WO2009150144A1 - New gpr119modulators - Google Patents

New gpr119modulators 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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PCT/EP2009/057074
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French (fr)
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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Publication of WO2009150144A1 publication Critical patent/WO2009150144A1/en

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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).

Abstract

The application relates to compounds of Formula (Ia): and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomersor N-oxides thereof. The application also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the prophylaxis and treatment of medical conditions relating to disorders of the G-protein- coupled receptor GPR119, such as diabetes, obesity and osteoporosis.

Description

NEW GPR119MODULATORS
FIELD OF INVENTION
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.
BACKGROUND ART
Diabetes mellitus is a group of disorders characterized by abnormal glucose homeostasis resulting in high levels of blood glucose. The most common cases of diabetes mellitus are Type 1 (also referred to as insulin-dependent diabetes mellitus or IDDM) and 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.
The increasing prevalence of obesity together with an ageing population is contributing to the predicted explosion in diabetes across the globe. Current projections suggest that 300 million people worldwide will have diabetes by 2025. The pathogenesis of 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. However, this enhanced insulin production is not glucose dependent and there is risk for developing hypoglycaemia. 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 gain 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.
The widespread availability and increased consumption of Western diet combined with the adoption of a sedentary life-style has increased the number of obese people. Obesity is linked to a wide range of medical complications, such as diabetes, cardiovascular disease and cancer. In addition, being overweight can exacerbate the development of osteoporosis and asthma. Obesity is also proven to double the risk of hypertension. Obesity has only recently been regarded as a disease in the sense of being a specific target for medical therapy. Current therapies for obesity are based on diet and exercise and stomach surgery for extremely obese patients. Only a few weight loss medications are today available for long-term use. Sibutramine, a serotonin- and noradrenaline-reuptake inhibitor, controls appetite by producing a feeling of satiety. However, a prominent side effect is hypertension. Orlistat inhibits the lipase-mediated breakdown of fat in the gastrointestinal tract, thereby limiting caloric intake resulting in weight loss. However, approximately 20% of the patients using Orlistat develop faecal incontinence and urgency. Thus, there is an unmet medical need for new and novel antidiabetic and antiobesity therapies.
Osteoporosis, or porus bone, 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. Anyone 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. It has recently been shown that one of the incretins, Glucose-dependent Insulinotropic Polypeptide (GIP, also known as gastric inhibitory polypeptide), promotes bone mass (Zhong et al., AM J Physiol Endocrinol Metab, 292, E543-E548, 2007).
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 LepΛ^ mice (WO 2004/065380 and Chu et al, Endocrinology 148, 2601- 2609, 2007). 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).
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.
WO 2004/065380, WO 2004/076413, WO 2005/007647, WO 2005/007658 and WO 2005/121121 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
It has surprisingly been found that 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. Examples of such 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.
In a first aspect, the present invention provides a compound of Formula (Ia),
Figure imgf000005_0001
or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer or JV-oxide thereof, wherein:
W, X and Y are each independently CH2, O, NH or N(CHs), provided that at least one of W and X is CH2; m is each independently 0 or 1 ;
R1 is -C(O)OR2, -C(O)R2, -C(O)NR2R3, -C(O)CH2NR2R3, -CH2C(O)NR2R3, -S(O)2R2, -C(O)C(O)R9 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;
Ar1 is phenyl or heteroaryl, each of which is optionally independently substituted in one or more positions with a substituent selected from:
(a) CF3SO3,
(b) halogen selected from bromine, chlorine and fluorine, (c) Ci-4-alkylsulfoximine, (d) -S(O)R4,
(e) -S(O)2R4,
(f) -S(O)2NR5R5,
(g) -NR6S(O)2R4,
CO -CH2-NR6C(O)R4,
(i) -NR6C(O)R4,
(D -C(O)NR5R5,
(k) -CH2-C(O)NR5R5,
(1) -C(O)R4,
(m) H2N-C(O)O-,
(n) CH3-NH-C(O)O-,
(o) (CHs)2NC(O)O-,
(P) CH3OC(O)NH-,
(q) C-heterocyclyl, optionally substituted with Ci_4-alkyl,
(r) N-heterocyclylcarbonylvinyl, wherein N-heterocyclyl is optionally substituted with Ci-4-alkyl,
(S) -CN,
(t) -OR8,
(u) -SCF3,
(v) -NO2,
(W) C-heterocyclylsulfonyl, optionally substituted with Ci_4-alkyl,
(x) -NR5R5,
(y) -C(OH)CH3CF3,
(z) [CF3CH3(OH)C]-Ci_6-alkyl,
(aa) cyano-Ci_6-alkyl,
(bb) guanidino,
(CC) amidino,
(dd) Cj-e-alkyl,
(ee) Ci_6-alkylthio,
(fit) Ci_4-alkoxy-Ci_4-alkyl,
(gg) fluoro-C i _4-alkyl,
(hh) C2_6-alkenyl,
(ϋ) fluoro-C2_4-alkenyl,
(D) hydroxy-C i _6-alkyl, - D -
(kk) Ci_4-alkylsulfonyl-Ci_4-alkyl,
(11) hydroxy-C2-4-alkoxy-Ci_4-alkyl,
(mm) C2-3-acyl-Ci_3-alkyl,
(nn) C2-6-alkynyl, (oo) C3-6-cycloalkyl,
(PP) hydroxy-C^-cycloalkyl,
(qq) fluoro-Cs-β-cycloalkyl,
(rr) methyl-Cs-β-cycloalkyl,
(ss) C3_6-cycloalkyl-Ci_4-alkyl, wherein C3-6-cycloalkyl is optionally substituted with methyl,
(tt) C-heterocyclylcarbonyl, optionally substituted with Ci_4-alkyl,
(uu) C3_6-cycloalkylthio,
(w) R5R5N-Ci_2-alkyl,
(ww) -(CH2)nC(O)OR7, wherein n is 0, 1, 2 or 3, (xx) phenyl, and
(yy) heteroaryl, wherein phenyl or heteroaryl as substituent on Ar1 is optionally substituted in one or more positions with a substituent independently selected from the group Z1 consisting of:
(a) halogen selected from bromine, chlorine and fluorine, (b) Ci_4-alkyl,
(c) hydroxy,
(d) Ci_4-alkoxy,
(e) -OCF3,
(f) -SCF3, (g) -CN,
(h) -C(OH)CH3CF3,
(i) hydroxy-Ci_4-alkyl,
0) "CF3,
(k) -S(O)2CH3, (1) -S(O)2NH2,
(m) -S(O)2NHCH3,
(n) -S(O)2N(CH3),,
(o) -N(CH3)S(O)2CH3,
(p) -N(CH3)C(O)CH3, (q) -C(O)NH2,
(r) -C(O)NHCH3,
(S) -C(O)N(CHs)2,
(t) -C(O)CH3,
(u) N-heterocyclylmethyl,
(v) N-heterocyclyl, optionally substituted with methyl,
(W) phenoxy,
(x) -NH2,
(y) -NHCH3,
(z) -N(CH3)2, and
(aa) methoxycarbonyl;
R2 is selected from:
(a) Cj-e-alkyl,
(b) Ci_6-alkoxy-Ci_6-alkyl,
(c) hydroxy-C2_6-alkyl,
(d) fluoro-C2_6-alkyl,
(e) amino-C2_6-alkyl,
(f) Ci_3-alkylamino-C2-6-alkyl,
(g) di(Ci_3-alkyl)amino-C2_6-alkyl,
CO cyano-Ci_6-alkyl,
(i) Ci_6-alkylsulfonyl-C2_6-alkyl,
G) C2_3-acylamino-C2_4-alkyl,
(k) Ci_4-alkylthio-C2_4-alkyl,
(1) C2_4-acyl-Ci_4-alkyl,
(m) C3_6-alkynyl,
(n) C3_6-alkenyl,
(o) C3_7-cycloalkyl,
(P) C5_8-cycloalkenyl,
(q) C-heterocyclyl, optionally substituted with Ci_4-alkyl,
(r) C7_8-bicyclyl, optionally substituted with hydroxy,
(s) C7-8 -bicy c Iy lmethyl,
(t) azabicyclyl, optionally substituted with hydroxy, — o —
(u) C3_7-cycloalkyl-Ci_4-alkyl, wherein cycloalkyl is optionally substituted with methyl or hydroxy,
(v) Ci_6-alkylsulfonyl-C2-6-alkyl,
(w) C2-3-acyl-C1-4-alkyl, (x) diphenylmethyl,
(y) arylcarbonyl-Ci_4-alkyl,
(z) heteroarylcarbonyl-Ci_4-alkyl,
(aa) [CF3CH3(OH)C]-Ci.6-alkyl,
(bb) Λ/-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(cc) C-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(dd) aminocarbonyl-C2-6-alkyl,
(ee) Ci_3-alkylaminocarbonyl-C2-6-alkyl, (ff) di(Ci_3-alkyl)aminocarbonyl-C2-6-alkyl,
(gg) hydroxy-C2-4-alkoxy-C2-4-alkyl,
(hh) hydroxy-C4_6-cycloalkyl,
(ii) oxo-C4-6-cycloalkyl,
(jj) fluoro-C4-6-cycloalkyl, (kk) Ci_3-alkoxy-C4-6-cycloalkyl,
(11) methyl-C3-6-cycloalkyl,
(mm) oxo-N-heterocyclyl-C2-4-alkyl,
(nn) fluoro-jV-heterocyclyl-C2-4-alkyl,
(oo) amino-Λ/-heterocyclyl-C2-4-alkyl, (pp) hydroxy-Λ/-heterocyclyl-C2-4-alkyl,
(qq) Λ/-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(rr) C-heterocyclyl-Ci_4-alkyl, wherein heterocyclyl is optionally substituted with methyl, (ss) aryl,
(tt) aryl-Ci_4-alkyl,
(uu) aryl-C3_6-alkenyl,
(w) aryl-C3-6-alkynyl,
(ww) aryloxymethyl, (xx) heteroaryl,
(yy) heteroaryl-Ci_4-alkyl,
(zz) heteroaryl-C3_6-alkenyl, and
(aaa) heteroaryl-C3_6-alkynyl, wherein any aryl or heteroaryl residue, alone or as part of another group, is optionally independently substituted in one or more position with a substituent selected from the group Z1 as defined above;
R3 is selected from: (a) hydrogen,
(b) d.6-alkyl,
(c) fluoro-C2-6-alkyl,
(d) hydroxy-C2-6-alkyl,
(e) C1.6-alkoxy-C2_6-alkyl, (f) amino-C2-6-alkyl,
(g) Ci_3-alkylamino-C2-6-alkyl,
(h) di(Ci_3-alkyl)amino-C2-6-alkyl,
(i) cyano-Ci_6-alkyl,
(j) Ci_6-alkylsulfonyl-C2-6-alkyl, (k) C2-3-acylamino-C2-4-alkyl,
(1) Ci_4-alkylthio-C2-4-alkyl, and
(m) C2-4-acyl-Ci_4-alkyl; or R2 and R3 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) Ci-3-alkyl,
(cc) amino,
(dd) methylamino, (ee) dimethylamino,
(ff) hydroxy-Ci-2-alkyl, and
(gg) aminomethyl; ii) one or two oxo groups; or iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom;
R4 is independently selected from:
(a) Ci_6-alkyl,
(b) fluoro-Ci_6-alkyl,
(c) hydroxy-C2-6-alkyl,
(d) Ci_4-alkoxy-C2-4-alkyl, (e) C2-4-acyl-Ci_4-alkyl,
(f) carboxy-Ci_3-alkyl,
(g) C3-6-cycloalkyl,
(h) oxo-C4-6-cycloalkyl,
(i) hydroxy-C4_6-cycloalkyl, (j) fluoro-C4_6-cycloalkyl,
(k) methyl-C3_6-cycloalkyl,
(1) Λ/-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(m) JV-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(n) oxo-Λ/-heterocyclyl-C2-4-alkyl,
(o) fluoro-Λ/-heterocyclyl-C2-4-alkyl,
(p) hydroxy- jV-heterocyclyl-C2-4-alkyl,
(q) amino-jV-heterocyclyl-C2-4-alkyl, (r) aminocarbonyl-C2-4-alkyl,
(s) Ci_3-alkylaminocarbonyl-C2-4-alkyl,
(t) di(Ci_3-alkyl)aminocarbonyl-C2-4-alkyl,
(u) C2-3-acylamino-C2-4-alkyl,
(v) hydroxy-C2-4-alkoxy-C2-4-alkyl, (w) C-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(x) C3_6-cycloalkyl-Ci_2-alkyl, wherein cycloalkyl is optionally substituted with methyl,
(y) amino-C2-4-alkyl, (z) Ci_2-alkylamino-C2-4-alkyl,
(aa) di(Ci_2-alkyl)amino-C2-4-alkyl,
(bb) phenyl, and
(cc) heteroaryl, wherein any phenyl or heteroaryl residue is optionally substituted in one or more positions with a substituent independently selected from the group Z2 consisting of:
(a) halogen selected from chlorine and fluorine,
(b) Ci_4-alkoxy,
(c) hydroxymethyl, (d) -CN,
(e) -CF3,
(f) Ci-4-alkyl,
(g) -OCF3, and (h) -C(O)CH3;
R5 is each independently selected from:
(a) hydrogen,
(b) Cj-e-alkyl,
(c) C3-6-alkenyl,
(d) C3_6-cycloalkyl,
(e) methyl-C3_6-cycloalkyl,
(f) C3_6-cycloalkyl-Ci-4-alkyl, wherein cycloalkyl is optionally substituted with hydroxy or methyl,
(g) N-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
CO heteroaryl-Ci-4-alkyl, wherein heteroaryl is optionally substituted with methyl,
(i) carboxy-Ci-3-alkyl,
G) fluoro-C2-4-alkyl,
(k) amino-C2-6-alkyl,
(1) cyano-Ci_6-alkyl,
(m) hydroxy-C2-6-alkyl,
(n) dihydroxy-C2-6-alkyl,
(o) Ci_4-alkoxy-C2-4-alkyl, (p) Ci_4-alkylamino-C2-4-alkyl,
(q) di(Ci_4-alkyl)amino-C2-4-alkyl,
(r) aminocarbonyl-Ci_4-alkyl,
(s) C2-3-acylamino-C2-4-alkyl, (t) Ci_4-alkylthio-C2-4-alkyl,
(u) C2-4-acyl-Ci_4-alkyl, and
(v) Ci_4-alkylsulfonyl-Ci_4-alkyl, or two R5 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) Ci-3-alkyl,
(cc) amino,
(dd) methylamino, (ee) dimethylamino,
(ff) hydroxy-Ci-2-alkyl, and
(gg) aminomethyl; ii) one or two oxo groups; or iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; or two R5 groups together with the nitrogen to which they are attached form the group 4-(pyrimidin-2-yl)piperazin- 1 -yl;
R6 is independently selected from:
(a) hydrogen,
(b) Ci_4-alkyl, and
(c) hydroxy-C2-4-alkyl;
R7 is independently selected from:
(a) hydrogen, and
(b) Ci-4-alkyl; R is independently selected from: (a) hydrogen,
(b) Cj-e-alkyl,
(c) fluoro-Ci_6-alkyl,
(d) hydroxy-C2-6-alkyl,
(e) amino-C2-6-alkyl,
(f) Ci_3-alkylamino-C2-4-alkyl,
(g) di(Ci_3-alkyl)amino-C2-4-alkyl,
CO Ci_4-alkylsulfonyl-C2-4-alkyl,
(i) Λ/-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
G) C-heterocyclyl, optionally substituted with methyl,
(k) C2-3-acylamino-C2-4-alkyl,
(1) [CF3CH3(OH)C]-Ci.6-alkyl,
(m) C3-6-cycloalkyl,
(n) methyl-Cs-β-cycloalkyl,
(o) C3_6-cycloalkyl-Ci_2-alkyl, wherein cycloalkyl is optionally substituted with methyl,
(P) aryl, and
(q) heteroaryl, wherein any aryl or heteroaryl residue is optionally independently substituted in one or two positions with a substituent selected from the group Z2 as defined above; and
R9 is aryl or heteroaryl, each of which is optionally substituted in one or more positions with a substituent independently selected from the group Z2 as defined above.
In a preferred embodiment of compounds of formula (Ia), 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.
In another preferred embodiment of compounds of formula (Ia), m is each 1. - -
A preferred group of compounds of the invention are compounds of Formula (Ib):
Figure imgf000015_0001
and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers or JV-oxides thereof; wherein:
W and X are each independently CH2 or O, provided that at least one of W and X is CH2; Y is CH2, O or NH; and Ar1, Z1, Z2, R1 to R9 are as defined in Formula (Ia).
A further preferred group of compounds of the invention are compounds of Formula (Ic):
Figure imgf000015_0002
and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers or //-oxides thereof; wherein:
Z1, Z2, R1 to R6 are as defined in Formula (Ia);
Ar1 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:
(a) CF3SO3,
(b) halogen selected from bromine, chlorine and fluorine,
(c) Ci-4-alkylsulfoximine,
(d) -S(O)R4,
(e) -S(O)2R4,
5r> 5
(f) -S(O)2NR3R3, (g) -NR6S(O)2R4, (h) -NR6C(O)R4,
(i) -CH2-NR6C(O)R4,
G) -C(O)NR5R5,
(k) -CH2-C(O)NR5R5,
(1) -C(O)R4,
(m) H2N-C(O)O-,
(n) CH3-NH-C(O)O-,
(o) (CHs)2NC(O)O-,
(P) -NHC(O)OCH3,
(q) C-heterocyclyl, optionally substituted with methyl,
(r) N-heterocyclylcarbonylvinyl, wherein N-heterocyclyl is optionally substituted with methyl,
(s) -CN,
(t) -OR8,
(u) -SCF3,
(v) nitro,
(W) C-heterocyclylsulfonyl, optionally substituted with methyl,
(x) -NR5R5,
(y) -C(OH)CH3CF3,
(z) cyano-Ci_6-alkyl,
(aa) guanidino,
(bb) Cj-e-alkyl,
(CC) Ci_3-alkylthio,
(dd) Ci_4-alkoxy-Ci_4-alkyl,
(ee) fluoro-Ci_4-alkyl,
(ff) C2_6-alkenyl,
(gg) fluoro-C2_4-alkenyl,
(hh) hydroxy-C i _6-alkyl,
(ϋ) Ci_4-alkylsulfonyl-Ci-4-alkyl,
(D) hydroxy-C2_4-alkoxy-Ci_4-alkyl,
(kk) C2_3-acyl-Ci_3-alkyl,
(H) C2_6-alkynyl,
(mm) C3_6-cycloalkyl, - -
(nn) hydroxy-Cs-β-cycloalkyl,
(oo) fluoro-Cs-β-cycloalkyl,
(pp) methyl-Cs-β-cycloalkyl,
(qq) C-heterocyclylcarbonyl, optionally substituted with methyl, (rr) C3-6-cycloalkyl-Ci_4-alkyl,
(ss) R5R5N-Ci_2-alkyl,
(tt) -(CH2)nC(O)OH, wherein n is 1, 2 or 3, and
(uu) heteroaryl, wherein any heteroaryl residue as substituent on Ar1 is optionally substituted in one or more positions with a substituent independently selected from the group Z2 as defined herein for Formula (Ia);
R8 is independently selected from:
(a) hydrogen, (b) Ci-4-alkyl,
(c) CF3,
(d) C3-5-cycloalkyl,
(e) methyl-C3-5-cycloalkyl,
(f) di(Ci_3-alkyl)amino-C2-3-alkyl, and (g) C-heterocyclyl, optionally substituted with methyl;
R9 is phenyl which is optionally substituted in one or two positions with a substituent independently selected from the group Z2 as defined herein for Formula (Ia).
A preferred subgroup of compounds of Formula (Ic) consists of compounds wherein:
Ar1 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 Z4 consisting of: (a) halogen selected from chlorine and fluorine,
(b) Ci-4-alkylsulfoximine,
(c) Ci_4-alkylsulfonyl,
(d) Ci.4-alkylsulfmyl,
(e) hydroxy-C2-4-alkylsulfonyl, (f) amino-C2-4-alkylsulfonyl,
(g) C3-5-cycloalkylsulfonyl,
CO methyl-C3-5-cycloalkylsulfonyl,
(i) trifluoromethylsulfonyl,
G) methylthio,
(k) -S(O)2NR5AR5A,
(1) C i _4-alkylsulfonamido,
(m) C2-4-acylamino,
(n) C2-4-acylaminomethyl,
(o) carboxy-Ci_3-alkylcarbonylamino,
(P) -C(O)NR5AR5A,
(q) -CH2-C(O)NR5AR5A,
(r) -NHC(O)OCH3,
(S) C2-4-acyl,
(t) C3_5-cycloalkylcarbonyl,
(u) Ci_4-alkoxy,
(v) C3_5-cycloalkyloxy,
(W) C-heterocyclyl,
(x) N-heterocyclylcarbonylvinyl, wherein N-heterocyclyl is optionally substituted with methyl,
(y) -CN,
(z) -OH,
(aa) -OCF3,
(bb) nitro,
(CC) -CF3,
(dd) -NR5AR5A,
(ee) di(Ci_2-alkyl)amino-C2-3-alkoxy,
(fit) -C(OH)CH3CF3,
(gg) cyano-Ci_2-alkyl,
(hh) guanidino,
(ϋ) Ci_4-alkyl,
(D) C3_5-cycloalkyl,
(kk) Ci_2-alkoxy-Ci_2-alkyl,
(H) vinyl, — o —
(mm) ethynyl,
(nn) 5-membered heteroaryl,
(oo) hydroxy-Ci_2-alkyl,
(pp) C-heterocyclyloxy, optionally substituted with methyl,
(qq) R5AR5AN-Ci_2-alkyl, and
(rr) -(CH2)nC(O)OH, wherein n is 1 , 2 or 3 ;
R1 is a group R1A, which is selected from -C(O)OR2A, -C(O)R2A, -C(O)NR2AR3A, -CH2C(O)NR2AR3A, -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;
R2A is selected from:
(a) Cj-e-alkyl,
(b) Ci_6-alkoxy-Ci_6-alkyl,
(C) hydroxy-C2-6-alkyl,
(d) hydroxy-C2-4-alkoxy-C2-4-alkyl,
(e) fluoro-C2-6-alkyl,
(f) C3-6-alkynyl,
(g) C3-7-cycloalkyl,
CO C5-8-cycloalkenyl,
(i) C-heterocyclyl, optionally substituted with methyl,
G) Cy-8-bicyclyl,
(k) 2-norbornylmethyl,
(1) azabicyclyl,
(m) C3_6-cycloalkyl-Ci_4-alkyl, wherein cycloalkyl is optionally substituted with methyl,
(n) C2-3-acyl-Ci_4-alkyl,
(o) diphenylmethyl,
(P) arylcarbonyl-C i _4-alkyl,
(q) heteroarylcarbonyl-C i _4-alkyl,
(r) [CF3CH3(OH)C]-Ci_6-alkyl,
(S) Λ/-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(t) hydroxy-C4_6-cycloalkyl, (u) oxo-C4-6-cycloalkyl,
(v) fluoro-C4_6-cycloalkyl,
(w) methoxy-C4_6-cycloalkyl,
(x) methyl-Cs-β-cycloalkyl, (y) oxo-Λ/-heterocyclyl-C2-4-alkyl,
(z) hydroxy-Λ/-heterocyclyl-C2-4-alkyl,
(aa) fluoro-Λ/-heterocyclyl-C2-4-alkyl,
(bb) amino-Λ/-heterocyclyl-C2-4-alkyl,
(dd) Λ/-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(ee) C-heterocyclyl-Ci_4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(ff) aryl,
(gg) aryl-Ci_4-alkyl, (hh) aryloxymethyl,
(ii) heteroaryl, and
(jj) heteroaryl-Ci_4-alkyl, wherein any aryl or heteroaryl residue, alone or as a part of another group, is optionally substituted in one or more positions with a substituent independently selected from the group Z5 consisting of:
(a) halogen selected from bromine, chlorine and fluorine,
(b) methyl,
(c) ethyl,
(d) methoxy, (e) ethoxy,
(f) isopropoxy,
(g) phenoxy,
(h) morpholin-4-ylmethyl,
(i) 4-methylpiperazin-l-yl, (j) hydroxy,
(k) -OCF3,
(1) -CF3,
(m) -CN,
(n) -C(OH)CH3CF3, (o) -N(CHs)2,
(p) hydroxymethyl,
(q) -S(O)2CH3,
(r) -C(O)CH3, and (s) -C(O)NH2;
R3A is selected from:
(a) hydrogen,
(b) d-4-alkyl, (c) hydroxy-C2_4-alkyl, and
(d) methoxy-C2_4-alkyl; or R2A and R3A 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, 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;
R5A is each independently selected from: (a) hydrogen,
(b) Ci.3-alkyl,
(c) C3-4-alkenyl,
(d) Ci_2-alkoxy-C2_4-alkyl,
(e) C3_4-cycloalkyl,
(f) C3_4-cycloalkyl-Ci-2-alkyl, wherein cycloalkyl is optionally substituted with hydroxy,
(g) hydroxy-C2-4-alkyl,
CO cyano-Ci_3-alkyl,
(i) N-heterocyclyl-C2-4-alkyl,
G) heteroaryl-Ci-2-alkyl,
(k) carboxy-Ci-2-alkyl,
(1) dihydroxy-C2-4-alkyl, (m) aminocarbonyl-Ci_2-alkyl,
(n) Ci_3-alkylamino-C2-3-alkyl, and
(o) di(Ci_3-alkyl)amino-C2-3-alkyl; or two R5A 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) methyl,
(cc) amino, (dd) methylamino,
(ee) dimethylamino,
(ff) hydroxy-Ci-2-alkyl, and
(gg) aminomethyl; ii) one or two oxo groups; or iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; or two R5 groups together with the nitrogen to which they are attached form the group 4-(pyrimidin-2-yl)piperazin- 1 -yl.
In another more preferred subgroup of compounds of Formula (Ic), Ar1 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-(iso- propylamino)ethyl]amino}(methylsulfonyl)phenyl, (methylsulfonyl)[(2-morpholin-4-yl- ethyl)amino]phenyl, [2-(dimethylamino)ethoxy] (methylsulfonyl)phenyl, [(methylamino)- carbonyljphenyl, [(ethylamino)carbonyl]phenyl, [(allylamino)carbonyl]phenyl, [(cyclo- propylamino)carbonyl]phenyl, [(2-hydroxyethylamino)carbonyl]phenyl, [(3 -hydroxy- propylamino)carbonyl]phenyl, [(2-methoxyethylamino)carbonyl]phenyl, { [(2-hydroxy- 1,1- dimethylethyl)amino] carbonyl} phenyl, [(3 -hydroxyazetidin- 1 -yl)carbonyl] -phenyl, [(4- methylpiperazin- 1 -yl)carbonyl]phenyl, { [2-(furyl)ethyl] amino } carbonyl)-phenyl, (amino- carbonyl)phenyl, (morpholin-4-ylcarbonyl)phenyl, [(2-hydroxyethyl)sulfonyl]phenyl, [(2- aminoethyl)sulfonyl]phenyl, { [(2-methylprop-2-en- 1 -yl)amino] carbonyl} phenyl, [(but-3 - en- 1 -ylamino)carbonyl] -phenyl, ( { [( 1 -hydroxy cyclopropyl)methyl] amino } carbonyl)- phenyl, { [2-(hydroxymethyl)morpho lin-4-yl] carbonyl} phenyl, (2-carboxyethyl)- isoxazolyl, {[(carboxymethyl)amino]carbonyl}furyl, (lH-tetrazol-5-yl)phenyl, {[amino- (imino)methyl] amino} -methyl- 1 ,3-thiazolyl, pyridinyl, [(4-methylpiperazin- 1 -yl)- carbonyljfuryl, [(4-methylpiperazin- l-yl)carbonyl]pyridinyl, [(lii)-3-(4-methylpiperazm- 1 -yl)-3-oxoprop- 1-en- 1 -yljthienyl, [(l£)-3-morpholin-4-yl-3-oxoprop- 1-en- 1 -yljthienyl, [(4-pyrimidin-2-ylpiperazin- 1 -yl)carbonyl]pyridinyl, { [ [2-(dimethylamino)ethyl] (methyl)- amino]carbonyl}pyridinyl, (morpholin-4-ylcarbonyl)pyridinyl and {[4-(2-hydroxyethyl)- piperazin- 1 -yljcarbonyl} -pyridinyl.
