KR20070021233A - Substituted aryl and heteroaryl derivatives as metabolic modulators, and the prevention and treatment of disorders associated therewith - Google Patents

Abstract

The present invention relates to certain substituted aryl and heteroaryl derivatives of formula (I) which are metabolic modulators referred to herein as RUP3, in particular modulators of GPCR activity. Accordingly, the compounds of the present invention are useful in the treatment of metabolic-related disorders and complications thereof such as diabetes and obesity.

<Formula I>

RUP3, metabolic modulators, substituted aryl and heteroaryl derivatives, metabolic-related disorders, diabetes.

Description

SUBSTITUTED ARYL AND HETEROARYL DERIVATIVES AS MODULATORS OF METABOLISM AND THE PROPHYLAXIS AND TREATMENT OF DISORDERS RELATED THERETO

The present invention relates to certain substituted aryl and heteroaryl derivatives that are glucose metabolism regulators. Accordingly, the compounds of the present invention are useful in the treatment of metabolic-related disorders and complications thereof such as diabetes and obesity.

Diabetes mellitus is a serious disease that affects more than 100 million people worldwide. In the United States, there are more than 12 million diabetics, and 600,000 new cases are diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis leading to elevated blood sugar levels. There are many types of diabetes, but the two most common are diabetes type I (also called insulin-dependent diabetes mellitus or IDDM) and type II (also called insulin non-dependent diabetes mellitus or NIDDM).

The etiology for the different types of diabetes is not the same, but all people with diabetes generally have little ability to move glucose from the blood and produce glucose from the blood and into the cells that make glucose the body's primary fuel. Or none at all.

People who do not have diabetes rely on insulin, a hormone made in the pancreas, to carry glucose from the blood into the body's cells. However, people with diabetes do not produce insulin, or are unable to use their insulin efficiently, and thus diabetics cannot carry glucose into their cells. Accumulation of glucose in the blood leads to a condition called hyperglycemia, which can cause serious health problems over time.

Diabetes is a syndrome in which metabolic, vascular and neuropathic factors are interrelated. Metabolic syndrome, generally characterized by hyperglycemia, includes alteration of carbohydrate, fat and protein metabolism resulting from insufficiency or markedly reduced insulin secretion and / or ineffective insulin action. Vascular syndrome consists of abnormalities of the blood vessels causing cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous system are also part of diabetic syndrome.

IDDM patients, who make up about 5% to 10% of patients with diabetes, do not produce insulin and therefore must inject insulin to keep their blood sugar levels normal. IDDM is characterized by low or undetectable levels of endogenous insulin production due to the destruction of the β cells of the insulin producing pancreas (the feature that IDDM is most easily distinguished from NIDDM). IDDM, also referred to as juvenile diabetes, also develops in young and old.

Approximately 90-95% of patients with diabetes are type II (ie, NIDDM). NIDDM patients produce insulin, but the cells in their bodies are insulin resistant, ie the cells do not respond properly to the hormone, so glucose accumulates in their blood. NIDDM is characterized by a relative mismatch between endogenous insulin production and insulin demand, thereby raising blood glucose levels. Unlike IDDM, some endogenous insulin is always produced in NIDDM, while many NIDDM patients have normal or slightly elevated blood insulin levels, while other NIDDM patients improperly produce insulin (Rotwein, R. et al. N. Engl. J. Med. 308, 65-71 (1983)]. Most patients diagnosed with NIDDM are older than 30 years and half of all new patients are older than 55 years. Compared to whites and Asians, NIDDM is more common among Native Americans, African Americans, Latinos, and Hispanics. In addition, the onset can be latent or even clinically unexplained, making diagnosis difficult.

Primary pathogenic lesions on NIDDM are not yet known. In most cases, primary insulin resistance of peripheral tissues is presented as an initiation event. Genetic epidemiological studies support this view. Similarly, insulin secretion abnormalities have been discussed as the primary drawback in NIDDM. Both of these phenomena are likely to contribute significantly to disease progression (Rimoin, DL, et.al. Emery and Rimoin's Principles and Practice of Medical Genetics 3 ^rd Ed. 1: 1401-1402 (1996)).

Many people with NIDDM are obese because of their sedentary lifestyle, and their weight exceeds approximately 20% of their recommended weight for their height and physique. Obesity is also characterized by hyperinsulinemia and insulin resistance (a feature common to NIDDM), hypertension and atherosclerosis.

Obesity and diabetes are health problems among most people in industrialized societies. In an industrialized society, one third of the population is at least 20% overweight. In the United States, the rate of obesity increased from 25% in the late 1970s to 33% in the early 1990s. Obesity is one of the most important risk factors for NIDDM. Although the definition of obesity varies from person to person, generally, a person with at least 20% more weight than the body weight recommended for his or her height and physique is considered to be obese. The risk of developing NIDDM is threefold in 30% overweight subjects, and three quarters of NIDDM patients are overweight.

Obesity, the result of an imbalance between calorie intake and energy expenditure, is highly associated with insulin resistance and diabetes in experimental animals and humans. However, the molecular mechanisms associated with obesity-diabetes syndrome are not clear. During the initial onset of obesity, increased insulin secretion is balanced with insulin resistance, protecting patients from hyperglycemia (Le Stunff, et al. Diabetes 43, 696-702 (1989)). However, decades later, β cell function deteriorates and insulin non-dependent diabetes develops in about 20% of the obese population (Pederson, P. Diab. Metab. Rev. 5, 505-509 (1989) And [Brancati, FL, et al., Arch. Intern. Med. 159, 957-963 (1999)]. Because obesity is so widespread in modern society, obesity has become a leading risk factor for NIDDM (Hill, J. O., et al., Science 280, 1371-1374 (1998)). However, the factors that alter insulin secretion in response to fat accumulation in some patients are not yet known.

Classifying someone as overweight or obese is generally determined based on the body mass index (BMI), which is calculated by dividing the weight (kg) by the square of the height (m ² ). Thus, the unit of BMI is kg / m ² , and it is possible to calculate the BMI range associated with the minimum mortality at each decade of life. It is defined as overweight when the BMI range is 25 to 30 kg / m ² , and as obesity when the BMI range is above 30 kg / m ² (see table below). This definition is problematic in that it does not take into account the ratio of body mass that is muscle to fat (fat tissue). In this regard, obesity can also be defined based on body fat content (greater than 25% and 30% in males and females, respectively).

As BMI increases, the risk of death from various causes independent of other death risk factors increases. The most common diseases caused by obesity are cardiovascular diseases (particularly high blood pressure), diabetes mellitus (obesity worsens the development of diabetes), gallbladder disease (particularly cancer) and reproductive diseases. Studies have shown that moderate weight loss can significantly reduce the risk of developing coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (XENICAL) and Sibutramine. Orlistat (lipase inhibitors) directly inhibit fat absorption and tend to have a high incidence of unpleasant side effects, such as diarrhea (relatively harmless). Sibutramine (mixed 5-HT / noradrenaline reuptake inhibitors) can increase blood pressure and heart rate in some patients. Fenfluramine (Pondimin) and dexfenfluramine (Redux), which are serotonin release / reuptake inhibitors, have been reported to reduce food intake and body weight over long periods of time (greater than six months). . However, the two products were banned after preliminary evidence was reported that heart valve abnormalities were associated with their use. Therefore, there is a need for the development of safer anti-obesity agents.

Obesity also significantly increases the risk of developing cardiovascular disease. Coronary artery failure, atherosclerosis and heart failure are precursors to cardiovascular complications caused by obesity. If the entire population has an ideal body weight, the risk of coronary artery failure is predicted to be reduced by 25% and the risk of heart failure and cerebral vascular injury is reduced by 35%. The incidence of coronary artery disease is doubled in 30% overweight subjects under age 50. Diabetics face a 30% reduced lifespan. After the age of 45, people with diabetes are more likely to have about three times more severe heart disease and up to five times more strokes than those without diabetes. This finding highlights the interrelationship between risk factors for NIDDM and coronary heart disease, and highlights the potential value of an integrated approach to preventing these symptoms based on the prevention of these symptoms based on the prevention of obesity. Perry, IJ, et al., BMJ 310, 560-564 (1995)].

Diabetes is also involved in the development of kidney disease, eye disease and nervous system problems. Kidney disease, also referred to as nephropathy, occurs when the "filtration mechanism" of the kidney is impaired and excess protein is leaked into the urine, resulting in kidney failure. Diabetes is also a leading cause of damaging the retina in the back of the eye and increasing the risk of cataracts and glaucoma. Finally, diabetes is particularly associated with nerve damage in the legs and feet, which impedes the ability to feel pain and contributes to serious infections. Overall, diabetes complications are one of the leading causes of death in the country.

Summary of the Invention

The present invention relates to compounds and their use for binding to and modulating its activity, referred to herein as RUP3. As used herein, the term “RUP3” includes human sequences, naturally occurring allelic variants, mammalian orthologs and recombinant mutants thereof listed under GeneBank Accession No. AY288416. Preferred human RUP3s for use in screening and testing compounds of the invention are provided in the nucleotide sequence of SEQ ID NO: 1 and the corresponding amino acid sequence of SEQ ID NO: 2.

One aspect of the invention includes certain substituted aryl and heteroaryl derivatives or pharmaceutically acceptable salts, solvates, hydrates or N-oxides thereof as shown in formula (I)

In the above formula,

A ₁ and A ₂ are, each independently, C _{1 -6} alkyl, C _{1 -6} alkoxy and carboxy groups, optionally C 1 _{1 -3} alkylene optionally substituted with one or more substituents independently selected from the consisting of a;

D is CR ₁ R ₂ or NR _2, wherein R ₁ is selected from H, C _{1 -6} alkyl, C _{1 -6} alkoxy, halo and hydroxyl indeed the group consisting of;

E is N, C or CR _3, where R ₃ is H or C _{1 -6} alkyl;

은 E가 N 또는 CR₃인 경우에 단일 결합이거나, 또는 E가 C인 경우에 이중 결합이고;

Is a single bond when E is N or CR ₃ , or a double bond when E is C;

K is absent, or C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and each being righteous C _{3 -6} cycloalkyl which may be substituted from the group consisting of halogen with one or more substituents independently selected alkylene or C _{1 -3} alkyl group;

Q ₁ is NR _4, O, S, and S (O) or S (O) _2, wherein R ₄ is H, C _{1 -6} acyl, C _{1 -6} alkyl, C _2-6 alkenyl, C _{2 - 6} alkynyl, C _{3 -7-cycloalkyl} or C _{3 -7} - cycloalkyl, -C _{1 -3} - alkylene, wherein said C _{1 -6} alkyl is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6-alkyl-sulfonamide,} di -C _{1 -6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio O, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, hydroxylamino and nitro;

Q ₂ is absent, or is NR ₅ or O, wherein R ₅ is H, C _{1 -6} acyl, C _{1 -6} alkyl, C _2-6 alkenyl, C _{2 -6-alkynyl,} C _{3 -7} cycloalkyl or C _{3 -7} - cycloalkyl, -C _{1 -3} - alkylene and wherein the C _{1 -6} alkyl is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 - 6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} al kilsul sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkyl amino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 - 6} Roal skill alkylthio, hydroxyl, hydroxyl, amino and nitro with one or more substituents independently selected from the group consisting of optionally may be substituted;

W is N or CH;

X is N or CR ₆ ;

Y is N or CR ₇ ;

Z is N or CR ₈ ;

V is absent, or C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, C _{1 -3} may each be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halogen in C _{1 -3} hetero alkylene or C _{1 -3} alkylene;

R _6, R ₇ and R ₈ are H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 - 6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 - 6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl amino, and the group consisting of nitro each of which is independently selected, wherein the C _{2 -6} alkenyl from, C _{1 -6} alkyl, C _{2 -6-alkynyl} and C _{3 -6} cycloalkyl is C _1-6 acyl, C _1-6 acyloxy, C _{2 -6} alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkyl-carboxamide, C _{2- 6} alkynyl, C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkyl thio, C _1-6 alkylthio-carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6-alkylamino,} C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di- C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen , C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl, amino and nitro one or more substituents independently selected from the group consisting of each optionally Can be substituted;

Ar is aryl or heteroaryl, which may be optionally substituted with R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ ;

R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, arylcarbonyl, arylsulfonyl, di -C _1-6 - alkyl, amino, carboxylic one night yimido , C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6-alkyl} carboxamide, di -C _{1 -6-alkyl-sulfonamide,} di- C _1-6 - alkylthio carboxamido, guanidine, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _1-6 haloalkylsulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, hydroxylamino, nitro, C _{3 -6} oxo-cycloalkyl, phenoxy, sulfonamide, sulfonic acid and thiol; Wherein each R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkyl amino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _1-6 alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _1-6 alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di -C _1-6 - alkyl, amino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} when claw alkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkyl Thio, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and Optionally it may be substituted from the group consisting of Trojan with one or more substituents independently selected;

R _10, R _11, R ₁₂ and R ₁₃ is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino , C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _1-6 alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy , cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl amino, nitro, and thiol Independently selected from the group consisting of; Or two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the atoms to which they are attached are 5-, 6- or 7-membered cycloalkyl, 5-, 6- or 7-membered cycloalkenyl, or A 5-, 6- or 7-membered heterocyclic group is formed, wherein the 5-, 6- or 7-membered group can be optionally substituted with halogen or oxo;

R ₂ is H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6} alkyl carboxylic carboxamide, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide , C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, arylcarbonyl, aryloxy, di -C _{1 -6} - alkylamino, carboxylic night yimido yl, C _{1 -6} alkoxycarbonyl carbonyl, C _{3 -7} - cycloalkyl alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide di -C _{1 -6} - alkylthio carboxamido, guanidine, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl , C _{1 -6} haloalkylthio, heteroaryl, heteroaryl -C _1-3 - alkylene, heteroaryl-carbonyl, heteroaryloxy, Heterocycliccarboxamides, hydroxyl, hydroxylamino and nitro; Wherein R ₂ are each C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6} alkyl carboxylic carboxamide, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide , C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _3-6 cycloalkyl, di -C _1-6 - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkenyl Kiel, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl amino, and Optionally substituted with one or more substituents independently selected from the group consisting of nitros And, wherein the C _{1 -6} alkyl is added as a C _{1 -6} acyl, C _{1 -6} alkoxy, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{1 -6} alkyl sulfonamide, C _{1 - 6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, amide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl , halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, hydroxyl, 1 is independently selected from the group consisting of hydroxyl, amino and nitro Optionally substituted with more than one substituent.

One aspect of the invention relates to a pharmaceutical composition comprising at least one compound of the invention and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to a method of treating a metabolic-related disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. .

One aspect of the invention relates to a method of reducing food intake in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.

One aspect of the present invention relates to a method of inducing satiety in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

One aspect of the invention relates to a method of controlling or reducing weight gain in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof will be.

One aspect of the invention relates to a method of modulating RUP3 receptors in a subject, comprising contacting the RUP3 receptor with a compound of the invention. In some embodiments, the compound is an agonist for the RUP3 receptor. In some embodiments, RUP3 receptor modulation is treatment of metabolic-related disorders.

Some embodiments of the invention include methods of modulating RUP3 receptors in a subject comprising contacting the RUP3 receptor with a compound of the invention, wherein the RUP3 receptor regulation reduces food intake of the subject.

Some embodiments of the invention include methods of modulating RUP3 receptors in a subject comprising contacting the RUP3 receptor with a compound of the invention, wherein the RUP3 receptor regulation induces satiety in the subject.

Some embodiments of the invention include methods of modulating RUP3 receptors in a subject comprising contacting the RUP3 receptor with a compound of the invention, wherein the RUP3 receptor regulation controls or decreases the weight gain of the subject.

One aspect of the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment of metabolic-related disorders.

One aspect of the invention relates to the use of a compound of the invention for the manufacture of a medicament for reducing food intake in a subject.

One aspect of the invention relates to the use of a compound of the invention for the manufacture of a medicament for inducing satiety in a subject.

One aspect of the invention relates to the use of a compound of the invention for the manufacture of a medicament for controlling or reducing weight gain in a subject.

One aspect of the invention relates to a compound of the invention for use in a method of treating a human or animal body by therapy.

One aspect of the invention relates to a compound of the invention for use in a method of treating metabolic-related disorders of the human or animal body by therapy.

Some embodiments of the invention relate to a method wherein the human body mass index is from about 18.5 to about 45. In some embodiments, the human body mass index is about 25 to about 45. In some embodiments, the human body mass index is about 30 to about 45. In some embodiments, the human body mass index is about 35 to about 45.

In some embodiments the individual is a mammal. In some embodiments the mammal is a human.

In some embodiments, the metabolic-related disorder is hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (type 1b), potential autoimmune diabetes (LADA) in adults, early-onset type 2 diabetes ( EOD), adolescent-onset atypical diabetes (YOAD), adult-onset diabetes (MODY) in young people, malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vessels Diseases, intermittent claudication, myocardial infarction (e.g., necrosis and apoptosis), dyslipidemia, postprandial hemostasis, impaired glucose tolerance (IGT), fasting blood glucose damage, metabolic acidosis, ketoneism, arthritis, obesity , Osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral artery disease, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, X syndrome, premenstrual Syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, glucose metabolism damage, Impaired glucose tolerance, impaired fasting glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and vascular elastic injury.

In some embodiments, the metabolic-related disorder is type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or X syndrome. In some embodiments, the metabolic-related disorder is type II diabetes. In some embodiments, the metabolic-related disorder is hyperglycemia. In some embodiments, the metabolic-related disorder is hyperlipidemia. In some embodiments, the metabolic-related disorder is hypertriglyceridemia. In some embodiments, the metabolic-related disorder is type I diabetes. In some embodiments, the metabolic-related disorder is dyslipidemia. In some embodiments, the metabolic-related disorder is X syndrome.

One aspect of the present invention relates to a method of making a pharmaceutical composition comprising admixing one or more compounds described herein with a pharmaceutically acceptable carrier.

The invention described herein is described by Arena Pharmaceuticals, Inc. Ortho-macnail Parmical, Inc., by Arna Pharmaceuticals Inc. (Ortho-McNeil Pharmaceutical, Inc.) and Arena Pharmaceuticals, Inc. It is the result of activities undertaken within the scope of the Joint Research Agreement dated 20 December 2004.

Applicant reserves the right to exclude any one or more compounds from any embodiment of the present invention. Applicant further reserves the right to exclude any disease, condition or disorder from any embodiment of the present invention.

1A shows RT-PCR analysis for RUP3 expression in human tissue. A total of 22 human tissues were analyzed.

1B shows cDNA Dot-blot Analysis for RUP3 Expression in Human Tissue.

1C shows RUP3 analysis by RT-PCR using isolated islets of Langerhans islet.

1D shows RUP3 expression analysis using cDNA of rat origin by RT-PCR.

2A shows polyclonal anti-RUP3 antibodies prepared in rabbits.

2B shows expression of RUP3 in β cells of the Islet of Langerhans in the insulin producing pancreas.

3 shows the in vitro functional activity of RUP3.

4 shows the RUP3 RNA blot.

<Definition>

Scientific literature dealing with receptors employs a number of terms that refer to ligands having various effects on the receptor. For clarity and consistency, the following definitions will be used throughout this patent document.

"Agonist" means a moiety that interacts with and activates a receptor, such as the RUP3 receptor, thereby initiating the characteristic physiological or pharmacological response of the receptor. For example, the residue activates an intracellular response or enhances GTP binding to the membrane upon binding to the receptor.

As used herein, “amino acid abbreviation” is as shown in Table 1 below.

The term “antagonist” competitively binds to a receptor at the same site as an agonist (eg, an endogenous ligand), but does not activate an intracellular response initiated by the active form of the receptor, thereby to an agonist or partial agonist. It means a residue capable of inhibiting the intracellular reaction by. Antagonists do not reduce basal intracellular response in the absence of agonists or partial agonists.

<Chemical group, Residue  or Radical >

The term "C _{1 -6} acyl" denotes a carbon directly attached to the carbonyl group of C _{1 -6} alkyl radical, wherein the definition of alkyl are as described herein, some examples include acetyl, propionyl, n- butanoyl, Iso-butanoyl, sec-butanoyl, t-butanoyl (also called pivaloyl), pentanoyl, and the like, but are not limited thereto.

The term "C _{1 -6} acyloxy" denotes an acyl radical attached directly to an oxygen atom _{[-OC (= O) -C 1} -6 alkyl, wherein acyl has the same definition as described herein, some examples Acetyloxy [-OC (= O) CH ₃ ], propionyloxy, butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and the like, but is not limited thereto.

로 나타낼 수 있다. 본 발명의 일부 실시양태는 아실술폰아미드가 C_{1 -5} 아실술폰아미드인 경우이고, 일부 실시양태는 C_{1 -4} 아실술폰아미드인 경우이고, 일부 실시양태는 C_{1 -3} 아실술폰아미드인 경우이고, 일부 실시양태는 C_{1 -2} 아실술폰아미드인 경우이다. 아실술폰아미드의 예로는 아세틸술파모일 [-S(=O)₂NHC(=O)Me], 프로피오닐술파모일 [-S(=O)₂NHC(=O)Et], 이소부티릴술파모일, 부티릴술파모일, 2-메틸-부티릴술파모일, 3-메틸-부티릴술파모일, 2,2-디메틸-프로피오닐술파모일, 펜타노일술파모일, 2-메틸-펜타노일술파모일, 3-메틸-펜타노일술파모일, 4-메틸-펜타노일술파모일 등이 있으나, 이에 제한되지는 않는다. The term "C _{1 -6-acyl} sulfonamide" refers to C _{1 -6} acyl attached directly to the nitrogen of the sulfonamide, wherein the C _{1 -6} definition of acyl and sulfonamide have the same meaning as described herein, C _{1 -6} acylsulfonamide has the formula

It can be represented as. And some embodiments of the present invention, when the amide is an acyl sulfonamide is C _{1 -5-acyl} sulfonamides, in some embodiments is the case of C _{1 -4} acyl sulfonamide, some embodiments is a C _{1 -3} acyl sulfonamide and, some embodiments are when the C _{1 -2} acyl sulfonamide. Examples of acylsulfonamides include acetylsulfamoyl [-S (= O) ₂ NHC (= O) Me], propionylsulfamoyl [-S (= O) ₂ NHC (= O) Et], isobutyrylsulfamoyl , Butyrylsulfamoyl, 2-methyl-butyrylsulfamoyl, 3-methyl-butyrylsulfamoyl, 2,2-dimethyl-propionylsulfamoyl, pentanoylsulfamoyl, 2-methyl-pentanoylsulfamoyl, 3 -Methyl-pentanoylsulfamoyl, 4-methyl-pentanoylsulfamoyl, and the like, but are not limited thereto.

The term "C _{2 -6} alkenyl" is 2 to 6 containing carbon and at least one carbon-carbon double bond represents a radical is present, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 Carbons, some embodiments have two carbons. Both E and Z isomers are included in the term "alkenyl". The term "alkenyl" also includes di-alkenyl and tri-alkenyl. Thus, when more than one double bond is present, all of the bonds may be E or Z, or a mixture of E and Z. Examples of alkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5 -Hexanyl, 2,4-hexadienyl and the like.

The term "C _{1 -6} alkoxy" represents an alkyl radical of herein defined attached directly to an oxygen atom (i.e., -OC _{1 -6} alkyl). Examples are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, sec-butoxy and the like.

The term "C _{1 -6} alkyl" denotes a straight-chain or branched carbon radical containing 1 to 6 carbons, some embodiments are 1 to 5 carbons, the 4 carbon is from 1 to some embodiments, some embodiments Embodiments have 1 to 3 carbons, and some embodiments have 1 or 2 carbons. Examples of alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, sec-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, pent- 3-yl, 2-methyl-but-1-yl, 1,2-dimethyl-prop-1-yl, n-hexyl, iso-hexyl, sec-hexyl, neo-hexyl, 1-ethyl-2-methyl -Prop-1-yl, 1,2,2-trimethyl-prop-1-yl, 1,1,2-trimethyl-prop-1-yl, 1-ethyl-1-methyl-prop-1 -Yl, 1,1-dimethyl-but-1-yl, 1,2-dimethyl-but-1-yl, 2,3-dimethyl-but-1-yl, 2,2-dimethyl-but-1-yl , 1,3-dimethyl-but-1-yl, hex-3-yl, 2-methyl-pent-1-yl, 3-methyl-pent-1-yl, and the like, but are not limited thereto.

The term "C _{1 -6} alkyl amino" nimyeo receive the one alkyl radical (-HN-C _1-6 alkyl), attached directly to an amino radical wherein the alkyl radical has the same meaning as described herein. Some examples thereof include methylamino (ie, -HNCH ₃ ), ethylamino, n-propylamino, iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino, t-butylamino, and the like. It is not limited to this.

The term "C _{1 -6-alkyl-carboxamide"} or "C _{1 -6-alkyl-carboxamido"} denotes a single C _{1 -6} alkyl group attached to the nitrogen of an amide group, wherein alkyl has the same definition as described herein Has The C _{1 -6} alkyl carboxamido may be represented as follows:

Examples include N-methylcarboxamide, N-ethylcarboxamide, Nn-propylcarboxamide, N-iso-propylcarboxamide, Nn-butylcarboxamide, N-sec-butylcarboxamide, N Iso-butylcarboxamide, Nt-butylcarboxamide, and the like, but is not limited thereto.

The term "C _{1 -3} alkylene" is a divalent C _{1 -3} represents a straight-chain carbon. Examples of the C _{1 -3} alkyl group is -CH ₂ - a -, -CH ₂ CH ₂ - and -CH ₂ CH ₂ CH _2. Other examples include = CH-, = CHCH _2- , = CHCH ₂ CH _2- , which is generally related to "A ₂ " when E is C (ie carbon atom).

The term "C _{1 -6} alkyl sulfinyl" of the formula -S (= O) - refers to an alkyl radical attached directly to a sulfoxide radical wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, iso-butylsulfinyl, t-butyl, and the like. It doesn't work.

또는

의 기를 나타내며, 여기서 C_{1 -6} 알킬은 상기 기재된 바와 동일한 정의를 갖는다.The term "C _{1 -6} alkyl sulphonamide" is

or

It represents a group of in which C _{1 -6} alkyl has the same definition as described above.

The term "C _{1 -6} alkylsulfonyl" of the formula -S (O) ₂ - denotes an alkyl radical attached to a sulfone radical wherein the alkyl radical has the same definition as described herein. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, t-butylsulfonyl, and the like. It is not limited to this.

The term "C _{1 -6} alkylthio" refers to an alkyl radical attached to a sulfide of the formula -S- wherein the alkyl radical has the same definition as described herein. Examples include methylsulfanyl (ie CH ₃ S-), ethylsulfanyl, n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, iso-butylsulfanyl, t Butylsulfanyl and the like, but is not limited thereto.

또는

(식 중, C_{1 -6} 알킬은 본원에 기재된 바와 동일한 정의를 갖는다)로 표시된다. The term "C _{1 -6} alkylthio carboxamide" refers to the directly attached to the thio-alkyl carboxamide at the nitrogen or carbon of the thiocarbonyl formula

or

_Wherein C _1-6 alkyl has the same definition as described herein.

The term "C _{1 -6} alkyl thioureido rail" of the formula -NC (= S) NH- represents a group of in which one or both of the nitrogen is substituted independently by the same or different C _{1 -6} alkyl, the alkyl Has the same definition as described herein. Examples of alkylthioureas include CH ₃ NHC (S) NH—, NH ₂ C (S) NCH ₃ −, (CH ₃ ) ₂ N (S) NH—, (CH ₃ ) ₂ N (S) NH—, (CH ₃ ) ₂ N (S) NCH ₃ −, CH ₃ CH ₂ NHC (S) NH—, CH ₃ CH ₂ NHC (S) NCH ₃ −, and the like, but is not limited thereto.

The term "C _{1 -6} alkyl urea one" of the formula -NC (= O) NH- represents a group of, wherein is independently substituted with one or the same or different C _{1 -6} alkyl group both of the nitrogen, wherein the alkyl is It has the same definition as described herein. Examples of alkylureyls include CH ₃ NHC (O) NH—, NH ₂ C (O) NCH ₃ —, (CH ₃ ) ₂ N (O) NH—, (CH ₃ ) ₂ N (O) NH—, ( CH ₃ ) ₂ N (O) NCH ₃ −, CH ₃ CH ₂ NHC (O) NH—, CH ₃ CH ₂ NHC (O) NCH ₃ — and the like, but is not limited thereto.

The term "C _{2 -6-alkynyl"} is from 2 to 6 carbons and at least one carbon - represents a radical containing a carbon-carbon triple bond (-C≡C-), some embodiments are 2 to 4 carbons, some Embodiments have 2 to 3 carbons and some embodiments have 2 carbons (-C≡CH). C _{2 -6} ethynyl Examples of alkynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl Yl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like, but are not limited thereto. The term "C _{2 -6-alkynyl"} includes diyne and the tree.

The term "amino" refers to an -NH ₂ group.

The term "aryl" refers to an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.

The term "arylcarbonyl" refers to an aryl group attached directly to the carbon of the carbonyl group, wherein said aryl has the same definition as described herein. Examples include phenylcarbonyl (also called benzoyl), naphthalene-1-carbonyl, naphthalene-2-carbonyl and the like.

The term "aryloxy" refers to an aryl group [ie, aryl-O-] attached directly to an oxygen atom, wherein said aryl has the same definition as described herein. Examples include, but are not limited to, phenoxy, naphthalen-1-yloxy, naphthalen-2-yloxy and the like.

The term "arylsulfonyl" refers to an aryl group [ie, -S (= 0) _2- ] attached directly to the sulfur of a sulfonyl group, wherein said aryl has the same definition as described herein. Examples include benzenesulfonyl, naphthalene-1-sulfonyl, naphthalene-2-sulfonyl and the like.

The term "C _{1 -6} - alkoxy-carbonyl" denotes a group attached directly to the carbon of a carbonyl alkoxy, the formula _{-C (= O) OC 1 -6} - is represented by alkyl, wherein the C _{1 -6} alkyl group is present As defined in. In some embodiments, C _{1 -6-alkoxy} group is further bonded to a nitrogen atom, together with that nitrogen atom, a carbamate group-forms _{(e.g., NC (= O) OC 1} -6 alkyl) . Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, iso-butoxycarbonyl, t-butoxycarbonyl , n-pentoxycarbonyl, iso-pentoxycarbonyl, t-pentoxycarbonyl, neo-pentoxycarbonyl, n-hexyloxycarbonyl, and the like, but are not limited thereto.

의 기를 나타낸다. The term "carbamimidoyl" refers to

Represents a group.

The term "carboxamide" denotes a -C (= 0) NH ₂ group.

The term "carboxy" or "carboxyl" denotes a -CO ₂ H group (also called a carboxylic acid group).

The term "cyano" denotes a -CN group.

The term "C _{3 -7-cycloalkyl"} denotes a saturated ring radical containing 3 to 7 carbon; Some embodiments contain 3 to 6 carbon ( "C _{3 -6} cycloalkyl"); Some embodiments from 3 to 5 carbons, and containing ( "C _{3 -5} cycloalkyl"); Some embodiments contain 3 to 4 carbons ( "C _{3 -4} cycloalkyl"). Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclophenyl, cyclohexyl, cycloheptyl and the like.

The term "C _{3 -7} - cycloalkyl, -C _{1 -3} - alkylene" C _{3 -7} - the second of the C _{1 -3} coupled to a cycloalkyl group denotes a straight-chain carbon. Examples are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropyl-ethyl, 2-cyclobutyl-ethyl, 2-cyclopentyl-ethyl and the like.

The term "C _{3 -7} - cycloalkoxy" refers to cycloalkyl (i.e., -OC _{3 -7} cycloalkyl) of the herein defined attached directly to an oxygen atom. Examples include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and the like.

The term "C _{3 -7} - cycloalkoxy-carbonyl" denotes a carbon directly attached to the C _{3 -7} cycloalkoxy carbonyl group, which is the formula _{-C (= O) OC 3 -7} - is represented by cycloalkyl, wherein Cycloalkyl groups are as defined herein. In some embodiments, C _3-7 - cycloalkoxy group by combining the nitrogen atom, a carbamate group with the nitrogen atoms to form a _{(e.g., NC (= O) OC 3} -7 cycloalkyl) . Examples include, but are not limited to, cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, and the like.

이 있다. 일부 실시양태에서, 2개의 결합기는 상이한 탄소 상에 있다.The term "C _{3 -6} cycloalkyl-alkylene" denotes a divalent cycloalkyl radical containing 3 to 6 carbon atoms, wherein cycloalkyl is as defined herein, some embodiments contain 3 to 5 carbon ; Some embodiments contain 3 to 4 carbons. In some embodiments, two bonding groups are on the same carbon, for example

There is this. In some embodiments, the two bonding groups are on different carbons.

The term "di -C _{1 -6} - dialkylamino" denotes an amino substituted with the same or different two C _{1 -6} alkyl radical, wherein the alkyl radical has the same definition as described herein. Some examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino, and the like.

또는

기에 의해 표시될 수 있으며, 식 중 C_{1 -6}은 본원에 기재된 바와 동일한 정의를 갖는다. 디알킬카르복스아미드의 예로는 N,N-디메틸카르복스아미드, N-메틸-N-에틸카르복스아미드, N,N-디에틸카르복스아미드, N-메틸-N-이소프로필카르복스아미드 등이 있으나, 이에 제한되지는 않는다.The term "di -C _{1 -6} - alkyl-carboxamide" or "di -C _{1 -6} - alkyl-carboxamido" refers to the same or different two C _{1 -6} alkyl radical attached to an amide, wherein Alkyl has the same definition as described herein. Di-C _{1-6 -alkylcarboxamido}

or

Groups may be represented by formula, C _{1 -6} has the same definition as described herein. Examples of dialkylcarboxamides include N, N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N, N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like. There is, but is not limited to this.

또는

기로 표시될 수 있다. 그 예로는 디메틸술파모일 [-S(=O)₂N(CH₃)₂], 에틸메틸술파모일, 메탄술포닐-메틸-아미노 [-N(CH₃)S(=O)₂CH₃], 에틸-메탄술포닐-아미노 [-N(CH₂CH₃)S(=O)₂CH₃] 등이 있으나, 이에 제한되지는 않는다. The term "di -C _{1 -6} - alkyl sulfonamide" refers to the same or different two C _{1 -6} alkyl radical attached to the sulfonamide, wherein said alkyl has the same definition as described herein. Di -C _{1 -6} - alkyl sulfonamide is

or

It may be represented by a group. Examples include dimethylsulfamoyl [-S (= O) ₂ N (CH ₃ ) ₂ ], ethylmethylsulfamoyl, methanesulfonyl-methyl-amino [-N (CH ₃ ) S (= O) ₂ CH ₃ ] , Ethyl-methanesulfonyl-amino [-N (CH ₂ CH ₃ ) S (= 0) ₂ CH ₃ ] and the like, but is not limited thereto.

또는

기에 의해 표시될 수 있다. 디알킬티오카르복스아미드의 예로는 N,N-디메틸티오카르복스아미드, N-메틸-N-에틸티오카르복스아미드 등이 있으나, 이에 제한되지는 않는다.The term "di -C _{1 -6} - alkylthio carboxamido" or "di -C _{1 -6} - alkylthio carboxamide" refers to the same or different two C _{1 -6} alkyl radical attached to a thioamide Wherein said alkyl has the same definition as described herein. Di-C _{1 -6} alkylthio carboxamido is

or

It can be represented by the group. Examples of dialkylthiocarboxamides include, but are not limited to, N, N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide, and the like.

의 기를 나타낸다.The term "guanidine" refers to

Represents a group.

The term "C _{1 -6} haloalkoxy" denotes a haloalkyl, as defined in the directly attached to an oxygen atom, herein. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy (OCF ₃ ), 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

The term "C _{1 -6} haloalkyl" denotes an alkyl group of the herein defined substitution until completely substituted by one halogen, a fully substituted haloalkyl of the formula C _n L _{2n +1} (where, L is a halogen, " n "may be 1, 2, 3, 4, 5 or 6, and when more than one halogen is present, they are the same or different and are selected from the group consisting of F, Cl, Br or I In some embodiments, the halogen is F. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

The term "C _{1 -6} haloalkylsulfinyl" of the formula -S (= O) - denotes a sulfur a C _{1 -6} haloalkyl radical directly attached to a sulfoxide group, wherein the C _{1 -6} haloalkyl radicals It has the same definition as described herein. Examples include, but are not limited to, trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl, and the like.

The term "C _{1 -6} haloalkylsulfonyl" of the formula -S (= O) ₂ - denotes a haloalkyl radical attached directly to the sulfur of a sulfone group, wherein haloalkyl has the same definition as described herein. Examples include, but are not limited to, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, and the like.

The term "C _{1 -6} haloalkylthio" denotes a haloalkyl radical directly attached to a sulfur wherein the haloalkyl has the same meaning as described herein. Examples include, but are not limited to, trifluoromethylthio (ie, CF ₃ S-), 1,1-difluoroethylthio, 2,2,2-trifluoroethylthio, and the like.

The term "halogen" or "halo" denotes a fluoro, chloro, bromo or iodo group.

등의 기가 있으나, 이에 제한되지는 않는다.The term "C _{1 -3} alkylene-heteroalkyl" is -O-, -S-, -S (= O ) - an alkylene bonded to a heteroatom selected from, and -NH- -, -S (= O) 2 Indicates. Some representative examples include

And the like, but are not limited thereto.

The term “heteroaryl” refers to an aromatic ring system which may be a single ring, two fused rings or three fused rings, wherein one or more ring carbons is not limited to O, S, N and NH Substituted with a heteroatom selected from the group consisting of: Examples of heteroaryl groups include pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole, benzothiazole, 1H-benzimidazole, isoquinoline, quinazoline, quinox Saline, pyrrole, indole and the like. Other examples include, but are not limited to, heteroaryl groups in Table 3, Table 4, and the like.

The term "heteroaryl, -C _{1 -3} - alkylene" represents a heteroaryl group attached directly to the alkylene group, wherein the heteroaryl and alkylene are the same as both described herein. Examples of heteroaryl-C _1-3 -alkylene are isoxazol-3-ylmethyl, isoxazol-4-ylmethyl, isoxazol-5-ylmethyl, 2-isoxazol-3-yl-ethyl, 2- Isoxazol-4-yl-ethyl, 2-isoxazol-5-yl-ethyl, [1,2,4] oxadiazol-3-ylmethyl, [1,2,4] oxadiazol-5-yl Methyl, 2- [1,2,4] oxadiazol-3-yl-ethyl, 2- [1,2,4] oxadiazol-5-yl-ethyl, and the like.

The term "heteroarylcarbonyl" refers to a heteroaryl group attached directly to the carbon of the carbonyl group, wherein said heteroaryl has the same definition as described herein. Examples include [1,2,4] oxadiazole-3-carbonyl, [1,2,4] oxadiazole-5-carbonyl, isoxazole-3-carbonyl, isoxazole-4-carbonyl , Isoxazole-5-carbonyl, furan-2-carbonyl, furan-3-carbonyl, furan-4-carbonyl, furan-5-carbonyl, thiophene-2-carbonyl, thiophen-3- Carbonyl, pyridine-2-carbonyl, pyridine-3-carbonyl, pyridine-4-carbonyl and the like.

The term “heteroaryloxy” refers to a heteroaryl group [ie, heteroaryl-O—] attached directly to an oxygen atom, where the heteroaryl has the same definition as described herein. Examples include [1,2,4] oxadiazol-3-yloxy, [1,2,4] oxadiazol-5-yloxy, isoxazol-3-yloxy, isoxazol-4-yloxy , Isoxazol-5-yloxy, furan-2-yloxy, furan-3-yloxy, thiophen-2-yloxy, thiophen-3-yloxy, pyridin-2-yloxy, pyridine-3- Iloxy, pyridin-4-yloxy, and the like, but are not limited thereto.

