 -yl.
  • the term 'W-heterocyclyl-C2-4-alkyl refers to a nitrogen-containing heterocyclyl group that is directly linked to a C 2 - 4 -alkyl group via a nitrogen atom of said heterocyclyl.
  • Exemplary JV-heterocyclyl-C 2 - 4 -alkyl groups include 2-(pyrrolidin-l-yl)ethyl, 3-(4-morpholinyl)propyl, 2-(piperazin-l-yl)ethyl and 2-(4- - - -
  • morpholinyl)ethyl means a methyl group substituted by a heterocyclyl group via a nitrogen atom thereof.
  • exemplary N- heterocyclylmethyl groups include morpholin-4-ylmethyl and piperazin-1-ylmethyl.
  • heterocyclyl as part of the group N-heterocyclyl-C 2 - 4 -alkyl is substituted by methyl, said heterocyclyl is selected from 1-piperazinyl or 1-homopiperazinyl and said methyl is attached to the 4-position of the piperazine or homopiperazine ring.
  • N-heterocyclyl-C 2 - 4 -alkyl groups wherein heterocyclyl is substituted with methyl are 2-(4-methylpiperazin- 1 -yl)ethyl and 2-(4-methylhomopiperazin- 1 -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-heterocyclyl-Ci_ 4 -alkyl groups include tetrahydropyran-4-yl- methyl, piperidin-4-ylmethyl, tetrahydrofuran-2-ylmethyl, oxetan-3-ylmethyl and 2- (piperidinyl-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-methylpiperidin-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-C2-4-alkyl refers to an oxo-N-heterocyclyl group that is directly linked to a C 2 - 4 -alkyl group through a nitrogen atom of its heterocyclyl portion and where oxo-N-heterocyclyl is as defined above.
  • Exemplary oxo-N-heterocyclyl-C 2 - 4 -alkyl groups include 2-(2-pyrrolidon-l-yl)ethyl, 3-(2-pyrrolidon- 1 -yl)propyl and 2-(2,5-dioxoimidazolidin- 1 -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-C2-4-alkyl refers to a fluoro-N-heterocyclyl group that is directly linked to a C2-4-alkyl group through a nitrogen atom of its heterocyclyl portion and where fluoro-N-heterocyclyl is as defined above.
  • exemplary fluoro-N-heterocyclyl-C 2 - 4 -alkyl groups include 2-(3-fluoropyrrolidin-l-yl)- ethyl and 3-(3-fluoropyrrolidin-l-yl)propyl. - -
  • hydroxy-iV-heterocyclyl denotes a nitrogen-containing heterocyclyl group that is substituted at a position other than alpha to a ring heteroatom with a hydroxy group.
  • hydroxy-jV-heterocyclyl-C 2 - 4 -alkyl refers to a hydroxy-jV-heterocyclyl group that is directly linked to a C2-4-alkyl group through a nitrogen atom of its heterocyclyl portion and where hydroxy-iV- heterocyclyl is as defined above.
  • exemplary hydroxy-jV-heterocyclyl-C 2 - 4 -alkyl groups include 2-(4-hydroxy- piperidin-l-yl)ethyl and 3-(3-hydroxypiperidin-l-yl)propyl.
  • amino-iV-heterocyclyl denotes a nitrogen- containing heterocyclyl group that is substituted at a position other than alpha to a ring heteroatom with an amino group.
  • amino-jV-heterocyclyl-C2-4-alkyl refers to a amino-jV-heterocyclyl group that is directly linked to a C2-4-alkyl group through a nitrogen atom of its heterocyclyl portion and where amino-iV-heterocyclyl is as defined above.
  • exemplary amino- ⁇ /-heterocyclyl-C 2 - 4 -alkyl groups include 2-(4-aminopiperidin-l- yl)ethyl and 3-(3-aminopiperidin-l-yl)propyl.
  • azabicyclyl denotes a bicyclic heterocyclyl group with seven or eight atoms (including bridgehead atoms), wherein at least one ring member is a nitrogen atom and the remainder ring atoms being carbon.
  • the said azabicyclyl may optionally contain a carbon-carbon double bond.
  • Examples of azabicyclyl groups include carbon radicals obtainable from l-azabicyclo[2.2.2]octane, 1-aza- bicyclo[2.2.1]heptane and azabicyclo[2.2.2]oct-2-ene.