More preferably, Ar1 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)phenyl, 2- { [2-(isopropylamino)ethyl] - amino } -4-(methylsulfonyl)phenyl, 4-(methylsulfonyl)-2- [(2-morpholin-4-ylethyl)amino] - phenyl, 2-[2-(dimethylamino)ethoxy]-4-(methylsulfonyl)phenyl, 4-[(methylamino)- carbonyljphenyl, 4-[(ethylamino)carbonyl]phenyl, 4-[(allylamino)carbonyl]phenyl, A- [(cyclopropylamino)carbonyl]phenyl, 4- {[(2-hydroxyethyl)amino]carbonyl}phenyl, 4- {[(3-hydroxypropyl)amino]carbonyl}phenyl, 4-{[(2-methoxyethyl)amino]carbonyl}- phenyl, 4- {[(2-hydroxy- 1 , 1 -dimethylethyl)amino]carbonyl}phenyl, 4-[(3-hydroxyazetidin- l-yl)carbonyl]phenyl, 4-[(4-methylpiperazin-l-yl)carbonyl]phenyl, 4-({[2-(2-furyl)ethyl]- amino}carbonyl)phenyl, 4-(aminocarbonyl)phenyl, 4-(morpholin-4-ylcarbonyl)phenyl, 4- [(2-hydroxyethyl)sulfonyl]phenyl, 4-[(2-aminoethyl)sulfonyl]phenyl, 4- {[(2-methylprop-2- en- 1 -yl)amino] carbonyl} phenyl, 4- [(but-3 -en- 1 -ylamino)carbonyl]phenyl, 4-( { [( 1 - hydroxycyclopropyl)methyl]amino}carbonyl)phenyl, 4-{[2-(hydroxymethyl)morpholin-4- yl]carbonyl}phenyl, 5-(2-carboxyethyl)isoxazol-3-yl, 5-{[(carboxymethyl)amino]- carbonyl}-2-furyl, 6-(methylsulfonyl)pyridin-3-yl, 4-(lH-tetrazol-5-yl)phenyl, 2-{[amino- (imino)methyl]amino}-4-methyl-l,3-thiazol-5-yl, 4-pyridinyl, 3-pyridinyl, 5-[(4- methylpiperazin- 1 -yl)carbonyl]pyridin-2-yl, 6-(morpholin-4-ylcarbonyl)pyridin-3-yl, 6- [(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3 -yl, 5 -(morpholin-4-ylcarbonyl)pyridin-2-yl, 5-[(4-methylpiperazin- 1 -yl)carbonyl]-2-furyl, 5-[(lii)-3-(4-methylpiperazm- 1 -yl)-3- oxoprop- 1 -en- 1 -yl]-2-thienyl, 5-[(l£)-3-morpholin-4-yl-3-oxoprop- 1-en- 1 -yl]-2-thienyl, 5- [(4-pyrimidin-2-ylpiperazin- 1 -yl)carbonyl]pyridin-2-yl, 5 - { [ [2-(dimethylamino)ethyl] - (methyl)amino]carbonyl}pyridin-2-yl, 5-{[4-(2-hydroxyethyl)piperazin-l-yl]carbonyl}- pyridin-2-yl and 6-{[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}pyridin-3-yl.
In another more preferred subgroup of compounds of Formula (Ic), R1A is selected from C(O)OR2A, C(O)R2A, -CH2-C(O)NR2AR3A, -C(O)C(O)-phenyl or a 6-membered heteroaryl group linked via a ring carbon atom.
In one embodiment, R1A is C(O)OR2A, wherein R2A is selected from benzyl, tert-butyl, ethyl, (l-methylcyclopropyl)methyl and isopropyl.
In another embodiment, R1A is C(O)R2A, wherein R2A 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,
3-oxo-butyl, 3-oxo-3-(pyrrolidin-l-yl)propyl, 2-furyl, (4-fluorophenoxy)methyl, IH- pyrrol-2-yl, (lH-tetrazol-l-yl)methyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 6-quinoxalinyl,
4-isopropoxyphenyl, 2-naphthyl, phenyl, 2-hydroxy-4-methylphenyl, 2-phenoxypyridin-5- yl, diphenylmethyl, 5-isopropoxypyridin-2-yl, 2,2,2-trifluoroethyl, 3-hydroxypyridin-2-yl, ethyl, 7-methoxy-l-benzofuran-2-yl, 3-(N,Λ/-dimethylamino)phenyl, 2-hydroxyphenyl, benzoyl, 2-( 1 -methylpiperazin-4-yl)ethyl, 4-( 1 -methylpiperazin-4-yl)phenyl, methoxymethyl, 3,5-difluoropyridin-2-yl, 4-[(morpholin-4-yl)methyl]phenyl, 6-bromo-3- hydroxypyridin-2-yl and 1-ethylpropyl.
In yet another embodiment, R1A is -CΗ2-C(O)NR2AR3A, wherein R2A and R3A are both ethyl.
In a further embodiment R1A is -C(O)C(O)-phenyl.
In yet a further embodiment, R1A is 2-pyrimidinyl. Particularly preferred compounds of Formula (Ic) are the compounds selected from the group consisting of:
• benzyl 4-(6- {4-[(dimethylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)piperidine- 1-carboxylate; • benzyl 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate;
• benzyl 4-(6-quinolin-5-yl-4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• 4- {2-[ 1 -(3,4-dichlorobenzoyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl} -iV,jV-dimethyl- benzamide; • 4-(2- { 1 -[(2,4-difluorophenyl)acetyl]piperidin-4-yl} -AH- 1 ,3-benzodioxin-6-yl)-N,N- dimethylbenzamide;
• N,N-dimethyl-4-[2-(l-{[3-(trifluoromethyl)phenyl]acetyl}piperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzamide;
• 4-(2- { 1 -[(4-methoxyphenyl)acetyl]piperidin-4-yl} -AH- 1 ,3-benzodioxin-6-yl)-N,N- dimethylbenzamide;
• 4-(2- { 1 -[(4-cyanophenyl)acetyl]piperidin-4-yl} -AH- 1 ,3-benzodioxin-6-yl)-iV,jV- dimethylbenzamide;
• 4- {2-[ 1 -(l/f-indol-3-ylacetyl)piperidin-4-yl]-4/f- 1 ,3-benzodioxin-6-yl} -N,N-dimethyl- benzamide; • JV,iV-dimethyl-4-(2- { 1 -[(1 -methyl- lH-indol-3-yl)acetyl]piperidin-4-yl} -AH- 1 ,3-benzo- dioxin-6-yl)benzamide;
• 4- {2-[ 1 -(cyclohexylacetyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl} -^//-dimethylbenzamide;
• JV,iV-dimethyl-4- {2-[ 1 -(3-methyl-3-phenylbutanoyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin- 6-yl}benzamide;
• 4-(2- { 1 -[3-(4-methoxyphenyl)propanoyl]piperidin-4-yl} -AH- 1 ,3-benzodioxin-6-yl)- N,Λ/-dimethylbenzamide;
• 4-(2- { 1 -[3-(3-chloro-4-methoxyphenyl)propanoyl]piperidin-4-yl} -AH- 1 ,3-benzodioxin- 6-yl)-N,Λ/-dimethylbenzamide; • 4-(2- { 1 -[3-(4-hydroxyphenyl)propanoyl]piperidin-4-yl} -AH- 1 ,3-benzodioxin-6-yl)-N,Λ/- dimethylbenzamide;
• 4-(2- { 1 -[3-(l/f-indol-3-yl)propanoyl]piperidin-4-yl} -4H- 1 ,3-benzodioxin-6-yl)-iV,JV- dimethylbenzamide; • 4- {2-[ 1 -(3-cyclohexylpropanoyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl} -N,N- dimethylbenzamide;
• 4-(2- { 1 -[4-(4-fluorophenyl)butanoyl]piperidin-4-yl} -AH- 1 ,3-benzodioxin-6-yl)-N,Λ/- dimethylbenzamide; • JV,JV-dimethyl-4- {2-[ 1 -(4-oxopentanoyl)piperidin-4-yl]-4/f- 1 ,3-benzodioxin-6-yl} - benzamide;
• JV,iV-dimethyl-4- {2-[ 1 -(4-oxo-4-pyrrolidin- 1 -ylbutanoyl)piperidin-4-yl]-4H- 1 ,3-benzo- dioxin-6-yl}benzamide;
• benzyl 4-(6- {4-[(diethylamino)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2-yl)piperidine- 1-carboxylate;
• benzyl 4-(6- {4-[(4-methylpiperidin- 1 -yl)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• benzyl 4-(6- {4-[(4-oxopiperidin- 1 -yl)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; • benzyl 4-{6-[5-(methylsulfonyl)pyridin-2-yl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate;
• 1 -(2-furoyl)-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine;
• 1 -[(4-fluorophenoxy)acetyl]-4- {6-[4-(methylsulfonyl)phenyl]-4/f- 1 ,3-benzodioxin-2- yl}piperidine; • 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - 1 -(lH-pyrrol-2-yl- carbonyl)piperidine;
• 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - 1 -(lH-tetrazol- 1 -ylacetyl)- piperidine;
• 2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]pyridine;
• 4-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyljpyridine;
• 2-[(4- {6-[4-(methylsulfonyl)phenyl]-4/f- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyljpyrazine; • 6-[(4- {6-[4-(methylsulfonyl)phenyl]-4/f- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]quinoxaline;
• 1 -(4-isopropoxybenzoyl)-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine;
• 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - 1 -(2-naphthoyl)piperidine; - -
• 1 -benzoyl-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine;
• 5-methyl-2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 - y l)carbony l]pheno 1;
• 5-[(4- {6-[4-(methylsulfonyl)phenyl]-4/f- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]-2-phenoxypyridine;
• 1 -(diphenylacetyl)-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine;
• 5-isopropoxy-2-[(4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin- 1 -yl)carbonyl]pyridine; • 4-{6-[4-(methylsulfonyl)phenyl]-4/f-l,3-benzodioxin-2-yl}-l-(3,3,3-trifluoro- propanoyl)piperidine;
• 2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]pyridin-3-ol;
• 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - 1 -propionylpiperidine; • 1 -[(7-methoxy- 1 -benzofuran-2-yl)carbonyl]-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1,3- benzodioxin-2-yl}piperidine;
• dimethyl{3-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 - yl)carbonyl]phenyl} amine;
• 2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]phenol;
• 2-(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)-2-oxo- 1 - phenylethanone;
• 1 -methyl-4-[3-(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 - yl)-3-oxopropyl]piperazine; « 1 -methyl-4- {4-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- l-yl)carbonyl]phenyl}piperazine;
• 1 -(methoxyacetyl)-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine;
• 3,5-difluoro-2-[(4- {6-[4-(methylsulfonyl)phenyl]-4/f- 1 ,3-benzodioxin-2-yl}piperidin- 1 - yl)carbonyl]pyridine;
• 4- {4-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyljbenzyl} morpho line;
• 6-bromo-2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]pyridin-3-ol; • benzyl 4-(6- {4-[(methylsulfonyl)amino]phenyl} -4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 - carboxylate;
• benzyl 4-[6-(4-{[(2-morpholin-4-ylethyl)amino]sulfonyl}phenyl)-4H-l,3-benzodioxin- 2-yl]piperidine- 1 -carboxylate; • benzyl 4-{6-[4-(methylsulfonyl)-2-nitrophenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate;
• benzyl 4- {6-[2-amino-4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 -carboxylate;
• benzyl 4- {6-[2- {[2-(dimethylamino)ethyl] amino} -4-(methylsulfonyl)phenyl]-4H- 1,3- benzodioxin-2-yl}piperidine- 1 -carboxylate;
• benzyl 4- {6-[2- {[2-(isopropylamino)ethyl] amino} -4-(methylsulfonyl)phenyl]-4H- 1,3- benzodioxin-2-yl}piperidine- 1 -carboxylate;
• benzyl 4-(6- {4-(methylsulfonyl)-2-[(2-morpholin-4-ylethyl)amino]phenyl} -AH- 1,3- benzodioxin-2-yl)piperidine- 1 -carboxylate; • benzyl 4-{6-[2-[2-(dimethylamino)ethoxy]-4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine- 1 -carboxylate;
• N,Λ/-diethyl-2-(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 - yl)acetamide;
• 1 -benzoyl-4- {(2R *)-6-[4-(methylsulfonyl)phenyl]-4/f- 1 ,3-benzodioxin-2-yl}piperidine; « 1 -benzoyl-4- {(2£*)-6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine;
• (1 -methylcyclopropyl)methyl 4-(6- {4-[(methylamino)carbonyl]phenyl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4-(6- {4-[(ethylamino)carbonyl]phenyl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate; • (l-methylcyclopropyl)methyl 4-(6-{4-[(allylamino)carbonyl]phenyl}-4H-l,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4-(6- {4-[(cyclopropylamino)carbonyl]phenyl} -4H- 1,3- benzodioxin-2-yl)piperidine- 1 -carboxylate;
• (l-methylcyclopropyl)methyl 4-[6-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4- [6-(4- { [(3 -hydroxypropyl)amino]carbonyl} phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4- [6-(4- { [(2-methoxyethyl)amino] carbonyl} phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate; — o —
• (1 -methylcyclopropyl)methyl 4- [6-(4- { [(2-hydroxy- 1 , 1 -dimethylethyl)amino] - carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4-(6- {4-[(3-hydroxyazetidin- 1 -yl)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate; • (l-methylcyclopropyl)methyl 4-(6-{4-[(4-methylpiperazin-l-yl)carbonyl]phenyl}-4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• (l-methylcyclopropyl)methyl 4-{6-[4-({[2-(2-furyl)ethyl]amino}carbonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 -carboxylate;
• tert-butyl 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 - carboxylate;
• tert-butyl 4- {6-[4-(aminocarbonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 - carboxylate;
• tert-butyl 4-(6- {4-[(dimethylamino)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; • tert-butyl 4-{6-[4-(morpholin-4-ylcarbonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine- 1 -carboxylate;
• 2-( {4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]phenyl} sulfonyl)ethanol;
• 2-( {4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]phenyl} sulfonyl)- ethanamine; • tert-butyl 4-(6-{4-[(methylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(ethylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(allylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(cyclopropylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin-2- yl]piperidine- 1 -carboxylate; • tert-butyl 4-[6-(4-{[(2-methylprop-2-en-l-yl)amino]carbonyl}phenyl)-4H-l,3-benzo- dioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(but-3-en- 1 -ylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; • tert-butyl 4-[6-(4-{[(3-hydroxypropyl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin-2- yl]piperidine- 1 -carboxylate;
• tert-butyl 4- [6-(4- { [(2-methoxyethyl)amino] carbonyl} phenyl)-4H- 1 ,3 -benzodioxin-2- yl]piperidine- 1 -carboxylate; • tert-butyl 4-{6-[4-({[(l-hydroxycyclopropyl)methyl]amino}carbonyl)phenyl]-4H-l,3- benzodioxin-2-yl}piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(4- {[(2-hydroxy- 1 , 1 -dimethylethyl)amino]carbonyl}phenyl)-4H- 1,3- benzodioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(3-hydroxyazetidin- 1 -yl)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2- yl)piperidine-l -carboxylate;
• tert-butyl 4-(6- {4-[(4-methylpiperazin- 1 -yl)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2- yl)piperidine- 1 -carboxylate;
• tert-butyl 4- {6-[4-( {[2-(2-furyl)ethyl] amino} carbonyl)phenyl]-4H- 1 ,3-benzodioxin-2- yl}piperidine- 1 -carboxylate; • 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-methylbenzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-ethylbenzamide;
• Λ/-allyl-4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4/f-l,3-benzodioxin-6-yl]-Λ/-cyclopropylbenzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-N-(2-hydroxyethyl)- benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-(2-methylprop-2-en-l-yl)- benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-but-3-en-l-ylbenzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-N-(3-hydroxypropyl)- benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-(2-methoxyethyl)- benzamide;
• 4- [2-( 1 -benzoylpiperidin-4-yl)-4/f- 1 ,3 -benzodioxin-6-yl] -N-[( 1 -hydroxycyclopropyl)- methyljbenzamide; • 4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3 -benzodioxin-6-yl] -JV-(2-hydroxy- 1 , 1 -dimethyl- ethyl)benzamide;
• 1 - {4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]benzoyl} azetidin-3-ol;
• 1 - {4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]benzoyl} -4-methyl- piperazine; • 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-N-[2-(2-furyl)ethyl]- benzamide;
• ethyl 4-(6- {4-[(methylamino)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2-yl)piperidine- 1 - carboxylate; • ethyl 4-(6-{4-[(ethylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)piperidine-l- carboxylate;
• ethyl 4-(6- {4-[(allylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 - carboxylate;
• ethyl 4-(6- {4-[(cyclopropylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine-1 -carboxylate;
• ethyl 4-[6-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin-2-yl]- piperidine- 1 -carboxylate;
• ethyl 4-[6-(4- {[(2-methylprop-2-en- 1 -yl)amino]carbonyl}phenyl)-4H- 1 ,3-benzodioxin- 2-yl]piperidine- 1 -carboxylate; • ethyl 4-(6-{4-[(but-3-en-l-ylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• ethyl 4- [6-(4- { [(3 -hydroxypropyl)amino]carbonyl} phenyl)-4H- 1 ,3 -benzodioxin-2-yl] - piperidine- 1 -carboxylate;
• ethyl 4- [6-(4- { [(2-methoxyethyl)amino] carbonyl} phenyl)-4H- 1 ,3 -benzodioxin-2-yl] - piperidine-1 -carboxylate;
• ethyl 4-{6-[4-({[(l-hydroxycyclopropyl)methyl]amino}carbonyl)phenyl]-4/f-l,3- benzodioxin-2-yl}piperidine- 1 -carboxylate;
• ethyl 4-[6-(4- {[(2-hydroxy- 1 , 1 -dimethylethyl)amino]carbonyl}phenyl)-4H- 1 ,3-benzo- dioxin-2-yl]piperidine- 1 -carboxylate; • ethyl 4-(6-{4-[(3-hydroxyazetidin-l-yl)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• ethyl 4-(6- {4-[(4-methylpiperazin- 1 -yl)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• ethyl 4- {6-[4-( {[2-(2-furyl)ethyl] amino} carbonyl)phenyl]-4/f- 1 ,3-benzodioxin-2-yl} - piperidine-1 -carboxylate;
• ethyl 4-[6-(4-{[2-(hydroxymethyl)morpholin-4-yl]carbonyl}phenyl)-4H-l,3-benzo- dioxin-2-yl]piperidine- 1 -carboxylate;
• 3-(3- {2-[ 1 -(tert-butoxycarbonyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl}isoxazol-5- yl)propanoic acid; • [(5- {2-[ 1 -(tert-butoxycarbonyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl} -2-furoyl)- amino] acetic acid;
• tert-butyl A- {6-[6-(methylsulfonyl)pyridin-3-yl]-4/f- 1 ,3-benzodioxin-2-yl}piperidine- 1 - carboxylate; • tert-butyl 4-{6-[5-(methylsulfonyl)pyridin-2-yl]-4/f-l,3-benzodioxin-2-yl}piperidine-l- carboxylate;
• tert-butyl 4- {6-[4-(lH-tetrazol-5-yl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 - carboxylate;
• tert-butyl 4-[6-(2- {[amino(imino)methyl]amino} -4-methyl- 1 ,3-thiazol-5-yl)-4H- 1,3- benzodioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-(6-pyridin-4-yl-4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6-pyridin-3-yl-4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {5-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-2-yl} -AH- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate; • tert-butyl 4-{6-[6-(morpholin-4-ylcarbonyl)pyridin-3-yl]-4H-l,3-benzodioxin-2-yl}- piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3-yl} -AH- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4- {6-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine-1 -carboxylate;
• tert-butyl 4-(6- {5-[(4-methylpiperazin- 1 -yl)carbonyl]-2-furyl} -AH- 1 ,3-benzodioxin-2- yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {5-[(l£)-3-(4-methylpiperazin- 1 -yl)-3-oxoprop- 1 -en- 1 -yl]-2-thienyl} - 4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate; • tert-butyl 4-(6-{5-[(lE)-3-morpholin-4-yl-3-oxoprop-l-en-l-yl]-2-thienyl}-4H-l,3- benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {5-[(4-pyrimidin-2-ylpiperazin- 1 -yl)carbonyl]pyridin-2-yl} -AH- 1,3- benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(5- {[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}pyridin-2-yl)- AH- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(5- {[4-(2-hydroxyethyl)piperazin- 1 -yl]carbonyl}pyridin-2-yl)-4H- 1,3- benzodioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(6- {[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}pyridin-3-yl)- AH- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate; • ethyl 4-(6- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3-yl} -AH- 1 ,3-benzodioxin-2- yl)piperidine- 1 -carboxylate;
• isopropyl 4-(6- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3-yl} -AH- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate; • ethyl 4-(6-{5-[(4-methylpiperazin-l-yl)carbonyl]pyridin-2-yl}-4H-l,3-benzodioxin-2- yl)piperidine- 1 -carboxylate;
• l-({5-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]pyridin-2-yl}carbonyl)-4- methylpiperazine;
• 1 -[(5- {2-[ 1 -(2-ethylbutanoyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl}pyridin-2-yl)- carbonyl]-4-methylpiperazine; and
• 2-[4-(6- {5-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-2-yl} -AH- 1 ,3-benzodioxin-2-yl)- piperidin- 1 -yl]pyrimidine.
A further preferred group of compounds of the invention are compounds of Formula (Id):
Figure imgf000033_0001
and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers or JV-oxides thereof; wherein:
Z1, Z2, R1 to R6 are as defined in Formula (Ia);
R8 and R9 are as defined in Formula (Ic);
Ar1 is phenyl which is optionally substituted in one or two positions with a substituent independently selected from the group Z3 as defined in Formula (Ic).
A preferred subgroup of compounds of the general Formula (Id) consists of compounds wherein:
Ar1 is phenyl, which is optionally substituted in one or two positions with a substituent independently selected from the group Z4 as defined in Formula (Ic); R1 is a group R1A, wherein R1A is as defined in Formula (Ic); R2A, R3A, and R5A are as defined in Formula (Ic).
In a more preferred subgroup of compounds of Formula (Id), Ar1 is methylsulfonylphenyl.
In another more preferred subgroup of compounds of Formula (Id), R IA is selected from C(O)OR2A and C(O)R2A
In one embodiment, R1A is C(O)OR2A, wherein R2A is Ci-6 alkyl. Preferably R2A is tert- butyl.
In another embodiment, R1A is C(O)R2A, wherein R2A is selected from C3-6-cycloalkyl- Ci-3-alkyl and phenyl. Preferably R2A is selected from cyclohexylmethyl and phenyl.
Particularly preferred compounds of Formula (Id) are the compounds selected from the group consisting of:
• tert-butyl 4-{7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H-l,4-benzoxazin-3-yl}- piperidine- 1 -carboxylate;
• 3-[l-(cyclohexylacetyl)piperidin-4-yl]-7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H- 1 ,4-benzoxazine; and • 3-(l-benzoylpiperidin-4-yl)-7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H-l,4- benzoxazine.
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.
In one aspect, the method for preparation of a pharmaceutical composition comprises combining a compound according to any of the formulae herein with a pharmaceutically acceptable carrier. In another aspect, 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.
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). 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).
In other aspects, 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. In other methods, 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. In one embodiment, 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. 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. In preferred embodiments, 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. In certain preferred embodiments, 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. In certain method embodiments, a level of Marker or Marker activity in a subject is determined at least once. Comparison of Marker levels, e.g., to another measurement of Marker level obtained previously or subsequently from the same patient, another patient, or a normal subject, may be useful in determining whether therapy according to the invention is having the desired effect, and thereby permitting adjustment of dosage levels as appropriate. Determination of Marker levels may be performed using any suitable sampling/expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first removed from a subject. Examples of 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. - -
DEFINITIONS
The following definitions shall apply throughout the specification and the appended claims. Unless otherwise stated or indicated, the term "Ci_6-alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. For parts of the range "Ci_6-alkyl", all subgroups thereof are contemplated, such as Ci_5-alkyl, Ci_4-alkyl, Ci_3-alkyl, Ci_2-alkyl, C2-6-alkyl, C2-5-alkyl, C2-4-alkyl, C2-3-alkyl, C3_6-alkyl, C4_5-alkyl, etc. Examples of said Ci_6-alkyl include methyl, ethyl, /? -propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
Unless otherwise stated or indicated, the term "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. Unless otherwise stated or indicated, the term "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.
Unless otherwise stated or indicated, the term "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.
Derived expressions such as "Ci_6-alkoxy", "Ci_6-alkylthio" and "Ci_6-alkylamino" are meant to refer to an Ci_6-alkyl group which is attached to the remainder of the molecule through an oxygen, sulfur or nitrogen atom, respectively. 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, C2-6-alkoxy, C2-5-alkoxy, C2-4-alkoxy, C2-3-alkoxy, C3_6-alkoxy, C4_5- alkoxy, etc. Examples of said "Ci_6-alkoxy" 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.
Unless otherwise stated or indicated, the term "Ci_4-alkylsulfinyl" denotes a group Ci_4- alkyl-S(O)— . Exemplary Ci_4-alkylsulfmyl groups include methylsulfinyl and ethylsulfinyl. Unless otherwise stated or indicated, the term "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-C2-6-alkyl groups include 2,3-dihydroxy- propyl and 2,4-dihydroxybutyl.
Unless otherwise stated or indicated, the term "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 N5N- diethylamino.
Unless otherwise stated or indicated, the term "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-C2-4-alkyl groups include 2-(dimethylamino)ethyl and 3-(diethyl- amino)propyl.
Unless otherwise stated or indicated, the term "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. Unless otherwise stated or indicated, the term "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. Unless otherwise stated or indicated, the term "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.
Unless otherwise stated or indicated, the term "arylcarbonyl-Ci_4-alkyl" denotes an arylcarbonyl group (e.g., benzoyl) that is attached through a Ci_4-alkyl group. Examples of said arylcarbonyl-Ci_4-alkyl include 3-oxo-3-phenylpropyl, 2-oxo-2-phenylethyl and 1 -methyl-S-oxo-S-phenylpropyl.
Unless otherwise stated or indicated, the term "heteroarylcarbonyl-Ci_4-alkyl" denotes a heteroarylcarbonyl group (e.g., 3-pyridinylcarbonyl) that is attached through a Ci-4-alkyl group. Examples of said heteroarylcarbonyl-Ci_4-alkyl include 3-oxo-3-(3-pyridinyl)- propyl, 2-oxo-2-(3-pyridinyl)ethyl and l-methyl-3-oxo-3-(3-pyridinyl)propyl. Unless otherwise stated or indicated, the term "aryloxymethyl" denotes a group aryl-O- CH2— . An exemplary aryloxymethyl group is phenoxymethyl.
Unless otherwise stated or indicated, the term "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 —
methoxymethyl, methoxyethyl, ethoxyethyl, isopropoxyethyl, n-butoxyethyl, t-butoxyethyl and straight- and branched-chain pentoxyethyl. 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, C2-6-alkoxy-Ci_6-alkyl, C2-5- alkoxy-Ci_6-alkyl, C2-4-alkoxy-Ci_6-alkyl, C2-3-alkoxy-Ci_6-alkyl, C3-6-alkoxy-Ci_6-alkyl, C4_5-alkoxy-Ci_6-alkyl, Ci_6-alkoxy-Ci_5-alkyl, Ci_6-alkoxy-Ci_4-alkyl, etc. Unless otherwise stated or indicated, the term "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 C2-6-alkenyl include vinyl, allyl, 2-methylallyl, 2,3- dimethylallyl, 1-butenyl, 1-pentenyl, and 1-hexenyl. For parts of the range "C2-6-alkenyl", all subgroups thereof are contemplated such as C2-5-alkenyl, C2-4-alkenyl, C2-3-alkenyl, C3- 6-alkenyl, C4-5-alkenyl, etc.
Unless otherwise stated or indicated, the term "aryl-C2-6-alkenyl" means a C2-6-alkenyl group substituted by an aryl group. Examples of said aryl-C2-6-alkenyl include styryl and cinnamyl.
Unless otherwise stated or indicated, the term "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 C2-6-alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and l-methylprop-2-yn-l-yl. Unless otherwise stated or indicated, the term "aryl-C2-6-alkynyl" means a C2-6-alkynyl group substituted by an aryl group. Examples of said aryl-C2-6-alkynyl include phenyl- ethynyl, 3 -phenyl- 1-propyn-l-yl, 3-phenyl-2-propyn-l-yl and 4-phenyl-2-butyn-l-yl.
The term "oxo" denotes 1^=O
Unless otherwise stated or indicated, the term "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. For parts of the range "C3_7-cycloalkyl" all subgroups thereof are contemplated such as C3-6-cycloalkyl, C3-5-cycloalkyl, C3-4- cycloalkyl, C4_7-cycloalkyl, C4_6-cycloalkyl, C4_5-cycloalkyl, Cs_7-cycloalkyl and C6-7- 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 C3_7-cycloalkyl-Ci_4-alkyl groups include cyclopropylmethyl, 1-cyclopropylethyl, cyclohexylmethyl and 2-cyclo- hexylethyl. When the cycloalkyl portion as part of the group C3_7-cycloalkyl-Ci_4-alkyl is substituted with methyl, examples of such groups include (l-methylcyclopropyl)methyl and 2-(4-methylcyclohexyl)ethyl.
When the cycloalkyl portion as part of the group C3-6-cycloalkyl-Ci_4-alkyl is substituted with hydroxy, examples of such groups include (1 -hydroxy cyclopropyl)methyl and A- hydroxycyclohexylmethyl.