The term “heteroarylsulfonyl” refers to a heteroaryl group [ie, —S (═O) ₂ —] attached directly to the sulfur of the sulfonyl group, wherein said heteroaryl has the same definition as described herein. Examples include [1,2,4] oxadiazole-3-sulfonyl, [1,2,4] oxadiazole-5-sulfonyl, isoxazole-3-sulfonyl, isoxazole-4-sulfonyl , Isoxazole-5-sulfonyl, furan-2-sulfonyl, furan-3-sulfonyl, thiophen-2-sulfonyl, thiophen-3-sulfonyl, pyridine-2-sulfonyl, pyridine-3- Sulfonyl, pyridine-4-sulfonyl, and the like, but is not limited thereto.

The term "heterocyclic" means that one, two or three ring carbons are not limited to -O-, -S-, -S (= 0)-, -S (= 0) ₂ -and -NH- A non-aromatic carbon ring (i.e. cycloalkyl or cycloal as defined herein) which is substituted with a heteroatom selected from the group consisting of and wherein the ring carbon atom is optionally substituted with oxo or thiooxo to form a carbonyl or thiocarbonyl group, respectively Kenyl). Heterocyclic groups may be three, four, five, six or seven membered rings. Examples of heterocyclic groups include aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, Piperidin-4-yl, morpholin-4-yl, piperazin-1-yl, piperazin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, [1,3] -Dioxolan-2-yl, etc., but is not limited thereto. Further examples of heterocyclic groups are shown in Table 2 below.

이 될 수 있다.It will be understood that any of the heterocyclic groups set forth herein may be attached to any ring carbon or ring nitrogen that is allowed in the respective formula, unless stated otherwise. For example, a 2,5-dioxo-imidazolidinyl group is bonded to one of ring carbons or two ring nitrogens, respectively,

This can be

등이 있으나, 이에 제한되지는 않는다. The term "heterocycliccarboxamide" or "heterocycliccarboxamido" has one or more nitrogen ring atoms and heterocyclic as defined herein, wherein the ring nitrogen binds directly to the carbon of the carbonyl group to form an amide. Represent a cyclic group. For example

Etc., but is not limited thereto.

등이 있으나, 이에 제한되지는 않는다.The term “heterocyclicsulfonyl” refers to a heterocyclic group as defined herein, having one or more ring nitrogens, which binds directly to the sulfur of the —S (═O) ₂ — group to form a sulfonamide group. For example

Etc., but is not limited thereto.

The term "hydroxyl" refers to an -OH group.

The term "hydroxylamino" denotes a -NHOH group.

The term "nitro" refers to the group -NO ₂ .

The term "oxo" generally denotes a double bonded oxygen, typically "oxo" is a substituent on carbon and together with carbon forms a carbonyl group.

으로 표시된다.The term "C _{3 -6-oxo-cycloalkyl"} refers to C _{3 -6} cycloalkyl optionally substituted as described in the dog one or two of the ring carbon sansogi to form a carbonyl group, as defined herein. Examples of oxo-cycloalkyl include 2-oxo-cyclobutyl, 3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 3-oxo-cyclohexyl, 2-oxo-cyclohexyl, 4-oxo-cyclohexyl, and the like. However, the present invention is not limited thereto, and each of them is a structural formula

Is displayed.

The term "phenoxy" refers to a C ₆ H ₅ O- group.

The term "phenyl" refers to a C ₆ H ₅ -group.

The term "sulfonamide" refers to the group -S (= 0) ₂ NH ₂ .

The term "sulfonic acid" denotes a -SO ₃ H group.

The term "thiol" refers to the group -SH.

"Composition" can mean a substance comprising two or more compounds or two or more components, for example, a pharmaceutical composition is, but is not limited to, a composition comprising a compound of the invention and a pharmaceutically acceptable carrier. .

"Compound potency" as opposed to receptor binding affinity, means a measure of the ability of a compound to inhibit or stimulate receptor function.

"Contact" or "contacting" means bringing together designated residues in an in vitro system or an in vivo system. Thus, "contacting" the RUP3 receptor with a compound of the invention not only administers the compound of the invention to an individual (eg, a human) having the RUP3 receptor, but also, for example, a cell preparation containing the RUP3 receptor or Introducing a compound of the invention into a sample containing a more purified formulation.

As used herein, “in need of treatment” means a caregiver (eg, doctor, nurse, apprentice nurse, etc. in a human being) whether an individual or animal needs treatment or would benefit from the treatment; In the case of animals, including the veterinarian). This determination is made based on various factors in the professional area of the caregiver, but this is a knowledge of whether or not the individual or animal is ill or will result as a result of a disease, symptom or disorder treatable by the compound of the present invention. It includes. The term "treatment" may also be expressed as a substitute for "prevention". Thus, in general, "treatment in need" means that the caregiver is judged that the individual is already ill, and therefore the compounds of the present invention are used to alleviate, suppress or ameliorate a disease, condition or disorder. The phrase also indicates a judgment by the caregiver that the subject would otherwise be ill. In such situations, the compounds of the present invention are used for protection or prevention.

As used herein, “individual” refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans. Indicates.

The term “inhibit” or “inhibiting” in relation to the term “react” means that the reaction is reduced or inhibited in the presence of the compound as opposed to in the absence of the compound.

"Inverse agonist" means a moiety that binds to an endogenous or constitutively activated form of a receptor, which in the absence of an agonist or partial agonist initiates an intracellular basal response initiated by the active form of the receptor. Inhibits below the normal basal level of activity observed, or reduces the binding of GTP to the membrane. Preferably, the intracellular basal response is inhibited by at least 30%, more preferably at least 50% and most preferably at least 75% in the presence of the inverse agonist compared to the basal response without the inverse agonist.

By "ligand" is meant a naturally occurring endogenous molecule specific for a naturally occurring endogenous receptor.

As used herein, the term “modulate” or “modulating” means increasing or decreasing the amount, quality, response, or effect of a particular activity, function, or molecule.

A “pharmaceutical composition” means a composition comprising one or more active ingredients that enable testing for specific and efficacious results in a mammal (eg, but not limited to a human). Those skilled in the art will understand and appreciate the appropriate techniques for determining whether the active ingredient has the desired efficacy result according to the needs of those skilled in the art.

As used herein, “therapeutically effective amount” refers to the amount of active compound or agent that elicits a biological or medical response in a tissue, strain, animal, individual, or human being sought by a researcher, veterinarian, doctor, or other clinician, wherein the biological Or medical reactions

(1) prevention of disease; For example, to prevent a disease, symptom or disorder in an individual who has not yet experienced or has shown the pathology or signs of the disease but may be susceptible to the disease, symptom or disorder,

(2) inhibition of disease; For example, inhibiting (ie, preventing further development of the pathology and / or signs) of the disease, condition or disorder in an individual experiencing or exhibiting the pathology or sign of the disease, symptom or disorder, and

(3) alleviation of the disease; For example, alleviating (ie, reversing the pathology and / or signs) of a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or sign of the disease, condition or disorder.

One or more of them are included.

Compounds of the Invention:

One aspect of the present invention relates to substituted aryl and heteroaryl derivatives of formula (I), or pharmaceutically acceptable salts, solvates, hydrates or N-oxides thereof.

<Formula I>

, A₁, A₂, D, W, X, Y 및 Z는 상기 및 하기 본원에 기재된 바와 동일한 정의를 갖는다. In the formula, Ar, V, Q ₁ , Q ₂ , K, E,

, A ₁ , A ₂ , D, W, X, Y and Z have the same definitions as described herein above and below.

It is to be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

As used herein, “substituted” means that one or more hydrogens of a chemical group have been replaced by a substituent or group other than hydrogen, and the substituents or groups other than hydrogen may be monovalent or divalent. When a substituent or group is divalent, it is understood that this group is further substituted with another substituent or group. Where a chemical group is "substituted" herein, it may be substituted up to the total substituent, for example the methyl group may be substituted by one, two or three substituents, and the methylene group may be substituted by one or two substituents The phenyl group may be substituted with 1, 2, 3, 4 or 5 substituents, and the naphthyl group may be substituted with 1, 2, 3, 4, 5, 6 or 7 substituents. Likewise, “substituted with one or more substituents” refers to the substitution of a given group by one substituent for the total number of substituents physically acceptable by the group. In addition, when a given group is substituted with more than one substituent, these substituents may be the same or different.

When a residue is referred to herein as being substituted, it is understood that this residue refers to one of the list of variables mentioned immediately above. For example, C _{1 -6} alkyl group is different C _{1 -6} alkyl, and when substituted by substituents selected from the other substituents, "may be optionally substituted with, where, C _{1 -6} alkyl is more", I mean the following original a C _{1 -6} represents, a straight C _{1 -6} alkyl substituent mentioned above other than alkyl, thereby the original C _{1 -6} alkyl is substituted by another C _{1 -6} alkyl which itself may be added, optionally substituted with Can be.

It is to be understood and appreciated that compounds of the present invention may have one or more chiral centers and may therefore exist as enantiomers and / or diastereomers. It is understood that the present invention extends to and encompasses all such enantiomers, diastereomers, and mixtures thereof including racemates and the like. Accordingly, some embodiments of the present invention relate to compounds of formula I that are R enantiomers, and to compounds of formula used throughout this disclosure. In addition, some embodiments of the invention relate to compounds of Formula I that are S enantiomers, and to compounds of formula used throughout this disclosure. When more than one chiral center is present (eg, two chiral centers), some embodiments of the invention relate to RS or SR enantiomeric compounds. In further embodiments, the compounds of the invention are RR or SS enantiomers. Unless stated or indicated otherwise, it will be understood that the compounds of Formula (I), and the compounds of the formulas used throughout this disclosure, are intended to represent all individual enantiomers and mixtures thereof.

Compounds of the invention may also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms may be in equilibrium or sterically immobilized in one form by appropriate substitution. It is understood that various tautomeric forms are within the scope of the compounds of the present invention.

Compounds of the present invention may also include all isotopes of atoms present in intermediates and / or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

In some embodiments, heteroaryl represents a 5-membered heteroaryl group. In some embodiments, heteroaryl represents a heteroatom-containing aromatic ring selected from the group consisting of the formulas in Table 3 below.

Wherein a 5-membered heteroaryl is bonded at any possible position of the ring, for example, the imidazolyl ring is one of ring nitrogen (ie, imidazol-1-yl group) or one of ring carbons (ie Imidazol-2-yl, imidazol-4-yl or imidazol-5-yl groups).

In some embodiments, heteroaryl represents a 6 membered heteroatom-containing aromatic ring selected from the group consisting of the formulas of Table 4 below.

Wherein the heteroaryl group is bonded to any ring carbon.

In some embodiments, A ₁ and A ₂ are both -CH ₂ -, each of C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy one or more substituents independently selected from the group consisting of (i. E., A ₁ May be optionally substituted with 1 or 2 substituents for, 1 or 2 substituents for A ₂ ).

Some embodiments of the invention relate to compounds wherein A ₁ and A ₂ are both —CH ₂ — and form a four membered ring, wherein A ₁ and A ₂ may each be optionally substituted with 1 or 2 methyl groups.

In some embodiments, A ₁ and A ₂ are both —CH ₂ — and may be represented by formula (Ib) shown below.

Wherein each variable of formula (lb) has the same meaning as described above and below herein.

In some embodiments, A ₁ is -CH ₂ - and, A ₂ is -CH ₂ CH ₂ -, and these are each 1 C _{1 -6} alkyl, independently selected from the group consisting of C _{1 -6} alkoxy, carboxy dog or more substituents may optionally be substituted with (that is, 1, 2, 3, or 4 substituents for one or two substituents, a ₂ for a _1).

Some embodiments of the present invention provide that A ₁ is -CH _2- , A ₂ is -CH ₂ CH _2- , form a 5-membered ring, A ₁ may be optionally substituted with 1 or 2 methyl groups, and A _It relates to a compound in which two may be optionally substituted with 1, 2, 3 or 4 methyl groups.

In some embodiments, A ₁ is —CH ₂ —, A ₂ is —CH ₂ CH ₂ — and may be represented by the formula (Id) shown below.

Wherein each variable of formula (Id) has the same meaning as described above and below herein.

In some embodiments, A ₁ and A ₂ are both -CH ₂ CH ₂ -, each of C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy one or more substituents independently selected from the group consisting of (i. E. Optionally 1, 2, 3 or 4 substituents for A ₁ , 1, 2, 3 or 4 substituents for A ₂ ).

Some embodiments of the present invention provide that A ₁ and A ₂ are both —CH ₂ CH ₂ — and form a six membered ring, wherein A ₁ and A ₂ may each be optionally substituted with 1, 2, 3 or 4 methyl groups The present invention relates to a compound.

In some embodiments, A ₁ and A ₂ are both —CH ₂ CH ₂ — and may be represented by the formula (If) shown below.

Wherein each variable of formula (If) has the same meaning as described above and below herein.

In some embodiments, A ₁ is -CH ₂ CH ₂ - and, A ₂ is -CH ₂ CH ₂ CH ₂ - independently from the group consisting of a, are each C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy at least one substituent group selected to be (i. e., one, two, three or four substituents, a 1, 2, 3, 4, 5, or 6 substituents for a ₂ for ₁₎ can optionally be substituted.

Some embodiments of the invention provide that A ₁ is —CH ₂ CH ₂ —, A ₂ is —CH ₂ CH ₂ CH ₂ —, forms a seven membered ring, and A ₁ and A ₂ are each 1, 2, 3 Or a compound which may be optionally substituted with 4 methyl groups.

In some embodiments, A ₁ is —CH ₂ CH ₂ — and A ₂ is —CH ₂ CH ₂ CH ₂ —, which may be represented by the formula (Ih) shown below.

Wherein each variable of formula (Ih) has the same meaning as described above and below herein.

In some embodiments, A ₁ and A ₂ are both -CH ₂ CH ₂ CH ₂ -, each of C _{1 -6} alkyl, C _1-6 alkoxy and carboxy one or more substituents independently selected from the group consisting of ( That is, 1, 2, 3, 4, 5 or 6 substituents for A ₁ , 1, 2, 3, 4, 5 or 6 substituents for A ₂ ).

Some embodiments of the invention are those in which A ₁ and A ₂ are both —CH ₂ CH ₂ CH ₂ — and form an 8 membered ring, wherein A ₁ and A ₂ are each optionally substituted with 1, 2, 3 or 4 methyl groups It relates to a compound that can be.

In some embodiments, A ₁ and A ₂ are both —CH ₂ CH ₂ CH ₂ —, which may be represented by the formula (Ij) shown below.

Wherein each variable of formula (Ij) has the same meaning as described above and below herein.

Some embodiments of the present invention provide that A ₁ is -CH ₂ -and A ₂ is = CHCH _2- ; Or A ₁ is -CH ₂ CH _2- , A ₂ is = CH-; Where possible, A ₁ and A ₂ are each directed to compounds which may be optionally substituted with 1, 2, 3 or 4 methyl groups.

In some embodiments, A ₁ is -CH ₂ -and A ₂ is = CHCH _2- ; Or A ₁ is -CH ₂ CH ₂ -and A ₂ is = CH-, which can be represented by the formulas (Ik) and (Im) respectively shown below.

Here, each variable of the formulas (Ik) and (Im) has the same meaning as described above and below herein.

Some embodiments of the invention provide that A ₁ is —CH ₂ CH ₂ —, A ₂ is = CHCH ₂ —, A ₁ may be optionally substituted with 1, 2, 3 or 4 methyl groups, and A ₂ is 1 The present invention relates to a compound which may be optionally substituted with 2, 3 or 3 methyl groups.

In some embodiments, A ₁ is —CH ₂ CH ₂ — and A ₂ is = CHCH _2- , which can be represented by the formula (Io) shown below.

Wherein each variable of formula (Io) has the same meaning as described above and below herein.

Some embodiments of the present invention provide that A ₁ is -CH ₂ CH ₂ -and A ₂ is = CHCH ₂ CH _2- ; Or A ₁ is -CH ₂ CH ₂ CH _2- , A ₂ is = CHCH _2- ; A ₁ and A ₂ are each directed to a compound which may be optionally substituted with 1, 2, 3 or 4 methyl groups.

In some embodiments, A ₁ is —CH ₂ CH ₂ — and A ₂ is = CHCH ₂ CH _2- ; Or A ₁ is -CH ₂ CH ₂ CH _2- , A ₂ is = CHCH _2- ; This can be represented by the formulas (Iq) and (Is) respectively shown below.

Wherein each variable of formula (Iq) and (Is) has the same meaning as described above and below herein.

Some embodiments of the present invention provide that A ₁ is -CH ₂ CH ₂ CH _2- , A ₂ is = CHCH ₂ CH ₂ -and A ₁ and A ₂ are each optionally substituted with 1, 2, 3 or 4 methyl groups It relates to a compound that can be.

In some embodiments, A ₁ is —CH ₂ CH ₂ CH ₂ — and A ₂ is = CHCH ₂ CH _2- , which can be represented by the formula (Iu) shown below.

Wherein each variable of formula (Iu) has the same meaning as described above and below herein.

이 단일 결합인 화합물에 관한 것이다. Some embodiments of the invention

It is related with the compound which is this single bond.

In some embodiments, compounds of the present invention may be represented by formula (Iw) shown below.

Wherein each variable of formula (Iw) has the same meaning as described above and below herein.

이 이중 결합인 화합물에 관한 것이다.

이 이중 결합인 경우, E는 C (즉, 탄소 원자)이고, E는 N (즉, 질소 원자)이 아님이 이해될 것이다. Some embodiments of the invention

It is related with the compound which is this double bond.

In the case of this double bond, it will be understood that E is C (ie carbon atom) and E is not N (ie nitrogen atom).

Some embodiments of the invention relate to compounds wherein K is absent.

In some embodiments, the compounds of the present invention can be represented by the formula (Iy) shown below.

Wherein each variable of formula (Iy) has the same meaning as described above and below herein.

In some embodiments, K is C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and with one or more substituents independently selected from the group consisting of halogen, which may be optionally substituted C _{3 -6} cycloalkylene to be.

Some embodiments of the present invention K is related to the C _{3 -6} cycloalkyl alkylene compound.

In some embodiments, K is selected from the group consisting of cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene.

In some embodiments, K is cyclobutylene.

In some embodiments, K is cyclopropylene.

In some embodiments, the compounds of the present invention can be represented by the formula (IIa) shown below.

Wherein each variable of formula (IIa) has the same meaning as described above and below herein.

Some embodiments of the present invention K is C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and C _{1 -3,} each optionally substituted from the group consisting of halogen with one or more substituents independently selected It relates to a compound which is an alkylene group.

Some embodiments of the present invention K is C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and halogen from the group consisting of 1, 2, 3 or 4 substituents independently selected which may be optionally substituted C _{1 -3} relates to alkylene.

Some embodiments of the present invention K is C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and halogen from the group consisting of 1, 2, 3 or 4 substituents independently selected which may be optionally substituted It relates to a compound that is -CH ₂ CH _2- .

Some embodiments of the present invention is -CH ₂ where K may be optionally substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and one or two substituents independently selected from the group consisting of halogen - It relates to a phosphorus compound.

In some embodiments, K is -CH _2- .

In some embodiments, the compounds of the present invention can be represented by the formula (IIc) shown below.

Wherein each variable of formula (IIc) has the same meaning as described above and below herein.

Some embodiments of the invention relate to compounds wherein V is absent.

In some embodiments, the compounds of the present invention may be represented by formula (IIe) shown below.

Wherein each variable of formula (IIe) has the same meaning as described above and below herein.

In some embodiments, V is C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, with one or more substituents independently selected from the group consisting of C _{1 -3} haloalkyl, and halogen, which may be optionally substituted a C _{1 -3} hetero alkylene.

Part of the invention embodiment is V is C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, C _1-3 haloalkyl, and 1 is independently selected from the group consisting of halogen, 2, 3 or 4 optionally C _1, which may be substituted with a substituent _-3 relates to a hetero-alkylene.

Some embodiments of the invention are optionally substituted with V is C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, C _1-3 haloalkyl, and one or two substituents independently selected from the group consisting of halogen It relates to a compound which is -OCH ₂ CH _2- .

In some embodiments, V is -OCH ₂ CH _2- , which can be represented by the formula (IIg) shown below.

Wherein each variable of formula (IIg) has the same meaning as described above and below herein.

In some embodiments, V is C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, with one or more substituents independently selected from the group consisting of C _{1 -3} haloalkyl, and halogen, which may be optionally substituted a C _1-3 alkylene group.

Some embodiments of the present invention, V is C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, C _{1 -3} haloalkyl and independently 1, 2, 3 or 4 selected from the group consisting of halogen It relates to an optionally C _{1 -3} alkylene compound, which may be substituted with a substituent.

Some embodiments of the invention are optionally substituted with V is C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, C _1-3 haloalkyl, and one or two substituents independently selected from the group consisting of halogen It relates to a compound which is -CH ₂ -which may be.

In some embodiments, V is -CH _2- , which can be represented by the formula (IIi) shown below.

Wherein each variable of formula (IIi) has the same meaning as described above and below herein.

Some embodiments of the invention relate to compounds wherein Q ₁ is NR ₄ .

In some embodiments, Q ₁ is NR ₄ , which may be represented by the formula (IIk) shown below.

Wherein each variable of formula (IIk) has the same meaning as described above and below herein.

Some embodiments of the present invention R ₄ is related to the H or C _{1 -6} alkyl.

Some embodiments of the invention relate to compounds wherein R ₄ is H.

Some embodiments of the invention have R ₄ on the C _{3 -7-cycloalkyl} compound. In some embodiments, R ₄ is cyclopropyl.

Some embodiments of the present invention R ₄ is C _{1 -3} - alkylene -C _{3 -7} - relates to the cycloalkyl compound. In some embodiments, R ₄ is cyclopropylmethyl (ie cC ₃ H ₅ CH _2- ).

Some embodiments of the invention relate to compounds wherein Q ₁ is O.

In some embodiments, Q ₁ is O, which may be represented by the formula (IIm) shown below.

Herein, each variable of formula (IIm) has the same meaning as described above and below herein.

In some embodiments, Q ₁ is S.

In some embodiments, Q ₁ is S (O) (also referred to as -S (= 0)-).

In some embodiments, Q ₁ is S (O) ₂ (also referred to as -S (= 0) _2- ).

Some embodiments of the invention relate to compounds wherein Q ₂ is absent.

In some embodiments, Q ₂ is absent, which can be represented by the formula (IIo) shown below.

Wherein each variable of formula (IIo) has the same meaning as described above and below herein.

Some embodiments of the invention relate to compounds wherein Q ₂ is NR ₅ .

In some embodiments, Q ₂ is NR ₅ , which can be represented by the formula (IIq) shown below.

Wherein each variable of formula (IIq) has the same meaning as described above and below herein.

Some embodiments of the present invention R ₅ is H, C _{1 -6} alkyl, C _{3 -7-cycloalkyl} or C _{3 -7-alkylene} relate to a compound-cycloalkyl -C _1-3.

Some embodiments of the invention relate to compounds wherein R ₅ is H.

Some embodiments of the invention relate to compounds wherein Q ₂ is O.

In some embodiments, Q ₂ is O, which can be represented by the formula (IIs) shown below.

Wherein each variable of formula (IIs) has the same meaning as described above and below herein.

In some embodiments, W is N.

In some embodiments, W is CH.

In some embodiments, X is N.

In some embodiments, X is CR ₆ .

In some embodiments, Y is N.

In some embodiments, Y is CR ₇ .

In some embodiments, Z is N.

In some embodiments, Z is CR ₈ .

In some embodiments of the invention, W is CH; X is N or N-oxide; Y is CR ₇ ; Z is N or N-oxide.

In some embodiments, W is CH; X is N; Y is CR ₇ ; Z is N; This can be represented by the formula (IIu) shown below.

Wherein each variable of formula (IIu) has the same meaning as described above and below herein.

In some embodiments of the invention, W is CH; X is N or N-oxide; Y is CR ₇ ; Z is CR ₈ .

In some embodiments, W is CH; X is N; Y is CR ₇ ; Z is CR ₈ ; This can be represented by the formula (IIw) shown below.

Wherein each variable of formula (IIw) has the same meaning as described above and below herein.

In some embodiments of the invention, W is CH; X is CR ₆ ; Y is CR ₇ ; Z is N or N-oxide.

In some embodiments, W is CH; X is CR ₆ ; Y is CR ₇ ; Z is N; This can be represented by the formula (IIy) shown below.

Wherein each variable of formula (IIy) has the same meaning as described above and below herein.

Some embodiments of the invention provide that W is N or N-oxide; X is CR ₆ ; Y is CR ₇ ; Z is CR ₈ .

In some embodiments, W is N; X is CR ₆ ; Y is CR ₇ ; Z is CR ₈ ; This can be represented by the formula (IIIa) shown below.

Wherein each variable of formula (IIIa) has the same meaning as described above and below herein.

In some embodiments of the invention, W is CH; X is CR ₆ ; Y is N or N-oxide; Z is CR ₈ .

In some embodiments, W is CH; X is CR ₆ ; Y is N; Z is CR ₈ ; This can be represented by the formula (IIIc) shown below.

Wherein each variable of formula (IIIc) has the same meaning as described above and below herein.

Some embodiments of the present invention relates to compounds that are R ₆ is selected from the group consisting of H, C _{1 -6} alkyl and halogen.

Some embodiments of the invention relate to compounds wherein R ₆ is H.

Some embodiments of the present invention relates to compounds that are R ₇ is selected from the group consisting of H, C _{1 -6} alkyl and halogen.

Some embodiments of the invention relate to compounds wherein R ₇ is H.

Some embodiments of the present invention relates to a compound selected from the group consisting of R ₈ is H, C _{1 -6} alkyl and halogen.

Some embodiments of the invention relate to compounds wherein R ₈ is H.

In some embodiments, X is CH.

In some embodiments, Y is CH.

In some embodiments, Z is CH.

Some embodiments of the invention relate to compounds wherein W and Y are both CH and X and Z are both N.

In some embodiments, W and Y are both CH and X and Z are both N; This can be represented by the formula (IIIe) shown below.

Wherein each variable of formula (IIIe) has the same meaning as described above and below herein.

Some embodiments of the invention relate to compounds wherein E is N.

Some embodiments of the invention relate to compounds wherein E is C (ie, carbon atoms).

Some embodiments of the invention relate to compounds wherein E is CR ₃ .

Some embodiments of the invention relate to compounds wherein E is CH.

Some embodiments of the invention relate to compounds wherein D is CR ₁ R ₂ .

Some embodiments of the invention relate to compounds wherein D is NR ₂ .

Some embodiments of the invention relate to compounds wherein E is N and D is CR ₁ R ₂ . In some embodiments, R ₁ is H.

Some embodiments of the invention can be represented by the formula (IIIg) shown below.

Wherein each variable of formula (IIIg) has the same meaning as described above and below herein.

Some embodiments of the invention relate to compounds wherein E is CR ₃ and D is NR ₂ .

Some embodiments of the invention can be represented by the formula (IIIi) shown below.

Wherein each variable of formula (IIIi) has the same meaning as described above and below herein.

Some embodiments of the present invention R ₂ is C _{1 -6} alkyl, aryl, aryloxy, heteroaryl, and heteroaryl relates to the compound is selected from the group consisting of oxy; Wherein R ₂ is C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, amino, di -C _{1 -6} - alkyl amino, C _{1 -6} alkoxycarbonyl, carboxy, halogen, and heteroaryl and 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of optionally be substituted, wherein the C _{1 -6} alkyl is added as a C _{1 -6} alkylamino, di -C _{1 -6} - alkylamino , optionally substituted with C _{3 -6} cycloalkyl, and one, two or three substituents independently selected from the group consisting of halogen.

Some embodiments of the present invention relates to a C _{1 -6} alkyl in the R ₂ may be optionally substituted with C _{1 -6} alkoxycarbonyl, or carboxy.

Some embodiments of the invention relate to compounds wherein R ₂ is ethoxycarbonylmethyl (ie, —CH ₂ CO ₂ Et) or carboxymethyl (ie, —CH ₂ CO ₂ H).

Some embodiments of the present invention relates to aryl compounds with R ₂ can be optionally substituted with one, two or three substituents selected from the group consisting of a C _{1 -6} alkoxy, C _{1 -6} alkyl.

Some embodiments of the invention relate to compounds wherein R ₂ is 4-isopropyl-phenyl, 4-isobutyl-phenyl or 4-isopropoxy-phenyl.

Some embodiments of the invention relate to compounds wherein R ₂ is aryloxy which may be optionally substituted with 1, 2, 3, 4 or 5 halogens.

Some embodiments of the invention relate to compounds wherein R ₂ is 3-fluoro-phenoxy.

In some embodiments, R ₂ is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkylamino, C _{1 - 6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, di -C _{1 -6} - alkylamino, carbonyl -C _1-6 - alkoxy, carboxamide, carboxy , cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, Optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxylamino, nitro and thiols 5 membered heteroaryl (eg, but not limited to those shown in Table 3).

In some embodiments, E is N, D is CHR _2, R ₂ is C _{1 -6} acyl, C _{1 -6} acyloxy, C _2-6 alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl , C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, di -C _1-6 - alkyl, amino, carbonyl -C _{1 -6-alkoxy,} carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _1-6 - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 - 6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio 1 to 4 selected from the group consisting of heterocyclic, heteroaryl, hydroxyl, hydroxylamino, nitro and thiol Optionally a heteroaryl of 5 which may be substituted with a vent (for example, but it is shown in Table 3, is not limited).

Some embodiments of the present invention R ₂ is C _{1 -6} alkyl and hetero aryl and heteroaryl may be optionally substituted with one, two or three substituents independently selected from the group consisting of, wherein the C _{1 -6} alkyl is further C _{1 -6} alkylamino, di -C _{1 -6} - alkylamino and C _{3 -6} about which would be optionally substituted with one or two substituents independently selected from the compound group consisting of cycloalkyl will be.

Some embodiments of the invention provide that R ₂ is 3-isopropyl- [1,2,4] oxadiazol-5-yl, 3-isobutyl- [1,2,4] oxadiazol-5-yl, 3-dimethylaminomethyl- [1,2,4] oxadiazol-5-yl, 3-cyclopropylmethyl- [1,2,4] oxadiazol-5-yl or 3-pyridin-2-yl- It relates to a compound which is [1,2,4] oxadiazol-5-yl.

Some exemplary embodiments of the present invention relates to a hetero aryloxy in R ₂ may be optionally substituted with one, two or three substituents independently selected from C _{1 -6} alkoxy.

Some embodiments of the invention relate to compounds wherein R ₂ is 5-isopropoxy-pyridin-2-yloxy.

Some embodiments of the invention, each R ₂ is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _1-6 alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, di -C _{1 -6} - alkylamino, carbonyl -C _{1 -6} - alkoxy, carboxamide, amide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _1-6 - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} - alkylthio carboxamido , C _1-6 haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heteroaryl, At least one tooth independently selected from the group consisting of hydroxyl, hydroxylamino, nitro and thiol An aryl group which may be optionally substituted, arylcarbonyl, C _{1 -6} alkoxycarbonyl, C _3-7 - cycloalkoxy-carbonyl, heteroaryl, and heteroaryl relates to carbonyl compounds.

Some embodiments of the present invention R ₂ is C _{1 -6} acyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{1 -6} alkyl alcohol sulfonyl, di -C _{1 -6} - alkylamino, carboxamide, carboxy, cyano, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkylsulfonyl, heterocyclic, and aryl which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl indeed, arylcarbonyl, C _{1 -6} alkoxycarbonyl, C _{3 -7} - cycloalkoxy-carbonyl, heteroaryl, and heteroaryl carboxylic It relates to a compound which is carbonyl.

Some embodiments of the invention are those in which R ₂ is H; C _{1 -6} optionally substituted with alkoxy, C _{1 -6} alkyl, C _{1 -6} alkoxycarbonyl, carboxy, C _{3 -6} cycloalkyl, and one, two, three or four substituents independently selected from the group consisting of halogen which may be C _{1 -6} alkyl, aryl, arylcarbonyl, C _{1 -6} alkoxycarbonyl, C _{3 -7} - cycloalkoxy-carbonyl, heteroaryl, heteroaryl -C _1-3 - alkylene and heteroaryl carboxylic A compound selected from the group consisting of carbonyl and heteroaryloxy.

Some embodiments of the invention are R ₂ C _{3 -6} cycloalkyl or C _{3 -7} - relates to a C _{1 -6} alkoxycarbonyl, C _{1 -6} alkoxycarbonyl is substituted by a cycloalkyl alkoxycarbonyl .

Some embodiments of the invention provide that R ₂ is tert-butoxycarbonyl, isobutoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclopropylmethoxycarbonyl, 3-methyl-butoxycarbonyl, cyclo A compound that is butoxycarbonyl or 1-ethyl-propoxycarbonyl.

Some embodiments of the present invention R ₂ is C _{1 -6} alkoxy, C _{1 -6} in which one, two, three or four substituents independently selected from the group consisting of halogen and alkyl may be optionally substituted heteroaryl-carbonyl It relates to a phosphorus compound.

Some embodiments of the invention provide that R ₂ is 5-butyl-pyridine-2-carbonyl, 6-chloro-pyridine-2-carbonyl, 6-bromo-pyridine-2-carbonyl, 6-methyl-pyridine- 2-carbonyl, 6-fluoro-pyridine-2-carbonyl, pyridine-2-carbonyl, 5-bromo-pyridine-3-carbonyl, 5-methyl-pyridine-3-carbonyl and 5,6 It relates to a compound selected from the group consisting of -dichloro-pyridine-3-carbonyl.

Some embodiments R ₂ is a C _{1 -6} alkoxy, C _{1 -6} heteroaryl compound in one, two, three or four substituents independently selected from the group consisting of halogen and alkyl may be optionally substituted according to the present invention It is about.

Some embodiments of the invention provide that R ₂ is 5-fluoro-pyridin-2-yl, 5-isopropoxy-pyridin-2-yl or 3-isopropyl- [1,2,4] oxadiazole-5 It relates to a compound which is one.

Some embodiments of the invention the heteroaryl in R ₂ is -C _{1 -3} may be optionally substituted with one, two or three substituents independently selected from C _{1 -6} alkyl- relates to alkylene.

Some embodiments of the invention provide that R ₂ is 3-isopropyl- [1,2,4] oxadiazol-5-ylmethyl or 2- (3-isopropyl- [1,2,4] oxadiazole- 5-yl) -ethyl.

Some embodiments of the present invention relates to a C _{1 -6} alkyl in the R ₂ may be optionally substituted with C _{1 -6} alkoxycarbonyl, or carboxy group.

Some embodiments of the invention provide that R ₂ is ethoxycarbonylmethyl (-CH ₂ CO ₂ Et), carboxymethyl (-CH ₂ CO ₂ H), 2-ethoxycarbonyl-ethyl (-CH ₂ CH ₂ CO ₂ Et) or 2-carboxy-ethyl (-CH ₂ CH ₂ CO ₂ H).

Some embodiments of the present invention relates to aryl compounds with R ₂ is a group 1, 2 or 3 C _{1 -6-alkoxy} can optionally be substituted.

Some embodiments of the invention relate to compounds wherein R ₂ is 4-isopropoxy-phenyl.

Some embodiments of the invention relate to compounds wherein Ar is aryl or heteroaryl, which may optionally be substituted with R ₉ , R ₁₀ , R ₁₁ , R _12, and R ₁₃ .

Some embodiments of the invention relate to compounds wherein Ar is phenyl which may be optionally substituted with R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ .

Some embodiments of the invention provide that Ar is pyridinyl, 4,5,6,7-tetrahydro-2H-indazolyl, quinolinyl, benzothiazolyl, thienyl, 1H-pyrazolo [3,4-b] Pyridinyl, thiazolyl, 5-oxo-4,5-dihydro-1H-pyrazolyl, isoxazolyl and [1,3,4] thiadiazolyl, or N-oxides thereof It is about.

Some embodiments of the invention provide that Ar is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4,5,6,7-tetrahydro-2H-indazol-3-yl, quinoline-6 -Yl, benzothiazol-6-yl, thien-2-yl, thien-3-yl, 1H-pyrazolo [3,4-b] pyridin-3-yl, thiazol-2-yl, 5-oxo -4,5-dihydro-1H-pyrazol-3-yl, isoxazol-4-yl and [1,3,4] thiadiazol-2-yl, or N-oxides thereof It relates to a compound that becomes.

Some embodiments of the invention can be represented by the formula (IIIk) shown below.

Wherein each variable of formula (IIIk) has the same meaning as described above and below herein.

Some embodiments of the invention can be represented by the formula (IIIm) shown below.

Herein, each variable of formula (IIIm) has the same meaning as described above and below herein.

Some embodiments of the invention can be represented by the formula (IIIo) shown below.

Wherein each variable of formula (IIIo) has the same meaning as described above and below herein.

Some embodiments of the invention R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl} carboxamide, amides, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, amino, aryl, arylsulfonyl, di- C _{1 -6} - alkylamino, carboxylic night yimido yl, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkoxy, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl sulfonamide, guar nidin, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkylsulfonyl, heteroaryl, heteroaryl-carbonyl, heteroaryl, sulfonyl, heterocyclic, heterocyclic-sulfonyl, hydroxyl, sulfonamide, and it relates to a thiol compound, wherein C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, amino, aryl, carboxamide yimido one night, heterocyclic clicks, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{2 -6-alkynyl,} C _1-6 alkyl sulfonamide, C _1-6 alkylsulfonyl, amino, aryl, C _{3 -6} cycloalkyl, di -C _1-6 - alkyl, halogen , Heteroaryl, heterocyclic, and hydroxyl may be optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of.

Some embodiments of the present invention relates to a C _{1 -6} alkyl in R ₉ may be optionally substituted with C _{1 -6-acyl} sulfonamide. In some embodiments, R ₉ is

Acetylsulfamoyl-methyl [ie -CH ₂ S (= 0) ₂ NHC (= 0) CH ₃ ],

Propionylsulfamoyl-methyl [ie -CH ₂ S (= 0) ₂ NHC (= 0) CH ₂ CH ₃ ],

2-acetylsulfamoyl-ethyl [ie -CH ₂ CH ₂ S (= 0) ₂ NHC (= 0) CH ₃ ] or

2-propionylsulfamoyl-ethyl [ie -CH ₂ CH ₂ S (= 0) ₂ NHC (= 0) CH ₂ CH ₃ ].

Some embodiments of the invention R _10, R _11, R ₁₂ and R ₁₃ is C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, carboxy, cyano, halogen, C _{1 -6} haloalkyl alkoxy, C _{1 -6} haloalkylsulfonyl and Hi selected from the group consisting of thread or deurok; Or two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the atoms to which they are attached form a 5 or 6 membered cycloalkyl or 5 or 6 membered heterocyclic group, wherein said 5 member Or a six-membered group relates to a compound which may be optionally substituted with halogen or oxo.

Some embodiments of the invention R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl} carboxamide, amides, C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, amino, di -C _{1 -6} - alkylamino, carboxylic night yimido one, C _{1 -6} alkoxycarbonyl, carboxy, cyano, C _{3 -6} cycloalkyl alkoxy, di -C _{1 -6} - alkyl, sulfonamide, guanidine, halogen, C _{1 -6} haloalkylsulfonyl, heteroaryl, heteroaryl-carboxylic carbonyl, heterocyclic sulfonyl, hydroxyl, sulfone, relates to an amide and a thiol compound, wherein C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, amino and carboxylic night yimido job C _{1 -} independently from ₆ alkoxy, C _{1 -6} alkyl, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonyl, amino, aryl, C _{3 -6} cycloalkyl, heteroaryl, heterocyclic, and hydroxyl indeed the group consisting of Selected May be optionally substituted with 1, 2, 3 or 4 substituents.

Some embodiments of the invention R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl} carboxamide, amides, C _{1 -6} alkyl sulfonamide, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, amino, carboxylic night yimido yl, C _{1 -6} alkoxycarbonyl, carboxylic, cyano, di -C _{1-6-alkyl-sulfonamide,} halogen, C _1-6 haloalkylsulfonyl, heteroaryl, heteroaryl-carbonyl, heterocyclic sulfonyl, hydroxyl, and relates to a sulfonamide compound, wherein C _1-6 alkyl , C _{1 -6} alkyl amino and carboxylic night yimido job C _{1 -6} alkyl, C _{1 -6} alkylsulfonyl, amino, heteroaryl, heterocyclic, and 1 is independently selected from the group consisting of hydroxyl chamber, 2, 3 Or optionally substituted with four substituents.

