WO2009106565A1 - Agonists of gpr119 - Google Patents

Abstract

The application relates to compounds of Formula (Ia): and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers and 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

AGONISTS OF GPR119

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-msulm-dependent diabetes mellitus or NIDDM) Type 2 diabetes accounts for approximately 90% of all diabetic cases. Type 2 diabetes is a serious progressive disease that results in the development of microvascular complications (e.g. retinopathy, neuropathy, nephropathy) as well as macrovascular complications (e.g. accelerated atherosclerosis, coronary heart disease, stroke) More than 75% of people with Type 2 diabetes die of cardiovascular diseases.

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 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 dyshpidemia, hypertension, endothelial dysfunction, reduced fibrinolysis, and chronic systemic inflammation - that together are responsible for the increased cardiovascular risk. Current antidiabetic therapy is targeting the defects mentioned above. 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 gam due to fluid retention and increase in total body fat. An earlier drug in this class, troglitazone, was withdrawn due to rare but serious cases of hepatotoxicity. Current therapies have limited durability and/or significant side effects.

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. Two 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 m 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 Riskfactors 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 mcretms, Glucose-dependent Insulmotropic 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 m pancreas and gastrointestinal tract Activation of GPRl 19 by lysophosphatidylcholme (LPC) induces glucose-dependent msulm secretion from pancreatic beta-cells (Soga et al., Biochem. Biophys. Res Commun. 326, 744-751, 2005). GPRl 19 agonists stimulate insulin secretion m rat islets and reduce blood glucose in diabetic LepΛ^ mice (WO 2004/065380 and Chu et al , Endocrinology 148, 2601-9, 2007) GPRl 19 agonists enhance the release of the lncretins, GLP-I and GIP in mice models and in GLUTag cells, which is a model used to investigate the function of intestinal L-cells (Chu et al , Endocrinology Jan 17, 2008)

Another endogenous ligand for GPRl 19, oleoylethanolamide (OEA), and a small molecule GPRl 19 agonist, PSN632408, both suppress food intake and reduce body weight gam in rat (Overton et al., Cell Metabolism 3, 167-175, 2006). Taken together, these data suggest that GPRl 19 is an interesting target for treating diabetes and/or obesity.

WO 2004/065380, WO 2004/076413, WO 2005/007647, WO 2005/007658 and WO 2005/121121 disclose compounds that are modulators of the Rup3 receptor, also referred to as SNORF25 (WO 00/50562) or as GPRl 19 (Fredriksson et al., FEBS Lett, 554, 381- 388, 2003), and which inter alia may be used for the treatment of metabolic disorders and complications thereof, such as diabetes and obesity

WO 2005/061489, WO 2006/067531, WO 2006/067532 and WO 2006/070208 disclose compounds that are agonists of GPRl 16, also referred to as SNORF25 or as GPRl 19 (see Overton et al, Cell Metabolism 3, 167-175, 2006), and which mter alia may be used for the treatment of metabolic disorders and complications thereof, such as diabetes and obesity. WO 2006/076231 discloses a synergistic effect of a GPRl 19 agonist in combination with a DPP-IV inhibitor, m lowering elevated glucose levels m mice. 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 wildtype mice.

DISCLOSURE OF THE INVENTION

It has surprisingly been found that compounds of the general Formula (Ia) to (Ic) are active as agonists of GPRl 19 and are potentially useful in the treatment or prophylaxis of disorders relating to GPRl 19 Examples of such disorders include Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperhpidemia, hypercholesterolemia, dyshpidemia, syndrome X, obesity, hypertension, chronic systemic mflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis

In a first aspect, the present invention provides a compound of Formula (Ia),

or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer or N-oxide thereof, wherein:

A is CH₂, O, NR¹⁰, C(O), S, S(O) or S(O)₂;

B is CH₂, O, NR¹⁰, C(O), S, S(O) or S(O)₂, provided that (i) when B is O, C(O), S, S(O) or S(O)₂, then A is CH₂, and (ii) when B is NR¹⁰, then A is CH₂ or CO; D is N, C or CR¹¹, provided that D must be CR¹¹ and said R¹¹ must be hydrogen or methyl when B is selected from O, NR¹⁰, C(O), S, S(O) and S(O)₂;

— is a single bond when D is N or CR¹¹ or a double bond when D is C;

E and G are independently Ci_3-alkylene, each optionally substituted with a substituent independently selected from the group consisting of Ci_₃-alkyl, Ci_₄-alkoxy, carboxy, fluoro-Ci_3-alkyl, hydroxy, hydroxymethyl, and fluoro, provided that the ring formed by D, E, N and G has not more than 7 ring atoms, and further provided that the said ring has 6 or 7 ring atoms when D is N, and yet further provided that the total number of substituents on E and G independently is not more than 2;

R¹ is C(O)OR², C(O)R², S(O)₂R², C(O)NR²R³ or -CH₂-C(O)NR²R³; 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 chlorine, bromine and fluorine,

(d) -S(O)IC,

(e) -S(O)₂R⁴,

(f) -S(O)₂NR⁵R⁵,

(g) -NR⁶S(O)₂R⁴,

(h) -CH₂-NR⁶C(O)R⁴,

(i) -NR⁶C(O)R⁴,

Ci) C(O)NR⁵R⁵,

(k) -CH₂-C(O)NR⁵R⁵,

(1) -C(O)R⁴,

(m) H₂N-C(O)O-,

(n) CH₃-NH-C(O)O-,

(o) (CH₃)₂NC(O)O-,

(P) CH₃OC(O)NH-,

(q) C-heterocyclyl, optionally substituted with Ci-4-alkyl, ω -CN,

(s) -OR⁸,

(t) -SCF₃,

(u) NO₂,

(v) C-heterocyclylsulfonyl, optionally substituted with Ci-₄-alkyl,

(w) -NR⁵R⁵,

W -C(OH)CH₃CF₃,

(y) [CF₃CH₃(OH)C]-C₁_₆-alkyl,

(z) cyano-Ci-₆-alkyl,

(aa) guanidino,

(bb) amidino,

(cc) Cw-alkyl,

(dd)

₄-alkyl,

(ee) fluoro-Ci_₄-alkyl,

(ff) C₂_₆-alkenyl, (gg) fluoro-C₂-₄-alkenyl,

(hh) hydroxy-Ci__θ-alkyl,

(ii) C_M-alkylsulfonyl-Ci_₄-alkyl,

(]j) hydroxy-C₂-₄-alkoxy-Ci_4-alkyl, (kk) C₂_₃-acyl-Ci.₃-alkyl,

(11) C^-alkynyl,

(mm) hydroxy-C₃_₆-cycloalkyl,

(nn) fluoro-C^-cycloalkyl,

(00) methyl-Q-₆-cycloalkyl, (pp) C-heterocyclylcarbonyl, optionally substituted with Ci-₄-alkyl,

(qq) C_3-6-cycloalkyl,

(rr) C₃-₆-cycloalkyl-Ci-₄-alkyl,

(ss) R⁵R⁵N-Ci_2-alkyl,

(tt) -C(O)OR⁷, (uu) -CH₂C(O)OR⁷,

(w) phenyl, and

(ww) heteroaryl, wherein phenyl or heteroaryl as substituent on Ar¹ is optionally substituted m one or more positions with a substituent independently selected from the group Z¹ consisting of (a) halogen selected from chlorine and fluorine,

(b) Ci-4-alkyl,

(c) hydroxy,

(d) Ci ₄-alkoxy,

(e) -OCF₃, (f) -SCF₃,

(g) -CN,

(h) -C(OH)CH₃CF₃,

(1) hydroxy-Ci_₄-alkyl,

Ci) -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(CH₃)₂, (t) -C(O)CH₃,

(u) -NH₂,

(v) -NHCH₃,

(w) -N(CH₃)₂, and

(x) methoxycarbonyl;

R² is selected from:

(a) Ci-6-alkyl,

(b) Ci_6-alkoxy-C₂-6-alkyl,

(c) hydroxy-Cz 6-alkyl, (d) fiuoro-C₂-₆-alkyl,

(e) C₃_₆-alkynyl,

(f) C₃_₆-alkenyl,

(g) C₃-₇-cycloalkyl, (h) Cs-₈-cycloalkenyl, (i) NR⁹R⁹, provided that R¹ is not selected from C(O)OR², C(O)NR²R³ and

-CH₂-C(O)NR²R³,

(j) C-heterocyclyl, optionally substituted with Ci_₄-alkyl,

(k) Cη ₈-bicyclyl, optionally substituted with hydroxy,

(1) Cy-s-bicyclylmethyl, (m) azabicyclyl, optionally substituted with hydroxy,

(n) C₃_₇-cycloalkyl-Ci_₄-alkyl, wherein cycloalkyl is optionally substituted with methyl,

(o) Ci_₆-alkylsulfonyl-C₂_₆-alkyl,

(p) C₂-₃-acyl-Ci_₄-alkyl, (q) arylcarbonyl-Ci_₄-alkyl,

(r) heteroarylcarbonyl-Ci_₄-alkyl,

(s) [CF₃CH₃(OH)C]-Ci ₆-alkyl,

(t) N-heterocyclylcarbonyl-C₂_₄-alkyl, wherein heterocyclyl is optionally substituted with methyl, (u) C-heterocyclylcarbonyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl,

(v) aminocarbonyl-C2 6-alkyl,

(w) Ci 3-alkylammocarbonyl-C2 6-alkyl, (x) di(Ci 3-alkyl)ammocarbonyl-C₂ 6-alkyl,

(y) hydroxy-C_{2 4}-alkoxy-C_{2 4}-alkyl,

(z) hydroxy-C₄ 6-cycloalkyl,

(aa) 0X0-C_{4 6}-cycloalkyl,

(bb) fluoro-C₄ g-cycloalkyl, (cc) Ci 3-alkoxy-C₄ 6-cycloalkyl,

(dd) methyl-C_{3 6}-cycloalkyl,

(bb) oxo-N-heterocyclyl-C₂^)-alkyl,

(cc) fluoro-N-heterocyclyl-C2 4-alkyl,

(dd) ammo-/V-heterocyclyl-C_{2 4}-alkyl, (ee) hydroxy-Λ^r-heterocyclyl-C_{2 4}-alkyl,

(11) N-heterocyclyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl,

(jj) C heterocyclyl Ci ₄ alkyl, wherein heterocyclyl is optionally substituted with methyl, (kk) aryl,

(11) aryl-Ci ₄-alkyl,

(mm) aryl-C3 6-alkenyl,

(nn) aryl-C_{3 6}-alkynyl,

(00) heteroaryl, (pp) heteroaryl-Ci ₄-alkyl,

(qq) heteroaryl-C_{3 6}-alkenyl, and

(rr) heteroaryl C_{3 6} alkynyl, wherein any aryl or heteroaryl residue, alone or as part of another group, is optionally independently substituted m one or more position with a substituent selected from the group Z¹ as defined above,

R³ is selected from

(a) hydrogen,

(b) Ci ₆-alkyl, (c) fluoro-C₂-₆-alkyl,

(d) hydroxy-C₂-₆-alkyl,

(e) Ci_₆-alkoxy-C₂-₆-alkyl,

(f) amino-C₂-5-alkyl, (g) Ci_₃-alkylamino-C₂-₆-alkyl,

(h) di(Ci_₃-alkyl)amino-C₂-₆-alkyl,

(i) cyano-Ci_₆-alkyl, and

(j) Ci_₆-alkylsulfonyl-C₂-₆-alkyl; ndependently selected from:

(a) d_₆-alkyl,

(b) fluoro-Ci_₆-alkyl,

(c) hydroxy-C₂-6-alkyl,

(d) Ci ₄-alkoxy-C_{2 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) N-heterocyclylcarbonyl-C₂-₄-alkyl, wherein heterocyclyl is optionally substituted with methyl,

(m) oxo-N-heterocyclyl-C₂^-alkyl, (n) fluoro-N-heterocyclyl-C₂-₄-alkyl,

(o) hydroxy-N-heterocyclyl-C₂-₄-alkyl,

(p) ammo-Λ^r-heterocyclyl-C₂-₄-alkyl,

(q) aminocarbonyl-C₂-₄-alkyl,

(r) Ci_₃-alkylaminocarbonyl-C₂ -₄-alkyl, (s) di(Ci_₃-alkyl)aminocarbonyl-C₂-₄-alkyl,

(t) C₂-3-acylamino-C₂-₄-alkyl,

(u) hydroxy-C_{2 4}-alkoxy-C_{2 4}-alkyl,

(v) C-heterocyclylcarbonyl-C₂ -₄-alkyl, wherein heterocyclyl is optionally substituted with methyl, (w) C₃_₆-cycloalkyl-Ci_₂-alkyl,

(x) amino-C₂-₄-alkyl,

(y) Ci_₂-alkylamino-C₂-₄-alkyl,

(z) di(Ci_₂-alkyl)amino-C₂-₄-alkyl, (aa) phenyl, and

(bb) 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) C_{1 4}-alkyl, (g) -OCF₃, and

(h) -C(O)CH₃;

R⁵ is each independently selected from:

(a) hydrogen, (b) Ci-6-alkyl,

(c) C₃_₄-cycloalkyl,

(d) fluoro-C₂-₄-alkyl,

(e) amino-C₂ β-alkyl,

(f) cyano-Ci-₆-alkyl, (g) hydroxy-C₂-₆-alkyl,

(h) dihydroxy-C₂-₆-alkyl,

(i) Ci_₄-alkoxy-C₂-₄-alkyl,

(]) Ci_₄-alkylamino-C₂-₄-alkyl,

(k) di(C]_₄-alkyl)amino-C₂-₄-alkyl, (1) aminocarbonyl-Ci_₄-alkyl,

(m) C₂-₃-acylamino-C₂-₄-alkyl,

(n) Ci ₄-alkylthio-C_{2 4}-alkyl,

(o) C₂-₄-acyl-Ci_₄-alkyl, and

(p) 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) amino,

(cc) methylammo,

(dd) dimethylammo,

(ee) hydroxymethyl, and

(ff) ammomethyl; ii) one or two oxo groups; or iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, ammo, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R⁵ groups form a piperazine ring, the nitrogen of the piperazine nng that allows the substitution is optionally substituted with Ci-4-alkyl;

R⁶ is independently selected from:

(a) hydrogen, (b) Ci-₄-alkyl, and

(c) hydroxy-C₂-₄-alkyl;

R is independently selected from Ci ₄-alkyl,

R⁸ is independently selected from:

(a) hydrogen,

(b) Ci-6-alkyl,

(c) fluoro-Ci_₆-alkyl,

(d) hydroxy-C₂-β-alkyl, (e) ammo-C₂-₅-alkyl,

(f) Ci_3-alkylamino-C2-4-alkyl,

(g) di(Ci 3-dialkyl)amino-C2 4-alkyl, (h) Ci_₄-alkylsulfonyl-C₂-₄-alkyl, (l) N-heterocyclyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl,

(j) C-heterocyclyl, optionally substituted with methyl, (k) C₂ 3-acylammo-C2 4-alkyl, (1) [CF₃CH₃(OH)C]-C_{1 6}-alkyl,

(m) C_{3 6}-cycloalkyl, (n) methyl-C_{3 6}-cycloalkyl, (o) C_{3 6}-cycloalkyl-Ci ₂-alkyl, (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,

R is each independently selected from (a) Ci ₄-alkoxy-C_{2 4}-alkyl,

(b) ammo-C_{2 4}-alkyl,

(c) Ci ₄-alkylammo-C_{2 4}-alkyl,

(d) di(Ci ₄ alkyl)ammo C_{2 4} alkyl,

(e) C_{2 3}-acylammo-C2 4-alkyl, (f) Ci ₄-alkylthio-C_{2 4}-alkyl, and

(g) C_{2 4}-acyl-Ci ₄-alkyl, or two R⁹ 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) ammo, (cc) methylammo, (dd) dimethylammo, (ee) hydroxymethyl, and (ff) ammomethyl,

II) one or two oxo groups, or

III) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, ammo, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R⁹ groups form a piperazine ring, the nitrogen of the piperazine nng that allows the substitution is optionally substituted with

R¹⁰ is independently selected from.