Unless otherwise stated or indicated, the term "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.
Unless otherwise stated or indicated, the term C7_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). Unless otherwise stated or indicated, the term "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). Unless otherwise stated or indicated, the term "oxo-C4_6-cycloalkyl" refers to a C4-6- cycloalkyl wherein two hydrogens on a cycloalkyl carbon atom are replaced by an oxo group as defined herein. Examples of "oxo-C4-6-cycloalkyl" include 2-oxocyclobutyl, 3- oxocyclobutyl, 2-oxocyclopentyl and 4-oxocyclohexyl.
Unless otherwise stated or indicated, the term "fluoro-C3_6-cycloalkyl" denotes a C3_6- cycloalkyl group substituted by one or two fluorine atoms. Examples of said "fluoro-C3_6- cycloalkyl" include 2,2-difluorocyclopropyl and 4-fluorocyclohexyl.
Unless otherwise stated or indicated, the term "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. Unless otherwise stated or indicated, the term "methyl-C3_6-cycloalkyl" denotes a C3_6- cycloalkyl group substituted by one or two methyl groups. Examples of said "methyl-C3-6- cycloalkyl" include 4-methylcyclohexyl and 3,3-dimethylcyclopentyl. Unless otherwise stated or indicated, the term "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. For parts of the range "Ci_6-acyl" all subgroups thereof are contemplated such as Ci_5-acyl, C1-4-acyl, C1-3-acyl, C1-2-acyl, C2-6-acyl, C2-5-acyl, C2-4-acyl, C2-3-acyl, C3-6-acyl, C4-5-acyl, etc. Exemplary acyl groups include formyl, acetyl (i.e., C2-acyl), propanoyl, butanoyl, pentanoyl, hexanoyl. Unless otherwise stated or indicated, the term "C2-6-acyl-Ci_6-alkyl" refers to a group Ci_5-alkyl-(C=O)-Ci_6-alkyl. Exemplary C2-6-acyl-Ci_6-alkyl groups include 2-acetylethyl and 3-acetylpropyl.
Unless otherwise stated or indicated, the term "Ci_6-alkylsulfonyl", which may be straight or branched, denotes a hydrocarbon having from 1 to 6 carbon atoms attached to a sulfonyl group. For parts of the range "Ci_6-alkylsulfonyl" all subgroups thereof are contemplated such as Ci_5-alkylsulfonyl, C1-4-alkylsulfonyl, C1-3-alkylsulfonyl, C1-2-alkylsulfonyl, C2-6- alkylsulfonyl, C2-5-alkylsulfonyl, C2-4-alkylsulfonyl, C2-3-alkylsulfonyl, C3-6-alkylsulfonyl, C4-5-alkylsulfonyl, etc. Exemplary Ci_6-alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl and hexylsulfonyl.
Unless otherwise stated or indicated, the term "hydroxy-C2-4-alkylsulfonyl" denotes a C2-4- alkylsulfonyl group as defined above substituted with a hydroxy group. Examples of said hydroxy-C2-4-alkylsulfonyl include 3-hydroxypropylsulfonyl and 2-hydroxyethylsulfonyl. Unless otherwise stated or indicated, the term "amino-C2-4-alkylsulfonyl" denotes a C2-4- alkylsulfonyl group as defined above substituted with a amino group. Examples of said amino-C2-4-alkylsulfonyl include 3-aminopropylsulfonyl and 2-aminoethylsulfonyl. Unless otherwise stated or indicated, the term "Ci_4-alkylsulfonamido" denotes a group Ci_4-alkyl-SO2NH— . Exemplary Ci_4-alkylsulfonamido groups include methylsulfonyl- amino and ethylsulfonylamino. The term "Ci-4-alkylsulfoximine" refers to a group with the following chemical structure:
Figure imgf000041_0001
, where Ra is Ci-4-alkyl.
Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine.
Unless otherwise stated or indicated, the term "aryl" refers to a hydrocarbon ring system having at least one aromatic ring, preferably mono- or bicyclic. Examples of aryls are phenyl, indenyl, 2,3-dihydroindenyl (indanyl), 1-naphthyl, 2-naphthyl or 1,2,3,4- tetrahydronaphthy 1. - -
Unless otherwise stated or indicated, the term "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. Examples of 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, isoindolinyl and chromanyl groups.
Unless otherwise stated or indicated, the term "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. Examples of 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. When present, the sulfur atom may be in an oxidized form (i.e., S=O or O=S=O). Exemplary heterocyclic groups containing sulfur in oxidized form are 1,1-dioxido-thiomorpholinyl and 1 , 1 -dioxido-isothiazolidinyl.
When (i) two groups R5, (ii) two groups R5A, (iii) R2 together with R3, or (iv) R2A together with R3A described herein form a heterocyclic ring and said heterocyclic ring is substituted with one or two oxo groups, examples of such groups include 4-piperidon-l-yl, 2- pyrrolidon-1-yl, 2-piperidon-l-yl, 2-azetidinon-l-yl, 2,5-dioxopyrrolidin-l-yl and hydantoin-1-yl (i.e., 2,5-dioxoimidazolidin-l-yl).
When (i) two groups R5, (ii) two groups R5A, (iii) R2 together with R3, or (iv) R2A together with R3A described herein form a heterocyclic ring and said heterocyclic ring is substituted with one or two fluoro atoms, examples of such groups include 4-fluoropiperidin-l-yl, 4,4- difluoropiperidin-1-yl, 3-fluoropyrrolidin-l-yl and 3,3-difluoropyrrolin-l-yl.
When (i) two groups R5, (ii) two groups R5A, (iii) R2 together with R3, or (iv) R2A together with R3A described herein form a heterocyclic ring and said heterocyclic ring is substituted with hydroxy, examples of such groups include 4-hydroxypiperidin-l-yl, 3- hydroxypiperidin-1-yl, 3-hydroxypyrrolidin-l-yl and 3-hydroxyazetidin-l-yl. When (i) two groups R5, (ii) two groups R5A, (iii) R2 together with R3, or (iv) R2A together with R3A described herein form a heterocyclic ring and said heterocyclic ring is substituted with amino, examples of such groups include 4-aminopiperidin-l-yl, 3-aminopiperidin-l- yl, and 3-aminopyrrolidin-l-yl. When (i) two groups R5, (ii) two groups R5A, (iii) R2 together with R3, or (iv) R2A together with R3A described herein form a heterocyclic ring and said heterocyclic ring is substituted with hydroxy-Ci-2-alkyl, examples of such groups include 2-(hydroxymethyl)pyrrolidin-l- yl, 2-(hydroxymethyl)morpholin-4-yl, 4-(hydroxymethyl)piperidin-l-yl and 4-(2-hydroxy- ethyl)piperazin- 1 -yl. When (i) two groups R5, (ii) two groups R5A, (iii) R2 together with R3, or (iv) R2A together with R3A described herein form a heterocyclic ring and said heterocyclic ring is substituted with methylamino or dimethylamino, examples of such groups include 3-dimethylamino- pyrrolidin-1-yl and 3-methylaminopyrrolidin-l-yl. When (i) two groups R5, (ii) two groups R5A, (iii) R2 together with R3, or (iv) R2A together with R3A described herein form a heterocyclic ring and said heterocyclic ring is substituted with Ci-3-alkyl, examples of such groups include 4-methylpiperidin-l-yl and 4- methylpiperazin- 1 -yl.
Unless otherwise stated or indicated, the term "heteroaryl-Ci_4-alkyl" denotes a heteroaryl group that is attached through a Ci_4-alkyl group. Examples of said heteroaryl-Ci_4-alkyl 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. 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 C 1-4- alkyl include l-methylpiperidin-4-yl and 3-methyloxetan-3-yl. 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.
Unless otherwise stated or indicated, the term 'W-heterocyclyl-C2-4-alkyl" refers to a nitrogen-containing heterocyclyl group that is directly linked to a C2-4-alkyl group via a nitrogen atom of said heterocyclyl. Exemplary JV-heterocyclyl-C2-4-alkyl groups include 2-(pyrrolidin-l-yl)ethyl, 3-(4-morpholinyl)propyl, 2-(piperazin-l-yl)ethyl and 2-(4- - -
morpholinyl)ethyl. Similarly, the term 'W-heterocyclylmethyl" 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. When heterocyclyl as part of the group N-heterocyclyl-C2-4-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-heterocyclyl-C2-4-alkyl groups wherein heterocyclyl is substituted with methyl are 2-(4-methylpiperazin- 1 -yl)ethyl and 2-(4-methylhomopiperazin- 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-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. When 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.
Unless otherwise stated or indicated, the term "oxo-N-heterocyclyl" denotes a nitrogen- containing heterocyclyl group that is substituted with one or two oxo groups. Unless otherwise stated or indicated, the term "oxo-N-heterocyclyl-C2-4-alkyl" refers to an oxo-N-heterocyclyl group that is directly linked to a C2-4-alkyl group through a nitrogen atom of its heterocyclyl portion and where oxo-N-heterocyclyl is as defined above. Exemplary oxo-N-heterocyclyl-C2-4-alkyl groups include 2-(2-pyrrolidon-l-yl)ethyl, 3-(2-pyrrolidon- 1 -yl)propyl and 2-(2,5-dioxoimidazolidin- 1 -yl)ethyl. Unless otherwise stated or indicated, the term "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.
Unless otherwise stated or indicated, the term "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-C2-4-alkyl groups include 2-(3-fluoropyrrolidin-l-yl)- ethyl and 3-(3-fluoropyrrolidin-l-yl)propyl. - -
Unless otherwise stated or indicated, the term "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.
Unless otherwise stated or indicated, the term "hydroxy-jV-heterocyclyl-C2-4-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-C2-4-alkyl groups include 2-(4-hydroxy- piperidin-l-yl)ethyl and 3-(3-hydroxypiperidin-l-yl)propyl. Unless otherwise stated or indicated, the term "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.
Unless otherwise stated or indicated, the term "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-Λ/-heterocyclyl-C2-4-alkyl groups include 2-(4-aminopiperidin-l- yl)ethyl and 3-(3-aminopiperidin-l-yl)propyl.
Unless otherwise stated or indicated, the term "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.
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. Unless otherwise stated or indicated, the term "C2-4-acylamino" denotes a group Rb(C=O)NH— wherein Rb is selected from Ci_3-alkyl. Exemplary C2-4-acylamino groups include acetylamino and propionylamino. - -
Unless otherwise stated or indicated, the term "C2-4-acylamino-Ci_4-alkyl" denotes a C2-4 acylamino group, as defined above, attached to a Ci_4-alkyl group. Examplary C2-4- acylamino-Ci_4-alkyl groups include (acetylamino)methyl and 2-(acetylamino)ethyl. Unless otherwise stated or indicated, the term "aminocarbonyl" refers to the radical NH2(C=O)-.
Unless otherwise stated or indicated, the term "aminocarbonyl-Ci_4-alkyl" denotes a C1-4- alkyl group, as defined above, substituted with an aminocarbonyl group. Exemplary aminocarbonyl-Ci_4-alkyl groups include 2-(aminocarbonyl)ethyl and 3-(aminocarbonyl)- propyl. Unless otherwise stated or indicated, the term "Ci_3-alkylaminocarbonyl" refers to the radical (Ci_3-alkyl)NH(C=O)-.
Unless otherwise stated or indicated, the term "Ci_3-alkylaminocarbonyl-C2-6-alkyl" denotes a group Ci_3-alkylaminocarbonyl, as defined above, attached to a C2-6-alkyl group. Exemplary Ci_3-alkylaminocarbonyl-C2-6-alkyl groups include 2-(methylaminocarbonyl)- ethyl and 2-(ethylaminocarbonyl)ethyl.
Unless otherwise stated or indicated, the term "di(Ci_3-alkyl)aminocarbonyl" refers to the radical (Ci_3-alkyl)2N(C=O)— , wherein the two alkyl portions may be the same or different. Unless otherwise stated or indicated, the term "di(Ci_3-alkyl)aminocarbonyl-C2-6-alkyl" denotes a group di(Ci_3-alkyl)aminocarbonyl, as defined above, attached to a C2-6-alkyl group. Exemplary di(Ci_3-alkyl)aminocarbonyl-C2-6-alkyl groups include 2- (dimethylaminocarbonyl)ethyl and 2-(diethylaminocarbonyl)ethyl. Unless otherwise stated or indicated, the term— C(O)- means a carbonyl group. Unless otherwise stated or indicated, the term "carboxy" denotes a group -C(O)OH. Unless otherwise stated or indicated, 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.
Unless otherwise stated or indicated, the term "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. Examples of JV-heterocyclylcarbonyl groups include 1-piperidinylcarbonyl, - -
1-piperazinylcarbonyl and 1-pyrrolidincarbonyl. Exemplary C-heterocyclylcarbonyl groups include 3-piperidinylcarbonyl, 4-piperidinylcarbonyl and tetrahydropyranyl-4-yl- carbonyl.
When C-heterocyclylcarbonyl is substituted by Ci_4-alkyl, said heterocyclyl is selected from a nitrogen-containing heterocyclyl, and said Ci_4-alkyl is attached to a ring nitrogen atom thereof. An exemplary C-heterocyclylcarbonyl group substituted by Ci_4-alkyl includes 1 -methylpiperidin-4-ylcarbonyl.
The term "N-heterocyclylcarbonyl^^-alkyl" refers to a N-heterocyclylcarbonyl group that is directly linked to a C2-4-alkyl group through its carbonyl carbon atom and where N- heterocyclylcarbonyl is as defined above. Exemplary N-heterocyclylcarbonyl-C2-4-alkyl groups include 2-(pyrrolidin-l-ylcarbonyl)ethyl, 2-(piperazin-l-ylcarbonyl)ethyl and 2- (piperidin- 1 -ylcarbonyl)ethyl.
When heterocyclyl as part of the group N-heterocyclylcarbonyl-C2-4-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-C2-4-alkyl groups wherein heterocyclyl is substituted with methyl are 2-(4-methylpiperazin- 1 -ylcarbonyl)ethyl, 2-(4-methylhomopiperazin- 1 -ylcarbonyl)- ethyl. The term "N-heterocyclylcarbonylvinyl" refers to a N-heterocyclylcarbonyl group, as defined above, that is directly linked to a vinyl group (i.e., — CH=ClHk) through its carbonyl carbon atom. Exemplary N-heterocyclylcarbonylvinyl groups include 2-(pyrrolidin-l- ylcarbonyl)vinyl, 2-(piperazin-l-ylcarbonyl)vinyl and 2-(piperidin-l-ylcarbonyl)vinyl. When the Ν-heterocyclyl portion as part of the group N-heterocyclylcarbonylvinyl is substituted with Ci-4-alkyl, an exemplary group is 2-(4-methylpiperazin-l-yl- carbonyl) vinyl.
The term "C-heterocyclylcarbonyl-C2-4-alkyl" refers to a C-heterocyclylcarbonyl group that is directly linked to a C2-4-alkyl group through its carbonyl carbon atom and where C- heterocyclylcarbonyl is as defined above. Exemplary C-heterocyclylcarbonyl-C2-4-alkyl groups include 2-(tetrahydropyran-4-ylcarbonyl)ethyl, 2-(piperidin-3-ylcarbonyl)ethyl and 2-(piperidin-4-ylcarbonyl)ethyl.
When heterocyclyl as part of the group C-heterocyclylcarbonyl-C2-4-alkyl is substituted by methyl, said heterocyclyl is selected from a nitrogen-containing heterocyclyl and said methyl is attached to a ring nitrogen atom thereof. An exemplary C-heterocyclylcarbonyl- C2-4-alkyl group wherein heterocyclyl is substituted with methyl is 2-(l-methylpiperidin-4- ylcarbonyl)ethyl.
The term "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. 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. The term "hydroxy-C2-4-alkoxy-Ci_4-alkyl" refers to a hydroxy-C2-4-alkoxy group that is directly attached to a Ci_4-alkyl group. Representative examples of such groups include:
The term "amidino" refers to a group with the following chemical structure:
NH
H2N A. The term "guanidino" refers to a group with the following chemical structure:
Figure imgf000048_0001
The chemical formula -C(OH)CHsCFs refers to a group with the following chemical structure:
OH
-CF,
CH, The term [CF3CH3(OH)C]-Ci_6-alkyl refers to a CF3CH3(OH)C- group that is directly attached to a Ci_6-alkyl group. Representative examples of such groups include:
Figure imgf000048_0002
The chemical formula CF3SO3 refers to a group with the following chemical structure:
Figure imgf000048_0003
The carbon-carbon double or triple bonds present in the groups C3_6-alkenyl, C3_6-alkynyl, aryl-C3_6-alkenyl and aryl-C3_6-alkynyl as values for any R , R or R 5A groups described - -
herein are meant to be located at positions other than conjugated with a carbonyl group or adjacent to a nitrogen, oxygen or sulfur atom.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
The term "coupling 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.
The terms "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.
The term "Syndrome X" (also called metabolic syndrome) 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. The term "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. The term 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" 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 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, 2nd 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. 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 (Id) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof. The 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. 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.
COMPOSITIONS
For clinical use, 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. Examples of 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. Usually, 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, α2 agonists, glitazones, PPAR-γ agonists, mixed PPAR-α/γ agonists, PvXR agonists, α-glucosidase inhibitors, PTPlB inhibitors, 11-β- 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, β3-agonists, leptin and leptin mimetics, serotonergic/dopaminergic antiobesity drugs, gastric lipase inhibitors, pancreatic lipase inhibitors, fatty acid oxidation inhibitors, lipid lowering agents and thyromimetics. It is particularly preferred that the compounds of Formula (Ia) to (Id) are administered in combination with a DPP-IV inhibitor. The term "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.
- -
PREPARATION OF COMPOUNDS OF THE INVENTION
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.
Scheme 1
Figure imgf000053_0001
wherein Ar1 and R1 are as defined in Formula (Ia); and R is benzyl, Boc or CBz;
Reagents and conditions:
(a) 4-bromo-2-(hydroxymethyl)phenol; a suitable acid, such as /?-toluenesulfonic acid or sulfuric acid; in a suitable solvent, such as chloroform or benzene; at reflux temperature;
(b) appropriate aryl- or heteroarylboronic acid; appropriate catalyst, such as Pd(PPtLs)4 or PdCl2(dppf)-DCM; a suitable base, such as K2CO3 or NaHCOs; in a suitable solvent mixture such as 1,4-dioxane and water; at elevated temperature, for example 90 0C or 160 0C (microwaves);
(c) (i) 5,5,5',5'-tetramethyl-2,2'-bi-l,3,2-dioxaborinane; a suitable base, such as KOAc; appropriate catalyst, such as PdCl2(dppf)-DCM; in a suitable solvent, such as DME; at elevated temperature, for example 120 0C (microwaves); (ii) appropriate aryl or heteroaryl halide; suitable base, such as NaHCO3; appropriate catalyst, such as - -
Pd(PPli3)4; in a suitable solvent mixture, such as water and DME; at elevated temperature, for example 120 0C (microwaves);
(d) a suitable deprotecting agent, such as TFA, HCl (g) or aqueous concentrated HCl; in a suitable solvent, such as DCM or ethanol; at ambient or elevated temperature; when R = Boc;
(e) hydrogeno lysis, a suitable catalyst, such as 10% Pd/C; a suitable hydrogen source, such as ammonium formate or H2 (g); in a suitable solvent, such as n-propanol, ethanol, water, or mixtures thereof; at elevated temperature, for example 90 0C; when R = benzyl or CBz;
(f) hydrolysis, a suitable base, such as NaOH or KOH; in a suitable solvent mixture, such as water and ethanol; at elevated temperature, for example 90 0C; when R = CBz;
(g) (i) appropriate carboxylic acid; a suitable base, such as triethylamine or DIPEA; in a suitable solvent, such as THF, dioxane or DMF; (ii) appropriate coupling reagent, such as HOBT/EDC, propylphosphonic anhydride or TBTU;
(h) appropriate acid chloride or chloroformate; a suitable base, such as triethylamine; in a suitable solvent, such as THF or DMF; at r.t.
Scheme 2
Figure imgf000054_0001
Figure imgf000054_0002
wherein Ar1 and R1 are as defined in Formula (Ia); and R is Boc.
Reagents and conditions:
(a) (i) BuLi, THF, -78 0C; (ii) B(OMe)3; (b) appropriate aryl or heteroaryl halide; a suitable base, such as K2CO3 or NaHCOs; appropriate catalyst, such as PdC^dppf-DCM or Pd(PPh3)4; in a suitable solvent mixture, such as water and DME or MeCN and water; at elevated temperature, for example 160 0C (microwaves); (c) a suitable deprotecting agent, such as TFA, HCl (g) or aqueous HCl; in a suitable solvent, such as DCM, dioxane, methanol or ethanol; at ambient or elevated temperature;
(d) (i) appropriate carboxylic acid; a suitable base, such as triethylamine or DIPEA; in a suitable solvent, such as THF, dioxane or DMF; (ii) appropriate coupling reagent, such as HOBT/EDC, propylphosphonic anhydride, HBTU or TBTU; at r.t.;
(e) appropriate acid chloride or chloroformate; a suitable base, such as triethylamine; in a suitable solvent, such as THF or DMF; at r.t.;
(f) appropriate alcohol; a suitable coupling reagent, such as l,l'-carbonylbis(l/f- imidazole); in a suitable solvent, such as DCM, acetonitrile or DCM/THF; at elevated temperature;
(g) appropriate heteroaryl halide, such as 2-bromopyrimidine; in a suitable solvent, such as DMSO or acetonitrile; at elevated temperature.
Scheme 3
Figure imgf000055_0001
wherein A is phenyl or heteroaryl; and R1 and R5 are as defined in Formula (Ia);
Reagents and conditions:
(a) (i) appropriate amine; a suitable base, such as triethylamine or or DIPEA; in a suitable solvent, such as THF, dioxane or DMF; (ii) appropriate coupling reagent, such as HOBT, EDC, propylphosphonic anhydride, HBTU or TBTU; at 0 0C or at elevated temperature. - -
Scheme 4
Figure imgf000056_0001
Figure imgf000056_0002
wherein Ar1 and R1 are as defined in Formula (Ia); and R is Boc.
Reagents and conditions:
(a) iron powder, NH4Cl, methanol and water, 70 0C; (b) (i) 1 M HBr, NaNO2, water, O 0C; (ii) CuBr, water, O 0C → r.t.;
(c) 3 M HCl, EtOH, 100 0C;
(d) (i) EDC, HOBT, DMF; (ii) 1 ,2-dimethylhydroxylamine hydrochloride, DIEA;
(e) bromo(methyl)magnesium, diethylether, 0 0C → r.t.;
(f) (i) lithium bis(trimethylsilyl)amide, THF, -78 0C; (ii) trimethylsilyl chloride, -78 0C → r.t. (iii) Br2, -78 0C;
(g) K2CO3, DMF, r.t;
(h) NaBH4, ethanol, HOAc, r.t;
(i) appropriate aryl- or heteroarylboronic acid, NaHCO3, PPh3, Pd(OAc)2, 80% aqueous ethanol, 80 0C; G) DCM, TFA, r.t;
(k) appropriate carboxylic acid, triethylamine, TBTU, DMF, r.t. - -
Definitions of variables in the structures in schemes herein are commensurate with those of corresponding positions in the formulae delineated herein.
The necessary starting materials for preparing the compounds of Formula (Ia) to (Id) and other compounds herein are either commercially available or may be prepared in analogy with the preparation of known compounds.
The processes described below in the example section may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. 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. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd 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. - -
The following abbreviations have been used:
Boc te/t-butyloxycarbonyl
Brine water saturated or nearly saturated with sodium chloride
CBz carbobenzyloxy
DCM dichloromethane
DIEA N-ethyl-N,N-diisopropylamine
DIPEA NN-diisopropylethyl amine
DME 1 ,2-dimethoxyethane
DMF dimethylformamide
DMSO dimethyl sulphoxide
EDC N-β-dimethylaminopropy^-N-ethylcarbodiimide, or
1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
ESI electrospray ionization
EtOAc ethyl acetate
GC Gas Chromatography
GCMS Gas Chromatography Mass Spectrometry h hour(s)
HDL High-Density Lipoprotein
HBTU O-benzotriazo Ie-N5N5TV ,N -tetramethyl-uronium-hexafluorophosphate
HOBT 1-hydroxybenzotriazole hydrate
HPLC High Performance Liquid Chromatography
HRESIMS High-Resolution Electrospray Ionization Mass Spectra
LCMS Liquid Chromatography Mass Spectrometry
LRESIMS Low-Resolution Electrospray Ionization Mass Spectra
MCPBA 3-chloroperoxybenzoic acid
MeCN acetonitrile
MeOH methanol PdCl2dppfDCM [1,1 '-bis(diphenylphosphino)-ferrocene]dichloro- palladium(II) complex with DCM (1:1)
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc)2 palladium(II) acetate
Pd(PPli3)4 tetrakis(triphenylphospine)palladium(0) r.t. room temperature — o —
sec second(s)
TBTU Λ/,Λ/,Λf',Λf'-tetramethyl-O-(benzotriazol- 1 -yl)uronium tetrafluoroborate,
THF tetrahydrofuran
Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)
A Angstrom
The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
The invention will now be further illustrated by the following non-limiting Examples. The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All references and publications cited herein are hereby incorporated by reference in their entirety.
EXAMPLES AND INTERMEDIATE COMPOUNDS
Experimental Methods
All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Low-resolution electrospray ionization mass spectra (LRESIMS) were obtained using an Agilent MSD mass spectrometer or a Waters ZQ mass spectrometer. High-resolution electrospray ionization mass spectra (HRESIMS) 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 μL/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 μm 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.
Analytical LCMS data were obtained with:
System A: Agilent MSD mass spectrometer; Agilent 1100 system; ACE 3 C8 column
(50x3.0 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
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 System C: Waters ZQ mass spectrometer; Waters 996 PDA detector (DAD 215 - 395 nm); ACE C8 (3μm) column (30x3.0 mm) (from ACT); Water containing 10 mM ammonium acetate (pH=7) and acetonitrile were used as mobile phases at a flow rate of 1 mL/min with gradient times of 3.2 min (gradient 5-100% acetonitrile). - -
Preparative HPLC was performed on Gilson system equipped with:
System D: ACE C8 5μm (21.2x50mm) column. Water containing 0.1% TFA and acetonitrile were used as mobile phases at a flow rate of 25 mL/min with gradient times of 6 min.; or System E: XTerra Prep MS C18 5 μm (19x50 mm) column. Water containing 5OmM NH4HCO3 (pH=10) and acetonitrile were used as mobile phases at a flow rate of 25 mL/min with gradient times of 6 min; or Xterra MS Cl 8 5 μm (30x100 mm) column. Water containing 5OmM NH4HCO3 (pH=10) and acetonitrile were used as mobile phases at a flow rate of 40 mL/min with gradient times of 8.5 min.
General Method Al: Suzuki-type cross-coupling reaction
A suspension of benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al; 20 mg, 0.046 mmol), the appropriate boronic acid (0.051 mmol), K2CO3 (16 mg, 0.12 mmol) and Pd(PPh3)4 (3 mg, 0.0023 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was heated at 90 0C overnight. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (System E).
General Method A2: Suzuki- type cross-coupling reaction
Prepared from tert-bvXy\ 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al 1 ; 20 mg, 0.05 mmol) and the appropriate boronic acid in accordance with general method Al .
General Method B: Suzuki- type cross-coupling reaction (microwave conditions)
A suspension of tert-hvXy\ 4-[6-(dimethoxyboryl)-4H-l,3-benzodioxin-2-yl]piperidine-l- carboxylate (Intermediate Al 9; 30 mg, 0.078 mmol), the appropriate aryl- or heteroarylbromide (0.10 mmol), K2CO3 (26 mg, 0.19 mmol), PdCl2dppfDCM (6 mg, 0.0077 mmol) in MeCN/H2O (1.5 mL; 2:1) was heated at 160 0C for 20 min in a microwave reactor. The mixture was filtered through a pad of silica, concentrated and the residue was purified by preparative HPLC (System E).
General Method Cl: Preparation of amides from carboxylic acids using HOBT and EDC as coupling reagents
To a vial containing the appropriate carboxylic acid (0.030 mmol) was added a solution of N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzodioxin-6-yl)benzamide (Intermediate A3; - o -
lO mg, 0.027 mmol) in THF (2 niL) and triethylamine (15 μL, 0.11 mmol). HOBT (7 mg, 0.054 mmol) and EDC (10 mg, 0.054 mmol) were added and the resulting mixture was shaken overnight and then concentrated. The residue was purified by preparative HPLC (System E).
5
General Method C2: Preparation of amides from carboxylic acids using HOBT and EDC as coupling reagents
Prepared from 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine (Intermediate A4; 15 mg, 0.040 mmol) and the appropriate carboxylic acid in accordance i o with general method C 1.