Some embodiments of the invention R ₉ is methanesulfonyl _{(CH 3 SO 2 -),} 2- methanesulfonyl-ethyl _{(CH 3 SO 2 CH 2 CH} 2 -), acetyl sulfamoyl [MeC (= O) NHS (= O) _2- ], propionylsulfamoyl [EtC (= O) NHS (= O) _2- ], ethylsulfanyl (CH ₃ CH ₂ S-), isopropylsulfanyl [(CH ₃ ) ₂ CHS -], Ethyl sulfamoyl (CH ₃ CH ₂ NHSO _2- ), methyl sulfamoyl (CH ₃ NHSO _2- ), dimethyl sulfamoyl [(CH ₃ ) ₂ NSO _2- ], methyl sulfamoylmethyl [CH ₃ NHSO ₂ CH _2- ], sulfamoyl (H ₂ NSO _2- ), [1,2,4] triazol-1-yl, [1,2,4] triazol-1-ylmethyl, 2- [1,2 , 4] triazol-1-yl-ethyl, methoxy (CH ₃ O-), 2-oxo-oxazolidin-4-ylmethyl, 1,1-dioxo-1λ ⁶ -thiomorpholine-4- Monomethyl, pyrazol-1-yl, trifluoromethanesulfonyl (CF ₃ SO _2- ), morpholine-4-sulfonyl, pyridine-2-carbonyl, F, Cl, cyano, Br, carboxy, Butyryl [CH ₃ CH ₂ CH ₂ C (═O) —], propoxycarbonyl [CH ₃ CH ₂ CH ₂ OC (═O) —], hydroxy, propylcarbamoyl [CH ₃ CH ₂ NHC ( = O)-], N- DE hydroxy carboxylic night yimido one _{[NH 2 C (= NOH)} -], carboxylic night yimido one _{[NH 2 C (= NH)} -], N- ethyl carboxamide night yimido one _{[CH 3 CH 2 NHC (=} NH) - ] And 2-amino-ethylamino [NH ₂ CH ₂ CH ₂ NH-].

Some embodiments of the invention R _10, R _11, R ₁₂ and R ₁₃ is C _{1 -6} alkoxy, C _{1 -6} alkyl, selected from the group consisting of carboxy and halogen or; Or two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the atoms to which they are attached form a five-membered heterocyclic group and may be optionally substituted with halogen.

Some embodiments of the invention relate to compounds wherein R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently selected from the group consisting of F, methoxy (CH ₃ O-), methyl, ethyl and carboxy.

Some embodiments of the invention R ₉ is C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6} alkynyl, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, amino, di -C _{1 -6} - alkylamino, carboxylic night yimido yl, cyano, C _{3 -6} cycloalkoxy, guanidine, C _{1 -6} relates to a compound selected from the group consisting of haloalkoxy and halogen, wherein C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, and amino is C _{1 -6} consisting of alkyl, amino, heteroaryl, and heterocyclic-alkoxy, C _{1 -6} alkyl, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonyl, aryl, C _{3 -6} cycloalkyl, di -C _1-6 Optionally 1, 2, 3 or 4 substituents independently selected from the group.

Some embodiments of the invention R ₉ is C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6} alkynyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, di -C _{1 -6} - alkylamino, cyano, C _{1 -6} relates to a compound selected from the group consisting of haloalkoxy and halogen, the C _{1 -6} alkoxy, C _{1 -6} alkylamino, and amino is C _{1 -6} alkoxy, C _{1 -6} alkyl, di -C _{1 -6} - ₁ is independently selected from the group consisting of alkyl, amino and heterocyclic Optionally substituted with 2, 3 or 4 substituents.

Some embodiments of the invention provide that R ₉ is methanesulfonyl (CH ₃ SO ₂ −), cyano, F, Cl, Br, I, methyl, methoxy (CH ₃ O—), ethylamino (CH ₃ CH ₂ NH-), ethylsulfanyl (CH ₃ CH ₂ S-), isopropylsulfanyl [(CH ₃ ) ₂ CHS-], hydroxy, isopropoxy [(CH ₃ ) ₂ CHO-], propoxy (CH ₃ CH ₂ CH ₂ O-), dimethylamino [(CH ₃ ) ₂ N-], propylamino (CH ₃ CH ₂ CH ₂ NH-), isopropylamino [(CH ₃ ) ₂ CHNH-], acetylamino [ CH ₃ C (═O) NH—], piperidin-1-yl, trifluoromethoxy (CF ₃ O-), oxazol-5-yl, ethynyl (HC≡C-), 3-methyl- Butylamino [(CH ₃ ) ₂ CHCH ₂ CH ₂ NH-], 2-morpholin-4-yl-ethylamino, acetylsulfamoyl [MeC (= O) NHS (= O) _2- ], propionylsulfamoyl [EtC (= 0) NHS (= 0) _2- ], tetrahydro-furan-2-ylmethoxy, morpholin-4-yl, 4-methyl-piperazin-1-yl, butylamino, 2-pyrroli Din-1-yl-ethoxy, 2-dimethylamino-ethoxy, 2-morpholin-4-yl-ethoxy, morpholin-4-ylamino, 2- Methoxy-ethylamino, and tetrahydro-furan-2-ylmethyl-it relates to a compound selected from the group consisting of amino.

Some embodiments of the invention R _10, R _11, R ₁₂ and R ₁₃ are selected from C _{1 -6} alkoxy, C _{1 -6} alkyl, cyano, halogen, C _{1 -6} haloalkoxy and hydroxyl indeed the group consisting of Or; Or two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the atoms to which they are attached form a 5- or 6-membered cycloalkyl, or 5- or 6-membered heterocyclic group, wherein 5 One- or six-membered groups relate to compounds which may be optionally substituted with oxo.

Some embodiments of the invention allow R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ to consist of F, Cl, Br, I, hydroxyl, methoxy (CH ₃ O-), cyano, methyl and trifluoromethoxy It relates to a compound selected from the group.

Some embodiments of the invention R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl} carboxamide, amides, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, amino, di -C _{1 -6} - alkylamino, carboxylic night yimido yl, carboxy, cyano, C _{3 - 6} cycloalkoxy, guanidine, C _{1 -6} relates to a compound selected from the group consisting of haloalkyl, and halogen, wherein C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, and amino is C _{1 - 6} alkoxy, C _{1 -6} alkyl, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonyl, aryl, C _{3 -6} cycloalkyl, heteroaryl, and 1, 2 is independently selected from the group consisting of heterocyclic clicking May be optionally substituted with 3 or 4 substituents.

Some embodiments of the invention R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6-alkyl-carboxamide,} C _{1 -6} alkyl alkylsulfonyl, carboxy, C _{1 -6} relates to a compound selected from the group consisting of haloalkyl, and halogen.

Some embodiments of the invention provide that R ₉ is methanesulfonyl (CH ₃ SO ₂ −), methoxy (CH ₃ O −), carboxy, acetylsulfamoyl [MeC (═O) NHS (═O) ₂ −], Propionylsulfamoyl [EtC (= 0) NHS (= 0) _2- ], acetylamino [CH ₃ C (= 0) NH-], F, Cl, Br, methyl and trifluoromethyl It relates to a compound that becomes.

Some exemplary embodiments of the present invention is directed to a compound R _10, R _11, R ₁₂ and R ₁₃ is a C _{1 -6} alkyl, independently selected from the group consisting of C _{1 -6} alkyl and halogen.

Some embodiments of the invention relate to compounds wherein R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently selected from the group consisting of methoxy (CH ₃ O—), methyl, F, Cl and Br.

Some embodiments of the invention R ₉ is C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{1 -6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _1-6 alkylthio, amino, aryl, arylsulfonyl, di -C _{1 -6} - alkylamino, carboxylic night yimido days, carboxamide, cyano, C _3-6 cycloalkoxy, guanidine, C _{1 -6} haloalkyl, halogen, heteroaryl, Oh relates to a reel and the heterocyclic compound is selected from the group consisting of clicks, in which C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, amino, and aryl is C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonyl, aryl, C _{3 -6} cycloalkyl, halogen, heteroaryl and Optionally 1, 2, 3 or 4 substituents independently selected from the group consisting of heterocyclic.

Some embodiments of the invention R ₉ is C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{1 -6} alkylthio, aryl, arylsulfonyl, carboxamide, cyano, C _{3 -6} cycloalkyl alkoxy, C _{1 -6} relates to a compound selected from haloalkyl, the group consisting of halogen, heteroaryl and heterocyclic, wherein aryl may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of C _{1 -6} alkyl and halogen.

Some embodiments of the invention provide that R ₉ is cyano, F, Cl, Br, acetylamino [CH ₃ C (= 0) NH-], methoxy (CH ₃ O-), methyl, propoxy (CH ₃ CH ₂ CH ₂ O-), propylamino (CH ₃ CH ₂ CH ₂ NH-), isopropylamino [(CH ₃ ) ₂ CHNH-], phenyl, t-butyl, 4-methylphenyl, ethyl, methylsulfanyl (CH ₃ S-), morpholin-4-yl, benzenesulfonyl, trifluoromethyl (CF _3- ), cyclopropyl, carbamoyl [H ₂ NC (O)-], 3,4-difluorophenyl , 4-chlorophenyl, 1-methyl-pyrrolidin-2-yl, acetylsulfamoyl [MeC (= O) NHS (= O) _2- ], propionylsulfamoyl [EtC (= O) NHS (= O ) 2-] and pyridin- ₂ -yl.

Some exemplary embodiments of the present invention is directed to a compound R _10, R _11, R ₁₂ and R ₁₃ is a C _{1 -6} alkyl, independently selected from the group consisting of C _{1 -6} alkyl and halogen.

Some embodiments of the invention relate to compounds wherein R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently methyl, F or Cl.

In some embodiments of the invention, Ar is phenyl and two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the carbon to which they are attached are 5-, 6- or 7-membered cycloalkyl, 5-membered, A 6- or 7-membered cycloalkenyl, or 5-, 6- or 7-membered heterocyclic group, wherein the 5-, 6- or 7-membered group relates to a compound that may be optionally substituted with halogen or oxo will be.

In some embodiments, Ar is phenyl and together with the two adjacent R ₁₀ and R ₁₁ groups form the 5-, 6- or 7-membered cycloalkyl shown in Table 5.

Wherein "a" is 1, 2 or 3, giving 5, 6 or 7 membered cycloalkyl fused with the phenyl group, wherein the two ring carbons are shared between the cycloalkyl and phenyl group.

In some embodiments, cycloalkyl carbons (ie, non-aromatic ring carbons) in Table 5 are replaced by 1, 2 or 3 heteroatoms selected from O, S and N, but not limited to, where N is substituted with H or C _{1 -6} alkyl group to form a heterocyclic 5-, 6-, or 7-membered.

In some embodiments, two adjacent groups form a 5-membered heterocyclic group with a phenyl group.

In some embodiments, the 5-membered heterocyclic group is a 2,3-dihydro-benzofuran-5-yl or benzo [1,3] dioxol-5-yl group with a phenyl group.

In some embodiments, two adjacent groups together with the phenyl group form a six membered heterocyclic group. In some embodiments, the 6-membered heterocyclic group is combined with a phenyl group 2,3-dihydro-benzo [1,4] dioxin-6-yl or 2,3-dihydro-benzo [1,4] dioxine It becomes -2- diary.

In some embodiments, two adjacent groups together with the phenyl group form a seven membered heterocyclic group. In some embodiments, the 7-membered heterocyclic group is a 3,4-dihydro-2H-benzo [b] [1,4] dioxe-7-yl group with a phenyl group.

Some embodiments of the invention include the compounds shown in Tables A and B below.

In addition, the compounds of formula (I) shown, for example, in Tables A and B include all pharmaceutically acceptable salts, solvates, in particular hydrates thereof.

In some embodiments, a compound of this invention is 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid iso Propyl ester.

In some embodiments, a compound of this invention is 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid iso It is not a propyl ester.

<Common Synthesis Method>

New biosynthesis of pyrimidine nucleotides provides an important precursor to many growth-related events in higher eukaryotes. Uracil and cytosine nucleotides assembled from ATP, bicarbonate and glutamine are fuels for the synthesis of RNA, DNA, phospholipids, UDP sugars and glycogen. Over the past two decades, significant progress has been made in identifying the mechanism by which cellular pyrimidines are regulated to meet cellular needs. These studies address increasing evidence for cooperation between key cell signaling pathways and the underlying components of cell mechanisms, suggesting that these events can determine distinct cell fates, including cell growth, differentiation and death. .

As a result of the profound biological significance of higher eukaryotes and the use of pyrimidine cores in many commercial drugs (Scheme 1) and other medicinal related compounds, pyrimidine and pyridine are chemotypes in drug development campaigns. Play a pivotal role. As a direct consequence of this, there are a number of scientific documents describing chemical modifications and assimilation as well as the procedures for the synthesis of this class of heterocycles.

The novel substituted pyrimidines and pyridines of the invention can be prepared according to a variety of synthetic procedures, all of which will be familiar to those skilled in the art of synthetic organic chemistry. Certain methods of preparing the compounds of the present invention include, but are not limited to, those described in Schemes 2-10 of this section of the present specification.

Common dihalo-substituted intermediates 8 used as starting points for the synthesis of the compounds of the present invention can be prepared as shown in Scheme 2. This reaction is di -C _1-6 - alkyl carbonate is achieved from the words in two steps, a particularly useful di -C _{1 -6} - alkyl malonate is diethyl malonate 5. Cyclization to 4,6-dihydroxypyrimidine (7) reacts (5) with formamidine in the presence of an alkali metal alkoxide, wherein malonate and all or part of formamidine are alkoxides or alkoxides and Achieved by mixing with the remaining formamide. Alternative reagents (eg, dimethylmalonate, sodium methoxide, formamide) in low molecular weight alcoholic solvents, including methanol, ethanol, 2-propanol, and the like, may be used at a temperature ranging from about 80 to about 100 ° C. for about 30 minutes to about 90 After heating for minutes, it can be used for synthesis by finishing with an inorganic acid. The preparation of dihydroxypyrimidines can also be accomplished using microorganisms (eg Rhodococcus ) (see WO97008152 A1).

Chlorination of the 4 ring and 6 ring positions to produce intermediate 8 results in (7) chlorination reagents such as phosgene, POCl ₃ (A. Gomtsyan et al., J. Med. Chem. 2002, 45, 3639-3648), thionyl chloride, oxalyl chloride, and a mixture of the above reagents, including PCl ₃ / POCl ₃ , at a reaction temperature of elevated temperature.

Conventional thermal aromatic substitution reactions of amines and alcohols with halogenated pyrimidines are well known (see, for example, AG Arvanitis et al., J. Medicinal Chemistry, 1999, 42, 805-818 and therein). See references). Nucleophilic aromatic (SN _Ar ) substitution reactions of electron deficient halogenated pyrimidines are generally fast and high in yield. However, in certain cases, for example, electron rich or neutral halogenated heterocycles, they are successfully substituted when extended heating. Microwave synthesis was used to facilitate rapid introduction into many of the compounds of the present invention (Scheme 3 and 4). The Smith synthesizer from Personal Chemistry is a commercial zone concentrated heating device that provides safer and more uniform conditions for carrying out the base catalyzed substitution reactions shown in Schemes 3a, 3b and 3c. Bases used in this conversion (where Q ₂ = N) include tertiary amines (eg triethylamine), Hunig's base (ie diisopropyl-ethylamine), N-methylmorpholine Etc. Alternatively, those skilled in the art will appreciate alkali metal hydrides, alkali metal carbonates (eg, Li ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO _3, etc.), alkali metal hydrogencarbonates (eg, LiHCO ₃ , NaHCO ₃ , KHCO _3). Etc.) can be used. When Q ₂ = N, an inert lower alkyl alcoholic solvent (eg, MeOH, EtOH, i-PrOH, n-BuOH, etc.) can be used, or when Q ₂ = O, ether solvents (eg , Tetrahydrofuran, 1,4-dioxane, etc.) can be used. The reaction time for producing typical intermediates (e.g., (9), (10) and (11)) can be from about 300 seconds to about 3000 seconds, using conventional thermal methods (where Q ₂ = 0) about 20 minutes to about 120 minutes.

The conversion to the intermediate monosubstituted pyrimidines and pyridines (9), (10) and (11) is shown in Scheme 4. Examples where Q ₁ = N (Scheme 4a, 4b, 4c) were obtained using palladium catalyzed amination. This synthesis method has recently emerged as a powerful tool for the synthesis of substituted aryl and heteroaryl anilines (see SL Buchwald., Top. Curr. Chem., 2002, 219, 131) and references therein. Anhydrous solvents suitable in the presence of palladium or alternative transition metal catalysts selected from Pd ₂ (dba) ₃ , Pd (OAc) ₂ , CuI, Cu (OTf) ₂ , Ni (COD) ₂ , Ni (acac) ₂ , and the like ( For example, suitably substituted amines (eg, intermediate 16) in THF, 1,4-dioxane, etc.) are reacted with strong alkali metal alkoxide bases (eg, NaO ^t Bu, KO ^t Bu, etc.). Suitable ligands used in this step may be selected from BINAP, P (o-tolyl) ₃ , tBu ₃ P, DPPF, P [N ( ⁱ Bu) CH ₂ CH ₃ ] ₃ N, etc., when the catalyst is a palladium-derived complex. Can be.

Alternatively, the base used for “Ullman-type” aryl amination catalyzed by a copper-derived complex is an aprotic with L-proline, N-methylglycine or diethylsalcyclamide as ligand. It may be selected from alkali metal carbonates in magnetic polar solvents (eg, N, N-dimethylacetamide, DMF, DMSO, etc.) (see D. Ma, Organic Lett., 2003, 5, 14, 2453-2455). ).

Compounds of formulas 12-15 may also be obtained by reversing the sequence of reaction steps (ie, introducing Q ₁ followed by Q ₂ ), wherein the first step is performed using a base in ⁱ PrOH followed by 4 N HCl in dioxane The addition consists of introducing intermediate 16 or 17.

As shown in Scheme 5, a similar transition metal catalyzed coupling was used to obtain molecules of formulas 21a and 21b (Scheme 5a), where the "Ar" substituent (Hal = Br, I) of intermediate 20 was modified to alkyl amino substituents (i.e., NR _a R _b, as described herein, wherein the R _a and R _b are each independently H, C _{1 -6} alkyl, or substituted C _{1 -6} alkyl or this, or R _a and R _b forms a heterocyclic ring with nitrogen). Alternatively, linker atoms are described in SL Buchwald; Organic Lett., 2002, 4, 6, 973-976, by using a process for forming CuI catalyzed aromatic CO, for example, 10 mol% CuI, 20 mol% 1,10- at 110 ° C. for 18 hours. By using phenanthroline, Cs ₂ CO ₃ 2 equivalents (Scheme 5b), “Ar” iodo in the substrate can also be substituted oxygen. One particular embodiment is where the Hal group of "Ar" is substituted at the para position of the phenyl ring.

Specific substitution of the compounds 12, 13, 14 and 15 are D = NCOOR _c (wherein, R _c is C _{1 -6} alkyl, or C _{3 -7-cycloalkyl} Im) when, each of which may be further substituted. This type of urethane can be prepared directly from the intermediates shown in Schemes 3 and 4 when D = NH. In certain reactions, the use of suitable nitrogen protecting groups (eg, ^t Boc, Cbz, Moz, Alloc, Fmoc, etc.) may be necessary during further chemical modification of the core. Deprotection may include standard reagents familiar to those skilled in the art, including TFA, inorganic acids, palladium / hydrogen gases, etc. in alcoholic or ethereal solvent systems selected from methanol, ethanol, tert-butanol, THF, 1,4-dioxane and the like. Can be achieved). If the target molecule contains two protecting groups, a right angle protection method can be employed. The deprotected secondary amine (D = NH) may later be modified as above.

Schemes 6 and 7 describe chemistries that can generate carbamate, urea, or amide using an appropriate reaction in an inert solvent system in the presence of a base (eg, a tertiary amine base such as TEA, DIEA, etc.).

As shown in Scheme 6, R _c OCO-halide in the presence or absence of a base in an inert solvent, where R _a is as described above and the halide is chloro, bromo or iodo, in particular chloro is useful The urethane 19 can be obtained by the urethane reaction used. Suitable bases include alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (eg, sodium bicarbonate, potassium hydrogen carbonate, etc.), alkali hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), 3 Secondary amines (eg, N, N-diisopropylethylamine, triethylamine, N-methylmorpholine, etc.) or aromatic amines (eg, pyridine, imidazole, poly- (4-vinylpyridine) and the like) . Inert solvents include lower halocarbon solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), ether solvents (eg, tetrahydrofuran, dioxane, etc.), aromatic solvents (eg, benzene, toluene, etc.) or polar solvents ( Such as N, N-dimethylformamide, dimethyl sulfoxide, etc.). The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 100 ° C.

As shown in Scheme 7a, the amine intermediate obtained from the acidic deprotection of (22) can be functionalized with amide (23). Carbamate 22 is first reacted with 4 N HCl in dioxane or alternatively with TFA in dichloromethane, and further with a carboxylic acid (R _d CO ₂ H, wherein Scheme 7a with a dehydrating condensing agent) R _d is Ar or C _1-6 -alkylene-Ar; Ar may be substituted or unsubstituted and has the same meaning as described herein) and reacted in the presence or absence of a base in an inert solvent to Amide 23 was obtained. Dehydrating condensing agents include dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl ), Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), benzotriazoloyloxytris (dimethylamino) -phosphonium hexafluorophosphate (BOP), O- (7-azabenzotria) Zol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) or 1-cyclohexyl-3-methylpolystyrene-carbodiimide. Bases include tertiary amines (eg, N, N-diisopropylethylamine, triethylamine, etc.). Inert solvents include lower halocarbon solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), ethereal solvents (eg, tetrahydrofuran, dioxane, etc.), nitrile solvents (eg, acetonitrile, etc.), amide solvents. (N, N-dimethylformamide, N, N-dimethylacetamide, etc.) and mixtures thereof. Optionally, 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxamidomethyl polystyrene or 1-hydroxy-7-azabenzotriazole (HOAT) can be used as the reactant. The reaction temperature is about -20 ° C to 50 ° C, preferably about 0 ° C to 40 ° C.

Alternatively, the amide (23) of the present invention can be obtained by an amidation reaction using an acid halide (such as R _d COCl) and a base in an inert solvent (Scheme 7a). Bases include alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali hydroxides (e.g. sodium hydroxide or potassium hydroxide, etc.), tertiary Amines (eg, N, N-diisopropyl ethylamine, triethylamine, N-methylmorpholine, etc.) or aromatic amines (eg, pyridine, imidazole, poly- (4-vinylpyridine) and the like). Inert solvents include lower halocarbon solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), ether solvents (eg, tetrahydrofuran, dioxane, etc.), amide solvents (eg, N, N-dimethylacetamide, N , N-dimethylformamide and the like), aromatic solvents (benzene, toluene, pyridine and the like) and mixtures thereof. The reaction temperature is about -20 ° C to 50 ° C, preferably about 0 ° C to 40 ° C.

As shown in Scheme 7, amide (23) can also be reacted with a reducing agent in an inert solvent to give the amine (24) of the present invention. Reducing agents include alkali metal aluminum hydrides (eg, lithium aluminum hydride, etc.), alkali metal borohydrides (eg, lithium borohydride, etc.), alkali metal trialkoxyaluminum hydrides (eg, lithium tri-tert-butoxyaluminum) Hydrides), dialkylaluminum hydrides (eg, di-isobutylaluminum hydrides, etc.), boranes, dialkylboranes (eg, di-isoamyl boranes, etc.), alkali metal trialkylboron hydrides (eg, lithium Triethylboron hydride and the like). Inert solvents include ether solvents (eg tetrahydrofuran, dioxane and the like), aromatic solvents (eg toluene and the like) and mixtures thereof. The reaction temperature is about -78 ° C to 200 ° C, for example about 50 ° C to 120 ° C.

Alternatively, the amines 24 of the present invention can be obtained by reductive amination reactions using aldehydes (R ₆ CHO) and reducing agents using acid deprotected secondary amine intermediates with or without acid in an inert solvent. have. Reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, borane-pyridine complexes and the like. Inert solvents include lower alkyl alcohol solvents (eg, methanol, ethanol, etc.), lower halocarbon solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), ether solvents (eg, tetrahydrofuran, dioxane, etc.), aromatic Solvents (eg benzene, toluene and the like) and mixtures thereof. Acids include inorganic acids (eg hydrochloric acid, sulfuric acid, etc.) or organic acids (eg acetic acid, etc.). The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 100 ° C. In addition, this reaction can optionally be carried out under microwave conditions.

Alternatively, (22) the de-protected acid intermediate amine product was the alkylating agent in the presence of a base and an inert solvent, such as R ₆ - halide (wherein, R ₆ is a substituted or unsubstituted C _{1 -6} alkyl, or substituted or an unsubstituted C _{1 -6} alkyl -Ar, halide by direct alkylation with the chloro, bromo, and iodo Im) can be obtained amine (24). Bases include alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal hydrides (e.g. sodium hydride, potassium hydride, etc.), alkali metal alkoxides (e.g. potassium tert-butoxide, sodium tert-butok) Seeds and the like); Alkyl lithiums (eg tert-butyl lithium, n-butyl lithium, etc.). Inert solvents include ether solvents (eg tetrahydrofuran, dioxane), aromatic solvents (eg benzene, toluene and the like), amide solvents (eg N, N-dimethylformamide and the like) and mixtures thereof. The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 100 ° C.

As also shown in Scheme 7, the nitrogen of urea (23) is alkylated using an alkyl-halide, wherein the halide is chloro, bromo and iodo, in an inert solvent in the presence of a base to give the di-substituted urea. By obtaining additional compounds of the present invention are prepared. Bases include alkali metal hydrides (eg, sodium hydrides, potassium hydrides, etc.), alkali metal alkoxides (eg, potassium tert-butoxide, sodium tert-butoxide, etc.); Alkyl lithiums (eg, tert-butyl lithium, n-butyl lithium, etc.). Inert solvents include ether solvents (eg tetrahydrofuran, dioxane), aromatic solvents (eg benzene, toluene and the like), amide solvents (eg N, N-dimethylformamide and the like) and mixtures thereof. The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 100 ° C.

In addition, as shown in Scheme 8a, urea 25a deprotects common intermediate 18, and the amine (i.e., D = NH) is subjected to various isocyanates (R _a NCO, Wherein R _a has the same meaning as described herein). Suitable bases include alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (eg, sodium bicarbonate, potassium hydrogen carbonate, etc.), alkali hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), 3 Secondary amines (eg, N, N-diisopropylenylamine, triethylamine, N-methylmorpholine, etc.) or aromatic amines (eg, pyridine, imidazole, etc.). Inert solvents include lower halo carbon solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), ether solvents (eg, tetrahydrofuran, dioxane, etc.), aromatic solvents (eg, benzene, toluene, etc.) or polar solvents ( Such as N, N-dimethylformamide, dimethyl sulfoxide, and the like. The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 100 ° C.

In addition, as shown in Scheme 8b, thiourea 25b deprotects common intermediate 18, and the amine (i.e., D = NH) can be used in a variety of thioisocyanates (R _a NCS, Where R _a has the same meaning as described herein). Suitable bases include alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (eg, sodium bicarbonate, potassium hydrogen carbonate, etc.), alkali hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), 3 Secondary amines (eg, N, N-diisopropylethylamine, triethylamine, N-methylmorpholine, etc.) or aromatic amines (eg, pyridine, imidazole, etc.). Inert solvents include lower halocarbon solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), ether solvents (eg, tetrahydrofuran, dioxane, etc.), aromatic solvents (eg, benzene, toluene, etc.) or polar solvents ( Such as N, N-dimethylformamide, dimethyl sulfoxide, and the like. The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 100 ° C.

Scheme 9 shows the synthesis of para-alkyl sulfones 27 used as aryl forming blocks in Scheme 4 of the present invention, wherein R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ have the same meanings as described herein. ). Typical methods for preparing such sulfones include oxidation of sulfides using aryl sulfonyl halides or aryl sulfonic acids in the presence of strong acid catalysts or sulfonylation of arene (the Organic Chemistry of Sulfur; Oae S., Ed Plenum Press: New York, 1977). Optionally 2,5-disubstituted arene optimum conversion to 27 Wang (Wang), such as _2, a 5 mol% (CuOTf) in DMSO by the method PhH and 10 mol% N, N'- dimethylethylene diamine Thermally using, wherein Hal is preferably iodo (see Wang Z .; Baskin JM, Org. Lett., 2002, 4, 25, 4423-4425). In some embodiments, R ₁₀ and R ₁₃ are each independently H, halogen or C _{1 -6} alkyl; R ₁₁ and R ₁₂ are both H; Hal = Br, I; Q ₁ = OH or NH ₂ .

Alternative standard organic synthesis methods can be used to introduce alternative substituents into the Ar component. In the example where the linker atom is Q ₁ = N, such manipulations have the standard FmocCl and CbzCl protection and deprotection steps familiar to those skilled in the art (Scheme 10 wherein R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ have the same meanings as described herein). Having a) aniline amino functionality and can be carried out by using deprotected aniline in a later step as described in Scheme 4. Nitrile (29) may alternatively be converted to amidine (A84), (A90) or (A103) by using hydroxylamine HCl and then reducing with zinc / acetic acid (see Table A). In some embodiments of the invention R ₁₀ is halogen and R ₁₃ is H or halogen.

The synthesis of the variants with 3,5-oxadiazole is shown in Scheme 11. Amidoxime (34) was coupled with 4-hydroxypiperidine and zinc (II) chloride catalysis to give forming block (37) after acidic finishing from (36) derived from CNBr, which was subsequently reacted. It was used in the reaction sequence as shown in 3.

During the synthesis of some compounds of the present invention, protecting groups may be necessary for various functional group (s). Accordingly, representative protecting groups suitable for a wide range of various synthetic modifications are described in this publication by Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999, which is hereby incorporated by reference in its entirety. It is.

The invention also includes diastereomers resulting from the structural asymmetry of certain compounds of formula (I), as well as mixtures of optical isomers such as racemic mixtures and enantiomers, including individual enantiomers and diastereomers. Separation of the individual isomers and selective synthesis of the individual isomers is accomplished by applying various methods known to those skilled in the art.

Prevention and / or treatment instructions and methods

The compounds of the present invention are useful in the treatment of further diseases in addition to the above advantageous uses of the compounds of the present invention disclosed herein. Although not limited thereto, these advantages include the following.

The most important pathology in type II diabetes is that insulin signal transduction is impaired in its target tissue (“insulin resistance”) and the pancreatic insulin-producing cells do not secrete an adequate amount of insulin in response to hyperglycemic signals. Current therapies for treating inadequate secretion of insulin include administering inhibitors of β-cell ATP-sensitive potassium channels to release stored endogenous insulin, or administering exogenous insulin. None of these can adequately normalize blood glucose levels, and both have a risk of inducing hypoglycemia. For this reason, attention is focused on the development of drugs that function in glucose-dependent action, namely glucose signal potentiators. Physiological signaling systems that function in this manner are well characterized and include the gut peptides GLP1, GIP and PACAP. These hormones act through receptors to which their cognate G-proteins are coupled to stimulate cAMP production in pancreatic β-cells. Increased cAMP does not appear to stimulate insulin release during the fasting or preprandial state. However, a series of biochemical targets for cAMP signals, including ATP-sensitive potassium channels, voltage-sensitive potassium channels, and exocytosis mechanisms, are modified in a way that significantly enhances the insulin secretory response to postprandial glucose stimulation. Thus, agonists of similarly functioning β-cell GPCRs, including RUP3, will stimulate the release of endogenous insulin and consequently promote normal blood glucose in type II diabetes.

In addition, increased cAMP, for example as a result of GLP1 stimulation, is known to promote β-cell proliferation and inhibit β-cell death and thus increase Langerhans islet mass. This positive effect on β-cell mass is expected to be beneficial for both type II diabetes (produces insufficient insulin) and type I diabetes (β-cells are destroyed by inappropriate autoimmune responses).

Some β-cell GPCRs, including RUP3, are also present in the hypothalamus, which regulates hunger, satiety, reduces food intake, controls or reduces body weight, and consumes energy. Thus, agonists or inverse agonists of these receptors act within the hypothalamic circuit to relieve hunger, promote satiety and thus control body weight.

Metabolic diseases are also well known to adversely affect other physiological systems. Thus, often multiple disease states (eg, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia in "X syndrome") , Obesity or cardiovascular disease) or secondary diseases that are apparently secondary to diabetes (eg, kidney disease, peripheral neuropathy). Thus, effective treatment of diabetic symptoms is expected to be beneficial for such correlated disease states.

In some embodiments of the invention, the metabolic-related disorder is hyperlipidemia, type 1 diabetes mellitus, type 2 diabetes mellitus, idiopathic type 1 diabetes (type 1b), potential autoimmune diabetes (LADA) in adults, early-onset Type 2 diabetes (EOD), adolescent-onset malformation diabetes (YOAD), adult-onset diabetes (MODY) in young people, malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty , Peripheral vascular disease, intermittent claudication, myocardial infarction (e.g., necrosis and apoptosis), dyslipidemia, postprandial hemostasis, impaired glucose tolerance (IGT), fasting blood glucose damage, metabolic acidosis, ketoneism, arthritis, obesity , Osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, X syndrome, monthly Precursor syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, glucose metabolism damage , Impaired glucose tolerance, impaired fasting glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcer and ulcerative colitis, endothelial dysfunction and vascular elastic injury.

Some embodiments of the invention include methods of treating metabolic-related disorders in a subject, comprising administering to the subject a compound of the invention or a pharmaceutical composition thereof in a therapeutically effective formulation. In some embodiments, the metabolic-related disorder is type I, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or X syndrome. In some embodiments, the metabolic-related disorder is type II diabetes. In some embodiments, the metabolic-related disorder is hyperglycemia. In some embodiments, the metabolic-related disorder is hyperlipidemia. In some embodiments, the metabolic-related disorder is hypertriglyceridemia. In some embodiments, the metabolic-related disorder is type I diabetes. In some embodiments, the metabolic disorder is dyslipidemia. In some embodiments, the metabolic-related disorder is X syndrome. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human.

One aspect of the present invention includes a method of reducing food intake in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human.

One aspect of the invention includes a method of inducing satiety in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human.

One aspect of the invention provides a method of controlling or reducing weight gain in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof. Include. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human.

Some embodiments of the invention include a method wherein the human body mass index is from about 18.5 to about 45. In some embodiments, the human body mass index is about 25 to about 45. In some embodiments, the human body mass index is about 30 to about 45. In some embodiments, the human body mass index is about 35 to about 45.

One aspect of the invention includes a method of modulating RUP3 receptors in a subject, comprising contacting the RUP3 receptor with a compound of any one of claims 1-127. In some embodiments, the compound is an agonist. In some embodiments, the compound is an inverse agonist. In some embodiments, the compound is an antagonist. In some embodiments, the regulation of the RUP3 receptor is the treatment of metabolic-related disorders and complications thereof. In some embodiments, the metabolic-related disorder is type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or X syndrome. In some embodiments, the metabolic-related disorder is type II diabetes. In some embodiments, the metabolic-related disorder is hyperglycemia. In some embodiments, the metabolic-related disorder is hyperlipidemia. In some embodiments, the metabolic-related disorder is hypertriglyceridemia. In some embodiments, the metabolic-related disorder is type I diabetes. In some embodiments, the metabolic-related disorder is dyslipidemia. In some embodiments, the metabolic-related disorder is X syndrome. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human.

Some embodiments of the invention include methods of modulating RUP3 receptors in a subject, comprising contacting the RUP3 receptor with a compound of the invention, wherein the regulation of the RUP3 receptor reduces food intake of the subject. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human body mass index is about 18.5 to about 45. In some embodiments, the human body mass index is about 25 to about 45. In some embodiments, the human body mass index is about 30 to about 45. In some embodiments, the human body mass index is about 35 to about 45.

Some embodiments of the invention include methods of modulating RUP3 receptors in a subject, comprising contacting the RUP3 receptor with a compound of the invention, wherein modulation of the RUP3 receptor induces satiety in the subject. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human body mass index is about 18.5 to about 45. In some embodiments, the human body mass index is about 25 to about 45. In some embodiments, the human body mass index is about 30 to about 45. In some embodiments, the human body mass index is about 35 to about 45.

Some embodiments of the invention include methods of modulating RUP3 receptors in a subject, comprising contacting the RUP3 receptor with a compound of the invention, wherein modulation of the RUP3 receptor controls or decreases the weight gain of the subject. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human body mass index is about 18.5 to about 45. In some embodiments, the human body mass index is about 25 to about 45. In some embodiments, the human body mass index is about 30 to about 45. In some embodiments, the human body mass index is about 35 to about 45.

Some embodiments of the invention include the use of a compound of the invention for the manufacture of a medicament for the treatment of metabolic-related disorders. In some embodiments, the metabolic-related disorder is type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or X syndrome.

One aspect of the present invention includes the use of a compound of the present invention for the manufacture of a medicament for reducing food intake of an individual. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human body mass index is about 18.5 to about 45. In some embodiments, the human body mass index is about 25 to about 45. In some embodiments, the human body mass index is about 30 to about 45. In some embodiments, the human body mass index is about 35 to about 45.

One aspect of the present invention includes the use of a compound of the present invention for the manufacture of a medicament for inducing satiety in a subject. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human body mass index is about 18.5 to about 45. In some embodiments, the human body mass index is about 25 to about 45. In some embodiments, the human body mass index is about 30 to about 45. In some embodiments, the human body mass index is about 35 to about 45.

One aspect of the present invention includes the use of a compound of the present invention for the manufacture of a medicament for controlling or reducing weight gain in a subject. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human body mass index is about 18.5 to about 45. In some embodiments, the human body mass index is about 25 to about 45. In some embodiments, the human body mass index is about 30 to about 45. In some embodiments, the human body mass index is about 35 to about 45.

One aspect of the invention relates to a compound as described herein for use in a method of treating a human or animal body by therapy.

One aspect of the invention relates to a compound as described herein for use in a method of treating metabolic-related disorders of the human or animal body by therapy.

Pharmaceutical Compositions and Salts

A further aspect of the present invention relates to pharmaceutical compositions comprising at least one compound of formula (I) or a compound of any of the formulas described herein, and at least one pharmaceutically acceptable carrier. Some embodiments of the present invention are directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of making a pharmaceutical composition comprising admixing one or more compounds according to any of the compound embodiments disclosed herein with a pharmaceutically acceptable carrier.

The formulations may be prepared by any suitable method, typically by uniformly mixing the active compound (s) with the liquid or finely divided solid carrier, or both, in the required proportions, and then forming the resulting mixture into the desired shape, if necessary Can be.

Conventional excipients such as binders, fillers, acceptable wetting agents, tableting lubricants and disintegrating agents can be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous and oily suspensions and syrups. Alternatively, oral formulations may be in the form of dry powders which may be reconstituted with water or another suitable liquid vehicle prior to use. Further additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavoring and coloring agents can be added to the liquid formulation. Parenteral dosage forms can be prepared by dissolving a compound of the invention in a suitable liquid vehicle, filter sterilizing the solution and then filling and sealing the appropriate vial or ampoule. This is just an example of some of the many suitable methods known in the art for preparing dosage forms.

The compounds of the present invention can be formulated into pharmaceutical compositions using techniques known to those skilled in the art. In addition to those mentioned herein, suitable pharmaceutically-acceptable carriers are known in the art and are described, for example, in Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, AR, et al.).

The compounds of the present invention for use in therapy may optionally be used and administered as raw chemicals or pure chemicals, but are present as a compound or active ingredient as a pharmaceutical formulation or pharmaceutical composition further comprising a pharmaceutically acceptable carrier. It is preferable.

Accordingly, the present invention also provides pharmaceutical formulations comprising a compound of the present invention or a pharmaceutically acceptable salt or derivative thereof together with at least one pharmaceutically acceptable carrier and / or prophylactic component. The carrier (s) should be "acceptable" in terms of compatibility with the other ingredients of the formulation and should not be excessively harmful to its recipient.