(a) hydrogen,

(b) Ci-6-alkyl, (c) cyclopropyl,

(d) cyclobutyl,

(e) cyclopropylmethyl,

(f) fluoro-C₂-6-alkyl,

(g) hydroxy-C_{2 6}-alkyl, (h) Ci_₂-alkoxy-C₂-₆-alkyl,

(i) amino-C₂-₆-alkyl,

(j) di(Ci_₃-alkyl)amino-C₂-₆-alkyl,

(k) Ci_₃-alkylammo-C₂-₆-alkyl,

(1) cyano-C₂-₄-alkyl, (m) C₂_₆-acyl,

(n) C₂-₆-acyl-Ci β-alkyl, and

(o) Ci_₆-alkylsulfonyl-Ci_6-alkyl,

R¹¹ is selected from'

(a) hydrogen, hydroxy,

(C) fluonne,

(d) Ci_4-alkoxy, and

(e) methyl;

R¹² is selected from

(a) hydrogen,

0>) Ci-₃-alkyl,

(c) Ci_₃-alkoxy-Ci_₃-alkyl, (d) hydroxy-C2 4-alkyl,

(e) dihydroxy-C2 4-alkyl,

(f) hydroxy-Ci 4-alkoxy-C2 4-alkyl,

(g) ammo-C2 4-alkyl,

(h) di(Ci 3-alkyl)ammo-C24-alkyl,

(i) Ci 3-alkylammo-C2 4-alkyl,

(j) aminocarbonyl-C2 4-alkyl,

(k) Ci 3-alkylammocarbonyl-C2 4-alkyl,

(1) di(Ci 3-alkyl)ammocarbonyl-C2 4-alkyl,

(m) C₂ 3-acyl-Ci ₄-alkyl,

(n) Ci ₄-alkylsulfonyl-Ci ₄-alkyl, and

(o) C₂ 3-acylammo-C2 4-alkyl

A preferred group of compounds of the invention are compounds of Formula (Ib),

and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers or N-oxides thereof, wherein

A iS CH₂, O or NR 10 , B is CH₂, O or NR¹⁰, provided that when B is O or NR¹⁰, then A is CH₂, m is each independently 0 or 1 ,

D is N or CR¹¹, provided that D must be CR¹¹ and said R¹¹ must be hydrogen or methyl when B is O or NR¹⁰, and further provided that each m is 1 when D is N,

Ar¹, Z\ Z\ R¹ to R^y and R^IZ are as defined in Formula (Ia),

R , 10 is selected from (a) hydrogen,

(b) Ci-4-alkyl,

(c) cyclopropyl,

(d) cyclobutyl,

(e) cyclopropylmethyl,

(f) fluoro-C₂-₄-alkyl,

(g) Ci_₂-alkoxy-C₂-3-alkyl,

(h) hydroxy-C₂-₄-alkyl,

Ci) amino-C₂-₄-alkyl,

(k) methylamino-C₂-₄-alkyl,

(1) dimethylamino-C₂-₄-alkyl, and

(m) cyano-C2-4-alkyl;

R is selected from:

(a) hydrogen, hydroxy,

(C) fluonne, and

(d) methyl.

A further preferred group of compounds of the invention are compounds of Formula (Ic),

and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers or N-oxides thereof; wherein:

A is O and B is CH₂, or A is CH₂ and B is O; Z¹, Z², R¹ to R , R⁹ and R¹² are as defined in Formula (Ia),

Ar¹ is phenyl or pyridinyl, each of which is optionally substituted m 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-alkylsulfoximme,

(d) -S(O)R⁴,

(e) -S(O)₂R⁴,

(f) -S(O)₂NR⁵R⁵,

(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) (CH₃)₂NC(O)O-,

(P) -NHC(O)OCH₃,

(q) C-heterocyclyl, optionally substituted with methyl,

W -CN,

(s) -OR⁸,

(0 -SCF₃,

(u) C-heterocyclylsulfonyl, optionally susbtituted with methyl,

(v) -NR⁵R⁵,

(W) -C(OH)CH₃CF₃,

(x) cyano-Ci ₆-alkyl,

(y) Ci 6-alkyl,

(z) Ci ₄-alkoxy-Ci ₄-alkyl,

(aa) fluoro-Ci 4-alkyl,

(bb) C₂ 6-alkenyl,

(CC) fluoro-C_{2 4}-alkenyl,

(dd) hydroxy-Ci ₆-alkyl,

(ee) Ci 4-alkylsulfonyl-Ci 4-alkyl, (ff) hydroxy-C2 4-alkoxy-Ci 4-alkyl,

(gg) C_{2 3}-acyl-d ₃-alkyl,

(hh) C₂ 6-alkynyl,

(11) C3 6-cycloalkyl, OJ) hydroxy-C3 6-cycloalkyl,

(kk) fluoro-C_{3 6}-cycloalkyl,

(11) methyl-C3 6-cycloalkyl,

(mm) C-heterocyclylcarbonyl, optionally substituted with methyl,

(nn) C_{3 6}-cycloalkyl-Ci ₄-alkyl, (00) R⁵R⁵N-Ci 2-alkyl,

(pp) -C(O)OR⁷,

(qq) CH₂C(O)OR⁷, and

(rr) heteroaryl, wherein any heteroaryl residue as substituent on Ar is optionally substituted m 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-C_{3 5}-cycloalkyl, and

(f) C-heterocyclyl, optionally substituted with methyl

A preferred subgroup of compounds of Formula (Ic) consists of compounds wherein

A is O and B is CH₂,

Ar¹ is phenyl or pyridmyl, 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-alkylsulfoximme,

(c) Ci ₄-alkylsulfonyl, (d) C i _₄-alkylsulfinyl,

(e) hydroxy-C₂-₄-alkylsulfonyl,

(Q C3_5-cycloalkylsulfonyl,

(g) methyl-C^s-cycloalkylsulfonyl,

(h) trifluoromethylsulfonyl,

(i) -S(O)₂NR^5AR^5A,

Ci) Ci_4-alkylsulfonamido,

(k) C₂-₄-acylamino,

(1) C₂-₄-acylaminomethyl,

(m) carboxy-C i _3 -alkylcarbonylamino ,

(n) -C(O)NR^5AR^5A,

(o) -CH₂-C(O)NR^5AR^5A,

(P) -NHC(O)OCH₃,

(q) C_{2 4}-acyl,

00 C₃_₅-cycloaLkylcarbonyl,

(S) Ci_4-alkoxy,

(t) C₃_₅-cycloalkyloxy,

(u) C-heterocycLyl,

(v) -CN,

(W) -OH,

(x) -OCF₃,

(y) -CF₃,

00 -NR^5AR^5A,

(aa) -C(OH)CH₃CF₃,

(bb) cyano-Ci_₂-alkyl,

(CC) Ci_₄-alkyl,

(dd) C₃_₅-cycloalkyl,

(ee) Ci_₂-alkoxy-Ci_₂-alkyl,

(ff) vinyl,

(gg) ethynyl,

(hh) hydroxy-C i _₂-alkyl,

(ϋ) C-heterocyclyloxy, optionally substituted with methyl,

(Jj) R^5AR^5AN-Ci_₂-alkyl,

(kk) -C(O)OR^7A, and (11) -CH₂C(O)OR^7A,

R¹ is a group R^1A selected from C(O)OR^2A, C(O)R^2A, S(O)₂R^2A, C(O)NR^2AR^3A, -CH2-C(O)NR^2AR^3A, or a 5- or 6-membered heteroaryl group linked via a ring carbon atom, wherein the said heteroaryl group is optionally substituted with Ci-₄-alkyl,

R^2A is selected from

(a) Ci ₆-alkyl,

(b) Ci 6-alkoxy-C₂ β-alkyl, (c) hydroxy-C₂ β-alkyl,

(d) hydroxy-C_{2 4}-alkoxy-C_{2 4}-alkyl,

(e) fluoro-C2 β-alkyl,

(f) C₃ 6-alkynyl,

(g) C_{3 7}-cycloalkyl, (h) C_{5 8}-cycloalkenyl,

(1) NR^9AR^9A provided that R^1A is not selected from C(O)OR^2A, C(O)NR^2AR^3A and -CH₂-C(O)NR^2AR^3A,

(j) C heterocycLyl, optionally substituted with methyl,

(k) C₇ 8-bicyclyl, (1) 2-norbornylmethyl,

(m) azabicyclyl,

(n) C₃ 6-cycloalkyl-Ci ₄-alkyl, wherein cycloalkyl is optionally substituted with methyl,

(o) C_{2 3}-acyl-Ci ₄-alkyl, (p) arylcarbonyl-Ci ₄-alkyl,

(q) heteroarylcarbonyl-Ci ₄-alkyl,

(r) [CF₃CH₃(OH)C]-Ci ₆-alkyl,

(s) N-heterocyclylcarbonyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl, (t) hydroxy-C_{4 6}-cycloalkyl,

(u) OXO-C₄ 6-cycloalkyl,

(v) fluoro-C_{4 6}-cycloalkyl,

(w) methoxy-C_{4 6}-cycloalkyl,

(x) methyl-C3 6-cycloalkyl, (y) oxo-iV-heterocyclyl-C₂v|-alkyl, (z) hydroxy-N-heterocyclyl-C2 4-alkyl, (aa) fluoro-jY-heterocyclyl-C2 4-alkyl, (bb) ammo-N-heterocyclyl-C2 4-alkyl, (cc) N-heterocyclyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl, (dd) C-heterocyclyl-Ci 4-alkyl, wherein heterocyclyl is optionally substituted with methyl, (ee) aryl, (S) aryl-Ci ₄-alkyl,

(gg) heteroaryl, and (hh) 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 chlorine and fluorine, methyl,

(C) ethyl,

(d) methoxy,

(e) ethoxy,

(f) isopropoxy,

(g) hydroxy,

(h) -OCF₃,

(i) CF₃,

(J) -CN,

(k) -C(OH)CH₃CF₃,

(1) dimethylammo,

(m) hydroxymethyl,

(n) -S(O)₂CH₃,

(o) -C(O)CH₃, and

(P) -C(O)NH₂,

R^3A is selected from

(a) hydrogen, (b) Ci-4-alkyl,

(c) hydroxy-C₂-₄-alkyl, and

(d) methoxy-C24-alkyl;

R^5A is each independently selected from:

(a) hydrogen,

(b) Ci-3-alkyl,

(C) Ci-₂-alkoxy-C₂-₄-alkyl,

(d) C₃_₄-cycloalkyl,

(e) hydroxy-C₂-₄-alkyl,

(f⁾ cyano-Ci_₃-alkyl,

(g) dihydroxy-C₂-₄-alkyl,

(h) aminocarbonyl-Ci_2-alkyl, and

(0 di(Ci 2-alkyl)amino-C23-alkyl; or two R^5A groups together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with: i) a substituent selected from: (aa) hydroxy, (bb) amino, (cc) methylammo,

(dd) dimethylammo, (ee) hydroxymethyl, and (ff) aminomethyl, 11) one or two oxo groups; or iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylammo and dimethylammo, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R^5A groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with methyl,

R^7A is independently selected from Ci-₄-alkyl; Two groups R^9A together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with: i) one hydroxy or amino group, ii) one or two fluorine atoms, or iii) one or two oxo groups, provided that when the substituent is selected from fluorine, hydroxy and amino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R^9A groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with methyl,

R¹² is selected from:

(a) hydrogen, and

(b) Ci ₃-alkyl.

In another more preferred subgroup of compounds of Formula (Ic), Ar¹ is selected from (ammocarbonyl)phenyl, fluoro(aminocarbonyl)phenyl, fluoro[(propylamino)carbonyl]- phenyl, [(dimethylammo)carbonyl]phenyl, (methylsulfmyl)phenyl, fluoro(methyl- sulfonyl)phenyl, (methylsulfonyl)pyridmyl, {[[2-(dimethylamino)ethyl](methyl)amino]- carbonyljpyridinyl, (aminocarbonyl)pyridinyl and (4-methylpiperazin-l-yl)carbonyl- pyridinyl.

More preferably, Ar is selected from 4-(aminocarbonyl)phenyl, 3-fluoro-4- (ammocarbonyl)phenyl, 3-fluoro-4-[(propylammo)carbonyl]phenyl, 4-[(drmethylamino)- carbonyl]phenyl, 2-fluoro-4-(methylsulfonyl)phenyl, 4-(methylsulfmyl)phenyl, 5-(methyl- sulfonyl)pyridin-2-yl, 6- { [ [2-(dimethylamino)ethyl](methyl)ammo] carbonyl} pyridin-3 -yl, 5-(ammocarbonyl)pyridm-2-yl, 6-(methylsulfonyl)pyπdm-3-yl, 6-[(4-methylpiperazm-l- yl)carbonyl]pyridm-3 -yl and 5 -[(4-methylpiperazin- 1 -yl)carbonyl]pyπdm-2-yl.

In another more preferred subgroup of compounds of Formula (Ic), R^1A is selected from C(O)OR^2A, C(O)R^2A or a 6-membered heteroaryl group

More preferably, R^1A is C(O)OR^2A, wherein R^2A is selected from tert-butyl, ethyl and isopropyl. In another embodiment, R^1A is C(O)R^2A, wherein R^2A is 1 -ethylpropyl.

In yet another embodiment, R^1A is 2-pyrimidinyl.

In another more preferred subgroup of compounds of Formula (Ic), R¹² is selected from hydrogen and methyl.