General Method D: Preparation of amides from carboxylic acids using propyl- phosphonic anhydride as coupling reagent
A suspension of the appropriate carboxylic acid (0.05 mmol) in dry DMSO (75 μL) and 15 DMF (0.75 μL) was treated with propylphosphonic anhydride (44 μL, 0.075 mmol; as a 50% solution in EtOAc) and stirred for 10 min. To the mixture were added a solution of the appropriate amine (0.06 mmol) and triethylamine (21 μL, 0.20 mmol) in dry DMF (100 μL) and the resulting mixture was shaken at r.t. overnight. Purification by preparative HPLC (System E) gave the title compound.
20
INTERMEDIATE Al
Benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000062_0001
A suspension of benzyl 4-formylpiperidine-l-carboxylate (2.81 g, 11.4 mmol), 4-bromo-2-
25 (hydroxymethyl)phenol (2.31 g, 11.4 mmol) and /?-toluenesulfonic acid and molecular sieves (4 A) in chloroform (100 mL) was refluxed for 3 hours using a Dean-Stark apparatus. The reaction mixture was then washed with 5% aqueous KΗCO3 (20 mL) and the water phase was extracted with chloroform (3 x 15 mL). The combined organic phases were washed with 5% aqueous KHCO3 (20 mL) and then concentrated. Yield 4.75 g
30 (97%). Analytical HPLC: purity 78% (System C); LRESIMS (ESI+) m/z = 433 (M+H)+. - -
INTERMEDIATE A2
4-(6-Bromo-4H- 1 ,3-benzodioxin-2-yl)piperidine
Figure imgf000063_0001
A suspension of benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al; 550 mg, 1.27 mmol) in 30% aqueous NaOH (10 niL) and MeOH (15 rnL) was heated in a sealed tube at 90 0C for 15 h. The MeOH was removed under reduced pressure and the remaining aqueous mixture was extracted with chloroform (3 x 15 mL). The organic layers were combined, dried (MgSO4) and concentrated. Yield 370 mg (97%). Analytical ΗPLC: purity 93% (System A); LRESIMS (ESI+) m/z = 298/300 (M+Η)+.
Alternative synthetic route:
A suspension of tert-hvXy\ 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al l; 5.0 g, 0.017 mol) in TFA/DCM (50 mL; 1 :4) was stirred at r.t. for 2 h. The solvents were removed under reduced pressure and the residue was partitioned between DCM and 1 M NaOH. The aqueous layer was extracted with DCM (3 x 50 mL). The organic layers were combined, washed with water and brine, dried (MgSO4) and concentrated to give the title compound. Yield 4.7 g (94%). Analytical HPLC: purity 90% (System A); LRESIMS m/z = 298/300 (M+H)+.
INTERMEDIATE A3
7V^V-Dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzodioxin-6-yl)benzamide
Figure imgf000063_0002
A suspension of 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine (Intermediate A2; 370 mg, 1.24 mmol), {4-[(dimethylamino)carbonyl]phenyl}boronic acid (264 mg, 1.36 mmol), Pd(PPh3)4 (72 mg, 0.0620 mmol) and K2CO3 (428 mg, 3.10 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was heated at 90 0C for 15 h. The solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica using EtOAc/DCM - -
(1:1) followed by DCM/MeOH/25% aqueous NH3 (90:9:1) as eluents. Yield 209 mg (46%). Analytical HPLC: purity 85% (System A); LRESIMS (ESI+) m/z = 367 (M+H)+.
INTERMEDIATE A4 4- {6- [4-(Methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidine
Figure imgf000064_0001
A suspension of benzyl 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine-1-carboxylate (Example A2; 1.75 g, 3.40 mmol) in 30% aqueous NaOH (10 mL) and MeOH (15 mL) was heated in a sealed tube at 90 0C for 72 h. The solvents were removed under reduced pressure and the residue was partitioned between water (75 mL) and chloroform (2 x 100 mL). The organic layers were combined, dried (MgSO4) and concentrated. Yield 1.23 g (97%). Analytical ΗPLC: purity 80% (System A); LRESIMS (ESI+) m/z = 374 (M+Η)+.
INTERMEDIATE A5 ό-Bromo-S-hydroxypyridine-l-carboxylic acid
Figure imgf000064_0002
To a stirred suspension of 3-hydroxypyridine-2-carboxylic acid (2.00 g, 0.0144 mol) in DMF (30 mL) was added a solution of N-bromosuccinimide (2.56 g, 0.0144 mol) in DMF (30 mL). After 1 h, water (50 mL) and 1 M aqueous NaOH (25 mL) were added and the resulting mixture was extracted with chloroform (3 x 150 mL). The organic layers were combined and concentrated and the residue was purified by preparative HPLC (System D). Yield 366 mg (12%). Analytical HPLC: purity 100% (System A and B); LRESIMS (ESI+) m/z = 218/220 (M+H)+. - -
INTERMEDIATE A6
Benzyl 4-{6-[2-iodo-4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000065_0001
To a stirred and cooled (0 0C) suspension of benzyl 4-{6-[2-amino-4-(methylsulfonyl)- phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l-carboxylate (Example A56; 450 mg, 0.86 mmol) in acetonitrile (2 mL) and 1 M HCl (6 rnL) was added a solution of sodium nitrite (89 mg, 1.3 mmol) in water (1.5 mL). The mixture was stirred at 0 0C for 20 min and then potassium iodide (214 mg, 1.29 mmol) was added. After stirring at r.t. for 2 h, water (20 mL) was added and the resulting solution was extracted with chloroform (3 x 30 mL). The organic layers were combined and concentrated. Yield 253 mg (46%). Analytical ΗPLC: purity 85% (System A).
INTERMEDIATE A7 Benzyl 4-(6-bromo-4Η-l,3-benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000065_0002
A mixture of 5-bromo-2-hydroxybenzyl alcohol (10.32 g, 50.85 mmol), benzyl 4-formyl- tetrahydro-l(2H)-pyridinecarboxylate (14.85 g, 60.05 mmol) and /?-toluenesulfonic acid (0.97 g, 5.08 mmol) was stirred under reflux for 1 h in benzene (111 mL) using a Dean- Stark apparatus. The organic phase was washed with 1 M NaOH, dried (Na2SO4), and concentrated to give the title compound. Yield 20.94 g (95%). - -
INTERMEDIATE A8
Methyl 4-(2-piperidin-4-yl-4H-l,3-benzodioxin-6-yl)benzoate
Figure imgf000066_0001
A suspension of benzyl 4-(6-bromo-4Η-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate A7; 5.00 g, 11.6 mmol), 4-methoxycarbonyl-phenylboronic acid (2.29 g, 12.7 mmol), Pd(PPh3)4 (0.67 g, 0.58 mmol) and K2CO3 (4.00 g, 28.9 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was stirred at 90 0C overnight. To the mixture was added water (50 mL) and the product was extracted with EtOAc (50 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure to give benzyl 4-{6-[4- (methoxycarbonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l-carboxylate. To a stirred suspension of this material in 1,4-dioxane (150 mL) and ethanol (100 mL) was added 10% Pd/C (0.5 g) and the mixture was heated at 60 0C under H2 overnight. The mixture was filtered (Celite) and the filtrate was concentrated and then dissolved in 1 M HCl (100 mL) and washed with Et2O (100 mL). The aqueous phase was collected and basified with 2 M NaOH (50 mL) and then extracted with EtOAc (100 mL). The organic phase was dried (Na2SO4) and concentrated to give the title compound. Yield 3.07 g (75%, over 2 steps). Analytical HPLC: purity 94% (System A); LRESIMS m/z = 354 (M+H)+.
INTERMEDIATE A9 (l-Methylcyclopropyl)methyl 4-{6-[4-(methoxycarbonyl)phenyl]-4H-l,3-benzodioxin- 2-yl}piperidine-l-carboxylate
Figure imgf000066_0002
To a suspension of l,l '-carbonyldiimidazole (1.15 g, 7.10 mmol) in acetonitrile (2 mL) and DMF (2 mL) was added 1-methylcyclopropane methanol (0.59 g, 7.10 mmol) and the mixture was stirred for 5 minutes. A solution of methyl 4-(2-piperidin-4-yl-4H-l,3- benzodioxin-6-yl)benzoate (Intermediate A8; 0.50 g, 1.41 mmol) in DMF (2 mL) was - DD -
added and the mixture was stirred at 50 0C for 2 h. EtOAc was added and the mixture was washed with 1 M NaOH. The organic phase was dried (Na2SO4) and concentrated. Gradient flash chromatography on silica using EtOAc and n-pentane (10:90 to 50:50) as eluent gave the title compound. Yield 0.4 g (51%). Analytical HPLC: purity 100% (System A); LRESIMS m/z = 466 (M+H)+.
INTERMEDIATE AlO
4-[2-(l-{[(l-Methylcyclopropyl)methoxy]carbonyl}piperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl] benzoic acid
Figure imgf000067_0001
A suspension of (l-methylcyclopropyl)methyl 4-{6-[4-(methoxycarbonyl)phenyl]-4H-l,3- benzodioxin-2-yl}piperidine-l-carboxylate (Intermediate A9; 0.40 g, 0.86 mmol) in TΗF (15 mL) and MeOH (10 mL) was treated with 6 M KOΗ (0.86 mL, 5.16 mmol) and stirred at 50 0C for 1 h. The mixture was diluted with water, neutralized with 4 M HCl (aq) and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated to give the title compound. Yield 0.38 g (99%). Analytical ΗPLC: purity 95% (System A); LRESIMS m/z = 452 (M+Η)+.
INTERMEDIATE Al 1 tert-Butyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000067_0002
A suspension of tert-butyi 4-formylpiperidine-l-carboxylate (7.62 g, 35.7 mmol), 4- bromo-2-(hydroxymethyl)phenol (7.25 g, 35.7 mmol), /?-toluenesulfonic acid (catalytic amount) and molecular sieves (4 A) in benzene (100 mL) was stirred under reflux for 24 h using a Dean-Stark apparatus. The mixture was washed with 5% aqueous NaHCO3 (50 mL) and the water phase was then extracted with chloroform (3 x 50 mL). The organic phases were combined and washed with 5% aqueous NaHCO3 (20 mL), dried (K2CO3) and - -
concentrated to give the title compound. Yield 14.2 g (70%). LRESIMS (ESI+) m/z = 298/300 (M+H-Boc)+.
Alternative synthetic route To a suspension of 4-bromo-2-(hydroxymethyl)phenol (9.00 g, 44.3 mmol) in chloroform (100 mL) were added tert-bvXy\ 4-formylpiperidine-l-carboxylate (9.45 g, 44.3 mmol), p- toluenesulfonic acid (0.38 g, 2.2 mmol) and molecular sieves (4 A). The mixture was stirred at reflux for 12 h and then allowed to reach r.t. The solution was filtered, the filtrate was washed with saturated aqueous NaHCCh (3 x 30 mL) and the aqueous layer was extracted with chloroform (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4) and concentrated and the residue was purified by flash chromatography on silica using 5% MeOH in DCM as eluent. Yield 14.5 g (85%). Analytical HPLC: purity 98% (System A and B); LRESIMS (ESI+) m/z = 298/300 (M+H-Boc)+.
INTERMEDIATE Al 2 l-Benzoyl-4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine
Figure imgf000068_0001
A suspension of 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine (Intermediate A2; 4.7 g, 15.8 mmol), benzoic acid (2.3 g, 18.9 mmol), Λ/,Λ/-diisopropylethylamine (11 mL, 63 mmol) and propylphosphonic anhydride (26 mL, 41 mmol; as a 50% solution in EtOAc) in dry DCM (80 mL) was stirred at r.t. for 2 h and then diluted with DCM (20 mL). The mixture was washed with 0.5 M HCl (aq), water, 5% aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. Yield 6.3 g (100%). Analytical HPLC: purity 95% (System A and B); LRESIMS m/z = 403 (M+H)+.
INTERMEDIATE Al 3
2- [(4-Bromophenyl)sulfonyl] ethanamine hydrochloride
Figure imgf000068_0002
A suspension of 4-bromothiophenol (3.52 g, 18.6 mmol), tert-bvXy\ 2-bromo-ethyl- carbamate (5.00 g, 22.3 mmol) and K2CO3 (9.25 g, 66.9 mmol) in acetone (100 mL) was — Do —
stirred at r.t. for 48 h. The mixture was filtrated and the filtrate was concentrated and dissolved in DCM (100 rnL). The solution was cooled in an ice-bath and MCPBA (7.70 g, 44.6 mmol) was added. After stirring at r.t. for 48 h, additional MCPBA (3.85 g, 22.3 mmol) was added and the mixture was stirred for another 24 h. The mixture was filtrated and the solid was washed with DCM. The filtrate was washed with aqueous saturated NaHSθ3, 5% aqueous NaHCCh and water, dried (MgSO4) and concentrated to give 6.4 g of tert-butyi 2-[(4-bromophenyl)sulfonyl]ethylcarbamate. The material was stirred in 1.25 M ethanolic HCl (100 mL) overnight. The mixture was concentrated and the residue was triturated with ethanol/Et2θ. The solid was collected by filtration and dried. Yield 4.23 g (80%). Analytical HPLC : purity 99% (System A); LRESIMS m/z = 264/266 (M+H)+.
INTERMEDIATE Al 4 4-{2-[l-(før^Butoxycarbonyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}benzoic acid
Figure imgf000069_0001
A suspension of tert-butyi 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al l; 4.0 g, 10 mmol), 4-(dihydroxyboryl)benzoic acid (1.8 g, 11 mmol), Pd(PPh3)4 (577 mg, 0.05 mmol), K2CO3 (3.5 g, 25 mmol) in 1,4-dioxane (200 mL) and water (50 mL) was heated at 90 0C overnight. The reaction mixture was filtered and concentrated and the residue was purified by flash chromatography on silica using EtOAc/n-pentane (1 :4) as eluent. Yield 2.3 g (53%). Analytical ΗPLC: purity 90% (System A and B); LRESIMS m/z = 440 (M+Η)+.
INTERMEDIATE Al 5
Methyl 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoate
Figure imgf000069_0002
- -
A suspension of methyl 4-(2-piperidin-4-yl-4H-l,3-benzodioxin-6-yl)benzoate (Intermediate A8; 1.1 g, 3.0 mmol), benzoic acid (0.55 g, 4.49 mmol), triethylamine (1.8 g, 18 mmol), propylphosphonic anhydride (3 mL, 47 mmol; as a 50% solution in EtOAc) in DMF (30 mL) was stirred at r.t. for 2 h and then diluted with DCM (20 mL). The mixture was extracted with 1 M NaOH (20 mL) and DCM (3 x 20 mL). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica using EtOAc/n- heptane (1 :4) as eluent. Yield 1.2 g (90%). Analytical HPLC: purity 94% (System A and B); LRESIMS m/z = 458 (M+H)+.
INTERMEDIATE Al 6 4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid
Figure imgf000070_0001
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 KOΗ (3 mL) in MeOΗ/TΗF (1 :2, 30 mL) at 60 0C 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 pΗ 2 with 6 M HCl and then extracted with DCM (3 x 30 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated to give the title compound. Yield 0.7 g (58%). Analytical ΗPLC: purity 95% (System A and B); LRESIMS m/z = 444 (M+Η)+.
INTERMEDIATE Al 7
Ethyl 4-{6-[4-(methoxycarbonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000070_0002
A suspension of methyl 4-(2-piperidin-4-yl-4H-l,3-benzodioxin-6-yl)benzoate (Intermediate A8; 1.4 g, 4.0 mmol), triethylamine (2.4 g, 24 mmol), ethyl chloridocarbonate (0.6 g, 5.9 mmol) in DMF (50 mL) was stirred at r.t. for 30 min. The mixture was concentrated and the residue was partitioned between 1 M NaOH (20 mL) and DCM (3 x 20 mL). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica using EtOAc/n-heptane (1 :4) as eluent. Yield 1.1 g (65%). Analytical HPLC: purity 97% (System A and B); LRESIMS m/z = 426 (M+H)+.
INTERMEDIATE Al 8
4- {2- [ l-(Ethoxycarbonyl)piperidin-4-yl] -4H- 1 ,3-benzodioxin-6-yl}benzoic acid
Figure imgf000071_0001
A suspension of ethyl 4-{6-[4-(methoxycarbonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine-1-carboxylate (Intermediate Al 7; 1.1 g, 2.5 mmol) in 6 M aqueous KOΗ (3 mL) and MeOΗ/TΗF (1:2, 30 mL) was heated at 60 0C 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 pΗ 2 using 6 M HCl and then extracted with DCM (3 x 30 mL). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried (MgSO4) and then concentrated. Yield 0.6 g (60%). Analytical ΗPLC: purity 95% (System A and B); LRESIMS m/z = 412 (M+Η)+.
INTERMEDIATE Al 9 tert-Butyl 4-[6-(dimethoxyboryl)-4H-l,3-benzodioxin-2-yl]piperidine-l-carboxylate
Figure imgf000071_0002
A stirred suspension of tert-butyi 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l- carboxylate (Intermediate Al l; 2.5 g, 6.27 mmol) in dry TΗF (100 mL) under N2 (g) was cooled to -78 0C and /?-BuLi (10 niL; 2 M in hexanes) was added dropwise. The mixture was stirred for 30 min at -78 0C and trimethylborate (0.84 mL, 0.78 g) was added over 10 min. Stirring was continued at -78 0C for 30 min and then at r.t. for 10 h before the reaction was quenched with saturated aqueous NaHCCh (10 mL). The mixture was dried (Na2SO4) and concentrated and the residue was purified by flash chromatography on silica using 5% MeOH in DCM as eluent. Yield 1.09 g (45%).
INTERMEDIATE A20
5-{2-[l-(tert-Butoxycarbonyl)piperidin-4-yl]-4^-r-l,3-benzodioxin-6-yl}pyridine-2- carboxylic acid
Figure imgf000072_0001
A suspension of tert-butyl 4-[6-(dimethoxyboryl)-4H-l,3-benzodioxin-2-yl]piperidine-l- carboxylate (Intermediate Al 9; 300 mg, 0.766 mmol), 5-bromopyridine-2-carboxylic acid (201 mg, 0.996 mmol), K2CO3 (265 mg, 1.92 mmol), PdCfcdppf-DCM (63 mg, 0.077 mmol) in MeCN/H2O (5 mL; 2:1) was heated at 160 0C for 20 min in a microwave reactor. The mixture was filtered through a pad of silica and concentrated to give the title compound. Yield 338 mg (100%). Analytical HPLC: purity 80% (System A).
INTERMEDIATE A21 6- {2- [ l-(ført-Butoxycarbonyl)piperidin-4-yl] -4H- 1 ,3-benzodioxin-6-yl} nicotinic acid
Figure imgf000072_0002
A suspension of tert-butyl 4-[6-(dimethoxyboryl)-4H-l,3-benzodioxin-2-yl]piperidine-l- carboxylate (Intermediate Al 9; 300 mg, 0.766 mmol), 2-bromopyridine-5 -carboxylic acid
(201 mg, 0.996 mmol), K2CO3 (265 mg, 1.92 mmol), PdCfcdppf-DCM (63 mg, 0.077 mmol) in MeCN/Η2O (5 mL; 2:1) was heated at 160 0C for 20 min in a microwave reactor. The mixture was filtered through a pad of silica and concentrated to give the title compound. Yield 338 mg (100%). Analytical HPLC: purity 80% (System A).
INTERMEDIATE A22 (2JE)-3-(5-{2-[l-(tert-Butoxycarbonyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}-2- thienyl)acrylic acid
Figure imgf000073_0001
A suspension of tert-butyi 4-[6-(dimethoxyboryl)-4H-l,3-benzodioxin-2-yl]piperidine-l- carboxylate (Intermediate Al 9; 100 mg, 0.255 mmol), (2E)-3-(5-bromo-2-thienyl)acrylic acid (77.4 mg, 0.332 mmol), K2CO3 (88 mg, 0.64 mmol), PdCfcdppf-DCM (22 mg, 0.025 mmol) in MeCNZH2O (4 mL; 2:1) was heated at 160 0C for 20 min in a microwave reactor. The mixture was filtered through a pad of silica and concentrated to give the title compound which was used directly in Example A137 and A138.
INTERMEDIATE A23 l-Methyl-4-{[5-(2-piperidin-4-yl-4H-l,3-benzodioxin-6-yl)pyridin-2-yl]carbonyl}- piperazine
Figure imgf000073_0002
A suspension of tert-butyl 4-(6-{6-[(4-methylpiperazin-l-yl)carbonyl]pyridin-3-yl}-4H- l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Example A134; 122 mg, 0.234 mmol) in 1 M HCl in MeOH (20 mL) was stirred at r.t. for 80 min. The mixture was concentrated and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic phase was dried (Na2SO4) and concentrated to give the title compound. Yield 64 mg (64%). Analytical ΗPLC: purity 99% (System A); LRESIMS m/z = 423 (M+Η)+. INTERMEDIATE A24 l-Methyl-4-{[6-(2-piperidin-4-yl-4H-l,3-benzodioxin-6-yl)pyridin-3-yl]carbonyl}- piperazine
Figure imgf000074_0001
A suspension of tert-butyl 4-(6-{5-[(4-methylpiperazin-l-yl)carbonyl]pyridin-2-yl}-4H- l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Example Al 32; 88 mg, 0.17 mmol) in 1 M HCl in MeOH (20 niL) was stirred at r.t. for 80 min. The mixture was concentrated and the residue was partitioned between EtOAc and saturated aqueous Na2COs. The organic phase was dried (Na2SO4) and concentrated to give the title compound. Yield 71 mg (99%). Analytical ΗPLC: purity 99% (System A); LRESIMS m/z = 423 (M+Η)+.
EXAMPLE Al
Benzyl 4-(6- {4- [(dimethylamino)carbonyl] phenyl}-4H- 1 ,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000074_0002
The title compound was prepared from benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al) and {4-[(dimethylamino)carbonyl]phenyl}- boronic acid using the conditions described in general method Al. Yield 12.2 mg (53%). Analytical ΗPLC: purity 94% (System A and B); ΗRESIMS (ESI+) calcd for C30H32N2O5 500.2311, found 500.2315. - -
EXAMPLE A2
Benzyl 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000075_0001
The title compound was prepared from benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al) and [4-(methylsulfonyl)phenyl]boronic acid using the conditions described in general method Al. Yield 10.5 mg (45%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C28H29NO6S 507.1716, found 507.1731.
EXAMPLE A3
Benzyl 4-(6-quinolin-5-yl-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000075_0002
The title compound was prepared from benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al) and quinolin-5-ylboronic acid using the conditions described in general method Al. Yield 8.6 mg (39%). Analytical ΗPLC: purity 96% (System A and B); ΗRESIMS (ESI+) calcd for C30H28N2O4 480.2049, found 480.2055.
EXAMPLE A4
4-{2-[l-(3,4-Dichlorobenzoyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}-7V^-dimethyl- benzamide
Figure imgf000075_0003
- -
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 3,4-dichlorobenzoic acid using the conditions described in general method Cl. Yield 8.0 mg (55%). Analytical HPLC: purity 100% (System C); HRESIMS (ESI+) calcd for C29H28Cl2N2O4 538.1426, found 538.1427.
EXAMPLE A5
4-(2-{l-[(2,4-Difluorophenyl)acetyl]piperidin-4-yl}-4H-l,3-benzodioxin-6-yl)-ΛyV- dimethylbenzamide
Figure imgf000076_0001
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and (2,4-difluorophenyl)acetic acid using the conditions described in general method Cl. Yield 8.2 mg (58%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C30H30F2N2O4 520.2174, found 520.2185.
EXAMPLE A6
7V^-Dimethyl-4-[2-(l-{[3-(trifluoromethyl)phenyl]acetyl}piperidin-4-yl)-4H-l,3- benzodioxin-6-yl] benzamide
Figure imgf000076_0002
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and [3 -(trifluoromethyl)phenyl] acetic acid using the conditions described in general method Cl. Yield 8.3 mg (56%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C31Η31F3N2O4 552.2236, found 552.2251. - -
EXAMPLE A7
4-(2-{l-[(4-Methoxyphenyl)acetyl]piperidin-4-yl}-4H-l,3-benzodioxin-6-yl)-7V^V- dimethylbenzamide
Figure imgf000077_0001
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and (4-methoxyphenyl)acetic acid using the conditions described in general method Cl. Yield 8.4 mg (60%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C3IH34N2O5 514.2468, found 514.2484.
EXAMPLE A8
4-(2-{l-[(4-Cyanophenyl)acetyl]piperidin-4-yl}-4H-l,3-benzodioxin-6-yl)-7V^V- dimethylbenzamide
Figure imgf000077_0002
The title compound was prepared from N,7V-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and (4-cyanophenyl)acetic acid using the conditions described in general method Cl. Yield 8.4 mg (61%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C31Η31N3O4 509.2315, found 509.2327.
EXAMPLE A9 4-{2-[l-(lH-Indol-3-ylacetyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}-7V^V-dimethyl- benzamide - -
Figure imgf000078_0001
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and lH-indol-3-ylacetic acid using the conditions described in general method Cl. Yield 8.9 mg (63%). Analytical HPLC: purity 100% (System C); HRESIMS (ESI+) calcd for C32H33N3O4 523.2471, found 523.2479.
EXAMPLE AlO
7V^V-Dimethyl-4-(2-{l-[(l-methyl-lH-indol-3-yl)acetyl]piperidin-4-yl}-4H-l,3- benzodioxin-6-yl)benzamide
Figure imgf000078_0002
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and (l-methyl-lH-indol-3-yl)acetic acid using the conditions described in general method Cl. Yield 8.8 mg (61%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C33H35N3O4 537.2628, found 537.2648.
EXAMPLE Al 1
4-{2-[l-(Cyclohexylacetyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}-7V^V-dimethyl- benzamide
Figure imgf000078_0003
— —
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and cyclohexylacetic acid using the conditions described in general method Cl. Yield 7.2 mg (54%). Analytical HPLC: purity 100% (System C); HRESIMS (ESI+) calcd for C30H38N2O4 490.2832, found 490.2851.
EXAMPLE A12
7Vr/V-Dimethyl-4-{2-[l-(3-methyl-3-phenylbutanoyl)piperidin-4-yl]-4H-l,3-benzo- dioxin-6-yl}benzamide
Figure imgf000079_0001
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 3-methyl-3-phenylbutanoic acid using the conditions described in general method Cl. Yield 8.5 mg (60%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C33H38N2O4 526.2832, found 526.2852.
EXAMPLE A13
4-(2- {1- [3-(4-Methoxyphenyl)propanoyl] piperidin-4-yl}-4H- 1 ,3-benzodioxin-6-yl)- 7\yV-dimethylbenzamide
Figure imgf000079_0002
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 3-(4-methoxyphenyl)propanoic acid using the conditions described in general method Cl. Yield 7.9 mg (55%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C32H36N2O5 528.2624, found 528.2642. - -
EXAMPLE A14
4-(2-{l-[3-(3-Chloro-4-methoxyphenyl)propanoyl]piperidin-4-yl}-4H-l,3-benzo- dioxin-6-yl)-7\yV-dimethylbenzamide
Figure imgf000080_0001
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 3-(3-chloro-4-methoxyphenyl)propanoic acid using the conditions described in general method Cl. Yield 9.0 mg (59%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C32H35ClN2O5 562.2234, found 562.2244.
EXAMPLE Al 5
4-(2- {1- [3-(4-Hydroxyphenyl)propanoyl] piperidin-4-yl}-4H- 1 ,3-benzodioxin-6-yl)-
7\yV-dimethylbenzamide
Figure imgf000080_0002
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 3-(4-hydroxyphenyl)propanoic acid using the conditions described in general method Cl. Yield 2.8 mg (20%). Analytical ΗPLC: purity 98% (System C); ΗRESIMS (ESI+) calcd for C3IH34N2O5 514.2468, found 514.2472. - -
EXAMPLE Al 6
4-(2-{l-[3-(lH-Indol-3-yl)propanoyl]piperidin-4-yl}-4H-l,3-benzodioxin-6-yl)-7V^V- dimethylbenzamide
Figure imgf000081_0001
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 3-(lH-indol-3-yl)propanoic acid using the conditions described in general method Cl. Yield 9.4 mg (65%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C33H35N3O4 537.2628, found 537.2632.
EXAMPLE Al 7
4-{2-[l-(3-Cyclohexylpropanoyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}-7V^V- dimethylbenzamide
Figure imgf000081_0002
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 3-cyclohexylpropanoic acid using the conditions described in general method Cl. Yield 7.9 mg (58%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C3IH40N2O4504.2988, found 504.2991.
EXAMPLE Al 8 4-(2-{l-[4-(4-Fluorophenyl)butanoyl]piperidin-4-yl}-4H-l,3-benzodioxin-6-yl)-ΛyV- dimethylbenzamide
Figure imgf000081_0003
— o —
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 4-(4-fluorophenyl)butanoic acid using the conditions described in general method Cl. Yield 7.6 mg (53%). Analytical HPLC: purity 100% (System C); HRESIMS (ESI+) calcd for C32H35FN2O4530.2581, found 530.2593.