Pharmaceutical formulations are those suitable for oral, rectal, nasal, topical (including oral and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or for administration by inhalation, inhalation, or transdermal patches. Include form. Transdermal patches are the distribution of drugs at a controlled rate by the presence of the drug to be absorbed in an efficient manner that minimizes degradation of the drug. Typically, the transdermal patch includes a removable protective layer with an impermeable backing layer, a unidirectional pressure sensitive adhesive, and a release liner. Those skilled in the art will understand and evaluate techniques suitable for making the desired efficient transdermal patches as required by those skilled in the art.

Thus, the compounds of the present invention may be in pharmaceutical preparations and unit dosage forms thereof in combination with conventional adjuvant, carrier or diluent, which forms all oral solids (e.g. tablets or filled capsules) or liquids ( As a solution, suspension, emulsion, elisir, gel or capsule filled with these), in the form of suppositories for rectal administration; Or in the form of sterile injectable solutions for parenteral use (including subcutaneous). The pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions with or without additional active compounds or elements, such unit dosage forms being suitable for the daily dosage range intended for use. It may contain an effective amount of any suitable active ingredient.

Pharmaceutical compositions for oral administration may be, for example, in the form of tablets, capsules, suspensions or solutions. Pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of active ingredient. Examples of such dosage units include conventional additives such as lactose, mannitol, corn starch or potato starch; Binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatin; Disintegrants such as corn starch, potato starch or sodium carboxymethyl-cellulose; And lubricants such as talc or magnesium stearate, capsules, tablets, powders, granules or suspensions. The active ingredient can also be administered by injection, for example as a composition in which saline, dextrose or water can be used as a suitable pharmaceutically acceptable carrier.

Compounds of the invention or solvates or physiologically active derivatives thereof can be used as active ingredients in pharmaceutical compositions, specifically as RUP3 receptor modulators. The term "active ingredient" can mean a pharmaceutical composition ingredient defined as the content of a "pharmaceutical composition" and which provides a major pharmacological effect, as opposed to a "inactive ingredient" which is generally recognized as not providing a pharmaceutical benefit. .

Dosages when using the compounds of the present invention can vary within wide limits, are customary, known to the surgeon, and each must be tailored to the individual condition. This depends, for example, on the nature and severity of the disease to be treated, depending on the condition of the patient, on the compound used, or on whether to treat or prevent an acute or chronic disease state, or other than a compound of the invention. It depends on whether additional active compounds are administered. Representative dosages of the present invention include about 0.001 mg to about 5000 mg, about 0.001 to about 2500 mg, about 0.001 to about 1000 mg, 0.001 to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, About 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg. Multiple doses may be administered for one day and may be administered, for example, in two, three or four doses, especially when relatively large amounts are required. Depending on the individual and as deemed appropriate by the patient's physician or caregiver, it may be necessary to deviate from the daily dose above or below.

The amount required for the treatment of the active ingredient, or active salt or derivative thereof, will vary not only with the particular salt selected, but also with the route of administration, the nature of the condition to be treated, and the age and symptoms of the patient and, ultimately, the attending physician or clinician. Will follow the decision. In general, those skilled in the art will understand how to extrapolate in vivo data, typically obtained from an animal model to another human, model system. Typically, animal models include rodent diabetes models described in Example 5 below, other animal models reported in Reed and Scribner in Diabetes, Obesity and Metabolism, 1, 1999, 75-86. But is not limited thereto. In some circumstances, such extrapolation may be based solely on the weight of each animal model compared to other models, such as mammals, preferably humans, but more often such extrapolation is not only based on weight, Include more arguments. Such representative factors include the type, age, weight, sex, diet and medical condition of the patient, severity of the disease, route of administration, pharmacological considerations, e.g. activity, efficacy, pharmacokinetics and toxicology profile of the specific compound used, Whether to use a drug delivery system, to treat or prevent an acute or chronic disease state, or to administer additional active compounds as part of a drug combination in addition to the compounds of formula (I). Dosage regimens for treating disease states using the compounds and / or compositions of the invention are selected in accordance with the various factors mentioned above. Thus, the actual dosage regimen used may vary widely and may deviate from the desired dosage regimen, and those skilled in the art can test doses and dosage regimens outside the typical ranges described above and, where appropriate, may be used in the methods of the present invention. It will be appreciated.

The desired dose may be present in single doses or as divided doses administered at appropriate intervals, eg, at least 2, 3, 4 or more sub doses per day. The sub-dose itself may, for example, be divided into several separate wide intervals of administration. In particular, where a relatively large amount is to be appropriately administered, the daily dose may be divided into several, for example two, three or four partial doses. If appropriate, depending on the behavior of the individual, it may be necessary to deviate above or below the daily dose indicated above.

The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention as an active ingredient.

For preparing pharmaceutical compositions from the compounds of the present invention, suitable pharmaceutically acceptable carriers may be selected from solids, liquids or mixtures thereof. Solid dosage forms include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more ingredients that can also act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

The carrier in the powder is a finely divided solid which is a mixture with the finely divided active component.

The active ingredient in the tablet is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

Powders and tablets may contain varying percentage amounts of the active compound. Representative amounts in powders or tablets may contain from 0.5 to about 90% of the active compound; Those skilled in the art will appreciate that amounts outside of the above ranges are required. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term "formulation" is intended to include preparations of the encapsulant and the active compound as a carrier for providing a capsule, wherein the active ingredient in the capsule with or without a carrier is surrounded by a carrier and thus Combined with Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

For suppository preparation, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and homogeneously dispersed therein by stirring the active ingredient. The molten homogeneous mixture is then solidified by pouring into a conventional size mold and cooling.

Formulations suitable for vaginal administration may be present as pessaries, tampons, creams, gels, foams or sprays which contain, in addition to the active ingredient, carriers suitably known in the art.

Liquid form preparations include solutions, suspensions and emulsions such as water or water-propylene glycol solutions. For example, parenteral injection liquid formulations can be formulated as solutions in aqueous polyethyleneglycol solutions. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the prior art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions as a solution, for example, in 1,3-butanediol, in a parenterally acceptable non-toxic diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile nonvolatile oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland non-volatile oil can be used including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

Thus, the compounds according to the invention can be formulated for parenteral administration (eg, by injection, for example by bolus injection or continuous infusion), and are ampoules, prefilled syringes, small volume injectors, or additions. In the form of unit doses of multi-dose containers with preservatives. Pharmaceutical compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by aseptic isolation of sterile solids or by lyophilization from solution and may be composed of a suitable vehicle, eg, sterile pyrogen-free water, before use.

Aqueous formulations suitable for oral use may dissolve or suspend the active ingredient in water and, if desired, add suitable colorants, flavors, stabilizers and thickeners.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water together with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. Such preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, synthetic or natural sweeteners, dispersants, thickeners, stabilizers and the like.

The compounds according to the invention for topical administration to the epidermis can be formulated as ointments, creams or lotions or as transdermal patches.

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents.

Formulations suitable for topical oral administration include lozenges comprising an active agent in a flavor base, generally sucrose and acacia or tragacanth; Pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; And mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example by dropping, pipettes or sprayers. Such formulations may be provided in a single or multidose form. In the dropping or multi-dose form of the pipette, this may be achieved by administering to the patient any suitable volume of solution or suspension. In the case of a nebulizer, this can be achieved for example using a metered atomizing nebulizer pump.

Administration to the respiratory tract can also be accomplished by an aerosol formulation which provides the active ingredient in a compressed pack with a suitable propellant. If the compound of formula (I) or a pharmaceutical composition comprising them is administered as an aerosol, for example as an intranasal aerosol or by inhalation, it is for example a nebulizer, a nebulizer, a pump nebulizer, an inhalation device, a metered dose inhaler Or using a dry powder inhaler. Pharmaceutical dosage forms of the compounds of formula (I) as aerosols can be prepared by methods known to those skilled in the art. To prepare them, for example, solutions or dispersions of the compounds of formula (I) in water, water / alcohol mixtures or suitable saline solutions can be absorbed to increase the bioavailability of conventional additives such as benzyl alcohol or other suitable preservatives. Enhancers, solubilizers, dispersants, and the like, and where appropriate, common propulsion agents include, for example, carbon dioxide, CFCs (e.g., dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane). Etc. may be included. Aerosols may also typically contain surfactants such as lecithin. The dose of drug can be adjusted by preparing a metered valve.

In formulations intended for respiratory tract administration, including intranasal formulations, the compounds generally have a small particle size, eg, order of 10 microns or less. The particle size can be obtained in a manner known in the art, for example by ultrafineness. If desired, formulations adapted to provide sustained release of the active ingredient can be used.

Alternatively, the active ingredient may be a powder mixture of the compound in a dry powder, such as a suitable powder substrate, such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). It may be provided in the form of. Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be in unit dosage form, for example in the form of a capsule or cartridge of, for example, a gelatin or blister pack, which allows the powder to be administered by an inhaler.

Pharmaceutical formulations are preferably in unit dosage form. In this form, the formulation is subdivided into unit dosages containing appropriate amounts of the active ingredient. Unit dosage forms can be packaged preparations (packages containing divided amounts of preparations), for example packet tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, casein or lozenge itself, or may be any packaged form in an appropriate number.

Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

The compounds according to the invention may optionally be present as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Representative acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, dichloroacetic acid formic acid, fumaric acid, gluconic acid, glutamic acid, hypofuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, Malic acid, mandelic acid, methanesulfonic acid, muxic acid, nitric acid, oxalic acid, palmic acid, pantothenic acid, phosphoric acid, succinic acid, sulfic acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like, and such pharmaceutically acceptable salts Is listed in the Journal of Pharmaceutical Science, 66,2 (1977), the entirety of which is incorporated herein by reference.

Acid addition salts can be obtained as direct products of compound synthesis. Alternatively, the salts can be isolated by dissolving the free base in a suitable solvent containing the appropriate acid and evaporating the solvent or otherwise separating the salt and solvent. The compounds of the present invention can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

In addition, the compounds according to the invention may optionally be present as pharmaceutically acceptable base addition salts. For example, these salts may be prepared in situ during the isolation and purification of the compounds of the present invention, or acidic residues (eg carboxylic acids) may be prepared by appropriate bases of pharmaceutically acceptable metal cations (eg, hydroxides, Carbonate or bicarbonate) or by reacting with ammonia or organic primary, secondary or tertiary amines. Pharmaceutically acceptable salts include salts with cations based on alkali and alkaline earth metals (eg, sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc.), as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, Salts with amine cations, including dimethylamine, trimethylamine, triethylamine, ethylamine, and the like, non-toxic ammonium, quaternary ammonium, but are not limited thereto. Other representative organic amines useful for the formation of salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

Compounds of the invention may be converted to "prodrugs". The term “prodrug” refers to a compound modified with a specific chemical group known in the art, which when administered into an individual is converted in vivo to provide the parent compound. Prodrugs may therefore be represented as compounds of the present invention which contain one or more specialized non-toxic protecting groups which are used in a temporary manner so as not to alter or eliminate the properties of the compound. In one general aspect, the “prodrug” approach is useful for promoting oral absorption. This previous discussion is described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.

Some embodiments of the invention for "combination therapy" comprising mixing one or more compounds according to any of the compound embodiments disclosed herein with one or more known agents and pharmaceutically acceptable carriers described herein. Methods of making pharmaceutical compositions.

In some embodiments the agent is a sulfonylurea, meglitinide, biguanide, α-glucosidase inhibitor, peroxysome growth factor-activated receptor-γ (ie PPAR-γ) agonist, insulin, insulin analog, HMG-CoA reductase inhibitors, cholesterol-lowering agents (eg, fibrate-based, including fenofibrate, bezafibrate, gemfibrozil, clofibrate, and the like; bile acid sequestrants, including cholestyramine, cholestipol, and the like; and Niacin), antiplatelets (eg, aspirin and adenosine diphosphate receptor antagonists including clopidogrel, ticlopidine, etc.), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and adiponectin.

Note that when RUP3 receptor modulators are used as active ingredients in pharmaceutical compositions, they are used in humans as well as in other non-human mammals. Indeed, recent advances in the field of animal health-management have led to the use of active agents, such as RUP3 receptor modulators, in the treatment of obesity in livestock (eg cats and dogs), and other livestock (eg, no obvious disease or disorder). For example, consideration should be given to using RUP3 receptor modulators in edible animals such as cattle, chickens, fish, and the like. Those skilled in the art will readily understand the usefulness of these compounds with such settings.

<Combination Therapy>

In the context of the present invention, the compounds of formula (I) or pharmaceutical compositions thereof may be useful for modulating the activity of RUP3 receptor mediated diseases, symptoms and / or disorders described herein. Examples of modulating the activity of RUP3 receptor mediated diseases include the treatment of metabolic-related disorders. Metabolic-related disorders include type 1 diabetes, type 2 diabetes and the resulting symptoms (eg, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (eg, necrosis and Apoptosis), dyslipidemia, postprandial hemostasis, impaired glucose tolerance (IGT), fasting blood glucose impairment, metabolic acidosis, ketoneosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetes Sex retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, X syndrome, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, Transient ischemic attack, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, impaired glucose tolerance, fasting Blood sugar damage states, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction, and vascular elastic impairment In some embodiments, metabolic related disorders include I Type diabetes mellitus, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X. Other examples of modulating activity of RUP3 receptor mediated diseases are Reduction in intake, induction of satiety (i.e. feeling full), control of weight gain, weight loss and / or metabolism to reduce and / or maintain weight for the recipient by preventing or treating obesity and / or overweight Include.

Where a compound of the invention can be administered as a single active agent (ie, mono-therapy), they can also be used in combination with other agents (ie co-therapy) to treat the diseases / symptoms / disorders described herein. Thus, a further aspect of the present invention provides for the prevention and / or prevention of a metabolic-related or weight-related disorder, for example obesity, in combination with a therapeutically effective amount of a compound of the invention, e. Methods of preventing and / or treating metabolic-related or weight-related disorders, such as obesity, comprising administering to a subject in need thereof.

Suitable agents that can be used with the compounds of the present invention include anti-obesity agents such as apolipoprotein-B secretion / microsomal triglyceride transfer protein (apo-B / MTP) inhibitors, MCR-4 agonists, cholessis Tokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (eg sibutramine), sympathomimetic agents, β ₃ adrenergic receptor agonists, dopamine agonists (eg bromocrip Tin), melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists [eg, SR141716: N- (piperidin-1-yl) -5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide], melanin enriched hormone antagonist, lepton (OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (eg For example, tetrahydrolipstatin, ie orlistat, an appetite suppressant (eg bombesin) Agonists), neuropeptide-Y antagonists, thyroid stimulants, dehydroepiandrosterone or analogues thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists Ciliary neurotrophic factor (e.g., from Regeneron Pharmaceuticals, Inc., Tarrytown, NY) and Procter & Gamble Company, Cincinnati, Ohio. Possible axokin®, human aguti-associated protein (AGRP), ghrelin receptor antagonist, histamine 3 receptor antagonist or inverse agonist, neuromedin U receptor agonist, noradrenaline appetite suppressant (eg, penter Min, marginal, etc.) and appetite suppressants (eg bupropion).

Other anti-obesity agents, including the anti-obesity agents mentioned below, are known or will be apparent to those skilled in the art in view of the present disclosure.

In some embodiments, the anti-obesity agent is selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin and pseudoephedrine. In a further embodiment, the compounds of the present invention and combination therapies are prescribed in combination with diet and exercise.

The scope of the combination therapy of the compounds of the present invention with anti-obesity agents, appetite suppressants, appetite suppressants and related agents is not limited to those listed above, but may be any combination with any medicament or pharmaceutical composition useful for the treatment of overweight and obese individuals. It will be understood that the formulation includes in principle.

Suitable agents other than anti-obesity agents that can be used with the compounds of the present invention include, but are not limited to, metabolic-related disorders and / or accompanying diseases, such as, but not limited to, congestive heart failure, type I diabetes, type II diabetes. Agents useful for the treatment of inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X, retinopathy, nephropathy and neuropathy. Treatment of one or more diseases referred to herein includes sulfonylureas, meglitinides, biguanides, α-glucosidase inhibitors, peroxysome growth factor-activated receptor-γ (ie, PPAR-γ) agonists, insulin , Insulin analogues, HMG-CoA reductase inhibitors, cholesterol-lowering agents (e.g., fibrates, including fenofibrate, bezafibrate, gemfibrozil, clofibrate, and the like; bile acids, including cholestyramine, cholestipol, and the like Sequestrants; and niacin), antiplatelet agents (e.g., aspirin and adenosine diphosphate receptor antagonists including clopidogrel, ticlopidine, etc.), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, adiponectin, and the like. The use of one or more agents known in the art, belonging to the class of drugs. According to one aspect of the present invention, the compounds of the present invention may be used with medicaments or agents belonging to one or more of the classes of drugs mentioned herein.

The scope of combination therapy of a compound of the invention with other agents is not limited to those listed hereinbefore or below, but includes any medicament or pharmaceutical composition useful for the treatment of a disease, condition or disorder associated with a metabolic-related disorder. It will be understood that in principle any combination of is included.

Some embodiments of the invention provide a therapeutically effective amount or dosage of a compound of the invention, such as sulfonylurea, meglitinide, biguanide, α-glucosidase inhibitor, peroxysome growth factor-activated receptor-γ (ie Fibrates, including agonists, PPAR-γ) agonists, insulins, insulin analogues, HMG-CoA reductase inhibitors, cholesterol-lowering agents (eg, fenofibrate, bezafibrate, gemfibrozil, clofibrate, etc .; Bile acid sequestrants including tyramine, cholestipol, and the like; and niacin), antiplatelet agents (e.g., aspirin and adenosine diphosphate receptor antagonists, including clopidogrel, ticlopidine, etc.), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and Treatment of a disease, disorder, symptom or complication thereof disclosed herein with one or more agents selected from the group consisting of adiponectin Include, diseases, disorders, symptoms or prevention of its complications and treatment methods disclosed herein comprising administering to a subject in need. In some embodiments, the methods of the invention comprise a compound of the invention, and the medicament is administered separately. In a further embodiment, the compounds of the present invention and medicaments are administered together.

Suitable agents that can be used with the compounds of the present invention include sulfonylureas. Sulfonylurea (SU) is a drug that promotes the secretion of insulin from pancreatic β cells by transmitting insulin secretion signals through the SU receptor on the cell membrane. Examples of sulfonylureas include glyburide, glyphide, glymepiride and other sulfonylureas known in the art.

Suitable agents that can be used with the compounds of the present invention include meglitinide. Meglitinide is a benzoic acid derivative that represents a new class of insulin secretagogues. This agent targets postprandial hyperglycemia and shows comparable efficacy to sulfonylurea in reducing HbAIc. Examples of meglitinides include repaglinides, nateglinides, and meglitinides known in the art.

Suitable agents that can be used with the compounds of the present invention include biguanides. Biguanides represent a class of drugs that stimulate anoxic glycolysis, increase sensitivity to insulin in peripheral tissues, inhibit glucose absorption in the small intestine, inhibit hepatic biosynthesis, and inhibit fatty acid oxidation. Examples of biguanides include phenformin, metformin, buformin and biguanides known in the art.

Suitable agents that can be used with the compounds of the present invention include α-glucosidase inhibitors. α-glucosidase inhibitors competitively inhibit digestive enzymes in the pancreas and / or small intestine, such as α-amylase, maltase, α-dextrinase, sucrase and the like. Reversible inhibition by α-glucosidase inhibitors slows, reduces or otherwise reduces blood sugar levels by delaying digestion of starch and sugar. Examples of α-glucosidase inhibitors include acarbose, N- (1,3-dihydroxy-2-propyl) valiolamin (common name: bogliboss), miglitol and α-glucose known in the art. Sidase inhibitors are included.

Suitable agents that can be used with the compounds of the present invention include peroxysome growth factor-activated receptor-γ (ie, PPAR-γ) agonists. Peroxysome growth factor-activated receptor- [gamma] agonists represent a class of compounds that activate nuclear receptor PPAR- [gamma] and thus regulate the transcription of insulin-responsive genes, including controlling glucose production, migration and use. Agents of this class also facilitate the regulation of fatty acid metabolism. Examples of PPAR-γ agonists include rosiglitazone, pioglitazone, desaglyzar, netoglitazone, GW-409544, GW-501516 and PPAR-γ agonists known in the art.

Suitable agents that can be used with the compounds of the present invention include HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors are agents that are referred to as statin compounds belonging to the class of drugs that lower blood cholesterol levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase. HMG-CoA reductase is a rate-limiting enzyme in cholesterol biosynthesis. Statins act to lower the serum LDL concentration and to remove LDL from the blood by upregulating the activity of the LDL receptor. Some representative examples of statin compounds include rosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, "superstatin" of BMS, and sugars HMG-CoA reductase inhibitors known in the art are included.

Suitable agents that can be used with the compounds of the present invention include fibrate. Fibrate compounds belong to the class of drugs that lower blood cholesterol levels by inhibiting the synthesis and secretion of triglycerides in the liver and activating lipoprotein lipases. Fibrates are known to activate peroxysome growth factor-activated receptors and induce lipoprotein lipase expression. Examples of fibrate compounds include bezafibrate, beclobrate, binifibrate, ciflofibrate, clinofbrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pyripi Brate, ronifibrate, simfibrate, theofibrate, and fibrate known in the art.

Suitable agents that can be used with the compounds of the present invention include angiotensin converting enzyme (ACE) inhibitors. Angiotensin converting enzyme inhibitors belong to the class of drugs that not only lower blood pressure by inhibiting angiotensin converting enzyme but also partially lower blood sugar levels. Examples of angiotensin converting enzyme inhibitors include captopril, enalapril, alasepril, delapril; Ramipril, Ricinopril, Imidapril, Benzaziprill, Cenarapril, Silazapril, Enalapril, Posinopril, Mobeltopril, Perindopril, Quinapril, Spirapril, Temocapril, Tran Dolapryl, and angiotensin converting enzyme inhibitors known in the art.

Suitable agents that can be used with the compounds of the present invention include angiotensin II receptor antagonists. Angiotensin II receptor antagonists target angiotensin II receptor subtype 1 (ie AT1) and demonstrate a beneficial effect on hypertension. Examples of angiotensin II receptor antagonists include losartan (and potassium salt forms), and angiotensin II receptor antagonists known in the art.

Suitable agents that can be used with the compounds of the present invention include squalene synthesis inhibitors. Squalene synthesis inhibitors belong to the class of drugs that inhibit the synthesis of squalene to lower blood cholesterol levels. Examples of squalene synthesis inhibitors include (S) -α- [bis [2,2-dimethyl-1-oxopropoxy) methoxy] phosphinyl] -3-phenoxybenzenebutanesulfonic acid, potassium monovalent salt (BMS-188494) And squalene synthesis inhibitors known in the art.

Suitable agents that may be used with the compounds of the present invention include amylin agonists (eg, frramintide), insulin secretagogues (eg, GLP-1 agonists; exendin-4; insulinnotropin (NN2211) dipeptyl peptidase inhibitors (eg, NVP-DPP-728), acyl CoA cholesterol acetyl transferase inhibitors (eg, Ezetimibe, eflucimibe and similar compounds ), Cholesterol absorption inhibitors (e.g. ezetimibe, Pharmacuside and similar compounds), cholesterol ester transfer protein inhibitors (e.g. CP-529414, JTT-705, CETi-1 and similar compounds), microsomes Triglyceride transfer protein inhibitors (e.g., implitapide and similar compounds), cholesterol modulators (e.g., NO-1886 and similar compounds), bile acid modulators (e.g., GT103-279 and similar compounds), insulin signaling Forwarding Path Conditioning , Analogous inhibitors of protein tyrosine phosphatase (PTPase), non-small molecule mimic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds affecting dysregulation of hepatic glucose production , A similar inhibitor of glucose-6-phosphatase (G6Pase), an inhibitor of fructose-1,6-bisphosphatase (F-1,6-BPase), an inhibitor of glycogen phosphorylase (GP), glucagon Inhibitors of receptor antagonists and phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, fasting inhibitors, α ₂ -adrenergic antagonists and retinoid X receptors (RXR) Agonists are, but are not limited to these.

In accordance with the present invention, the combination is prepared by mixing each active ingredient together or independently with all of the physiologically acceptable carriers, excipients, binders, diluents and the like as described above and administering said mixture or mixtures as oral or parenteral as a pharmaceutical composition. Can be used. When the compound or mixture of compounds of formula (I) is administered together with other active compounds as a combination therapy, the therapeutic agents may be formulated as separate pharmaceutical compositions administered simultaneously or at different times, or the therapeutic agents may be administered as a single composition.

<Other usability>

Another object of the present invention is to identify RUP3 ligands by in vitro and in vivo assays for RUP3 localization and quantification in radio-contrast as well as in tissue samples, including humans, and by inhibiting binding of radiolabeled compounds. Useful radiolabeled compounds of formula (I) are disclosed. It is also an object of the present invention to develop a novel RUP3 assay comprising such radiolabeled compounds.

The present invention includes isotopically-labeled compounds of Formula (I) and any sub-compounds, such as, but not limited to, compounds of Formulas (Ia) to (IIIo). An “isotope” or “radiolabeled” compound is the same compound as the compounds disclosed herein, but in fact one or more atoms have an atomic or mass number that is different from the atomic or mass number typically found (ie, naturally occurring) in nature. It is replaced or substituted by an atom. Suitable radionuclides that can be incorporated into the compounds of the invention include ² H (also described as D for deuterium), ³ H (also described as T for tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N , ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I It doesn't work. The radionuclide incorporated immediately into the radiolabeled compound will depend on the specific application of the radiolabeled compound. For example, for in vitro RUP3 labeling and competition assays, compounds incorporating ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I or ³⁵ S will generally be most useful. For radio-contrast, ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br will generally be most useful.

“Radio-labeled” or “labeled compound” is understood to be a compound of Formula I in which one or more radionuclides are incorporated; In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S and ⁸² Br.

Certain isotopically-labelled compounds of the invention are useful in compound and / or matrix tissue distribution assays. In some embodiments radionuclides ³ H and / or ¹⁴ C isotopes are useful for such studies. In addition, substitution with heavier isotopes, such as deuterium (ie, ² H), is desirable for some environments because it can increase metabolic stability (e.g., increase half-life in vivo or decrease dosage requirements) and thus provide certain therapeutic benefits. can do. Isotopically labeled compounds of the present invention can generally be prepared according to procedures analogous to those described in the above schemes and examples below, by replacing isotopically labeled reagents with isotopically labeled reagents. Other useful synthetic methods are discussed below. In addition, it will be appreciated that all atoms present in the compounds of the present invention may be the most commonly occurring isotopes of these atoms or the lesser radio-isotopes or nonradioactive isotopes.

Synthetic methods for incorporating radio-isotopes into organic compounds, including those corresponding to compounds of the present invention, are known in the art and include incorporating active levels of tritium in target molecules:

A. Catalytic Reduction Using Tritium Gas—Usually this procedure yields very specific active products, requiring halogenated or unsaturated precursors.

B. Reduction with Sodium Borohydride [ ³ H] —This procedure is also inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.

C. Reduction with lithium aluminum hydride [ ³ H] —This procedure gives a product of almost theoretical specific activity. There is also a need for precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.

D. Tritium Gas Exposure Labeling—This procedure involves exposing a precursor containing protons exchangeable with tritium gas in the presence of a suitable catalyst.

E. N-Methylation with Methyl Iodide [ ³ H]-This procedure generally results in the treatment of O-methyl or N-methyl ( ³ H) products by treatment of the appropriate precursor with high specific activity of methyl iodide ( ³ H). It is used to make. The method generally allows for high specific activity, for example about 70 to 90 Ci / mmol.

Synthetic methods for incorporating an activity level of ¹²⁵ I into a target molecule include the following:

A. Sandmeyer and similar reactions—This procedure transforms aryl or heteroaryl amines to diazonium salts, such as tetrafluoroborate salts, followed by Na ¹²⁵ I to ¹²⁵ I labeled compounds. Let's do it. Representative procedures are described in Zhu, D.-G. and co-workers, J. Org. Chem. 2002, 67, 943-948.

B. Ortho ¹²⁵ Iodide of Phenol—This procedure is described in Collier, TL and co-workers, J. Labeled Compd Radiopharm. 1999, 42, S264-S266, incorporate ¹²⁵ I at the ortho position of the phenol.

C. Exchange of aryl and heteroaryl bromide with ¹²⁵ I-This method is generally a two step process. The first step is in the presence of _tri- alkyltin halide or hexaalkylditin [eg, (CH ₃ ) ₃ SnSn (CH ₃ ) ₃ ], for example Pd catalysis [ie, Pd (Ph ₃ P ₄ ) or via aryl or heteroaryl lithium, conversion of the aryl or hetero aryl bromide to the corresponding tri-alkyltin intermediate. The procedure shown is described in Bas, M.-D. and co-workers, J. Labeled Compd Radiopharm. 2001, 44, S280-S282.

Radiolabeled RUP3 compounds of formula I can be used in screening assays for identifying / evaluating compounds. In general, newly synthesized or identified compounds (ie test compounds) can be assessed for their ability to reduce the binding of “radiolabeled compounds of formula (I)” to the RUP3 receptor. Thus, the ability of a test compound to compete with a "radiolabeled compound of Formula I" for binding to the RUP3 receptor is directly correlated with its binding affinity.

Labeled compounds of the invention bind to the RUP3 receptor. In one embodiment, the IC ₅₀ of the labeled compound is less than about 500 μM, in another embodiment the IC ₅₀ of the labeled compound is less than about 100 μM, and in another embodiment the IC ₅₀ of the labeled compound is less than about 10 μM In another embodiment, the IC ₅₀ of the labeled compound is less than about 1 μM, and in another embodiment the IC ₅₀ of the labeled inhibitor is less than about 0.1 μM.

Other uses of the disclosed receptors and methods will be particularly apparent to those skilled in the art upon reviewing this patent document.

As will be appreciated, the steps of the method of the invention need not be performed at any particular number of times or in any particular order. Further objects, advantages and novel features of the invention will be apparent to those skilled in the art upon examination of the following examples, which are intended to illustrate, but not limit, the invention.

The following examples are presented to further illustrate the invention and are not intended to limit the invention to this particular example.

Example  One

RUP3 96-well for Cyclic AMP  Membrane assay

Material :

1) Perkin Elmer's Adenylyl Cyclase Activation Flashplate Assay Kit-96 wells (SMP004B) and ¹²⁵ I tracer (NEX130) are provided with the kit. Store in a box in the refrigerator and do not expose the flashplate to light.

2) Phosphocreatin-Sigma P-7936

Creatine phosphokinase-sigma C-3755

4) GTP-Sigma G-8877

5) ATP-Sigma A-2383

6) IBMX-Sigma I-7018

7) Hepes-1M solution in distilled water-Gibco # 15630080

8) MgCl ₂ -Sigma M-1028-1M Solution

9) NaCl-Sigma-S6546-5M Solution

10) Bradford Protein Assay Kit-Biorad # 5000001

11) Proclin 300-Sigma # 4-8126

Binding Buffer -Filter through a 45-micron Nalgene filter and store in the refrigerator. All buffers and membranes should be kept cold (maintained in ice buckets) during the analysis.

20 mM Hepes, pH7.4

1 mM MgCl ₂

100 mM NaCl

2X Regeneration Buffer (Prepared in Binding Buffer):

20 mM phosphocreatin (1.02 g / bin buffer 200 ml)

20 units of creatine phosphokinase (4 mg / 200 ml)

20 μM GTP (prepared at 10.46 mg / ml in binding buffer, added at 200 μl / 200 ml)

0.2 mM ATP (22.04 mg / 200 ml)

100 mM IBMX (44.4 mg of IBMX was first dissolved in 1 ml of 100% DMSO, then the entire amount was added until the buffer was 200 ml).

Regeneration buffer can be aliquoted in 40-45 ml (50 ml sterile tubes) and frozen for up to 2 months. On the day of the assay, the tubes were simply placed in a beaker containing room temperature water to thaw regeneration buffer.

A. Analysis Procedure

1) Pipette 50 μl of regeneration buffer into all 96 wells using a Matrix 1250 8-channel pipette.

2) Pipet 5 μl of DMSO into column 1 and columns 11 and 12.

3) Pipette 50 μl of cAMP standards into pipes 11 and 12 in the following manner: 50 pmol / well in column A, 25 pmol / well in column B, 12.5 pmol / well in column C, 5 pmol / well in column D, 2.5 pmol / well in column E, 1.25 pmol / well in column F, 0.5 pmol / well in column G, and 0 pmol / well in column H (buffer only).

4) Pipette 5 μl of compound from each well of the compound dilution plate according to the following dilution procedure for IC ₅₀ measurements by pipette:

Well H: 400 μM compound (final concentration of compound in reaction mixture = 5/100 x 400 μM = 20 μM)

Well G: 1:10 dilution of Well H (ie 5 μl of compound from Well H + 45 μl of 100% DMSO) (final concentration = 2 μM)

Well F: 1:10 dilution of Well G (final concentration = 0.2 μM)

Well E: 1:10 dilution of Well F (final concentration = 0.02 μM)

Well D: 1:10 dilution of Well E (final concentration = 0.002 μM)

Well C: 1:10 dilution of Well D (final concentration = 0.0002 μM)

Well B: 1:10 dilution of Well C (final concentration = 0.00002 μM)

Well A: 1:10 dilution of Well B (final concentration = 0.000002 μM)

IC ₅₀ or EC ₅₀ was measured in triplicates. Thus, one flashplate can be set to measure three compounds. (Ie, columns 2, 3, and 4 can be set for compound # 1, columns 5, 6, and 7 for compound # 2, columns 8, 9, and 10 for compound # 3)

5) 50 μl of RUP3 membrane was added to all wells of columns 2-10. (Before starting the assay, frozen membrane pellets for both RUP3 and CMV (cells transfected with expression plasmids containing no RUP3 sequence) were placed in binding buffer (typically 1 ml of binding buffer for one plate of membrane). The membrane was kept on ice and polytron (Brinkmann polytron, Model # PT-3100) was used (set 6-7 for 15-20 seconds) to obtain a homogeneous membrane suspension. ). Protein concentrations were measured using the Bradford Protein Assay Kit as reference material based on the standard supplied with the kit according to the instructions provided in the kit. Binding buffer was used to adjust the protein concentration of the membrane to 50 μl membrane = 15 μg protein (ie 0.3 mg / ml protein).

6) In column 1, 50 μl of RUP3 membrane was added to wells A, B, C and D. Wells E, F, G, and H were added with 50 μl of CMV membrane (CMV membrane had the same protein concentration as the RUP3 membrane).

7) Incubate for 1 hour at room temperature with stirring on a rotating platform shaker. Cover with foil while shaking.

8) After 1 hour, ProClean was added to the detection buffer supplied to the flashplate kit according to the following manner, and 100 μl of ¹²⁵ I tracer was added thereto (to all 96 wells).

Pipette 10 ml per flashplate: 100 ml detection buffer + 1 ml of ¹²⁵ I + 0.2 ml of proclean (proclean helps to stop cAMP production). If the number of plates is smaller, a smaller amount of detection buffer mixture is prepared.

9) Cover the plate with a lead sheet and shake the plate for 2 hours on a rotating platform shaker.

10) Seal the plate with the plastic film sealer provided in the flashplate kit.

11) Plates were counted using TRILUX 1450 Microbeta Counter. Refer to the counter's guide to determine the counting protocol to use.

12) Analyze the data on an Arena database according to RUP3 non-fusion, IC ₅₀ , EC ₅₀ for 96-well cAMP membrane assay, with compound number and compound concentrations being entered by the user.

B. Membrane Cyclase  Measure

1) Signal to Noise:

Acceptable signal-to-noise ratios for RUP3 can vary from 4 to 6. Initial cpm is approximately 1800 to 2500 for RUP3 and 3500 to 4500 for CMV. cpm (or ultimately pmol / well of cAMP) cannot be outside of the standard curve and will not be close to well A (50 pmol / well) and well H (no cAMP) of the standard curve. In general, the pmol of cAMP produced by the RUP3 receptor is about 11-13 pmol / well (15 μg / well protein) and 2-3 pmol / well (15 μg / well protein) for CMV.

2) standard curve:

The slope can be linear and the error bars for the duplicate test should be very small. Receptor and CMV controls should not deviate from the standard curve as described above. If the receptor control is outside the peak of the standard curve, i.e. above 50 pmol / well, the experiment must be repeated with a smaller amount of protein. However, this case is not observed using transiently transfected RUP3 membranes (DNA 10 μg / 15 cm plate, 60 μl of Lipofectamine, membrane preparation 24 hours after transfection).

3) The IC ₅₀ or EC ₅₀ curve should be in the top 100% (+ or -20%) of the control RUP3 membrane and down to 0 (or less than 20%) at the bottom. The standard error of three tests shall be + or -10%.

C. HIT - T15  In the cell cAMP  stimulus

HIT-T15 (ATCC CRL # 1777) is a hamster's immortalized insulin-producing cell line. The cells express RUP3 and thus can be used to assess the ability of the RUP3 ligand to stimulate or inhibit cAMP accumulation via its receptor expressed endogenously. In this assay, cells were grown to 80% and then dispensed into 96-well flashplates (50,000 cells / well) for cAMP detection via a "cAMP flashplate assay" (NEN, Cat # SMP004). Briefly, cells were placed in an anti-cAMP antibody-coated well containing vehicle, test ligand (s) at concentrations of interest or 1 μM forskolin. Forskolin is a direct activator of adenylyl cyclase and functions as a positive control for cAMP stimulation in HIT-T15 cells. All conditions were tested in duplicates. After incubation for 1 hour to stimulate cAMP, a detection mixture containing ¹²⁵ I-cAMP was added to each well and the plate was further incubated for 1 hour. The wells were then aspirated to remove unbound ¹²⁵ I-cAMP. Bound ¹²⁵ I-cAMP was detected using the Wallac Microbeta Counter. The amount of cAMP in each sample was determined by comparing a known concentration of cAMP to a standard curve obtained by placing some wells in the plate.

D. HIT - T15  Stimulation of insulin secretion in cells

It is known that cAMP stimulation in HIT-T15 cells increases insulin secretion when the glucose concentration in the culture medium changes from 3 mM to 15 mM. Thus, the ability of the RUP3 ligand to stimulate glucose-dependent insulin secretion (GSIS) in HIT-T15 cells can also be tested. In this assay, 30,000 cells / well in 12-well plates were incubated for 2 hours in culture medium containing 3 mM glucose and no serum. The medium was then exchanged and the wells filled with medium containing 3 mM or 15 mM glucose, in both cases the medium contained vehicle (DMSO) or RUP3 ligand at the concentration of interest. Some wells were filled with medium containing 1 μM Forskolin as a positive control. All conditions were tested in duplicates. Cells were incubated for 30 minutes, and secreted of insulin secreted into the medium using a kit of Peninsula Laboratories (Cat # ELIS-7536) or Crystal Chem Inc. (Cat # 90060). The amount was measured by ELISA.

E. Isolated Rat  Stimulation of Insulin Secretion in the Islet of Langerhans

As in HIT-T15 cells, when glucose in the culture medium is changed from 60 mg / dl to 300 mg / dl, it is known that stimulation of cAMP in isolated islets of rats increases insulin secretion. RUP3 is a GPCR expressed endogenously in insulin-producing cells in Rat Langerhans. Thus, the ability of RUP3 ligands to stimulate GSIS in rat Langerhans islet cultures can also be tested. This analysis was performed as follows:

A. A dissecting microscope was used to select 75-150 Langerhans Island equivalents (IEQ) for each assay condition. Incubate overnight in low glucose culture medium. (options)

B. 25-40 Langerhans Island equivalents per sample were divided into three samples. A 40 μm mesh sterile cell strainer of 6-well plates was transferred to 5 ml of low glucose (60 mg / dl) Kreb-Ringer buffer (KRB) assay medium.

C. 30 min incubation at 37 ° C. and 5% CO ₂ (1 hour without overnight step omitted). Supernatants are collected if a positive control for RIA is needed.