Particularly preferred compounds of Formula (Ia) to (Ic) are the compounds selected from the group consisting of

• tert-Butyl 4-( { [4'-(aminocarbonyl)-3 -(hydroxymethyl)biphenyl-4-yl]oxy } methyl)- pipeπdme- 1 -carboxylate;

• tert-Butyl 4-( { [4'-(aminocarbonyl)-3 -(methoxymethyl)biphenyl-4-yl]oxy } methyl)- piperidine- 1 -carboxylate; • tert-Butyl 4-({[4'-(aminocarbonyl)-3'-fluoro-3-(methoxymethyl)biphenyl-4-yl]oxy}- methyl)piperidine- 1 -carboxylate;

• tert-Butyl 4-[({3'-fluoro-3-(methoxymethyl)-4'-[(propylammo)carbonyl]biphenyl-4-yl}- oxy)methyl]pipendme- 1 -carboxylate;

• tert-Butyl 4-( { [4'- [(dimethylammo)carbonyl] -3 -(methoxymethyl)biphenyl-4-yl]oxy } - methyl)piperidine- 1 -carboxylate;

• tert-Butyl 4-({[2'-fluoro-3-(methoxymethyl)-4'-(methylsulfonyl)biphenyl-4-yl]oxy}- methyl)piperidine- 1 -carboxylate,

• tert-Butyl 4-({[3-(methoxymethyl)-4'-(methylsulfinyl)biphenyl-4-yl]oxy}methyl)- pipeπdme- 1 -carboxylate; • tert-Butyl 4-({2-(methoxymethyl)-4-[5-(methylsulfonyl)pyridm-2-yl]phenoxy}methyl)- piperidine- 1 -carboxylate;

• tert-Butyl 4- {[4-(6- {[[2-(dimethylammo)ethyl](methyl)ammo]carbonyl}pyridm-3-yl)- 2-(methoxymethyl)phenoxy]methyl}pipendme- 1 -carboxylate;

• tert-Butyl 4-{[4-[5-(aminocarbonyl)pyridin-2-yl]-2-(methoxymethyl)phenoxy]methyl}- pipeπdme- 1 -carboxylate;

• tert-Butyl 4-({2-(methoxymethyl)-4-[6-(methylsulfonyl)pyridm-3-yl]phenoxy}methyl)- piperidine- 1 -carboxylate;

• tert-Butyl 4-[(2-(methoxymethyl)-4- {6-[(4-methylpiperazm- 1 -yl)carbonyl]pyridin-3- yl}phenoxy)methyl]piperidine-l-carboxylate; • tert-Butyl 4-[(2-(methoxymethyl)-4- {5-[(4-methylpiperazm- 1 -yl)carbonyl]pyridm-2- yl}phenoxy)methyl]piperidme-l-carboxylate,

• Ethyl 4- [(2-(methoxymethyl)-4- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridm-3 -yl} - phenoxy)methyl]pipendme- 1 -carboxylate, • Isopropyl 4-[(2-(methoxymethyl)-4-{6-[(4-methylpiperazm-l-yl)carbonyl]pyridm-3- yl}phenoxy)methyl]piperidme-l-carboxylate,

• 2-{4-[(2-(Methoxymethyl)-4-{6-[(4-methylpiperazm-l-yl)carbonyl]pyridin-3-yl}- phenoxy)methyl]pipendm-l-yl}pyrimidine,

• Ethyl 4- [(2-(methoxymethyl)-4- {5 -[(4-methylpiperazin- 1 -yl)carbonyl]pyridm-2-yl} - phenoxy)methyl]piperidme- 1 -carboxylate,

• Isopropyl 4-[(2-(methoxymethyl)-4- {5-[(4-methylpiperazm- 1 -yl)carbonyl]pyridm-2- yl}phenoxy)methyl]pipendme-l-carboxylate,

• l-({6-[4-{[l-(2-Ethylbutanoyl)piperidm-4-yl]methoxy}-3-(methox3τnethyl)phenyl]- pyridm-3-yl}carbonyl)-4-methylpiperazme, and « 2- {4-[(2-(Methoxymethyl)-4- {5 -[(4-methylpiperazm- 1 -yl)carbonyl]pyπdin-2-yl} - phenoxy)methyl]piperidm- 1 -yl } pyrimidine

Another object of the invention is a compound of Formula (Ia) to (Ic) for use m therapy The compounds can be used m the treatment or prophylaxis of disorders relating to GPRl 19 Examples of such disorders are Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperhpidemia, hypercholesterolemia, dyshpidemia, syndrome X, obesity, hypertension, chrome systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis

Another object of the invention is the use of a compound of Formula (Ia) to (Ic) in the manufacture of a medicament for use m the treatment or prophylaxis of disorders related to GPRl 19 The GPR119-related disorder is any disorder or symptom wherein GPRl 19 is involved in the process or presentation of the disorder or the symptom The GPRl 19- related disorders include, but are not limited to, Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperhpidemia, hypercholesterolemia, dyshpidemia, syndrome X, obesity, hypertension, chrome systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis Another object of the invention is a method for modulating the GPRl 19 receptor activity (e g , agonizing human GPRl 19), comprising administering to a subject (e g , mammal, human, or animal) rn need thereof an effective amount of a compound of Formula (Ia) to (Ic) or a composition comprising such a compound

Yet another object of the invention is a method for the treatment or prophylaxis of disorders related to GPRl 19, said method comprising administering to a subject (e.g , mammal, human, or animal) m need of such treatment an effective amount of a compound of Formula (Ia) to (Ic) The GPRl 19-related disorder is any disorder or symptom wherein GPRl 19 is involved m the process or presentation of the disorder or the symptom The GPRl 19-related disorders include, but are not limited to Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperhpidemia, hypercholesterolemia, dyslipidemia, syndrome X, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis

Methods delineated herein include those wherein the subject is identified as in need of a particular stated treatment. Identifying a subject m need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e g opinion) or objective (e.g. measurable by a test or diagnostic method).

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) m a subject suffering from or susceptible to a disorder or symptoms thereof delineated herein, m which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof The level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status In preferred embodiments, a second level of Marker m the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy In certain preferred embodiments, a pre-treatment level of Marker m the subject is determined prior to beginning treatment according to this invention, this pre-treatment level of Marker can then be compared 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 m determining whether therapy according to the invention is having the desired effect, and thereby permitting adjustment of dosage levels as appropriate Determination of Marker levels may be performed using any suitable sampling/expression assay method known m the art or described herein 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 m the art Determination of protein levels and/or mRNA levels (e g , Marker levels) m the sample can be performed using any suitable technique known m the art, including, but not limited to, enzyme immunoassay, ELISA, radio labelling/assay techniques, blottmg/chemilummescence methods, real-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 C] 5-alkyl, Ci ₄-alkyl, Ci 3-alkyl, Ci ₂-alkyl, Cj 6-alkyl, C2 5-alkyl, C24-alkyl, C23-alkyl, C3 6-alkyl, C4 5-alkyl, etc Examples of said Ci 6-alkyl include methyl, ethyl, ^-propyl, isopropyl, w-butyl, isobutyl, sec-butyl, f-butyl and straight- and branched-cham pentyl and hexyl 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-hydroxyethyl, 2-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxybutyl and 2-hydroxy-2-methylpropyl.

Derived expressions such as "C]_6-alkoxy", "Ci_6-alkylthio" and "Ci-6-alkylamino" are to be construed accordingly where an Ci-6-alkyl group 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, «-butoxy, isobutoxy, sec-butoxy, ?-butoxy and straight- and branched-chain pentoxy and hexoxy etc. Subgroups of "Ci-β-alkylthio" and "Ci_₆-alkylammo" are to be construed accordingly. Unless otherwise stated or indicated, the term "Ci_₄-alkylsulfmyl" denotes a group C₁^- alkyl-S(O)— . Exemplary Ci_₄-alkylsulfinyl 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 N,N- diethylamino. Unless otherwise stated or indicated, the term "di(Ci_4-alkyl)ammo-C₂_4-alkyl" denotes a group

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. 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 Q^-alkyl group. Examples of said arylcarbonyl-Ci-₄-alkyl include 3-oxo-3-phenylpropyl, 2-oxo-2-phenylethyl and l-methyl-3-oxo-3-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 "Ci_6-alkoxy-C2-6-alkyl" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms connected to an alkyl group having from from 2 to 6 carbon atoms. Examples of said Ci_₆-alkoxy-C₂-₆-alkyl include methoxyethyl, ethoxyethyl, isopropoxyethyl, n-butoxyethyl, ?-butoxyethyl and straight- and branched-chain pentoxyethyl. For parts of the range "Ci_e-alkoxy-C₂-6-alkyl" all subgroups thereof are contemplated such as Ci_5-alkoxy-C₂-6-alkyl, Ci_₄-alkoxy-C₂-6-alkyl, Ci_3-alkoxy-C2-6-alkyl, Ci_2-alkoxy-C2-6-alkyl, C2-6-alkoxy-C2_6-alkyl, C2-5-alkoxy-C2-6- alkyl, C2 4-alkoxy-C26-alkyl, C2 3-alkoxy-C2-6-alkyl, C3 6-alkoxy-C2 6-alkyl, C4 ₅-alkoxy- C₂-₆-alkyl, Ci_₆-alkoxy-C₂-₅-alkyl, Ci.₆-alkoxy-C₂ -₄-alkyl, etc. Unless otherwise stated or indicated, the term "C∑-δ-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, 2,3-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. Likewise, "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-biitynyl, 2-butynyl, and l-methylprop-2-yn-l-yl.

Likewise, aryl-C2-6-alkynyl means a C2-β-alkynyl group substituted by an aryl group. Examples of said aryl-C2-6-alkynyl include phenylethynyl, 3-phenyl-l-propyn-l-yl, 3-phenyl-2-propyn- 1 -yl and 4-phenyl-2-butyn- 1 -yl.

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, C46-cycloalkyl, C45-cycloalkyl, C5 7-cycloalkyl, Ce 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.

Unless otherwise stated or indicated, the term "C7_8-bicyclyl" denotes a carbobicyclic saturated aliphatic ring system in which two non-adjacent carbon atoms of a monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms.

Examples of said C7_g-bicyclyl include radicals obtainable from bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane (norbornane) and bicyclo[2.2.2]octane.

Unless otherwise stated or indicated, the term C7_8-bicyclylalkyl means a Ci_6-alkyl group substituted by a C₇_₈-bicyclyl group as defined above. An exemplary C₇_₈-bicyclylalkyl 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_e- cycloalkyl wherein one of the ring carbons is a carbonyl Examples of "0X0-C₄-6- cycloalkyl" include 2-oxocyclobutyl, 3-oxocyclobutyl, 2-oxocyclopentyl and 4-oxo- cyclohexyl.

Unless otherwise stated or indicated, the term "fluoro-C3_6-cycloalkyl" denotes a C3_β- 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 C/ι_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_e-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, Ci-4-acyl, Ci_-3-acyl, Ci_-2-acyl, C₂-6-acyl, C₂-₅-acyl, C₂.₄-acyl, C_2-3-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)-C]_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 with a sulfonyl group. For parts of the range "Ci_6-alkylsulfonyl" all subgroups thereof are contemplated such as Ci-5-alkylsulfonyl, Ci_₄-alkylsulfonyl, Cu-alkylsulfonyl, Ci_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, «-butylsulfonyl, seobutylsulfonyl, ter?-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-C_{2 4}-alkylsulfonyl include hydroxymethylsulfonyl and 2-hydroxy ethylsulfonyl. Unless otherwise stated or indicated, the term "Ci 4-alkylsulfonamido" denotes a group C] ₄-alkyl-Sθ₂NH— Exemplary Ci ₄-alkylsulfonamido groups include methylsulfonyl- ammo and ethylsulfonylammo.

The term "Ci-4-alkylsulfoximine" refers to a group with the following chemical structure O

Il N^H , where R^a is Ci-₄-alkyl.

Unless otherwise stated or indicated, the term "Ci ₃-alkylene" refers to the diradicals methylene (-CH₂-), ethylene (-CH₂-CH₂-) and propylene (-CH₂-CH₂-CH₂-) In case the group denoted by E in Formula (Ia) to (Ic) forms a double bond with D, then E is a trivalent radical selected from (=CH₂-CH₂-) and (=CH₂-CH₂-CH₂-) Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodme

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- tetrahydronaphthyl

Unless otherwise stated or indicated, the term "heteroaryl" refers to a mono- or bicyclic heteroaromatic ring system having 5 to 10 ring atoms m which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur or oxygen Only one ring need be aromatic and said heteroaryl moiety can be linked to the remainder of the molecule via a carbon or nitrogen atom m any ring Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, lmidazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidmyl, quinazolmyl, mdolyl, lsomdolyl, 1,3-dihydro-isomdolyl, pyrazolyl, pyndazmyl, qumolmyl, quinoxalinyl, thiadiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4- benzodioxinyl, 2,3-dihydro-l,4-benzodioxmyl, benzothiazolyl, benzimidazolyl, benzothiadiazolyl, benzotnazolyl, mdolmyl, lsoindolmyl, and chromanyl groups.

Unless otherwise stated or indicated, the term "heterocyclyl" or "heterocyclic ring" refers to a non-aromatic fully saturated or partially unsaturated monocyclic ring system having 4 to 7 ring atoms with at least one heteroatom such as O, N, or S, and the remaining ring atoms are carbon Examples of heterocyclic groups include pipeπdmyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, azepmyl, azetidinyl, pyrrolidmyl, morpholmyl, imidazolmyl, lmidazohdmyl, thiomorpholmyl, pyranyl, dioxanyl, piperazinyl and 5,6-dihydro-4H-l,3- oxazin-2-yl. When present, the sulfur atom may be in an oxidized form (1 e., S=O or O=S=O). Exemplary heterocyclic groups containing sulfur in oxidized form are 1,1- dioxido-thiomorpholmyl and 1,1-dioxido-isothiazolidinyl

When two groups R⁵, two groups R^5A, two groups R⁹ or two groups R^9A described herein form a heterocyclic ring and said heterocyclic ring is substituted with one or two oxo groups, examples of such groups include 2-pyrrolidon-l-yl, 2-piperidon- 1 -yl, 2-azetidinon- 1-yl, 2,5-dioxopyrrolidm-l-yl and hydantom-1-yl (i e , 2,5-dioxoimidazolidm-l-yl) When two groups R⁵, two groups R^5A, two groups R⁹ or two groups R^9A described herein form a heterocyclic ring and said heterocyclic ring is substituted with one or two fluoro atoms, examples of such groups include 4-fluoropiperidm-l-yl, 4,4-difluoropiperidin- 1 -yl, 3-fluoropyrrohdm-l-yl and 3,3-difluoropyrrolm-l-yl.

When two groups R⁵, two groups R^5A, two groups R⁹ or two groups R^9A described herein form a heterocyclic ring and said heterocyclic rmg is substituted with hydroxy, examples of such groups include 4-hydroxypiperidin-l-yl, 3-hydroxypiperidin-l-yl, 3-hydroxy- pyrrolidm- 1 -yl and 3-hydroxyazetidin-l-yl When two groups R⁵, two groups R^5A, two groups R⁹ or two groups R^9A described herein form a heterocyclic ring and said heterocyclic rmg is substituted with amino, examples of such groups include 4-ammopiperidin-l-yl, 3-aminopiperidm-l-yl, and 3-ammopyrrolidin- 1-yl When two groups R⁵, two groups R^5A, two groups R⁹ or two groups R^9A described herein form a heterocyclic ring and said heterocyclic rmg is substituted with hydroxymethyl, examples of such groups include 2-(hydroxymethyl)pyrrolidm- 1 -yl, 2-(hydroxymethyl)- morpholin-4-yl and 4-(hydroxymethyl)piperidin-l-yl

When two groups R⁵, two groups R^5A, two groups R⁹ or two groups R^9A described herein form a heterocyclic rmg and said heterocyclic ring is substituted with methylammo or dimethylammo, examples of such groups include 3-dimethylammopyrrolidin-l-yl and 3- methylammopyrrolidin- 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 and 1,3 benzodioxol-5-ylmethyl. "C-heterocyclyl" indicates bonding via a carbon atom of said heterocyclyl, for example pipeπdm-4-yl, tetrahydrofuran-2-yl, oxetan-3-yl, tetrahydrofuran-3-yl and 5,6-dihydro-4H- l,3-oxazin-2-yl, while "N-heterocyclyl" indicates bonding through nitrogen m a nitrogen- contammg heterocyclyl group, for example pipeπdm- 1 -yl and piperazm-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 Ci -4- alkyl include l-methylpiperidin-4-yl and 3-methyloxetan-3-yl

Unless otherwise stated or indicated, the term "N-heterocyclyl-C2 4-alkyl" refers to a nitrogen-containing heterocyclyl group that is directly linked to a C24-alkyl group via a nitrogen atom of said heterocyclyl Exemplary N-heterocyclyl-C_{2 4}-alkyl groups include 2-(pyrrolidm-l-yl)ethyl, 3-(4-morpholmyl)propyl, 2-(piperazm- 1 -yl)ethyl and 2-(4- morpholinyl)ethyl.