EXAMPLE Al 9
7\yV-Dimethyl-4- {2- [ l-(4-oxopentanoyl)piperidin-4-yl] -4H- 1 ,3-benzodioxin-6-yl}- benzamide
Figure imgf000082_0001
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 4-oxopentanoic acid using the conditions described in general method Cl. Yield 7.6 mg (61%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C27H32N2O5464.2311, found 464.2334.
EXAMPLE A20
7\yV-Dimethyl-4- {2- [ l-(4-oxo-4-pyrrolidin- l-ylbutanoyl)piperidin-4-yl] -4H- 1 ,3-benzo- dioxin-6-yl}benzamide
Figure imgf000082_0002
The title compound was prepared from N,Λ/-dimethyl-4-(2-piperidin-4-yl-4/f-l,3-benzo- dioxin-6-yl)benzamide (Intermediate A3) and 4-oxo-4-pyrrolidin-l-ylbutanoic acid using the conditions described in general method Cl. Yield 9.0 mg (64%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C30H37N3O5 519.2733, found 519.2750. — —
EXAMPLE A21
Benzyl 4-(6- {4- [(diethylamino)carbonyl] phenyl}-4H- 1 ,3-benzodioxin-2-yl)piperidine-
1-carboxylate
Figure imgf000083_0001
The title compound was prepared from benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al) and {4-[(diethylamino)carbonyl]phenyl}- boronic acid using the conditions described in general method Al. Yield 10.3 mg (42%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C32H36N2O5 528.2624, found 528.2628.
EXAMPLE A22
Benzyl 4-(6-{4-[(4-methylpiperidin-l-yl)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000083_0002
The title compound was prepared from benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al) and {4-[(4-methylpiperidin-l-yl)carbonyl]- phenyl}boronic acid using the conditions described in general method Al. Yield 13.3 mg (52%). Analytical ΗPLC: purity 100% (System C); ΗRESIMS (ESI+) calcd for C34H38N2O5 554.2781, found 554.2800. — o —
EXAMPLE A23
Benzyl 4-(6-{4-[(4-oxopiperidin-l-yl)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000084_0001
The title compound was prepared from benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al) and {4-[(4-oxopiperidin-l-yl)carbonyl]- phenyl}boronic acid using the conditions described in general method Al. Yield 2.9 mg (11%). Analytical ΗPLC: purity 90% (System C); ΗRESIMS (ESI+) calcd for C33H34N2O6 554.2417, found 554.2395.
EXAMPLE A24
Benzyl 4- {6- [5-(methylsulfonyl)pyridin-2-yl] -4H- 1 ,3-benzodioxin-2-yl}piperidine- 1- carboxylate
Figure imgf000084_0002
A suspension of 2-bromo-5-(methylsulfonyl)pyridine (25 mg, 0.11 mmol), 5, 5,5', 5'- tetramethyl-2,2'-bi-l,3,2-dioxaborinane (36 mg, 0.16 mmol), KOAc (31 mg, 0.32 mmol) and PdCl2dppfDCM (4 mg, 0.005 mmol) in DME (2 mL) was heated at 120 0C for 20 min in a microwave reactor. To the mixture were added benzyl 4-(6-bromo-4H-l,3- benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al; 46 mg, 0.11 mmol), NaHCO3 (18 mg, 0.21 mmol), Pd(PPh3)4 (1 mg, 0.001 mmol) and water (0.5 mL). The resulting mixture was heated at 120 0C for 800 sec in a microwave reactor and then concentrated. The residue was purified by gradient flash chromatography on silica (DCM/heptane 3 : 1 — > DCM/EtOAc 9:1). Yield 11 mg (20%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C27H28N2O6S 508.1668, found 508.1676. - -
EXAMPLE A25 l-(2-Furoyl)-4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine
Figure imgf000085_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 2-furoic acid using the conditions described in general method C2. Yield 3.2 mg (17%). Analytical ΗPLC: purity 97% (System C); ΗRESIMS (ESI+) calcd for C25H25NO6S 467.1403, found 467.1409.
EXAMPLE A26
1- [(4-Fluorophenoxy)acetyl] -4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2- yl}piperidine
Figure imgf000085_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and (4-fluorophenoxy)acetic acid using the conditions described in general method C2. Yield 5.2 mg (25%). Analytical ΗPLC: purity 99% (System C); ΗRESIMS (ESI+) calcd for C28H28FNO6S 525.1621, found 525.1622.
EXAMPLE A27
4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}-l-(lH-pyrrol-2-yl- carbonyl)piperidine
Figure imgf000085_0003
- -
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and lH-pyrrole-2-carboxylic acid using the conditions described in general method C2. Yield 2.9 mg (16%). Analytical HPLC: purity 99% (System C); HRESIMS (ESI+) calcd for C25H26N2O5S 466.1562, found 466.1567.
EXAMPLE A28
4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}-l-(lH-tetrazol-l-ylacetyl)- piperidine
Figure imgf000086_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and lH-tetrazol-1-ylacetic acid using the conditions described in general method C2. Yield 1.5 mg (8%). Analytical ΗPLC: purity 96% (System C); ΗRESIMS (ESI+) calcd for C23H25N5O5S 483.1576, found 483.1585.
EXAMPLE A29
2-[(4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l-yl)- carbonyl] pyridine
Figure imgf000086_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and pyridine-2-carboxylic acid using the conditions described in general method C2. Yield 4.7 mg (25%). Analytical ΗPLC: purity 99% (System C); ΗRESIMS (ESI+) calcd for C26H26N2O5S 478.1562, found 478.1564. - -
EXAMPLE A30
4-[(4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l-yl)- carbonyl] pyridine
Figure imgf000087_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and isonicotinic acid using the conditions described in general method C2. Yield 4.1 mg (21%). Analytical ΗPLC: purity 98% (System C); ΗRESIMS (ESI+) calcd for C26H26N2O5S 478.1562, found 478.1568.
EXAMPLE A31
2-[(4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l-yl)- carbonyl] pyrazine
Figure imgf000087_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and pyrazine-2-carboxylic acid using the conditions described in general method C2. Yield 3.2 mg (17%). Analytical ΗPLC: purity 98% (System C); ΗRESIMS (ESI+) calcd for C25H25N3O5S 479.1515, found 479.1516.
EXAMPLE A32 6-[(4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l-yl)- carbonyl] quinoxaline
Figure imgf000087_0003
— o —
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and quinoxaline-6-carboxylic acid using the conditions described in general method C2. Yield 4.5 mg (21%). Analytical HPLC: purity 98% (System C); HRESIMS (ESI+) calcd for C29H27N3O5S 529.1671, found 529.1665.
EXAMPLE A33 l-(4-Isopropoxybenzoyl)-4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine
Figure imgf000088_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 4-isopropoxybenzoic acid using the conditions described in general method C2. Yield 4.9 mg (23%). Analytical ΗPLC: purity 99% (System C); ΗRESIMS (ESI+) calcd for C30H33NO6S 535.2029, found 535.2039.
EXAMPLE A34
4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}-l-(2-naphthoyl)piperidine
Figure imgf000088_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 2-naphthoic acid using the conditions described in general method C2. Yield 5.0 mg (24%). Analytical ΗPLC: purity 99% (System C); ΗRESIMS (ESI+) calcd for C3iΗ29NO5S 527.1766, found 527.1771. - -
EXAMPLE A35 l-Benzoyl-4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidine
Figure imgf000089_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and benzoic acid using the conditions described in general method C2. Yield 4.4 mg (23%). Analytical ΗPLC: purity 98% (System C); ΗRESIMS (ESI+) calcd for C27H27NO5S 477.1610, found 477.1615.
EXAMPLE A36
5-Methyl-2-[(4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l- yl)carbonyl] phenol
Figure imgf000089_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 2-hydroxy-4-methylbenzoic acid using the conditions described in general method C2. Yield 0.7 mg (3%). Analytical ΗPLC: purity 90% (System C); ΗRESIMS (ESI+) calcd for C28H29NO6S 507.1716, found 507.1716.
EXAMPLE A37
5-[(4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l-yl)- carbonyl] -2-phenoxypyridine
Figure imgf000089_0003
- -
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 6-phenoxynicotinic acid using the conditions described in general method C2. Yield 4.7 mg (21%). Analytical HPLC: purity 90% (System C); HRESIMS (ESI+) calcd for C32H30N2O6S 570.1825, found 570.1826.
EXAMPLE A38 l-(Diphenylacetyl)-4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine
Figure imgf000090_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and diphenylacetic acid using the conditions described in general method C2. Yield 4.5 mg (20%). Analytical ΗPLC: purity 99% (System C); ΗRESIMS (ESI+) calcd for C34H33NO5S 567.2079, found 567.2088.
EXAMPLE A39
5-Isopropoxy-2- [(4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidin- l-yl)carbonyl] pyridine
Figure imgf000090_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 5-isopropoxypyridine-2-carboxylic acid using the conditions described in general method C2. Yield 1.9 mg (9%). Analytical ΗPLC: purity 96% (System C); ΗRESIMS (ESI+) calcd for C29H32N2O6S 536.1981, found 536.1990. EXAMPLE A40
4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}-l-(3,3,3-trifluoro- propanoyl)piperidine
Figure imgf000091_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 3,3,3-trifluoropropanoic acid using the conditions described in general method C2. Yield 3.6 mg (19%). Analytical ΗPLC: purity 94% (System C); ΗRESIMS (ESI+) calcd for C23H24F3NO5S 483.1327, found 483.1332.
EXAMPLE A41
2-[(4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l-yl)- carbonyl] pyridin-3-ol
Figure imgf000091_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 3-hydroxypyridine-2-carboxylic acid using the conditions described in general method C2. Yield 2.5 mg (13%). Analytical ΗPLC: purity 97% (System C); LRESIMS m/z = 495 (M+Η)+.
EXAMPLE A42 4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}-l-propionylpiperidine
Figure imgf000091_0003
- -
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and propionic acid using the conditions described in general method C2. Yield 5.1 mg (30%). Analytical HPLC: purity 98% (System C); HRESIMS (ESI+) calcd for C23H27NO5S 429.1610, found 429.1614.
EXAMPLE A43
1- [(7-Methoxy- l-benzofuran-2-yl)carbonyl] -4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3- benzodioxin-2-yl}piperidine
Figure imgf000092_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 7-methoxy-l-benzofuran-2-carboxylic acid using the conditions described in general method C2. Yield 5.1 mg (23%). Analytical ΗPLC: purity 99% (System C); ΗRESIMS (ESI+) calcd for C30H29NO7S 547.1665, found 547.1674.
EXAMPLE A44
Dimethyl{3- [(4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidin- 1- yl)carbonyl] phenyl} amine
Figure imgf000092_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4/f-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 3-(dimethylamino)benzoic acid using the conditions described in general method C2. Yield 4.9 mg (24%). Analytical ΗPLC: purity 98% (System C); ΗRESIMS (ESI+) calcd for C29H32N2O5S 520.2032, found 520.2047. EXAMPLE A45
2-[(4-{6-[4-(Methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l-yl)- carbonyl] phenol
Figure imgf000093_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and salicylic acid using the conditions described in general method C2. Yield 3.6 mg (18%). Analytical ΗPLC: purity 95% (System C); ΗRESIMS (ESI+) calcd for C27H27NO6S 493.1559, found 493.1560.
EXAMPLE A46
2-(4- {6- [4-(Methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidin- l-yl)-2-oxo- 1- phenylethanone
Figure imgf000093_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and oxo(phenyl)acetic acid using the conditions described in general method C2. Yield 3.8 mg (19%). Analytical ΗPLC: purity 98% (System C); ΗRESIMS (ESI+) calcd for C28H27NO6S 505.1559, found 505.1564.
EXAMPLE A47 l-Methyl-4-[3-(4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidin-l- yl)-3-oxopropyl] piperazine
Figure imgf000093_0003
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 3-(4-methylpiperazin-l-yl)propanoic acid using the conditions described in general method C2. Yield 3.7 mg (18%). Analytical HPLC: purity 99% (System C); HRESIMS (ESI+) calcd for C28H37N3O5S 527.2454, found 527.2465.
EXAMPLE A48 l-Methyl-4- {4- [(4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidin- 1- yl)carbonyl]phenyl}piperazine
Figure imgf000094_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 4-(4-methylpiperazin-l-yl)benzoic acid using the conditions described in general method C2. Yield 4.3 mg (19%). Analytical ΗPLC: purity 97% (System C); ΗRESIMS (ESI+) calcd for C32H37N3O5S 575.2454, found 575.2470.
EXAMPLE A49 l-(Methoxyacetyl)-4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine
Figure imgf000094_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and methoxyacetic acid using the conditions described in general method C2. Yield 4.0 mg (22%). Analytical ΗPLC: purity 98% (System C); ΗRESIMS (ESI+) calcd for C23H27NO6S 445.1559, found 445.1560. - -
EXAMPLE A50
3,5-Difluoro-2- [(4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidin- l-yl)carbonyl] pyridine
Figure imgf000095_0001
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4/f-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 3,5-difluoropyridine-2-carboxylic acid using the conditions described in general method C2. Yield 4.7 mg (23%). Analytical ΗPLC: purity 99% (System C); ΗRESIMS (ESI+) calcd for C26H24F2N2O5S 514.1374, found 514.1372.
EXAMPLE A51
4- {4- [(4- {6- [4-(Methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidin- 1-yl)- carbonyl]benzyl}morpholine
Figure imgf000095_0002
The title compound was prepared from 4-{6-[4-(methylsulfonyl)phenyl]-4/f-l,3-benzo- dioxin-2-yl}piperidine (Intermediate A4) and 4-(morpholin-4-ylmethyl)benzoic acid using the conditions described in general method C2. Yield 4.3 mg (28%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C32H36N2O6S 576.2294, found 576.2296. - -
EXAMPLE A52
6-Bromo-2- [(4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidin- 1- yl)carbonyl] pyridin-3-ol
Figure imgf000096_0001
To a vial containing β-bromo-S-hydroxypyridine-l-carboxylic acid (Intermediate A5; 61 mg, 0.28 mmol) was added a solution of 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3- benzodioxin-2-yl}piperidine (Intermediate A4; 95 mg, 0.25 mmol) in TΗF (5 mL) and triethylamine (140 μL, 1.0 mmol) followed by ΗOBT (69 mg, 0.51 mmol) and EDC (97 mg, 0.51 mmol). The resulting mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by preparative ΗPLC (System D). Yield 20 mg (14%). Analytical ΗPLC: purity 91% (System A and B); ΗRESIMS (ESI+) calcd for C26H25BrN2O6S 572.0618, found 572.0613.
EXAMPLE A53
Benzyl 4-(6-{4-[(methylsulfonyl)amino]phenyl}-4H-l,3-benzodioxin-2-yl)piperidine-l- carboxylate
Figure imgf000096_0002
A suspension of benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al; 10 mg, 0.023 mmol), 4-(methanesulfonylamino)phenylboronic acid (5.4 mg, 0.025 mmol), Pd(OAc)2 (2 mg, 0.009 mmol), K2CO3 (8.0 mg, 0.058 mmol) in MeCN (2 mL) and water (0.5 mL) was heated at 90 0C for 1.5 h. The mixture was filtered and then purified by preparative ΗPLC (System D). Yield 3.0 mg (25%). Analytical GC: purity 99%; ΗRESIMS (ESI+) calcd for C28H30N2O6S 522.1825, found 522.1824. - -
EXAMPLE A54
Benzyl 4- [6-(4- { [(2-morpholin-4-ylethyl)amino] sulfonyl}phenyl)-4H- 1 ,3-benzodioxin-
2-yl]piperidine-l-carboxylate trifluoroacetate
Figure imgf000097_0001
A suspension of benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al; 100 mg, 0.23 mmol), 5,5,5',5'-tetramethyl-2,2'-bi-l,3,2-dioxaborinane (78 mg, 0.35 mmol), KOAc (68 mg, 0.69 mmol) and PdCl2dppfDCM (10 mg, 0.012 mmol) in DME (3 mL) was heated at 90 0C for 1 h. To the mixture was then added 4-iodo- Λ/-(2-morpholin-4-yl-ethyl)benzene-sulfonamide (91 mg, 0.23 mmol) followed by NaHCO3 (39 mg, 0.46 mmol), Pd(PPh3)4 (27 mg, 0.023 mmol) and water (1 mL). The resulting mixture was heated at 90 0C overnight and then concentrated. The residue was purified by preparative HPLC (System D). Yield 4.2 mg (2%). Analytical HPLC: purity 99% (System A and B); LRESIMS (ESI+) m/z = 622 (M+H)+.
EXAMPLE A55
Benzyl 4-{6-[4-(methylsulfonyl)-2-nitrophenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000097_0002
A suspension of benzyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al; 2.0 g, 0.0046 mol), 5,5,5',5'-tetramethyl-2,2'-bi-l,3,2-dioxaborinane (1.6 g, 0.0069 mol), potassium acetate (1.4 g, 0.014 mol) and PdCl2dppfDCM (190 mg, 0.23 mmol) in DME (20 mL) was heated at 90 0C for 1 h. To the mixture were then added
NaHCO3 (0.77 g, 0.0092 mol), Pd(PPh3)4 (53 mg, 0.046 mmol), 2-bromo-5- methylsulfonylnitrobenzene (1.29 g, 0.0046 mol) and water (5 mL). The mixture was heated at 90 0C for 15 h. The solvents were removed under reduced pressure and the residue was partitioned between water (50 mL) and chloroform (3 x 75 mL). The organic layers were combined and concentrated. The residue was purified by flash chromatography on silica using heptane/EtOAc (1 :1). Yield 1.89 g (74%). Analytical HPLC: purity 98% (System A and B); HRESIMS (ESI+) calcd for C28H28N2O8S 552.1566, found 552.1579.
EXAMPLE A56
Benzyl 4-{6-[2-amino-4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine- 1-carboxylate
Figure imgf000098_0001
A suspension of benzyl 4-{6-[4-(methylsulfonyl)-2-nitrophenyl]-4H-l,3-benzodioxin-2- yl}piperidine-l-carboxylate (Example A55; 675 mg, 1.22 mmol) and indium powder (560 mg, 4.89 mmol) in saturated NH4Cl (8 mL) and MeOH (10 mL) was heated in a sealed tube at 85 0C for 15 h. The mixture was filtered and concentrated. The residue was partitioned between water (75 mL) and chloroform (2 x 100 mL) and the organic layers were combined and concentrated. Purification by flash chromatography on silica using EtOAc/DCM (1 :3) gave an off-white solid. Yield 515 mg (81%). Analytical HPLC: purity
99% (System A and B); HRESIMS (ESI+) calcd for C28H30N2O6S 522.1825, found
522.1825.
EXAMPLE A57 Benzyl 4- {6- [2- { [2-(dimethylamino)ethyl] amino}-4-(methylsulfonyl)phenyl] -4H- 1 ,3- benzodioxin-2-yl}piperidine-l-carboxylate trifluoroacetate
Figure imgf000098_0002
A suspension of benzyl 4-{6-[2-iodo-4-(methylsulfonyl)phenyl]-4/f-l,3-benzodioxin-2- yl}piperidine-l-carboxylate (Intermediate A6; 50 mg, 0.079 mmol), N,7V-dimethylethane- 1,2-diamine (8 mg, 0.095 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), Xantphos (5 mg, 0.008 mmol) and potassium te/t-butoxide (12 mg, 0.11 mmol) in toluene (4 mL) was heated at 110 0C overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC (System D). Yield 12 mg (21%). Analytical HPLC: purity 90% (System A and B); HRESIMS (ESI+) calcd for C32H39N3O6S 593.2560, found 593.2572.
EXAMPLE A58
Benzyl 4- {6- [2- { [2-(isopropylamino)ethyl] amino}-4-(methylsulfonyl)phenyl] -4H- 1 ,3- benzodioxin-2-yl}piperidine-l-carboxylate trifluoroacetate
Figure imgf000099_0001
The title compound was prepared from benzyl 4-{6-[2-iodo-4-(methylsulfonyl)phenyl]- 4/f-l,3-benzodioxin-2-yl}piperidine-l-carboxylate (Intermediate A6; 50 mg, 0.079 mmol) and JV-isopropylethane-l,2-diamine (10 mg, 0.095 mmol) using the conditions described for Example A57. Yield 6 mg (11%). Analytical HPLC: purity 98% (System A and B); HRESIMS (ESI+) calcd for C33H4IN3O6S 607.2716, found 607.2728.
EXAMPLE A59
Benzyl 4-(6-{4-(methylsulfonyl)-2-[(2-morpholin-4-ylethyl)amino]phenyl}-4H-l,3- benzodioxin-2-yl)piperidine-l-carboxylate trifluoroacetate
Figure imgf000099_0002
The title compound was prepared from benzyl 4-{6-[2-iodo-4-(methylsulfonyl)phenyl]- 4/f-l,3-benzodioxin-2-yl}piperidine-l-carboxylate (Intermediate A6; 50 mg, 0.079 mmol) and (2-morpholin-4-ylethyl)amine (12 mg, 0.095 mmol) using the conditions described for Example A57. Yield 19 mg (32%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C34H4iN3O7S 635.2665, found 635.2679. EXAMPLE A60
Benzyl 4- {6- [2- [2-(dimethylamino)ethoxy] -4-(methylsulfonyl)phenyl] -4H- 1 ,3- benzodioxin-2-yl}piperidine-l-carboxylate trifluoroacetate
Figure imgf000100_0001
A suspension of benzyl 4-{6-[2-iodo-4-(methylsulfonyl)phenyl]-4/f-l,3-benzodioxin-2- yl}piperidine-l-carboxylate (Intermediate A6; 50 mg, 0.079 mmol), CuI (3 mg, 0.016 mmol), 1,10-phenanthroline monohydrate (6 mg, 0.032 mmol) and CS2CO3 (64 mg, 0.20 mmol) in N,Λ/-dimethylethanolamine (1 mL) was heated at 110 0C for 15 h. The reaction mixture was purified by preparative HPLC (System D). Yield 7 mg (13%). Analytical HPLC: purity 97% (System A and B); HRESIMS (ESI+) calcd for C32H38N2O7S 594.2400, found 594.2411.
EXAMPLE A61
7\yV-Diethyl-2-(4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidin- 1- yl)acetamide trifluoroacetate
Figure imgf000100_0002
A suspension of 4-{6-[4-(methylsulfonyl)phenyl]-4/f-l,3-benzodioxin-2-yl}piperidine (Intermediate A4; 10 mg, 0.054 mmol), 2-chloro-iV,jV-diethylacetamide (9 mg, 0.059 mmol) and K2CO3 (30 mg, 0.22 mmol) in MeCN (2 mL) was heated at 90 0C overnight. The reaction mixture was filtered and purified by preparative HPLC (System D). Yield 5.6 mg (17%). Analytical HPLC: purity 96% (System A and B); HRESIMS (ESI+) calcd for C26H34N2O5S 486.2188, found 486.2204. EXAMPLE A62 l-Benzoyl-4- {(2R *)-6- [4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidine
Figure imgf000101_0001
The racemic 1 -benzoyl-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine (Example A35; 60 mg, 0.13 mmol) was separated by Chiral Technologies
Europe using the following conditions: Column: CΗIRALPAK® IA 5 μm, 250 x 21 mm;
Mobile phase: n-heptane/ethanol/diethylamine 40/60/0.1 (v/v/v); Flow rate: 15 mL/min;
Detection: UV 220 nm; Temperature: 25 0C. The retention times of the first eluting enantiomer (the title compound) and the second eluting enantiomer (Example A63) were 26.8 min and 32.4 min, respectively. Yield 23 mg (38%). Analytical ΗPLC: purity 97%
(System A and B); ΗRESIMS (ESI+) calcd for C27H27NO5S 477.1610, found 477.1613.
EXAMPLE A63 l-benzoyl-4-{(2S*)-6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine
Figure imgf000101_0002
The title compound was prepared from 1 -benzoyl-4- {6-[4-(methylsulfonyl)phenyl]-4H- l,3-benzodioxin-2-yl}piperidine (Example A35) in accordance with the method described for Example A62. Yield 29 mg (48%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C27H27NO5S 477.1610, found 477.1634.
EXAMPLE A64
(l-Methylcyclopropyl)methyl 4-(6-{4-[(methylamino)carbonyl]phenyl}-4H-l,3-benzo- dioxin-2-yl)piperidine-l-carboxylate
Figure imgf000102_0001
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and methylamine using the conditions described in general method D. Yield 1.3 mg (6%). Analytical HPLC: purity 95% (System A); HRESIMS (ESI+) calcd for C27H32N2O5 464.2311, found 464.2303.
EXAMPLE A65
(l-Methylcyclopropyl)methyl 4-(6-{4-[(ethylamino)carbonyl]phenyl}-4H-l,3-benzo- dioxin-2-yl)piperidine-l-carboxylate
Figure imgf000102_0002
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4/f-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and ethylamine using the conditions described in general method D. Yield 4.4 mg (18%). Analytical ΗPLC: purity 94% (System A); ΗRESIMS (ESI+) calcd for C28H34N2O5 478.2468, found 478.2458.
EXAMPLE A66
(l-Methylcyclopropyl)methyl 4-(6-{4-[(allylamino)carbonyl]phenyl}-4H-l,3-benzo- dioxin-2-yl)piperidine-l-carboxylate
Figure imgf000102_0003
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}-piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and allylamine using the conditions described in general method D. Yield 0.6 mg (2%). Analytical HPLC: purity 98% (System A); HRESIMS (ESI+) calcd for C29H34N2O5 490.2468, found 490.2469.
EXAMPLE A67
(l-Methylcyclopropyl)methyl 4-(6-{4-[(cyclopropylamino)carbonyl]phenyl}-4H-l,3- benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000103_0001
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and cyclopropylamine using the conditions described in general method D. Yield 1.9 mg (8%). Analytical ΗPLC: purity 100% (System A); ΗRESIMS (ESI+) calcd for C29H34N2O5 490.2468, found 490.2459.
EXAMPLE A68
(l-Methylcyclopropyl)methyl 4-[6-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl] piperidine- 1-carboxylate
Figure imgf000103_0002
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and ethanolamine using the conditions described in general method D. Yield 0.6 mg (2%). Analytical ΗPLC: purity 99% (System A); ΗRESIMS (ESI+) calcd for C28H34N2O6 494.2417, found 494.2395. EXAMPLE A69
(l-Methylcyclopropyl)methyl 4-[6-(4-{[(3-hydroxypropyl)amino]carbonyl}phenyl)- 4H- 1 ,3-benzodioxin-2-yl] piperidine- 1-carboxylate
Figure imgf000104_0001
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and 3- amino-1-propanol using the conditions described in general method D. Yield 1.2 mg (5%). Analytical ΗPLC: purity 100% (System A); ΗRESIMS (ESI+) calcd for C29H36N2O6 508.2573, found 508.2561.
EXAMPLE A70
(l-Methylcyclopropyl)methyl 4-[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl] piperidine- 1-carboxylate
Figure imgf000104_0002
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and 2- methoxyethylamine using the conditions described in general method D. Yield 1.2 mg (5%). Analytical ΗPLC: purity 100% (System A); ΗRESIMS (ESI+) calcd for C29H36N2O6 508.2573, found 508.2575.
EXAMPLE A71
(l-Methylcyclopropyl)methyl 4-[6-(4-{[(2-hydroxy-l,l-dimethylethyl)amino]- carbonyl}phenyl)-4H-l,3-benzodioxin-2-yl]piperidine-l-carboxylate - -
Figure imgf000105_0001
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and 2- amino-2-methyl-l-propanol using the conditions described in general method D. Yield 2.0 5 mg (8%). Analytical HPLC: purity 100% (System A); HRESIMS (ESI+) calcd for C30H38N2O6 522.273, found 522.2736.
EXAMPLE A72
(l-Methylcyclopropyl)methyl 4-(6-{4-[(3-hydroxyazetidin-l-yl)carbonyl]phenyl}-4H- i o 1 ,3-benzodioxin-2-yl)piperidine- 1-carboxylate
Figure imgf000105_0002
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and 3- hydroxazetidine hydrochloride using the conditions described in general method D. Yield 15 0.8 mg (3%). Analytical ΗPLC: purity 100% (System A); ΗRESIMS (ESI+) calcd for C29H34N2O6 506.2417, found 506.2398.
EXAMPLE A73
(l-Methylcyclopropyl)methyl 4-(6-{4-[(4-methylpiperazin-l-yl)carbonyl]phenyl}-4H- 20 l,3-benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000105_0003
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and 1- methylpiperazine using the conditions described in general method D. Yield 1.5 mg (6%). Analytical HPLC: purity 99% (System A); HRESIMS (ESI+) calcd for C31H39N3O5 533.2890, found 533.2896.
EXAMPLE A74
(l-Methylcyclopropyl)methyl 4-{6-[4-({[2-(2-furyl)ethyl]amino}carbonyl)phenyl]-4H- l,3-benzodioxin-2-yl}piperidine-l-carboxylate
Figure imgf000106_0001
The title compound was prepared from 4-[2-(l-{[(l-methylcyclopropyl)methoxy]- carbonyl}piperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoic acid (Intermediate AlO) and 2- furan-2-yl-ethylamine using the conditions described in general method D. Yield 1.2 mg (4%). Analytical ΗPLC: purity 98% (System A); ΗRESIMS (ESI+) calcd for C32H36N2O6 544.2573, found 544.2568.
