MXPA06011198A

MXPA06011198A - Pyrimidine derivatives and methods of treatment related to the use thereof

Info

Publication number: MXPA06011198A
Application number: MXPA/A/2006/011198A
Authority: MX
Inventors: Semple Graeme; Tran Thuyanh; A Kramer Bryan; Sekiguchi Yoshinori; Kanuma Kosuke; Omodera Katsunori
Original assignee: Arena Pharmaceuticals Inc; Kanuma Kosuke; A Kramer Bryan; Omodera Katsunori; Sekiguchi Yoshinori; Semple Graeme; Taisho Pharmaceutical Co Ltd; Tran Thuyanh
Priority date: 2004-03-30
Filing date: 2006-09-28
Publication date: 2007-04-20

Abstract

The present invention encompasses novel substituted pyrimidine compounds of Formula (I):which act as MCH receptor antagonists. These compounds are useful in pharmaceutical compositions whose use includes prophylaxis or treatment of improving memory function, sleeping and arousal, anxiety, depression, mood disorders, seizure, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, binge eating disorders including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson’s disease, epilepsy, and addiction.

Description

PIRIMIDINE DERIVATIVES AND TREATMENT METHODS RELATED TO THEIR USE Field of the Invention The present invention relates to compounds that act as antagonists for MCH receptors and to the use of these compounds in pharmaceutical compositions. Background of the Invention The melanin concentration hormone (MCH), a cyclic peptide, has been identified as the endogenous ligand of the orphan protein G coupled to the SLC-1 receptor. See, for example, Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). Studies have indicated that MCH acts as a neurotransmitter / neuromodulator to modify a variety of behavioral responses such as eating habits. For example, the injection of MCH in rats has reported increasing their feed intake. Reports indicate that genetically engineered mice that lack HCM show lower body weight and increased metabolism. See, Saito et al., TEM, vol. 11, 299 (2000). As such, the literature suggests that the discovery of MCH antagonists that interact with cells that express SCL-1 will be useful in the development of anti-obesity treatments. See, Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). The G-protein coupled receptors (GPCRs) share a common structural motif. All these receptors have seven sequences of 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which expands the membrane. The fourth and fifth transmembrane helices are bound on the extracellular side of the membrane by a chain of amino acids that forms a relatively large circuit. Another larger circuit, composed mainly of hydrophilic amino acids, joins the transmembrane helices five and six on the intracellular side of the membrane. The carboxy terminal of the receptor resides intracellularly, and the amino terminal resides in the extracellular space. It is believed that the circuit linking the helices five and six, as well as the carboxy terminal, interact with the G protein. Currently, Gq, Gs, Gi, and Go are G proteins that have been identified as possible proteins that interact with the receptor . Under physiological conditions, GPCRs exist in the cell membrane in equilibrium between two different states or conformations: an "inactive" state and an "active" state. A receptor in an inactive state is unable to bind to the intracellular transduction path to produce a biological response. The change of the conformation of the receptor to the active state allows the link to the transduction path and produces a biological response.

A receptor can be stabilized in an active state by an endogenous ligand or an exogenous agonist ligand. Recent discoveries, including, but not limited to, modifications to the amino acid sequence of the receptor, provide alternative mechanisms to the ligands to stabilize the conformation of the active state. These methods effectively stabilize the receptor in an active state by stimulating the effect of a ligand that binds to the receptor. Stabilization by such ligand-independent procedures is termed "constitutive activation of the receptor." In contrast, antagonists can competitively bind to the receptor at the same site as agonists, but do not activate the intracellular response initiated by the active form of the receptor, and consequently inhibit intracellular responses by agonists. Certain 2-aminoquinazoline derivatives have been reported as NPY antagonists that are said to be effective in the treatment of disorders and diseases associated with the Y5 subtype of the NPY receptor. See, PCT Patent Application 97/20823. It has also been found that quinazoline derivatives are useful in increasing anti-tumor activity. See, Patent Application PCT 92/07844. And quinoline derivatives having antagonist activity for such an MCH receptor in these patents are also known., WO 03/070244, WO 03/105850, WO 03/45313, WO 03/045920, and WO 04/04726. Recently, our current knowledge of human obesity has advanced dramatically. Previously, obesity was observed as an opposite behavior. of inappropriate ingestion of food in the setting of attractive foods. Studies in animal models of obesity, biochemical alterations in both humans and animals, and the complex interactions of psychosocial and cultural factors that create receptivity to human obesity, indicate that this disease in humans is ultifacetico and deeply hidden in biological systems. Therefore, it is almost certain that obesity has multiple causes and that there are different types of obesity. The MCHRI antagonist not only has potent and durable anti-obesity effects in rodents, surprisingly it also has antidepressant and anxiolytic properties (Borowsky et al., Nature Medicine, 8, 825-830, 2002). It has been reported that antagonists show antidepressant and anxiolytic activities in rodent models such as social interaction, forced swimming test and ultrasonic vocalization. These findings indicate that MCHRI antagonists could be useful for the treatment of obesity in patients with multiple causes. In addition, MCHRI antagonists could be used to treat subjects not only with obesity, but also those with depression and anxiety. These advantages make them different from the NPY receptor antagonists, with which an activity similar to anxiogenic can be expected, since NPY itself has an effect similar to anxiolytic. Obesity is also considered a chronic disease and the possibility of long-term treatment is a concept that receives more attention. In this context, it is notable that depletion of HCM leads to hypophagia as well as shortage (Shimada et al., Nature, 396, 670-674, 1998). In contrast, mice with NPY receptors (Erickson et al., Nature, 381, 415-418, 1996), as well as Yl (Pedrazzini et al., Nature Medicine, 4, 722-726, 1998) Y5 (Marsh et al. ., Nature Medicine, 4, 718-721, 1998) disorganized maintained a stable body weight or instead became obese. Considering previous reports, MCHR1 antagonists may be more attractive than Yl or Y5 receptor antagonists in terms of the long-term treatment of obese patients. Obesity, which is the result of an imbalance between caloric intake and energy expenditure, is highly correlated with insulin resistance and diabetes in experimental animals and humans. However, the molecular mechanisms involved in the obesity-diabetes syndromes are unclear. During the early development of obesity, the balance of insulin secretion and insulin resistance are increased and patients are protected from hyperglycemia (Le Stunff, et al., Diabetes 43, 696-702 (1989)). However, after several decades, β-cell function deteriorates and non-insulin-dependent diabetes develops in approximately 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)). Given its high prevalence in modern societies, obesity has thus become the main risk factor for NIDDM (Hill, J. O., et al., Science 280, 1371-1374 (1998)). However, the factors that predispose a fraction of patients to the alteration of insulin secretion in response to the accumulation of fats remain unknown. Whether someone is determined to be overweight or obese, it is usually determined based on their body mass index (BMI) which is calculated by dividing body weight. (kg) between the head height (m2). Therefore, the BMI units are kg / m2 and it is possible to calculate the BMI range associated with the minimum mortality in each decade of life. Overweight is defined as a BMI in the range of 25-30 kg / m2, and obesity as a BMI greater than 30 kg / m2 (See, TABLE below). There are problems with this definition since the proportion of body mass that is muscle in relation to fat (adipose tissue) is not taken into account. Counting on this, obesity can also be defined based on the body fat content: greater than 25% and 30% in males and females, respectively. CLASSIFICATION OF WEIGHT BY BODY MASS INDEX (BMI) As BMI increases there is an increased risk of death from a variety of causes independent of other risk factors. The most common diseases with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), bladder irritation disease (particularly cancer) and reproductive diseases. Research has shown that even modest resuscitation in body weight may correspond to a significant reduction in the risk of developing coronary heart disease. Compounds marketed as anti-obesity agents include Orlístat (XENICAL ™) and Sibutramine. Orlistat (a lipase inhibitor) directly inhibits the absorption of fats and tends to produce a high incidence of unpleasant (though relatively harmless) side effects. as diarrhea. Sibutramine (a mixed 5-HT / noradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. Inhibitors of release / reuptake of The serotonin, fenfluramine (Pondimin ™) and dexfenfluramine (Redux ™) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were discontinued after reports of preliminary evidence of cardiac valve abnormalities associated with their use. Consequently, there is a need to develop a safer anti-obesity agent. Obesity considerably increases the risk of developing cardiovascular diseases as well. Coronary insufficiency, atheromatous disease, heart failure are at the forefront of cardiovascular complications induced by obesity. It is estimated that if the total population had the ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of heart failure and stroke by 35%. The incidence of coronary heart disease doubles in subjects under 50 years of age who are 30% overweight. The diabetic patient faces a 30% reduction in their life extension. After age 45, people with diabetes are about three times more likely than people without diabetes to have significant heart disease and up to five times more likely to have a heart attack. These findings emphasize the inter-relations between risk factors for NIDDM and coronary heart disease and the potential value of an integrated procedure for the prevention of these conditions based on the prevention of obesity (Perry, IJ, et al., BMJ 310 , 560-564 (1995)). An increasing number of children and adolescents are overweight. Although not all overweight children will necessarily become overweight adults, it is likely that the increasing occurrence of obesity in childhood will be reflected in an increase in obesity in adulthood. The high prevalence of obesity in our adult population and the likelihood that the nation of the future will be even more obese, demands a re-examination of the health implications of this disease. See, Health Implications of Obesity. NIH Consens. Statement Online 1985 Feb 11-13; 5 (9): 1-7. "Clinical obesity" is a measure of excess body fat in relation to the shortage of body mass and is defined as a body weight of more than 20% above the ideal body weight. Recent estimates suggest that 1 out of every 2 adults in the United States is clinically obese, an increase of more than 25% over the past decades. Flegal M.D. et al., 22 Int. J. Obes. Rela t. Metab. Disor. 39 (1998). Both the condition of overweight and clinical obesity are important health problems throughout the world, in particular because clinical obesity is often accompanied by numerous complications, ie, hypertension and Type II Diabetes, which in turn can cause disease. the coronary artery, infarction, complications in the terminal stage of diabetes and premature death. (See, e.g., Nishina P.M. et al., 43 Metab. 554 (1994)). Although the etiological mechanisms on which obesity is based require further clarification, the net effect of such mechanisms leads to an imbalance between intake and energy expenditure. It is likely that both genetic and environmental factors are involved in the pathogenesis of obesity. These include excess caloric intake, decreased physical activity, and metabolic and endocrine abnormalities. The treatment of conditions of overweight and clinical obesity through pharmaceutical agents is not only important with respect to the conditions themselves, but also with respect to the possibility of preventing other diseases associated with, e. g. , clinical obesity, as well as the increase in the positive feeling of self-esteem that frequently accompanies those who are overweight or who are clinically obese and who find a significant reduction in body weight. Given the above, it is apparent that the compounds that help in the treatment of such disorders would be useful and would provide an advance in both clinical and research medicine. The present invention is directed to these, as well as to other important purposes. SUMMARY OF THE INVENTION The present invention is directed to compounds, which bind to and modulate the activity of a GPCR referred to herein as MCH, and to its uses. The term MCH, as used herein, includes the human sequences found in GeneBank accession number NM_005297, allelic variants of natural origin, mammalian orthologs, biologically active fragments and their recombinant mutants. One aspect of the present invention relates to certain substituted pyrimidine compounds represented by Formula (I): (I) where Q is (Ha) or (Ilb) Ri is selected from the group consisting of: (i) CH6 alkyl, and C? -16 alkyl substituted by the independently selected substituent (s) from the group consisting of: • halogen, • hydroxy, • oxo , "C 1 -C 5 alkoxy, C 1 -C 5 alkoxy substituted by the substituent (s) independently selected from the group consisting of: •• carbocyclic aryl, •• heterocyclyl, and •• heterocyclyl substituted by Ci_5 alkyl • C 1-5 alkylcarbonyloxy, • carbocyclyloxy, • carbocyclic aryloxy, • carbocyclic aryloxy substituted by the independently selected substituent (s) from the group consisting of: • 'halogen, • -hydroxy, • • carboxy, • • carbamoyl, • "nitro, • * cyano, • • amino, •• carbocyclic aryl, • carbocyclic aryl substituted by alkoxy C? _5, •• alkoxy C? _5, •• alkoxy C? _5 substituted by halogen, • «Alkyl? -5, and •• alkyl C? _5 substituted by the (s) independently selected (s) of the group consisting of: • • "halogen, • •" hydroxy, • • • carboxy, • • • oxo, ••• mono-alkylamino C? -5, • • • di -alkylamino C? _5, ••• mono-alkylamino C? _5 substituted by carbocyclic aryl, ••• di-alkylamino C? _5 substituted by carbocyclic aryl, • • 'mono-alkylamino C! _5 substituted by halogenated carbocyclic aryl, • •• di-alkylamino C? Substituted by halogenated carbocyclic aryl, • • • carbocyclic arylcarbonylamino, and • • 'carbocyclic arylcarbonylamino substituted by halogen, • heterocyclyloxy, • heterocyclyloxy substituted by the independently selected substituent (s) of the group consisting of: • 'halogen, • * hydroxy, • • carboxy, • • carbamoyl, •' nitro, • • cyano, • • amino, •• carbocyclic aryl, •• carbocyclic aryl substituted by C? _5 alkoxy, •• alkoxy C? -5, •• a C.sub.1 -C.sub.1 substituted by the substituent (s) independently selected from the group consisting of: • • -halogen, • • • hydroxy, and • • • carboxy, • alkyl Cj_5, and •• alkyl C? _5 substituted by the substituent (s) independently selected from the group consisting of: • • 'halogen, • • "hydroxy, and • • • carboxy, • substituted heterocyclyl-ethylideneaminooxy, • alkoxycarbonyl C? _5, "alkoxycarbonyl" -5 substituted by carbocyclic aryl, • mono-alkylaminocarbonyl C1-5, • di-alkylaminocarbonyl C1-5, • mono-alkylamino C? _s, • mono-alkylamino C? _5 substituted by the substituent (s) independently selected from the group consisting of: • "cyano, •• carbocyclic aryl, and • • heterocyclyl," di-alkylamino C? ~ 5, • di-C1- alkylamino substituted by the ) substituent (s) independently selected from the group consisting of: • 'cyano,' * aryl car bocyl, and • • heterocyclyl, • carbocyclic mono-arylamino, • carbocyclic mono-arylamino substituted by the independently selected substituent (s) from the group consisting of: • 'halogen, • • hydroxy, • • carboxy , • • carbamoyl, • "nitro, • • cyano, • • amino, •• carbocyclic aryl, •• carbocyclic aryl substituted by alkoxy C? _5, •• alkoxy C? -5, •• alkoxy Ca-s substituted by The substitute (s) independently selected from the group consisting of: • • "halogen, • • 'hydroxy, and • • * carboxy, •' alkyl C___5, and •• alkyl C? _5 substituted for ( The substitute (s) independently selected from the group consisting of: • • 'halogen, • •' hydroxy, and • • • carboxy, • carbocyclic di-arylamino, • carbocyclic di-arylamino substituted by the (s) substituent (s) independently selected from the group consisting of: "Halogen, •" hydroxy, • • carboxy, •• carbamoyl, • "nitro, •" cyano, • • amino, •• carbocyclic aryl, •• carbocyclic aryl substituted by C1-5 alkoxy, • • alkoxy C? _5, •• C1-5 alkoxy substituted by the independently selected substituent (s) from the group consisting of: • • 'halogen, • •' hydroxy, and • • • carboxy, • C 1 -C 5 alkyl, and C 1 -C 5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • • 'halogen, • • • hydroxy, and • • • carboxy, • mono-heterocyclylamino, mono-heterocyclylamino substituted by the independently selected substituent (s) from the group consisting of: • "halogen, * 'hydroxy, • • carboxy, • • carbamoyl, • "Nitro, •" cyano, • • amino, "" carbocyclic aryl, •• carbocyclic aryl substituted by C1-5 alkoxy, • • C5-5 alkoxy, •• C5-5 alkoxy substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • • hydroxy, and • • • carboxy, •" alkyl C _.- 5, and •• C-5 alkyl substituted by the substituent (s) (s) independently selected from the group consisting of: • • 'halogen, • •' hydroxy, and • • • carboxy, 'di-hetero cyclilamino, • di-heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "hydroxy, • • carboxy, • • carbamoyl, •" nitro, • " cyano, •• amino, •• carbocyclic aryl, •• carbocyclic aryl substituted by C5-5 alkoxy, • • C5-5 alkoxy, •• C5-5 alkoxy substituted by the independently selected substituent (s) ) of the group consisting of: • • '' halogen, • • 'hydroxy, and • •' carboxy, • 'C 1 _5 alkyl, and •' C 1-5 alkyl substituted by the independently selected substituent (s) ( s) of the group consisting of: • • 'halogen, • •' hydroxy, and • • • carboxy, • C5 alkylcarbonylamino, • C5-5 alkylcarbonylamino substituted by the independently selected substituent (s) from the group consisting of: •• alkylcarbonylamino C___5, •• carbocyclic arylcarbonylamino, and • heterocyclyl, • C5-5 alkoxycarbonylamino, • carbocyclic arylcarbonylamino, • carbonylamino heterocyclyl, • carbocyclic arylsulfonylamino, • carbocyclic arylsulfonylamino substituted by the independently selected substituent (s) from the group consisting of: • «nitro, • "alkyl C___5, •" mono-alkylamino C? S, and •• di-C1-5 alkylamino. • C 1 -C 5 alkylthio-C 1-5 alkylthio substituted by the substituent (s) independently selected from the group consisting of: • • carbocyclic mono-arylaminocarbonyl, • carbocyclic mono-arylaminocarbonyl substituted by halogen, • • carbocyclic di-arylaminocarbonyl, • • carbocyclic di-arylaminocarbonyl substituted by halogen, • • carbocyclic mono-arylamino, • • carbocyclic mono-arylamino substituted by halogen, •• carbocyclic di-arylamino, • * carbocyclic di-arylamino substituted by halogen , •• carbocyclic aryl, and • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, and • • * C1-5 alkoxy, • carbocyclic arylthio, * carbocyclic arylthio substituted by the substituent (s) independently selected from the group consisting of: • "halogen, • • C5_5 alkyl, and •• substituted C5_5 alkyl by halogen, • carbocyclic arylsulfinyl, • carbocyclic arylsulfinyl substituted by the substituent (s) independently selected from the group consisting of: • 'halogen, •' C -C _ alkyl, and • C -C5 alkyl substituted by halogen, • carbocyclic arylsulfonyl, • carbocyclic arylsulfonyl substituted by the independently selected substituent (s) from the group consisting of: • 'halogen, •• C1-5 alkyl, and •• C1-5 alkyl substituted by halogen, * heterocyclylthio, • heterocyclicthio substituted by the substituent (s) independently selected from the group consisting of: • * nitro, and • «C? -5 alkyl,« C3-6 cycloalkyl, • cycloalkyl C3-6 substituted by C1-5 alkyl, • C3_6 cycloalkyl substituted by carbocyclic aryl, • C3_6 cycloalkenyl, • carbocyclyl, * carbocyclyl substituted by the independently selected substituent (s) from the group consisting of: 'halogen• "C 1 _ 5 alkyl, • • C 1 -C 5 alkoxy," "C 2-5 alkenyl, and C 2 -C 5 alkenyl substituted by the independently selected substituent (s) from the group consisting of: •• carbocyclic aryl, and ••• carbocyclic aryl substituted by alkylsulfinyl C? _5, • carbocyclic aryl, • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • «halogen, • "hydroxy, • • carboxy, • • carbamoyl, •• cyano, •" nitro, • • amino, •• alkylcarbonylamino Cj._5, • • cycloalkylcarbonylamino C3_6. • C1-5 alkyl, •• C1-5 alkyl substituted by the substituent (s) independently selected from the group consisting of: halogen, • • • hydroxy, • • carboxy, • • carbamoyl, • * oxo, •• carbocyclic aryl, • • 'heterocyclyl, • • carbocyclic mono-arylamino, •• carbocyclic di-arylamino, • • carbocyclic mono-arylamino substituted by the independently selected substituent (s) from the group which consists of: • «halogen, •« nitro, • «alkyl C? _5, • • alkoxy C; L_5; and •••• C5_5 alkoxy substituted by halogen, ••• carbocyclic di-arylamino substituted by the independently selected substituent (s) from the group consisting of: • • • 'halogen, • • • • "nitro, • • • 'alkyl C? _5, • • • • alkoxy C? _5, and •••• C? -5 alkoxy substituted by halogen, •• C2-5 alkenyl, • • alkoxy C? _5, •• Cj.-5 alkoxy substituted by the substituent (s) independently selected from the group consisting of: • • «halogen, and ••• carbocyclic aryl, •• carbocyclic aryloxy, •• alkoxycarbonyl C? -5,? C5-alkylcarbonyloxy,? C5-5 mono-alkylamino, C5-5-di-alkylamino, carbocyclic mono-arylamino, carbocyclic mono-arylamino substituted by halogen,? carbocyclic di-arylamino, • * carbocyclic di-arylamino substituted by halogen, • • mono-arylaminocarbonyl carbocyclic, • 'mono-arylaminocarbonyl is substituted by the substituent (s) selected from the group consisting of: • 'halogen, •' nitro, • 'alkyl C? -5, • • C1-5 alkoxy, and •• alkoxy C? -5 substituted by halogen, • • carbocyclic di-arylaminocarbonyl, •• carbocyclic di-arylaminocarbonyl substituted by the substituent (s) selected from the group consisting of: • «halogen, •« nitro, ••• alkyl C? -5, • • C5-alkoxy, and •• C5-5 alkoxy substituted by halogen, • "mercapto, •• alkylthio C? _5, •• C5-5 alkylthio substituted by halogen, •• alkylsulfonyl C Β5, •• C3_6 cycloalkyl, •• carbocyclic aryl, and • "heterocyclyl, • heterocyclyl, and • heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • -halogen, • «Hydroxy, • • carboxy, • • carbamoyl, •« cyano, • «nitro, • • amino, •« alkyl C? _5, •• alq uilo C? -5 substituted by the substituent (s) independently selected from the group consisting of: • • -halogen, • • hydroxy, • • • carboxy, and • • • carbamoyl, •• alkyl C.sub.5 substituted by carbocyclic aryl, • • C5-5alkoxy, •• C5-5alkoxy substituted by halogen, •• C5-5alkoxy substituted by carbocyclic aryl, •• carbocyclic aryl, and • carbocyclic aryl substituted by halogen, (ii) C2_8 alkenyl, and C2-alkenyl substituted by the substituent (s) independently selected from the group consisting of: • halogen, • oxo, "alkoxy C? -5, • alkoxy C? _5 substituted by carbocyclic aryl, • carbocyclic aryl, • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • -halogen, • • hydroxy, • "nitro, •" alkyl C? -5, • "C1-5 alkyl substituted by halogen, •" alkoxy C? _5, and •• a C 1 -C 5 -coxy substituted by halogen, • heterocyclyl, and • heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • • hydroxy, • "nitro, •" alkyl C? _5 , and • • C5-5 alkoxy, (iii) C2-5 alkynyl, and C3_5 alkynyl substituted by carbocyclic aryl, (iv) C3_2 cycloalkyl, and C3_2 cycloalkyl substituted by the independently selected substituent (s) (s) of the group consisting of: * C? _5 alkyl,? C5_5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • "hydroxy, • • oxo, and •• carbocyclic aryl, • mono-alkylamino C? -5, • mono-alkylamino Ci_5 substituted by carbocyclic aryl, • di-alkylamino C? _5, • di-alkylamino C? _5 substituted by carbocyclic aryl, • carbocyclic arylcarbonylamino, • aryl carbocyclic, and • carbocyclic aryl substituted by halogen, (v) C3_6 cycloalkenyl, and cyclic C 3-6 alkenyl substituted by C 1 -C 5 alkyl, (vi) carbocyclyl, and carbocyclyl substituted by substituent (s) independently selected from the group consisting of: • hydroxy, and • nitro, (vii) carbocyclic aryl, and carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • halogen, "hydroxy, • cyano, • nitro, • Cuo alkyl, • C 1 -C 0 alkyl substituted by the substituent (s) independently selected from the group consisting of: • "halogen, •" hydroxy, • • carboxy, • • carbamoyl, • XO, • • C5-, C5-, C5-C6-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C2-C2-C5-C2-C2 • di-alkylamino C? _5, • • mono-C1-5 alkylamino substituted by carbocyclic aryl, •• di-C1-5 alkylamino substituted by carbocyclic aryl, • 'carbocyclic mono-arylamino, •• carbocyclic di-arylamino, • • carbocyclicimino, • • carbocyclicimino substituted by carbocyclic aryl, • "mono-arylamino carbocyclic, •• di-arylamino carbocyclic, • • mono-arylamino carbocyclic substituted by alkoxy C? -5, •• carbocyclic di-arylamino substituted by alkoxy • "carbocyclic mono-arylaminocarbonyl, • carbo-cyclic carbocarboxylaminocarbonyl, • carbocyclic mono-arylaminocarbonyl substituted by C1-5 alkoxy, carbocyclic di-arylaminocarbonyl substituted by carbocyclic alkoxy, carbocyclic aryl, carbocyclic aryl. substituted by the independently selected substituent (s) from the group consisting of: • • "halogen, • • • C alquilo-5 alkyl, and ••• C alquilo?? 5 alkyl substituted by halogen, •• heterocyclyl, and • • heterocyclyl substituted by C? _5 alkyl, • C2-s alkenyl, • C2-5 alkenyl substituted by carbocyclic aryl, • C? _9 alkoxy, "C? -9 alkoxy substituted by the substituent (s) ) independently selected from the group consisting of: • • hydroxy, • 'halogen, •' carboxy, • 'mono-alkylamino C? -5, •• di-alkylamino C? _5, •• carbocyclic aryl, •• halogenated carbocyclic aryl, • 'heterocyclyl, •• substituted heterocyclyl by the independently selected substituent (s) from the group consisting of: • • 'halogen, • •' heterocyclyl, and • • 'heterocyclyl substituted by the independently selected substituent (s) of the group consisting of: • • • "halogen, •••• C-alkyl -5, and •••• C5_5 alkyl substituted by halogen, • C2-5 alkenyloxy, • C3_6 cycloalkoxy, • C5_5 alkylcarbonyloxy , • carbocyclic aryloxy, carbocyclic aryloxy substituted by the substituent (s) independently selected from the group consisting of: • 'halogen, • • hydroxy, •' carboxy, • • carbamoyl, • • cyano, • Nitro, • • amino, •• C5 alkyl, •• C5-5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • • 'halogen, • •' hydroxy , • • • carboxy, and • • • carbamoyl, • • C1-5 alkoxy, and •• alkoxy C? -5 substituted by halogen, "heterocyclyloxy, • heterocyclyloxy substituted by the substituent (s) independently selected from the group consisting of: •" halogen, • 'hydroxy, •' carboxy, • • carbamoyl, • 'cyano, • 'Nitro, • • amino, •' C5_5 alkyl, •• C5_5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • • 'halogen, • • "Hydroxy, • • • carboxy, and • • • carbamoyl, •• alkoxy C? _5, and •• C? -5 alkoxy substituted by halogen, • (carbocyclic aryl) S (0) 20, • carboxy, • carbamoyl, • C 1 -C 5 alkoxycarbonyl, • C 1 -C 5 mono-alkylaminocarbonyl, • C 1 -C 5 di-alkylaminocarbonyl, • C 1 -C 5 mono-alkylaminocarbonyl substituted by carbocyclic aryl, • C 1 -5 alkylaminocarbonyl substituted by carbocyclic aryl, carbocyclic mono-arylaminocarbonyl , • di-arylaminocarbonyl carbocyclic, • mono-arylaminocarbonyl carboc Clico substituted by C ___ 5 alkyl, • carbocyclic di-arylaminocarbonyl substituted by C 1-5 alkyl, • amino, • mono-C 1-5 alkylamino, • C 1 -5 alkylamino, • C 1 -C 5 mono-alkylamino substituted by cyano, di-C5-alkylamino substituted by cyano, • carbocyclic mono-arylamino, • carbocyclic di-arylamino, • C5-alkylcarbonylamino, • C6 cycloalkylcarbonylamino, • C2_5 alkynylocarbonylamino, • C2-5 alkynylocarbonylamino substituted by carbocyclic aryl, • alkoxycarbonylamino C_ .5, • carbocyclic arylsulfonylamino, • carbocyclic arylsulfonylamino substituted by Cl-5 alkyl, • (carbocyclic aryl) NHC (O) H, • (carbocyclic aryl) NHC (O) NH substituted by C5-alkoxy, • (carbocyclic aryl) ) NHC (O) NH substituted by halogenated C? _5 alkoxy, • carbocyclic aryl azo, • carbocyclic aryl azo substituted by mono-alkylamino C-5, carbocyclic aryl azo substituted by di-alkylamino C? , • C 1_5 alkylthio, • C-5 alkylthio substituted by halogen, • carbocyclic arylthio, • carbocyclic arylthio substituted by the substituent (s) independently selected from the group consisting of: • «halogen, •« nitro , • "cyano, and •" alkyl C? _5, "aminosulfonyl, • heterocyclicthio, • alkylsulfonyl C? _5Mono-alkylaminosulfonyl C? -5,? Di-alkylaminosulfonyl C? _5,? Heterocyclylsulfonyl,? C3_6 cycloalkyl,? C3_6 cycloalkyl substituted by C? _5 alkyl ,? carbocyclic aryl ,? carbocyclic aryl substituted by the substituent ( s) independently selected from the group consisting of: "C" _7 alkyl, and •• C7_7 alkyl substituted by halogen, "heterocyclyl, and • heterocyclyl substituted by the independently selected substituent (s) ( s) of the group consisting of: • C5 _5 alkyl, •• carbocyclic aryl, and • halogenated carbocyclic aryl, • C1-5 alkoxycarbonyl substituted by carbocyclic aryl, and (viii) heterocyclyl, and heterocyclyl substituted by the ) substituent (s) independently selected from the group consisting of: • halogen, • hydroxy, • carboxy, • carbamoyl, • cyano, • nitro, • amino, • alkyl C? _5, "alkyl C ^ s substituted by the substituent (s) in Dependently selected from the group consisting of: • "halogen, • • hydroxy, • • carboxy, •• carbamoyl, • • oxo, •" alkylcarbonyloxy C ^ s, • • carbocyclic arylcarbonylamino, •• carbocyclic arylcarbonylamino substituted by halogen , • C 1 -C 5 alkoxycarbonyl, •• C 1-5 alkylthio, C 5 alkylthio substituted by carbocyclic aryl, C 5 substituted alkylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, substituted carbocyclic aryl ) substituent (s) independently selected from the group consisting of: ••• halogen, and • • "nitro, •" heterocyclyl, and •• heterocyclyl substituted by the independently selected substituent (s) of the group consisting of: • • "halogen, • •" alkyl C ^ s, and ••• alkyl Ca_5 substituted by halogen, • alkoxy C1-5, -alkoxy C? -5 substituted by halogen, • alkoxy C? 5 replaced by ari carbocyclic, • carbocyclic aryloxy, • carbocyclic aryloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen, •" nitro, • "cyano, • • hydroxy, • • carboxy , • • carbamoyl, • • amino, • "C 1 -C 5 alkyl, •• C 1 -C 5 alkyl substituted by the independently selected substituent (s) from the group consisting of: •" halogen, • 'hydroxy • • carboxy, and • • carbamoyl, •• mono-alkylamino C? _5, •• di-alkylamino C? _5, •• alkylcarbonylamino C? _5, • • C3-6 cycloalkylcarbonylamino, • • C1-5 alkoxy, • • C1-5 alkoxy substituted by halogen, •• C3-6 cycloalkyl, •• C2-5 alkenyl, •• C2_5 alkynyl, • • carboxy, •• C1-5 alkoxycarbonyl, • • mono-alkylaminocarbonyl C? _5, • • di-alkylaminocarbonyl C___5, • • C3_6 mono-cycloalkylaminocarbonyl, • • C3-6 cycloalkylaminocarbonyl, • mono-alkylaminocarbonylamino C? -¡, • • di-alkylaminocarbonylamino C? -5, • * mono-cicloalquilaminocarbonilamino C3_6, • "di-cycloalkylaminocarbonylamino C3-6," "alkylthio C? -5,? Alkylthio C? _5 substituted by halogen,? Alkylsulfinyl C? -5,? Alkylsulfinyl C._5 substituted by halogen,? Alkylsulfonyl C? _5, and C.sub.5 alkylsulfonyl substituted by halogen, • heterocyclyloxy, • heterocyclyloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen, • * nitro, • 'hydroxy, • • carboxy, • • carbamoyl, • • cyano, • • amino, •• C5 _5 alkyl, •• C -s alkyl substituted by the independently selected substituent (s) from the group consisting of; ••• halogen, • • hydroxy, • • carboxy, and • • carbamoyl, •• alkoxy C? _5, and «'alkoxy C? -5 substituted by halogen, • mono-alkylamino C? -5, • di-alkylamino C5.5, C5 alkylcarbonylamino, C5.5 alkylthio, C2.5 alkenylthio, carbocyclic arylthio, carbocyclic arylthio substituted by halogen, carbocyclic arylthio substituted by alkoxycarbonyl C5.5, • heterocyclicthio, "heterocyclicthio substituted by C 1 -C 5 alkyl, • C 1 -C 5 alkylsulfinyl, • C 1 -C 5 alkylsulfonyl, • carbocyclic arylsulfinyl, • carbocyclic substituted arylsulfinyl by halogen, • carbocyclic arylsulfonyl, • carbocyclic arylsulfonyl substituted by halogen, • substituted carbocyclic arylsulfonyl for alkyl C? _5, • C5-5alkoxycarbonyl, • C5-5alkoxycarbonyl substituted by carbocyclic aryl, "carbocyclic aryl, • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • 'halogen, • "Nitro, • • C4 alkyl, •• C5-5 alkyl substituted by halogen, • • C5-5 alkoxy, and •• C5-5 alkoxy substituted by halogen, • heterocyclyl, and • heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "C1-5 alkyl," "C5-alkyl substituted by halogen, • • alkoxy Ca-5, and •• alkoxycarbonyl C? -; R 2 is halogen, C 1-7 alkyl, C 1-5 alkyl substituted by halogen, C 1-5 alkyl substituted by hydroxy, C 1-5 alkyl substituted by carbocyclic aryl, C 1-5 alkyl substituted by halogenated carbocyclic aryl, C? 5 alkyl substituted by heterocyclyl, C1-5 alkyl substituted by halogenated heterocyclyl, C2-5 alkenyl, C2_5 alkynyl, C5_5 alkoxy, C1-5 alkoxy substituted by halogen, C_5_alkyl, -N (R2a) (R2b); wherein R2a and R2b are each independently hydrogen, C5 alkyl, or C5-5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • halogen, hydroxy, • carboxy, • carbamoyl, • C5-5 alkoxy, • a, "C3_6 cycloalkyl, • carbocyclic aryl, • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • -halogen • "C 1 _5 alkyl," "C 1 _5 alkoxy, • C" _5 alkyl substituted by halogen, •• C 5 -alkoxy substituted by halogen, and "-S02NH2, • heterocyclyl, and • heterocyclyl substituted by the (the) substituent (s) independently selected from the group consisting of: • "halogen," "C alquilo _5 alkyl, • • C?-5 alkoxy, • C alquilo _5 alkyl substituted by halogen, and •" C5-5 alkoxy substituted by halogen, C3_e cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by the independently selected (s) from the group consisting of: • halogen, • C ?_5 alkyl, • Ci-5 alkoxy, • C 1-5 alkyl substituted by halogen, and • C 1-5 alkoxy substituted by halogen, heterocyclyl, or heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • halogen, • C 1, 5 alkyl, • C 1 -C 5 alkoxy, • C 5 alkyl substituted by halogen , and • C5-alkoxy substituted by halogen; L is selected from the group consisting of Formulas (III), (IIIa), (IIIb), (IV), (IVa) and (IVb); (Illa) (Illb) (IV) (IVa) (IVb) wherein R3 and R4 are each independently hydrogen or -5 alkyl; and A and B are each independently a unique bond, -CH2-, or - (CH2) 2 ~; Z, Z2, Z3, and Z4 are each independently hydrogen, halogen, C5 alkyl, C5 alkyl substituted by halogen, C5 alkyl substituted by hydroxy, C5 alkyl substituted by carbocyclic aryl, C alkyl? _5 substituted by halogenated carbocyclic aryl, C5_5alkyl substituted by heterocyclyl, C1-5alkyl substituted by halogenated heterocyclyl, C2_5alkenyl, C2_5alkynyl, C3_6 cycloalkyl, C1-5alkoxy, C5_5alkyl substituted by halogen, monoalkylamino C5_5 , di-alkylamino Ca_5. alkylthio C? -5, carbocyclic aryl, substituted carbocyclic aryl, heterocyclyl, or substituted heterocyclyl; or R2 and Z2 are linked together to form a ring and -R2-Z2- is - (CH2) n- or - (CH2) or -CH = CH- (CH2) p-; wherein a -CH2- group can optionally -R2-Z2- replaced by C (O), NR6, O, S, S (O) or S (0) 2; where n is 2, 3, 4, 5, or 6; or and p are each independently 0, 1, 2, 3, or 4 provided that o + p = 0, 1, 2, 3, or 4; and R & is hydrogen, C alquilo _ alkyl, or substituted C___5 alkyl; and Y represents: (i) -C (0) NR5-, -C (S) NR5-, -C (0) 0-, -S (0) 2-, -C (O) -, -C (S ) -, or - (CH2) m- when L is selected from the group consisting of Formulas (III), (Illa), and (Illb); or (ii) -C (0) NR5-, -C (S) NR5-, -C (0) 0-, or -0C (0) - when L is selected from the group consisting of the Formulas (IV), (IVa), and (IV); wherein R5 is hydrogen or C__5 alkyl; and m is 0, 1, 2, 3, 4, or 5; wherein carbocyclic aryl is phenyl, naphthyl, anthranil, phenanthryl, or biphenyl; carbocyclyl is 10, 11-dihydro-5-oxo-dibenzo [a, d] cycloheptyl, 1-oxo-indanyl, 7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptyl, 9H-fluorenyl, 9- oxo-fluorenyl, acenaphthyl, anthraquinonyl, C-fluoren-9-ylidene, i'ndanil, indenyl, menthyl, 1,2,3,4-tetrahydro-naphthyl, or bicyclo [2.2. ljheptenil; heterocyclyl is 1, 2, 3, 4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3,4-thiadiazolyl, 1,3-dioxo-isoindolyl, 1,3-dioxolanyl, 1H-indolyl, Iff-pyrrolo [2, 3-c] pyridyl, li? -pyrrolyl, l-oxo-3-isobenzofuranyl, 2, 2 ', 5' , 2 '' -tertiiophenyl, 2, 2 '-bitiofenil, 2,3-dihydro-l-oxo-isoindolyl, 2,3-dihydro-benzo [1,4] dioxinyl, 2,3-dihydro-benzofuryl, 2, 4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl, 3,4-dihydro-2i-benzo [1,4] oxazinyl, 3,4-dihydro-2i? -benzo [b] [1,4] dioxepinyl, 4ii-benzo [1, 3] dioxinil, 4H-benzopyranyl, 4-oxo-l, 5, 6, 7-tetrahydro-indolyl, 4-oxo-3,4- dihydro-phthalazinyl, 4-oxo-benzopyranyl, 9, 10, 10-trioxo-thioxanthenyl, 9-carbazolyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo [1,3] dioxolyl, benzo [2, 1, 3] oxadiazolyl, benzo [1, 2, 5] oxadiazolyl, benzo [b] thienyl, benzofuryl, benzothiazolyl, cinnolyl, furyl, imidazo [2, lb] thiazolyl, i idazolyl, isoxazolyl, morpholino, morpholinyl, oxazolyl, oxolanyl, piperazyl, piperidyl, pyridyl, pyrazolo [5, 1-b] thiazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, 2, 3- dihydro-benzofuryl, tetrahydro-thienyl, or benzofuranyl; halogen is fluoro, chloro, bromo, or iodo; or a pharmaceutically acceptable hydrate or solvate salt thereof. An aspect of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound, as described herein, in combination with a pharmaceutically acceptable carrier. One aspect of the present invention relates to methods for prophylaxis or treatment to improve memory function, sleep and wakefulness, anxiety, depression, mood disorders, seizures, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, eating disorders including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson's disease, epilepsy, and addiction comprising administering to an individual suffering from said condition a therapeutically effective amount of a compound, as described herein, or a pharmaceutical composition thereof. An aspect of the present invention relates to methods for the prophylaxis or treatment of an eating disorder, obesity or an obesity-related disorder comprising administering to an individual suffering from said condition a therapeutically effective amount of a compound, as described in the present, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for the prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy comprising administering to an individual suffering from said condition a therapeutically effective amount of a compound, as described in present, or a pharmaceutical composition. One aspect of the present invention relates to compounds of the present invention, as described herein, or a pharmaceutical composition thereof, for use in a method of treating the human or animal body by therapy. One aspect of the present invention relates to compounds of the present invention, as described herein, or a pharmaceutical composition thereof, for use in a method of prophylaxis or treatment of an eating disorder, obesity or disorder related to the obesity of the human or animal body through therapy. One aspect of the present invention relates to compounds of the present invention, as described herein, or a pharmaceutical composition thereof, for use in a method of prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy of the human or animal body through therapy. One aspect of the present invention relates to compounds of the present invention, as described herein, for the manufacture of a medicament for use in the prophylaxis or treatment of an eating disorder, obesity or disorders related to obesity. One aspect of the present invention relates to compounds of the present invention, as described herein, for the manufacture of a medicament for use in the prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy. One aspect of the present invention relates to methods of decreasing food intake of an individual comprising administering to the individual a therapeutically effective amount of a compound, as described herein, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for inducing satiety in an individual comprising administering to said individual a therapeutically effective amount of a compound, as described herein, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for controlling or reducing weight gain in an individual comprising administering to said individual a therapeutically effective amount of a compound, as described herein, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for modulating an MCH receptor in an individual comprising contacting the receptor with a compound, as described herein. In some embodiments, the compound is an antagonist. In some embodiments, the modulation of the receptor MCH receptor is for the prophylaxis or treatment of an eating disorder, obesity or disorder related to obesity. In some embodiments, modulation of the MCH receptor reduces the individual's food intake. In some embodiments, the modulation of the MCH receiver induces satiety in the individual. In some embodiments, the modulation of the MCH receiver controls or reduces the weight of the individual. In some embodiments, the modulation of the MCH receptor is for prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy. In some modalities, the individual is a mamñifero. In some modalities, the mammal is a human. In some embodiments, the human has a body mass index of about 18.5 to about 45. In some embodiments, the human has a body mass index of about 25 to about 45. In some embodiments, the human has a body mass index from about 30 to about 45. In some embodiments, the human has a body mass index of from about 35 to about 45. One aspect of the present invention relates to methods for producing a pharmaceutical composition comprising mixing a compound, as described in US Pat. present, and a pharmaceutically acceptable carrier. Detailed Description of the Invention One aspect of the present invention relates to certain substituted pyrimidine compounds represented by Formula (I): ^ XX, (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Q, L, Y, and Ri are as described herein, supra and infra. It is appreciated that certain features of the invention, which, for clarity are described in the context of separate embodiments, may also be provided in combination in a single embodiment. On the contrary, several features of the invention which, for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. In some embodiments, the compounds of the present invention are of Formula (I) wherein Q is Formula (lia); Zi is hydrogen, halogen, C? _5 alkyl, C? _5 alkyl substituted by halogen, C3_6 cycloalkyl, C? -5 alkoxy, C1-5 alkoxy substituted by halogen, or C1-5 alkylthio or a pharmaceutically acceptable hydrate or solvate salt of the same . In some embodiments, the compounds of the present invention are of Formula (I) wherein Ri is selected from the group consisting of: (i) C 1-10 alkyl, and C 1 -C 0 alkyl substituted by the substituent (s) independently selected from the group consisting of: 'halogen, • oxo, • C 1 -C 5 alkoxy, • C 1-5 alkoxy substituted by carbocyclic aryl, • C 1 -C 5 alkylcarbonyloxy, • C 5 -C 5 alkoxycarbonyl, C 5-alkoxycarbonyl substituted by carbocyclic aryl, carbocyclic aryloxy, and carbocyclic aryloxy substituted by the independently selected substituent (s) from the group consisting of: halogen, nitro, alkyl C ? _5, and •• C___5 alkyl substituted by oxo, 'heterocyclyloxy, • heterocyclyloxy substituted by C? -5 alkyl, • carbocyclic mono-arylamino, • carbocyclic di-arylamino, • carbocyclic arylsulfonylamino, • carbocyclic arylsulfonylamino substituted by alkyl • alkylthio C ? _5, • al C.sub.5 -thylthio substituted by carbocyclic aryl, carbocyclic arylthio, carbocyclic arylthio substituted by halogen, carbocyclic arylthio substituted by C? 5 alkyl, carbocyclic arylsulfonyl, carbocyclic arylsulfonyl substituted by halogen, heterocyclicthio, heterocyclicthio substituted by alkyl. C? _5, • C3_6cycloalkyl, • C3_6 cycloalkenyl, • carbocyclyl, • carbocyclyl substituted by C5_5alkoxy, • carbocyclic aryl, and • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of consists of: • 'halogen, •' nitro, • 'alkyl C? _5, and •• C 1-5 alkyl substituted by the (; substituent (s) independently selected from the group consisting of: • • "halogen, ••• carbocyclic aryl, and • • • heterocyclyl, •" C1-5 alkoxy, •• C1-5 alkoxy substituted by halogen, • • C 1-5 alkoxy substituted by carbocyclic aryl, • carbocyclic aryloxy, • mono-arylaminocarbonyl carbocyclic, and • • carbocyclic mono-arylaminocarbonyl substituted by the substituent (s) selected from the group consisting of: • Halogen, C5 alkyl, C5-5alkoxy, and C5-5alkoxy substituted by halogen, carbohydric di-arylaminocarbonyl, and carbocyclic di-arylaminocarbonyl substituted by (the) substituent (s) selected from the group consisting of: • • 'halogen, ••' alkyl C? _5, • • * alkoxy C? _5, and ••• alkoxy C? _5 substituted by halogen, •• alkylthio C? -5, •• Cx_5 alkylthio substituted by halogen, •• alkylsulfonyl C? _5, • carbocyclic aryl, and • 'heterocyclyl, • heterocyclyl, and • heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • "C alquilo5 alkyl, • • C?-5 alkoxy •• C5-5 alkoxy substituted by carbocyclic aryl, •• carbocyclic aryl, and •• carbocyclic aryl substituted by halogen, (ii) C2-5 alkenyl? and C2-5 alkenyl substituted by the substituent (s) independently selected from the group consisting of: • carbocyclic aryl, and "carbocyclic aryl substituted by the independently selected substituent (s) of the group consisting of: • 'nitro, • 'halogen, • "C5-alkyl, •• C5-5 alkyl substituted by halogen, • * C5-5 alkoxy, and •• C5-5 alkoxy substituted by halogen, (iii) C3_s cycloalkyl, and cycloalkyl C3_s substituted by the independently selected substituent (s) from the group consisting of: • C5 _5 alkyl, • C5_5 alkyl substituted by carbocyclic aryl, • carbocyclic arylcarbonylamino, and * carbocyclic aryl, (iv) carbocyclyl, and carbocyclyl substituted by nitro, (v) carbocyclic aryl, and carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • halogen, • cyano, • nitro, "C1 alkyl -9, and • C-.9 alkyl substituted by the independently selected substituent (s) from the group consisting of: • 'halogen, •? XO, •' mono-arylaminocarbonyl carbocyclic, carbocyclic arylaminocarbonyl, carbocyclic • 'ono-arylaminocarbonyl substituted by alkoxy Carboxylic carbocyclic di-arylaminocarbonyl substituted by carbocyclic C 1 -C 5 alkoxy, carbocyclic aryloxy, carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) group consisting of: • • "halogen, • • 'alkyl C? _5, and ••• C5-alkyl substituted by halogen, •• heterocyclyl, and • • heterocyclyl substituted by C1-5 alkyl, • C2- alkenyl 5, • C 1-7 alkoxy, • C 1-7 alkoxy substituted by halogen, • C alkoxy;? __ 7 substituted by carbocyclic aryl, * C3_ecycloalkoxy, • carbocyclic aryloxy, and • carbocyclic aryloxy substituted by the substituent (s) independently selected from the group consisting of: • «halogen, •« nitro, and • • C 1-5 alkoxy • heterocyclyloxy, and • heterocyclyloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "alkyl C" _5, and •• C alkyl _5 substituted by halogen, • C 1-5 alkoxycarbonyl, • C 1 -C 5 mono-alkylaminocarbonyl, • C 1 -C 5 di-alkylaminocarbonyl, • C___ 5 mono-alkylaminocarbonyl substituted by carbocyclic aryl, • C 1 -5 alkylaminocarbonyl substituted by carbocyclic aryl, • mono -carbocyclic arylaminocarbonyl, • carbocyclic di-arylaminocarbonyl, • carbocyclic mono-arylaminocarbonyl substituted by C? _5 alkyl,? carbocyclic di-arylaminocarbonyl substituted by C? _5 alkyl, • mono-alkylamino -5, • di-al Quilamino C? _5, C 1-5 alkylthio, C? -5 alkylthio substituted by halogen, C? _5 alkylsulfonyl,? carbocyclic aryl, and? carbocyclic aryl substituted by the independently selected substituent (s) of the group consisting of: alkyl C, and C alkyl substituted by halogen, (vi) heterocyclyl, and heterocyclyl substituted by the independently selected substituent (s) from the group consisting of of: • halogen, • C5_5alkyl, and • C5_5alkyl substituted by the independently selected substituent (s) from the group consisting of: • "halogen, • 'OXO, •• carbocyclic aryl , •• carbocyclic aryl substituted by halogen, •• heterocyclyl, and •• heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • •" alkyl C? 5, and •• «C alquilo5 alkyl substituted by halogen, • C alco5 alkoxy , • C 1 -C 5 alkylthio, • carbocyclic arylthio, • C 1 -C 5 alkylsulfonyl, "carbocyclic arylsulfonyl, • carbocyclic arylsulfonyl substituted by halogen, • carbocyclic arylsulfonyl substituted by C 1 -C 5 alkyl, • C 1 -C 5 alkoxycarbonyl, • carbocyclic aryl, and -carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • 'halogen, •' nitro, and • 'C-5 alkyl, • heterocyclyl, and • heterocyclyl substituted by the (the) substituent (s) independently selected from the group consisting of: • "halogen," "C -C5 alkyl, and C5 alkyl substituted by halogen; wherein carbocyclic aryl is phenyl, naphthyl, or anthranil; carbocyclyl is 1-oxo-indanyl, 9i? -fluorenyl, 9-oxo-fluorenyl, anthraquinonyl, C-fluoren-9-ylidene, indanyl, or menthyl; heterocyclyl is 1, 2, 3, 4-tetrahydro-isoquinolyl, 1, 2, 3-thiadiazolyl, 1,2,3-triazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl, li? -pyrrolyl, 2,3-dihydro-l-oxo-isoindolyl, 2,3-dihydro -benzo [1,4] dioxinyl, 2-t-benzopyranyl, 2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl, 4-oxo-benzopyranyl, 9H-xanthenyl, benzo [1, 3] dioxolyl, benzo [2, 1, 3 ] oxadiazolyl, benzo [1, 2, 5] oxadiazolyl, benzo [b] thienyl, furyl, isoxazolyl, morpholinyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolyl, thienyl, imidazolyl, or piperazil; halogen is fluoro, chloro, bromo, or iodo; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein R 2 is halogen, C 1-5 alkyl, C 1-5 alkoxy, -N (R 2a) (R 2b), heterocyclyl; wherein R2a and R2b are each independently hydrogen, C1-5 alkyl, C5-5 alkyl substituted by hydroxy, C5-5 alkyl substituted by carbocyclic aryl, C5-5 alkyl substituted by heterocyclyl, C3_6 cycloalkyl, or carbocyclic aryl; L is selected from the group consisting of the Formulas (Illa) and (IVa); wherein R 3 and R 4 are each independently hydrogen or C! _5 alkyl; and A and B are each independently a unique bond, -CH2-, or - (CH2) 2_; Zi is hydrogen, halogen, C 1-5 alkyl, C 5 alkyl substituted by halogen, C 5 alkoxy, or C 1-5 alkylthio; Z2 is hydrogen, halogen, or C! _5 alkyl; or R2 and Z2 are linked together to form a ring and -R2-Z2-is -NR6-CH = CH-; wherein Re is hydrogen or C? _s alkyl; and Y represents: (i) -C (0) NR5-, -C (S) NR5-, -C (0) 0-, -S (0) 2-, -C (0) -, or - (CH2 ) m- when L is selected from the group consisting of the Formula (Illa); or (ii) -C (0) NR5- or -C (0) 0- when L is selected from the group consisting of Formula (IVa); wherein R5 is hydrogen or C1-5 alkyl; and m is 0, 1, or 2; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein Ri is selected from the group consisting of: (i) C 1-5 alkyl substituted by the independently selected substituent (s) of the group consisting of: • hydroxy, • carbocyclic aryl, • carbocyclic aryl substituted by halogen, and • Cilt5 alkylthio, (ii) C3_6 cycloalkyl, and carbocyclic aryl, and carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: "halogen, • nitro, • cyano, • C1-5 alkyl, • C1-5 alkyl substituted by halogen," C-5 alkoxy, • C5-5 alkoxy substituted by halogen, • C5-alkoxy substituted by carbocyclic aryl, • carbocyclic aryloxy, and • carbocyclic aryloxy substituted by C5-5 alkoxy, (iv) heterocyclyl, and heterocyclyl substituted by the independently selected substituent (s) from the group consisting of : • halogen, • alqui C? _5, "carbocyclic aryl, and? carbocyclic aryl substituted by halogen; R2 is -N (R2a) (R2b) or heterocyclyl; wherein R2a and R2b are each independently hydrogen or C1-5alkyl; Zx is hydrogen, Ci-5 alkyl, or C? _5 alkylthio; Z2 is hydrogen or C? _5 alkyl; or R2 and Z2 are linked together to form a ring and -R2-Z2- is -NR6 ~ CH = CH-; wherein Rβ is hydrogen or C? _s alkyl; L is Formula (Illa) or (IVa), wherein R3 and R4 are hydrogen, A is a single bond and B is a single bond or -CH2-; and Y represents: (i) -C (0) NH-, -C (S) NH, -C (0) -, or -CH2 ~ when L is selected from the group consisting of the Formula (Illa); or (ii) -C (0) NH- when L is selected from the group consisting of Formula (IVa); wherein carbocyclic aryl is phenyl or naphthyl; heterocyclyl is furyl, li? -indolyl, morpholinyl, oxazolyl, piperidyl, pyridyl, pyrrolidyl, or 9iT-xanthenyl; halogen is fluoro, chloro, or bromo; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein Ri is selected from the group consisting of: (i) carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) ( s) of the group consisting of: • halogen, • C alquilo5 alkyl, • C ?5 alkyl substituted by halogen, • C alco5 alkoxy, and • C?-5 alkoxy substituted by halogen, (ii) heterocyclyl, and heterocyclyl replaced by halogenIME ; and Zi is hydrogen, C? _5 alkyl, or C? _5 alkylthio; Z2 is hydrogen or C1-5 alkyl; wherein carbocyclic aryl is phenyl; heterocyclyl is furyl, pyridyl, or pyrrolidyl; halogen is fluoro, chloro, or bromo; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodts, the compounds of the present invention are of Formula (I) wherein the compound is selected from the group consisting of: N- (cis-4- { [6- (dhylamino) pyrimidin-4-yl) ] mino} cyclohexyl) -3,4-difluorobenzamide; N- (cís-4- { [6- (dhylamino) -2-methylpyrimidin-4-yl] mino} cydohexyl) -4-fluorobenzamide; 4-chloro-N- (cis-4. {[[6- (dhylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -3-fluorobenzamide; N- (cis-4- { [6- (dhylamino) -2-methylpyrimidin-4-yl] mino} cydohexyl) -3,5-difluorobenzamide; 3-chloro-W- (cis-4- { [6- (dhylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) -4- (trifluoromethoxy) benzamide; 3-Chloro-4-fluoro-i-7- (cis-4 { [2-methyl-6- (methylamino) pyrimidin-4-yl] amino} ciciohexyl) benzamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3-fluorobenzamide; 4-chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) benzamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3-fluoro-5- (trifluoromethyl) benzamide; IX- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,5-bis (trifluoromethyl) benzamide; 3-chloro-4-f luoro-N-. { cis-4- [(2-methyl-6-piperidin-l-ylpyrimidin-4-yl) amino] cyclohexyl} benzamide; 3-chloro-4-f luoro-N-. { cis-4- [(2-methyl-6-morpholin-4-ylpyrimidin-4-yl) amino] cyclohexyl} benzamide; 3-chloro-4-fluoro-N-. { cis-4- [(7-methyl-7'-T-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclohexyl} benzamide; 3, 4, 5-trif luoro-N-. { cis-4- [(7-methyl-7J? -pyrrolo [2, 3-d] pyrimidin-4-yl) amino] ciciohexyl} benzamide; 3, 4, 5-trif luoro-N- (cis-4 { [2-methyl-6- (methylamino) pyrimidin-4-yl] amino.} Ciciohexyl) benzamide; cis-N- (3,4-difluorophenyl) -4-. { [6- (dimethylamino.} -2-methylpyrimidin-4-yl] amino.}. Cyclohexanecarboxamide; 1- (4-chlorophenyl) -N- (cis-4- { [6- (dimethylamino) -2- methylpyrimidin-4-yl] amino.}. cyclohexyl) cyclopentanecarboxamide; 3- (2-chloro-6-fluorophenyl) -N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl) amino]} cydohexyl) -5-methylisoxazole-4-carboxamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -2- (-methoxyphenoxy) -5-nitrobenzamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -5-iodo-2-furamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino}. Cydohexyl) -2- (ethylthio) -2,2-diphenylacetamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -9i? -xanthene-9-carboxamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -N '- [1- (1-naphthyl) ethylurea; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -N '- (3,4,5-trimethoxyphenyl) urea; N- (5-chloro-2, -dimethoxyphenyl) -N 1 - (cis -4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) urea; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -N '- (2,4,6-tribromophenyl) urea; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -N 1 -methylthiourea; N- (2,6-diethylphenyl) -N '-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) thiourea; N- (2,4-dichloro-6-methylphenyl) -i \ 7 '- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) thiourea; N- (5-chloro-2,4-dimethoxyphenyl) -N '- (cis -4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) thiourea; N- [4-bromo-2- (trifluoromethyl) phenyl] ~ N '- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) thiourea; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3-nitrobenzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) cyclohexyl] -3, -dietoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) • cyclohexyl] -3-ethoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-diethoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) • ciciohexyl] -3-isopropoxy-benzamide; 3-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycdohexyl] -4-fluoro-benzamide; 4-difluoromethoxy-? I- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 4-Chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methyl-benzamide; 3-difluoromethoxy-I \ 7- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cy cdohexyl] -benzamide; 3-Chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-methyl-benzamide; 4-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-dimethoxy-benzamide; 4-cyano-i \ 7- [cis-4-. { 6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-methoxy-benzamide; 3-cyano-N- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methoxy-benzamide; N- [cis-4-. { 6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-fluoro-3-methyl-benzamide; 4-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-fluoro-4-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethyl-benzamide; 3-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-fluoro-4-trifluoromethyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-trifluoromethoxy-benzamide; A7- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-trifluoromethyl-benzamide; 2,2-difluoro-benzo [1,3] dioxolo-5-carboxylic acid [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; N-. { cis-4- [(1 J? -indol-2-ylmethyl) -amino] -cyclohexyl} -2, N ', N' -trimethyl-pyrimidine-4,6-diamine; 2, N, N-trimethyl-N '- [cis-4- (3-trifluoromethoxy-benzylamino) -cy chenohexyl] -pyrimidine-4,6-diamine; N- [cis-4- (3,4-difluoro-benzylamino) -cydohexyl] -2, W, N '-trimethyl-pyrimidine-4,6-diamine; 1- (3, 4-dimethoxy-phenyl) -3- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -urea; 1- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3- (2-ethoxy-phenyl) -urea; 1- (4-benzyloxy-phenyl) -3- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycotehexyl] -urea; 3, 5-dibromo-N ~ [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 3-bromo-4-chloro-I \ 7- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 4-chloro-N- [cis-4 -. { 6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-trifluoromethyl-benzamide; 2- (3,5-bis-trifluoromethyl-phenyl) -N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -2-hydroxy-acetamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-fluoro-4-trifluoromethyl-benzaraide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-trifluoromethoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-methoxy-benzamide; 4-chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; N- [cis-4-. { 6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-trifluoromethyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-trifluoromethyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-methyl-benzamide; N- [cis-4-. { 6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,5-difluoro-benzamide, • N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) - cyclohexylmethyl] -3-ethyl-benzamide; 2, 2-difluoro-benzo [1,3] dioxolo-5-carboxylic acid [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -amide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-fluoro-4-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-fluoro-benzamide; 3, 4-dichloro-? 7- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; 4-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,4-difluoro-benzamide; 3, 5-dichloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; 3-chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-fluoro-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-fluoro-3-methyl-benzamide; and 3-chloro-? 7- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein the compound is selected from the group consisting of: N-. { cis- 4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide; N-. { cis-4-. { [6- (dimethylamino) -2-ethylpyrimidin-4-yl] amino} cyclohexyl) -3, -difluorobenzamide; 3-Chloro-N- (cis-4. {[[6- (dimethylamine) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -4-fluorobenzamide; 3, 4-dichloro-M- (cis -4- {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) benzamide; 3-chloro-N- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -5-fluorobenzamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3,4,5-trifluorobenzamide; 5-bromo-N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) nicotinamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -4-fluoro-3- (trifluoromethyl) benzamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -3- (trifluoromethyl) benzamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3- (trifluoromethoxy) benzamide; 3, 5-dichloro-A? - (cis -4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) benzamide; 3-chloro-N- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) benzamide; 3-chloro-4-f luoro-N-. { cis-4- [(2-methyl-6-pyrrolidin-1-yl-pyrimidin-4-yl) amino] cyclohexyl-J-benzamide; N- (cis-4- { [6- (dimethylamino) -2-ethylpyrimidin-4-yl] amino} ciciohexyl) -3,4,5-trifluorobenzamide; cis-N- (3-chloro-4-fluorophenyl) -4-. { [6- (dimethylamine) -2-methylpyrimidin-4-yl] amino} cyclohexanecarboxamide; N- (cis-4 { [2-benzyl-6- (dimethylamino) pyrimidin-4-yl] amino}. Cydohexyl) -3-chloro-4-fluorobenzamide; cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -N- (3,4,5-trifluorophenyl) cyclohexanecarboxamide; N- (4-bromo-2,6-dimethylphenyl) -? 7 '- (cis -4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) urea; N- (4-bromo-2,6-dimethylphenyl) -N '- (cis -4- {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) thiourea; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -N '- (3, 4, 5-trimethoxyphenyl) thiourea; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -N '- (2,4,6-tribromophenyl) thiourea; 5-bromo-furan-2-carboxylic acid [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; N- [cis-4- (3,5-dimethoxy-benzylamino) -cydohexyl] -2, W, N '-trimethyl-pyrimidine-4,6-diamine; N- [cis-4- (3-bromo-benzylamino) -cydohexyl] -2, N ', N 1 -trimethyl-pyrimidine-4,6-diamine; 1- [cis ~ 4-. { 6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3- (3-methoxy-phenyl) -urea; 1- (3, 5-difluoro-phenyl) -3- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycotehexyl] -urea; N- [cis-4- (6-dimethylamino-2-methylsulfanyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide; N- [cis-4- (6-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,5-bis-trifluoromethyl-benzamide; and N- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-trifluoromethoxy-benzamide; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein Ra represents: (i) hydrogen, -C02tBu, or -C02Bn (Bn is a benzyl group) when L is selected from the group consisting of Formulas (III), (Illa), and (Illb); or (ii) hydrogen, C? _5 alkyl, substituted C1_5 alkyl, Bn, or substituted Bn when L is selected from the group consisting of Formulas (IV), (IVa), and (IVb); wherein R3 and R are each independently hydrogen or C? -5 alkyl; and A and B are each independently a unique bond, -CH2-, or - (CH2) 2-; R2 is halogen, C5_5alkyl, C5_5alkoxy, -N (R2a) (R2b), or heterocyclyl; wherein R2a and R2b are each independently hydrogen, C1-5alkyl, C5_5alkyl substituted by hydroxy, C1_5alkyl substituted by carbocyclic aryl, C1-5alkyl substituted by heterocyclyl, C3_6 cycloalkyl, or carbocyclic aryl; Zi is hydrogen, halogen, C? _5 alkyl, C? _5 alkyl substituted by halogen, C? _5 alkoxy, or C? _5 alkylthio; Z is hydrogen, halogen, or C? _s alkyl; or R2 and Z2 are linked together to form a ring and -R2-Z2- is -NRe-CH = CH ~; wherein R6 is hydrogen or C? _5 alkyl; and Y represents: (i) a single bond when L is selected from the group consisting of Formulas (III), (Illa), and (Illb); or (ii) -C (0) 0- when L is selected from the group consisting of Formulas (IV), (IVa), and (IVb); or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein Ri represents: (i) hydrogen, -C02tBu, or -C02Bn (Bn is a benzyl group) when L is selected from the group consisting of Formula (Illa); or (ii) hydrogen, C? _5 alkyl, substituted C? _5 alkyl, Bn, or substituted Bn when L is selected from the group consisting of Formula (IVa); wherein R3 and R4 are each hydrogen; and A and B are each independently a single bond or -CH2-; R2 is -N (R2a) (R2b) ° heterocyclyl; wherein R2a and R2b are each independently hydrogen or C? _5 alkyl; Zi is hydrogen, C 1-5 alkyl, or C 1-5 alkylthio; Z2 is hydrogen or C? _s alkyl; or R and Z2 are linked together to form a ring and -R2-Z2- is -NR6-CH = CH-; wherein Re is hydrogen or C1-5 alkyl; and Y represents: (i) a single bond when L is selected from the group consisting of the Formula (Illa); or (ii) -C (0) 0- when L is selected from the group consisting of Formula (IVa); heterocyclyl is furyl, lff-indolyl, morpholinyl, oxazolyl, piperidyl, pyridyl, pyrrolidyl, or 9i? -antenhenyl; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein Q is Formula (Ilb); R2 is C5_5alkyl substituted by hydroxy, C5_5alkyl substituted by carbocyclic aryl, C5_5alkyl substituted by halogenated carbocyclic aryl, C5_5alkyl substituted by heterocyclyl, C5_5alkyl substituted by halogenated heterocyclyl, C2_5alkenyl, alkynyl C2_5, or -N (R2a) (R2b); wherein R2a and R2b are each independently hydrogen, C5_5alkyl, or C5_5alkyl substituted by the independently selected substituent (s) from the group consisting of: • halogen, • hydroxy, • carboxy , • carbamoyl, • C5-5 alkoxy, • amino, • C3 ~ β cycloalkyl, "carbocyclic aryl, • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • 'halogen , • 'C 1-5 alkyl, • • C5-5 alkoxy, • C5-5 alkyl substituted by halogen, •• C5-5 alkoxy substituted by halogen, and • «-S02NH2,« heterocyclyl, and • heterocyclyl substituted by the (the) substituent (s) independently selected from the group consisting of: • "halogen, • 'C5_5 alkyl, •" C1-5 alkoxy, •• C5_5 alkyl substituted by halogen, and •• alkoxy C1-5 substituted by halogen, carbocyclic aryl, carbocyclic aryl substituted by the substituent (s) ) independently selected from the group consisting of: • halogen, • C 1-5 alkyl, • C 5 alkoxy, • C 5 alkyl substituted by halogen, and C 5 alkoxy substituted by halogen, heterocyclyl, or heterocyclyl substituted by the independently selected substituent (s) from the group consisting of: halogen, C5 alkyl, C5 alkoxy, C5 alkyl substituted by halogen, and C alkoxy? _5 substituted by halogen; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein R 1 is selected from the group consisting of: (i) C 1 -C 0 alkyl, and C___-C alkyl or substituted by the substituent (s) independently selected from the group consisting of: • halogen, • hydroxy, • oxo, "C 1 -C 5 alkoxy, • C 1-5 alkoxy substituted by carbocyclic aryl, • C 1-5 alkylcarbonyloxy, • alkoxycarbonyl Q. 5, • C5 alkoxycarbonyl substituted by carbocyclic aryl, carbocyclic aryloxy, and carbocyclic aryloxy substituted by the independently selected substituent (s) from the group consisting of: halogen, nitro, alkyl. C? _5, and • C alkyl substituted by oxo, • heterocyclyloxy, • heterocyclyloxy substituted by C1-5 alkyl, • carbocyclic mono-arylamino, • carbocyclic di-arylamino, • carbocyclic arylsulfonylamino, • carbocyclic arylsulfonylamino substituted by alkyl C1-5, "C 1-5 alkylthio, C 5 -C alkylthio substituted by carbocyclic aryl, carbocyclic arylthio, carbocyclic arylthio substituted by halogen, carbocyclic arylthio substituted by C 1-5 alkyl, carbocyclic arylsulfonyl, carbocyclic arylsulfonyl substituted by halogen, • heterocyclicthio, • heterocyclicthio substituted by C-5 alkyl, • C3_s cycloalkyl, • C3_s cycloalkenyl, • carbocyclyl, • carbocyclyl substituted by C1-5 alkoxy, • carbocyclic aryl, and • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • «halogen, •« nitro, • «C1-5 alkyl, and •« C5_5 alkyl substituted by the independently selected substituent (s). ) of the group consisting of: • • "halogen, ••• carbocyclic aryl, and • •" heterocyclyl, • • C5-5alkoxy, •• C5-5alkoxy substituted by halogen, •• C1-5alkoxy substituted by to • carbocyclic, carbocyclic aryloxy, • • carbocyclic mono-arylaminocarbonyl, and • • carbocyclic mono-arylaminocarbonyl substituted by the selected substituent (s) from the group consisting of: • • • halogen, ••• alkyl C? _5, • • • C1-5 alkoxy, and ••• C5-alkoxy substituted by halogen, •• di-arylaminocarbonyl carbocyclic, and •• carbocyclic di-arylaminocarbonyl substituted by the substituent (s) selected from the group consisting of: • • 'halogen, • •' alkyl C? _5, ••• alkoxy C? _5, and ••• alkoxy C? _5 substituted by halogen, •• alkylthio C? _5, •• C 1 -C 5 alkylthio substituted by halogen, •• C 1 -C 5 alkylsulfonyl, •• carbocyclic aryl, and • "heterocyclyl, • heterocyclyl, and • heterocyclyl substituted by the independently selected substituent (s) of the group consisting of: • 'alkyl C? _5, •' C1-5 alkoxy, •• alkoxy C_5 substitute and carbocyclic aryl, carbocyclic aryl, and carbocyclic aryl substituted by halogen, (i) C2_5 alkenyl, and C2-alkenyl substituted by the substituent (s) independently selected from the group consisting of : • carbocyclic aryl, and • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • "nitro, •" halogen, •• C5_5 alkyl, •• C alkyl? _5 substituted by halogen, •• C5 alkoxy, and •• C5-5 alkoxy substituted by halogen, (iii) C3-6 cycloalkyl, and C3-6 cycloalkyl substituted by the independently selected substituent (s) from the group consisting of: "C alquilo _ alquilo alkyl, • C alquilo _-substituted alkyl by carbocyclic aryl, • carbocyclic arylcarbonylamino, and • carbocyclic aryl, (iv) carbocyclyl, and carbocyclyl substituted by nitro, (v) carbocyclic aryl, and aryl carbocyclic substituted by the (the) substitute independently selected entity (s) from the group consisting of: "halogen, • cyano, • nitro, • C? _9 alkyl, and • Cs alkyl substituted by the independently selected substituent (s) of the group consisting of: • «halogen, •« oxo, • «mono-arylaminocarbonyl carbocyclic, •« di-arylaminocarbonyl carbocyclic, • «mono-arylaminocarbonyl carbocyclic substituted by C1-5 alkoxy, •• di-arylaminocarbonyl carbocyclic substituted by C1-alkoxy -5, •• carbocyclic aryloxy, • carbocyclic aryl, and • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, ••" alkyl C? _5, and ••• -5-alkyl substituted by halogen, •• heterocyclyl, and • • heterocyclyl substituted by C5 alkyl, • C2-5 alkenyl, -alkoxy C7-7, • C7-7 alkoxy substituted by halogen, • C1 alkoxy -7 substituted by carbocyclic aryl, C3_6 cycloalkoxy, • carbocyclic aryloxy, and carbocyclic aryloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen, •" nitro, and • • C5-5 alkoxy • heterocyclyloxy, and • heterocyclyloxy substituted by the independently selected substituent (s) from the group consisting of: • 'halogen• C 1 -C 5 alkyl, and • C 1 -C 5 alkyl substituted by halogen, • C 1 -C 5 alkoxycarbonyl, • C 1-5 monoalkylaminocarbonyl, • C 1-5 alkylaminocarbonyl, C 1 -C 5 monoalkylaminocarbonyl substituted by carbocyclic aryl, • C 1 -C 5 di-alkylaminocarbonyl substituted by carbocyclic aryl, • carbocyclic mono-arylaminocarbonyl, carbocyclic di-arylaminocarbonyl, • carbocyclic mono-arylaminocarbonyl substituted by C 5 alkyl, carbocyclic di-arylaminocarbonyl substituted by C 1 -C 5 alkyl, C1-5 monoalkylamino, • di-alkylamino C5-5, • C5-5 alkylthio, • C5 alkylthio substituted by halogen, • C5-5 alkylsulfonyl, "carbocyclic aryl, and • carbocyclic aryl substituted by the substituent ( s) independently selected from the group consisting of: • C '_7 alkyl, and • "C 1-7 alkyl substituted by halogen, (vi) heterocyclyl, and heterocyclyl substituted by the independently selected substituent (s). (s) of the group consisting of: • halogen, "alkyl C" _5, and • C5_5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • 'halogen, • "OXO, •• carbocyclic aryl, • carbocyclic aryl substituted by halogen, •• heterocyclyl, and •• heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • •" alkyl C? -5, and ••• C5_5 alkyl substituted by halogen, • C5_5alkoxy,? C5_5 alkylthio, • carbocyclic arylthio, • C5_5 alkylsulfonyl, • carbocyclic arylsulfonyl, • carbocyclic arylsulfonyl substituted by halogen, • carbocyclic arylsulfonyl substituted by C 1 -C 5 alkyl, • C 1-5 alkoxycarbonyl, • carbocyclic aryl, and • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • «halogen , • «nitro, and •« al C.sub.1.5, • heterocyclyl, and • heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "C1-5 alkyl, and •• C5 alkyl. replaced by halogen; wherein carbocyclic aryl is phenyl, naphthyl, or anthranil; carbocyclyl is 1-oxo-indanyl, 9J? -fluorenyl, 9-oxo-fluorenyl, anthraquinonyl, C-fluoren-9-ylidene, indanyl, or menthyl; heterocyclyl is 1, 2, 3, 4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl, 1, 2, 3-triazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl, lH-pyrrolyl, 2, 3- dihydro-l-oxo-isoindolyl, 2,3-dihydro-benzo [1,4] dioxinyl, 2E-benzopyranyl, 2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl, 4-oxo-benzopyranyl, 9iT-xanthenyl, benzo [ 1,3] dioxolyl, benzo [2, 1, 3] oxadiazolyl, benzo [1, 2, 5] oxadiazolyl, benzo [b] thienyl, furyl, isoxazolyl, morpholinyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolin, quinoxalyl, thiazolyl, or thienyl; halogen is fluoro, chloro, bromo, or iodo; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein R 2 is C 1-5 alkyl substituted by carbocyclic aryl, C 1-5 alkyl substituted by halogenated carbocyclic aryl, C 1 5 alkyl substituted by heterocyclyl, C alkyl. ? 5 substituted by halogenated heterocyclyl, carbocyclic aryl, carbocyclic aryl substituted by halogen, heterocyclyl, heterocyclyl substituted by halogen, or -N (R 2a) (R 2b); wherein R 2a and R 2b are each independently hydrogen, C 1 -C 5 alkyl, C 1 alkyl substituted by hydroxy, or C 5 alkyl substituted by halogen; L is the Formula (Illa); wherein R3 and R4 are each independently hydrogen or C? _5 alkyl; and A and B are each independently a unique bond, -CH2-, or - (CH2) 2-; Z3 and Z4 are each independently hydrogen, halogen, C5_5 alkyl, C1-5 alkyl substituted by halogen, C1-5 mono-alkylamino, or di-C1-6 alkylamino; and Y is -C (O) -, -C (0) NR5-, -C (S) NR5-, or - (CH2) m-; wherein R5 is hydrogen or C? _5 alkyl; and m is 0, 1, or 2; And it is not - (CH2) m-provided that either R2a or R2b is hydrogen; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein Ri is selected from the group consisting of: (i) C 1 -C 5 alkyl substituted by the independently selected substituent (s) of the group consisting of: • hydroxy, • carbocyclic aryl, "carbocyclic aryl substituted by halogen, and • carbocyclic aryl substituted by halogenated C 1 -C 5 alkyl, (ii) carbocyclic aryl, and carbocyclic aryl substituted by the substituent ( s) independently selected from the group consisting of: halogen, cyano, C5 alkyl, C5 alkyl substituted by halogen, C5-5 alkoxy, and C5-5 alkoxy substituted by halogen, (iii) heterocyclyl , and heterocyclyl substituted by halogen; R2 is C5_5alkyl substituted by carbocyclic aryl or -N (R2a) (R2b) wherein R2a and R2b are each independently hydrogen or C5_5alkyl; L is the Formula (Illa); wherein R3 and R4 are each hydrogen; and A and B are each a unique link; Z3 and Z4 are each independently hydrogen, C5_5alkyl, C5_5 monoalkylamino, or C5_5alkylamino; and Y is -C (O) -; wherein carbocyclic aryl is phenyl; heterocyclyl is furyl or pyridyl; halogen is fluoro, chloro, or bromo; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein Ri is selected from the group consisting of: carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) of the group consisting of: • halogen, • cyano, and • alkoxy C? _5; Z3 is hydrogen when Z4 is C? _5 alkyl; or Z3 is alkyl? -5, mono-alkylamino C? _5, or di-C1-alkylamino when Z4 is hydrogen; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein the compound is selected from the group consisting of: 3-chloro-N- (cis-4- { [2- (dimethylamino) - 6-methylpyrimidin-4-yl] amino.} Cydohexyl) -4-fluorobenzamide; N- (cis-4- { [2- (dimethylamino) -6-methylpyrimidin-4-yl] amino.} Ciciohexyl) -3,4-difluorobenzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methoxy-benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-trifluoromethyl-benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-bis-trifluoromethyl-benzamide; 2, 2-difluoro-benzo [1,3] dioxolo-5-carboxylic acid [cis-4- (2'-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; 4-cyano-i \ 7- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 4-chloro-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethyl-benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide; 5-bromo-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -nicotinamide; 5-bromo-furan-2-carboxylic acid [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; 3, 5-dibromo-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethoxy-benzamide; 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [cys-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -2-hydroxy-acetamide; 2- (4-bromo-phenyl) -N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -2-hydroxy-acetamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-diethoxy-benzamide; 3-bromo-N- [cís-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-fluoro-benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethoxy-benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-trifluoromethyl-benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-bis-trifluoromethyl-benzamide; 2, 2-difluoro-benzo [1,3] dioxolo-5-carboxylic acid [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; 4-Chloro-N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cycdohexyl] -benzamide; N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethyl-benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cycdohexyl] -4-methyl-benzamide; 5-bromo- - [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -nicotinamide; 5-bromo-furan-2-carboxylic acid [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamine) -cydohexyl] -amide; 3, 5-dibromo-A7- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethoxy-benzamide; 2- (3,5-bis-trifluoromethyl-phenyl) -N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -2-hydroxy-aceta-ida; 2- (4-bromo-phenyl) -N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cy cdohexyl] -2-hydroxy-acetamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-diethoxy-benzamide; and 3-bromo-Af- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-fluoro-benzamide; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, compounds of the present invention are of Formula (I) wherein the compound is selected from the group consisting of: 3-chloro-N- (cis-4- { [2- (dimethylamino) pyrimidine- 4-yl] amino.} Cydohexyl) -4-fluorobenzamide; N-. { cis-4-. { [2,6-bis (dimethylamino) pyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide; N- (cis-4 { [2-benzyl-6- (dimethylamino) pyrimidin-4-yl] amino.}. Cyclohexyl) -3-chloro-4-fluorobenzamide; 3, 4-dichloro-N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 4-cyano-N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3, -dietoxy-benzamide; 3-Chloro-N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -5-fluoro-benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-dimethoxy-benzamide; 3, 4-dichloro-N- [cis-4- (2'-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-diethoxy-benzamide; and 3-chloro-? 7- [cis -4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -5-fluoro-benzamide; or a pharmaceutically acceptable hydrate or solvate salt thereof. In some embodiments, the compounds of the present invention are of Formula (I) wherein Ri is selected from hydrogen, -C02Bu, or -C02Bn (Bn is a benzyl group); R2 is C5_5alkyl substituted by carbocyclic aryl, C5_5alkyl substituted by halogenated carbocyclic aryl, C5_5alkyl substituted by heterocyclyl, C5_5alkyl substituted by halogenated heterocyclyl, carbocyclic aryl, carbocyclic aryl substituted by halogen, heterocyclyl, heterocyclyl substituted by halogen, or -N (R2a) (R2b); wherein R2a and R? b are each independently hydrogen, C? _5 alkyl, C1-5 alkyl substituted by hydroxy, or C5 alkyl substituted by halogen; L is the Formula (Illa); wherein R3 and R4 are each independently hydrogen or C? _5 alkyl; and A and B are each independently a unique bond, -CH2-, or - (CH2) 2 ~; Z3 and Z4 are each independently hydrogen, halogen, C? _5 alkyl, C? _5 alkyl substituted by halogen, monoalkylamino C? _5, or di-alkylamino C? 5; and Y is a unique link; or a pharmaceutically acceptable hydrate or solvate salt thereof.