When heterocyclyl as part of the group N-heterocyclyl-C_{2 4}-alkyl is substituted by methyl, said heterocyclyl is selected from 1 -piperazmyl or 1-homopiperazinyl and said methyl is attached to the 4-position of the piperazme or homopiperazme ring. Exemplary N-heterocyclyl-C₂-₄-alkyl groups wherein heterocyclyl is substituted with methyl are 2-(4-methylpiperazm-l-yl)ethyl and 2-(4-methylhomopiperazm- 1 -yl)ethyl Unless otherwise stated or indicated, the term "C-heterocyclyl-Ci 4-alkyl" refers to a heterocyclyl group that is directly linked to a Ci ₄-alkyl group via a carbon atom of said heterocyclyl Exemplary C-heterocyc IyI-C _{1 4}-alkyl groups include tetrahydropyran-4- ylmethyl, piperidin-4-ylmethyl, tetrahydrofuran-2-ylmethyl, oxetan-3-ylmethyl and 2- (pipeπdmyl-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-methylpiperidm-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-C_{2 4}-alkyl" refers to an oxo-N-heterocyclyl group that is directly linked to a C24-alkyl group through a nitrogen atom of its heterocyclyl portion and where oxo-N-heterocyclyl is as defined above Exemplary oxo-iV-heterocyclyl-C_{2 4}-alkyl groups include 2-(2-pyrrolidon-l-yl)ethyl, 3-(2-pyrrohdon-l-yl)propyl and 2-(2,5-dioxoimidazohdm-l-yl)ethyl. 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-C_{2 4}-alkyl" refers to a fluoro-N-heterocyclyl group that is directly linked to a C_{2 4}-alkyl group through a nitrogen atom of its heterocyclyl portion and where fluoro-N-heterocyclyl is as defined above Exemplary fiuoro-N-heterocyclyl-C_{2 4}-alkyl groups include 2-(3-fluoropyrrolidin-l-yl)- ethyl and 3-(3-fluoropyrrolidm-l-yl)propyl.

Unless otherwise stated or indicated, the term "hydroxy-N-heterocyclyl" denotes a nitrogen-contammg heterocyclyl group that is substituted at a position other than alpha to a ring heteroatom with a hydroxy group

Unless otherwise stated or indicated, the term "hydroxy-N-heterocyclyl-C_{2 4}-alkyL" refers to a hydroxy-N-heterocyclyl group that is directly linked to a C24-alkyl group through a nitrogen atom of its heterocyclyl portion and where hydroxy-N-heterocyclyl is as defined above Exemplary hydroxy-N-heterocyclyl-C_{2 4}-alkyl groups include 2-(4-hydroxy- pipendm- 1 -yl)ethyl and 3-(3-hydroxypipeπdm- 1 -yl)propyl.

Unless otherwise stated or indicated, the term "ammo-N-heterocyclyl" denotes a nitrogen- containing heterocyclyl group that is substituted at a position other than alpha to a ring heteroatom with an ammo group. Unless otherwise stated or indicated, the term "amino-N-heterocyclyl-C_{2 4}-alkyl" refers to a ammo-N-heterocyclyl group that is directly linked to a C_{2 4}-alkyl group through a nitrogen atom of its heterocyclyl portion and where amino-N-heterocyclyl is as defined above Exemplary amino-N-heterocyclyl-C_{2 4}-alkyl groups include 2-(4-aminopiperidin-l- yl)ethyl and 3-(3-ammopipeπdm-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 ljheptane 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-piperidmylsulfonyl 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 -methylpiperidm-4-ylsulfonyl

Unless otherwise stated or indicated, the term "C_{2 4}-acylamino" denotes a group R^b(C=O)ΝH— wherein R^b is selected from Ci ₃-alkyl Exemplary C_{2 4}-acylammo groups include acetylammo and propionylammo Unless otherwise stated or indicated, the term "C 24-acylarmno-Ci 4-alkyl" denotes a C24 acylammo group, as defined above, attached to a Ci ₄-alkyl group Examplary C_{2 4}-

groups include (acetylammo)methyl and 2-(acetylammo)ethyl. Unless otherwise stated or indicated, the term "amino carbonyl" refers to the radical NH₂(C=O)-

Unless otherwise stated or indicated, the term "ammocarbonyl-Ci ₄-alkyl" denotes a Ci ₄- alkyl group, as defined above, substituted with an aminocarbonyl group. Exemplary aminocarbonyl-Ci ₄-alkyl groups include 2-(aminocarbonyl)ethyl and 3-(ammocarbonyl)- propyl. 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 carbonylammo (i e , -C(O)NH-). Exemplary carboxy-Ci 3-alkylcarbonylamino groups include (2-carboxyethyl)carbonylammo and (3-carboxypropyl)carbonylamino "C-heterocyclylcarbonyl" refers to a heterocyclyl group that is directly bonded to a carbonyl group via a carbon atom while "N-heterocyclylcarbonyl" refers to a mtrogen- containing heterocyclyl group that is directly bonded to a carbonyl group via a nitrogen atom Examples of N-heterocyclylcarbonyl groups include 1-pipeπdmylcarbonyl, 1-piperazinylcarbonyl and 1-pyrrolidmcarbonyl Exemplary C-heterocyclylcarbonyl groups include 3-pipeπdinylcarbonyl, 4-piperidmylcarbonyl and tetrahydropyranyl-4- ylcarbonyl 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-C_{2 4}-alkyl" refers to a N-heterocyclylcarbonyl group that is directly linked to a C_{2 4}-alkyl group through its carbonyl carbon atom and where N- heterocyclylcarbonyl is as defined above Exemplary N-heterocyclylcarbonyl-C24-alkyl groups include 2-(pyrrolidm-l-ylcarbonyl)ethyl, 2-(piperazin-l-ylcarbonyl)ethyl and 2- (pipeπdm- 1 -ylcarbonyl)ethyl When heterocyclyl as part of the group N-heterocyclylcarbonyl-C24-alkyl is substituted by methyl, said heterocyclyl is selected from 1-piperazmyl or 1 -homopiperazmyl and said methyl is attached to the 4-position of the piperazme or homopiperazme ring. Exemplary jV-heterocyclylcarbonyl-C2^-alkyl groups wherein heterocyclyl is substituted with methyl are 2-(4-methylpiperazm-l-ylcarbonyl)ethyl, 2-(4-methylhomopiperazin-l-ylcarbonyl)- ethyl

The term "C-heterocyclylcarbonyl-C24-alkyl" refers to a C-heterocyclylcarbonyl group that is directly linked to a C_{2 4}-alkyl group through its carbonyl carbon atom and where C- heterocyclylcarbonyl is as defined above. Exemplary C-heterocyclylcarbonyl-C_{2 4}-alkyl groups include 2-(tetrahydropyran-4-ylcarbonyl)ethyl, 2-(pipeπdin-3-ylcarbonyl)ethyl and 2-(pipeπdm-4-ylcarbonyl)ethyl

When heterocyclyl as part of the group C-heterocyclylcarbonyl-C24-alkyl is substituted by methyl, said heterocyclyl is selected from a nitrogen-containing heterocyclyl and said methyl is attached to a ring nitrogen atom thereof An exemplary C-heterocyclylcarbonyl- C_{2 4}-alkyl group wherein heterocyclyl is substituted with methyl is 2-(l-methylpipeπdm-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-piperidmyloxy, 4-piperidmyloxy, 3-tetrahydrofuranyloxy, and 4-tetrahydropyranyloxy When C-heterocyclyloxy is substituted by Ci ₄-alkyl, said heterocyclyl is selected from a nitrogen-contammg heterocyclyl, and said Ci ₄-alkyl is attached to a ring nitrogen atom thereof An exemplary C-heterocyclyloxy group substituted by Ci 4-alkyl includes 1 -methylpiperidin-4-ylo xy The term "hydroxy^ ₄-alkoxy-Ci ₄-alkyl" refers to a hydroxy^ ₄-alkoxy group that is directly attached to a Ci 4-alkyl group Representative examples of such groups include

HO^^ ^^ _HO^v^uvyv- HO ^-" Ό

The term "amidino" refers to a group with the following chemical structure

NH

H₂N

The term "guanidmo" refers to a group with the following chemical structure NH

H₂N ^ΛN A 2 H The chemical formula -C(OH)CH₃CF₃ refers to a group with the following chemical structure

OH

CF, CH '3

The term [CF₃CH₃(OH)C]-C_{1 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

The chemical formula CF₃ S O₃ refers to a group with the following chemical structure

F₃C^O-^*

The carbon-carbon double or triple bonds present in the groups C₃ e-alkenyl, C_{3 6}-alkynyl, aryl-C_{3 6}-alkenyl and aryl-C_{3 6}-alkynyl as values for R² 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 m which it does not.

The term "coupling agent" refers to a substance capable of catalyzing a coupling reaction, such as amidation, or esterifϊcation Examples of coupling agents include, but are not limited to, carbonyldiimidazole, dicyclohexylcarbodiimide, pyridine, 4-dimethylamino- pyridine, and triphenylphosphme Another example of a coupling agent is l-ethyl-3-(3- dimethylammopropyl)carbodumide hydrochloride, which is used in the presence of 1-hydroxybenzotriazole and a base such as tnethylamine

The terms "exo" and "endό" are stereochemical prefixes that describe the relative configuration of a substituent on a bridge (not a bridgehead) of a bicyclic system such as l-azabicyclo[2 2 l]heptane and bicyclo[2 2 ljheptane If a substituent is oriented toward the larger of the other bridges, it is endo. If a substituent is oriented toward the smaller bridge it is exo Both exo and endo forms and their mixtures are part of the present invention

The term "Syndrome X" (also called metabolic syndrome) refers to a syndrome comprising some or all of the following diseases 1) dyshpoprotememia (combined hypercholesterolemia-hypertriglyceridemia, low HDL-cholesterol), 2) obesity (in particular upper body obesity), 3) impaired glucose tolerance (IGT) leading to noninsulin-dependent diabetes melhtus (NIDDM), 4) essential hypertension and (5) thrombogemc/fibrmolytic defects "Pharmaceutically acceptable" means being useful m preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use. "Treatment" as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established

"An effective amount" refers to an amount of a compound that confers a therapeutic effect (e g , treats, controls, ameliorates, prevents, delays the onset of, or reduces the risk of developing a disease, disorder, or condition or symptoms thereof) on the treated subject The therapeutic effect may be objective (i e , measurable by some test or marker) or subjective (i e , subject gives an indication of or feels an effect)

"Prodrugs" refers to compounds that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, e g by hydrolysis m the blood. The prodrug compound usually offers advantages of solubility, tissue compatibility or delayed release m a mammalian organism (see Silverman, R. 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 Throughout the specification and the appended claims, a given chemical formula or name shall also encompass all salts, hydrates, solvates, N-oxides and prodrug forms thereof Further, a given chemical formula or name shall encompass all tautomeric and stereoisomeric forms thereof Stereoisomers include enantiomers and diastereomers Enantiomers can be present in their pure forms, or as racemic (equal) or unequal mixtures of two enantiomers. Diastereomers can be present in their pure forms, or as mixtures of diastereomers. Diastereomers also include geometrical isomers, which can be present in their pure cis or trans forms or as mixtures of those.

The compounds of the Formula (Ia) to (Ic) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof. The pharmacologically acceptable addition salts mentioned below are meant to compπse the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form. Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, ^-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylammes, benzathine, and ammo acids, such as, e.g. arginme and 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, emulsifϊers, 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 m doses, e.g from about 0 01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen

The formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc The formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles Tablets and granules may be coated in a conventional manner

The compounds of Formula (Ia) to (Ic) may be administered with other active compounds for the treatment of diabetes and/or obesity, for example insulin and insulin analogs, DPP- IV inhibitors, sulfonyl ureas, biguamdes, α2 agonists, glitazones, PPAR-γ agonists, mixed PPAR-α/γ agonists, RXR 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), amylm antagonists, CCK receptor agonists, p3-agomsts, leptm and leptm 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 (Ic) are administered m 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 m WO 2005/056003, WO 2005/056013, WO 2005/095343, WO 2005/113510, WO 2005/120494, WO 2005/121131, WO 2005/121089, WO 2006/013104, or WO 2006/076231, including references therein PREPARATION OF COMPOUNDS OF THE INVENTION

The compounds of the Formula (Ia) to (Ic) above may be prepared by, or in analogy with, conventional methods. The preparation of intermediates and compounds according to the examples of the invention may in particular be illuminated by the following Schemes 1-3

Scheme 1

wherein Ar is as defined m Formula (Ia);

Reagents and conditions

(a) methanesulfonyl chloride, a suitable base, such as triethylamine; m a suitable solvent such as dry DCM, at 0 ⁰C;

(b) 5-bromo-2-hydroxybenzaldehyde, a suitable base, such as K₂CO3 and CS₂CO3, in a suitable solvent such as dry acetonitrile, at elevated temperature, for example 65-85 0C;

(c) appropriate aryl- or heteroarylboromc acid, appropriate catalyst, such as Pd(PPt^ or [ l , r-bis(diphenylphosphmo)-ferrocene]dichloropalladium(II), a suitable base, such as K₂CO₃ or Na₂COs; in a suitable solvent mixture such as dimethoxyethane/water, 1 ,4-dioxane/water or toluene/isopropyl alcohol/water, at elevated temperature, for example 120 ⁰C (microwaves);

(d) appropriate aryl- or heteroarylboromc ester; appropriate catalyst, such as Pd(PPh3)₄, a suitable base, such as K2CO3 or NaHCθ3, in a suitable solvent mixture such as 1 ,4- dioxane/water or toluene/isopropyl alcohol/water, at elevated temperature, for example 90 ⁰C, (e) (i) bis(neopentylglycolato)diboron, suitable base, such as KOAc, appropπate catalyst, such as PdC^dppf) DCM; in a suitable solvent, such as DME, at elevated temperature, for example 120 ⁰C (microwaves), (u) appropriate aryl hahde; suitable base, such as NaHCCh, appropriate catalyst, such as Pd(PPti3)4, in a suitable solvent mixture, such as water and DME, at elevated temperature, for example 120 ⁰C (microwaves),

(f) suitable reducing agent, such as NaBH.4, in a suitable solvent, such as ethanol or methanol; at r t.

Scheme 2

wherein Ar¹ and R¹ are as defined in Formula (Ia),

Reagents and conditions:

(a) tert-butyl 4-(hydroxymethyl)piperidme- 1 -carboxylate, triphenylphosphine, dusopropyl azodicarboxylate, in a suitable solvent, such as THF; at r.t;

(b) appropriate aryl- or heteroarylboronic acid, appropnate catalyst, such as Pd(PPh₃)₄, a suitable base, such as K2CO3 or NaHCCh, in a suitable solvent mixture such as 1,4- dioxane/water or toluene/isopropyl alcohol/water; at elevated temperature, for example 90 ⁰C,

(c) appropriate aryl- or heteroarylboronic ester; appropriate catalyst, such as Pd(PPli3)4, a suitable base, such as K₂CO3 or NaHCO₃, in a suitable solvent mixture such as 1,4- dioxane/water or toluene/isopropyl alcohol/water; at elevated temperature, for example 90 ⁰C,

(d) (1) bis(neopentylglycolato)diboron; suitable base, such as KOAc, appropπate catalyst, such as PdCi₂(dppf)-DCM, m a suitable solvent, such as DME, at elevated temperature, for example 120 ⁰C (microwaves), (u) appropriate aryl hahde, suitable base, such as NaHCθ₃, appropriate catalyst, such as Pd(PPh₃)₄; m a suitable solvent mixture, such as water and DME, at elevated temperature, for example 120 ⁰C

(microwaves), (e) suitable deprotecting agent, such as TFA, HCl (g) or aqueous HCl, m a suitable solvent, such as DCM, dioxane or ethanol, at ambient or elevated temperature, (f) (i) appropriate carboxylic acid, suitable base, such as tπethylamine, in a suitable solvent, such as THF, dioxane or DMF, (ii) appropriate coupling reagent, such as

HOBT/EDC, propylphosphomc anhydride, HBTU or TBTU; at ambient temperature; (g) appropriate acid chloride or chloroformate, suitable base, such as triethylamme, in a suitable solvent, such as THF or DMF; at ambient temperature; (h) appropπate alcohol; suitable coupling reagent, such as l,l'-carbonylbis(lH- lmidazole), m a suitable solvent, such as DCM, acetomtrile or DCM/THF, at elevated temperature, (i) appropriate halogenated heteroaromatic ring, such as 2-bromopyπmidine; m a suitable solvent, such as DMSO or acetomtrile; at elevated temperature.