EXAMPLE A75 tert-Butyl 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000106_0002
The title compound was prepared from tert-butyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al l; 20 mg, 0.05 mmol), and [4-(methylsulfonyl)- phenyl]boronic acid (11 mg, 0.055 mmol) using the conditions described in general method A2. Yield 7 mg (42%). Analytical ΗPLC: purity 90% (System A and B); ΗRESIMS (ESI+) calcd for C25Η3iNO6S 473.1872, found 473.1872. - -
EXAMPLE A76 før^Butyl 4-{6-[4-(aminocarbonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000107_0001
The title compound was prepared from tert-butyi 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al l; 20 mg, 0.05 mmol), and [4-(aminocarbonyl)- phenyljboronic acid (9 mg, 0.055 mmol) using the conditions described in general method A2. Yield 6.6 mg (30%). Analytical ΗPLC: purity 94% (System A and B); ΗRESIMS (ESI+) calcd for C25H30N2O5 438.2155, found 438.2152.
EXAMPLE A77 tert-Butyl 4-(6-{4-[(dimethylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000107_0002
The title compound was prepared from tert-butyi 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al l; 20 mg, 0.05 mmol) and (4-[(dimethylamino)- carbonyl]phenyl}boronic acid (11 mg, 0.055 mmol) using the conditions described in general method A2. Yield 10.5 mg (46%). Analytical ΗPLC: purity 90% (System A and B); ΗRESIMS (ESI+) calcd for C27H34N2O5 466.2468, found 466.2469. EXAMPLE A78 før^Butyl 4-{6-[4-(morpholin-4-ylcarbonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine-1-carboxylate
The title compound was prepared from tert-butyi 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al l; 20 mg, 0.05 mmol) and [4-(morpholin-4-yl- carbonyl)phenyl]boronic acid (13 mg, 0.055 mmol) using the conditions described in general method A2. Yield 8.5 mg (34%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C29H36N2O6 508.2573, found 508.2573.
EXAMPLE A79 2-({4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]phenyl}sulfonyl)ethanol
Figure imgf000108_0002
A mixture of 2-[(4-bromophenyl)sulfonyl]ethanol (prepared using similar conditions as described in Verhart, C. G. J et al, Rec. Trav. Chim. Pays-Bas. 1988, 107(11), 621-626) (66 mg, 0.25 mmol), 5,5,5',5'-tetramethyl-2,2'-bi-l,3,2-dioxaborinane (84 mg, 0.37 mmol), K2CO3 (73 mg, 0.75 mmol), PdCfcdppf-DCM (10 mg, 0.01 mmol) and DME (2 mL) was heated at 120 0C for 20 min in a microwave reactor. To the same tube were then added NaHCO3 (42 mg, 0.5 mmol), Pd(PPh3)4 (9 mg, 0.01 mmol), l-benzoyl-4-(6-bromo-4/f-l,3- benzodioxin-2-yl)piperidine (Intermediate A12; 100 mg, 0.25 mmol) and water (0.5 mL). The reaction mixture was heated at 120 0C for 800 sec in a microwave reactor and then filtered through Celite. The filtrate was concentrated and the crude material was purified by preparative HPLC (System E). Yield 30 mg (24%). Analytical HPLC: purity 95% (System A and B); HRESIMS (ESI+) calcd for C28H29NO6S 507.1716, found 507.1733. — o —
EXAMPLE A80
2-({4- [2-(l-Benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl] phenyl} sulfonyl)- ethanamine
Figure imgf000109_0001
A mixture of l-benzoyl-4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine (Intermediate A12; 100 mg, 0.25 mmol), 5,5,5',5'-tetramethyl-2,2'-bi-l,3,2-dioxaborinane (84 mg, 0.37 mmol), potassium acetate (73 mg, 0.75 mmol), PdCl2dppfDCM (10 mg, 0.01 mmol ) and DME (2 mL) was heated at 120 0C for 20 min in a microwave reactor. To the same tube were added NaHCO3 (42 mg, 0.5 mmol), Pd(PPh3)4 (9.0 mg, 0.01 mmol), 2-[(4- bromophenyl)sulfonyl]ethanamine hydrochloride (Intermediate Al 3; 75 mg, 0.25 mmol) and water (0.5 mL). The reaction mixture was heated at 120 0C for 800 sec in a microwave reactor and then filtered through Celite. The filtrate was concentrated and the residue was purified by preparative HPLC (System E). Yield 30 mg (24%). Analytical HPLC: purity 93% (System A and B); HRESIMS (ESI+) calcd for C28H30N2O5S 506.1875, found 506.1882.
EXAMPLE A81 tert-Butyl 4-(6-{4-[(methylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000109_0002
The title compound was prepared from 4-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and methylamine using the conditions described in general method D. Yield 2.1 mg (9%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C26H32N2O5 452.2311, found 452.2305. EXAMPLE A82 tert-Butyl 4-(6-{4-[(ethylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)piperidine-
1-carboxylate
Figure imgf000110_0001
The title compound was prepared from 4-{2-[l-(tert-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and ethylamine using the conditions described in general method D. Yield 2.5 mg (11%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C27H34N2O5 466.2468, found 466.2471.
EXAMPLE A83 tert-Butyl 4-(6-{4-[(allylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)piperidine- 1-carboxylate
Figure imgf000110_0002
The title compound was prepared from 4-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and allylamine using the conditions described in general method D. Yield 0.7 mg (3%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C28H34N2O5 478.2468, found 478.2466.
EXAMPLE A84 tert-Butyl 4-(6-{4-[(cyclopropylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000110_0003
The title compound was prepared from 4-{2-[l-(tert-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and cyclopropylamine using the conditions described in general method D. Yield 3.6 mg (15%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C28H34N2O5 478.2468, found 478.2469.
EXAMPLE A85 tert-Butyl 4-[6-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin-2- yl] piperidine- 1-carboxylate
Figure imgf000111_0001
The title compound was prepared from 4-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and ethanolamine using the conditions described in general method D. Yield 2.8 mg (12%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C27H34N2O6 482.2417, found 482.2418.
EXAMPLE A86 tert-Buty\ 4-[6-(4-{[(2-methylprop-2-en-l-yl)amino]carbonyl}phenyl)-4H-l,3-benzo- dioxin-2-yl]piperidine-l-carboxylate
Figure imgf000111_0002
The title compound was prepared from 4-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and (2-methylprop-2-en-l-yl)amine using the conditions described in general method D. Yield 0.3 mg (1%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C29H36N2O5 492.2624, found 492.2617. EXAMPLE A87 tert-Buty\ 4-(6- {4- [(but-3-en- l-ylamino)carbonyl] phenyl}-4H- 1 ,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000112_0001
The title compound was prepared from 4-{2-[l-(tert-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and but-3-en- 1 -amine using the conditions described in general method D. Yield 1.2 mg (5%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C29H36N2O5 492.2624, found 492.2622.
EXAMPLE A88 før^Butyl 4-[6-(4-{[(3-hydroxypropyl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin-2- yl] piperidine- 1-carboxylate
Figure imgf000112_0002
The title compound was prepared from 4-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and 3-amino-l-propanol using the conditions described in general method D. Yield 3.8 mg (15%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C28H36N2O6 496.2573, found 496.2580.
EXAMPLE A89 tert-Butyl 4-[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin-2- yl] piperidine- 1-carboxylate - -
Figure imgf000113_0001
The title compound was prepared from 4-{2-[l-(tert-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and 2-methoxyethylamine using the conditions described in general method D. Yield 3.8 mg (15%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C28H36N2O6 496.2573, found 496.2580.
EXAMPLE A90 tert-Butyl 4-{6-[4-({[(l-hydroxycyclopropyl)methyl]amino}carbonyl)phenyl]-4H-l,3- benzodioxin-2-yl}piperidine-l-carboxylate
Figure imgf000113_0002
The title compound was prepared from 4-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and l-(aminomethyl)cyclopropanol using the conditions described in general method D. Yield 3.9 mg (16%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C29H36N2O6 508.2573, found 508.2581.
EXAMPLE A91 tert-Butyl 4-[6-(4-{[(2-hydroxy-l,l-dimethylethyl)amino]carbonyl}phenyl)-4H-l,3- benzodioxin-2-yl]piperidine-l-carboxylate
Figure imgf000113_0003
The title compound was prepared from 4-{2-[l-(tert-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and 2-amino-2-methyl-l-propanol using the conditions described in general method D. Yield 3.6 mg (14%). Analytical HPLC: purity 97% (System A and B); HRESIMS (ESI+) calcd for C29H38N2O6 510.2730, found 510.2748.
EXAMPLE A92 tert-Butyl 4-(6- {4- [(3-hydroxyazetidin- l-yl)carbonyl] phenyl}-4H- 1 ,3-benzodioxin-2- yl)piperidine-l-carboxylate
Figure imgf000114_0001
The title compound was prepared from 4-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and 3-hydroxazetidine hydrochloride using the conditions general method D. Yield 3.8 mg (15%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C28H34N2O6 494.2417, found 494.2345.
EXAMPLE A93 tert-Buty\ 4-(6- {4- [(4-methylpiperazin- l-yl)carbonyl] phenyl}-4H- 1 ,3-benzodioxin-2- yl)piperidine-l-carboxylate
Figure imgf000114_0002
The title compound was prepared from 4-{2-[l-(tert-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and 1-methylpiperazine using the conditions described in general method D. Yield 4.0 mg (15%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C30H39N3O5 521.289, found 521.2906. EXAMPLE A94 tert-Butyl 4-{6-[4-({[2-(2-furyl)ethyl]amino}carbonyl)phenyl]-4H-l,3-benzodioxin-2- yl}piperidine-l-carboxylate
Figure imgf000115_0001
The title compound was prepared from 4-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}benzoic acid (Intermediate A14) and 2-furan-2-yl-ethylamine using the conditions described in general method D. Yield 3.9 mg (14%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C3IH36N2O6 532.2573, found 532.2567.
EXAMPLE A95 4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-methylbenzamide
Figure imgf000115_0002
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and methylamine using the conditions described in general method D. Yield 2.9 mg (13%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C28H28N2O4 456.2049, found 456.2058.
EXAMPLE A96 4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-ethylbenzamide
Figure imgf000115_0003
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and ethylamine using the conditions described in general method D. Yield 7.6 mg (32%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C29H30N2O4 470.2206, found 470.2202.
EXAMPLE A97
7V-Allyl-4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzamide
Figure imgf000116_0001
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and allylamine using the conditions described in general method D. Yield 5.5 mg (23%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C30H30N2O4 482.2206, found 482.2200.
EXAMPLE A98 4- [2-(l-Benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl] -TV-cyclopropylbenzamide
Figure imgf000116_0002
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and cyclopropylamine using the conditions described in general method D. Yield 8.7 mg (36%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C30H30N2O4 482.2206, found 482.2200. — —
EXAMPLE A99
4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-(2-hydroxyethyl)- benzamide
Figure imgf000117_0001
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and ethanolamine using the conditions described in general method D. Yield 8.7 mg (36%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C29H30N2O5 486.2155, found 486.2164.
EXAMPLE AlOO
4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-(2-methylprop-2-en-l-yl)- benzamide
Figure imgf000117_0002
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and 2-methylprop-2-en-l -amine using the conditions described in general method D. Yield 6.0 mg (24%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C3IH32N2O4 496.2362, found 496.2356.
EXAMPLE AlOl
4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-but-3-en-l-ylbenzamide
Figure imgf000117_0003
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and but-3-en-l -amine using the conditions described in general method D. Yield 9.2 mg (37%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C3IH32N2O4 496.2362, found 496.2352.
EXAMPLE A102
4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-(3-hydroxypropyl)- benzamide
Figure imgf000118_0001
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and 3-amino-l-propanol using the conditions described in general method D. Yield 9.2 mg (37%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C30H32N2O5 500.2311, found 500.2310.
EXAMPLE A103
4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-(2-methoxyethyl)- benzamide
Figure imgf000118_0002
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and 2-methoxyethylamine using the conditions described in general method D. Yield 6.0 mg (24%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C30H32N2O5 500.2311, found 500.2317. — —
EXAMPLE A104
4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-[(l-hydroxycyclopropyl)- methyl] benzamide
Figure imgf000119_0001
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and 1 -(amino methyl)cyclopropanol using the conditions described in general method D. Yield 7.9 mg (30%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C3IH32N2O5 512.2311, found 512.2311.
EXAMPLE A105
4- [2-(l-Benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl] -7V-(2-hydroxy- 1,1- dimethylethyl)benzamide
Figure imgf000119_0002
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and 2-amino-2-methyl-l-propanol according to general method D. Yield 5.6 mg (22%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C3IH34N2O5 514.2468, found 514.2464.
EXAMPLE A106 l-{4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoyl}azetidin-3-ol
Figure imgf000119_0003
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and 3-hydroxazetidine hydrochloride using the conditions described in general method D. Yield 11.7 mg (47%). Analytical HPLC: purity 100% (System A and B); LRESIMS m/z = 499 (M+H)+.
EXAMPLE A107 l-{4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzoyl}-4-methyl- piperazine
Figure imgf000120_0001
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and 1-methylpiperazine using the conditions described in general method D. Yield 10 mg (38%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C32H35N3O4 525.2628, found 525.2627.
EXAMPLE A108
4-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-7V-[2-(2-furyl)ethyl]- benzamide
Figure imgf000120_0002
The title compound was prepared from 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzo- dioxin-6-yl]benzoic acid (Intermediate Al 6) and 2-furan-2-yl-ethylamine using the conditions described in general method D. Yield 3.7 mg (14%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C33H32N2O5 536.2311, found 536.2291. EXAMPLE Al 09
Ethyl 4-(6-{4-[(methylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)piperidine-l- carboxylate
Figure imgf000121_0001
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and methylamine using the conditions described in general method D. Yield 3.0 mg (14%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C24H28N2O5 424.1998, found 424.1980.
EXAMPLE Al 10
Ethyl 4-(6-{4-[(ethylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)piperidine-l- carboxylate
Figure imgf000121_0002
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and ethylamine using the conditions described in general method D. Yield 3.8 mg (17%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C25H30N2O5 438.2155, found 438.2142.
EXAMPLE Al 11 Ethyl 4-(6-{4-[(allylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)piperidine-l- carboxylate
Figure imgf000121_0003
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and allylamine using the conditions described in general method D. Yield 4.8 mg (22%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C26H30N2O5 450.2155, found 450.2142.
EXAMPLE Al 12
Ethyl 4-(6- {4- [(cyclopropylaminojcarbonyl] phenyl}-4H- 1 ,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000122_0001
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and cyclopropylamine using the conditions described in general method D. Yield 3.5 mg (16%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C26H30N2O5 450.2155, found 450.2142.
EXAMPLE Al 13
Ethyl 4- [6-(4- { [(2-hydroxyethyl)amino] carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl] - piperidine-1-carboxylate
Figure imgf000122_0002
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and ethanolamine using the conditions described in general method D. Yield 8.6 mg (39%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C25H30N2O6 454.2104, found 454.2107. EXAMPLE Al 14
Ethyl 4-[6-(4-{[(2-methylprop-2-en-l-yl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin-
2-yl] piperidine- 1-carboxylate
Figure imgf000123_0001
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 2-methylprop-2-en-l -amine according to general method D. Yield 8.1 mg (35%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C27H32N2O5 464.2311, found 464.2314.
EXAMPLE Al 15
Ethyl 4-(6-{4-[(but-3-en-l-ylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000123_0002
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and but-3-en-l -amine according to general method D. Yield 6.4 mg (28%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C27H32N2O5 464.2311, found 464.2308.
EXAMPLE Al 16 Ethyl 4- [6-(4- { [(3-hydr oxypropyl)amino] carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl] - piperidine-1-carboxylate
Figure imgf000123_0003
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 3-amino-l-propanol using the conditions described in general method D. Yield 6.8 mg (30%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C26H32N2O6 468.2260, found 468.2248.
EXAMPLE Al 17
Ethyl 4- [6-(4- { [(2-methoxyethyl)amino] carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl] - piperidine-1-carboxylate
Figure imgf000124_0001
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 2-methoxyethylamine using the conditions described in general method D. Yield 8.3 mg (36%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C26H32N2O6 468.2260, found 468.2255.
EXAMPLE Al 18
Ethyl 4-{6-[4-({[(l-hydroxycyclopropyl)methyl]amino}carbonyl)phenyl]-4H-l,3- benzodioxin-2-yl}piperidine-l-carboxylate
Figure imgf000124_0002
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 1 -(amino methyl)cyclopropanol using the conditions described in general method D. Yield 8.4 mg (35%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C27H32N2O6 480.2260, found 480.2242. EXAMPLE Al 19
Ethyl 4- [6-(4- { [(2-hydroxy- 1 , l-dimethylethyl)amino] carbonyl}phenyl)-4H- 1 ,3- benzodioxin-2-yl]piperidine-l-carboxylate
Figure imgf000125_0001
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 2-amino-2-methyl-l-propanol according to general method D. Yield 4.4 mg (18%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C27H34N2O6 482.2417, found 482.2408.
EXAMPLE A120
Ethyl 4-(6-{4-[(3-hydroxyazetidin-l-yl)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000125_0002
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 3-hydroxazetidine hydrochloride according to general method D. Yield 8.2 mg (36%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C26H30N2O6 466.2104, found 466.2101.
EXAMPLE Al 21 Ethyl 4-(6-{4-[(4-methylpiperazin-l-yl)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate
Figure imgf000125_0003
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 1-methylpiperazine using the conditions described in general method D. Yield 8.6 mg (34%). Analytical HPLC: purity 100% (System A and B); HRESIMS (ESI+) calcd for C28H35N3O5 493.2577, found 493.2576.
EXAMPLE Al 22
Ethyl 4-{6-[4-({[2-(2-furyl)ethyl]amino}carbonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine-1-carboxylate
Figure imgf000126_0001
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 2-furan-2-yl-ethylamine using the conditions described in general method D. Yield 8.6 mg (34%). Analytical ΗPLC: purity 100% (System A and B); ΗRESIMS (ESI+) calcd for C29H32N2O6 504.2260, found 504.2256.
EXAMPLE Al 23
Ethyl 4- [6-(4- { [2-(hydroxymethyl)morpholin-4-yl] carbonyl}phenyl)-4H- 1 ,3-benzo- dioxin-2-yl]piperidine-l-carboxylate
Figure imgf000126_0002
The title compound was prepared from 4-{2-[l-(ethoxycarbonyl)piperidin-4-yl]-4H-l,3- benzodioxin-6-yl}benzoic acid (Intermediate Al 8) and 2-morpholinemethanol using the conditions described in general method D. Yield 9.9 mg (38%). Analytical ΗPLC: purity 95% (System A and B); ΗRESIMS (ESI+) calcd for C28H34N2O7 510.2366, found 510.2367. - -
EXAMPLE Al 24
3-(3-{2-[l-(tert-Butoxycarbonyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}isoxazol-5- yl)propanoic acid
Figure imgf000127_0001
The title compound was prepared from tert-butyl 4-[6-(dimethoxyboryl)-4H-l,3-benzo- dioxin-2-yl]piperidine-l-carboxylate (Intermediate Al 9) and 3-(3-bromoisoxazol-5-yl)- propanoic acid according to general method B. Yield 3 mg (9%). Analytical HPLC: purity 92% (System A and B); LRESIMS (ESI+) m/z = 358 (M+H-Boc)+.
EXAMPLE A125
[(5-{2-[l-(før^Butoxycarbonyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}-2-furoyl)- amino] acetic acid
Figure imgf000127_0002
The title compound was prepared from tert-butyl 4-[6-(dimethoxyboryl)-4H-l,3-benzo- dioxin-2-yl]piperidine-l-carboxylate (Intermediate A19) and Λ/-(5-bromo-2-furoyl)glycine using the conditions described in general method B. Yield 4.4 mg (12%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C25H30N2O8 486.2002, found 486.1992.
EXAMPLE Al 26 tert-Butyl 4-{6-[6-(methylsulfonyl)pyridin-3-yl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000127_0003
The title compound was prepared from tert-butyi 4-[6-(dimethoxyboryl)-4H-l,3-benzo- dioxin-2-yl]piperidine-l-carboxylate (Intermediate Al 9) and 5-bromo-2-(methylsulfonyl)- pyridine using the conditions described in general method B. Yield 3.2 mg (9%). Analytical HPLC: purity 99% (System A and B); HRESIMS (ESI+) calcd for C24H30N2O6S 474.1825, found 474.1826.
EXAMPLE Al 27 tert-Butyl 4-{6-[5-(methylsulfonyl)pyridin-2-yl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000128_0001
The title compound was prepared from tert-butyl 4-[6-(dimethoxyboryl)-4H-l,3-benzo- dioxin-2-yl]piperidine-l-carboxylate (Intermediate Al 9) and 2-bromo-5-(methylsulfonyl)- pyridine according to general method B. Yield 4.9 mg (13%). Analytical ΗPLC: purity 99% (System A and B); LRESIMS (ESI+) m/z = 419 (M+Η-Φu)+.
EXAMPLE Al 28 tert-Butyl 4-{6-[4-(lH-tetrazol-5-yl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate
Figure imgf000128_0002
The title compound was prepared from tert-butyi 4-[6-(dimethoxyboryl)-4H-l,3-benzo- dioxin-2-yl]piperidine-l-carboxylate (Intermediate Al 9) and 5-(4-bromophenyl)-lH- tetrazole using the conditions described in general method B. Yield 2.8 mg (8%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C25H29N5O4 463.2220, found 463.2240. — —
EXAMPLE Al 29 tert-Butγ\ 4- [6-(2- { [amino(imino)methyl] amino}-4-methyl- 1 ,3-thiazol-5-yl)-4H- 1 ,3- benzodioxin-2-yl]piperidine-l-carboxylate
Figure imgf000129_0001
The title compound was prepared from tert-butyl 4-[6-(dimethoxyboryl)-4H-l,3-benzo- dioxin-2-yl]piperidine-l-carboxylate (Intermediate Al 9) and JV-(5-bromo-4-methyl-l,3- thiazol-2-yl)guanidine according to general method B. Yield 1.5 mg (4%). Analytical ΗPLC: purity 93% (System A and B); LRESIMS (ESI+) m/z = 474 (M+Η)+.
EXAMPLE Al 30 før^Butyl 4-(6-pyridin-4-yl-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000129_0002
A suspension of tert-butyl 4-(6-bromo-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate (Intermediate Al l; 100 mg, 0.251 mmol), pyridin-4-ylboronic acid (37 mg, 0.301 mmol), K2CO3 (87 mg, 0.63 mmol), PdCfcdppf-DCM (21 mg, 0.025 mmol) in MeCN/Η2O (3 mL; 2:1) was heated at 160 0C for 20 min in a microwave reactor. The mixture was filtered through a pad of silica, concentrated and the residue was purified by preparative HPLC (System E). Yield 45 mg (45%). Analytical HPLC: purity 99% (System A and B); HRESIMS (ESI+) calcd for C23H28N2O4396.2049, found 396.2068.
EXAMPLE Al 31 tert-Butyl 4-(6-pyridin-3-yl-4H-l,3-benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000129_0003
The title compound was prepared from tert-butyi 4-(6-bromo-4H-l,3-benzodioxin-2-yl)- piperidine-1-carboxylate (Intermediate Al l; 70 mg, 0.18 mmol) and pyridin-3-ylboronic acid (26 mg, 0.21 mmol) using the conditions described for Example Al 30. Yield 29 mg (42%). Analytical HPLC: purity 99% (System A and B); HRESIMS (ESI+) calcd for C23H28N2O4396.2049, found 396.2061.
EXAMPLE Al 32 tert-Butyl 4-(6- {5- [(4-methylpiperazin- l-yl)carbonyl] pyridin-2-yl}-4H- 1 ,3-benzo- dioxin-2-yl)piperidine-l-carboxylate
Figure imgf000130_0001
To a suspension of 6-{2-[l-(tert-butoxycarbonyl)piperidin-4-yl]-4H-l,3-benzodioxin-6- yl}nicotinic acid (Intermediate A21; 50 mg, 0.11 mmol), ΗOBT (31 mg, 0.23 mmol), EDC (44 mg, 0.23 mmol) and triethylamine (46 mg, 0.45 mmol) in DMF (3 mL) was added 1- methylpiperazine (17 mg, 0.17 mmol). The mixture was stirred at r.t. for 12 h and then at 100 0C for 24 h. The solvent was removed under reduced pressure and the residue was purified by preparative ΗPLC (System E). Yield 10.3 mg (17%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C29H38N4O5 522.2842, found 522.2853.
EXAMPLE Al 33 tert-Butyl 4-{6-[6-(morpholin-4-ylcarbonyl)pyridin-3-yl]-4H-l,3-benzodioxin-2-yl}- piperidine-1-carboxylate
Figure imgf000130_0002
The title compound was prepared from 5-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}pyridine-2-carboxylic acid (Intermediate A20; 50 mg, 0.11 mmol) and morpholine (15 mg, 0.17 mmol) using the conditions described for Example Al 32. Yield 1.4 mg (2%). Analytical HPLC: purity 99% (System A and B); HRESIMS (ESI+) calcd for C28H35N3O6509.2526, found 509.2540.
EXAMPLE Al 34 tert-Buty\ 4-(6- {6- [(4-methylpiperazin- l-yl)carbonyl] pyridin-3-yl}-4H- 1 ,3-benzo- dioxin-2-yl)piperidine-l-carboxylate
Figure imgf000131_0001
The title compound was prepared from 5-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}pyridine-2-carboxylic acid (Intermediate A20; 50 mg, 0.11 mmol) and 1-methylpiperazine (17 mg, 0.17 mmol) using the conditions described for Example A132. Yield 1.7 mg (3%). Analytical ΗPLC: purity 96% (System A and B); ΗRESIMS (ESI+) calcd for C29H38N4O5522.2842, found 522.2854.
EXAMPLE Al 35 tert-Buty\ 4- {6- [5-(morpholin-4-ylcarbonyl)pyridin-2-yl] -4H- 1 ,3-benzodioxin-2-yl}- piperidine-1-carboxylate
Figure imgf000131_0002
The title compound was prepared from 6-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}nicotinic acid (Intermediate A21; 50 mg, 0.11 mmol) and morpholine (15 mg, 0.17 mmol) using the conditions described for Example A132. Yield 7.7 mg (17%). Analytical ΗPLC: purity 96% (System B and C); ΗRESIMS (ESI+) calcd for C28H35N3O6509.2526, found 509.2529. EXAMPLE Al 36 tert-Butyl 4-(6-{5-[(4-methylpiperazin-l-yl)carbonyl]-2-furyl}-4H-l,3-benzodioxin-2- yl)piperidine-l-carboxylate
Figure imgf000132_0001
A suspension of tert-butyi 4-[6-(dimethoxyboryl)-4H-l,3-benzodioxin-2-yl]piperidine-l- carboxylate (Intermediate A19; 100 mg, 0.254 mmol), 5-bromo-2-furoic acid (58 mg, 0.31 mmol), K2CO3 (88 mg, 0.64 mmol), PdCl2dppfDCM (22 mg, 0.025 mmol) in MeCN/Η2O (4 mL; 2:1) was heated at 160 0C for 20 min in a microwave reactor. The mixture was filtered through a pad of silica and concentrated to give 5-{2-[l-(te/t-butoxycarbonyl)- piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}-2-furoic acid.
Part of this material (50 mg, 0.116 mmol), HOBT (32 mg, 0.23 mmol), EDC (45 mg, 0.23 mmol), triethylamine (47 mg, 0.47 mmol) and 1-methylpiperazine (35 mg, 0.35 mmol) was dissolved in DMF (4 mL) amd stirred at r.t. for 24 h. The mixture was concentrated and the residue was purified by preparative HPLC (System E). Yield 17 mg (29%). Analytical HPLC: purity 99% (System A and B); HRESIMS (ESI+) calcd for C28H37N3O6 511.2682, found 511.2683.
EXAMPLE Al 37 tert-Butyl 4-(6-{5-[(lJE)-3-(4-methylpiperazin-l-yl)-3-oxoprop-l-en-l-yl]-2-thienyl}- 4H- 1 ,3-benzodioxin-2-yl)piperidine- 1-carboxylate
Figure imgf000132_0002
A suspension of (2E)-3-(5- {2-[ 1 -(te/t-butoxycarbonyl)piperidin-4-yl]-4/f- 1 ,3-benzodioxin- 6-yl}-2-thienyl)acrylic acid (Intermediate A22; 50 mg, 0.116 mmol) ΗOBT (29 mg, 0.21 mmol), ΕDC (41 mg, 0.21 mmol), triethylamine (43 mg, 0.42 mmol) and 1-methyl- piperazine (32 mg, 0.32 mmol) in DMF (3 mL) was stirred at r.t. for 24 h. The mixture was concentrated and the residue was purified by preparative ΗPLC (System Ε). Yield 12 mg (20%). Analytical HPLC: purity 90% (System A and B); HRESIMS (ESI+) calcd for C30H39N3O5S 553.2610, found 553.2623.