The filter containing D. Langerhans was transferred to a new well filled with 5 ml / well of low glucose KRB. This is a second preincubation and acts to remove residual or residual insulin from the culture medium. Incubate for 30 minutes.

E. The filter was transferred to wells (1 row) containing 4 or 5 ml of low glucose KRB. Incubate at 37 ° C. for 30 minutes. Supernatants were collected in pre-labeled low-binding polypropylene tubes for identification and kept cold.

F. The filter was moved to high glucose wells (300 mg / dl, equal to 16.7 mM). Supernatants were immediately incubated and collected. In their filter in low glucose the island of Langerhans was rinsed to remove residual insulin. When the rinse was collected for analysis, one rinse well was used for each condition (ie, three sets).

G. The strainer was transferred to the final well (2 rows) containing low-glucose assay medium. Supernatants were immediately incubated and collected.

H. The supernatant was kept cold and centrifuged at 4800 ° C. for 5 minutes at 1800 rpm to remove small Langerhans / Langerhans island pieces exiting the 40 mm mesh. All, but less, 0.5-1 ml were removed and dispersed in two in pre-labeled low-binding tubes. Frozen and stored at <-20 ° C. until insulin concentration could be determined.

I. Insulin was measured as above or by Linco Labs' consumer service using rat insulin RIA (Cat. # RI-13K).

Example  2

A. In human tissue RUP3  Manifestation RT - PCR  Assay (FIG. 1A).

RT-PCR was used to determine the tissue distribution of RUP3. Oligonucleotides used for PCR had the following sequence:

Human multi-tissue cDNA panel (MTC, Clontech) was used as template (1 ng cDNA per PCR amplification). 22 human tissues were analyzed. PCR was performed in 50 μl reaction using Platinum PCR SuperMix (Life Technologies, Inc .; according to manufacturer's instructions) in the following sequence: Step 1, 4 minutes at 95 ° C; Step 2, 1 min at 95 ° C .; Step 3, 30 sec at 60 ° C .; Step 4, 1 min at 72 ° C .; And step 5, 7 min at 72 ° C. Steps 2 to 4 were repeated 35 times.

The resulting PCR reaction (15 μl) was loaded onto a 1.5% agarose gel to analyze the RT-PCR product, and specific 466 base pair DNA fragments representing RUP3 were specifically amplified from cDNA of pancreatic origin. It was clear that the expression was low in the lower regions of the brain.

B. In human tissue RUP3  About manifestation cDNA  Dot-Blot Assay (FIG. 1B).

Results from the RT-PCR analysis were further confirmed in the cDNA dot-blot analysis. In this assay, dot-blot membranes (clontech) containing cDNA from 50 human tissues were hybridized with ³² P-radiolabeled DNA probes having sequences derived from human RUP3. Hybridization signals appear in the liver of the pancreas and fetus and have been suggested to express RUP3 in these tissues. No significant expression was detected in other tissues analyzed.

C. RUP3 analysis by RT - PCR using isolated islets of Langerhans islet ( FIG. 1C).

In addition, RUP3 analysis by RT-PCR using isolated human pancreas of Langerhans islet showed strong RUP3 expression in islet cells but not in control samples.

D. Rat  Origin cDNA Using RT - PCR On by RUP3  Analysis of Expression (FIG. 1D).

RUP3 expression was further analyzed using cDNA of rat origin by RT-PCR technique. Tissue cDNA used for the assay was obtained from Clontech except for the self-prepared hypothalamus and Langerhans's cDNA. Prior to analyzing RUP3 expression, the concentration of each cDNA sample was normalized through a control RT-PCR analysis of the house-keeping gene GAPDH. Oligonucleotides used for PCR had the following sequence:

PCR was performed in 50 μl of reaction using platinum PCR supermix (Life Technologies, Inc .; according to manufacturer's instructions): Step 1, 4 min at 95 ° C .; Step 2, 1 min at 95 ° C .; Step 3, 30 sec at 60 ° C .; Step 4, 1 min at 72 ° C .; And step 5, 7 min at 72 ° C. Steps 2 to 4 were repeated 35 times.

The resulting PCR reaction (15 μl) was loaded onto a 1.5% agarose gel to analyze the RT-PCR product, and specific 547 base pair DNA fragments representing rat RUP3 were amplified from cDNA, especially from pancreatic origin, similar to that in humans. Expression profile is shown. In particular, strong expression was observed in isolated islets and hypothalamus.

Example  3

RUP3  Protein expression is limited to the β cell line of the Islet of Langerhans in the pancreas (FIG. 2).

A. Polyclonal  term- RUP3  Antibodies In the rabbit  Preparation (Figure 2A).

Rabbits were immunized with antigenic peptides with sequences derived from rat RUP3 (“rRUP3”). The peptide sequence was RGPERTRESAYHIVTISHPELDG (SEQ ID NO: 7) and shared 100% identity with mouse RUP3 in corresponding parts. Rabbits were injected after incorporating cysteine residues at the N-terminus of the antigenic peptide to facilitate KLH crosslinking. The resulting antiserum (“anti-rRUP3”) and corresponding preimmune serum (“pre-rRUP3”) were tested for immune responsiveness to mouse RUP3 in immunoblot analysis (lanes 1 to 4). In this assay, GST-RUP3 fusion protein is rapidly recognized by anti-rRUP3 antiserum (lane 4) but not by pre-immune serum (lane 2). If immunoblot analysis is performed in the presence of excess antigenic peptide, immunoreactive signals can be effectively eliminated (lane 6).

B. Insulin-producing β cells of the Islet of Langerhans in the Pancreas RUP3  Expression (FIG. 2B).

Rat pancreas was sparged with 4% paraformaldehyde (PFA) in PBS and included in OCT containing medium. Sections of 10 microns were prepared, fixed on glass slides, and immunostained with pre-rRUP3 (FIG. 2B, panel a) or anti-rRUP3 antiserum (FIG. 2B, panels c and e), followed by fluorochrome Cy- Second staining with donkey anti-rabbit IgG conjugated to 3. Each fragment was also co-immunostained with a monoclonal anti-insulin antibody (Santa Cruz, Figure 2B, panels b and d) in the primary staining and then with donkey anti-mouse IgG conjugated with FITC, Or secondary staining with goat anti-glucagon antibody (Santa Cruz, FIG. 2B, panel f) and donkey anti-goat IgG coupled to FITC. Immunofluorescence signals were examined under fluorescence microscopy. RUP3 was expressed in insulin producing cells (panels c and d), but not in glucagon producing cells (panels e and f). These data demonstrate that RUP3 is expressed in β cells of the Islet of Langerhans in rat pancreas but not in α cells. Similar results were obtained when mouse pancreatic sections were examined for RUP3 expression.

Example  4

In vitro RUP3 Functional activity of (Figure 3).

Co-transfecting 293 cells with (1) a CRE-luciferase reporter, wherein the ability to stimulate the production of firefly luciferase depends on increased cAMP in the cells and (2) an expression plasmid encoding humanized RUP3 RUP3 stimulated cAMP production was achieved (FIG. 3A). Cells co-transfected with an expression plasmid that did not contain the RUP3 sequence (“CMV” in FIG. 3A) produced very little luciferase activity, whereas cells transfected with an expression plasmid encoding RUP3 (“ RUP3 ") recognizes an increase in luciferase activity of at least 10-fold. This indicates that RUP3 stimulates cAMP production when introduced into 293 cells. This property of RUP3 was also maintained between species, so hamster RUP3 stimulated luciferase activity when introduced into 293 cells in a manner similar to that described for human RUP3 (FIG. 3B).

When cAMP is increased in insulin-producing cells of the pancreas, it has been confirmed that these cells exhibit an improved ability to secrete insulin at elevated glucose concentrations. In testing whether RUP3 can confer enhanced glucose-dependent insulin release, retrovirus containing human RUP3 was used to generate Tu6 cells expressing high levels of RUP3. When increased glucose is present in the culture medium, Tu6 cells produce insulin but do not express a detectable level of RUP3 and generally do not show an increase in insulin release. As shown in FIG. 3C, Tu6 cells transduced with the control virus containing no receptor were still able to produce insulin, but did not show an increase in insulin secretion when the glucose concentration in the culture medium was changed from 1 mM to 16 mM. In contrast, Tu6 cells transduced with RUP3-containing retroviruses showed significant glucose-dependent insulin secretion (FIG. 3C).

Example  5

In the rat Glucose  For homeostasis RUP3  Agonists of In vivo  effect.

A. Oral glucose tolerance test ( oGTT )

Male C57bl / 6J mice, approximately 8 weeks of age, were fasted for 18 hours and randomly grouped (n = 5) to administer RUP3 agonists (Compound B3 or B124) at 1, 3 or 10 mg / kg. Compounds were delivered orally via gavage needles (oral administration, volume 10 ml / kg). At time zero, blood glucose levels were measured using Glucometer Elite XL (Bayer) and mice were administered vehicle (20% hydroxypropyl-beta-cyclodextrin) or test compound. Thirty minutes after the test compound was administered, blood glucose levels were measured again and mice were orally dosed with 3 g / kg of dextrose. Blood glucose was then measured 20, 40, 60 and 120 minutes after this time. Table 6 shows the average percentage of glucose excursion inhibition relative to the dose of each test compound, which averaged five animals in each treatment group. These results demonstrated that the RUP3 agonists, compounds B3 and B124, lowered blood glucose in a dose-dependent manner after induction into glucose in mice.

Average Inhibition Rate of Glucose Transport (%) compound Dosage 1 mg / Kg 3 mg / Kg 10 mg / Kg B3 14.83 22.03 39.31 B124 0 5.49 21.94

Example  6

Tu6 Of RUP3 Stable cell line production

To generate Tu6 cells expressing high levels of RUP3, an expression cassette for RUP3 was generated with retroviruses. Briefly, the RUP3 coding sequence was cloned into the retroviral vector pLNCX2 (Clontech, Cat # 6102-1). The curing package cell line PT-67 (Clontech, K1060-D) was then transfected into the parent vector pLNCX2 or pLNCX2 / RUP3 with lipofectamine and a stable cell line was established using the instructions provided by the PT-67 vendor. It was. Media was collected from stable cell lines generated according to manufacturer's instructions to obtain retrovirus-containing supernatants. Tu6 cells in a 10 cm dish were then infected with the retrovirus by incubating for 24 hours in a solution of 1 ml of viral supernatant / 9 ml of culture medium containing 40 μg / ml polybrene. The medium was then exchanged with a culture medium containing 300 μg / ml of G418. The neomycin-resistant gene cassette present in the pLNCX2 vector eventually produced a G418-resistant clone, thus indicating successful incorporation of retroviruses into the Tu6 genome. RUP3 expression in Tu6 / RUP3 G418-resistant colonies was confirmed by Northern blot.

Example  7

Insulin secretion, Tu6  Stable cell lines

To measure insulin secretion from insulin-producing cell lines in rodents, cells were first cultured overnight in serum-free glucose-deficient media. Next morning, cells were placed in the same medium supplemented with 1 mM or 16 mM glucose. After 4 hours incubation, media was collected and insulin content was analyzed using a rat insulin enzyme-immunoassay (EIA) system (Amersham Pharmacia Biotech, Cat. # RPN 2567). Typically, multiple dilutions of the sample medium were analyzed to ensure that sample measurements were within the boundaries of the standard curve recommended by the manufacturer (made with known amounts of insulin).

Example  8

Receptor binding assay

In addition to the methods described herein, another means for evaluating test compounds is to measure binding affinity for the RUP3 receptor. This type of assay generally requires radiolabeled ligand for the RUP3 receptor. Without the use of known ligands for the RUP3 receptor and radiolabels thereof, the compounds of formula I can be labeled with radioisotopes and used in the assay to assess the affinity of the test compound for the RUP3 receptor.

Radiolabeled RUP3 Compounds of Formula I can be used for screening assays to identify / evaluate compounds. In general, newly synthesized or identified compounds (ie test compounds) may be evaluated for their ability to reduce the binding of “radiolabeled compounds of formula (I)” to the RUP3 receptor. Thus, the ability to compete with a "radiolabeled compound of formula I" or a "radiolabeled RUP3 ligand" to bind to the RUP3 receptor is directly related to the binding affinity of the test compound for the RUP3 receptor.

RUP3 Assay Protocol for Measuring Receptor Binding to

A. RUP3  Receptor Preparation

293 cells (human kidney, ATCC) transiently transfected with 10 μg of human RUP3 receptor and 60 μl of lipofectamine (per 15-cm dish) were exchanged for 24 hours in a dish (75% congenital growth), Removed with 10 ml / dish of Hepes-EDTA buffer (20 mM Hepes + 10 mM EDTA, pH 7.4). Cells were then centrifuged for 20 minutes in a Beckman Coulter centrifuge at 17,000 rpm (JA-25.50 rotor). The pellet was then resuspended in 20 mM Hepes + 1 mM EDTA, pH 7.4, homogenized with a 50-ml Dounce homogenizer and then centrifuged again. After removing the supernatant, the pellets were stored at -80 ° C until used for binding assays. When used for analysis, the membrane was thawed on ice for 20 minutes, then 10 mL of incubation buffer (20 mM Hepes, 1 mM MgCl ₂ , 100 mM NaCl, pH 7.4) was added. The membrane was then vortexed to resuspend the crude membrane pellet and homogenized for 6 to 15 seconds set with the Brinkmann PT-3100 polytron homogenizer. The concentration of membrane protein was measured by BRL Bradford protein assay.

B. Binding Analysis

For total binding, a total volume of 50 μl of appropriately diluted membrane (assay buffer containing 50 mM Tris HCl, pH 7.4, 10 mM MgCl ₂ and 1 mM EDTA; 5-50 μg protein) was prepared in 96-well polypropylene. After addition to the microtiter plate, 100 μl of assay buffer and 50 μl of radiolabeled RUP3 ligand were added. For nonspecific binding, 50 μl of assay buffer was added instead of 100 μl of 10 μM cold RUP3 and an additional 50 μl, followed by 50 μl of radiolabeled RUP3 ligand. The plate was then incubated at room temperature for 60-120 minutes. Microplate apparatus equipped with Brandell 96-well plate harvester terminates the binding reaction by filtration of the assay plate through a GF / C Unifilter filtration plate, followed by cold 50 mM Tris containing 0.9% NaCl. Washed with HCl (pH 7.4). The bottom of the filtration plate was then sealed, 50 μl of Optiphase Supermix was added to each well, the plate top was sealed and the plate counted on a Trilux MicroBeta scintillation counter. For compound competition studies, instead of adding 100 μl of assay buffer, 100 μl of appropriately diluted test compound was added to appropriate wells followed by 50 μl of radiolabeled RUP3 ligand.

C. conclusion

Test compounds were initially analyzed at 1 and 0.1 μM and then at selected concentration ranges (ie IC ₅₀ ) such that intermediate doses inhibited about 50% of radio-RUP3 ligand binding. The specific binding in the absence of the test compound (B _O ) is the difference of the total binding (B _T ) minus the nonspecific binding (NSB), and similarly the specific binding in the presence of the test compound (B) is in the substitution bond (B _D ) Difference minus nonspecific binding (NSB). IC ₅₀ can be determined from the inhibition response curve (logit-log plot of% B / B ₀ versus test compound concentration).

K _i was calculated by Cheng and Prustoff deformation:

K _i = IC ₅₀ / (1 + [L] / K _D )

Wherein [L] is the concentration of radio-RUP3 ligand used in the analysis, and K _D is the dissociation constant of the radio-RUP3 ligand measured independently under the same binding conditions.

<Chemistry>

Synthesis of Compound of the Invention

The compounds of the present invention and their synthesis are further illustrated by the following examples. However, the following examples are intended to further define the invention and are not intended to limit the invention to the details of these examples. The compounds described above and below herein are named according to CS Chem Draw Ultra Version 7.0.1. In certain instances, common names are used, and such generic names will be understood by those skilled in the art. do.

chemistry:

Proton nuclear magnetic resonance ( ¹ H NMR) spectra are Varian Mercury Vx-400, or QNP (Quad nuclear probe) or BBI (wideband, with four nuclear auto-switchable probes and z-gradient Recorded on Bruker Avance-400 equipped with Broad Band Inverse and z-gradient. Chemical shifts are expressed in parts per million (ppm) relative to the residual solvent signal used as reference. NMR abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = wide. Microwave irradiation was performed using a Smith Synthesizer (Personal Chemistry). Thin layer chromatography (TLC) was performed on silica gel 60 F ₂₅₄ (Merck), preparative thin layer chromatography (TLC for purification) was performed on a PK6F silica gel 60 A 1 mm plate (Whatman), Column chromatography was performed on silica gel columns using Kisselgel 60, 0.063 to 0.200 mm (Merck). Evaporation was carried out in vacuo on a Buchi rotary evaporator. Celite 545 ^(R) was used during palladium filtration.

LCMS Spectrum: 1) PC: HPLC-Pump: LC-10AD VP, Shimadzu Inc. Shimadzu Inc .; HPLC system regulator: SCL-10A VP, Shimadzu Inc .; UV-detector: SPD-10A VP, Shimadzu Inc .; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX, AB / MDS Sciex with Turbo Ion Spray source; Software: Analyst 1.2. 2) Mac: HPLC-pump: LC-8A VP, Shimadzu Inc .; HPLC system regulator: SCL-10A VP, Shimadzu Inc.

UV-detector: SPD-10A VP, Shimadzu Inc .; Autosampler: 215 Liquid Handler, Gilson Inc .; Mass spectrometer: API 150EX, AB / MDS SIEX with turbo ion spray source; Software: Masschrom 1.5.2.

Example  9:

Example 9.1: 4-({[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-car Acid tert -Butyl ester, ie the preparation of compound A4

Step 1: 4-{[(6-chloro-pyrimidin-4-yl) -methyl-amino] -methyl} -piperidine-1-carboxylic acid tert Preparation of -Butyl Ester

4,6-dichloropyrimidine (194 mg, 1.31 mmol), 4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.31 mmol) in isopropyl alcohol (2 mL) and The compound of diisopropylethyl amine (0.45 mL, 2.62 mmol) was heated at 100 ° C. for 5 minutes under microwave radiation. The crude mixture was concentrated in vacuo and purified by HPLC to afford 4-{[(6-chloro-pyrimidin-4-yl) -methyl-amino] -methyl} -piperidine-1-carboxylic acid tert as an oil. -Butyl ester was obtained (240 mg, 54%).

Step 2: 4-({[6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert Preparation of Butyl Ester (Compound A4).

4-{[(6-Chloro-pyrimidin-4-yl) -methyl-amino] -methyl} -piperidine-1-carboxylic acid tert-butyl ester in dioxane (2 ml) (240 mg, 0.71 mmol), 2-fluoro-4-methanesulfonylaniline (113 mg, 0.60 mmol), palladium acetate (1.4 mg, 0.006 mmol), di-t-butyl-biphenylphosphine (2 mg, 0.0066 mmol) and A mixture of sodium t-butoxide (144 mg, 1.5 mmol) was heated at 120 ° C. for 2 hours under microwave radiation. The crude mixture was purified by HPLC to give compound A4 as a solid.

Using the same methods and procedures as described in the Schemes and Examples herein, the following compounds were prepared from suitable materials.

Example  9.2: (2- Fluoro -4- Methanesulfonyl - Phenyl )-{6- [4- (3- Fluoro - Phenoxy ) -Piperidin-1-yl] -pyrimidin-4-yl} -amine (Compound A8).

Compound A8 was obtained as a tan solid (48 mg, 52%).

Example  9.3: 4-({[6- (4- Cyano -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A14).

Compound A14 was obtained as a white solid (13 mg, 20%).

Example  9.4: 4-[({6- [4- (2- Methanesulfonyl -ethyl)- Phenylamino ] -Pyrimidin-4-yl}- methyl -Amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A15).

Compound A15 was obtained as a yellow solid (5 mg, 7%).

Example  9.5: 4-({[6- (4- Ethylsulfanyl - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A16).

Compound A16 was obtained as a yellow solid (9 mg, 13%). Exact mass calculation for C ₂₄ H ₃₅ N ₅ O ₂ S 457.2, LCMS (ESI) m / z 458.3 (M + H ⁺ , 100%).

Example  9.6: 4-({[6- (4- Isopropylsulfanyl - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A17).

Compound A17 was obtained as a yellow solid (18 mg, 25%). Exact mass calcd. For C ₂₅ H ₃₇ N ₅ O ₂ S 471.3, LCMS (ESI) m / z 472.4 (M + H ⁺ , 100%).

Example  9.7: 4-({[6- (4- Ethyl sulfamoyl - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (compound A18)

Compound A18 was obtained as a white solid (4 mg, 5%).

Example  9.8: 4-({ methyl -[6- (4- Methylsulfamoyl - Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A19).

Compound A19 was obtained as a white solid (3 mg, 4%).

Example  9.9: 4-({[6- (4- Dimethyl sulfamoyl - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A20).

Compound A20 was obtained as a white solid (25 mg, 33%).

Example  9.10: 4-({ methyl -[6- (4- Methylsulfamoylmethyl - Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A21).

Compound A21 was obtained as a yellow solid (7 mg, 9%). Exact mass calcd. For C ₂₄ H ₃₆ N ₆ O ₄ S 504.2, LCMS (ESI) m / z 505.3 (M + H ⁺ , 100%).

Example  9.11: 4-({ methyl -[6- (4- Sulfa Mole - Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A22).

Compound A22 was obtained as a white solid (4 mg, 6%). Exact mass calcd. For C ₂₂ H ₃₂ N ₆ O ₄ S 476.2, LCMS (ESI) m / z 477.2 (M + H ⁺ , 100%).

Example  9.12: 4-({ methyl -[6- (4- [1,2,4] Triazole -1 day- Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A23).

Compound A23 was obtained as a white solid (12 mg, 17%). Exact mass calculation for C ₂₄ H ₃₂ N ₈ O ₂ 464.3, LCMS (ESI) m / z 465.4 (M + H ⁺ , 100%).

Example  9.13: 4-({ methyl -[6- (4- [1,2,4] Triazole -One- Methyl - Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A24).

Compound A24 was obtained as a yellow solid (3 mg, 4%). Exact mass calcd. For C ₂₅ H ₃₄ N ₈ O ₂ 478.3, LCMS (ESI) m / z 479.1 (M + H ⁺ , 100%).

Example  9.14: 4-[( methyl -{6- [4- (2- [1,2,4] Triazole -1-yl-ethyl)- Phenylamino ] -Pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A25).

Compound A25 was obtained as a white solid (6 mg, 8%). Exact mass calculation for C ₂₆ H ₃₆ N ₈ O ₂ 492.3, LCMS (ESI) m / z 493.4 (M + H ⁺ , 100%).

Example  9.16: 4-({[6- ( Benzo [1,3] dioxol -5- Monoamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A26).

Compound A26 was obtained as a tan solid (11 mg, 17%). Exact mass calcd. For C ₂₃ H ₃₁ N ₅ O ₄ 441.2. Found LCMS (ESI) m / z 442.3 (M + H ⁺ , 100%).

Example  9.17: 4-({[6- (6- Methanesulfonyl -Pyridine-3- Monoamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A27).

Compound A27 was obtained as an off-white solid (3 mg, 4%). Exact mass calcd. For C ₂₂ H ₃₂ N ₆ O ₄ S 476.2. Found LCMS (ESI) m / z 477.4 (M + H ⁺ , 100%).

Example  9.18: 4-({[6- (3,5- Dimethoxy - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A28).

Compound A28 was obtained as a yellow solid (13 mg, 19%). Exact mass calcd. For C ₂₄ H ₃₅ N ₅ O ₄ 457.3. Found LCMS (ESI) m / z 458.3 (M + H ⁺ , 100%).

Example  9.19: 4-[(Methyl- {6- [4- (2-oxo-oxazolidin-4-ylmethyl) -phenylamino] -pyrimidin-4-yl} -amino) -methyl] -piperidine -1-carboxylic acid tert -Butyl ester (Compound A29).

Compound A29 was obtained as a yellow solid (30 mg, 40%). Exact mass calcd. For C ₂₆ H ₃₆ N ₆ O ₄ 496.3. Found LCMS (ESI) m / z 497.5 (M + H ⁺ , 100%).

Example  9.20: 4-[({6- [4- (1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl) -phenylami furnace ] -Pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-l-carboxylic acid tert -Butyl ester (Compound A30).

Compound A30 was obtained as a white solid (12 mg, 15%). Exact mass calcd. For C ₂₇ H ₄₀ N ₆ O ₄ S 544.3, found LCMS (ESI) m / z 545.4 (M + H ⁺ , 100%).

Example  9.21: 4-({ methyl -[6- (4- Pyrazole -1 day- Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A31).

Compound A31 was obtained as a white solid (6 mg, 9%). Exact mass calculation for C ₂₅ H ₃₃ N ₇ O ₂ 463.3, found LCMS (ESI) m / z 464.3 (M + H ⁺ , 100%).

Example  9.22: 4-({[6- (2,2- Difluoro - Benzo [1,3] dioxol -5- Monoamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A32).

Compound A32 was obtained as a white solid (3 mg, 4%). Exact mass calcd. For C ₂₃ H ₂₉ F ₂ N ₅ O ₄ 477.2. Found LCMS (ESI) m / z 478.3 (M + H ⁺ , 100%).

Example  9.23: 4-({ methyl -[6- (4- Trifluoromethanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A33).

Compound A33 was obtained as a white solid (13 mg, 16%). Exact mass calcd. For C ₂₃ H ₃₀ F ₃ N ₅ O ₄ S 529.2. Found LCMS (ESI) m / z 530.2 (M + H ⁺ , 100%).

Example  9.24: 4-[( methyl -{6- [4- (morpholine-4- Sulfonyl )- Phenylamino ] -Pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A34).

Compound A34 was obtained as a white solid (13 mg, 16%). Exact mass calculated for C ₂₆ H ₃₈ N ₆ O ₅ S 546.3, found LCMS (ESI) m / z 547.3 (M + H ⁺ , 100%)

Example  9.25: 4-[( methyl -{6- [2- (pyridine-2-carbonyl)- Phenylamino ] -Pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A35).

Compound A35 was obtained as a brown solid (0.4 mg, 0.5%). Exact mass calcd. For C ₂₈ H ₃₄ N ₆ O ₃ , 502.3, found LCMS (ESI) m / z 503.5 (M + H ⁺ , 100%).

Example  9.26: 4-({[6- (2- Fluoro -5- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A36).

Compound A36 was obtained as a solid (11 mg, 15%). Exact mass calcd. For C ₂₅ H ₃₂ FN ₅ O ₄ S. 493.2. Found 494.3 (M + H ⁺ ).

Example  9.27: 4-({[6- (3,4- Difluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A39).

Compound A39 was obtained as a solid (6 mg, 9%). Exact mass calcd. For C ₂₂ H ₂₉ F ₂ N ₅ O ₂ 433.2. Found 434.3 (M + H ⁺ ).

Example  9.28: 4-({[6- (2,6- Difluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A40).

Compound A40 was obtained as a solid (28 mg, 43%). Exact mass calcd. For C ₂₂ H ₂₉ F ₂ N ₅ O ₂ 433.2. Found 434.3 (M + H ⁺ ).

Example  9.29: 4-({[6- (2,5- Difluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A41).

Compound A41 was obtained as a solid (22 mg, 34%). Exact mass calcd. For C ₂₂ H ₂₉ F ₂ N ₅ O _2. 433.2. Found 434.0 (M + H ⁺ ).

Example  9.30: 4-({[6- (2,3- Difluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A42).

Compound A42 was obtained as a solid (10 mg, 15%). Exact mass calcd. For C ₂₂ H ₂₉ F ₂ N ₅ O _2. 433.2. Found 434.2 (M + H ⁺ ).

Example  9.31: 4-({ methyl -[6- (2,3,5- Trifluoro - Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A43).

Compound A43 was obtained as a solid (4 mg, 6%). Exact mass calcd. 451.2 for C ₂₂ H ₂₈ F ₃ N ₅ O ₂ , found 452.2 (M + H ⁺ ).

Example  9.32: 4-({[6- (2- Fluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A44).

Compound A44 was obtained as a solid (11 mg, 18%). Exact mass calculation for C ₂₂ H ₃₀ FN ₅ O ₂ 415.2, found 416.3 (M + H ⁺ ).

Example  9.33: 4-({[6- (2- Fluoro -4- methyl - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A45).

Compound A45 was obtained as a solid (7 mg, 11%). Exact mass calcd. For C ₂₃ H ₃₂ FN ₅ O _2. 429.2. Found 430.1 (M + H ⁺ ).

Example  9.34: 4-({[6- (3- Chloro -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A46).

Compound A46 was obtained as a solid (19 mg, 28%). Exact mass calcd. For C ₂₂ H ₂₉ FCIN ₅ O _2. 449.2. Found 450.4 (M + H ⁺ ).

Example  9.35: 4-({[6- (2,4- Difluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A47).

Compound A47 was obtained as a solid (26 mg, 40%). Exact mass calculation for C ₂₂ H ₂₉ F ₂ N ₅ O ₂ 433.2. Found 434.4 (M + H ⁺ ).

Example  9.36: 4-[( methyl -{6- [2- (1- Oxy -Pyridin-3-yl)- Ethylamino ] -Pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A48).

Compound A48 was obtained as a solid (6 mg, 9%). Exact mass calculated for C ₂₃ H ₃₄ N ₆ O ₃ 442.2, found 443.3 (M + H ⁺ ).

Example  9.37: 4-({[6- (4- Cyano -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester (Compound A51).

Compound A51 was obtained as a trifluoroacetic acid salt (37 mg, 9%).

Example  9.38: 4-({[6- (4- Ethyl sulfamoyl -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A58).

Compound A58 was obtained as a white solid (6 mg, 8%). Accurate mass calcd. 522.2 for C ₂₄ H ₃₅ FN ₆ O ₄ S, found LCMS (ESI) m / z 523.4 (M + H ⁺ , 100%).

Example  9.39: 4-({[6- (2- Fluoro -4- Isopropyl sulfamoyl - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A59).

Compound A59 was obtained as a white solid (7 mg, 9%). Exact mass calcd. For C ₂₅ H ₃₇ FN ₆ O ₄ S 536.3. Found LCMS (ESI) m / z 537.4 (M + H ⁺ , 100%).

Example  9.40: 4-({[6- (4- Cyano -2,5- Difluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A60).

Compound A60 was obtained as a white solid (4 mg, 6%). Exact mass calcd. For C ₂₃ H ₂₈ F ₂ N ₆ O _2. 458.2, found LCMS (ESI) m / z 459.3 (M + H ⁺ , 100%).

Example  9.41: 4-({[6- (4- Bromo -2,5- Difluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A61).

Compound A61 was obtained as a yellow solid (25 mg, 32%). Exact mass calcd. For C ₂₂ H ₂₈ BrF ₂ N ₅ O ₂ 511.1. Found LCMS (ESI) m / z 512.2 (M + H ⁺ , 100%).

Example  9.42: 4-({[6- (5- Carboxy -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A62).

Compound A62 was obtained as a brown solid (2 mg, 3%). Exact mass calcd. For C ₂₃ H ₃₀ FN ₅ O _4. 459.2. Found LCMS (ESI) m / z 460.3 (M + H ⁺ , 100%).

Example  9.43: 4-({[6- (6- Methoxy -Pyridine-3- Monoamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A63).

Compound A63 was obtained as a brown solid (11 mg, 17%). Exact mass calcd. For C ₂₂ H ₃₂ N ₆ O _3. 428.3. Found LCMS (ESI) m / z 429.2 (M + H ⁺ , 100%).

Example  9.44: 4-({[6- (2,6- Dimethoxy -Pyridine-3- Monoamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A64).

Compound A64 was obtained as a brown solid (8 mg, 12%). Exact mass calcd. For C ₂₃ H ₃₄ N ₆ O _4. 458.3. Found LCMS (ESI) m / z 459.3 (M + H ⁺ , 100%).

Example  9.45: 6- {6-[(1- tert - Butoxycarbonyl Piperidine-4- Methyl )- methyl -Amino] -pyrimidin-4-ylamino} -nicotinic acid (compound A65).

Compound A65 was obtained as a tan solid (2 mg, 3%). Exact mass calcd. For C ₂₂ H ₃₀ N ₆ O ₄ 442.2. Found LCMS (ESI) m / z 443.4 (M + H ⁺ , 100%).

Example  9.46: 4-({[6- (6- Acetylamino -Pyridine-3- Monoamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A66).

Compound A66 was obtained as a yellow solid (3 mg, 4%). Exact mass calcd. For C ₂₃ H ₃₃ N ₇ O ₃ 455.3. Found LCMS (ESI) m / z 456.2 (M + H ⁺ , 100%).

Example  9.47: 4-({[6- (5- Fluoro Pyridine-2- Monoamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A67).

Compound A67 was obtained as a yellow solid (19 mg, 31%). Exact mass calculation 416.2 for C ₂₁ H ₂₉ FN ₆ O ₂ , found LCMS (ESI) m / z 417.3 (M + H ⁺ , 100%).

Example  9.48: 4-({[6- (4- Cyano 2-ethyl- Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A68).

Compound A68 was obtained as a white solid (8 mg, 12%). Exact mass calcd. For C ₂₅ H ₃₄ N ₆ O ₂ 450.3. Found LCMS (ESI) m / z 451.3 (M + H ⁺ , 100%).

Example  9.49: 4-({[6- (4- Butyryl - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A69).

Compound A69 was obtained as a yellow solid (9 mg, 13%). Exact mass calcd. For C ₂₆ H ₃₇ N ₅ O ₃ 467.3. Found LCMS (ESI) m / z 468.5 (M + H ⁺ , 100%).

Example  9.50: 4-({[6- (5- Bromo -3- methyl Pyridine-2- Monoamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A70).

Compound A70 was obtained as a yellow solid (4 mg, 5%). Exact mass calcd. For C ₂₂ H ₃₁ BrN ₆ O ₂ 490.2. Found LCMS (ESI) m / z 491.3 (M + H ⁺ , 100%).

Example  9.51: 4-({[6- (3- Bromo -5- methyl Pyridine-2- Monoamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A71).

Compound A71 was obtained as a yellow solid (17 mg, 23%). Exact mass calcd. For C ₂₂ H ₃₁ BrN ₆ O ₂ 490.2. Found LCMS (ESI) m / z 491.3 (M + H ⁺ , 100%).

Example  9.52: 4-({ methyl -[6- (5- Trifluoromethyl Pyridine-2- Monoamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A72).

Compound A72 was obtained as a yellow solid (2 mg, 3%). Exact mass calculated for C ₂₂ H ₂₉ F ₃ N ₆ O ₂ 466.2. Found LCMS (ESI) m / z 467.3 (M + H ⁺ , 100%).

Example  9.53: 4-({[6- (4- Bromo -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A73).

Compound A73 was obtained as a cream solid (9 mg, 12%). Exact mass calcd. For C ₂₂ H ₂₉ BrFN ₅ O _2. 493.2. Found LCMS (ESI) m / z 496.4 (M + H ⁺ , 100%).

Example  9.54: 4-({[6- (3- Carboxy -4- Fluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A74).

Compound A74 was obtained as a cream solid (1 mg, 1%). Exact mass calcd. For C ₂₃ H ₃₀ FN ₅ O _4. 459.2. Found LCMS (ESI) m / z 460.4 (M + H ⁺ , 100%).

Example  9.55: 4-({[6- (4- Ethoxycarbonyl -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester (Compound A75).

And

Example  9.56: 4-({[6- (4- Carboxy -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester (Compound A76).

Step 1: (4- Cyano -2- Fluoro - Phenyl )- Carbamic acid  9H- Fluorene -9- Methyl  Preparation of esters.

A mixture of 2.05 g (15.06 mmol) of 4-amino-3-fluorobenzonitrile and 2 g (23.8 mmol) of sodium bicarbonate in 30 mL of acetonitrile was cooled in an ice bath and 4.4 g (17.0 mmol) of FMOC-Cl were added. . The mixture was allowed to warm to room temperature. After 16 h, the mixture was concentrated and extracted with 1 M HCl and ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Crystallization with ethyl acetate / hexanes gave (4-cyano-2-fluoro-phenyl) -carbamic acid 9H-fluorene-9-ylmethyl ester as a white solid (2.68 g, 50%).

Step 2: 4-amino-3- Fluoro Preparation of -benzoic acid ethyl ester

HCl was slowly bubbled through a solution of 1.6 g (4.46 mmol) of (4-cyano-2-fluoro-phenyl) -carbamic acid 9H-fluorene-9-ylmethyl ester in 300 mL of EtOH. After 5 hours the solution was concentrated. The residue was dissolved in 100 mL of THF and 100 mL of 6 M HCl in water. After stirring at 50 ° C. for 4 hours, the mixture was concentrated. The residue was treated with NHEt ₂ in 2 M MeOH. After 3 hours, the mixture was concentrated and the residue was purified by HPLC to give 4-amino-3-fluoro-benzoic acid ethyl ester as a white solid (TFA salt, 0.696 g, 42%).

Step 3: Preparation of Compound A75 and Compound A76.

Compound A75 was prepared as a TFA salt (13.2 mg, 11%, tan solid) in a similar manner as described above, and compound A76 was also obtained as a TFA salt (24.4 mg, 21%, tan solid).

Compound A75:

Compound A76:

Example  9.57: 4-({[6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yl] -meth Teal -Amino} -methyl) -piperidine-1-carboxylic acid isopropyl ester (Compound A77).

Compound A77 was obtained as a solid (20 mg, 48%).

Example  9.58: 4-({[6- (4- Cyano -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid butyl ester (Compound A78).

Compound A78 was obtained as a trifluoroacetic acid salt (30 mg, 68%).

Example  9.59: 4-({[6- (4- Cyano -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid Cyclopropylmethyl  Esters (Compound A79).

Compound A79 was obtained as a solid (26 mg, 45%). Exact mass calcd. For C ₂₃ H ₂₇ FN ₆ O _2. 438.2. Found 439.3 (M + H ⁺ ).

Example  9.60: {4- [6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -piperazin-1-yl} -acetic acid ethyl ester (Compound A80).

Step 1: [4- (6- Chloro Preparation of -pyrimidin-4-yl) -piperazin-1-yl] -acetic acid ethyl ester.

A mixture of 4,6-dichloropyrimidine (1 g, 6.75 mmol), 1- (ethoxycarbonylmethyl) piperazine (1.16 g, 6.75 mmol) and diisopropyl ethyl amine in isopropyl alcohol (8 mL) Heat under microwave spinning at 100 ° C. for 2 minutes. The crude was purified by flash chromatography (hexane: ethyl acetate = 1: 2) to give [4- (6-chloro-pyrimidin-4-yl) -piperazin-1-yl] -acetic acid ethyl ester as oil. Obtained (1.80 g, 93%).

Step 2: {4- [6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -piperazin-1-yl} -acetic acid ethyl ester (Compound A80).

Compound A80 was prepared as a solid in a similar manner as described above (290 mg, 62%).

Example  9.61: (2- Fluoro -4- Methanesulfonyl - Phenyl )-{6- [4- (3-isopropyl- [1,2,4] oxadiazol-5-ylmethyl) -piperazin-1-yl] -pyrimidin-4-yl} -amine (compound A81).

Compound A81 was obtained as a solid (30 mg, 14%). Exact mass calcd. For C ₂₁ H ₂₆ FN ₇ O ₃ S 475.2, found 476.2 (M + H ⁺ ).

Example  9.62: 4-({[6- (2,5- Difluoro -4-hydroxy- Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester (Compound A82).

Compound A82 (TFA salt, 77.9 mg, 44%) was obtained as a tan solid.

Example  9.63: 4-({[6- (4- Ethylcarbamoyl -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester (Compound A83).

A mixture of compound A76 (TFA salt, 35.2 mg, 0.061 mmol) and HBTU (49 mg, 0.13 mmol) in 1 mL 2 M ethyl amine was stirred at room temperature. After 10 minutes, the solution was constantly stirred with microwave at 180 ° C. After 1 h, the mixture was purified by HPLC to give compound A83 as a white solid (TFA salt, 9.5 mg, 26%).

