WO2008121570A1 - Compounds and methods for modulating g protein-coupled receptors - Google Patents

Abstract

The invention provides methods for modulating G protein-coupled receptor 20 (GPR20), and methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated GPR20.

Description

COMPOUNDS AND METHODS FOR MODULATING G PROTEIN-COUPLED RECEPTORS

Cross-Reference to Related Applications

[0001] This application claims the benefit of U.S. provisional application serial number 60/908,779, filed March 29, 2007, which is incorporated herein by reference in its entirety.

Technical Field

[0002] The present invention generally relates to G protein-coupled receptors.

Background Art

[0003] G-protein coupled receptors (GPCRs) constitute a major class of proteins responsible for transducing a signal within a cell. Upon binding of a ligand to an extracellular portion of a GPCR, a signal is transduced within the cell that results in a change in a biological or physiological property of the cell. GPCRs, along with G-proteins and effectors (intracellular enzymes and channels modulated by G-proteins), are the components of a modular signaling system that connects the state of intracellular second messengers to extracellular inputs.

[0004] GPCR genes and gene-products are potential causative agents of disease (Spiegel et al., J. Clin. Invest. 92: 1119 1125 (1993)). For example, specific defects in the rhodopsin gene and the V2 vasopressin receptor gene have been shown to cause various forms of retinitis pigmentosum (Nathans et al., Annu. Rev. Genet. 26:403 424 (1992)), and nephrogenic diabetes insipidus (Holtzman et al., Hum. MoI. Genet. 2:1201 1204 (1993)). These receptors are important to both the central nervous system and peripheral physiological processes.

[0005] G protein coupled receptor 120 (GPR120) is an orphan G protein-coupled receptor that is abundantly expressed in intestine, and functions as a receptor for unsaturated long-chain free fatty acids (FFAs). (Hirasawa et al., Nature Medicine 11:90-94 (2005)). Stimulation of GPR120 by FFAs has been reported to promote the secretion of glucagon-like peptide-1 (GLP- 1) and increase circulating insulin, and to activate the extracellular signal-regulated kinase (ERK) cascade. (Katsuma et al, J. Biol. Chem. 280:19507-19515 (2005)). Peripherally, GLP-I affects gut motility, and inhibits gastric acid and glucagon secretion. In the central nervous system, GLP-I induces satiety, leading to reduced weight gain. In the pancreas, GLP-I induces expansion of insulin- secreting β-cell mass, in addition to the augmentation of glucose-stimulated insulin secretion. (MacDonald et al., Diabetes 51:Supp. 3 S434-S442 (2002)).

[0006] Given the significance of GLP- 1 as a potent insulinotropic incretin and in appetite and feeding control, GPR120 is a promising target for the treatment of diabetes, obesity and other eating disorders. Because of the importance of GPCRs as targets for drug action and development, there remains a need for the development of agents which modulate GPCR function.

Disclosure of the Invention

[0007] The invention provides methods for modulating G protein-coupled receptors, more particularly GPR120.

[0008] In one aspect, the present invention provides methods for modulating G protein- coupled receptor 20 (GPR20), comprising administering to a cell or tissue system or to a mammalian subject, a therapeutically effective amount of a compound of Formula (1):

O Il HO— C— X— N— (CR₂)_m-Y— L— Z

R¹ (1)

or pharmaceutically acceptable salts or pharmaceutical compositions thereof, wherein:

L is a bond, Ci_-2 alkyl, C₂ alkenyl, O(CR₂)_n or NR(CR₂)_O;

X and Y are independently a 5-10 membered monocyclic or fused aryl or heteroaryl;

Z is an optionally substituted C_1-6 alkyl, C_1-6 alkoxy, C3-7 cycloalkyl, or a 5-10 membered monocyclic or fused aryl, heteroaryl or heterocyclic ring containing N, O or S;

R and R¹ are independently H or C_1-6 alkyl; m and 0 are independently 0- 1 ; n is 0-3; thereby modulating said GPR20.

[0009] In the above Formula (1), X may be phenyl, naphthalenyl, pyridyl, pyrimidyl or thiazolyl. In other examples, Y is phenyl, naphthalenyl or pyridyl. In some examples, each X, Y and Z is an optionally substituted phenyl.

[0010] In another embodiment, the present invention provides methods for modulating G protein-coupled receptor 20 (GPR20), comprising administering to a cell or tissue system or to a mammalian subject, a therapeutically effective amount of a compound of Formula (2):

wherein R² is halo, optionally halogenated C_1-6 alkyl, C₂_6 alkenyl, C₂_6 alkynyl, cyano, nitro or (CR₂)_PR⁸;

R³, R⁴, R⁵, R⁶ and R⁷ are independently CR¹⁰ or N; or R³, R⁴, R⁵, R⁶ and R⁷ are independently C when attached to the NR¹ moiety;

R⁸ is O(CR₂)_qR⁹, S(CR₂)_qR⁹, CO₂R⁹, CONR⁹(CR₂)_qR⁹, SO₂NR⁹(CR₂)_qR⁹ or NR⁹(CR₂)_qR⁹ or R⁹;

R⁹ is H, optionally halogenated C]_₆ alkyl, or an optionally substituted C₃_₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl;

R¹⁰ is H or R²; j is 0-4; m is 0-1; p and q are independently 0-4; and

R, R¹, L and Z are as defined in Formula (1).

[0011] In yet another embodiment, the invention provides methods for preventing, ameliorating or treating a condition mediated by G protein-coupled receptor 20 (GPR20), comprising administering to a cell or tissue system or to a mammalian subject, an effective amount of a compound of Formula (2),

or pharmaceutically acceptable salts or pharmaceutical compositions thereof, wherein:

L is a bond, Ci_₂ alkyl, C₂ alkenyl, O(CR₂)_n or NR(CR₂)_O;

Z is an optionally substituted Ci_₆ alkyl, Ci_₆ alkoxy, C₃_₇ cycloalkyl, or a 5-10 membered monocyclic or fused aryl, heteroaryl or heterocyclic ring containing N, O or S, provided Z is not quinolinyl; R and R¹ are independently H or Ci_₆ alkyl;

R² is halo, optionally halogenated C_1-6 alkyl, C₂_6 alkenyl, C₂_6 alkynyl, cyano, nitro or (CR₂)_PR⁸;

R³, R⁴, R⁵, R⁶ and R⁷ are independently CR¹⁰ or N; or R³, R⁴, R⁵, R⁶ and R⁷ are independently C when attached to the NR¹ moiety;

R⁸ is O(CR₂)_qR⁹, S(CR₂)_qR⁹, (CR₂)_qCO₂R⁹, CONR⁹(CR₂)_PR⁹, SO₂NR⁹(CR₂)_PR⁹ or NR⁹(CR₂)_qR⁹ or R⁹;

R⁹ is H, optionally halogenated Ci_₆ alkyl, or an optionally substituted C₃_₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl;

R¹⁰ is H, halo, optionally halogenated C_1-6 alkyl, C₂_6 alkenyl or C₂_6 alkynyl; j is 0-4; m is 0-1; and p and q are independently 0-4; thereby treating said condition.

[0012] In the above Formula (2), R⁴ and R⁶ may independently be CH or N; or R⁴ and R⁶ are independently C when attached to NR¹; and R³, R and R⁷ are each CH. In other examples, R¹⁰ is H, halo, optionally halogenated Ci_6 alkyl, C₂_6 alkenyl or C₂_6 alkynyl.

[0013] In the above Formula (1) and (2), Z is an optionally substituted phenyl, naphthalenyl, thiazolyl, pyridyl, benzoxazoyl,

cycloalkyl, furanyl, benzotriazolyl, benzothiophenyl, thiophenyl, oxazolyl, indolyl, or pyrimidyl. In particular examples, Z is an optionally substituted phenyl. In other examples, L is 0(CR₂),, and n is 0-1.

[0014] Furthermore, the present invention provides the use of a compound of Formula (1) or (2), for treating a condition mediated by G protein-coupled receptor 120 (GPR120). The present invention also provides the use of a compound of Formula (1) or (2) in the manufacture of a medicament for treating a condition mediated by GPR 120.

[0015] Examples of conditions which may be ameliorated or treated using the compounds of the invention include but are not limited to diabetes such as diabetes mellitus, dyslipidemia such as hyperlipidemia, obesity or anorexia.

Definitions

[0016] "Alkyl" refers to a moiety and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, and may be straight-chained or branched. An optionally substituted alkyl, alkenyl or alkynyl as used herein may be optionally halogenated (e.g., CF₃), or may have one or more carbons that is substituted or replaced with a heteroatom, such as NR, O or S (e.g., -OCH₂CH₂O-, alkylthiols, thioalkoxy, alkylamines, etc).

[0017] "Aryl" refers to a monocyclic or fused bicyclic aromatic ring containing carbon atoms. For example, aryl may be phenyl or naphthyl. "Arylene" means a divalent radical derived from an aryl group.

[0018] "Heteroaryl" as used herein is as defined for aryl above, where one or more of the ring members is a heteroatom. Examples of heteroaryls include but are not limited to pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.