EXAMPLE Al 38 tert-Butyl 4-(6-{5-[(lJE)-3-morpholin-4-yl-3-oxoprop-l-en-l-yl]-2-thienyl}-4H-l,3- benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000133_0001
The title compound was prepared from (2ii)-3-(5-{2-[l-(te/t-butoxycarbonyl)piperidin-4- yl]-4H-l,3-benzodioxin-6-yl}-2-thienyl)acrylic acid (Intermediate A22; 50 mg, 0.12 mmol) and morpholine (27 mg, 0.32 mmol) using the conditions described for Example A137. Yield 14 mg (25%). Analytical ΗPLC: purity 93% (System A and B); ΗRESIMS (ESI+) calcd for C29H36N2O6S 540.2294, found 540.2299.
EXAMPLE Al 39 tert-Buty\ 4-(6- {5- [(4-pyrimidin-2-ylpiperazin- 1 -yl)carbonyl] pyridin-2-yl}-4H- 1 ,3- benzodioxin-2-yl)piperidine-l-carboxylate
Figure imgf000133_0002
The title compound was prepared from 6-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}nicotinic acid (Intermediate A21; 50 mg, 0.11 mmol) and 2-(l- piperazinyl)pyrimidine (28 mg, 0.17 mmol) using the conditions described for Example A137. Yield 9 mg (13%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C32H38N6O5 586.2904, found 586.2913. EXAMPLE Al 40 tert-Buty\ 4- [6-(5- { [ [2-(dimethylamino)ethyl] (methyl)amino] carbonyl}pyridin-2-yl)-
4H- 1 ,3-benzodioxin-2-yl] piperidine- 1-carboxylate
Figure imgf000134_0001
The title compound was prepared from 6-{2-[l-(ter£-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}nicotinic acid (Intermediate A21; 50 mg, 0.12 mmol) and N^N1- trimethylethane-l,2-diamine (17 mg, 0.17 mmol) using the conditions described for Example A137. Yield 9 mg (15%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C29H40N4O5524.2999, found 524.3005.
EXAMPLE Al 41 tert-Butyl 4-[6-(5-{[4-(2-hydroxyethyl)piperazin-l-yl]carbonyl}pyridin-2-yl)-4H-l,3- benzodioxin-2-yl]piperidine-l-carboxylate
Figure imgf000134_0002
The title compound was prepared from 6-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}nicotinic acid (Intermediate A21; 50 mg, 0.11 mmol) and N-(I- hydroxyethyl)piperazine (22 mg, 0.17 mmol) using the conditions described for Example A137. Yield 17 mg (17%). Analytical ΗPLC: purity 99% (System A and B); MS (ESI+) calcd for C30H40N4O6 552.2948, found 552.2958. - —
EXAMPLE Al 42 tert-Butyl 4-[6-(6-{[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}pyridin-3-yl)- 4H- 1 ,3-benzodioxin-2-yl] piperidine- 1-carboxylate
Figure imgf000135_0001
The title compound was prepared from 5-{2-[l-(te/t-butoxycarbonyl)piperidin-4-yl]-4H- l,3-benzodioxin-6-yl}pyridine-2-carboxylic acid (Intermediate A20; 50 mg, 0.11 mmol;) and Λ/,Λ/,Λ/"-trimethylethane-l,2-diamine (17 mg, 0.17 mmol) using the conditions described for Example Al 37. Yield 1.5 mg (3%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C29H40N4O5524.2999, found 524.3010.
EXAMPLE Al 43
Ethyl 4-(6-{6-[(4-methylpiperazin-l-yl)carbonyl]pyridin-3-yl}-4H-l,3-benzodioxin-2- yl)piperidine-l-carboxylate
Figure imgf000135_0002
A suspension of l,r-carbonyldiimidazole (24 mg, 0.14 mmol), ethanol (7 mg, 0.14 mmol) and DCM (0.5 mL) under N2 (g) was treated with a solution of l-methyl-4-{[5-(2- piperidin-4-yl-4H- 1 ,3-benzodioxin-6-yl)pyridin-2-yl]carbonyl}piperazine (Intermediate A23; 30 mg, 0.071 mmol;) in DCM (0.5 mL) and stirred at r.t. for 24 h. The solvent was removed under reduced pressure and the residue was purified by preparative ΗPLC (System E). Yield 5.2 mg (15%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C27H34N4O5494.2529, found 494.2543. EXAMPLE Al 44
Isopropyl 4-(6-{6-[(4-methylpiperazin-l-yl)carbonyl]pyridin-3-yl}-4H-l,3-benzo- dioxin-2-yl)piperidine-l-carboxylate
Figure imgf000136_0001
The title compound was prepared from l-methyl-4-{[5-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)pyridin-2-yl]carbonyl}piperazine (Intermediate A23; 30 mg, 0.071 mmol) and 2-propanol (9 mg, 0.14 mmol) using the conditions described for Example A143. Yield 6.9 mg (19%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C28H36N4O5508.2686, found 508.2700.
EXAMPLE Al 45
Ethyl 4-(6-{5-[(4-methylpiperazin-l-yl)carbonyl]pyridin-2-yl}-4H-l,3-benzodioxin-2- yl)piperidine-l-carboxylate
Figure imgf000136_0002
The title compound was prepared from l-methyl-4-{[6-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)pyridin-3-yl]carbonyl}piperazine (Intermediate A24; 22 mg, 0.052 mmol) and ethanol (5 mg, 0.1 mmol) using the conditions described for Example A143. Yield 2.3 mg (9%). Analytical ΗPLC: purity 96% (System A and B); ΗRESIMS (ESI+) calcd for C27H34N4O5494.2529, found 494.2529. - -
EXAMPLE Al 46 l-({5-[2-(l-Benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]pyridin-2-yl}carbonyl)-4- methylpiperazine
Figure imgf000137_0001
A cooled (5 0C) suspension of l-methyl-4-{[5-(2-piperidin-4-yl-4H-l,3-benzodioxin-6-yl)- pyridin-2-yl]carbonyl}piperazine (Intermediate A23; 30 mg, 0.071 mmol) in dry pyridine (2 mL) was stirred under N2 for 10 min. To the mixture was then added benzoyl chloride (12 mg, 0.071 mmol) and the resulting mixture was stirred for 1 h. The solvent was removed under reduced pressure and the residue was purified by preparative ΗPLC (System E). Yield 6.3 mg (17%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C31Η34N4O4 526.2580, found 526.2601.
EXAMPLE Al 47 l-[(5-{2-[l-(2-Ethylbutanoyl)piperidin-4-yl]-4H-l,3-benzodioxin-6-yl}pyridin-2-yl)- carbonyl] -4-methylpiperazine
Figure imgf000137_0002
The title compound was prepared from l-methyl-4-{[5-(2-piperidin-4-yl-4H-l,3-benzo- dioxin-6-yl)pyridin-2-yl]carbonyl}piperazine (Intermediate A23; 30 mg, 0.071 mmol) and 2-ethylbutanoyl chloride (12 mg, 0.071 mmol) using the conditions described for Example A146. Yield 5.6 mg (15%). Analytical ΗPLC: purity 99% (System A and B); ΗRESIMS (ESI+) calcd for C30H40N4O4 520.3050, found 520.3068. EXAMPLE Al 48
2- [4-(6- {5- [(4-Methylpiperazin- l-yl)carbonyl] pyridin-2-yl}-4H- 1 ,3-benzodioxin-2- yl)piperidin- 1-yl] pyrimidine
Figure imgf000138_0001
A suspension of 2-bromopyrimidine (6 mg, 0.037 mmol) and l-methyl-4-{[6-(2-piperidin- 4-yl-4Η-l,3-benzodioxin-6-yl)pyridin-3-yl]carbonyl}piperazine (Intermediate A24; 14 mg, 0.033 mmol) in dry DMSO (1 mL) under N2 (g) was stirred at 50 0C for 12 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (System E). Yield 2.1 mg (13%). Analytical HPLC: purity 99% (System A and B); HRESIMS (ESI+) calcd for C28H32N6O3500.2536, found 500.2551.
INTERMEDIATE Bl
2-Methyl- 1 ,3-benzoxazol-6-amine
Figure imgf000138_0002
To a heated suspension (70 0C) of 6-nitro-2-methyl-benzoxazole (4.00 g, 22.4 mmol) in MeOH (60 mL) was added a solution of ammonium chloride (12.1 g, 0.227 mol) in water (40 mL) followed by iron powder (4.52 g, 80.1 mmol). The mixture was stirred for 2 h at 70 0C and then filtered through Celite and washed with MeOH. The filtrate was concentrated and the residue was partitioned between water and EtOAc. The organic layers were combined and the solvent was removed under reduced pressure to give the title compound. Yield 2.83 g (85%). Analytical HPLC: purity 100% (System A); LRESIMS (ESI+) m/z = 149 (M+H)+.
INTERMEDIATE B2 7V-(4-Bromo-2-hydroxyphenyl)acetamide
Figure imgf000138_0003
— —
To a cooled (0 0C) suspension of 2-methyl-l,3-benzoxazol-6-amine (Intermediate Bl; 1.96 g, 13.2 mmol) in 1 M HBr (40 niL) was carefully added NaNO2 (1.38 g, 20 mmol). After stirring for 10 min, a solution of CuBr (2.92 g, 20 mmol) in water (14 mL) was added and the mixture was stirred at 0 0C for 5 min. The ice-bath was removed and the mixture was stirred overnight and then 25% aqueous ammonia (5 mL) was added. The mixture was extracted with EtOAc (500 mL) and the organic layer was concentrated. The residue was purified by flash chromatography on silica using MeOH/CHCl3 (0.05:1) as eluent. Yield 1.47 g (32%). Analytical HPLC: purity 100% (System A); LRESIMS (ESI+) m/z = 230/232 (M+H)+.
INTERMEDIATE B3 2-Amino-5-bromophenol
Figure imgf000139_0001
A suspension of iV-(4-bromo-2-hydroxyphenyl)acetamide (Intermediate B2; 1.35 g, 5.87 mmol) in EtOH (30 mL) and 3 M HCl (30 mL) was heated to 100 0C (reflux) for 3 h. To the mixture was then added 1 M Na2CO3 (45 mL) and the ethanol was removed under reduced pressure. The residue was extracted with DCM (3 x 250 mL), dried and concentrated. Yield 988 mg (89%). Analytical HPLC: purity 100% (System A); LRESIMS (ESI+) m/z = 188/190 (M+H)+.
INTERMEDIATE B4 tert-Butyl 4-{[methoxy(methyl)amino]carbonyl}piperidine-l-carboxylate
Figure imgf000139_0002
A suspension of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.8 mmol), EDC (6.27 g, 32.7 mmol) and HOBT (2.95 g, 21.8 mmol) in DMF (10 mL) was stirred for
20 min. To the mixture were then added 1 ,2-dimethylhydroxylamine hydrochloride (3.19 g, 32.7 mmol) and DIEA (13 mL, 76.3 mmol) and the stirring continued overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was concentrated and the residue was purified by flash chromatography on silica using EtOAc as eluent. Yield 5.22 g (88%). Analytical HPLC: purity 100% (System A and B);
LRESIMS (ESI+) m/z = 217 (M+H-Φu)+. INTERMEDIATE B5 ført-ButyM-acetylpiperidine-l-carboxylate
K>i A 3 M solution of bromo(methyl)magnesium in diethylether (13.8 niL, 41.4 mmol) was cooled in an ice-bath and a solution of tert-butyi 4-{[methoxy(methyl)amino]carbonyl}- piperidine-1-carboxylate (Intermediate B4; 5.2 g 19.2 mmol) in Et2O (25 mL) was added dropwise. The ice-bath was removed and the mixture was stirred at r.t. for 2 h. The excess bromo(methyl)magnesium was quenched by dropwise addition of water, and the water phase was then extracted with ether. Yield 3.35 g (77%). Analytical HPLC: purity 95% (System A); LRESIMS (ESI+) m/z = 172 (M+H-?Bu)+.
INTERMEDIATE B6 tert-Butyl 4-(bromoacetyl)piperidine-l-carboxylate
Figure imgf000140_0001
To a cooled (-78 0C) suspension of tert-butyi 4-acetylpiperidine-l-carboxylate (Intermediate B5; 2.87 g, 12.6 mmol) in THF (30 mL) was added 1 M lithium bis(trimethylsilyl)amide in THF (13.3 mL) over 20 min. The mixture was stirred for 1 h before the addition of trimethylsilyl chloride (1.74 mL, 13.7 mmol). After stirring at 0 0C for 30 min, the solution was cooled to -78 0C and bromine (0.645 mL, 12.6 mmol) was added. The mixture was allowed to reach r.t. and then poured into a solution of 10% Na2S2O3 (20 mL) and saturated NH4Cl (20 mL). Extraction with EtOAc (2 x 80 mL) gave the title compound. Yield 3.69 g (96%).
INTERMEDIATE B7 ført-Butyl 4-(7-bromo-2H-l,4-benzoxazin-3-yl)piperidine-l-carboxylate
Figure imgf000140_0002
To a stirred solution of 2-amino-5-bromophenol (Intermediate B3; 898 mg, 4.78 mmol) in DMF (10 mL) was added K2CO3 (660 mg, 4.78 mmol). After 45 min, a solution of tert- butyl 4-(bromoacetyl)piperidine-l-carboxylate (Intermediate B6; 1.53 g, ca 5 mmol) in DMF (2 rnL) was added and the mixture was stirred at r.t. overnight. Water was added and the product was extracted with toluene. The organic phase was washed with water and brine, dried and evaporated to give 952 mg of crude title compound (used in Intermediate B8). The aqueous layer was extracted with CHCI3 and the organic layer was concentrated. The residue was purified by flash chromatography on silica using 1% MeOH/CHCl3 as eluent to give an additional 628 mg of the title compound. Total yield 1.58 g (84%). Analytical HPLC: purity 83% (System A); LRESIMS (ESI+) m/z = 339/341 (M+FRBu)+.
INTERMEDIATE B8 tert-Butyl 4-(7-bromo-3,4-dihydro-2H-l,4-benzoxazin-3-yl)piperidine-l-carboxylate
Figure imgf000141_0001
A suspension of tert-butyi 4-(7-bromo-2H-l,4-benzoxazin-3-yl)piperidine-l-carboxylate (crude Intermediate B7; 952 mg, 2.4 mmol) in ethanol (25 mL) was treated with NaBH4 (200 mg, 5.26 mmol) and stirred for 6 h. To the reaction mixture was then added HOAc (1.5 mL) followed by 2 M NaOH (13 mL). The ethanol was removed under reduced pressure and the residue was extracted with DCM. The organic layer was concentrated and the residue was purified by flash chromatography on silica using EtOAc/n-hexane (1 :2) as eluent. Yield 306 mg. Analytical HPLC: purity 100% (System A); LRESIMS (ESI+) m/z = 341/343 (M+H-Φu)+.
EXAMPLE Bl tert-Butyl 4-{7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H-l,4-benzoxazin-3-yl}- piperidine-1-carboxylate
Figure imgf000141_0002
A suspension of tert-butyl 4-(7-bromo-3,4-dihydro-2H-l,4-benzoxazin-3-yl)piperidine-l- carboxylate (Intermediate B8; 200 mg, 0.50 mmol), (4-methylsulfonylphenyl)boronic acid (120 mg, 0.6 mmol), NaHCO3 (126 mg, 1.5 mmol), PPh3 (20 mg, 0.075 mmol) and Pd(OAc)2 (6 mg, 0.025 mmol) in 80% EtOH (4 mL) was heated at 80 0C overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved in DCM and washed with 5% NaHCO3 and brine. Flash chromatography using gradient elution (45 — > 60% EtOAc in n-hexane) gave the title compound. Yield 30 mg (13%). Analytical HPLC: purity 98% (System A); HRESIMS (ESI+) calcd for C25H32N2O5S 472.2032, found 472.2039.
EXAMPLE B2 3-[l-(Cyclohexylacetyl)piperidin-4-yl]-7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H- 1,4-benzoxazine trifluoroacetate
Figure imgf000142_0001
A suspension of tert-butyi 4-{7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H-l,4- benzoxazin-3-yl}piperidine-l-carboxylate (Example Bl; 63 mg, 0.13 mmol) in DCM (0.8 mL) and TFA (0.2 mL) was stirred for 30 min and then concentrated. The residue was partitioned between CHCl3 (20 + 10 mL) and 1 M Na2CO3 (2 mL) and the combined organic layers were concentrated to give 7-[4-(methylsulfonyl)phenyl]-3-piperidin-4-yl- 3,4-dihydro-2H-l,4-benzoxazine. The deprotected material was then treated with DMF (0.8 mL), triethylamine (0.031 mL, 23 mg, 0.226 mmol) and cyclohexylacetic acid (816 mg, 0.113 mmol) followed by the addition of TBTU (43 mg, 0.135 mmol). The mixture was stirred at r.t. overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (System D). Yield 16 mg (20%). Analytical HPLC: purity 100% (System A); HRESIMS (ESI+) calcd for C28H36N2O4S 496.2396, found 496.2407. EXAMPLE B3
3-(l-Benzoylpiperidin-4-yl)-7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H-l,4- benzoxazine trifluoroacetate
Figure imgf000143_0001
The title compound was prepared from tert-butyi 4-{7-[4-(methylsulfonyl)phenyl]-3,4- dihydro-2H-l,4-benzoxazin-3-yl}piperidine-l-carboxylate (Example Bl; 42 mg, 0.089 mmol) and benzoic acid (14 mg, 0.113 mmol) using the conditions described for Example B2. Yield 15 mg (28%). Analytical HPLC: purity 100% (System A); HRESIMS (ESI+) calcd for C27H28N2O4S 476.1770, found 476.1763.
BIOLOGICAL TESTS
Human GPRl 19 Activity Assay
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.
Briefly, 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 μg/mL Hygromycin B (Roche Diagnostics 843555). At 80% confluency, cells were detached using Trypsine and aliquoted at a density of 5x106 cells/mL in freezing medium (DMEM (Gibco # 31966-021), 20% BCS (Hyclone # SH30072.03), 10% DMSO (Sigma #D2650) and stored at -135 0C. On the experimental day, HEK293-hGPR119 cells were thawn and diluted to 0.4xl06 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. After addition of HTRF reagents diluted in lysis buffer, the 96- or 384-well plates were incubated 1 hour, followed by measuring the fluorescence ratio at 665 nm / 620 nm. Test substances was diluted in compound buffer (Ix HBSS (Gibco Cat. no. 14025-049), 20 rnM Hepes (Gibco Cat. no.15630-056), 0.1% BSA, 2 mM IBMX (Sigma-Aldrich Cat. No. 17018, pH 7.4). The potency of the agonist was quantified by determining the concentration that caused 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 μM.
Hamster GPRl 19 Activity Assay
Agonists to the GPRl 19 receptor are characterized by measuring receptor-mediated stimulation of cyclic AMP in HIT-T 15 cells (Hamster beta-cell line, American Type Culture Collection) endogenously expressing the hamster GPRl 19. HIT-T15 cells are grown in suitable media (typically F 12 Kaighn's Nutrient Mixture Kaighn's modification supplemented with 10% Horse serum, 1.5 g/L sodium bicarbonate, 2.5% dialyzed and heat-inactivated Fetal Bovine Serum) as recommended by the provider. Cells are trypsinated, resuspended in growth media supplemented with 10 % DMSO, aliquoted and frozen as ready-to-use vials. 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).
Effects of GPRl 19 Agonists on Glucose-Stimulated Insulin Release
In vitro experiments
The effect of GPRl 19 agonists on glucose-stimulated insulin release is determined in isolated 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. On the experimental day, batches of three islets are preincubated in KRB (Rrebs-Ringer bicarbonate) buffer and 3.3 mM glucose for 30 min, 37 0C. Thereafter the batches with islets are incubated in 16.7 mM glucose and - -
KRB buffer supplemented with vehicle or test compounds for 60min at 37 0C. Aliquots of the medium will be frozen for measurement of insulin using a radioimmunoassay with rabbit ant-porcine insulin antibodies.
In vivo experiments
The effects of GPRl 19 agonists on glucose stimulated insulin release is determined in diabetic mice models (eg. Lepob/ob or diet-induced obese (DIO) mice) undergoing an oral glucose tolerance test. Briefly, overnight fasted mice is given either vehicle or test compound at desired doses via oral gavage. Based on the pharmacokinetic of the test compounds, a glucose boluse dose is delivered via oral gavage 30min-2hrs following the test compound. 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 heparinated tubes and centrifugation. For GLP-I and GIP pharmacodynamic studies, vehicle or test compounds are administered orally prior to glucose bolus dose. Blood is collected in tubes containing EDTA and a DPPIV inhibitor at desired time points. After centrifugation, plasma is collected and analysed for active GLP-I and GIP (using ELISA kit).
Effects of GPRl 19 Agonists on Incretin Secretion and Body Weight
In vivo experiments
The effect of GPRl 19 agonists on body weight is determined in diabetic and obese mice models, eg. Lepob/ob or diet-induced obese (DIO) mice. The food intake and body weight gain is measured during subchronic treatment with vehicle or test compound via oral gavage. At the end of the experiment, vena cava blood is collected and e.g. HbAIc, GLP-I, insulin, ALAT, ASAT are measured.

Claims

1. A compound of Formula (Ia)
Figure imgf000146_0001
or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer or JV-oxide thereof, wherein:
W, X and Y are each independently CH2, O, NH or N(CH3), provided that at least one of W and X is CH2; m is each independently 0 or 1 ;
R1 is -C(O)OR2, -C(O)R2, -C(O)NR2R3, -C(O)CH2NR2R3, -CH2C(O)NR2R3, -S(O)2R2, -C(O)C(O)R9 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;
Ar1 is phenyl or heteroaryl, each of which is optionally independently substituted in one or more positions with a substituent selected from: (a) CF3SO3,
(b) halogen selected from bromine, chlorine and fluorine,
(c) Ci-4-alkylsulfoximine,
(d) -S(O)R4,
(e) -S(O)2R4, (f) -S(O)2NR5R5,
(g) -NR6S(O)2R4,
(h) -CH2-NR6C(O)R4,
(i) -NR6C(O)R4,
O) -C(O)NR5R5, (k) -CH2-C(O)NR5R5, - -
(1) -C(O)R4,
(m) H2N-C(O)O-,
(n) CH3-NH-C(O)O-,
(o) (CHs)2NC(O)O-,
(P) CH3OC(O)NH-,
(q) C-heterocyclyl, optionally substituted with Ci_4-alkyl,
(r) N-heterocyclylcarbonylvinyl, wherein N-heterocyclyl is optionally substituted with Ci-4-alkyl,
(S) -CN,
(t) -OR8,
(u) -SCF3,
(v) -NO2,
(W) C-heterocyclylsulfonyl, optionally substituted with Ci_4-alkyl,
(x) -NR5R5,
(y) -C(OH)CH3CF3,
(z) [CF3CH3(OH)C]-Ci_6-alkyl,
(aa) cyano-Ci_6-alkyl,
(bb) guanidino,
(CC) amidino,
Figure imgf000147_0001
(ee) Ci_6-alkylthio,
(fit) Ci_4-alkoxy-Ci_4-alkyl,
(gg) fluoro-C i _4-alkyl,
(hh) C2_6-alkenyl,
(ϋ) fluoro-C2_4-alkenyl,
(D) hydroxy-C i _6-alkyl,
(kk) Ci_4-alkylsulfonyl-Ci_4-alkyl,
(H) hydroxy-C2_4-alkoxy-Ci_4-alkyl,
(mm) C2_3-acyl-Ci_3-alkyl,
(nn) C2_6-alkynyl,
(oo) C3_6-cycloalkyl,
(PP) hydroxy-C3_6-cycloalkyl,
(qq) fluoro-C3_6-cycloalkyl,
(IT) methyl-C3_6-cycloalkyl, (SS) C3_6-cycloalkyl-Ci_4-alkyl, wherein C3-6-cycloalkyl is optionally substituted with methyl,
(tt) C-heterocyclylcarbonyl, optionally substituted with Ci_4-alkyl,
(UU) C3_6-cycloalkylthio,
(W) R5R5N-Ci_2-alkyl,
(ww) l -(CH2)nC(O)OR7, wherein n is 0, 1, 2 or 3,
(XX) phenyl, and
(yy) heteroaryl, wherein phenyl or heteroaryl as substituent on Ar1 is optionally substituted in one or more positions with a substituent independently selected from the group Z1 consisting of:
(a) halogen selected from bromine, chlorine and fluorine,
(b) Ci_4-alkyl,
(c) hydroxy,
(d) Ci_4-alkoxy,
(e) -OCF3,
(f) -SCF3,
(g) -CN,
CO -C(OH)CH3CF3,
(i) hydroxy-C i _4-alkyl,
G) -CF3,
(k) -S(O)2CH3,
(1) -S(O)2NH2,
(m) -S(O)2NHCH3,
(n) -S(O)2N(CH3)2,
(o) -N(CH3)S(O)2CH3,
(P) -N(CH3)C(O)CH3,
(q) -C(O)NH2,
(r) -C(O)NHCH3,
(S) -C(O)N(CH3)2,
(t) -C(O)CH3,
(u) N-heterocyclylmethyl,
(v) N-heterocyclyl, optionally substituted with methyl,
(W) phenoxy, (x) -NH2,
(y) -NHCH3,
(z) -N(CHs)2, and
(aa) methoxycarbonyl;
R2 is selected from:
(a) d-e-alkyl,
(b) Ci_6-alkoxy-Ci_6-alkyl,
(C) hydroxy-C2-6-alkyl,
(d) fluoro-C2_6-alkyl,
(e) amino-C2_6-alkyl,
(f) Ci_3-alkylamino-C2_6-alkyl,
(g) di(Ci_3-alkyl)amino-C2_6-alkyl,
CO cyano-Ci_6-alkyl,
(i) Ci_6-alkylsulfonyl-C2_6-alkyl,
G) C2_3-acylamino-C2_4-alkyl,
(k) Ci_4-alkylthio-C2_4-alkyl,
(1) C2_4-acyl-Ci_4-alkyl,
(m) C3-6-alkynyl,
(n) C3-6-alkenyl,
(o) C3-7-cycloalkyl,
(P) C5_8-cycloalkenyl,
(q) C-heterocyclyl, optionally substituted with Ci_4-alkyl,
(r) C7_8-bicyclyl, optionally substituted with hydroxy,
(S) C7_8 -bicy c Iy lmethy 1,
(t) azabicyclyl, optionally substituted with hydroxy,
(u) C3_7-cycloalkyl-Ci_4-alkyl, wherein cycloalkyl is optionally substituted with methyl or hydroxy,
(v) Ci_6-alkylsulfonyl-C2_6-alkyl,
(W) C2_3-acyl-Ci_4-alkyl,
(x) diphenylmethyl,
(y) arylcarbonyl-C i _4-alkyl,
(z) heteroarylcarbonyl-C i _4-alkyl,
(aa) [CF3CH3(OH)C]-Ci-6-alkyl, (bb) Λ/-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl, (cc) C-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl, (dd) aminocarbonyl-C2-6-alkyl,
(ee) Ci_3-alkylaminocarbonyl-C2-6-alkyl, (ff) di(Ci_3-alkyl)aminocarbonyl-C2-6-alkyl, (gg) hydroxy-C2-4-alkoxy-C2-4-alkyl, (hh) hydroxy-C4-6-cycloalkyl, (ii) oxo-C4_6-cycloalkyl,
(jj) fluoro-C4_6-cycloalkyl, (kk) Ci_3-alkoxy-C4-6-cycloalkyl, (11) methyl-C3_6-cycloalkyl, (mm) oxo-Λ/-heterocyclyl-C2-4-alkyl, (nn) fluoro-Λ/-heterocyclyl-C2-4-alkyl,
(oo) amino-Λ/-heterocyclyl-C2-4-alkyl, (pp) hydroxy-Λ/-heterocyclyl-C2-4-alkyl, (qq) JV-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl, (rr) C-heterocyclyl-Ci_4-alkyl, wherein heterocyclyl is optionally substituted with methyl, (ss) aryl,
(tt) aryl-Ci_4-alkyl, (uu) aryl-C3-6-alkenyl, (w) aryl-C3_6-alkynyl,
(ww) aryloxymethyl, (xx) heteroaryl, (yy) heteroaryl-Ci_4-alkyl, (zz) heteroaryl-C3_6-alkenyl, and (aaa) heteroaryl-C3_6-alkynyl, wherein any aryl or heteroaryl residue, alone or as part of another group, is optionally independently substituted in one or more position with a substituent selected from the group Z1 as defined above; R3 is selected from:
(a) hydrogen,
(b) d.6-alkyl,
(c) fluoro-C2-6-alkyl, (d) hydroxy-C2-6-alkyl,
(e) Ci_6-alkoxy-C2-6-alkyl,
(f) amino-C2-6-alkyl,
(g) Ci_3-alkylamino-C2-6-alkyl, (h) di(Ci_3-alkyl)amino-C2-6-alkyl, (i) cyano-Ci_6-alkyl,
(J) Ci_6-alkylsulfonyl-C2-6-alkyl, (k) C2-3-acylamino-C2-4-alkyl, (1) Ci_4-alkylthio-C2-4-alkyl, and (m) C2-4-acyl-Ci_4-alkyl; or R2 and R3 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) Ci-3-alkyl, (cc) amino,
(dd) methylamino, (ee) dimethylamino, (ff) hydroxy-Ci-2-alkyl, and (gg) aminomethyl; ii) one or two oxo groups; or iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom;
R4 is independently selected from:
(a) Ci_6-alkyl,
(b) fluoro-Ci_6-alkyl,
(c) hydroxy-C2-6-alkyl, (d) Ci_4-alkoxy-C2-4-alkyl,
(e) C2-4-acyl-Ci_4-alkyl,
(f) carboxy-Ci_3-alkyl,
(g) C3-6-cycloalkyl, (h) oxo-C4-6-cycloalkyl,
(i) hydroxy-C4_6-cycloalkyl,
(j) fluoro-C4_6-cycloalkyl,
(k) methyl-Cs-β-cycloalkyl,
(1) Λ/-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(m) jV-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(n) oxo-Λ/-heterocyclyl-C2-4-alkyl,
(o) fluoro-Λ/-heterocyclyl-C2-4-alkyl, (p) hydroxy- jV-heterocyclyl-C2-4-alkyl,
(q) amino-jV-heterocyclyl-C2-4-alkyl,
(r) aminocarbonyl-C2-4-alkyl,
(s) Ci_3-alkylaminocarbonyl-C2-4-alkyl,
(t) di(Ci_3-alkyl)aminocarbonyl-C2-4-alkyl, (u) C2-3-acylamino-C2-4-alkyl,
(v) hydroxy-C2-4-alkoxy-C2-4-alkyl,
(w) C-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(x) C3_6-cycloalkyl-Ci_2-alkyl, wherein cycloalkyl is optionally substituted with methyl,
(y) amino-C2-4-alkyl,
(z) Ci_2-alkylamino-C2-4-alkyl,
(aa) di(Ci_2-alkyl)amino-C2-4-alkyl,
(bb) phenyl, and (cc) heteroaryl, wherein any phenyl or heteroaryl residue is optionally substituted in one or more positions with a substituent independently selected from the group Z2 consisting of:
(a) halogen selected from chlorine and fluorine,
(b) Ci_4-alkoxy, (C) hydroxymethyl,
(d) -CN,
(e) -CF3,
(f) d.4-alkyl,
(g) -OCF3, and
CO -C(O)CH3;
R5 is each independently selected from:
(a) hydrogen, (b) Ci_6-alkyl,
(c) C3-6-alkenyl,
(d) C3_6-cycloalkyl,
(e) methyl-C3_6-cycloalkyl,
(f) C3_6-cycloalkyl-Ci-4-alkyl, wherein cycloalkyl is optionally substituted with hydroxy or methyl,
(g) N-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(h) heteroaryl-Ci-4-alkyl, wherein heteroaryl is optionally substituted with methyl, (i) carboxy-Ci-3-alkyl,
(J) fluoro-C2-4-alkyl,
(k) amino-C2-6-alkyl,
(1) cyano-Ci_6-alkyl,
(m) hydroxy-C2-6-alkyl, (n) dihydroxy-C2-6-alkyl,
(o) Ci_4-alkoxy-C2-4-alkyl,
(p) Ci_4-alkylamino-C2-4-alkyl,
(q) di(Ci_4-alkyl)amino-C2-4-alkyl,
(r) aminocarbonyl-Ci_4-alkyl, (s) C2-3-acylamino-C2-4-alkyl,
(t) Ci_4-alkylthio-C2-4-alkyl,
(u) C2-4-acyl-Ci_4-alkyl, and
(v) Ci_4-alkylsulfonyl-Ci_4-alkyl, or two R5 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:
(a) hydroxy, (b) Ci-3-alkyl,
(c) amino,
(d) methylamino,
(e) dimethylamino,
(f) hydroxy-Ci-2-alkyl, and (g) amino methyl; ii) one or two oxo groups; or iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; or two R5 groups together with the nitrogen to which they are attached form the group 4-(pyrimidin-2-yl)piperazin- 1 -yl;
R6 is independently selected from: (a) hydrogen,
(b) Ci_4-alkyl, and
(c) hydroxy-C2-4-alkyl;
R7 is independently selected from: (a) hydrogen, and
(b) d-4-alkyl;
R8 is independently selected from:
(a) hydrogen, (b) d-6-alkyl,
(c) fluoro-Ci_6-alkyl,
(d) hydroxy-C2-6-alkyl,
(e) amino-C2-6-alkyl,
(f) Ci_3-alkylamino-C2-4-alkyl, - —
(g) di(Ci_3-alkyl)amino-C2-4-alkyl,
(h) Ci_4-alkylsulfonyl-C2-4-alkyl,
(i) JV-heterocyclyl-C^-alkyl, wherein heterocyclyl is optionally substituted with methyl, (j) C-heterocyclyl, optionally substituted with methyl,
(k) C2-3-acylamino-C2-4-alkyl, (1) [CF3CH3(OH)C]-C1.6-alkyl, (m) C3-6-cycloalkyl, (n) methyl-Cs-β-cycloalkyl, (o) C3_6-cycloalkyl-Ci_2-alkyl, wherein cycloalkyl is optionally substituted with methyl, (p) aryl, and (q) heteroaryl, wherein any aryl or heteroaryl residue is optionally independently substituted in one or two positions with a substituent selected from the group Z2 as defined above; and
R9 is aryl or heteroaryl, each of which is optionally substituted in one or more positions with a substituent independently selected from the group Z2 as defined above.