In some embodiments, the compounds of the present invention are of Formula (I) wherein R 2 is C alkyl substituted by carbocyclic aryl or -N (R 2a) (R b) wherein R 2a and R 2b are each independently hydrogen or C? _5 alkyl; L is the Formula (Illa); wherein R3 and R4 are each hydrogen; and A and B are each a unique link; and Z3 and Z4 are each independently hydrogen, C? _5 alkyl, C? -5 monoalkylamino, or C? _5 di-alkylamino; wherein carbocyclic aryl is phenyl; heterocyclyl is furyl or pyridyl; halogen is fluoro, chloro, or bromo; or a pharmaceutically acceptable hydrate or solvate salt thereof. One aspect of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound, as described herein, in combination with a pharmaceutically acceptable carrier. One aspect of the present invention relates to methods for prophylaxis or treatment to improve memory function, sleep and wakefulness, anxiety, depression, mood disorders, seizures, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, disorders of excess food including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson's disease, epilepsy, and addiction comprising administering to an individual suffering from said condition a therapeutically effective amount of a compound, as described herein, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for the prophylaxis or treatment of an eating disorder, obesity or an obesity-related disorder comprising administering to a subject suffering from said condition a therapeutically effective amount of a compound, as described in the present, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for the prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy comprising administering to an individual suffering from said condition a therapeutically effective amount of a compound, as described in present, or a pharmaceutical composition. One aspect of the present invention relates to compounds of the present invention, as described herein, or a pharmaceutical composition thereof, for use in a method of treating the human or animal body by therapy. One aspect of the present invention relates to compounds of the present invention, as described herein, or a pharmaceutical composition thereof, for use in a method of prophylaxis or treatment of an eating disorder, obesity or a related disorder with the obesity of the human or animal body through therapy. One aspect of the present invention relates to compounds of the present invention, as described herein, or a pharmaceutical composition thereof, for use in a method of prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy of the human or animal body through therapy. One aspect of the present invention relates to compounds of the present invention, as described herein, for the manufacture of a medicament for use in the prophylaxis or treatment of an eating disorder, obesity or disorders related to obesity. One aspect of the present invention relates to compounds of the present invention, as described herein, for the manufacture of a medicament for use in the prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy. One aspect of the present invention relates to methods of decreasing food intake of an individual comprising administering to the individual a therapeutically effective amount of a compound, as described herein, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for inducing satiety in an individual comprising administering to said individual a therapeutically effective amount of a compound, as described herein, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for controlling or reducing weight gain in an individual comprising administering to said individual a therapeutically effective amount of a compound, as described herein, or a pharmaceutical composition thereof. One aspect of the present invention relates to methods for modulating an MCH receptor in an individual comprising contacting the receptor with a compound, as described herein. In some embodiments, the compound is an antagonist. In some embodiments, the modulation of the MCH receptor is for the prophylaxis or treatment of an eating disorder, obesity or disorder related to obesity. In some embodiments, the modulation of the MCH receptor reduces the individual's dietary intake. In some modalities, the modulation of the MCH receptor induces satiety in the individual. In some embodiments, the modulation of the MCH receptor controls or reduces the individual's weight gain. In some modalities, modulation of the MCH receptor is for the prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy. In some modalities, the individual is a mammal. In some modalities, the mammal is a human. In some embodiments, the human has a body mass index of about 18.5 to about 45. In some embodiments, the human has a body mass index of about 25 to about 45. In some embodiments, the human has a body mass index from about 30 to about 45. In some embodiments, the human has a body mass index of from about 35 to about 45. One aspect of the present invention relates to methods for producing a pharmaceutical composition comprising mixing a compound, as described in US Pat. present, and a pharmaceutically acceptable carrier. One embodiment of the invention includes any compound of the invention that selectively binds to an MCH receptor, such a selective linkage is preferably demonstrated by a Ki for one or more different GPCR (s), preferably NPY, being at least 10 times greater than the Ki for any particular MCH receiver, preferably MCHR1. As used herein, the term "alkyl" is intended to denote hydrocarbon compounds including straight chain and branched chain, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, and the like. The term "alkoxy" is intended to denote substituents of the formula -O-alkyl. At several sites in the present specification, substituents of the compounds of the invention are described in groups. It is specifically intended that the invention include each and every one of the individual subcombinations of the members of such groups. G-protein coupled receptors (GPCRs) represent a major class of cell surface receptors with which many neurotransmitters interact to mediate their effects. GPCRs are predetermined to have seven membrane extension domains and are coupled to their effectors via G proteins linking receptor activation with intracellular biochemical sequelae such as adenylyl cyclase stimulation.

The melanin concentration hormone (MCH), a cyclic peptide, has been identified as the endogenous ligand of the orphan protein G coupled to the SLC-1 receptor. See, for example, Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). Studies have indicated that MCH acts as a neurotransmitter / modulator / regulator to modify a number of behavioral responses. Mammalian HCM (19 amino acids) is highly conserved among rats, mice, and humans, exhibiting 100% amino acid identity, but its physiological role is less clear. It has been reported that MCH participates in a variety of processes including diet, water balance, energy metabolism, general state of arousal / attention, memory and cognitive functions and psychiatric disorders. For review, see, 1. Baker, Int. Rev. Cytol. 126: 1-47 (1991); 2. Baker, TEM 5: 120-126 (1994); 3. Nahon, Critical Rev. in Neurobiol 221: 221-262, (1994); 4. Knigge et al., Peptides 18 (7): 1095-1097, (1996). The role of MCH in diet or regulation of body weight is supported by Qu et al., Nature 380: 243-247, (1996), demonstrating that MCH is overexpressed in the hypothalamus of ob / ob mice compared to mice ob / +, and that fasting increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles as reported by Rossi et al., Endocrinology 138: 351-355, (1997). It has also been reported that MCH functionally antagonizes the effects on the behavior of a-MSH; see: Miller et al., Peptides 14: 1-10, (1993); Gonzalez et al, Peptides 17: 171-177, (1996); and Sánchez et al., Peptides 18: 3933-396, (1997). Additionally, stress has been shown to increase the levels in POMC mRNA while decreasing mRNA levels of preproMCH (ppMCH) the precursor of MCH; Presse et al., Endocrinology 131: 1241-1250, (1992). Therefore MCH can serve as a neuropeptide of integration involved in the reaction to stress, as well as in the regulation of diet and sexual activity; Baker, Int. Rev. Cytol. 126: 1-47, (1991); Knigge et al., Peptides 17: 1063-1073, (1996). The location and biological activities of the MCH peptide suggest that modulation of MCH receptor activity may be useful in a number of therapeutic applications. MCH is expressed in the lateral hypothalamus, a brain area involved in the regulation of thirst and hunger: Grillon et al., Neuropeptides 31: 131-136, (1997); Recently, orexins A and B, which are potent orexigenic agents, have been shown to have a location very similar to that of HCM in the lateral hypothalamus; Sakurai et al., Cell 92: 573-585 (1998). MCH mRNA levels in this region of the brain increase in rats after 24 hours of food deprivation; Herve and Fellmann, Neuropeptides 31: 237-242 (1997); after insulin injection, a significant increase in the abundance and intensity of coloration of the pericardium and immunoreactive fibers of concurrent HCM was observed with a significant increase in the level of HCM in mRNA; Bahjaoui-Bouhaddi et al., Neuropeptides 24: 251-258, (1994). Consistent with the ability of MCH to stimulate feeding in rats; Rossi et al., Endocrinology 138: 351-355, (1997); is the observation that MCH levels in mRNA are upregulated in the hypothalamus of ob / ob obese mice; Qu et al., Nature 380: 243-247, (1996); and decreased in the hypothalamus of rats treated with leptin, whose food intake and weight gain also decrease; Sahu, Endocrinology 139: 795-798, (1998). MCH seems to act as a functional antagonist of the melanocortin system in its effects on food intake and the secretion of hormones within the HPA (hypothalamopituitary / adrenal axis); Ludwig et al., Am. J. Physiol. Endocrinol Metab. 274: E627-E633, (1998). On the whole, these data suggest a role for endogenous HCM in the regulation of energy balance and stress response, and provide a rationale for the development of specific compounds that act on receptor MCHs for use in the treatment of obesity and related disorders with stress. Accordingly, an MCH receptor antagonist is desirable for the prophylaxis or treatment of obesity or disorders related to obesity. An obesity-related disorder is a disorder that has been directly or indirectly associated with obesity, such as Type II diabetes, syndrome X, impaired glucose tolerance, dyslipidemia, hypertension, coronary heart disease and other cardiovascular disorders including arterosclerosis, insulin resistance associated with obesity and psoriasis, for the treatment of diabetic complications and other diseases such as polycystic ovarian syndrome (PCOS), certain kidney diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, diseases end-stage renal disease and microalbuminuria as well as certain eating disorders. In species currently studied, a significant portion of the neurons of the MCH cell group occupy a somewhat constant location in those areas of the lateral hypothalamus and subthalamus where it resides and may be part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striatal-palido-legal trajectories involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to the subthalamic nucleus, substantia nigra, and middle brain centers; Bittencourt et al., J. Comp. Neurol. 319: 218-245, (1992). In its location, the cellular group of HCM can offer a bridge or mechanism to express hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically, it may be of some value to consider the involvement of this system of HCM in movement disorders, such as Parkinson's disease and Huntington's disease in which it is known that extrapyramidal circuits are involved. Human genetic linkage studies have located an authentic hMCH site on chromosome 12 (12q23-24) and the variable hMCH site on chromosome 5 (5ql2-13) (Pedeutour et al., 1994). The 12q23-24 site coincides with a site in which autosomal dominant autosomal cerebellar ataxia type II (SCA2) has been traced; Auburger et al., Cytogenet. Cell. Genet 61: 252-256, (1992); Twells et al., Cytogenet. Cell. Genet 61: 262-265, (1992). This disease comprises neurodegenerative disorders, including olivopontocerebellar atrophy. In addition, the gene for Darier's disease has been plotted at site 12q23-24; Craddock et al., Hum. Mol. Genet 2: 1941-1943, (1993). Darier's disease is characterized by abnormalities in adhesion of keratinocytes and mental illness in some families. In view of the functional and neuroanatomical patterns of the MCH neuronal system in rat and human brains, the MCH gene may represent a good candidate for SCA2 or Darier's disease. Interestingly, diseases with high social impact have been traced on this site. In fact, the gene responsible for the chronic and acute forms of spinal muscular atrophies has been assigned to chromosome 5ql2-13 using a genetic linkage analysis; Melki et al., Nature (London) 344: 767-768, (1990); Westbrook et al., Cytogenet. Cell. Genet 61: 225-231, (1992). In addition, independent lines of evidence support the assignment of a major schizophrenia site to chromosome 5qll .2-13.3; Sherrington et al., Nature (London) 336: 164-167, (1988); Bassett et al., Lancet 1: 799-801, (1988); Gilliam et al., Genomics 5: 940-944, (1989). Previous studies suggest that MCH may play a role in neurodegenerative diseases and emotional disorders. Additional therapeutic applications for compounds related to HCM are suggested by the observed effects of HCM in other biological systems. For example, MCH can regulate reproductive functions in male and female rats. The MCH transcripts and the MCH peptide were found within germ cells in testis of adult rats, suggesting that MCH can participate in the renewal of progenitor cells and / or in the differentiation of premature spermatocytes; Hervieu et al., Biology of Reduction 54: 1161-1172, (1996). MCH injected directly into the preoptic medial area (MPOA) or ventro edio nucleus (VMN) stimulated sexual activity in female rats; González et al., Peptides 17: 171-177, (1996). In ovariectomized rats prepared with estradiol, the MCH stimulated the release of lutenizing hormone (LH) while the anti-MCH antiserum inhibited the release of LH; González et al., Neuroendocrinology 66: 254-262, (1997). The incerta zone, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the emergence of preovulatory LH; MacKenzie et al., Neuroendocrinology 39: 289-295, (1984). It has been reported that MCH influences the release of pituitary hormones including ACTH and oxytocin. MCH analogs may also be useful in the treatment of epilepsy. In the PTZ model of attack, the injection of MCH prior to the induction of attacks prevented the activity of attacks in both rats and guinea pigs, suggesting that neurons that contain HCM can participate in the neural circuitry that favors attacks induced by PTZ; Knigge and Wagner, Peptides 18: 1095-1097, (1997). It has also been observed that MCH affects the behavioral correlations of cognitive functions. Treatment with MCH hastened the extinction of the passive prevention response in rats; McBride et al., Peptides 15: 757-759, (1994); leading to the possibility that MCH receptor antagonists may be beneficial for storage and / or retention of memory. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of periaqueductal gray (PAG) by MCH-positive fibers. Finally, the MCH can participate in the regulation of fluid intake. The ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and caliuretic changes in response to the increase in plasma volume; Parkes, J. Neuroendocrinol. 8: 57-63, (1996). In conjunction with the anatomical data that report the presence of HCM in fluid regulatory areas of the brain, the results indicate that HCM may be an important peptide involved in the central control of fluid homeostasis in mammals. In a recent citation, the MCHRI antagonists surprisingly demonstrated their use as antidepressant and / or anti-anxiety agents. It has been reported that MCHR1 antagonists show antidepressant and anxiolytic activities in rodent models, such as social interaction, forced swimming test and ultrasonic vocalization. Accordingly, MCHRI antagonists could be useful to independently treat subjects with depression and / or anxiety. Also, MCHRI antagonists could be useful for treating subjects suffering from depression and / or anxiety and obesity.