Example  9.64: 4-[({6- [2- Fluoro -4- (N- Hydroxycarbamimidoyl )- Phenylamino ] -Pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1-carboxylic acid isobutyl ester (Compound A84).

4-({[6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperi in 1 mL EtOH and 0.5 mL H ₂ O A mixture of dine-1-carboxylic acid isobutyl ester (Compound A51, 33.5 mg, 0.060 mmol), hydroxylamine hydrochloride (430 mg, 6.19 mmol) and potassium carbonate (870 mg, 6.29 mmol) was added for 80 minutes. Stir at ° C. The mixture was purified by HPLC to give compound A84 as a white solid (TFA salt, 32.2 mg, 91%).

Example  9.65: 4-({[6- (4- Carbamimidoil -2- Fluoro - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester (Compound A90).

To a solution of compound A84 (TFA salt, 22.6 mg, 0.0385 mmol) in 1 mL of acetic acid was added zinc powder (50 mg, 0.76 mmol). After the mixture was stirred for 10 minutes, zinc was filtered, the filtrate was concentrated and purified by HPLC to give Compound A90 as a white solid (8.4 mg, 38%).

Example  9.66: 4-({[6- (2,5-Difluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1- Carboxylic acid tert -Butyl ester (Compound A86).

Compound A86 was obtained as a solid (57 mg, 37%). Exact mass calcd. For C ₂₃ H ₃₁ F ₂ N ₅ O ₄ S 511.2, found 512.3 (M + H ⁺ ).

Example  9.67: N- (2- Fluoro -4- Methanesulfonyl - Phenyl )- N ' -(5'- Fluoro -3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylmethyl) -N'-methyl-pyrimidine-4,6-diamine (Compound A89).

Compound A89 was obtained as a solid (3 mg, 6%). Exact mass calcd. For C ₂₃ H ₂₆ F ₂ N ₆ O ₂ S. 488.2. Found 489.2 (M + H ⁺ ).

Example  9.68: 4- [6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidine-4- Monoamino ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound A92).

Compound A92 was obtained as a solid (18 mg, 13%). Exact mass calcd. For C ₂₁ H ₂₈ FN ₅ O ₄ S 465.2. Found 466.3 (M + H ⁺ ).

Example  9.69: N- (2- Fluoro -4- Methanesulfonyl - Phenyl )- N ' -[1- (3-Isopropyl- [1,2,4] oxadiazol-5-ylmethyl) -piperidin-4-ylmethyl] -N'-methyl-pyrimidine-4,6-diamine (Compound A93).

Compound A93 was obtained as a solid (45 mg, 38%). Exact mass calcd. For C ₂₄ H ₃₂ FN ₇ O ₃ S 517.2. Found 518.4 (M + H ⁺ ).

Example  9.70: 4-({[6- (4- Cyano -2,5- Difluoro - Phenylamino ) -Pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxylic acid isopropyl ester (Compound A97).

4- [6- (ethyl-piperidin-4-ylmethyl-amino) -pyrimidin-4-ylamino] -2,5-difluoro-benzonitrile (HCl salt, 1.8712 in 100 mL of CH ₃ CN) g, 4.57 mmol), a mixture of triethylamine (1.91 mL, 13.71 mmol) and isopropyl chloroformate (1 M in toluene, 9.14 mL, 9.14 mmol) were stirred at room temperature for 30 minutes. The mixture was purified by HPLC to give compound A97 as a white solid (TFA salt, 600 mg, 23%).

Example  9.71: 4-({[6- (2,5- Difluoro -4- Methoxy - Phenylamino ) -Pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A99).

4-({[6- (2,5-Difluoro-4-hydroxy-phenylamino) -pyrimidin-4-yl] -ethyl-amino} in 0.5 mL CH ₃ CN / MeOH (9: 1) -Methyl) -piperidine-1-carboxylic acid tert-butyl ester (61.9 mg, 0.134 mmol), diisopropyl ethylamine (33 μl, 0.189 mmol) and (trimethylsilyl) diazomethane (Et ₂ O) 2 M, 94 μl, 0.188 mmol) was stirred at rt for 15 h. The mixture was purified by HPLC to give compound A99 as a white solid (TFA salt, 24.3 mg, 31%).

Example  9.72: 4-({[6- (2,5- Difluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A100).

Compound A100 was obtained as an off-white powder (32.5 mg, 22%). Exact mass calcd. For C ₂₄ H ₃₃ F ₂ N ₅ O ₄ S 525.2, found LCMS (ESI) m / z 526.5 (M + H ⁺ , 89%).

Example  9.73: 4-({ethyl- [6- (2,4,5- Trifluoro - Phenylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A101).

Compound A101 was obtained as an off-white powder (16.3 mg, 13%). Exact mass calcd. For C ₂₃ H ₃₀ F ₃ N ₅ O ₂ 465.2. Found LCMS (ESI) m / z 466.4 (M + H ⁺ , 100%).

Example  9.74: 4-({[6- (4- Bromo -2,5- Difluoro - Phenylamino ) -Pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A104).

Compound A104 was obtained as a white powder (20.1 mg, 14%). Exact mass calcd. For C ₂₃ H ₃₀ BrF ₂ N ₅ O ₂ 525.2. Found LCMS (ESI) m / z 528.5 (M + H ⁺ , 74%).

Example  9.75: {1- [6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -piperidin-4-yl} -acetic acid methyl  Esters (Compound A106).

Compound A106 was obtained as a solid (62 mg, 30%). Exact mass calculated for C ₁₉ H ₂₃ FN ₄ O ₄ S 422.1, found 423.1 (M + H ⁺ )

Example  9.76: 3- {4- [6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -piperazin-1-yl} -propionic acid ethyl ester (Compound A107).

Compound A107 was obtained as a solid (50 mg, 23%). Exact mass calcd. 451.2 for C ₂₀ H ₂₆ FN ₅ O ₄ S, found 452.1 (M + H ⁺ ).

Example  9.77: (2- Fluoro -4- Methanesulfonyl - Phenyl )-{6- [4- (4-isobutyl- Phenyl ) -Piperidin-1-yl] -pyrimidin-4-yl} -amine (Compound A108).

Compound A108 was obtained as a solid (35 mg, 15%). Exact mass calcd. For C ₂₆ H ₃₁ FN ₄ O ₂ S 482.2, found 483.4 (M + H ⁺ ).

Example  9.78: (2- Fluoro -4- Methanesulfonyl - Phenyl )-{6- [4- (4-isopropyl- Phenyl ) -Piperidin-1-yl] -pyrimidin-4-yl} -amine (Compound A109).

Compound A109 was obtained as a solid (44 mg, 19%). Exact mass calcd. For C ₂₅ H ₂₉ FN ₄ O ₂ S 468.2. Found 469.4 (M + H ⁺ ).

Example  9.79: (2- Fluoro -4- Methanesulfonyl - Phenyl )-(6- {4- [2- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -ethyl] -piperazin-1-yl} -pyrimidin-4-yl ) -Amine (Compound A116).

Compound A116 was obtained as a solid (160 mg, 100%). Exact mass calcd. For C ₂₂ H ₂₈ FN ₇ O ₃ S 489.2. Found 490.2 (M + H ⁺ ).

Example  9.80: (2- Fluoro -4- Methanesulfonyl - Phenyl )-{6- [4- (5- Isopropoxy -Pyridin-2-yloxy) -piperidin-1-yl] -pyrimidin-4-yl} -amine (Compound A117).

Compound A117 was obtained as a solid (180 mg, 70%).

Example  9.81: 4-({[6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -isopropyl-amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A122).

Compound A122 was obtained as a solid (33 mg, 32%). Accurate mass calcd. 521.2 for C ₂₅ H ₃₆ FN ₅ O ₄ S, found 522.5 (MH ⁺ ).

Example  9.82: 4-({[6- (4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A5).

(6-Chloro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl) -amine (57 mg, 0.2 mmol), 4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl Ester (0.2 mmol, 1.0 equiv) and K ₂ CO ₃ (0.4 mmol, 2 equiv) were dissolved in DMF (3 mL) and then stirred at 120 ° C. for 24 h. The crude was purified via HPLC to give Compound A5 as a white solid (48 mg, 51%).

Using substantially the same methods and procedures as described in the Schemes and Examples herein, the following compounds were prepared from suitable materials.

Example  9.83: 4-{[6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yl] -methyl-amino} -piperidine-1-carboxylic acid tert -Butyl ester (Compound A3).

Compound A3 was obtained as a solid (6 mg, 20%). Exact mass calcd. For C ₂₂ H ₃₀ FN ₅ O ₄ S. 479.2. Found 480.4 (M + H ⁺ ).

Example  9.84: 4-({ methyl -[6- (2-pyridin-4-yl-) Ethylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A9).

Compound A9 was obtained as a yellow solid (7 mg, 8%). Exact mass calculation for C ₂₃ H ₃₄ N ₆ O ₂ 426.3, LCMS (ESI) m / z 427.2 (M + H ⁺ , 100%).

Example  9.85: 4-({ methyl -[6- (2-pyridin-3-yl-) Ethylamino ) -Pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A10).

Compound A10 was obtained as a yellow solid (13 mg, 15%). Exact mass calcd. For C ₂₃ H ₃₄ N ₆ O ₂ 426.3, LCMS (ESI) m / z 427.3 (M + H ⁺ , 100%).

Example  9.86: 4-[( methyl -{6-[(pyridine-3- Methyl ) -Amino] -pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A11).

Compound A11 was obtained as a yellow solid (5 mg, 6%). Exact mass calculation for C ₂₂ H ₃₂ N ₆ O ₂ 412.3, LCMS (ESI) m / z 413.4 (M + H ⁺ , 100%).

Example  9.87: 4-[( methyl -{6- [2- (1- Oxy -Pyridin-3-yl)- Ethylamino ] -Pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid isobutyl ester (Compound A49).

Compound A49 was obtained as a solid (24 mg, 55%). Exact mass calcd. For C ₂₇ H ₃₉ FN ₆ O ₄ S 562.2, found 563.5 (M + H ⁺ ).

Example  9.88: 4-[({6- [2- (2- Fluoro - Phenoxy )- Ethylamino ] -Pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A52)

Compound A52 was obtained as a solid (1 mg, 2%). Exact mass calcd. For C ₂₄ H ₃₄ FN ₅ O _3. 459.2. Found 460.3 (M + H ⁺ ).

Example  9.89: 4-({[6- (2- Fluoro - Phenoxy ) -Pyrimidin-4-yl]- methyl -Amino}- Me Tyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A53).

Compound A53 was obtained as a solid (12 mg, 20%). Exact mass calcd. For C ₂₂ H ₂₉ FN ₄ O ₃ 416.2. Found 417.4 (M + H ⁺ ).

Example  9.90: 4-({[6- (2,5- Difluoro - Phenoxy ) -Pyrimidin-4-yl]- methyl -Amino} -methyl) -piperidine-1-carboxylic acid tert -Butyl ester (Compound A54).

Compound A54 was obtained as a solid (6 mg, 9%). Exact mass calcd. For C ₂₂ H ₂₈ F ₂ N ₄ O _3. 434.2. Found 435.2 (M + H ⁺ ).

Example  9.91: 4-[({6- [2- (2- Chloro - Phenoxy )- Ethylamino] -Pyrimidin-4-yl}- methyl -Amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A55).

Compound A55 was obtained as a solid (5 mg, 9%). Exact mass calcd. For C ₂₄ H ₃₄ ClN ₅ O ₃ 475.2. Found 476.3 (M + H ⁺ ).

Example  9.92: 4-({[6- (2- Chloro - Phenoxy ) -Pyrimidin-4-yl]- methyl -Amino}- methyl ) -Piperidine-1-carboxylic acid tert -Butyl ester (Compound A56).

Compound A56 was obtained as a solid (16 mg, 25%). Exact mass calcd. For C ₂₂ H ₂₉ ClN ₄ O ₃ 432.2. Found 433.2 (M + H ⁺ ).

Example  9.93: 4-[({6- [2- (4- Fluoro - Phenoxy )- Propylamino ] -Pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1-carboxylic acid tert -Butyl ester (Compound A57).

Compound A57 was obtained as a solid (12 mg, 17%). Exact mass calcd. For C ₂₅ H ₃₆ FN ₅ O _3. 473.2. Found 474.4 (M + H ⁺ ).

Example  10:

Example  10.1: 4- [6- (2- Fluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidine-4- Jade Ci] -piperidine-1-carboxylic acid tert Preparation of butyl ester, ie compound B1.

Step 1: 4- (6- Chloro -Pyrimidine-4- Iloxy ) -Piperidine-1- Carboxylic acid tert Preparation of butyl esters.

4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (46 mmol, 1.3 equiv) and NaH (92 mmol, 2 equiv, 60% in mineral oil) were added to N ₂ Dissolved in THF (30 ml) and stirred at 60 ° C. for 40 minutes, then 4,6-dichloropyrimidine (5.237 g, 35.4 mmol) was added dropwise to the solution. The reaction mixture was stirred for an additional 20 minutes at room temperature. The reaction was quenched with water, extracted with ethyl acetate, concentrated in vacuo and purified by flash column (hexane: ethyl acetate = 2: 1, Rf = 0.48) to give 4- (6-chloro-pyrimidine- as yellow oil. 4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester was obtained (3.236 g, 29%). Exact mass calcd. For C ₁₄ H ₂₀ ClN ₃ O ₃ 313.1. Found 314.2 (MH ⁺ ).

Step 2: 2- Fluoro -4-( Methanesulfonyl Aniline production.

Copper (II) trifluoromethanesulfonate-benzene complex (30.74 g, 61.1 mmol) in sodium methanesulphi in a solution of 2-fluoro-4-iodoaniline (206.8 g, 872.3 mmol) in DMSO (1.1 L) Nate (106.9 g, 1.047 mol) and N, N'-dimethylethylenediamine (13.2 mL, 122 mmol) were added sequentially. The reaction vessel was then placed in an oil bath preheated to 120 ° C. and stirred overnight. After cooling to room temperature, the reaction was diluted with water and extracted repeatedly with EtOAc. The combined organic extracts were washed with brine (5 X), dried over MgSO ₄ and the solvent removed. The resulting purple solid was washed with diisopropyl ether and then dried in a vacuum oven at room temperature overnight to give 151.5 g (92% yield) as a turbid purple solid.

Step 3: 4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert Preparation of -butyl ester (Compound B1).

4- (6-Chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (3.23 g, 10.3 mmol) in dioxane (20 ml), 2-fluoro-4 Methanesulfonylaniline (1.95 g, 10.3 mmol), palladium acetate (115 mg, 0.515 mmol), di-t-butyl-biphenylphosphine (184 mg, 0.618 mmol) and sodium t-butoxide (2.47 g, 25.75 mmol) was heated to reflux under nitrogen gas for 2 hours. The crude mixture was quenched with water, extracted with ethyl acetate and concentrated in vacuo. The crude material was purified by flash column (hexanes: ethyl acetate = 1: 1) to give compound B1 as a solid (1.69 g, 35%).

Using substantially the same methods and procedures as described in the Schemes and Examples herein, the following compounds were prepared from suitable materials.

Example  10.2: (2- Fluoro -4- Methanesulfonyl - Phenyl )-{6- [1- (3-isopropyl- [1,2,4] oxadiazol-5-ylmethyl) -piperidin-4-yloxy] -pyrimidin-4-yl} -amine (Compound B2).

Compound B2 was obtained as a solid (253 mg, 93%). Exact mass calcd. For C ₂₂ H ₂₇ FN ₆ O ₄ S 490.2. Found 491.2 (M + H ⁺ ).

Example  10.3: 4- [6- (2,5- Difluoro -4- Methanesulfonyl - Phenylamino ) -Pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B13).

Compound B13 was obtained as a yellow powder (2.3 mg, 2%). Exact mass calcd. For C ₂₁ H ₂₆ F ₂ N ₄ O ₅ S 484.2. Found LCMS (ESI) m / z 485.2 (M + H ⁺ , 86%).

Example  10.4: 4- [6- (2,4,5- Trifluoro - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (compound B14).

Compound B14 was obtained as a yellow powder (6 mg, 7%). Exact mass calcd. For C ₂₀ H ₂₃ F ₃ N ₄ O ₃ 424.2. Found LCMS (ESI) m / z 425.3 (M + H ⁺ , 99%).

Example  10.5: 4- [6- (4- Bromo -2,5- Difluoro - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B15).

Compound B15 was obtained as a yellow powder (1 mg, 1%). Exact mass calcd. For C ₂₀ H ₂₃ BrF ₂ N ₄ O ₃ 484.1. Found LCMS (ESI) m / z 501.5 (M + H ⁺ , 78%).

Example  10.6: 4- [6- (6- Chloro -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B20).

Compound B20 was obtained as a tan powder (10.3 mg, 10%). Exact mass calcd. For C ₁₉ H ₂₄ ClN ₅ O ₃ 405.2. Found LCMS (ESI) m / z 406.2 (M + H ⁺ , 100%).

Example  10.7: 4- [6- (4- Ethylsulfanyl - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B27).

Compound B27 was obtained as a white powder (1 mg, 1%). Exact mass calcd. For C ₂₂ H ₂₉ FN ₄ O ₃ S 430.2. Found LCMS (ESI) m / z 431.2 (M + H ⁺ , 76%).

Example  10.8: 4- [6- (4- Isopropylsulfanyl - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (compound B28).

Compound B28 was obtained as an oil (1.4 mg, 2%). Exact mass calculated for C ₂₃ H ₃₁ FN ₄ O ₃ S 484.1. Found LCMS (ESI) m / z 445.6 (M + H ⁺ , 80%).

Example  10.9: 4- [6- (5- Chloro -3- methyl Pyridine-2- Monoamino ) -Pyrimidine-4- Jade Ci] -piperidine-1-carboxylic acid tert -Butyl ester (compound B30).

Compound B30 was obtained as an off-white powder (9 mg, 10%). Exact mass calcd. For C ₂₀ H ₂₆ ClN ₅ O ₃ 419.2. Found LCMS (ESI) m / z 420.6 (M + H ⁺ , 80%).

Example  10.10: 4- [6- (6- Acetylamino -4- methyl -Pyridine-3- Monoamino ) -Pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B31).

Compound B31 was obtained as a brown powder (2.3 mg, 2%). Exact mass calcd. For C ₂₂ H ₃₀ N ₆ O ₄ 442.2, found LCMS (ESI) m / z 443 (M + H ⁺ , 41%).

Example  10.11: 4- [6- (5- Fluoro -4- methyl Pyridine-2- Monoamino ) -Pyrimidine-4- Work Oxy] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B32).

Compound B32 was obtained as a peach powder (15.4 mg, 20%). Exact mass calcd. For C ₂₀ H ₂₆ FN ₅ O _3. 403.2. Found LCMS (ESI) m / z 404.3 (M + H ⁺ , 99%).

Example  10.12: 4- [6- (6- Methoxy -5- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Jade Ci] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B33).

Compound B33 was obtained as an off-white powder (10.7 mg, 10%). Exact mass calcd. For C ₂₁ H ₂₉ N ₅ O ₄ 415.2. Found LCMS (ESI) m / z 416.3 (M + H ⁺ , 92%).

Example  10.13: 4- [6- (6- Methoxy -2- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Jade Ci] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B34).

Compound B34 was obtained as an off-white powder (2 mg, 2%). Exact mass calcd. For C ₂₁ H ₂₉ N ₅ O ₄ 415.2, found LCMS (ESI) m / z 416.3 (M + H ⁺ , 94%).

Example  10.14: 4- [6- (6- Fluoro -5- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B35).

Compound B35 was obtained as a tan powder (12.7 mg, 20%). Exact mass calcd. For C ₂₀ H ₂₆ FN ₅ O _3. 403.2. Found LCMS (ESI) m / z 404.3 (M + H ⁺ , 92%).

Example  10.15: 4- [6- (2- Chloro -6- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Jade Ci] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B36).

Compound B36 was obtained as a yellow powder (11.5 mg, 10%). Exact mass calcd. For C ₂₀ H ₂₆ ClN ₅ O ₃ 419.2. Found LCMS (ESI) m / z 420.5 (M + H ⁺ , 99%).

Example  10.16: 4- [6- (4- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B37).

Compound B37 was obtained as an off-white powder (8.2 mg, 10%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₃ 385.2. Found LCMS (ESI) m / z 386.2 (M + H ⁺ , 97%).

Example  10.17: 4- [6- (2- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B38).

Compound B38 was obtained as an off-white powder (7 mg, 10%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₃ 385.2. Found LCMS (ESI) m / z 386.2 (M + H ⁺ , 99%).

Example  10.18: 4- [6- (6- Chloro -2- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Jade Ci] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B39).

Compound B39 was obtained as a yellow powder (3.7 mg, 4%). Exact mass calculation for C ₂₀ H ₂₆ ClN ₅ O ₃ 419.2. Found LCMS (ESI) m / z 420.5 (M + H ⁺ , 95%).

Example  10.19: 4- [6- (6- Fluoro -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B40).

Compound B40 was obtained as a tan powder (13.8 mg, 20%). Exact mass calcd. For C ₁₉ H ₂₄ FN ₅ O ₃ 389.2. Found LCMS (ESI) m / z 390.2 (M + H ⁺ , 91%).

Example  10.20: 4- [6- (2- Chloro -4- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Jade Ci] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B41).

Compound B41 was obtained as an off-white powder (7.8 mg, 10%). Exact mass calcd. For C ₂₀ H ₂₆ ClN ₅ O ₃ 419.2. Found LCMS (ESI) m / z 420.5 (M + H ⁺ , 99%).

Example  10.21: 4- [6- (6- Methoxy -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B42).

Compound B42 was obtained as a gold powder (17.4 mg, 20%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₄ 401.2. Found LCMS (ESI) m / z 402.2 (M + H ⁺ , 99%).

Example  10.22: 4- [6- (5- Fluoro Pyridine-2- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B43).

Compound B43 was obtained as a peach powder (16.2 mg, 20%). Exact mass calcd. For C ₁₉ H ₂₄ FN ₅ O ₃ 389.2. Found LCMS (ESI) m / z 390.4 (M + H ⁺ , 96%).

Example  10.23: 4- [6- (2- Fluoro -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B44).

Compound B44 was obtained as a brown powder (9.6 mg, 10%). Exact mass calcd. For C ₁₉ H ₂₄ FN ₅ O ₃ 389.2. Found LCMS (ESI) m / z 390.1 (M + H ⁺ , 99%).

Example  10.24: 4- [6- (6- Chloro -5- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Jade Ci] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B45).

Compound B45 was obtained as a gold powder (13.3 mg, 20%). Exact mass calculation for C _{2 O} H ₂₆ ClN ₅ O ₃ 419.2. Found LCMS (ESI) m / z 420.6 (M + H ⁺ , 100%).

Example  10.25: 4- [6- (2- methyl -Pyridine-4- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B46).

Compound B46 was obtained as an off-white powder (13.1 mg, 20%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₃ 385.2. Found LCMS (ESI) m / z 386.1 (M + H ⁺ , 88%).

Example  10.26: 4- [6- (2- Methoxy -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B47).

Compound B47 was obtained as a beige powder (14.1 mg, 20%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₄ 401.2. Found LCMS (ESI) m / z 402.1 (M + H ⁺ , 99%).

Example  10.27: 4- [6- (2,5- Difluoro - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B48).

Compound B48 was obtained as a light brown powder (16 mg, 20%). Exact mass calcd. For C ₂₀ H ₂₄ F ₂ N ₄ O ₃ , 406.2. Found LCMS (ESI) m / z 407.3 (M + H ⁺ , 99%).

Example  10.28: 4- [6- (4- Chloro -2- Fluoro - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (Compound B49).

Compound B49 was obtained as an ivory powder (18.3 mg, 20%). Exact mass calculation for C ₂₀ H ₂₄ ClFN ₄ O ₃ 422.2, found LCMS (ESI) m / z 423.1 (M + H ⁺ , 99%).

Example  10.29: 4- [6- (2,5- Difluoro - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B50).

Compound B50 was obtained as a yellow powder (282.4 mg, 18%). Exact mass calcd. For C ₁₉ H ₂₂ F ₂ N ₄ O ₃ 392.2. Found LCMS (ESI) m / z 393.5 (M + H ⁺ , 98%).

Example  10.30: 4- [6- (6- Methoxy -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B51).

Compound B51 was obtained as a yellow powder (7.1 mg, 10%). Exact mass calcd. For C ₁₉ H ₂₅ N ₅ O ₄ 387.2. Found LCMS (ESI) m / z 388.2 (M + H ⁺ , 93%).

Example  10.31: 4- [6- (4- Cyano -3- Methoxy - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B52).

Compound B52 was obtained as a yellow powder (6.3 mg, 7%). Exact mass calculation 411.2 for C ₂₁ H ₂₅ N ₅ O ₄ , found LCMS (ESI) m / z 412.1 (M + H ⁺ , 80%).

Example  10.32: 4- [6- (3- Fluoro -4-hydroxy- Phenylamino ) -Pyrimidine-4- Jade C] -piperidine-1-carboxylic acid isopropyl ester (Compound B53).

Compound B53 was obtained as an off-white powder (1.5 mg, 2%). Exact mass calcd. For C ₁₉ H ₂₃ FN ₄ O ₄ 390.2. Found LCMS (ESI) m / z 391.2 (M + H ⁺ , 98%).

Example  10.33: 4- [6- (6- Ethoxy -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B54).

Compound B54 was obtained as an off-white powder (3.1 mg, 4%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₄ 401.2. Found LCMS (ESI) m / z 402.3 (M + H ⁺ , 96%).

Example  10.34: 4- [6- (2,5- Difluoro -4- Isopropoxy - Phenylamino ) -Pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B55).

Compound B54 was obtained as a brown powder (18.9 mg, 20%). Exact mass calcd. For C ₂₂ H ₂₈ F ₂ N ₄ O ₄ 450.2. Found LCMS (ESI) m / z 451.3 (M + H ⁺ , 87%).

Example  10.35: (2- Fluoro -4- Methanesulfonyl - Phenyl )-[6- (5'- Isopropoxy -3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yloxy) -pyrimidin-4-yl] -amine (Compound B56).

Compound B56 was obtained as a solid (18 mg, 25%). Exact mass calcd. For C ₂₄ H ₂₈ FN ₅ O ₄ S 501.2, found 502.3 (M + H ⁺ ).

Example  10.36: 4- [6- (2,5- Difluoro -4- Propoxy - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B61).

Step 1: (2,5- Difluoro -4-hydroxy- Phenyl )- Carbamic acid  Preparation of Benzyl Ester.

A mixture of 4-amino-2,5-difluorophenol (2.1 g, 14.5 mmol) and sodium bicarbonate (1.33 g, 15.9 mmol) in 20 mL acetonitrile was cooled in an ice bath. Benzylcarbonate (2.3 ml, 15.9 mmol) was added and the mixture was allowed to warm to room temperature. After 3 hours, the mixture was concentrated and the residue was extracted with CH ₂ Cl ₂ and 1 M HCl solution. The resulting organic phase was extracted with 2 M NaOH. The H ₂ O layer was acidified with concentrated HCl and extracted with CH ₂ Cl ₂ . The organic phase was dried over MgSO ₄ , filtered and concentrated to give (2,5-difluoro-4-hydroxy-phenyl) -carbamic acid benzyl ester as a red solid (3.84 g, 95%).

Step 2: (2,5- Difluoro -4- Propoxy - Phenyl )- Carbamic acid  Preparation of Benzyl Ester.

(2,5-difluoro-4-hydroxy-phenyl) -carbamic acid benzyl ester (743 mg, 2.66 mmol), potassium carbonate (703 mg, 5.72 mmol) and 1-iodine propane (556 μl, 5.72 mmol) The mixture was stirred at 60 ° C for 16 h. The mixture was concentrated and the residue was extracted with CH ₂ Cl ₂ and 1 M NaOH solution. The organic phase was dried over MgSO ₄ , filtered and concentrated to give (2,5-difluoro-4-propoxy-phenyl) -carbamic acid benzyl ester as a reddish compound (846 mg, 99%).

Step 3: 2,5- Difluoro -4- Propoxy - Phenylamine  Produce.

To a solution of (2,5-difluoro-4-propoxy-phenyl) -carbamic acid benzyl ester (2.50 g, 7.81 mmol) in 100 mL of methanol is added 10% palladium on carbon (50% water) and hydrogen Was bubbled through the mixture for 1 minute. The mixture was stirred at room temperature under a hydrogen atmosphere (balloon). After 4 hours, Pd / C was filtered off and washed with MeOH. 5 mL of 4 M HCl in dioxane was added to the filtrate and concentrated to give 2,5-difluoro-4-propoxy-phenylamine as a red solid (1.65 g, 94%). Exact mass calcd. For C ₉ H ₁₁ F ₂ NO. 187.08. Found 188.2 (MH ⁺ ).

Step 4: 4- [6- (2,5- Difluoro -4- Propoxy - Phenylamino ) -Pyrimidine-4- Iloxy ]-Preparation of piperidine-1-carboxylic acid isopropyl ester (Compound B61).

4- (6-Chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester and 2,5-difluoro-4-propoxyphenyl in a similar manner as described herein Amine was used to prepare compound B61 as a brown solid (TFA salt, 280 mg, 30%).

Example  10.37: 4- [6- (2- methyl -6- Propylamino -Pyridine-3- Monoamino ) -Pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B66).

Compound B66 was obtained as a solid (15 mg, 16%). Exact mass calcd. For C ₂₂ H ₃₂ N ₆ O _3. 428.2. Found 429.3 (M + H ⁺ ).

Example  10.38: 4- [6- (2- methyl -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B67).

Compound B67 was obtained as a solid. Exact mass calcd. For C ₁₉ H ₂₅ N ₅ O ₃ 371.2. Found 372.2 (M + H ⁺ ).

Example  10.39: 4- [6- (6-Isopropylamino-2-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B68 ).

Compound B68 was obtained as a solid (7 mg, 10%). Exact mass calcd. For C ₂₂ H ₃₂ N ₆ O _3. 428.2. Found 429.3 (M + H ⁺ ).

Example  10.40: 4- [6- (2- methyl -6- Propoxy -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B69).

Compound B69 was obtained as a solid (40 mg, 55%). Exact mass calcd. For C ₂₁ H ₃₁ N ₅ O ₄ 429.2. Found 430.2 (M + H ⁺ ).

Example  10.41: 4- [6- (2- Fluoro -4- Iodo - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B71).

Compound B71 was obtained as a brown powder (216.2 mg, 43%). Exact mass calcd. For C ₁₉ H ₂₂ FIN ₄ O ₃ , 500.1. Found LCMS (ESI) m / z 501.1 (M + H ⁺ , 90%).

Example  10.42: 4- {6- [ methyl -(2- methyl -4,5,6,7- Tetrahydro -2H- Indazole -3-yl) -amino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester (Compound B72).

Compound B72 was obtained as a white powder (0.5 mg, 1%). Exact mass calcd. For C ₂₂ H ₃₂ N ₆ O ₃ 428.3. Found LCMS (ESI) m / z 429.3 (M + H ⁺ , 58%).

Example  10.43: 4- [6- (2- methyl -2H- Pyrazole -3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B73).

Compound B73 was obtained as an off-white powder (0.4 mg, 1%). Exact mass calcd. For C ₁₇ H ₂₄ N ₆ O ₃ 360.2, found LCMS (ESI) m / z 360.9 (M + H ⁺ , 100%).

Example  10.44: 4- [6- (2-phenyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B74).

Compound B74 was obtained as an off-white powder (6.5 mg, 20%). Exact mass calcd. For C ₂₂ H ₂₆ N ₆ O ₃ 422.2. Found LCMS (ESI) m / z 423.1 (M + H ⁺ , 100%).

Example  10.45: 4- [6- (5- tert -Butyl-1H- Pyrazole -3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B75).

Compound B75 was obtained as a yellow powder (1.9 mg, 5%). Exact mass calcd. For C ₂₀ H ₃₀ N ₆ O ₃ 402.2. Found LCMS (ESI) m / z 403.1 (M + H ⁺ , 92%).

Example  10.46: 4- [6- (5-p-tolyl-1H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B76) .

Compound B76 was obtained as an off-white powder (2.8 mg, 6%). Exact mass calcd. For C ₂₃ H ₂₈ N ₆ O ₃ 436.2. Found LCMS (ESI) m / z 437.3 (M + H ⁺ , 97%).

Example  10.47: 4- [6- (6-methoxy-5-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B77) .

Compound B77 was obtained as a white powder (4 mg, 10%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₄ 401.2. Found LCMS (ESI) m / z 402.1 (M + H ⁺ , 100%).

Example  10.48: 4- [6- (4-Methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B78).

Compound B78 was obtained as an off-white powder (1.2 mg, 3%). Exact mass calcd. For C ₁₉ H ₂₅ N ₅ O ₃ 371.2. Found LCMS (ESI) m / z 372.3 (M + H ⁺ , 79%).

Example  10.49: 4- [6- (4-acetylamino-3-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B79).

Compound B79 was obtained as an off-white powder (1.2 mg, 3%). Exact mass calcd. For C ₂₂ H ₂₉ N ₅ O ₄ 427.2. Found LCMS (ESI) m / z 428.1 (M + H ⁺ , 98%).

Example  10.50: 4- [6- (3- Chloro -4- Fluoro - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B80).

Compound B80 was obtained as an off-white powder (7.2 mg, 20%). Exact mass calculation for C ₁₉ H ₂₂ ClFN ₄ O ₃ 408.1, found LCMS (ESI) m / z 409.3 (M + H ⁺ , 96%).

Example  10.51: 4- [6- (3,5-Dimethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B81).

Compound B81 was obtained as a white powder (1.5 mg, 4%). Exact mass calcd. 416.2 for C ₂₁ H ₂₈ N ₄ O ₅ , found LCMS (ESI) m / z 417.4 (M + H ⁺ , 100%).

Example  10.52: 4- [6- (6-Ethyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B82).

Compound B82 was obtained as an off-white powder (3.7 mg, 10%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₃ 385.2. Found LCMS (ESI) m / z 386.1 (M + H ⁺ , 78%).

Example  10.53: 4- [6- (5-Methyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B83).

Compound B83 was obtained as an off-white powder (4.9 mg, 10%). Exact mass calcd. For C ₁₉ H ₂₅ N ₅ O ₃ 371.2. Found LCMS (ESI) m / z 372.3 (M + H ⁺ , 88%).

Example  10.54: 4- [6- (2- methyl -Quinoline-6- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B84).

Compound B84 was obtained as a yellow powder (2.6 mg, 10%). Exact mass calcd. For C ₂₃ H ₂₇ N ₅ O ₃ 421.2. Found LCMS-(ESI) m / z 422.1 (M + H ⁺ , 100%).

Example  10.55: 4- [6- (2- Methylsulfanyl - Benzothiazole -6- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B85).

Compound B85 was obtained as a white powder (0.4 mg, 1%). Exact mass calcd. For C ₂₁ H ₂₅ N ₅ O ₃ S ₂ 459.1, found LCMS (ESI) m / z 460.3 (M + H ⁺ , 85%).

Example  10.56: 4- [6- (6-Morpholin-4-yl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B86) .

Compound B86 was obtained as a purple powder (3 mg, 7%). Exact mass calcd. For C ₂₂ H ₃₀ N ₆ O ₄ 442.2, found LCMS (ESI) m / z 443.4 (M + H ⁺ , 99%).

Example  10.57: 4- [6- (4-Benzenesulfonyl-thiophen-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B87).

Compound B87 was obtained as an off-white powder (3.9 mg, 8%). Exact mass calcd. For C ₂₃ H ₂₆ N ₄ O ₅ S ₂ , 502.1, found LCMS (ESI) m / z 503.3 (M + H ⁺ , 98%).

Example  10.58: 4- [6- (4-Piperidin-1-yl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B88).

Compound B88 was obtained as a purple powder (1 mg, 2%). Exact mass calcd. For C ₂₄ H ₃₃ N ₅ O ₃ 439.3. Found LCMS (ESI) m / z 440.4 (M + H ⁺ , 100%).

Example  10.59: 4- [6- (3-Trifluoromethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B89).

Compound B89 was obtained as a beige powder (6.3 mg, 10%). Exact mass calcd. For C ₂₀ H ₂₃ F ₃ N ₄ O ₄ 440.2, found LCMS (ESI) m / z 441.2 (M + H ⁺ , 80%).

Example  10.60: 4- [6- (5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid iso Propyl ester (compound B90).

Compound B90 was obtained as a yellow powder (0.5 mg, 1%). Exact mass calcd. For C ₂₃ H ₂₈ N ₄ O ₄ 424.2. Found LCMS (ESI) m / z 425.1 (M + H ⁺ , 89%).

Example  10.61: 4- [6- (6-Methyl-1H-pyrazole [3,4-b] pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid iso Propyl ester (compound B91).

Compound B91 was obtained as a yellow powder (0.5 mg, 1%). Exact mass calculated 411.2 for C ₂₀ H ₂₅ N ₇ O ₃ , found LCMS (ESI) m / z 412.3 (M + H ⁺ , 78%).

Example  10.62: 4- [6- (5-Cyano-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B92).

Compound B92 was obtained as a white powder (1.3 mg, 3%). Exact mass calcd. For C ₁₉ H ₂₂ N ₆ O ₃ 382.2, found LCMS (ESI) m / z 383.3 (M + H ⁺ , 88%).

Example  10.63: 4- [6- (4-Bromo-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B93) .

Compound B93 was obtained as a tan solid (TFA salt, 286.5 mg, 29%).

Example  10.64: 4- [6- (4-Trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl Oxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B94).

Compound B94 was obtained as a white powder (2.3 mg, 5%). Exact mass calcd. For C ₁₉ H ₂₂ F ₃ N ₅ O ₃ 425.2, found LCMS (ESI) m / z 426 (M + H ⁺ , 75%).

Example  10.65: 4- [6- (5-Methyl-1H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B95).

Compound B95 was obtained as a white powder (0.4 mg, 1%). Exact mass calcd. For C ₁₇ H ₂₄ N ₆ O ₃ 360.2, found LCMS (ESI) m / z 360.9 (M + H ⁺ , 84%).

Example  10.66: 4- [6- (5- Cyclopropyl -1H- Pyrazole -3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B96).

Compound B96 was obtained as a brown powder (1.7 mg, 4%). Exact mass calcd. For C ₁₉ H ₂₆ N ₆ O ₃ 386.2. Found LCMS (ESI) m / z 387.3 (M + H ⁺ , 66%).

Example  10.67: 4- [6- (2,6-Dimethyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B97).

Compound B97 was obtained as a solid (28 mg, 36%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₃ 385.2. Found 386.3 (M + H ⁺ ).

Example  10.68: 4- [6- (4-Cyano-2-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B98).

Compound B98 was obtained as a solid (20 mg, 25%). Exact mass calcd. For C ₂₁ H ₂₅ N ₅ O ₃ 395.2. Found 396.1 (M + H ⁺ ).

Example  10.69: 4- [6- (4-methoxy-2-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B99).

Compound B99 was obtained as a solid (24 mg, 30%). Exact mass calcd. For C ₂₁ H ₂₈ N ₄ O ₄ 400.2. Found 401.4 (M + H ⁺ ).

Example  10.70: 4- [6- (2,4-Dimethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B100).

Compound B100 was obtained as a solid (20 mg, 24%). Exact mass calculation 416.2 for C ₂₁ H ₂₈ N ₄ O ₅ , found 417.3 (M + H ⁺ ).

Example  10.71: 4- [6- (5-Carbamoyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B102).

Compound B102 was obtained as an off-white powder (2.9 mg, 5%). Exact mass calcd. For C ₁₉ H ₂₄ N ₆ O ₄ 400.2, found LCMS (ESI) m / z 401.3 (M + H ⁺ , 68%).

Example  10.72: 4- {6- [4- (3,4-Difluoro-phenyl) -thiazol-2-ylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid iso Propyl ester (compound B103).

Compound B103 was obtained as a pale yellow powder (4.9 mg, 7%). Exact mass calcd. For C ₂₂ H ₂₃ F ₂ N ₅ O ₃ S 475.2. Found LCMS (ESI) m / z 476.2 (M + H ⁺ , 66%).