Scheme 3

wherein R and R are as defined in Formula (Ia),

W¹ and W² are both CH, or one of W¹ and W² is CH and the other of W¹ and W² is N; and n = 0, 1 or 2.

Reagents and conditions:

(a) (i) appropriate amine, suitable base, such as triethylamme, in a suitable solvent, such as THF, dioxane or DMF, (ii) appropπate coupling reagent, such as HOBT, EDC, propylphosphomc anhydride, HBTU or TBTU, at 0 ⁰C or ambient temperature Defϊnitions 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 (Ic) and other compounds herein are either commercially available or may be prepared m 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 Ui a suitable organic solvent and treating the solution with an acid, m accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above.

The compounds of Formula (Ia) to (Ic) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers 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, 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. The following abbreviations have been used:

Boc ter?-butyloxycarbonyl

Brine water saturated or nearly saturated with sodium chloride

DCM dichloromethane

DME 1 ,2-dimethoxyethane

DMF dimethylformamide

DMSO dimethyl sulphoxide

EDC N-(3-dimethylaminopropyl)-Λ^-ethylcarbodiimide, or

1 -ethyl-3-(3-dimethylammopropyl)carbodiimide hydrochloride

ESI electrospray ionization

EtOAc ethyl acetate h hour(s)

HDL High-Density Lipoprotein

HBTU O-Benzotriazo Ie-N₁N₁N⁵ ,N⁵ -tetramethyl-uronium-hexafluorophosphate

HOBT 1 -hydroxybenzotriazo Ie 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

MeCN acetomtrile

MeOH methanol

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

AU 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 polaπty: 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/mm isocratic Flash chromatography was performed on Merck silica gel 60 (230-400 mesh). Analytical LCMS data was performed on an Agilent MSD mass spectrometer connected to an Agilent 1100 system Preparative HPLC was performed on a Gilson system. The compounds were automatically named using ACD 8.0.

Analytical LCMS data were obtained with:

System A ACE 3 C8 (50 x 3 0 mm), H₂O (+ 0 1% TFA) and MeCN were used as mobile phases, flow rate 1 mL/min, with a gradient time of 3 0 mm, or

System B- Xterra MSC18 (50x3 0 mm); H₂O (containing 10 mM NH₄HCO₃, pH=10) and MeCN were used as mobile phases, flow rate 1 mL/mm, with a gradient time of 3 0 mm

Preparative HPLC was performed with

System C: Xbπdge Prep C18 5 μM CBD (30x75 mm), H₂O (containing 50 mM NH₄HCO_S; pH=10) and MeCN were used as mobile phases, flow rate 40 mL/mm, with a gradient time of 9 mm; or

System D XTerra Prep MS C18 5 μm (19 x 50 mm), H₂O (containing 50 mM NH₄HCO₃, pH=10) and MeCN were used as mobile phases, flow rate 25 mL/mm, with a gradient time of 6 mm; or System E Xterra MS C18 5 μm (30 x 100 mm), H₂O (containing 50 mM NH₄HCO₃, pH=10) and MeCN were used as mobile phases, flow rate 40 mL/mm, with a gradient time of 8 5 mm

INTERMEDIATE 1

^rt-Butyl 4-{[4-bromo-2-(methoxymethyl)phenoxy]methyl}piperidine-l-carboxylate

4-Bromo-2-(methoxymethyl)phenol (317 mg, 1 46 mmol), prepared m accordance with a literature procedure (Macromolecules, 1995 28, 4415-4420), tπphenylphosphine (498 mg, 1.9 mmol) and tert-butyl 4-(hydroxymethyl)pipendme-l-carboxylate (409 mg, 1.9 mmol) were dissolved m THF (8 mL). Then dnsopropyl azodicarboxylate (384 mg, 1 9 mmol) was added. The solution was evaporated after the reaction mixture had been stirred for 3 h The residue (1 85 g) was purified by flash chromatography on silica using EtO Ac/petroleum ether (1 :3) as eluent to give the title compound Yield 491 mg (81%) Analytical HPLC. purity 96%, (System A), LRESIMS m/z = 326/328.

INTERMEDIATE 2 tert-Butyl 4-{[4-(dimethoxyboryl)-2-(methoxymethyl)phenoxy]methyl}piperidine-l- carboxylate

A solution of n-butyllithium in hexane (1.6 M; 14 mL, 16.0 mmol) was added over 30 min to a stirred solution of

4-{[4-bromo-2-(methoxymethyl)phenoxy]methyl}- piperidme-1-carboxylate (4.14 g, 9 99 mmol, Intermediate 1) in dry THF under N₂ (g) at -78 ⁰C The reaction mixture was stirred at -78 ⁰C for 30 min, after which time tπmethyl borate (1 78 mL, 15 98 mmol) was added dropwise The resulting mixture was stirred for an additional 30 mm at -78 ⁰C and then at r.t. for 2 h The reaction was quenched by addition of MeOH (7 mL) followed by concentration under reduced pressure to give the crude product. Purification via column chromatography on silica using chloroform/methanol (9 1) as eluent gave the title compound as a white solid. Yield 2.24 g (55%). Analytical HPLC purity 99% (System A), 99% (System B).

INTERMEDIATE 3

5-[4-{[l-(te^Butoxycarbonyl)piperidin-4-yl]methoxy}-3-(methoxymethyl)phenyl]- pyridine-2-carboxylic acid

tert-Butyl 4-{[4-(dimethoxyboryl)-2-(methoxymethyl)phenoxy]methyl}piperidine-l- carboxylate (100 mg, 0 245 mmol, Intermediate 2) was dissolved in a solvent mixture of acetonitrile water (2:1; 3 mL). To the homogenous mixture was added [1,1 '-bis(diphenyl- phosphmo)-ferrocene]dichloropalladium(II)-dichloromethane complex (20.05 mg, 0 0245 mmol), potassium carbonate (84.8 mg, 0.614 mmol) and 5-bromo-2-picolinic acid (59.5 mg, 0.295 mmol). The resulting mixture was heated at 160 ⁰C for 30 min using microwave heating. The mixture was allowed to reach room temperature and concentrated under reduced pressure to give the crude title compound as a dark brown solid. Analytical HPLC purity 95% (System B); LRESIMS (ESI⁺) m/z = 457 (M+H)⁺.

INTERMEDIATE 4 6-[4-{[l-(/erf-Butoxycarbonyl)piperidin-4-yl]methoxy}-3-(methoxymethyl)phenyl]- nicotinic acid

tert-Butyl 4-{[4-(dimethoxyboryl)-2-(methoxymethyl)phenoxy]methyl}piperidine-l- carboxylate (100 mg, 0 245 mmol, Intermediate 2) was dissolved in a solvent mixture of acetonitrile water (2 1; 3 mL) To the homogenous mixture was added [1,1 '- bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethane complex (20.05 mg, 0.0245 mmol), potassium carbonate (84.8 mg, 0.614 mmol) and 6-bromonicotimc acid (59.5 mg, 0 295 rnmol). The resulting mixture was heated at 160 ⁰C for 30 mm using microwave heating. The mixture was allowed to reach room temperature and concentrated under reduced pressure to give the crude title compound as a dark brown solid Analytical HPLC. purity 95% (System B), LRESIMS (ESI⁺) m/z = 457 (M+H)⁺.

INTERMEDIATE 5 l-({5-[3-(Methoxymethyl)-4-(piperidin-4-ylmethoxy)phenyllpyridin-2-yl}carbonyl)-4- methylpiperazine

tert-Butyi 4-[(2-(methoxymethyl)-4-{6-[(4-methylpiperazm-l-yl)carbonyl]pyπdin-3-yl}- phenoxy)methyl]piperidme-l-carboxylate (119 mg, 0 221 mmol, obtained in Example 12) was dissolved m a IM solution of HCl in MeOH (2 mL) and stirred at r.t over night. The solution was concentrated under reduced pressure followed by addition of aqueous sodium carbonate. The water phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure to give the title compound as a light brown solid Yield 96 mg (99%), Analytical HPLC purity 99% (System A), LRESIMS m/z = 439 (M+H)⁺

INTERMEDIATE 6 l-({6-[3-(Methoxymethyl)-4-(piperidin-4-ylmethoxy)phenyllpyridin-3-yl}carbonyl)-4- methylpiperazine

tert-Butyl 4-[(2-(methoxymethyl)-4-{5-[(4-methylpiperazm-l-yl)carbonyl]pyπdin-2-yl}- phenoxy)methyl]piperidine- 1 -carboxylate (37 mg, 0 0687 mmol, obtained in Example 13) was dissolved m a IM solution of HCl in MeOH (2 mL) and stirred at r.t over night. The solution was concentrated under reduced pressure followed by addition of aqueous sodium carbonate The water phase was extracted three times with EtOAc The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure to give the title compound as a light brown solid Yield 28 mg (93%); Analytical HPLC purity 99% (System A); LRESIMS m/z = 439 (M+H)⁺

General procedure A for Suzuki-type cross-coupling reaction via in situ boronic acid formation: tert-Butyl 4- { [4-bromo-2-(methoxymethyl)phenoxy]methyl} pipendine- 1 -carboxylate (41 mg, 0 10 mmol, Intermediate 1), bis(neopentylglycolato)diboron (34 mg, 0 15 mmol) and KOAc (44 mg, 0 45 mmol) were mixed with DME (1 mL) Then PdCl₂(dppf) DCM (8 mg, 0.01 mmol) was added. The mixture was stirred 90 ⁰C for 3 h. The appropriate aryl halide (0 13 mmol), K₂CO₃ (27 mg, 0.2 mmol), Pd(PPh₃)₄ (6 mg, 0 005 mmol), DME (1 mL) and water (0.4 mL) were added and the mixture was stirred at 90 ⁰C over 2.5 h Aqueous NaHCθ3 (5%, 0.8 mL) and EtOAc (8 mL) were added. The organic phase was separated and filtered The solvent was evaporated and the residue was purified by preparative HPLC (System D)

General procedure B for Suzuki-type cross-coupling reaction: terϊ-Butyl 4- { [4-bromo-2-(methoxymethyl)phenoxy]methyl}pipendine- 1 -carboxylate (316 mg, 0.76 mmol, Intermediate 1) was dissolved in 80% aqueous dioxane (6.0 mL) to give a concentration of 0 125 mmol/mL. This solution was distributed into six 4-mL vials (0.8 mL, 0 1 mmol to each vial). The appropriate arylboronic acid (0.12 mmol), K2CO3 (0.25 mmol) and Pd(PPt^ (6 mg, 0 05 mmol) were added and the mixture was stirred overnight at 80 ⁰C. The solvent was evaporated under reduced pressure and the residue mixed with 10% aqueous Na₂Cθ3 (0.8 mL) and EtOAc (7 mL) The organic phase was separated and evaporated The residue was mixed with MeOH (2 mL) and filtered The crude product was purified by preparative HPLC (System D) to give the title compound

EXAMPLE 1 tert-Butyl 4-({[4'-(aminocarbonyl)-3-(hydroxymethyl)biphenyl-4-yl]oxy}methyl)- piperidine-1-carboxylate

tert-Butyl 4-(hydroxymethyl)pipeπdme- 1 -carboxylate (4 31 g, 20 0 mmol) and triethylamme (2.63 g, 26.0 mmol) were dissolved m dry DCM (50 mL) and cooled on an ice-bath Methanesulfonyl chloride (2.52 g, 22.0 mmol) dissolved in a few mL dry DCM was added dropwise over 15 mm. The reaction mixture was stirred at 0 ⁰C for 1 h and then poured into saturated aqueous NaHCθ3 (100 mL) The resulting mixture was shaken and then the organic phase and the aqueous phase were allowed to separate The aqueous phase was extracted with DCM (50 mL). The combined organic phases were washed with aqueous saturated NaHCC^, dried (MgSO^, filtered and evaporated to give 6 124 g of tert- butyl 4- {[(methylsulfonyl)oxy]methyl}pipeπdme-l -carboxylate as a tea-colored very viscous oil. LRESIMS m/z=194 (M+H-Boc).

tert-Butyl 4- {[(methylsulfonyl)oxy]methyl}pipendine-l -carboxylate (1.17 g, 4.00 mmol), 5-bromo-2-hydroxybenzaldehyde (0 80 g, 4.0 mmol), K2CO3 (0.61 g, 6 0 mmol) and dry MeCN (20 mL) were mixed and stirred at 80 ⁰C overnight, then for further 24 h at 85 ⁰C CS₂CO3 (1 30 g, 4 0 mmol) was added and the stirring continued at 65 ⁰C for 4 5 days The reaction mixture was filtered, rinsed with DCM (100 mL) and evaporated to give 2.19 g of a brown semisolid residue The crude material was purified twice through silica eluted with EtOAc (gradient, 2.5-50%) in DCM Product-containing fractions were evaporated to give 602 mg (38%) of tert-butyl 4-[(4-bromo-2-formylphenoxy)methyl]pipeπdine-l- carboxylate as a clear viscous oil, which slowly crystallized into white needles LRESIMS m/z=344 (M+H-tBu).

tert-Butyl 4-[(4-bromo-2-formylphenoxy)methyl]piperidine-l -carboxylate (398 mg, 1 00 mmol), [4-(ammocarbonyl)phenyl]boromc acid (181 mg, 1 10 mmol), [l,l '-bis(diphenyl- phosphmo)-ferrocene]dichloropalladium(II) [complex with dichloromethane (1 :1)] (41 mg, 0.050 mmol), IM aqueous Na₂CC^ (1 50 mL, 1.50 mmol) and dimethoxyethane (1.5 mL) were heated at 120 ⁰C for 10 mm by microwaves in a Smith synthesizer The reaction mixture was diluted with EtOAc (100 mL), washed with IM HCl (2x100 mL) and then with saturated aqueous NaHCθ3 (2x100 mL) The organic phase was dried (MgSO₄), filtered and evaporated to give 405 mg (92%) of tert-butyl 4-({[4'-(ammocarbonyl)-3- formylbiphenyl-4-yl]oxy}methyl)piperidme-l -carboxylate as a grey-brown solid LRESIMS m/z=339 (M+H-Boc) tert-Butyl 4-( { [4'-(aminocarbonyl)-3-formylbiphenyl-4-yl]oxy}methyl)pipendine- 1 - carboxylate (22 mg, 0.050 mmol) was dissolved m ethanol (1 0 mL) and treated with NaBH4 (2.8 mg, 0.075 mmol) at r.t. overnight. The crude product was purified by preparative HPLC (System C) to give 7 0 mg (32%) of the title compound as a white solid Analytical HPLC purity 99% (System A) 98% (System B), HRESIMS (ESI⁺) calcd for C₂₅H₃₂N₂O₅ 440 2311 , found 440 2312

EXAMPLE 2 tert-Butyl 4-({[4'-(aminocarbonyl)-3-(methoxymethyl)biphenyl-4-yl]oxy}methyl)- piperidine-1-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l -carboxylate (Intermediate 1) and (4-aminocarbonylphenyl)- boromc acid using the conditions described in general procedure B Yield 15 mg (33%) Analytical HPLC: purity 100% (System A), 100% (System B); HRESIMS (ESI⁺) calcd for C₂₆H₃₄N₂O₅ 454 2468, found 454.2466.