This invention provides a method for treating an abnormality in a subject wherein the abnormality is alleviated by decreasing the activity of a mammalian MCH1 receptor comprising administering to the subject an amount of a compound that is an antagonist of the mammalian MCH1 receptor. effective to treat the abnormality. In separate embodiments, the abnormality is a regulation of a steroid or pituitary hormone disorder, an epinephrine release disorder, an anxiety disorder, gastrointestinal gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a disorder of reproductive function, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder, a modulation disorder and sensory transmission, a coordination disorder motor disorder, a sensory integration disorder, a motor integration disorder, a sensory transmission disorder, an olfactory disorder, a sympathetic innervation disorder, an affective disorder, a stress-related disorder, a fluid balance disorder, a attack, pain, psychotic behavior, tolerance to morph ina, opioid addiction or migraine. The compositions of the invention can be conveniently administered in a single dose form and can be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA , 1980). The compounds of the invention can be used as the sole active agent in a drug or can be used in combination with other active ingredients that could facilitate the therapeutic effect of the compound. The compounds of the present invention or a physiologically functional solvate or derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as an antagonist of the MCHs receptor. The term "active ingredient" is defined in the context of a "pharmaceutical composition" and means a component of a pharmaceutical composition that provides the primary pharmaceutical benefit, as opposed to an "active ingredient" that would generally be recognized as not providing a pharmaceutical benefit . The term "pharmaceutical composition" means a composition comprising at least one active ingredient and at least one ingredient that is not an active ingredient (e.g., and without limitation, a filler, colorant, or slow release mechanism), by which the composition is amenable to use for a specific effective result in a mammal (eg, and without limitation, a human). Pharmaceutical compositions, including, but not limited to, pharmaceutical compositions comprising at least one compound of the present invention and / or an acceptable salt or solvate thereof. { e. g. , a pharmaceutically acceptable salt or solvate) as an active ingredient combined with at least one vehicle or excipient. { e. g. , vehicle or pharmaceutical excipient) can be used in the treatment of clinical conditions for which an MCH receptor antagonist is indicated. At least one compound of the present invention can be combined with the carrier either in solid or liquid form in a single dose formulation. The pharmaceutical carrier must be compatible with the other ingredients in the composition and must be tolerated by the recipient individual. Other physiologically active ingredients can be incorporated into the pharmaceutical composition of the invention if desired, and if such ingredients are compatible with the other ingredients in the composition. The formulations can be prepared by any suitable method, typically, by uniformly mixing the active compound (s) with liquid carriers or finely divided solids., or both, in the required proportions, and then, if necessary, forming the resulting mixture in the desired configuration. Conventional excipients, such as binding agents, fillers, acceptable wetting agents, acceptable lubricants, and disintegrants in tablets and capsules for oral administration can be used. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oleaginous suspensions, and syrups. Alternatively, the oral preparations may be in the form of dry powders that can be reconstituted with water or other suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles can be added to the liquid preparations (including edible oils), preservatives, and flavorings and colorants. Parenteral dosage forms can be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing in a suitable vial or vial. These are just some examples of the many appropriate methods well known in the art for preparing dosage forms. It is noted that when antagonists of MCH receptors are used as active ingredients in a pharmaceutical composition, they are not intended for use only in humans, but also in other non-human mammals. In fact, recent advances in the area of animal health care demand consideration of the use of MCH receptor antagonists for the treatment of obesity in domestic animals. { e. g. , cats and dogs), and antagonists of MCH receptors in other domestic animals in which no disease or disorder is evident (e.g., animals with special feeding such as cows, chickens, fish, etc.). Those of ordinary skill in the art easily credit for understanding the usefulness of such compounds in such applications. The pharmaceutically acceptable salts of the compounds of the invention can be prepared by reactivating the free acid or base forms of these compounds with the appropriate base or acid in water, in an organic solvent, or in a mixture of the two; Generally, a non-aqueous medium such as ether, ethylacetate, ethanol, isopropanol, dioxane, or acetonitrile is preferred. For example, when the compound (I) possesses an acidic functional group, it can form an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt ( eg calcium salt, magnesium salt, barium salt, etc.), and an ammonium salt. When the compound (I) possesses a basic functional group, it can form an inorganic salt (eg, hydrochloride, sulfate, phosphate, hydrobromate, etc.) or an organic salt (eg, acetate, maleate, fumarate, succinate, methanesulfonate, p- toluenesulfonate, citrate, tartrate, etc.).

When a compound of the invention contains optical isomers, stereoisomers, regio isomers, rotational isomers, a single substance and a mixture thereof are included as a compound of the invention. For example, when a chemical formula is represented without showing stereochemical designation (s), such as Formula (III), then all possible stereoisomers, optical isomers and mixtures thereof are considered to be within the scope of that formula. Accordingly, the Formula (Illa) specifically designates the cis-relationship between the amino groups in the cyclohexyl ring and accordingly, this formula is also fully embraced by Formula (III). Preparation of the Compound of Formula (I) - General Synthetic Methods The novel substituted pyrimidines of the present invention can be easily prepared according to a variety of synthetic manipulations, all of which will be familiar to the skilled artisan. Preferred methods for the preparation of the compounds of the present invention include, but are not limited to, those described in Scheme 1-8. The pyrimidine (C) can be prepared as shown in Scheme 1. 4,6-Dihydroxypyrimidine (A), which is commercially available or is condensed from malonic acid derivatives and amidine derivatives, wherein Zi and Z2 are as previously defined, it is converted to 4,6-dihalo-pyrimidine (B) by a halogenating agent with or without a base (wherein X is halogen such as chlorine, bromine, or iodine). The halogenating agent includes phosphorous oxychloride (P0C13), phosphorous oxybromide (POBr3), or phosphorous pentachloride (PC15). The base includes a tertiary amine (preferably N, N-diisopropylethylamine, etc.) or an aromatic amine (preferably N, N-dimethylaniline, etc.). The reaction temperature ranges from about 100 ° C to 200 ° C, preferably from about 140 ° C to 180 ° C. The introduction of the substituent R2 to 4,6-dihalo-pyrimidine (B) gives the pyrimidine (C). Also the pyrimidine (C) can be prepared from commercially available 2,4,6-trihalo-pyrimidine (D), wherein Z 2 is as defined above and X is halogen such as chlorine, bromine, or iodine, followed by introduction of the substituent R2 and the substituent Zi. Esguema 1 -ir T [D. [The common intermediate (H) of the new substituted pyrimidines can be prepared as shown in Scheme 2. The pyrimidine (C) is replaced by the mono-protected diamine (F), where R3, R4, A, and B they are as defined above and P is a protecting group, with or without a base in an inert solvent to provide the coupling adduct (G). The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydroxide (preferably sodium hydroxide, etc.), or a tertiary amine (preferably N, A-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.). The inert solvent includes solvents of lower alkyl alcohol (preferably methanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents (preferably N, W-dimethylformamide or l-methyl-pyrrolidin-2-one, etc.) . The reaction temperature ranges from about 50 ° C to 200 ° C, preferably from about 80 ° C to 150 ° C. This reaction can also be carried out under microwave conditions. Representative protective groups suitable for a wide variety of synthetic transformations are described in Greene and Wuts, Protective Groups in Organic Synthesis, second edition, John Wiley & Sons, New York, 1991, whose description is incorporated herein by reference in its entirety. Deprotection of the protecting group leads to the common intermediate (H) of the new substituted pyrimidines. Esguema 2 lH3 The conversion of the common intermediate (H) to the new substituted pyrimidines (I), (J), and (V) - (X) of the present invention is detailed in Scheme 3. The amine (H) is reactivated with acid carboxylic (R! C02H) and a dehydrating condensation agent in an inert solvent with or without a base to provide the novel amides (I) of the present invention. The dehydration condensing agent includes dicyclohexylcarbodiimide (DCC), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC'HCl), bromo-tris-pyrrolidino-phosphine hexafluorophosphate (PyBroP), O- (7-) hexafluorophosphate azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium (HATU), or l-cyclohexyl-3-methylpolystyrene-carbodiimide. The base includes a tertiary amine (preferably N, N-diisopropylethylamine or triethylamine, etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), nitrile solvents (preferably acetonitrile, etc.), or amide solvents (preferably N, N-dimethylformamide , etc.). If necessary, 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxaamidomethyl polystyrene, or l-hydroxy-7-azabenzotriazolo (HOAT) can be used as a reactive agent. The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. Alternatively, the new amide (I) of the present invention can be obtained by amidation reaction using an acid chloride (RiCOCl) and a base in an inert solvent. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogen carbonate. (preferably sodium hydrogencarbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.), or an aromatic amine (preferably pyridine, imidazole, poly (4). -vinylpyridine), etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), amide solvents (preferably N, N-dimethylformamide, etc.), or aromatic solvents (preferably toluene) or pyridine, etc.). The reaction temperature varies from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. The new amide (I) of the present invention is reactivated with a reducing agent in an inert solvent to provide the new amine (J) of the present invention. The reducing agent includes alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal borohydrides (preferably lithium borohydride), alkali metal trialkoxyaluminum hydrides (preferably tri-tert-butoxyaluminium lithium hydride), dialkyl aluminum hydrides. (preferably diisobutylaluminum hydride), borane, dialkyloborane (preferably di-isoamyl borane), alkali metal trialkyl boron hydrides (preferably triethyl boron lithium hydride). The inert solvent includes ether solvents (preferably tetrahydrofuran or dioxane) or aromatic solvents (preferably toluene, etc.). The reaction temperature ranges from about -78 ° C to 200 ° C, preferably from about 50 ° C to 120 ° C. Alternatively, the novel amine (J) of the present invention can be obtained by reductive amidation reaction using aldehyde (RiCHO) and a reducing agent in an inert solvent with or without an acid. The reducing agent includes sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, or borane-pyridine complex, preferably sodium triacetoxyborohydride or sodium cyanoborohydride. The inert solvent includes lower alkyl alcohol solvents (preferably methanol or ethanol, etc.), lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), or aromatic solvents (preferably toluene, etc.). The acid includes an inorganic acid (preferably hydrochloric acid or sulfuric acid) or an organic acid (preferably acetic acid). The reaction temperature ranges from about -20 ° C to 120 ° C, preferably from about 0 ° C to 100 ° C. This reaction can also be carried out under microwave conditions. The amine (I) is reactivated with sulfonyl halide (R? S02X), wherein X is halogen such as chlorine, bromine, or iodine, and a base in an inert solvent to provide the novel sulfonamide (V) of the present invention. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogencarbonate (preferably sodium hydrogen carbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.), or an aromatic amine (preferably pyridine or imidazole, etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), alcohol solvents (preferably 2-propanol, etc.), or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. The new urea (W) or thiourea (W) of the present invention can be obtained by reaction of urea or thiourea reaction using an isocyanate (RxNCO) or isothiocyanate (RiNCS) in an inert solvent with or without a base. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogencarbonate (preferably sodium hydrogencarbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, A7-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.), or an aromatic amine (preferably pyridine or imidazole, etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), aromatic solvents (preferably benzene or toluene, etc.), or polar solvents (preferably N, N dimethylformamide or dimethyl sulfoxide, etc.). The reaction temperature ranges from about -20 ° C to 120 ° C, preferably from about 0 ° C to 100 ° C. The new urethane (X) of the present invention can be obtained by reaction of urethane using RxOCOX, wherein X is halogen such as chlorine, bromine, or iodine, in an inert solvent with or without a base. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrocarbonate (preferably sodium hydrogencarbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide. (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine, oi 7-methylmorpholine, etc.), or an aromatic amine (preferably pyridine, imidazole, or poly (4-vinylpyridine), etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), aromatic solvents (preferably benzene or toluene, etc.), or polar solvents (preferably N, N dimethylformamide or dimethyl sulfoxide, etc.). The reaction temperature ranges from about -20 ° C to 120 ° C, preferably from about 0 ° C to 100 ° C. Esguema 3 reaction of urea R, N CO or reaction of urethane reaction of tic-urea * R, OCOX R, N CS (V) (J) Also the new substituted pyrimidine (M) of the present invention can be prepared as shown in Scheme 4. First 4, 6-dihalo-pyrimidine (B) is replaced by the amine (K) which either installed by the desired substituent Ri, wherein R3, R4, A, B, Y, and Rx are as defined above, with or without a base in an inert solvent to provide the coupling adduct (L). The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydroxide (preferably sodium hydroxide, etc.), or a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine , or N-methylmorpholine, etc.). The inert solvent includes solvents of lower alkyl alcohol (preferably methanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents (preferably N, N-dimethylformamide or l-methyl-pyrrolidin-2-one, etc.) . The reaction temperature ranges from about 50 ° C to 200 ° C, preferably from about 80 ° C to 150 ° C. This reaction can also be carried out under microwave conditions. The introduction of the substituent R2 leads to the new substituted pyrimidine (M) of the present invention.

Esguema 4 The common intermediate (R) of the new substituted pyrimidines can be prepared as shown in Scheme 5. The commercially available 2,4-dihydroxypyrimidine (N), wherein Z3 and Z4 are as defined above, becomes 2, 4 -dihalo-pyrimidine (O) by a halogenating agent with or without a base (wherein X is halogen such as chlorine, bromine, or iodine). The halogenating agent includes phosphorous oxychloride (POCI3), phosphorous oxybromide (POBr3), or phosphorous pentachloride (PC15). The base includes a tertiary amine (preferably N, N-diisopropylethylamine, etc.) or an aromatic amine (preferably N, N-di-ethylaniline, etc.). The reaction temperature ranges from about 100 ° C to 200 ° C, preferably from about 140 ° C to 180 ° C. The introduction of the substituent R2 to 2,4-dihalo-pyrimidine (O) gives the pyrimidine (P). The pyrimidine (P) is replaced by the mono-protected diamine (F), wherein R3, R4, A, and B are as defined above and P is a protecting group, with or without a base in an inert solvent to provide the coupling adduct (Q). The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydroxide (preferably sodium hydroxide, etc.), or a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine , or N-methylmorpholine, etc.). The inert solvent includes solvents of lower alkyl alcohol (preferably methanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents (preferably N, N-dimethylformamide or l-methyl-pyrrolidin-2-one, etc.) . The reaction temperature ranges from about 50 ° C to 200 ° C, preferably from about 80 ° C to 150 ° C. This reaction can also be carried out under microwave conditions. It is understood that the regioisomers can be formed using certain methods described herein, such as Scheme 5, and that these regioisomers could be separated using methods known to those skilled in the art. Representative protective groups suitable for a wide variety of synthetic transformations are described in Greene and Wuts, Protective groups in Organic Synthesis, second edition, John Wiley & Sons, New York, 1991, whose description is incorporated herein by reference in its entirety. The deprotection of the protective group leads to the common intermediate (R) of the new substituted pyrimidines.

Esquema 5 introduction R- (N) (O) : The conversion of the common intermediate (R) to the new substituted pyrimidines (S), (T), and (V) - (A ') of the present invention is detailed in Scheme 6. The amine (R) is reactivated with acid carboxylic (R? C02H) and a dehydrating condensation agent in an inert solvent with or without a base to provide the novel amide (S) of the present invention. Dehydration condensation agent includes dicyclohexylcarbodiimide (DCC), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC'HCl), bromo-tris-pyrrolidino-phosphine hexafluorophosphate (PyBroP), 0- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU), or l-cyclohexyl-3-methylpolystyrene-carbodiimide. The base includes a tertiary amine (preferably N,? T-diisopropylethylamine or triethylamine, etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), nitrile solvents (preferably acetonitrile, etc.), or amide solvents (preferably N, N-dimethylformamide , etc.). If necessary, 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxaamidomethyl polystyrene, or l-hydroxy-7-azabenzotriazolo (HOAT) can be used as a reactive agent. The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. Alternatively, the novel amide (S) of the present invention can be obtained by amidation reaction using an acid chloride (RiCOCl) and a base in an inert solvent. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogen carbonate. (preferably sodium hydrogencarbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine, or A-methylmorpholine, etc.), or an aromatic amine (preferably pyridine, imidazole, poly (4). -vinylpyridine), etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), amide solvents (preferably N, N-dimethylformamide, etc.), or aromatic solvents ( preferably toluene or pyridine, etc.). The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. The new amide (S) of the present invention is reactivated with a reducing agent in an inert solvent to provide the new amine (T) of the present invention. The reducing agent includes aluminum alkali metal hydrides (preferably lithium aluminum hydride), alkali metal borohydrides (preferably lithium borohydride), alkali metal trialkoxyaluminum hydrides. (preferably tri-tert-butoxyaluminium lithium hydride), dialkylaluminum hydrides (preferably di-isobutylaluminum hydride), borane, dialkyloboranes (preferably di-isoamyl borane), alkali metal trialkylborohydrides (preferably triethyl boron lithium hydride). The inert solvent includes ether solvents (preferably tetrahydrofuran or dioxane) or aromatic solvents (preferably toluene, etc.). The reaction temperature ranges from about -78 ° C to 200 ° C, preferably from about 50 ° C to 120 ° C. Alternatively, the novel amine (T) of the present invention can be obtained by reductive amidation reaction using aldehyde (RiCHO) and a reducing agent in an inert solvent with or without an acid. The reducing agent includes sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, or borane-pyridine complex, preferably sodium triacetoxyborohydride or sodium cyanoborohydride. The inert solvent includes lower alkyl alcohol solvents (preferably methanol or ethanol, etc.), lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), or aromatic solvents (preferably toluene, etc.). The acid includes an inorganic acid (preferably hydrochloric acid or sulfuric acid) or an organic acid (preferably acetic acid). The reaction temperature ranges from about -20 ° C to 120 ° C, preferably from about 0 ° C to 100 ° C. This reaction can also be carried out under microwave conditions. The amine (R) is reactivated with sulfonyl halide (R? S02X), wherein X is halogen such as chlorine, bromine, or iodine, and a base in an inert solvent to provide the novel sulfonamide (Y) of the present invention. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogencarbonate (preferably sodium hydrogen carbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide. (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.), or an aromatic amine (preferably pyridine or imidazole, etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), alcohol solvents (preferably 2-propanol, etc.), or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. The new urea (Z) or thiourea (Z) of the present invention can be obtained by reaction of urea or thiourea reaction using an isocyanate (R ??CO) or isothiocyanate (RiNCS) in an inert solvent with or without a base. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogencarbonate (preferably sodium hydrogen carbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, i \ 7-diisopropylethylamine, triethylamine, or N-methyl orpholine, etc.), or an aromatic amine (preferably pyridine or imidazole, etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), aromatic solvents (preferably benzene or toluene, etc.), or polar solvents (preferably N, N dimethylformamide or dimethyl sulfoxide, etc.). The reaction temperature ranges from about -20 ° C to 120 ° C, preferably from about 0 ° C to 100 ° C. The new urethane (A ') of the present invention can be obtained by urethane reaction using RiOCOX, wherein X is halogen such as chlorine, bromine, or iodine, in an inert solvent with or without a base. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogencarbonate (preferably sodium hydrogen carbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine, or I-7-methylmorpholine, etc.), or an aromatic amine (preferably pyridine, imidazole, or poly- (4-vinylpyridine) , etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), aromatic solvents (preferably benzene or toluene, etc.), or polar solvents (preferably N, N dimethylformamide or dimethyl sulfoxide, etc.). The reaction temperature ranges from about -20 ° C to 120 ° C, preferably from about 0 ° C to 100 ° C.

Esguema 6 reaction of urea R, NC O or _s-- 'urethane reaction reaction of thiourea R, O O / R, NC S - ^ reduction of amine sulfonamidation \ R | CHO reduction R ¡SC X '"v." *.

IV) m Alternatively, the new pipmidmas (M) and (U) of the present invention are synthesized directly from the pyrimidine core (C), which is synthesized in Scheme 1 and the pyrimid (a) core, which is synthesized in Scheme 5, as shown in Scheme 7. This coupling is carried out with or without a base in an inert solvent. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydroxide (preferably sodium hydroxide, etc.), or a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine , or N-methylmorpholine, etc.). The inert solvent includes solvents of lower alkyl alcohol (preferably methanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents (preferably N, N-dimethylformamide or l-methyl-pyrrolidin-2-one, etc.) . The reaction temperature ranges from about 50 ° C to 200 ° C, preferably from about 80 ° C to 180 ° C. This reaction can also be carried out under microwave conditions.

Esguema 7 The common intermediate (C) of the new amide (D ') and the new ester (E') in the present invention is prepared from the condensation between the pyrimidine nucleus (C) which is synthesized in Scheme 1 and the acid carboxylic (B '), wherein R3, A, and B are as defined above, as shown in Scheme 8. The carboxylic acid (C) is reactivated with amine (RXNHR4) and a dehydrating condensation agent in a solvent inert with or without a base to provide the new amide (D ') of the present invention. The dehydration condensation agent includes dicyclohexylcarbodiimide (DCC), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC'HCl), bromo-tris-pyrrolidino-phosphine hexafluorophosphate (PyBroP), O- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (HATU), or l-cyclohexyl-3-methylpolystyrene-carbodiimide. The base includes a tertiary amine (preferably N, N-diisopropylethylamine or triethylamine, etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), nitrile solvents (preferably acetonitrile, etc.), or amide solvents (preferably N, N-dimethylformamide , etc.). If necessary, 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxaamidomethyl polystyrene, or l-hydroxy-7-azabenzotriazolo (HOAT) can be used as a reactive agent. The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. Alternatively, the novel amide (D ') of the present invention can be obtained by amidation reaction through an acid chloride prepared from the carboxylic acid (C) and a base in an inert solvent. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogencarbonate (preferably sodium hydrogen carbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.), or an aromatic amine (preferably pyridine, imidazole, poly- (4-vinylpyridine), etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), amide solvents (preferably N, N-dimethylformamide, etc.), or aromatic solvents (preferably toluene or pyridine, etc.). The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. The carboxylic acid (C) is reactivated with alcohol (RiOH) and a dehydrating condensation agent in an inert solvent with or without a base to provide the new ester (E ') of the present invention. The dehydration condensation agent includes dicyclohexylcarbodiimide (DCC), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC «HC1), bromo-tris-pyrrolidino-phosphine hexafluorophosphate (PyBroP), 0- (7-azabenzotriazole hexafluorophosphate -l-il) -1, 1, 3, 3-tetramethyluronium (HATU), or l-cyclohexyl-3-methylpolystyrene-carbodiimide. The base includes a tertiary amine (preferably N, N-diisopropylethylamine or triethylamine, etc.). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), nitrile solvents (preferably acetonitrile, etc.), or amide solvents (preferably N, N-dimethylformamide , etc.). If necessary, 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxaamidomethyl polystyrene, or l-hydroxy-7-azabenzotriazolo (HOAT) can be used as a reactive agent. The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. Alternatively, the new ester (E ') of the present invention can be obtained by esterification through an acid chloride prepared from the carboxylic acid (C) and a base in an inert solvent. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogencarbonate (preferably sodium hydrogencarbonate or potassium hydrogen carbonate, etc.), an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide, etc.), a tertiary amine (preferably N, N-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.), or an aromatic amine (preferably pyridine, imidazole, poly- (4-vinylpyridine), etc. ). The inert solvent includes lower halocarbon solvents (preferably dichloromethane, dichloroethane, or chloroform, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane), amide solvents (preferably N, N-dimethylformamide, etc.), or aromatic solvents (preferably toluene) or pyridine, etc.). The reaction temperature ranges from about -20 ° C to 50 ° C, preferably from about 0 ° C to 40 ° C. Alternatively, the new pyrimidines (D ') and (E ') of the present invention are synthesized directly from the pyrimidine core (C), which is synthesized in Scheme 1. This coupling is carried out with or without a base in an inert solvent. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydroxide (preferably sodium hydroxide, etc.), or a tertiary amine (preferably N, W-diisopropylethylamine, triethylamine, or N-methylmorpholine, etc.). The inert solvent includes solvents of lower alkyl alcohol (preferably methanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents (preferably N,? J-dimethylformamide or l-methyl-pyrrolidin-2-one, etc. ). The reaction temperature ranges from about 50 ° C to 200 ° C, preferably from about 80 ° C to 180 ° C. This reaction can also be carried out under microwave conditions.

Esquema 8 I; D ') Examples The compounds of the invention and their synthesis are further illustrated by the following examples. The following examples are provided to further define the invention, however, without limiting the invention to the particular of these examples. "Ambient temperature" as referred to in the following example is intended to indicate a temperature that falls between 0 ° C and 40 ° C. The following compounds are named by Beilstein Auto Nom Version 4.0, CS Chem Draw Ultra Version 7.0.1, CS Chem Draw Ultra Version 6.0.2, CS Chem Draw Ultra Version 6.0, or ACD ame Version 7.0. The abbreviations used in the present specification, particularly in the Schemes and Examples, are as follows: 1H NMR: proton nuclear magnetic resonance spectrum AcOH: acetic acid APCI: chemical ionization at atmospheric pressure (Boc) 20: di-tertiary butyl dicarbonate BuLi: butyl lithium BuOH: butanol Cbz: carbobenzoxy CDC13: deuterated chloroform CH2C12: dichloromethane CHC13: chloroform Cl: chemical ionization DCM: dichloromethane DIEA: diisopropylethylamine DMSO: dimethyl sulfoxide EDC-HC1: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride The: ionization of electron ESI: ionization of electroroated Et3N: triethylamine Et20: diethyl ether EtOAc: ethyl ester of acetic acid EtOH: ethanol FAB: rapid atomic bombardment HOBt-H20: 1-hydroxybenzotriazole hydrate H2S04: sulfuric acid HCl: hydrogen chloride IPA : iPr2NEt isopropanol: diisopropylethylamine K2CO3: potassium carbonate MeNH: dimethyl MeNH2 mine: methylamine MeOH: methanol MgSO: magnesium sulfate NaBH (OAc) 3: sodium triacetoxyborohydride NaBH3CN: sodium cyanoborohydride NaBH4: sodium borohydride NaH: sodium hydride NaHC03: sodium hydrogencarbonate NH3: ammonium NH4C1: ammonium chloride Pd / C: palladium carbon POCI3: phosphoryl chloride SOCI2: thionyl chloride TFA: trifluoroacetic acid THF: tetrahydrofuran ZC1: benzyloxycarbonyl chloride ZnBr2: zinc bromide s: single d: double t: triple q: quadruple dd: double double dt: double triple ddd: double double double brs: single broad m: multiple J: coupling constant Hz: Hertz Example 1 dihydrochloride N '- ( cis-4- { [4-Bromo-2- (trifluoromethoxy) benzyl] amino} cyclohexyl) -N, N-dimethylpyrimidine-4,6-diamine Step A: Synthesis of (6-chloro-pyrimidin-4) -yl) -dimethyl-amine. To a solution of 4,6-dichloro-pyrimidine (10.0 g) in THF (10 mL) was added iPr2NEt (10.4 g) and 50% aqueous Me2NH (6.05 g). The mixture was stirred at room temperature for 28 hours and was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was suspended in Et20. The precipitate was collected by filtration, washed with Et20 and dried under reduced pressure to give (6-chloro-pyrimidin-4-yl) -dimethyl-amine (6.37 g). ESI MS m / e 157, M +; H NMR (300 MHz, CDCl 3) d 3.12 (s, 6 H), 6.41 (s, 1 H), 8.37 (s, 1 H). Step B: Synthesis of N- (cis-4-bromo-2-trifluoromethoxy-benzyl) -cyclohexane-1,4-diamine. To a solution of (4-amino-cyclohexyl) -carbamic acid tert-butyl ester (6.72 g) in CHC13 (67 mL) was added 4-bromo-2-trifluoromethoxy-benzaldehyde (8.44 g), acetic acid (1.88 g). ), and NaBH (OAc) 3 (9.97 g). The mixture was stirred at room temperature for 4 hours and was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 33% EtOAc in hexane) to give [cis-4- (4-tert-butyl) ester. -bromo-2-trifluoromethoxy-benzylamino) -cycotehexyl] -carbamic acid. To a solution of the above material (3.00 g) in EtOAc (30 mL) was added 4 M hydrogen chloride in EtOAc (60 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was alkalized with saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCl3 (seven times). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give M-. { cis-4-bromo-2-trifluoromethoxy-benzyl) -cyclohexane-1,4-diamine (2.39 g). ESI MS m / e 367, M +; ^ NMR (300 MHz, CDC13) d 1.22-1.96 (m, 8 H), 2.51-2.71 (m, 1 H), 2.87-3.13 (m, 1 H), 3.74 (brs, 2 H), 7.28-7.50 (m, 3 H). Step C: Synthesis of dihydrochloride N '- (cis-4 { [4-bromo-2- (rifluoromethoxy) benzyl] amino} cydohexyl) -N, N-dimethylpyrimidine-4,6-diamin. A mixture of N- (cis-4-bromo-2-trifluoromethoxy-benzyl) -cyclohexane-1,4-diamine (466 mg), (6-chloro-pyrimidin-4-yl) -dimethyl-amine (200 mg) , and ethylene glycol (0.5 mL) was stirred under reflux for 4 hours in a sealed tube. The mixture was poured into saturated aqueous NaHC03 and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography.

(NH-silica gel, 50% EtOAc in hexane and silica gel, 5% MeOH in CHC13) to give N '- (cis-4 { [4-bromo-2- (trifluoromethoxy) benzyl] amino} cyclohexyl) -N, N-dimethylpyrimidine-4,6-diamine. To a solution of the above material in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was suspended in Et2? (20 mL) and the suspension was stirred at room temperature for 4 hours. The precipitate was collected by filtration, washed with Et20, and dried under reduced pressure to give N '- (cis-4. {[4-bromo-2- (trifluoromethoxy) benzyl] amino} cyclohexyl dihydrochloride) -N, N-dimethylpyrimidine-4,6-diamine (67 mg). ESI MS m / e 488, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.64-1.86 (m, 2 H), 1.96-2.34 (m, 8 H), 2.98-3.44 (m, 8 H), 4.27 (s, 2 H), 7.40-7.59 (m, 3 H), 8.06-8.24 (m, 2 H). EXAMPLE 2 N- (cis-4- { [6- (dimethylamino) pyrimidin-4-yl] amino}. Cyclohexyl) -3,4-difluorobenzamide hydrochloride Step A: Synthesis of tert-butyl ester of acid (cis -4- { [1- (3, 4-difluoro-enyl) -methanoyl] -amino.} - cyclohexyl) -carbamic acid. To a solution of 3,4-difluoro-benzoic acid (4.10 g) and tert-butyl ester of (cis-4-amino-cyclohexyl) -carbamic acid (5.05 g) in DMF (50 L) was added Et3N (90 mL ), HOBt-H20 (5.41 g), and EDC-HC1 (4.97 g). The mixture was stirred at room temperature for 17 hours. Water (200 mL) was added to the reaction mixture and the suspension was stirred at room temperature for 10 min. The precipitate was collected by filtration, washed with H20 and EtOH, and dried at 80 ° C under reduced pressure to give tert-butyl ester of acid (cis-4. {[1- (3,4-difluoro- phenyl) -methanoyl] -amino.} - cyclohexyl) -carbamic acid (5.20 g). ESI MS m / e 377, M + Na +; XH NMR (300 MHz, CDC13) d 1.45 (s, 9 H), 1.53-1.95 (m, 8 H), 3.60-3.74 (, 1 H), 4.00-4.16 (m, 1 H), 4.50-4.68 ( m, 1 H), 5.95-6.09 (, 1 H), 7.15-7.28 (m, 1 H), 7.43-7.68 (m, 2 H). Step B: Synthesis of N- (c? S-4-amino-cyclohexyl) -3,4-di-luoro-benzamide. A solution of tert-butyl ester of acid (cis-4- { [1- (3,4-difluoro-phenyl) -methanoyl] -amino}. -cyclohexyl) -carbamic acid (5.20 g) in EtOAc (52 mL) was cooled in an ice bath and 4 M hydrogen chloride in EtOAc (104 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in 1M aqueous NaOH and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO 4, filtered, concentrated under reduced pressure, and dried at 60 ° C under reduced pressure to give N- (cis-4-amino-cyclohexyl) -3,4-difluoro-benzamide ( 3.00 g). ESI MS m / e 255, M + H +; XH NMR (300 MHz, CDC13) d 1.15-1.52 (m, 3 H), 1.59-1.89 (m, 5 H), 2.94-3.06 (m, 1 H), 4.06-4.20 (m, 1 H), 6.01 -6.18 (m, 1 H), 7.13-7.26 (m, 1 H), 7.43-7.50 (m, 1 H), 7.57-7.67 (m, 1 H). Step C: Synthesis of N- (cis-4. {[[6- (dimethylamino) pyrimidin-4-yl] amino]} cydohexyl) -3,4-difluorobenzamide hydrochloride. To a solution of N- (cis-4-amino-cyclohexyl) -3,4-difluoro-benzamide (442 mg) was added (6-chloro-pyrimidin-4-yl) -dimethyl-amine obtained in step A of example 1 (250 mg). The mixture was stirred at 180 ° C for 8 hours in a sealed tube. Aqueous saturated NaHCO3 was added to the mixture and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (NH-silica gel, 33% to 50% EtOAc in hexane and silica gel, 3% MeOH in CHC1) to give N-. { cis-4 ~. { [6- (dimethylamino) pyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide. To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.2 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was suspended in Et20 (20 mL) and the suspension was stirred at room temperature for 4 hours. The precipitate was collected by filtration, washed with Et20, and dried at 70 ° C under reduced pressure to give N- hydrochloride. { cis-4-. { [6- (di ethylamino) pyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide (99 mg). ESI MS m / e 398, M (free) + NaX? H NMR (300 MHz, 3) d 1.69-2.15 (m, 8 H), 3.00-3.42 (m, 6 H), 3.69-3.81 (m, 1 H), 4.03-4.21 (m, 1 H), 5.26 (s, 1 H), 6.66-6.80 (m, 1 H), 7.13- 7.26 (m, 1 H), 7.51-7.62 (m, 1 H) , 7.68-7.80 (m, 1 H), 8.01 (s, 1 H), 8.68-8.91 (m, 1 H), 13.84-14.09 (m, 1 H). EXAMPLE 3 Hydrochloride N- [cis-4- ( { [6- (dimethylamino) pyrimidin-4-yl] amino.} Methyl) cydohexyl] -3,4-difluorobenzamide Step A: Synthesis of tert-butyl ester of acid (cis-4-hydroxymethyl-cyclohexyl) -carbamic acid. A suspension of cis-4-amino-cyclohexanecarboxylic acid (244 g) in MeOH (2.45 L) was cooled to -8 ° C. Tionyl chloride (45.0 mL) was added dropwise. The mixture was stirred at room temperature for 4.5 hours and concentrated under reduced pressure to give a white solid. To a suspension of the above solid in CHCl3 (3.00 L) was added triethylamine (261 mL) and (Boc) 0 (409 g) successively. The mixture was stirred at room temperature for 5 hours and was poured into water. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (silica gel, CHC13 at 10% MeOH in CHC13) to give a colorless oil (531 g). To a suspension cooled to -4 ° C of lithium aluminum hydride (78.3 g) in Et20 (7.9 L) was added a solution of the above oil (530.9 g) in Et20 (5.3 L) at 0 ° C. The resulting suspension was stirred at room temperature for 2 hours. The mixture was cooled in an ice bath, satiated with cold water, and filtered through a pad of celite. The filtrate was dried over MgSO4, filtered, and concentrated under reduced pressure. The precipitate was suspended in hexane (300 mL), filtered, washed with hexane, and dried under reduced pressure to give (tert-butyl-4-hydroxymethyl-cyclohexyl) -carbamic acid tert-butyl ester (301 g). ESI MS m / e 252, M + Na +; XH NMR (300 MHz, CDC13) d 1.16-1.36 (m, 2 H), 1.45 (s, 9 H), 1.52-1.77 (m, 7 H), 3.51 (d, J = 6.2 Hz, 2 H), 3.75 (brs, 1 H), 4.30-4.82 (m, 1 H). Step B: Synthesis of [cis-4- (benzyloxycarbonylamino-methyl) -cydohexyl] -carbamic acid tert-butyl ester. To a solution of (cis-4-hydroxymethyl-cyclohexyl) -carbamic acid tert-butyl ester (17.7 g) in THF (245 L) was added triphenylphosphine (20.2 g) and phthalimide (11.4 g) successively. The resulting suspension was cooled in an ice bath and 40% diethyl azodicarboxylate in toluene (33.6 mL) was added over 1 hour. The mixture was stirred at room temperature for 2.5 days, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 33% EtOAc in hexane) to give a white solid. To a suspension of the above solid (27.5 g) in EtOH (275 mL) was added hydrazine hydrate (5.76 g). The mixture was stirred at reflux for 2.25 hours, cooled to room temperature, and concentrated under reduced pressure. The precipitate was dissolved in 10% aqueous sodium hydroxide (350 mL). The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. To a solution of the above residue in CHC13 (275 mL) was added triethylamine (8.54 g). The resulting solution was cooled to 0 ° C and ZC1 (14.4 g) was added under 5 ° C. The mixture was stirred at room temperature for 16 hours and was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 2% MeOH in CHCl3) to give [cis-4- (benzyloxycarbonylamino] tert-butyl ester. -methyl) -cydohexyl] -carbamic acid (25.3 g). ESI MS m / e 385, M + Na +; Xí NMR (300 MHz, CDC13) d 1.13-1.31 (m, 2 H), 1.44 (s, 9 H), 1.48-1.75 (m, 7 H), 3.10 (t, J = 6.4 Hz, 2 H), 3.72 (brs, 1 H), 4.42-4.76 (m, 1 H), 4.76-4.92 (m, 1 H), 5.09 (s, 2 H), 7.27-7.38 (m, 5 H).

Step C: Synthesis of benzyl ester of (c? S-4-amino-cyclohexylmethyl) -carbamic acid. To a solution of [cis-4- (benzyloxycarbonylamino-methyl) -cydohexyl] -carbamic acid tert-butyl ester (12.9 g) in EtOAc (129 L) was added 4 M hydrogen chloride in EtOAc (129 mL). The mixture was stirred at room temperature during 3 hours, it was filtered, washed with EtOAc, and dried under reduced pressure. Saturated aqueous NaHCO3 was added to the residue. The aqueous layer was extracted with CHC13 (five times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and dried under reduced pressure to give benzyl ester of (cis-4-amino-cyclohexylmethyl) -carbamic acid (8.88 g). ESI MS m / e 263, M + H +; XH NMR (300 MHz, CDC13) d 1.36-1.98 (m, 9 H), 2.96-3.32 (m, 3 H), 5.12 (brs, 3 H), 7.36 (s, 5 H). Step D: Synthesis of benzyl ester of [cis-4- (3,4-difluoro-benzoylamino) -cyclohexylmethyl] -carbamic acid. To a solution of benzyl ester of (cis-4-amino-cyclohexylmethyl) -carbamic acid (2.00 g) in CHC13 (16 mL) was added Et3N (2.23 mL) and 3,4-difluoro-benzoyl chloride (1.48 g) in CHCl3 (4 mL). The mixture was stirred at room temperature for 12 hours and was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give benzyl acid ester [ cis-4- (3, -difluoro-benzoylamino) -cyclohexylmethyl] -carbamic acid (2.66 g) • ESI MS m / e 425, M +; aH NMR (300 MHz, CDC13) d 1.22-1.44 (m, 2 H), 1.57-1.88 (m, 6 H), 3.07-3.25 (m, 2 H), 4.08-4.28 (m, 1 H), 4.78 -4.93 (m, 1 H), 5.10 (s, 2 H), 6.02-6.24 (m, 1 H), 7.13-7.39 (m, 6 H), 7.43-7.52 (m, 1 H), 7.58-7.68 ( , 1 HOUR) . Step E: Synthesis of N- (cis-4-aminomethyl-cyclohexyl) -3,4-difluoro-benzamide. To a solution of benzyl ester of [cis-4- (3,4-difluoro-benzoylamino) -cyclohexylmethyl] -carbamic acid (2.60 g) in MeOH (26 mL) was added 10% Pd / C (260 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 84 hours. The mixture was filtered through a pad of celite, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 9% to 17% EtOAc in hexane and silica gel, 1% MeOH in CHC13) to give N- (cis-4-aminomethyl-cyclohexyl) -3,4-difluoro-benzamide (1.43 g). ESI MS m / e 269, M + H +; H NMR (300 MHz, CDCl 3) d 1.13-1.86 (m, 9 H), 2.64 (d, J = 6.5 Hz, 2 H), 4.16-4.28 (m, 1 H), 6.09-6.30 (m, 1 H ), 7.15-7.27 (m, 1 H), 7.46-7.53 (m, 1 H), 7.58-7.67 (m, 1 H). Step F: Synthesis of N- [cis-4- ( { [6- (dimethylamino) pyrimidin-4-yl] amino} methyl) cyclohexyl] -3, -difluorobenzamide hydrochloride. To a solution of N- (cis-4-aminomethyl-cyclohexyl) -3,4-difluoro-benzamide (373 mg) in BuOH (1 mL) was added (6-chloro-pyrimidin-4-yl) -dimethyl-amine obtained in step A of example 1 (200 mg). The mixture was heated on a microwave synthesizer at 220 ° C for 20 min. Aqueous saturated NaHCO3 was added to the mixture and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO 4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give 'N- [cis -4- ( { [6- (dimethylamino) pyrimidin-4-yl] amino.} Methyl) cyclohexyl] -3,4-difluorobenzamide. To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. A suspension of the above material in Et20 (12 mL) was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with Et20, and dried at 70 ° C under reduced pressure to give N- [cis-4- ( { [6- (dimethylamino) pyrimidin-4-yl] amino hydrochloride} -methyl) ciciohexyl] -3,4-difluorobenzamide (106 mg). ESI MS m / e 390, M (free) + H +; aH NMR (300 MHz, CDC13) d 1.31-2.14 (m, 8 H), 2.96-3.46 (m, 8 H), 4.40-4.61 (m, 1 H), 5.18 (s, 1 H), 7.14-7.35 (m, 2 H), 7.83-8.09 (m, 3 H), 8.79-9.14 (m, 1 H). EXAMPLE 4 N- [(cis-4. {[[6- (dimethylamino) pyrimidin-4-yl] amino} cydohexyl) methyl] -3, -difluorobenzamide hydrochloride Step A: Synthesis of tert-butyl ester of acid . { cis-4- [(3, 4-difluoro-benzoylamino) -methyl] -cydohexyl} -carbámico To a solution of [cis-4- (benzyloxycarbonylamino-methyl) -cyclichexyl] -carbamic acid tert-butyl ester obtained in step B of Example 3 (5.00 g) in MeOH (50 mL) was added 10% Pd / C (500 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 84 hours, filtered through a pad of celite, and concentrated under reduced pressure to give a pale brown oil. To a solution of the above oil in CHC13 (40 mL) was added Et3N (4.03 mL) and 3,4-difluoro-benzoyl chloride (2.68 g) in CHC13 (10 mL). The mixture was stirred at room temperature for 12 hours. Aqueous saturated NaHCO3 was added to the mixture and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give the acid tert-butyl ester. { cis-4- [(3, 4-difluoro-benzoylamino) -methyl] -cydohexyl} -carbámico (3.48 g).