  • C-heterocyclylsulfonyl refers to a heterocyclyl group that is directly bonded to SO2 via a carbon atom.
  • exemplary C-heterocyclylsulfonyl groups include 4-piperidinylsulfonyl and tetrahydropyran-4-ylsulfonyl.
  • 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 -methylpiperidin-4-ylsulfonyl.
  • Exemplary C 2 - 4 -acylamino groups include acetylamino and propionylamino. - -
  • C2-4-acylamino-Ci_4-alkyl denotes a C2-4 acylamino group, as defined above, attached to a Ci_4-alkyl group.
  • Examplary C 2-4 - acylamino-Ci_ 4 -alkyl groups include (acetylamino)methyl and 2-(acetylamino)ethyl.
  • aminocarbonyl-Ci_4-alkyl denotes a C 1-4 - alkyl group, as defined above, substituted with an aminocarbonyl group.
  • exemplary aminocarbonyl-Ci_ 4 -alkyl groups include 2-(aminocarbonyl)ethyl and 3-(aminocarbonyl)- propyl.
  • Ci_ 3 -alkylaminocarbonyl-C 2 - 6 -alkyl denotes a group Ci_3-alkylaminocarbonyl, as defined above, attached to a C2-6-alkyl group.
  • exemplary Ci_ 3 -alkylaminocarbonyl-C 2 - 6 -alkyl groups include 2-(methylaminocarbonyl)- ethyl and 2-(ethylaminocarbonyl)ethyl.
  • di(Ci_ 3 -alkyl)aminocarbonyl-C 2 - 6 -alkyl denotes a group di(Ci_ 3 -alkyl)aminocarbonyl, as defined above, attached to a C 2 - 6 -alkyl group.
  • Exemplary di(Ci_ 3 -alkyl)aminocarbonyl-C 2 - 6 -alkyl groups include 2- (dimethylaminocarbonyl)ethyl and 2-(diethylaminocarbonyl)ethyl.
  • the term— C(O)- means a carbonyl group.
  • the term “carboxy” denotes a group -C(O)OH.
  • the term “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 carbonylamino (i.e., -C(O)NH-).
  • exemplary carboxy-Ci_3-alkylcarbonylamino groups include (2-carboxyethyl)carbonylamino and (3-carboxypropyl)carbonylamino.
  • C-heterocyclylcarbonyl refers to a heterocyclyl group that is directly bonded to a carbonyl group via a carbon atom while 'W-heterocyclylcarbonyl” refers to a nitrogen- containing heterocyclyl group that is directly bonded to a carbonyl group via a nitrogen atom.
  • JV-heterocyclylcarbonyl groups include 1-piperidinylcarbonyl, - -
  • C-heterocyclylcarbonyl groups include 3-piperidinylcarbonyl, 4-piperidinylcarbonyl and tetrahydropyranyl-4-yl- carbonyl.
  • C-heterocyclylcarbonyl is substituted by Ci_4-alkyl
  • said heterocyclyl is selected from a nitrogen-containing heterocyclyl
  • said Ci_ 4 -alkyl is attached to a ring nitrogen atom thereof.
  • An exemplary C-heterocyclylcarbonyl group substituted by Ci_ 4 -alkyl includes 1 -methylpiperidin-4-ylcarbonyl.
  • N-heterocyclylcarbonyl ⁇ -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-(pyrrolidin-l-ylcarbonyl)ethyl, 2-(piperazin-l-ylcarbonyl)ethyl and 2- (piperidin- 1 -ylcarbonyl)ethyl.
  • heterocyclyl as part of the group N-heterocyclylcarbonyl-C 2 - 4 -alkyl is substituted by methyl
  • said heterocyclyl is selected from 1-piperazinyl or 1-homopiperazinyl and said methyl is attached to the 4-position of the piperazine or homopiperazine ring.
  • Exemplary N-heterocyclylcarbonyl-C 2 - 4 -alkyl groups wherein heterocyclyl is substituted with methyl are 2-(4-methylpiperazin- 1 -ylcarbonyl)ethyl, 2-(4-methylhomopiperazin- 1 -ylcarbonyl)- ethyl.
  • exemplary N-heterocyclylcarbonylvinyl groups include 2-(pyrrolidin-l- ylcarbonyl)vinyl, 2-(piperazin-l-ylcarbonyl)vinyl and 2-(piperidin-l-ylcarbonyl)vinyl.