EXAMPLE 3 tert-Butyl 4-({[4'-(aminocarbonyl)-3'-fluoro-3-(methoxymethyl)biphenyl-4-yl]oxy}- methy])piperidine-l-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l -carboxylate (Intermediate 1) and 4-carbamoyl-3-fluoro- phenylboronic acid using the conditions described m general procedure B. Yield 18 mg (38%) Analytical HPLC purity 100% (System A), 100% (System B), HRESIMS (ESI⁺) calcd for C₂₆H₃₃FN₂O₅ 472 2374, found 472 2378 EXAMPLE 4 tert-Butyl 4-[({3'-fluoro-3-(methoxymethyl)-4'-[(propylamino)carbonyl]bipheny]-4- yl}oxy)methyl]piperidine-l-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l-carboxylate (Intermediate 1) and 3-fhioro-4-(n-propyl- carbamoyl)phenylboronic acid using the conditions described in general procedure B Yield 18 mg (35%). Analytical HPLC: purity HPLC 100% (System A), 100% (System B); HRESIMS (ESI⁺) calcd for C₂₉H₃₉FN₂O₅ 514.2843, found 514 2842.

EXAMPLE 5 tert-Butγl 4-({[4'-[(dimethylamino)carbonyl]-3-(methoxymethyl)biphenyl-4-yl]oxy}- methy])piperidine-l-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l-carboxylate (Intermediate 1) and {4-[(dimethylamino)- carbonyl]phenyl}boronic acid using the conditions described m general procedure B. Yield 22 mg (45%). Analytical HPLC: purity 100% (System A), 100% (System B); HRESIMS (ESI⁺) calcd for C₂₈H₃₈N₂O₅ 482 2781, found 482 2782

EXAMPLE 6 tert-Butyl 4-({[2'-fluoro-3-(methoxymethyl)-4'-(methylsulfonyl)biphenyl-4-y]]oxy}- methy])piperidine-l-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l-carboxylate (Intermediate 1) and 2-fluoro-4-(methyl- sulfonyl)phenylboronic acid using the conditions described in general procedure B. Yield 18 mg (35%). Analytical HPLC: purity 99% (System A), 99% (System B); HRESIMS (ESI⁺) calcd for C₂₆H₃₄FNO₆S 507.2091, found 507.2092.

EXAMPLE 7 tert-Butyl 4-({[3-(methoxymethyl)-4'-(methylsulfinyl)biphenyl-4-yl]oxy}methyl)- piperidine-1-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l-carboxylate (Intermediate 1) and 4-(methanesulfmyl)- benzene boronic acid using the conditions described in general procedure B. Yield 19 mg (40%). Analytical HPLC: purity 100% (System A), 100% (System B); HRESIMS (ESI+) calcd for C₂₆H₃₅NO₅S 473.2236, found 473.2237.

EXAMPLE 8 tert-Butyl 4-({2-(methoxymethyl)-4-[5-(methylsulfonyl)pyridin-2-yl]phenoxy}methyl)- piperidine-1-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l-carboxylate (Intermediate 1) and 2-bromo-5-methane- sulfonyl-pyridine using the conditions described in general procedure A. Yield 16 mg (33%). Analytical HPLC: purity 100% (System A), 100% (System B); HRESIMS (ESI⁺) calcd for C₂₅H₃₄N₂O₆S 490.2137, found 490.2132.

EXAMPLE 9 tert-Butγl 4- { [4-(6- { [ [2-(dimethylamino)ethyl] (methyl)amino] carbonyl}pyridin-3-yl)- 2-(methoxymethyl)phenoxy]methyl}piperidine-l-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l-carboxylate (Intermediate 1) and 5-bromo-N-[2-(dimethyl- amino)ethyl]-N-methylpyridine-2-carboxamide (which was prepared from 5-bromo-2- picolinic acid and N,N,jV-trimethylethylenediamine) using the conditions described in general procedure A. Yield 15 mg (27%). Analytical HPLC: purity 100% (System A), 98% (System B); HRESIMS (ESI⁺) calcd for C₃₀H₄₄N₄O₅ 540.3312, found 540.3327.

EXAMPLE 10 tert-Butyl 4-{[4-[5-(aminocarbonyl)pyridin-2-yl]-2-(methoxymethy])phenoxy]methy]}- piperidine-1-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l-carboxylate (Intermediate 1) and 6-chloronicotinamide using the conditions described in general procedure A. Yield 11 mg (24%). Analytical HPLC: purity 100% (System A), 96% (System B); HRESIMS (ESI⁺) calcd for C₂₅H₃₃N₃O₅ 455.2420, found 455.2423.

EXAMPLE 11 tert-Butyl 4-({2-(methoxymethyl)-4-[6-(methylsulfonyl)pyridin-3-yl]phenoxy}methyl)- piperidine-l-carboxylate

The title compound was prepared from tert-butyl 4-{[4-bromo-2-(methoxymethyl)- phenoxy]methyl}piperidine-l-carboxylate (Intermediate 1) and 5-bromo-2-rnethane- sulfonyl-pyridine using the conditions described in general procedure A. Yield 21 mg (43%). Analytical HPLC: purity 100% (System A), 100% (System B); HRESIMS (ESI⁺) calcd for C₂₅H₃₄N₂O₆S 490.2136, found 490.2142. EXAMPLE 12 tert-Butyl 4-[(2-(methoxymethyl)-4-{6-[(4-methylpiperazin-l-yl)carbonyl]pyridin-3- yl}phenoxy)methyl]piperidine-l-carboxylate

To a stirred mixture of 5-[4-{[l-(?ert-butoxycarbonyl)piperidin-4-yl]methoxy}-3- (methoxymethyl)phenyl]pyridine-2-carboxylic acid (120 mg, 0.263 mmol; Intermediate 3), N-methylpiperazine (79 mg, 87.5 μL, 0.789 mmol) and Et₃N (106.4 mg, 0.146 mL, 1.05 mmol) in DMF (5 mL) were added EDC (151 mg, 0.789 mmol) and HOBT-H₂O (106.6 mg, 0 789 mmol). After stirring at r.t. for 72 h, HPLC-UV/MS analysis indicated 50% product formation (m/z) =539 (M+H)⁺. Two more equivalents each of HOBT, EDC, Et₃N and N-methylpiperazine were added and the mixture was stirred overnight. Concentration in vacuo followed by purification by preparative HPLC (System E) gave the title compound as a brown solid. Yield 48.8 mg (34%). Analytical HPLC: purity 99% (System B), 99% (System A); HRESIMS (ESI⁺) calcd for C₃₀H₂₄N₄O₅ 538.3155, found 538.3176.

EXAMPLE 13 tert-Butyl 4-[(2-(methoxymethyl)-4-{5-[(4-methylpiperazin-l-yl)carbonyl]pyridin-2- yl}phenoxy)methy]]piperidine-l-carboxylate

o

The title compound was prepared from 6-[4-{[l-(rerz-butoxycarbonyl)piperidin-4-yl]- methoxy}-3-(methoxymethyl)phenyl]nicotmic acid (120 mg, 0.263 mmol; Intermediate 4) and jY-methylpiperazme (78.9 mg, 87.47 μL, 0.789 mmol) in accordance with the procedure described for Example 12. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (System E) to give the title product as a solid Yield 13 4 mg (9%), Analytical HPLC purity 97% (System B), 97% (System A); HRESIMS (ESI⁺) calcd for C₃₀H₂₄N₄O₅ 538.3155, found 538.3150. EXAMPLE 14

Ethyl 4- [(2-(methoxymethyl)-4- {6- [(4-methylpiperazin- l-yl)carbonyl] pyridin-3-yl}- phenoxy)methyl]piperidine-l-carboxylate

The title compound was prepared by addition of ethyl chloro formate (6 mg, 5 9 μL, 0 027 mmol) to a mixture containing l-({5-[3-(methoxymethyl)-4-(piperidin-4-ylmethoxy)- phenyl]pyridm-2-yl}carbonyl)-4-methylpiperazine (10 mg, 0 0288 mmol, Intermediate 5) and pyridine (5 mg, 5.1 μL, 0.0632 mmol) in DCM (0.5 mL). The resulting mixture was stirred for 10 h at r.t. and concentrated under reduced pressure. The residue was purified by preparative HPLC (System E) to give the title compound as a solid. Yield 8.8 mg (76%). Analytical HPLC: purity 99% (System B), 99% (System A), LRESIMS m/z = 511 (M+H)⁺. HRESIMS (ESI⁺) calcd for C₂₈H₃₈N₄O₅: 510.2842, found 510.2862.

EXAMPLE 15 Isopropyl 4- [(2-(methoxymethyl)-4-{6- [(4-methylpiperazin- l-yl)carbonyl] pyridin-3- yl}phenoxy)methy]]piperidine-l-carboxylate

The title compound was prepared by adding a IM solution of isopropyl chloroformate in toluene (33 μL, 0.027 mmol) to a mixture containing l-({5-[3-(methoxymethyl)-4- (pipeπdin-4-ylmethoxy)phenyl]pyridin-2-yl}carbonyl)-4-methylpiperazine (10 mg, 0.0288 mmol, Intermediate 5) and pyridine (5 mg, 5.1 μL, 0.0632 mmol) in DCM (0.5 mL). The resulting mixture was stirred for 10 h at r.t The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (System E) to give the title compound as a solid. Yield 7.4 mg (62%). Analytical HPLC: purity 99% (System B), 99% (System A), HRESIMS (ESI⁺) calcd for C₂₉H₄₀N₄O₅ 524.2999, found 524.3011. EXAMPLE 16

2-{4-[(2-(Methoxymethyl)-4-{6-[(4-methylpiperazin-l-yl)carbonyl]pyridin-3-yl}- phenoxy)methyl]piperidin-l-yl}pyrimidine

The title compound was prepared by addition of 2-bromopyrimidine (7.66 mg, 0.0482 mmol) to a solution of l-({5-[3-(methoxymethyl)-4-(piperidin-4-ylmethoxy)phenyl]- pyridin-2-yl}carbonyl)-4-methylpiperazine (19.2 mg, 0.0438 mmol; Intermediate 5) in DMSO (1 mL). The resulting homogenous solution was stirred for 1O h at r.t, for 16 h at 35 ⁰C and then concentrated under reduced pressure. The residue was redissolved in MeOH and purified by preparative HPLC (System E) to give the title compound as a slightly yellow solid. Yield 4.4 mg (19%). Analytical HPLC: purity 99% (System B), 99% (System A); HRESIMS (ESI⁺) calcd for C₂₉H₃₆N₆O₃ 516.2849, found 516.2862.

EXAMPLE 17 Ethyl 4- [(2-(methoxymethyl)-4- {5- [(4-methylpiperazin- l-yl)carbonyl] pyridin-2-yl}- phenoxy)methyl]piperidine-l-carboxylate

The title compound was prepared by addition of ethyl chloroformate (6 mg, 5.9 μL, 0.054 mmol) to a mixture containing l-({6-[3-(methoxymethyl)-4-(piperidin-4-ylmethoxy)- phenyl]pyridin-3-yl}carbonyl)-4-methylpiperazine (10 mg, 0.0288 mmol, Intermediate 6) and pyridine (5 mg, 5.1 μL, 0.0632 mmol) in DCM (0.5 mL). The resulting mixture was stirred for 10 h at r.t. and concentrated under reduced pressure. The residue was purified by preparative HPLC (System E) to give the title compound as a solid. Yield 8.6 mg (74%). Analytical HPLC: purity 99% (System B), 99% (System A); HRESIMS (ESI⁺) calcd for C₂₈H₃₈N₄O₅ 510.2842, found 510.2856. EXAMPLE 18

Isopropyl 4-[(2-(methoxymethyl)-4-{5-[(4-methylpiperazin-l-yl)carbonyl]pyridin-2- yl}phenoxy)methy]]piperidine-l-carboxylate

The title compound was prepared by adding a IM solution of isopropyl chloroformate in toluene (33 μL, 0.027 mmol) to a mixture containing l-({6-[3-(methoxymethyl)-4- (pipeπdm-4-ylmethoxy)phenyl]pyridin-3-yl}carbonyl)-4-methylpiperazine (10 mg, 0.0288 mmol, Intermediate 6) and pyridine (5 mg, 5.1 μL, 0.0632 mmol) in DCM (0.5 mL). The resulting mixture was stirred for 10 h at r.t. and concentrated under reduced pressure. The residue was purified by preparative HPLC (System E) to give the title compound as a solid. Yield 7.3 mg (61%). Analytical HPLC: purity 99% (System B), 99% (System A); HRESIMS (ESI⁺) calcd for C₂₉H₄₀N₄O₅ 524.2999, found 524.3010.

EXAMPLE 19 l-({6-[4-{[l-(2-Ethylbutanoyl)piperidin-4-yl]methoxy}-3-(methoxymethyl)phenyl]- pyridin-3-yl}carbonyl)-4-methylpiperazine

The title compound was prepared by addition of 2-ethylbutyryl chloride (3.50 mg, 3 6 μL 0.0212 mmol) to a mixture of l-({6-[3-(methoxymethyl)-4-(piperidin-4-ylmethoxy)- phenyl]pyridin-3-yl}carbonyl)-4-methylpiperazine (9.30 mg, 0.0212 mmol; Intermediate 6) and pyridine (0.5 mL). The resulting homogenous solution was stirred for 10 h at r.t. and concentrated under reduced pressure. The residue was redissolved in MeOH and purified by preparative HPLC (System E) to give the title compound as a slightly yellow solid. Yield 3.5 mg (31%). Analytical HPLC: purity 99% (System B), 99% (System A); HRESIMS (ESI⁺) calcd for C₃iH₄₄N₄O₄ 536.3379, found 536.3379. EXAMPLE 20

2-{4-[(2-(Methoxymethyl)-4-{5-[(4-methylpiperazin-l-yl)carbonyl]pyridin-2-yl}- phenoxy)methyl]piperidin-l-yl}pyrimidine

The title compound was prepared by addition of 2-bromopyrimidine (3.67 mg, 0.0231 mmol) to a solution of l-({6-[3-(methoxymethyl)-4-(piperidin-4-ylmethoxy)phenyl]- pyridin-3-yl}carbonyl)-4-methylpiperazine (9.2 mg, 0.0209 mmol; Intermediate 6) in DMSO (0.5 mL). The resulting homogenous solution was stirred for 10 h at r.t, for 16 h at 35 ⁰C and then concentrated under reduced pressure. The residue was redissolved in MeOH and purified by preparative HPLC (System E) to give the title compound as a slightly yellow solid. Yield 1.8 mg (17%). Analytical HPLC: purity 99% (System B), 99% (System A); HRESIMS (ESI⁺) calcd for C₂₉H₃₆N₆O₃ 516.2849, found 516.2849.