[0019] A "carbocyclic ring" as used herein refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring containing carbon atoms, which may optionally be substituted, for example, with =0. Examples of carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.

[0020] A "heterocyclic ring" as used herein is as defined for a carbocyclic ring above, wherein one or more ring carbons is a heteroatom. For example, a heterocyclic ring may contain N, O, S, -N=, -S-, -S(O), -S(O)₂-, or -NR- wherein R may be hydrogen, Ci^alkyl or a protecting group. Examples of heterocyclic rings include but are not limited to morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.

[0021] Unless otherwise indicated, when a substituent is deemed to be "optionally substituted," it is meant that the substituent is a group that may be substituted with one or more group(s) individually and independently selected from, for example, an optionally halogenated alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, alkynyl, amide, amino, including mono- and di-substituted amino groups, aryl, aryloxy, arylthio, carbonyl, carbocyclic, cyano, cycloalkyl, halogen, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclic, hydroxy, isocyanato, isothiocyanato, mercapto, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, perhaloalkyl, perfluoroalkyl, silyl, sulfonyl, thiocarbonyl, thiocyanato, trihalomethanesulfonyl, and the protected compounds thereof. The protecting groups that may form the protected compounds of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference in their entirety.

[0022] The terms "co-administration" or "combined administration" or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0023] The term "pharmaceutical combination" as used herein refers to a product obtained from mixing or combining active ingredients, and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0024] The term "therapeutically effective amount" means the amount of the subject compound that will elicit a biological or medical response in a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0025] The term "administration" and or "administering" of the subject compound should be understood to mean as providing a compound of the invention including a pro-drug of a compound of the invention to the individual in need of treatment.

[0026] As used herein, the terms "treat", "treating" and "treatment" refer to a method of alleviating or abating a disease and/or its attendant symptoms.

Modes of Carrying Out the Invention

[0027] The invention provides methods for modulating G protein-coupled receptors, more particularly GPR120. [0028] In one aspect, the present invention provides methods for modulating G protein- coupled receptor 20 (GPR20), comprising administering to a cell or tissue system or to a mammalian subject, a therapeutically effective amount of a compound of Formula (1):

HO— ? C— X— N— (CR₂)_m-Y— L— Z

R¹ (1)

or pharmaceutically acceptable salts or pharmaceutical compositions thereof, wherein:

L is a bond, Ci_₂ alkyl, C₂ alkenyl, O(CR₂)_n or NR(CR₂)_O;

X and Y are independently a 5-10 membered monocyclic or fused aryl or heteroaryl;

Z is an optionally substituted Ci_₆ alkyl, Ci_₆ alkoxy,

cycloalkyl, or a 5-10 membered monocyclic or fused aryl, heteroaryl or heterocyclic ring containing N, O or S;

R and R¹ are independently H or C_1-6 alkyl; m and o are independently 0- 1 ; n is 0-3; thereby modulating said GPR20.

[0029] The present invention also provides methods for modulating G protein-coupled receptor 20 (GPR20), comprising administering to a cell or tissue system or to a mammalian subject, a therapeutically effective amount of a compound of Formula (2):

wherein R is halo, optionally halogenated C]_₆ alkyl, C₂-₆ alkenyl, C₂_₆ alkynyl, cyano, nitro or (CR₂)_pR⁸;

R³, R⁴, R⁵, R⁶ and R⁷ are independently CR¹⁰ or N; or R³, R⁴, R⁵, R⁶ and R⁷ are independently C when attached to the NR¹ moiety;

R⁸ is O(CR₂)_qR⁹, S(CR₂)_qR⁹, CO₂R⁹, CONR⁹(CR₂)_qR⁹, SO₂NR⁹(CR₂)_qR⁹ or

NR⁹(CR₂)_qR⁹ or R⁹;

R⁹ is H, optionally halogenated Ci_₆ alkyl, or an optionally substituted

cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl; R¹⁰ is H or R²; j is 0-4; m is 0-1; p and q are independently 0-4; and

R, R¹, L and Z are as defined in Formula (1).

[0030] Furthermore, the invention provides methods for preventing, ameliorating or treating a condition mediated by G protein-coupled receptor 20 (GPR20), comprising administering to a cell or tissue system or to a mammalian subject, an effective amount of a compound of Formula (2),

or pharmaceutically acceptable salts or pharmaceutical compositions thereof, wherein:

L is a bond, Ci_₂ alkyl, C₂ alkenyl, O(CR₂)_n or NR(CR₂)_O;

Z is an optionally substituted C_1-6 alkyl, C_1-6 alkoxy, C3-7 cycloalkyl, or a 5-10 membered monocyclic or fused aryl, heteroaryl or heterocyclic ring containing N, O or S, provided Z is not quinolinyl;

R and R¹ are independently H or Ci_₆ alkyl;

R² is halo, optionally halogenated C_1-6 alkyl, C₂_6 alkenyl, C₂_6 alkynyl, cyano, nitro or (CR₂)_PR⁸;

R³, R⁴, R⁵, R⁶ and R⁷ are independently CR¹⁰ or N; or R³, R⁴, R⁵, R⁶ and R⁷ are independently C when attached to the NR¹ moiety;

R⁸ is O(CR₂)_qR⁹, S(CR₂)_qR⁹, (CR₂)_qCO₂R⁹, CONR⁹(CR₂)_PR⁹, SO₂NR⁹(CR₂)_PR⁹ or NR⁹(CR₂)_qR⁹ or R⁹;

R⁹ is H, optionally halogenated C_1-6 alkyl, or an optionally substituted C₃-₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl;

R¹⁰ is H, halo, optionally halogenated C_1-6 alkyl, C₂_6 alkenyl or C₂_6 alkynyl; j is 0-4; m is 0-1; and p and q are independently 0-4; thereby treating said condition.

[0031] The present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof. An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³⁵S, ¹⁸F, ³⁶Cl and ¹²³I. Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples, ³H and ¹⁴C isotopes may be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as ²H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

[0032] Compounds of Formula (1) and (2) may be useful for modulating G protein-coupled receptors (GPCRs), particularly GPR120. For example, compounds of Formula (1) and (2) may be useful as GPR120 agonists. Compounds of Formula (1) and (2) may also be useful for treating conditions mediated by GPR120, including but are not limited to diabetes such as diabetes mellitus, dyslipidemia such as hyperlipidemia, obesity or anorexia.

Pharmacology and Utility

[0033] Compounds of Formula (1) or (2) may modulate G protein-coupled receptors, and as such, are useful for treating diseases or disorders in which GPCR contribute to the pathology and/or symptomology of the disease. More particularly, compounds of Formula (1) or (2) may be used to prevent, ameliorate or treat a condition mediated by G protein-coupled receptor 120 (GPR120).

[0034] Examples of conditions mediated by GPR120 include but are not limited to obesity, diabetes, hyperphagia, endocrine abnormalities, triglyceride storage disease, Bardet-Biedl syndrome, Lawrence-Moon syndrome, Prader-Labhart- Willi syndrome, anorexia, and cachexia. In particular examples, obesity is defined as a body mass index (BMI) of 30 kg/m or more (National Institute of Health, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults (1998)). However, compounds of Formula (1) or (2) may be used to prevent, ameliorate or treat a condition characterized by a body mass index (BMI) of 25 kg/m or more, 26 kg/m or more, 27 kg/m or more, 28 kg/m or more, 29 kg/m or more, 29.5 kg/m or more, or 29.9 kg/m or more, all of which are typically referred to as overweight (National Institute of Health, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults (1998)).

[0035] In some embodiments, the methods of the invention comprise administering compounds of Formula (1) or (2) as an agent for regulating glycerol production from adipocytes, an agent for regulating blood glycerol, an agent for regulating lipolysis, an insulin resistance regulating agent, a stress regulating agent, an agent for regulating adrenocorticotropic hormone (ACTH) secretion, an agent for regulating growth hormone secretion, and an agent for regulating glucagon-like peptide- 1 (GLP-I) secretion.

[0036] Compounds of Formula (1) or (2) that are GPR120 agonists, or that potentiate the binding affinity of free fatty acids to GPR 120, may be useful as an agent for suppressing glycerol production from adipocytes, an agent for lowering blood glycerol, an agent for suppressing lipolysis, an agent for suppressing insulin resistance, a stress regulating agent, an adrenocorticotropic hormone (ACTH) secretion suppressing agent, a growth hormone secretion suppressing agent and a glucagon-like peptide-1 (GLP-I) secretion promoting agent. In particular examples, the GPR agonists useful as an adrenocorticotropic hormone (ACTH) secretion suppressing agent may be useful for preventing/treating related diseases, such as ACTH-producing tumor, Cushing's disease, infectious disease, secondary adrenocortical insufficiency, peptic ulcer, diabetes mellitus, mental disorder, cataract, glaucoma, tuberculous disease, hypertension, Cushing's syndrome (e.g., central obesity, edema, hypertension, menstrual disorder, extensive stretch mark, hirsutism, diabetes mellitus, full moon face, osteoporosis, hemorrhagic diathesis, mental disorder (e.g., depression, anxiety), muscular atrophy, loss of muscle strength, hypokalemia, hypercholesterolemia, impaired glucose resistance, leukocytosis), adrenocortical atrophy, etc.