2. A compound according to claim 1 having Formula (Ib):
Figure imgf000155_0001
wherein W and X are each independently CH2 or O, provided that at least one of W and X is CH2; Y is CH2, O or NH; and
Ar1, Z1, Z2, R1 to R9 are as defined in claim 1.
3. A compound according to claim 1 or 2 having Formula (Ic):
Figure imgf000156_0001
wherein Z1, Z2, R1 to R6 are as defined in claim 1;
Ar1 is phenyl or heteroaryl, each of which is optionally substituted in one or two positions with a substituent independently selected from the group Z3 consisting of:
(a) CF3SO3,
(b) halogen selected from bromine, chlorine and fluorine, (c) Ci-4-alkylsulfoximine,
(d) -S(O)R4,
(e) -S(O)2R4,
(f) -S(O)2NR5R5,
(g) -NR6S(O)2R4,
CO -NR6C(O)R4,
(i) -CH2-NR6C(O)R4,
G) -C(O)NR5R5,
(k) -CH2-C(O)NR5R5,
(1) -C(O)R4, (m) H2N-C(O)O-,
(n) CH3-NH-C(O)O-,
(o) (CHs)2NC(O)O-,
(p) -NHC(O)OCH3,
(q) C-heterocyclyl, optionally substituted with methyl, (r) N-heterocyclylcarbonylvinyl, wherein N-heterocyclyl is optionally substituted with methyl,
(s) -CN,
(t) -OR8,
(u) -SCF3, (v) nitro, - -
(w) C-heterocyclylsulfonyl, optionally substituted with methyl,
(x) -NR5R5,
(y) -C(OH)CH3CF3,
(z) cyano-Ci_6-alkyl, (aa) guanidino,
(bb) d.6-alkyl,
(cc) Ci_3-alkylthio,
(dd) Ci_4-alkoxy-Ci_4-alkyl,
(ee) fluoro-Ci_4-alkyl, (ff) C2-6-alkenyl,
(gg) fluoro-C2-4-alkenyl,
(hh) hydroxy-Ci_6-alkyl,
(ii) Ci_4-alkylsulfonyl-Ci_4-alkyl,
(jj) hydroxy-C2-4-alkoxy-Ci_4-alkyl, (kk) C2-3-acyl-Ci_3-alkyl,
(11) C2_6-alkynyl,
(mm) C3_6-cycloalkyl,
(nn) hydroxy-C3_6-cycloalkyl,
(oo) fluoro-C3_6-cycloalkyl, (pp) methyl-C3_6-cycloalkyl,
(qq) C-heterocyclylcarbonyl, optionally substituted with methyl,
(rr) C3_6-cycloalkyl-Ci_4-alkyl,
(ss) R5R5N-Ci_2-alkyl,
(tt) -(CH2)nC(O)OH, wherein n is 1, 2 or 3, and (uu) heteroaryl, wherein any heteroaryl residue as substituent on Ar1 is optionally substituted in one or more positions with a substituent independently selected from the group Z2 as defined in claim 1 ;
R8 is independently selected from:
(a) hydrogen,
(b) Ci-4-alkyl,
(c) CF3,
(d) C3_5-cycloalkyl, (e) methyl-Cs-s-cycloalkyl,
(f) di(Ci_3-alkyl)amino-C2-3-alkyl, and
(g) C-heterocyclyl, optionally substituted with methyl;
R9 is phenyl which is optionally substituted in one or two positions with a substituent independently selected from the group Z2 as defined in claim 1.
4. A compound according to claim 1 or 2 having Formula (Id):
Figure imgf000158_0001
wherein Z1, Z2, R1 to R6 are as defined in claim 1; R8 and R9 are as defined in claim 3;
Ar1 is phenyl which is optionally substituted in one or two positions with a substituent independently selected from the group Z3 as defined in claim 3.
5. A compound according to any one of claims 1 to 4, which is selected from:
• benzyl 4-(6- {4-[(dimethylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; • benzyl 4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine-l- carboxylate;
• benzyl 4-(6-quinolin-5-yl-4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• 4- {2-[ 1 -(3,4-dichlorobenzoyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl} -N,N- dimethylbenzamide; • 4-(2- { 1 -[(2,4-difluorophenyl)acetyl]piperidin-4-yl} -4H- 1 ,3-benzodioxin-6-yl)-
JV,iV-dimethylbenzamide;
• JV, JV-dimethyl-4- [2-( 1 - { [3 -(trifluoromethyl)phenyl] acetyl} piperidin-4-yl)-4/f- 1,3- benzodioxin-6-yl]benzamide;
• 4-(2- { 1 -[(4-methoxyphenyl)acetyl]piperidin-4-yl} -4H- 1 ,3-benzodioxin-6-yl)-iV,jV- dimethylbenzamide; — o —
• 4-(2- { 1 -[(4-cyanophenyl)acetyl]piperidin-4-yl} -4H- 1 ,3-benzodioxin-6-yl)-N,N- dimethylbenzamide;
• 4- {2-[ 1 -(lH-indol-3-ylacetyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl} -N5N- dimethylbenzamide; • N,N-dimethyl-4-(2- { 1 -[(1 -methyl- lH-indol-3-yl)acetyl]piperidin-4-yl} -4H- 1 ,3- benzodioxin-6-yl)benzamide;
• 4- {2-[ 1 -(cyclohexylacetyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl} -N5N- dimethylbenzamide;
• N,N-dimethyl-4- {2-[ 1 -(3-methyl-3-phenylbutanoyl)piperidin-4-yl]-4H- 1,3- benzodioxin-6-yl}benzamide;
• 4-(2- { 1 -[3-(4-methoxyphenyl)propanoyl]piperidin-4-yl} -4H- 1 ,3-benzodioxin-6- yl)-N,N-dimethylbenzamide;
• 4-(2- { 1 -[3-(3-chloro-4-methoxyphenyl)propanoyl]piperidin-4-yl} -4H- 1,3- benzodioxin-6-yl)-N,N-dimethylbenzamide; • 4-(2- { 1 -[3-(4-hydroxyphenyl)propanoyl]piperidin-4-yl} -4H- 1 ,3-benzodioxin-6- yl)-N,N-dimethylbenzamide;
• 4-(2- { 1 -[3-(lH-indol-3-yl)propanoyl]piperidin-4-yl} -4H- 1 ,3-benzodioxin-6-yl)- N,N-dimethylbenzamide;
• 4- {2-[ 1 -(3-cyclohexylpropanoyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl} -N5N- dimethylbenzamide;
• 4-(2- { 1 -[4-(4-fluorophenyl)butanoyl]piperidin-4-yl} -4H- 1 ,3-benzodioxin-6-yl)- N,N-dimethylbenzamide;
• N,N-dimethyl-4- {2-[ 1 -(4-oxopentanoyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6- yl}benzamide; • N,N-dimethyl-4- {2-[ 1 -(4-oxo-4-pyrrolidin- 1 -ylbutanoyl)piperidin-4-yl]-4H- 1,3- benzodioxin-6-yl}benzamide;
• benzyl 4-(6- {4-[(diethylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• benzyl 4-(6- {4-[(4-methylpiperidin- 1 -yl)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2- yl)piperidine-l -carboxylate;
• benzyl 4-(6- {4-[(4-oxopiperidin- 1 -yl)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2- yl)piperidine- 1 -carboxylate;
• benzyl 4- {6-[5-(methylsulfonyl)pyridin-2-yl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine- 1 -carboxylate; • 1 -(2-furoyl)-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine;
• 1 -[(4-fluorophenoxy)acetyl]-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzo- dioxin-2-yl}piperidine; • 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - 1 -(lH-pyrrol-2-yl- carbonyl)piperidine;
• 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - 1 -(1/f-tetrazol- 1 -yl- acetyl)piperidine;
• 2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]pyridine;
• 4-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]pyridine;
• 2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyljpyrazine; • 6-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyljquinoxaline;
• 1 -(4-isopropoxybenzoyl)-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2- yl}piperidine;
• 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - 1 -(2-naphthoyl)- piperidine;
• 1 -benzoyl-4- {6-[4-(methylsulfonyl)phenyl]-4/f- 1 ,3-benzodioxin-2-yl}piperidine;
• 5-methyl-2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidin- 1 -yl)carbonyl]phenol;
• 5-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]-2-phenoxypyridine;
• 1 -(diphenylacetyl)-4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine;
• 5-isopropoxy-2-[(4-{6-[4-(methylsulfonyl)phenyl]-4/f-l,3-benzodioxin-2-yl}- piperidin- 1 -yl)carbonyl]pyridine; • 4-{6-[4-(methylsulfonyl)phenyl]-4/f-l,3-benzodioxin-2-yl}-l-(3,3,3-trifluoro- propanoyl)piperidine;
• 2-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]pyridin-3-ol; — —
• 4- {6-[4-(methylsulfonyl)prienyl]-4H- 1 ,3-benzodioxin-2-yl} - 1 -propionyl- piperidine;
• 1 -[(7-methoxy- 1 -benzofuran-2-yl)carbonyl]-4- {6-[4-(methylsulfonyl)prienyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine; • dimethyl{3-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidin- 1 -yl)carbonyl]phenyl} amine;
• 2-[(4- {6-[4-(methylsulfonyl)prienyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbony ljpheno 1;
• 2-(4- {6-[4-(methylsulfbnyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)-2- oxo-1-phenylethanone;
• 1 -methyl-4-[3-(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidin- 1 -yl)-3-oxopropyl]piperazine;
• 1 -methyl-4- {4-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidin- 1 -yl)carbonyl]phenyl}piperazine; « 1 -(methoxyacetyl)-4- {6-[4-(methylsulfonyl)prienyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine;
• 3,5-difluoro-2-[(4-{6-[4-(methylsulfonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidin- 1 -yl)carbonyl]pyridine;
• 4- {4-[(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidin- 1 -yl)- carbonyl]benzyl}morpholine;
• 6-bromo-2-[(4- {6-[4-(methylsulfonyl)phenyl]-4/f- 1 ,3-benzodioxin-2-yl} - piperidin- 1 -yl)carbonyl]pyridin-3-ol;
• benzyl 4-(6- {4-[(methylsulfonyl)amino]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; • benzyl 4-[6-(4-{[(2-morpholin-4-ylethyl)amino]sulfonyl}phenyl)-4H-l,3- benzodioxin-2-yl]piperidine- 1 -carboxylate;
• benzyl 4- {6-[4-(methylsulfonyl)-2-nitrophenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine- 1 -carboxylate;
• benzyl 4- {6-[2-amino-4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine- 1 -carboxylate;
• benzyl 4-{6-[2-{[2-(dimethylamino)ethyl]amino}-4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 -carboxylate;
• benzyl 4-{6-[2-{ [2-(isopropylamino)ethyl] amino } -4-(methylsulfonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 -carboxylate; - -
• benzyl 4-(6- {4-(methylsulfonyl)-2-[(2-morpholin-4-ylethyl)amino]phenyl} -4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• benzyl 4- {6-[2-[2-(dimethylamino)ethoxy]-4-(methylsulfonyl)phenyl]-4H- 1,3- benzodioxin-2-yl}piperidine- 1 -carboxylate; • N,N-diethyl-2-(4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidin- 1 -yl)acetamide;
• 1 -benzoyl-4- {(2R *)-6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine;
• 1 -benzoyl-4- {(25'*)-6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine;
• (1 -methylcyclopropyl)methyl 4-(6- {4-[(methylamino)carbonyl]phenyl} -4Η- 1,3- benzodioxin-2-yl)piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4-(6- {4-[(ethylamino)carbonyl]phenyl} -4H- 1,3- benzodioxin-2-yl)piperidine- 1 -carboxylate; • (l-methylcyclopropyl)methyl 4-(6-{4-[(allylamino)carbonyl]phenyl}-4H-l,3- benzodioxin-2-yl)piperidine- 1 -carboxylate;
• (l-methylcyclopropyl)methyl 4-(6-{4-[(cyclopropylamino)carbonyl]phenyl}-4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4- [6-(4- { [(2-hydroxyethyl)amino] carbonyl} - phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4- [6-(4- { [(3 -hydroxypropyl)amino] carbonyl} - phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4- [6-(4- { [(2 -methoxyethyl)amino] carbonyl} - phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate; • (l-methylcyclopropyl)methyl 4-[6-(4-{[(2-hydroxy-l,l-dimethylethyl)amino]- carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4-(6- {4-[(3-hydroxyazetidin- 1 -yl)carbonyl]phenyl} ■ 4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• (1 -methylcyclopropyl)methyl 4-(6- {4-[(4-methylpiperazin- 1 -yl)carbonyl]phenyl} ■ 4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• (l-methylcyclopropyl)methyl 4-{6-[4-({[2-(2-furyl)ethyl]amino}carbonyl)- phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 -carboxylate;
• tert-butyi 4- {6-[4-(methylsulfonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 -carboxylate; — —
• tert-butyl A- {6-[4-(aminocarbonyl)phenyl]-4H- 1 ,3-benzodioxin-2-yl}piperidine- 1-carboxylate;
• tert-butyl 4-(6- {4-[(dimethylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; • tert-butyl 4-{6-[4-(morpholin-4-ylcarbonyl)phenyl]-4H-l,3-benzodioxin-2-yl}- piperidine- 1 -carboxylate;
• 2-( {4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]phenyl} sulfonyl)- ethanol;
• 2-( {4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]phenyl} sulfonyl)- ethanamine;
• tert-butyl 4-(6- {4-[(methylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(ethylamino)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; • tert-butyl 4-(6-{4-[(allylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(cyclopropylamino)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2- yl)piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4H-l,3-benzo- dioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(4- {[(2-methylprop-2-en- 1 -yl)amino]carbonyl}phenyl)-4H- 1,3- benzodioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(but-3-en- 1 -ylamino)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2- yl)piperidine- 1 -carboxylate; • tert-butyl 4-[6-(4-{[(3-hydroxypropyl)amino]carbonyl}phenyl)-4H-l,3-benzo- dioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)-4H-l,3-benzo- dioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-{6-[4-({[(l -hydroxycyclopropyl)methyl] amino } carbonyl)phenyl] -4H- 1 ,3-benzodioxin-2-yl}piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(4- {[(2-hydroxy- 1 , 1 -dimethylethyl)amino]carbonyl}phenyl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {4-[(3-hydroxyazetidin- 1 -yl)carbonyl]phenyl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate; - -
• tert-butyi 4-(6- {4-[(4-methylpiperazin- 1 -yl)carbonyl]phenyl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyi 4- {6-[4-( {[2-(2-flιryl)ethyl] amino} carbonyl)phenyl]-4/f- 1 ,3-benzo- dioxin-2-yl}piperidine- 1 -carboxylate; • 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-methylbenzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-ethylbenzamide;
• Λ/-allyl-4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-cyclopropyl- benzamide; • 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-(2-hydroxyethyl)- benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-Λ/-(2-methylprop-2-en- l-yl)benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-N-but-3-en-l-yl- benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-N-(3-hydroxypropyl)- benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-N-(2-methoxyethyl)- benzamide; • 4- [2-( 1 -benzoylpiperidin-4-yl)-4H- 1 ,3 -benzodioxin-6-yl] -N- [( 1 -hydroxy- cyclopropyl)methyl]benzamide;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-N-(2-hydroxy-l,l- dimethylethyl)benzamide;
• 1 - {4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]benzoyl} azetidin-3- ol;
• 1 - {4-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]benzoyl} -4-methyl- piperazine;
• 4-[2-(l-benzoylpiperidin-4-yl)-4H-l,3-benzodioxin-6-yl]-N-[2-(2-furyl)ethyl]- benzamide; • ethyl 4-(6-{4-[(methylamino)carbonyl]phenyl}-4H-l,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate;
• ethyl 4-(6- {4-[(ethylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; - -
• ethyl 4-(6- {4-[(allylamino)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2-yl)piperidine- 1-carboxylate;
• ethyl 4-(6- {4-[(cyclopropylamino)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2-yl)- piperidine- 1 -carboxylate; • ethyl 4-[6-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin-2- yl]piperidine- 1 -carboxylate;
• ethyl 4-[6-(4- {[(2-methylprop-2-en- 1 -yl)amino]carbonyl}phenyl)-4H- 1 ,3-benzo- dioxin-2-yl]piperidine- 1 -carboxylate;
• ethyl 4-(6- {4-[(but-3-en- 1 -ylamino)carbonyl]phenyl} -4H- 1 ,3-benzodioxin-2-yl)- piperidine-1 -carboxylate;
• ethyl 4-[6-(4-{[(3-hydroxypropyl)amino]carbonyl}phenyl)-4H-l,3-benzodioxin- 2-yl]piperidine- 1 -carboxylate;
• ethyl 4- [6-(4- { [(2-methoxyethyl)amino] carbonyl} phenyl)-4H- 1 ,3 -benzodioxin-2- yl]piperidine- 1 -carboxylate; • ethyl 4-{6-[4-({[(l-hydroxycyclopropyl)methyl]amino}carbonyl)phenyl]-4H-l,3- benzodioxin-2-yl}piperidine- 1 -carboxylate;
• ethyl 4-[6-(4- {[(2-hydroxy- 1 , 1 -dimethylethyl)amino]carbonyl}phenyl)-4H- 1,3- benzodioxin-2-yl]piperidine- 1 -carboxylate;
• ethyl 4-(6- {4-[(3-hydroxyazetidin- 1 -yl)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2- yl)piperidine-l -carboxylate;
• ethyl 4-(6- {4-[(4-methylpiperazin- 1 -yl)carbonyl]phenyl} -AH- 1 ,3-benzodioxin-2- yl)piperidine- 1 -carboxylate;
• ethyl 4- {6-[4-( {[2-(2-furyl)ethyl] amino} carbonyl)phenyl]-4H- 1 ,3-benzodioxin-2- yl}piperidine- 1 -carboxylate; • ethyl 4-[6-(4-{[2-(hydroxymethyl)morpholin-4-yl]carbonyl}phenyl)-4H-l,3- benzodioxin-2-yl]piperidine- 1 -carboxylate;
• 3-(3- {2-[ 1 -(tert-butoxycarbonyl)piperidin-4-yl]-4/f- 1 ,3-benzodioxin-6-yl} - isoxazol-5-yl)propanoic acid;
• [(5- {2-[ 1 -(tert-butoxycarbonyl)piperidin-4-yl]-4/f- 1 ,3-benzodioxin-6-yl} -2- furoyl)amino] acetic acid;
• tert-bvXy\ A- {6-[6-(methylsulfonyl)pyridin-3-yl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine- 1 -carboxylate;
• tert-bvXy\ A- {6-[5-(methylsulfonyl)pyridin-2-yl]-4H- 1 ,3-benzodioxin-2-yl} - piperidine- 1 -carboxylate; — —
• tert-butyl 4-{6-[4-(lH-tetrazol-5-yl)phenyl]-4H-l,3-benzodioxin-2-yl}piperidine- 1-carboxylate;
• tert-butyl 4- [6-(2- { [amino(imino)methyl]amino } -4-methyl- 1 ,3 -thiazo 1-5 -yl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate; • tert-butyl 4-(6-pyridin-4-yl-4H-l,3-benzodioxin-2-yl)piperidine-l -carboxylate;
• tert-butyl 4-(6-pyridin-3-yl-4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {5-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-2-yl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4- {6-[6-(morpholin-4-ylcarbonyl)pyridin-3-yl]-4H- 1 ,3-benzodioxin-2- yl}piperidine-l -carboxylate;
• tert-butyl 4-(6- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3-yl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4- {6-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]-4H- 1 ,3-benzodioxin-2- yl}piperidine- 1 -carboxylate; • tert-butyl 4-(6-{5-[(4-methylpiperazin-l-yl)carbonyl]-2-furyl}-4H-l,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {5-[(lii)-3-(4-methylpiperazin- 1 -yl)-3-oxoprop- 1 -en- 1 -yl]-2- thienyl} -AH- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6-{5-[(lE)-3-morpholin-4-yl-3-oxoprop-l-en-l-yl]-2-thienyl}-4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-(6- {5-[(4-pyrimidin-2-ylpiperazin- 1 -yl)carbonyl]pyridin-2-yl} -4H- 1 ,3-benzodioxin-2-yl)piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(5- {[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}pyridin-2- yl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate; • tert-butyl 4-[6-(5-{[4-(2-hydroxyethyl)piperazin-l-yl]carbonyl}pyridin-2-yl)-4H-
1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• tert-butyl 4-[6-(6- {[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}pyridin-3- yl)-4H- 1 ,3-benzodioxin-2-yl]piperidine- 1 -carboxylate;
• ethyl 4-(6- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3-yl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• isopropyl 4-(6- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3-yl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate;
• ethyl 4-(6- {5-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-2-yl} -4H- 1 ,3-benzo- dioxin-2-yl)piperidine- 1 -carboxylate; — —
• 1 -( {5-[2-(l -benzoylpiperidin-4-yl)-4H- 1 ,3-benzodioxin-6-yl]pyridin-2-yl} - carbonyl)-4-methylpiperazine;
• 1 -[(5- {2-[ 1 -(2-ethylbutanoyl)piperidin-4-yl]-4H- 1 ,3-benzodioxin-6-yl}pyridin-2- yl)carbonyl]-4-methylpiperazine; • 2-[4-(6- {5-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-2-yl} -AH- 1 ,3-benzodioxin-
2-yl)piperidin- 1 -yljpyrimidine;
• tert-butyl 4-{7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H-l,4-benzoxazin-3-yl}- piperidine- 1 -carboxylate;
• 3 - [ 1 -(cyclohexylacetyl)piperidin-4-yl] -7- [4-(methylsulfonyl)phenyl] -3 ,4-dihydro- 2H-l,4-benzoxazine; and
• 3-(l-benzoylpiperidin-4-yl)-7-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2H-l,4- benzoxazine.
6. A compound according to any one of claims 1 to 5 for use in therapy.
7. A compound according to any one of claims 1 to 5 for use in the treatment or prophylaxis of disorders relating to GPRl 19 activity, wherein said disorders are selected from the group consisting of 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.
8. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment or prophylaxis of disorders relating to GPRl 19 activity, wherein said disorders are selected from the group consisting of 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.
9. A method for the treatment or prophylaxis of disorders relating to GPRl 19 activity which comprises administering to a mammal, including man, in need of such — —
treatment an effective amount of a compound according to any one of claims 1 to 5, wherein said disorders relating to GPRl 19 activity are selected from the group consisting of 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.
10. A pharmaceutical formulation containing a compound according to any one of claims 1 to 5 as active ingredient in combination with a pharmaceutically acceptable diluent or carrier.
11. The pharmaceutical formulation according to claim 10 for use in the treatment or prophylaxis of disorders relating to GPRl 19 activity, wherein said disorders are selected from the group consisting of 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.
12. Use of a compound according to any one of claims 1 to 5, in combination with a DPP-IV inhibitor, in the manufacture of a medicament for the treatment or prophylaxis of disorders relating to GPRl 19 activity, wherein said disorders are selected from the group consisting of 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.
13. A method for the treatment or prophylaxis of disorders relating to GPRl 19 activity which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to any one of claims 1 to 5 in combination with a DPP-IV inhibitor, wherein said disorders relating to GPRl 19 activity are selected from the group consisting of Type 1 diabetes, Type 2 diabetes, — oo —
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.
14. The pharmaceutical formulation according to claim 10 which in addition comprises a DPP-IV inhibitor.
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