  • an exemplary group is 2-(4-methylpiperazin-l-yl- carbonyl) vinyl.
  • C-heterocyclylcarbonyl-C 2 - 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-(piperidin-3-ylcarbonyl)ethyl and 2-(piperidin-4-ylcarbonyl)ethyl.
  • heterocyclyl as part of the group C-heterocyclylcarbonyl-C 2 - 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-methylpiperidin-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-piperidinyloxy, 4-piperidinyloxy, 3-tetrahydrofuranyloxy, and 4-tetrahydropyranyloxy.
  • Ci_4-alkyl When C-heterocyclyloxy 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-heterocyclyloxy group substituted by Ci_4-alkyl includes 1 -methylpiperidin-4-yloxy.
  • hydroxy-C 2 - 4 -alkoxy-Ci_ 4 -alkyl refers to a hydroxy-C 2 - 4 -alkoxy group that is directly attached to a Ci_4-alkyl group.
  • Representative examples of such groups include:
  • amino refers to a group with the following chemical structure:
  • CF 3 CH 3 (OH)C]-Ci_ 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 chemical formula CF 3 SO 3 refers to a group with the following chemical structure: The carbon-carbon double or triple bonds present in the groups C 3 _ 6 -alkenyl, C 3 _ 6 -alkynyl, aryl-C 3 _ 6 -alkenyl and aryl-C 3 _ 6 -alkynyl as values for any R , R or R 5A groups described - -
  • Coupled agent refers to a substance capable of catalyzing a coupling reaction, such as amidation, or esterification.
  • Examples of coupling agents include, but are not limited to, carbonyldiimidazole, dicyclohexylcarbodiimide, pyridine, 4-dimethylamino- pyridine, and triphenylphosphine.
  • Another example of a coupling agent is l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, which is used in the presence of 1-hydroxybenzotriazole and a base such as triethylamine.
  • 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[2.2.1]heptane and bicyclo[2.2.1]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 refers to a syndrome comprising of some or all of the following diseases: 1) dyslipoproteinemia (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) thrombogenic/fibrinolytic defects.
  • agonists refers to compounds that have affinity for a biochemical receptor and that increase the receptor's pharmacological response upon binding. Depending on the efficacy with which they activate the receptor, agonists can be either full agonists or partial agonists.
  • agonists as used herein shall include both full agonists and partial agonists.
  • “Pharmaceutically acceptable” means being useful in 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 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 in the blood.
  • the prodrug compound usually offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see Silverman, R. B., The Organic Chemistry of Drug Design and Drug Action, 2 nd Ed., Elsevier Academic Press (2004), pp. 498-549).
  • 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.
  • Examples of prodrugs include, but are not limited to, acetate, formate and succinate derivatives of hydroxy functional groups or phenyl carbamate derivatives of amino functional groups.
  • 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 (Id) 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.
  • 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.
  • 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, tolu
  • 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 amino acids, such as, e.g. arginine 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, emulsifiers, 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 in 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 (Id) 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, PvXR 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), amylin antagonists, CCK receptor agonists, ⁇ 3-agonists, leptin and leptin mimetics, serotonergic/dopaminergic antiobesity drugs, gastric lipase inhibitors, pancreatic lipase inhibitors, fatty
  • 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 (Id) 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 1-4.
  • Ar 1 and R 1 are as defined in Formula (Ia); and R is benzyl, Boc or CBz;
  • Pd(PPli3)4 in a suitable solvent mixture, such as water and DME; at elevated temperature, for example 120 0 C (microwaves);
  • A is phenyl or heteroaryl; and R 1 and R 5 are as defined in Formula (Ia);
  • 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 (Id) 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.
  • 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 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. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. - -
  • LRESIMS Low-resolution electrospray ionization mass spectra
  • High-resolution electrospray ionization mass spectra were obtained on an Agilent LC/MSD TOF connected to an Agilent 1100 LC-system, Ion Source: ESI, Ion polarity: pos, Data: profile mode, Scan range: 100-1100 Da, MS parameters: Fragmentor 215V, Skimmer 560V och OCT RF (octpole rods) 250 V.; Reference Masses 121.050873 and 922.009798 (Agilent reference Mix); LC: A 15 mM ammonium acetate; B 100 MeCN; flow rate 400 ⁇ L/min isocratic.