ESI MS m / e 391, M + Na +; XH NMR (300 MHz, CDC13) d 1.19-1.81 (m, 16 H), 3.33-3.43 (m, 2 H), 3.68-3.79 (m, 1 H), 4.54-4.73 (m, 1 H), 6.10 -6.21 (m, 1 H), 7.17-7.27 (m, 1 H), 7.46-7.54 (m, 1 H), 7.59-7.68 (m, 1 H). Step B: Synthesis of N- (cis-4-amino-cyclohexylmethyl) -3,4-difluoro-benzamide. To a solution of tert-butyl ester of (cis-4- [(3,4-difluoro-benzoylamino) -methyl] -cydohexyl] -carbamic acid. (3.48 g) in EtOAc (35 mL) was added 4 M hydrogen chloride in EtOAc (35 L). The mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was dissolved in 1M aqueous NaOH and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure to give N-. { cis-4-amino-cyclohexylmethyl) -3,4-difluoro-benzamide (2.50 g). ESI MS m / e 269, M + H +; ? H NMR (300 MHz, CDC13) d 1.16-1.81 (m, 9 H), 2.93-3.08 (m, 1 H), 3.32-3.42 (, 2 H), 6.41-6.57 (, 1 H), 7.14- 7.27 (m, 1 H), 7.48-7.57 (m, 1 H), 7.60-7.71 (m, 1 H). Step C: Synthesis of hydrochloride N- [(cis-4. {[[6- (dimethylamino) pyrimidin-4-yl] amino} ciciohexyl) methyl] -3,4-difluorobenzamid. To a solution of N-. { cis-4-amino-cyclohexylmethyl) -3,4-difluoro-benzamide (469 mg) in BuOH (1 mL) was added (6-chloro-pyrimidin-4-yl) -dimethyl-amine obtained in step A of the example 1 (250 mg). The mixture was heated on a microwave synthesizer at 220 ° C for 20 min. Aqueous saturated NaHCO3 was added to the mixture and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give N- [(cis -4- { [6- (dimethylamino) pyrimidin-4-yl] amino.} Cyclohexyl) methyl] -3,4-difluorobenzamide. To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. A suspension of the residue in Et20 (12 mL) was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with Et20, and dried at 70 ° C under reduced pressure to give N- [hydrochloride. { cis-4-. { [6- (dimethylamino) pyrimidin-4-y1] amino} -cycdohexyl) ethyl] -3,4-difluorobenzamide (82 mg). ESI MS m / e 390, M (free) + H +; XH NMR (300 MHz, CDC13) d 1.50-2.04 (m, 9 H), 2.93-3.57 (m, 8 H), 3.67-3.85 (m, 1 H), 5.23 (s, 1 H), 6.85-7.35 (m, 2 H), 7.73-8.05 (m, 3 H), 8.75-9.01 (, 1 H), 13.64-13.95 (m, 1 H). EXAMPLE 5 Hydrochloride N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,4-difluorobenzamide Stage A: Synthesis of 4,6-dichloro -2-methyl-pyrimidine. A suspension of 2-methyl-pyrimidine-4,6-diol (20.0 g) in POC13 (162 mL) was stirred at reflux for 4 hours and cooled to room temperature. The mixture was poured into ice water (3 L). The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 4,6-dichloro-2-methyl-pyrimidine (22.37 g). Cl MS m / e 163, M +; XH NMR (300 MHz, CDC13) d 2.71 (s, 3 H), 7.25 (s, 1 H). Step B: Synthesis of (6-chloro-2-methyl-pyrimidin-4-yl) -dimethyl-amine. To a solution of 4,6-dichloro-2-methyl-pyrimidine (11.1 g) in THF (110 mL) was added iPr2NEt (14.2 mL) and 50% aqueous Me2NH (8.5 mL). The mixture was stirred at room temperature for 2 hours. To the mixture was added 50% aqueous Me2NH (3.5 mL) and stirred at room temperature for 7 hours and concentrated under reduced pressure. To the residue was added saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and dried under reduced pressure to give (6-chloro-2-methyl-pyrimidin-4-yl) -dimethyl-amine (11.6 g). ESI MS m / e 172, M + H +; 1H NMR (300 MHz, CDC13) d 2.49 (s, 3 H), 3.10 (s, 6 H), 6.24 (s, 1 H). Step C: Synthesis of hydrochloride N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -3,4-difluorobenzamide. To a solution of N- (cis-4-amino-cyclohexyl) -3,4-difluoro-benzamide obtained in step B of example 2 (407 mg) in BuOH (1 mL) was added (6-chloro-2-). methyl-pyrimidin-4-yl) -dimethyl-amine (250 mg). The mixture was heated in a microwave synthesizer at 200 ° C for 20 min and at 230 ° C for 20 min. To the mixture was added aqueous saturated NaHCO 3 and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -cyclohexyl) -3,4-difluorobenzamide. To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.2 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et20 (12 mL) was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with Et20, and dried at 70 ° C under reduced pressure to give N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] hydrochloride] amino.}. cydohexyl) -3,4-difluorobenzamide (325 mg). ESI MS m / e 412, M (free) + Na +; XH NMR (300 MHz, CDC13) d 1.63-2.03 (m, 8 H), 2.49 (s, 3 H), 2.91-3.43 (m, 6 H), 3.67- 3.79 (m, 1 H), 4.03-4.22 (m, 1 H), 5.15 (s, 1 H), 6.89-7.02 (m, 1 H), 7.14-7.27 (m, 1 H), 7.56-7.64 (m, 1 H), 7.69-7.81 (m , 1 H), 8.40-8.55 (m, 1 H). EXAMPLE 6 3-Chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -4-fluorobenzamide hydrochloride Step A: Synthesis of cis-N -benzyl-cyclohexane-1,4-diamine. To a solution of tert-butyl ester of (cis-4-amino-cyclohexyl) -carbamic acid (5.00 g) in CHC13 (100 mL) was added benzaldehyde (2.48 g) and acetic acid (1.40 g). The mixture was stirred at room temperature for 1 hour. NaBH (OAc) 3 (7.42 g) was added to the mixture and the mixture was stirred at room temperature for 15 hours. The reaction was quenched with saturated aqueous aHC03 and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (silica gel, 2% to 9% MeOH in CHC13) to give acid tert-butyl ester ( cis-4-benzylamino-cyclohexyl) -carbamic acid (76.9 g). To a solution of the above material (76.9 g) in EtOAc (77 mL) was added 4 M hydrogen chloride in EtOAc (38.5 mL). The mixture was stirred at room temperature for 10 hours and concentrated under reduced pressure. The residue was dissolved in 2M aqueous NaOH (150 mL) and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and dried under reduced pressure to give cis-N-benzyl-cyclohexane-1,4-diamine (4.12 g). ESI MS m / e 205, M + H +; R NMR (300 MHz, CDC13) d 1.42-1.72 (, 8 H), 2.63-2.74 (m, 1 H), 2.80-2.91 (, 1 H), 3.77 (s, 2 H), 7.20-7.39 (, 5 H). Step B: Synthesis of N- (cis-4-benzylamino-cyclohexyl) -2, N ', W'-trimethyl-pyrimidine-4,6-diamine. To a solution of (6-chloro-2-methyl-pyrimidin-4-yl) -dimethyl-amine obtained in step B of example 5 (763 mg) in BuOH (0.8 mL) was added cis-N-benzyl-cyclohexane. -1, 4-diamine (1.00 g). The mixture was heated on a microwave synthesizer at 220 ° C for 25 min. To the mixture was added NaHCO3 saturated aqueous and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 9% to 60% EtOAc in hexane) to give N- (cis-). 4-benzylamino-cyclohexyl) -2, N ', N'-trimethyl-pyrimidine ~ 4,6-diamine (952 mg). ESI MS m / e 340, M + H +; ñ NMR (300 MHz, CDC13) d 1.47-1.92 (m, 8 H), 2.35 (s, 3 H), 2.63-2.74 (m, 1 H), 3.04 (s, 6 H), 3.56- 3.69 ( m, 1 H), 3.79 (s, 2 H), 4.67-4.80 (m, 1 H), 5.14 (s, 1 H), 7.20-7.36 (m, 5 H). Step C: Synthesis of N- (cis-4-amino-cyclohexyl) -2, N ', N'-trimethyl-pyrimidine-4,6-diamine. To a solution of N- (cis-4-benzylamino-cyclohexyl) -2, N ',? -P-trimethyl-pyrimidine-4,6-diamine (940 mg) in MeOH (9.4 mL) was added 20% Pd (OH 2 (188 mg). The mixture was stirred at 50 ° C under hydrogen atmosphere for 10 hours. The mixture was filtered through a pad of celite, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 2% to 5% MeOH in CHC13) to give N- (cyanide). 4-amino-cyclohexyl) -2, N ', 2 \ 7'-trimethyl-pyrimidine-4,6-diamine (566 mg). ESI MS m / e 250, M + H +; XR NMR (300 MHz, CDC13) d 1.05-1.89 (m, 10 H), 2.35 (s, 3 H), 2.75-2.90 (m, 1 H), 3.05 (s, 6 H), 3.54-3.70 (m , 1 H), 4.68-4.82 (m, 1 H), 5.14 (s, 1 H). Step D: Synthesis of 3-chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino]} -cydohexyl) -4-fluorobenzamide hydrochloride. To a solution of 3-chloro-4-fluoro-benzoic acid (192 mg) and N- (cis-4-amino-cyclohexyl) -2, N ', N'-trimethyl-pyrimidine-4,6-diamine (250 mg) in DMF (4 mL) was added Et3N (0.34 mL), HOBt-H20 (230 mg), and EDC-HC1 (211 mg.) The mixture was stirred at room temperature for 12 hours, water (20 mL) was added to the mixture and the aqueous layer was added. extracted with CHCl3 (three times) The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 25% to 50% EtOAc in hexane ) to give 3-chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -cydohexyl) -4-fluorobenzamide To a solution of the above material in EtOAc (10 L) was added 4 M hydrogen chloride in EtOAc (0.2 mL) The mixture was stirred at room temperature for 1 hour and concentrated The residue was suspended in Et20 (20 mL) and the suspension was stirred at RT. room temperature for 2 hours.The precipitate was collected by filtration, washed with Et20, and dried at 70 ° C under reduced pressure to give 3-chloro-I-7- hydrochloride (cis-4. (gave methylamino) -2-methylpyrimidin-4-yl] amino} -cycdohexyl) -4-fluorobenzamide (196 mg). ESI MS m / e 406, M (free) + H +; ^ NMR (300 MHz, CDC13) d 1.62-2.00 (m, 8 H), 2.49 (s, 3 H), 2.99-3.40 (, 6 H), 3.67-3.79 (m, 1 H), 4.02-4.20 ( m, 1 H), 5.15 (s, 1 H), 6.59-6.70 (m, 1 H), 7.11-7.26 (m, 1 H), 7.67-7.79 (, 1 H), 7.89-8.02 (, 1 H) ), 8.48-8.61 (m, 1 H). EXAMPLE 7 Hydrochloride N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -4-fluorobenzamide To a solution of N- (cis-4-amino) -cyclohexyl) -2, N ', I \ 7'-trimethyl-pyrimidine-4,6-diamine obtained in step C of example 6 (250 mg) in CHC13 (3 ml) was added Et3N (0.29 ml) and 4 g. -fluoro-benzoyl chloride (174 mg). The mixture was stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 25% to 50% EtOAc in hexane) to give N- (cis-). 4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} - ciciohexyl) -4-fluorobenzamide. To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.2 L). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was suspended in Et20 (20 mL) and the suspension was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with Et20, and dried at 70 ° C under reduced pressure to give N- hydrochloride. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -4-fluorobenzamide (255 mg). ESI MS m / e 372, M (free) + H +; XH NMR (300 MHz, CDC13) d 1.66-2.03 (m, 8 H), 2.49 (s, 3 H), 2.93-3.43 (m, 6 H), 3.64-3.78 (m, 1 H), 4.04-4.20 (m, 1 H), 5.14 (s, 1 H), 6.43-6.56 (m, 1 H), 7.05-7.15 (, 2 H), 7.75-7.91 (m, 2 H), 8.47-8.63 (, 1 H). Example 8 Hydrochloride 3,4-dichloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -benzamide Using the procedure for step A of the Example 7, the title compound was obtained. ESI MS m / e 422, M (free) +; 1 H NMR (300 MHz, CDC13) d 1.63-2.02 (m, 8 H), 2.49 (s, 3 H), 2.96-3.38 (m, 6 H), 3.67-3.80 (m, 1 H), 4.02-4.21 (m, 1 H), 5.14 (s, 1 H), 6.69-6.80 (m, 1 H), 7.47-7.53 (m, 1 H), 7.62-7.70 (m, 1 H), 7.93-8.00 (m , 1 H), 8.48-8.59 (m, 1 H), 13.70-13.90 (m, 1 H). EXAMPLE 9 4-Chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -3-fluorobenzamide hydrochloride using the procedure for step D of the Example 6, the title compound was obtained. ESI MS m / e 406, M (free) + H +; XH NMR (300 MHz, CDC13) d 1.66-2.07 (m, 8 H), 2.48 (s, 3 H), 2.94-3.40 (m, 6 H), 3.66-3.79 (m, 1 H), 4.00-4.21 (m, 1 H), 5.14 (s, 1 H), 6.88-7.00 (m, 1 H), 7.40-7.48 (m, 1 H), 7.52-7.60 (m, 1 H), 7.65-7.73 (m , 1 H), 8.45-8.54 (, 1 H), 13.66-13.86 (m, 1 H). EXAMPLE 10 3-Chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -5-fluorobenzamide hydrochloride Using the procedure for step D of the Example 6, the title compound was obtained. ESI MS m / e 406, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.61-2.07 (m, 8 H), 2.49 (s, 3 H), 2.96-3.41 (m, 6 H), 3.65- 3.79 (m, 1 H), 4.00-4.22 (, 1 H), 5.14 (s, 1 H), 6.78-6.88 (, 1 H), 7.16-7.23 (m, 1 H), 7.42-7.50 (m, 1 H), 7.60-7.64 (m, 1 H), 8.36-8.62 (m, 1 H), 13.75-13.95 (m, 1 H). EXAMPLE 11 Hydrochloride N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,4,5-trifluorobenzamide Using the procedure for step D of the Example 6, the title compound was obtained. ESI MS m / e 408, M (free) + H +; XH NMR (300 MHz, CDC13) d 1.64-2.04 (m, 8 H), 2.48 (s, 3 H), 2.92-3.42 (m, 6 H), 3.65-3.79 (m, 1 H), 4.00-4.20 (, 1 H), 5.15 (s, 1 H), 6.73-6.84 (m, 1 H), 7.48-7.58 (m, 2 H), 8.47-8.60 (m, 1 H), 13.70-13.86 (m, 1 HOUR) . Example 12 5-Bromo-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -nicotinamide dihydrochloride Using the procedure for step D of example 6 , the title compound was obtained. ESI MS m / e 433, M (free) +; XH NMR (300 MHz, CDC13) d 1.67-2.18 (m, 8 H), 2.49 (s, 3 H), 2.91-3.45 (, 6 H), 3.60-3.80 (m, 1 H), 4.10-4.28 ( m, 1 H), 5.11-5.20 (, 1 H), 7.70-7.87 (m, 1 H), 8.33-8.49 (m, 1 H), 8.60-8.67 (m, 1 H), 8.90-9.02 (m , 1 H), 9.17-9.30 (m, 1 H). Example 13 N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -3,5-difluorobenzamide hydrochloride Using the procedure for step A of example 7 , the title compound was obtained. ESI MS m / e 390, M (free) + H +; XH NMR (300 MHz, CDC13) d 1.63-2.03 (m, 8 H), 2.48 (s, 3 H), 2.99-3.45 (m, 6 H), 3.69-3.79 (m, 1 H), 4.03-4.19 (, 1 H), 5.14 (s, 1 H), 6.58-6.71 (m, 1 H), 6.86-6.98 (m, 1 H), 7.28-7.44 (m, 2 H), 8.50-8.64 (m, 1 H), 13.75-13.93 (m, 1 H). EXAMPLE 14 Hydrochloride N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -4-fluoro-3- (trifluoromethyl) benzamide Using the procedure for the Step A of Example 7, the title compound was obtained. ESI MS m / e 440, M (free) + H +; aH NMR (300 MHz, CDC13) d 1.65-2.03 (m, 8 H), 2.49 (s, 3 H), 2.97-3.40 (m, 6 H), 3.67-3.81 (m, 1 H), 4.02-4.23 (m, 1 H), 5.15 (s, 1 H), 6.63-6.79 (m, 1 H), 7.19-7.31 (m, 1 H), 7.97-8.08 (m, 1 H), 8.13-8.20 (m , 1 H), 8.50-8.60 (, 1 H), 13.74-13.88 (m, 1 H). Example 15 N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3-fluoro-4- (trifluoromethyl) benzamide hydrochloride Using the procedure for Step A of Example 7, the title compound was obtained. ESI MS m / e 462, M (free) + Na +; XH NMR (300 MHz, CDC13) d 1.64-2.06 (m, 8 H), 2.49 (s, 3 H), 2.97-3.39 (m, 6 H), 3.67-3.81 (, 1 H), 4.02-4.23 ( m, 1 H), 5.15 (s, 1 H), 6.76-6.95 (m, 1 H), 7.52-7.81 (m, 2 H), 8.47-8.62 (m, 1 H), 13.71-13.85 (m, 1 HOUR) . EXAMPLE 16 3-Chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -4- (trifluoromethoxy) benzamide hydrochloride Using the procedure for Step A of Example 7, the title compound was obtained. ESI MS m / e 494, M (free) + Na +; XH NMR (300 MHz, CDC13) d 1.60-2.06 (, 8 H), 2.49 (s, 3 H) 2.95-3.40 (m, 6 H), 3.70-3.78 (, 1 H), 4.02-4.24 (, 1 H), 5.15 (s, 1 H), 6.59-6.72 (m, 1 H), 7.34-7.41 (m, 1 H), 7.71-7.80 (m, 1 H), 7.96-8.04 (m, 1 H) , 8.48-8.62 (m, 1 H), 13.75-13.90 (m, 1 H). Example 17 Hydrochloride N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] mino} cyclohexyl) -3- (trifluoromethyl) -benzamide Using the procedure for step A of example 7, the title compound was obtained. ESI MS m / e 444, M (free) + Na +; XH NMR (300 MHz, CDC13) d 1.66-2.17 (m, 8 H), 2.49 (s, 3 H), 2.97-3.38 (m, 6 H), 3.65-3.80 (m, 1 H), 4.06-4.23 (m, 1 H), 5.15 (s, 1 H), 6.59-6.71 (m, 1 H), 7.52-7.62 (m, 1 H), 7.69-7.80 (m, 1 H), 7.93-8.02 (m , 1 H), 8.13 (s, 1 H), 8.51-8.68 (m, 1 H), 13.81-13.96 (m, 1 H). EXAMPLE 18 Hydrochloride N- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3- (trifluoromethoxy) benzamide Using the procedure for step A of the example 7, the title compound was obtained. ESI MS m / e 438, M (free) + Na +; 1 H NMR (300 MHz, CDC13) d 1.68-2.06 (m, 8 H), 2.49 (s, 3 H), 2.94-3.44 (m, 6 H), 3.67-3.81 (m, 1 H), 4.03-4.23 (m, 1 H), 5.14 (s, 1 H), 6.51-6.66 (m, 1 H), 7.29-7.37 (m, 1 H), 7.42-7.53 (m, 1 H), 7.65-7.74 (m , 2 H), 8.46-8.69 (m, 1 H), 13.79-13.95 (m, 1 H). Example 19 N- Hydrochloride { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -4- (trifluoromethyl) benzamide Using the procedure for step A of example 7, the title compound was obtained. ESI MS m / e 422, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.64-2.06 (m, 8 H), 2.49 (s, 3 H), 2.97-3.39 (m, 6 H), 3.65-3.81 (m, 1 H), 4.05-4.23 (m, 1 H), 5.15 (s, 1 H), 6.71-6.84 (, 1 H), 7.69 (d, J = 8.2 Hz, 2 H), 7.95 (d, J = 8.2 Hz, 2 H), 8.48-8.62 (m, 1 H). Example 20 Hydrochloride N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -4- (trifluoromethoxy) benzamide Using the procedure for Step A of Example 7, the title compound was obtained. ESI MS m / e 460, M (free) + Na +; 1ñ NMR (300 MHz, CDC13) d 1. 63-2.02, (m, 8 H), 2.48 (s, 3 H), 2.89-3.42 (m, 6 H), 3.66-3.78 (m, 1 H), 4.03-4.25 (m, 1 H), 5.14 (s, 1 H), 6.72-6.86 (m, 1 H), 7.26 (d, J = 7.6 Hz, 2 H), 7.89 (d, J = 8.9 Hz, 2 H), 8.45-8.59 (m, 1 H). Example 21 Hydrochloride 3, 5-dichloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -benzamide Using the procedure for step A of the Example 7, the title compound was obtained. ESI MS m / e 444, M (free) + Na +; ? E NMR (300 MHz, CDC13) d 1.65-2.02 (m, 8 H), 2.49 (s, 3 H), 2.93-3.42 (m, 6 H), 3.68- 3.79 (m, 1 H), 4.02- 4.19 (m, 1 H), 5.14 (s, 1 H), 6.47-6.57 (m, 1 H), 7.45-7.48 (m, 1 H), 7.68 (d, J = 1.8 Hz, 2 H), 8. 52-8.65 (m, 1 H). EXAMPLE 22 N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -2-fluorobenzamide hydrochloride Using the procedure for step A of example 7, obtained the title compound. ESI MS m / e 394, M (free) + Na +; 1H NMR (300 MHz, CDC13) d 1. 65-2.06 (m, 8 H), 2.48 (s, 3 H), 2.93-3.40 (m, 6 H), 3.63- 3.71 (m, 1 H), 4.08-4.24 (m, 1 H), 5.12 ( s, 1 H), 6.69-6.85 (m, 1 H), 7.06-7.30 (m, 2 H), 7.39-7.53 (m, 1 H), 7.95-8.05 (, 1 H), 8.51-8.61 (m , 1 HOUR) . EXAMPLE 23 N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3-fluorobenzamide hydrochloride using the procedure for step A of example 7, obtained the title compound. ESI MS m / e 394, M (free) + Na +; XH NMR (300 MHz, CDC13) d 1.64-2.05 (, 8 H), 2.49 (s, 3 H), 2.99-3.45 (m, 6 ti), 3.66-3.77 (m, 1 H), 4.04-4.23 ( m, 1 H), .5.14 (s, 1 H), 6.40-6.53 (m, 1 H), 7.13-7.22 (m, 1 H), 7.34-7.45 (m, 1 H), 7.52-7.58 (m , 2 H), 8.52-8.62 (m, 1 H). EXAMPLE 24 3-Chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -benzamide hydrochloride Using the procedure for step A of example 7 , the title compound was obtained. ESI MS m / e 388, M (free) + H +; Xi NMR (300 MHz, CDC13) d 1.68-2.03 (m, 8 H), 2.49 (s, 3 H), 2.97-3.37 (, 6 H), 3.66-3.77 (m, 1 H), 4.02-4.21 ( m, 1 H), 5.14 (s, 1 H), 6.48-6.57 (m, 1 H), 7.32-7.49 (m, 2 H), 7.63-7.69 (m, 1 H), 7.81-7.85 (m, 1 H), 8.53-8.62 (m, 1 H), 13.86-13.97 (m, 1 H). Example 25 4-Chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -benzamide hydrochloride Using the procedure for step A of example 7 , the title compound was obtained. ESI MS m / e 388, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.67-2.07 (m, 8 H), 2.49 (s, 3 H), 2.98-3.38 (m, 6 H), 3.67-3.79 (m, 1 H), 4.01-4.21 (m, 1 H), 5.14 (s, 1 H), 6.42-6.55 (m, 1 H), 7.37-7.43 (m, 2 H), 7.73-7.80 (m, 2 H), 8.52-8.63 (m , 1 H), 13.82-13.98 (m, 1 H). Example 26 N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3-fluoro-5- (trifluoromethyl) benzamide hydrochloride using the procedure for Step A of Example 7, the title compound was obtained. ESI MS m / e 462, M (free) + Na +; XH NMR (300 MHz, CDC13) d 1.70-2.05 (m, 8 H), 2.48 (s, 3 H), 2.93-3.45 (m, 6 H), 3.67-3.79 (m, 1 H), 4.04-4.23 (, 1 H), 5.15 (s, 1 H), 6.71-6.84 (m, 1 H), 7.40-7.47 (, 1 H), 7.72-7.79 (m, 1 H), 7.90 (s, 1 H) 8.49-8.63 (m, 1 H). EXAMPLE 27 Hydrochloride N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,5-bis- (trifluoromethyl) benzamide Using the procedure for the Step A of Example 7, the title compound was obtained. ESI MS m / e 512, M (free) + Na +; 1 H NMR (300 MHz, CDC13) d 1.66-2.09 (m, 8 H), 2.48 (s, 3 H), 2.91-3.44 (m, 6 H), 3.67-3.83 (m, 1 H), 4.04-4.27 (m, 1 H), 5.15 (s, 1 H), 6.92-7.05 (m, 1 H), 7.98 (s, 1 H), 8.32 (s, 2 H), 8.50-8.64 (m, 1 H) .

EXAMPLE 28 Hydrochloride N- [cis-4- ( { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Methyl) cyclohexyl] -3,4-difluorobenzamide Using the procedure for step F from Example 3, the title compound was obtained. ESI MS m / e 404, M (free) + H +; xti NMR (300 MHz, CDC13) d 1.50-2.08 (m, 9 H), 2.46 (s, 3 H), 2.88 (s, 8 H), 4.43-4.58 (m, 1 H), 5.06 (s, 1 H), 7.10-7.35 (, 2 H), 7.88-8.08 (m, 2 H), 8.58-8.78 (m, 1 H), 13.44-13.62 (m, 1 H). EXAMPLE 29 Hydrochloride N- [(cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) methyl] -3,4-difluorobenzamide Using the procedure for step C from Example 4, the title compound was obtained. ESI MS m / e 404, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.50-2.01 (, 9 H), 2.47 (s, 3 H), 2.89-3.56 (m, 8 H), 3.66-3.86 (, 1 H), 5.12 (s, 1 H), 6.82-6.98 (m, 1 H), 7.11-7.32 (m, 1 H), 7.72-7.97 (, 2 H), 8.61-8.75 (m, 1 H), 13.61-13.89 (m, 1 H) ). Example 30 Hydrochloride 3,4-difluoro-N- (cis-4 { [2-methyl-6- (methylamino) pyrimidin-4-yl] amino.}. Cyclohexyl) -benzamide Step A: Synthesis of (6 -chloro-2-methyl-pyrimidin-4-yl) -methylamine. To a solution of 4,6-dichloro-2-methyl-pyrimidine obtained in step A of example 5 (11.1 g) in THF (110 mL) was added iPr2NEt (14.2 mL) and 40% aqueous MeNH2 (10.1 mL). The mixture was stirred at room temperature for 7 hours and concentrated under reduced pressure. To the residue was added saturated aqueous NaHCOs and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and dried under reduced pressure to give (6-chloro-2-methyl-pyrimidin-4-yl) -methyl-amine (10.7 g). ESI MS m / e 157, M +; 1 H NMR (200 MHz, CDC13) d 2.48 (s, 3 H), 2.93 (d, J = 5.2 Hz, 3 H), 5.20-5.70 (m, 1 H), 6.18 (s, 1 H). Step B: Synthesis of 3, 4-difluoro-N- (cis-4 { [2-methyl-6- (methylamino) pyrimidin-4-yl] amino} -cydohexyl) -benzamide hydrochloride. Using the procedure for step C of example 5, the title compound was obtained. ESI MS m / e 376, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.58-2.13 (, 8 H), 2.37 (s, 3 H), 2.82-3.19 (m, 3 H), 3.56-3.86 (m, 1 H), 3.98-4.27 ( m, 1 H), 5.03-5.30 (m, 1 H), 6.07-6.52 (, 1 H), 6.71-6.96 (m, 1 H), 7.11-7.33 (m, 1 H), 7.49-7.82 (m , 2 H), 8.34-8.60 (, 1 H). EXAMPLE 31 3-Chloro-4-fluoro-N- (cis-4. {[[2-methyl-6- (methylamino) pyrimidin-4-yl] amino} cydohexyl) -benzamide hydrochloride Step A: Synthesis of N- (cis-4-amino-cyclohexyl) -3-chloro-4-fluoro-benzamide. To a solution of 3-chloro-4-fluoro-benzoic acid (26.9 g) and cis- (4-amino-cyclohexyl) -carbamic acid tert-butyl ester (30.0 g) in DMF (300 mL) was added Et3N ( 46.8 mL), HOBt-H20 (32.2 g), and EDC-HC1 (29.5 g). The mixture was stirred at room temperature for 20 hours. Water (1.20 L) was added to the mixture and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. A solution of the residue in EtOAc (650 mL) was cooled in an ice bath and 4 M hydrogen chloride in EtOAc (325 mL) was added. The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was dissolved in 1M aqueous NaOH (300 mL) and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO 4, filtered, concentrated under reduced pressure, and dried under reduced pressure to give N- (cis-4-amino-cyclohexyl) -3-chloro-4-fluoro-benzamide (44.4 g ). ESI MS m / e 271, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.37-1.92 (m, 8 H), 2.94-3.08 (m, 1 H), 4.06-4.22 (m, 1 H), 6.13-6.31 (, 1 H), 7.19 ( t, J = 8.5 Hz, 1 H), 7.61-7.70 (m, 1 H), 7.79-7.87 (m, 1 H). Step B: Synthesis of 3-chloro-4-fluoro-N- (cis-4 { [2-methyl-6- (methylamino) pyrimidin-4-yl] -amino} cyclohexyl) -benzamide hydrochloride.

To a solution of N- (cis-4-amino-cyclohexyl) -3-chloro-4-fluoro-benzamide (472 mg) in BuOH (1 mL) was added (6-chloro-2-methyl-pyrimidin-4-). il) -methyl-amine obtained in step A of example 30 (250 mg). The mixture was heated on a microwave synthesizer at 220 ° C for 20 min. Aqueous saturated NaHCO3 was added to the mixture and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give 3-chloro-4-fluorocarbon. iV- (cis-4- { [2-methyl-6- (methylamino) pyrimidin-4-yl] -amino.} cydohexyl) -benzamide. To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.2 L). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et20 (12 L) was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with Et20, and dried at 70 ° C under reduced pressure to give 3-chloro-4-fluoro-i-7- hydrochloride. { cis-4-. { [2-methyl-6- (methylamino) pyrimidin-4-yl] -aminojcyclohexyl) -benzamide (64 mg). ESI MS m / e 392, M (free) + H +; 1 H NMR (300 MHz, DMSO-d 6) d 1.54-1.90 (m, 8 H), 2.29-2.43 (m, 3 H), 2.74-2.94 (m, 3 H), 3.80-3.96 (m, 2 H) , 5.44-5.64 (m, 1 H), 7.53 (t, J = 8.9 Hz, 1 H), 7.86-7.94 (m, 2 H), 8.07-8.13 (m, 2 H), 8.31-8.47 (, 1 H). Example 32 Hydrochloride N-. { cis-4-. { [6- (dimethylamino) -2-ethylpyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide Step A: Synthesis of (2,6-dichloro-pyrimidin-4-yl) -dimethylamine. To a solution of 2,4,6-trichloro-pyrimidine (10.0 g) in THF (50 mL) was added 50% aqueous Me2NH (4.92 g) and iPr2NEt (8.46 g). The mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The residue was poured into saturated aqueous aHC? 3 and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by flash chromatography (NH-silica gel, 3% EtOAc in hexane) to give (2,6-dichloro-pyrimidin-4-). il) -dimethyl-amine (6.03 g). ESI MS m / e 192, M + H +; H NMR (300 MHz, CDC13) d 2.77-3.46 (, 6 H), 6.34 (s, 1 H). Step B: Synthesis of (6-chloro-2-ethyl-pyrimidin-4-yl) -dimethyl-amine. A solution of ZnBr2 (3.87 g) in THF (60 mL) was cooled to -60 ° C and 1 M EtMgBr in THF (17.2 mL) was added. The mixture was stirred at -60 ° C for 1 hour and warmed to room temperature. To the mixture was added tetrakis- (triphenylphosphine) -palladium (903 mg) and (2,6-dichloro-pyrimidin-4-yl) -dimethyl-amine in THF (60 L) and the mixture was stirred under reflux for 5 days . Aqueous saturated NH4C1 was added to the mixture and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (silica gel, 17% to 33% EtOAc in hexane) to give (2-chloro-6-). ethyl-pyrimidin-4-yl) -dimethyl-amine (352 mg) and (6-chloro-2-ethyl-pyrimidin-4-yl) -dimethyl-amine (622 mg). (2-chloro-6-ethyl-pyrimidin-4-yl) -dimethyl-amine; ESI MS m / e 208, M (free) + NaX 1R NMR (300 MHz, CDC13) d 1.25 (t, J = 7.6 Hz, 3 H), 2.54-2.66 (m, 2 H), 3.11 (s, 6 H), 6.15 (s, 1 H). (6-chloro-2-ethyl-pyrimidin-4-yl) -dimethyl-amine; ESI MS m / e 186, M + H +; ? E NMR (300 MHz, CDCI3) d 1.29 (t, J = 7.6 Hz, 3 H), 2.74 (q, J = 7.7 Hz, 2 H), 3.10 (s, 6 H), 6.24 (s, 1 H) ). Step C: Synthesis of N- (cis-4. {[[6- (dimethylamino) -2-ethylpyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide hydrochloride. Using the procedure for step C of example 5, the title compound was obtained. ESI MS m / e 404, M (free) + H +; XH NMR (300 MHz, CDCl 3) d 1.37 (t, J = 7.5 Hz, 3 H), 1.64-2.03 (m, 8 H), 2.76 (q, J = 7.5 Hz, 2 H), 2.97-3.42 (m , 6 H), 3.65-3.80 (m, 1 H), 4.02-4.21 (m, 1 H), 5.14 (s, 1 H), 6.42-6.66 (, 1 H), 7.12-7.27 (m, 1 H), 7.45-7.60 (, 1 H), 7.65-7.81 (m, 1 H), 8.60-8.73 (, 1 H), 13.61-13.77 (m, 1 H). Example 33 N- (cis-4. {[2,6-bis (dimethylamino) pyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide hydrochloride Step A: Synthesis of 6-chloro-N , N, W, W -tetramethyl-pyrimidine-2,4-diamine. To a suspension of (2,6-dichloro-pyrimidin-4-yl) -dimethyl-amine obtained in step A of example 32 (1.60 g) in IPA (2 mL) was added 50% aqueous Me2NH (789 mg). The mixture was stirred at reflux for 3.5 hours in a sealed tube. The mixture was poured into saturated aqueous NaHC03 and the aqueous layer was extracted with CHC1 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (silica gel, 20% EtOAc in hexane) to give 2-chloro-N, N, N1, W -tetramethyl-pyrimidine-4,6-diamine (203 mg) and 6-chloro-N, N, N1, N '-tetramethyl-pyrimidine-2,4-diamine (1.43 g). 2-chloro-N, N, N ', W -tetramethyl-pyrimidine-4,6-diamine; ESI MS m / e 201, M (free) + H +; Xi NMR (300 MHz, CDC13) d 3.05 (s, 12 H), 5.15 (s, 1 H). 6-chloro-N, N, N ', N' -tetramethyl-pyrimidine-2,4-diamine; SI MS m / e 201, M + H +; XH NMR (300 MHz, CDC13) d 3.04 (s, 6 H), 3.13 (s, 6 H), 5.76 (s, 1 H). Stage B: Hydrochloride synthesis N- (cis-4- { [2,6-bis (dimethylamino) pyrimidin-4-yl] amino.}. Cyclohexyl) -3,4-difluorobenzamide Using the procedure for step C of example 5, the title compound. ESI MS m / e 419, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.58-2.16 (m, 8 H), 2.97-3.45 (m, 12 H), 3.62-3.74 (m, 1 ti), 4.03-4.21 (m, 1 H), 4.81 (s, 1 H), 6.76-6.90 (m, 1 H), 7.13-7.26 (, 1 H), 7.55-7.64 (m, 1 H), 7.70-7.79 (m, 1 H), 8.57-8.70 ( m, 1 H), 11.86-11.94 (m, 1 H). EXAMPLE 34 Hydrochloride N- (cis-4 { [2- (ethylamino) pyrimidin-4-yl] amino.}. Cyclohexyl) -3,4-difluorobenzamide Step A: Synthesis of (4-chloro-pyrimidin-2) -yl) -ethyl-amine. To a solution of 2,4-dichloro-pyrimidine (5.00 g) in THF (50 mL) was added 70% aqueous EtNH2 (5.40 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in CHC13 and the solution was poured into saturated aqueous NaHCO3. The two layers were separated and the aqueous layer was extracted with CHC13 (twice). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 17% to 50% EtOAc in hexane) to give (2-chloro-pyrimidin-4-yl). ) -ethyl-amine (3.69 g) and (4-chloro-pyrimidin-2-yl) -ethyl-amine (1.28 g). (2-chloro-pyrimidin-4-yl) -ethyl-amine; ESI MS m / e 157, M +; XH NMR (500 MHz, CDC13) d 1.26 (t, J = 7.3 Hz, 3 H), 3.16-3.62 (m, 2 H), 4.80-5.95 (m, 1 H), 6.23 (d, J = 5.8 Hz , 1 H), 8.02-8.22 (m, 1 H). (4-chloro-pyrimidin-2-yl) -ethyl-amine; Cl MS m / e 158, M + H +; 1 H NMR (500 MHz, CDC13) d 1.23 (t, J = 7.5 Hz, 3 H), 3.42-3.49 (m, 2 H), 5.30-5.62 (m, 1 H), 6.54 (d, J = 5.2 Hz , 1 H), 8.02-8.22 (m, -1 H). Stage B: Synthesis of N- hydrochloride. { cis-4-. { [2- (ethylamino) pyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide Using the procedure for step C of Example 5, the title compound was obtained. ESI MS m / e 376, M (free) + H +; Xi NMR (300 MHz, CDC13) d 1.22 (t, J = 7.1 Hz, 3 H), 1.61 (s, 8 H), 3.31-3.56 (m, 2 H), 4.05-4.47 (m, 2 H), 6.31-6.56 (m, 1 H), 6.75-6.95 (m, 1 H), 7.07-7.34 (m, 2 H), 7.48-7.87 (m, 3 H), 8.01-8.24 (m, 1 H), 12.39-12.52 (m, 1 H). EXAMPLE 35 Hydrochloride N- [cis-4- (. {2- [ethyl (methyl) amino] pyrimidin-4-yl] amino) cyclohexyl] -3,4-difluorobenzamide Stage A: Synthesis of (4-chloro-pyrimidine -2-il) -ethyl-methyl-amine. To a solution of 2,4-dichloro-pyrimidine (5.00 g) in THF (50 mL) was added ethyl-methyl-amine (2.08 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in CHCl3 and the solution was poured into saturated aqueous aHCOs. The two layers were separated and the aqueous layer was extracted with CHC13 (twice). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 17% to 50% EtOAc in hexane) to give (2-chloro-pyrimidin-4-yl). ) -ethyl-methyl-amine (4.49 g) as (4-chloro-pyrimidin-2-yl) -ethyl-methyl-amine (0.91 g). (2-chloro-pyrimidin-4-yl) -ethyl-methyl-amine; Cl MS m / e 172, M (free) + H +; xti NMR (500 MHz, CDC13) d 1.18 (t, J = 3.0 Hz, 3 H), 3.06 (brs, 3 H), 3.35-3.70 (m, 2 H), 6.29 (d, J = 4.8 Hz, 1 H), 7.99 (d, J = 6.1 Hz, 1 H). (4-chloro-pyrimidin-2-yl) -ethyl-methyl-amine; Cl MS m / e 172, M + H +; Xi NMR (500 MHz, CDC13) d 1.17 (t, J = 3.0 Hz, 3 H), 3.10 (s, 3 H), 3.66 (q, J = 7.0 Hz, 2 H), 6.45 (d, J = 5.0 Hz, 1 H), 8.14 (d, J = 5.0 Hz, 1 H). Step B: Synthesis of N- [cis-4- (. {2- [ethyl (methyl) amino] pyrimidin-4-yl] amino) cydohexyl] -3,4-difluorobenzamide hydrochloride Using the procedure for step C of the Example 5, the title compound was obtained. ESI MS m / e 390, M (free) + H +; Xi NMR (300 MHz, CDC13) d 1.11-1.29 (, 3 H), 1.63-2.20 (m, 8 H), 3.23 (brs, 3 H), 3.61-3.76 (m, 2 H), 4.06-4.42 ( m, 2 H), 6.53-6.68 (m, 1 H), 6.88-7.24 (m, 2 H), 7.39-7.52 (m, 1 H), 7.59-7.86 (m, 2 H), 8.39-8.54 (m m, 1 H), 12.26-12.44 (m, 1 H). EXAMPLE 36 Hydrochloride 3,4-difluoro-N- [cis-4- (. {2- 2- [(2-hydroxyethyl) (methyl) amino] pyrimidin-4-yl] amino) -cydohexyl] benzamide Stage A: Synthesis of 2- [(4-chloro-pyrimidin-2-yl) -methyl-amino] -ethanol. To a solution of 2,4-dichloro-pyrimidine (5.00 g) in THF (50 mL) was added 2-methylamine-ethanol (2.65 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in CHCl3 and the solution was poured into saturated aqueous NaHCO3. The two layers were separated and the aqueous layer was extracted with CHC13 (twice). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 17% to 50% EtOAc in hexane) to give 2- [(2-chloro-pyrimidin- 4-yl) -methylamino] -ethanol (3.50 g) and 2- [(4-chloro-pyrimidin-2-yl) -methylamino] -ethanol (827 mg). 2- [(2-chloro-pyrimidin-4-yl) -methyl-amino] -ethanol; ESI MS m / e 188, M (free) + H +; XH NMR (500 MHz, CDC13) 5 2.91 (brs, 3 H), 3.13 (s, 3 H), 3.64-3.92 (m, 4 H), 6.46-6.49 (m, 1 H), 7.99 (d, J = 6.1 Hz, 1 H). 2- [(-chloro-pyrimidin-2-yl) -methyl-amino] -ethanol; ESI MS m / e 210, M + Na +; ? ti NMR (500 MHz, CDC13) d 3.23 (s, 3 H), 3.76-3.92 (m, 4 H), 6.52 (d, J = 5.2 Hz, 1 H), 8.12 (d, J = 4.6 Hz, 1 HOUR) . Step B: Synthesis of 3, 4-difluoro-W- [cis-4- (. {2- 2- [(2-hydroxyethyl) (methyl) amino] pyrimidin-4-yl] amino) -cydohexyl] benzamide hydrochloride Using the procedure for step C of example 5, the title compound was obtained. ESI MS m / e 406, M (free) + H +; Xi NMR (300 MHz, DMSO-d6) d 1.59-1.96 (m, 8 H), 3.16 (s, 3 H) 3.57-3.71 (m, 2 H), 3.80-4.07 (, 3 H), 4.20-4.30 (, 1 H), 6.20-6.34 (m, 1 H), 7.49-7.80 (m, 3 H), 7.88-7.99 (, 1 H), 8.31-8.40 (m, 1 H), 8.64-8.79 (m , 1 HOUR) . Example 37 Hydrochloride 3-chloro-4-fluoro-N-. { cis-4- [(2-methyl-6-piperidin-1-yl-pyrimidin-4-yl) amino] cyclohexyl} -benzamide To a solution of 4,6-dichloro-2-methyl-pyrimidine obtained in step A of example 5 (3.00 g) in THF (30 mL) was added N- (cis-4-amino-cyclohexyl) -3 -chloro-4-fluorobenzamide obtained in step A of example 31 (5.98 g) and iPrNEt2 (3.85 ml). The mixture was stirred at reflux for 60 hours and was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHC1 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% EtOAc in hexane) to give 3-chloro-N- [cis -4- (6-chloro-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-fluoro-benzamide (6.34 g). To a solution of the above solid (250 mg) in BuOH (1 mL) was added piperidine (80 mg) and iPrNEt2 (121 mg). The mixture was heated on a microwave synthesizer at 220 ° C for 10 min and 230 ° C for 20 min and was poured into saturated aqueous NaHCO 3. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% EtOAc in hexane) to give 3-chloro-4-fluorocarbon. N-. { cis-4- [(2-methyl-6-piperidin-l-ylpyrimidin-4-yl) amino] cyclohexyl} -benzamide. To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.2 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. a suspension of the residue in Et20 (12 mL) was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with Et20, and dried at 70 ° C under reduced pressure to give 3-chloro-4-fluoro-N- hydrochloride. { cis-4- [(2-methyl-6-piperidin-1-yl-pyrimidin-4-yl) amino] cyclohexyl} -benzamide (6 mg). ESI MS m / e 446, M (free) + H +; ? ti NMR (300 MHz, CDC13) d 1.28-2.10 (m, 14 H), 2.46 (s, 3 H), 2.92-3.11 (m, 1 H), 3.27- 3.89 (m, 4 H), 4.00- 4.21 (, 1 H), 5.16-5.31 (m, 1 H), 6.69-6.88 (m, 1 H), 7.13-7.27 (, 1 H), 7.60-8.03 (m, 2 H), 8.40- 8.55 ( m, 1 H). EXAMPLE 38 Dihydrochloride 3-chloro-4-f luoro-N- (cis-4 { [6- (lH-imidazol-1-yl) -2-methylpyrimidin-4-yl] amino.}. Ciciohexyl) - benzamide Using the procedure for step A of example 37, the title compound was obtained. ESI MS m / e 451, M (free) + Na +; Xi NMR (300 MHz, CDC13) d 1. 69-2.21 (m, 8 H), 2.56-2.87 (m, 3 H), 4.04-4.58 (m, 2 H), 6. 41-6.70 (m, 1 H), 7.10-7.25 (m, 1 H), 7.42-7.51 (m, 1 H), 7. 58-7.80 (m, 1 H), 7.84-8.22 (m, 3 H). Example 39 Hydrochloride 3-chloro-4-fluoro-N-. { cis-4- [(2-methyl-6-morpholin-4-ylpyrimidin-4-yl) amino] cyclohexyl} -benzamide Using the procedure for step A of example 37, the title compound was obtained. ESI MS m / e 470, M (free) + Na +; aH NMR (300 MHz, CDC13) d 1.65-2.02 (m, 8 H), 2.49 (s, 3 H), 3.58-3.92 (m, 9 H), 4.03- 4.22 (m, 1 H), 5.25 (s) , 1 H), 6.51-6.62 (m, 1 H), 7.18 (t, J = 8.5 Hz, 1 H), 7.67-7.74 (m, 1 H), 7.91-7.96 (m, 1 H), 8.63- 8.75 (m, 1 H). Example 40 Hydrochloride 3-chloro-4-fluoro-N-. { cis-4- [(2-methyl-6-pyrrolidin-1-yl-pyrimidin-4-yl) amino] cyclohexyl} -benzamide Using the procedure for step A of example 37, the title compound was obtained. ESI MS m / e 432, M (free) + H +; Xi NMR (300 MHz, CDC13) d 1.41-2.24 (m, 12 H), 2.48 (s, 3 H), 3.09-3.56 (m, 3 H), 3.60- 3.78 (m, 2 H), 3.99-4.18 (m, 1 H), 5.02 (s, 1 H), 6.52-6.66 (m, 1 H), 7.18 (t, J = 8.6 Hz, 1 H), 7.63-7.77 (m, 1 H), 7. 88-7.99 (m, 1 H), 8.40-8.55 (m, 1 H). Example 41 3-Chloro-4-fluoro-N- (cis-4. {[[2-methyl-6- (4-methyl-piperazin-1-yl) -pyrimidin-4-yl] -amino} -cydohexyl dihydrochloride benzamide Using the procedure for step A of example 37, the title compound was obtained. ESI MS m / e 461, M (free) + H +; xti NMR (300 MHz, DMSO-d6) d 1. 63-1.88 (, 8 H), 2.37-2.46 (m, 3 H), 2.73-2.83 (m, 3 H), 2. 97-3.15 (, 2 H), 3.24-3.62 (m, 6 H), 3.78-4.01 (m, 2 H), . 99 (s, 1 H), 7.52 (t, J = 8.9 Hz, 1 H), 7.81-7.97 (m, 1 H), 8. 04-8.16 (m, 2 H), 8.40-8.54 (m, 1 H). EXAMPLE 42 Dihydrochloride N 4 - (cis-4 { [4-Bromo-2- (trifluoromethoxy) benzyl] amino.}. Cyclohexyl) -W 2, 2J 2 -dimethylpyrimidine-2,4-diamine Step A: Synthesis of (4) -chloro-pyrimidin-2-yl) -dimethyl-amine. To a solution of 2,4-dichloro-pyrimidine (15.0 g) in THF (150 mL) was added 50% aqueous Me2NH (22.7 g). The mixture was stirred at room temperature for 2 hours and was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (NH-silica, 20% EtOAc in hexane) to give (2-chloro-pyrimidin-4-yl) -dimethyl. -amine (8.66 g) and (4-chloro-pyrimidin-2-yl) -dimethylamine (0.87 g). (2-chloro-pyrimidin-4-yl) -dimethyl-amine; Cl MS m / e 158, M + H +; aH NMR (300 MHz, CDC13) d 3.12 (s, 6 H), 6.32 (d, J = 6.1 Hz, 1 H), 8.00 (d, J = 6.1 Hz, 1 H). (4-chloro-pyrimidin-2-yl) -dimethyl-amine; ESI MS m / e 157, M +; 1 NMR (300 MHz, CDC13) d.3.21 (s, 6 H), 6.50 (d, J = 5.1 Hz, 1 H), 8.18 (d, < J = 5.1 Hz, 1 H). Step B: Synthesis of dihydrochloride i- (cis-4 { [4-bromo-2- (trifluoromethoxy) benzyl] amino} cydohexyl) -IJ2, W2-dimethylpyrimidine-2,4-diamine. A mixture of N-. { cis-4-bromo-2-trifluoromethoxy-benzyl) -cyclohexane-1,4-diamine obtained in step B of example 1 (466 mg), (4-chloro-pyrimidin-2-yl) -dimethyl-amine (200 mg), and BuOH (1 mL) was stirred at reflux for 13 hours.