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 mM Hepes (Gibco Cat. no.15630-056), 0.1% BSA, 2mM IBMX (Sigma-Aldrich Cat No. 17018, pH 7.4). The potency of the agonist was quantified by determine the concentration that cause 50% activation of hGPRl 19 evoked increase in cAMP, EC50. Compounds of the invention showed a concentration-dependant increase in intracellular cAMP level and generally had an EC50 value of <10 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 F12 Kaighn's Nutrient Mixture Kaighn's modification supplemented with 10% Horse serum, 1.5 g/L sodium bicarbonate, 2.5% dialyzed and heat-mactivated Fetal Bovme Serum) as recommended by the provider. Cells are trypsmated, resuspended in growth media supplemented with 10 % DMSO, aliquoted and frozen as ready-to-use vials. 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 Modulators on Glucose-Stimulated Insulin Release

In vitro experiments

The effect of GPRl 19 modulators 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 premcubated in KRB (Krebs-Ringer bicarbonate) buffer and 3.3 mM glucose for 30 min, 37 °C Thereafter the batches with islets are incubated in 16.7 mM glucose and KRB buffer supplemented with vehicle or test compounds for 60 mm at 37 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 modulators on glucose stimulated insulin release is determined in diabetic mice models (eg Lep^ob/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 30mm-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 hepaπnated 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 Modulators on Incretin Secretion and Body Weight

In vivo experiments

The effect of GPRl 19 modulators on body weight is determined m diabetic and obese mice models, eg Lep^ob/ob or diet-induced obese (DIO) mice The food intake and body weight gain is measured during subchromc treatment with vehicle or test compound via oral gavage 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),

or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer or N-oxide thereof, wherein:

A is CH₂, O, NR¹⁰, C(O), S, S(O) or S(O)₂;

B is CH₂, O, NR¹⁰, C(O), S, S(O) or S(O)₂, provided that (i) when B is O, C(O), S, S(O) or S(O)₂, then A is CH₂; and (ii) when B is NR¹⁰, then A is CH₂ or CO; D is N, C or CR¹¹, provided that D must be CR¹¹ and said R¹¹ must be hydrogen or methyl when B is selected from O, NR¹⁰, C(O), S, S(O) and S(O)₂; ^₁₁₁ is a single bond when D is N or CR¹¹ or a double bond when D is C;

E and G are independently Cu-alkylene, each optionally substituted with a substituent independently selected from the group consisting of Ci_3-alkyl, Ci_₄- alkoxy, carboxy, fluoro-Ci_3-alkyl, hydroxy, hydroxymethyl, and fluoro, provided that the ring formed by D, E, N and G has not more than 7 ring atoms, and further provided that the said ring has 6 or 7 ring atoms when D is N, and yet further provided that the total number of substituents on E and G independently is not more than 2;

R¹ is C(O)OR², C(O)R², S(O)₂R², C(O)NR²R³ or -CH₂-C(O)NR²R³; 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 chlorine, bromine and fluorine, (c) Ci_₄-alkylsulfoximine,

(d) -S(O)ET,

(e) -S(O)₂R⁴,

(f) -S(O)₂NR⁵R⁵,

(g) -NR⁶S(O)₂R⁴,

(h) -CH₂-NR⁶C(O)R⁴,

(i) -NR⁶C(O)R⁴, ω C(O)NR⁵R⁵,

(k) -CH₂-C(O)NR⁵R⁵,

(1) -C(O)R⁴,

(m) H₂N-C(O)O ,

(n) CH₃-NH-C(O)O-,

(o) (CH₃)₂NC(O)O-,

(P) CH₃OC(O)NH ,

(q) C-heterocyclyl, optionally substituted with

ω -CN,

(s) -OR⁸,

(0 -SCF₃,

(u) NO₂,

(v) C-heterocyclylsulfonyl, optionally substituted with Ci-₄-alkyl,

(W) -NR⁵R⁵,

(X) -C(OH)CH₃CF₃,

(y) [CF₃CH₃(OH)C]-Ci_₆-alkyl,

(z) cyano-Ci.₆-alkyl,

(aa) guanidino,

(bb) amidino,

(cc) Cw-alkyl,

(ee) fluoro-Ci-₄-alkyl,

(ff) C₂_₆-alkenyl, (gg) fluoro-C_{2 4}-alkenyl,

(hh) hydroxy-C] β-alkyl,

(11) Ci ₄-alkylsulfonyl-Ci ₄-alkyl,

(JJ) hydroxy-C2 4-alkoxy-Ci 4-alkyl, (kk) C₂ 3-acyl-Ci 3-alkyl,

(11) C_{2 6}-alkynyl,

(mm) hydroxy-C₃ 6-cycloalkyl,

(nn) fluoro-C_{3 6}-cycloalkyl,

(00) methyl-C_{3 6}-cycloalkyl, (pp) C-heterocyclylcarbonyl, optionally substituted with Ci ₄-alkyl,

(qq) C_{3 6}-cycloalkyl,

(rr) C_{3 6}-cycloalkyl-Ci ₄-alkyl,

(ss) R⁵R⁵N-Ci ₂-alkyl,

(tt) -C(O)OR⁷, (uu) CH₂C(O)OR⁷,

(w) phenyl, and

(ww) 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 chlorine and fluorine,

(b) Ci ₄-alkyl,

(C) hydroxy,

(d) Ci ₄-alkoxy,

(e) -OCF₃,

(f) -SCF₃,

(g) CN,

GO -C(OH)CH₃CF₃,

(1) hydroxy-C] 4-alkyl,

(J) -CF₃,

(k) -S(O)₂CH₃,

(1) -S(O)₂NH₂,

(m) -S(O)₂NHCH₃,

(n) -S(O)₂N(CH₃),, (0) -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) -NH₂,

(v) -NHCH₃,

(w) -N(CH₃)₂, and (x) methoxycarbonyl;

R² is selected from:

(a) d-6-alkyl,

(b) Ci ₆-alkoxy-C₂_₆-alkyl, (c) hydroxy-C₂_₆-alkyl,

(d) fluoro-C₂-₆-alkyl,

(e) C₃_₆-alkynyl,

(f) C₃_₆-alkenyl,

(g) C₃_₇-cycloalkyl, (h) C₅_₈-cycloalkenyl,

(1) NR⁹R⁹, provided that R¹ is not selected from C(O)OR², C(O)NR²R³ and -CH₂-C(O)NR²R³,

(j) C-heterocyclyl, optionally substituted with

(k) C₇_₈-bicyclyl, optionally substituted with hydroxy, (1) C_7-8-bicyclylmethyl,

(m) azabicyclyl, optionally substituted with hydroxy,

(n) C₃_₇-cycloalkyl-Ci_₄-alkyl, wherein cycloalkyl is optionally substituted with methyl,

(o) C]_₆-alkylsulfonyl-C₂-₆-alkyl, (p) C₂_₃-acyl-Ci_₄-alkyl,

(q) arylcarbonyl-Ci_₄-alkyl,

(r) heteroarylcarbonyl-Ci ₄-alkyl,

(s) [CF₃CH₃(OH)C]-Ci_₆-alkyl, (t) iV-heterocyclylcarbonyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl, (u) C-heterocyclylcarbonyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl, (v) ammocarbonyl-C₂ e-alkyl,

(w) Ci ₃-alkylammocarbonyl-C₂-₆-alkyl, (x) di(Ci 3-alkyl)aminocarbonyl-C2 6-alkyl, (y) hydroxy-C_{2 4}-alkoxy-C_{2 4}-alkyl, (z) hydroxy-C₄ β-cycloalkyl, (aa) oxo-C_{4 6}-cycloalkyl,

(bb) fluoro-C_{4 6}-cycloalkyl, (cc) Ci ₃-alkoxy-C₄_₆-cycloalkyl, (dd) methyl-C3 6-cycloalkyl, (bb) oxo-N-heterocyclyl-C₂^t-alkyl, (cc) fluoro-Λ/-heterocyclyl-C_{2 4}-alkyl,

(dd) ammo-jV-heterocyclyl-C2 4-alkyl, (ee) hydroxy-N-heterocyclyl-C_{2 4}-alkyl, (ii) Λ^r-heterocyclyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl, (jj) C-heterocyclyl-Ci ₄-alkyl, wherein heterocyclyl is optionally substituted with methyl, (kk) aryl, (11) aryl-Ci ₄-alkyl, (mm) aryl-C_{3 6}-alkenyl, (nn) aryl-C3 6-alkynyl,

(oo) heteroaryl, (pp) heteroaryl-Ci ₄-alkyl, (qq) heteroaryl-C3 6-alkenyl, and (rr) heteroaryl-C_{3 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) Ci-₆-alkyl,

(c) fluoro-C₂-₆-alkyl,

(d) hydroxy-C₂-6-alkyl,

(e) Ci_₆-alkoxy-C₂-₆-alkyl,

(f> ammo-C₂-₆-alkyl,

(g) Ci_₃-alkylamino-C₂-₆-alkyl,

CO di(Ci .₃-alkyl)amino-C₂-₆-alkyl,

(O cyano-Ci-₆-alkyl, and ω Ci_₆-alkylsulfbnyl-C₂-₆-alkyl;

R⁴ is independently selected from:

(a) d-6-alkyl,

(b) fluoro-Ci ₆-alkyl,

(C) hydroxy-C₂-₆-alkyl,

(Φ Ci_₄-alkoxy-C₂-₄-alkyl,

(e) C₂-₄-acyl-Ci-₄-alkyl, ω carboxy-Ci_₃-alkyl,

(g) C₃_₆-cycloalkyl,

CO oxo-C₄-₆-cycloalkyl,

(O hydroxy-C₄_₆-cycloalkyl,

(D fluoro-C₄-₆-cycloalkyl,

(k) methyl-C_{3 6}-cycloalkyl,

(1) JV-heterocyclylcarbonyl-C₂-₄-alkyl, wherein heterocyclyl is optionally substituted with methyl,

(m) oxo-7V-heterocyclyl-C₂-₄-alkyl,

(n) fluoro-Λ^r-heterocyclyl-C₂-₄-alkyl,

(o) hydroxy-N-heterocyclyl-C₂-₄-alkyl,

(P) amino-N-heterocyclyl-C₂-₄-alkyl,

(q) aminocarbonyl-C₂-₄-alkyl,

(r) Ci-3-alkylaminocarbonyl-C2-4-alkyl,

(S) di(Ci ₃-alkyl)aminocarboiryl-C2 4-alkyl,

O) C₂-₃-acylamino-C₂-₄-alkyl,

(u) hydroxy-C₂-₄-alkoxy-C₂-₄-alkyl, (v) C-heterocyclylcarbonyl-C₂-₄-alkyl, wherein heterocyclyl is optionally substituted with methyl,

(w) C₃_₆-cycloalkyl-Ci_₂-alkyl,

(x) amino-C2-4-alkyl, (y) Ci_₂-alkylamino-C₂-₄-alkyl,

(z) di(Ci _₂-alkyl)amino-C₂-₄-alkyl,

(aa) phenyl, and

(bb) 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,

(Φ -CN,

(e) -CF₃,

(f> d-₄-alkyl,

(g) -OCF₃, and

CO -C(O)CH₃;

R⁵ is each independently selected from:

(a) hydrogen,

(b) Cw-alkyl,

(c) C_{3 4}-cycloalkyl,

(d) fluoro-C₂-₄-alkyl,

(e) amino-C₂-₆-alkyl,

(f) cyano-Ci-₆-alkyl,

(g) hydroxy-C₂-₆-alkyl,

CO dihydroxy-C₂-₆-alkyl,

(i) C]_₄-alkoxy-C₂^-alkyl, ω Ci_₄-alkylamino-C₂-₄-alkyl,

(k) di(Ci _4-alkyl)amino-C2-4-alkyl,

(1) aminocarbonyl-Ci ₄-alkyl,

(m) C₂-₃-acylamino-C₂-₄-alkyl,

CO Ci_₄-alkylthio-C₂-₄-alkyl, (o) C₂-₄-acyl-Ci_₄-alkyl, and

(p) C]_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) amino,

(cc) methylamino,

(dd) dimethylamino, (ee) hydroxymethyl, and

(ff) ammomethyl; 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; and when the two R⁵ groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with Ci ₄-alkyl;

R⁶ is independently selected from:

(a) hydrogen,

(b) d_₄-alkyl, and

(c) hydroxy-C_{2 4}-alkyl,

R⁷ is independently selected from

R⁸ is independently selected from:

(a) hydrogen,

(b) Ci_₆-alkyl, (c) fluoro-Ci-₆-alkyl,

(d) hydroxy-C₂-6-alkyl,

(e) ammo-C_{2 6}-alkyl,

(f) Ci_₃-alkylamino-C₂-₄-alkyl,

(g) di(Ci ₃-dialkyl)amino-C₂^-alkyl, (h) Ci ₄-alkylsulfonyl-C_{2 4}-alkyl,

(i) N-heterocyclyl-C_{2 4}-alkyl, wherein heterocyclyl is optionally substituted with methyl,

(j) C-heterocyclyl, optionally substituted with methyl, (k) C₂ 3-acylammo-C_{2 4}-alkyl,

(1) [CF₃CH₃(OH)C]-Ci ₆-alkyl, (m) C_{3 6}-cycloalkyl, (n) methyl-C₃ β-cycloalkyl, (0) C_{3 6}-cycloalkyl-Ci ₂-alkyl, (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,

R⁹ is each independently selected from

(b) ammo-C_{2 4}-alkyl,

(c) Ci ₄ alkylammo C_{2 4} alkyl,

(d) di(Ci 4-alkyl)ammo-C2 4-alkyl, (e) C_{2 3}-acylammo-C_{2 4}-alkyl,

(f) Ci 4-alkylthio-C2 4-alkyl, and

(g) C_{2 4}-acyl-Ci ₄-alkyl, or two R groups together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with 1) a substituent selected from

(aa) hydroxy, (bb) ammo, (cc) methylammo, (dd) dimethylamino, (ee) hydroxymethyl, and

(ff) ammomethyl,

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; and when the two R⁹ groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with Ci_₄-alkyl;

R¹⁰ is independently selected from:

(a) hydrogen,

(b) Ci-6-alkyl,

(c) cyclopropyl,

(d) cyclobutyl,

(e) cyclopropylmethyl,

(f) fluoro-C2-6-alkyl,

(g) hydroxy-C2 e-alkyl,

CO Ci_₂-alkoxy-C₂-₆-alkyl,

(i) amino-C₂-₆-alkyl,

(D di(Ci _₃-alkyl)amino-C₂-₆-alkyl,

(k) Ci_₃-alkylamino-C₂-₆-alkyl,

(1) cyano-C₂-₄-alkyl,

(m) C₂-₆-acyl,

(n) C₂-₆-acyl-Ci_₆-alkyl, and

(o) Ci_6-alkylsulfonyl-Ci_6-alkyl;

R¹¹ is selected from:

(a) hydrogen,

(b) hydroxy,

(C) fluorine,

(d) Ci_4-alkoxy, and

(e) methyl;

R¹² is selected from:

(a) hydrogen,

(b) Ci-3-aIkyl,

(C) Ci_₃-alkoxy-Ci_₃-alkyl, (d) hydroxy-C2-4-alkyl,

(e) dihydroxy-C₂-₄-alkyl,

(f) hydroxy-C₂-₄-alkoxy-C₂-₄-alkyl,

(g) ammo-C2-4-alkyl,

(h) di(Ci _₃-alkyl)amino-C₂-₄-alkyl,

(i) Ci_₃-alkylamino-C₂-₄-alkyl,

(j) aminocarbonyl-C₂-₄-alkyl,

(k) C^-alkylaminocarbonyl-C^-alkyl,

(1) di(Ci _₃-alkyl)aminocarbonyl-C₂-₄-alkyl,

(m) C₂-₃-acyl-Ci_₄-alkyl,

(n) C]_₄-alkylsulfonyl-Ci_₄-alkyl, and

(o) C₂-₃-acylamino-C₂-₄-alkyl.