[0037] Compounds of Formula (1) or (2) that are GPR 120 antagonists, or that reduce the binding affinity of free fatty acids to GPR 120, may be useful as an agent for promoting glycerol production from adipocytes, an agent for increasing blood glycerol, an agent for promoting lipolysis, an agent for promoting insulin resistance, a stress regulating agent, an agent for promoting adrenocorticotropic hormone (ACTH) secretion, an agent for promoting growth hormone secretion and an agent for suppressing glucagon-like peptide- 1 (GLP-I) secretion). In particular examples, the GPR 120 antagonists useful as an agent for promoting adrenocorticotropic hormone (ACTH) secretion may be useful for preventing/treating connective tissue diseases (e.g., chronic articular rheumatism, systemic lupus erythematosus, polymyositis, rheumatic fever, scleroderma), kidney diseases (e.g., nephrosis), respiratory diseases (e.g., bronchial asthma, pulmonary tuberculous pleuritis, sarcoidosis, diffuse interstitial pneumonia), alimentary diseases (e.g., ulcerative colitis, cholestatic acute hepatitis, fulminant hepatitis, chronic hepatitis, cirrhosis), neuromuscular diseases (e.g., encephalomyelitis, peripheral neuritis, multiple sclerosis, myasthenia gravis, facial paralysis), blood diseases (e.g., hemolytic anemia, agranulocytosis, purpura, aplastic anemia, leukemia, malignant lymphoma), endocrine-metabolic diseases (e.g., acute or chronic adrenocortical insufficiency, adrenogenital syndrome, malignant exophthalmos due to thyroid gland disease, ACTH isolated deficiency), skin diseases (e.g., urticaria, eczema, dermatitis, herpes zoster, psoriasis, drug allergy) or anaphylactic shock, etc.

[0038] Compounds of Formula (1) or (2) may also be useful as an agent for preventing/treating, for example, diabetes mellitus, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipemia, arteriosclerosis, angina pectoris, myocardial infarction, sexual dysfunction, obesity, pituitary dysfunctions (e.g., hypopituitarism, pituitary dwarfism, diabetes insipidus, acromegaly, Cushing's disease, hyperprolactinemia, syndrome of inappropriate secretion of anti-diuretic hormone), cancer (e.g., colorectal cancer), deficits in memory and learning, pancreatic exhaustion, hypoglycemia, insulin allergy, lipotoxicity, fatty atrophy, cancerous cachexia, hyperinsulinemia, hyperglycemia, disorder caused by high FFA flux, hypertriglyceridemia, fatty liver, dysfunction of heat production, cholelithiasis, eating disorder, anorexia, secretion disorders of intestinal hormones (e.g., cholecystokinin (CCK), gastric inhibitory peptide (GIP), gastrin, glucagon-like peptide-1 (GLP-I), somatostatin, gastrin-releasing peptide, secretin, vasoactive intestinal peptide, motilin, substance P, neurotensin, galanin, neuropeptide Y, enkephalins, peptide YY, etc.) or circulatory diseases. GPR120 agonists may be particularly useful for preventing/treating diabetes mellitus, hyperlipemia, arteriosclerosis, angina pectoris or myocardial infarction, while GPR120 antagonists may be useful for preventing/treating anorexia and obesity, such as obesity with visceral fat accumulation).

[0039] Furthermore, compounds of Formula (1) or (2) may be useful as an agent for preventing/treating diseases, for example, arteriosclerosis, arteriosclerotic diseases and their secondary diseases [e.g., acute coronary syndrome such as atherosclerosis, peripheral arterial disease, acute myocardial infarction, unstable angina, etc., ischemic heart diseases such as restenosis after percutaneous transluminal coronary angioplasty (PTCA), myocardial infarction, angina pectoris, etc., arteriosclerosis including angiocalcinosis, etc., intermittent claudication, apoplexy (cerebral infarction, cerebral embolism, brain hemorrhage, etc.), lacunar infarction, cerebrovascular dementia, gangrene, glomerulosclerosis, nephropathy, Tangier disease, etc.], vascular lesions in atherosclerosis and their secondary diseases (e.g., coronary heart disease (CHD), cerebral ischemia, etc.), lipid dysbolism and its secondary diseases, etc.

Administration and Pharmaceutical Compositions

[0040] In general, compounds of Formula (1) or (2) will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. Compounds of Formula (1) or (2) may be mixed with the other therapeutic agent in a fixed pharmaceutical composition, or may be administered separately, before, simultaneously with or after the other therapeutic agent.

[0041] Accordingly, the invention encompasses methods for using compounds of Formula (1) or (2) in combination with other therapeutic substances such as therapeutic agents for treating diabetes, diabetic complications, dyslipidemia and more particularly hyperlipidemia; antihypertensive agents, antiobesity agents, diuretics, chemotreating agents, immunotreating agents, immunomodulators, anti-inflammatory agents, antithrombotic agents, therapeutic agents for osteoporosis, antibacterial agents, antifungal agents, antiprotozoal agents, antibiotics, antitussives and expectorant drugs, sedatives, anesthetics, antiulcer agents, tranquilizers, antipsychotic agents, antitumor agents, muscle relaxants, antiepileptics, antidepressants, antiallergic agents, cardiac stimulants, antiarrhythmic agents, vasodilators, vasoconstrictors, narcotic antagonists, vitamins, vitamin derivatives, antiasthmatic agents, antidementia agents, treating agents for pollakiuria or urinary incontinence, therapeutic agents for dysuria, treating agents for atopic dermatitis, therapeutic agents for allergic rhinitis, vasopressors, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory mediator effect suppressants, inflammatory mediator effect suppressing antibodies, anti-inflammatory mediator effect suppressants, anti-inflammatory mediator effect suppressing antibodies and the like.

[0042] Therapeutic agents for diabetes include but are not limited to insulin preparations (e.g., animal insulin preparations extracted from pancreas of bovine or pig; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-I, etc.), oral insulin preparation and the like), insulin sensitizers (e.g., pioglitazone or a salt thereof (preferably hydrochloride), troglitazone, rosiglitazone or a salt thereof (preferably maleate), Reglixane (JTT-501), Netoglitazone (MCC- 555), YM-440, GI-262570, KRP-297, FK-614, CS-011, ( E)- -[[[4-[(5-methyl-2-phenyl-4- oxazolyl)methoxy]phenyl]methoxy]imino]benzenebutanoic acid and the like, compounds described in WO 99/58510 (e.g., (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)- benzyloxyimino]-4-phenylbutyric acid), compounds described in WO 01/38325, Tesaglitazar (AZ-242), Ragaglitazar (NN-622), BMS-298585, ONO-5816, BM-13-1258, LM-4156, MBX- 102, LY-519818, MX-6054, LY-510929, Balaglitazone (NN-2344), T-131 or a salt thereof, THR-0921), -glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (e.g., phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.), repaglinide, senaglinide, mitiglinide or calcium salt hydrate thereof, nateglinide, etc.], GLP-I receptor agonists [e.g., GLP-I, GLP-IMR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib(8,35)hGLP-l(7,37)NH2, CJC-1131, etc.], dipeptidyl peptidase IV inhibitors (e.g., NVP-DPP-278, PT-100, P32/98, P93/01, NVP-DPP-728, LAF237, TS-021, etc.), 3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), amylin agonists (e.g., pramlintide, etc.), phosphotyrosine phosphatase inhibitors (e.g., vanadic acid, etc.), gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors, glucose-6- phosphatase inhibitors, glucagon antagonists, etc.), SGLT (sodium-glucose cotransporter) inhibitors (e.g., T-1095, etc.), 11 -hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498, etc.), adiponectin or agonists thereof, IKK inhibitors (e.g., AS-2868, etc.), leptin resistance improving drugs, somatostatin receptor agonists (compounds described in WO 01/25228, WO 03/42204, compounds described in WO 98/44921, WO 98/45285, WO 99/22735, etc.), glucokinase activators (e.g., Ro-28-1675) and the like.

[0043] Therapeutic agents for treating diabetic complications include but are not limited to aldose reductase inhibitors (e.g., Tolrestat, Epalrestat, Zenarestat, Zopolrestat, Fidarestat (SNK- 860), Minalrestat (ARI-509), CT- 112, etc.), neurotrophic factors and increasing drugs thereof (e.g., NGF, NT-3, BDNF, neurotrophin production- secretion promoters described in WO 01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-l-imidazolyl)-5-[3-(2- methylphenoxy)propyl]oxazole, etc.) and the like), protein kinase C (PKC) inhibitors (e.g., LY- 333531, etc.), AGE inhibitors (e.g., ALT-945, pimagedine, pyratoxanthine, N- phenacylthiazolium bromide (ALT-766), EXO-226, ALT-711, Pyridorin, Pyridoxamine, etc.), active oxygen scavengers (e.g., thioctic acid, etc.), cerebral vasodilators (e.g., tiapuride, etc.), somatostatin receptor agonist (BIM23190), apoptosis signal regulating kinase-1 (ASK-I) inhibitors and the like.