  • Analytical GCMS was performed on a Hewlett-Packard 5890/6890 gas chromatograph equipped with a HP-5MS crosslinked 5% PhMe Siloxane column (30 m x 0.25 mm x 0.25 ⁇ m film thickness) with a Hewlett-Packard 5971A/5972A mass selective detector using electron impact. Flash chromatography was performed on Merck silica gel 60 (230-400 mesh). The compounds were automatically named using ACD 8.0.
  • System B Agilent MSD mass spectrometer; Agilent 1100 system; YMC ODS-AQ column (33x3.0 mm); Water containing 0.1% TFA and acetonitrile were used as mobile phases at a flow rate of 1 mL/min with gradient times of 3.0 min (gradient 10-97% acetonitrile); or
  • DAD 215 - 395 nm Waters 996 PDA detector
  • ACE C8 (3 ⁇ m) column (30x3.0 mm) (from ACT)
  • Methyl 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoate (Intermediate A15; 1.2 g, 2.6 mmol) was reacted with aqueous 6 M KO ⁇ (3 mL) in MeO ⁇ /T ⁇ F (1 :2, 30 mL) at 60 0 C for 1 h. The solvents were removed under reduced pressure and the residue was dissolved in water (30 mL). The water solution was acidified to p ⁇ 2 with 6 M HCl and then extracted with DCM (3 x 30 mL).

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Abstract

La présente invention concerne des composés de formule (Ia) : et leurs sels, solvates, hydrates, isomères géométriques, tautomères, isomères optiques ou N-oxydes, pharmaceutiquement acceptables. La présente invention concerne également des compositions pharmaceutiques comprenant ces composés et l'utilisation de ces composés pour la prophylaxie et le traitement d'affections médicales liées à des troubles du récepteur couplé aux protéines G GPR119, comme le diabète, l'obésité et l'ostéoporose.
PCT/EP2009/057074 2008-06-10 2009-06-09 Nouveaux modulateurs de gpr119 Ceased WO2009150144A1 (fr)

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Cited By (26)

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JP2008110964A (ja) * 2005-01-10 2008-05-15 Arena Pharmaceuticals Inc 糖尿病および糖尿病に関連する状態の治療のため、ならびに血中ｇｌｐ−１レベルの増加によって改善される状態の治療のための併用療法
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
WO2011140160A1 (fr) * 2010-05-06 2011-11-10 Bristol-Myers Squibb Company Composés hétéroaryles bicycliques en tant que modulateurs de gpr119
WO2011148922A1 (fr) * 2010-05-24 2011-12-01 田辺三菱製薬株式会社 Nouveau composé de quinazoline
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
CN102351780A (zh) * 2011-09-15 2012-02-15 兰州沃丰生物科技有限公司 一种1-叔丁氧羰基-4-乙酰基哌啶的合成方法
WO2012046249A1 (fr) 2010-10-08 2012-04-12 Cadila Healthcare Limited Nouveaux agonistes de gpr119
WO2012036523A3 (fr) * 2010-09-17 2012-06-07 건국대학교 산학협력단 Nouveau composé à activité antibiotique et composition antibiotique comprenant le composé
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
WO2013050341A1 (fr) * 2011-10-05 2013-04-11 F. Hoffmann-La Roche Ag Dérivés d'azabenzoxazine utilisés comme modulateurs des crac
WO2013050270A1 (fr) * 2011-10-05 2013-04-11 F. Hoffmann-La Roche Ag Dérivés de benzoxazine utilisés comme modulateurs des crac
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
EP2670746A1 (fr) * 2011-01-31 2013-12-11 Centaurus Biopharma Co., Ltd. Composés hétéroaryles bicycliques en tant qu'agonistes du récepteur gpr119
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
CN103819466A (zh) * 2014-01-27 2014-05-28 温州医科大学附属第二医院、育英儿童医院 一种药物活性化合物Cephalandole A的合成方法
CN103880740A (zh) * 2014-04-14 2014-06-25 西华大学 4-硝基-3-羟基-2-吡啶甲酸的合成
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
JP2015500267A (ja) * 2011-12-09 2015-01-05 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 新規化合物、医薬組成物及びその使用
CN105218437A (zh) * 2015-10-31 2016-01-06 高大元 一种3-氯-5-溴-2-吡啶甲酸的合成方法