The mixture was poured into saturated aqueous NaHC03 and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (NH-silica gel, 20% in EtOAc) to give N4- (cis-4- { [4 -bromo-2- (trifluoromethoxy) benzyl] amino.} - cyclohexyl) -AJ2, lX-dimethylpyrimidine-2,4-diamine. To a solution of the above material in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was suspended in Et20 (20 mL) and the suspension was stirred at room temperature for 4 hours. The precipitate was collected by filtration, washed with Et20, and dried under reduced pressure to give N4- dihydrochloride (cis -4- {[4-bromo-2- (trifluoromethoxy) benzyl] -amino} cyclohexyl) -N2, i \ J2-dimethylpyrimidine-2,4-diamine (294 mg).

ESI MS m / e 488, M (free) + H +; ^ NMR (300 MHz, CDC13) d 1.42-1.67 (m, 2 H), 2.03-2.39 (m, 6 H), 2.79-3.38 (m, 7 H), 4. 13-4.36 (m, 3 H), 6.89-7.00 (m, 1 H), 7.42-7.46 (m, 1 H), 7. 50-7.57 (m, 1 H), 7.90-8.01 (m, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 8.90-9.00 (m, 1 H), 9.98-10.18 (m, 2 H), 12.21-12.37 (m, 1 HOUR) . Example 43 N- (cis-4 { [2- (dimethylamino) -6-methylpyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide hydrochloride Step A: Synthesis of (4-chloro- 6-methyl-pyrimidin-2-yl) -dimethyl-amine. To a solution of 2,4-dichloro-6-methylpyrimidine (20.0 g) in THF (200 mL) was added 50% aqueous Me2NH (13.3 g) and the mixture was stirred at room temperature for 24 hours. Aqueous saturated NaHCO3 was added to the mixture and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (NH-silica gel, 5% to 16% EtOAc in hexane) to give (2-chloro-6-methyl) -pyrimidin-4-yl) -dimethyl-amine (14.4 g) and (4-chloro-6-methyl-pyrimidin-2-yl) -dimethyl-amine (6.57 g). (2-chloro-6-methyl-pyrimidin-4-yl) -dimethyl-amine; ESI MS m / e 194, M + + Na +; XH NMR (300 MHz, CDC13) d 2.34 (s, 3 H), 3.10 (s, 6 H), 6.16 (s, 1 H). (4-chloro-6-methyl-pyrimidin-2-yl) -dimethyl-amine; Cl MS m / e 172, M + HX Xi NMR (300 MHz, CDC13) d 2.29 (s, 3 H), 3.16 (s, 6 H), 6.34 (s, 1 H). Step B: Synthesis of hydrochloride N- (cis-4 { [2- (dimethylamino) -6-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,4-difluorobenzamide. To a solution of N- (cis-4-amino-cyclohexylmethyl) -3,4-difluoro-benzamide (652 mg) in BuOH (1 mL) was added (4-chloro-6-methyl-pyrimidin-2-yl) dimethyl amine (400 mg). The mixture was stirred at reflux for 8 days. Aqueous saturated NaHCO3 was added to the mixture and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 10% to 20% EtOAc in hexane) to give N- (cis-). 4- { [2- (dimethylamino) -6-methylpyrimidin-4-yl] amino} ciciohexyl) -3,4-difluorobenzamide. To a solution of the above material in EtOAc (5 L) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et20 (20 mL) was stirred at room temperature for 4 hours. The precipitate was collected by filtration, washed with Et20, and dried at 80 ° C under reduced pressure to give N- (cis-4 { [2- (dimethylamino) -6-methylpyrimidin-4-yl hydrochloride] amino.}. cydohexyl) -3,4-difluorobenzamide (507 mg). Xi NMR (300 MHz, CDC13) d 1.62-2.21 (, 8 H), 2.39 (s, 3 H), 3.15-3.45 (m, 6 H), 4.09-4.43 (m, 2 H), 6.28-6.37 ( m, 1 H), 7.06-7.24 (m, 1 H), 7.61-7.87 (m, 2 H), 8.24-8.37 (, 1 H), 11.55-11.67 (, 1 H). Example 44 Hydrochloride 3-chloro-N- (cys-4. {[[2- (dimethylamino) pyrimidin-4-yl] amino} cyclohexyl) -4-fluorobenzamide Using the procedure for step B of example 31, the title compound was obtained. ESI MS m / e 392, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.58-2.20 (m, 8 H), 3.07 (s, 6 H), 4.03-4.48 (m, 2 H), 6.52-6.73 (m, 1 H), 6.95-6.95 (, 2 H), 7.36-7.51 (m, 1 H), 7.72- 7.85 (m, 1 H), 7.94-8.05 (m, 1 H), 8.50-8.69 (m, 1 H), 12.20-12.41 ( , 1 HOUR) . Example 45 Hydrochloride 3-chloro-N- (cys-4 { [2- (dimethylamino) -6-methylpyrimidin-4-yl] amino} ciciohexyl) -4-fluorobenzamide Using the procedure for step B of the Example 31, the title compound was obtained. ESI MS m / e 406, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.56-2.22 (m, 11 H), 3.05-3.45 (m, 6 H), 4.07-4.42 (, 2 H), 6.25-6.40 (m, 1 H), 7.03- 7.26 (m, 2 H), 7.73-8.07 (m, 2 H), 8.30-8.44 (m, 1 H), 11.51-11.64 (m, 1 H). Example 46 3-Chloro-N- (cis-4. {[[2- (dimethylamino) -5-methylpyrimidin-4-yl] amino} cydohexyl) -4-fluorobenzamide hydrochloride Step A: Synthesis of 4-chloro -2-dimethylamino-5-methylpyrimidine. To a solution of 2,4-dichloro-5-methylpyrimidine (20.0 g) in THF (200 mL) was added 50% aqueous Me2NH (13.3 g).

The mixture was stirred at room temperature for 5 days and concentrated under reduced pressure. The residue was poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (NH-silica gel, 2% EtOAc in hexane) to give 2-chloro-4-dimethylamino-5-methylpyrimidine (19.9 g) and 4-chloro-2-dimethylamino-5-methylpyrimidine (1.53 g). 2-chloro-4-dimethylamino-5-methylpyrimidine; ESI MS m / e 172, M + H +; XH NMR (300 MHz, CDC13) d 2.27 (s, 3 H), 3.15 (s, 6 H), 7.82 (s, 1 H). 4-chloro-2-dimethylamino-5-methylpyrimidine; ESI MS m / e 194, M + Na +; XH NMR (300 MHz, CDC13) d 2.14 (s, 3 H), 3.15 (s, 6 H), 8.06 (s, 1 H). Step B: Synthesis of 3-chloro-1 - (cis-4 { [2- (dimethylamino) -5-methylpyrimidin-4-yl] amino] -cydohexyl) -4-fluorobenzamide hydrochloride. Using the procedure for step B of example 31, the title compound was obtained. ESI MS m / e 406, M (free) + H +; 2H NMR (300 MHz, DMSO-d6) d 1. 56-2.02 (m, 8 H), 2.04 (s, 3 H), 3.16 (s, 6 H), 3.90-4.18 (m, 2 H), 7.47-7.66 (, 3 H), 7.91-8.00 (m , 1 H), 8.13-8.21 (m, 1 H), 8.28-8.36 (, 1 H), 12.39-12.48 (m, 1 H). EXAMPLE 47 3-Chloro-N- (cis-4. {[[6- (dimethylamino) -2- (trifluoromethyl) pyrimidin-4-yl] amino} cydohexyl) -4-fluorobenzamide hydrochloride Step A: Synthesis of 2-trifluoromethyl-pyrimidine-4,6-diol. To a suspension of 60% NaH in oil (11.7 g) in toluene (98 mL) was added BuOH (21.8 g). The mixture was stirred at room temperature for 16 hours. To the mixture was added malonamide (10.0 g) and trifluoro-ethyl ester of acetic acid (13.9 g). The mixture was stirred at 100 ° C for 3.5 hours and at room temperature for 16 hours. The organic layer was extracted with water (twice) and the aqueous layer was filtered through activated carbon. Concentrated HCl (pH 1) was added to the aqueous layer and the suspension was stirred at 4 ° C for 2 hours. The precipitate was collected by filtration and dried at 80 ° C under reduced pressure to give 2-trifluoromethyl-pyrimidine-4,6-diol (3.25 g). ESI MS m / e 178, M-H +; XH NMR (300 MHz, CDC13) d 6.00 (s, 1 H), 12.48 (brs, 2 H). Step B: Synthesis of (6-chloro-2-trifluoromethyl-pyrimidin-4-yl) -dimethyl-amine. To a suspension of 2-trifluoromethyl-pyrimidine-4,6-diol (3.25 g) in P0C13 (7.89 mL) was added Et3N (5.00 mL). The mixture was stirred at 120 ° C for 3 hours, cooled to room temperature, and poured into ice water. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 4,6-dichloro-2-trifluoromethyl-pyrimidine. To the solution of the above material (1.00 g) in THF (10 mL) was added iPr2NEt (0.98 L) and 50% aqueous Me2NH (0.48 mL). The mixture was stirred at room temperature for 60 hours. Aqueous saturated NaHCOs were added to the solution and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (silica gel, 5% to 25% EtOAc in hexane) to give (6-chloro-2-). trifluoromethyl-pyrimidin-4-yl) -dimethyl-amine (728 mg). ESI MS m / e 225 M +; Xi NMR (300 MHz, CDC13) d 2.77-3.61 (m, 6 H), 6.50 (s, 1 H). Step C: Synthesis of 3-chloro-N- (cis-4. {[[6- (dimethylamino) -2- (trifluoromethyl) pyrimidin-4-yl] amino} cydohexyl) -4-fluorobenzamide hydrochloride. Using the procedure for step B of example 31, the title compound was obtained. ESI MS m / e 482, M (free) + H +; 1 H NMR (300 MHz, CDC13) d 1.66-2.08 (m, 8 H), 3.20 (s, 6 H), 3.68-3.83 (m, 1 H), 4.04-4.21 (m, 1 H), 5.30 (s) , 1 H), 6.34-6.46 (m, 1 H), 7.18 (t, J = 8.5 Hz, 1 H), 7.63-7.73 (m, 2 H), 7.87-7.93 (m, 1 H). Example 48 Trifluoroacetate 5-bromo-furan-2-carboxylic acid [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide Step A: Synthesis of tert-butyl ester of acid [ cis-4- (6-Chloro-2-methyl-pyrimidin-4-ylamino) -cycdohexyl] -carbamic acid. To a solution of 4, 6-dichloro-2-methyl-pyrimidine (4.87 g, 0.030 mol) in 50 mL MeOH was added DIEA (10.4 mL, 0.059 mol) and cis- (4-amino-cyclohexyl) -carbamic acid tert-butyl ester ( 6.4g, 0.030 mol). The mixture was stirred at reflux overnight and the solvent was concentrated. The resulting oil was subjected to chromatography (0-70% ethylacetate in hexanes) to produce [cis-4- (6-chloro-2-methyl-pyrimidin-4-ylamino) -cyclohexyl] -carbamic acid tert-butyl ester ( 9.7 g, 0.028 mol, 95%) as a white solid. ESI MS (M + H) +; XH NMR (400 MHz, CD3OD) d 6.38 (s, 1H), 4.14 (, 1H), 3.56 (m, 1H), 2.40 (s, 3H), 1.78-1.63 (m, 8H), 1.47 (s, 9H) ). Step B: Synthesis of [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycothexyl] -carbamic acid tert-butyl ester. To a solution ter-butyl ester of [cis-4- (6-chloro-2-methyl-pyrimidin-4-ylamino) -cidiohexyl] -carbamic acid (0.5 g, 0.0015 mol) in 2 mL 2-propanol was added dimethylamine (2.20 mL, 0.0044 mol) and DIEA (511 uL, 0.0029 mol). The mixture was heated on a microwave synthesizer at 160 ° C for 2 hours. The reaction was repeated 17 times more (9 g total material) and the reaction mixtures were emptied. The solvent was evaporated and the material was subjected to chromatography (2-4% 2M NH 3 in MeOH / CH 2 Cl 2) to produce [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino] tert-butyl ester. ) -ciciohexyl] -carbamic acid (7.5 g, 0.021 mol, 81%) as a white solid. ESI MS 350.4 (M + H) +; Xi NMR (400 MHz, CD3OD) d 5.35 (s, 1H), 3.72 (m, 1H), 3.54 (m, 1H), 3.05 (s, 6H), 2.30 (s, 3H), 1.75- 1.61 (m, 8H), 1.47 (s, 9H). Step C: Synthesis of N- (cis-4-amino-cyclohexyl) -2, Nr, N '-trimethyl-pyrimidine-4,6-diamine. To a solution of [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -carbamic acid tert-butyl ester (7.5 g, 0.021 mol) in 50 mL CH2C12 was added TFA ( 3.3 mL, 0.043 mol). The solution was stirred at room temperature for 4 hours (or until the reaction was complete judging by TLC). The excess solvent was evaporated and the resulting oil was dissolved in 30 mL CH2Cl2. The organic layer was extracted with 30 mL of diluted NaOH (ac) / solution (ac) NaHCO3 (it was confirmed that the aqueous layer ined basic during the extraction using pH indicator paper). The aqueous layer was extracted in reverse twice with CH2C12 and the combined organic layers, dried over MgSO4, and concentrated to yield N ~ (cis-4-amino-cyclohexyl) -2, N ', N' -trimethyl- pyrimidine-4,6-diamine (5.3 g, 0.021 mol, 99%) as a white solid. ESI MS 250.2 (M + H) +; 2 H NMR (400 MHz, CD 3 OD) d 5.37 (s, 1 H), 3.78 (m, 1 H), 3.06 (s, 6 H), 2.84 (m, 1 H), 2.30 (s, 3 H), 1.82-1.69 (, 6 H) ), 1.55-1.50 (m, 2H). Step D: Synthesis of 5-bromo-furan-2-carboxylic acid trifluoroacetate [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide. To a solution of N- (cis-4-amino-cyclohexyl) -2, N ', N' -trimethyl-pyrimidine-4,6-diamine (30 mg, 0.12 mmol) in 0.5 mL DMF was added 5-bromine acid -2-furoic acid (23 mg, 0.12 mmol), pyridine (14.6 uL, 0.18 mmol), and HATU (54.9 mg, 0.14 mmol). The reaction mixture was stirred overnight and then 0.5 mL DMSO was added to the mixture. The compound was then subjected to purification by LCMS of preparation to produce 5-bromo-furan-2-carboxylic acid trifluoroacetate [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide (25 mg, 0.047 mmol, 39%) as a white solid salt of TFA. ESI MS 422.2 (M + H) +; 1 H NMR (400 MHz, CD 3 OD) d 7.15 (d, 1 H, J = 3.6 Hz), 6.64 (d, 1 H, J = 3.6 Hz), 5.60 (s, 1 H), 4.01 (m, 1 H), 3.87 (m , 1H), 3.16 (s, 6H), 2.49 (s, 3H), 1.89-1.80 (m, 8H). Example 49 Trifluoroacetate 5-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -nicotinamide Using the procedure of step D of example 48, the compound of title (35 mg, 53%.) as a white solid ESI MS 433.0 (M + H) +; XH NMR (400 MHz, CD3OD) d 8. 5 (d, 1H, J = 1.6 Hz), 8.84 ( d, 1H, J = 2.0 Hz), 8.58 (, 1H), 8.43 (t, 1H, J = 2.0 Hz), 5.60 (s, 1H), 4.05 (m, 1H), 3.88 (m, 1H), 3.22 (s, 6H), 2.49 (s, 3H), 1.93-1.84 (m, 8H) Example 50 Trifluoroacetate N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycothexyl] 3,5-bis-trifluoromethyl-benzamide To a solution of N- (cis-4-amino-cyclohexyl) -2, N ', N' -trimethyl-pyrimidine-4,6-diamine (30 mg, 0.12 mmol) in 0.5 mL DMF pyridine (14.6 uL, 0.18 mmol) and 3,5-bis (trifluoromethyl) benzoyl chloride (21.8 uL, 0.12 mmol) was added.The reaction mixture was stirred overnight and then 0.5 mL of DMSO was added. to the mixture.The compound was then subjected to purification by LCMS of preparation to produce trifluoroacetate N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycotehexyl] -3,5-bis-trifluoromethyl-benzamide (12 mg, 0.020 mmol, 17%) as a white solid salt of TFA. ESI MS 490.4 (M + H) +; XH NMR (400 MHz, CD3OD) d 8.46 (s, 2H), 8.19 (s, 1H), 5.42 (s, 1H), 4.06 (m, 1H), 3.86 (, lH), 3.09 (s, 6H), 2.34 (s, 3H), 1.93-1.79 (m, 9H). EXAMPLE 51 Trifluoroacetate N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-difluoro-benzamide Using the procedure of step A of example 50, the title compound (22 mg, 0.044 mmol, 36%) as a white solid. ESI MS 390.2 (M + H) +; Xi NMR (400 MHz, CD3OD) d 7.50-7.46 (m, 2H), 7.22-7.16 (m, 1H), 5.60 (s, 1H), 4.02 (m, lH), 3.87 (m, 1H), 3.22 ( s, 6H), 2.49 (s, 3H), 1.90-1.81 (m, 8H). Example 52 Bis-trifluoroacetate N- [cis-4- (3,5-dimethoxy-benzylamino) -cydohexyl] -2, N ', N' -trimethyl-pyrimidine-4,6-diamine To a solution of N- (cis 4-amino-cyclohexyl) -2, N ', N' -trimethyl-pyrimidine-4,6-diamine (24.9 mg, 0.1 mmol) in 0.5 mL MeOH was added 3,5-dimethoxybenzaldehyde (16.6 mg, 0.1 mmol) . The mixture was stirred at room temperature for half an hour and then sodium triacetoxyborohydride (84.8 mg, 0.4 mmol) was added. The mixture was stirred at room temperature overnight and then 0.5 mL of DMSO was added to the mixture. The compound was then subjected to purification by LCMS of preparation to produce bis- trifluoroacetate N- [cis-4- (3,5-dimethoxy-benzylamino) -cycotehexyl] -2, N ', I \ 7' -trimethyl-pyrimidine- 4,6-diamine (27 mg, 0.043 mmol, 43%) as a white solid salt of TFA. ESI MS 400.5 (M + H) +; XH NMR (400 MHz, CD3OD) d 6.72 (d, 2H, J = 2.0 Hz), 6.59 (t, 1H, J = 2.0 Hz), 5.59 (s, 1H), 4.22 (s, 2H), 3.97 (m , 1H), 3.84 (m, 1H), 3.79 (s, 6 H), 3.22 (s, 6H), 2.48 (s, 3H), 2.11-2.02 (m, 4H), 1.95-1.81 (m, 4H) . EXAMPLE 53 Bis-trifluoroacetate N- [cis-4- (3-brorno-benzylamino) -cycotehexyl] -2, N ', N' -trimethyl-pyrimidine-4,6-diamine Using the procedure of step A of example 52 , the title compound (35 mg, 0.054 mmol, 54%) was obtained as a white solid. ESI MS 418.0 (M + H) +; 1 H NMR (400 MHz, CD 3 OD) d 7.78 (s, 1 H), 7.68 (d, 1 H, J = 8.0 Hz), 7.55 (d, 1 H, 7.6 Hz), 7.43 (t, 1 H, J = 8.0 Hz), 5.60 (s, 1H), 4.29 (s, 2H), 3.21 (s, 6H), 2.48 (s, 3H), 2.12-2.03 (m, 4H), 1.95-1.85 (m, 4H). Example 54 Trifluoroacetate 1- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3- (3-methoxy-phenyl) -urea To a solution of N- (cis-4) -amino-cyclohexyl) -2, N ', N' -trimethyl-pyrimidine-4,6-diamine (24.9 mg, 0.1 mmol) in 0.5 mL DMSO was added 3-methoxyphenyl isocyanate (11.8 uL, 0.09 mmol). The mixture was stirred at room temperature overnight and then 0.5 mL of DMSO was added to the mixture. The compound was then subjected to purification by LCMS of preparation to produce trifluoroacetate l- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycdohexyl] -3- (3-methoxy-phenyl) -urea (19 mg, 0.037 mmol, 41%) as a white solid salt of TFA. ESI MS 399.2 (MfH) X? Ñ NMR (400 MHz, CD3OD) d 7.15 (s, 1H), 7.14 (t, 1H, J = 2.4Hz), 6.86 (dd, lH, i = 8.0 Hz, < J2 = 2.0Hz), 6.57 (dd, 1H, Ji = 8.0 Hz, J2 = 2.4 Hz), 5.57 (s, 1H), 3.84 (m, 1H), 3.79 (s, 3H), 3.78 (m, 1H), 3.21 (s, 6H), 2.47 (s, 3H), 1.90-1.75 (m, 8H). Example 55 Trifluoroacetate 1- (3,5-difluoro-phenyl) -3- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -urea Using the procedure of step A of Example 54, the title compound (22 mg, 0.043 mmol, 47%) was obtained as a white solid. ESI MS 405.4 (M + H) +; X H NMR (400 MHz, CD 3 OD) d 7.07-7.04 (m, 2 H), 6.54-6.50 (m, 1 H), 5.60 (s, 1 H), 3.83 (m, 1 H), 3.82 (m, 1 H), 3.18 ( s, 6H), 2.48 (s, 3H), 1.90-1.83 (m, 4H), 1.79-1.75 (m, 4H). Example 56 Trifluoroacetate N- [cis-4- (6-dimethylamino-2-methylsulfanyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide Step A: Synthesis of cis-tert-butyl ester 4- (3,4-difluoro-benzoylamino) -cydohexyl] -carbamic acid. To a solution of cis- (4-amino-cyclohexyl) -carbamic acid tert-butyl ester (3 g, 0.014 mol) in CH2C12 (50 mL) was added DIEA (3.6 mL, 0.021 mol). The mixture was cooled in an ice bath and 3,4-difluorobenzoyl chloride (1.9 mL, 0.015 mol) was added slowly. The mixture was brought to room temperature and stirred for 1 hour. The solvent was then concentrated and the resulting oil chromatographed (0-70% ethyl acetate in hexanes). Upon evaporation of the solvents, a precipitate was broken off which was filtered and washed with 70% cold ether in hexanes to produce cis- [4- (3,4-difluoro-benzoylamino) -cycothexyl] tert-butyl ester] - Carbamic (4.4 g, 0.012 mol, 89%) as a white solid. ESI 355.4 M + H +; Xi NMR (400 MHz, CD3OD) d 7.78-7.72 (m, 1H), 7.68-7.64 (m, 1H), 7.39-7.33 (m, 1H), 3.93 (m, 1H), 3.61 (m, 1H), 1.78-1.68 (m, 8H), 1.45 (s, 9H). Step B: Synthesis of cis-N- (4-amino-cyclohexyl) -3,4-difluorobenzamide. To a solution of cis- [4- (3,4-difluoro-benzoylamino) -cidiohexyl] -carbamic acid tert-butyl ester (4.4 g, 0.012 mol) in CH2C12 (50 mL) was added TFA (1.9 mL, 0.025). mol). The solution was stirred at room temperature for 4 hours (or until the reaction was complete judging by TLC). The excess solvent was evaporated and the resulting oil was dissolved in 30 mL CH2C12 • The organic layer was extracted with 30 mL of dilute NaOH (ac) / NaHC03 solution (ac) (it was confirmed that the aqueous layer remained basic during the extraction using pH indicator paper). The aqueous layer was extracted in reverse twice with CH2C12 and the combined organic layers, dried over MgSO4, and concentrated to yield cis-N- (4-amino-cyclohexyl) -3,4-difluoro-benzamide (2.9 g. , 0.011 mol, 90%) as a white solid. ESI 255.4 M + H +; XH NMR (400 MHz, CD3OD) d 8.17 (d, 1H, J = 4. 8 Hz), 7.93-7.88 (m, 1H), 7.80-7.70 (m, 4H), 7.58-7.51 (m, 1H), 3.86 (m, 1H), 3.12 (m, 1H), 1.91-1.87 (m, 2H), 1.73-1.60 (m, 6H). Step C: Synthesis of cis-N- [4- (6-chloro-2-methylsulfanyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide.

To a solution of 4,6-dichloro-2- (methylthio) -pyrimidine (19.5 mg, 0.1 mmol) in IPA (0.6 mL) was added DIEA (35 uL, 0.2 mmol) and cis-N- (4-amino- cyclohexyl) -3,4-difluorobenzamide (25.4 mg, 0.1 mmol). The mixture was then heated in a microwave at 170 ° C for 30 minutes. The reaction mixture was cooled and concentrated and the resulting oil was purified by column (0-100% ethyl acetate in hexanes) to produce cis-N- [4- (6-chloro-2-methylsulfanyl-pyrimidin-4-ylamino) -cycdohexyl] -3,4-difluoro-benzamide (37 mg, 0.090 mmol, 90%) as a colorless oil. ESI MS 413.2 (M + H) X X H NMR (400 MHz, CD 3 OD) d 8.23 (m, 1 H), 7.81-7.76 (m, 1 H), 7.72-7.68 (m, 1 H), 7.43-7.36 (m, 1 H ), 6.27 (s, 1H), 4.17 (m, 1H), 4.00 (m, 1H), 2.51 (s, 3H), 1.94-1.79 (m, 8H). Step D: Synthesis of trifluoroacetate N- [cis-4- (6-dimethylamino-2-methylsulfanyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide. To a solution of cis-N- [4- (6-chloro-2-methylsulfanyl-pyrimidin-4-ylamino) -cidiohexyl] -3,4-difluoro-benzamide (73 mg, 0.18 mmol) in IPA (0.8 mL) DIEA was added (62 uL, 0.35 mmol) and dimethylamine (265 uL, 0.53 mmol). The mixture was then heated in a microwave at 170 ° C for 1 hour. The reaction mixture was cooled and concentrated and the resulting oil was redissolved in 1 L DMSO and purified by LCMS preparation to produce trifluoroacetate N- [cis-4- (6-dimethylamino-2-methylsulfanyl-pyrimidin-4 -ylamino) -cyclohexyl] -3,4-difluoro-benzamide (18.4 mg, 0.034 mmol, 19%) as a TFA salt. ESI MS 422.2 (M + H) +; 1 H NMR (400 MHz, CD 3 OD) d 8.28 (m, 1 H), 7.82-7.76 (m, 1 H), 7.73-7.69 (m, 1 H), 7.43-7.36 (m, 1 H), 4.88 (s, 1 H), 4.02 (m, 1H), 3.89 (m, 1H), 3.11 (s, 6H), 2.66 (s, 3H), 1.92-1.79 (m, 8H). Example 57 Trifluoroacetate N- [cis-4- (6-dimethylamino-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide To a solution of 4,6-dichloropyrimidine (14.9 mg, 0.1 mmol) in IPA (1 L) was added DIEA (35 uL, 0.2 mmol) and cis-N- (4-amino-cyclohexyl) -3, -difluoro-benzamide from step B Example 56 (25.4 mg, 0.1 mmol). The mixture was then heated in a microwave at 170 ° C for 15 minutes. The reaction mixture was cooled and then DIEA (35 uL, 0.2 mmol) and dimethylamine (150 uL, 0.3 mmol) were added. The mixture was then heated in a microwave at 170 ° C for 1 hour. The reaction mixture was cooled and concentrated and the resulting oil was redissolved in 1 mL DMSO and purified by LCMS preparation to produce trifluoroacetate N- [cis-4- (6-dimethylamino-pyrimidin-4-ylamino) - cyclohexyl] -3,4-difluoro-benzamide (11.7 mg, 0.024 mmol, 24%) as a TFA salt. ESI MS 376.3 (M + H) +; aH? MR (400 MHz, CD3OD) d 8.27 (m, 1H), 8.18 (s, 1H), 7.82-7.76 (m, 1H), 7.73-7.69 (m, 1H), 7.43-7.36 (m, 1H) , 5.71 (s, 1H), 4.02 (m, 1H), 3.88 (, 1H), 3.23 (s, 6H), 1.90-1.84 (m, 8H). EXAMPLE 58 Trifluoroacetate N- [cis-4- (6-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide To a solution of 2-methyl-4,6-dichloropyrimidine (32.6 mg, 0.2 mmol) in IPA (1 mL) was added DIEA (70 uL, 0.4 mmol) and cis-N- (4-amino-cyclohexyl) -3,4-difluoro-benzamide from step B Example 56 ( 50.8 mg, 0.2 mmol). The mixture was then heated in a microwave at 170 ° C for 15 minutes. The reaction mixture was cooled and then DIEA (70 uL, 0.4 mmol) and dimethylamine (300 uL, 0.3 mmol) was added. The mixture was then heated in a microwave at 170 ° C for 1 hour. The reaction mixture was cooled and concentrated and the resulting oil was redissolved in 1 mL DMSO and purified by LCMS preparation to produce trifluoroacetate N- [cis-4- (6-dimethylamino-5-methyl-pyrimidin-4 -ylamino) -cycdohexyl] -3,4-difluoro-benzamide (32.2 mg, 0.064 mmol, 64%) as a TFA salt. ESI MS 390.2 (M + H) +; XH ™ MR (400 MHz, CD3OD) d 8.20 (s, 1H), 8.17 (m, 1H), 7.81-7.78 (m, 1H), 7.72-7.71 (m, 1H), 7.42-7.40 (, 1H), 4.10 (, 1H), 4.09 (m, 1H), 3.16 (s, 6H), 2.16 (s, 3H), 2.02-1.82 (m, 8H). Example 59 Trifluoroacetate 3,4-dichloro-N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide Step A: Synthesis of cis-tert-butyl ester 4- (2-Chloro-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -carbamic acid. To a solution of 2,4-dichloro-6-methylpyrimidine (3.7 g, 0.023 mol) in 30 mL of methanol was added DIEA (5.89 mL, 0.034 mmol) and cis- (4-amino-cyclohexyl) tert-butyl ester. ) -carbamic (5.3 g, 0.025 mol). The mixture was refluxed overnight, cooled, and concentrated. The resulting oil was subjected to chromatography (0-100% ethyl acetate in hexanes) to produce cis- [4- (2-chloro-6-methyl-pyrimidin-4-ylamino) -cycothexyl] -carbamic acid tert-butyl ester ( 5.1 g, 0.015 mol, 66%) as a white solid. ESI MS 341.4 (M + H) +; XH NMR (400 MHz, CD3OD) d 6.31 (s, 1H), 4.12 (m, 1H), 3.56 (m, 1H), 2.26 (s, 3H), 1.78-1.67 (m, 8H), 1.48 (s, 9H). Step B: Synthesis of cis- [4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cycothexyl] -carbamic acid tert-butyl ester. To a solution of cis- [4- (2-chloro-6-methyl-pyrimidin-4-ylamino) -cycothexyl] -carbamic acid tert-butyl ester (0.5 g, 0.0015 mol) in 2 mL of 2-propanol was added dimethylamine (1.47 mL, 0.0029 mol) and DIEA (511 uL, 0.0029 mol). The mixture was heated on a microwave synthesizer at 170 ° C for 1 hour. The reaction was repeated 9 times more (5 g total material) and the reaction mixtures were emptied. The solvent was evaporated and the material was subjected to chromatography (2-4% 2M NH 3 in MeOH / CH 2 Cl 2) to produce cis- [4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino] tert-butyl ester. ) -ciciohexyl] -carbamic acid (2.2 g, 0.0063 mol, 43%) as a white solid. ESI MS 350.2 (M + H) +; 1 H NMR (400 MHz, CD 3 OD) d 5.68 (s, 1 H), 3.95 (, 1 H), 3.54 (m, 1 H), 3.11 (s, 6 H), 2.16 (s, 3 H), 1.77-1.64 (m, 8 H) ), 1.47 (s, 9H). Step C: Synthesis of cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -1-amino-cyclohexane. To a solution of cis- [4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cidiohexyl] -carbamic acid tert-butyl ester (2.2 g, 0.0063 mol) in 15 ml of CH2C12 was added TFA (0.97 mL, 0.013 mol). The solution was stirred at room temperature for 4 hours (or until the reaction was complete judging by TLC). The excess solvent was evaporated and the resulting oil was dissolved in 30 L CH2C12. The organic layer was extracted with 30 mL of dilute NaOH (aq) / solution (aq) NaHCO3 (it was confirmed that the aqueous layer remained basic during the extraction using pH indicator paper). The aqueous layer was extracted in reverse twice with CH2C12 and the combined organic layers, dried over MgSO4, and concentrated to yield cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -1- amino-cyclohexane (1.3 g, 0.0052 mol, 83%) as a white solid. ESI MS 250.2 (M + H) +; XE NMR (400 MHz, CD3OD) d 5.70 (s, 1H), 4. 00 (m, 1H), 3.11 (s, 6H), 2.84 (m, 1H), 2.16 (s, 3H), 1.86-1.80 (m, 2H), 1.76-1.66 (m, 4H), 1.57-1.49 ( m, 2H). Step D: Synthesis of trifluoroacetate 3,4-dichloro-N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide. To a solution of cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -1-amino-cyclohexane (20 mg, 0.080 mmol) in 0.5 mL DMF was added pyridine (9.7 uL, 0.12 mmol) and 3,4-dichlorobenzoyl chloride (11.1 uL, 0.076 mmol). The reaction mixture was stirred overnight and then 0.5 L of DMSO was added to the mixture. The compound was then subjected to purification by LCMS of preparation to produce trifluoroacetate 3,4-dichloro-N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide (10 mg , 0. 019 mmol, 24%) as a TFA salt. ESI MS 422.2 (M + H) +; ? E NMR (400 MHz, CD3OD) d 8.00 (d, 1H, J = 2.0 Hz), 7.76 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz), 7.65 (d, 1H, J = 8.4 Hz), 6.01 (s, 1H), 4.23 (m, 1H), 4.00 (m, 1H), 3.26 (s, 6H), 2.34 (s, 3H), 1.98-1.81 (m, 8H). EXAMPLE 60 Trifluoroacetate 4-cyano-N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide Using the procedure of step D of example 59, the compound of title (11 mg, 0.022 mmol, 29%). ESI MS 379.2 (M + H) +; X H NMR (400 MHz, CD 3 OD) d 7.97 (d, 2 H, J = 8.0 Hz), 7.86 (d, 2 H, J = 8.4 Hz), 6.01 (s, 1 H), 4.23 (m, 1 H), 4.03 (m , 1H), 3.26 (s, 6H), 2.34 (s, 3H), 1.99-1.82 (m, 8H). EXAMPLE 61 Trifluoroacetate N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-diethoxy-benzamide To a solution of cis-4- (2-dimethylamino-6) -methyl-pyrimidin-4-ylamino) -1-amino-cyclohexane (20 mg, 0.080 mmol) in 0.5 mL DMF was added 3,4-diethoxy-benzoic acid (16.0 mg, 0.076 mmol), pyridine (9.7 uL, 0.12 mmol), and HATU (36.6 mg, 0.096 mmol). The reaction mixture was stirred overnight and then 0.5 mL of DMSO was added to the mixture. The compound was then subjected to purification by LCMS of preparation to produce trifluoroacetate N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-diethoxy-benzamide (11 mg , 0.020 mmol, 26%) as a TFA salt. ESI MS 442.4 (M + H) +; XE NMR (400 MHz, CD3OD) d 7.47-7.44 (m, 2H), 7.02-7.00 (m, 1H), 6.01 (s, 1H), 4.23 (m, 1H), 4.15 (q, 4H, J = 7.0 Hz), 4.00 (m, 1H), 3.26 (s, 3H), 2.34 (s, 3H), 1.99-1.81 (m, 8H), 1.45 (t, 6H, J = 7.2 Hz). EXAMPLE 62 Trifluoroacetate 3-chloro-N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -5-fluoro-benzamide Using the procedure of step A of example 61, obtained the title compound (12 mg, 0.023 mmol, 30%). ESI MS 406.4 (M + H) +; SH NMR (400 MHz, CD3OD) d 7.71 (s, 1H), 7.57-7.53 (m, 1H), 7.45-7.42 (m, 1H), 6.00 (s, 1H), 4.23 (m, 1H), 4.00 ( m, 1H), 3.26 (s, 6H), 2.34 (s, 3H), 1.99-1.82 (m, 8H). Example 63 Trifluoroacetate N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-dimethoxy-benzamide Step A: Synthesis of cis-tert-butyl ester 4- (2-Chloro-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -carbamic acid. To a solution of 2,4-dichloro-5-methylpyrimidine (1.0 g, 6.13 mmol) in 2 mL 2-propanol was added DIEA (1.6 mL, 9.20 mmol) and cis-tert-butyl ester (4-amino- cyclohexyl) -carbamic acid (1.45 g, 6.75 mmol). The mixture was heated on a microwave synthesizer at 150 ° C for 15 minutes. The solvent was evaporated and the material was subjected to chromatography (0-70% ethyl acetate in hexanes) to produce cis- [4- (2-chloro-5-methyl-pyrimidin-4-ylamine) -cycothexyl) tert-butyl ester ] -carbamic (1.7 g, 4.86 mmol, 79%) as a white solid. ESI MS 341.2 (M + H) +; XE NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 4.12 (, 1H), 3.67 (m, 1H), 2.05 (s, 3H), 1.82-1.70 (m, 8H), 1.48 (s, 9H) ). Step B: Synthesis of cis- [4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cycothexyl] -carbamic acid tert-butyl ester. To a solution of cis- [4- (2-chloro-5-methyl-pyrimidin-4-ylamino) -cycothexyl] -carbamic acid tert-butyl ester (0.5 g, 0.0015 mol) in 2 mL of 2-propanol was added dimethylamine (1.47 mL, 0.0029 mol) and DIEA (511 uL, 0.0029 mol). The mixture was heated on a microwave synthesizer at 170 ° C for 1 hour. The reaction was repeated twice more (1.5 g total material) and the reaction mixtures were emptied. The solvent was evaporated and the material was subjected to chromatography (2-4% 2M NH 3 in MeOH / CH 2 Cl 2) to produce cis- [4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino] tert-butyl ester ) -ciciohexyl] -carbamic acid (1.3 g, 0.0037 mol, 85%) as a white solid. ESI MS 350.2 (M + H) +; Xi NMR (400 MHz, CD3OD) d 7.53 (s, 1H), 4.13 (m, 1H), 3.63 (m, 1H), 3.09 (s, 6H), 1.94 (s, 3H), 1.83-1.70 (, 8H) ), 1.48 (s, 9H). Step C: Synthesis of cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -1-amino-cyclohexane. To a solution of cis- [4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cycothexyl] -carbamic acid tert-butyl ester (1.3 g, 0.0037 mol) in 10 mL of CH2C12 was added TFA (0.57 mL, 0.0074 mol). The solution was stirred at room temperature for 4 hours (or until the reaction was complete judging by TLC). The excess solvent was evaporated and the resulting oil was dissolved in 30 mL CH2Cl2. The organic layer was extracted with 30 mL of dilute NaOH (aq) / solution (aq) NaHCO3 (it was confirmed that the aqueous layer remained basic during the extraction using pH indicator paper). The aqueous layer was extracted in reverse twice with CH2C12 and the combined organic layers, dried over MgSO4, and concentrated to yield cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -1- amino-cyclohexane (0.88 g, 0.0035 mol, 95%) as a white solid. ESI MS 250.2 (M + H) +; 1ti NMR (400 MHz, CD3OD) d 7.53 (s, lH), 4.17 (m, 1H), 3.09 (s, 6H), 2.94 (, 1H), 1.96 (s, 3H), 1.86-1.71 (m, 6H) ), 1.62-1.59 (m, 2H). Step D: Synthesis of trifluoroacetate N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-dimethoxy-benzamid. To a solution of cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -1-amino-cyclohexane (20 mg, 0.080 mmol) in 0.5 mL DMF was added pyridine (9.7 uL, 0.12 mmol) and 3,5-dimethoxybenzoyl chloride (15.3 mg, 0.076 mmol). The reaction mixture was stirred overnight and then 0.5 mL of DMSO was added to the mixture. The compound was then subjected to purification by LCMS of preparation to produce trifluoroacetate N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cyclohexyl] -3,5-dimethoxy-benzamide (14 mg , 0.027 mmol, 35%) as a TFA salt. ESI MS 414.4 (M + H) +; XH NMR (400 MHz, CD3OD) d 8.00 (s, 1H), 7. 48 (s, 1H), 7.19 (d, 1H, J = 2.4 Hz), 6.69 (t, 1H, J = 2.4 Hz), 4.31 (m, 1H), 4.10 (m, 1H), 3.85 (s, 6H) ), 3.23 (s, 6H), 2. 32 (s, 3H), 2.10-1.82 (m, 8H). Example 64 Trifluoroacetate 3,4-dichloro-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide Using the procedure of step D of example 63, the compound of the title (15 mg, 0.028 mmol, 37%). ESI MS 422.2 (M + H) +; Xi NMR (400 MHz, CD3OD) d 8.24 (m, 1H), 8. 02 (d, 1H, J = 2.0 Hz), 7.78 (dd, lH, J = 8.4 Hz, J2 = 2.0 Hz), 7.67 (d, 1H, J = 8.4 Hz), 7.48 (s, 1H), 4.31 ( m, 1H), 4. 10 (, 1H), 3.23 (s, 6H), 2.10 (s, 3H), 2.00-1.82 (m, 8H).