[0044] Therapeutic agents for treating hyperlipidemia include but are not limited to statin compounds which are cholesterol synthesis inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or a salt thereof (e.g., sodium salt, etc.), etc.), squalene synthase inhibitors (e.g., compounds described in WO 97/10224, such as N-[[(3R,5S)-l-(3- acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo- 1,2,3, 5-tetrahydro-4,l- benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid and the like), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate, etc.), antioxidants (e.g., lipoic acid, probucol) and the like.

[0045] Examples of the antihypertensive agents include but are not limited to angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g., losartan, candesartan, cilexetil, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1- [[2'-(2,5-dihydro-5-oxo-4H-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-lH- benzimidazole-7-carboxylic acid, etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), clonidine and the like.

[0046] Examples of the antiobesity agents include but are not limited to antiobesity agents acting on the central nervous system (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP-7941; compounds encompassed in WO 01/82925 and WO 01/87834, etc.); neuropeptide Y antagonists (e.g., CP-422935, etc.); cannabinoid receptor antagonists (e.g., SR-141716, SR-147778, etc.); ghrelin antagonists; 11 - hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498, etc.) and the like), pancreatic lipase inhibitors (e.g., orlistat, ATL-962, etc.), 3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, AJ -9671 ^', AZ40140, etc.), peptide anorexiants (e.g., leptin, CNTF (Ciliary Neurotropic Factor), etc.), cholecystokinin agonists (e.g., lintitript, FPL-15849, etc.), feeding deterrent (e.g., P-57, etc.) and the like.

[0047] Examples of the diuretics include but are not limited to xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate, etc.), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclo thiazide, etc.), antialdosterone preparations (e.g., spironolactone, triamterene, etc.), carbonate dehydratase inhibitors (e.g., acetazolamide and the like), chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

[0048] Examples of the chemotreating agents include but are not limited to alkylating agents (e.g., cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g., methotrexate, 5- fluorouracil, etc.), antitumor antibiotics (e.g., mitomycin, adriamycin, etc.), plant-derived antitumor agent (e.g., vincristine, vindesine, Taxol, etc.), cisplatin, carboplatin, etoposide and the like.

[0049] Examples of the immunotreating agents include but are not limited to microorganism or bacterial components (e.g., muramyl dipeptide derivative, Picibanil, etc.), polysaccharides having immunity potentiating activity (e.g., lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (e.g., interferon, interleukin (IL), etc.), colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin, etc.) and the like, with preference given to interleukins such as IL-I, IL-2, IL- 12 and the like.

[0050] Examples of the anti-inflammatory agents include but are not limited to non-steroidal anti-inflammatory agents such as aspirin, acetaminophen, indomethacin and the like.

[0051] Examples of the antithrombotic agents include but are not limited to heparin (e.g., heparin sodium, heparin calcium, dalteparin sodium, etc.), warfarin (e.g., warfarin potassium, etc.), antithrombin drugs (e.g., aragatroban, etc.), thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, etc.), platelet aggregation suppressors (e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, etc.) and the like.

[0052] Therapeutic agents for treating osteoporosis include but are not limited to alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium and the like. [0053] Examples of the vitamins which may be used in combination with compounds of Formula (1) or (2) include but are not limited to vitamin Bl, vitamin B12 and the like, and derivatives thereof.

[0054] Examples of the antidementia agents include but are not limited to tacrine, donepezil, rivastigmine, galantamine and the like.

[0055] Therapeutic agents for pollakiuria or urinary incontinence include but are not limited to flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.

[0056] Therapeutic agents for dysuria include but are not limited to acetylcholine esterase inhibitors (e.g., distigmine) and the like.

[0057] Furthermore, therapeutic agents having a cachexia-improving effect in animal models and clinical situations, may be used in combination with the compound of the invention. Examples of such therapeutic agents include but are not limited to cyclooxygenase inhibitors (e.g., indomethacin, etc.) [Cancer Research, Vol. 49, pp. 5935-5939, 1989], progesterone derivatives (e.g., megestrol acetate) [Journal of Clinical Oncology, Vol. 12, pp. 213-225, 1994], glucosteroids (e.g., dexamethasone, etc.), metoclopramide agents, tetrahydrocannabinol agents (publications are all as mentioned above), fat metabolism improving agents (e.g., eicosapentanoic acid, etc.) [British Journal of Cancer, Vol. 68, pp. 314-318, 1993], growth hormones, IGF-I, or antibodies to a cachexia-inducing factor such as TNF- , LIF, IL-6, oncostatin M and the like.

[0058] Furthermore, glycosylation inhibitors (e.g., ALT-711, etc.), nerve regeneration promoting drugs (e.g., Y-128, VX853, prosaptide, etc.), antidepressants (e.g., desipramine, amitriptyline, imipramine, etc.), antiepileptics (e.g., lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride, carbamazepine), antiarrhythmic agents (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), monoamine uptake inhibitors (e.g., tramadol), narcotic analgesics (e.g., morphine), GABA receptor agonists (e.g., gabapentin, gabapentin MR preparations), 2 receptor agonists (e.g., clonidine), local analgesics (e.g., capsaicin), antianxiety drugs (e.g., benzodiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine) and the like may also be used in combination with compounds of Formula (1) or (2).

[0059] A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.01 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.01 mg/kg per body weight to about 100 mg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 0.01 to 50 mg/kg per body weight. For example, a compound of the invention (as an active ingredient) may be orally administered to a patient with hyperlipidemia in about 0.01 to about 30 mg/kg of body weight per day; in some examples, from about 0.1 to about 20 mg/kg of body weight per day; and in other examples, from about 1 to about 20 mg/kg of body weight per day, which may be given at once or in several portions a day.

[0060] Compounds of Formula (1) or (2) may be administered as pharmaceutical compositions by any conventional route known in the art, such as those described in EP 1688138, incorporated by reference herein in its entirety. For example, compounds of Formula (1) or (2) may be administered enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.

[0061] Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions may be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets, together with c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; and if desired, d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions may be aqueous isotonic solutions or suspensions, and suppositories may be prepared from fatty emulsions or suspensions.

[0062] The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier may include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used. Suitable formulations for topical application, e.g., to the skin and eyes, may be aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

Processes for Making Compounds of Formula (1) or (2)

[0063] Compounds of Formula (1) or (2) may be prepared, following procedures exemplified in the Examples.

[0064] Compounds of Formula (1) or (2) may also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compounds of Formula (1) or (2) may be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, salt forms of compounds of Formula (1) or (2) may be prepared using salts of the starting materials or intermediates.

[0065] Free acid or free base forms of compounds of Formula (1) or (2) may be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example, a compound of Formula (1) or (2) in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of Formula (1) or (2) in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0066] Compounds of Formula (1) or (2) in unoxidized form may be prepared from the corresponding N-oxides by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 8O⁰C. [0067] Protected derivatives of compounds of Formula (1) or (2) may be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal may be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3^rd edition, John Wiley and Sons, Inc., 1999.

[0068] Compounds of Formula (1) or (2) may be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of Formula (1) or (2) may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

[0069] The invention also encompasses methods for using prodrug derivatives of compounds of Formula (1) or (2) for regulating GPR120. Conversion of prodrug derivatives to the compounds of Formula (1) or (2) may occur under physiological conditions as described in "Pharmaceutical Development", vol. 7 (Molecular Design), pp. 163-198 (1990), or with a reaction by an enzyme, a gastric acid, etc. in the living body (e.g., conversion by enzymatic oxidation, reduction, hydrolysis, etc.).

[0070] Prodrug derivatives of compounds of Formula (1) or (2) may be prepared by methods known to those of ordinary skill in the art (e.g., Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs may be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like). Other examples include compounds of Formula (1) or (2) wherein an amino group is substituted with acyl, alkyl, phosphoric acid, etc. (e.g., substitution of an amino group with eicosanyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc,); a compound wherein a hydroxy group is substituted with acyl, alkyl, phosphoric acid, boric acid, etc. (e.g., substitution of a hydroxyl group with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.); a compound wherein a carboxyl group is substituted with ester, amide, etc. (e.g., modification of a carboxyl group with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester, methyl amide, etc.); etc. In particular examples, the prodrug derivatives are prepared by esterification of a carboxyl group with a Cl-6 alkyl group such as methyl, ethyl, tert-butyl and the like. [0071] Compounds of Formula (1) or (2) may be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers may be carried out using covalent diastereomeric derivatives of compounds of Formula (1) or (2), dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and may be readily separated by taking advantage of these dissimilarities. The diastereomers may be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture may be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.