2. A compound according to claim 1 having Formula (Ib),

wherein A is CH₂, O or NR^iυ;

B is CH₂, O or NR¹⁰, provided that when B is O or NR¹⁰, then A is CH₂; m is each independently 0 or 1 ,

D is N or CR¹¹, provided that D must be CR¹¹ and said R¹¹ must be hydrogen or methyl when B is O or NR¹⁰, and further provided that each m is 1 when D is N;

Ar , Z , Z , R to R and R are as defined in claim 1 ;

R¹⁰ is selected from:

(a) hydrogen,

(b) C_M-alkyl,

(c) cyclopropyl, (d) cyclobutyl,

(e) cyclopropylmethyl,

(f> fluoro-C₂-₄-alkyl,

(g) Ci_2-alkoxy-C2-3-alkyl,

(h) hydroxy-C₂-₄-alkyl,

CD ammo-C₂-₄-alkyl,

(k) methylamino-C₂-₄-alkyl,

(1) dimethylamino-C₂-₄-alkyl, and

(m) cyano-C24-alkyl;

R¹¹ is selected from:

(a) hydrogen,

(b) hydroxy,

(C) fluorine, and

(Φ methyl.

3. A compound according to claim 1 or 2 having Formula (Ic),

wherein A is O and B is CH₂, or A is CH₂ and B is O;

Z¹, Z², R¹ to R⁷, R⁹ and R¹² are as defined in claim 1 ;

Ar¹ is phenyl or pyridinyl, each of which is optionally substituted m 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,

(h) -NR⁶C(O)R⁴,

(0 -CH₂-NR⁶C(O)R⁴,

CD -C(O)NR⁵R⁵,

(k) -CH₂-C(O)NR⁵R⁵,

(1) C(O)R⁴,

(m) H₂N-C(O)O-,

(n) CH₃-NH-C(O)O-,

(o) (CH₃)₂NC(O)O ,

(P) -NHC(O)OCH₃,

(q) C-heterocyclyl, optionally substituted with methyl,

(r) -CN,

(S) -OR⁸,

0) -SCF₃,

(u) C-heterocyclylsulfonyl, optionally susbtituted with methyl,

(v) -NR⁵R⁵,

(W) -C(OH)CH₃CF₃,

(x) cyano-Ci-₆-alkyl,

(y) Cw-alkyl,

(aa) fluoro-Ci-₄-alkyl,

(bb) C₂_₆-alkenyl,

(CC) fluoro-C₂_₄-alkenyl,

(dd) hydroxy- C i -β-alkyl,

(ee) Ci_₄-alkylsulfonyl-Ci-₄-alkyl,

(ff) hydroxy-C₂_₄-alkoxy-Ci -₄-alkyl,

(gg) C₂_₃-acyl-Ci_₃-alkyl,

(hh) C₂_6-alkynyl,

(ϋ) C_{3 6}-cycloalkyl,

Oi) hydroxy-C₃_₆-cycloalkyl,

(kk) fluoro-C₃_₆-cycloalkyl, (11) methyl-C3 β-cycloalkyl,

(mm) C-heterocyclylcarbonyl, optionally substituted with methyl,

(nn) C3 6-cycloalkyl-Ci ₄-alkyl,

(00) R⁵R⁵N-Ci 2-alkyl, (pp) -C(O)OR⁷,

(qq) -CH₂C(O)OR⁷, and

(rr) 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 claim 1 ,

R⁸ is independently selected from

(a) hydrogen,

(b) C_{1 4}-alkyl, (c) CF₃,

(d) C3 s-cycloalkyl,

(e) methyl-C_{3 5}-cycloalkyl, and

(f) C heterocyclyl, optionally substituted with methyl

A compound according to any one of claims 1 to 3, wherein A is O and B is CH₂

A compound according to any one of claims 1 to 4, wherein Ar¹ is phenyl or pyridmyl, each of which is optionally substituted m one or two positions with a substituent independently selected from the group Z⁴ consisting of (a) halogen selected from chloπne and fluorine,

(b) Ci ₄-alkylsulfoximme,

(c) Ci ₄ alkylsulfonyl,

(d) Ci ₄-alkylsulfmyl,

(e) hydroxy-C_{2 4}-alkylsulfonyl, (f) C_{3 5}-cycloalkylsulfonyl,

(g) methyl-C3 5-cycloalkylsulfonyl, (h) tπfluoromethylsulfonyl,

(1) -S(O)₂NR^5AR^5A,

(j) Ci ₄-alkylsulfonamido, (k) C₂-₄-acylamino,

(1) C₂-₄-acylaminomethyl,

(m) carboxy-Cu-alkylcarbonylamino,

(n) -C(O)NR^3AR^5A,

(o) -CH₂-C(O)NR^5AR^5A,

(P) -NHC(O)OCH₃,

(q) C₂-₄-acyl,

(r) C₃_₅-cycloalkylcarbonyl,

(S) Ci_₄-alkoxy,

(t) C3-5-cycloalkyloxy,

(u) C-heterocyclyl,

(v) -CN,

(w) -OH,

(x) -OCF₃,

(y) -CF₃,

00 -NR^5AR^5A,

(aa) -C(OH)CH₃CF₃,

(bb) cyano-Ci-₂-alkyl,

(CC) C_M-alkyl,

(dd) C₃_₅-cycloalkyl,

(ee) Ci_₂-alkoxy-Ci_₂-alkyl,

(ff) vinyl,

(gg) ethynyl,

(hh) hydroxy- C i _-2-alkyl,

(ϋ) C-heterocyclyloxy, optionally substituted with methyl,

Cu) R^5AR^5AN-Ci_₂-alkyl,

(kk) -C(O)OR^7A, and

(H) -CH₂C(O)OR^7A;

R¹ is a group R^1A selected from C(O)OR^2A, C(O)R^2A, S(O)₂R^2A, C(O)NR^2AR^3A,

-CH₂-C(O)NR^2AR^3A, or a 5- or 6-membered heteroaryl group linked via a ring carbon atom, wherein the said heteroaryl group is optionally substituted with Ci -₄- alkyl; R^2Λ is selected from

(a) Ci-e-alkyl,

(b) Ci_₆-alkoxy-C₂-₆-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, (h) C₅_₈-cycloalkenyl, (i) NR^9AR^9A provided that R^1A is not selected from C(O)OR^2A,

C(O)NR^2AR^3A and -CH₂-C(O)NR^2AR^3A,

(j) C-heterocyclyl, optionally substituted with methyl,

(k) C7-8-bicyclyl,

(1) 2-norbornylmethyl, (m) azabicyclyl,

(n) C₃_₆-cycloalkyl-Ci_₄-alkyl, wherein cycloalkyl is optionally substituted with methyl,

(o) C₂-₃-acyl-Ci-₄-alkyl,

(p) arylcarbonyl-Ci_₄-alkyl, (q) heteroarylcarbonyl-Ci_₄-alkyl,

(r) [CF₃CH₃(OH)C]-Ci_₆-alkyl,

(s) N-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,

(t) hydroxy-C₄_₆-cycloalkyl, (u) oxo-C_{4 6}-cycloalkyl,

(v) fluoro-C₄_₆-cycloalkyl,

(w) methoxy-C₄-₆-cycloalkyl,

(x) methyl-C_{3 6}-cycloalkyl,

(y) oxo-N-heterocyclyl-C₂^-alkyl, (z) hydroxy-N-heterocyclyl-C₂_₄-alkyl,

(a) fluoro-N-heterocyclyl-C2 4-alkyl,

(a) ammo-iV-heterocyclyl-C_{2 4}-alkyl,

(cc) iV-heterocyclyl-C₂-₄-alkyl, wherein heterocyclyl is optionally substituted with methyl, (dd) C-heterocyclyl-Ci_₄-alkyl, wherein heterocyclyl is optionally substituted with methyl, (ee) aryl, (ff) aiyl-Ci 4-alkyl, (gg) heteroaryl, and

(hh) 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 chlorine and fluorine,

(b) methyl,

(c) ethyl,

(d) methoxy,

(e) ethoxy, ω isopropoxy,

(g) hydroxy,

CO -OCF₃,

(i) -CF₃, ω -CN,

(k) -C(OH)CH₃CF₃,

(1) dimethylamino,

(m) hydroxymethyl,

CO -S(O)₂CH₃,

(O) -C(O)CH₃, and

(P) -C(O)NH₂;

R^3Λ is selected from

(a) hydrogen,

(b) Ci-₄-alkyl,

(c) hydroxy-C₂-₄-alkyl, and

(d) methoxy-C₂_4-alkyl;

R^5A is each independently selected from (a) hydrogen, (b) C_{1 3}-alkyl,

(c) C] ₂-alkoxy-C₂-₄-alkyl,

(d) C_{3 4}-cycloalkyl,

(e) hydroxy-C2 4-alkyl, (f) cyano-Ci ₃-alkyl,

(g) dihydroxy-C_{2 4}-alkyl, (h) ammocarbonyl-Ci ₂-alkyl, and (1) di(Ci ₂-alkyl)ammo-C₂ 3-alkyl, or two R^5A groups together with the nitrogen to which they are attached form a heterocyclic πng, wherein said heterocyclic ring may be optionally substituted with

I) a substituent selected from

(aa) hydroxy,

(bb) ammo,

(cc) methylammo, (dd) dimethylamino,

(ee) hydroxymethyl, and

(ff) ammomethyl,

II) one or two oxo groups, or

III) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylammo and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom, and when the two R groups form a piperazme ring, the nitrogen of the piperazme ring that allows the substitution is optionally substituted with methyl,

R^7A is independently selected from Ci -₄-alkyl,

Two groups R^9A together with the nitrogen to which they are attached form a heterocyclic πng, wherein said heterocyclic ring may be optionally substituted with 1) one hydroxy or ammo 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 ammo, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R^9A groups form a piperazme ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with methyl,

R¹² is selected from.

(a) hydrogen, and

(b) C_{1 3}-alkyl.

6. A compound according to claim 5, wherein Ar¹ is selected from (aminocarbonyl)phenyl, fluoro(aminocarbonyl)phenyl, fiuoro [(propylammo)- carbonyl]phenyl, [(dimethylamino)carbonyl]phenyl, (methylsulfϊnyl)phenyl, fluoro- (methylsulfonyl)phenyl, (methylsulfonyl)pyridinyl, {[[2-(dimethylammo)ethyl]- (methyl)ammo]carbonyl}pyridinyl, (ammocarbonyl)pyπdmyl and (4-methyl- piperazin- 1 -yl)carbonylpyridmyl

7. A compound according to claim 5 or 6, wherein R^1A is selected from C(O)OR^2A, C(O)R^2A or a 6-membered heteroaryl group.

8. A compound according to any one of claims 5 to 7, wherein R^1A is C(O)OR^2A and wherein R^2A is selected from tert -butyl, ethyl and isopropyl

9 A compound according to any one of claims 5 to 7, wherein R^1A is C(O)R^2A and wherein R^2A is 1-ethylpropyl.

10. A compound according to any one of claims 5 to 7, wherein R^1A is 2-pyrimidmyl

11. A compound according to any one of claims 5 to 10, wherein R¹² is selected from hydrogen and methyl

12 A compound according to any one of claims 1 to 11, which is selected from

• tørt-Butyl 4-({[4'-(ammocarbonyl)-3-(hydroxymethyl)biphenyl-4-yl]oxy}methyl)- piperidme- 1 -carboxylate, • tert-Butyl 4-({[4'-(aminocarbonyl)-3-(methoxymethyl)biphenyl-4-yl]oxy} - methyl)piperidine- 1 -carboxylate;

• tert-Butyl 4-({[4'-(aminocarbonyl)-3'-fluoro-3-(methoxymethyl)biphenyl-4-yl]- oxy} methyl)piperidine- 1 -carboxylate; • tert-Butyl 4-[({3'-fluoro-3-(methoxymethyl)-4'-[(propylammo)carbonyl]biphenyl-

4-yl} oxy)methyl]piperidme- 1 -carboxylate;

• tert-Butyl 4-({[4'-[(dimethylamino)carbonyl]-3-(methoxymethyl)biphenyl-4-yl]- oxy} methyl)piperidine- 1 -carboxylate;

• tert-Butyl 4-({[2'-fluoro-3-(methoxymethyl)-4'-(methylsulfonyl)biphenyl-4-yl]- oxy} methyl)piperidine-l -carboxylate;

• tert-Butyl 4-({[3-(methoxymethyl)-4'-(methylsulfϊnyl)biphenyl-4-yl]oxy}methyl)- piperidme- 1 -carboxylate;

• tert-Butyl 4-( {2-(methoxymethyl)-4- [5 -(methylsulfonyl)pyridin-2-yl]phenoxy } - methyl)piperidine- 1 -carboxylate; • tert-Butyl 4-{[4-(6-{[[2-(dimethylammo)ethyl](methyl)amino]carbonyl}pyridm-

3-yl)-2-(methoxymethyl)phenoxy]methyl}piperidine-l -carboxylate;

• tert-Butyl 4- {[4-[5-(aminocarbonyl)pyridin-2-yl]-2-(methoxymethyl)phenoxy]- methyl} piperidme- 1 -carboxylate;

• tert-Butyl 4-({2-(methoxymethyl)-4-[6-(methylsulfonyl)pyridin-3-yl]phenoxy}- methyl)piperidine- 1 -carboxylate;

• tert-Butyl 4- [(2-(methoxymethyl)-4- {6- [(4-methylpiperazin- 1 -yl)carbonyl] - pyridin-3-yl}phenoxy)methyl]piperidme-l-carboxylate,

• tert-Butyl 4- [(2-(methoxymethyl)-4- {5 - [(4-methylpiperazin- 1 -yl)carbonyl] - pyridin-2-yl} phenoxy)methyl]piperidine- 1 -carboxylate; • Ethyl 4-[(2-(methoxymethyl)-4-{6-[(4-methylpiperazin-l-yl)carbonyl]pyridin-3- yl} phenoxy)methyl]piperidine- 1 -carboxylate;

• Isopropyl 4-[(2-(methoxymethyl)-4-{6-[(4-methylpiperazm-l-yl)carbonyl]- pyridin-3-yl}phenoxy)methyl]piperidine-l-carboxylate;

• 2-{4-[(2-(Methoxymethyl)-4-{6-[(4-methylpiperazin-l-yl)carbonyl]pyridin-3-yl}- phenoxy)methyl]piperidin- 1 -yljpyrimidme;

• Ethyl 4-[(2-(methoxymethyl)-4-{5-[(4-methylpiperazin-l-yl)carbonyl]pyridin-2- yl} phenoxy)methyl]piperidine- 1 -carboxylate,

• Isopropyl 4-[(2-(methoxymethyl)-4-{5-[(4-methylpiperazin-l-yl)carbonyl]- pyridin-2-yl} phenoxy)methyl]piperidine- 1 -carboxylate; • l-({6-[4-{[l-(2-Ethylbutanoyl)piperidm-4-yl]methoxy}-3-(memoxymethyl)- phenyl]pyridm-3-yl}carbonyl)-4-methylpiperazme, and

• 2-{4-[(2-(Methoxymethyl)-4-{5-[(4-methylpiperazm-l-yl)carbonyl]pyridm-2-yl}- phenoxy)methyl]piperidin- 1 -yl}pyrimidme

13 A compound according to any one of claims 1 to 12 for use m therapy

14. A compound according to any one of claims 1 to 12 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

15. Use of a compound according to any one of claims 1 to 12 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

16. A method for the treatment or prophylaxis of disorders relating to GPRl 19 activity which comprises administering to a mammal, including man, m need of such treatment an effective amount of a compound according to any one of claims 1 to 12, 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

17. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 12 as active ingredient in combination with a pharmaceutically acceptable diluent or earner.

18 The pharmaceutical formulation according to claim 17 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

19. Use of a compound according to any one of claims 1 to 12, m 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

20 A method for the treatment or prophylaxis of disorders relating to GPRl 19 activity which comprises administering to a mammal, including man, m need of such treatment an effective amount of a compound according to any one of claims 1 to 12 m 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, inadequate glucose tolerance, msuhn resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, endothelial dysfunction and osteoporosis

21 The pharmaceutical formulation according to claim 17 which m addition comprises a DPP-IV inhibitor.