Example  10.73: 4- [6- (5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-car Acid isopropyl ester (compound B104).

Compound B104 was obtained as a pale yellow powder (0.5 mg, 0.8%). Exact mass calcd. For C ₂₂ H ₂₆ N ₆ O ₄ 438.2. Found LCMS (ESI) m / z 439.4 (M + H ⁺ , 98%).

Example  10.74: 4- [6- (3-Oxazol-5-yl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B105).

Compound B105 was obtained as a pale yellow powder (5.4 mg, 9%). Exact mass calcd. For C ₂₂ H ₂₅ N ₅ O ₄ 423.2. Found LCMS (ESI) m / z 424.3 (M + H ⁺ , 100%).

Example  10.75: 4- [6- (5-Trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl Oxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B106).

Compound B106 was obtained as an off-white powder (4.8 mg, 7%). Exact mass calcd. For C ₁₉ H ₂₂ F ₃ N ₅ O ₃ 425.2, found LCMS (ESI) m / z 426.4 (M + H ⁺ , 44%).

Example  10.76: 4- [6- (4-Chloro-2-trifluoromethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B107).

Compound B107 was obtained as a brown powder (32.6 mg, 46%). Exact mass calcd. For C ₂₀ H ₂₂ ClF ₃ N ₄ O ₄ 474.1, found LCMS (ESI) m / z 475.3 (M + H ⁺ , 93%).

Example  10.77: 4- {6-[(5-Pyridin-2-yl-thiophen-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester (Compound B108).

Compound B108 was obtained as an off-white powder (1.6 mg, 2%). Exact mass calcd. For C ₂₃ H ₂₇ N ₅ O ₃ S. 453.2. Found LCMS (ESI) m / z 451.4 (M + H ⁺ , 71%).

Example  10.78: 4- {6- [5- (4-Chloro-phenyl) -2H-pyrazol-3-ylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester (Compound B109).

Compound B109 was obtained as a brown powder (1.1 mg, 2%). Exact mass calcd. For C ₂₂ H ₂₅ ClN ₆ O ₃ 456.2. Found LCMS (ESI) m / z 457.1 (M + H ⁺ , 77%).

Example  10.79: 4- [6- (1-Oxo-Indan-5-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B110).

Compound B110 was obtained as a brown powder (3.6 mg, 6%). Exact mass calculation 410.2 for C ₂₂ H ₂₆ N ₄ O ₄ , found LCMS (ESI) m / z 411.0 (M + H ⁺ , 42%).

Example  10.80: 4- {6- [5- (1-Methyl-pyrrolidin-2-yl) -pyridin-2-ylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid Isopropyl ester (Compound B111).

Compound B111 was obtained as an off-white powder (0.6 mg, 0.9%). Exact mass calcd. For C ₂₃ H ₃₂ N ₆ O ₃ 440.3. Found LCMS (ESI) m / z 440.4 (M + H ⁺ , 100%).

Example  10.81: 4- [6- (6-methoxy-2-methyl-pyridin-3-ylamino) -pyrimidin-4-yljade city ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B112).

Compound B112 was obtained as a yellow powder (3.4 mg, 6%). Exact mass calcd. For C ₂₀ H ₂₇ N ₅ O ₄ 401.2. Found LCMS (ESI) m / z 402.1 (M + H ⁺ , 99%).

Example  10.82: 4- [6- (5-Bromo-3-methyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B113) .

Compound B113 was obtained as a white powder (6.6 mg, 10%). Exact mass calcd. For C ₁₉ H ₂₄ BrN ₅ O ₃ 449.1. Found LCMS (ESI) m / z 452.2 (M + H ⁺ , 94%).

Example  10.83: 4- [6- (2-Chloro-6-methyl-pyridin-3-ylamino) -pyrimidin-4-yljade city ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B114).

Compound B114 was obtained as a beige powder (7.9 mg, 13%). Exact mass calculated for C ₁₉ H ₂₄ ClN ₅ O ₃ 405.2. Found LCMS (ESI) m / z 406.2 (M + H ⁺ , 98%).

Example  10.84: 4- [6- (2-Ethynyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B115).

Compound B115 was obtained as a brown powder (2.3 mg, 4%). Exact mass calcd. For C ₂₁ H ₂₄ N ₄ O ₃ 380.2, found LCMS (ESI) m / z 381.2 (M + H ⁺ , 56%).

Example  10.85: 4- [6- (4-Bromo-2-trifluoromethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B116).

Compound B116 was obtained as a beige powder (16.6 mg, 21%). Exact mass calcd. For C ₂₀ H ₂₂ BrF ₃ N ₄ O ₄ 518.1, found LCMS (ESI) m / z 519.2 (M + H ⁺ , 91%).

Example  10.86: 4- [6- (3- Iodo -4- methyl - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B117).

Compound B117 was obtained as an off-white powder (0.7 mg, 0.8%). Exact mass calcd. For C ₂₀ H ₂₅ IN ₄ O ₃ 496.1. Found LCMS (ESI) m / z 497.3 (M + H ⁺ , 98%).

Example  10.87: 4- [6- (2-Fluoro-5-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B118).

Compound B118 was obtained as an off-white powder (10.6 mg, 18%). Exact mass calcd. For C ₂₀ H ₂₅ FN ₄ O ₃ 388.2. Found LCMS (ESI) m / z 389.4 (M + H ⁺ , 95%).

Example  10.88: 4- {6- [5- (4-methoxy-phenyl)-[1,3,4] thiadiazol-2-ylamino] -pyrimidin-4-yloxy} -piperidine-1 -Carboxylic acid isopropyl ester (compound B119).

Compound B119 was obtained as an off-white powder (2.5 mg, 4%). Exact mass calcd. For C ₂₂ H ₂₆ N ₆ O ₄ S 470.2. Found LCMS (ESI) m / z 473.3 (M + H ⁺ , 52%).

Example  10.89: 4- [6- (3,5-Dimethyl-isoxazol-4-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B120).

Compound B120 was obtained as a white powder (3.1 mg, 6%). Exact mass calcd. For C ₁₈ H ₂₅ N ₅ O ₄ 375.2. Found LCMS (ESI) m / z 376.1 (M + H ⁺ , 100%).

Example  10.90: 4- [2- (2,5-Difluoro-4-propoxy-phenylamino) -pyridin-4-yljade city ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B121).

Compound B121 was obtained as a solid.

Example  10.91: (2,5-Difluoro-4-propoxy-phenyl)-{6- [1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperidine -4-yloxy] -pyrimidin-4-yl} -amine (Compound B133).

Compound B133 was obtained as a tan solid (HCl salt, 65.9 mg, 18%).

Example  10.92: 4- [6- (2,5-Difluoro-4-propylamino-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B122) .

4- [6- (4-Bromo-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (TFA in 1.5 mL of DMSO Salt, 51.2 mg, 0.087 mmol), copper iodide (17.6 mg, 0.092 mmol), potassium carbonate (37.3 mg, 0.269 mmol), propyl amine (57.4 μL, 0.698 mmol) and L-proline (21.2 mg, 0.184 mmol) The mixture was heated at 80 ° C. for 9 hours in a microwave oven. The mixture was purified by HPLC to give compound B122 as a tan solid (TFA salt, 13 mg, 26%).

Example  10.93: 4- [6- (2,5-Difluoro-4-morpholin-4-yl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B123).

Compound B123 was obtained as a tan solid (TFA salt, 9.8 mg, 12%).

Example  10.94: 4- (6- {2,5-Difluoro-4-[(tetrahydro-furan-2-ylmethyl) -amino] -phenylamino} -pyrimidin-4-yloxy) -piperidine -1-carboxylic acid isopropyl ester (compound B136).

Compound B136 was obtained as a white solid (HCl salt, 48.8 mg, 22%).

Example  10.95: 4- {6- [2,5-Difluoro-4- (2-methoxy-ethylamino) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid Isopropyl ester (Compound B135).

Compound B135 was obtained as a white solid (HCl salt, 44.5 mg, 21%).

Example  10.96: 4- [6- (4-Butylamino-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B137) .

Compound B137 was obtained as a white solid (HCl salt, 70.1 mg, 33%).

Example  10.97: 4- {6- [2,5- Difluoro -4- (3- methyl - Butylamino )- Phenylamino ] -Pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester (Compound B138).

Compound B138 was obtained as a white solid (HCl salt, 100 mg, 45%).

Example  10.98: 4- {6- [2,5-difluoro-4- (tetrahydro-furan-2-ylmethoxy) -phen Nylamino ] -Pyrimidin-4-yloxy} -piperidine-l-carboxylic acid isopropyl ester (Compound B145).

Compound B145 was obtained as a solid (4 mg, 4%). Exact mass calculated for C ₂₄ H ₃₀ F ₂ N ₄ O ₅ 492.2, found 493.6 (MH ⁺ ).

The following compound Example  Prepared using the general method described in 10.1.

Example  10.99: 4- [6- (3-Fluoro-4-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert -Butyl ester (compound B16).

Compound B16 was obtained as a yellow solid (16 mg, 27%). Exact mass calcd. For C ₂₁ H ₂₇ FN ₄ O ₃ 402.2, found LCMS (ESI) m / z 403.2 (M + H ⁺ , 100%).

Example  10.100: 4- [6- (3-hydroxy-4-methoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert -Butyl ester (compound B17).

Compound B17 was obtained as a yellow solid (11 mg, 18%). Exact mass calcd. For C ₂₁ H ₂₈ N ₄ O ₅ 416.2. Found LCMS (ESI) m / z 417.1 (M + H ⁺ , 100%)

Example  10.101: 4- [6- (6- Cyano -Pyridine-3- Monoamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (compound B18).

Compound B18 was obtained as a yellow solid (7 mg, 12%). Exact mass calcd. For C ₂₀ H ₂₄ N ₆ O ₃ 396.2. Found LCMS (ESI) m / z 397.1 (M + H ⁺ , 100%).

Example  10.102: 4- [6- (3-Chloro-4-cyano-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B19).

Compound B19 was obtained as a yellow solid (19 mg, 30%). Accurate mass calcd. For C ₂₁ H ₂₄ ClN ₅ O ₃ 429.2. Found LCMS (ESI) m / z 430.2 (M + H ⁺ , 100%).

Example  10.103: 4- [6- (3- Fluoro -4- Methoxy - Phenylamino ) -Pyrimidine-4- Iloxy ] -Piperidine-1-carboxylic acid tert -Butyl ester (compound B21).

Compound B21 was obtained as a brown solid (12 mg, 19%). Exact mass calcd. For C ₂₁ H ₂₇ FN ₄ O ₄ 418.2. Found LCMS (ESI) m / z 419.4 (M + H ⁺ , 100%).

Example  10.104: 4- [6- (3,4-Dimethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert -Butyl ester (compound B22).

Compound B22 was obtained as a brown solid (9 mg, 14%). Exact mass calcd. For C ₂₂ H ₃₀ N ₄ O ₅ 430.2. Found LCMS (ESI) m / z 431.3 (M + H ⁺ , 100%).

Example  10.105: 4- [6- (2,3-Dihydro-benzo [1,4] dioxin-6-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert -Butyl ester (Compound B23).

Compound B23 was obtained as a brown solid (7 mg, 11%). Exact mass calcd. For C ₂₂ H ₂₈ N ₄ O _5. 428.2. Found LCMS (ESI) m / z 429.3 (M + H ⁺ , 100%).

Example  10.106: 4- [6- (4-cyano-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B24) .

2,5-difluoro-4- [6- (piperidin-4-yloxy) -pyrimidin-4-ylamino] -benzonitrile (1.793 g, 4.6 mmol) and TEA (18.4 mmol, 4 equivalents) ) Was dissolved in THF (10 mL), then isopropyl chloroformate (5.98 mmol, 1.3 equiv) was added to the solution. The reaction mixture was stirred at rt for 2 h. The crude was purified via flash column (hexanes: ethyl acetate = 1: 1) to afford compound B24 as a white solid (400 mg, 21%).

Example  10.107: 4- [6- (4-ethoxy-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-car Acid  Isopropyl ester (compound B26).

Compound B26 was obtained as a tan solid (17 mg, 20%). Exact mass calcd. For C ₂₁ H ₂₆ F ₂ N ₄ O ₄ 436.2. Found LCMS (ESI) m / z 437.3 (M + H ⁺ , 100%).

Example  10.108: (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidine-4 -Yloxy] -pyrimidin-4-yl} -amine (Compound B57).

Step 1: Isopropyl Army  Produce.

A solution of isobutylonitrile (276 g, 4.0 mol) in EtOH (2.0 L) was combined with hydroxylamine (50% aqueous solution, 1.1 L, 16 mol) and refluxed for 5 hours. The solvent was then removed in vacuo and the remaining water was removed by azeotropic distillation with toluene. The residue was then dissolved in CH ₂ Cl ₂ , dried over MgSO ₄ and the solvent removed to give a white solid (402 g, 98% yield).

Step 2: 1- Cyano -4- Of hydroxypiperidine  Produce.

The 5-liter 3-neck flask was equipped with a mechanical stirrer, reflux concentrator and powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via a powder funnel with stirring, followed by the gradual addition of water (about 300-400 mL) with vigorous stirring to form a high viscosity, uniform slurry. The flask was then placed in an ice bath and a solution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH ₂ Cl ₂ (1.0 L) was added and the contents were mixed vigorously while cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH ₂ Cl ₂ (600 mL) was added dropwise over 2 hours and stirring continued for an additional 30 minutes. The ice bath was removed, the mechanical stirrer was replaced with a magnetic stirrer and the reaction mixture was stirred for 16 hours. The flask was once again under mechanical stirring and sodium carbonate (100 g) was added to ensure neutralization completion. MgSO ₄ (500 g) was added and stirring continued vigorously for 15 minutes. The resulting suspension was filtered and washed with CH ₂ Cl ₂ (2.0 L). The solvent was removed to give a light yellow viscous oil (574 g, 91% yield).

Step 3: 4-hydroxy-1- (3-isopropyl-1,2,4- Oxadiazole -5-day) piperidine

Yarovenko et al., Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1924, ZnCl in a magnetically stirred solution of compound of step 1 (12.2 g, 120 mmol) and compound of step 2 (12.6 g, 100 mmol) in ethyl acetate (500 mL) ₂ (IN in ether, 120 mL, 120 mmol) was added in dropwise form over 15 minutes. A precipitate formed immediately upon addition, at which point the stir bar was fixed to the matrix and manually shaken while adding the rest of the reaction. After standing for 15 minutes, the supernatant was decanted, filtered and the residue washed twice with ether, and the resulting white precipitate was collected by filtration. LC / MS confirmed the precipitate was an intermediate O-amidinoamidoxime (m / z 229). This material was dissolved in concentrated HCl (50 mL), diluted to 4 N with EtOH (100 mL) and refluxed for 1 h. After cooling off the white precipitate by filtration, the filtrate was reduced to 50 mL and diluted with 100 mL of water. Solid Na ₂ CO ₃ was added until the mixture became basic, CH ₂ Cl ₂ was added, and the resulting mixture was filtered and washed with CH ₂ Cl ₂ . The organic extract was separated, dried over MgSO ₄ , and the solvent removed to give a viscous yellow oil (15.0 g, 71% yield).

Step 4: (2- Fluoro -4- Methanesulfonyl - Phenyl )-{6- [1- (3-isopropyl- [1,2,4] Oksa Preparation of Diazol-5-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -amine (Compound B57).

Compound B57 was prepared as a brown oil in a similar manner as described above (230 mg, 20%).

Example  10.109: 4- [6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B58).

Compound B58 was obtained as a yellow solid (34 mg, 57%).

Example  10.110: 4- [6- (Pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B59).

Compound B59 was obtained as a yellow solid (34 mg, 46%).

Example  10.111: 4- [6- (Pyridin-4-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B60).

Compound B60 was obtained as a yellow solid (21 mg, 30%).

Example  10.112: 4- [6- (2,5-Difluoro-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B142).

Compound B142 was obtained as a solid.

Example  10.113: 4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-2-yloxy] -piperidine-1-carboxylic acid tert Preparation of Butyl Ester (Compound B146).

4- (6-Bromo-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (2.93 g, 8.23 mmol) and 2-fluoro-4 in anhydrous toluene (82 mL) A suspension of methanesulfonyl-phenylamine (1.87 g, 9.87 mmol) was degassed by bubbling with nitrogen gas through the suspension for 15 minutes. Tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ dba ₃ ) (754 mg, 0.82 mmol), 1,3-bis (diphenylphosphino) propane (dppp) (678 mg, 1.65 mmol) and NaOtBu (1.11 g, 11.5 mmol) was added, the reaction vessel was purged with nitrogen gas and the reaction mixture was heated at 70 ° C. under a nitrogen atmosphere for 9 hours. The reaction mixture was diluted with ether (83 mL) and washed three times with brine (3 × 83 mL), then the solids of the organic and aqueous layers were filtered off and washed three times with ether. The organic extracts and washes were combined, dried over MgSO ₄ , the solvent was evaporated in vacuo and the solid obtained was purified by flash chromatography using hexane-EtOAc (50:50, v / v) to give 4- [as a pale yellow solid. 6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-2-yloxy] -piperidine-1-carboxylic acid tert-butyl ester (Compound B146) was obtained (3.47 g, 91%).

Example  10.114: Preparation of 4- [2- (2-fluoro-4-methanesulfonyl-phenylamino) -pyridin-4-yloxy] -piperidine-l-carboxylic acid isopropyl ester (Compound B151).

Compound B151 was prepared with 4- (2-chloro-pyridin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester and 2-fluoro using the general method as described in step 3 of Example 10.1. Prepared from ro-4-methanesulfonyl-phenylamine.

Example  10.115: Preparation of 4- [4- (2-fluoro-4-methanesulfonyl-phenylamino) -pyridin-2-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B149).

4- (4-Chloro-pyridin-2-yloxy) -piperidine-1-carboxylic acid isopropyl ester (82 mg, 0.274 mmol), palladium acetate (8.3 mg, 0.037 mmol), 2,8,9 -Triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo [3,3,3] undecane (26.3 μl, 0.077 mmol), 2-fluoro-4-methanesulfonyl A mixture of -phenylamine (77.8 mg, 0.41 mmol), sodium tert-butoxide (53 mg, 0.55 mmol) and 4 ml of dioxane was heated in a microwave oven at 120 ° C. for 2 hours. The mixture was purified by HPLC to give 4- [4- (2-fluoro-4-methanesulfonyl-phenylamino) -pyridin-2-yloxy] -piperidine-1-carboxylic acid isopropyl as a tan solid. Ester was obtained (TFA salt, 88 mg, 57%).

Example  10.116: 4- [5- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-3-yloxy] -piperidine-1-carboxylic acid tert Preparation of Butyl Ester (Compound B147).

Sodium t-butoxide (17 mg, 0.180 mmol), BINAP (96 mg, 0.154 mmol), Pd ₂ (dba) ₃ (75 mg, 0.0824 mmol), 4- (5-bromo-pyridin-3-yloxy ) -Piperidine-1-carboxylic acid tert-butyl ester (46 mg, 0.0129 mmol) and 2-fluoro-4-methanesulfonyl-phenylamine (29 mg, 0.155 mmol) in toluene (5 mL) Suspended and the mixture was heated at 70 ° C. under nitrogen atmosphere for 18 hours. The oil obtained by evaporation of the solvent in vacuo was dissolved in DMSO (1 mL), and this crude material was purified by mass-triggered preparative LCMS (4-MS) as an oil. Rho-4-methanesulfonyl-phenylamino) -pyridin-3-yloxy] -piperidine-1-carboxylic acid tert-butyl ester was obtained (4 mg). Mass calculated for C ₂₂ H ₂₈ FN ₃ O ₅ S: 465.17, found 466.4 (M + H) ⁺ , 410.3 (M-56 + H) ⁺ .

Example  10.117: Preparation of 4- [6- (2-methyl-4-propylamino-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B124).

Step 1: 4- [6- (4- Iodo -2- methyl - Phenylamino ) -Pyrimidine-4- Iloxy ]-Preparation of piperidine-1-carboxylic acid isopropyl ester.

4- (6-Chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester (687 mg, 2.29 mmol), 2-methyl-4-iodineaniline in 20 mL of dioxane ( 533 mg, 2.29 mmol) and sodium tert-butoxide (220 mg, 2.29 mmol) were heated at 80 ° C. for 90 minutes under microwave radiation. The mixture was purified by HPLC to give 4- [6- (4-iodine-2-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester as white solid. Obtained (TFA salt, 188 mg, 13%).

Step 2: Preparation of 4- [6- (2-methyl-4-propylamino-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B124).

Compound B124 was prepared as a white solid using a procedure similar to that described herein (TFA salt, 120 mg, 74%).

Example  10.117: Preparation of 4- [6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester (Compound B3) .

(2-Fluoro-4-methanesulfonyl-phenyl)-[6- (piperidin-4-yloxy) -pyrimidin-4-yl] -amine (697 mg, 1.3 mmol) and TEA (5.2 mmol , 4 equiv) was dissolved in DMF (10 mL), then isopropyl chloroformate (1.69 mmol, 1.3 equiv) was added to the solution. The reaction mixture was stirred at rt for 1 h. The crude was purified via HPLC to give compound B3 as a yellow solid (476 mg, 81%).

Example  10.118: 4- [6- (2-Methyl-pyridin-3-yloxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert Preparation of -butyl ester (Compound B157).

4- (6-Chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester in anhydrous DMF (10 mL) containing K ₂ CO ₃ (1.38 g, 10 mmol) (1.57 g, 5.0 mmol) and a solution of 2-methyl-pyridin-3-ol (654 mg, 6.0 mmol) were heated at 150 ° C. for 1.5 h. The reaction mixture was cooled to ambient temperature, filtered over celite and the solvent was removed from the filtrate under high vacuum. The residue was dissolved in ethyl acetate, washed with water and brine and the organic extracts were dried over MgSO ₄ . The solution was concentrated to dryness, the residue dissolved in diethyl ether, filtered over celite and the filtrate was treated with 1 N HCl / ether (5 mL). The resulting precipitate was collected by filtration to give the title compound as a white solid (1.83 g, 87% yield): MS m / z 387.3, 331.4;

Example  10.119: 4- [6- (6-Bromo-2-methyl-pyridin-3-yloxy) -pyrimidin-4-yljade city ] -Piperidine-1-carboxylic acid isopropyl ester (Compound B156).

4- (6-Chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester in anhydrous DMF (20 mL) containing K ₂ CO ₃ (2.76 g, 20 mmol) ( 3.0 g, 10 mmol) and 6-bromo-2-methyl-pyridin-3-ol (2.25 g, 12 mmol) were heated at 125 ° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was filtered over celite and the solvent was removed from the filtrate under high vacuum. The residue was dissolved in ethyl acetate and the resulting solution was washed twice with 1 N NaOH and subsequently washed with water and brine. The organic extract was dried over MgSO ₄ , the solution was concentrated to dryness and the residue was dissolved in diethyl ether. 1 N HCl / ether (10 mL) was added to form a small dark precipitate which was removed by filtration. The solvent was removed from the filtrate to give a colorless oil (which became a free base due to the loss of HCl with removal of the solvent), which was allowed to settle gradually to form the title compound as a white solid (3.91 g, 87% yield):

Example  10.120: 4- (6- {6-[(2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -amino] -2-methyl-pyridin-3-yloxy} -pyrimidine- Preparation of 4-yloxy) -piperidine-1-carboxylic acid isopropyl ester (Compound B154).

4- [6- (6-Bromo-2-methyl-pyridin-3-yloxy) -pyrimidin-4-yloxy] -piperidine-1- in anhydrous toluene (10 mL) in a sealed vial Carboxylic acid isopropyl ester (1.13 g, 2.5 mmol), 4- (aminomethyl) -2,2-dimethyl-1,3-dioxolane (393 mg, 3.0 mmol), 2- (di-t-butylforce Pino) biphenyl (75 mg, 0.25 mmol), tris (dibenzylideneacetone) dipalladium (115 mg, 0.125 mmol) and sodium t-butoxide (480 mg, 5.0 mmol) at 150 ° C. for 2 hours Heated. After cooling, the reaction mixture was washed twice with water and then the organic extract was filtered over celite while washing with a small amount of ethyl acetate. The filtrate was then subjected to direct flash chromatography (25-30% ethyl acetate / hexanes). Removal of solvent gave the title compound as a yellow gum (505 mg, 40% yield): MS m / z 462.3 (due to loss of protecting group at the same time as ionization);

Example  10.121: 4- {6- [6- (2,3-Dihydroxy-propylamino) -2-methyl-pyridin-3-yloxy] -pyrimidin-4-yloxy} -piperidine-1- Preparation of Carboxylic Acid Isopropyl Esters (Compound B153).

4- (6- {6-[(2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -amino] -2-methyl-pyridin-3-yloxy} -pyrimidine- in THF A solution of 4-yloxy) -piperidine-1-carboxylic acid isopropyl ester (Compound 154, 480 mg, 0.96 mmol) was treated with 6 mL of concentrated HCl and stirred for 2 h. The solvent was removed and the residue was dissolved in CH ₂ Cl _2, to which diethyl ether was added, at which point a precipitate formed. This material was collected by filtration to give a hygroscopic solid, which quickly formed a sticky rubber. The filter cake was then dissolved in CH ₂ Cl ₂ and the resulting solution was washed with 2 M Na ₂ CO ₃ and dried over MgSO ₄ . Removal of solvent gave a yellow rubber (238 mg, 54% yield): MS m / z 462.6;

Example  11: in black parcel RUP3  Protocol for Dose Response

Black vesicles are described in Potenza, M. N. and Lerner, M. R., Pigment Cell Research, Vol. 5, 372-378, 1992 and stored in culture as reported and transfected with RUP3 expression vector (pCMV) using electroporation. After electroporation, the transfected cells were plated in 96 well plates for analysis. The cells were then grown for 48 hours to recover from electroporation and to obtain maximum receptor expression levels.

On the day of analysis, the growth medium on the cells was replaced with serum free buffer containing 10 nM melatonin. Melatonin acts through endogenous Gi-coupled GPCRs in black vesicles to lower intracellular cAMP levels. In response to reduced cAMP levels, mesovesicles localize their pigments in the center of the cell. Its net effect is that it shows a significant decrease when measured at 600-650 nM in absorbance readings of cell monolayers in wells.

After 1 hour incubation in melatonin, the pigment was fully aggregated in the cells. At this point, basal absorbance readings were collected. Dilutions of a series of test compounds are then added to the plate, and compounds that stimulate RUP3 production increase intracellular cAMP levels. In response to this increased cAMP level, the vesicles relocalize the pigment around the cell. After 1 hour, the pigment is fully dispersed in the stimulated cells. The dispersed cell monolayer absorbs more light in the 600-650 nm range. The absorbance increase measured in comparison to the basal reading allows to quantify the extent of receptor stimulation and to show the dose-response curve.

The compound of this example was screened using the black vesicle dispersion assay described above. Representative compounds of the invention and their corresponding EC ₅₀ values are shown in Table 6 below. Certain other compounds shown in the Examples have an EC ₅₀ activity of less than about 10 μΜ in a black vesicle dispersion assay.

compound RUP3 (EC ₅₀ ) (nM) B16 62 B21 128 B143 48

Each embodiment of the present invention may be modified in a limited manner with respect to those compounds that have been demonstrated to bind about 100-fold or better compared to RUP3 as compared to the corticotropin-releasing factor-1 (CRF-1) receptor A recent review of compounds is described in Expert Opin. Ther. Patents 2002, 12 (11), 1619-1630.

Those skilled in the art will recognize that various modifications, additions, substitutions and variations to the exemplary embodiments shown herein may be made without departing from the spirit of the invention and are therefore considered to be within the scope of the invention. All documents referred to above include, but are not limited to, printed publications, and provisional and general patent applications, which are hereby incorporated by reference in their entirety.

                         SEQUENCE LISTING <110> Arena Pharmaceuticals, Inc.        Jones, Robert M.        Semple, Graeme        Xiong, Yifeng        Shin, Young Jun        Ren, Albert        Lehmann, Juerg        Fioravanti, Beatriz        Bruce, Marc        Choi, Jin Sun Karoline   <120> SUBSTITUTED ARYL AND HETEROARYL DERIVATIVES AS MODULATORS OF        METABOLISM AND THE PROPHYLAXIS AND TREATMENT OF DISORDERS RELATED        THERETO <130> 70.WO1 <160> 7 <170> PatentIn version 3.2 <210> 1 <211> 1191 <212> DNA <213> Homo sapien <400> 1 atgtacccat acgacgtccc agactacgct ggaagcttgg aatcatcttt ctcatttgga 60 gtgatccttg ctgtcctggc ctccctcatc attgctacta acacactagt ggctgtggct 120 gtgctgctgt tgatccacaa gaatgatggt gtcagtctct gcttcacctt gaatctggct 180 gtggctgaca ccttgattgg tgtggccatc tctggcctac tcacagacca gctctccagc 240 ccttctcggc ccacacagaa gaccctgtgc agcctgcgga tggcatttgt cacttcctcc 300 gcagctgcct ctgtcctcac ggtcatgctg atcacctttg acaggtacct tgccatcaag 360 cagcccttcc gctacttgaa gatcatgagt gggttcgtgg ccggggcctg cattgccggg 420 ctgtggttag tgtcttacct cattggcttc ctcccactcg gaatccccat gttccagcag 480 actgcctaca aagggcagtg cagcttcttt gctgtatttc accctcactt cgtgctgacc 540 ctctcctgcg ttggcttctt cccagccatg ctcctctttg tcttcttcta ctgcgacatg 600 ctcaagattg cctccatgca cagccagcag attcgaaaga tggaacatgc aggagccatg 660 gctggaggtt atcgatcccc acggactccc agcgacttca aagctctccg tactgtgtct 720 gttctcattg ggagctttgc tctatcctgg acccccttcc ttatcactgg cattgtgcag 780 gtggcctgcc aggagtgtca cctctaccta gtgctggaac ggtacctgtg gctgctcggc 840 gtgggcaact ccctgctcaa cccactcatc tatgcctatt ggcagaagga ggtgcgactg 900 cagctctacc acatggccct aggagtgaag aaggtgctca cctcattcct cctctttctc 960 tcggccagga attgtggccc agagaggccc agggaaagtt cctgtcacat cgtcactatc 1020 tccagctcag agtttgatgg cgaattcgga tccaagggca attctgcaga tatccagcac 1080 agtggcggcc gctcgagtct agagggcccg cggttcgaag gtaagcctat ccctaaccct 1140 ctcctcggtc tcgattctac gcgtaccggt catcatcacc atcaccattg a 1191 <210> 2 <211> 396 <212> PRT <213> Homo sapien <400> 2 Met Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Gly Ser Leu Glu Ser Ser 1 5 10 15 Phe Ser Phe Gly Val Ile Leu Ala Val Leu Ala Ser Leu Ile Ile Ala             20 25 30 Thr Asn Thr Leu Val Ala Val Ala Val Leu Leu Leu Ile His Lys Asn         35 40 45 Asp Gly Val Ser Leu Cys Phe Thr Leu Asn Leu Ala Val Ala Asp Thr     50 55 60 Leu Ile Gly Val Ala Ile Ser Gly Leu Leu Thr Asp Gln Leu Ser Ser 65 70 75 80 Pro Ser Arg Pro Thr Gln Lys Thr Leu Cys Ser Leu Arg Met Ala Phe                 85 90 95 Val Thr Ser Ser Ala Ala Ala Ser Val Leu Thr Val Met Leu Ile Thr             100 105 110 Phe Asp Arg Tyr Leu Ala Ile Lys Gln Pro Phe Arg Tyr Leu Lys Ile         115 120 125 Met Ser Gly Phe Val Ala Gly Ala Cys Ile Ala Gly Leu Trp Leu Val     130 135 140 Ser Tyr Leu Ile Gly Phe Leu Pro Leu Gly Ile Pro Met Phe Gln Gln 145 150 155 160 Thr Ala Tyr Lys Gly Gln Cys Ser Phe Phe Ala Val Phe His Pro His                 165 170 175 Phe Val Leu Thr Leu Ser Cys Val Gly Phe Phe Pro Ala Met Leu Leu             180 185 190 Phe Val Phe Phe Tyr Cys Asp Met Leu Lys Ile Ala Ser Met His Ser         195 200 205 Gln Gln Ile Arg Lys Met Glu His Ala Gly Ala Met Ala Gly Gly Tyr     210 215 220 Arg Ser Pro Arg Thr Pro Ser Asp Phe Lys Ala Leu Arg Thr Val Ser 225 230 235 240 Val Leu Ile Gly Ser Phe Ala Leu Ser Trp Thr Pro Phe Leu Ile Thr                 245 250 255 Gly Ile Val Gln Val Ala Cys Gln Glu Cys His Leu Tyr Leu Val Leu             260 265 270 Glu Arg Tyr Leu Trp Leu Leu Gly Val Gly Asn Ser Leu Leu Asn Pro         275 280 285 Leu Ile Tyr Ala Tyr Trp Gln Lys Glu Val Arg Leu Gln Leu Tyr His     290 295 300 Met Ala Leu Gly Val Lys Lys Val Leu Thr Ser Phe Leu Leu Phe Leu 305 310 315 320 Ser Ala Arg Asn Cys Gly Pro Glu Arg Pro Arg Glu Ser Ser Cys His                 325 330 335 Ile Val Thr Ile Ser Ser Ser Glu Phe Asp Gly Glu Phe Gly Ser Lys             340 345 350 Gly Asn Ser Ala Asp Ile Gln His Ser Gly Gly Arg Ser Ser Leu Glu         355 360 365 Gly Pro Arg Phe Glu Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu     370 375 380 Asp Ser Thr Arg Thr Gly His His His His His His 385 390 395 <210> 3 <211> 24 <212> DNA <213> Artificial <220> <223> Homo sapien Primer <400> 3 cattgccggg ctgtggttag tgtc 24 <210> 4 <211> 24 <212> DNA <213> Artificial <220> <223> Homo sapien Primer <400> 4 ggcatagatg agtgggttga gcag 24 <210> 5 <211> 22 <212> DNA <213> Artificial <220> <223> Rat Primer <400> 5 catgggccct gcaccttctt tg 22 <210> 6 <211> 24 <212> DNA <213> Artificial <220> <223> Rat Primer <400> 6 gctccggatg gctgatgata gtga 24 <210> 7 <211> 23 <212> PRT <213> Artificial <220> <223> Novel Sequence <400> 7 Arg Gly Pro Glu Arg Thr Arg Glu Ser Ala Tyr His Ile Val Thr Ile 1 5 10 15 Ser His Pro Glu Leu Asp Gly             20

Claims (42)

Compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or N-oxides thereof. <Formula I>

In the above formula, A ₁ and A ₂ are, each independently, C _{1 -6} alkyl, C _{1 -6} alkoxy and carboxy groups, optionally C 1 _{1 -3} alkylene optionally substituted with one or more substituents independently selected from the consisting of a; D is CR ₁ R ₂ or NR _2, wherein R ₁ is selected from H, C _{1 -6} alkyl, C _{1 -6} alkoxy, halo and hydroxyl indeed the group consisting of; E is N, C or CR _3, where R ₃ is H or C _{1 -6} alkyl;

Is a single bond when E is N or CR ₃ , or a double bond when E is C; K is absent, or C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and each being righteous C _{3 -6} cycloalkyl which may be substituted from the group consisting of halogen with one or more substituents independently selected alkylene or C _{1 -3} alkyl group; Q ₁ is NR _4, O, S, and S (O) or S (O) _2, wherein R ₄ is H, C _{1 -6} acyl, C _{1 -6} alkyl, C _2-6 alkenyl, C _{2 - 6} alkynyl, C _{3 -7-cycloalkyl} or C _{3 -7} - cycloalkyl, -C _{1 -3} - alkylene, wherein said C _{1 -6} alkyl is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6-alkyl-sulfonamide,} di -C _{1 -6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio O, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, hydroxylamino and nitro; Q ₂ is NR ₅ or O, wherein R ₅ is H, C _{1 -6} acyl, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{3 -7-cycloalkyl} or C _{3 7} - cycloalkyl, -C _{1 -3-alkylene,} wherein the C _{1 -6} alkyl is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkyl sulfonyl carbonyl , C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 - 6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} -alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, Hydroxyl Optionally substituted with one or more substituents independently selected from the group consisting of hydroxylamino and nitro; W is N or CH; X is N or CR ₆ ; Y is N or CR ₇ ; Z is N or CR ₈ ; V is absent, or C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, C _{1 -3} may each be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halogen in C _{1 -3} hetero alkylene or C _{1 -3} alkylene; R _6, R ₇ and R ₈ are H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 - 6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 - 6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl amino, and the group consisting of nitro each of which is independently selected, wherein the C _{2 -6} alkenyl from, C _{1 -6} alkyl, C _{2 -6-alkynyl} and C _{3 -6} cycloalkyl is C _1-6 acyl, C _1-6 acyloxy, C _{2 -6} alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkyl-carboxamide, C _{2- 6} alkynyl, C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkyl thio, C _1-6 alkylthio-carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6-alkylamino,} C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di- C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen , C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl, amino and nitro one or more substituents independently selected from the group consisting of each optionally Can be substituted; Ar is aryl or heteroaryl, which may be optionally substituted with R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ ; R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, arylcarbonyl, arylsulfonyl, di -C _1-6 - alkyl, amino, carboxylic one night yimido , C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6-alkyl} carboxamide, di -C _{1 -6-alkyl-sulfonamide,} di- C _1-6 - alkylthio carboxamido, guanidine, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _1-6 haloalkylsulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, hydroxylamino, nitro, C _{3 -6} oxo-cycloalkyl, phenoxy, sulfonamide, sulfonic acid and thiol; Wherein each R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkyl amino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _1-6 alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _1-6 alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di -C _1-6 - alkyl, amino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} when claw alkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkyl Thio, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and Optionally it may be substituted from the group consisting of Trojan with one or more substituents independently selected; R _10, R _11, R ₁₂ and R ₁₃ is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino , C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _1-6 alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy , cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl amino, nitro, and thiol Independently selected from the group consisting of; Or two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the atoms to which they are attached are 5-, 6- or 7-membered cycloalkyl, 5-, 6- or 7-membered cycloalkenyl, or A 5-, 6- or 7-membered heterocyclic group is formed, wherein the 5-, 6- or 7-membered group can be optionally substituted with halogen or oxo; R ₂ is H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6} alkyl carboxylic carboxamide, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide , C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, arylcarbonyl, aryloxy, di -C _{1 -6} - alkylamino, carboxylic night yimido yl, C _{1 -6} alkoxycarbonyl carbonyl, C _{3 -7} - cycloalkyl alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide di -C _{1 -6} - alkylthio carboxamido, guanidine, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl , C _{1 -6} haloalkylthio, heteroaryl, heteroaryl -C _1-3 - alkylene, heteroaryl-carbonyl, heteroaryloxy, Heterocycliccarboxamides, hydroxyl, hydroxylamino and nitro; Wherein R ₂ are each C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6} alkyl carboxylic carboxamide, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide , C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _3-6 cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkenyl Kiel, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl amino, and Optionally substituted with one or more substituents independently selected from the group consisting of nitros And, wherein the C _{1 -6} alkyl is added as a C _{1 -6} acyl, C _{1 -6} alkoxy, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{1 -6} alkyl sulfonamide, C _{1 - 6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, amide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl , halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, hydroxyl, 1 is independently selected from the group consisting of hydroxyl, amino and nitro Optionally substituted with more than one substituent, Provided that the compound is not 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester. The compound of claim 1, wherein A ₁ and A ₂ are both —CH ₂ CH ₂ — and A ₁ and A ₂ may each be optionally substituted with 1, 2, 3 or 4 methyl groups. The method according to claim 1 or 2,