[0072] Compounds of Formula (1) or (2) may be prepared as exemplified in the Examples, and may optionally involve:

(a) converting a compound of the invention into a pharmaceutically acceptable salt;

(b) converting a salt form of a compound of the invention to a non-salt form;

(c) converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;

(d) converting an N-oxide form of a compound of the invention to its unoxidized form;

(e) resolving an individual isomer of a compound of the invention from a mixture of isomers;

(f) converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and

(g) converting a prodrug derivative of a compound of the invention to its non- derivatized form.

[0073] Insofar as the production of the starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter. One of skill in the art will appreciate that the synthetic methodologies described herein are only representative of methods for preparation of the compounds of the present invention, and that other well known methods may similarly be used. The present invention is further exemplified, but not limited, by the following Examples that illustrate the preparation of compounds of Formula (1) or (2).

Example 1

Examples Al -Al 4

4-(3-phenoxybenzylamino)benzoic acid (Al)

[0074] A solution of 4-aminobenzoic acid (164 mg, 1.2 mmol) and 3-phenoxybenzaldehyde (198 mg, 1 mmol) in DCM (15 niL) is stirred at rt with Na₂SO₄ (0.2 g, 1.4 mmol) for Ih. Sodium triacetoxyborohydride (636 mg, 3 mmol) is added, and the mixture is stirred for 16 h at rt. Water (10 mL) is added and the product is extracted with DCM (3 x 10 mL). The organic layers are combined, dried (Na₂SO₄), filtered and concentrated. The mixture is purified on reverse phase HPLC (H₂0/MeCN gradient) to afford the title compound 4-(3- phenoxybenzylamino)benzoic acid (Al) as a white solid. ¹H-NMR (400 MHz, DMSO-d6) δ = 12.02 (s, IH), 7.63 (d, 2H, J = 8.7 Hz), 7.35 (m, 3H), 7.13 (m, 2H), 7.05 (t, IH, J = 6.0 Hz), 6.97 (m, 3H), 6.85 (m, IH), 6.56 (d, 2H, J = 8.7 Hz), 4.33(d, 2H, J = 6.0 Hz). MS calcd. for C₂₀H₁₈NO₃ (M+H⁺) 320.1, found 320.2.

Example 2

Examples B1-B13

4-(3-(2-fluorobenzyloxy)benzylamino)benzoic acid (Bl)

[0075] Step A: Methyl 4-aminobenzoate (1.98 g, 13.1 mmol) and 3-hydroxybenzaldehyde (1.6 g, 13.1 mmol) are dissolved in 1 ,2-dichloroethane (40 mL). Anhydrous Na₂SO₄ (9.3 g, 65.5 mmol) is added and the mixture is stirred at rt for 30 min. Sodium triacetoxyborohydride (8.3 g, 39.3 mmol) is added and stirred at rt for 16 h. The mixture is diluted with H₂O (20 mL) and extracted into DCM (3 x 20 mL). The organic layers are combined, washed with aqueous NaHCO₃ (20 mL), and brine (20 mL), dried (MgSO₄), filtered and concentrated. The residue is recrystallized from ethyl acetate/hexane to give methyl 4-(3-hydroxybenzylamino)benzoate as a white crystalline solid: ¹H-NMR (400MHz, DMSO-d6) δ = 9.37 (s, IH), 7.66 (d, J = 8.8 Hz, 2H), 7.12 (m, 2H), 6.75 (d, J = 7.6 Hz, IH), 6.73 (t, J = 2.0 Hz, IH), 6.62 (dd, J = 1.6, 8.4 Hz, IH), 6.59 (d, J = 8.8 Hz, 2H), 4.26 (d, J = 6.0 Hz, IH), 3.73 (s, 3H). MS calcd. for Ci₅H₁₆NO₃ (M+H⁺) 258.1, found 258.1.

[0076] Step B: Methyl 4-(3-hydroxybenzylamino)benzoate (30 mg, 0.116 mmol) and 2- fluorobenzyl chloride (20 mg, 0.139 mmol) are dissolved in dry acetonitrile (3 mL). Cesium carbonate (114 mg, 0.349 mmol) is added and the mixture is heated to 70°C for 2 h. LiOH (IN, 0.5 mL) is added and stirred at 70°C for 1 h, then the mixture is cooled, acidified with IN HCl (5 mL) and extracted into ethyl acetate (2 x 5 mL). The organic layers are combined, dried (MgSO₄), filtered, concentrated, and purified on reverse phase HPLC (H₂0/MeCN gradient) to afford the title compound 4-(3-(2-fluorobenzyloxy)benzylamino)benzoic acid (Bl). ¹H-NMR (400MHz, CDCl₃) δ = 7.92 (d, J = 9.2 Hz, 2H), 7.48 (td, J = 7.6, 1.6 Hz, IH), 7.30 (m, 2H), 7.15 (td, J = 7.2, 1.2 Hz, IH), 7.07 (td, J = 8.4, 1.2 Hz, IH), 6.94 (m, 3H), 6.59 (d, J = 8.8 Hz, 2H), 5.13 (s, 2H), 4.38 (s, 2H). MS calcd. for C₂]H₁₉FNO₃ (M+H⁺) 352.1, found 352.1.

Example 3

Examples D1-D6

Examples Ξ1-Ξ3 4-(3-(3-chlorophenoxy)benzylamino)benzoic acid (Cl)

[0077] Step A: A solution of methyl 4-aminobenzoate (1.0 g, 6.6 mmol) and 3- bromobenzaldehyde (1.11 g, 6 mmol)in DCM (80 mL) is stirred at rt with Na₂SO₄ (4.3 g, 30 mmol) for Ih. Sodium triacetoxyborohydride (2.54 g, 12 mmol) is added and the mixture is stirred for 16 h at rt. Water (60 mL) is added and the product is extracted with DCM (3 x 60 mL). The organic layers are combined, dried (Na₂SO₄), filtered and concentrated. The mixture is purified by flash chromatography on silica gel (hexanes/EtOAc gradient) to afford the methyl 4-(3-bromobenzylamino)benzoate as a white solid. ¹H- MR (400 MHz, DMSO-d6) δ = 7.67 (d, J = 8.9 Hz, 2H), 7.53 (s, IH), 7.43 (ddd, J = 7.7, 1.9, 1.4 Hz, IH), 7.34 (d, J = 7.7 Hz, IH), 7.29 (t, J = 7.7 Hz, IH), 7.18 (t, J = 6.1 Hz, IH), 6.61 (d, J = 8.9 Hz, 2H), 4.36 (d, J = 6.2 Hz, 2H), 3.72 (s, 3H). ( MS calcd. for Ci₅H₁₅BrNO₂ (M+H⁺) 320.0, found 320.0.

[0078] Step B: A mixture of methyl 4-(3-bromobenzylamino)benzoate (32 mg, 0.1 mmol), N,N-dimethylglycine (9 mg, 0.09 mmol), CuI (5 mg, 0.026 mmol, and Cs₂CO₃ (98 mg, 0.3 mmol) in dioxane (0.25 mL) is heated at 95°C for 22 h. THF (0.7 mL), MeOH (1 mL), H₂O (1 mL) and LiOH (0.5 g) is added and stirred at 60⁰C for 10 h. Reaction mixture is acidified with citric acid solution and extracted with DCM (3 x 20 mL) and dried (Na₂SO₄), filtered and concentrated. The mixture is purified on reverse phase HPLC (H₂O/MeCN gradient) to afford the title compound 4-(3-(3-chlorophenoxy)benzylamino)benzoic acid (Cl). ¹H-NMR (400 MHz, DMSO-d6) δ = 12.03 (s, IH), 7.63 (d, J = 8.8 Hz, 2H), 7.37 (m, 2H), 7.17 (m, 2H), 7.07 (t, J = 6.0 Hz, IH), 7.04 (s, IH), 7.00 (t, J = 2.1 Hz, IH), 6.92 (m, 2H), 6.57 (d, J =8.8 Hz, 2H),4.35 (d, J = 5.8 Hz, 2H). MS calcd. for C₂₀H₁₇ClNO₃ (M+H⁺) 354.1, found 354.1.

4-((biphen-3-ylmethyl)amino)benzoic acid (Dl)

[0079] Step C: A mixture of methyl 4-(3-bromobenzylamino)benzoate (31.9 mg, 0.1 mmol), (Example Cl, step A), phenylboronic acid (14.6 mg, 0.12 mmol), Na₂CO₃ (32 mg, 0.3 mmol), Pd(PPh₃)₄ (5.8 mg, 0.005 mmol), EtOH (0.36 mL), DME (1.44 mL), and H₂O (0.48 mL) is heated in a sealed vial in a microwave oven at 180⁰C for 10 min. To a resulting mixture is added MeOH (1 mL), THF (1 mL), H₂O (2 mL), and LiOH-H₂O (420 mg, 10 mmol) and stirred at 60⁰C overnight. Reaction mixture is acidified with citric acid solution and extracted with DCM (3 x 20 mL) and dried (Na₂SO₄), filtered and concentrated. The mixture is purified on reverse phase HPLC (H₂0/MeCN gradient) to afford the title compound 4-((biphen-3- ylmethyl)amino)benzoic acid (Dl). ¹H-NMR (400 MHz, DMSO-d6) δ = 12.01 (s, IH), 7.64 (m, 5H), 7.53 (d, J = 7.7 Hz, IH), 7.44 (m, 3H), 7.35 (m, 2H), 7.09 (t, J = 5.4 Hz, 1 H), 6.63 (d, J = 8.7 Hz, 2H), 4.41 (d, J = 5.2 Hz, 2H). MS calcd. for C₂₀H₁₈NO₂ (M+H⁺) 304.1, found 304.1.