CN113929587A (zh) * 2021-11-23 2022-01-14 长沙贝塔医药科技有限公司 一种2-氨基-5-氯苯酚的制备方法

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WO2006067532A1 (fr) * 2004-12-24 2006-06-29 Prosidion Ltd Agonistes du récepteur couplé aux protéines g
WO2008008895A1 (fr) * 2006-07-13 2008-01-17 Smithkline Beecham Corporation Agonistes gpr119 destinés au traitement du diabète et des troubles associés

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2006067532A1 (fr) * 2004-12-24 2006-06-29 Prosidion Ltd Agonistes du récepteur couplé aux protéines g
WO2008008895A1 (fr) * 2006-07-13 2008-01-17 Smithkline Beecham Corporation Agonistes gpr119 destinés au traitement du diabète et des troubles associés

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008110964A (ja) * 2005-01-10 2008-05-15 Arena Pharmaceuticals Inc 糖尿病および糖尿病に関連する状態の治療のため、ならびに血中ｇｌｐ−１レベルの増加によって改善される状態の治療のための併用療法
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
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
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
WO2011140160A1 (fr) * 2010-05-06 2011-11-10 Bristol-Myers Squibb Company Composés hétéroaryles bicycliques en tant que modulateurs de gpr119
CN102971311A (zh) * 2010-05-06 2013-03-13 百时美施贵宝公司 作为gpr119调节剂的二环杂芳基化合物
CN102971311B (zh) * 2010-05-06 2015-07-08 百时美施贵宝公司 作为gpr119调节剂的二环杂芳基化合物
WO2011148922A1 (fr) * 2010-05-24 2011-12-01 田辺三菱製薬株式会社 Nouveau composé de quinazoline
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
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
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012036523A3 (fr) * 2010-09-17 2012-06-07 건국대학교 산학협력단 Nouveau composé à activité antibiotique et composition antibiotique comprenant le composé
WO2012046249A1 (fr) 2010-10-08 2012-04-12 Cadila Healthcare Limited Nouveaux agonistes de gpr119
US20120322784A1 (en) * 2010-12-17 2012-12-20 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical compositions and uses thereof
JP2013545791A (ja) * 2010-12-17 2013-12-26 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 糖尿病、肥満および関連疾患の治療のためのｇｐｒ１１９モジュレーターとしての縮合ジヒドロピラン
US8669271B2 (en) * 2010-12-17 2014-03-11 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical compositions and uses thereof
EP2670746A4 (fr) * 2011-01-31 2014-07-30 Centaurus Biopharma Co Ltd Composés hétéroaryles bicycliques en tant qu'agonistes du récepteur gpr119
EP2670746A1 (fr) * 2011-01-31 2013-12-11 Centaurus Biopharma Co., Ltd. Composés hétéroaryles bicycliques en tant qu'agonistes du récepteur 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
CN102351780A (zh) * 2011-09-15 2012-02-15 兰州沃丰生物科技有限公司 一种1-叔丁氧羰基-4-乙酰基哌啶的合成方法
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
WO2013050341A1 (fr) * 2011-10-05 2013-04-11 F. Hoffmann-La Roche Ag Dérivés d'azabenzoxazine utilisés comme modulateurs des crac
WO2013050270A1 (fr) * 2011-10-05 2013-04-11 F. Hoffmann-La Roche Ag Dérivés de benzoxazine utilisés comme modulateurs des crac
JP2015500267A (ja) * 2011-12-09 2015-01-05 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 新規化合物、医薬組成物及びその使用
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
CN103819466A (zh) * 2014-01-27 2014-05-28 温州医科大学附属第二医院、育英儿童医院 一种药物活性化合物Cephalandole A的合成方法
CN103880740A (zh) * 2014-04-14 2014-06-25 西华大学 4-硝基-3-羟基-2-吡啶甲酸的合成
CN103880740B (zh) * 2014-04-14 2016-02-17 西华大学 4-硝基-3-羟基-2-吡啶甲酸的合成
CN105218437A (zh) * 2015-10-31 2016-01-06 高大元 一种3-氯-5-溴-2-吡啶甲酸的合成方法
CN113929587A (zh) * 2021-11-23 2022-01-14 长沙贝塔医药科技有限公司 一种2-氨基-5-氯苯酚的制备方法
CN113929587B (zh) * 2021-11-23 2024-05-03 长沙贝塔医药科技有限公司 一种14c标记的2-氨基-5-氯苯酚的制备方法

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