Example 65 Trifluoroacetate N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin--ylamino) -cydohexyl] -3,4-diethoxy-benzamide To a solution of cis-4- (2-dimethylamino-5-) methyl-pyrimidin-4-ylamino) -1-amino-cyclohexane (20 mg, 0.080 mmol) in 0.5 mL DMF was added 3,4-diethoxy-benzoic acid (16.0 mg, 0. 076 mmol), pyridine (9.7 uL, 0.12 mmol), and HATU (36.6 mg, 0. 096 mmol). The reaction mixture was stirred overnight and then 0.5 mL DMSO was added to the mixture. The compound was then subjected to purification by LCMS of preparation to produce trifluoroacetate N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3, -dietoxy-benzamide (12 mg, 0. 022 mmol, 28%) as a TFA salt. ESI MS 442.4 (M + H) +; 1H NMR (400 MHz, CD3OD) d 7.49-7.46 (, 3H), 7.02 (d, 1H, J = 8.0 Hz), 4.31 (m, 1H), 4.16 (q, 4H, J = 7. 0 Hz), 4.10 (m, 1H), 3.23 (s, 6H), 2.10 (s, 3H), 2.01-1.81 (m, 8H), 1.46 (t, 6H, J = 7.0 Hz). EXAMPLE 66 Trifluoroacetate 3-chloro-.N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -5-fluoro-benzamide using the procedure of step A of example 65, the title compound was obtained (12 mg, 0.023 mmol, 30%). ESI MS 406.2 (M + H) +; Xi NMR (400 MHz, CD3OD) d 7.73 (s, 1H), 7. 59-7.56 (m, lH), 7.48 (s, 1H), 7.46-7.43 (m, 1H), 4.31 (m, 1H), 4.10 (m, 1H), 3.23 (s, 6H), 2.10 (s, 3H), 2.03-1.81 (, 8H). Example 67 Trifluoroacetate N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,5-bis-trifluoromethyl-benzamide Step A: Synthesis of benzyl ester of cis- (4-amino-cyclohexylmethyl) -carbamic acid. To a solution of cis- (4-aminomethyl-cyclohexyl) -carbamic acid tert-butyl ester (25 g, 0.11 mol) in CH2Cl2 (300 mL) was added DIEA (22.9 mL, 0.13 mol). The mixture was cooled in an ice bath and benzyl chloroformate (17.3 mL, 0.12 mol) was slowly added. The mixture was removed from the ice bath and stirred overnight. The solvent was removed in vacuo and the resulting oil was dissolved in MeOH (250 mL). Concentrated HCl (75 mL) was slowly added to the mixture with stirring. The reaction was allowed to stir for a further 4 hours and then the solvent was removed in vacuo resulting in a precipitate. A copious amount of water (2 L) was added to dissolve the resulting HCl salt precipitate, which was then made basic with a slow addition of a concentrated solution of NaOH. The aqueous layer was extracted 3 times with ethyl acetate (1 L). The organic layers were combined, dried over MgSO4, and concentrated to yield benzyl ester of cis- (4-amino-cyclohexylmethyl) -carbamic acid (24.5 g, 0.093 mol, 85%) as an oil. ESI MS m / e 263.2 (M + H) +; Xi NMR (400 MHz, DMSO-d6) d 7.36-7.25 (m, 5H), 4.99 (s, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.81 (m, 1H), 143-1.34 ( m, 8H). Step B: Synthesis of cis- [4- (6-chloro-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -carbamic acid benzyl ester. To a solution of 4,6-dichloro-2-methyl-pyrimidine (1.0 g, 6.1 mmol) in 2 mL 2-propanol was added DIEA (1.6 mL, 9.2 mmol) and benzyl ester of cis- (4-amino- cyclohexylmethyl) -carbamic acid (1.8 g, 6.7 mmol). The mixture was heated on a microwave synthesizer at 160 ° C for 20 minutes. The reaction was repeated twice more (3 g total material) and the reaction mixtures were emptied. The solvent was evaporated and the material was subjected to chromatography (0-100% ethylacetate in hexanes) to produce benzyl ester of cis- [4- (6-chloro-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] - Carbamic (6.5 g, 0.017 mol, 91%) as a white solid. ESI MS m / e 389.2 (M + H) X X H NMR (400 MHz, CDC13) d 7.35-7.26 (, 5H), 6.17 (s, 1H), 5.09 (s, 2H), 4.89 (m, 1H), 3.10 (t, J = 6.0 Hz, 2H), 2.46 (s, 3H), 1.80-1.67 (m, 2H), 1.66-1.60 (m, 4H), 1.30-1.22 (m, 2H). Step C: Synthesis of cis- [4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexyl-ethyl] -carbamic acid benzyl ester. To a solution of benzyl ester of cis- [4- (6-chloro-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -carbamic acid (0.5 g, 1.3 mmol) in 2 mL of 2-propanol was added DIEA (224 uL, 1.3 mmol) and dimethylamine (1.3 mL, 2.6 mmol). The mixture was heated on a microwave synthesizer at 170 ° C for 30 minutes. The reaction was repeated 7 times more (8g total material) and the reaction mixtures were emptied. The solvent was evaporated and the material was subjected to chromatography (0-100% ethyl acetate in hexanes to remove the starting material, followed by <5% MeOH in CH2C12) to produce benzyl ester of cis- [4- (6- dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -carbamic acid (3.8 g, 9.6 mmol, 94%) as a white solid. ESI MS m / e 398.2 (M + H) +; XH NMR (400 MHz, CDC13) d 7.6-7.26 (m, 5H), 5.10 (s, 1H), 5.09 (s, 2H), 5.06 (m, 1H), 3.69 (m, 1H), 3.09 (m, 8H), 2.40 (s, 3H), 1.87-1.83 (, 2H), 1.65-1.56 (m, 4H), 1.42-1.36 (m, 2H) - Step D: Synthesis of cis-N- (4-aminomethyl-cyclohexyl) -2, N ', N' -trimethyl-pyrimidine-4,6-diamine. To a solution of benzyl ester of cis- [4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -carbamic acid (3.8 g, 9.6 mmol) in EtOH (100 L) was added 10% Pd / C (380 mg). The reaction mixture was stirred at room temperature under an atmosphere of H2 (g) for 15 hours. The atmosphere of H2 (g) was removed and the mixture was washed through a plug of celite with ethyl acetate. The solvent was concentrated and the material was subjected to chromatography (2-4% 2M NH 3 in MeOH / CH 2 Cl 2) to produce cis-N- (4-aminomethyl-cyclohexyl) -2, N ', N' -trimethyl-pyrimidine-4 , 6-diamine (1.7 g, 6.5 mmol, 64%) as a white solid. ESI MS m / e 264.2 (M + H) +; 1ti NMR (400 MHz, DMSO) d 6.29 (m, 1H), 5.33 (s, 1H), 3.87 (m, 1H), 2.91 (s, 6H), 2.42 (s, 2H), 2.15 (s, 3H) , 1.55-1.29 (m, 8H). Step E: Synthesis of trifluoroacetate N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,5-bis-trifluoromethyl-benzamide To a solution of cis-N- ( 4-aminomethyl-cyclohexyl) -2, N ', N' -trimethyl-pyrimidine-4,6-diamine (26 mg, 0.10 mmol) in 0.5 mL DMF was added pyridine (12.1 uL, 0.15 mmol) and 3.5- bis (trifluoromethyl) benzoyl chloride (18.1 uL, 0.10 mmol). The reaction mixture was stirred overnight and then 0.5 mL of DMSO was added to the mixture. The compound was then subjected to purification by LCMS of preparation to produce trifluoroacetate N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,5-bis-trifluoromethyl-benzamide ( 11.9 mg, 0.019 mmol, 19%) as a white solid salt of TFA. ESI MS m / e 504.2 (M + H) +; XH NMR (400 MHz, CD3OD) d 9.03 (m, 1H), 8.47 (s, 2H), 8.20 (s, 1H), 5.58 (s, 1H), 3.88 (s, 1H), 3.43 (t, J = 6.4 Hz, 2H), 3.20 (s, 6H), 2.48 (s, 3H), 1.90-1.75 (m, 6H), 1.54-1.46 (m, 2H). Example 68 Trifluoroacetate N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-trifluoromethoxy-benzamide Using the procedure of step E of Example 67, the compound of title (18.7 mg, 0.033 mmol, 33%) as a white solid. ESI MS m / e 452.2 (M + H) +; 1 H NMR (400 MHz, CD 3 OD) d 8.65 (m, 1 H), 7.96 (d, J = 9.4 Hz, 2 H), 7.40 (d, J = 8.4 Hz), 5.58 (s, 1 H), 3.87 (s, 1 H) ), 3.39 (t, J = 6.4 Hz), 3.19 (s, 6H), 2.48 (s, 3H), 1.88-1.75 (m, 6H), 1.53-1.44 (m, 2H).

Examples 69-72 Compounds 69 to 72 were prepared in a manner similar to that described in Example 48 using the appropriate carboxylic acid and the amine intermediate of step D. Examples 73-107 Compounds 73 to 107 were prepared in a similar manner to that described in Example 50 using the appropriate acid chloride and the amine intermediate of step A. Examples 108-110 Compounds 108 to 110 were prepared in a manner similar to that described in Example 52 using the appropriate aldehyde and the amine intermediate of step A. Examples 111-113 Compounds 111 to 113 were prepared in a manner similar to that described in Example 54 using the appropriate isocyanate and amine intermediate from step A. Examples 114-117 Compounds 114 to 117 were prepared from similarly to that described in Example 48 using the appropriate carboxylic acid and the amine intermediate of stage D. Examples 118-125 Compounds 118 to 125 were prepared in a manner similar to written in Example 63 using the appropriate acid chloride and the amine intermediate of step D. Examples 126-133 Compounds 126-133 were prepared in a manner similar to that described in Example 65 using the appropriate carboxylic acid and the amine intermediate of step A. Examples 134-140 Compounds 134 to 140 were prepared in a manner similar to that described in Example 59 using the appropriate acid chloride and the amine intermediate of step D. Examples 141-148 Compounds 141 to 148 were prepared in a manner similar to that described in Example 61 using the appropriate carboxylic acid and the amine intermediate of step A. Examples 149-167 Compounds 149 to 167 were prepared in a manner similar to that described in Example 67 using the appropriate acid chloride and the amine intermediate of stage E.

Example 168 Hydrochloride N-. { cis-4- [(6-amino-2-methylpyrimidin-4-yl) amino] cydohexyl} 3, 4, 5-trifluorobenzamide Step A: Synthesis of N- (cis-4-aminocyclohexyl) -3,4,5-trifluorobenzamide. To a solution of tert-butyl (cis-4-aminocyclohexyl) carbamate (44.3 g) in DMF (450 mL) was added 3,4,4-trifluorobenzoic acid (40.1 g), Et3N (69.2 L), HOBt-H20 ( 47.5 g), and EDC-HC1 (43.6 g). The mixture was stirred at room temperature for 12 hours. Water (1 L) was added to the mixture and the suspension was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with water and hexane, and dried at 80 ° C under reduced pressure to give a pale brown solid (82.7 g). To a suspension of the above solid in EtOAc (800 mL) was added 4 M hydrogen chloride in EtOAc (600 mL) under 10 ° C. The mixture was stirred at room temperature for 6 hours and concentrated under reduced pressure. The residue was dissolved in CHC13 (300 mL) and emptied into aqueous 1 M NaOH (500 mL). The aqueous layer was extracted with CHC13 three times. The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (65.3 g). Xi NMR (300 MHz, CDC13, d): 1.38-1.91 (m, 8H), 2.97-3.09 (m, 1H), 4.04-4.20 (m, 1H), 6.15-6.27 (, 1H), 7.35-7.50 ( m, 2H); ESI MS m / z 273 (M ++ 1, 100%). Step B: Synthesis of 6-chloro-2-methylpyrimidin-4-amine. To a solution of 4,6-dichloro-2-methyl-pyrimidine obtained in step A of example 5 (15.0 g) in 2-propanol (30 mL) was added 28% aqueous NH 3 (30 mL). The mixture was stirred at reflux for 6 hours in a sealed tube and cooled to room temperature. The precipitate was collected by filtration, washed with 2-propanol, and dried at 80 ° C under reduced pressure to give the title compound (7.58 g). a H NMR (300 MHz, DMSO-d 6, d): 2.29 (s, 3 H), 6.27 (s, 1 H), 7.12 (brs, 2 H); ESI MS m / z 144 (M ++ l, 100%). Stage C: Hydrochloride synthesis. { cis-4- [(6-amino-2-methylpyrimidin-4-yl) amino] cydohexyl} 3,4,4,5-trifluorobenzamide. To a suspension of N- (cis-4-aminocyclohexyl) -3,4,5-trifluorobenzamide (1.20 g) in BuOH (2 mL) was added 6-chloro-2-methylpyrimidin-4-amine (534 mg). The mixture was heated on a microwave synthesizer at 220 ° C for 30 min. The mixture was diluted with CHC13 and added to saturated aqueous NaHC? 3. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% to 80% EtOAc in hexane) to give an oil. To a solution of the above oil in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. A suspension of the residue in Et20 (10 mL) was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with Et20, and dried at 80 ° C under reduced pressure to give the title compound (627 mg). and NMR (300 MHz, DMSO-d6, d): 1.60-1.75 (m, 8H), 2.36 (s, 3H), 3.80-4.13 (m, 2H), 5.43-5.78 (, 1H), 7.16-7.70 ( m, 1H), 7.74-7.95 (m, 2H), 8.37-8.48 (m, 1H), 13.29-13.55 (m, 1H); ESI MS m / z 380 [M (free) ++ l, 100%]. EXAMPLE 169 3, 4, 5-Trifluoro-N- (cis-4. {[[2-methyl-6- (methylamino) pyrimidin-4-yl] amino} cyclohexyl) -benzamide hydrochloride Step A: Synthesis of 6-chloro-N, 2-dimethylpyrimidin-4-amine. To a solution of 4,6-dichloro-2-methyl-pyrimidine obtained in step A of example 5 (15.0 g) in THF (150 mL) was added 40% aqueous MeNH2 (17.9 g) and the mixture was stirred at room temperature. environment for 3 hours. The mixture was diluted with CHC13 and added to saturated aqueous NaHCO3. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and dried under reduced pressure to give the title compound (13.6 g). ? E NMR (300 MHz, CDC13, d): 2.48 (s, 3H), 2.93 (d, J = 5.1 Hz, 3H), 5.02-5.29 (m, 1H), 6.18 (s, 1H); ESI MS m / z 158 (M ++ 1, 100%). Step B: Synthesis of 3, 4, 5-trifluoro-N- (cis-4 { [2-methyl-6- (methylamino) pyrimidin-4-yl] amino} cydohexyl) benzamide hydrochloride. The title compound (312 mg) was prepared from N- (cis-4-aminocyclohexyl) -3,4,5-trifluorobenzamide obtained in step A of example 168 (952 mg) and 6-chloro-N, 2 -dimethylpyrimidin-4-amine (500 mg) using the procedure for step C of example 168. Xi NMR (300 MHz, CDC13, d): 1.55-1.91 (, 8H), 2.22-2.46 (m, 3H), 2.71 -2.94 (m, 3H), 3.73-4.11 (m, 2H), 5.36-5.67 (m, 2H), 7.74-7.90 (m, 2H), 8.09-8.52 (m, 2H); ESI MS m / z 394 [M (free) ++ l, 100%]. EXAMPLE 170 Methanesulfonate N- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,4,5-trifluorobenzamide To a solution of N- (cys -4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,4,5-trifluorobenzamide (3.00 g) obtained in Example 11 in EtOH (21 mL) MsOH (743 mg) was added. The mixture was stirred at room temperature for 1 hour and at 4 ° C for 4 hours.

The precipitate was collected by filtration, washed with cold EtOH, and dried at 80 ° C under reduced pressure to give the title compound (3.16 g).

XH NMR (300 MHz, CDC13, d): 1.60-2.08 (m, 8H), 2.48 (s, 3H), 2.92 (s, 3H), 3.07 (brs, 3H), 3.30 (brs, 3H), 3.71- 3.80 (m, 1H), 4.07-4.24 (m, 1H), 5.18 (s, 1H), 7.65-7.83 (m, 4H), 12.63 (brs, 1H); ESI MS m / z 408 [M (free) ++ l, 100%]. Example 171 Hydrochloride 3-chlor -N-. { cis-4- [(2,6-dimethylpyrimidin-4-yl) amino] cyclohexyl} -4-fluorobenzamide Stage A: Synthesis of 4-chloro-2,6-dimethylpyrimidine. A solution of ZnBr2 (4.14 g) in THF (15 mL) was cooled to -60 ° C and 3 M methylmagnesium bromide in Et20 was added. (6.13 mL). The mixture was stirred at -60 ° C for 1 hour and warmed to room temperature. To the mixture was added tetrakis- (triphenylphosphine) -palladium (1.06 g) and 4,6-dichloro-2-methyl-pyrimidine obtained in step A of example 5 (3.0 g) in THF (15 mL). The mixture was stirred at 60 ° C for 8 hours. Aqueous saturated NH4C1 was added to the mixture and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (silica gel, 5% to 16% EtOAc in hexane) to give the title compound (940 mg ). a H NMR (300 MHz, CDC13, d): 2.49 (s, 3 H), 2.68 (s, 3 H), 7.05 (s, 1 H); Cl MS m / z 143 (M ++ 1, 100%). Stage B: Synthesis of 3-chloro-N- hydrochloride. { cis-4- [(2,6-dimethylpyrimidin-4-yl) amino] cyclohexyl} -4-fluorobenzamide.

The title compound (454 mg) was prepared from N- (cis-4-amino-cyclohexyl) -3-chloro-4-fluoro-benzamide obtained in step A of example 31 (520 mg) and 4-chloro -2, 6-dimethylpyrimidine (250 mg) using the procedure for step C of example 168. 1ti NMR (600 MHz, CDC13, d): 1.68-2.16 (m, 8H), 2.38 (brs, 3H), 2.62 ( s, 3H), 4.10-4.22 (m, 1H), 4.43-4.53 (m, 1H), 6.80-6.91 (m, 1H), 7.08-7.18 (m, 2H), 7.75-7.86 (m, lH), 7.92-8.12 (, 1H), 8.90-9.06 (m, 1H); ESI MS m / z 377 [M (free) ++ 1, 100%]. Example 172 N-. { cis-4- [(6-Chloro-2-methylpyrimidin-4-yl) amino] cydohexyl} 3,4,4,5-trifluorobenzamide To a suspension of N- (cis-4-aminociclohexyl) -3,4,5-trifluorobenzamide obtained in step A of example 168 (16.7 g) in BuOH (9.1 mL) was added 4-trifluorobenzamide. , 6-dichloro-2-methyl-pyrimidine obtained in step A of example 5 (9.10 g) and iPrNEt2 (10.7 ml). The mixture was stirred at reflux for 1.5 hours. The mixture was diluted with CHC1 and added to saturated aqueous NaHCOs. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 33% to 66% EtOAc in hexane) to give the title compound ( 21.0 g). and NMR (300 MHz, CDC13, d): 1.56-2.03 (m, 8H), 2.47 (s, 3H), 3.74-3.92 (m, 1H), 4.03-4.18 (m, 1H), 5.08-5.24 (m , 1H), 6.08 (d, J = 7.3 Hz, 1H), 6.18 (s, 1H), 7.33-7.50 (, 2H); ESI MS m / z 399 (M ++ 1, 100%). EXAMPLE 173 N- (cis-4. {[[6- (cyclopropylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -3,4,5-trifluorobenzamide hydrochloride To a suspension of N-. { cis-4- [(6-chloro-2-methylpyrimidin-4-yl) amino] cyclohexyl} -3,4,5-trifluorobenzamide obtained in Example 172 (250 mg) in 3-methyl-butan-1-ol (0.5 L) was added cyclopropylamine (43 mg). The mixture was stirred at 190 ° C for 1.5 hours in a sealed tube. The mixture was diluted with CHCl3 and added to saturated aqueous NaHCO3. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% to 50% EtOAc in hexane and silica gel, 2% a 9% MeOH in CHC13) to give a colorless oil. To a solution of the above oil in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. A suspension of the residue in Et20 (10 mL) was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with Et20, and dried at 80 ° C under reduced pressure to give the title compound (90 mg). lE NMR (300 MHz, CDC13, d): 0.62-0.74 (m, 2H), 0.88-1.00 (m, 2H), 1.72-2.02 (m, 8H), 2.45 (s, 3H), 2.50-2.64 (m , lH), 3.71-3.87 (m, 1H), 4.03-4.19 (m, 1H), 5.52 (s, 1H), 6.80-6.96 (m, 1H), 7.48-7.62 (m, 2H); ESI MS m / z 420 [M (free) ++ 1, 100%]. Example 174 3,4,5-Trifluoro-N- [cis-4- (. {2-methyl-6- [methyl (phenyl) amino] pyrimidin-4-yl] amino) -cydohexyl] benzamide hydrochloride The compound of title (210 mg) was prepared from N-. { cis-4- [(6-chloro-2-methylpyrimidin-4-yl) amino] cyclohexyl} 3, 4, 5-trifluorobenzamide obtained in Example 172 (250 mg) and N-methylaniline (81 mg) using the procedure for Example 173. Xi NMR (300 MHz, CDC13, d): 1.50-1.91 (m, 8H), 2.55 (s, 3H), 3.31-3.40 (m, 1H), 3.54 (s, 3H), 3.95-4.09 (m, 1H), 4.96 (s, 1H), 6.81 (d, J = 8.4 Hz , 1H), 7.21-7.27 (m, 2H), 7.40-7.58 (m, 4H), 8.43 (d, J = 8.4 Hz, 1H); ESI MS m / z 470 [M (free) ++ l, 100%]. Example 175 Hydrochloride N- [cis-4- (. {6- [benzyl (methyl) amino] -2-methylpyrimidin-4-yl] amino) cyclohexyl] -3,4,5-trifluorobenzamide The title compound (121 mg) was prepared from N-. { cis-4- [(6-chloro-2-methylpyrimidin-4-yl) amino] cyclohexyl} 3, 4, 5-trifluorobenzamide obtained in Example 172 (250 mg) and N-methylbenzylamine (91 mg) using the procedure for Example 173.? NMR (300 MHz, CDC13, d): 1.57-2.07 (m, 8H), 2.51 (s, 3H), 2.98 (s, 3H), 3.28-3.45 (m, 1H), 3.68-3.81 (, 1H), 3.98-4.20 (m, 1H), 4.94-5.23 (m, 2H), 6.93-7.04 (m, 1H), 7.12-7.24 (m, 2H), 7.30-7.42 (m, 3H), 7.48-7.61 (m , 2H), 8.54-8.67 (m, 1H), 13.78-13.89 (m, 1H); ESI MS m / z 484 [M (free) ++ l, 100%]. EXAMPLE 176 Hydrochloride N- [cis-4- (. {6- [Ethyl (methyl) amino] -2-methylpyrimidin-4-yl] amino) cydohexyl] -3,4,5-trifluorobenzamide The title compound (71 mg) was prepared from N-. { cis-4- [(6-chloro-2-methylpyrimidin-4-yl) amino] cyclohexyl} 3, 4, 5-trifluorobenzamide obtained in Example 172 (250 mg) and N-ethylmethylamine (44 mg) using the procedure for example 173.? E NMR (300 MHz, CDC13, d): 1.06-1.35 (m , 3H), 1.62-2.11 (m, 8H), 2.48 (s, 3H), 2.96-3.49 (m, 4H), 3.67-3.85 (m, 2H), 4.01-4.20 (m, 1H), 5.04-5.20 (m, 1H), 6.98 (d, J = 8.5 Hz, 1H), 7.47-7.63 (m, 2H), 8.36-8.55 (, 1H), 13.57-13.77 (m, 1H); ESI MS m / z 422 [M (free) ++ l, 100%]. Example 177 N- (cis-4. {[[6- (dimethylamino) -2-ethylpyrimidin-4-yl] amino} cydohexyl) -3,4,5-trifluorobenzamide hydrochloride The title compound (126 mg) was prepared from N-. { cis-4- [(6-chloro-2-methylpyrimidin-4-yl) amino] cyclohexyl} 3, 4, 5-trifluorobenzamide obtained in step A of example 168 (403 mg) and (6-chloro-2-ethyl-pyrimidin-4-yl) -dimethyl-amine in Step B of example 32 (250 mg ) using the procedure for step C of example 168. XE NMR (300 MHz, CDC13, d): 1.36 (t, J = 7.5 Hz, 3H), 1.65-2.02 (, 8H), 2.75 (q, J = 7.5 Hz, 2H), 2.97-3.41 (m, 6H), 3.68-3.77 (m, 1H), 4.02-4.17 (m, 1H), 5.15 (s, 1H), 6.89 (d, J = 8.7 Hz, 1H) , 7.48-7.60 (m, 2H), 8.58 (d, J = 8.5 Hz, 1H), 13.48-13.72 (m, 1H); ESI MS m / z 422 [M (free) ++ l, 100%]. Example 178 3-Chloro-N- (cis-4. {[[6- (dimethylamino) -2-phenylpyrimidin-4-yl] amino} cydohexyl) -4-fluorobenzamide hydrochloride Step A: Synthesis of 6-chloro -N, N-dimethyl-2-phenylpyrimidin-4-amine. To a solution of 4,6-dichloro-2-phenylpyrimidine (2.00 g) in THF (10 mL) was added 50% aqueous Me2NH (2.30 mL) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with CHC13 and added to saturated aqueous NaHCO3. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and dried under reduced pressure to give the title compound (2.05 g). aH NMR (300 MHz, CDC13, d): 3.19 (brs, 6H), 6.34 (s, 1H), 7. 39-7.49 (m, 3H), 8.35-8.45 (m, 2H); ESI MS m / z 234 (M ++ l, 100%). Step B: Synthesis of 3-chloro-N- (cis-4 { [6- (dimethylamino) -2-phenylpyrimidin-4-yl] amino} cydohexyl) -4-fluorobenzamide hydrochloride. The title compound (85 mg) was prepared from 6-chloro-N,? / - dimethyl-2-phenylpyrimidin-4-amine (250 mg) and N- (cis-4-amino-cyclohexyl) -3- chloro-4-fluoro-benzamide obtained in step A of example 31 (319 mg) using the procedure for step C of example 168. H NMR (300 MHz, CDC13, d): 1.69-2.13 (m, 8H), 3.05-3.53 (m, 6H), 3.75-3.84 (m, 1H), 4.07-4.23 (m, 1H), 5.26 (s, 1H), 6. 56-6.67 (m, 1H), 7.18 (t, J = 8.6 Hz, 1H), 7.51-7.75 (, 4H), 7.95 (d, J = 8.5 Hz, 1H), 8.48 (d, J = 6.5 Hz, 2H), 9. 25-9.37 (m, 1H), 13.71-13.88 (m, 1H); ESI MS m / z 468 [M (free) ++ l, 100%]. EXAMPLE 179 Hydrochloride N- (cis-4 { [2-benzyl-6- (dimethylamino) pyrimidin-4-yl] amino.}. Cyclohexyl) -3-chloro-4-fluorobenzamide Step A: Synthesis of 2- benzyl-6-chloro-N, N-dimethylpyrimidin-4-amine. The title compound (2.02 g) was prepared from 2-benzyl-4,6-dichloropyrimidine (2.00 g) and 50% aqueous Me2NH (2.20 mL) using the procedure for step A of example 178. XH NMR (300 MHz, CDC13, d): 3.06 (s, 6H), 4.02 (s, 2H), 6.23 (s, 1H), 7.16-7.43 (m, 5H); ESI MS m / z 248 (M ++ 1, 100%). Step B: Synthesis of hydrochloride N- (cis-4 { [2-benzyl-6- (dimethylamino) pyrimidin-4-yl] amino} ciciohexyl) -3-chloro-4-fluorobenzamide. The title compound (132 mg) was prepared from 2-benzyl-6-chloro-, N-dimethylpyrimidin-4-amine (250 mg) and N- (cis-4-amino-cyclohexyl) -3-chloro- 4-fluoro-benzamide obtained in step A of example 31 (301 mg) using the procedure for step C of example 168. Xi NMR (300 MHz, CDC13, d): 1.65-2.04 (m, 8H), 2.94- 3.38 (m, 6H), 3.63-3.75 (m, 1H), 3.98 (s, 2H), 4.02-4.21 (m, 1H), 5.11 (s, 1H), 6.63 (d, J = 8.1 Hz, lH) , 7.14-7.38 (m, 4H), 7.46-7.54 (m, 2H), 7.67-7.75 (m, 1H), 7.91-7.97 (m, 1H), 8.57 (d, J = 7.9 Hz, 1H); ESI MS m / z 482 [M (free) ++ l, 100%]. EXAMPLE 180 3-Chloro-N- (cis-4. {[[6- (dimethylamino) -2,5-dimethylpyrimidin-4-yl] amino} cydohexyl) -4-fluorobenzamide hydrochloride Step A: Synthesis of 2 , 5-dimethylpyrimidine-4,6-diol. To a solution of Na (1.39 g) in EtOH (42 mL) was added diethyl methylmalonate (5.00 g) and acetamidine hydrochloride (2.71 g). The mixture was stirred at reflux for 2.5 hours and cooled to room temperature. The precipitate was collected by filtration, washed with EtOH, and dried at 80 ° C under reduced pressure to give a white solid. To a solution of the above solid in H20 (30 mL) was added concentrated HCl (2.5 mL) and the mixture was stirred at 4 ° C for 1 hour. The precipitate was collected by filtration, washed with H20 (twice), EtOH (twice), and Et20 (twice), and dried at 80 ° C under reduced pressure to give the title compound (3.02 g). X H NMR (300 MHz, DMSO-d 6, d): 1.69 (s, 3 H), 2.19 (s, 3 H), 11.42-11.66 (m, 2 H); ESI MS m / z 139 (M ~ -l, 100%). Step B: Synthesis of 4,6-dichloro-2,5-dimethylpyrimidine. A mixture of 2,5-dimethylpyrimidine-4,6-diol (3.02 g), POC13 (4.2 mL), and N, N-dimethylaniline (3.0 mL) was stirred at reflux for 1.5 hours and cooled to room temperature. The mixture was poured into ice water (20 mL) and stirred for 2 hours. The precipitate was collected by filtration, washed with H20 and hexane, and dried at 60 ° C to give the title compound (1.66 g). 1 H NMR (300 MHz, CDC13, d): 2.45 (s, 3 H), 2.66 (s, 3 H); Cl MS m / z 177 (MX 100%). Step C: Synthesis of 6-chloro-N, N, 2,5-tetramethylpyrimidin-4-amine. The title compound (1.65 g) was prepared from 4,6-dichloro-2,5-dimethylpyrimidine (1.66 g) and 50% aqueous Me 2 NH (2.40 mL) using the procedure for step A of example 178. xti NMR (300 MHz, CDC13, d): 2.25 (s, 3H), 2.48 (s, 3H), 3.02 (s, 6H); ESI MS m / z 186 (M ++ 1, 100%). Stage D: Synthesis of 3-chloro-N- (cis-4- { [6- (dimethylamino) -2 hydrochloride, 5-dimethylpyrimidin-4-yl] amino} cyclohexyl) -4-fluorobenzamide. The title compound (231 mg) was prepared from 6-chloro-N, N, 2,5-tetramethylpyrimidin-4-amine (300 mg) and N- (cis-4-amino-cyclohexyl) -3-chloro ~ 4-fluoro-benzamide obtained in step A of example 31 (481 mg) using the procedure for step C of example 168. ^ • H NMR (300 MHz, CDC13, d): 1.63-2.19 (m, 11H) , 2.56 (brs, 3H), 3.18 (s, 6H), 3.92-4.27 (m, 2H), 6.82-6.94 (, 1H), 7.10-7.25 (m, 2H), 7.80-7.88 (m, 1H), 8.03 (d, J = 6.2 Hz, 1H); ESI MS m / z 420 [M (free) ++ l, 100%]. Example 181 Hydrochloride 3-chloro-N- (cis-4 { [6- (dimethylamino) -5-fluoro-2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -4-fluorobenzamide Step A: Synthesis of 5-fluoro-2-methylpyrimidine-4,6-diol. The title compound (3.21 g) was prepared from diethyl fluoromalonate (5.27 g) and acetamidine hydrochloride (2.80 g) using the procedure for step A of example 180.? NMR (300 MHz, DMSO-d6, d): 2.22 (d, J = 0.9 Hz, 3H); ESI MS m / z 143 (M "-l, 100%) Step B: Synthesis of 4,6-dichloro-5-fluoro-2-methylpyrimidine.

The title compound (3.13 g) was prepared from 5-fluoro-2-methylpyrimidine-4,6-diol (3.20 g) using the procedure for step B of example 180. lE NMR (200 MHz, CDC13, d ): 2.69 (d, J = 1.3 Hz, 3H); Cl MS m / z 181 (M ++ 1, 100%). Step C: Synthesis of 6-chloro-5-fluoro-N, N, 2-trimethylpyrimidin-4-amin. The title compound (2.02 g) was prepared from 4,6-dichloro-5-fluoro-2-methylpyrimidine (3.10 g) using the procedure for step C of example 180. 1 H NMR (300 MHz, CDC13, d ): 2.44 (d, J = 0.9 Hz, 3H), 3.22 (d, J = 2.5 Hz, 6H); ESI MS m / z 190 (M ++ l, 100%). Step D: Synthesis of 3-chloro-N- (cis-4. {[[6- (dimethylamino) -5-fluoro-2-methylpyrimidin-4-yl] amino} cydohexyl) -4-fluorobenzamide hydrochloride. The title compound (135 mg) was prepared from 6-chloro-5-fluoro-ij, N, 2-trimethylpyrimidin-4-amine (300 mg) and N- (cis-4-amino-cyclohexyl) 3-chloro-4-fluoro-benzamide obtained in step A of example 31 (471 mg) using the procedure for step C of example 168. 1 H NMR (300 MHz, CDC13, d): 1.70-2.13 (m, 8H), 2.48 (s, 3H), 3.29 (d, J = 3.1 Hz, 6H), 4.06-4.21 (m, 2H), 6.52-6.70 (, 1H), 7.12-7.25 (m, 1H), 7.66- 8.02 (m, 3H); ESI MS m / z 424 [M (free) ++ l, 100%]. EXAMPLE 182 Hydrochloride 3-chloro-N- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -4-fluorobenzenesulfonamide The title compound (271 mg) was prepared from N- (cis-4-amino-cyclohexyl) -2, N ', N'-trimethyl-pyrimidine-4,6-diamine obtained in step C of example 6 (250 mg) and 3-chloro-4-fluorobenzenesulfonyl chloride (275 mg) using the procedure for example 7. 1 H NMR (300 MHz, CDC13, d): 1.57-1.96 (m, 8H), 2.47 (s, 3H ), 2.94-3.39 (m, 7H), 3.50-3.61 (m, 1H), 5.08 (s, 1H), 5.83 (d, J = 6.7 Hz, 1H), 7.21-7.31 (m, 1H), 7.85- 7.93 (m, 1H), 8.00-8.06 (m, 1H), 8.38 (d, J = 8.2 Hz, 1 H); ESI MS m / z 442 [M (free) ++ l, 100%]. EXAMPLE 183 Hydrochloride N- (3-chloro-4-fluorophenyl) -N1 - (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Ciciohexyl) thiourea To a solution of N- (cis-4-amino-cyclohexyl) -2, N ', A7'-trimethyl-pyrimidine-4,6-diamine obtained in the step C of Example 6 (250 mg) in DMSO (2 mL) was added 3-chloro-4-fluorophenyl isothiocyanate (206 mg) in DMSO (1 mL). The mixture was stirred at room temperature for 14 hours and was poured into water. The precipitate was collected by filtration, washed with water, and purified by medium pressure liquid chromatography (NH-silica gel, 20% to 50% EtOAc in hexane). To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et? 0 (10 L) was stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with Et20, and dried at 80 ° C under reduced pressure to give the title compound (186 mg). 1 H NMR (300 MHz, CDC13, d): 1.70-2.12 (m, 8H), 2.40 (s, 3H), 2.95-3.40 (m, 6H), 3.46-3.61 (m, 1H), 4.38-4.54 (m , 1H), 5.09 (brs, 1H), 6.99-7.13 (m, 1H), 7.37-7.57 (m, 2H), 7.65-7.77 (m, 1H), 7.88-8.01 (m, 1H), 9.16-9.29 (m, 1H), 13.26-13.42 (, 1H); ESI MS m / z 437 [M (free) ++ l, 100%]. EXAMPLE 184 4-Bromophenyl (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) carbamate To a solution of N- (cis-4-amino-cyclohexyl) -2, N ', i \ 7'-trimethyl-pyrimidine-4,6-diamine obtained in step C of example 6 (250 mg) in CHC13 (3 mL) was added Et3N (0.21 mL) and 4-bromophenyl chloroformate (283 mg). The mixture was stirred at room temperature for 14 hours. The reaction was quenched with saturated aqueous NaHC03 and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (silica gel, 2% to 9% MeOH in CHC13) to give the title compound (100 mg ). XH NMR (300 MHz, CDC13, d): 1.54-1.95 (m, 8H), 2.36 (s, 3H), 3. 06 (s, 6H), 3.58-3.81 (, 2H), 4.66-4.77 (m, 1H), 4.96-5.04 (m, 1H), 5.15 (s, 1H), 7.03 (d, J = 9.0 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H); ESI MS m / z 448 (M ++ 1, 100%). Example 185 Hydrochloride 3-chloro-N-. { cis-4- [(2,6-dimethoxypyrimidin-4-yl) amino] cyclohexyl} -4-fluorobenzamide The title compound (16 mg) was prepared from 6-chloro-2,4-dimethoxypyrimidine (250 mg) and N- (cis-4-amino-cyclohexyl) -3-chloro-4- fluoro-benzamide obtained in the stage A of Example 31 (426 mg) using the procedure for step C of example 168. 1 H NMR (300 MHz, CDC13, d): 1.66-2.04 (m, 8H), 3.64-3.78 (m, 1H), 4.03 ( s, 3H), 4.06-4.22 (m, 4H), 5.52 (s, 1H), 6.71-6.86 (m, 1H), 7.12-7.24 (m, 1H), 7.68-7.79 (m, 1H), 7.95 (d, J = 8. 2 Hz, 1H), 9.14-9.28 (m, 1H); ESI MS m / z 409 [M (free) ++ l, 40%], 423 [M (free) ++ 15, 100%]. Example 186 Hydrochloride 3-chloro-4-fluoro-N- [cys-4- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) cyclohexyl] benzamide The title compound (113 mg) was prepared from of 4-chloro-7H-? irrolo [2, 3-d] pyrimidine (300 mg) and N- (cis-4-amino-cyclohexyl) -3-chloro-4-fluoro-benzamide obtained in step A of the example 31 (582 mg) using the procedure for step C of example 168. XH NMR (300 MHz, DMSO-d6, d): 1.61-2.09 (m, 8H), 3.91-4.17 (m, 2H), 7.01-7.12 (m, 1H), 7.35-7.47 (m, 1H), 7.49-7.59 (m, 1H), 7.88-7.98 (m, 1H), 8.11-8.18 (m, 1H), 8.25-8.41 (m, 2H) , 9.10-9.33 (m, 1H), 12.58-12.78 (m, 1H); ESI MS m / z 388 [M (free) ++ l, 100%]. Example 187 Hydrochloride 3-chloro-4-fluoro-N-. { cis-4- [(7-methyl-7'i-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclohexyl} -benzamide Step A: Synthesis of 4-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine. To a solution of 4-chloro-7-pyrrolo [2,3-d] pyrimidine (1.00 g) in DMF (10 mL) under N2 was added 60% NaH in oil (287 mg) and the mixture was stirred at room temperature for 10 min. Yodomethane (0.45 mL) was added to the mixture and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous NH 4 Cl and the aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (silica gel, 50% EtOAc in hexane) to give the title compound (999 mg). XH NMR (300 MHz, CDC13, d): 3.90 (s, 3H), 6.61 (d, J = 3.6 Hz, 1H), 7.22 (d, J = 3.6 Hz, 1H), 8.65 (s, 1 H); ESI MS m / z 168 [M (free) ++ l, 100%].

Stage B: Synthesis of 3-chloro-4-fluoro-W- hydrochloride. { cis-4- [(7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclohexyl} benzamide. The title compound (765 mg) was prepared from 4-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine (400 mg) and N- (cis-4-amino-cyclohexyl) -3 -chloro-4-fluoro-benzamide obtained in step A of example 31 (711 mg) using the procedure for step C of example 168. Xi NMR (300 MHz, DMSO-d5, d): 1.64-2.11 (m, 8H), 3.81 (s, 3H), 3.91-4.23 (, 2H), 7.00-7.17 (m, 1H), 7.40-7.59 (m, 2H), 7.87-7.98 (, 1H), 8.14 (dd, J = 7.1, 2.2 Hz, 1H), 8.29-8.41 (m, 2H), 9.17-9.37 (m, 1H); ESI MS m / z 402 [M (free) ++ 1, 100%]. Example 188 3,4,5-trifluoro-N- hydrochloride. { cis-4- [(7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclohexyl} benzamide The title compound (168 mg) was prepared from N- (cis-4-aminocyclohexyl) -3,4,5-trifluorobenzamide obtained in step A of example 168 (487 mg) and 4-chloro-7- methyl-7H-pyrrolo [2,3-d] pyrimidine (250 mg) using the procedure for step C of example 168. XH NMR (300 MHz, DMSO-d6, d): 1.60-2.15 (m, 8H), 3.81 (s, 3H), 3.90-4.26 (m, 2H), 6.94-7.17 (m, 1H), 7.35-7.53 (, 1H), 7.73-7.98 (m, 2H), 8.22-8.47 (m, 2H) , 9.14-9.42 (m, 1H); ESI MS m / z 404 [M (free) ++ l, 100%].

Example 189 Hydrochloride 3-chloro-N-. { cis-4- [(7-ethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] ciciohexyl} -4-fluorobenzamide Step A: Synthesis of 4-chloro-7-ethyl-7H-pyrrolo [2,3-d] pyrimidine. The title compound (577 mg) was prepared from 4-chloro-7i? -pyrrolo [2,3-d] pyrimidine (500 mg) and iodoethane (0.31 mL) using the procedure for step A of example 187. xti NMR (300 MHz, CDC13, d): 1.50 (t, J = 7.3 Hz, 3H), 4.34 (q, J = 7.3 Hz, 2H), 6.61 (d, J = 3.6 Hz, 1H), 7.27 (d , J = 3.6 Hz, 1H), 8.64 (s, 1H); ESI MS m / z 182 (M ++ l, 100%). Stage B: Synthesis of 3-chloro-N- hydrochloride. { cís-4- [(7-ethyl-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino] ciciohexyl} -4-fluorobenzamide. The title compound (299 mg) was prepared from 4-chloro-7-ethyl-7H-pyrrolo [2,3-d] -pyrimidine (250 mg) and N- (cis-4-amino-cyclohexyl) - 3-chloro-4-fluoro-benzamide obtained in step A of example 31 (410 mg) using the procedure for step C of example 168. 1 H NMR (300 MHz, DMSO-d 6, d): 1.37 (t, J = 7.2 Hz, 3H), 1.63-2.08 (m, 8H), 3.92-4.20 (m, 2H), 4.26 (q, J = 7.3 Hz, 2H), 7.03-7.13 (m, 1H), 7.47-7.59 ( m, 2H), 7.88-7.97 (m, 1H), 8.14 (dd, J = 7.2, 2.1 Hz, 1H), 8.27-8.39 (m, 2H), 9.18-9.35 (m, 1H); ESI MS m / z 416 [M (free) ++ l, 100%].

Example 190 Hydrochloride 3-chloro-4-fluoro-N-. { cis-4- [(9-methyl-9H-purin-6-yl) amino] ciciohexyl} benzamide Stage A: Synthesis of 6-chloro-9-methyl-9H-purine. The title compound (1.08 g) was prepared from 6-chloro-9J? -purine (2.00 g) and iodomethane (0.96 mL) using the procedure for step A of example 187. xti NMR (300 MHz, CDC13, d): 3.95 (s, 3H), 8.12 (s, 1H), 8.78 (s, 1H); ESI MS m / z 182 (M ++ l, 100%). Stage B: Synthesis of hydrochloride 3-chloro-4-f luoro-N-. { cis-4- [(9-methyl-9H-purin-6-yl) amino] -cydohexyl} benzamide. The title compound (170 mg) was prepared from 6-chloro-9-methyl-9J? -purine (250 mg) and N- (cis-4-amino-cyclohexyl) -3-chloro-4-fluoro- benzamide obtained in step A of example 31 (410 mg) using the procedure for step C of example 168. 1H NMR (300 MHz, DMSO-d6, d): 1.61-2.06 (m, 8H), 3.83 (s, 3H), 3.86-4.31 (m, 2H), 4.72-4.98 (m, 1H), 7.48-7.59 (m, 1H), 7.86-7.95 (m, 1H), 8.11 (dd, J = 7.3, 2.2 Hz, 1H), 8.20-8.61 (m, 3H); ESI MS m / z 403 [M (free) ++ l, 90%], 425 [M (free) ++ 23, 100%]. Example 191 C-N- (3-chloro-4-fluorophenyl) -4- hydrochloride. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} Cyclohexanecarboxamide Stage A: Synthesis of cis-4- acid. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -carboxylic cyclohexane. A cis-4- acid was added to a suspension of (6-chloro-2-methyl-pyrimidin-4-yl) -dimethyl-amine obtained in step B of example 5 (20.0 g) in toluene (300 mL) under N2. amino-cyclohexane carboxylic (16.7 g), biphenyl-2-yl (di-tert-butyl) phosphine (346 mg), palladium (II) acetate (260 mg), and sodium tert -butoxide (21.6 g). The mixture was stirred at reflux for 6 hours and cooled to room temperature. To the mixture was added 1 M aqueous NaOH (300 mL) and the two layers were separated. The aqueous layer was washed with EtOAc. The aqueous layer was cooled in an ice bath and c.HCl (15 mL) was added (pH = 6). The precipitate was collected by filtration, washed with H20 and EtOAc, and dried at 80 ° C under reduced pressure to give the title compound (22.1 g). 1 H NMR (300 MHz, CDC13, d): 1.64-2.16 (m, 8H), 2.35-2.48 (m, 4H), 3.10 (s, 6H), 3.46-3.59 (, 1H), 5.11 (s, 1H) 8.74-8.84 (m, 1H); ESI MS m / z 279 (M ++ 1, 100%). Step B: Synthesis of cis-N- (3-chloro-4-fluorophenyl) -4- hydrochloride. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexanecarboxamide. To a suspension of cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} Cyclohexane-carboxylic acid (180 mg) and 3-chloro-4-fluoroaniline (114 mg) in DMF (2 mL) were added Et3N (0.22 mL), HOBt-H20 (150 mg), and EDC-HCl (150 mg).

The mixture was stirred at room temperature for 14 hours. Water (20 mL) was added to the mixture and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (NH-silica gel, 20% to 50% EtOAc in hexane) to give a colorless oil. To a solution of the above oil in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated. The residue was suspended in Et2? (10 L) and the suspension was stirred at room temperature for 4 hours. The precipitate was collected by filtration, washed with Et20, and dried at 80 ° C under reduced pressure to give the title compound (27 mg). 1H NMR (300 MHz, CDC13, d): 1.53-1.73 (m, 2H), 1.81-2.02 (m, 4H), 2.13-2.34 (m, 2H), 2.37-2.58 (m, 4H), 3.03-3.36 (m, 6H), 3.76-3.89 (m, 1H), 5.17 (s, 1H), 6.96-7.12 (m, 1H), 7.64-7.77 (m, 1H), 8.02-8.22 (m, 1H), 8.80 -8.93 (m, 1H), 9.30-9.46 (m, 1H); ESI MS m / z 406 [M (free) ++ l, 100%]. Example 192 cis-N- (3,4-difluorophenyl) -4- hydrochloride. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexanecarboxamide To a suspension of cis-4- acid. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -carboxylic cyclohexane obtained in step A of example 191 (2.1 g) in CHC13 (21 mL) was added thionyl chloride (1.21 mL) and DMF (6 mg). The mixture was stirred at reflux for 1.5 hours, concentrated under reduced pressure, and the residue dissolved in CHC13. { Four . 9 mL). To a solution of 3,4-difluoroaniline (223 mg) in CHC13 (3 mL) was added Et3N (0.42 mL) and acid chloride in CHC13 (1 mL). The mixture was stirred at room temperature for 14 hours and added to saturated aqueous NaHCOs. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium pressure liquid chromatography.

(NH-silica gel, 11% to 50% EtOAc in hexane) to give a colorless oil. To a solution of the previous oil in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL).