4-(3-phenethylbenzyl)amino)benzoic acid (El)

[0080] Step D: A solution of 4-(3-styrylbenzyl)amino)benzoic acid (25 mg, 0.076 mmol), obtained by procedure described in Example Dl, in EtOAc (10 mL) is hydrogenated over 10% Pd/C (10 mg) at rt and 1 atm of H₂ for approximately 30 min. Progress of the reaction is controlled by reverse phase LCMS (H₂0/MeCN gradient). Hydrogenation is stopped immediately after MS spectrum showed no starting material left. The solution is filtered and concentrated. The mixture is purified on reverse phase HPLC (H₂0/MeCN gradient) to afford the title compound 4-(3-phenethylbenzyl)amino)benzoic acid (El). ¹H-NMR (600 MHz, DMSO-d6) δ = 11.98 (bs, IH), 7.64 (d, J = 8.8 Hz, 2H), 7.23 (m, 6H),7.16 (m, 2H), 7.09 (d, J =7.5 Hz, IH) 6.99 (bs, IH), 6.58 (d, J = 8.8 Hz, 2H), 4.29 (s, 2H), 2.85 (s, 4H). MS calcd. for C₂₂H₂₂NO₂ (M+H⁺) 332.2, found 332.2.

4-(3-(benzylamino)benzylamino)benzoic acid (Fl)

[0081] Step E: Methyl 4-(3-bromobenzylamino)benzoate (40 mg, 0.13 mmol) and benzylamine (15 μL, 0.14 mmol) are dissolved in dry dioxane (1 mL). Pd₂(dba)₃ (11 mg, 0.013 mmol), (YBu^PHBF₄ (7 mg, 0.025 mmol) and cesium carbonate (81 mg, 0.26 mmol) are added and the mixture is degassed with bubbling Ar for 15 min. The vessel is sealed and heated at 120°C for 18 h. LiOH (IN, 0.5 niL) is added and heated at 90°C for 3 h, then is cooled, quenched with IN HCl (5 mL) and extracted into EtOAc (10 mL). The organic layer is dried (MgSO₄), filtered, concentrated and purified on reverse phase HPLC (H₂OMeCN gradient) to afford the title compound 4-(3-(benzylamino)benzylamino)benzoic acid (Fl). ¹H-NMR (400 MHz, MeOD) δ = 7.63 (d, J = 8.8 Hz, 2H), 7.17 (m, 4H), 7.11 (m, IH), 6.96 (t, J = 8.0 Hz, IH), 6.59 (s, IH), 6.56 (d, J = 7.6 Hz, IH), 6.47 (d, J = 2.8 Hz, IH), 6.44 (d, J = 8.8 Hz, 2H), 4.19 (s, 2H), 4.15 (s, 2H). MS calcd. for C₂]H_2IN₂O₂ (M+H⁺) 333.2, found 333.1.

Example 4

Examples Gl- G4

6-(3-benzyloxybenzyl)amino)nicotinic acid (Gl)

[0082] Step A: A solution of 6-chloronicotinic acid ethyl ester (37.1 mg, 0.2 mmol), 3- benzyloxybenzylamine (21.3 mg, 0.1 mmol, obtained by a procedure described in J.-F.Briere, P.Charpentier, G.Dupas, G.Queguiner and J.Bourguignon. Tetrahedron, 1997, v.53, 2075- 2086.), and DIEA (70 μL, 0.4 mmol) in 0.3 mL of NMP is heated at 130⁰C for 3h. The resulting ester is hydrolyzed by the addition of THF (1 mL), MeOH (1 mL), H₂O (1 mL), and LiOH-H₂O (420 mg, 10 mmol) and stirred at 60⁰C overnight. Reaction mixture is acidified with citric acid solution and extracted with EtOAc (3 x 20 mL) and dried (Na₂SO₄), filtered and concentrated. The mixture is purified on reverse phase HPLC (H₂0/MeCN gradient) to afford the title compound 6-(3-benzyloxybenzyl)amino)nicotinic acid (Gl). ¹H-NMR (400 MHz, DMSO-d6) δ = 12.45 (bs, IH), 8.53 (d, J = 2.1 Hz, IH), 7.91 (bs, IH), 7.83 (dd, J = 8.8, 2.3 Hz, IH), 7.42 (m, 2H), 7.38 (m, 2H), 7.32 (m, IH), 7.24 (t, J = 7.9 Hz, IH), 6.98 (s, IH), 6.90 (m, 2H), 6.56 (d, J = 8.7 Hz, IH), 5.07 (s, 2H), 4.53 (d, J = 5.5 Hz, 2H). MS calcd. for C₂₀H₁₉N₂O₃ (M+H⁺) 335.1, found 335.2.

Example 5

Examples H1-H2

4-(3-(benzyloxy)phenylamino)benzoic acid (Hl)

[0083] Step A: Methyl 4-bromobenzoate (49 mg, 0.23 mmol) and 3 -benzyloxy aniline (50 mg, 0.25 mmol) are dissolved in dry dioxane (1 mL). Pd₂(dba)₃ (21 mg, 0.023 mmol), (^Bu)₃PHBF₄ (13 mg, 0.046 mmol) and cesium carbonate (149 mg, 0.46 mmol) are added and the mixture is degassed with bubbling Ar for 15 min. The vessel is sealed and heated at 120°C for 72 h. LiOH (IN, 0.5 mL) is added and heated at 90°C for 1 h, then is cooled, quenched with IN HCl (5 mL) and extracted into EtOAc (10 mL). The organic layer is dried (MgSO₄), filtered, concentrated and purified on reverse phase HPLC (H₂O/MeCN gradient) to afford the title compound 4-(3-(benzyloxy)phenylamino)benzoic acid (Hl). ¹H-NMR (400 MHz, CDC13) δ = 7.96 (d, J = 8.8 Hz, 2H), 7.40 (m, 5H), 7.25 (t, J = 8.0 Hz, IH), 6.97 (d, J = 8.8 Hz, 2H), 6.81 (t, J = 2.4 Hz, IH), 6.76 (ddd, J = 1.2, 2.4, 8.0 Hz, IH), 6.71 (dd, J = 1.8 Hz, 8.0 Hz, IH), 5.07 (s, 2H). MS calcd. for C₂₀H₁₈NO₃ (M+H⁺) 320.1, found 320.2.

[0084] Representative compounds useful for regulating GPR 120, and prepared following procedures described in the above examples using appropriate starting materials that would be apparent to those skilled in the art, are described in Table 1. Table 1

Compound Physical Data Structure ¹H NMR 400 MHz (DMSO-rf₆) and/or MS (m/z)

¹H-NMR (400 MHz, DMSO-d6) δ = 12.02 (s, IH), 7.63 (d, 2H, J = 8.7 Hz), 7.35 (m, 3H), 7.13 (m, 2H), 7.05 (t, IH, J = 6.0

Al Hz), 6.97 (m, 3H), 6.85 (m, IH), 6.56 (d, 2H, J = 8.7 Hz), 4.33(d, 2H, J = 6.0 Hz).

MS calcd. for C₂₀H₁₈NO₃ (M+H⁺) 320.1, found 320.2.

¹H-NMR (400MHz, DMSO-d6) δ = 12.01 (s, IH), 7.65 (d, J = 8.7 Hz, 2H), 7.36 (m, 4H), 7.12 (t, J = 7.4 Hz, IH), 7.03 (t, J

A2 =5.9 Hz, IH), 6.98 (d, J = 8.6 Hz, 4H), 6.60 (d, 8.7 =Hz, 2H), 4.31 (d, 5.9 Hz,

2H). MS calcd. for C₂₀H₁₈NO₃ (M+H⁺) 320.1, found 320.1.

¹H-NMR (400MHz, DMSO-d6) δ = 12.02 (s, IH), 7.63 (d, J = 8.7 Hz, 2H), 7.31 (t, J = 7.8 Hz, IH), 7.15 (d, J = 8.5, 2H), 7.08 (d, J = 7.6 Hz, IH), 7.04 (t, J = 6.0, IH),

A3 6.94 (s, IH), 6.87 (d, J = 8.4 Hz, 2H), 6.80 (dd, J = 8.0, 2.3 Hz, IH), 6.56 (d, J = 8.7

Hz, 2H), 4.32 (d, J = 5.8 Hz, 2H). MS calcd. for C₂₁H₂₀NO₃ (M+H⁺) 334.1, found 334.1.