This compound is a single bond. The compound of any of claims 1-3, wherein K is absent. The compound of any one of claims 1-3, wherein K is —CH ₂ —. 6. The compound of claim 1, wherein V is absent. 7. The compound of any one of claims 1-6 wherein Q ₁ is O. 8. The compound of any one of claims 1-6 wherein Q ₁ is NH. The compound of any one of claims 1-8 wherein Q ₂ is O. 10. The compound of any one of claims 1-8, wherein Q ₂ is NR ₅ . 11. The method of claim 10 wherein, R ₅ is H or C _{1 -6} alkyl. The method according to any one of claims 1 to 11, W is CH; X is N; Y is CR ₇ (wherein, R ₇ is H, C _{1 -6} alkyl or halogen Im) and; Z is N. The method according to any one of claims 1 to 11, W is CH; X is N; Y is CR ₇ (wherein, R ₇ is H, C _{1 -6} alkyl or halogen Im) and; Z is CR ₈ (wherein, R ₈ is H, C _{1 -6} alkyl or halogen Im) compounds. The compound of any one of claims 1-13, wherein E is CH and D is NR ₂ . The method according to any one of claims 1 to 14, R ₂ is aryl, arylcarbonyl, C _{1 -6} alkoxycarbonyl, C _{3 -7} - cycloalkoxy-carbonyl, heteroaryl, and heteroaryl-carbonyl, and; Each of the C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide} , C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _1-6 alkylthio OY rail, C _1-6 alkyl, urea, amino, aryl, di -C _1-6 - alkyl, amino, carbonyl -C _1-6 - alkoxy, carboxamide, carboxy, cyano, C _3-6 cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl amino, nitro And thiol, which may be optionally substituted with one or more substituents independently selected from the group consisting of Compound. Any one of claims 1 to 14 as claimed in any one of the preceding according to, R ₂ is C _{1 -6} alkoxycarbonyl, C _{3 -6} cycloalkyl optionally substituted with a C _{1 -6} alkoxycarbonyl, C _{3 -7} - cycloalkyl alkoxycarbonyl carbonyl, or one, two or three C _{1 -6} heteroatoms, which may be optionally substituted with alkyl, aryl -C _{1 -3} - alkylene. The method according to any one of claims 1 to 16, Ar is phenyl which may be optionally substituted with R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ ; R ₉ is methanesulfonyl, 2-methanesulfonyl-ethyl, acetylsulfamoyl, propionylsulfamoyl, ethylsulfanyl, isopropylsulfanyl, ethylsulfamoyl, methylsulfamoyl, dimethylsulfamoyl, methylsulfamoylmethyl, Sulfamoyl, [1,2,4] triazol-1-yl, [1,2,4] triazol-1-ylmethyl, 2- [1,2,4] triazol-1-yl-ethyl, Methoxy, 2-oxo-oxazolidin-4-ylmethyl, 1,1-dioxo-1λ ⁶ -thiomorpholin-4-ylmethyl, pyrazol-1-yl, trifluoromethanesulfonyl, mor Polline-4-sulfonyl, pyridine-2-carbonyl, F, Cl, cyano, Br, carboxy, butyryl, propoxycarbonyl, hydroxy, propylcarbamoyl, N-hydroxycarbamimidoyl, Carbamimidoyl, N-ethylcarbamidoyl and 2-amino-ethylamino; R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently selected from the group consisting of F, methoxy, methyl, ethyl and carboxy. The method according to any one of claims 1 to 16, Ar is phenyl which may be optionally substituted with R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ ; R ₉ is methanesulfonyl, cyano, F, Cl, Br, I, methyl, methoxy, ethylamino, ethylsulfanyl, isopropylsulfanyl, hydroxy, isopropoxy, propoxy, dimethylamino, propylamino Isopropylamino, acetylamino, piperidin-1-yl, trifluoromethoxy, oxazol-5-yl, ethynyl, 3-methyl-butylamino, 2-morpholin-4-yl-ethylamino, Acetylsulfamoyl, propionylsulfamoyl, tetrahydro-furan-2-ylmethoxy, morpholin-4-yl, 4-methyl-piperazin-1-yl, butylamino, 2-pyrrolidin-1-yl- Ethoxy, 2-dimethylamino-ethoxy, 2-morpholin-4-yl-ethoxy, morpholin-4-ylamino, 2-methoxy-ethylamino and tetrahydro-furan-2-ylmethyl-amino It is selected from the group consisting of; R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently selected from the group consisting of F, Cl, Br, I, hydroxyl, methoxy, cyano, methyl and trifluoromethoxy. The method according to any one of claims 1 to 16, Ar is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4,5,6,7-tetrahydro-2H-indazol-3-yl, quinolin-6-yl, benzothiazole- 6-yl, thien-2-yl, thien-3-yl, 1H-pyrazolo [3,4-b] pyridin-3-yl, thiazol-2-yl, 5-oxo-4,5-dihydro -1H-pyrazol-3-yl, isoxazol-4-yl and [1,3,4] thiadiazol-2-yl, each of which is R ₉ , R ₁₀ , R ₁₁ , R ₁₂ And R ₁₃ optionally; R ₉ is selected from the group consisting of methanesulfonyl, methoxy, carboxy, acetylsulfamoyl, propionylsulfamoyl, acetylamino, F, Cl, Br, methyl and trifluoromethyl; R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently selected from the group consisting of methoxy, methyl, F, Cl and Br. The method according to any one of claims 1 to 16, Pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4,5,6,7-tetra, wherein Ar may be optionally substituted with R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ Hydro-2H-indazol-3-yl, quinolin-6-yl, benzothiazol-6-yl, thien-2-yl, thien-3-yl, 1H-pyrazolo [3,4-b] pyridine- 3-yl, thiazol-2-yl, 5-oxo-4,5-dihydro-1H-pyrazol-3-yl, isoxazol-4-yl and [1,3,4] thiadiazole-2 -Selected from the group consisting of days; R ₉ is cyano, F, Cl, Br, acetylamino, methoxy, methyl, propoxy, propylamino, isopropylamino, phenyl, t-butyl, 4-methylphenyl, ethyl, methylsulfanyl, morpholine-4 -Yl, benzenesulfonyl, trifluoromethyl, cyclopropyl, carbamoyl, 3,4-difluorophenyl, 4-chlorophenyl, 1-methyl-pyrrolidin-2-yl, acetylsulfamoyl, propy Onylsulfamoyl and pyridin-2-yl; R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently methyl, F or Cl. The compound of formula (IIIi) according to claim 1. <Formula IIIi>

In the formula, K is absent, or C _{1 -3} alkyl group; Q ₁ is NH or O; Q ₂ is NR ₅ or O, wherein R ₅ is H or C _{1 -6} alkyl; W is CH, X is N, Y is CH and Z is N; or W is CH, X is N, Y is CH, Z is CH; V does not exist; Ar is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4,5,6,7-tetrahydro-2H-indazol-3-yl, quinolin-6-yl, benzothiazole- 6-yl, thien-2-yl, thien-3-yl, 1H-pyrazolo [3,4-b] pyridin-3-yl, thiazol-2-yl, 5-oxo-4,5-dihydro -1H-pyrazol-3-yl, isoxazol-4-yl and [1,3,4] thiadiazol-2-yl, each of which is R ₉ , R ₁₀ , R ₁₁ , R ₁₂ And optionally substituted with R ₁₃ ; R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _1-6 alkyl-carboxamide, C _{2 -6} alkynyl carbonyl, C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, amino, aryl, arylsulfonyl, di -C _{1 -6} - alkylamino , carboxylic night yimido yl, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkoxy, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl, sulfonamide, guanidine, C _{1 -6} haloalkoxy, C _1-6 - haloalkyl, halogen, C _{1 -6} haloalkylsulfonyl, heteroaryl, heteroaryl-carbonyl, heteroaryl, sulfonyl, heterocyclic, heterocyclic sulfonyl, hydroxy Roxyl, sulfonamide and thiol; The C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, amino, aryl, carboxamide yimido one night, H. Tero cyclic is C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{2 -6} alkynyl, C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfonyl, amino, aryl, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkylamino, halogen, heteroaryl, heterocyclic, and hydroxyl Optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of hydroxyl; R _10, R _11, R ₁₂ and R ₁₃ is C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, carboxy, cyano, halogen, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl Independently selected from the group consisting of alkylsulfonyl and hydroxyl; Or two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the atoms to which they are attached form a 5- or 6-membered cycloalkyl, or 5- or 6-membered heterocyclic group, wherein 5 6-membered or 6-membered groups may be optionally substituted with halogen or oxo; R ₂ is tert-butoxycarbonyl, isobutoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclopropylmethoxycarbonyl, 3-methyl-butoxycarbonyl or 3-isopropyl- [1, 2,4] oxadiazol-5-yl. The method of claim 1, 4-{[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert- Butyl esters; 4-({[6- (4-Methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (2,5-Difluoro-benzylamino) -pyrimidin-4-yl] -methyl-amino} -methyl)-piperidine-1-carboxylic acid tert-butyl ester; 4-[({6-[(benzo [1,3] dioxol-5-ylmethyl) -amino] -pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1-car Acid tert-butyl esters; 4-({methyl- [6- (2-pyridin-4-yl-ethylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (2-pyridin-3-yl-ethylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-[(methyl- {6-[(pyridin-3-ylmethyl) -amino] -pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid tert-butyl ester; 4-[({6-[(2-Fluoro-4-methanesulfonyl-phenyl) -methyl-amino] -pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1- Carboxylic acid tert-butyl esters; 4-({[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester; 4-({[6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-[({6- [4- (2-Methanesulfonyl-ethyl) -phenylamino] -pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1-carboxylic acid tert Butyl ester; 4-({[6- (4-ethylsulfanyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (4-Isopropylsulfanyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (4-ethylsulfamoyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (4-methylsulfamoyl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (4-dimethylsulfamoyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl)-piperidine-1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (4-methylsulfamoylmethyl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (4-sulfamoyl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (4- [1,2,4] triazol-1-yl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1- Carboxylic acid tert-butyl esters; 4-({methyl- [6- (4- [1,2,4] triazol-1-ylmethyl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1 Carboxylic acid tert-butyl esters; 4-[(methyl- {6- [4- (2- [1,2,4] triazol-1-yl-ethyl) -phenylamino] -pyrimidin-4-yl} -amino) -methyl]- Piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (benzo [1,3] dioxol-5-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert- Butyl esters; 4-({[6- (6-Methanesulfonyl-pyridin-3-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (3,5-Dimethoxy-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-[(Methyl- {6- [4- (2-oxo-oxazolidin-4-ylmethyl) -phenylamino] -pyrimidin-4-yl} -amino) -methyl] -piperidine-1 Carboxylic acid tert-butyl esters; 4-[({6- [4- (1,1-Dioxo-1λ ⁶ -thiomorpholin-4-ylmethyl) -phenylamino] -pyrimidin-4-yl} -methyl-amino) -methyl] -Piperidine-1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (4-pyrazol-1-yl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (2,2-Difluoro-benzo [1,3] dioxol-5-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine -1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (4-trifluoromethanesulfonyl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-[(Methyl- {6- [4- (morpholin-4-sulfonyl) -phenylamino] -pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid tert Butyl ester; 4-[(Methyl- {6- [2- (pyridine-2-carbonyl) -phenylamino] -pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxylic acid tert- Butyl esters; 4-({[6- (2-Fluoro-5-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert- Butyl esters; N-ethyl-3-fluoro-4- [6- (methyl-piperidin-4-ylmethyl-amino) -pyrimidin-4-ylamino] -benzenesulfonamide; 3-Fluoro-N-isopropyl-4- [6- (methyl-piperidin-4-ylmethyl-amino) -pyrimidin-4-ylamino] -benzenesulfonamide; 4-({[6- (3,4-Difluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (2,6-Difluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (2,5-Difluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (2,3-Difluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (2,3,5-trifluoro-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (2-Fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (2-Fluoro-4-methyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (3-Chloro-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (2,4-Difluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-[(Methyl- {6- [2- (1-oxy-pyridin-3-yl) -ethylamino] -pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxyl Acid tert-butyl esters; 4-[(Methyl- {6- [2- (1-oxy-pyridin-3-yl) -ethylamino] -pyrimidin-4-yl} -amino) -methyl] -piperidine-1-carboxyl Acid isobutyl esters; 4-({[6- (2,5-Difluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester; 4-({[6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester ; 4-[({6- [2- (2-Fluoro-phenoxy) -ethylamino] -pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1-carboxylic acid tert Butyl ester; 4-({[6- (2-Fluoro-phenoxy) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1 -carboxylic acid tert-butyl ester; 4-({[6- (2,5-Difluoro-phenoxy) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-[({6- [2- (2-Chloro-phenoxy) -ethylamino] -pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1-carboxylic acid tert- Butyl esters; 4-({[6- (2-Chloro-phenoxy) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-[({6- [2- (4-Fluoro-phenoxy) -propylamino] -pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine-1-carboxylic acid tert Butyl ester; 4-({[6- (4-ethylsulfamoyl-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert- Butyl esters; 4-({[6- (2-Fluoro-4-isopropylsulfamoyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert Butyl ester; 4-({[6- (4-cyano-2,5-difluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (4-Bromo-2,5-difluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (5-carboxy-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (6-methoxy-pyridin-3-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (2,6-Dimethoxy-pyridin-3-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert- Butyl esters; 6- {6-[(1-tert-Butoxycarbonyl-piperidin-4-ylmethyl) -methyl-amino] -pyrimidin-4-ylamino} -nicotinic acid; 4-({[6- (6-acetylamino-pyridin-3-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (5-Fluoro-pyridin-2-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (4-cyano-2-ethyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl)-piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (4-butyryl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (5-Bromo-3-methyl-pyridin-2-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (3-Bromo-5-methyl-pyridin-2-ylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({methyl- [6- (5-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert- Butyl esters; 4-({[6- (4-Bromo-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (3-carboxy-4-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester ; 4-({[6- (4-ethoxycarbonyl-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid iso Butyl esters; 4-({[6- (4-carboxy-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester; 4-({[6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isopropyl ester ; 4-({[6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid butyl ester; 4-({[6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid cyclopropylmethyl ester; 4-({[6- (2,5-Difluoro-4-hydroxy-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid Isobutyl ester; 4-({[6- (4-ethylcarbamoyl-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid iso Butyl esters; 4-[({6- [2-fluoro-4- (N-hydroxycarbamidomiyl) -phenylamino] -pyrimidin-4-yl} -methyl-amino) -methyl] -piperidine- 1-carboxylic acid isobutyl ester; 4-({[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid 3- Methyl-butyl ester; 4-({[6- (2,5-Difluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxyl Acid tert-butyl esters; 4-({[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isopropyl ester; (5-Butyl-pyridin-2-yl)-[4-({[6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl ) -Piperidin-1-yl] -methanone; N- (2-fluoro-4-methanesulfonyl-phenyl) -N '-(5'-fluoro-3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl- 4-ylmethyl) -N'-methyl-pyrimidine-4,6-diamine; 4-({[6- (4-Carbamimidoyl-2-fluoro-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid iso Butyl esters; 4-({[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid cyclobutyl ester; 4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-ylamino] -piperidine-1-carboxylic acid tert-butyl ester; N- (2-Fluoro-4-methanesulfonyl-phenyl) -N '-[1- (3-isopropyl- [1,2,4] oxadiazol-5-ylmethyl) -piperidine- 4-ylmethyl] -N'-methyl-pyrimidine-4,6-diamine; 4-({[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid 1- Ethyl-propyl ester; 4-({ethyl- [6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert- Butyl esters; 4-({ethyl- [6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid isopropyl ester; 4-({[6- (4-cyano-2,5-difluoro-phenylamino) -pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxylic acid Isopropyl ester; 4-({[6- (4-Amino-2,5-difluoro-phenoxy) -pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxylic acid tert Butyl ester; 4-({[6- (2,5-Difluoro-4-methoxy-phenylamino) -pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-({[6- (2,5-Difluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxyl Acid tert-butyl esters; 4-({ethyl- [6- (2,4,5-trifluoro-phenylamino) -pyrimidin-4-yl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-[(ethyl- {6- [4- (N-ethylcarbamimidoyl) -2,5-difluoro-phenylamino] -pyrimidin-4-yl} -amino) -methyl] -piperi Dine-1-carboxylic acid isopropyl ester; 4-({[6- (4-Bromo-2,5-difluoro-phenylamino) -pyrimidin-4-yl] -ethyl-amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester; 4-[({6- [5- (2-amino-ethylamino) -4-cyano-2-fluoro-phenylamino] -pyrimidin-4-yl} -ethyl-amino) -methyl] -pi Ferridine-1-carboxylic acid isopropyl ester; 4-{[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-ylamino] -methyl}-piperidine-1-carboxylic acid tert-butyl ester; 4-{[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-ylamino] -methyl} -piperidine-1-carboxylic acid isopropyl ester; 4-({[6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -isopropyl-amino} -methyl) -piperidine-1-carboxylic acid tert Butyl ester; 4-({[4- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-2-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester ; And 4-({[2- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-4-yl] -methyl-amino} -methyl) -piperidine-1-carboxylic acid isobutyl ester A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof. The method of claim 1, 4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [1- (3-isopropyl- [1,2,4] oxadiazole-5-ylmethyl) -piperidine-4- Iloxy] -pyrimidin-4-yl} -amine; 4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; (6-Chloro-pyridin-2-yl)-{4- [6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidin-1-yl } -Methanone; (6-Bromo-pyridin-2-yl)-{4- [6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1- Yl-methanone; {4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidin-1-yl}-(6-methyl-pyridin-2-yl ) -Methanone; {4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidin-1-yl}-(6-fluoro-pyridine-2- Yl) -methanone; {4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidin-1-yl} -pyridin-2-yl-methanone; (5-Bromo-pyridin-3-yl)-{4- [6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1- Yl-methanone; {4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidin-1-yl}-(5-methyl-pyridin-3-yl ) -Methanone; (5,6-Dichloro-pyridin-3-yl)-{4- [6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1 -Yl} -methanone; 4- [6- (4-cyano-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2,5-Difluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2,4,5-Trifluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (4-Bromo-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (3-Fluoro-4-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (3-hydroxy-4-methoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-Cyano-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (3-Chloro-4-cyano-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (3-Fluoro-4-methoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (3,4-Dimethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2,3-Dihydro-benzo [1,4] dioxin-6-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester ; 4- [6- (4-cyano-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-cyano-5-ethylamino-2-fluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (4-Ethoxy-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-ethylsulfanyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (4-Isopropylsulfanyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; (5-Butyl-pyridin-2-yl)-{4- [6- (2-fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidin-1-yl } -Methanone; 4- [6- (5-Chloro-3-methyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-acetylamino-4-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (5-Fluoro-4-methyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-methoxy-5-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-methoxy-2-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-Fluoro-5-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2-Chloro-6-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (4-Methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2-Methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-Chloro-2-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-Fluoro-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2-Chloro-4-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-methoxy-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (5-Fluoro-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2-Fluoro-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (6-Chloro-5-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2-Methyl-pyridin-4-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2-methoxy-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2,5-Difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (4-Chloro-2-fluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2,5-Difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (6-methoxy-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-cyano-3-methoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (3-Fluoro-4-hydroxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (6-Ethoxy-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2,5-Difluoro-4-isopropoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; (2-fluoro-4-methanesulfonyl-phenyl)-[6- (5'-isopropoxy-3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4 -Yloxy) -pyrimidin-4-yl] -amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-yljade Cy] -pyrimidin-4-yl} -amine; 4- [6- (4-cyano-2-fluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (pyridin-4-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2,5-Difluoro-4-propoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-ethylamino-2-fluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-Dimethylamino-2-fluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Fluoro-4-propylamino-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Fluoro-4-isopropylamino-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Methyl-6-propylamino-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (6-Isopropylamino-2-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Methyl-6-propoxy-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-iodo-2-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Fluoro-4-iodo-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [Methyl- (2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) -amino] -pyrimidin-4-yloxy} -piperidine- 1-carboxylic acid isopropyl ester; 4- [6- (2-Methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-phenyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-tert-butyl-1H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-p-tolyl-1H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (6-methoxy-5-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-Methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-acetylamino-3-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (3-Chloro-4-fluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (3,5-Dimethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (6-ethyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-Methyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Methyl-quinolin-6-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Methylsulfanyl-benzothiazol-6-ylamino) -pyrimidin-4-yloxy] -piperidine-1 -carboxylic acid isopropyl ester; 4- [6- (6-Morpholin-4-yl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-benzenesulfonyl-thiophen-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-piperidin-1-yl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (3-Trifluoromethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester ; 4- [6- (6-Methyl-1H-pyrazolo [3,4-b] pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester ; 4- [6- (5-Cyano-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-Bromo-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-Trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-methyl-1H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-cyclopropyl-1H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2,6-Dimethyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-cyano-2-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-methoxy-2-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2,4-Dimethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [acetyl- (2-fluoro-4-methanesulfonyl-phenyl) -amino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-Carbamoyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [4- (3,4-Difluoro-phenyl) -thiazol-2-ylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester ; 4- [6- (5-Oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid Isopropyl ester; 4- [6- (3-oxazol-5-yl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-Trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-Chloro-2-trifluoromethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6-[(5-Pyridin-2-yl-thiophen-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [5- (4-Chloro-phenyl) -2H-pyrazol-3-ylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (1-oxo-indan-5-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [5- (1-Methyl-pyrrolidin-2-yl) -pyridin-2-ylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (6-methoxy-2-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (5-Bromo-3-methyl-pyridin-2-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Chloro-6-methyl-pyridin-3-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Ethynyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-Bromo-2-trifluoromethoxy-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (3-iodo-4-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Fluoro-5-methyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [5- (4-methoxy-phenyl)-[1,3,4] thiadiazol-2-ylamino] -pyrimidin-4-yloxy} -piperidine-1-car Acid isopropyl esters; 4- [6- (3,5-Dimethyl-isoxazol-4-ylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [2- (2,5-Difluoro-4-propoxy-phenylamino) -pyridin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2,5-Difluoro-4-propylamino-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2,5-Difluoro-4-morpholin-4-yl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Methyl-4-propylamino-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [2,5-Difluoro-4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxyl Acid isopropyl esters; 4- {6- [2,5-Difluoro-4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1- Carboxylic acid isopropyl esters; 4- {6- [4- (2-Dimethylamino-ethoxy) -2,5-difluoro-phenylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [2,5-Difluoro-4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1-car Acid isopropyl esters; 4- [6- (2,4-Difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2,4,5-Trifluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-Methanesulfonyl-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [acetyl- (4-methanesulfonyl-phenyl) -amino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; (2,5-Difluoro-4-propoxy-phenyl)-{6- [1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperidine-4 -Yloxy] -pyrimidin-4-yl} -amine; 4- {6- [2,5-Difluoro-4- (morpholin-4-ylamino) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [2,5-Difluoro-4- (2-methoxy-ethylamino) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; 4- (6- {2,5-Difluoro-4-[(tetrahydro-furan-2-ylmethyl) -amino] -phenylamino} -pyrimidin-4-yloxy) -piperidine-1 Carboxylic isopropyl esters; 4- [6- (4-butylamino-2,5-difluoro-phenylamino) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [2,5-Difluoro-4- (3-methyl-butylamino) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester ; 4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -2-methyl-pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [2,5-Difluoro-4- (2-morpholin-4-yl-ethylamino) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1-car Acid isopropyl esters; 4- {6- [2- (2,5-Difluoro-phenoxy) -ethylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2,5-Difluoro-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (4-Bromo-2-fluoro-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Fluoro-4-morpholin-4-yl-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- {6- [2,5-Difluoro-4- (tetrahydro-furan-2-ylmethoxy) -phenylamino] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid Isopropyl ester; 4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-2-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [5- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-3-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; 4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-2-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [4- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-2-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [4- (2,5-Difluoro-4-propoxy-phenylamino) -pyridin-2-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [2- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyridin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; And 4- [2- (2,5-Difluoro-4-propoxy-phenylamino) -pyridin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof. The method of claim 1, 4- {6- [6- (2,3-Dihydroxy-propylamino) -2-methyl-pyridin-3-yloxy] -pyrimidin-4-yloxy} -piperidine-1-carboxyl Acid isopropyl esters; 4- (6- {6-[(2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -amino] -2-methyl-pyridin-3-yloxy} -pyrimidine-4- Yloxy) -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Methyl-pyridin-3-yloxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (6-Bromo-2-methyl-pyridin-3-yloxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester; 4- [6- (2-Methyl-pyridin-3-yloxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester; And 4- [2- (2-Fluoro-4-methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof. Compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or N-oxides thereof. <Formula I>

In the above formula, A ₁ and A ₂ are, each independently, C _{1 -6} alkyl, C _{1 -6} alkoxy and carboxy groups, optionally C 1 _{1 -3} alkylene optionally substituted with one or more substituents independently selected from the consisting of a; D is CR ₁ R ₂ or NR _2, wherein R ₁ is selected from H, C _{1 -6} alkyl, C _{1 -6} alkoxy, halo and hydroxyl indeed the group consisting of; E is N, C or CR _3, where R ₃ is H or C _{1 -6} alkyl;

Is a single bond when E is N or CR ₃ , or a double bond when E is C; K is absent, or C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and halogen from the group consisting of with one or more substituents selected independently from C, each optionally substituted _3-6 cycloalkyl alkylene or C _{1 -3} alkyl group; Q ₁ is NR _4, O, S, and S (O) or S (O) _2, wherein R ₄ is H, C _{1 -6} acyl, C _{1 -6} alkyl, C _2-6 alkenyl, C _{2 - 6} alkynyl, C _{3 -7-cycloalkyl} or C _{3 -7} - cycloalkyl, -C _{1 -3} - alkylene, wherein said C _{1 -6} alkyl is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkylthio urea yl, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6-alkyl-sulfonamide,} di -C _{1 -6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkyl O, hydroxyl, hydroxyl, amino and nitro with one or more substituents independently selected from the group consisting of optionally may be substituted; Q ₂ is absent; W is N or CH; X is N or CR ₆ ; Y is N or CR ₇ ; Z is N; V is absent, or C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, C _{1 -3} may each be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halogen in C _{1 -3} hetero alkylene or C _{1 -3} alkylene; R _6, R ₇ and R ₈ are H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 - 6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 - 6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl amino, and the group consisting of nitro each of which is independently selected, wherein the C _{2 -6} alkenyl from, C _{1 -6} alkyl, C _{2 -6-alkynyl} and C _{3 -6} cycloalkyl is C _1-6 acyl, C _1-6 acyloxy, C _{2 -6} alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkyl-carboxamide, C _{2- 6} alkynyl, C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkyl thio, C _1-6 alkylthio-carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6-alkylamino,} C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di- C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen , C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl, amino and nitro one or more substituents independently selected from the group consisting of each optionally Can be substituted; Ar is aryl or heteroaryl, which may be optionally substituted with R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ ; R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, arylcarbonyl, arylsulfonyl, di -C _1-6 - alkyl, amino, carboxylic one night yimido , C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6-alkyl} carboxamide, di -C _{1 -6-alkyl-sulfonamide,} di- C _1-6 - alkylthio carboxamido, guanidine, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _1-6 haloalkylsulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, hydroxylamino, nitro, C _{3 -6} oxo-cycloalkyl, phenoxy, sulfonamide, sulfonic acid and thiol; Wherein each R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkyl amino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _1-6 alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _1-6 alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di -C _1-6 - alkyl, amino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} when claw alkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkyl Thio, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and Optionally it may be substituted from the group consisting of Trojan with one or more substituents independently selected; R _10, R _11, R ₁₂ and R ₁₃ is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino , C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _1-6 alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy , cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl amino, nitro, and thiol Independently selected from the group consisting of; Or two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the atoms to which they are attached are 5-, 6- or 7-membered cycloalkyl, 5-, 6- or 7-membered cycloalkenyl, or A 5-, 6- or 7-membered heterocyclic group is formed, wherein the 5-, 6- or 7-membered group can be optionally substituted with halogen or oxo; R ₂ is H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6} alkyl carboxylic carboxamide, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide , C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, arylcarbonyl, aryloxy, di -C _{1 -6} - alkylamino, carboxylic night yimido yl, C _{1 -6} alkoxycarbonyl carbonyl, C _{3 -7} - cycloalkyl alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide di -C _{1 -6} - alkylthio carboxamido, guanidine, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl , C _{1 -6} haloalkylthio, heteroaryl, heteroaryl -C _1-3 - alkylene, heteroaryl-carbonyl, heteroaryloxy, Heterocycliccarboxamides, hydroxyl, hydroxylamino and nitro; Wherein R ₂ are each C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6} alkyl carboxylic carboxamide, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide , C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _3-6 cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkenyl Kiel, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl amino, and Optionally substituted with one or more substituents independently selected from the group consisting of nitros And, wherein the C _{1 -6} alkyl is added as a C _{1 -6} acyl, C _{1 -6} alkoxy, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{1 -6} alkyl sulfonamide, C _{1 - 6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, amide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl , halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, hydroxyl, 1 is independently selected from the group consisting of hydroxyl, amino and nitro Optionally substituted with more than one substituent. The compound of claim 25, wherein K is absent. The compound of claim 25 or 26, wherein V is absent. The compound of any one of claims 25-27 wherein Q ₁ is O. ₂₉ . The compound of any one of claims 25-27 wherein Q ₁ is NH. The compound of any one of claims 25-29 wherein E is N and D is CHR ₂ . 31. The compound of any of claims 25-30, wherein A ₁ and A ₂ are both —CH ₂ CH ₂ — and A ₁ and A ₂ may each be optionally substituted with 1, 2, 3 or 4 methyl groups. Compound. The method of any one of claims 25 to 31, W is CH; X is N; Y is CR ₇ (wherein, R ₇ is H, C _{1 -6} alkyl or halogen being shown below); Z is N. The method of claim 25, 4- [4- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-1-yl] -6- (4-methanesulfonyl-phenoxy) -pyri Midine; {6- [4- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-1-yl] -pyrimidin-4-yl}-(4-methanesulphate Ponyl-phenyl) -amine; (2-fluoro-4-methanesulfonyl-phenyl)-{6- [4- (3-fluoro-phenoxy) -piperidin-1-yl] -pyrimidin-4-yl} -amine; {4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -piperazin-1-yl} -acetic acid ethyl ester; (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [4- (3-isopropyl- [1,2,4] oxadiazol-5-ylmethyl) -piperazin-1-yl ] -Pyrimidin-4-yl} -amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [4- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-1-yl ] -Pyrimidin-4-yl} -amine; {1- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -piperidin-4-yl} -acetic acid methyl ester; 3- {4- [6- (2-Fluoro-4-methanesulfonyl-phenylamino) -pyrimidin-4-yl] -piperazin-1-yl} -propionic acid ethyl ester; (2-fluoro-4-methanesulfonyl-phenyl)-{6- [4- (4-isobutyl-phenyl) -piperidin-1-yl]-pyrimidin-4-yl} -amine; (2-fluoro-4-methanesulfonyl-phenyl)-{6- [4- (4-isopropyl-phenyl) -piperidin-1-yl] -pyrimidin-4-yl} -amine; {6- [4- (3-Cyclopropylmethyl- [1,2,4] oxadiazol-5-yl) -piperidin-1-yl] -pyrimidin-4-yl}-(2-fluoro Ro-4-methanesulfonyl-phenyl) -amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [4- (3-isobutyl- [1,2,4] oxadiazol-5-yl) -piperidin-1-yl ] -Pyrimidin-4-yl} -amine; (2-fluoro-4-methanesulfonyl-phenyl)-{6- [4- (4-isopropoxy-phenyl) -piperazin-1-yl] -pyrimidin-4-yl} -amine; (2-fluoro-4-methanesulfonyl-phenyl)-{6- [4- (4-isopropoxy-phenyl) -piperidin-1-yl] -pyrimidin-4-yl} -amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [4- (5-isopropoxy-pyridin-2-yl) -piperazin-1-yl] -pyrimidin-4-yl} Amines; {6- [4- (3-Dimethylaminomethyl- [1,2,4] oxadiazol-5-yl) -piperidin-1-yl] -pyrimidin-4-yl}-(2-fluoro Ro-4-methanesulfonyl-phenyl) -amine; (2-Fluoro-4-methanesulfonyl-phenyl)-(6- {4- [2- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -ethyl] -pipe Razin-1-yl} -pyrimidin-4-yl) -amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [4- (5-isopropoxy-pyridin-2-yloxy) -piperidin-1-yl] -pyrimidine-4- Mono} -amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [4- (3-pyridin-3-yl- [1,2,4] oxadiazol-5-yl) -piperidine- 1-yl] -pyrimidin-4-yl} -amine; And 2,5-Difluoro-4- {6- [4- (4-isopropoxy-phenyl) -piperazin-1-yl] -pyrimidin-4-ylamino} -benzonitrile A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof. Compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or N-oxides thereof. <Formula I>

In the above formula, A ₁ and A ₂ are, each independently, C _{1 -6} alkyl, C _{1 -6} alkoxy and carboxy groups, optionally C 1 _{1 -3} alkylene optionally substituted with one or more substituents independently selected from the consisting of a; D is CR ₁ R ₂ or NR _2, wherein R ₁ is selected from H, C _{1 -6} alkyl, C _{1 -6} alkoxy, halo and hydroxyl indeed the group consisting of; E is N, C or CR _3, where R ₃ is H or C _{1 -6} alkyl;

Is a single bond when E is N or CR ₃ , or a double bond when E is C; K is C _{1 -6} alkyl, C _{1 -6} alkoxy, carboxy, cyano, and halogen from the group consisting of with one or more substituents selected independently from C, each optionally substituted _3-6 cycloalkylene or C _{1 - 3} alkylene group; Q ₁ is NR _4, O, S, and S (O) or S (O) _2, wherein R ₄ is H, C _{1 -6} acyl, C _{1 -6} alkyl, C _2-6 alkenyl, C _{2 - 6} alkynyl, C _{3 -7-cycloalkyl} or C _{3 -7} - cycloalkyl, -C _{1 -3} - alkylene, wherein said C _{1 -6} alkyl is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6-alkyl-sulfonamide,} di -C _{1 -6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio O, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, hydroxylamino and nitro; Q ₂ is absent; W is N or CH; X is N or CR ₆ ; Y is N or CR ₇ ; Z is N or CR ₈ ; V is absent, or C _{1 -3} alkyl, C _{1 -6} alkoxy, carboxy, cyano, C _{1 -3} may each be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halogen in C _{1 -3} hetero alkylene or C _{1 -3} alkylene; R _6, R ₇ and R ₈ are H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 - 6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl amino, and the group consisting of nitro each of which is independently selected, wherein the C _{2 -6} alkenyl from, C _{1 -6} alkyl, C _{2 -6-alkynyl} and C _{3 -6} cycloalkyl is C _1-6 acyl, C _1-6 acyloxy, C _{2 -6} alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkyl-carboxamide, C _{2- 6} alkynyl, C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkyl thio, C _1-6 alkylthio-carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6-alkylamino,} C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di- C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen , C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl, amino and nitro one or more substituents independently selected from the group consisting of each optionally Can be substituted; Ar is aryl or heteroaryl, which may optionally be substituted with R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ ; R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 - 6} alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, arylcarbonyl, arylsulfonyl, di -C _1-6 - alkyl, amino, carboxylic one night yimido , C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6-alkyl} carboxamide, di -C _{1 -6-alkyl-sulfonamide,} di- C _1-6 - alkylthio carboxamido, guanidine, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _1-6 haloalkylsulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, hydroxylamino, nitro, C _{3 -6} oxo-cycloalkyl, phenoxy, sulfonamide, sulfonic acid and thiol; Wherein each R ₉ is C _{1 -6} acyl, C _{1 -6-acyl} sulfonamide, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _1-6 alkyl, C _{1 -6} alkyl amino, C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _1-6 alkylthio carboxamide, C _1-6 alkyl thioureido rail, C _1-6 alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di -C _1-6 - alkyl, amino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, di -C _{1 - 6-alkylthio-carboxamido,} C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio , Heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and ni Optionally substituted with one or more substituents independently selected from the group consisting of tro; R _10, R _11, R ₁₂ and R ₁₃ is C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino , C _{1 -6-alkyl-carboxamide,} C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _1-6 alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide, C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy , cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, hydroxyl amino, nitro, and thiol Independently selected from the group consisting of; Or two adjacent groups of the groups R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ together with the atoms to which they are attached are 5-, 6- or 7-membered cycloalkyl, 5-, 6- or 7-membered cycloalkenyl, or A 5-, 6- or 7-membered heterocyclic group is formed, wherein the 5-, 6- or 7-membered group can be optionally substituted with halogen or oxo; R ₂ is H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6} alkyl carboxylic carboxamide, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide , C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, arylcarbonyl, aryloxy, di -C _{1 -6} - alkylamino, carboxylic night yimido yl, C _{1 -6} alkoxycarbonyl carbonyl, C _{3 -7} - cycloalkyl alkoxycarbonyl, carboxamide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide di -C _{1 -6} - alkylthio carboxamido, guanidine, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl , C _{1 -6} haloalkylthio, heteroaryl, heteroaryl -C _1-3 - alkylene, heteroaryl-carbonyl, heteroaryloxy, Heterocycliccarboxamides, hydroxyl, hydroxylamino and nitro; Wherein R ₂ are each C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, C _{1 -6} alkylamino, C _{1 -6} alkyl carboxylic carboxamide, C _{2 -6-alkynyl,} C _{1 -6} alkyl sulfonamide, C _{1 -6} alkyl sulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkylthio carboxamide , C _{1 -6} alkyl thioureido rail, C _{1 -6} alkyl urea, amino, aryl, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, carboxy, cyano, C _3-6 cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _1-6 - alkyl sulfonamide, di -C _{1 -6} - alkylthio-carboxamido, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl, amino and nitro May be optionally substituted with one or more substituents independently selected from the group consisting of And, wherein the C _{1 -6} alkyl is added as a C _{1 -6} acyl, C _{1 -6} alkoxy, C _{1 -6} alkylamino, C _{1 -6-alkyl-carboxamide,} C _{1 -6} alkyl sulfonamide, C _{1 - 6} alkylsulfinyl, C _{1 -6} alkylsulfonyl, C _{1 -6} alkylthio, C _{1 -6} alkyl urea, amino, di -C _{1 -6} - alkylamino, C _{1 -6} alkoxycarbonyl, carboxamide, amide, carboxy, cyano, C _{3 -6} cycloalkyl, di -C _{1 -6} - alkyl carboxamides, di -C _{1 -6} - alkyl sulfonamide, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl , halogen, C _{1 -6} haloalkyl sulfinyl, C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, heterocyclic, hydroxyl, 1 is independently selected from the group consisting of hydroxyl, amino and nitro Optionally substituted with more than one substituent. 35. At least one compound according to any one of claims 1 to 34 or 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -piperi A pharmaceutical composition comprising dine-1-carboxylic acid isopropyl ester, and a pharmaceutically acceptable carrier. A therapeutically effective amount of a compound according to any one of claims 1 to 34 or 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -piperi A method of treating a metabolic-related disorder in an individual comprising administering a din-1-carboxylic acid isopropyl ester, or a pharmaceutical composition according to claim 35, to a subject in need thereof. 37. The group of claim 36, wherein said metabolic-related disorder consists of type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and X syndrome. Which is selected from. 35. At least one compound according to any one of claims 1 to 34 or 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -piperi A process for preparing a pharmaceutical composition comprising admixing a dine-1-carboxylic acid isopropyl ester and a pharmaceutically acceptable carrier. 35. A compound according to any one of claims 1 to 34 or 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) -pyrimidine for the manufacture of a medicament for the treatment of metabolic-related disorders. Use of 4-yloxy] -piperidine-1-carboxylic acid isopropyl ester. Medicament for the treatment of metabolic-related disorders selected from the group consisting of type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X 35. A compound according to any one of claims 1 to 34 or 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -pi for preparation Use of ferridine-1-carboxylic acid isopropyl ester. 35. A compound according to any one of claims 1 to 34 or 4- [6- (2-fluoro-4-methanesulfonyl-phenoxy) for use in a method of treating a human or animal body by therapy. -Pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester. 35. A compound according to any one of claims 1 to 34 or 4- [6- (2-fluoro-4) for use in a method of preventing or treating metabolic-related disorders of the human or animal body by therapy. Methanesulfonyl-phenoxy) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester.

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