The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. A suspension of the residue in Et20 (10 mL) was stirred at room temperature for 4 hours. The precipitate was collected by filtration, washed with Et20, and dried at 80 ° C under reduced pressure to give the title compound (102 mg). XH NMR (300 MHz, CDC13, d): 1.51-2.37 (m, 8H), 2.40-2.55 (s, 4H), 3.07 (brs, 3H), 3.31 (brs, 3H), 3.77-3.91 (m, 1H ), 5.18 (s, 1H), 6.98-7.12 (m, lH), 7.56-7.66 (m, 1H), 7.96-8.07 (, 1H), 8.82 (d, J = 9.8 Hz, 1H), 9.21-9.28 (m, 1H), 13.10-13.26 (m, 1H); ESI MS m / z 390 [M (free) ++ l, 100%]. Example 193 cis-4- hydrochloride. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -N- (3,4,5-trifluorophenyl) -cyclohexanecarboxamide The title compound (173 mg) was prepared from 3,5-trifluoroaniline (254 mg) using the procedure for example 192. 1 H NMR (300 MHz , CDC13, d): 1.54-1.72 (m, 2H), 1.81-2.01 (m, 4H), 2.15-2.36 (m, 2H), 2.40-2.55 (m, 4H), 3.07 (brs, 3H), 3.31 (brs, 3H), 3.80-3.90 (m, 1H), 5.18 (s, 1H), 7.69-7.81 (m, 2H), 8.79 (d, J = 9.6 Hz, 1H), 9.37 (brs, 1H), 13.05 (brs, 1H); ESI MS m / z 408 [M (free) ++ l, 100%]. Example 194 3-Chloro-4-fluorophenyl cis-4-hydrochloride. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -cyclohexanecarboxylate The title compound (4 mg) was prepared from 3-chloro-4-fluorophenol (254 mg) using the procedure for example 192. Xi NMR (300 MHz, CDC13, d): 1.61-2.33 (m , 8H), 2.38-2.56 (m, 3H), 2.60-2.77 (m, 1H), 2.91-3.44 (m, 6H), 3.48-3.71 (m, 1H), 5.10 (s, 1H), 6.91-7.34 (m, 3H), 8.38-8.55 (m, 1H); ESI MS m / z 407 [M (free) ++ l, 100%]. Example 195 cis-N- (3,5-dichlorophenyl) -4- hydrochloride. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} Cyclohexanecarboxamide The title compound (35 mg) was prepared from 3,5-dichlorophenol (282 mg) using the procedure for example 192. XH NMR (300 MHz, CDC13, d): 1.72-2.31 (m, 8H ), 2.49 (s, 3H), 2.60-2.73 (m, 1H), 2.97-3.41 (m, 6H), 3.52-3.68 (m, 1H), 5.11 (s, 1H), 7.08 (d, J = 1.9) Hz, 2H), 7.21-7.24 (m, 1H), 8.49 (d, J = 7.1 Hz, 1H); ESI MS m / z 423 [M (free) ++ l, 100%]. Example 196 Hydrochloride 3, 4-difluorophenyl cis-4. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -cyclohexanecarboxylate The title compound (3 mg) was prepared from 3,4-difluorophenol (225 mg) using the procedure for example 192. E NMR (300 MHz, CDC13, d): 1.69-2.32 (m, 8H ), 2.49 (s, 3H), 2.58-2.77 (, 1H), 2.93-3.41 (m, 6H), 3.51-3.67 (m, 1H), 5.11 (s, 1H), 6.82-7.24 (m, 3H) , 8.32-8.58 (m, 1H); ESI MS m / z 391 [M (free) ++ l, 100%]. Example 197-274 To a suspension of poly (4-vinylpyridine) (150 μL) in CHC13 (200 μL) was added N- (cis-4-amino-cyclohexyl) -2, N ', 6-diamine obtained in the step C of example 6 (60 μmol) in CHC13 (200 μL) and acid chloride (120 μmol) in CHC13 (200 μL) at room temperature.

After stirring at the same temperature for 14 hours, the mixture was filtered and concentrated under reduced pressure. To the residue was added CHC13 (685 μL) and PSA (300 μL). After stirring at room temperature for 14 hours, the mixture was purified by silica gel chromatography (NH-silica gel, 50% to 100% EtOAc in hexane and silica gel, 6% CHC13 2M NH3 / MeOH in CHC13) to give the desired product. The product was determined by ESI-MS or APCI-MS. Example 275-352 To a suspension of l-cyclohexyl-3-ethyl-polystyrene-carbodiimide (150 μL) in CHC13 (400 μL) was added N- (cis-4-amino-cyclohexyl) -2, N ', N' -trimethyl -pyrimidine-4,6-diamine obtained in step C of example 6 (30 μmol) in CHC13 (200 μL) and carboxylic acid (60 μmol) in CHC13 (200 μL) at room temperature. After stirring at the same temperature for 13 hours, the mixture was filtered through NH-silica gel. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (silica gel, 6% CHC13 2M NH3 / MeOH in CHC13) to give the desired product. The product was determined by ESI-MS or APCI-MS. Example 353-410 To a solution of half the weight of the amide product obtained in Example 197-274 in THF (200 μl) was added 1 M borane-THF complex in THF (300 μl). The mixture was stirred at 80 ° C for 1 hour, and concentrated under reduced pressure. To the residue was added 1 M aqueous HCl (300 μl) and THF (200 μl). The mixture was stirred at 80 ° C for 1 hour and concentrated under reduced pressure. The residue was divided between CHC13 and 2M aqueous sodium hydroxide. The aqueous layer was extracted with CHC13 (300 μL, twice) and EtOAc (300 μL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography (silica gel, 33% EtOAc in 6% hexane 2 M NH3 / MeOH in CHC13) to give the desired product . The product was determined by ESI-MS or APCI-MS. Example 411-451 To a solution of N- (cis-4-amino-cyclohexyl) -2, N ', W-trimethyl-pyrimidine-4,6-diamine obtained in step C of example 6 (30 μmol) in DMSO (300 μL) isocyanate or isothiocyanate (60 μmol) in DMSO (200 μL) was added at room temperature. The mixture was stirred at the same temperature for 12 hours and filtered through an SCX. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (silica gel, 50% EtOAc in 6% hexane 2 M NH3 / MeOH in CHC13) to give the desired product. The product was determined by ESI-MS or APCI-MS. Example 452-522 To a suspension of poly (4-vinylpyridine) (75 μL) in CHC13 (200 μL) N- was added. { cis-4-amino-cyclohexyl) -2, N ', W-trimethyl-pyrimidine-4,6-diamine obtained in step C of example 6 (30 μmol) in CHC1 (200 μL) and chloroformate or sulfonylchloride (60 μmol) ) in CHC13 (200 μL) at room temperature. After stirring at the same temperature for 14 hours, the mixture was filtered and concentrated under reduced pressure. To the residue was added CHCl3 (685 μL) and PSA (300 μL). After stirring at room temperature for 14 hours, the mixture was purified by silica gel chromatography (NH-silica gel, 50% to 100% EtOAc in hexane and silica gel, 33% EtOAc in 6% hexane). M NH3 / MeOH in CHC13) to give the desired product. The product was determined by ESI-MS or APCI-MS.

N- (cis-4- { [6- (dimethylan? Mo) -2-methylpyrimidin-4,42-yl] aniino.}. Cyclohexyl) -N '- (3, 4,5-tri-ethoxy ?? il) thiourea 475 (M + H) N- (5-CloiO-2,4-dimethoxyphenyl) -N '- (cis -4- { [6- (dimethylamino) -2- 443 methylpyrimidin-4-yl] an? I? O.}. -cyclohexyl) thiourea ¿jgg ^ + j¡- \ N- [2,4-bis (methyloxy) phenyl] -N '- (cis -4- { [6- (dimethylamino) -2,44-methylpyrimidin-4-yl] an? I? O.}. cyclohexyl) thiourea 445 (M + H) N- [3,4-bis (n-ethyloxy) phenyl] -N '- (cis-4- { [6- (din? Ethylamino) -2- 445 methylpyrin? Idin-4-yl] an? Ino .}. cyclol? exil) thiourea 445 (M + H) N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4,496-yl] amino.}. Cyclol? Exyl) -N '- [2- (ethyloxy) phenyl] thiourea 429 (M + H) N- (cis-4- { [6- (din? Ethylamino) -2-methylpyrimidin-4,467 l] amino.}. Cyclohexyl) -N '- (2,4,6-tribromophenyl) thio? Rea 621 (M + H) N- (2,4-dibromo-6-fluorophenyl) -N '- (cis -4- { [6- (dimethylamino) -2- 448 methylpyrimidin-4-yl] amino.} Cyclohexyl) thiourea 559 ( M + H) N- (cis-4- { [6- (dimethylan-ino) -2-methylpyrimidin-4,49-yl] amino.}. Cyclohexyl) -N '- (4-iodophenyl) thiourea 511 (M + H ) N- (4-cyanophenyl) -N '- (cis-4 { [6- (dimethylamino) -2- 450 methylpyrimidin-4-yl] amino.} Cyclohexyl) thiourea 410 (M + H) methyl 3 - ( { [(cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl-yl] amino]. cyclohexyl) amino] carbonothioyl.} amino) -4- 463 (M + H) methylthiophene-2-carboxilate 2,2-dimethylpropyl (cis-4 { [6- (dimethylammo) -2-methylpyrimidin-452 4-yl] amino.}. Cyclohexyl) carbamate 364 (M + H) [4,5-bis (methyloxy) -2-nitiOphenyl] methyl (cis-4 { [6- (dimethylamino) -453 2-methylpyrimidin-4-yl] amino.}. -cyclohexyl) carbamate 489 (M + H) 3- (trifluoromethyl) phenyl (cis-4- { [6- (dimethylamino) -2- 454 methylpyrimidin-4-yl] amino.} Cyclohexyl) carbamate 438 (M + H) 4-Bromophenyl (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4,45-yl] amino.}. Cyclohexy] carbamate 448 (M + H) 2- (methyloxy) phenyl (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4,46-ylkylamino} cyclohexyl) carbamate 400 (M + H) 2- (methyloxy) ethyl (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4,47 yl] amino.} Cyclohexyl) carbamate 352 (M + H) octyl (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4,48-ylkylamino} cyclohexyl) carbamate 406 (M + H) Analysis procedures ANALYSIS FOR THE DETERMINATION OF THE ACTIVITY OF NON-ENDOGENOUS GPCRS Example 523 Analysis of intracellular IP3 accumulation On day 1, the cells to be transfected can be plated on 24-well plates, commonly lxlO5 cells / well (Although their shadow can be optimized). On day 2 cells can be transfected first by mixing 0.25μg of DNA (eg, pCMV vector or pCMV vector comprising a receptor encoding polynucleotide) in 50 μl serum free DMEM / well and 2 μl lipofectamine in 50 μl free DMEM of serum / well. The solutions are mixed gently and incubated for 15-30 min at room temperature. The cells are washed with 0.5 mL of PBS and 400 μl of serum free medium is mixed with the transfection medium and added to the cells. The cells are then incubated for 3-4 hours at 37 ° C / 5% C02 and then the transfection medium is removed and replaced with 1 ml / well of normal growth medium. On day 3 the cells are labeled with 3H-myo-inositol. Briefly, the medium is removed and the cells are washed with 0.5 ml of PBS. After 0.5 mL inositol free / serum free medium (GIBCO BRL) is added per well with 0.25 μCi of 3H-myo-inositol / well and the cells are incubated for 16-18 hours or / n at 37 ° C / 5% C02 On day 4 the cells are washed with 0.5 ml of PBS and 0.45 ml of analysis medium containing free medium of inositol / serum free is added lOμM pargyline 10 mM lithium chloride or 0.4 ml of analysis medium and 50 μl of lOx ketanserin (ket) to a final concentration of 10 μM. The cells are then incubated for 30 min at 37 ° C. The cells are then washed with 0.5 ml of PBS and 200 μl of fresh / freeze stop solution (1M KOH, 18 mM Na-borate, 3.8 mM EDTA) is added per well. The solution is kept on ice for 5-10 min or until the cells are lysed and then neutralized by 200 μl fresh / frozen neutralization solution. (7.5% HCL). The lysate is then transferred into 1.5 mL eppendorf tubes and 1 mL of chloroform / methanol (1: 2) is added / per tube. The solution is brought to the vortex for 15 seconds and the upper phase is applied to a Biorad AG1-X8 ™ anion exchange resin (100-200 mesh). First, the resin is washed with water at 1: 1.25 w / v and 0.9 mL of the upper phase is loaded onto the column. The column is washed with 10 ml of 5 mM myo-inositol and 10 ml of 5 mM Na-borate / 60 mM Na-forma. Tris phosphates of inositol are eluted in scintillation vials containing 10 mL of scintillation cocktail with 2 mL of 0.1 M formic acid / 1 M ammonium formate. The columns are regenerated by washing with 10 ml of 0.1 M formic acid / 3M ammonium format and rinsed twice with H2O and stored at 4 ° C in water.

Example 524 Functional high performance display: FLIPR ™ Subsequently, a functional basis analysis was used to confirm the main goals, referred to as FLIPR ™ (the Fluorometric Display Plate Reader) and FDSS6000 ™ (Functional Drug Display System). This analysis used a non-endogenous, constitutively active version of the MCH receptor. The FLIPR and FDSS analyzes are able to detect the concentration of intracellular Ca2 + in the cells, which can be used to establish the activation of the receptor and determine whether a candidate compound is, for example, an antagonist, inverse agonist or agonist for a coupled receptor. Gq The concentration of free Ca2 + in the cytosol of any cell is extremely low, while its concentration in the extracellular fluid and the endoplasmic reticulum (ER) is very high. Therefore, there is a high gradient that tends to lead Ca2 + into the cytosol through the plasma membrane and the ER. The FLIPR ™ and FDSS6000 ™ systems (Molecular Devices Corporation, HAMAMATSÜ Photonics K.K.) are designed to perform cell-based functional analyzes, such as intracellular calcium measurement for high-throughput visualization. Fluorescence measurement is associated with the release of calcium upon activation of Gq-coupled receptors. Receivers coupled to Gi or Go are not monitored as easily through the FLIPR ™ and FDSS6000 ™ systems because these G proteins do not match the calcium signal trajectories. The fluorometric display plate reader system was used to allow rapid kinetic measurements of intracellular fluorescence in 96 well microplates (or 384 well microplates). Simultaneous fluorescence measurements can be made in all wells using FLIPR or FDSS6000 ™ every second with high sensitivity and precision. These systems are ideal for functional analysis of cell-based measurement such as the monitoring of intracellular calcium fluxes that occur within seconds after activation of the Gq coupled receptor. Briefly, cells are cultured in 96 wells at 5.5x144 cells / well with complete culture medium (Dulbecco 's Modified Eagle Medium with 10% fetal bovine serum, 2 mM L-glutamine, 1 mM sodium pyruvate and 0.5 mg / mL G418, pH 7.4) for the next day's analysis. On the day of analysis, the medium is removed and the cells are incubated with 100 μl of loading buffer (4 μM Fluo4-AM in complete culture medium containing 2.5 mM Probenicid, 0.5 mg / ml and 0.2% bovine serum albumin ) in a 5% C02 incubator at 37 ° C for 1 hour. The charge buffer is removed, and the cells are washed with wash buffer (Hank's Balanced Salt Solution containing 2.5 mM Probenicid, 20 mM HEPES, 0.5 mg / mL and 0.2% bovine serum albumin, pH 7.4). One hundred fifty μl of wash buffer containing various concentrations of the test compound are added to the cells, and the cells are incubated in a 5% C02 incubator at 37 ° C for 30 min. Fifty μl of wash buffer containing various concentrations of MCH are added to each well, and transient changes in [Ca2 +] i evoked by MCH are monitored using FLIPR or FDSS in 96-well plates at Ex. 488 nm and Em. 530 nm for 290 seconds. When analyzing the antagonist activity of the compound, 50 nM of MCH are used. The use of FLIPR ™ and FDSS6000 ™ can be completed following the manufacturer's instructions (Molecular Device Corporation and HAMAMATSU Photonics K.K.).

Representative examples are shown below, The results were shown in the tables in the Examples section and in the table on the next page according to the classification as defined below. Class 1: The percentage value of control at 10 ~ 7 M was less than 40% or the IC50 value was less than 50 nM. Class 2: The percentage value of control at 10 ~ 7 M was 40% at 60% or the IC50 value was 50 nM at 200 nM. Class 3: The percentage value of control at 10 ~ 7 M was greater than 60% or the value of IC5o was greater than 200 nM.

Example 525 Receptor linkage analysis In addition to the methods described herein, another means for evaluating a test compound is by determining the binding affinities to the MCH receptor. This type of analysis generally requires a radiolabeled ligand for the MCH receptor. Absent the use of known ligands for the MCH receptor and its radiolabels, the compounds of Formula (I) can be labeled with a radioisotope and used in an assay to evaluate the affinity of a test compound to the MCH receptor. A radiolabeled MCH compound of Formula (I) can be used in a visualization analysis to identify / evaluate the compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce the binding of the "radiolabelled compound of Formula (I)" to the MCH receptor. Accordingly, the ability to compete with the "radiolabelled compound of Formula (I)" or the radiolabelled MCH ligand for the link to the MCH receptor directly correlates with the binding affinity of the test compound to the MCH receptor. ANALYSIS PROTOCOL TO DETERMINE THE RECEIVER LINK FOR MCH: A. PREPARATION OF THE RECEPTOR MCH 293 cells (human kidney, ATCC), transiently transfected with 10 μg of the human MCH receptor and 60 μl of Lípofectamina (per 15-cm dish), are grown on the dish for 24 hours (confluence 75 %) with a change of medium and removed with 10 mL / plate of Hepes-EDTA buffer (20mM Hepes + 10mM EDTA, pH 7.4). The cells are then centrifuged in a Beckman Coulter centrifuge for 20 minutes, 17,000 rpm (rotor JA-25.50). Subsequently, the pill is resuspended in 20 mM Hepes + 1 mM EDTA, pH 7.4 and homogenized with a homogenizer of 50-L Dounce and centrifuged again. After removing the supernatant, the pills can be stored at -80 ° C, until used in the linkage analysis. When used in the analysis, the membranes are frozen on ice for 20 minutes and then 10 mL of incubation buffer (20 mM Hepes, 1 mM MgCl2, 100 mM NaCl, pH 7.4) is added. The membranes are then brought to the vortex to resuspend the crude membrane pill and homogenized with a Brinkmann PT-3100 Polytron homogenizer for 15 seconds at a setting of 6. The concentration of the membrane protein is determined using BRL Bradford analysis. protein B. LINK ANALYSIS For total binding, a total volume of 50ul of appropriately diluted membranes (diluted in a test buffer containing 50mM Tris HCl (pH 7.4), 10mM MgCl2, and 1mM EDTA, 5-50ug protein) is added 96-well polypropylene microtiter plates followed by the addition of 100 μl of test buffer and 50 μl of the radiolabeled MCH ligand. For a non-specific binding, 50 μl of test buffer is added instead of 100 μl and an additional 50 μl of cold MCH lOuM is added before adding 50 μl of radiolabelled MCH Ligand. The plates are then incubated at room temperature for 60-120 minutes. The binding reaction is terminated by filtering the test plates through a Microplate Devices GF / C Unifilter filtration plate with a Brandell 96-well plate harvester followed by washing with 50 M cold Tris HCl, pH 7.4 containing 0.9 % NaCl. After, the bottom of the filtration plate is sealed, 50ul of Optiphase Supermix is added to each well, the upper part of the plates is sealed, and the plates are counted in a Trilux MicroBeta scintillation counter. For competition studies of the compound, instead of adding 100 μl of the test buffer, add 100 μl of the appropriately diluted test compound to appropriate wells followed by the addition of 50 μl of the radiolabelled MCH Ligand. C. CALCULATIONS The test compounds are analyzed initially at 1 and 0.1 μM and then at a range of concentrations selected such that the average dose results in approximately 50% inhibition of the binding of a radiolabelled MCH ligand (ie, IC50). specific in the absence of the test compound (B0) is the difference of the total bond (B) minus the non-specific binding (NSB) and similarly, the specific binding (in the presence of the test compound) (B) is the difference of the displacement link (BD) minus the non-specific link (NSB). The IC5o is determined from an inhibition response curve, logit-log diagram of% B / B0 vs. concentration of the test compound. Ki is calculated by the Cheng and Prustoff transformation: Ki = IC5o / (l + [L] / KD) where [L] is the concentration of a radiolabelled MCH Ligand used in the analysis and KD is the dissociation constant of an MCH Ligand radiolabel determined independently under the same binding conditions. It is intended that each of the patents, applications, printed publications and other published documents mentioned or referred to in this specification be incorporated herein by reference in its entirety. Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the invention and that such changes and modifications may be made without departing from the essence of the invention. Accordingly, it is intended that the appended claims cover all such equivalent variations that fell within the essence and actual scope of the invention.

Claims

CLAIMS 1. A compound of the Formula (I) Q A, / -YA Ri (I) where Q is (Ha) or (Ilb) R 1 is selected from the group consisting of: (i) C 1-16 alkyl, and C 1-6 alkyl substituted by the independently selected substituent (s) from the group consisting of: • halogen, • hydroxy, • oxo, "C5-5alkoxy, C5-5alkoxy substituted by the substituent (s) independently selected from the group consisting of: •• carbocyclic aryl, • • heterocyclyl, and •• heterocyclyl substituted by alkyl C.sub.1 -C.sub.5 -C.sub.4 alkyl, carbocyclyloxy, carbocyclic aryloxy, carbocyclic aryloxy substituted by the independently selected substituent (s) from the group consisting of: • "halogen, • • hydroxy, • • carboxy, •• carbamoyl, • "nitro, •" cyano, • • amino, •• carbocyclic aryl, •• carbocyclic aryl substituted by alkoxy C? S, • • alkoxy C? _5, •• C? -5 alkoxy substituted by halogen, • "alkyl C? _5, and •• C alkyl substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • •" hydroxy, • • • carboxy, • • "oxo, • •" mono-alkylamino C? _s, ••• di- alkylamino C? _5, • • 'mono-alkylamino C? _5 substituted by carbocyclic aryl, ••• di-alkylamino C? _5 substituted by carbocyclic aryl, • • • mono-alkylamino C? _5 substituted by halogenated carbocyclic aryl, •• • di-alkylamino C substituted by halogenated carbocyclic aryl, carbocyclic arylcarbonylamino, and carbocyclic arylcarbonylamino substituted by halogen, heterocyclyloxy, heterocyclyloxy substituted by the independently selected substituent (s) of the group consisting of: • 'halogen, •' hydroxy, • • carboxy, • 'carbamoyl, •' nitro, • 'cyano, • • amino, •• carbocyclic aryl, •• carbocyclic aryl substituted by C1-5 alkoxy, • • C1-5 alkoxy, •• Cx_5 alkoxy substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • •" hydroxy, and • • • carboxy, • 'C1-5 alkyl, and •• alkyl C? _5 substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • • • hydroxy, and • • • carboxy, • substituted heterocyclyl-ethylideneaminooxy, • alkoxycarbonyl C? _5, • C1-5 alkoxycarbonyl substituted by carbocyclic aryl, • mono-alkylaminocarbonyl Ci_5, • di-alkylaminocarbonyl C? _5, • mono-alkylamino C? _5, • mono-alkylamino C? _5 substituted by the substituent (s) ) independently selected from the group consisting of: • -cyano, •• carbocyclic aryl, and •• heterocyclyl, • di-alkylamino C? _5, • di-alkylamino C? _5 substituted by the substituent (s) ) independently selected from the group consisting of: • • cyano, •• a carbocyclic rile, and • • heterocyclyl, • carbocyclic mono-arylamino, • carbocyclic mono-arylamino substituted by the independently selected substituent (s) from the group consisting of: • «halogen, •« hydroxy, • • carboxy, • "carbamoyl, •" nitro, • "cyano, • • amino, •• carbocyclic aryl, •• carbocyclic aryl substituted by alkoxy C? _5, • • alkoxy C? -5, •• C? _5 alkoxy substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • •" hydroxy, and • • • carboxy, • "alkyl C? _5, and •• substituted C? _5 alkyl by the independently selected substituent (s) from the group consisting of: • • "halogen, • •" hydroxy, and • • • carboxy, • carbocyclic di-arylamino, "carbocyclic di-arylamino substituted by the (the) independently selected substituent (s) of the group consisting of: • halogen, • hydroxy, • "carboxy, • carbamoyl, • nitro, • cyano, • amino, •• carbocyclic aryl, • carbocyclic aryl substituted by alkoxy C? _5, • alkoxy C? -5, • alkoxy C? _5 substituted by the substituent (s) independently selected from the group consisting of: • • «halogen, • • • hydroxy, and • • • carboxy, • C alquilo5 alkyl, and • C alquilo5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • • - halogen, • • hydroxy, and • • • carboxy, "mono-heterocyclylamino, • mono-heterocyclylamino substituted by the substituent (s) independently selected from the group consisting of: •" halogen, • "hydroxy , • • carboxy, • • carbamoyl, • 'nitro, •' cyano, • • amino, •• carbocyclic aryl, •• carbocyclic aryl substituted by alkoxy C? _5, • • alkoxy C? _5, •• alkoxy C? _5 substituted by the independently selected substituent (s) from the group consisting of: • • "halogen, • •" hydroxy, and • • • carboxy, • • alkyl C? _5, and • "C1- alkyl" 5 substituted by the independently selected substituent (s) from the group consisting of: • • «halogen, • • "hydroxy, and • •" carboxy, • di-heterocyclylamino, • di-heterocyclylamino substituted by the independently selected substituent (s) from the group consisting of: • 'halogen, • • hydroxy, • • carboxy, • • carbamoyl, • 'nitro, •' cyano, • • amino, •• carbocyclic aryl, • carbocyclic aryl substituted by alkoxy C? _5, • • alkoxy C? _5, '' alkoxy C? -5 substituted by the substituent (s) independently selected from the group consisting of: • • -halogen, • • 'hydroxy, and • • • carboxy, • "C alquilo _5 alkyl, and •• substituted C! _5 alkyl; by the substituent (s) independently selected from the group consisting of: • • 'halogen, • • • hydroxy, and • • • carboxy, • alkylcarbonylamino C? _5, • alkylcarbonylamino C? substituted by the (the) substituent (s) independently selected from the group consisting of: •• alkylcarbonylamines no C? _5, •• carbocyclic arylcarbonylamino, and • * heterocyclyl, • C5-5 alkoxycarbonylamino, • carbocyclic arylcarbonylamino, • carbonylamino heterocyclyl, • carbocyclic arylsulfonylamino, • carbocyclic arylsulfonylamino substituted by the independently selected substituent (s) ) of the group consisting of: • 'nitro, •' alkyl C? _5, • 'mono-alkylamino C? _s, and •• di-alkylamino C? _5,' alkylthio C? _5, • alkylthio C? -5 substituted by the substituent (s) independently selected from the group consisting of: • • carbocyclic mono-arylaminocarbonyl, • «mono-arylaminocarbonyl carbocyclic substituted by halogen, •« carbocyclic di-arylaminocarbonyl, •• di-arylaminocarbonyl carbocyclic substituted by halogen, • "mono-arylamino carbocyclic," "mono-arylamino carbocyclic substituted by halogen, •• di-arylamino carbocyclic, • 'di-arylamino carbocyclic substituted by halogen no, carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: halogen, and C5-alkoxy, carbocyclic arylthio. , • carbocyclic arylthio substituted by the substituent (s) independently selected from the group consisting of: • "halogen, • -alkyl C? _5, and •• C5_5 alkyl substituted by halogen, • carbocyclic arylsulfinyl , • carbocyclic arylsulfinyl substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "C 1 _5 alkyl, and •• C 1-5 alkyl substituted by halogen, • arylsulfonyl carbocyclic, "carbocyclic arylsulfonyl substituted by the substituent (s) independently selected from the group consisting of: •" halogen, "" C1-5 alkyl, and • "C1-5 alkyl substituted by halogen, • heterocyclylthio • Heterocyclized is substituted by the substituent (s) independently selected from the group consisting of: • "nitro, and •" C5_5 alkyl, • C3-6 cycloalkyl, • C3_6 cycloalkyl substituted by C5_5 alkyl, • C3-6 cycloalkyl substituted by carbocyclic aryl, • C3_6 cycloalkenyl, • carbocyclyl, • carbocyclyl substituted by the independently selected substituent (s) from the group consisting of: • 'halogen(C) -5 alkyl, • "C5-5 alkoxy, • C2-5 alkenyl, and C2-alkenyl substituted by the independently selected substituent (s) from the group consisting of : ••• carbocyclic aryl, and ••• carbocyclic aryl substituted by C1-5 alkylsulfinyl, • carbocyclic aryl, • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • « halogen, • "hydroxy, • • carboxy, • • carbamoyl, •" cyano, • "nitro, • • amino, •• alkylcarbonylamino Ci_5, • • cycloalkylcarbonylamino C3_6, •« C5_5 alkyl, •• C5_5 substituted alkyl by the independently selected substituent (s) from the group consisting of: • • 'halogen, •' hydroxy, • • carboxy, • • carbamoyl, •? XO, ••• carbocyclic aryl, • 'heterocyclyl , • • carbocyclic mono-arylamino, •• carbocyclic di-arylamino, • • mon carbocyclic o-arylamino substituted by the independently selected substituent (s) from the group consisting of: • • • "halogen, • • •" nitro, • • • 'alkyl C? _5, •••• C.sub.5 alkoxy, and C.sub.5 -C.sub.5 alkoxy substituted by halogen, carbocyclic di-arylamino substituted by the substituent (s) independently selected from the group consisting of: • 'halogen, • 'nitro, •' alkyl C? _5, • 'alkoxy C? _5, and •• C5-5 alkoxy substituted by halogen, •• C2-alkenyl, • • C5-5 alkoxy, •• C5-5 alkoxy substituted by the independently selected substituent (s) from the group consisting of: • • "halogen, and ••• carbocyclic aryl, •• carbocyclic aryloxy, • • C5-5 alkoxycarbonyl, • * alkylcarbonyloxy C? , •• mono-alkylamino C1-.5, •• di-C1-5 alkylamino, • * mono-arylamino carbocyclic, • «mono-arylamino carbocyclic substituted by halocarboxylamino, carbocyclic di-arylamino, carbocyclic di-arylamino substituted by halogen, carbocyclic mono-arylaminocarbonyl, carbocyclic monoalkylaminocarbonyl substituted by the selected substituent (s) of the group consisting of : • -halogen, • 'nitro, •' C5_5 alkyl, • • C5_5alkoxy, and •• C1-5alkoxy substituted by halogen, •• carbocyclic di-arylaminocarbonyl, •• carbocyclic di-arylaminocarbonyl substituted by (the) substituent (s) selected from the group consisting of: • 'halogen, ••' nitro, •• alkyl C? _5 / • • alkoxy C? _5, and •• alkoxy C? _5 substituted by halogen , • "mercapto, •" alkylthio C? _5, •• C5_5 alkylthio substituted by halogen, •• C5_5 alkylsulfonyl, • C3_6 cycloalkyl, •• carbocyclic aryl, and • 'heterocyclyl, • heterocyclyl, and • heterocyclyl replaced by the independently selected substituent (s) ( s) of the group consisting of: • 'halogen, •' hydroxy, • • carboxy, • • carbamoyl, • * cyano, • 'nitro, • • amino, •' C1-5 alkyl, •• substituted C5_5 alkyl by the independently selected substituent (s) from the group consisting of: • • '' halogen, • • '' hydroxy, • • • carboxy, and • • • carbamoyl, •• C5_5 alkyl substituted by aryl carbocyclic, •• C5-5 alkoxy, • C5-5 alkoxy substituted by halogen, • C5-5 alkoxy substituted by carbocyclic aryl, •• carbocyclic aryl, and • carbocyclic aryl substituted by halogen, (ii) C2- alkenyl 8? and C2-alkenyl substituted by the substituent (s) independently selected from the group consisting of: • halogen, * oxo, • C5-5 alkoxy, • C1-5 alkoxy substituted by carbocyclic aryl, • aryl carbocyclic, carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: halogen, hydroxy, nitro, C, alkyl, C alkyl; _5 substituted by halogen, •• C5-alkoxy, and • C5-5 alkoxy substituted by halogen, • heterocyclyl, and • heterocyclyl substituted by the independently selected substituent (s) from the group consisting of : • 'hydroxy, •' nitro, •• alkyl C? _5, and * • • alkoxy C? _5, (iii) C2_5 alkynyl, and C2-alkynyl substituted by carbocyclic aryl, (iv) C3_2 cycloalkyl, and C3_2 cycloalkyl substituted by the independently selected substituent (s) from the group consisting of: C1-5 alkyl, C1-5 alkyl substituted by (the) substituent (s) independently selected from the group consisting of: • "hydroxy, •? XO, and •• carbocyclic aryl, • mono-alkylamino C? _s, • mono-C1-5 alkylamino substituted by aryl carbocyclic, • di-alkylamino C? _5, • di-C5-alkylamino substituted by carbocyclic aryl, • carbocyclic arylcarbonylamino, • carbocyclic aryl, and • carbocyclic aryl substituted by halogen, (v) C3_6 cycloalkenyl, and C3_6 cycloalkenyl substituted by C-alkyl? _5, (vi) carbocyclyl, and carbocyclyl substituted by substituent (s) independently selected from the group consisting of: • hydroxy, and * nitro, (vii) carbocyclic aryl, and carbocyclic aryl substituted by the substituent (s) s) independently selected from the g A group consisting of: "halogen, • hydroxy, • cyano, • nitro, • Ci -ioalkyl," C 1 -C 0 alkyl substituted by the independently selected substituent (s) from the group consisting of : • "halogen, • • hydroxy, • • carboxy, •• carbamoyl, • * oxo, • • C5-alkoxy, •• carbocyclic aryloxy, • • mono-alkylamino-N-oxy C-5, • * di -alkylamino-N-oxy C? _5, • • mono-alkylamino C? _5, •• di-alkylamino C? _5, • «mono-alkylamino C? substituted by carbocyclic aryl, •• di-alkylamino C -5 substituted carbocyclic aryl, carbocyclic monoalkylamino, carbocyclic, carbocyclic, carbocyclic, carbocyclic, carbocyclic, carbocyclic monoalkylamino, carbocyclic arylamino, carbocyclic monoalkylamino, carbocyclic monoalkylamino, carbocyclic monoalkylamino substituted by alkoxy C? _5, •• carbocyclic di-arylamino substituted by alkoxy C 1-5 r • • carbocyclic mono-arylaminocarbonyl, • • carbocyclic di-arylaminocarbonyl, • • carbocyclic mono-arylaminocarbonyl substituted by carbocyclic C 1 -C 5 alkoxy, •• di-arylaminocarbonyl carbocyclic substituted by C 1 -C 5 alkoxy, carbocyclic aryl, •• carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • • • C5 alkyl, and ••• C5-alkyl substituted by halogen , •• heterocyclyl, and •• heterocyclyl substituted by C? _5 alkyl, • C2-s alkenyl, • C2-s alkenyl substituted by carbocyclic aryl, "C1-9 alkoxy, • C? _9 alkoxy substituted by the (sub) substituent (s) independently selected from the group consisting of: • • hydroxy, • 'halogen, •' carboxy, • • mono-alkylamino C? _5, •• di-alkylamino C? _5, •• carbocyclic aryl, • • halogenated carbocyclic aryl, • «heterocyclyl, •• heterocyclic substituted by the independently selected substituent (s) from the group consisting of: • • 'halogen, ••• heterocyclyl, and ••• heterocyclyl substituted by the independently selected substituent (s) ( s) of the group consisting of: • • • • "halogen, •••• alkyl C? _5, and •••• C_5 alkyl substituted by halogen, • C2_5 alkenyloxy, • C3-6 cycloalkoxy, • alkylcarbonyloxy C? _5, 'carbocyclic aryloxy, • carbocyclic aryloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "hydroxy, • • carboxy, •" carbamoyl, • "cyano, • "nitro, • • amino, •" C alquilo _s alkyl, •• C alquilo _5 alkyl substituted by the independently selected substituent (s) from the group consisting of: ••• halogen, • • « hydroxy, • • • carboxy, and • • • carbamoyl, • «alkoxy C? _5, and •• al C1-5 coxy substituted by halogen, • heterocyclyloxy, • heterocyclyloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "hydroxy, • • carboxy, • • carbamoyl, • • cyano, • "nitro, • • amino, •" C 1 -C 5 alkyl, •• C 1 -C 5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • • « halogen, • • hydroxy, • • • carboxy, and • • • carbamoyl, • • C5-5 alkoxy, and •• C5-alkoxy substituted by halogen, • (carbocyclic aryl) S (O) 20, • carboxy , • carbamoyl, • C 1 -C 5 alkoxycarbonyl, • C 1 -C 5 monoalkylaminocarbonyl, C 1 -C 5 di-alkylaminocarbonyl, • C 1 -C 5 monoalkylaminocarbonyl substituted by carbocyclic aryl, • C 1 -C 5 alkylaminocarbonyl substituted by aryl carbocyclic, • mono-arylaminocarbonyl carbocyclic, • di-arylaminocarbonyl carbocyclic, • mono- carbocyclic arylaminocarbonyl substituted by C? _5 alkyl,? carbocyclic di-arylaminocarbonyl substituted by C? _5 alkyl,? amino,? mono-C1-.5 alkylamino,? di-alkylamino C? _5, • mono-alkylamino C? _5 substituted by cyano, • di-C 1 -C 5 alkylamino substituted by cyano, • carbocyclic mono-arylamino, • carbocyclic di-arylamino, • C 5 alkylcarbonylamino, C 3 cycloalkylcarbonylamino, C 2-5 alkynylocarbonylamino, C 2-5 alkynylocarbonylamino substituted by carbocyclic aryl, alkoxycarbonylamino C? _5, * carbocyclic arylsulfonylamino, • carbocyclic arylsulfonylamino substituted by alkyl • (carbocyclic aryl) HC (O) NH, • (carbocyclic aryl) NHC (0) NH substituted by C5-5alkoxy, • (carbocyclic aryl) HC (0) NH substituted by halogenated C5-5alkoxy, • carbocyclic aryl azo , • carbocyclic aryl azo substituted by mono-alkylamino * carbocyclic aryl azo substituted by di-alkylamino C? _ Alkylthio C5.5, C1-5 alkylthio substituted by halogen, carbocyclic arylthio, carbocyclic arylthio substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "nitro" , • "cyano, and •" alkyl C? ~ 5, • aminosulfonyl, • heterocyclylthio, • alkylsulfonyl C1-5, • mono-alkylaminosulfonyl C? _5, • di-alkylaminosulfonyl C? _5, • heterocyclylsulfonyl, • C3_6 cycloalkyl, • C3-6 cycloalkyl substituted by C5_5alkyl, * carbocyclic aryl, • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: alkyl C? _7, and? C? _7 alkyl substituted by halogen,? heterocyclyl, and? heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: ??? alkyl C? _5, "Carbocyclic aryl, and halogenated carbocyclic aryl," C5-5 alkoxycarbonyl substituted by carbocyclic aryl, and (viii) heterocyclyl, and heterocyclyl substituted by the independently selected substituent (s) from the group consisting of : • halogen, • hydroxy, • carboxy, • carbamoyl, • cyano, • nitro, • amino, -alkyl C? _5, • C? _5 alkyl substituted by the substituent (s) independently selected from the group consisting of: • «hal hydrogen, • • hydroxy, • • carboxy, • • carbamoyl, • * oxo, • "C5-alkylcarbonyloxy, • • carbocyclic arylcarbonylamino, •• carbocyclic arylcarbonylamino substituted by halogen, •• C1-5 alkoxycarbonyl, •• alkylthio C1 .5, •• C5_5 alkylthio substituted by carbocyclic aryl, •• alkylthio C substituted by halogenated carbocyclic aryl, • carbocyclic aryl, • carbocyclic aryl substituted by the independently selected substituent (s) of the group consisting of: • • 'halogen, and • •' nitro, •• heterocyclyl, and •• heterocyclyl substituted by the independently selected substituent (s) from the group consisting of: • • 'halogen , ••• C5 alkyl, and ••• C5-5 alkyl substituted by halogen, "C5-5alkoxy, • C5-5alkoxy substituted by halogen, • C5alkoxy substituted by carbocyclic aryl, • carbocyclic aryloxy, • carbocyclic aryloxy substituted The substituent (s) independently selected from the group consisting of: • "halogen, • * nitro, • * cyano, • 'hydroxy, • • carboxy, • • carbamoyl, • • amino, • • C 1 -5 alkyl, •• C 1-5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • • "halogen, • • 'hydroxy, • • • carboxy, and • • «carbamoyl, •" mono-alkylamino C? _5, •• di-alkylamino C? _5, •• alkylcarbonylamino C? _5, • • cycloalkylcarbonylamino C3"5, •• alkoxy C? _5, •• alkoxy C? _5 replaced by halogen, •• C3_6 cycloalkyl? •• C2-5 alkenyl, •• C2_5 alkynyl, • • carboxy, •• C1-5 alkoxycarbonyl, • • C5-5 mono-alkylaminocarbonyl, •• di-alkylaminocarbonyl C1-.5, • 'mono-cycloalkylaminocarbonyl C3_e, • • C3-6 di-cycloalkylaminocarbonyl, • • mono-alkylaminocarbonylamino C? _5, • "di-alkylaminocarbonylamino C1-5, • • mono-cycloalkylaminocarbonylamino C3_6 / - • • di-cycloalkylaminocarbonylamino C3_6, • • alkylthio C? _5, •• C.sub.5 alkylthio substituted by halogen, C.sub.5 -C.sub.5 alkylsulfinyl, C.sub.1 -C.sub.55 alkylsulfinyl substituted by halogen, C.sub.5 -C.sub.5 alkylsulfonyl, and C.sub.5 -C.sub.5 alkylsulfonyl substituted by halogen, • heterocyclyloxy, • substituted heterocyclyloxy. by the substituent (s) independently selected from the group consisting of: • "halogen, •" nitro, • "hydroxy, • • carboxy, • • carbamoyl, •" cyano, • • amino, • « C1-5 alkyl, •• C5 alkyl substituted by ( the) independently selected substituent (s) from the group consisting of: • halogen, • hydroxy, • carboxy, and • carbamoyl, •• C5-5 alkoxy, and •• C5-5 alkoxy substituted by halogen, • mono -alkylamino C? _5, • di-alkylamino C? _5, • alkylcarbonylamino C? _5, "alkylthio C? _5, • C2-5 alkenylthio, • carbocyclic arylthio, • carbocyclic arylthio substituted by halogen, • carbocyclic arylthio substituted by alkoxycarbonyl C ? 5,? Heterocyclicthio,? Heterocyclicthio substituted by C? 5 alkyl,? C5-5 alkylsulfinyl, C5-5 alkylsulfonyl, carbocyclic arylsulfinyl, carbocyclic substituted arylsulfinyl by halogen, carbocyclic arylsulfonyl, carbocyclic arylsulfonyl substituted by halogen• carbocyclic arylsulfonyl substituted by C alquilo5 alkyl, • C5_5 alkoxycarbonyl, "C5_5alkoxycarbonyl substituted by carbocyclic aryl, • carbocyclic aryl, • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • "halogen, • 'nitro, • -alkyl C? _5, •• alkyl C? -5 substituted by halogen, • * C1-5 alkoxy, and ** C1-5 alkoxy substituted by halogen, • heterocyclyl, and • heterocyclyl substituted by the independently selected substituent (s) from the group consisting of: "halogen, •" C _5 alkyl, C _5 alkyl •• substituted by halogen, • C * _5 alkoxy, alkoxycarbonyl •• C and -5????; R is halogen, C? _5 alkyl, C? _5 alkyl substituted by halogen, C? _5 alkyl substituted by hydroxy, C? _5 alkyl substituted by carbocyclic aryl, C? _5 alkyl substituted by halogenated carbocyclic aryl, C? _5 alkyl substituted by heterocyclyl, C 1 -C 5 alkyl substituted by halogenated heterocyclyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 alkoxy, C 1-5 alkoxy substituted by halogen, C 1 5 alkylthio -N (R 2a) (R 2b); wherein R2a and R2b are each independently hydrogen, C5_5alkyl, or C5_5alkyl substituted by the independently selected substituent (s) from the group consisting of: "halogen, • hydroxy, • carboxy , • carbamoyl, • C5-5 alkoxy, • amino, • C3_6 cycloalkyl, • carbocyclic aryl, • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • -halogen, • "Alkyl C? _s, • • alkoxy C? _5, •• C1-5 alkyl substituted by halogen, •• C5-5 alkoxy substituted by halogen, and •• -S02NH2, • heterocyclyl, and • heterocyclyl substituted by the ) substituent (s) independently selected from the group consisting of: • "halogen," "C alquilo _5 alkyl, •" C1-5 alkoxy, •• C alquilo _5 alkyl substituted by halogen, and •• C alco alkoxy? _5 substituted by halogen, C3_6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by ( The substituent (s) independently selected from the group consisting of: • halogen, • C alquilo _5 alkyl, "C1-5 alkoxy, • C1-5 alkyl substituted by halogen, and • C ?5 alkoxy substituted by halogen , heterocyclyl, or heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • halogen, • C5_5 alkyl, • C5_5 alkoxy, • C5 alkyl substituted by halogen, and • C 1-5 alkoxy substituted by halogen; L is selected from the group consisting of Formulas (III), (IIIa), (IIIb), (IV), (IVa) and (IVb); (ni) (girl) (ipb) (? V) (IVa) IVb) wherein R3 and R4 are each independently hydrogen or C? _5 alkyl; and A and B are each independently a single bond, -CH2-, or - (CH2) 2_Zi, Z2, Z3, and Z4 are each independently hydrogen, halogen, C? _5 alkyl, C? _5 alkyl substituted by halogen C 1 -C 5 alkyl substituted by hydroxy, C 1 -C 5 alkyl substituted by carbocyclic aryl, C 1 -C 5 alkyl substituted by halogenated carbocyclic aryl, C 1 -C 5 alkyl substituted by heterocyclyl, C 1 alkyl substituted by halogenated heterocyclyl, C 2 5 alkenyl, C 2 5 alkynyl , C3_6 cycloalkyl, C5_5alkoxy, C1-5alkoxy substituted by halogen, C1-5alkylaminoalkyl, C5_5alkylamino, C5_5alkylthio, carbocyclic aryl, substituted carbocyclic aryl, heterocyclyl, or substituted heterocyclyl; or 2 and Z2 are bonded together to form a ring and -R2-Z2- is - (CH2) n- or - (CH2) o-CH = CH- (CH2) p-; wherein a -CH2- group can optionally -R2-Z2- replaced by C (O), NR6, O, S, S (O) or S (0) 2; where n is 2, 3, 4, 5, or 6; or and p are each independently 0, 1, 2, 3, or 4 provided that o + p = 0, 1, 2, 3, or 4; and R? is hydrogen, -5-alkyl, or substituted C5-alkyl; and Y represents: (i) -C (0) NR 5, -C (S) NR 5, -C (0) 0-, -S (0) 2-, -C (O) -, -C (S ) -, or - (CH __) m- when L is selected from the group consisting of Formulas (III), (Illa), and (Illb); or (ii) -C (0) NR5-, -C (S) NR5-, -C (0) 0-, or -0C (0) - when L is selected from the group consisting of the Formulas (IV), (IVa), and (IVb); wherein R5 is hydrogen or C1-5 alkyl; and m is 0, 1, 2, 3, 4, or 5; wherein carbocyclic aryl is phenyl, naphthyl, anthranil, phenanthryl, or biphenyl; carbocyclyl is 10, 11-dihydro-5-oxo-dibenzo [a, d] cycloheptyl, 1-oxo-indanyl, 7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptyl, 9H-fluorenyl, 9- oxo-fluorenyl, acenaphthyl, anthraquinonyl, C-fluoren-9-ylidene, indanyl, indenyl, menthyl, 1,2,3,4-tetrahydro-naphthyl, or bicyclo [2.2.1] heptenyl; heterocyclyl is 1, 2, 3, 4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3,4-thiadiazolyl, 1,3-dioxo-isoindolyl, 1,3-dioxolanyl, l-indolyl, l-pyrrolo [2, 3-c] pyridyl, li? -pyrrolyl, l-oxo-3H-isobenzofuranyl, 2, 2 ', 5' , 2 '' -tertiiophenyl, 2, 2 '-bitiofenil, 2,3-dihydro-l-oxo-isoindolyl, 2,3-dihydro-benzo [1,4] dioxinyl, 2,3-dihydro-benzofuryl, 2, 4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, 3,4-dihydro-2i? -benzo [b] [1,4] dioxepinyl, 4-f-benzo [1, 3] dioxinyl, 4J7-benzopyranyl, 4-oxo-l, 5, 6, 7-tetrahydro-indolyl, 4-oxo-3,4- dihydro-phthalazinyl, 4-oxo-benzopyranyl, 9, 10, 10-trioxo-thioxanthenyl, 9-carbazolyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo [1,3] dioxolyl, benzo [2, 1, 3] oxadiazolyl, benzo [1, 2, 5] oxadiazolyl, benzo [b] thienyl, benzofuryl, benzothiazolyl, cinnolyl, furyl, imidazo [2, lb] thiazolyl, imidazolyl, isoxazolyl, mo rfolino, morpholinyl, oxazolyl, oxolanyl, piperazyl, piperidyl, pyridyl, pyrazolo [5,