¹H-NMR (400MHz, DMSO-d6) δ = 12.03 (s, IH), 7.64 (d, J = 8.8 Hz, 2H), 7.39 (m, 2H), 7.36 (t, J = 7.9 Hz, IH), 7.15 (d, J =

A4 7.8 Hz, IH), 7.05 (t, J = 6.1 Hz, IH), 6.99 (m, 3H), 6.89 (dd, J = 8.1, 1.9 Hz, IH), 6.56 (d, J = 8.8 Hz, 2H), 3.34 (d, J = 5.6

Hz, 2H). MS calcd. for C₂₀H₁₇ClNO₃ (M+H⁺) 354.1, found 353.9.

¹H-NMR (400MHz, DMSO-d6) δ = 7.64 (d, J = 8.8 Hz, 2H), 7.40 (m, 3H), 7.28 (td, J = 8.0, 1.6 Hz, IH), 7.14 (td, J = 7.2, 0.8

A5 Hz, 2H), 7.00 (m, 3H), 6.90 (dd, J = 8.0, 0.8 Hz, IH), 6.56 (d, J = 8.8 Hz, 2H), 4.33

(d, J = 6.0 Hz, 2H). MS calcd. for C₂₀H₁₈NO₃ (M+H⁺) 320.1, found 320.1. 12.02 (t, J 5H), (d, J = 3.73

12.04 (m, IH), (tt, J = IH), for 338.1. 12.23,

(dd,

12.02 (t, J

Hz, J =

7.64 Hz, J = (s,

388.0.

12.01 (m, (t, J

(d, J = = 6.0

7.64 (t, J J = 6.59 (s,

7.64 Hz,

2H). 334.1,

12.37 7.36 Hz,

Hz,

(d, J Hz, 1.2

for 352.1.

12.00 (d, J

341.1,

12.00 (m, J = 6.0 8.8 Hz,

8.62 (d, J

8.4 MS

(d, J IH), 7.6 (t, J J = 2H), for 402.1. (d, J 2H), 8.4, 5.09 402.1.

Compound Physical Data Structure ¹H NMR 400 MHz (DMSO-rf₆) and/or MS (m/z)

¹H-NMR (400MHz, CDCl₃) δ = 7.91 (d, J = 8.8 Hz, 2H), 7.32 (m, 2H), 7.13 (m, 2H), 7.00 (td, J = 8.4, 2.0 Hz, IH), 6.95 (m,

B7 2H), 6.89 (dd, J = 7.6, 2.0 Hz, IH), 6.59 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 4.38 (s,

2H). MS calcd. for C₂iH₁₉FNO₃ (M+H⁺) 352.1, found 352.1.

¹H-NMR (400MHz, CDCl₃) δ = 7.92 (d, J = 8.8 Hz, 2H), 7.38 (m, 2H), 7.28 (t, J = 8.0 Hz, IH), 7.06 (tt, J = 8.4, 2.0 Hz, 2H),

B8 6.95 (m, 2H), 6.89 (dd, J = 8.4, 2.0 Hz, IH), 6.59 (d, J = 8.8 Hz, 2H), 5.00 (s, 2H),

4.38 (s, 2H). MS calcd. for C₂iH₁₉FNO₃ (M+H⁺) 352.1, found 352.1.

¹H-NMR (400MHz, DMSO-d6) δ = 12.01 (s, IH), 7.65 (d, J = 8.8 Hz, 2H), 7.38 (dd, J = 7.6, 1.6 Hz, IH), 7.33 (td, J = 8.4, 2.0 Hz, IH), 7.24 (t, J = 8.0 Hz, IH), 7.04 (m,

B9 2J), 6.95 (m, 3H), 6.86 (dd, J = 8.0, 2.4 Hz, IH), 6.59 (d, J = 8.8 Hz, 2H), 5.02 (s,

2H), 4.31 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H). MS calcd. for C₂₂H₂₂NO₄ (M+H⁺) 364.2, found 364.1.

¹H-NMR (400MHz, CDCl₃) δ = 7.91 (d, J = 8.8 Hz, 2H), 7.27 (m, 2H), 6.96 (m, 4H), 6.90 (dd, J = 8.0, 2.0 Hz, IH), 6.86 (dd, J

BlO = 7.6 , 2.0 Hz, IH), 6.59 (d, J = 8.8 Hz, 2H), 5.03 (s, 2H), 4.38 (s, 2H), 3.81 (s,

3H). MS calcd. for C₂₂H₂₂NO₄ (M+H⁺) 364.2, found 364.1.

¹H-NMR (400MHz, CDCl₃) δ = 7.92 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H),

BI l 7.27 (t, J = 8.0 Hz, IH), 6.91 (m, 5H), 6.59 (d, J = 8.8 Hz, 2H), 4.98 (s, 2H), 4.38

(s, 2H), 3.82 (s, 3H). MS calcd. for C₂₂H₂₂NO₄ (M+H⁺) 364.2, found 364.1. 12.00 (t, J J = for 378.1. 12.00 (m, J = 6.90 6.0 (t, J

12.03 (m, IH),

354.1. 12.03 (dd, 7.7 8.8

12.03 (m,

J = for 334.1.

12.03 (t, J 5.3 =8.8 (s,

12.02 (t, J 1.8

6.83 5.8 350.1. 12.03 (t, J (d, J IH), J 2H), 8.1, 3.69

12.01 Hz, (t, J 2H), for 304.1. 12.00 (m, (d, J

12.01 7.35 6.61 Hz,

12.01 (m,

J =

12.00 (m,

5.9

11.98 (m, IH) for 332.2. 11.99 (m,

11.98 (m, J = 2.84

(d, J IH), 6.56 2H),

(d, IH),

349.1. (d, (d, J =

for 333.1. (d, 2H), 1.6 (m, (s, 347.1. (d, (s, J = IH), 363.2,

12.45

IH), 6.90 (s,

12.54

Hz,

12.80 (d, Hz,

12.80 Hz, (m, 5.06

(d, (t, J = 6.81 2.4, Hz, 320.2.

Compound Physical Data Structure ¹H NMR 400 MHz (DMSO-rf₆) and/or MS (m/z)

¹H-NMR (400 MHz, CDC13) δ = 7.97 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.4 Hz, IH), 7.58 (d, J = 8.4 Hz, IH), 7.47 (t, J = 8.0

H2 Hz, IH), 7.33 (t, J = 7.2 Hz, IH), 7.25 (d, J = 8.8 Hz, 2H), 7.13 (dd, J = 2.0, 8.0 Hz,

IH), 6.90 (t, J = 2.2 Hz, IH), 6.76 (dd, J = 2.6, 8.0 Hz, IH). MS calcd. for C₁₉H₁₆NO₃ (M+H⁺) 306.1, found 306.2.

Example 6 Solid phase synthesis of analogs

[0085] Step A: Irori Mikrokans are dry-loaded with an average of 35 mg Merrifield resin (LCC-Dynosphere-p-chloromethyl, 200μM, 2.00 mmol/g). The kans are enumerated (Afferent software), sorted and distributed into reaction vessels accordingly. The loaded Mikrokans are then generally handled according to standard Irori Mikrokan protocol. The amounts of reagents used are indicated as equivalents with respect to the maximal loading capacity of the resin. First the encapsulated resin is swelled in dry DMF for 30 min at rt. A suspension of the appropriate aryl aminoacid (3 equ.), KI (1 equ.) and Cs₂CO₃ (9 equ.) in dry DMF is added and the mixture is shaken at 60⁰C for 36h. The kans are drained, subsequently washed with DMF (4x), DCM (3x), IPA (2x), MeOH (3x) and Et₂O (2x), and dried in vacuo.

[0086] Step B: The kans obtained from Step A are enumerated, sorted and distributed into reaction vessels accordingly. The encapsulated resin is swelled in dry DMF for 30 min at rt. A solution of the appropriate aryl aldehyde (25 equ.) in DMF containing 3% AcOH is added and the mixture is allowed to shake for 30 min at rt. Then Na(OAc)₃BH (25 equ.) is added and the mixture is shaken for 48h at rt. The kans are drained, washed and dried as described in Step A. The kans obtained from Step B (containing a phenolic or bromide functionality) are enumerated, sorted and distributed into reaction vessels accordingly.

[0087] Step C: The encapsulated resin (containing a phenolic functionality) is swelled in dry DMF for 30 min at rt. A solution of the appropriate benzyl halide (10 equ.) and DBU (12 equ.) in DMF is added and the mixture is allowed to shake for 48h at rt. The kans are then drained, washed and dried as described in Step A.

[0088] Step D: Alternatively, a solution of the appropriate alcohol (5 equ.), PPh₃ (5 equ.) and DEAD (5 equ.) in DCM is added to the kans containing a resin with a phenolic functionality. The mixture is allowed to shake for 48h at rt. Then the kans are drained, washed and dried as described in Step A.

[0089] Step E: Alternatively, a solution of the appropriate boronic acid (5 equ.), pyridine (15 equ.) and copper (II) acetate (3 equ.) in dry DCM is added to the kans containing a resin with a phenolic functionality. The mixture is allowed to shake for 48h at rt. Then the kans are drained, washed and dried as described in Step A.

[0090] Step F: Alternatively, a solution of the appropriate boronic acid (10 equ.), K₃PO₄ (10 equ.) and Pd(PPh₃)₄ (0.1 equ.) in DMF is added to the kans containing a resin with a bromide functionality. The mixture is allowed to shake for 48h at rt. Then the kans are drained, washed and dried as described in Step A.

[0091] Step G (Cleavage): The mikrokans are enumerated, sorted and distributed into IRORI cleavage blocks accordingly. A cleavage cocktail containing LiOH (5 equ.) in a mixture of THF/MeOH (3 : 1) is added. The blocks are sealed and shaken at 60⁰C for 24h. After cooling to rt the cleavage block wells are drained into 48 well plates and washed with 0.5 M HCl in THF/H₂O (1:1). Then the plates are dried in vacuo, DMSO is added and the crude compounds are purified using a mass-triggered, 4 channel reverse phase preparative LCMS. Every member of the library is quality controlled by analytical LCMS post purification. [0092] Illustrative examples of analogs derived using solid phase synthesis are described in Table 2.

Table 2

Table 2

Table 2

Table 2

Table 2

Table 2

Table 2

Assays

[0093] The suitability of a compound to modulate G protein-coupled receptor 120 (GPR120) may be tested following the assays described below, or using methods known in the art, such as those described in EP 1688138, incorporated herein by reference in its entirety.

Generation of GPR120-Expressing Cells

[0094] Human GPR120 stable cell-line is generated in HEK293 cells. GPR120 (Accession number BClOl 175) is fused to a promiscuous G protein, Gαl6. The expression plasmid is transfected into HEK293 cells using Fugeneό following manufacturer's instruction. Stable cell- lines are generated following drug selection.

FLIPR Assay

[0095] FLIPR (Fluorimetric Imaging Plate Reader, Molecular Devices) assays are performed to measure agonist-induced calcium mobilization in the GPR120-expressing cells. One day before the FLIPR assay, HEK293-GPR120-Gal6 cells are seeded into poly-D-lysine coated black- wall-clear bottom 384 well plates (Falcon) at 25,000 cells per well in 40 μl DMEM supplemented with 1% of FBS. The cells are incubated overnight at 37⁰C in a humidified incubator. The medium is aspirated on the day of the FLIPR assay. The cells are incubated with 50 μl/well of the assay buffer (HBSS, 2OmM HEPES, 2.5mM probenecid, pH 7.4) containing Fluo-4 NM dye (Invitrogen cat# F36205) at 37°C for 45 minutes, and then equilibrated at room temperature for 30 minutes. Compounds are dissolved in DMSO and diluted to desired concentrations with assay buffer. Fluorescent output is measured immediately following compound addition (12.5 μl/well) on the FLIPR machine.

[0096] An EC₅₀ value is calculated using the change of fluorescent intensity from the reaction initiation. In general, compounds of Formula (1) or (2) may have EC₅₀ values of 10 μM or less, for example from 0.1 μM to 10 μM. In some examples, compounds of Formula (1) or (2) may have EC₅₀ values from 0.1 μM to 5 μM; or more particularly from 0.5 μM to 5 μM. In other examples, compounds of Formula (1) or (2) may have EC₅₀ values of 3 μM or less; for example from 0.1 μM to 3 μM. In yet other examples, compounds of Formula (1) or (2) may have EC₅₀ values less than 0.1 μM or more than 10 μM.

[0097] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

Claims

1. The use of a compound having Formula (1) or pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, for modulating G protein-coupled receptor 20 (GPR20),

HO— ? C— -xX—— N— (CR₂)_m-Y— L— Z

R¹ (1)

wherein L is a bond, Ci_₂ alkyl, C₂ alkenyl, O(CR₂)_n or NR(CR₂)_O; X and Y are independently a 5-10 membered monocyclic or fused aryl or heteroaryl; Z is an optionally substituted Ci_₆ alkyl, Ci_₆ alkoxy, cycloalkyl, or a 5-10 membered monocyclic or fused aryl, heteroaryl or heterocyclic ring containing N, O or S; R and R¹ are independently H or Ci_₆ alkyl; m and o are independently 0- 1 ; and n is 0-3; thereby modulating said GPR20.

2. The use of a compound according to claim 1, wherein Z is an optionally substituted phenyl, naphthalenyl, thiazolyl, pyridyl, benzoxazoyl, C₃-₇ cycloalkyl, furanyl, benzotriazolyl, benzothiophenyl, thiophenyl, oxazolyl, indolyl, or pyrimidyl.

3. The use of a compound according to claim 1, wherein X is phenyl, naphthalenyl, pyridyl, pyrimidyl or thiazolyl.

4. The use of a compound according to claim 1, wherein Y is phenyl, naphthalenyl or pyridyl.

5. The use of a compound according to claim 1, wherein each X, Y and Z is an optionally substituted phenyl.

6. The use of a compound according to any one of claims 1-5, wherein L is O(CR₂)_n and n is 0-1.

7. The use of a compound according to claim 1, wherein said compound is of Formula (2):

wherein R² is halo, optionally halogenated C_1-6 alkyl, C₂_6 alkenyl, C₂_6 alkynyl, cyano, nitro or (CR₂)_PR⁸;

R³, R⁴, R⁵, R⁶ and R⁷ are independently CR¹⁰ or N; or R³, R⁴, R⁵, R⁶ and R⁷ are independently C when attached to the NR¹ moiety;

R⁸ is O(CR₂)_qR⁹, S(CR₂)_qR⁹, CO₂R⁹, CONR⁹(CR₂)_qR⁹, SO₂NR⁹(CR₂)_qR⁹ or NR⁹(CR₂)_qR⁹ or R⁹;

R⁹ is H, optionally halogenated C_1-6 alkyl, or an optionally substituted C₃-₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl;

R¹⁰ is H or R²; j is 0-4; m is 0-1; and p and q are independently 0-4.

8. The use of a compound according to claim 7, wherein R⁴ and R⁶ are independently CH or N; or R⁴ and R are independently C when attached to NR¹; and R³, R and R⁷ are each CH.

9. The use of a compound according to claim 7, wherein L is O(CR₂)_n and n is 0-1.

10. The use of a compound according to claim 1, wherein Z is an optionally substituted phenyl.

11. The use of a compound according to claim 7, wherein R¹⁰ is H, halo, optionally halogenated C_1-6 alkyl, C₂_6 alkenyl or C₂_6 alkynyl.

12. The use of a compound having Formula (2), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, for treating a condition mediated by G protein-coupled receptor 20 (GPR20),

wherein L is a bond, Ci_₂ alkyl, C₂ alkenyl, O(CR₂)_n or NR(CR₂)_O;

Z is an optionally substituted Ci_₆ alkyl, Ci_₆ alkoxy,

cycloalkyl, or a 5-10 membered monocyclic or fused aryl, heteroaryl or heterocyclic ring containing N, O or S, provided Z is not quinolinyl;

R and R¹ are independently H or Ci_₆ alkyl;

R² is halo, optionally halogenated C_1-6 alkyl, C₂-6 alkenyl, C₂-6 alkynyl, cyano, nitro or

(CR₂)_PR⁸;

R³, R⁴, R⁵, R⁶ and R⁷ are independently CR¹⁰ or N; or R³, R⁴, R⁵, R⁶ and R⁷ are independently C when attached to the NR¹ moiety;

R⁸ is O(CR₂)_qR⁹, S(CR₂)_qR⁹, (CR₂)_qCO₂R⁹, CONR⁹(CR₂)_pR⁹, SO₂NR⁹(CR₂)_pR⁹ or NR⁹(CR₂)_qR⁹ or R⁹;

R⁹ is H, optionally halogenated Ci_₆ alkyl, or an optionally substituted cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl;

R¹⁰ is H, halo, optionally halogenated Ci_6 alkyl, C₂_6 alkenyl or C₂_6 alkynyl; j is 0-4; m is 0-1; and p and q are independently 0-4; thereby treating said condition.

13. The use of a compound of claim 12, wherein R⁴ and R are independently CH or N; or R⁴ and R⁶ are independently C when attached to NR¹; and R³, R⁵ and R⁷ are each CH.

14. The use of a compound of claim 12, wherein L is 0(CR₂),, and n is 0-1.

15. The use of a compound of claim 12, wherein Z is an optionally substituted phenyl, naphthalenyl, thiazolyl, pyridyl, benzoxazoyl,

cycloalkyl, furanyl, benzotriazolyl, benzothiophenyl, thiophenyl, oxazolyl, indolyl, or pyrimidyl.

16. The use of a compound of claim 12, wherein Z is an optionally substituted phenyl.

17. The use of a compound of any one of claims 12-16, wherein said condition is diabetes, dyslipidemia, obesity or anorexia.

18. The use of a compound of claim 17, wherein said diabetes is diabetes mellitus, and said dyslipidemia is hyperlipidemia.