1-b] thiazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, 2, 3- dihydro-benzofuryl, tetrahydro-thienyl, or benzofuranyl; halogen is fluoro, chloro, bromo, or iodo; or a pharmaceutically acceptable hydrate or solvate salt thereof. 2, The compound, according to claim 1 wherein Q is Formula (lia); Zi is hydrogen, halogen, C ?5 alkyl, C5 alkyl substituted by halogen, C3_6 cycloalkyl, C1-5 alkoxy, C ?5 alkoxy substituted by halogen, or Cilt_5 alkylthio or a pharmaceutically acceptable hydrate or solvate salt thereof. 3. The compound, according to the claim

2 wherein Ri is selected from the group consisting of: (i) C alquilo _? Alquilo alkyl, and C? _ Alquiloalkyl substituted by the independently selected substituent (s) from the group consisting of: "Halogen, • oxo, • C5-5alkoxy, • C5alkoxy substituted by carbocyclic aryl, • C5-5alkyloxycarbonyl," C5-5alkoxycarbonyl, • C5-5alkoxycarbonyl substituted by carbocyclic aryl, • carbocyclic aryloxy, and • carbocyclic aryloxy substituted by the independently selected substituent (s) from the group consisting of: • "halogen," "nitro," "C -C5 alkyl, and C alkyl substituted by oxo," "heterocyclyloxy," • heterocyclyloxy substituted by C? _5 alkyl, • carbocyclic mono-arylamino, • carbocyclic di-arylamino, • carbocyclic arylsulfonylamino, • carbocyclic arylsulfonylamino substituted by alkyl • C 1 -5 alkylthio, C 1 -C 5 alkylthio substituted by carbocyclic aryl, • carbocyclic arylthio, "carbocyclic arylthio substituted by halogen, • carbocyclic arylthio substituted by C 1 -C 5 alkyl, • carbocyclic arylsulfonyl, • carbocyclic arylsulfonyl substituted by halogen, • heterocyclicthio, 'heterocyclicthio substituted by C? _5 alkyl,? C3_s cycloalkyl,? C3-? cycloalkenyl,? carbocyclyl ,? carbocyclyl substituted by C? -5 alkoxy, * carbocyclic aryl, and? carbocyclic aryl substituted by the substituent (?) s) independently selected from the group consisting of: • • halogen, • 'nitro, •' C5_5 alkyl, and • C5_5 alkyl substituted by the independently selected substituent (s) of the group consisting of: • • 'halogen, ••• carbocyclic aryl, and • •' heterocyclyl, •• C5-5 alkoxy, • C5-5 alkoxy substituted by halogen, '' C5-5 alkoxy substituted by aryl carbocyclic or, • carbocyclic aryloxy, • "carbocyclic mono-arylaminocarbonyl, and • • carbocyclic mono-arylaminocarbonyl substituted by the substituent (s) selected from the group consisting of: • •" halogen, • • "alkyl C? _5, • • • alkoxy C? _5, and ••• C5-5 alkoxy substituted by halogen, •• di-arylaminocarbonyl carbocyclic, and •• carbocyclic di-arylaminocarbonyl substituted by the selected substituent (s) ( s) of the group consisting of: • • 'halogen, ••' alkyl C? _5, • • 'alkoxy C? _5, and ••• alkoxy C? _5 substituted by halogen, •• alkylthio C? _5, •• C.sub.5 alkylthio substituted by halogen, •• C5-5 alkylsulfonyl, •• carbocyclic aryl, and • • heterocyclyl, • heterocyclyl, and • heterocyclyl substituted by the independently selected substituent (s) from the group consisting of of: • «C C _5 alkyl, • * C 1 5 5 alkoxy, • C 1-5 alkoxy substituted by aryl or carbocyclic, •• carbocyclic aryl, and •• carbocyclic aryl substituted by halogen, (ii) C2-5 alkenyl, and C2-5 alkenyl substituted by the independently selected substituent (s) from the group consisting of : • carbocyclic aryl, and * carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • "nitro, • 'halogen, •" C 1-5 alkyl, •• C alkyl? _5 substituted by halogen, • • C1-5 alkoxy, and •• C1-5 alkoxy substituted by halogen, (iii) C3_6 cycloalkyl, and C3 cycloalkyl substituted by the independently selected substituent (s) from the group consists of: • C1-5 alkyl, • C1-5 alkyl substituted by carbocyclic aryl, • carbocyclic arylcarbonylamino, and "carbocyclic aryl, (iv) carbocyclyl, and carbocyclyl substituted by nitro, (v) carbocyclic aryl, and carbocyclic aryl substituted by the substituent (s) indepe selected from the group consisting of: • halogen, • cyano, • nitro, "C 1 _ 9 alkyl, and • C 1 _ 9 alkyl substituted by the independently selected substituent (s) from the group consists of: • «halogen, •? XO, •« mono-arylaminocarbonyl carbocyclic, • «di-arylaminocarbonyl carbocyclic, •« mono-arylaminocarbonyl carbocyclic substituted by alkoxy C? -5, •• di-arylaminocarbonyl carbocyclic substituted by alkoxy C? _5, •• carbocyclic aryloxy, • carbocyclic aryl, and • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • • "halogen, • • 'alkyl C? _5, and ••• C5_5 alkyl substituted by halogen, • • heterocyclyl, and •• heterocyclyl substituted by C5_5 alkyl, • C2_5 alkenyl, • C7_7 alkoxy, • C7_7 alkoxy substituted by halogen, • C7 alkoxy substituted by carbocyclic aryl, • C3_6cycloalkoxy, • carbocyclic aryloxy, and • carbocyclic aryloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "nitro, and •• alkoxy C? _5 • heterocyclyloxy, and • heterocyclyloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen," "C? _5 alkyl, and C? -C alkyl substituted by halogen, • alkoxycarbonyl C? _5, * mono-alqu C 1-5 alkylaminocarbonyl, C 1 -5-di-alkylaminocarbonyl, C 1 -C 5 monoalkylaminocarbonyl substituted by carbocyclic aryl, C 1 -5-alkylaminocarbonyl substituted by carbocyclic aryl, carbocyclic mono-arylaminocarbonyl, carbocyclic di-arylaminocarbonyl, carbocyclic mono-arylaminocarbonyl substituted by C? _5 alkyl,? carbocyclic di-arylaminocarbonyl substituted by C? _5 alkyl,? mono-C? 5 alkylamino,? C 1-5 alkylamino, C? 5 alkylthio, C? alkyl? _5 substituted by halogen, • C5_5 alkylsulfonyl, • carbocyclic aryl, and • carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • "C? -7 alkyl, and • • C7_7 alkyl substituted by halogen, (vi) heterocyclyl, and heterocyclyl substituted by the independently selected substituent (s) from the group consisting of: • halogen, • C alquilo_alkyl, and • C-alkyl ? _5 replaced by the s) substituent (s) independently selected from the group consisting of: • 'halogen, •? XO, •• carbocyclic aryl, •• carbocyclic aryl substituted by halogen, • * heterocyclyl, and •• heterocyclyl substituted by the (? the) substituent (s) independently selected from the group consisting of: • • 'halogen, • •' alkyl C? _5, and •• 'C-5 alkyl substituted by halogen, • C1-5 alkoxy, • alkylthio C1-5, • carbocyclic arylthio, • C5-5 alkylsulfonyl, * carbocyclic arylsulfonyl, • carbocyclic arylsulfonyl substituted by halogen, • carbocyclic arylsulfonyl substituted by C1-5 alkyl, • C1-5 alkoxycarbonyl, • carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • "halogen, •" nitro, and • "C alquilo _5 alkyl, • heterocyclyl, and • heterocyclyl substituted by the substituent (s) (s) independent Selected from the group consisting of: • "halogen," "alkyl C? _5, and •• C? -5 alkyl substituted by halogen.; wherein carbocyclic aryl is phenyl, naphthyl, or anthranil; carbocyclyl is 1-oxo-indanyl, 9-fluorenyl, 9-oxo-fluorenyl, anthraquinonyl, C-fluoren-9-ylidene, indanyl, or menthyl; heterocyclyl is 1, 2, 3, 4-tetrahydro-isoquinolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-triazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl, l-pyrrolyl, 2, 3- dihydro-l-oxo-isoindolyl, 2,3-dihydro-benzo [1,4] dioxinyl, 2H-benzopyranyl, 2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl, 4-oxo-benzopyranyl, 9H-xanthenyl, benzo [ 1,3] dioxolyl, benzo [2, 1, 3] oxadiazolyl, benzo [1, 2, 5] oxadiazolyl, benzo [b] thienyl, furyl, isoxazolyl, morpholinyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolyl, thienyl, imidazolyl, or piperazil; halogen is fluoro, chloro, bromo, or iodo; or a pharmaceutically acceptable hydrate or solvate salt thereof. 4. The compound, according to the claim 3 wherein: R2 is halogen, C? -5 alkyl, C? _5 alkoxy, -N (R2a) (R2t?), Or heterocyclyl; wherein R2a and R2b are each independently hydrogen, C5_5alkyl, C1-5alkyl substituted by hydroxy, C5_5alkyl substituted by carbocyclic aryl, C5_5alkyl substituted by heterocyclyl, C3_6 cycloalkyl. or carbocyclic aryl; L is selected from the group consisting of the Formulas (Illa) and (IVa); wherein R3 and R are each independently hydrogen or C? _5 alkyl; and A and B are each independently a unique bond, -CH2-, or - (CH2) 2-; Zi is hydrogen, halogen, C? _5 alkyl, C1-5 alkyl substituted by halogen, C1-5 alkoxy, or C? _5 alkylthio; Z2 is hydrogen, halogen, or C? _5 alkyl; or R2 and Z2 are linked together to form a ring and -R2-Z2- is -NR6-CH = CH-; wherein R6 is hydrogen or C? _5 alkyl; and Y represents: (i) -C (0) NR5 ~, -C (S) NR5-, -C (0) 0-, -S (0) 2-, "C (0) -, or - (CH2 ) m- when L is selected from the group consisting of Formula (Illa), or (ii) -C (0) NR5- or -C (0) 0- when L is selected from the group consisting of the Formula (IVa) ) wherein R5 is hydrogen or C? -5 alkyl, and m is 0, 1, or 2, or a pharmaceutically acceptable hydrate or solvate salt thereof 5. The compound, according to claim 4 wherein Rx is selects from the group consisting of: (i) C5-alkyl substituted by the substituent (s) independently selected from the group consisting of: • hydroxy, • carbocyclic aryl, * carbocyclic aryl substituted by halogen, and • alkylthio C? _5, (ii) C3_6 cycloalkyl, and (iii) carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • halogen, • nitro, • cyano, 'alkyl C? _5, • alkyl C? _5 substituted by halogen, • alc C1-5 oxy, • C1-5 alkoxy substituted by halogen, • C5-5 alkoxy substituted by carbocyclic aryl, carbocyclic aryloxy, and carbocyclic aryloxy substituted by C alkoxy, (iv) heterocyclyl, and heterocyclyl substituted by (the) substituent (s) independently selected from the group consisting of: "halogen,? C? _5 alkyl,? carbocyclic aryl, and? carbocyclic aryl substituted by halogen; R2 is -N (Ra) (R2b) or heterocyclyl; wherein R2a and R2b are each independently hydrogen or C? -5alkyl; Zx is hydrogen, C ?5 alkyl, or Cilt5 alkylthio; Z2 is hydrogen or C? _5 alkyl; or R2 and Z2 are linked together to form a ring and -R2-Z2- is -NR6-CH = CH-; wherein R is hydrogen or C? _5 alkyl; L is Formula (Illa) or (IVa), wherein R3 and R4 are hydrogen, A is a single bond and B is a single bond or -CH2-; and Y represents: (i) -C (0) NH-, -C (S) NH, -C (0) -, or -CH2- when L is selected from the group consisting of the Formula (Illa); or (ii) -C (0) NH- when L is selected from the group consisting of Formula (IVa); wherein carbocyclic aryl is phenyl or naphthyl; heterocyclyl is furyl, lH-indolyl, morpholinyl, oxazolyl, piperidyl, pyridyl, pyrrolidyl, or 9H-? antenil; halogen is fluoro, chloro, or bromo; or a pharmaceutically acceptable hydrate or solvate salt thereof. 6. The compound according to claim 5 wherein Rx is selected from the group consisting of: (i) carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) of the group consisting of of: • halogen, • C alquilo5 alkyl, • C 1-5 alkyl substituted by halogen, • C 1-5 alkoxy, and • C ?5 alkoxy substituted by halogen, (ii) heterocyclyl, and heterocyclyl substituted by halogen; and Zi is hydrogen, C? _5 alkyl, or C? -5 alkylthio; Z2 is hydrogen or C? _5 alkyl; wherein carbocyclic aryl is phenyl; heterocyclyl is furyl, pyridyl, or pyrrolidyl; halogen is fluoro, chloro, or bromo; or a pharmaceutically acceptable hydrate or solvate salt thereof. 7. The compound, according to claim 1 selected from the group consisting of: N-. { cis-4-. { [6- (dimethylamino) pyrimidin-4-yl] amino} cyclohexyl) -3, 4-difluorobenzamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -4-fluorobenzamide; 4-chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -3-fluorobenzamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) -3,5-difluorobenzamide; 3-chloro-N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -4- (trifluoromethoxy) benzamide; 3-chloro-4-f luoro-N- (cis-4 { [2-methyl-6- (methylamino) pyrimidin-4-yl] amino.} Ciciohexyl) benzamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3-fluorobenzamide; 4-chloro-A? - (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) benzamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3-fluoro-5- (trifluoromethyl) benzamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,5-bis (trifluoromethyl) benzamide; 3-chloro-4-fluoro-N-. { cis-4- [(2-methyl-6-piperidin-1-yl-pyrimidin-4-yl) amino] cyclohexyl} benzamide; 3-chloro-4-f luoro-N-. { cis-4- [(2-methyl-6-morpholin-4-ylpyrimidin-4-yl) amino] cyclohexyl} benzamide; 3-chloro-4-f luoro-N-. { cis-4- [(7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclohexyl} benzamide; 3, 4, 5-trif luoro-N-. { cis-4- [(7-methyl-7i? -pyrrolo [2, 3-d] pyrimidin-4-yl) amino] ciciohexyl} benzamide; 3, 4, 5-trifluoro-N- (cis-4 { [2-methyl-6- (methylo) pyrimidin-4-yl] amino.} Cyclohexyl) benzamide; cis-N- (3,4-difluorophenyl) -4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexanecarboxamide; 1- (4-chlorophenyl) -N- (is-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) cyclopentanecarboxamide;

3- (2-chloro-6-fluorophenyl) -N-. { cis-

4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) -

5-methylisoxazole-4-carboxamide; N-. { cis-4-. { [

6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -2- (4-methoxyphenoxy) -5-nitrobenzamide; N- (cís-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) -5-iodo-2-furamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -2- (ethylthio) -2, 2-diphenylacetamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -9i? -xantene-9-carboxamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -N '- [1- (1-naphthyl) ethylurea; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -N '- (3,, 5-trimethoxyphenyl) urea; N- (5-chloro-2,4-dimethoxyphenyl) -N '- (cis -4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) urea; N- (cís-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Ciciohexyl) -? 7 '- (2,4,6-tribromophenyl) urea; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) -? J '-methylthiourea; N- (2,6-diethylpheniD-N '- (cis -4- {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) thiourea; N- (2, -dichloro) -6-methylphenyl) -N1 - (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) thiourea; N- (5-chloro-2, 4- dimethoxyphenyl) -N '- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cydohexyl) thiourea; N- [4-bromo-2- (trifluoromethyl) phenyl) ] -N1 - { Cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) thiourea; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3-nitrobenzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) cyclohexyl] -3,4-diethoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) cyclohexyl] -3-ethoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) cyclohexyl] -3,5-diethoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) cyclohexyl] -3-isopropoxy-benzamide; 3-bromo-N- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycdohexyl] -4-fluoro-benzamide; 4-difluoromethoxy-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 4-Chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methyl-benzamide; 3-difluoromethoxy-W- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 3-Chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-methyl-benzamide; 4-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4-. { 6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-dimethoxy-benzamide; 4-cyano-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-methoxy-benzamide; 3-cyano-N- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-fluoro-3-methyl-benzamide; 4-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-fluoro-4-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethyl-benzamide; 3-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycdohexyl] -3-fluoro-4-trifluoromethyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-trifluoromethoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-trifluoromethyl-benzamide; 2,2-difluoro-benzo [1,3] dioxolo-5-carboxylic acid [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; N-. { cis-4- [(lH-indol-2-ylmethyl) -amino] -cyclohexyl} -2, N ', N' -trimethyl-pyrimidine-4,6-diamine; 2, N, W-trimethyl-W - [cis-4- (3-trifluorora-ethoxy-benzylamino) -cycdohexyl] -pyrimidine-4,6-diamine; N- [cis-4- (3,4-difluoro-benzylamino) -cydohexyl] -2, N ', N' -trimethyl-pyrimidine-, 6-diamine; 1- (3, 4-dimethoxy-phenyl) -3- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -urea; 1- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3- (2-ethoxy-phenyl) -urea; 1- (4-benzyloxy-phenyl) -3- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycotehexyl] -urea; 3, 5-dibromo-I \

7- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 3-bromo-4-chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 4-chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-trifluoromethyl-benzamide; 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycdohexyl] -2-hydroxy-acetamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-fluoro-4-trifluoromethyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-trifluoromethoxy-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-methoxy-benzamide; 4-chloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-trifluoromethyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-trifluoromethyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,5-difluoro-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-ethyl-benzamide; 2, 2-difluoro-benzo [1,3] dioxolo-5-carboxylic acid [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -amide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3-fluoro-4-methyl-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-fluoro-benzamide; 3, 4-dichloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; 4-bromo-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,4-difluoro-benzamide; 3, 5-dichloro-N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; S-chloro- - [is-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-fluoro-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-fluoro-3-methyl-benzamide; and 3-chloro-AÍ- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -benzamide; or a pharmaceutically acceptable hydrate or solvate salt thereof. 8. The compound according to claim 1 selected from the group consisting of: N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide; N-. { cis-4-. { [6- (dimethylamino) -2-ethylpyrimidin-4-yl] amino} cyclohexyl) -3,4-difluorobenzamide; 3-chloro-W- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -4-fluorobenzamide; 3, 4-dichloro-N- (cis-4. {[[6- (di-ethyl-amino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) benzamide; 3-chloro-N- (cis-4. {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -5-fluorobenzamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -3,4,5-trifluorobenzamide; 5-bromo-N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) nicotinamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -4-fluoro-3- (trifluoromethyl) benzamide; N-. { cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} cyclohexyl) -3- (trifluoromethyl) benzamide; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) -3- (trifluoromethoxy) benzamide; 3, 5-dichloro-W- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.} Ciciohexyl) benzamide; 3-chloro-N- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) benzamide; 3-chloro-4-fluoro-W-. { cis-4- [(2-methyl-6-pyrrolidin-1-yl-pyrimidin-4-yl) amino] cyclohexyl} benzamide; N-. { cis-4-. { [6- (dimethylamino) -2-ethylpyrimidin-4-yl] amino} cyclohexyl) -3,4,5-trifluorobenzamide; cis-N-. { 3-chloro-4-fluorophenyl) -4-. { [6- (dimethylamino) -2-rnetylpyrimidin-4-yl] amino} cyclohexanecarboxamide; N- (cis-4 { [2-benzyl-6- (dimethylamino) pyrimidin-4-yl] amino}. Cydohexyl) -3-chloro-4-fluorobenzamide; cis-4-. { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} -N- (3,4,5-trifluorophenyl) cyclohexanecarboxamide; N- (4-bromo-2,6-dimethylphenyl) ~ N [- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cydohexyl) urea; N- (4-bromo-2,6-dimethylphenyl) -N '- (cis -4- {[[6- (dimethylamino) -2-methylpyrimidin-4-yl] amino} ciciohexyl) thiourea; N- (cis-4 { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -N '- (3,4, 5-trimethoxyphenyl) thiourea; N- (cis-4- { [6- (dimethylamino) -2-methylpyrimidin-4-yl] amino.}. Cyclohexyl) -N '- (2,4,6-tribromophenyl) thiourea; 5-bromo-furan-2-carboxylic acid [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; N- [cis-4- (3,5-dimethoxy-benzylamino) -cydohexyl] -2, N 1, N 1 -trimethyl-pyrimidine-4,6-diamine; N- [cis-4- (3-bromo-benzylamino) -cydohexyl] -2, W, N '-trimethyl-pyrimidine-4,6-diamine; 1- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cydohexyl] -3- (3-methoxy-phenyl) -urea; 1- (3, 5-difluoro-phenyl) -3- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cycdohexyl] -urea; N- [cis-4- (6-dimethylamino-2-methylsulfanyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide; N- [cis-4- (6-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide; N- [cis-4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -3,5-bis-trifluoromethyl-benzamide; and N- [cis -4- (6-dimethylamino-2-methyl-pyrimidin-4-ylamino) -cyclohexylmethyl] -4-trifluorornetoxy-benzamide; or a pharmaceutically acceptable hydrate or solvate salt thereof. 9. The compound according to claim 2 wherein: Ri represents: (i) hydrogen, -C02tBu, or -C02Bn (Bn is a benzyl group) when L is selected from the group consisting of the Formulas (III), (Illa), and (Illb); or (ii) hydrogen, C? _s alkyl, substituted C ?5 alkyl, Bn, or substituted Bn when L is selected from the group consisting of Formulas (IV), (IVa), and (IVb); wherein R 3 and R are each independently hydrogen or C 1-5 alkyl; and A and B are each independently a unique link, -CH2-, or - (CH2) 2-; R2 is halogen, C1-5 alkyl, C5-5 alkoxy, -N (R2a) (R2b), or heterocyclyl; wherein R2a and Rb are each independently hydrogen, C? _5 alkyl, C? _5 alkyl substituted by hydroxy, C? -5 alkyl substituted by carbocyclic aryl, C? _5 alkyl substituted by heterocyclyl, C3_6 cycloalkyl, or carbocyclic aryl; Zx is hydrogen, halogen, C ?5 alkyl, C ?5 alkyl substituted by halogen, C ?5 alkoxy, or Cilt _ alqu alkylthio; Z2 is hydrogen, halogen, or C? _5 alkyl; or R2 and Z2 are linked together to form a ring and -R2-Z2- is -NR6-CH = CH-; wherein R6 is hydrogen or C? _5 alkyl; Y represents: (i) a single bond when L is selected from the group consisting of Formulas (III), (Illa), and (Illb); or (ii) -C (0) 0- when L is selected from the group consisting of Formulas (IV), (IVa), and (IVb); or a pharmaceutically acceptable hydrate or solvate salt thereof. 10. The compound, according to the claim 9 wherein: Ri represents: (i) hydrogen, -C02tBu, or -C02Bn (Bn is a benzyl group) when L is selected from the group consisting of the Formula (Illa); or (ii) hydrogen, C? _5 alkyl, substituted C? _5 alkyl, Bn, or substituted Bn when L is selected from the group consisting of Formula (IVa); wherein R3 and R4 are each hydrogen; and A and B are each independently a single bond or ~ CH2-; R2 is -N (R2a) (R2b) or heterocyclyl; wherein R2a and R2b are each independently hydrogen or C? _5 alkyl; Z is hydrogen, C 1 -C 5 alkyl, or C 1 -C 5 alkylthio; Z2 is hydrogen or C? _5 alkyl; or R2 and Z2 are linked together to form a ring and -R2-Z2- is -NR5-CH = CH-; wherein R6 is hydrogen or alkyl C1-5 r And Y represents: (i) a single bond when L is selected from the group consisting of the Formula (Illa); or (ii) -C (0) 0- when L is selected from the group consisting of Formula (IVa); heterocyclyl is furyl, iH-indolyl, raorfolinyl, oxazolyl, piperidyl, pyridyl, pyrrolidyl, or 9i? -xantenil; or a pharmaceutically acceptable hydrate or solvate salt thereof. 11. The compound according to claim 1 wherein Q is Formula (Ilb); R2 is C ?5 alkyl substituted by hydroxy, alkyl C? _5 substituted by carbocyclic aryl, C5 alkyl substituted by halogenated carbocyclic aryl, C5_5 alkyl substituted by heterocyclyl, C5_5 alkyl substituted by halogenated heterocyclyl, C2-5 alkenyl, C2_5 alkynyl, or -N (R2a) (R2b); wherein R2a and R2b are each independently hydrogen, C? -5 alkyl, or C? _5 alkyl substituted by the independently selected substituent (s) from the group consisting of: -halogen, • hydroxy, • carboxy, • carbamoyl, • C 1-5 alkoxy, • amino, • C3_5 cycloalkyl, • carbocyclic aryl, • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • «halogen, • C1-5 alkyl, • • C1-5 alkoxy, •• C1-5 alkyl substituted by halogen, «« C5-5 alkoxy substituted by halogen, and • '-S02NH2, • heterocyclyl, and • heterocyclyl substituted by the ( the) independently selected substituent (s) from the group consisting of: • 'halogen• "C" -5 alkyl, • "C5-5 alkoxy, • C" -5 alkyl substituted by halogen, and •• C5-5 alkoxy substituted by halogen, carbocyclic aryl, carbocyclic aryl substituted by the substituent. (s) independently selected from the group consisting of: • halogen, • C?-5 alkyl, "C?-5 alkoxy, • C C5 alkyl substituted by halogen, and • C?-5 alkoxy substituted by halogen, heterocyclyl , or heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • halogen, • C5_5 alkyl, • C1-5 alkoxy, • C5_5 alkyl substituted by halogen, and « C5-5 alkoxy substituted by halogen; or a pharmaceutically acceptable hydrate or solvate salt thereof. The compound according to claim 11 wherein R x is selected from the group consisting of: (i) C 1 - 0 alkyl, and C 1 io alkyl substituted by the independently selected substituent (s) ( s) of the group consisting of: • halogen, • hydroxy, * oxo, • C 1 -C 5 alkoxy, • C 1-5 alkoxy substituted by carbocyclic aryl, • C 1-5 alkylcarbonyloxy, • C 1 -C 5 alkoxycarbonyl, • C 1 -C 5 alkoxycarbonyl substituted by carbocyclic aryl, carbocyclic aryloxy, and carbocyclic aryloxy substituted by the independently selected substituent (s) from the group consisting of: halogen, nitro, C 1-5 alkyl, and •• C5_5 alkyl substituted by oxo, • heterocyclyloxy, "heterocyclyloxy substituted by C5_5 alkyl, • carbocyclic mono-arylamino, • carbocyclic di-arylamino, • carbocyclic arylsulfonylamino, • carbocyclic arylsulfonylamino substituted by C1-5 alkyl, • alkylthio C? _5, • alkylthio C? _5 sust with carbocyclic aryl, carbocyclic arylthio, carbocyclic arylthio substituted by halogen, carbocyclic arylthio substituted by C5-5alkyl, carbocyclic arylsulfonyl, carbocyclic arylsulfonyl substituted by halogen, heterocyclicthio, heterocyclicthio substituted by C5alkyl, C3-6 cycloalkyl, • C3_6 cycloalkenyl, • carbocyclyl, • carbocyclyl substituted by C5-5 alkoxy, • carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) from the group consisting of: • "halogen," "nitro," "C alquilo _5 alkyl, and C• -5 alkyl substituted by the independently selected substituent (s) from the group consisting of: • • 'halogen, • •• carbocyclic aryl, and • • "heterocyclyl, • * C5-5alkoxy, •• C5-5alkoxy substituted by halogen, •• C5-5alkoxy substituted by carbocyclic aryl, •• carbocyclic aryloxy, "Carbocyclic mono-arylaminocarbonyl, and • • carbocyclic mono-arylaminocarbonyl substituted by the substituent (s) selected from the group consisting of: • •" halogen, • • "alkyl C? -5, • • • C.sub.5-alkoxy, and ••• C.sub.5-5 alkoxy substituted by halogen, •• di-arylaminocarbonyl carbocyclic, and •• carbocyclic di-arylaminocarbonyl substituted by the selected substituent (s) of the group consisting of of: • • «halogen, • •« alkyl C? -5, «« «alkoxy C? _5, and ••• alkoxy C? _5 substituted by halogen, •• alkylthio C? _5, •• alkylthio C? _5 substituted by halogen, •• C5-5 alkylsulfonyl, •• carbocyclic aryl, and • 'heterocyclyl, • heterocyclyl, and • heterocyclyl substituted by the substituent (s) independently selected from the group consisting of: • -alkyl C? _5, • • alkoxy C? _5, •• C1-5 alkoxy substituted by carbocyclic aryl, •• carbocyclic aryl ly, and •• carbocyclic aryl substituted by halogen, (ii) C2_5 alkenyl, and C2-5 alkenyl substituted by the independently selected substituent (s) from the group consisting of: • carbocyclic aryl, and • aryl carbocyclic substituted by the substituent (s) independently selected from the group consisting of: • miter, • "halogen, •" C1-5 alkyl, • "C1-5 alkyl substituted by halogen, • • alkoxy C ? _5, and •• C_5 alkoxy substituted by halogen, (iii) C3_5 cycloalkyl, and C3_6 cycloalkyl substituted by the independently selected substituent (s) from the group consisting of: • C5_5 alkyl, • alkyl C1-5 substituted by carbocyclic aryl, carbocyclic arylcarbonylamino, and carbocyclic aryl, (iv) carbocyclyl, and carbocyclyl substituted by nitro, (v) carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) ( s) of the g a group consisting of: • halogen, • cyano, • nitro, • C 1-9 alkyl, and "C 1-9 alkyl substituted by the independently selected substituent (s) from the group consisting of: •" halogen, • «oxo, •« mono-arylaminocarbonyl carbocyclic• "carbocyclic di-arylaminocarbonyl, • • carbocyclic mono-arylaminocarbonyl substituted by carboalicyclic alkoxy, •• di-arylaminocarbonyl carbocyclic substituted by carboxylic alkoxy, carbocyclic aryloxy, carbocyclic aryl, and substituted carbocyclic aryl. by the independently selected substituent (s) from the group consisting of: • • "halogen, • •" C5 _5 alkyl, and ••• C5_5 alkyl substituted by halogen, • • heterocyclyl, and • • heterocyclyl substituted by C ?5alkyl, * C2-5alkenyl, • C ?7alkoxy, • C ?7alkoxy substituted by halogen, • C?-7alkoxy substituted by carbocyclic aryl, • C6 cycloalkoxy, "carbocyclic aryloxy, and • carbocyclic aryloxy substituted by the substituent (s) independently selected from the group consisting of: • "halogen, •" nitro, and • • C 1 -C 5 alkoxy • heterocyclyloxy, and • heterocyclyloxy substituted by the the) substituent (s) independently selected from the group consisting of: • 'halogen, •' C5_5 alkyl, and •• C5 alkyl substituted by halogen, • C5_5 alkoxycarbonyl, • C5_5 mono-alkylaminocarbonyl, * di-alkylaminocarbonyl C? _5,? C5-5 mono-alkylaminocarbonyl substituted by carbocyclic aryl,? C5_5alkylaminocarbonyl substituted by carbocyclic aryl, • carbocyclic mono-arylaminocarbonyl, • carbocyclic di-arylaminocarbonyl, • carbocyclic mono-arylaminocarbonyl substituted by C-alkyl? ~ 5, • carbocyclic di-arylaminocarbonyl substituted by C? _5alkyl, • mono-alkylamino C? _s, • di-alkylamino C? _5, • alkylthio C? _5, • alkylthio C? _5 substituted by halogen, «alkylsulfonyl C? _5, • carbocyclic aryl, and • carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: • "C alquilo_7 alkyl, and •• C_7 alkyl substituted by halogen, (vi) heterocyclyl, and heterocyclic ilo substituted by the independently selected substituent (s) from the group consisting of: -halogen, • C ?5 alkyl, and • C ?5 alkyl substituted by the independently selected substituent (s) ( s) of the group consisting of: • 'halogen, •? XO, •• carbocyclic aryl, • carbocyclic aryl substituted by halogen, •' heterocyclyl, and •• heterocyclyl substituted by the independently selected substituent (s) ( s) of the group consisting of: • • "halogen, • •" alkyl C? _5, and ••• C5_5 alkyl substituted by halogen, * alkoxy C? _5, • alkylthio C? _5, • carbocyclic arylthio, • C5-5alkylsulfonyl, • carbocyclic arylsulfonyl, "carbocyclic arylsulfonyl substituted by halogen, • carbocyclic arylsulfonyl substituted by C5_5alkyl, • C1-5alkoxycarbonyl, • carbocyclic aryl, and • carbocyclic aryl substituted by the substituent (s) independently selected (s) of the group consisting of: • "halogen," "nitro," and "C" -5 alkyl, "heterocyclyl, and • heterocyclyl substituted by the independently selected substituent (s) from the group consists of: • -halogen, •• C-5-alkyl, and • 'C-5-alkyl substituted by halogen; wherein carbocyclic aryl is phenyl, naphthyl, or anthranil; carbocyclyl is 1-oxo-indanyl, 9i? -fluorenyl, 9-oxo-fluorenyl, anthraquinonyl, C-fluoren-9-ylidene, indanyl, or menthyl; heterocyclyl is 1, 2, 3, 4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl, 1, 2, 3-triazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl, li? -pyrrolyl, 2, 3 -dihydro-l-oxo-isoindolyl, 2,3-dihydro-benzo [1,4] dioxinyl, 2i-benzopyranyl, 2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl, 4-oxo-benzopyranyl, 9H-xanthenyl, benzo [1, 3] dioxolyl, benzo [2, 1, 3] oxadiazolyl, benzo [1, 2, 5] oxadiazolyl, benzo [b] thienyl, furyl, isoxazolyl, morpholinyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl , quinoxalyl, thiazolyl, or thienyl; halogen is fluoro, chloro, bromo, or iodo; or a pharmaceutically acceptable hydrate or solvate salt thereof. 13. The compound according to claim 12 wherein: R2 is C1-5 alkyl substituted by carbocyclic aryl, C1 alkyl substituted by halogenated carbocyclic aryl, C5-5 alkyl substituted by heterocyclyl, C5-5 alkyl substituted by heterocyclyl halogenated, carbocyclic aryl, carbocyclic aryl substituted by halogen, heterocyclyl, heterocyclyl substituted by halogen, or -N (R2a) (R2b); wherein R2a and R2b are each independently hydrogen, C? -5 alkyl, C? _5 alkyl substituted by hydroxy, or C? _5 alkyl substituted by halogen; L is the Formula (Illa); wherein R3 and R4 are each independently hydrogen or C? _5 alkyl; and A and B are each independently a unique bond, ~ CH2-, or - (CH2) 2-; Z3 and Z4 are each independently hydrogen, halogen, C1-5alkyl, C alquilo _alkyl substituted by halogen, monoalkylamino C? _5, or di-alkylamino C? _5; Y is -C (0) -, -C (0) NR5-, -C (S) NR5-, or - (CH2) m-; wherein R5 is hydrogen or C? _5 alkyl; and m is 0, 1, or 2; And it is not - (CH2) m-provided that either R2a or R2b is hydrogen; or a pharmaceutically acceptable hydrate or solvate salt thereof. The compound according to claim 13 wherein R is selected from the group consisting of: (i) C 1 -C 5 alkyl substituted by the independently selected substituent (s) from the group consisting of: 'hydroxy, • carbocyclic aryl, • carbocyclic aryl substituted by halogen, and • carbocyclic aryl substituted by halogenated C? _5 alkyl, (ii) carbocyclic aryl, and carbocyclic aryl substituted by the independently selected substituent (s) ) of the group consisting of: • halogen, "cyano, • C? -5 alkyl, • C5_5 alkyl substituted by halogen, • C5_5 alkoxy, and • C5_5 alkoxy substituted by halogen, (iii) heterocyclyl, and heterocyclyl substituted by halogen; R2 is C5_5alkyl substituted by carbocyclic aryl or -N (R2a) (R2b) wherein R2a and R2b are each independently hydrogen or C5_5alkyl; L is the Formula (Illa); wherein R3 and R are each hydrogen; and A and B are each a unique link; Z3 and Z are each independently hydrogen, C? -5alkyl, monoalkylamino C? _5, or di-alkylamino C? _5; and Y is -C (O) -; wherein carbocyclic aryl is phenyl; heterocyclyl is furyl or pyridyl; halogen is fluoro, chloro, or bromo; or a pharmaceutically acceptable hydrate or solvate salt thereof. 15. The compound according to claim 14 wherein Ri is selected from the group consisting of: carbocyclic aryl, and carbocyclic aryl substituted by the substituent (s) independently selected from the group consisting of: halogen, • cyano, and • alkoxy C? _5; Z is hydrogen when Z4 is C? _5 alkyl; or Z3 is C? _5 alkyl, C? -5 monoalkylamino, or C? -skylamino when Z4 is hydrogen; or a pharmaceutically acceptable hydrate or solvate salt thereof. 16. The compound, according to the claim 1 selected from the group consisting of: 3-chloro-N- (cis-4 { [2- (dimethylamino) -6-methylpyrimidin-4-yl] amino.}. Cydohexyl) -4-fluorobenzamide; N- (cis-4- { [2- (dimethylamino) -6-methylpyrimidin-4-yl] amino} ciciohexyl) -3,4-difluorobenzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-methoxy-benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-trifluoromethyl-benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-bis-trifluoromethyl-benzamide; 2, 2-difluoro-benzo [1,3] dioxolo-5-carboxylic acid [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; 4-cyano-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 4-chloro-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethyl-benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,4-difluoro-benzamide; 5-bromo-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -nicotinamide; 5-bromo-furan-2-carboxylic acid [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; 3, 5-dibromo-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethoxy-benzamide; 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -2-hydroxy-acetamide; 2- (4-bromo-phenyl) -N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -2-hydroxy-acetamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-diethoxy-benzamide; 3-bromo-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -4-fluoro-benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethoxy-benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-trifluoromethyl-benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-bis-trifluoromethyl-benzamide; 2, 2-difluoro-benzo [1,3] dioxolo-5-carboxylic acid [cis-4- (2'-dimethylamine-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; 4-Chloro-N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cycdohexyl] -benzamide; N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethyl-benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cycdohexyl] -4-methyl-benzamide; 5-bromo-A7- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -nicotinamide; 5-bromo-furan-2-carboxylic acid [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -amide; 3, 5-dibromo-_V- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3-ethoxy-benzamide; 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -2-hydroxy-acetamide; 2- (4-bromo-phenyl) -N- [cys-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -2-hydroxy-acetamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-diethoxy-benzamide; and 3-bromo-N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cycdohexyl] -4-fluoro-benzamide; or a pharmaceutically acceptable hydrate or solvate salt thereof. 17. The compound according to claim 1 selected from the group consisting of: 3-chloro-N- (cis-4- { [2- (dimethylamino) pyrimidin-4-yl] amino.} Ciciohexyl) -4-fluorobenzamide; N- (cis-4- { [2,6-bis (dimethylamino) pyrimidin-4-yl] amino} ciciohexyl) -3,4-difluorobenzamide; N- (cis-4 { [2-benzyl-6- (dimethylamino) irimidin-4-yl] amino.}. Cyclohexyl) -3-chloro-4-fluorobenzamide; 3, 4-dichloro-N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; 4-cyano-N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -3, -dietoxy-benzamide; 3-Chloro-N- [cis -4- (2-dimethylamino-6-methyl-pyrimidin-4-ylamino) -cydohexyl] -5-fluoro-benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -3,5-dimethoxy-benzamide; 3, 4-dichloro-N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -benzamide; N- [cis-4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cyclohexyl] -3,4-diethoxy-benzamide; and 3-chloro-N- [cis -4- (2-dimethylamino-5-methyl-pyrimidin-4-ylamino) -cydohexyl] -5-fluoro-benzamide; or a pharmaceutically acceptable hydrate or solvate salt thereof. 18. The compound, according to the claim 11 wherein: Ri is selected from hydrogen, -C02tBu, or -C02Bn (Bn is a benzyl group); R2 is C5-5 alkyl substituted by carbocyclic aryl, C5-5 alkyl substituted by halogenated carbocyclic aryl, C5-5 alkyl substituted by heterocyclyl, C5-5 alkyl substituted by halogenated heterocyclyl, carbocyclic aryl, carbocyclic aryl substituted by halogen, heterocyclyl, heterocyclyl substituted by halogen, or -N (R2a) (R2b); wherein R2a and R2b are each independently hydrogen, C?-alkyl, C 1-5 alkyl substituted by hydroxy, or C? _ alquilo alkyl substituted by halogen; L is the Formula (Illa); wherein R3 and R4 are each independently hydrogen or C? _5 alkyl; and A and B are each independently a unique bond, -CH2-, or - (CH2) 2-; Z and Z4 are each independently hydrogen, halogen, C? -5 alkyl, C? _5 alkyl substituted by halogen, mono-C? _5 alkylamino, or C1-5-alkylamino; and Y is a unique link; or a pharmaceutically acceptable hydrate or solvate salt thereof. 19. The compound according to claim 18, wherein: R 2 is C 1 -C 5 alkyl substituted by carbocyclic aryl or -N (R 2a) (R 2b); wherein R2a and R? b are each independently hydrogen or C? _5 alkyl; L is the Formula (Illa); wherein R3 and R4 are each hydrogen; and A and B are each a unique link; and Z3 and Z4 are each independently hydrogen, C? -5 alkyl, mono-C? _5 alkylamino, or C1-5-alkylamino; wherein carbocyclic aryl is phenyl; heterocyclyl is furyl or pyridyl; halogen is fluoro, chloro, or bromo; or a pharmaceutically acceptable hydrate or solvate salt thereof. 20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of claims 1 to 19 in combination with a pharmaceutically acceptable carrier. 21. A method for prophylaxis or treatment to improve memory function, sleep and wakefulness, anxiety, depression, mood disorders, seizures, obesity, diabetes, appetite and feeding disorders, cardiovascular disease, hypertension, dyslipidemia , myocardial infarction, disorders of excess food including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson's disease, epilepsy, and addiction comprising the administration to an individual suffering from said condition a therapeutically effective amount of a compound, according to any of claims 1 to 19, or a pharmaceutical composition according to claim 20. 22. A method for the prophylaxis or treatment of an eating disorder, obesity or a tra obesity-related condition comprising administering to an individual suffering from said condition a therapeutically effective amount of a compound according to any of claims 1 to 19 or a pharmaceutical composition according to claim 20. 23. A method for the prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy comprising the administration to an individual suffering from said condition of a therapeutically effective amount of a compound according to any of claims 1 to 19 or a pharmaceutical composition according to claim 20. 24. A compound according to any of claims 1 to 19 or a pharmaceutical composition according to claim 20 for use in a method of treating the human or animal body by therapy. 25. A compound according to any of claims 1 to 19 or a pharmaceutical composition according to claim 20 for use in a method of prophylaxis or treatment of an eating disorder, obesity or an obesity-related disorder of the human body. or animal through therapy. 26. A compound according to any of claims 1 to 19 or a pharmaceutical composition according to claim 20 for use in a method of prophylaxis or treatment of anxiety., depression, schizophrenia, addiction, or epilepsy of the human or animal body through therapy. 27. A compound according to any of claims 1 to 19 for the manufacture of a medicament for use in the prophylaxis or treatment of an eating disorder, obesity or disorders related to obesity. 28. A compound according to any of claims 1 to 19 for the manufacture of a medicament for use in the prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy. 29. A method for decreasing the food intake of an individual comprising administering to said individual a therapeutically effective amount of a compound according to any of claims 1 to 19 or a pharmaceutical composition according to claim 20. A method for inducing satiety in an individual comprising administering to said individual a therapeutically effective amount of a compound according to any of claims 1 to 19 or a pharmaceutical composition according to claim 20. 31. A method for controlling or reducing the weight gain in an individual comprising administering to said individual a therapeutically effective amount of a compound according to any of claims 1 to 19 or a pharmaceutical composition according to claim 20. 32. ün method for modulating an MCH receptor in an individual comprising putting in contact with the receptor with a compound according to any of claims 1 to 19. 33. The method for modulating the MCH receptor according to claim 32 wherein the compound is an antagonist. 34. The method for modulating the MCH receptor according to claim 32 or 33 wherein the modulation of the MCH receptor is for the prophylaxis or treatment of an eating disorder, obesity or disorder related to obesity. 35. The method for modulating the MCH receptor according to claim 32 or 33 wherein the modulation of the MCH receptor reduces the dietary intake of the individual. 36. The method for modulating the MCH receptor according to claim 32 or 33 wherein the modulation of the MCH receptor induces satiety in the individual. 37. The method for modulating the MCH receptor according to claim 32 or 33 wherein the modulation of the MCH receptor controls or reduces the weight gain of the individual. 38. The method for modulating the MCH receptor according to claim 32 or 33 wherein the modulation of the MCH receptor is for the prophylaxis or treatment of anxiety, depression, schizophrenia, addiction, or epilepsy. 39. The method for modulating the MCH receiver according to any of claims 22, 23 and 29 a 38 where the individual is a mammal. 40. The method for modulating the MCH receptor according to claim 39 wherein the mammal is a human. 41. The method according to claim 40 wherein the human has a body mass index of about 18.5 to about 45. The method according to claim 41 wherein the human has a body mass index of about 25. at about 45. 43. The method according to claim 42 wherein the human has a body mass index of from about 30 to about 45. The method according to claim 43 wherein the human has a mass index body from about 35 to about 45. 45. A method for producing a pharmaceutical composition comprising mixing a compound according to any of claims 1 to 19 and a pharmaceutically acceptable carrier.